CA2536181A1 - Polymer compositions and methods for their use - Google Patents

Abstract

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Description

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2 PCT/US2004/039389 POLYMER COMPOSITIONS AND METHODS FOR THEIR USE
BACKGROUND OF THE INVENTION
Field of the Invention This invention relates generally to polymer compositions that include a therapeutic agent (e.g., a fibrosis-inhibiting agent or an anti-infective agent), and to methods of making and using such compositions.
Description of the Related Art Polymeric compositions, particularly those that include synthetic polymers or a combination of synthetic and naturally occurring polymers, have been used in a variety of medical applications, such as the prevention of surgical adhesions, tissue engineering, and as bioadhesive materials. U.S.
Patent No. 5,162,430 describes the use of collagen-synthetic polymer conjugates prepared by covalently binding collagen to synthetic hydrophilic polymers such as various derivatives of polyethylene glycol. In a related patent, U.S. Patent No. 5,328,955, various activated forms of polyethylene glycol and various linkages are described, which can be used to produce collagen-synthetic polymer conjugates having a range of physical and chemical properties. U.S. Patent No. 5,324,775 also describes synthetic hydrophilic polyethylene glycol conjugates, but the conjugates involve naturally occurring polymers such as polysaccharides. EP 0 732 109 A1 discloses a crosslinked biomaterial composition that is prepared using a hydrophobic crosslinking agent, or a mixture of hydrophilic and hydrophobic crosslinking agents. U.S.
Patent No. 5,614,587 describes bioadhesives that comprise collagen that is crosslinked using a multifunctionally activated synthetic hydrophilic polymer.
U.S. application Ser. No. 08/403,360, filed Mar. 14, 1995, discloses a composition useful in the prevention of surgical adhesions comprising a substrate material and an anti-adhesion binding agent, where the substrate material may comprise collagen and the binding agent may comprise at least one tissue-reactive functional group and at least one substrate-reactive functional group. U.S. application Ser. No. 08/476,825, filed Jun. 7, 1995, discloses bioadhesive compositions comprising collagen crosslinked using a multifunctionally activated synthetic hydrophilic polymer, as well as methods of using such compositions to effect adhesion between a first surface and a second surface, wherein at least one of the first and second surfaces may be a native tissue surface. U.S. Patent No. 5,874,500 describes a crosslinked polymer composition that comprises one component having multiple nucleophilic groups and another component having multiple electrophilic groups. Covalently bonding of the nucleophilic and electrophilic groups forms a three dimensional matrix that has a variety of medical uses including tissue adhesion, surface coatings for synthetic implants, and drug delivery. More recent developments include the addition of a third component having either nucleophilic or electrophilic groups, as is described in U.S. Patent No.
6,458,889 to Trollsas et al. US 5,874,500, US 6,051,648 and US 6,312,725 disclose the in situ crosslinking or crosslinked polymers, in particular polyethylene glycol) based polymers, to produce a crosslinked composition.
West and Hubbell, Biomaterials (1995) 16:1153-1156, disclose the prevention of post-operative adhesions using a photopolymerized polyethylene glycol-co-lactic acid diacrylate hydrogel and a physically crosslinked polyethylene glycol-co-polypropylene glycol hydrogel, POLOXAMER 407 (BASF Corporation, Mount Olive, NJ). Polymerizable cyanoacrylates have also been described for use as tissue adhesives (Ellis, et al., J. Otolaryngol. 19:68-72 (1990)). Two-part synthetic polymer compositions have been described that, when mixed together, form covalent bonds with one another, as well as with exposed tissue surfaces (PCT WO 97/22371, which corresponds to U.S. application Ser. No.
08/769,806 U.S. Pat. No. 5,874,500).

BRIEF SUMMARY OF THE INVENTION
Briefly, in one aspect, the present invention provides compositions that contain both an anti-fibrotic agent and either a polymer or a pre-polymer, i.e., a compound that forms a polymer. In one embodiment, these compositions are formed in-situ when precursors thereof are delivered to a site in the body, or a site on an implant. For example, the compositions of the invention include the crosslinked reaction product that forms when two compounds (a multifunctional polynucleophilic compound and a multi-functional polyelectrophilic compound) are delivered to a site in a host (in other words, a patient) in the presence of an anti-fibrotic agent. However, the compositions of the invention also include a mixture of anti-fibrotic agent and a polymer, where the composition can be delivered to a site in a patient's body to achieve beneficial affects, e.g., the beneficial affects described herein.
In some instances, the polymers themselves are useful in various methods, including the prevention of surgical adhesions.
In another aspect, the present invention provides methods for treating and/or preventing surgical adhesions. The surgical adhesions can be the result of, for example, spinal or neurosurgical procedures, of gynecological procedures, of abdominal procedures, of cardiac procedures, of orthopedic procedures, of reconstructive procedures, and cosmetic procedures.
In another aspect, the present invention provides methods for treating or preventing inflammatory arthritis, such as osteoarthritis and rheumatoid arthritis. The method includes delivering to patient in need thereof an anti-fibrotic agent, optionally with a polymer.
In another aspect, the present invention provides for the prevention of cartilage loss as can occur, for example after a joint injury.
The method includes delivering to the joint of the patient in need therof an anti-fibrotic agent, optionally with a polymer.
In another aspect, the present invention provides for treating hypertrophic scars and keloids. The method includes delivering to the scar or

3 keloid of the patient in need thereof an anti-fibrotic agent, optionally with a polymer.
In another aspect, the present invention provides a method for the treatment of vascular disease, e.g., stenosis, restenosis or atherosclerosis.
The method includes the perivascular delivery of an anti-fibrotic agent.
In one aspect, the present invention provides a method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with i) an anti-fibrotic agent, ii) an anti-infective agent, iii) a polymer; iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.
Optionally, in separate aspects, the invention provides: a method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-fibrotic agent, and (b) implanting the medical device into the host; a method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-infective agent, and (b) implanting the medical device into the host; a method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a polymer; and (b) implanting the medical device into the host; a method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent and a polymer, and (b) implanting the medical device into the host; a method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-infective agent and a polymer, and (b) implanting the medical device into the host; and a method for implanting a medical device

4 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.
These and other aspects of the present invention will become evident upon reference to the following detailed description and attached drawings. In addition, various references are set forth herein which describe in more detail certain procedures and/or compositions, and are therefore incorporated by reference in the entirety.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a diagram showing how a cell cycle inhibitor acts at one or more of the steps in the biological pathway.
Figure 2 is a graph showing the results for the screening assay for assessing the effect of mitoxantrone on nitric oxide production by THP-1 macrophages.
Figure 3 is a graph showing the results for the screening assay for assessing the effect of Bay 11-7082 on TNF-alpha production by THP-1 macrophages.
Figure 4 is a graph showing the results for the screening assay for assessing the effect of rapamycin concentration for TNFa production by THP-1 macrophages.
Figure 5 is graph showing the results of a screening assay for assessing the effect of mitoxantrone on proliferation of human fibroblasts.
Figure 6 is graph showing the results of a screening assay for assessing the effect of rapamycin on proliferation of human fibroblasts.
Figure 7 is graph showing the results of a screening assay for assessing the effect of paclitaxel on proliferation of human fibroblasts.
Figure 8 is a picture that shows an uninjured carotid artery from a rat balloon injury model.

5 Figure 9 is a picture that shows an injured carotid artery from a rat balloon injury model.
Figure 10 is a picture that shows a paclitaxel/mesh treated carotid artery in a rat balloon injury model.
Figure 11A schematically depicts the transcriptional regulation of matrix metalloproteinases.
Figure 11 B is a blot which demonstrates that IL-1 stimulates AP-1 transcriptional activity.
Figure 11 C is a graph which shows that IL-1 induced binding activity decreased in lysates from chondrocytes which were pretreated with paclitaxel.
Figure 11 D is a blot which shows that IL-1 induction increases collagenase and stromelysin in RNA levels in chondrocytes, and that this induction can be inhibited by pretreatment with paclitaxel.
Figures 12A-H are blots that show the effect of various anti-microtubule agents in inhibiting collagenase expression.
Figure 13 is a graph showing the results of a screening assay for assessing the effect of paclitaxel on smooth muscle cell migration.
Figure 14 is a graph showing the results of a screening assay for assessing the effect of geldanamycin on IL-1 ~i production by THP-1 macrophages.
Figure 15 is a graph showing the results of a screening assay for assessing the effect of geldanamycin on IL-8 production by THP-1 macrophages.
Figure 16 is a graph showing the results of a screening assay for assessing the effect of geldanamycin on MCP-1 production by THP-1 macrophages.
Figure 17 is graph showing the results of a screening assay for assessing the effect of paclitaxel on proliferation of smooth muscle cells.

6 Figure 18 is graph showing the results of a screening assay for assessing the effect of paclitaxel for proliferation of the murine RAW 264.7 macrophage cell line.
Figure 19 is a graph showing the average rank of joint scores of Hartley guinea pig knees with ACL damage treated with paclitaxel. A reduction in score indicates an improvement in cartilage score. The dose response trend is statistically significant (p < 0.02).
Figures 20A-C are examples of cross sections of Hartley guinea pig knees of control and paclitaxel treated animals. Figure 20A. Control speciment showing erosion of cartilage to the bone. Figure 20B. Paclitaxel dose 1 (low dose) showing fraying of cartilage. Figure 20C. Paclitaxel dose 2 (medium dose) showing minor defects to cartilage.
Figures 21A-F are Safranin-O stained histological slides of representative synovial tissues from naive (healthy) knees (Figures 21A and 21 D) and knees with arthritis induced by administration of albumin in Freund's complete adjuvant (Figures 21 B and 21 C) or carrageenan (Figures 21 E and 21 F). Arthritic knees received either control (Figures 21 B and 21 E) or 20%
paclitaxel-loaded microspheres (Figures 21 C and 21 F). The data illustrate decreased proteoglycan red staining in arthritic knees treated with control microspheres and the proteoglycan protection properties of the paclitaxel-loaded formulation.
DETAILED DESCRIPTION OF THE INVENTION
Definitions Prior to setting forth the invention, it may be helpful to an understanding thereof to first set forth definitions of certain terms that are used herein.
"Fibrosis," or "scarring," or "fibrotic response" refers to the formation of fibrous (scar) tissue in response to injury or medical intervention.

7 Therapeutic agents which inhibit fibrosis or scarring are referred to herein as "fibrosis-inhibiting agents", "fibrosis-inhibitors", "anti-scarring agents", and the like, where these agents inhibit fibrosis through one or more mechanisms including: inhibiting inflammation or the acute inflammatory response, inhibiting migration or proliferation of connective tissue cells (such as fibroblasts, smooth muscle cells, vascular smooth muscle cells), inhibiting angiogenesis, reducing extracellular matrix (ECM) production or promoting ECM breakdown, and/or inhibiting tissue remodeling. When scarring occurs in a confined space (e.g., within a lumen) following surgery or instrumentation (including implantation of a medical device or implant), such that a body passageway (e.g., a blood vessel, the gastrointestinal tract, the respiratory tract, the urinary tract, the female or male reproductive tract, the eustacian tube etc.) is partially or completely obstructed by scar tissue, this is referred to as "stenosis" (narrowing). When scarring subsequently occurs to re-occlude a body passageway after it was initially successfully opened by a surgical intervention (such as placement of a medical device or implant), this is referred to as "restenosis."
"Host", "person", "subject", "patient" and the like are used synonymously to refer to the living being into which a device or implant of the present invention is implanted.
"Implanted" refers to having completely or partially placed a device or implant within a host. A device is partially implanted when some of the device reaches, or extends to the outside of, a host.
"Inhibit fibrosis", "reduce fibrosis", "inhibits scarring" and the like are used synonymously to refer to the action of agents or compositions which result in a statistically significant decrease in the formation of fibrous tissue that can be expected to occur in the absence of the agent or composition.
"Anti-infective agent" refers to an agent or composition which prevents microrganisms from growing and/or slows the growth rate of microorganisms and/or is directly toxic to microorganisms at or near the site of the agent. These processes would be expected to occur at a statistically significant level at or near the site of the agent or composition relative to the effect in the absence of the agent or composition.
"Inhibit infection" refers to the ability of an agent or composition to prevent microorganisms from accumulating andlor proliferating near or at the site of the agent. These processes would be expected to occur at a statistically significant level at or near the site of the agent or composition relative to the effect in the absence of the agent or composition.
"Inhibitor" refers to an agent which prevents a biological process from occurring or slows the rate or degree of occurrence of a biological process. The process may be a general one such as scarring or refer to a specific biological action such as, for example, a molecular process resulting in release of a cytokine.
"Antagonist" refers to an agent which prevents a biological process from occurring or slows the rate or degree of occurrence of a biological process. While the process may be a general one, typically this refers to a drug mechanism where the drug competes with a molecule for an active molecular site or prevents a molecule from interacting with the molecular site. In these situations, the efFect is that the molecular process is inhibited.
"Agonist" refers to an agent which stimulates a biological process or rate or degree of occurrence of a biological process. The process may be a general one such as scarring or refer to a specific biological action such as, for example, a molecular process resulting in release of a cytokine.
"Anti-microtubule agents" should be understood to include any protein, peptide, chemical, or other molecule which impairs the function of microtubules, for example, through the prevention or stabilization of polymerization. Compounds that stabilize polymerization of microtubules are referred to herein as "microtubule stabilizing agents." A wide variety of methods may be utilized to determine the anti-microtubule activity of a particular compound, including for example, assays described by Smith et al.

(Cancer Lett 79(2):213-219, 1994) and Mooberry et al., (Cancer Lett. 96(2):261-266, 1995).
"Medical device", "implant", ""device", medical device", "medical implant", "implant/device" and the like are used synonymously to refer to any object that is designed to be placed partially or wholly within a patient's body for one or more therapeutic or prophylactic purposes such as for restoring physiological function, alleviating symptoms associated with disease, delivering therapeutic agents, and/or repairing, replacing, or augmenting etc. damaged or diseased organs and tissues. While normally composed of biologically compatible synthetic materials (e.g., medical-grade stainless steel, titanium and other metals; polymers such as polyurethane, silicon, PLA, PLGA and other materials) that are exogenous, some medical devices and implants include materials derived from animals (e.g.', "xenografts" such as whole animal organs;
animal tissues such as heart valves; naturally occurring or chemically-modified molecules such as collagen, hyaluronic acid, proteins, carbohydrates and others), human donors (e.g., "allografts" such as whole organs; tissues such as bone grafts, skin grafts and others), or from the patients themselves (e.g., "autografts" such as saphenous vein grafts, skin grafts, tendon/ligament/muscle transplants). Representative examples of medical devices that are of particular utility in the present invention include, but are not restricted to, vascular stents, gastrointestinal stents, tracheal/bronchial stents, genital-urinary stents, ENT
stents, intra-articular implants, intraocular lenses, implants for hypertrophic scars and keloids, vascular grafts, anastomotic connector devices, implantable sensors, implantable pumps, soft tissue implants (e.g., cosmetic implants and implants for reconstructive surgery), implantable electrical devices, such as implantable neurostimulators and implantable electrical leads, surgical adhesion barriers, glaucoma drainage devices, surgical films and meshes, prosthetic heart valves, tympanostomy tubes, penile implants, endotracheal and tracheostomy tubes, peritoneal dialysis catheters, intracranial pressure monitors, vena cava fitters, central venous catheters (CVC's), ventricular assist devices (e.g., LVAD), spinal prostheses, urinary (Foley) catheters, prosthetic bladder sphincters, orthopedic implants, and gastrointestinal drainage tubes.
"Chondroprotection" refers to the prevention of cartilage loss.
Cartilage is formed from chondrocytes, and chondroprotection is the protection of the chrondrocytes so that they do not die.
"Release of an agent" refers to a statistically significant presence of. the agent, or a subcomponent thereof, which has disassociated from the implant/device and/or remains active on the surface of (or within) the device/implant.
"Biodegradable" refers to materials for which the degradation process is at least partially mediated by, and/or performed in, a biological system. "Degradation" refers to a chain scission process by which a polymer chain is cleaved into oligomers and monomers. Chain scission may occur through various mechanisms, including, for example, by chemical reaction (e.g., hydrolysis) or by a thermal or photolytic process. Polymer degradation may be characterized, for example, using gel permeation chromatography (GPC), which monitors the polymer molecular mass changes during erosion and drug release. Biodegradable also refers to materials may be degraded by an erosion process mediated by, and/or performed in, a biological system. "Erosion"
refers to a process in which material is lost from the bulk. In the case of a polymeric system, the material may be a monomer, an oligomer, a part of a polymer backbone, or a part of the polymer bulk. Erosion includes (i) surface erosion, in which erosion affects only the surface and not the inner parts of a matrix;
and (ii) bulk erosion, in which the entire system is rapidly hydrated and polymer chains are cleaved throughout the matrix. Depending on the type of polymer, erosion generally occurs by one of three basic mechanisms (see, e.g., Heller, J., CRC Critical Review in Therapeutic Drug Carrier Systems (1984), 1 (1 ), 39-90); Siepmann, J. et al., Adv. Drug Del. Rev. (2001 ), 48, 229-247): (1 ) water-soluble polymers that have been insolubilized by covalent cross-links and that solubilize as the cross-links or the backbone undergo a hydrolytic cleavage;
(2) polymers that are initially water insoluble are solubilized by hydrolysis, ionization, or pronation of a pendant group; and (3) hydrophobic polymers are converted to small water-soluble molecule's by backbone cleavage.
Techniques for characterizing erosion include thermal analysis (e.g., DSC), X-ray diffraction, scanning electron microscopy (SEM), electron paramagnetic resonance spectroscopy (EPR), NMR imaging, and recording mass loss during an erosion experiment. For microspheres, photon correlation spectroscopy (PCS) and other particles size measurement techniques may be applied to monitor the size evolution of erodible devices versus time.
As used herein, "analogue" refers to a chemical compound that is structurally similar to a parent compound, but differs slightly in composition (e.g., one atom or functional group is different, added, or removed). The analogue may or may not have different chemical or physical properties than the original compound and may or may not have improved biological and/or chemical activity. For example, the analogue may be more hydrophilic or it may have altered reactivity as compared to the parent compound. The analogue may mimic the chemical and/or biologically activity of the parent compound (i.e., it may have similar or identical activity), or, in some cases, may have increased or decreased activity. The analogue may be a naturally or non-naturally occurring (e.g., recombinant) variant of the original compound. An example of an analogue is a mutein (i.e., a protein analogue in which at least one amino acid is deleted, added, or substituted with another amino acid).
Other types of analogues include isomers (enantiomers, diasteromers, and the like) and other types of chiral variants of a compound, as well as structural isomers. The analogue may be a branched or cyclic variant of a linear compound. For example, a linear compound may have an analogue that is branched or otherwise substituted to impart certain desirable properties (e.g., improve hydrophilicity or bioavailability).
As used herein, "derivative" refers to a chemically or biologically modified version of a chemical compound that is structurally similar to a parent compound and (actually or theoretically) derivable from that parent compound.
A "derivative" differs from an "analogue" in that a parent compound may be the starting material to generate a "derivative," whereas the parent compound may not necessarily be used as the starting material to generate an "analogue." A
derivative may or may not have different chemical or physical properties of the parent compound. For example, the derivative may be more hydrophilic or it may have altered reactivity as compared to the parent compound.
Derivatization (i.e., modification) may involve substitution of one or more moieties within the molecule (e.g., a change in functional group). For example, a hydrogen may be substituted with a halogen, such as fluorine or chlorine, or a hydroxyl group (-OH) may be replaced with a carboxylic acid moiety (-COOH).
The term "derivative" also includes conjugates, and prodrugs of a parent compound (i.e., chemically modified derivatives which can be converted into the original compound under physiological conditions). For example, the prodrug may be an inactive form of an active agent. Under physiological conditions, the prodrug may be converted into the active form of the compound. Prodrugs may be formed, for example, by replacing one or two hydrogen atoms on nitrogen atoms by an acyl group (acyl prodrugs) or a carbamate group (carbamate prodrugs). More detailed information relating to prodrugs is found, for example, in Fleisher et al., Advanced Drug Delivery Reviews 19 (1996) 115; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; or H. Bundgaard, Drugs of the Future 16 (1991 ) 443. The term "derivative" is also used to describe all solvates, for example hydrates or adducts (e.g., adducts with alcohols), active metabolites, and salts of the parent compound. The type of salt that may be prepared depends on the nature of the moieties within the compound. For example, acidic groups, for example carboxylic acid groups, can form, for example, alkali metal salts or alkaline earth metal salts (e.g., sodium salts, potassium salts, magnesium salts and calcium salts, and also salts with physiologically tolerable quaternary ammonium ions and acid addition salts with ammonia and physiologically tolerable organic amines such as, for example, triethylamine, ethanolamine or tris-(2-hydroxyethyl)amine). Basic groups can form acid addition salts, for example with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic acids and sulfonic acids such as acetic acid, citric acid, benzoic acid, malefic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. Compounds which simultaneously contain a basic group and an acidic group, for example a carboxyl group in addition to basic nitrogen atoms, can be present as zwitterions. Salts can be obtained by customary methods known to those skilled in the art, for example by combining a compound with an inorganic or organic acid or base in a solvent or diluent, or from other salts by cation exchange or anion exchange.
"Hyaluronic acid" or "HA" as used herein refers to all forms of hyaluronic acid that are described or referenced herein, including those that have been processed or chemically or physically modified, as well as hyaluronic acid that has been crosslinked (for example, covalently, ionically, thermally or physically). HA is a glycosaminoglycan composed of a' linear chain of about 2500 repeating disaccharide units. Each disaccharide unit is composed of an N-acetylglucosamine residue linked to a glucuronic acid. Hyaluronic acid is a natural substance that is found in the extracellular matrix of many tissues including synovial joint fluid, the vitreous humor of the eye, cartilage, blood vessels, skin and the umbilical cord. Commercial forms of hyaluronic acid having a molecular weight of approximately 1.2 to 1.5 million Daltons (Da) are extracted from rooster combs and other animal sources. Other sources of HA
include HA that is isolated from cell culture / fermentation processes. Lower molecular weight HA formulations are also available from a variety of commercial sources. The molecule can be of variable lengths (i.e., different numbers of repeating disaccharide units and different chain branching patterns) and can be modified at several sites (through the addition or subtraction of different functional groups) without deviating from the scope of the present invention.

The term "inter-react" refers to the formulation of covalent bonds, noncovalent bonds, or both. The term thus includes crosslinking, which involves both intermolecular crosslinks and optionally intramolecular crosslinks as well, arising from the formation of covalent bonds. Covalent bonding between two reactive groups may be direct, in which case an atom in reactive group is directly bound to an atom in the other reactive group, or it may be indirect, through a linking group. Noncovalent bonds include ionic (electrostatic) bonds, hydrogen bonds, or the association of hydrophobic molecular segments, which may be the same or different. A crosslinked matrix may, in addition to covalent bonds, also include such intermolecular and/or intramolecular noncovalent bonds.
When referring to polymers, the terms "hydrophilic" and "hydrophobic" are generally defined in terms of an HLB value, i.e., a hydrophilic lipophilic balance. A high HLB value indicates a hydrophilic compound, while a low HLB value characterizes a hydrophobic compound. HLB values are well known in the art, and generally range from 1 to 18. Preferred multifunctional compound cores are hydrophilic, although as long as the multifunctional compound as a whole contains at least one hydrophilic component, crosslinkable hydrophobic components may also be present.
The term "synthetic" is used to refer to polymers, compounds and other such materials that are "chemically synthesized." For example, a synthetic material in the present compositions may have a molecular structure that is identical to a naturally occurring material, but the material per se, as incorporated in the compositions of the invention, has been chemically synthesized in the laboratory or industrially. "Synthetic" materials also include semi-synthetic materials, i.e., naturally occurring materials, obtained from a natural source, that have been chemically modified in some way. Generally, however, the synthetic materials herein are purely synthetic, i.e., they are neither semi-synthetic nor have a structure that is identical to that of a naturally occurring material.

The term "effective amount" refers to the amount of composition required in order to obtain the effect desired. For example, a "tissue growth-promoting amount" of a composition refers to the amount needed in order to stimulate tissue growth to a detectable degree. Tissue, in this context, includes connective tissue, bone, cartilage, epidermis and dermis, blood, and other tissues. The actual amount that is determined to be an effective amount will vary depending on factors such as the size, condition, sex and age of the patient and can be more readily determined by the caregiver.
The term "in situ" as used herein means at the site of administration. Thus, compositions of the invention can be injected or otherwise applied to a specific site within a patient's body, e.g., a site in need of augmentation, and allowed to crosslink at the site of injection. Suitable sites will generally be intradermal or subcutaneous regions for augmenting dermal support, at a bone fracture site for bone repair, within sphincter tissue for sphincter augmentation (e.g., for restoration of continence), within a wound or suture, to promote tissue regrowth; and within or adjacent to vessel anastomoses, to promote vessel regrowth.
The term "aqueous medium" includes solutions, suspensions, dispersions, colloids, and the like containing water. The term "aqueous environment" means an environment containing an aqueous medium.
Similarly, the term "dry environment" means an environment that does not contain an aqueous medium.
With regard to nomenclature pertinent to molecular structures, the following definitions apply:
The term "alkyl" as used herein refers to a branched or unbranched saturated hydrocarbon group typically although not necessarily containing 1 to about 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl and the like. Generally, although again not necessarily, alkyl groups herein contain 1 to about 12 carbon atoms. The term "lower alkyl" intends an alkyl group of one to six carbon atoms, preferably one to four carbon atoms. "Substituted alkyl" refers to alkyl substituted with one or more substituent groups. "Alkylene," "lower alkylene" and "substituted alkylene" refer to divalent alkyl, lower alkyl, and substituted alkyl groups, respectively.
The term "aryl" as used herein, and unless otherwise specified, refers to an aromatic substituent containing a single aromatic ring (monocyclic) or multiple aromatic rings that are fused together, linked covalently, or linked to a common group such as a methylene or ethylene moiety. The common linking group may also be a carbonyl as in benzophenone, an oxygen atom as in diphenylether, or a nitrogen atom as in diphenylamine. Preferred aryl groups contain one aromatic ring or two fused or linked aromatic rings, e.g., phenyl, naphthyl, biphenyl, diphenylether, diphenylamine, benzophenone, and the like.
"Substituted aryl" refers to an aryl moiety substituted with one or more substituent groups, and the terms "heteroatom-containing aryl" and "heteroaryl"
refer to aryl in which at least one carbon atom is replaced with a heteroatom.
The terms "arylene" and "substituted arylene" refer to divalent aryl and substituted aryl groups as just defined.
The term "heteroatom-containing" as in a "heteroatom-containing hydrocarbyl group" refers to a molecule or molecular fragment in which one or more carbon atoms is replaced with an atom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus or silicon.
"Hydrocarbyl" refers to univalent hydrocarbyl radicals containing 1 to about 30 carbon atoms, preferably 1 to about 24 carbon atoms, most preferably 1 to about 12 carbon atoms, including branched or unbranched, saturated or unsaturated species, such as alkyl groups, alkenyl groups, aryl groups, and the like. The term "lower hydrocarbyl" intends a hydrocarbyl group of one to six carbon atoms, preferably one to four carbon atoms. The term "hydrocarbylene" intends a divalent hydrocarbyl moiety containing 1 to about carbon atoms, preferably 1 to about 24 carbon atoms, most preferably 1 to about 12 carbon atoms, including branched or unbranched, saturated or unsaturated species, or the like. The term "lower hydrocarbylene" intends a hydrocarbylene group of one to six carbon atoms, preferably one to four carbon atoms. "Substituted hydrocarbyl" refers to hydrocarbyl substituted with one or more substituent groups, and the terms "heteroatom-containing hydrocarbyl"
and "heterohydrocarbyl" refer to hydrocarbyl in which at least one carbon atom is replaced with a heteroatom. Similarly, "substituted hydrocarbylene" refers to hydrocarbylene substituted with one or more substituent groups, and the terms "heteroatom-containing hydrocarbylene" and "heterohydrocarbylene" refer to hydrocarbylene in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, "hydrocarbyl" indicates both unsubstituted and substituted hydrocarbyls, "heteroatom-containing hydrocarbyl" indicates both unsubstituted and substituted heteroatom-containing hydrocarbyls and so forth.
By "substituted" as in "substituted hydrocarbyl," "substituted alkyl,"
and the like, as alluded to in some of the aforementioned definitions, is meant that in the hydrocarbyl, alkyl, or other moiety, at least one hydrogen atom bound to a carbon atom is replaced with one or more substituents that are functional groups such as alkoxy, hydroxy, halo, vitro, and the like. Unless otherwise indicated, it is to be understood that specified molecular segments can be substituted with one or more substituents that do not compromise a compound's utility. For example, "succinimidyl" is intended to include unsubstituted succinimidyl as well as sulfosuccinimidyl and other succinimidyl groups substituted on a ring carbon atom, e.g., with alkoxy substituents, polyether substituents, or the like.
Any concentration ranges, percentage range, or ratio range recited herein are to be understood to include concentrations, percentages or ratios of any integer within that range and fractions thereof, such as one tenth and one hundredth of an integer, unless otherwise indicated. Also, any number range recited herein relating to any physical feature, such as polymer subunits, size or thickness, are to be understood to include any integer within the recited range, unless otherwise indicated. As used herein, the term "about" refers to ~
15% of any indicated structure, value, or range.
"A" and "an" refer to one or more of the indicated items. For example, "a" polymer refers to both one polymer or a mixture comprising two or more polymers; "a multifunctional compound " refers not only to a single multifunctional compound but also to a combination of two or more of the same or different multifunctional compounds; "a reactive group" refers to a combination of reactive groups as well as to a single reactive group, and the like.
As discussed above, the present invention provides polymeric compositions which greatly increase the ability to inhibit the formation of reactive scar tissue on, or around, the surface of a device or implant or at a treatment site. Numerous polymeric compositions and therapeutic agents are described herein.
The present invention provides for the combination of compositions (e.g., polymers) which include one or more therapeutic agents, described below. Also described in more detail below are methods for making and methods for utilizing such compositions.
A. Therapeutic Agents In one aspect, the present invention discloses pharmaceutical agents which inhibit one or more aspects of the production of excessive fibrous (scar) tissue. Suitable fibrosis-inhibiting or stenosis-inhibiting agents may be readily determined based upon the in vitro and in vivo (animal) models such as those provided in Examples 20-33. Agents which inhibit fibrosis may be identified through in viv~ models including inhibition of intimal hyperplasia development in the rat balloon carotid artery model (Examples 25 and 33). The assays set forth in Examples 24 and 32 may be used to determine whether an agent is able to inhibit cell proliferation in fibroblasts and/or smooth muscle cells. In one aspect of the invention, the agent has an IC5° for inhibition of cell proliferation within a range of about 10-6 to about 10-x° M. The assay set forth in Example 28 may be used to determine whether an agent may inhibit migration of fibroblasts and/or smooth muscle cells. In one aspect of the invention, the agent has an IC5° for inhibition of cell migration within a range of about 10-6 to about 10-9M. Assays set forth herein may be used to determine whether an agent is able to inhibit inflammatory processes, including nitric oxide production in macrophages (Example 20), and/or TNF-alpha production by macrophages (Example 21 ), and/or IL-1 beta production by macrophages (Example 29), and/or IL-8 production by macrophages (Example 30), and/or inhibition of MCP-1 by macrophages (Example 31 ). In one aspect of the invention, the agent has an IC5° for inhibition of any one of these inflammatory processes within a range of about 10-6 to about 10-~°M. The assay set forth in Example 26 may be used to determine whether an agent is able to inhibit MMP production. In one aspect of the invention, the agent has an IC5° for inhibition of MMP
production within a range of about 10-4 to about 10-$M. The assay set forth in Example 27 (al'so known as the CAM assay) may be used to determine whether an agent is able to inhibit angiogenesis. In one aspect of the invention, the agent has an IC5° for inhibition of angiogenesis within a range of about 10-6 to about 10-~°M. Agents which reduce the formation of surgical adhesions may be identified through in vivo models including the rabbit surgical adhesions model (Examples 23, 42 and 43) and the rat caecal sidewall model (Example 22). These pharmacologically active agents (described below) can then be delivered at appropriate dosages into to the tissue either alone, or via carriers (described herein), to treat the clinical problems described herein.
Numerous therapeutic compounds capable of inhibiting fibrosis have been identified that are of utility in the invention including:

1 ) Anaiogenesis Inhibitors In one embodiment, the pharmacologically active fibrosis-inhibiting compound is an angiogenesis inhibitor (e.g., 2-ME (NSC-659853), PI-88 (D-mannose, O-6-O-phosphono-alpha-D-mannopyranosyl-(1-3)-O-alpha-D-mannopyranosyl-(1-3)-O-alpha-D-mannopyranosyl-(1-3)-O-alpha-D-mannopyranosyl-(1-2)- hydrogen sulfate), thalidomide (1H-isoindole-1,3(2H)-dione, 2-(2,6-dioxo-3-piperidinyl)-), CDC-394, CC-5079, ENMD-0995 (S-3-amino-phthalidoglutarimide), AVE-8062A, vatalanib, SH-268, halofuginone hydrobromide, atiprimod dimaleate (2-azaspivo(4.5)decane-2-propanamine, N,N-diethyl-8,8-dipropyl, dimaleate), ATN-224, CHIR-258, combretastatin A-4 (phenol, 2-methoxy-5-(2-(3,4,5-trimethoxyphenyl)ethenyl)-, (Z)-), GCS-100LE, or an analogue or derivative thereof).
2) 5-Lipoxygenase Inhibitors and Antagonists In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a 5-lipoxygenase inhibitor or antagonist (e.g., Wy-(2-naphthaleneacetic acid, alpha-methyl-6-(2-quinolinylmethoxy)-, (S)-), ONO-LP-269 (2,11,14-eicosatrienamide, N-(4-hydroxy-2-(1H-tetrazol-5-yl)-8-quinolinyl)-, (E,Z,Z)-), licofelone (1 H-pyrrolizine-5-acetic acid, 6-(4-chlorophenyl)-2,3-dihydro-2,2-dimethyl-7-phenyl-), CMI-568 (urea, N-butyl-N-hydroxy-N'-(4-(3-(methylsulfonyl)-2-propoxy-5-(tetrahydro-5-(3,4,5-trimethoxyphenyl)-2-furanyl)phenoxy)butyl)-,trans-), IP-751 ((3R,4R)-(delta 6)-THC-DMH-11-oic acid), PF-5901 (benzenemethanol, alpha-pentyl-3-(2-quinolinylmethoxy)-), LY-293111 (benzoic acid, 2-(3-(3-((5-ethyl-4'-fluoro-2-hydroxy(1,1'-biphenyl)-4-yl)oxy)propoxy)-2-propylphenoxy)-), RG-5901-A
(benzenemethanol, alpha-pentyl-3-(2-quinolinylmethoxy)-, hydrochloride), rilopirox (2(1 H)-pyridinone, 6-((4-(4-chlorophenoxy)phenoxy)methyl)-1-hydroxy-4-methyl-), L-674636 (acetic acid, ((4-(4-chlorophenyl)-1-(4-(2-quinolinylmethoxy)phenyl)butyl)thio)-AS)), 7-((3-(4-methoxy-tetrahydro-2H-pyran-4-yl)phenyl)methoxy)-4-phenylnaphtho(2,3-c)furan-1 (3H)-one, MK-886 (1H-indole-2-propanoic acid, 1-((4-chlorophenyl)methyl)-3-((1,1-dimethylethyl)thio)-alpha, alpha-dimethyl-5-(1-methylethyl)-), quiflapon (1 H-indole-2-propanoic acid, 1-((4-chlorophenyl)methyl)-3-((1,1-dimethylethyl)thio)-alpha, alpha-dimethyl-5-(2-quinolinylmethoxy)-), quiflapon (1 H-Indole-2-propanoic acid, 1-((4-chlorophenyl)methyl)-3-((1,1-dimethylethyl)thio)-alpha, alpha-dimethyl-5-(2-quinolinylmethoxy)-), docebenone (2,5-cyclohexadiene-1,4-dione, 2-(12-hydroxy-5,10-dodecadiynyl)-3,5,6-trimethyl-), zileuton (urea, N-(1-benzo(b)thien-2-ylethyl)-N-hydroxy-), or an analogue or derivative thereof).
3) Chemokine Receptor Antagonists CCR (1, 3, and 5) In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a chemokine receptor antagonist which inhibits one or more subtypes of CCR (1, 3, and 5) (e.g., ONO-4128 (1,4,9-triazaspiro(5.5)undecane-2,5-dione, 1-butyl-3-(cyclohexylmethyl)-9-((2,3-dihydro-1,4-benzodioxin-6-yl)methyl-), L-381, CT-112 (L-arginine, L-threonyl-L-threonyl-L-seryl-L-glutaminyl-L-valyl-L-arginyl-L-prolyl-), AS-900004, SCH-C, ZK-811752, PD-172084, UK-427857, SB-380732, vMIP II, SB-265610, DPC-168, TAK-779 (N, N-dimethyl-N-(4-(2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-ylcarboxamido)benyl)tetrahydro-2H-pyran-4-aminium chloride), TAK-220, KRH-1120), GSK766994, SSR-150106, or an analogue or derivative thereof). Other examples of chemokine receptor antagonists include a-Immunokine-NNS03, BX-471, CCX-282, Sch-350634; Sch-351125; Sch-417690; SCH-C, and analogues and derivatives thereof.
4) Cell Cycle Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a cell cycle inhibitor. Representative examples of such agents include taxanes (e.g., paclitaxel (discussed in more detail below) and docetaxel) (Schiff et al., Nature 277:665-667, 1979; Long and Fairchild, Cancer Research 54:4355-4361, 1994; Ringel and Horwitz, J. Nat'I Cancer Inst.

83(4):288-291, 1991; Pazdur et al., Cancer Treat. Rev. 79(40):351-386, 1993), etanidazole, nimorazole (B.A. Chabner and D.L. Longo. Cancer Chemotherapy and Biotherapy - Principles and Practice. Lippincott-Raven Publishers, New York,.1996, p.554), perfluorochemicals with hyperbaric oxygen, transfusion, erythropoietin,~BW12C, nicotinamide, hydralazine, BSO, WR-2721, IudR, DUdR, etanidazole, WR-2721, BSO, mono-substituted keto-aldehyde compounds (L.G. Egyud. Keto-aldehyde-amine addition products and method of making same. U.S. Patent No. 4,066,650, Jan 3, 1978), nitroimidazole (K.C.
Agrawal and M. Sakaguchi. Nitroimidazole radiosensitizers for Hypoxic tumor cells and compositions thereof. U.S. Patent No. 4,462,992, Jul. 31, 1984), 5-substituted-4-nitroimidazoles (Adams et al., Int. J. Radiat. 8i~1. Relat.
Stud.
Phys., Chem. Med. 40(2):153-61, 1981 ), SR-2508 (Brown et al., Int. J. Radiat.
Oncol., Biol. Phys. 7(6):695-703, 1981 ), 2H-isoindolediones (J.A. Myers, 2H-Isoindolediones, the synthesis and use as radiosensitizers. Patent 4,494,547, Jan. 22, 1985), chiral (((2-bromoethyl)-amino)methyl)-nitro-1 H-imidazole-1-ethanol (V.G. Beylin, et al., Process for preparing chiral (((2-bromoethyl)-amino)methyl)-nitro-1 H-imidazole-1-ethanol and related compounds. U.S.
Patent No. 5,543,527, Aug. 6, 1996; U.S. Patent No. 4,797,397; Jan. 10, 1989;
U.S. Patent No. 5,342,959, Aug. 30, 1994), nitroaniline derivatives (W.A.
Denny, et al. Nitroaniline derivatives and the use as anti-tumor agents. U.S.
Patent No. 5,571,845, Nov. 5, 1996), DNA-affinic hypoxia selective cytotoxins (M.V. Papadopoulou-Rosenzweig. DNA-affinic hypoxia selective cytotoxins.
U.S. Patent No. 5,602,142, Feb. 11, 1997), halogenated DNA ligand (R.F.
Martin. Halogenated DNA ligand radiosensitizers for cancer therapy. U.S.
Patent No. 5,641,764, Jun 24, 1997), 1,2,4 benzotriazine oxides (W.W. Lee et al. 1,2,4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents. U.S. Patent No. 5,616,584, Apr. 1, 1997; U.S. Patent No. 5,624,925, Apr. 29, 1997; Process for Preparing 1,2,4 Benzotriazine oxides. U.S. Patent No. 5,175,287, Dec. 29, 1992), nitric oxide (J.B. Mitchell et al., Use of Nitric oxide releasing compounds as hypoxic cell radiation sensitizers. U.S. Patent No. 5,650,442, Jul. 22, 1997), 2-nitroimidazole derivatives (M.J. Suto et al.

Nitroimidazole derivatives useful as radiosensitizers for hypoxic tumor cells.
U.S. Patent No. 4,797,397, Jan. 10, 1989; T. Suzuki. 2-Nitroimidazole derivative, production thereof, and radiosensitizer containing the same as active ingredient. U.S. Patent No. 5,270,330, Dec. 14, 1993; T. Suzuki et al. 2-Nitroimidazole derivative, production thereof, and radiosensitizer containing the same as active ingredient. U.S. Patent No. 5,270,330, Dec 14, 1993; T.
Suzuki. 2-Nitroimidazole derivative, production thereof and radiosensitizer containing the same as active ingredient; Patent EP 0 513 351 B1, Jan. 24, 1991 ), fluorine-containing nitroazole derivatives (T. Kagiya. Fluorine-containing nitroazole derivatives and radiosensitizer comprising the same. U.S. Patent No. 4,927,941, May 22, 1990), copper (M.J. Abrams. Copper Radiosensitizers.
U.S. Patent No. 5,100,885, Mar. 31, 1992), combination modality cancer therapy (D.H. Picker et al. Combination modality cancer therapy. U.S. Patent No. 4,681,091, Jul. 21, 1987). 5-CIdC or (d)H4U or 5-halo-2'-halo-2'-deoxy-cytidine or -uridine derivatives (S.B. Greer. Method and Materials for sensitizing neoplastic tissue to radiation. U.S. Patent No. 4,894,364 Jan. 16, 1990), platinum complexes (K.A. Skov. Platinum Complexes with one radiosensitizing ligand. U.S. Patent No. 4,921,963. May 1, 1990; K.A. Skov.
Platinum Complexes with one radiosensitizing ligand. Patent EP 0 287 317 A3), fluorine-containing nitroazole (T. Kagiya, et al. Fluorine-containing nitroazole derivatives and radiosensitizer comprising the same. U.S. Patent No. 4,927,941. May 22,1990), benzamide (W.W. Lee. Substituted Benzamide Radiosensitizers. U.S. Patent No. 5,032,617, Jul. 16, 1991 ), autobiotics (L.G.
Egyud. Autobiotics and the use in eliminating nonself cells in vivo. U.S.
Patent No. 5,147,652. Sep. 15,1992), benzamide and nicotinamide (W.W. Lee et al.
Benzamide and Nictoinamide Radiosensitizers. U.S. Patent No. 5,215,738, Jun 1 1993), acridine-intercalator (M. Papadopoulou-Rosenzweig. Acridine Intercalator based hypoxia selective cytotoxins. U.S. Patent No. 5,294,715, Mar. 15,1994), fluorine-containing nitroimidazole (T. Kagiya et al. Fluorine containing nitroimidazole compounds. U.S. Patent No. 5,304,654, Apr. 19, 1994), hydroxylated texaphyrins (J.L. Sessler et al. Hydroxylated texaphrins.
U.S. Patent No. 5,457,183, Oct. 10, 1995), hydroxylated compound derivative (T. Suzuki et al. Heterocyclic compound derivative, production thereof and radiosensitizer and antiviral agent containing said derivative as active ingredient. Publication Number 011106775 A (Japan), Oct. 22,1987; T. Suzuki et al. Heterocyclic compound derivative, production thereof and radiosensitizer, antiviral agent and anti cancer agent containing said derivative as active ingredient. Publication Number 01139596 A (Japan), Nov. 25, 1987; S.
Sakaguchi et al. Heterocyclic compound derivative, its production and radiosensitizer containing said derivative as active ingredient; Publication Number 63170375 A (Japan), Jan. 7, 1987), fluorine containing 3-vitro-1,2,4-triazole (T. Kagitani et al. Novel fluorine-containing 3-vitro-1,2,4-triazole and radiosensitizer containing same compound. Publication Number 02076861 A
(Japan), Mar. 31, 1988), 5-thiotretrazole derivative or its salt (E. Kano et al.
Radiosensitizer for Hypoxic cell. Publication Number 61010511 A (Japan), Jun.
26, 1984), Nitrothiazole (T. Kagitani et al. Radiation-sensitizing agent.
Publication Number 61167616 A (Japan) Jan. 22, 1985), imidazole derivatives (S. Inayma et al. Imidazole derivative. Publication Number 6203767 A (Japan) Aug. 1,1985; Publication Number 62030768 A (Japan) Aug. 1, 1985;
Publication Number 62030777 A (Japan) Aug. 1, 1985), 4-vitro-1,2,3-triazole (T. Kagitani et al. Radiosensitizer. Publication Number 62039525 A (Japan), Aug. 15,1985), 3-vitro-1,2,4-triazole (T. Kagitani et al. Radiosensitizer.
Publication Number 62138427 A (Japan), Dec. 12, 1985), Carcinostatic action regulator (H. Amagase. Carcinostatic action regulator. Publication Number 63099017 A (Japan), Nov. 21, 1986), 4,5-dinitroimidazole derivative (S.
Inayama. 4,5-Dinitroimidazole derivative. Publication Number 63310873 A
(Japan) Jun. 9, 1987), nitrotriazole Compound (T. Kagitanil Nitrotriazole Compound. Publication Number 07149737 A (Japan) Jun. 22, 1993), cisplatin, doxorubin, misonidazole, mitomycin, tiripazamine, nitrosourea, mercaptopurine, methotrexate, flurouracil, bleomycin, vincristine, carboplatin, epirubicin, doxorubicin, cyclophosphamide, vindesine, etoposide (1.F. Tannock. Review Article: Treatment of Cancer with Radiation and Drugs. Journal of Clinical Oncology 14(12):3156-3174, 1996), camptothecin (Ewend M.G. et al. Local delivery of chemotherapy and concurrent external beam radiotherapy prolongs survival in metastatic brain tumor models. Cancer Research 56(22):5217-5223, 1996) and paclitaxel (Tishler R.B. et al. Taxol: a novel radiation sensitizer.
International Journal of Radiation Oncology and Biological Physics 22(3):613-617, 1992).
A number of the above-mentioned cell cycle inhibitors also have a wide variety of analogues and derivatives, including, but not limited to, cisplatin, cyclophosphamide, misonidazole, tiripazamine, nitrosourea, mercaptopurine, methotrexate, flurouracil, epirubicin, doxorubicin, vindesine and etoposide.
Analogues and derivatives include (CPA)2Pt(DOLYM) and (DACH)Pt(DOLYM) cisplatin (Choi et al., Areh. Pharmacal Res. 22(2):151-156, 1999), Cis-(PtCl2(4,7-H-5-methyl-7-oxo)1,2,4(triazolo(1,5-a)pyrimidine)2) (Navarro et al., J.
Med. Chem. 41(3):332-338, 1998), (Pt(cis-1,4-DACH)(trans-C12)(CBDCA)) ~'/~MeOH cisplatin (Shamsuddin et al., Inorg. Chem.
36(25):5969-5971, 1997), 4-pyridoxate diammine hydroxy platinum (Tokunaga et al., Pharm. Sci. 3(7):353-356, 1997), Pt(II) ~ ~ ~ Pt(II) (Pt2(NHCHN(C(CH2)(CH3)))4) (Navarro et al., Inorg. Chem. 35(26):7829-7835, 1996), 254-S cisplatin analogue (Koga et al., Neurol. Res. 13(3):244-247, 1996), o-phenylenediamine ligand bearing cisplatin analogues (Koeckerbauer &
Bednarski, J. Inorg. Biochem. 62(4):281-298, 1996), trans,cis-(Pt(OAc)~I~(en)) (Kratochwil et al., J. Med. Chem. 39(13):2499-2507, 1996), estrogenic 1,2-diarylethylenediamine ligand (with sulfur-containing amino acids and glutathione) bearing cisplatin analogues (Bednarski, J. Inorg. Biochem.
62(1):75, 1996), cis-1,4-diaminocyclohexane cisplatin analogues (Shamsuddin et al., J. Inorg. Biochem. 61(4):291-301, 1996), 5' orientational isomer of cis-(Pt(NH3)(4-aminoTEMP-O){d(GpG)}) (Dunham & Lippard, J. Am. Chem. Soc.

7 7 7(43):10702-12, 1995), chelating diamine-bearing cisplatin analogues (Koeckerbauer & Bednarski, J. Pharm. Sci. 84(7):819-23, 1995), 1,2-diarylethyleneamine ligand-bearing cisplatin analogues (Otto et al., J. Cancer Res. Clin. Oncol. 727(1):31-8, 1995), (ethylenediamine)platinum(II) complexes (Pasini et al., J. Chem. Soc., Dalton Trans. 4:579-85, 1995), CI-973 cisplatin analogue (Yang et al., Int. J. Oncol. 5(3):597-602, 1994), cis-diamminedichloroplatinum(11) and its analogues cis-1,1-cyclobutanedicarbosylato(2R)-2-methyl-1,4-butanediam-mineplatinum(II) and cis-diammine(glycolato)platinum (Claycamp & Zimbrick, J. Inorg. Biochem., 26(4):257-67, 1986; Fan et al., Cancer Res. 48(11 ):3135-9, 1988; Heiger-Bernays et al., Biochemistry 29(36):8461-6, 1990; Kikkawa et al., J. Exp.
Clin.
Cancer Res. 72(4):233-40, 1993; Murray et al., Biochemistry 37(47):11812-17, 1992; Takahashi et al., Cancer Chemother. Pharmacol. 33(1 ):31-5, 1993), cis-amine-cyclohexylamine-dichloroplatinum(II) (Yoshida et al., Biochem.
Pharmacol. 48(4):793-9, 1994), gem-diphosphonate cisplatin analogues (FR
2683529), (meso-1,2-bis(2,6-dichloro-4-hydroxyplenyl)ethylenediamine) dichloroplatinum(II) (Bednarski et al., J. Med. Chem. 35(23):4479-85, 1992), cisplatin analogues containing a tethered dansyl group (Hartwig et al., J. Am.
Chem. Soc. 7 74(21 ):8292-3, 1992), platinum(II) polyamines (Siegmann et al., Inorg. Met.-Containing Polym. Mater., (Pros. Am. Chem. Soc. Int. Symp.), 335-61, 1990), cis-(3H)dichloro(ethylenediamine)platinum(II) (Eastman, Anal.
Biochem. 797(2):311-15, 1991 ), trans-diamminedichloroplatinum(II) and cis-(Pt(NH3)2(N3-cytosine)CI) (Bellon & Lippard, Biophys. Chem. 35(2-3):179-88, 1990), 3H-cis-1,2-diaminocyclohexanedichloroplatinum(II) and 3H-cis-1,2-diaminocyclohexanemalonatoplatinum (II) (Oswald et al., Res. Commun. Chem.
Pathol. Pharmacol. 64(1 ):41-58, 1989), diaminocarboxylatoplatinum (EPA
296321 ), trans-(D,1 )-1,2-diaminocyclohexane carrier ligand-bearing platinum analogues (Wyrick & Chaney, J. Labelled Compd. Radiopharm. 25(4):349-57, 1988), aminoalkylaminoanthraquinone-derived cisplatin analogues (Kitov et al., Eur. J. Med. Chem. 23(4):381-3, 1988), spiroplatin, carboplatin, iproplatin and JM40 platinum analogues (Schroyen et al., Eur. J. Cancer Clin. Oncol.
24(8):1309-12, 1988), bidentate tertiary diamine-containing cisplatinum derivatives (Orbell et al., Inorg. Chim. Acta 752(2):125-34, 1988), platinum(II), platinum(IV) (Liu & Wang, Shandong Yike Daxue Xuebao 24(1):35-41, 1986), cis-diammine(1,1-cyclobutanedicarboxylato-)platinum(II) (carboplatin, JM8) and ethylenediammine-malonatoplatinum(II) (JM40) (Begg et al., Radiother. Oncol.
9(2):157-65, 1987), JM8 and JM9 cisplatin analogues (Harstrick et al., Int. J.
Androl. 70(1); 139-45, 1987), (NPr4)2((PtCL4).cis-(PtCl2-(NH2Me)2)) (Brammer et al., J. Chem. Soc., Chem. Commun. 6:443-5, 1987), aliphatic tricarboxylic acid platinum complexes (EPA 185225), cis-dichloro(amino acid)(tert-butylamine)platinum(II) complexes (Pasini & Bersanetti, Inorg.
Chim.
Acta 707(4):259-67, 1985); 4-hydroperoxycylcophosphamide (Ballard et al., Cancer Chemother. Pharmacol. 26(6):397-402, 1990), acyclouridine cyclophosphamide derivatives (Zakerinia et al., Helv. Chim. Acta 73(4):912-15, 1990), 1,3,2-dioxa- and -oxazaphosphorinane cyclophosphamide analogues (Yang et al., Tetrahedron 44(20):6305-14, 1988), C5-substituted cyclophosphamide analogues (Spada, University of Rhode Island Dissertation, 1987), tetrahydrooxazine cyclophosphamide analogues (Valente, University of Rochester Dissertation, 1988), phenyl ketone cyclophosphamide analogues (Hales et al., Teratology 39(1):31-7, 1989), phenylketophosphamide cyclophosphamide analogues (Ludeman et al., J. Med. Chem. 29(5):716-27, 1986), ASTA Z-7557 cyclophosphamide analogues (Evans et al., Int. J. Cancer 34(6):883-90, 1984), 3-(1-oxy-2,2,6,6-tetramethyl-4-piperidinyl)cyclophosphamide (Tsui et al., J. Med. Chem. 25(9):1106-10, 1982), 2-oxobis(2-(3-chloroethylamino)-4-,6-dimethyl-1,3,2-oxazaphosphorinane cyclophosphamide (Carpenter et al., Phosphorus Sulfur 72(3):287-93, 1982), 5-fluoro- and 5-chlorocyclophosphamide (Foster et al., J. Med. Chem.
24(12):1399-403, 1981 ), cis- and trans-4-phenylcyclophosphamide (Boyd et al., J. Med. Chem. 23(4):372-5, 1980), 5-bromocyclophosphamide, 3,5-dehydrocyclophosphamide (Ludeman et al., J. Med. Chem. 22(2):151-8, 1979), 4-ethoxycarbonyl cyclophosphamide analogues (Foster, J. Pharm. Sci.
67(5):709-10, 1978), arylaminotetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide cyclophosphamide analogues (Hamacher, Arch. Pharm. (Weinheim, Ger.) 310(5):J,428-34, 1977), NSC-26271 cyclophosphamide analogues (Montgomery & Struck, Cancer Treat. Rep. 60(4):J381-93, 1976), benzo annulated cyclophosphamide analogues (Ludeman & Zon, J. Med. Chem.
18(12):J1251-3, 1975), 6-trifluoromethylcyclophosphamide (Farmer & Cox, J.
Med. Chem. 18(11 ):J1106-10, 1975), 4-methylcyclophosphamide and 6-methycyclophosphamide analogues (Cox et al., Biochem. Pharmacol.
24(5):J599-606, 1975); FCE 23762 doxorubicin derivative (Quaglia et al., J.
Liq.
Chromatogr. 17(18):3911-3923, 1994), annamycin (Zoo et al., J. Pharm. Sci.
82(11 ):1151-1154, 1993), ruboxyl (Rapoport et al., J. Controlled Release 58(2):153-162, 1999), anthracycline disaccharide doxorubicin analogue (Pratesi et al., Clin. Cancer Res. 4(11 ):2833-2839, 1998), N-(trifluoroacetyl)doxorubicin and 4'-O-acetyl-N-(trifluoroacetyl)doxorubicin (Berube & Lepage, Synth.
Common. 28(6):1109-1116, 1998), 2-pyrrol~inodoxorubicin (Nagy et al., Proc.
Nat'1 Acad. Sci. U.S.A. 95(4):1794-1799, 1998), disaccharide doxorubicin analogues (Arcamone et al., J. Nat'I Cancer Inst. 89(16):1217-1223, 1997), 4-demethoxy-7-O-(2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-a-L-lyxo-hexopyranosyl)-cc-L-lyxo-hexopyranosyl)adriamicinone doxorubicin disaccharide analogue (Monteagudo et al., Carbohydr. Res. 300(1 ):11-16, 1997), 2-pyrrolinodoxorubicin (Nagy et al., Proc. Nat'I Acad. Sci. U.S.A.
94(2):652-656, 1997), morpholinyl doxorubicin analogues (Duran et al., Cancer Chemother. Pharmacol. 38(3):210-216, 1996), enaminomalonyl-~-alanine doxorubicin derivatives (Seitz et al., Tetrahedron Lett. 36(9):1413-16, 1995), cephalosporin doxorubicin derivatives (Vrudhula et al., J. Med. Chem.
38(8):1380-5, 1995), hydroxyrubicin (Solary et al., Int. J. Cancer 58(1 ):85-94, 1994), methoxymorpholino doxorubicin derivative (Kohl et al., Cancer Chemother. Pharmacol. 33(1 ):10-16, 1993), (6-maleimidocaproyl)hydrazone doxorubicin derivative (Willner et al., Bioconjugate Chem. 4(6):521-7, 1993), N-(5,5-diacetoxypent-1-yl) doxorubicin (Cherif & Farquhar, J. Med. Chem.
35(17):3208-14, 1992), FCE 23762 methoxymorpholinyl doxorubicin derivative (Ripamonti et al., Br. J. Cancer 65(5):703-7, 1992), N-hydroxysuccinimide ester doxorubicin derivatives (Demant et al., Biochim. Biophys. Acta 7778(1):83-90, 1991 ), polydeoxynucleotide doxorubicin derivatives (Ruggiero et al., Biochim.
Biophys. Acta 7729(3):294-302, 1991), morpholinyl doxorubicin derivatives (EPA 434960), mitoxantrone doxorubicin analogue (Krapcho et al., J. Med.
Chem. 34(8):2373-80. 1991 ), AD198 doxorubicin analogue (Traganos et al., Cancer Res. 57(14):3682-9, 1991 ), 4-demethoxy-3'-N-trifluoroacetyldoxorubicin (Horton et al., Drug Des. Delivery 6(2):123-9, 1990), 4'-epidoxorubicin (Drzewoski et al., Pol. J. Pharmacol. Pharm. 40(2):159-65, 1988; Weenen et al., Eur. J. Cancer Clin. Oncol. 20(7):919-26, 1984), alkylating cyanomorpholino doxorubicin derivative (Scudder et al., J. Nat'I Cancer Inst. 80(16):1294-8, 1988), deoxydihydroiodooxorubicin (EPA 275966), adriblastin (Kalishevskaya et al., Vestn. Mosk. Univ., 16(Biol. 1 ):21-7, 1988), 4'-deoxydoxorubicin (Schoelzel et al., Leuk. Res. 70(12):1455-9, 1986), 4-demethyoxy-4'-o-methyldoxorubicin (Giuliani et al., Proc. Int. Congr. Chemother. 76:285-70-285-77, 1983), 3'-deamino-3'-hydroxydoxorubicin (Horton et al., J. Antibiot. 37(8):853-8, 1984), demethyoxy doxorubicin analogues (Barbieri et al., Drugs Exp. Clin. Res.
10(2):85-90, 1984), N-L-leucyl doxorubicin derivatives (Trouet et al., Anthracyclines (Proc. Int. Symp. Tumor Pharmacother.), 179-81, 1983), 3'-deamino-3'-(4-methoxy-1-piperidinyl) doxorubicin derivatives (4,314,054), 3'-deamino-3'-(4-mortholinyl) doxorubicin derivatives (4,301,277), 4'-deoxydoxorubicin and 4'-o-methyldoxorubicin (Giuliani et al., Int. J. Cancer 27(1 ):5-13, 1981 ), aglycone doxorubicin derivatives (Chan & Watson, J.
Pharm.
Sci. 67(12):1748-52, 1978), SM 5887 (Pharma Japan 7468:20, 1995), MX-2 (Pharma Japan 7420:19, 1994), 4'-deoxy-13(S)-dihydro-4'-iododoxorubicin (EP
275966), morpholinyl doxorubicin derivatives (EPA 434960), 3'-deamino-3'-(4-methoxy-1-piperidinyl) doxorubicin derivatives (4,314,054), doxorubicin-14-valerate, morpholinodoxorubicin (5,004,606), 3'-deamino-3'-(3"-cyano-4"-morpholinyl doxorubicin; 3'-deamino-3'-(3"-cyano-4"-morpholinyl)-13-dihydoxorubicin; (3'-deamino-3'-(3"-cyano-4"-morpholinyl) daunorubicin; 3'-deamino-3'-(3"-cyano-4"-morpholinyl)-3-dihydrodaunorubicin; and 3'-deamino-3'-(4"-morpholinyl-5-iminodoxorubicin and derivatives (4,585,859), 3'-deamino-3'-(4-methoxy-1-piperidinyl) doxorubicin derivatives (4,314,054) and 3-deamino-3-(4-morpholinyl) doxorubicin derivatives (4,301,277); 4,5-dimethylmisonidazole (Born et al., Biochem. Pharmacol. 43(6):1337-44, 1992), azo and azoxy misonidazole derivatives (Gattavecchia & Tonelli, Int. J. Radiat. BioL Relat.
Stud. Phys., Chem. Med. 45(5):469-77, 1984); RB90740 (Wardman et al., Br. J.
Cancer, 74 Suppl. (27):S70-S74, 1996); 6-bromo and 6-chloro-2,3-dihydro-1,4-benzothiazines nitrosourea derivatives (Rai et al., Heterocyel. Common.
2(6):587-592, 1996), diamino acid nitrosourea derivatives (Dulude et al., Bioorg.
Med. Chem. Lett. 4(22):2697-700, 1994; Dulude et al., Bioorg. Med. Chem.
3(2):151-60, 1995), amino acid nitrosourea derivatives (Zheleva et al., Pharmazie 50(1 ):25-6, 1995), 3',4'-didemethoxy-3',4'-dioxo-4-deoxypodophyllotoxin nitrosourea derivatives (Miyahara et al., Heterocycles 39(1 ):361-9, 1994), ACNU (Matsunaga et al., Immunopharmacology 23(3):199-204, 1992), tertiary phosphine oxide nitrosourea derivatives (Guguva et al., Pharmazie 46(8):603, 1991 ), sulfamerizine and sulfamethizole nitrosourea derivatives (Chiang et al., Zhonghua Yaozue Zazhi 43(5):401-6, 1991 ), thymidine nitrosourea analogues (Zhang et al., Cancer Common. 3(4):119-26, 1991 ), 1,3-bis(2-chloroethyl)-1-nitrosourea (August et al., Cancer Res.
57(6):1586-90, 1991 ), 2,2,6,6-tetramethyl-1-oxopiperidiunium nitrosourea derivatives (U.S.S.R. 1261253), 2- and 4-deoxy sugar nitrosourea derivatives (4,902,791 ), nitroxyl nitrosourea derivatives (U.S.S.R. 1336489), fotemustine (Boutin et al., Eur. J. Cancer Clin. Oncol. 25(9):1311-16, 1989), pyrimidine (II) nitrosourea derivatives (Wei et al., Chung-hua Yao Hsueh Tsa Chih 41(1 ):19-26, 1989), CGP 6809 (Schieweck et al., Cancer Chemother. Pharmacol.
23(6):341-7, 1989), B-3839 (Prajda et al., In Vivo 2(2):151-4, 1988), 5-halogenocytosine nitrosourea derivatives (Chiang & Tseng, T'ai-wan Yao Hsueh Tsa Chih 38(1 ):37-43, 1986), 1-(2-chloroethyl)-3-isobutyl-3-(~i-maltosyl)-1-nitrosourea (Fujimoto & Ogawa, J. Pharmacobio-Dyn. 10(7):341-5, 1987), sulfur-containing nitrosoureas (Tang et al., Yaoxue Xuebao 21(7):502-9, 1986), sucrose, 6-((((2-chloroethyl)nitrosoamino-)carbonyl)amino)-6-deoxysucrose (NS-1 C) and 6'-((((2-chloroethyl)nitrosoamino)carbonyl)amino)-6'-deoxysucrose (NS-1 D) nitrosourea derivatives (Tanoh et al., Chemotherapy (Tokyo) 33(11):969-77, 1985), CNCC, RFCNU and chlorozotocin (Mena et al., Chemotherapy (Basel) 32(2):131-7, 1986), CNUA (Edanami et al., Chemotherapy (Tokyo) 33(5):455-61, 1985), 1-(2-chloroethyl)-3-isobutyl-3-(~-maltosyl)-1-nitrosourea (Fujimoto & Ogawa, Jpn. J. Cancer Res. (Gann) 76(7):651-6, 1985), choline-like nitrosoalkylureas (Belyaev et al., Izv. Akad.
NAUK SSSR, Ser. Khim. 3:553-7, 1985), sucrose nitrosourea derivatives (JP
84219300), sulfa drug nitrosourea analogues (Chiang et al., Proc. Nat'I Sci.
Counc., Repub. China, Part A 8(1 ):18-22, 1984), DONU (Asanuma et al., J.
Jpn. Soc. Cancer Ther. 17(8):2035-43, 1982), N,N'-bis (N-(2-chloroethyl)-N-nitrosocarbamoyl)cystamine (CNCC) (Blazsek et al., Toxicol. Appl. Pharmacol.
74(2):250-7, 1984), dimethylnitrosourea (4Crutova et al., Izv. Akad. NAUK
SSSR, Ser. Biol. 3:439-45, 1984), GANU (Sava & Giraldi, Cancer Chemother.
Pharmacol. 10(3):167-9, 1983), CCNU (Capelli et al., Med., Biol., Environ.
11(1 ):111-16, 1983), 5-aminomethyl-2'-deoxyuridine nitrosourea analogues (Shiau, Shih Ta Hsueh Pao (Taipei) 27:681-9, 1982), TA-077 (Fujimoto ~
Ogawa, Cancer Chemother. Pharmacol. 9(3):134-9, 1982), gentianose nitrosourea derivatives (JP 82 80396), CNCC, RFCNU, RPCNU AND
chlorozotocin (CZT) (Marzin et al., INSERM Symp., 19(Nitrosoureas Cancer Treat.):165-74, 1981 ), thiocolchicine nitrosourea analogues (George, Shih Ta Hsueh Pao (Taipei) 25:355-62, 1980), 2-chloroethyl-nitrosourea (teller &
Eisenbrand, Oncology 38(1 ):39-42, 1981 ), ACNU, (1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride) (Shibuya et al., Gan To Kagaku Ryoho 7(8):1393-401, 1980), N-deacetylmethyl thiocolchicine nitrosourea analogues (Lin et al., J. Med. Chem. 23(12):1440-2, 1980), pyridine and piperidine nitrosourea derivatives (Crider et al., J. Med.
Chem. 23(8):848-51, 1980), methyl-CCNU (Zimber & Perk, Refu. Vet. 35(1 ):28, 1978), phensuzimide nitrosourea derivatives (Crider et al., J. Med. Chem.
23(3):324-6, 1980), ergoline nitrosourea derivatives (Crider et al., J. Med.
Chem. 22(1 ):32-5, 1979), glucopyranose nitrosourea derivatives (JP 78 95917), 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (Farmer et al., J. Med. Chem.
27(6):514-20, 1978), 4-(3-(2-chloroethyl)-3-nitrosoureid-o)-cis-cyclohexanecarboxylic acid (Drewinko et al., Cancer Treat. Rep. 61(8):J1513-18, 1977), RPCNU (ICIG 1163) (Larnicol et al., Biomedicine 26(3):J176-81, 1977), IOB-252 (Sorodoc et al., Rev. Rouen. Med., Virol. 28(1 ):J 55-61, 1977), 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) (Siebert & Eisenbrand, Mutat. Res.
42(1 ):J45-50, 1977), 1-tetrahydroxycyclopentyl-3-nitroso-3-(2-chloroethyl)-urea (4,039,578), d-1-1-(~-chloroethyl)-3-(2-oxo-3-hexahydroazepinyl)-1-nitrosourea (3,859,277) and gentianose nitrosourea derivatives (JP 57080396); 6-S-aminoacyloxymethyl mercaptopurine derivatives (Harada et al., Chem. Pharm.
Bull. 43(10):793-6, 1995), 6-mercaptopurine (6-MP) (Kashida et al., Biol.
Pharm. Bull. 18(11 ):1492-7, 1995), 7,8-polymethyleneimidazo-1,3,2-diazaphosphorines (Nilov et al., Mendeleev Commun. 2:67, 1995), azathioprine (Chifotides et al., J. Inorg. Biochem. 56(4):249-64, 1994), methyl-D-glucopyranoside mercaptopurine derivatives (Da Silva et al., Eur. J. Med.
Chem. 29(2):149-52, 1994) and s-alkynyl mercaptopurine derivatives (Ratsino et al., Khim.-Farm. Zh. 75(8):65-7, 1981 ); indoline ring and a modified ornithine or glutamic acid-bearing methotrexate derivatives (Matsuoka et al., Chem.
Pharm. Bull. 45(7):1146-1150, 1997), alkyl-substituted benzene ring C bearing methotrexate derivatives (Matsuoka et al., Chem. Pharm. Bull. 44(12):2287-2293, 1996), benzoxazine or benzothiazine moiety-bearing methotrexate derivatives (Matsuoka et al., J. Med. Chem. 40(1 ):105-111, 1997), 10-deazaaminopterin analogues (DeGraw et al., J. Med. Chem. 40(3):370-376, 1997), 5-deazaaminopterin and 5,10-dideazaaminopterin methotrexate analogues (Piper et al., J. Med. Chem. 40(3):377-384, 1997), indoline moiety-bearing methotrexate derivatives (Matsuoka et al., Chem. Pharm. Bull.
44(7):1332-1337, 1996), lipophilic amide methotrexate derivatives (Pignatello et al., World Meet. Pharm., Biopharm. Pharm. Technol., 563-4, 1995), L-threo-(2S, 4S)-4-fluoroglutamic acid and DL-3,3-difluoroglutamic acid-containing methotrexate analogues (Hart et al., J. Med. Chem. 39(1 ):56-65, 1996), methotrexate tetrahydroquinazoline analogue (Gangjee, et al., J. Heterocycl.
Chem. 32(1 ):243-8, 1995), N-(a-aminoacyl) methotrexate derivatives (Cheung et al., Pteridines 3(1-2):101-2, 1992), biotin methotrexate derivatives (Fan et al., Pteridines 3(1-2):131-2, 1992), D-glutamic acid or D-erythrou, threo-4-fluoroglutamic acid methotrexate analogues (McGuire et al., Biochem.
Pharmacol. 42(12):2400-3, 1991 ), ~,y-methano methotrexate analogues (Rosowsky et al., Pteridines 2(3):133-9, 1991 ), 10-deazaaminopterin (10-EDAM) analogue (Braakhuis et al., Chem. Biol. Pteridines, Proc. Int Symp.
Pteridines Folic Acid Deriv., 1027-30, 1989), y-tetrazole methotrexate analogue (Kalman et al., Chem. Biol. Pteridines, Proc. Int. Symp. Pteridines Folic Acid Deriv., 1154-7, 1989), N-(L-a-aminoacyl) methotrexate derivatives (Cheung et al., Heterocycles 28(2):751-8, 1989), meta and ortho isomers of aminopterin (Rosowsky et al., J. Med. Chem. 32(12):2582, 1989), hydroxymethylmethotrexate (DE 267495), y-fluoromethotrexate (McGuire et al., Cancer Res. 49(16):4517-25, 1989), polyglutamyl methotrexate derivatives (Kumar et al., Cancer Res. 46(10):5020-3, 1986), gem-diphosphonate methotrexate analogues (WO 88/06158), a- and y-substituted methotrexate analogues (Tsushima et al., Tetrahedron 44(17):5375-87, 1988), 5-methyl-5-deaza methotrexate analogues (4,725,687), N5-acyl-Na-(4-amino-4-deoxypteroyl)-L-ornithine derivatives (Rosowsky et al., J. Med. Chem.
37(7):1332-7, 1988), 8-deaza methotrexate analogues (Kuehl et al., Caneer Res. 48(6):1481-8, 1988), acivicin methotrexate analogue (Rosowsky et al., J.
Med. Chem. 30(8):1463-9, 1987), polymeric platinol methotrexate derivative (Carraher et al., Polym. Sci. Technol. (Plenum), 35(Adv. Biomed. Polym.):311-24, 1987), methotrexate-y-dimyristoylphophatidylethanolamine (Kinsky et al., Biochim. Biophys. Acta 917(2):211-18, 1987), methotrexate polyglutamate analogues (Rosowsky et al., Chem. Biol. Pteridines, Pteridines Folic Acid Deriv., Proc. Int. Symp. Pteridines Folic Acid Deriv.: Chem., Biol. Clin.
Aspects:
985-8, 1986), poly-y-glutamyl methotrexate derivatives (Kisliuk et al., Chem.
Biol. Pteridines, Pteridines Folic Acid Deriv., Proc. Int. Symp. Pteridines Folic Acid Deriv.: Chem., Biol. Clin. Aspects: 989-92, 1986), deoxyuridylate methotrexate derivatives (Webber et al., Chem. Biol. Pteridines, Pteridines Folic Acid Deriv., Proc. Int. Symp. Pteridines Folic Acid Deriv.: Chem., Biol. Clin.
Aspects: 659-62, 1986), iodoacetyl lysine methotrexate analogue (Delcamp et al., Chem. Biol. Pteridines, Pteridines Folic Acid Deriv., Proc. Int. Symp.
Pteridines Folic Acid Deriv.: Chem., Biol. Clin. Aspects: 807-9, 1986), 2,.omega.-diaminoalkanoid acid-containing methotrexate analogues (McGuire et al., Biochem. Pharmacol. 35(15):2607-13, 1986), polyglutamate methotrexate derivatives (Kaman & Winick, Methods Enzymol. 122 (Vitam.
Coenzymes, Pt. G):339-46, 1986), 5-methyl-5-deaza analogues (Piper et al., J.
Med. Chem. 29(6):1080-7, 1986), quinazoline methotrexate analogue (Mastropaolo et al., J. Med. Chem. 29(1 ):155-8, 1986), pyrazine methotrexate analogue (Lever & Vestal, J. Heterocycl. Chem. 22(1 ):5-6, 1985), cysteic acid and homocysteic acid methotrexate analogues (4,490,529), y-tart-butyl methotrexate esters (Rosowsky et al., J. Med. Chem. 28(5):660-7, 1985), fluorinated methotrexate analogues (Tsushima et al., Heterocycles 23(1 ):45-9, 1985), folate methotrexate analogue (Trombe, J. Bacteriol. 160(3):849-53, 1984), phosphonoglutamic acid analogues (Sturtz & Guillamot, Eur. J. Med.
Chem.--Chim. Ther. 19(3):267-73, 1984), poly (L-lysine) methotrexate conjugates (Rosowsky et al., J. Med. Chem. 27(7):888-93, 1984), dilysine and trilysine methotrexate derivates (Forsch & Rosowsky, J. Org. Chem.
' 49(7):1305-9, 1984), 7-hydroxymethotrexate (Fabre et al., Cancer Res.
43(10):4648-52, 1983), poly-y-glutamyl methotrexate analogues (Piper &
Montgomery, Adv. Exp. Med. Biol., 163(Folyl Antifolyl Polyglutamates):95-100, 1983), 3',5'-dichloromethotrexate (Rosowsky & Yu, J. Med. Chem. 26(10):1448-52, 1983), diazoketone and chloromethylketone methotrexate analogues (Gangjee et al., J. Pharm. Sci. 71(6):717-19, 1982), 10-propargylaminopterin and alkyl methotrexate homologs (Piper et al., J. Med. Chem. 25(7):877-80, 1982), lectin derivatives of methotrexate (Lin et al., JNCI 66(3):523-8, 1981 ), polyglutamate methotrexate derivatives (Galivan, Mol. Pharmacol. 17(1 ):105-10, 1980), halogentated methotrexate derivatives (Fox, JNCI 58(4):J955-8, 1977), 8-alkyl-7,8-dihydro analogues (Chaykovsky et al., J. Med. Chem.
20(10):J1323-7, 1977), 7-methyl methotrexate derivatives and dichloromethotrexate (Rosowsky & Chen, J. Med. Chem. 17(12):J1308-11, 1974), lipophilic methotrexate derivatives and 3',5'-dichloromethotrexate (Rosowsky, J. Med. Chem. 16(10):J1190-3, 1973), deaza amethopterin analogues (Montgomery et al., Ann. N. Y. Acad. Sci. 186:J227-34, 1971 ), MX068 (Pharma Japan, 1658:18, 1999) and cysteic acid and homocysteic acid methotrexate analogues (EPA 0142220); N3-alkylated analogues of 5-fluorouracil (Kozai et al., J. Chem. Soc., Perlein Trans. 1(19):3145-3146, 1998), 5-fluorouracil derivatives with 1,4-oxaheteroepane moieties (Gomez et al., Tetrahedron 54(43):13295-13312, 1998), 5-fluorouracil and nucleoside analogues (Li, Anticancer Res. 17(1A):21-27, 1997), cis- and trans-5-fluoro-5,6-dihydro-6-alkoxyuracil (Van der Wilt et al., Br. J. Cancer 68(4):702-7, 1993), cyclopentane 5-fluorouracil analogues (Hronowski & Szarek, Can. J. Chem.
70(4):1162-9, 1992), A-OT-fluorouracil (Zhang et al., Zongguo Yiyao Gongye Zazhi 20(11 ):513-15, 1989), N4-trimethoxybenzoyl-5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine (Miwa et al., Chem. Pharm. Bull. 38(4):998-1003, 1990), 1-hexylcarbamoyl-5-fluorouracil (Hoshi et al., J. Pharmacobio-Dun.
3(9):478-81, 1980; Maehara et al., Chemotherapy (Basel) 34(6):484-9, 1988), B-3839 (Prajda et al., In Vivo 2(2):151-4, 1988), uracil-1-(2-tetrahydrofuryl)-fluorouracil (Anai et al., Oncology 45(3):144-7, 1988), 1-(2'-deoxy-2'-fluoro-(i-D-arabinofuranosyl)-5-fluorouracil (Suzuko et al., Mol. Pharmacol. 31(3):301-6, 1987), doxifluridine (Matuura et al., Oyo Yakuri 29(5):803-31, 1985), 5'-deoxy-fluorouridine (Bollag & Hartmann, Eur. J. Cancer 16(4):427-32, 1980), 1-acetyl-3-O-toluyl-5-fluorouracil (Okada, Hiroshima J. Med. Sci. 28(1 ):49-66, 1979), fluorouracil-m-formylbenzene-sulfonate (JP 55059173), N'-(2-furanidyl)-5-fluorouracil (JP 53149985) and 1-(2-tetrahydrofuryl)-5-fluorouracil (JP
52089680); 4'-epidoxorubicin (Lanius, Adv. Chemother. Gastrointest. Cancer, (Int. Symp.), 159-67, 1984); N-substituted deacetylvinblastine amide (vindesine) sulfates (Conrad et al., J. Med. Chem. 22(4):391-400, 1979); and Cu(II)-VP-16 (etoposide) complex (Tawa et al., Bioorg. Med. Chem. 6(7):1003-1008, 1998), pyrrolecarboxamidino-bearing etoposide analogues (Ji et al., Bioorg. Med.
Chem. Lett. 7(5):607-612, 1997), 4~i-amino etoposide analogues (Hu, University of North Carolina Dissertation, 1992), y-lactone ring-modified arylamino etoposide analogues (Zhou et al., J. Med. Chem. 37(2):287-92, 1994), N-glucosyl etoposide analogue (Allevi et al., Tetrahedron Lett.
34(45):7313-16, 1993), etoposide A-ring analogues (Kadow et al., Bioorg. Med.
Chem. Lett. 2(1 ):17-22, 1992), 4'-deshydroxy-4'-methyl etoposide (Saulnier et al., Bioorg. Med. Chem. Lett. 2(10):1213-18, 1992), pendulum ring etoposide analogues (Sinha et al., Eur. J. Cancer 26(5):590-3, 1990) and E-ring desoxy etoposide analogues (Saulnier et al., J. Med. Chem. 32(7):1418-20, 1989).
Within one embodiment of the invention, the cell cycle inhibitor is paclitaxel, a compound which disrupts mitosis (M-phase) by binding to tubulin to form abnormal mitotic spindles or an analogue or derivative thereof.
Briefly, paclitaxel is a highly derivatized diterpenoid (Wani et al., J. Am. Chem. Soc.
93:2325, 1971 ) which has been obtained from the harvested and dried bark of Taxus brevifolia (Pacific Yew) and Taxomyces Andreanae and Endophytic Fungus of the Pacific Yew (Stierle et al., Science 60:214-216, 1993).
"Paclitaxel" (which should be understood herein to include formulations, prodrugs, analogues and derivatives such as, for example, TAXOL (Bristol Myers Squibb, New York, NY, TAXOTERE (Aventis Pharmaceuticals, France), docetaxel, 10-desacetyl analogues of paclitaxel and 3'N-desbenzoyl-3'N-t-butoxy carbonyl analogues of paclitaxel) may be readily prepared utilizing techniques known to those skilled in the art (see, e.g., Schiff et al., Nature 277:665-667, 1979; Long and Fairchild, Cancer Research 54:4355-4361, 1994;
Ringel and Horwitz, J. Nat'1 Cancer Inst. 83(4):288-291, 1991; Pazdur et al., Cancer Treat. Rev. 79(4):351-386, 1993; WO 94/07882; WO 94/07881; WO
94/07880; WO 94/07876; WO 93/23555; WO 93/10076; W094/00156;
WO 93/24476; EP 590267; WO 94/20089; U.S. Patent Nos. 5,294,637;
5,283,253; 5,279,949; 5,274,137; 5,202,448; 5,200,534; 5,229,529; 5,254,580;
5,412,092; 5,395,850; 5,380,751; 5,350,866; 4,857,653; 5,272,171; 5,411,984;
5,248,796; 5,248,796; 5,422,364; 5,300,638; 5,294,637; 5,362,831; 5,440,056;
4,814,470; 5,278,324; 5,352,805; 5,411,984; 5,059,699; 4,942,184;
Tetrahedron Letters 35(52):9709-9712, 1994; J. Med. Chem. 35:4230-4237, 1992; J. Med. Chem. 34:992-998, 1991; J. Natural Prod. 57(10):1404-1410, 1994; J. Natural Prod. 57(11 ):1580-1583, 1994; J. Am. Chem. Soc. 110:6558-6560, 1988), or obtained from a variety of commercial sources, including for example, Sigma Chemical Co., St. Louis, Missouri (T7402 - from Taxus brevifolia).
Representative examples of paclitaxel derivatives or analogues include 7-deoxy-docetaxol, 7,8-cyclopropataxanes, N-substituted 2-azetidones, 6,7-epoxy paclitaxels, 6,7-modified paclitaxels, 10-desacetoxytaxol, 10-deacetyltaxol (from 10-deacetylbaccatin III), phosphonooxy and carbonate derivatives of taxol, taxol 2',7-di(sodium 1,2-benzenedicarboxylate, 10-desacetoxy-11,12-dihydrotaxol-10,12(18)-diene derivatives, 10-desacetoxytaxol, Protaxol (2'-and/or 7-O-ester derivatives), (2'-and/or 7-O-carbonate derivatives), asymmetric synthesis of taxol side chain, fluoro taxols, 9-deoxotaxane, (13-acetyl-9-deoxobaccatine III, 9-deoxotaxol, 7-deoxy-9-deoxotaxol, 10-desacetoxy-7-deoxy-9-deoxotaxol, Derivatives containing hydrogen or acetyl group and a hydroxy and tert-butoxycarbonylamino, sulfonated 2'-acryloyltaxol and sulfonated 2'-O-acyl acid taxol derivatives, succinyltaxol, 2'-y-aminobutyryltaxol formate, 2'-acetyl taxol, 7-acetyl taxol, 7-glycine carbamate taxol, 2'-OH-7-PEG(5000) carbamate taxol, 2'-benzoyl and 2',7-dibenzoyl taxol derivatives, other prodrugs (2'-acetyltaxol; 2',7-diacetyltaxol; 2'succinyltaxol; 2'-(beta-alanyl)-taxol); 2'gamma-aminobutyryltaxol formate; ethylene glycol derivatives of 2'-succinyltaxol; 2'-glutaryltaxol; 2'-(N,N-dimethylglycyl) taxol; 2'-(2-(N,N-dimethylamino)propionyl)taxol; 2'orthocarboxybenzoyl taxol; 2'aliphatic carboxylic acid derivatives of taxol, Prodrugs (2'(N,N-diethylaminopropionyl)taxol, 2'(N,N-dimethylglycyl)taxol, 7(N,N-dimethylglycyl)taxol, 2',7-di-(N,N-dimethylglycyl)taxol, 7(N,N-diethylaminopropionyl)taxol, 2',7-di(N,N-diethylaminopropionyl)taxol, 2'-(L-glycyl)taxol, 7-(L-glycyl)taxol, 2',7-di(L-glycyl)taxol, 2'-(L-alanyl)taxol, 7-(L-alanyl)taxol, 2',7-di(L-alanyl)taxol, 2'-(L-leucyl)taxol, 7-(L-leucyl)taxol, 2',7-di(L-leucyl)taxol, 2'-(L-isoleucyl)taxol, 7-(L-isoleucyl)taxol, 2',7-di(L-isoleucyl)taxol, 2'-(L-valyl)taxol, 7-(L-valyl)taxol, 2'7-di(L-valyl)taxol, 2'-(L-phenylalanyl) taxol, 7-(L-phenylalanyl)taxol, 2',7-di(L-phenylalanyl)taxol, 2'-(L-prolyl)taxol, 7-(L-prolyl)taxol, 2',7-di(L-prolyl)taxol, 2'-(L-lysyl)taxol, 7-(L-lysyl)taxol, 2',7-di(L-lysyl)taxol, 2'-(L-glutamyl)taxol, 7-(L-glutamyl)taxol, 2',7-di(L-glutamyl)taxol, 2'-(L-arginyl)taxol, 7-(L-arginyl)taxol, 2',7-di(L-arginyl)taxol}, taxol analogues with modified phenylisoserine side chains, TAXOTERE, (N-debenzoyl-N-tert-(butoxycaronyl)-10-deacetyltaxol, and taxanes (e.g., baccatin III, cephalomannine, 10-deacetylbaccatin III, brevifoliol, yunantaxusin and taxusin);
and other taxane analogues and derivatives, including 14-beta-hydroxy-10 deacetybaccatin III, debenzoyl-2-acyl paclitaxel derivatives, benzoate paclitaxel derivatives, phosphonooxy and carbonate paclitaxel derivatives, sulfonated 2'-acryloyltaxol; sulfonated 2'-O-aryl acid paclitaxel derivatives, 18-site-substituted paclitaxel derivatives, chlorinated paclitaxel analogues, C4 methoxy ether paclitaxel derivatives, sulfenamide taxane derivatives, brominated paclitaxel analogues, Girard taxane derivatives, nitrophenyl paclitaxel, 10-deacetylated substituted paclitaxel derivatives, 14- beta -hydroxy-10 deacetylbaccatin III
taxane derivatives, C7 taxane derivatives, C10 taxane derivatives, 2-debenzoyl-2-acyl taxane derivatives, 2-debenzoyl and -2-acyl paclitaxel derivatives, taxane and baccatin III analogues bearing new C2 and C4 functional groups, n-acyl paclitaxel analogues, 10-deacetylbaccatin III and 7-protected-10-deacetylbaccatin III derivatives from 10-deacetyl taxol A, 10-deacetyl taxol B, and 10-deacetyl taxol, benzoate derivatives of taxol, 2-aroyl-4-acyl paclitaxel analogues, orthro-ester paclitaxel analogues, 2-aroyl-4-acyl paclitaxel analogues and 1-deoxy paclitaxel and 1-d'eoxy paclitaxel analogues.
In one aspect, the cell cycle inhibitor is a taxane having the formula (C1 ):
(C1 ), where the gray-highlighted portions may be substituted and the non-highlighted portion is the taxane core. A side-chain (labeled "A" in the diagram) is desirably present in order for the compound to have good activity as a cell cycle inhibitor.
Examples of compounds having this structure include paclitaxel (Merck Index entry 7117), docetaxol (TAXOTERE, Merck Index entry 3458), and 3'-desphenyl-3'-(4-ntirophenyl)-N-debenzoyl-N-(t-butoxycarbonyl)-10-deacetyltaxol.
In one aspect, suitable taxanes such as paclitaxel and its analogues and derivatives are disclosed in U.S. Patent No. 5,440,056 as having the structure (C2):
v HgC~~

R~O'~ '_ ~ O
Rb =
Rs0 Ra0 (C2) wherein X may be oxygen (paclitaxel), hydrogen (9-deoxy derivatives), thioacyl, or dihydroxyl precursors; R~ is selected from paclitaxel or TAXOTERE side chains or alkanoyl of the formula (C3) O
R~
' (C3) wherein R~ is selected from hydrogen, alkyl, phenyl, alkoxy, amino, phenoxy (substituted or unsubstituted); R$ is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, phenyl (substituted or unsubstituted), alpha or beta-naphthyl; and R9 is selected from hydrogen, alkanoyl, substituted alkanoyl, and aminoalkanoyl; where substitutions refer to hydroxyl, sulfhydryl, allalkoxyl, carboxyl, halogen, thioalkoxyl, N,N-dimethylamino, alkylamino, dialkylamino, nitro, and -OS03H, and/or may refer to groups containing such substitutions;

is selected from hydrogen or oxygen-containing groups, such as hydrogen, hydroxyl, alkoyl, alkanoyloxy, aminoalkanoyloxy, and peptidyalkanoyloxy; R3 is selected from hydrogen or oxygen-containing groups, such as hydrogen, hydroxyl, alkoyl, alkanoyloxy, aminoalkanoyloxy, and peptidyalkanoyloxy, and may further be a silyl containing group or a sulphur containing group; R4 is selected from acyl, alkyl, alkanoyl, aminoalkanoyl, peptidylalkanoyl and aroyl;
R5 is selected from acyl, alkyl, alkanoyl, aminoalkanoyl, peptidylalkanoyl and aroyl; R6 is selected from hydrogen or oxygen-containing groups, such as hydrogen, hydroxyl alkoyl, alkanoyloxy, aminoalkanoyloxy, and peptidyalkanoyloxy.
In one aspect, the paclitaxel analogues and derivatives useful as cell cycle inhibitors are disclosed in PCT International Patent Application No.
WO 93/10076. As disclosed in this publication, the analogue or derivative should have a side chain attached to the taxane nucleus at C~3, as shown in the structure below (formula C4), in order to confer antitumor activity to the taxane.

(C4) WO 93/10076 discloses that the taxane nucleus may be 5 substituted at any position with the exception of the existing methyl groups.
The substitutions may include, for example, hydrogen, alkanoyloxy, alkenoyloxy, aryloyloxy. In addition, oxo groups may be attached to carbons labeled 2, 4, 9, and/or 10. As well, an oxetane ring may be attached at carbons 4 and 5. As well, an oxirane ring may be attached to the carbon labeled 4.
10 In one aspect, the taxane-based cell cycle inhibitor useful in the present invention is disclosed in U.S. Patent 5,440,056, which discloses 9-deoxo taxanes. These are compounds lacking an oxo group at the carbon labeled 9 in the taxane structure shown above (formula C4). The taxane ring may be substituted at the carbons labeled 1, 7 and 10 (independently) with H, OH, O-R, or O-CO-R where R is an alkyl or an aminoalkyl. As well, it may be substituted at carbons labeled 2 and 4 (independently) with aryol, alkanoyl, aminoalkanoyl or alkyl groups. The side chain of formula (C3) may be substituted at R7 and R$ (independently) with phenyl rings, substituted phenyl rings, linear alkanes/alkenes, and groups containing H, O or N. R9 may be substituted with H, or a substituted or unsubstituted alkanoyl group.
Taxanes in general, and paclitaxel is particular, is considered to function as a cell cycle inhibitor by acting as an anti-microtubule agent, and more specifically as a stabilizer. These compounds have been shown useful in the treatment of proliferative disorders, including: non-small cell (NSC) lung;
small cell lung; breast; prostate; cervical; endometrial; head and neck cancers.
In another aspect, the anti-microtuble agent (microtubule inhibitor) is albendazole (carbamic acid, (5-(propylthio)-1 H-benzimidazol-2-yl)-, methyl ester), LY-355703 (1,4-dioxa-8,11-diazacyclohexadec-13-ene-2,5,9,12-tetrone, 10-((3-chloro-4-methoxyphenyl)methyl)-6,6-dimethyl-3-(2-methylpropyl)-16-((1S)-1-((2S,3R)-3-phenyloxiranyl)ethyl)-, (3S,10R,13E,16S)-), vindesine (vincaleukoblastine, 3-(aminocarbonyl)-04-deacetyl-3-de(methoxycarbonyl)-), or WAY-174286 In another aspect, the cell cycle inhibitor is a vinca alkaloid. Vinca alkaloids have the following general structure. They are indole-dihydroindole dimers.
ale dihydroindole U-Kp As disclosed in U.S. Patent Nos. 4,841,045 and 5,030,620, R~ can be a formyl or methyl group or alternately H. R~ can also be an alkyl group or an aldehyde-substituted alkyl (e.g., CH2CH0). R~ is typically a CH3 or NH2 group. However it can be alternately substituted with a lower alkyl ester or the ester linking to the dihydroindole core may be substituted with C(O)-R where R
is NH2, an amino acid ester or a peptide ester. R3 is typically C(O)CH3, CH3 or H. Alternately, a protein fragment may be linked by a bifunctional group, such as maleoyl amino acid. R3 can also be substituted to form an alkyl ester which may be further substituted. R4 may be -CH2- or a single bond. R5 and R6 may be H, OH or a lower alkyl, typically -CH2CH3. Alternatively R6 and R~ may together form an oxetane ring. R7 may alternately be H. Further substitutions include molecules wherein methyl groups are substituted with other alkyl groups, and whereby unsaturated rings may be derivatized by the addition of a side group such as an alkane, alkene, alkyne, halogen, ester, amide or amino group.
Exemplary vinca alkaloids are vinblastine, vincristine, vincristine sulfate, vindesine, and vinorelbine, having the structures:
R1 Rz R3 Ra Rs Vinblastine:CH3 C(O)CH3 CHZ

Vincristine:CH3 C(O)CH3 CHZ

Vindesine: NHZ H OH CH2 Vinorelbine:CH3 CH3 H single CH3 bond Analogues typically require the side group (shaded area) in order to have activity. These compounds are thought to act as cell cycle inhibitors by functioning as anti-microtubule agents, and more specifically to inhibit polymerization. These compounds have been shown useful in treating proliferative disorders, including NSC lung; small cell lung; breast;
prostate;
brain; head and neck; retinoblastoma; bladder; and penile cancers; and soft tissue sarcoma.
In another aspect, the cell cycle inhibitor is a camptothecin, or an analog or derivative thereof. Camptothecins have the following general structure.

In this structure, X is typically O, but can be other groups, e.g., NH
in the case of 21-lactam derivatives. R1 is typically H or OH, but may be other groups, e.g., a terminally hydroxylated C1_3 alkane. R2 is typically H or an amino containing group such as (CH3)2NHCH~, but may be other groups e.g., NO~, NHS, halogen (as disclosed in, e.g., U.S. Patent 5,552,156) or a short alkane containing these groups. R3 is typically H or a short alkyl such as C2H5.
R4 is typically H but may be other groups, e.g., a methylenedioxy group with R1.
Exemplary camptothecin compounds include topotecan, irinotecan (CPT-11 ), 9-aminocamptothecin, 21-lactam-20(S)-camptothecin, 10,11-methylenedioxycamptothecin, SN-38, 9-nitrocamptothecin, 10-hydroxycamptothecin. Exemplary compounds have the structures:
R~ R3 O
R~
\ ~N ~ ~X
E
/ N \ o H3C- ' OH
Ri R2 R3 Camptothecin: H H H
Topotecan: OH (CH3)2NHCHz H
SN-3S: OH H CZHS
x: O for most analogs, NH for 21-lactam analogs Camptothecins have the five rings shown here. The ring labeled E must be intact (the lactone rather than carboxylate form) for maximum activity and minimum toxicity. These compounds are useful to as cell cycle inhibitors, where they can function as topoisomerase I inhibitors and/or DNA cleavage agents. They have been shown useful in the treatment of proliferative disorders, including, for example, NSC lung; small cell lung; and cervical cancers.
In another aspect, the cell cycle inhibitor is a podophyllotoxin, or a derivative or an analogue thereof. Exemplary compounds of this type are etoposide or teniposide, which have the following structures:
Etoposide C'N3 Teniposide s HgC~
OH
These compounds are thought to function as cell cycle inhibitors by being topoisomerase II inhibitors and/or by DNA cleaving agents. They have been shown useful as antiproliferative agents in, e.g., small cell lung, prostate, and brain cancers, and in retinoblastoma.
Another example of a DNA topoisomerase inhibitor is lurtotecan dihydrochloride (11H-1,4-dioxino(2,3-g)pyrano(3',4':6,7)indolizino(1,2-b)quinoline-9,12(8H,14H)-dione, 8-ethyl-2,3-dihydro-8-hydroxy-15-((4-methyl-1-piperazinyl)methyl)-, dihydrochloride, (S)-).
In another aspect, the cell cycle inhibitor is an anthracycline.
Anthracyclines have the following general structure, where the R groups may be a variety of organic groups:

According to U.S. Patent 5,594,158, suitable R groups are: R~ is CH3 or CH20H; R2 is daunosamine or H; R3 and R4 are independently one of OH, N02, NH2, F, Cl, Br, I, CN, H or groups derived from these; R5_~ are all H
or R5 and R6 are H and R~ and R$ are alkyl or halogen, or vice versa: R~ and R$
are H and R5 and R6 are alkyl or halogen.
According to U.S. Patent 5,843,903, R2 may be a conjugated peptide. According to U.S. Patent Nos. 4,215,062 and 4,296,105, R5 may be OH or an ether linked alkyl group. R~ may also be linked to the anthracycline ring by a group other than C(O), such as an alkyl or branched alkyl group having the C(O) linking moiety at its end, such as -CH2CH(CH2-X)C(O)-R~, wherein X is H or an alkyl group (see, e.g., U.S. Patent 4,215,062). R2 may alternately be a group linked by the functional group =N-NHC(O)-Y, where Y is a group such as a phenyl or substituted phenyl ring. Alternately R3 may have the following structure:
HsC O
NH

R,o in which R9 is OH either in or out of the plane of the ring, or is a second sugar moiety such as R3. Ran may be H or form a secondary amine with a group such as an aromatic group, saturated or partially saturated 5 or 6 membered heterocyclic having at least one ring nitrogen (see U.S. Patent 5,843,903).
Alternately, R~o may be derived from an amino acid, having the structure -C(O)CH(NHR~~)(R~2), in which R~~ is H, or forms a C3_4 membered alkylene with R~2. R~2 may be H, alkyl, aminoalkyl, amino, hydroxy, mercapto, phenyl, benzyl or methylthio (see U.S. Patent 4,296,105).
Exemplary anthracyclines are doxorubicin, daunorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, and carubicin. Suitable compounds have the structures:

O OH
R, ....OH
R, o OH O
H,C O
NHz R, R. R3 Doxorubicin:OCH,CHzOHOH out of ring plane Epirubicin:OCH,CHiOHOH in dng plane (4' oxoruhicin) epimer of d Daunorubicin: CHe - OH
OCH3 out of ring plane Idarubicin:H CH, OH out of ring plane PirarubicinOCH,OH A

ZorubicinOCH3=N-NHC(0)CeHe B

CarubicinOH CH3 B

A: ~ / 3: O /
O CHI O
OH
NH, Other suitable anthracyclines are anthramycin, mitoxantrone, menogaril, nogalamycin, aclacinomycin A, olivomycin A, chromomycin A3, and plicamycin having the structures:
OH OH
H
HaC ~ N Anthramycin N
NHS
O
O
R, Rz R3 Menogaril H OCH3 H
off O HN~NH~OH Nogalamycin O-sugar H COOCH3 cH3 sugar: H3C O
O
OH O HN~ ~ 'OH H3C0 CH3 OCHa N' VH
Mitoxantrone i O OCHa O

W~ OH
HO - HO~ ~ ~

O O ~/

HaC O
R,O

HO
R, RZ R3 RQ

Olivomycin A COCH(CH3)zCOCHeH
CHI

Chromomycin A, COCH~ COCH,CH3 Plicamycin H H H CH3 These compounds are thought to function as cell cycle inhibitors by being topoisomerase inhibitors andlor by DNA cleaving agents. They have been shown useful in the treatment of proliferative disorders, including small cell lung; breast; endometrial; head and neck; retinoblastoma; liver; bile duct;
islet cell; and bladder cancers; and soft tissue sarcoma.
In another aspect, the cell cycle inhibitor is a platinum compound.
In general, suitable platinum complexes may be of Pt(II) or Pt(IV) and have this basic structure:

X
R1 ~/Pt~
R/

wherein X and Y are anionic leaving groups such as sulfate, phosphate, carboxylate, and halogen; R1 and R2 are alkyl, amine, amino alkyl any may be further substituted, and are basically inert or bridging groups. For Pt(II) complexes Z1 and Z~ are non-existent. For Pt(IV) Z1 and Z2 may be anionic groups such as halogen, hydroxy, carboxylate, ester, sulfate or phosphate.
See, e.g., U.S. Patent Nos. 4,588,831 and 4,250,189.
Suitable platinum complexes may contain multiple Pt atoms. See, e.g., U.S. Patent Nos. 5,409,915 and 5,380,897. For example bisplatinum and triplatinum complexes of the type:

Z~ Zt X~ I / Rt X~ I ~ R2 Y/ It\A~ It\Y
Zz Zz X Zt R X Zt A Zt X
\Pt/ \ ~t~ ~ It/
Y/ I ~A~ I \Y Rz~ I \Y

Zt Zt X\ I / Rz Rz\ / X
Y/ It\A~ It\Y
Z2 Zz Zz~ / R3 Pt Y/I\Zt X
Exemplary platinum compounds are cisplatin, carboplatin, oxaliplatin, and miboplatin having the structures:

NH3 O O~
Pt CI~ t-NH3 I ~NH3 O
CI
O
Cisplatin Carboplatin O O
NHZ O NHZ
~Pt ~ H
NHZ~'1~ O HN
O// O
Oxaliplatin Miboplatin These compounds are thought to function as cell cycle inhibitors by binding to DNA, i.e., acting as alkylating agents of DNA. These compounds have been shown useful in the treatment of cell proliferative disorders, including, e.g., NSC lung; small cell lung; breast; cervical; brain; head and neck;

esophageal; retinoblastom; liver; bile duct; bladder; penile; and vulvar cancers;
and soft tissue sarcoma.
In another aspect, the cell cycle inhibitor is a nitrosourea.
Nitrosourease have the following general structure (C5), where typical R
groups are shown below.

R'~ ~R
N NH
N~
~O
(C5) R Group:

O
'CI OH
Carmu~stine OH OH O-CHs Ranimustine Lomustine CH3 ~ NHS OH
\CH3 O
OH
O /~
~CHa ~ ~CH3 OH OH
Fotemustine Nimustine Chlorozotocin Streptozocin Other suitable R groups include cyclic alkanes, alkanes, halogen substituted groups, sugars, aryl and heteroaryl groups, phosphonyl and sulfonyl groups. As disclosed in U.S. Patent No. 4,367,239, R may suitably be CH2-C(X)(Y)(Z), wherein X and Y may be the same or different members of the following groups: phenyl, cyclyhexyl, or a phenyl or cyclohexyl group substituted with groups such as halogen, lower alkyl (C~_4), trifluore methyl, cyano, phenyl, cyclohexyl, lower alkyloxy (C~_4). Z has the following structure:
-alkylene-N-R~ R2, where R~ and R2 may be the same or different members of the following group: lower alkyl (C~_4) and benzyl, or together R~ and R2 may form a saturated 5 or 6 membered heterocyclic such as pyrrolidine, piperidine, morfoline, thiomorfoline, N-lower alkyl piperazine, where the heterocyclic may be optionally substituted with lower alkyl groups.
As disclosed in U.S. Patent No. 6,096,923, R and R' of formula (C5) may be the same or different, where each may be a substituted or unsubstituted hydrocarbon having 1-10 carbons. Substitutions may include hydrocarbyl, halo, ester, amide, carboxylic acid, ether, thioether and alcohol groups. As disclosed in U.S. Patent No. 4,472,379, R of formula (C5) may be an amide bond and a pyranose structure (e.g., methyl 2'-(N-(N-(2-chloroethyl)-N-nitroso-carbamoyl)-glycyl)amino-2'-deoxy-a-D-glucopyranoside). As disclosed in U.S. Patent No. 4,150,146, R of formula (C5) may be an alkyl group of 2 to 6 carbons and may be substituted with an ester, sulfonyl, or hydroxyl group. It may also be substituted with a carboxylic acid or CONH~
group.
Exemplary nitrosoureas are BCNU (carmustine), methyl-CCNU
(semustine), CCNU (lomustine), ranimustine, ~nimustine, chlorozotocin, fotemustine, and streptozocin, having the structures:

CI~ ~ ~R
NH R Group:
N
O
'CI
Carmustine HZC OH
OH O OH O
OH OH O-CH OH OH
Ranimustine Lomustine O
H3C~ ~
NHZ OH N"NH
N
OH O \O
N CH3 OH ~ pH
Nimustine Chlorozotocin \CH3 ~~ \O~CH3 O
Fotemustine These nitrosourea compounds are thought to function as cell cycle inhibitors by binding to DNA, that is, by functioning as DNA alkylating agents. These cell cycle inhibitors have been shown useful in treating cell proliferative disorders such as, for example, islet cell; small cell lung;
melanoma; and brain cancers.
In another aspect, the cell cycle inhibitor is a nitroimidazole, where exemplary nitroimidazoles are metronidazole, benznidazole, etanidazole, and misonidazole, having the structures:
R~

R3~
Ri Rz R3 Metronidazole OH CH3 NOz Benznidazole C(O)NHCHz benzyl NOz H
Etanidazole CONHCHZCH20H NOz H
Suitable nitroimidazole compounds are disclosed in, e.g., U.S.
Patent Nos. 4,371,540 and 4,462,992.
In another aspect, the cell cycle inhibitor is a folic acid antagonist, such as methotrexate or derivatives or analogues thereof, including edatrexate, trimetrexate, raltitrexed, piritrexim, denopterin, tomudex, and pteropterin.
Methotrexate analogues have the following general structure:
The identity of the R group may be selected from organic groups, particularly those groups set forth in U.S. Patent Nos. 5,166,149 and 5,382,582.

For example, R~ may be N, R2 may be N or C(CH3), R3 and R3' may H or alkyl, e.g., CH3, R4 may be a single bond or NR, where R is H or alkyl group. 85,6,8 may be H, OCH3, or alternately they can be halogens or hydro groups. R7 is a side chain of the general structure:
HO
wherein n = 1 for methotrexate, n = 3 for pteropterin. The carboxyl groups in the side chain may be esterified or form a salt such as a Zn~+ salt. R9 and Rio can be NH2 or may be alkyl substituted.
Exemplary folic acid antagonist compounds have the structures:
N NHp ~N

RO
RaRi R: Rs Ra RsRa Re Rn MelholrexateNH,N N H N(CHa)H H A(n.t)H

EdalrexaieNH,N N H N(CH,CHa)H H A(n=t)H

TrimetrexateNHzN C(CHa)H NH H OCH, OCHa OCH, PteroplennNH,N N H N(CH,)H H A H
(n=3) DenoplerinOHN N CH,N(CH,)H H A(n=t)H

PiritreximNH,N C(CH,)singleOCH~H H OCHaH
H

bond A: 0 ,,yy NH
H0~
O
0 off n N CHa HOOC~ O ~ H3 5 N ~ ~ NH
HOOC NH
O
Tomudex These compounds are thought to function as cell cycle inhibitors by serving as antimetabolites of folic acid. They have been shown useful in the treatment of cell proliferative disorders including, for example, soft tissue sarcoma, small cell lung, breast, brain, head and neck, bladder, and penile cancers.
In another aspect, the cell cycle inhibitor is a cytidine analogue, such as cytarabine or derivatives or analogues thereof, including enocitabine, FMdC ((E(-2'-deoxy-2'-(fluoromethylene)cytidine), gemcitabine, 5-azacitidine, ancitabine, and 6-azauridine. Exemplary compounds have the structures:
R, RZ R3 RQ

Cytarabine OH H CH
H

Enocitabine OH H CH
C(O)(CHZ)ZOCH3 Gemcitabine F F CH
H

Azacitidine H OH N
H

FMdC H CHzFH CH

Ancitabine 6-Azauridine These compounds are thought to function as cell cycle inhibitors as acting as antimetabolites of pyrimidine. These compounds have been shown useful in the treatment of cell proliferative disorders including, for example, pancreatic, breast, cervical, NSC lung, and bile duct cancers.
In another aspect, the cell cycle inhibitor is a pyrimidine analogue.
In one aspect, the pyrimidine analogues have the general structure:

wherein positions 2', 3' and 5' on the sugar ring (R2, R3 and R4, respectively) can be H, hydroxyl, phosphoryl (see, e.g., U.S. Patent 4,086,417) or ester (see, e.g., U.S. Patent 3,894,000). Esters can be of alkyl, cycloalkyl, aryl or heterocyclo/aryl types. The 2' carbon can be hydroxylated at either R2 or R~', the other group is H. Alternately, the 2' carbon can be substituted with halogens e.g., fluoro or difluoro cytidines such as Gemcytabine. Alternately, the sugar can be substituted for another heterocyclic group such as a furyl group or for an alkane, an alkyl ether or an amide linked alkane such as C(O)NH(CH2)5CH3. The 2° amine can be substituted with an aliphatic acyl (R~) linked with an amide (see, e.g., U.S. Patent 3,991,045) or urethane (see, e.g., U.S. Patent 3,894,000) bond. It can also be further substituted to form a quaternary ammonium salt. R5 in the pyrimidine ring may be N or CR, where R
is H, halogen containing groups, or alkyl (see, e.g., U.S. Patent No.
4,086,417).
R6 and R~ can together can form an oxo group or R6 = -NH-R~ and R~ = H. R$
is H or R~ and R$ together can form a double bond or R$ can be X, where X is:
CN
O ~ ~ O O

Specific pyrimidine analogues are disclosed in U.S. Patent No.
3,894,000 (see, e.g., 2'-O-palmityl-ara-cytidine, 3'-O-benzoyl-ara-cytidine, and more than 10 other examples); U.S. Patent No. 3,991,045 (see, e.g., N4-acyl-1-(3-D-arabinofuranosylcytosine, and numerous acyl groups derivatives as listed therein, such as palmitoyl.

In another aspect, the cell cycle inhibitor is a fluoropyrimidine analogue, such as 5-fluorouracil, or an analogue or derivative thereof, including carmofur, doxifluridine, emitefur, tegafur, and floxuridine. Exemplary compounds have the structures:

Rz F
O '~N~
R~
R1 Rz 5-FluorouracilH H

CarmofurC(O)NH(CHZ)5CH3 H

DoxifluridineA, H

FloxuridineA2 H

EmitefurCH20CHZCH3 B

TegafurH

A, HO Hz HO
p O CH3 off off off B CN
O ~ ~ O O
O N O
C
O
Other suitable fluoropyrimidine analogues include 5-FudR (5-fluoro-deoxyuridine), or an analogue or derivative thereof, including 5-iododeoxyuridine (5-IudR), 5-bromodeoxyuridine (5-BudR), fluorouridine triphosphate (5-FUTP), and fluorodeoxyuridine monophosphate (5-dFUMP).
Exemplary compounds have the structures:

5-Fluoro-2'-deoxyuridine: R = F
5-Bromo-2'-deoxyuridine: R = Br 5-lodoo-2'-deoxyuridine: R = I
These compounds are thought to function as cell cycle inhibitors by serving as antimetabolites of pyrimidine. These compounds have been shown useful in the treatment of cell proliferative disorders such as breast, cervical, non-melanoma skin, head and neck, esophageal, bile duct, pancreatic, islet cell, penile, and vulvar cancers.
In another aspect, the cell cycle inhibitor is a purine analogue.
Purine analogues have the following general structure.

N
N
R~ N

wherein X is typically carbon; R~ is H, halogen, amine or a substituted phenyl;
R2 is H, a primary, secondary or tertiary amine, a sulfur containing group, typically -SH, an alkane, a cyclic alkane, a heterocyclic or a sugar; R3 is H, a sugar (typically a furanose or pyranose structure), a substituted sugar or a cyclic or heterocyclic alkane or aryl group. See, e.g., U.S. Patent No.
5,602,140 for compounds of this type.
In the case of pentostatin, X-R2 is -CH2CH(OH)-. In this case a second carbon atom is inserted in the ring between X and the adjacent nitrogen atom. The X-N double bond becomes a single bond.

U.S. Patent No. 5,446,139 describes suitable purine analogues of the type shown in the formula.
R~
X~
\Y
wherein N signifies nitrogen and V, W, X, Z can be either carbon or nitrogen with the following provisos. Ring A may have 0 to 3 nitrogen atoms in its structure. If two nitrogens are present in ring A, one must be in the W
position.
If only one is present, it must not be in the Q position. V and Q must not be simultaneously nitrogen. Z and Q must not be simultaneously nitrogen. If Z is nitrogen, R3 is not present. Furthermore, R~_3 are independently one of H, halogen, C~_~ alkyl, C~_~ alkenyl, hydroxyl, mercapto, C~_~ alkylthio, C~_~
alkoxy, C~_7 alkenyloxy, aryl oxy, nitro, primary, secondary or tertiary amine containing group. R5_$ are H or up to two of the positions may contain independently one of OH, halogen, cyano, azido, substituted amino, R5 and R~ can together form a double bond. Y is H, a C~_7 alkylcarbonyl, or a mono- di or tri phosphate.
Exemplary suitable purine analogues include 6-mercaptopurine, thiguanosine, thiamiprine, cladribine, fludaribine, tubercidin, puromycin, pentoxyfilline; where these compounds may optionally be phosphorylated.
Exemplary compounds have the structures:

Ra R~~N~ ~~
R~
Ft, FtzRs A: o~ B,'Ho 6-Mercaptopurine SH H
H

ThioguanosineNHzSH B~ j OH OH

ThiamiprineNHzA H

Ba:

CladribineCINHzBz Ho Ho FludarabineF NH,Ba H o"

PuromycinH N(CH,)z ON ON
Bq Tubercidin H NHz B, Be' H
NH OH

O N
HaC N
N
~Hg Pentoxyfilline These compounds are thought to function as cell cycle inhibitors by serving as antimetabolites of purine.
In another aspect, the cell cycle inhibitor is a nitrogen mustard.
Many suitable nitrogen mustards are known and are suitably used as a cell cycle inhibitor in the present invention. Suitable nitrogen mustards are also known as cyclophosphamides.
A preferred nitrogen mustard has the general structure:

N
A~ ~CI

where A is:
P\O
N~
Rz or -CH3 or other alkane, or chloronated alkane, typically CH2CH(CH3)CI, or a polycyclic group such as B, or a substituted phenyl such as C or a heterocyclic group such as D.
HO
o 1l O
H3~ H ~~''H
~~''H
HOOC
NHZ
(iii) H
N
O
H
(IV) Examples of suitable nitrogen mustards are disclosed in U.S.
Patent No. 3,808,297, wherein A is:

O~P
\O
N~

R~_2 are H or CH2CH2C1; R3 is H or oxygen-containing groups such as hydroperoxy; and R4 can be alkyl, aryl, heterocyclic.
The cyclic moiety need not be intact. See, e.g., U.S. Patent Nos.
5,472,956, 4,908,356, 4,841,085 that describe the following type of structure:

R ~\P~N~CI
O
R Rs N F22 wherein R~ is H or CH~CH2CI, and R2_6 are various substituent groups.
Exemplary nitrogen mustards include methylchloroethamine, and analogues or derivatives thereof, including methylchloroethamine oxide 10' hydrohchloride, novembichin, and mannomustine (a halogenated sugar).
Exemplary compounds have the structures:
CI
N I CI
R
\ ~ I HCI
R \

Mechlorethanime CH3 Mechlorethanime Oxide HCI
Novembichin CH~CH(CH3)CI
The nitrogen mustard may be cyclophosphamide, ifosfamide, perfosfamide, or torofosfamide, where these compounds have the structures:

Ri RZ R3 Cyclophosphamide CHZCH2C1H
H

Ifosfamide CH~CHzCIH H

PerfOSfamide CHZCH~CIH OOH

Torofosfamide CH~CHZCICH2CHZCIH

The nitrogen mustard may be estramustine, or an analogue or derivative thereof, including phenesterine, prednimustine, and estramustine P04. Thus, suitable nitrogen mustard type cell cycle inhibitors of the present invention have the structures:
The nitrogen mustard may be chlorambucil, or an analogue or derivative thereof, including melphalan and chlormaphazine. Thus, suitable nitrogen mustard type cell cycle inhibitors of the present invention have the structures:

R
Estramustine OH
Phenesterine C(CH3)(CHZ)3CH(CH3)z N I
R~
R~ R3 I
R~ RZ R3 Chlorambucil H H

Melphalan COOH NHZ H

Chlornaphazine together H forms a benzene ring The nitrogen mustard may be uracil mustard, which has the structure:
H
O V ~ ~ I
H
CI
The nitrogen mustards are thought to function as cell cycle inhibitors by serving as alkylating agents for DNA. Nitrogen mustards have been shown useful in the treatment of cell proliferative disorders including, for example, small cell lung, breast, cervical, head and neck, prostate, retinoblastoma, and soft tissue sarcoma.
The cell cycle inhibitor of the present invention may be a hydroxyurea. Hydroxyureas have the following general structure:

~N N~
R2 R~
Suitable hydroxyureas are disclosed in, for example, U.S. Patent No. 6,080,874, wherein R~ is:
S

Rs and R2 is an alkyl group having 1-4 carbons and R3 is one of H, acyl, methyl, ethyl, and mixtures thereof, such as a methylether.
Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent No. 5,665,768, wherein R~ is a cycloalkenyl group, for example N-(3-(5-(4-fluorophenylthio)-furyl)-2-cyclopenten-1-yl)N-hydroxyurea; R2 is H or an alkyl group having 1 to 4 carbons and R3 is H; X is H or a cation.
Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent No. 4,299,778, wherein R~ is a phenyl group substituted with on or more fluorine atoms; R2 is a cyclopropyl group; and R3 and X is H.
Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent No. 5,066,658, wherein R2 and R3 together with the adjacent nitrogen form:
c~~Zm Y . N-(CHZ)m wherein m is 1 or 2, n is 0-2 and Y is an alkyl group.
In one aspect, the hydroxy urea has the structure:

,oH

Hydroxyurea Hydroxyureas are thought to function as cell cycle inhibitors by serving to inhibit DNA synthesis.
In another aspect, the cell cycle inhibitor is a mytomicin, such as mitomycin C, or an analogue or derivative thereof, such as porphyromycin.
Exemplary compounds have the structures:

R
Mitomycin C H
Porphyromycin CH3 (N-methyl Mitomycin C) These compounds are thought to function as cell cycle inhibitors by serving as DNA alkylating agents. Mitomycins have been shown useful in the treatment of cell proliferative disorders such as, for example, esophageal, liver, bladder, and breast cancers.
In another aspect, the cell cycle inhibitor is an alkyl sulfonate, such as busulfan, or an analogue or derivative thereof, such as treosulfan, improsulfan, piposulfan, and pipobroman. Exemplary compounds have the structures:

H ~~ ~R~/O ~~ CH3 O p R
Busulfan single bond Improsulfan -CHz NH-GHZ
Piposulfan ~ p ~--N~i --~

B N Br O
Pipobroman These compounds are thought to function as cell cycle inhibitors by serving as DNA alkylating agents.

In another aspect, the cell cycle inhibitor is a benzamide. In yet another aspect, the cell cycle inhibitor is a nicotinamide. These compounds have the basic structure:
A
wherein X is either O or S; A is commonly NH2 or it can be OH or an alkoxy group; B is N or C-R4, where R4 is H or an ether-linked hydroxylated alkane such as OCH2CH20H, the alkane may be linear or branched and may contain one or more hydroxyl groups. Alternately, B may be N-R5 in which case the double bond in the ring involving B is a single bond. R5 may be H, and alkyl or an aryl group (see, e.g., U.S. Patent No. 4,258,052); R2 is H, OR6, SR6 or NHR6, where R6 is an alkyl group; and R3 is H, a lower alkyl, an ether linked lower alkyl such as -O-Me or-O-ethyl (see, e.g., U.S. Patent No. 5,215,738).
Suitable benzamide compounds have the structures:
x z ~NHZ
Y
N
Benzamides X=OorS
Y = H, OR, CH3, or acetoxy Z = H, OR, SR, or NHR
R = alkyl group where additional compounds are disclosed in U.S. Patent No. 5,215,738, (listing some 32 compounds).
Suitable nicotinamide compounds have the structures:

x z \~ ~NHZ
N
Nicotinamides X=OorS
Z = H, OR, SR, NHR
R = alkyl group where additional compounds are disclosed in U.S. Patent No.
5,215,738, R O
z O
Rz /I'I~
N-~~-NH~O~R~
Rz~ I O
N
Rz ~ H3C N
O
Rz Ra Rz Rz ~II
N O"NHz R' Ra Benzodepa phenyl H

Meturedepa CH3 CH3 Carboquone Uredepa CH3 H
In another aspect, the cell cycle inhibitor is a halogenated sugar, such as mitolactol, or an analogue or derivative thereof, including mitobronitol and mannomustine. Examplary compounds have the structures:
CH~Br CHpBr CHzNHZ~CH2CHzCl H OH HO H HO H
HO H NO H HO H
HO H H OH H OH
H OH H OH H OH
CHaBr CHaBr CHaNHp+CHZCH~CI
Mitolactol Mitobronitol Mannomustine In another aspect, the cell cycle inhibitor is a diazo compound, such as azaserine, or an analogue or derivative thereof, including 6-diazo-5-oxo-L-norleucine and 5-diazouracil (also a pyrimidine analog). Examplary compounds have the structures:

O
N=N~ Rt~RZ
OH
O N H~
R~ Rz Azaserine O single bond 6-diazo-5-oxo-L-norleucine single bond GHz Other compounds that may serve as cell cycle inhibitors according to the present invention are pazelliptine; wortmannin;
metoclopramide; RSU; buthionine sulfoxime; tumeric; curcumin; AG337, a thymidylate synthase inhibitor; levamisole; lentinan, a polysaccharide;
razoxane, an EDTA analogue; indomethacin; chlorpromazine; a and ~3 interferon; MnBOPP; gadolinium texaphyrin; 4-amino-1,8-naphthalimide;
staurosporine derivative of CGP; and SR-2508.
Thus, in one aspect, the cell cycle inhibitor is a DNA alylating agent. In another aspect, the cell cycle inhibitor is an anti-microtubule agent.
In another aspect, the cell cycle inhibitor is a topoisomerase inhibitor. In another aspect, the cell cycle inhibitor is a DNA cleaving agent. In another aspect, the cell cycle inhibitor is an antimetabolite. In another aspect, the cell cycle inhibitor functions by inhibiting adenosine deaminase (e.g., as a purine analogue). In another aspect, the cell cycle inhibitor functions by inhibiting purine ring synthesis and/or as a nucleotide interconversion inhibitor (e.g., as a purine analogue such as mercaptopurine). In another aspect, the cell cycle inhibitor functions by inhibiting dihydrofolate reduction and/or as a thymidine monophosphate block (e.g., methotrexate). In another aspect, the cell cycle inhibitor functions by causing DNA damage (e.g., bleomycin). In another aspect, the cell cycle inhibitor functions as a DNA intercalation agent and/or RNA synthesis inhibition (e.g., doxorubicin, aclarubicin, or detorubicin (acetic acid, diethoxy-, 2-(4-((3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-1,2,3,4,6,11-hexahydro-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-2-naphthacenyl)-2-oxoethyl ester, (2S-cis)-)). In another aspect, the cell cycle inhibitor functions by inhibiting pyrimidine synthesis (e.g., N-phosphonoacetyl-L-aspartate). In another aspect, the cell cycle inhibitor functions by inhibiting ribonucleotides (e.g., hydroxyurea). In another aspect, the cell cycle inhibitor functions by inhibiting thymidine monophosphate (e.g., 5-fluorouracil). In another aspect, the cell cycle inhibitor functions by inhibiting DNA synthesis (e.g., cytarabine). In another aspect, the cell cycle inhibitor functions by causing DNA adduct formation (e.g., platinum compounds). In another aspect, the cell cycle inhibitor functions by inhibiting protein synthesis (e.g., L-asparginase). In another aspect, the cell cycle inhibitor functions by inhibiting microtubule function (e.g., taxanes). In another aspect, the cell cycle inhibitor acts at one or more of the steps in the biological pathway shown in FIG. 1.
Additional cell cycle inhibitor s useful in the present invention, as well as a discussion of the mechanisms of action, may be found in Hardman J.G., Limbird L.E. Molinoff R.B., Ruddon R W., Gilman A.G. editors, Chemotherapy of Neoplastic Diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics Ninth Edition, McGraw-Hill Health Professions Division, New York, 1996, pages 1225-1287. See also U.S. Patent Nos. 3,387,001; 3,808,297; 3,894,000; 3,991,045; 4,012,390; 4,057,548;
4,086,417; 4,144,237; 4,150,146; 4,210,584; 4,215,062; 4,250,189; 4,258,052;
4,259,242; 4,296,105; 4,299,778; 4,367,239; 4,374,414; 4,375,432; 4,472,379;
4,588,831; 4,639,456; 4,767,855; 4,828,831; 4,841,045; 4,841,085; 4,908,356;
4,923,876; 5,030,620; 5,034,320; 5,047,528; 5,066,658; 5,166,149; 5,190,929;
5,215,738; 5,292,731; 5,380,897; 5,382,582; 5,409,915; 5,440,056; 5,446,139;
5,472,956; 5,527,905; 5,552,156; 5,594,158; 5,602,140; 5,665,768; 5,843,903;
6,080,874; 6,096,923; and RE030561.
In another embodiment, the cell-cycle inhibitor is camptothecin, mitoxantrone, etoposide, 5-fluorouracil, doxorubicin, methotrexate, peloruside A, mitomycin C, or a CDK-2 inhibitor or an analogue or derivative of any member of the class of listed compounds.

In another embodiment, the cell-cycle inhibitor is HTI-286, plicamycin; or mithramycin, or an analogue or derivative thereof.
Other examples of cell cycle inhibitors also include, e.g., 7-hexanoyltaxol (QP-2), cytochalasin A, lantrunculin D, actinomycin-D, Ro-31 7453 (3-(6-nitro-1-methyl-3-indolyl)-4-(1-methyl-3-indolyl}pyrrole-2,5-dione), PNU-151807, brostallicin, C2-ceramide, cytarabine ocfosfate (2(1 H) pyrimidinone, 4-amino-1-(5-O-(hydroxy(octadecyloxy)phosphinyl)-f3-D-arabinofuranosyl)-, monosodium salt), paclitaxel (5f3,20-epoxy-1,2 alpha,4,7f3,10f3,13 alpha-hexahydroxytax-11-en-9-one-4,10-diacetate-2-benzoate-13-(alpha-phenylhippurate)), doxorubicin (5,12-naphthacenedione, 10-((3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, (8S)-cis-), daunorubicin (5,12-naphthacenedione, 8-acetyl-10-((3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihyd roxy-1-methoxy-, (8S-cis)-), gemcitabine hydrochloride (cytidine, 2'-deoxy-2', 2'-difluoro-,monohydrochloride), nitacrine (1,3-propanediamine, N,N-dimethyl-N'-(1-nitro-9-acridinyl)-), carbopiatin (platinum, diammine(1,1-cyclobutanedicarboxylato(2-))-, (SP-4-2)-), altretamine (1,3,5-triazine-2,4,6-triamine, N,N,N',N',N",N"-hexamethyl-), teniposide (furo(3',4':6,7)naphtho(2,3-d)-1,3-dioxol-6(5aH)-one, 5,8,8a,9-tetrahydro-5-(4-hydroxy-3,5-dimethoxyphenyl)-9-((4,6-O-(2-thienylmethylene)-f3-D-glucopyranosyl)oxy)-, (5R-(5alpha,5a(3,8aAlpha,9(3(R*)))-), eptaplatin (platinum, ((4R,5R)-2-(1-methylethyl)-1,3-dioxolane-4,5-dimethanamine-kappa N4,kappa N5)(propanedioato(2-)-kappa 01, kappa 03)-, (SP-4-2)-), amrubicin hydrochloride (5,12-naphthacenedione, 9-acetyl-9-amino-7-((2-deoxy-f3-D-erythro-pentopyranosyl)oxy)-7,8,9,10-tetrahydro-6,11-dihydroxy-, hydrochloride, (7S-cis)-), ifosfamide (2H-1,3,2-oxazaphosphorin-2-amine, N,3-bis(2-chloroethyl)tetrahydro-,2-oxide), cladribine (adenosine, 2-chloro-2'-deoxy-), mitobronitol (D-mannitol, 1,6-dibromo-1,6-dideoxy-), fludaribine phosphate (9H-purin-6-amine, 2-fluoro-9-(5-O-phosphono-f3-D-arabinofuranosyl)-), enocitabine (docosanamide, N-(1-f3-D-arabinofuranosyl-1,2-dihydro-2-oxo-4-pyrimidinyl)-), vindesine (vincaleukoblastine, 3-(aminocarbonyl)-O4-deacetyl-3-de(methoxycarbonyl)-), idarubicin (5,12-naphthacenedione, 9-acetyl-7-((3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,9,11-trihydroxy-, (7S-cis)-), zinostatin (neocarzinostatin), vincristine (vincaleukoblastine, 22-oxo-), tegafur (2,4(1 H,3H)-pyrimidinedione, 5-fluoro-(tetrahydro-2-furanyl)-), razoxane (2,6-piperazinedione, 4,4'-(1-methyl-1,2-ethanediyl)bis-), methotrexate (L-glutamic acid, N-(4-(((2,4-diamino-6-pteridinyl)methyl)methylamino)benzoyl)-), raltitrexed (L-glutamic acid, N-((5-(((1,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)methylamino)-2-thienyl)carbonyl)-), oxaliplatin (platinum, (1,2-cyclohexanediamine-N,N')(ethanedioato(2-)-O,O')-, (SP-4-2-(1 R-trans))-), doxifluridine (uridine, 5'-deoxy-5-fluoro-), mitolactol (galactitol, 1,6-dibromo-1,6-dideoxy-), piraubicin (5,12-naphthacenedione, 10-((3-amino-2,3,6-trideoxy-4-O-(tetrahydro-2H-pyran-2-yl)-alpha-L-lyxo-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, (8S-(8 alpha, 10 alpha(S*)))-), docetaxel ((2R,3S)-N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester with 5(3,20-epoxy-1,2 alpha,4,7f3,10(3,13 alpha-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate-), capecitabine (cytidine, 5-deoxy-5-fluoro-N-((pentyloxy)carbonyl)-), cytarabine (2(1 H)-pyrimidone, 4-amino-1-f3-D-arabino furanosyl-), valrubicin (pentanoic acid, 2-(1,2,3,4,6,11-hexahydro-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-4-((2,3,6-trideoxy-3-((trifluoroacetyl)amino)-alpha-L-lyxo-hexopyranosyl)oxy)-2-naphthacenyl)-2-oxoethyl ester (2S-cis)-), trofosfamide (3-2-(chloroethyl)-2-(bis(2-chloroethyl)amino)tetrahydro-2H-1,3,2-oxazaphosphorin 2-oxide), prednimustine (pregna-1,4-diene-3,20-dione, 21-(4-(4-(bis(2-chloroethyl)amino)phenyl)-1-oxobutoxy)-11,17-dihydroxy-, (11(3)-), lomustine (Urea, N-(2-chloroethyl)-N'-cyclohexyl-N-nitroso-), epirubicin (5,12-naphthacenedione, 10-((3-amino-2,3,6-trideoxy-alpha-L-arabino-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, (8S-cis)-), or an analogue or derivative thereof).

5) Cyclin Dependent Protein Kinase Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a cyclin dependent protein kinase inhibitor (e.g., R-roscovitine, CYC-101, CYC-103, CYC-400, MX-7065, alvocidib (4H-1-Benzopyran-4-one, 2-(2-chlorophenyl)-5,7-dihydroxy-8-(3-hydroxy-1-methyl-4-piperidinyl)-, cis-(-)-), SU-9516, AG-12275, PD-0166285, CGP-79807, fascaplysin, GW-8510 (benzenesulfonamide, 4-(((Z)-(6,7-dihydro-7-oxo-8H-pyrrolo(2,3-g)benzothiazol-8-ylidene)methyl)amino)-N-(3-hydroxy-2,2-dimethylpropyl)-), GW-491619, Indirubin 3' monoxime, GW8510, AZD-5438, ZK-CDK or an analogue or derivative thereof).
6) EGF (Epidermal Growth Factor) Receptor Kinase Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is an EGF (epidermal growth factor) kinase inhibitor (e.g., erlotinib (4-quinazolinamine, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-, monohydrochloride), erbstatin, BIB?C-1382, gefitinib (4-quinazolinamine, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-(4-morpholinyl)propoxy)), or an analogue or derivative thereof).
7) Elastase Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is an elastase inhibitor (e.g., ONO-6818, sivelestat sodium hydrate (glycine, N-(2-(((4-(2,2-dimethyl-1-oxopropoxy)phenyl)sulfonyl)amino)benzoyl)-), erdosteine (acetic acid, ((2-oxo-2-((tetrahydro-2-oxo-3-thienyl)amino)ethyl)thio)-), MDL-100948A, MDL-104238 (N-(4-(4-morpholinylcarbonyl)benzoyl)-L-valyl-N'-(3,3,4,4,4-pentafluoro-1-(1-methylethyl)-2-oxobutyl)-L-2-azetamide), MDL-27324 (L-prolinamide, N-((5-(dimethylamino)-1-naphthalenyl)sulfonyl)-L-alanyl-L-alanyl-N-(3,3,3-trifluoro-(1-methylethyl)-2-oxopropyl)-, (S)-), SR-26831 (thieno(3,2-c)pyridinium, 5-((2-chlorophenyl)methyl)-2-(2,2-dimethyl-1-oxopropoxy)-4,5,6,7-tetrahydro-5-hydroxy-), Win-68794, Win-63110, SSR-69071 (2-(9(2-piperidinoethoxy)-4-oxo-4H-pyrido(1,2-a)pyrimidin-2-yloxymethyl)-4-(1-methylethyl)-6-methyoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide), (N(Alpha)-(1-adamantylsulfonyl)N(epsilon)-succinyl-L-lysyl-L-prolyl-L-valinal), Ro-31-3537 (N
alpha-(1-adamantanesulphonyl)-N-(4-carboxybenzoyl)-L-lysyl-alanyl-L-valinal), R-665, FCE-28204, ((6R,7R)-2-(benzoyloxy)-7-methoxy-3-methyl-4-pivaloyl-3-cephem 1,1-dioxide), 1,2-benzisothiazol-3(2H)-one, 2-(2,4-dinitrophenyl)-, 1,1-dioxide, L-658758 (L-proline, 1-((3-((acetyloxy)methyl)-7-methoxy-8-oxo-5-thia-1-azabicyclo(4.2.0)oct-2-en-2-yl)carbonyl)-, S,S-dioxide, (6R-cis)-), L-659286 (pyrrolidine, 1-((7-methoxy-8-oxo-3-(((1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-yl)thio)methyl)-5-this-1-azabicyclo(4.2.0)oct-2-en-2-yl)carbonyl)-, S,S-dioxide, (6R-cis)-), L-680833 (benzeneacetic acid, 4-((3,3-diethyl-1-(((1-(4-methylphenyl)butyl)amino)carbonyl)-4-oxo-2-azetidinyl)oxy)-, (S-(R*,S*))-), FK-706 (L-prolinamide, N-(4-(((carboxymethyl)amino)carbonyl)benzoyl)-L-valyl-N-(3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl)-, monosodium salt), Roche 8-665, or an analogue or derivative thereof).

8) Factor Xa Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a factor Xa inhibitor (e.g., CY-222, fondaparinux sodium (alpha-D-glucopyranoside, methyl O-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranosyl-( 1-4)-O-f3-D-glucopyranuronosyl-( 1-4)-O-2-deoxy-3,6-di-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranosyl-( 1-4)-O-2-O-sulfo-alpha-L-idopyranuronosyl-(1-4)-2-deoxy-2-(sulfoamino)-, 6-(hydrogen sulfate)), danaparoid sodium, or an analogue or derivative thereof).

9) Farnesyltransferase Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a farnesyltransferase inhibitor (e.g., dichlorobenzoprim (2,4-diamino-5-(4-(3,4-dichlorobenzylamino)-3-nitrophenyl)-6-ethylpyrimidine), B-581, B-956 (N-(8(R)-amino-2(S)-benzyl-5(S)-isopropyl-9-sulfanyl-3(Z),6(E)-nonadienoyl)-L-methionine), OSI-754, perillyl alcohol (1-cyclohexene-1-methanol, 4-(1-methylethenyl)-, RPR-114334, lonafarnib (1-piperidinecarboxamide, 4-(2-(4-((11 R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo(5,6)cyclohepta(1,2-b)pyridin-11-yl)-1-piperidinyl)-2-oxoethyl)-), Sch-48755, Sch-226374, (7,8-dichloro-5H-dibenzo(b,e)(1,4)diazepin-11-y1)-pyridin-3-ylmethylamine, J-104126, L-639749, L-731734 (pentanamide, 2-((2-((2-amino-3-mercaptopropyl)amino)-3-methylpentyl)amino)-3-methyl-N-(tetrahydro-2-oxo-3-furanyl)-, (3S-(3R*(2R*(2R*(S*),3S*),3R*)))-), L-744832 (butanoic acid, 2-((2-((2-((2-amino-3-mercaptopropyl)amino)-3-methylpentyl)oxy)-1-oxo-3-phenylpropyl)amino)-4-(methylsulfonyl)-, 1-methylethyl ester, (2S-(1(R*(R*)),2R*(S*),3R*))-), L-745631 (1-piperazinepropanethiol, f3-amino-2-(2-methoxyethyl)-4-(1-naphthalenylcarbonyl)-, (f3R,2S)-), N-acetyl-N-naphthylmethyl-2(S)-((1-(4-cyanobenzyl)-1 H-imidazol-5-yl)acetyl)amino-3(S)-methylpentamine, (2alpha)-2-hydroxy-24,25-dihydroxylanost-8-en-3-one, BMS-316810, UCF-1-C (2,4-decadienamide, N-(5-hydroxy-5-(7-((2-hydroxy-5-oxo-1-cyclopenten-I-yl)amino-oxo-1,3,5-heptatrienyl)-2-oxo-7-oxabicyclo(4.1.0)hept-3-en-3-yl)-2,4,6-trimethyl-, (1S-(1alpha,3(2E,4E,6S*),5 alpha, 5(1E,3E,5E), 6 alpha))-), UCF-116-B, ARGLABIN (3H-oxireno(8,8a)azuleno(4,5-b)furan-8(4aH)-one, 5,6,6a,7,9a,9b-hexahydro-1,4a-dimethyl-7-methylene-, (3aR,4aS,6aS,9aS,9bR)-) from ARGLABIN - Paracure, Inc. (Virginia Beach, VA), or an analogue or derivative thereof).

10) Fibrinogen Antagonists In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a fibrinogen antagonist (e.g., 2(S)-((p-toluenesulfonyl)amino)-3-(((5,6,7,8,-tetrahydro-4-oxo-5-(2-(piperidin-4-yl)ethyl)-4H-pyrazolo-(1,5-a)(1,4)diazepin-2-yl)carbonyl)-amino)propionic acid, streptokinase (kinase (enzyme-activating), strepto-), urokinase (kinase (enzyme-activating), uro-), plasminogen activator, pamiteplase, monteplase, heberkinase, anistreplase, alteplase, pro-urokinase, picotamide (1,3-benzenedicarboxamide, 4-methoxy-N,N'-bis(3-pyridinylmethyl)-), or an analogue or derivative thereof).

11 ) Guanylate Cyclase Stimulants In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a guanylate cyclase stimulant (e.g., isosorbide-5-mononitrate (D-glucitol, 1,4:3,6-dianhydro-, 5-nitrate), or an analogue or derivative thereof).

12) Heat Shock Protein 90 Antagonists In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a heat shock protein 90 antagonist (e.g., geldanamycin;
NSC-33050 (17-allylaminogeldanamycin), rifabutin (rifamycin XIV, 1',4-didehydro-1-deoxy-1,4-dihydro-5'-(2-methylpropyl)-1-oxo-), 17AAG, or an analogue or derivative thereof).

13) HMGCoA Reductase Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is an HMGCoA reductase inhibitor (e.g., BCP-671, BB-476, fluvastatin (6-heptenoic acid, 7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1 H-indol-2-yl)-3,5-dihydroxy-, monosodium salt, (R*,S*-(E))-(~)-), dalvastatin (2H-pyran-2-one, 6-(2-(2-(2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethyl-1-cyclohexen-1-yl)ethenyl)tetrahydro)-4-hydroxy-, (4alpha,6f3(E))-(+/-)-), glenvastatin (2H-pyran-2-one, 6-(2-(4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl)ethenyl)tetrahydro-4-hydroxy-, (4R-(4alpha,6(3(E)))-), S-2468, N-(1-oxododecyl)-4Alpha,10-dimethyl-8-aza-trans-decal-3(3-0l, atorvastatin calcium (1 H-Pyrrole-1-heptanoic acid, 2-(4-fluorophenyl)-(3,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-((phenylamino)carbonyl)-, calcium salt (R-(R*,R*))-), CP-83101 (6,8-nonadienoic acid, 3,5-dihydroxy-9,9-diphenyl-, methyl ester, (R*,S*-(E))-(+/-)-), pravastatin (1-naphthaleneheptanoic acid, 1,2,6,7,8,8a-hexahydro-(3,delta,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-, monosodium salt, (1 S-(1 alpha(f3S*,deltaS*),2 alpha,6 alpha,8f3(R*),8a alpha))-), U-20685, pitavastatin (6-heptenoic acid, 7-(2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl)-3,5-dihydroxy-, calcium salt (2:1), (S-(R*,S*-(E)))-), N-((1-methylpropyl)carbonyl)-8-(2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-perhydro-isoquinoline, dihydromevinolin (butanoic acid, 2-methyl-, 1,2,3,4,4a,7,8,8a-octahydro-3,7-dimethyl-8-(2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-1-naphthalenyl ester(1 alpha(R*), 3 alpha, 4a alpha,7f~,8f3(2S*,4S*),8af3))-), HBS-107, dihydromevinolin (butanoic acid, 2-methyl-, 1,2,3,4,4a,7,8,8a-octahydro-3,7-dimethyl-8-(2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-1-naphthalenyl ester(1 alpha(R*), 3 alpha,4a alpha,7f3,8f3(2S*,4S*),8af~))-), L-669262 (butanoic acid, 2,2-dimethyl-, 1,2,6,7,8,8a-hexahydro-3,7-dimethyl-6-oxo-8-(2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-1-naphthalenyl(1S-(1Alpha,7(3,8(3(2S*,4S*),8af3))-), simvastatin (butanoic acid, 2,2-dimethyl-, 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-(2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-1-naphthalenyl ester, (1S-(1alpha, 3alpha,7f3,8(3(2S*,4S*),8af3))-), rosuvastatin calcium (6-heptenoic acid, 7-(4-(4-fluorophenyl)-6-(1-methylethyl)-2-(methyl(methylsulfonyl)amino)-pyrimdinyl)-3,5-dihydroxy- calcium salt (2:1 ) (S-(R*, S*-(E)))), meglutol (2-hydroxy-2-methyl-1,3-propandicarboxylic acid), lovastatin (butanoic acid, 2-methyl-, 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-(2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-1-naphthalenyl ester, (1S-(1 alpha.(R*),3 alpha,7f~,8f3(2S*,4S*),8af3))-), or an analogue or derivative thereof).

14) Hydroorotate Dehydrogenase Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a hydroorotate dehydrogenase inhibitor (e.g., leflunomide (4-isoxazolecarboxamide, 5-methyl-N-(4-(trifluoromethyl)phenyl)-), laflunimus (2-propenamide, 2-cyano-3-cyclopropyl-3-hydroxy-N-(3-methyl-4(trifluoromethyl)phenyl)-, (Z)-), or atovaquone (1,4-naphthalenedione, 2-(4-(4-chlorophenyl)cyclohexyl)-3-hydroxy-, traps-, or an analogue or derivative thereof).

15) IKK2lnhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is an IKK2 inhibitor (e.g., MLN-120B, SPC-839, or an analogue or derivative thereof).

16) IL-1, ICE and IRAK Antagonists In another embodiri~ent, the pharmacologically active fibrosis-inhibiting compound is an IL-1, ICE or an IRAK antagonist (e.g., E-5090 (2-propenoic acid, 3-(5-ethyl-4-hydroxy-3-methoxy-1-naphthalenyl)-2-methyl-, (Z)-), CH-164, CH-172, CH-490, AMG-719, iguratimod (N-(3-(formylamino)-4-oxo-6-phenoxy-4H-chromen-7-yl) methanesulfonamide), AV94-88, pralnacasan (6H-pyridazino(1,2-a)(1,2)diazepine-1-carboxamide, N-((2R,3S)-2-ethoxytetrahydro-5-oxo-3-furanyl)octahydro-9-((1-isoquinolinylcarbonyl)amino)-6,10-dioxo-, (1S,9S)-), (2S-cis)-5-(benzyloxycarbonylamino-1,2,4,5,6,7-hexahydro-4-(oxoazepino(3,2,1-hi)indole-2-carbonyl)-amino)-4-oxobutanoic acid, AVE-9488, esonarimod (benzenebutanoic acid, alpha-((acetylthio)methyl)-4-methyl-gamma-oxo-), pralnacasan (6H-pyridazino(1,2-a)(1,2)diazepine-1-carboxamide, N-((2R,3S)-2-ethoxytetrahydro-5-oxo-3-furanyl)octahydro-9-((1-isoquinolinylcarbonyl)amino)-6,10-dioxo-, (1S,9S)-), tranexamic acid (cyclohexanecarboxylic acid, 4-(aminomethyl)-, traps-), Win-72052, romazarit (Ro-31-3948) (propanoic acid, 2-((2-(4-chlorophenyl)-4-methyl-5-oxazolyl)methoxy)-2-methyl-), PD-163594, SDZ-224-015 (L-alaninamide N-((phenylmethoxy)carbonyl)-L-valyl-N-((1S)-3-((2,6-dichlorobenzoyl)oxy)-1-(2-ethoxy-2-oxoethyl)-2-oxopropyl)-), L-709049 (L-alaninamide, N-acetyl-L-tyrosyl-L-valyl-N-(2-carboxy-1-formylethyl)-, (S)-), TA-383 (1 H-imidazole, 2-(4-chlorophenyl)-4,5-dihydro-4,5-diphenyl-, monohydrochloride, cis-), EI-1507-1 (6a,12a-epoxybenz(a)anthracen-1,12(2H,7H)-dione, 3,4-dihydro-3,7-dihydroxy-8-methoxy-3-methyl-), ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-yl methyl)quinoline-3-carboxylate, EI-1941-1, TJ-114, anakinra (interleukin 1 receptor antagonist (human isoform x reduced), N2-L-methionyl-), IX-207-887 (acetic acid, (10-methoxy-4H-benzo(4,5)cyclohepta(1,2-b)thien-4-ylidene)-), K-832, or an analogue or derivative thereof).

17) IL-4 Aaonists In another embodiment, the pharmacologically active fibrosis-inhibiting compound is an IL-4 agonist (e.g., glatiramir acetate (L-glutamic acid, polymer with L-alanine, L-lysine and L-tyrosine, acetate (salt)), or an analogue or derivative thereof).

18) Immunomodulatory Agents In another embodiment, the pharmacologically active fibrosis-inhibiting compound is an immunomodulatory agent (e.g., biolimus, ABT-578, methylsulfamic acid 3-(2-methoxyphenoxy)-2-(((methylamino)sulfonyl)oxy)propyl ester, sirolimus (also referred to as rapamycin or RAPAMUNE (American Home Products, Inc., Madison, NJ)), CCI-779 (rapamycin 42-(3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate)), LF-15-0195, NPC15669 (L-leucine, N-(((2,7-dimethyl-9H-fluoren-9-yl)methoxy)carbonyl)-), NPC-15670 (L-leucine, N-(((4,5-dimethyl-9H-fluoren-9-yl)methoxy)carbonyl)-), NPC-16570 (4-(2-(fluoren-9-yl)ethyloxy-carbonyl)aminobenzoic acid), sufosfamide (ethanol, 2-((3-(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-yl)amino)-, methanesulfonate (ester), P-oxide), tresperimus (2-(N-(4-(3-aminopropylamino)butyl)carbamoyloxy)-N-(6-guanidinohexyl)acetamide), 4-(2-(fluoren-9-yl)ethoxycarbonylamino)-benzo-hydroxamic acid, iaquinimod, PBI-1411, azathioprine (6-((1-Methyl-4-nitro-1 H-imidazol-5-yl)thio)-1 H-purine), PB10032, beclometasone, MDL-28842 (9H-purin-6-amine, 9-(5-deoxy-5-fluoro-(3-D-threo-pent-4-enofuranosyl)-, (Z)-), FK-788, AVE-1726, ZK-90695, ZK-90695, Ro-54864, didemnin-B, Illinois (didemnin A, N-(1-(2-hydroxy-1-oxopropyl)-L-prolyl)-, (S)-), SDZ-62-826 (ethanaminium, 2-((hydroxy((1-((octadecyloxy)carbonyl)-3-piperidinyl)methoxy)phosphinyl)oxy)-N, N, N-trimethyl-, inner salt), argyrin B ((4S,7S,13R,22R)-13-Ethyl-4-(1 H-indol-3-ylmethyl)-7-(4-methoxy-1 H-indol-3-ylmethyl)18,22-dimethyl-16-methyl-ene-24-thia-3,6, 9,12,15,18,21,26-octaazabicyclo(21.2.1 )-hexacosa-1 (25),23(26)-diene-2,5,8,11,14,17,20-heptaone), everolimus (rapamycin, 42-O-(2-hydroxyethyl)-), SAR-943, L-687795, 6-((4-chlorophenyl)sulfinyl)-2,3-dihydro-2-(4-methoxy-phenyl)-5-methyl-3-oxo-4-pyridazinecarbonitrile, 91Y78 (1 H-imidazo(4,5-c)pyridin-4-amine, 1-f3-D-ribofuranosyl-), auranofin (gold, (1-thio-f3-D-glucopyranose 2,3,4,6-tetraacetato-S)(triethylphosphine)-), 27-0-demethylrapamycin, tipredane (androsta-1,4-dien-3-one, 17-(ethylthio)-9-fluoro-11-hydroxy-17-(methylthio)-, (11 (3,17 alpha)-), AI-402, LY-178002 (4-thiazolidinone, 5-((3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene)-), SM-8849 (2-thiazolamine, 4-(1-(2-fluoro(1,1'-biphenyl)-4-yl)ethyl)-N-methyl-), piceatannol, resveratrol, triamcinolone acetonide (pregna-1,4-diene-3,20-dione, 9-fluoro-11,21-dihydroxy-16,17-((1-methylethylidene)bis(oxy))-, (1113,16 alpha)-), ciclosporin (cyclosporin A), tacrolimus (15,19-epoxy-3H-pyrido(2,1-c)(1,4)oxaazacyclotricosine-1,7,20,21 (4H,23H)-tetrone, 5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahyd ro-5,19-d ihydroxy-3-(2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl)-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-, (3S-(3R*(E(1S*,3S*,4S*)),4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*)) -), gusperimus (heptanamide, 7-((aminoiminomethyl)amino)-N-(2-((4-((3-aminopropyl)amino)butyl)amino)-1-hydroxy-2-oxoethyl)-, (+/-)-), tixocortol pivalate (pregn-4-ene-3,20-dione, 21-((2,2-dimethyl-1-oxopropyl)thio)-11,17-dihydroxy-, (11 f3)-), alefacept (1-92 LFA-3 (antigen) (human) fusion protein with immunoglobulin G1 (human hinge-CH2-CH3 gamma1-chain), dimer), halobetasol propionate (pregna-1,4-diene-3,20-dione, 21-chloro-6,9-difluoro-11-hydroxy-16-methyl-17-(1-oxopropoxy)-, (6Alpha,11 f~,16f3)-), iloprost trometamol (pentanoic acid, 5-(hexahydro-5-hydroxy-4-(3-hydroxy-4-methyl-1-octen-6-ynyl)-2(1 H)-pentalenylidene)-), beraprost (1 H-cyclopenta(b)benzofuran-5-butanoic acid, 2,3,3a,8b-tetrahydro-2-hydroxy-1-(3-hydroxy-4-methyl-1-octen-6-ynyl)-), rimexolone (androsta-1,4-dien-3-one,11-hydroxy-16,17-dimethyl-17-(1-oxopropyl)-, (11f5,16Alpha,17f3)-), dexamethasone (pregna-1,4-diene-3,20-dione,9-fluoro-11,17,21-trihydroxy-16-methyl-, (11f3,16alpha)-), sulindac (cis-fluoro-2-methyl-1-((p-methylsulfinyl)benzylidene)indene-3-acetic acid), proglumetacin (1 H-Indole-3-acetic acid, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-, 2-(4-(3-((4-(benzoylamino)-5-(dipropylamino)-1,5-dioxopentyl)oxy)propyl)-1-piperazinyl)ethylester, (+/-)-), alclometasone dipropionate (pregna-1,4-diene-3,20-dione, 7-chloro-11-hydroxy-16-methyl-17,21-bis(1-oxopropoxy)-, (7alpha,11f~,16alpha)-), pimecrolimus (15,19-epoxy-3H-pyrido(2,1-c)(1,4)oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, 3-(2-(4-chloro-3-methoxycyclohexyl)-1-methyletheny)-8-ethyl-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-14,16-d imethoxy-4,10,12,18-tetramethyl-, (3S-(3R*(E(1 S*,3S*,4R*)),4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*)) -), hydrocortisone-17-butyrate (pregn-4-ene-3,20-dione, 11,21-dihydroxy-17-(1 oxobutoxy)-, (11f3)-), mitoxantrone (9,10-anthracenedione, 1,4-dihydroxy-5,8 bis((2-((2-hydroxyethyl)amino)ethyl)amino)-), mizoribine (1 H-imidazole-4-carboxamide, 5-hydroxy-1-f3-D-ribofuranosyl-), prednicarbate (pregna-1,4-' diene-3,20-dione, 17-((ethoxycarbonyl)oxy)-11-hydroxy-21-(1-oxopropoxy)-, (11 f3)-), iobenzarit (benzoic acid, 2-((2-carboxyphenyl)amino)-4-chloro-), glucametacin (D-glucose, 2-(((1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1 H-indol-3-yl)acetyl)amino)-2-deoxy-), fluocortolone monohydrate ((6 alpha)-fluoro-16alpha-methylpregna-1,4-dien-11 f5,21-diol-3,20-dione), fluocortin butyl (pregna-1,4-dien-21-oic acid, 6-fluoro-11-hydroxy-16-methyl-3,20-dioxo-, butyl ester, (6alpha,11f3,16alpha)-), difluprednate (pregna-1,4-diene-3,20-dione, 21-(acetyloxy)-6,9-difluoro-11-hydroxy-17-(1-oxobutoxy)-, (6 alpha,11 f3)-), diflorasone diacetate (pregna-1,4-diene-3,20-dione, 17,21-bis(acetyloxy)-6,9-difluoro-11-hydroxy-16-methyl-, (6Alpha,11f3,16f3)-), dexamethasone valerate (pregna-1,4-diene-3,20-dione, 9-fluoro-11,21-dihydroxy-16-methyl-17-((1-oxopentyl)oxy)-, (11f3,16Alpha)-), methylprednisolone, deprodone propionate (pregna-1,4-diene-3,20-dione, 11-hydroxy-17-(1-oxopropoxy)-, (11~)-), bucillamine (L-cysteine, N-(2-mercapto-2-methyl-1-oxopropyl)-), amcinonide (benzeneacetic acid, 2-amino-3-benzoyl-, monosodium salt, monohydrate), acemetacin (1 H-indole-3-acetic acid, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-, carboxymethyl ester), or an analogue or derivative thereof).
Further, analogues of rapamycin include tacrolimus and derivatives thereof (e.g., EP0184162B1 and U.S. Patent No. 6,258,823) everolimus and derivatives thereof (e.g., U.S. Patent No. 5,665,772). Further representative examples of sirolimus analogues and derivatives can be found in PCT Publication Nos. WO 97/10502, WO 96/41807, WO 96/35423, WO
96/03430, WO 96/00282, WO 95/16691, WO 95/15328, WO 95/07468, WO
95/04738, WO 95/04060, WO 94/25022, WO 94/21644, WO 94/18207, WO
94/10843, WO 94/09010, WO 94/04540, WO 94/02485, WO 94/02137, WO
94/02136, WO 93/25533, WO 93/18043, WO 93/13663, WO 93/11130, WO
93/10122, WO 93/04680, WO 92/14737, and WO 92/05179. Representative U.S. patents include U.S. Patent Nos. 6,342,507; 5,985,890; 5,604,234;
5, 597, 715; 5, 583,139; 5, 563,172; 5, 561,228; 5, 561,137; 5, 541,193; 5, 541,189;
5,534,632; 5,527,907; 5,484,799; 5,457,194; 5,457,182; 5,362,735; 5,324,644;
5,318,895; 5,310,903; 5,310,901; 5,258,389; 5,252,732; 5,247,076; 5,225,403;
5,221,625; 5,210,030; 5,208,241; 5,200,411; 5,198,421; 5,147,877; 5,140,018;
5,116,756; 5,109,112; 5,093,338; and 5,091,389.
The structures of sirolimus, everolimus, and tacrolimus are provided below:

Name Code Name Company Structure Everolimus SAR-943 Novartis See below Sirolimus AY-22989 Wyeth See below Rapamycin Tacrolimus FK506 Fujusawa See below a,~'~,..-°
~4 Everolimus ..~5 0 Tacrolimus 'i'a a --~., ~. ~- a .I
a a 'a~' 41' ~~.,~..- I ai a~
a Sirolimus Further sirolimus analogues and derivatives include tacrolimus and derivatives thereof (e.g., EP0184162B1 and U.S. Patent No. 6,258,823) everolimus and derivatives thereof (e.g., US Patent No. 5,665,772). Further representative examples of sirolimus analogues and derivatives include ABT-578 and others may be found in PCT Publication Nos. WO 97/10502, WO
96/41807, WO 96135423, WO 96/03430, WO 9600282, WO 95/16691, WO
9515328, WO 95/07468, WO 95/04738, WO 95/04060, WO 94/25022, WO
94/21644, WO 94/18207, WO 94/10843, WO 94/09010, WO 94/04540, WO
94/02485, WO 94/02137, WO 94/02136, WO 93/25533, WO 93/18043, WO
93/13663, WO 93/11130, WO 93/10122, WO 93/04680, WO 92114737, and WO
92/05179. Representative U.S. patents include U.S. Patent Nos. 6,342,507;
5,985,890; 5,604,234; 5,597,715; 5,583,139; 5,563,172; 5,561,228; 5,561,137;
5,541,193; 5,541,189; 5,534,632; 5,527,907; 5,484,799; 5,457,194; 5,457,182;
5,362,735; 5,324,644; 5,318,895; 5,310,903; 5,310,901; 5,258,389; 5,252,732;
5,247,076; 5,225,403; 5,221,625; 5,210,030; 5,208,241, 5,200,411; 5,198,421;
5,147,877; 5,140,018; 5,116,756; 5,109,112; 5,093,338; and 5,091,389.
In one aspect, the fibrosis-inhibiting agent may be, e.g., rapamycin (sirolimus), everolimus, biolimus, tresperimus, auranofin, 27-0-demethylrapamycin, tacrolimus, gusperimus, pimecrolimus, or ABT-578.

19) Inosine monophosphate dehydroe~enase inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is an inosine monophosphate dehydrogenase (IMPDH) inhibitor (e.g., mycophenolic acid, mycophenolate mofetil (4-hexenoic acid, 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-2-(4-morpholinyl)ethyl ester, (E)-), ribavirin (1H-1,2,4-triazole-3-carboxamide, 1-f3-D-ribofuranosyl-), tiazofurin (4-thiazolecarboxamide, 2-f3-D-ribofuranosyl-), viramidine, aminothiadiazole, thiophenfurin, tiazofurin) or an analogue or derivative thereof. Additional representative examples are included in U.S.
Patent Nos. 5,536,747, 5,807,876, 5,932,600, 6,054,472, 6,128,582, 6,344,465, 6,395,763, 6,399,773, 6,420,403, 6,479,628, 6,498,178, 6,514,979, 6,518,291, 6,541,496, 6,596,747, 6,617,323, 6,624,184, Patent Application Publication Nos. 2002/0040022A1, 2002/0052513A1, 2002/0055483A1, 2002/0068346A1, 2002/0111378A1, 2002/0111495A1, 2002/0123520A1, 2002/0143176A1, 2002/0147160A1, 2002/0161038A1, 2002/0173491 A1, 2002/0183315A1, 2002/0193612A1, 2003/0027845A1, 2003/0068302A1, 2003/0105073A1, 2003/0130254A1, 2003/0143197A1, 2003/0144300A1, 2003/0166201 A1, 2003/0181497A1, 2003/0186974A1, 2003/0186989A1, 2003/0195202A1, and PCT Publication Nos. WO 0024725A1, WO 00/25780A1, WO 00/26197A1, WO
00/51615A1, WO 00/56331 A1, WO 00/73288A1, WO 01/00622A1, WO
01/66706A1, WO 01/79246A2, WO 01/81340A2, WO 01/85952A2, WO
02/16382A1, WO 02/18369A2, WO 2051814A1, WO 2057287A2, W02057425A2, WO 2060875A1, WO 2060896A1, WO 2060898A1, WO
2068058A2, WO 3020298A1, WO 3037349A1, WO 3039548A1, WO
3045901 A2, WO 3047512A2, WO 3053958A1, WO 3055447A2, WO
3059269A2, WO 3063573A2, WO 3087071 A1, WO 90/01545A1, WO
97/40028A1, WO 97/41211 A1, WO 98/40381 A1, and WO 99/55663A1 ).

20) Leukotriene Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a leukotreine inhibitor (e.g., ONO-4057(benzenepropanoic acid, 2-(4-carboxybutoxy)-6-((6-(4-methoxyphenyl)-5-hexenyl)oxy)-, (E)-), ONO-LB-448, pirodomast 1,8-naphthyridin-2(1 H)-one, 4-hydroxy-1-phenyl-3-(1-pyrrolidinyl)-, Sch-40120 (benzo(b)(1,8)naphthyridin-5(7H)-one, 10-(3-chlorophenyl)-6,8,9,10-tetrahydro-), L-656224 (4-benzofuranol, 7-chloro-2-((4-methoxyphenyl)methyl)-3-methyl-5-propyl-), MAFP
(methyl arachidonyl fluorophosphonate), ontazolast (2-benzoxazolamine, N-(2-cyclohexyl-1-(2-pyridinyl)ethyl)-5-methyl-, (S)-), amelubant (carbamic acid, ((4-((3-((4-(1-(4-hydroxyphenyl)-1-methylethyl)phenoxy)methyl)phenyl)methoxy)phenyl)iminomethyl)- ethyl ester), SB-201993 (benzoic acid, 3-((((6-((1 E)-2-carboxyethenyl)-5-((8-(4-methoxyphenyl)octyl)oxy)-2-pyridinyl)methyl)thio)methyl)-), LY-203647 (ethanone, 1-(2-hydroxy-3-propyl-4-(4-(2-(4-(1 H-tetrazol-5-yl)butyl)-2H-tetrazol-5-yl)butoxy)phenyl)-), LY-210073, LY-223982 (benzenepropanoic acid, 5-(3-carboxybenzoyl)-2-((6-(4-methoxyphenyl)-5-hexenyl)oxy)-, (E)-), LY-293111 (benzoic acid, 2-(3-(3-((5-ethyl-4'-fluoro-2-hydroxy(1,1'-biphenyl)-4-yl)oxy)propoxy)-2-propylphenoxy)-), SM-9064 (pyrrolidine, 1-(4,11-dihydroxy-13-(4-methoxyphenyl)-1-oxo-5,7,9-tridecatrienyl)-, (E,E,E)-), T-0757 (2,6-octadienamide, N-(4-hydroxy-3,5-dimethylphenyl)-3,7-dimethyl-, (2E)-), or an analogue or derivative thereof).

21 ) MCP-1 Antagonists In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a MCP-1 antagonist (e.g., nitronaproxen (2-napthaleneacetic acid, 6-methoxy-alpha-methyl 4-(nitrooxy)butyl ester (alpha S)-), bindarit (2-(1-benzylindazol-3-ylmethoxy)-2-methylpropanoic acid), 1-alpha-25 dihydroxy vitamin D3, or an analogue or derivative thereof).

22) MMP Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a matrix metalloproteinase (MMP) inhibitor (e.g., D-9120, doxycycline (2-naphthacenecarboxamide, 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo- (4S-(4 alpha, 4a alpha, 5 Ipha, 5a alpha, 6 alpha, 12a alpha))-), BB-2827, BB-1101 (2S-allyl-N1-hydroxy-3R-isobutyl-N4-(1 S-methylcarbamoyl-2-phenylethyl)-succinamide), BB-2983, solimastat (N'-(2,2-dimethyl-1(S)-(N-(2-pyridyl)carbamoyl)propyl)-N4-hydroxy-2(R)-isobutyl-3(S)-methoxysuccinamide), batimastat (butanediamide, N4-hydroxy-N1-(2-(methylamino)-2-oxo-1-(phenylmethyl)ethyl)-2-(2-methylpropyl)-3-((2-thienylthio)methyl)-, (2R-(1(S*),2R*,3S*))-), CH-138, CH-5902, D-1927, D-5410, EF-13 (gamma-linolenic acid lithium salt),CMT-3 (2-naphthacenecarboxamide, 1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-, (4aS,5aR,12aS)-), marimastat (N-(2,2-dimethyl-1 (S)-(N-methylcarbamoyl)propyl)-N,3(S)-dihydroxy-2(R)-isobutylsuccinamide), TIMP'S,ONO-4817, rebimastat (L-Valinamide, N-((2S)-2-mercapto-1-oxo-4-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)butyl)-L-leucyl-N,3-dimethyl-), PS-508, CH-715, nimesulide (methanesulfonamide, N-(4-nitro-2-phenoxyphenyl)-), hexahydro-2-(2(R)-(1(RS)-(hydroxycarbamoyl)-4-phenylbutyl)nonanoyl)-N-(2,2,6,6-etramethyl-4-piperidinyl)-3(S)-pyridazine carboxamide, Rs-113-080, Ro-1130830, cipemastat (1-piperidinebutanamide, f3-(cyclopentylmethyl)-N-hydroxy-gamma-oxo-alpha-((3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)methyl)-,(alpha R,f~R)-), 5-(4'-biphenyl)-5-(N-(4-nitrophenyl)piperazinyl)barbituric acid, 6-methoxy-1,2,3,4-tetrahydro-norharman-1-carboxylic acid, Ro-31-4724 (L-alanine, N-(2-(2-(hydroxyamino)-2-oxoethyl)-4-methyl-1-oxopentyl)-L-leucyl-, ethyl ester), prinomastat (3-thiomorpholinecarboxamide, N-hydroxy-2,2-dimethyl-4-((4-(4-pyridinyloxy) phenyl)sulfonyl)-, (3R)-), AG-3433 (1H-pyrrole-3-propanic acid, 1-(4'-cyano(1,1'-bi phenyl)-4-yl )-b-((((3S )-tetra hyd ro-4,4-d imethyl-2-oxo-3-furanyl)amino)carbonyl)-, phenylmethyl ester, (bS)-), PNU-142769 (2H-Isoindole-2-butanamide, 1,3-dihydro-N-hydroxy-alpha-((3S)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidinyl)-1,3-dioxo-, (alpha R)-), (S)-1-(2-((((4,5-dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)amino)-carbonyl)amino)-1-oxo-3-(pentafluorophenyl)propyl)-4-(2-pyridinyl)piperazine, SU-5402 (1 H-pyrrole-3-propanoic acid, 2-((1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl)-4-methyl-), SC-77964, PNU-171829, CGS-27023A, N-hydroxy-2(R)-((4-methoxybenzene-sulfonyl)(4-picolyl)amino)-2-(2-tetrahydrofuranyl)-acetamide, L-758354 ((1,1'-biphenyl)-4-hexanoic acid, alpha-butyl-gamma-(((2,2-dimethyl-1-((methylamino)carbonyl)propyl)amino)carbonyl)-4'-fluoro-, (alpha S-(alpha R*, gammaS*(R*)))-, GI-155704A, CPA-926, TMI-005, XL-784, or an analogue or derivative thereof). Additional representative examples are included in U.S.
Patent Nos. 5,665,777; 5,985,911; 6,288,261; 5,952,320; 6,441,189; 6,235,786;
6,294,573; 6,294,539; 6,563,002; 6,071,903; 6,358,980; 5,852,213; 6,124,502;
6,160,132; 6,197,791; 6,172,057; 6,288,086; 6,342,508; 6,228,869; 5,977,408;
5,929,097; 6,498,167; 6,534,491; 6,548,524; 5,962,481; 6,197,795; 6,162,814;
6,441,023; 6,444,704; 6,462,073; 6,162,821; 6,444,639; 6,262,080; 6,486,193;
6,329,550; 6,544,980; 6,352,976; 5,968,795; 5,789,434; 5,932,763; 6,500,847;
5,925,637; 6,225,314; 5,804,581; 5,863,915; 5,859,047; 5,861,428; 5,886,043;
6,288,063; 5,939,583; 6,166,082; 5,874,473; 5,886,022; 5,932,577; 5,854,277;
5,886,024; 6,495,565; 6,642,255; 6,495,548; 6,479,502; 5,696,082; 5,700,838;
6,444,639; 6,262,080; 6,486,193; 6,329,550; 6,544,980; 6,352,976; 5,968,795;
5,789,434; 5,932,763; 6,500,847; 5,925,637; 6,225,314; 5,804,581; 5,863,915;
5,859,047; 5,861,428; 5,886,043; 6,288,063; 5,939,583; 6,166,082; 5,874,473;
5,886,022; 5,932,577; 5,854,277; 5,886,024; 6,495,565; 6,642,255; 6,495,548;
6,479,502; 5,696,082; 5,700,838; 5,861,436; 5,691,382; 5,763,621; 5,866,717;
5,902,791; 5,962,529; 6,017,889; 6,022,873; 6,022,898; 6,103,739; 6,127,427;
6,258,851; 6,310,084; 6,358,987; 5,872,152; 5,917,090; 6,124,329; 6,329,373;
6,344,457; 5,698,706; 5,872,146; 5,853,623; 6,624,144; 6,462,042; 5,981,491;
5,955,435; 6,090,840; 6,114,372; 6,566,384; 5,994,293; 6,063,786; 6,469,020;
6,118,001; 6,187,924; 6,310,088; 5,994,312; 6,180,611; 6,110,896; 6,380,253;

5,455,262; 5,470,834; 6,147,114; 6,333,324; 6,489,324; 6,362,183; 6,372,758;
6,448,250; 6,492,367; 6,380,258; 6,583,299; 5,239,078; 5,892,112; 5,773,438;
5,696,147; 6,066,662; 6,600,057; 5,990,158; 5,731,293; 6,277,876; 6,521,606;
6,168,807; 6,506,414; 6,620,813; 5,684,152; 6,451,791; 6,476,027; 6,013,649;
6,503,892; 6,420,427; 6,300,514; 6,403,644; 6,177,466; 6,569,899; 5,594,006;
6,417,229; 5,861,510; 6,156,798; 6,387,931; 6,350,907; 6,090,852; 6,458,822;
6,509,337; 6,147,061; 6,114,568; 6,118,016; 5,804,593; 5,847,153; 5,859,061;
6,194,451; 6,482,827; 6,638,952; 5,677,282; 6,365,630; 6,130,254; 6,455,569;
6,057,369; 6,576,628; 6,110,924; 6,472,396; 6,548,667; 5,618,844; 6,495,578;
6,627,411; 5,514,716; 5,256,657; 5,773,428; 6,037,472; 6,579,890; 5,932,595;
6,013,792; 6,420,415; 5,532,265; 5,691,381; 5,639,746; 5,672,598; 5,830,915;
6,630,516; 5,324,634; 6,277,061; 6,140,099; 6,455,570; 5,595,885; 6,093,398;
6,379,667; 5,641,636; 5,698,404; 6,448,058; 6,008,220; 6,265,432; 6,169,103;
6,133,304; 6,541,521; 6,624,196; 6,307,089; 6,239,288; 5,756,545; 6,020,366;
6,117,869; 6,294,674; 6,037,361; 6,399,612; 6,495,568; 6,624,177; 5,948,780;
6,620,835; 6,284,513; 5,977,141; 6,153,612; 6,297,247; 6,559,142; 6,555,535;
6,350,885; 5,627,206; 5,665,764; 5,958,972; 6,420,408; 6,492,422; 6,340,709;
6,022,948; 6,274,703; 6,294,694; 6,531,499; 6,465,508; 6,437,177; 6,376,665;
5,268,384; 5,183,900; 5,189,178; 6,511,993; 6,617,354; 6,331,563; 5,962,466;
5,861,427; 5,830,869; and 6,087,359.

23) NF kappa B Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a NF kappa B (NFKB) inhibitor (e.g., AVE-0545, Oxi-104 (benzamide, 4-amino-3-chloro-N-(2-(diethylamino)ethyl)-), dexlipotam, R-flurbiprofen ((1,1'-biphenyl)-4-acetic acid, 2-fluoro-alpha-methyl), SP100030 (2-chloro-N-(3,5-di(trifluoromethyl)phenyl)-4-(trifluoromethyl)pyrimidine-5-carboxamide), AVE-0545, Viatris, AVE-0547, Bay 11-7082, Bay 11-7085, 15 deoxy-prostaylandin J2, bortezomib (boronic acid, ((1 R)-3-methyl-1-(((2S)-1-oxo-3-phenyl-2-((pyrazinylcarbonyl)amino)propyl)amino)butyl)-, benzamide an d nicotinamide derivatives that inhibit NF-kappaB, such as those described in U.S. Patent Nos. 5,561,161 and 5,340,565 (OxiGene), PG490-88Na, or an analogue or derivative thereof).

24) NO Aaonists In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a NO antagonist (e.g., NCX-4016 (benzoic acid, 2-(acetyloxy)-, 3-((nitrooxy)methyl)phenyl ester, NCX-2216, L-arginine or an analogue or derivative thereof).

25) P38 MAP Kinase Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a p38 MAP kinase inhibitor (e.g., GW-2286, CGP-52411, BIRB-798, SB220025, RO-320-1195, RWJ-67657, RWJ-68354, SCIO-469, SCIO-323, AMG-548, CMC-146, SD-31145, CC-8866, Ro-320-1195, PD-98059 (4H-1-benzopyran-4-one, 2-(2-amino-3-methoxyphenyl)-), CGH-2466, doramapimod, SB-203580 (pyridine, 4-(5-(4-fluorophenyl)-2-(4-(methylsulfinyl)phenyl)-1 H-imidazol-4-yl)-), SB-220025 ((5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole), SB-281832, PD169316, SB202190, GSK-681323, EO-1606, GSK-681323, or an analogue or derivative thereof). Additional representative examples are included in U.S.
Patent Nos. 6,300,347; 6,316,464; 6,316,466; 6,376,527; 6,444,696; 6,479,507;
6,509,361; 6,579,874; 6,630,485, U.S. Patent Application Publication Nos.
2001 /0044538A1; 2002/0013354A1; 2002/0049220A1; 2002/0103245A1;
2002/0151491 A1; 2002/0156114A1; 2003/0018051 A1; 2003/0073832A1;
2003/0130257A1; 2003/0130273A1; 2003/0130319A1; 2003/0139388A1;
20030139462A1; 2003/0149031 A1; 2003/0166647A1; 2003/0181411 A1; and PCT Publication Nos. WO 00/63204A2; WO 01/21591 A1; WO 01/35959A1;
WO 01/74811A2; WO 02/18379A2; WO 2064594A2; WO 2083622A2; WO
2094842A2; WO 2096426A1; WO 2101015A2; WO 2103000A2; WO

3008413A1; WO 3016248A2; WO 3020715A1; WO 3024899A2; WO
3031431 A1; W03040103A1; WO 3053940A1; WO 3053941 A2; WO
3063799A2; WO 3079986A2; WO 3080024A2; WO 3082287A1; WO
97/44467A1; WO 99/01449A1; and WO 99/58523A1.

26) Phosphodiesterase Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a phosphodiesterase inhibitor (e.g., CDP-840 (pyridine, 4-((2R)-2-(3-(cyclopentyloxy)-4-methoxyphenyl)-2-phenylethyl)-), CH-3697, CT-2820, D-22888 (imidazo(1,5-a)pyrido(3,2-e)pyrazin-6(5H)-one, 9-ethyl-2-methoxy-7-methyl-5-propyl-), D-4418 (8-methoxyquinoline-5-(N-(2,5-dichloropyridin-3-yl))carboxamide), 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-dichloro-4-pyridyl) ethanone oxime, D-4396, ONO-6126, CDC-998, CDC-801, V-11294A (3-(3-(cyclopentyloxy)-4-methoxybenzyl)-6-(ethylamino)-8-isopropyl-3H-purine hydrochloride), S,S'-methylene-bis(2-(8-cyclopropyl-3-propyl-6-(4-pyridylmethylamino)-2-thio-3H-purine)) tetrahyrochloride, rolipram (2-pyrrolidinone, 4-(3-(cyclopentyloxy)-4-methoxyphenyl)-), CP-293121, CP-353164 (5-(3-cyclopentyloxy-4-methoxyphenyl)pyridine-2-carboxamide), oxagrelate (6-phthalazinecarboxylic acid, 3,4-dihydro-1-(hydroxymethyl)-5,7-dimethyl-4-oxo-, ethyl ester), PD-168787, ibudilast (1-propanone, 2-methyl-1-(2-(1-methylethyl)pyrazolo(1,5-a)pyridin-3-yl)-), oxagrelate (6-phthalazinecarboxylic acid, 3,4-dihydro-1-(hydroxymethyl)-5,7-dimethyl-4-oxo-, ethyl ester), griseolic acid (alpha-L-talo-oct-4-enofuranuronic acid, 1-(6-amino-9H-purin-9-yl)-3,6-anhydro-6-C-carboxy-1,5-dideoxy-), KW-4490, KS-506, T-440, roflumilast (benzamide, 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-), rolipram, milrinone, triflusinal (benzoic acid, 2-(acetyloxy)-4-(trifluoromethyl)-), anagrelide hydrochloride (imidazo(2,1-b)quinazolin-2(3H)-one, 6,7-dichloro-1,5-dihydro-, monohydrochloride), cilostazol (2(1 H)-quinolinone, 6-(4-(1-cyclohexyl-1 H-tetrazol-5-yl)butoxy)-3,4-dihydro-), propentofylline (1 H-purine-2,6-dione, 3,7-dihydro-3-methyl-1-(5-oxohexyl)-7-propyl-), sildenafil citrate (piperazine, 1-((3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1 H-pyrazolo(4,3-d)pyrimidin-5-yl)-4-ethoxyphenyl)sulfonyl)-4-methyl, 2-hydroxy-1,2,3-propanetricarboxylate- (1:1 )), tadalafil (pyrazino(1',2':1,6)pyrido(3,4-b)indole1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R-trans)), vardenafil (piperazine, 1-(3-(1,4-dihydro-5-methyl(-4-oxo-7-propylimidazo(5,1-f)(1,2,4)-triazin-2-yl)-4-ethoxyphenyl)sulfonyl)-4-ethyl-), milrinone ((3,4'-bipyridine)-5-carbonitrile, 1,6-dihydro-2-methyl-6-oxo-), enoximone (2H-imidazol-2-one, 1,3-dihydro-4-methyl-5-(4-(methylthio)benzoyl)-), theophylline (1 H-purine-2,6-dione, 3,7-dihydro-1,3-dimethyl-), ibudilast (1-propanone, 2-methyl-1-(2-(1-methylethyl)pyrazolo(1,5-a)pyridin-3-yl)-), aminophylline (1H-purine-2,6-dione, 3,7-dihydro-1,3-dimethyl-, compound with 1,2-ethanediamine (2:1 )-), acebrophylline (7H-purine-7-acetic acid, 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-,compd. with trans-4-(((2-amino-3,5-dibromophenyl)methyl)amino)cyclohexanol (1:1 )), plafibride (propanamide, 2-(4-chlorophenoxy)-2-methyl-N-(((4-morpholinylmethyl)amino)carbonyl)-), ioprinone hydrochloride (3-pyridinecarbonitrile, 1,2-dihydro-5-imidazo(1,2-a)pyridin-6-yl-6-methyl-2-oxo-, monohydrochloride-), fosfosal (benzoic acid, 2-(phosphonooxy)-), amrinone ((3,4'-bipyridin)-6(1 H)-one, 5-amino-, or an analogue or derivative thereof).
Other examples of phosphodiesterase inhibitors include denbufylline (1H-purine-2,6-dione, 1,3-dibutyl-3,7-dihydro-7-(2-oxopropyl)-), propentofylline (1 H-purine-2,6-dione, 3,7-dihydro-3-methyl-1-(5-oxohexyl)-7-propyl-) and pelrinone (5-pyrimidinecarbonitrile, 1,4-dihydro-2-methyl-4-oxo-6-((3-pyridinylmethyl)amino)-).
Other examples of phosphodiesterase III inhibitors include enoximone (2H-imidazol-2-one, 1,3-dihydro-4-methyl-5-(4-(methylthio)benzoyl)-), and saterinone (3-pyridinecarbonitrile, 1,2-dihydro-5-(4-(2-hydroxy-3-(4-(2-methoxyphenyl)-1-piperazinyl)propoxy)phenyl)-6-methyl-2-oxo-).
Other examples of phosphodiesterase IV inhibitors include AWD-12-281, 3-auinolinecarboxylic acid, 1-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-), tadalafil (pyrazino(1',2':1,6)pyrido(3,4-b)indole1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R-trans)), and filaminast (ethanone, 1-(3-(cyclopentyloxy)-4-methoxyphenyl)-, O-(aminocarbonyl)oxime, (1 E)-) Another example of a phosphodiesterase V inhibitor is vardenafil (piperazine, 1-(3-(1,4-dihydro-5-methyl(-4-oxo-7-propylimidazo(5,1-f)(1,2,4)-triazin-2-yl)-4-ethoxyphenyl)sulfonyl)-4-ethyl-).

27) TGF beta Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a TGF beta Inhibitor (e.g., mannose-6-phosphate, LF-984, tamoxifen (ethanamine, 2-(4-(1,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl-, (Z)-), tranilast, or an analogue or derivative thereof).

28) Thromboxane A2 Antagonists In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a thromboxane A2 antagonist (e.g., CGS-22652 (3-pyridineheptanoic acid, y-(4-(((4-chlorophenyl)sulfonyl)amino)butyl)-, (±)-), ozagrel (2-propenoic acid, 3-(4-(1 H-imidazol-1-ylmethyl)phenyl)-, (E)-), argatroban (2-piperidinecarboxylic acid, 1-(5-((aminoiminomethyl)amino)-1-oxo-2-(((1,2,3,4-tetrahydro-3-methyl-8-quinolinyl)sulfonyl)amino)pentyl)-4-methyl-), ramatroban (9H-carbazole-9-propanoic acid, 3-(((4-fluorophenyl)sulfonyl)amino)-1,2,3,4-tetrahydro-, (R)-), torasemide (3-pyridinesulfonamide, N-(((1-methylethyl)amino)carbonyl)-4-((3-methylphenyl)amino)-), gamma linoleic acid ((Z,Z,Z)-6,9,12-octadecatrienoic acid), seratrodast (benzeneheptanoic acid, zeta-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)-, (+/-)-, or an analogue or derivative thereof).

29) TNF alpha Antagonists and TACE Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a TNF alpha antagonist or TACE inhibitor (e.g., E-5531 (2-deoxy-6-0-(2-deoxy-3-0-(3(R)-(5(Z)-dodecenoyloxy)-decyl)-6-0-methyl-2-(3-oxotetradecanamido)-4-O-phosphono-f3-D-glucopyranosyl)-3-0-(3(R)-hydroxydecyl)-2-(3-oxotetradecanamido)-alpha-D-glucopyranose-1-O-phosphate), AZD-4717, glycophosphopeptical, UR-12715 (B=benzoic acid, 2-hydroxy-5-((4-(3-(4-(2-methyl-1 H-imidazol(4,5-c)pyridin-1-yl)methyl)-1-piperidinyl)-3-oxo-1-phenyl-1-propenyl)phenyl)azo) (Z)), PMS-601, AM-87, xyloadenosine (9H-purin-6-amine, 9-f3-D-xylofuranosyl-), RDP-58, RDP-59, BB2275, benzydamine, E-3330 (undecanoic acid, 2-((4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)methylene)-, (E)-), N-(D,L-2-(hydroxyaminocarbonyl)methyl-4-methylpentanoyl)-L-3-(2'-naphthyl)alanyl-L-alanine, 2-aminoethyl amide, CP-564959, MLN-608, SPC-839, ENMD-0997, Sch-23863 ((2-(10,11-dihydro-5-ethoxy-5H-dibenzo (a,d) cyclohepten-S-yl)-N, N-dimethyl-ethanamine), SH-636, PKF-241-466, PKF-242-484, TNF-484A, cilomilast (cis-4-cyano-4-(3-(cyclopentyloxy)-4-methoxyphenyl)cyclohexane-1-carboxylic acid), GW-3333, GW-4459, BMS-561392, AM-87, cloricromene (acetic acid, ((8-chloro-3-(2-(diethylamino)ethyl)-4-methyl-2-oxo-2H-1-benzopyran-7-yl)oxy)-, ethyl ester), thalidomide (1H-Isoindole-1,3(2H)-dione, (2,6-dioxo-3-piperidinyl)-), vesnarinone (piperazine, 1-(3,4-dimethoxybenzoyl)-4-(1,2,3,4-tetrahydro-2-oxo-6-puinolinyl)-), infliximab, lentinan, etanercept (1-235-tumor necrosis factor receptor (human) fusion protein with 236-467-immunoglobulin G1 (human gamma1-chain Fc fragment)), diacerein (2-anthracenecarboxylic acid, 4,5-bis(acetyloxy)-9,10-dihydro-9,10-dioxo-, or an analogue or derivative thereof).

30) Tyrosine Kinase Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a tyrosine kinase inhibitor (e.g., SKI-606, ER-068224, SD-208, N-(6-benzothiazolyl)-4-(2-(1-piperazinyl)pyrid-5-yl)-2-pyrimidineamine, celastrol (24,25,26-trinoroleana-1(10),3,5,7-tetraen-29-oic acid, 3-hydroxy-9,13-dimethyl-2-oxo-, (9 beta.,13alpha,14f3,20 alpha)-), CP-127374 (geldanamycin, 17-demethoxy-17-(2-propenylamino)-), CP-564959, PD-171026, CGP-52411 (1 H-Isoindole-1,3(2H)-dione, 4,5-bis(phenylamino)-), CGP-53716 (benzamide, N-(4-methyl-3-((4-(3-pyridinyl)-2-pyrimidinyl)amino)phenyl)-), imatinib (4-((methyl-1-piperazinyl)methyl)-N-(4-methyl-3-((4-(3-pyridinyl)-2-pyrimidinyl)amino)-phenyl)benzamide methanesulfonate), NVP-AAK980-NX, KF-250706 (13-chloro,5(R),6(S)-epoxy-14,16-dihydroxy-11-(hydroyimino)-3(R)-methyl-3,4,5,6,11,12-hexahydro-1H-2-benzoxacyclotetradecin-1-one), 5-(3-(3-methoxy-4-(2-((E)-2-phenylethenyl)-4-oxazolylmethoxy)phenyl)propyl)-3-(2-((E)-2-phenylethenyl)-4-oxazolylmethyl)-2,4-oxazolidinedione, genistein, Nv-06, or an analogue or derivative thereof).

31 ) Vitronectin Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a vitronectin inhibitor (e.g., O-(9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4-((1,4,5,6-tetrahydro-2-pyrimidinyl)hydrazono)-8-benz(e)azulenyl)-N-((phenylmethoxy)carbonyl)-DL-homoserine 2,3-dihydroxypropyl ester, (2S)-benzoylcarbonylamino-3-(2-((4S)-(3-(4,5-dihydro-1 H-imidazol-2-ylamino)-propyl)-2,5-dioxo-imidazolidin-1-yl)-acetylamino)-propionate, Sch-221153, S-836, SC-68448 ((3-((2-2-(((3-((aminoiminomethyl)amino)-phenyl)carbonyl)amino)acetyl)amino)-3,5-dichlorobenzenepropanoic acid), SD-7784, S-247, or an analogue or derivative thereof).
' 32) Fibroblast Growth Factor Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a fibroblast growth factor inhibitor (e.g., CT-052923 (((2H-benzo(d)1,3-dioxalan-5-methyl)amino)(4-(6,7-dimethoxyquinazolin-4-yl)piperazinyl)methane-1-thione), or an analogue or derivative thereof).
33) Protein Kinase Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a protein kinase inhibitor (e.g., KP-0201448, NPC15437 (hexanamide, 2,6-diamino-N-((1-(1-oxotridecyl)-2-piperidinyl)methyl)-), fasudil (1 H-1,4-diazepine, hexahydro-1-(5-isoquinolinylsulfonyl)-), midostaurin (benzamide, N-(2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1 H,9H-diindolo(1,2,3-gh:3',2',1'-Im)pyrrolo(3,4-j)(1,7)benzodiazonin-11-yl)-N-methyl-, (9Alpha,10f3,11 f3,13Alpha)-),fasudil (1 H-1,4-diazepine, hexahydro-1-(5-isoquinolinylsulfonyl)-, dexniguldipine (3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-, 3-(4,4-diphenyl-1-piperidinyl)propyl methyl ester, monohydrochloride, (R)-), LY-317615 (1 H-pyrole-2,5=dione, 3-(1-methyl-1 H-indol-3-yl)-4-(1-(1-(2-pyridinylmethyl)-4-piperidinyl)-1 H-indol-3-yl)-, monohydrochloride), perifosine (piperidinium, 4-((hydroxyloctadecyloxy)phosphinyl)oxy)-1,1-dimethyl-, inner salt), LY-333531 (9H,18H-5,21:12,17-dimethenodibenzo(e,k)pyrrolo(3,4-h)(1,4,13)oxadiazacyclohexadecine-18,20(19H)-dione,9-((dimethylamino)methyl)-6,7,10,11-tetrahydro-, (S)-), Kynac; SPC-100270 (1,3-octadecanediol, 2-amino-, (S-(R*,R*))-), Kynacyte, or an analogue or derivative thereof).
34) PDGF Receptor Kinase Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a PDGF receptor kinase inhibitor (e.g., RPR-127963E, or an analogue or derivative thereof).

35) Endothelial Growth Factor Receptor Kinase Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is an endothelial growth factor receptor kinase inhibitor (e.g., CEP-7055, SU-0879 ((E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(aminothiocarbonyl)acrylonitrile), BIBF-1000, AG-013736 (CP-868596), AMG-706, AVE-0005, NM-3 (3-(2-methylcarboxymethyl)-6-methoxy-8-hydroxy-isocoumarin), Bay-43-9006, SU-011248, or an analogue or derivative thereof).
36) Retinoic Acid Receptor Antagonists In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a retinoic acid receptor antagonist (e.g., etarotene (Ro-15-1570) (naphthalene, 6-(2-(4-(ethylsulfonyl)phenyl)-1-methylethenyl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-, (E)-), (2E,4E)-3-methyl-5-(2-((E)-2-(2,6,6-trimethyl-1-cyclohexen-1-yl)ethenyl)-1-cyclohexen-1-yl)-2,4-pentadienoic acid, tocoretinate (retinoic acid, 3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl ester, (2R*(4R*,8R*))-(~)-), aliretinoin (retinoic acid, cis-9, trans-13-), bexarotene (benzoic acid, 4-(1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl)-), tocoretinate (retinoic acid, 3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-benzopyran-6-yl ester, (2R*(4R*,8R*))-(~)-, or an analogue or derivative thereof).
37) Platelet Derived Growth Factor Receptor Kinase Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a platelet derived growth factor receptor kinase inhibitor (e.g., leflunomide (4-isoxazolecarboxamide, 5-methyl-N-(4-(trifluoromethyl)phenyl)-, or an analogue or derivative thereof).

38) Fibrinogen Antagonists In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a fibrinogin antagonist (e.g., picotamide (1,3-benzenedicarboxamide, 4-methoxy-N,N'-bis(3-pyridinylmethyl)-, or an analogue or derivative thereof).
39) Antimycotic Agents In another embodiment, the pharmacologically active fibrosis-inhibiting compound is an antimycotic agent (e.g., miconazole, sulconizole, parthenolide, rosconitine, nystatin, isoconazole, fluconazole, ketoconasole, imidazole, itraconazole, terpinafine, elonazole, bifonazole, clotrimazole, conazole, terconazole (piperazine, 1-(4-((2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl)methoxy)phenyl)-4-(1-methylethyl)-, cis-), isoconazole (1-(2-(2-6-dichlorobenzyloxy)-2-(2-,4-dichlorophenyl)ethyl)), griseofulvin (spiro(benzofuran-2(3H),1'-(2)cyclohexane)-3,4'-dione, 7-chloro-2',4,6-trimeth-oxy-6'methyl-, (1'S-trans)-), bifonazole (1H-imidazole, 1-((1,1'-biphenyl)-4-ylphenylmethyl)-), econazole nitrate (1-(2-((4-chlorophenyl)methoxy)-2-(2,4-dichlorophenyl)ethyl)-1 H-imidazole nitrate), croconazole (1 H-imidazole, 1-(1-(2-((3-chlorophenyl)methoxy)phenyl)ethenyl)-), sertaconazole (1H-Imidazole, 1-(2-((7-chlorobenzo(b)thien-3-yl)methoxy)-2-(2,4-dichlorophenyl)ethyl)-), omoconazole (1 H-imidazole, 1-(2-(2-(4-chlorophenoxy)ethoxy)-2-(2,4-dichlorophenyl)-1-methylethenyl)-, (Z)-), flutrimazole (1 H-imidazole, 1-((2-fluorophenyl)(4-fluorophenyl)phenylmethyl)-), fluconazole (1 H-1,2,4-triazole-1-ethanol, alpha-(2,4-difluorophenyl)-alpha-(1 H-1,2,4-triazol-1-ylmethyl)-), neticonazole (1H-Imidazole, 1-(2-(methylthio)-1-(2-(pentyloxy)phenyl)ethenyl)-, monohydrochloride, (E)-), butoconazole (1 H-imidazole, 1-(4-(4-chlorophenyl)-2-((2,6-dichlorophenyl)thio)butyl)-, (+/-)-), clotrimazole (1-((2-chlorophenyl)diphenylmethyl)-1 H-imidazole, or an analogue or derivative thereof).

40) Bisphosphonates In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a bisphosphonate (e.g., clodronate, alendronate, pamidronate, zoledronate, or an analogue or derivative thereof).
41 ) Phospholipase A1 Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a phospholipase A1 inhibitor (e.g., ioteprednol etabonate (androsta-1,4-diene-17-carboxylic acid, 17-((ethoxycarbonyl)oxy)-11-hydroxy-3-oxo-, chloromethyl ester, (11 f3,17 alpha)-, or an analogue or derivative thereof).
42) Histamine HllH2/H3 Receptor Antagonists In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a histamine H1, H2, or H3 receptor antagonist (e.g., ranitidine (1,1-ethenediamine, N-(2-(((5-((dimethylamino)methyl)-2-furanyl)methyl)thio)ethyl)-N'-methyl-2-nitro-), niperotidine (N-(2-((5-((dimethylamino)methyl)furfuryl)thio)ethyl)-2-nitro-N'-piperonyl-1,1-ethenediamine), famotidine (propanimidamide, 3-(((2-((aminoiminomethyl)amino)-4-thiazolyl)methyl)thio)-N-(aminosulfonyl)-), roxitadine acetate HCI (acetamide, 2-(acetyloxy)-N-(3-(3-(1-piperidinylmethyl)phenoxy)propyl)-, monohydrochloride), lafutidine (acetamide, 2-((2-furanylmethyl)sulfinyl)-N-(4-((4-(1-piperidinylmethyl)-2-pyridinyl)oxy)-butenyl)-, (Z)-), nizatadine (1,1-ethenediamine, N-(2-(((2-((dimethylamino)methyl)-4-thiazolyl)methyl)thio)ethyl)-N'-methyl-2-nitro-), ebrotidine (benzenesulfonamide, N-(((2-(((2-((aminoiminomethyl)amino)-4-thiazoly)methyl)thio)ethyl)amino)methylene)-4-bromo-), rupatadine (5H-benzo(5,6)cyclohepta(1,2-b)pyridine, 8-chloro-6,11-dihydro-11-(1-((5-methyl-3-pyridinyl)methyl)-4-piperidinylidene)-, trihydrochloride-), fexofenadine HCI
(benzeneacetic acid, 4-(1-hydroxy-4-(4(hydroxydiphenylmethyl)-1-piperidinyl)butyl)-alpha, alpha-dimethyl-, hydrochloride, or an analogue or derivative thereof).
43) Macrolide Antibiotics In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a macrolide antibiotic (e.g., dirithromycin (erythromycin, 9-deoxo-11-deoxy-9,11-(imino(2-(2-methoxyethoxy)ethylidene)oxy)-, (9S(R))-), flurithromycin ethylsuccinate (erythromycin, 8-fluoro-mono(ethyl butanedioate) (ester)-), erythromycin stinoprate (erythromycin, 2'-propanoate, compound with N-acetyl-L-cysteine (1:1 )), clarithromycin (erythromycin, 6-O-methyl-), azithromycin (9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin-A), telithromycin (3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribo-hexopyranosyl)oxy)-11,12-dideoxy-6-O-methyl-3-oxo-12,11-(oxycarbonyl((4-(4-(3-pyridinyl)-1 H-imidazol-1-yl)butyl)imino))-), roxithromycin (erythromycin, 9-(O-((2-methoxyethoxy)methyl)oxime)), rokitamycin (leucomycin V, 4B-butanoate 3B-propanoate), RV-11 (erythromycin monopropionate mercaptosuccinate), midecamycin acetate (leucomycin V, 3B,9-diacetate 3,4B-dipropanoate), midecamycin (leucomycin V, 3,4B-dipropanoate), josamycin (leucomycin V, 3-acetate 4B-(3-methylbutanoate), or an analogue or derivative thereof).
44) GPllb Illa Receptor Antagonists In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a GPllb Illa receptor antagonist (e.g., tirofiban hydrochloride (L-tyrosine, N-(butylsulfonyl)-O-(4-(4-piperidinyl)butyl)-, monohydrochloride-), eptifibatide (L-cysteinamide, N6-(aminoiminomethyl)-N2-(3-mercapto-1-oxopropyl)-L-lysylglycyl-L-alpha-aspartyl-L-tryptophyl-L-prolyl-, cyclic(1->6)-disulfide), xemilofiban hydrochloride, or an analogue or derivative thereof).

45) Endothelin Receptor Antagonists In another embodiment, the pharmacologically active fibrosis-inhibiting compound is an endothelin receptor antagonist (e.g., bosentan (benzenesulfonamide, 4-(1,1-dimethylethyl)-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)(2,2'-bipyrimidin)-4-yl)-, or an analogue or derivative thereof).
46) Peroxisome Proliferator-Activated Receptor Agonists In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a peroxisome proliferator-activated receptor agonist (e.g., gemfibrozil (pentanoic acid, 5-(2,5-dimethylphenoxy)-2,2-dimethyl-), fenofibrate (propanoic acid, 2-(4-(4-chlorobenzoyl)phenoxy)-2-methyl-, 1-methylethyl ester), ciprofibrate (propanoic acid, 2-(4-(2,2-dichlorocyclopropyl)phenoxy)-2-methyl-), rosiglitazone maleate (2,4-thiazolidinedione, 5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl)methyl)-, (Z)-2-butenedioate (1:1 )), pioglitazone hydrochloride (2,4-thiazolidinedione, 5-((4-(2-(5-ethyl-2-pyridinyl)ethoxy)phenyl)methyl)-, monohydrochloride (+/-)-), etofylline clofibrate (propanoic acid, 2-(4-chlorophenoxy)-2-methyl-, 2-(1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purin-7-yl)ethyl ester), etofibrate (3-pyridinecarboxylic acid, 2-(2-(4-chlorophenoxy)-2-methyl-1-oxopropoxy)ethyl ester), clinofibrate (butanoic acid, 2,2'-(cyclohexylidenebis(4,1-phenyleneoxy))bis(2-methyl-)), bezafibrate (propanoic acid, 2-(4-(2-((4-chlorobenzoyl)amino)ethyl)phenoxy)-2-methyl-), binifibrate (3-pyridinecarboxylic acid, 2-(2-(4-chlorophenoxy)-2-methyl-1-oxopropoxy)-1,3-propanediyl ester), or an analogue or derivative thereof).
In one aspect, the pharmacologically active compound is a peroxisome proliferator-activated receptor alpha agonist, such as GW-590735, GSK-677954, GSK501516, pioglitazone hydrochloride (2,4-thiazolidinedione, 5-((4-(2-(5-ethyl-2-pyridinyl)ethoxy)phenyl)methyl)-, monohydrochloride (+/-)-, or an analogue or derivative thereof).

47) Estrogen Receptor Agents In another embodiment, the pharmacologically active fibrosis-inhibiting compound is an estrogen receptor agent (e.g., estradiol, 17-~3-estradiol, or an analogue or derivative thereof).
48) Somatostatin Analogues In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a somatostatin analogue (e.g., angiopeptin, or an analogue or derivative thereof).
49) Neurokinin 1 Antagonists In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a neurokinin 1 antagonist (e.g., GW-597599, lanepitant ((1,4'-bipiperidine)-1'-acetamide, N-(2-(acetyl((2-methoxyphenyl)methyl)amino)-1-(1 H-indol-3-ylmethyl)ethyl)- (R)-), nolpitantium chloride (1-azoniabicyclo(2.2.2)octane, 1-(2-(3-(3,4-dichlorophenyl)-1-((3-(1-methylethoxy)phenyl)acetyl)-3-piperidinyl)ethyl)-4-phenyl-, chloride, (S)-), or saredutant (benzamide, N-(4-(4-(acetylamino)-4-phenyl-1-piperidinyl)-2-(3,4-dichlorophenyl)butyl)-N-methyl-, (S)-), or vofopitant (3-piperidinamine, N-((2-methoxy-5-(5-(trifluoromethyl)-1 H-tetrazol-1-yl)phenyl)methyl)-2-phenyl-, (2S,3S)-, or an analogue or derivative thereof).
50) Neurokinin 3 Antagonist In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a neurokinin 3 antagonist (e.g., talnetant (4-quinolinecarboxamide, 3-hydroxy-2-phenyl-N-((1S)-1-phenylpropyl)-, or an analogue or derivative thereof).

51 ) Neurokinin Antagonist In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a neurokinin antagonist (e.g., GSK-679769, GSK-823296, SR-489686 (benzamide, N-(4-(4-(acetylamino)-4-phenyl-1-piperidinyl)-2-(3,4-dichlorophenyl)butyl)-N-methyl-, (S)-), SB-223412; SB-235375 (4-quinolinecarboxamide, 3-hydroxy-2-phenyl-N-((1S)-1-phenylpropyl)-), UK-226471, or an analogue or derivative thereof).
52) VLA-4 Antagonist In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a VLA-4 antagonist (e.g., GSK683699, or an analogue or derivative thereof).
53) Osteoclast Inhibitor In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a osteoclast inhibitor (e.g., ibandronic acid (phosphonic acid, (1-hydroxy-3-(methylpentylamino)propylidene) bis-), alendronate sodium, or an analogue or derivative thereof).
54) DNA topoisomerase ATP Hydrolyzing Inhibitor In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a DNA topoisomerase ATP hydrolyzing inhibitor (e.g., enoxacin (1,8-naphthyridine-3-carboxylic acid, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-), levofloxacin (7H-Pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid, 9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-, (S)-), ofloxacin (7H-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid, fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-, (+/-)-), pefloxacin (3-quinolinecarboxylic acid, 1-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-), pipemidic acid (pyrido(2,3-d)pyrimidine-6-carboxylic acid, 8-ethyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)-), pirarubicin (5,12-naphthacenedione, 10-((3-amino-2,3,6-trideoxy-4-O-(tetrahydro-2H-pyran-2-yl)-alpha-L-lyxo-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, (8S-(8 alpha,10 alpha(S*)))-), sparfloxacin (3-quinolinecarboxylic acid, 5-amino-1-cyclopropyl-7-(3,5-dimethyl-1-piperazinyl)-6,8-difluoro-1,4-dihydro-4-oxo-, cis-), AVE-6971, cinoxacin ((1,3)dioxolo(4,5-g)cinnoline-3-carboxylic acid, 1-ethyl-1,4-dihydro-4-oxo-), or an analogue or derivative thereof).
55) Angiotensin I Converting Enzyme Inhibitor In another embodiment, the pharmacologically active fibrosis-inhibiting compound is an angiotensin I converting enzyme inhibitor (e.g., ramipril (cyclopenta(b)pyrrole-2-carboxylic acid, 1-(2-((1-(ethoxycarbonyl)-3-phenylpropyl)amino)-1-oxopropyl)octahydro-, (2S-(1(R*(R*)),2 alpha, 3af3, 6a(3))-), trandolapril (1 H-indole-2-carboxylic acid, 1-(2-((1-carboxy-3-phenylpropyl)amino)-1-oxopropyl)octahydro-, (2S-(1(R*(R*)),2 alpha,3a alpha,7af3))-), fasidotril (L-alanine, N-((2S)-3-(acetylthio)-2-(1,3-benzodioxol-5-ylmethyl)-1-oxopropyl)-, phenylmethyl ester), cilazapril (6H-pyridazino(1,2-a)(1,2)diazepine-1-carboxylic acid, 9-((1-(ethoxycarbonyl)-3-phenylpropyl)amino)octahydro-10-oxo-, (1S-(1 alpha, 9 alpha(R*)))-), ramipril (cyclopenta(b)pyrrole-2-carboxylic acid, 1-(2-((1-(ethoxycarbonyl)-3-phenylpropyl)amino)-1-oxopropyl)octahydro-, (2S-(1(R*(R*)), 2 alpha,3af3,6af3))-, or an analogue or derivative thereof).
56) Angiotensin II Antagonist In another embodiment, the pharmacologically active fibrosis-inhibiting compound is an angiotensin II antagonist (e.g., HR-720 (1 H-imidazole-5-carboxylic acid, 2-butyl-4-(methylthio)-1-((2'-((((propylamino)carbonyl)amino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl)-, dipotassium salt, or an analogue or derivative thereof).

57) Enkephalinase Inhibitor In another embodiment, the pharmacologically active fibrosis-inhibiting compound is an enkephalinase inhibitor (e.g., Aventis 100240 (pyrido(2,1-a)(2)benzazepine-4-carboxylic acid, 7-((2-(acetylthio)-1-oxo-3-phenylpropyl)amino)-1,2,3,4,6,7,8,12b-octahydro-6-oxo-, (4S-(4 alpha, 7 alpha(R*),12bf3))-), AVE-7688, or an analogue or derivative thereof).
58) Peroxisome Proliferator-Activated Receptor Gamma Agonist Insulin Sensitizer In another embodiment, the pharmacologically active fibrosis-inhibiting compound is peroxisome proliferator-activated receptor gamma agonist insulin sensitizer (e.g., rosiglitazone maleate (2,4-thiazolidinedione, 5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl)methyl)-, (Z)-2-butenedioate (1:1 ), farglitazar (GI-262570, GW-2570, GW-3995, GW-5393, GW-9765), LY-929, LY-519818, LY-674, or LSN-862), or an analogue or derivative thereof).
59) Protein Kinase C Inhibitor In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a protein kinase C inhibitor, such as ruboxistaurin mesylate (9H,18H-5,21:12,17-dimethenodibenzo(e,k)pyrrolo(3,4-h)(1,4,13)oxadiazacyclohexadecine-18,20(19H)-dione,9-((dimethylamino)methyl)-6,7,10,11-tetrahydro-, (S)-), safingol (1,3-octadecanediol, 2-amino-, (S-(R*,R*))-), or enzastaurin hydrochloride (1 H-pyrole-2,5-dione, 3-(1-methyl-1 H-indol-3-yl)-4-(1-(1-(2-pyridinylmethyl)-4-piperidinyl)-1 H-indol-3-yl)-, monohydrochloride), or an analogue or derivative thereof.
60) ROCK (rho-associated kinase) Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a ROCK (rho-associated kinase) inhibitor, such as Y-27632, HA-1077, H-1152 and 4-1-(aminoalkyl)-N-(4-pyridyl) cyclohexanecarboxamide or an analogue or derivative thereof.
61 ) CXCR3 Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a CXCR3 inhibitor such as T-487, T0906487 or analogue or derivative thereof.
62) Itk Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is an Itk inhibitor such as BMS-509744 or an analogue or derivative thereof.
63) Cytosolic phospholipase A2-alpha Inhibitors In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a cytosolic phospholipase A2-alpha inhibitor such as efipladib (PLA-902) or analogue or derivative thereof.
64) PPAR Aaonist In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a PPAR Agonist (e.g., Metabolex ((-)-benzeneacetic acid, 4-chloro-alpha-(3-(trifluoromethyl)-phenoxy)-, 2-(acetylamino)ethyl ester), balaglitazone (5-(4-(3-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl-methoxy)-benzyl)-thiazolidine-2,4-dione), ciglitazone (2,4-thiazolidinedione, 5-((4-((1-methylcyclohexyl)methoxy)phenyl)methyl)-), DRF-10945, farglitazar, GSK-677954, GW-409544, GW-501516, GW-590735, GW-590735, K-111, KRP-101, LSN-862, LY-519818, LY-674, LY-929, muraglitazar; BMS-298585 (Glycine, N-((4-methoxyphenoxy)carbonyl)-N-((4-(2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy)phenyl)methyl)-), netoglitazone; isaglitazone (2,4-thiazolidinedione, 5-((6-((2-fluorophenyl)methoxy)-2-naphthalenyl)methyl)-), Actos AD-4833; U-72107A (2,4-thiazolidinedione, 5-((4-(2-(5-ethyl-2-pyridinyl)ethoxy)phenyl)methyl)-, monohydrochloride (+/-)-), JTT-501; PNU-182716 (3,5-Isoxazolidinedione, 4-((4-(2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy)phenyl)methyl)-), AVANDIA (from SB Pharmco Puerto Rico, Inc. (Puerto Rico); BRL-48482;BRL-49653;BRL-49653c; NYRACTA and Venvia (both from (SmithKline Beecham (United Kingdom)); tesaglitazar ((2S)-2-ethoxy-3-(4-(2-(4-((methylsulfonyl)oxy)phenyl)ethoxy)phenyl) propanoic acid), troglitazone (2,4-Thiazolidinedione, 5-((4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)phenyl)methyl)-), and analogues and derivatives thereof).
65) Immunosuppressants In another embodiment, the pharmacologically active fibrosis-inhibiting compound is an immunosuppressant (e.g., batebulast (cyclohexanecarboxylic acid, 4-(((aminoiminomethyl)amino)methyl)-, 4-(1,1-dimethylethyl)phenyl ester, trans-), cyclomunine, exalamide (benzamide, 2-(hexyloxy)-), LYN-001, CCI-779 (rapamycin 42-(3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate)), 1726; 1726-D; AVE-1726, or an analogue or derivative thereof).
66) Erb Inhibitor In another embodiment, the pharmacologically active fibrosis-inhibiting compound is an Erb inhibitor (e.g., canertinib dihydrochloride (N-(4-(3-(chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl)-acrylamide dihydrochloride), CP-724714, or an analogue or derivative thereof).
67) Apoptosis Aaonist In another embodiment, the pharmacologically active fibrosis-inhibiting compound is an apoptosis agonist (e.g., CEFLATONIN (CGX-635) (from Chemgenex Therapeutics, Inc., Menlo Park, CA), CHML, LBH-589, metoclopramide (benzamide, 4-amino-5-chloro-N-(2-(diethylamino)ethyl)-2-methoxy-), patupilone (4,17-dioxabicyclo(14.1.0)heptadecane-5,9-dione, 7,11-dihyd roxy-8,8,10,12,16-pentamethyl-3-( 1-methyl-2-(2-methyl-4-thiazolyl)ethenyl, (1R,3S,7S,10R,11S,12S,16R)), AN-9; pivanex (butanoic acid, (2,2-dimethyl-1-oxopropoxy)methyl ester), SL-100; SL-102; SL-11093; SL-11098; SL-11099; SL-93; SL-98; SL-99, or an analogue or derivative thereof).
68) Lipocortin Agonist In another embodiment, the pharmacologically active fibrosis-inhibiting compound is an lipocortin agonist (e.g., CGP-13774 (9Alpha-chloro-6Alpha-fluoro-11 (3,17alpha-dihydroxy-16AIpha-methyl-3-oxo-1,4-androstadiene-17f3-carboxylic acid-methylester-17-propionate), or analogue or derivative thereof).
69) VCAM-1 antagonist In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a VCAM-1 antagonist (e.g., DW-908e, or an analogue or derivative thereof).
70) Collagen Antae~onist In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a collagen antagonist (e.g., E-5050 (Benzenepropanamide, 4-(2,6-dimethylheptyl)-N-(2-hydroxyethyl)-f3-methyl-), lufironil (2,4-Pyridinedicarboxamide, N,N'-bis(2-methoxyethyl)-), or an analogue or derivative thereof).
71 ) Alpha 2 Integrin Antagonist In another embodiment, the pharmacologically active fibrosis-inhibiting compound is an alpha 2 integrin antagonist (e.g., E-7820, or an analogue or derivative thereof).

72) TNF Alpha Inhibitor In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a TNF alpha inhibitor (e.g., ethyl pyruvate, Genz-29155, lentinan (Ajinomoto Co., Inc. (Japan)), linomide (3-quinolinecarboxamide, 1,2-dihydro-4-hydroxy-N,1-dimethyl-2-oxo-N-phenyl-), UR-1505, or an analogue or derivative thereof).
73) Nitric Oxide Inhibitor In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a nitric oxide inhibitor (e.g., guanidioethyldisulfide, or an analogue or derivative thereof).
74) Cathepsin Inhibitor In another embodiment, the pharmacologically active fibrosis-inhibiting compound is a cathepsin inhibitor (e.g., SB-462795 or an analogue or derivative thereof).
Anti-Infective Agents The present invention also provides for the combination of a polymeric composition and an agent which reduces the likelihood of infection upon implantation of the composition or a medical implant.
Infection is a common complication of the implantation of foreign bodies such as, for example, medical devices and implants. Foreign materials provide an ideal site for micro- organisms to attach and colonize. It is also hypothesized that there is an impairment of host defenses to infection in the microenvironment surrounding a foreign material. These factors make medical implants particularly susceptible to infection and make eradication of such an infection difficult, if not impossible, in most cases. In many cases, an infected implant or device must be surgically removed from the body in order to irradicate the infection.

The present invention provides agents (e.g., chemotherapeutic agents) that can be released from a composition, and which have potent antimicrobial activity at extremely low doses. A wide variety of anti-infective agents can be utilized in combination with the present compositions. Suitable anti-infective agents may be readily determined based upon the assays provided in Example 34). Discussed in more detail below are several representative examples of agents that can be used as anti-infective agents, such as: (A) anthracyclines (e.g., doxorubicin and mitoxantrone), (B) fluoropyrimidines (e.g., 5-FU), (C) folic acid antagonists (e.g., methotrexate), (D) podophylotoxins (e.g., etoposide), (E) camptothecins, (F) hydroxyureas, and (G) platinum complexes (e.g., cisplatin).
A. Anthracyclines In one aspect, the therapeutic anti-infective agent is an anthracycline. Anthracyclines have the following general structure, where the R
groups may be a variety of organic groups:
R
R
According to U.S. Patent 5,594,158, suitable R groups are as follows: R~ is CH3 or CH20H; R2 is daunosamine or H; R3 and R4 are independently one of OH, N02, NH2, F, CI, Br, 1, CN, H or groups derived from these; R5 is hydrogen, ydroxyl, or methoxy; and R6_$ are all hydrogen.
Alternatively, R5 and R6 are hydrogen and R~ and R$ are alkyl or halogen, or vice versa.
According to U.S. Patent 5,843,903, R~ may be a conjugated peptide. According to U.S. Patent 4,296,105, R5 may be an ether linked alkyl group. According to U.S. Patent 4,215,062, R5 may be OH or an ether linked alkyl group. R~ may also be linked to the anthracycline ring by a group other than C(O), such as an alkyl or branched alkyl group having the C(O) linking moiety at its end, such as -CH2CH(CH2-X)C(O)-R~, wherein X is H or an alkyl group (see, e.g., U.S_ Patent 4,215,062). R~ may alternately be a group linked by the functional group =N-NHC(O)-Y, where Y is a group such as a phenyl or substituted phenyl ring. Alternately R3 may have the following structure:
HsC O
~NH
Rio in which R9 is OH either in or out of the plane of the ring, or is a second sugar moiety such as R3. Rio may be H or form a secondary amine with a group such as an aromatic group, saturated or partially saturated 5 or 6 membered heterocyclic having at least one ring nitrogen (see U.S. Patent 5,843,903).
Alternately, Rio may be derived from an amino acid, having the structure -C(O)CH(NHR~~)(R~2), in which R~~ is H, or forms a C3_4 membered alkylene with R~2. R~~ may be H, alkyl, aminoalkyl, amino, hydroxyl, mercapto, phenyl, benzyl or methylthio (see U.S. Patent 4,296,105).
Exemplary anthracyclines are doxorubicin, daunorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, and carubicin. Suitable compounds have the structures:

H

'NH2 R~ R2 R3 Doxorubicin:OCH3 C(O)CH20H OH out of ring plane Epirubicin:

(4' epimer OCH3 C(O)CH2OH OH in ring plane of doxorubicin) Daunorubicin:OCH3 C(O)CH3 OH out of ring plane Idarubicin: H C(O)CH3 OH out of ring plane Pirarubicin:OCH3 C(O)CH20H

~- i Zorubicin: OCH3 C(CH3)(=N)NHC(O)C6H5 OH

Carubicin: OH C(O)CH3 OH out of ring plane Other suitable anthracyclines are anthramycin, mitoxantrone, menogaril, nogalamycin, aclacinomycin A, olivomycin A, chromomycin A3, and plicamycin having the structures:
R, RZ R
Menogaril H OCH3 H
OH o HN~NH~OH tJogalarrycin O-sugar H COOCH3 ~ sugar H O OH' ~/ ~~J~I/0 OH O HN OH H3C0 ~~ OCH3 ~NH~
Mitoxantrone HO " HO- '_'~~ O

O ~1/

~CH~3~
R,O
~ ~' Ho R~ Rz Ra Ra OlivorcrycinCOCH(CH3)ZCH3COCN3H
A

ChromorrrycinCOCH3 CH3COCH3CH3 PlicamycinH H H CH3 Other representative anthracyclines include, FCE 23762 doxorubicin derivative (Quaglia et al., J. Liq. Chromatogr. 77(18):3911-3923, 1994), annamycin (Zou et al., J. Pharm. Sci. 82(11 ):1151-1154, 1993), ruboxyl (Rapoport et al., J. Controlled Release 58(2):153-162, 1999), anthracycline disaccharide doxorubicin analogue (Pratesi et al., Clin. Cancer Res.
4(11 ):2833-2839, 1998), N-(trifluoroacetyl)doxorubicin and 4'-O-acetyl-N-(trifluoroacetyl)doxorubicin (Berube & Lepage, Synth. Commun. 28(6):,1109-1116, 1998), 2-pyrrolinodoxorubicin (Nagy et al., Proc. Nat'I Acad. Sci.
U.S.A.
95(4):1794-1799, 1998), disaccharide doxorubicin analogues (Arcamone et al., J. Nat'I Cancer Inst. 89(16):1217-1223, 1997), 4-demethoxy-7-O-(2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-a-L-lyxo-hexopyranosyl)-a-L-lyxo-hexopyranosyl)-adriamicinone doxorubicin disaccharide analogue (Monteagudo et al., Carbohydr. Res. 300(1):11-16, 1997), 2-pyrrolinodoxorubicin (Nagy etal., Proc.
Nat'I Acad. Sci. U. S. A. 94(2):652-656, 1997), morpholinyl doxorubicin analogues (Duran et al., Cancer Chemother. Pharmacol. 38(3}:210-216, 1996), enaminomalonyl-~-alanine doxorubicin derivatives (Seitz et al., Tetrahedron Lett. 36(9):1413-16, 1995), cephalosporin doxorubicin derivatives (Vrudhula et al., J. Med. Chem. 38(8):1380-5, 1995), hydroxyrubicin (Solary et al., Int. J.
Cancer 58(1 ):85-94, 1994), methoxymorpholino doxorubicin derivative (Kuhl et al., Cancer Chemother. Pharmacol. 33(1 ):10-16, 1993), (6-maleimidocaproyl)hydrazone doxorubicin derivative (Willner et al., Bioconjugate Chem. 4(6):521-7, 1993), N-(5,5-diacetoxypent-1-yl) doxorubicin (Cherif &
Farquhar, J. Med. Chem. 35(17):3208-14, 1992), FCE 23762 methoxymorpholinyl doxorubicin derivative (Ripamonti et al., Br. J. Cancer 65(5):703-7, 1992), N-hydroxysuccinimide ester doxorubicin derivatives (Demant et al., Biochim. Biophys. Acta 1118(1 ):83-90, 1991 ), polydeoxynucleotide doxorubicin derivatives (Ruggiero et al., Biochim.
Biophys.
Acta 1129(3):294-302, 1991 ), morpholinyl doxorubicin derivatives (EPA
434960), mitoxantrone doxorubicin analogue (Krapcho et al., J. Med. Chem.
34(8):2373-80. 1991 ), AD198 doxorubicin analogue (Traganos et al., Cancer Res. 51(14):3682-9, 1991 ), 4-demethoxy-3'-N-trifluoroacetyldoxorubicin (Horton et al., Drug Des. Delivery 6(2):123-9, 1990), 4'-epidoxorubicin (Drzewoski et al., Pol. J. Pharmacol. Pharm. 40(2):159-65, 1988; Weenen et al., Eur. J. Cancer Clin. Oncol. 20(7):919-26, 1984), alkylating cyanomorpholino doxorubicin derivative (Scudder et al., J. Nat'I Cancer Inst. 80(16):1294-8, 1988), deoxydihydroiodooxorubicin (EPA 275966), adriblastin (Kalishevskaya et al., Vestn. Mosk. Univ., 96(Biol. 1):21-7, 1988}, 4'-deoxydoxorubicin (Schoelzel et al., Leuk. Res. 70(12):1455-9, 1986), 4-demethyoxy-4'-o-methyldoxorubicin (Giuliani et al., Proc. Int. Congr. Chemother. 76:285-70-285-77, 1983), 3'-deamino-3'-hydroxydoxorubicin (Norton et al., J. Antibiot. 37(8):853-8, 1984), demethyoxy doxorubicin analogues (Barbieri et al., Drugs Exp. Clin. Res.
10(2):85-90, 1984), N-L-leucyl doxorubicin derivatives (Trouet et al., Anthracyclines (Proc. Int. Symp. Tumor Pharmacother.), 179-81, 1983), 3'-deamino-3'-(4-methoxy-1-piperidinyl) doxorubicin derivatives (U.S. 4,314,054), 3'-deamino-3'-(4-mortholinyl) doxorubicin derivatives (U.S. 4,301,277), 4'-deoxydoxorubicin and 4'-o-methyldoxorubicin (Giuliani et al., Int. J. Cancer 27(1 ):5-13, 1981 ), aglycone doxorubicin derivatives (Chan & Watson, J.
Pharm.
Sci. 67(12):1748-52, 1978), SM 5887 (Pharma Japan 7468:20, 1995), MX-2 (Pharma Japan 7420:19, 1994), 4'-deoxy-13(S)-dihydro-4'-iododoxorubicin (EP
275966), morpholinyl doxorubicin derivatives (EPA 434960), 3'-deamino-3'-(4-methoxy-1-piperidinyl) doxorubicin derivatives (U.S. 4,314,054), doxorubicin-14-valerate, morpholinodoxorubicin (U.S. 5,004,606), 3'-deamino-3'-(3"-cyano-4"-morpholinyl doxorubicin; 3'-deamino-3'-(3"-cyano-4"-morpholinyl)-13-dihydoxorubicin; (3'-deamino-3'-(3"-cyano-4"-morpholinyl) daunorubicin; 3'-deamino-3'-(3"-cyano-4"-morpholinyl)-3-dihydrodaunorubicin; and 3'-deamino-3'-(4"-morpholinyl-5-iminodoxorubicin and derivatives (U.S. 4,585,859), 3'-deamino-3'-(4-methoxy-1-piperidinyl) doxorubicin derivatives (U.S. 4,314,054) and 3-deamino-3-(4-morpholinyl) doxorubicin derivatives (U.S. 4,301,277).
B. Fluoropyrimidine analogues In another aspect, the ant-infective therapeutic agent is a fluoropyrimidine analog, such as 5-fluorouracil, or an analogue or derivative thereof, including carmofur, doxifluridine, emitefur, tegafur, and floxuridine.
Exemplary compounds have the structures:

R~~ F
N
O N
R~
R~ R2 5-FluorouracilH H

Carmofur C(O)NH(CH2)5CH3 H

DoxifluridineA~ H

Floxuridine A2 H

Emitefur CH20CH2CH3 B

Tegafur C H

CN
O ~ ~ 0 O
O N O
Cr Other suitable fluoropyrimidine analogues include 5-FudR (5-fluoro-deoxyuridine), or an analogue or derivative thereof, including 5-iododeoxyuridine (5-IudR), 5-bromodeoxyuridine (5-BudR), fluorouridine triphosphate (5-FUTP), and fluorodeoxyuridine monophosphate (5-dFUMP) Exemplary compounds have the structures:

H
5-Fluoro-2'-deoxyuridine: R = F
5-Bromo-2'-deoxyuridine: R = Br 5-lodo-2'-deoxyuridine: R = I
Other representative examples of fluoropyrimidine analogues include N3-alkylated analogues of 5-fluorouracil (Kozai et al., J. Chem. Soc., Per6cin Trans. 7(19):3145-3146, 1998), 5-fluorouracil derivatives with 1,4-oxaheteroepane moieties (Gomez et al., Tetrahedron 54(43):13295-13312, 1998), 5-fluorouracil and nucleoside analogues (Li, Anticancer Res. 17(1A):21-27, 1997), cis- and trans-5-fluoro-5,6-dihydro-6-alkoxyuracil (Van der Wilt et al., Br. J. Cancer 68(4):702-7, 1993), cyclopentane 5-fluorouracil analogues (Hronowski & Szarek, Can. J. Chem. 70(4):1162-9, 1992), A-OT-fluorouracil (Zhang et al., Zongguo Yiyao Gongye Zazhi 20(11 ):513-15, 1989), N4-trimethoxybenzoyl-5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine (Miwa et al., Chem. Pharm. Bull. 38(4):998-1003, 1990), 1-hexylcarbamoyl-5-fluorouracil (Hoshi et al., J. Pharmacobio-Dun. 3(9):478-81, 1980; Maehara et al., Chemotherapy (Basel) 34(6):484-9, 1988), B-3839 (Prajda et al., In Vivo 2(2):151-4, 1988), uracil-1-(2-tetrahydrofuryl)-5-fluorouracil (Anai et al., Oncology 45(3):144-7, 1988), 1-(2'-deoxy-2'-fluoro-~i-D-arabinofuranosyl)-5-fluorouracil (Suzuko et al., Mol. Pharmacol. 37(3):301-6, 1987), doxifluridine (Matuura et al., Oyo Yakuri 29(5):803-31, 1985), 5'-deoxy-5-fluorouridine (Bollag & Hartmann, Eur. J. Cancer 76(4):427-32, 1980), 1-acetyl-3-O-toluyl-5-fluorouracil (Okada, Hiroshima J. Med. Sci. 28(1 ):49-66, 1979), 5-fluorouracil-m-formylbenzene-sulfonate (JP 55059173), N'-(2-furanidyl)-5-fluorouracil (JP
53149985) and 1-(2-tetrahydrofuryl)-5-fluorouracil (JP 52089680).
These compounds are believed to function as therapeutic agents by serving as antimetabolites of pyrimidine.
C. Folic acid antagonists In another aspect, the anti-infective therapeutic agent is a folic acid antagonist, such as methotrexate or derivatives or analogues thereof, including edatrexate, trimetrexate, raltitrexed, piritrexim, denopterin, tomudex, and pteropterin. Methotrexate analogues have the following general structure:
The identity of the R group may be selected from organic groups, particularly those groups set forth in U.S. Patent Nos. 5,166,149 and 5,382,582. For example, R~ may be N, R2 may be N or C(CH3), R3 and R3' may H or alkyl, e.g., CH3, R4 may be a single bond or NR, where R is H or alkyl group. R5,6,$ may be H, OCH3, or alternately they can be halogens or hydro groups. R~ is a side chain of the general structure:
H

HO

O

i n wherein n = 1 for methotrexate, n = 3 for pteropterin. The carboxyl groups in the side chain may be esterified or form a salt such as a ~n2+ salt. R9 and Rio can be NH2 or may be alkyl substituted.
Exemplary folic acid antagonist compounds have the structures:

Ro R~ Ra R3 R4 R5 Rs R~ Ra MethotrexateNH2 N N H N(CH3) H H A (n=1 H
) EdatrexateNH2 N N H CH(CH2CH3)H H A (n=1 H
) TrimetrexateNHS CH C(CH3)H NH H OCH3 OCH3 OCH3 PteropterinOH N N H NH H H A (n=3)H

DenopterinOH N N CH3 N(CH3) H H A (n=1 H
) PeritreximNH2 N C(CH3)H single OCH3 H H OCH3 bond A: o NH
HO
O
O OH

HOOC~ O ~ H3 S N ~ ~ NH
HOOC NH
O
Tomudex Other representative examples include 6-S-aminoacyloxymethyl mercaptopurine derivatives (Harada et al., Chem. Pharm. Bull. 43(10):793-6, 1995), 6-mercaptopurine (6-MP) (Kashida et al., Biol. Pharm. Bull. 78(11 ):1492-7, 1995), 7,8-polymethyleneimidazo-1,3,2-diazaphosphorines (Nilov et al., Mendeleev Commun. 2:67, 1995), azathioprine (Chifotides et al., J. Inorg.
Biochem. 56(4):249-64, 1994), methyl-D-glucopyranoside mercaptopurine derivatives (Da Silva et al., Eur. J. Med. Chem. 29(2):149-52, 1994) and s-alkynyl mercaptopurine derivatives (Ratsino et al., Khim.-Farm. Zh. 75(8):65-7, 1981 ); indoline ring and a modified ornithine or glutamic acid-bearing methotrexate derivatives (Matsuoka et al., Chem. Pharm. Bull. 45(7):1146-1150, 1997), alkyl-substituted benzene ring C bearing methotrexate derivatives (Matsuoka et al., Chem. Pharm. Bull. 44(12):2287-2293, 1996), benzoxazine or benzothiazine moiety-bearing methotrexate derivatives (Matsuoka et al., J.
Med. Chem. 40(1 ):105-111, 1997), 10-deazaaminopterin analogues (DeGraw et al., J. Med. Chem. 40(3):370-376, 1997), 5-deazaaminopterin and 5,10-dideazaaminopterin methotrexate analogues (Piper et al., J. Med. Chem.
40(3):377-384, 1997), indoline moiety-bearing methotrexate derivatives (Matsuoka et al., Chem. Pharm. Bull. 44(7):1332-1337, 1996), lipophilic amide methotrexate derivatives (Pignatello et al., World Meet. Pharm., Biopharm.
Pharm. Technol., 563-4, 1995), L-threo-(2S,4S)-4-fluoroglutamic acid and DL-3,3-difluoroglutamic acid-containing methotrexate analogues (Hart et al., J.
Med. Chem. 39(1):56-65, 1996), methotrexate tetrahydroquinazoline analogue (Gangjee, et al., J. Heterocycl. Chem. 32(1 ):243-8, 1995), N-(a-aminoacyl) methotrexate derivatives (Cheung et al., Pteridines 3(1-2):101-2, 1992), biotin methotrexate derivatives (Fan et al., Pteridines 3(1-2):131-2, 1992), D-glutamic acid or D-erythrou, threo-4-fluoroglutamic acid methotrexate analogues (McGuire et al., Biochem. Pharmacol. 42(12):2400-3, 1991 ), ~,y-methano methotrexate analogues (Rosowsky et al., Pteridines 2(3):133-9, 1991 ), 10-deazaaminopterin (10-EDAM) analogue (Braakhuis et al., Chem. Biol.
Pteridines, Proc. Int. Symp. Pteridines Folic Acid Deriv., 1027-30, 1989), y-tetrazole methotrexate analogue (Kalman et al., Chem. Biol. Pteridines, Proc.
Int. Symp. Pteridines Folic Acid Deriv., 1154-7, 1989), N-(L-a-aminoacyl) methotrexate derivatives (Cheung et al., Heterocycles 28(2):751-8, 1989), meta and ortho isomers of aminopterin (Rosowsky et al., J. Med. Chem. 32(12):2582, 1989), hydroxymethylmethotrexate (DE 267495), y-fluoromethotrexate (McGuire et al., Cancer Res. 49(16):4517-25, 1989), polyglutamyl methotrexate derivatives (Kumar et al., Cancer Res. 46(10):5020-3, 1986), gem-diphosphonate methotrexate analogues (WO 88/06158), a- and y-substituted methotrexate analogues (Tsushima et al., Tetrahedron 44(17):5375-87, 1988), 5-methyl-5-deaza methotrexate analogues (4,725,687), N8-acyl-Na-(4-amino-4-deoxypteroyl)-L-ornithine derivatives (Rosowsky et al., J. Med. Chem.
31(7):1332-7, 1988), 8-deaza methotrexate analogues (Kuehl et al., Cancer Res. 48(6):1481-8, 1988), acivicin methotrexate analogue (Rosowsky et al., J.
Med. Chem. 30(8):1463-9, 1987), polymeric platinol methotrexate derivative (Carraher et al., Polym. Sci. Technol. (Plenum), 35(Adv. Biomed. Polym.):311-24, 1987), methotrexate-y-dimyristoylphophatidylethanolamine (Kinsky et al., Biochim. Biophys. Acta 917(2):211-18, 1987), methotrexate polyglutamate analogues (Rosowsky et al., Chem. Biol. Pteridines, Pteridines Folic Acid Deriv., Proc. Int. Symp. Pteridines Folic Acid Deriv.: Chem., Biol. Clin.
Aspects:
985-8, 1986), poly-y-glutamyl methotrexate derivatives (Kisliuk et al., Chem.
Biol. Pteridines, Pteridines Folic Acid Deriv., Proc. Int. Symp. Pteridines Folic Acid Deriv.: Chem., Biol. Clin. Aspects: 989-92, 1986), deoxyuridylate methotrexate derivatives (Webber et al., Chem. Biol. Pteridines, Pteridines Folic Acid Deriv., Proc. Int. Symp. Pteridines Folic Acid Deriv.: Chem., Biol. Clin.
Aspects: 659-62, 1986), iodoacetyl lysine methotrexate analogue (Delcamp et al., Chem. Biol. Pteridines, Pteridines Folic Acid Deriv., Proc. Int. Symp.
Pteridines Folic Acid Deriv.: Chem., Biol. Clin. Aspects: 807-9, 1986), 2,.omega.-diaminoalkanoid acid-containing methotrexate analogues (McGuire et al., Biochem. Pharmacol. 35(15):2607-13, 1986), polyglutamate methotrexate derivatives (Kamen & Winick, Methods Enzymol. 122(Vitam.
Coenzymes, Pt. G):339-46, 1986), 5-methyl-5-deaza analogues (Piper et al., J.
Med. Chem. 29(6):1080-7, 1986), quinazoline methotrexate analogue (Mastropaolo et al., J. Med. Chem. 29(1 ):155-8, 1986), pyrazine methotrexate analogue (Lever & Vestal, J. Heterocycl. Chem. 22(1 ):5-6, 1985), cysteic acid and homocysteic acid methotrexate analogues (4,490,529), y-tert-butyl methotrexate esters (Rosowsky et al., J. Med. Chem. 28(5):660-7, 1985), fluorinated methotrexate analogues (Tsushima et al., Heterocycles 23(1 ):45-9, 1985), folate methotrexate analogue (Trombe, J. Bacteriol. 160(3):849-53, 1984), phosphonoglutamic acid analogues (Sturtz & Guillamot, Eur. J. Med.
Chem.--Chim. Ther. 19(3):267-73, 1984), poly (L-lysine) methotrexate conjugates (Rosowsky et al., J. Med. Chem. 27(7):888-93, 1984), dilysine and trilysine methotrexate derivates (Forsch ~ Rosowsky, J. Org. Chem.
49(7):1305-9, 1984), 7-hydroxymethotrexate (Fabre et al., Cancer Res.
43(10):4648-52, 1983), poly-y-glutamyl methotrexate analogues (Piper &
Montgomery, Adv. Exp. Med. Biol., 163(F~lyl Antifolyl Polyglutamates):95-100, 1983), 3',5'-dichloromethotrexate (Rosowsky & Yu, J. Med. Chem. 26(10):1448-52, 1983), diazoketone and chloromethylketone methotrexate analogues (Gangjee et al., J. Pharm. Sci. 71(6):717-19, 1982), 10-propargylaminopterin and alkyl methotrexate homologs (Piper et al., J. Med. Chem. 25(7):877-80, 1982), lectin derivatives of methotrexate (Lin et al., JNCI 66(3):523-8, 1981 ), polyglutamate methotrexate derivatives (Galivan, Mol. Pharmacol. 17(1 ):105-10, 1980), halogentated methotrexate derivatives (Fox, JNCI 58(4):J955-8, 1977), 8-alkyl-7,8-dihydro analogues (Chaykovsky et al., J. Med. Chem.
20(10):J1323-7, 1977), 7-methyl methotrexate derivatives and dichloromethotrexate (Rosowsky & Chen, J. Med. Chem. 17(12):J1308-11, 1974), lipophilic methotrexate derivatives and 3',5'-dichloromethotrexate (Rosowsky, J. Med. Chem. 16(10):J1190-3, 1973), deaza amethopterin analogues (Montgomery et al., Ann. N. Y. Acad. Sci. 186:J227-34, 1971 ), MX068 (Pharma Japan, 1658:18, 1999) and cysteic acid and homocysteic acid methotrexate analogues (EPA 0142220).
These compounds are believed to act as antimetabolites of folic acid.
D. Podophyllotoxins In another aspect, the anti-infective therapeutic agent is a Podophyllotoxin, or a derivative or an analogue thereof. Exemplary compounds of this type are etoposide or teniposide, which have the following structures:

Etoposide CH3 Teniposide s OH
Other representative examples of podophyllotoxins include Cu(II)-VP-16 (etoposide) complex (Tawa et al., Bioorg. Med. Chem. 6(7):1003-1008, 1998), pyrrolecarboxamidino-bearing etoposide analogues (Ji et al., Bioorg.
Med. Chem. Lett. 7(5):607-612, 1997), 4a-amino etoposide analogues (Hu, University of North Carolina Dissertation, 1992), y-lactone ring-modified arylamino etoposide analogues (Zhou et al., J. Med. Chem. 37(2):287-92, 1994), N-glucosyl etoposide analogue (Allevi et al., Tetrahedron Lett.
34(45):7313-16, 1993), etoposide A-ring analogues (Kadow et al., Bioorg. Med.
Chem. Lett. 2(1 ):17-22, 1992), 4'-deshydroxy-4'-methyl etoposide (Saulnier et al., Bioorg. Med. Chem. Lett. 2(10):1213-18, 1992), pendulum ring etoposide analogues (Sinha et al., Eur. J. Cancer 26(5):590-3, 1990) and E-ring desoxy etoposide analogues (Saulnier et al., J. Med. Chem. 32(7):1418-20, 1989).
These compounds are believed to act as topoisomerase II
inhibitors and/or DNA cleaving agents.
E. Camptothecins In another aspect, the anti-infective therapeutic agent is camptothecin, or an analogue or derivative thereof. Camptothecins have the following general structure.

In this structure, X is typically O, but can be other groups, e.g., NH
in the case of 21-lactam derivatives. R1 is typically H or OH, but may be other groups, e.g., a terminally hydroxylated C1_3 alkane. R2 is typically H or an amino containing group such as (CH3)2NHCH2, but may be other groups e.g., NO2, NH2, halogen (as disclosed in, e.g., U.S. Patent 5,552,156) or a short alkane containing these groups. R3 is typically H or a short alkyl such as C2H5.
R4 is typically H but may be other groups, e.g., a methylenedioxy group with R1, Exemplary camptothecin compounds include topotecan, irinotecan (CPT-11 ), 9-aminocamptothecin, 21-lactam-20(S)-camptothecin, 10,11-methylenedioxycamptothecin, SN-3~, 9-nitrocamptothecin, 10-hydroxycamptothecin. Exemplary compounds have the structures:
R~ Rz R3 Camptothecin: H H H
Topotecan: OH (CH3)zNHCHz H
SN-38: OH H CZHS
X: O for most analogs, NH for 21-lactam analogs Camptothecins have the five rings shown here. The ring labeled E must be intact (the lactone rather than carboxylate form) for maximum activity and minimum toxicity.
Camptothecins are believed to function as topoisomerase I
inhibitors and/or DNA cleavage agents.
F. Hydroxyureas The anti-infective therapeutic agent of the present invention may be a hydroxyurea. Hydroxyureas have the following general structure:

O

~N N~
R2 R~
Suitable hydroxyureas are disclosed in, for example, U.S. Patent No. 6,080,874, wherein R~ is:
and R2 is an alkyl group having 1-4 carbons and R3 is one of H, acyl, methyl, ethyl, and mixtures thereof, such as a methylether.
Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent No. 5,665,768, wherein R~ is a cycloalkenyl group, for example N-(3-(5-(4-fluorophenylthio)-furyl)-2-cyclopenten-1-yl)N-hydroxyurea; R2 is H or an alkyl group having 1 to 4 carbons and R3 is H; X is H or a cation.
Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent No. 4,299,778, wherein R~ is a phenyl group substituted with one or more fluorine atoms; R2 is a cyclopropyl group; and R3 and X is H.
Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent No. 5,066,658, wherein R2 and R3 together with the adjacent nitrogen form:
(c~z)~
Y . N-(CH2)m where in m is 1 or 2, n is 0-2 and Y is an alkyl group.
In one aspect, the hydroxyurea has the structure:

OOH

Hydroxyurea These compounds are thought to function by inhibiting DNA
synthesis.
G. Platinum complexes In another aspect, the anti-infective therapeutic agent is a platinum compound. In general, suitable platinum complexes may be of Pt(II) or Pt(IV) and have this basic structure:
z2 wherein X and Y are anionic leaving groups such as sulfate, phosphate, carboxylate, and halogen; R~ and R2 are alkyl, amine, amino alkyl any may be further substituted, and are basically inert or bridging groups. For Pt(II) complexes Z~ and Z2 are non-existent. For Pt(IV) Z~ and ~2 may be anionic groups such as halogen, hydroxy, carboxylate, ester, sulfate or phosphate.
See, e.g., U.S. Patent Nos. 4,588,831 and 4,250,189.
Suitable platinum complexes may contain multiple Pt atoms. See, e.g., U.S. Patent Nos. 5,409,915 and 5,380,897. For example bisplatinum and triplatinum complexes of the type:

Zt Zt R X
X~ / ~ ~ , Rz Y~ It\A~ ~t~Y
Zz Zz Zt Zt Zt X\ I /Rt X\ I A\ I /X
Pt Pt/ \ Pt Y/ I ~ A~ I \ Y Rz~ I \ Y
Zz Zz Z2 Zt Zt X\ ~ / Rz Rz~ ~ / X
Y~ It\A/ It~Y
Z2 ~ Z2 Z2~ I / R3 Pt Y~~\ZI
X
Exemplary platinum compounds are cisplatin, carboplatin, oxaliplatin, and miboplatin having the structures:

NH3 O O~
It CIIt-NH3 I ~NH3 O
CI
O
Cisplatin Carboplatin O O H H
\/
O NHz O N
Pt / \ ~ / ' H
O NH ~~~" O N
z O l O H
Oxaliplatin Miboplatin Other representative platinum compounds include (CPA)~Pt(DOLYM) and (DACH)Pt(DOLYM) cisplatin (Choi et al., Arch.
Pharmacal Res. 22(2):151-156, 1999), Cis-(PtCl2(4,7-H-5-methyl-7-oxo)1,2,4(triazolo(1,5-a)pyrimidine)2) (Navarro etal., J. Med. Chem. 47(3):332-338, 1998), (Pt(cis-1,4-DACH)(trans-CI2)(CBDCA))~'/ZMeOH cisplatin (Shamsuddin et al., Inorg. Chem. 36(25):5969-5971, 1997), 4-pyridoxate diammine hydroxy platinum (Tokunaga et al., Pharm. Sci. 3(7):353-356, 1997), Pt(II) ... Pt(II) (Pt2(NHCHN(C(CH2)(CH3)))4) (Navarro et al., Inorg. Chem.
35(26):7829-7835, 1996), 254-S cisplatin analogue (Koga et al., Neurol. Res.
18(3):244-247, 1996), o-phenylenediamine ligand bearing cisplatin analogues (Koeckerbauer ~ Bednarski, J. Inorg. Biochem. 62(4):281-298, 1996), trans, cis-(Pt(OAc)21~(en)) (Kratochwil et al., J. Med. Chem. 39(13):2499-2507, 1996), estrogenic 1,2-diarylethylenediamine ligand (with sulfur-containing amino acids and glutathione) bearing cisplatin analogues (Bednarski, J. Inorg. Biochem.
62(1 ):75, 1996), cis-1,4-diaminocyclohexane cisplatin analogues (Shamsuddin et al., J. Inorg. Biochem. 61(4):291-301, 1996), 5' orientational isomer of cis-(Pt(NH3)(4-aminoTEMP-O){d(GpG))) (Dunham & Lippard, J. Am. Chem. Soc.
117(43):10702-12, 1995), chelating diamine-bearing cisplatin analogues (Koeckerbauer & Bednarski, J. Pharm. Sci. 84(7):819-23, 1995),1,2-diarylethyleneamine ligand-bearing cisplatin analogues (Otto et al., J. Cancer Res. Clin. Oncol. 121(1 ):31-8, 1995), (ethylenediamine)platinum(II) complexes (Pasini et al., J. Chem. Soc., Dalton Trans. 4:579-85, 1995), CI-973 cisplatin analogue (Yang et al., Int. J. Oncol. 5(3):597-602, 1994), cis-diaminedichloroplatinum(II) and its analogues cis-1,1-cyclobutanedicarbosylato(2R)-2-methyl-1,4-butanediamineplatinum(II) and cis-diammine(glycolato)platinum (Claycamp & Zimbrick, J. Inorg. Biochem.
26(4):257-67, 1986; Fan et al., Cancer Res. 48(11 ):3135-9, 1988; Heiger-Bernays et al., Biochemistry 29(36):8461-6, 1990; Kikkawa et al., J. Exp.
Clin.
Cancer Res. 12(4):233-40, 1993; Murray et al., Biochemistry 31(47):11812-17, 1992; Takahashi et al., Cancer Chemother. Pharmacol. 33(1 ):31-5, 1993), cis-amine-cyclohexylamine-dichloroplatinum(II) (Yoshida et al., Biochem.
Pharmacol. 48(4):793-9, 1994), gem-diphosphonate cisplatin analogues (FR
2683529), (meso-1,2-bis(2,6-dichloro-4-hydroxyplenyl)ethylenediamine) dichloroplatinum(II) (Bednarski et al., J. Med. Chem. 35(23):4479-85, 1992), cisplatin analogues containing a tethered dansyl group (Hartwig et al., J. Am.
Chem. Soc. 114(21 ):8292-3, 1992), platinum(II) polyamines (Siegmann et al., Inorg. Met.-Containing Polym, Mater., (Proc. Am. Chem. Soc. Int. Symp.), 335-61, 1990), cis-(3H)dichloro(ethylenediamine)platinum(II) (Eastman, Anal.
Biochem. 197(2):311-15, 1991 ), trans-diamminedichloroplatinum(II) and cis-(Pt(NH3)~(N3-cytosine)CI) (Bellon & Lippard, Biophys. Chem. 35(2-3):179-88, 1990), 3H-cis-1,2-diaminocyclohexanedichloroplatinum(II) and 3H-cis-1,2-diaminocyclohexanemalonatoplatinum (II) (Oswald et al., Res. Commun. Chem.
Pathol. Pharmacol. 64(1 ):41-58, 1989), diaminocarboxylatoplatinum (EPA
296321 ), trans-(D,1 )-1,2-diaminocyclohexane carrier ligand-bearing platinum analogues (Wyrick & Chaney, J. Labelled Compd. Radiopharm. 25(4):349-57, 1988), aminoalkylaminoanthraquinone-derived cisplatin analogues (Kitov et al., Eur. J. Med. Chem. 23(4):381-3, 1988), spiroplatin, carboplatin, iproplatin and JM40 platinum analogues (Schroyen et al., Eur, J. Cancer Clin. Oncol.
24(8):1309-12, 1988), bidentate tertiary diamine-containing cisplatinum derivatives (Orbell et al., Inorg. Chim. Acta 152(2):125-34, 1988), platinum(11), platinum(IV) (Liu & Wang, Shandong Yike Daxue Xuebao 24(1 ):35-41, 1986), cis-diammine(1,1-cyclobutanedicarboxylato-)platinum(II) (carboplatin, JM8) and ethylenediammine-malonatoplatinum(II) (JM40) (Begg et al., Radiother. Oncol.
9(2):157-65, 1987), JM8 and JM9 cisplatin analogues (Harstrick et al., Int. J.
Androl. 10(1 ); 139-45, 1987), (NPr4)2((PtCL4).cis-(PtCl2-(NH2Me)2)) (Brammer et al., J. Chem. Soc., Chem. Commun. 6:443-5, 1987), aliphatic tricarboxylic acid platinum complexes (EPA 185225), and cis-dichloro(amino acid)(tert-butylamine)platinum(II) complexes (Pasini & Bersanetti, Inorg, Chim.
Acta 107(4):259-67, 1985). These compounds are thought to function by binding to DNA, i.e., acting as alkylating agents of DNA.
Dosages of Anti-Infective Agents The drug dose administered from the present compositions for prevention or inhibition of infection in accordance with the present invention will depend on a variety of factors, including the type of formulation, the location of the treatment site, and the type of condition being treated. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the treatment site), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Drugs are to be used at concentrations that range from several times more than to 50%, 20%, 10%, 5%, or even less than 1 % of the concentration typically used in a single anti-infective systemic dose application. In certain aspects, the anti- infective agent is released from the polymer composition in effective concentrations in a time period that may be measured from the time of infiltration into tissue adjacent to the device, which ranges from about less than 1 day to about 180 days. Generally, the release time may also be from about less than 1 day to about 180 days; from about 7 days to about 14 days; from about 14 days to about 28 days; from about 28 days to about 56 days; from about 56 days to about 90 days; from about 90 days to about 180 days.
The exemplary anti-infective agents, used alone or in combination, should be administered under the following dosing guidelines.
The total amount (dose) of anti-infective agent in the composition can be in the range of about 0.01 ~g-1 fig, or about 1 p,g-10 fig, or about 10 pg-1 mg, or about 1 mg to 10 mg, or about 10 mg-100 mg, or about 100 mg to 250 mg, or about 250 mg-1000 mg. The dose (amount) of anti-infective agent per unit area of device or tissue surface to which the agent is applied may be in the range of about 0.01 ~g/mm2 - 1 p,g/mm2, or about 1 wg/mm2 - 10 pg/mm2, or about 10 ~,g/mm2 -100 pg/mm2, or about 100 ~,g/mm2 to 250 ~g/mm~, or about 250 ~g/mm2 - 1000 ~,g/mm2. As different polymer compositions will release the anti-infective agent at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the composition such that a minimum concentration of about 10-$ M to 10-' M, or about 10-' M
to 10'6 M about 10-6 M to 10'5 M or about 10'5 M to 10'4 M of the agent is maintained on the tissue surface.
(a) Anthracyclines. Utilizing the anthracycline doxorubicin as an example, whether applied as a polymer coating, incorporated into the polymers which make up the implant components, or applied without a carrier polymer, the total dose of doxorubicin applied to the device or implant should not exceed 25 mg (range of 0.1 ~g to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 pg to 5 mg. The dose per unit area (i.e., the amount of drug as a function of the surface area of the portion of the implant to which drug is applied and/or incorporated) should fall within the range of 0.01 ~g - 100 p,g per mm2 of surface area. In a particularly preferred embodiment, doxorubicin should be applied to the implant surface at a dose of 0.1 ~,g/mm2 - 10 p.g/mm2. As different polymer and non-polymer coatings will release doxorubicin at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the implant surface such that a minimum concentration of 10''- 104 M of doxorubicin is maintained on the surface. It is necessary to insure that surface drug concentrations exceed concentrations of doxorubicin known to be lethal to multiple species of bacteria and fungi (i.e., are in excess of 10-4 M;
although for some embodiments lower concentrations are sufficient). In a preferred embodiment, doxorubicin is released from the surface of the implant such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week - 6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of doxorubicin (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g., a compound twice as potent as doxorubicin is administered at half the above parameters, a compound half as potent as doxorubicin is administered at twice the above parameters, etc.).
Utilizing mitoxantrone as another example of an anthracycline, whether applied as a polymer coating, incorporated into the polymers which make up the device or implant, or applied without a carrier polymer, the total dose of mitoxantrone applied should not exceed 5 mg (range of 0.01 ~.g to 5 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 0.1 ~g to 1 mg. The dose per unit area (i.e., the amount of drug as a function of the surface area of the portion of the implant to which drug is applied and/or incorporated) should fall within the range of 0.01 pg - 20 p.g per mm2 of surface area. In a particularly preferred embodiment, mitoxantrone should be applied to the implant surface at a dose of 0.05 ~,g/mm2 - 3 pg/mm2. As different polymer and non-polymer coatings will release mitoxantrone at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the implant surface such that a minimum concentration of 10-5- 10-6 M of mitoxantrone is maintained. It is necessary to insure that drug concentrations on the implant surface exceed concentrations of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e., are in excess of 10-5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, mitoxantrone is released from the surface of the implant such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week - 6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of mitoxantrone (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g., a compound twice as potent as mitoxantrone is administered at half the above parameters, a compound half as potent as mitoxantrone is administered at twice the above parameters, etc.).
(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil as an example, whether applied as a polymer coating, incorporated into the polymers which make up the device or implant, or applied without a carrier polymer, the total dose of 5-fluorouracil applied should not exceed 250 mg (range of 1.0 p.g to 250 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 10 pg to 25 mg. The dose per unit area (i.e., the amount of drug as a function of the surface area of the portion of the implant to which drug is applied and/or incorporated) should fall within the range of 0.1 ~,g -1 mg per mm2 of surface area. In a particularly preferred embodiment, 5-fluorouracil should be applied to the implant surface at a dose of 1.0 p.g/mm2 - 50 p.glmm2. As different polymer and non-polymer coatings will release 5-fluorouracil at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the implant surface such that a minimum concentration of 10-4- 10-' M of 5-fluorouracil is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of 5-fluorouracil known to be lethal to numerous species of bacteria and fungi (i.e., are in excess of 10-4 M;
although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, 5-fluorouracil is released from the implant surface such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week - 6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of 5-fluorouracil (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g., a compound twice as potent as 5-fluorouracil is administered at half the above parameters, a compound half as potent as 5-fluorouracil is administered at twice the above parameters, etc.).
(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an example, whether applied as a polymer coating, incorporated into the polymers which make up the device or implant, or applied without a carrier polymer, the total dose of etoposide applied should not exceed 25 mg (range of 0.1 ~.g to mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 pg to 5 mg. The dose per unit area (i.e., the amount of drug as a function of the surface area of the portion of the implant to which drug is applied and/or incorporated) should fall within the range of 0.01 pg -p,g per mm2 of surface area. In a particularly preferred embodiment, etoposide should be applied to the implant surface at a dose of 0.1 p,g/mmz -10 ~glmm2.
As different polymer and non-polymer coatings will release etoposide at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the implant surface such that a concentration of 10-5 - 10-6 M of etoposide is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of etoposide known to be lethal to a variety of bacteria and fungi (i.e., are in excess of 10-5 M;
although for some embodiments lower drug levels will be sufFicient). In a preferred embodiment, etoposide is released from the surface of the implant such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week - 6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of etoposide (as described previously) with similar functional activity can be utilized for the purposes of this invention;
the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g., a compound twice as potent as etoposide is administered at half the above parameters, a compound half as potent as etoposide is administered at twice the above parameters, etc.).
It should be readily evident based upon the discussions provided herein that combinations of anthracyclines (e.g., doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists (e.g., methotrexate and/or podophylotoxins (e.g., etoposide) can be utilized to enhance the antibacterial activity of the composition.
It should be readily evident based upon the discussions provided herein that combinations of anthracyclines (e.g., doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists (e.g., methotrexate and/or podophylotoxins (e.g., etoposide) may be utilized to enhance the antibacterial activity of the composition.
Combination Therapies In addition to incorporation of the above-mentioned therapeutic agents (i.e., anti-infective agents or fibrosis-inhibiting agents), one or more other pharmaceutically active agents can be incorporated into the present compositions to improve or enhance efficacy. In one aspect, the composition may further include a compound which acts to have an inhibitory effect on pathological processes in or around the treatment site. Representative examples of additional therapeutically active agents include, by way of example and not limitation, anti-thrombotic agents, anti-proliferative agents, anti-inflammatory agents, neoplastic agents, enzymes, receptor antagonists or agonists, hormones, antibiotics, antimicrobial agents, antibodies, cytokine inhibitors, IMPDH (inosine monophosplate dehydrogenase) inhibitors tyrosine kinase inhibitors, MMP inhibitors, p38 MAP kinase inhibitors, immunosuppressants, apoptosis antagonists, caspase inhibitors, and JNK
inhibitor.
The polymeric composition may further include an anti-thrombotic agent and/or antiplatelet agent and/or a thrombolytic agent, which reduces the likelihood of thrombotic events upon implantation of a medical implant.
Representative examples of anti-thrombotic and/or antiplatelet and/or thrombolytic agents include heparin, heparin fragments, organic salts of heparin, heparin complexes (e.g., benzalkonium heparinate, tridodecylammonium heparinate), dextran, sulfonated carbohydrates such as dextran sulfate, coumadin, coumarin, heparinoid, danaparoid, argatroban chitosan sulfate, chondroitin sulfate, danaparoid, lepirudin, hirudin, AMP, adenosine, 2-chloroadenosine, acetylsalicylic acid, phenylbutazone, indomethacin, meclofenamate, hydrochloroquine, dipyridamole, iloprost, streptokinase, factor Xa inhibitors, such as DX9065a, magnesium, and tissue plasminogen activator. Further examples include plasminogen, lys-plasminogen, alpha-2-antiplasmin, urokinase, aminocaproic acid, ticlopidine, clopidogrel, trapidil (triazolopyrimidine), naftidrofuryl, auriritricarboxylic acid and glycoprotein Ilb/Illa inhibitors such as abcixamab, eptifibatide, and tirogiban.
Other agents capable of affecting the rate of clotting include glycosaminoglycans, danaparoid, 4-hydroxycourmarin, warfarin sodium, dicumarol, phenprocoumon, indan-1,3-dione, acenocoumarol, anisindione, and rodenticides including bromadiolone, brodifacoum, diphenadione, chlorophacinone, and pidnone.
The polymeric formulation may be or include a hydrophilic polymer gel that itself has anti-thrombogenic properties. For example, the composition can be in the form of a coating that can comprise a hydrophilic, biodegradable polymer that is physically removed from the surface of the device over time, thus reducing adhesion of platelets to the device surface.
The gel composition can include a polymer or a blend of polymers.
Representative examples include alginates, chitosan and chitosan sulfate, hyaluronic acid, dextran sulfate, PLURONIC polymers (e.g., F-127 or F87), chain extended PLURONIC polymers, various polyester-polyether block copolymers of various configurations (e.g., AB, ABA, or BAB, where A is a polyester such as PLA, PGA, PLGA, PCL or the like), examples of which include MePEG-PLA, PLA-PEG-PLA, and the like). In one embodiment, the anti-thrombotic composition can include a crosslinked gel formed from a combination of molecules (e.g., PEG) having two or more terminal electrophilic groups and two or more nucleophilic groups.
The polymeric formulation may further include an agent from one of the following classes of compounds: anti-inflammatory agents (e.g., dexamethasone, cortisone, fludrocortisone, prednisone, prednisolone, 6a-methylprednisolone, triamcinolone, betamethasone, and aspirin); MMP
inhibitors (e.g., batimistat, marimistat, TIMP's representative examples of which are included in U.S. Patent Nos. 5,665,777; 5,985,911; 6,288,261; 5,952,320;
6,441,189; 6,235,786; 6,294,573; 6,294,539; 6,563,002; 6,071,903; 6,358,980;
5,852,213; 6,124,502; 6,160,132; 6,197,791; 6,172,057; 6,288,086; 6,342,508;
6,228,869; 5,977,408; 5,929,097; 6,498,167; 6,534,491; 6,548,524; 5,962,481;
6,197,795; 6,162,814; 6,441,023; 6,444,704; 6,462,073; 6,162,821; 6,444,639;
6,262,080; 6,486,193; 6,329,550; 6,544,980; 6,352,976; 5,968,795; 5,789,434;
5,932,763; 6,500,847; 5,925,637; 6,225,314; 5,804,581; 5,863,915; 5,859,047;
5,861,428; 5,886,043; 6,288,063; 5,939,583; 6,166,082; 5,874,473; 5,886,022;
5,932,577; 5,854,277; 5,886,024; 6,495,565; 6,642,255; 6,495,548; 6,479,502;
5,696,082; 5,700,838; 6,444,639; 6,262,080; 6,486,193; 6,329,550; 6,544,980;
6,352,976; 5,968,795; 5,789,434; 5,932,763; 6,500,847; 5,925,637; 6,225,314;
5,804,581; 5,863,915; 5,859,047; 5,861,428; 5,886,043; 6,288,063; 5,939,583;
6,166,082; 5,874,473; 5,886,022; 5,932,577; 5,854,277; 5,886,024; 6,495,565;
6,642,255; 6,495,548; 6,479,502; 5,696,082; 5,700,838; 5,861,436; 5,691,382;
5,763,621; 5,866,717; 5,902,791; 5,962,529; 6,017,889; 6,022,873; 6,022,898;
6,103,739; 6,127,427; 6,258,851; 6,310,084; 6,358,987; 5,872,152; 5,917,090;
6,124,329; 6,329,373; 6,344,457; 5,698,706; 5,872,146; 5,853,623; 6,624,144;
6,462,042; 5,981,491; 5,955,435; 6,090,840; 6,114,372; 6,566,384; 5,994,293;
6,063,786; 6,469,020; 6,118,001; 6,187,924; 6,310,088; 5,994,312; 6,180,611;
6,110,896; 6,380,253; 5,455,262; 5,470,834; 6,147,114; 6,333,324; 6,489,324;
6,362,183; 6,372,758; 6,448,250; 6,492,367; 6,380,258; 6,583,299; 5,239,078;

5,892,112; 5,773,438; 5,696,147; 6,066,662; 6,600,057; 5,990,158; 5,731,293;
6,277,876; 6,521,606; 6,168,807; 6,506,414; 6,620,813; 5,684,152; 6,451,791;
6,476,027; 6,013,649; 6,503,892; 6,420,427; 6,300,514; 6,403,644; 6,177,466;
6,569,899; 5,594,006; 6,417,229; 5,861,510; 6,156,798; 6,387,931; 6,350,907;
6,090,852; 6,458,822; 6,509,337; 6,147,061; 6,114,568; 6,118,016; 5,804,593;
5,847,153; 5,859,061; 6,194,451; 6,482,827; 6,638,952; 5,677,282; 6,365,630;
6,130,254; 6,455,569; 6,057,369; 6,576,628; 6,110,924; 6,472,396; 6,548,667;
5,618,844; 6,495,578; 6,627,411; 5,514,716; 5,256,657; 5,773,428; 6,037,472;
6,579,890; 5,932,595; 6,013,792; 6,420,415; 5,532,265; 5,639,746; 5,672,598;
5,830,915; 6,630,516; 5,324,634; 6,277,061; 6,140,099; 6,455,570; 5,595,885;
6,093,398; 6,379,667; 5,641,636; 5,698,404; 6,448,058; 6,008,220; 6,265,432;
6,169,103; 6,133,304; 6,541,521; 6,624,196; 6,307,089; 6,239,288; 5,756,545;
6,020,366; 6,117,869; 6,294,674; 6,037,361; 6,399,612; 6,495,568; 6,624,177;
5,948,780; 6,620,835; 6,284,513; 5,977,141; 6,153,612; 6,297,247; 6,559,142;
6,555,535; 6,350,885; 5,627,206; 5,665,764; 5,958,972; 6,420,408; 6,492,422;
6,340,709; 6,022,948; 6,274,703; 6,294,694; 6,531,499; 6,465,508; 6,437,177;
6,376,665; 5,268,384; 5,183,900; 5,189,178; 6,511,993; 6,617,354; 6,331,563;
5,962,466; 5,861,427; 5,830,869; and 6,087,359), cytolcine inhibitors (chlorpromazine, mycophenolic acid, rapamycin, 1a-hydroxy vitamin D3), IMPDH (inosine monophosplate dehydrogenase) inhibitors (e.g., mycophenolic acid, ribaviran, aminothiadiazole, thiophenfurin, tiazofurin, viramidine) (Representative examples are included in U.S. Patent, Nos. 5,536,747;
5,807,876; 5,932,600; 6,054,472; 6,128,582; 6,344,465; 6,395,763; 6,399,773;
6,420,403; 6,479,628; 6,498,178; 6,514,979; 6,518,291; 6,541,496; 6,596,747;
6,617,323; and 6,624,184, U.S. Patent Application Nos. 2002/0040022A1, 2002/0052513A1, 2002/0055483A1, 2002/0068346A1, 2002/0111378A1, 2002/0111495A1, 2002/0123520A1, 2002/0143176A1, 2002/0147160A1, 2002/0161038A1, 2002/0173491 A1, 2002/0183315A1, 2002/0193612A1, 2003/0027845A1, 2003/0068302A1, 2003/0105073A1, 2003/0130254A1, 2003/0143197A1, 2003/0144300A1, 2003/0166201 A1, 2003/0181497A1, 2003/0186974A1, 2003/0186989A1, and 2003/0195202A1, and PCT
Publication Nos. WO 00/24725A1, WO 00/25780A1, WO 00/26197A1, WO
00/51615A1, WO 00/56331 A1, WO 00/73288A1, WO 01 /00622A1, WO
01/66706A1, WO 01/79246A2, WO 01/81340A2, WO 01/85952A2, WO
02/16382A1, WO 02/18369A2, WO 02/051814A1, WO 02/057287A2, WO
02/057425A2, WO 02/060875A1, WO 02/060896A1, WO 02/060898A1, WO
02/068058A2, WO 03/020298A1, WO 03/037349A1, WO 03/039548A1, WO
03/045901A2, WO 03/047512A2, WO 03/053958A1, WO 03/055447A2, WO
03/059269A2, WO 03/063573A2, WO 03/087071 A1, WO 99/001545A1, WO
97/40028A1, WO 97/41211 A1, WO 98/40381 A1, and WO 99/55663A1 ), p38 MAP kinase inhibitors (MAPK) (e.g., GW-2286, CGP-52411, BIRB-798, SB220025, RO-320-1195, RWJ-67657, RWJ-68354, SCIO-469) (Representative examples are included in U.S. Patent Nos. 6,300,347;
6,316,464; 6,316,466; 6,376,527; 6,444,696; 6,479,507; 6,509,361; 6,579,874, and 6,630,485, and U.S. Patent Application Publication Nos. 2001/0044538A1, 2002/0013354A1, 2002/0049220A1, 2002/0103245A1, 2002/0151491 A1, 2002/0156114A1, 2003/0018051 A1, 2003/0073832A1, 2003/0130257A1, 2003/0130273A1, 2003/0130319A1, 2003/0139388A1, 2003/0139462A1, 2003/0149031 A1, 2003/0166647A1, and 2003/0181411 A1, and PCT
Publication Nos. WO 00/63204A2, WO 01/21591A1, WO 01/35959A1, WO
01/74811A2, WO 02/18379A2, WO 02/064594A2, WO 02/083622A2, WO
02/094842A2,W0 02/096426A1, WO 02/101015A2, WO 02/103000A2, WO
03/008413A1, WO 03/016248A2, WO 03/020715A1, WO 03/024899A2, WO
03/031431A1, WO 03/040103A1, WO 03/053940A1, WO 03/053941 A2, WO
03/063799A2, WO 03/079986A2, WO 03/080024A2, WO 03/082287A1, WO
97/44467A1, WO 99/01449A1, and WO 99158523A1 ), and immunomodulatory agents (rapamycin, everolimus, ABT-578, azathioprine azithromycin, analogues of rapamycin, including tacrolimus and derivatives thereof (e.g., EP 018416281 and those described in U.S. Patent No. 6,258,823) and everolimus and derivatives thereof (e.g., U.S. Patent No. 5,665,772). Further representative examples of sirolimus analogues and derivatives include ABT-578 and those found in PCT Publication Nos. WO 97/10502, WO 96/41807, WO 96/35423, WO 96/03430, WO 96/00282, WO 95/16691, WO 95/15328, WO 95/07468, WO 95/04738, WO 95/04060, WO 94/25022, WO 94/21644, WO 94/18207, WO 94/10843, WO 94109010, WO 94/04540, WO 94/02485, WO 94/02137, WO 94/02136, WO 93/25533, WO 93/18043, WO 93/13663, WO 93/11130, WO
93/10122, WO 93/04680, WO 92114737, and WO 92/05179 and in U.S. Patent Nos. 6,342,507; 5,985,890; 5,604,234; 5,597,715; 5,583,139; 5,563,172;
5,561,228; 5,561,137; 5,541,193; 5,541,189; 5,534,632; 5,527,907; 5,484,799;
5,457,194; 5,457,182; 5,362,735; 5,324,644; 5,318,895; 5,310,903; 5,310,901;
5,258,389; 5,252,732; 5,247,076; 5,225,403; 5,221,625; 5,210,030; 5,208,241;
5,200,411; 5,198,421; 5,147,877; 5,140,018; 5,116,756; 5,109,112; 5,093,338;
and 5,091,389.
Other examples of biologically active agents which may be included in the compositions of the invention include tyrosine kinase inhibitors, such as imantinib, ZK-222584, CGP-52411, CGP-53716, NVP-AAK980-NX, CP-127374, CP-564959, PD-171026, PD-173956, PD-180970, SU-0879, and SKI-606; MMP inhibitors such as nimesulide, PKF-241-466, PKF-242-484, CGS-27023A, SAR-943, primomastat, SC-77964, PNU-171829, AG-3433, PNU-142769, SU-5402, and Dexlipotam; p38 MAP kinase inhibitors such as include CGH-2466 and PD-98-59; immunosuppressants such as argyrin B, macrocyclic lactone, ADZ-62-826, CCI-779, tilomisole, amcinonide, FK-778, AVE-1726, and MDL-28842; cytokine inhibitors such as TNF-484A, PD-172084, CP-293121, CP-353164, and PD-168787; NFKB inhibitors, such as, AVE-0547, AVE-0545, and IPL-576092; HMGCoA reductase inhibitors, such as, pravestatin, atorvastatin, fluvastatin, dalvastatin, glenvastatin, pitavastatin, CP-83101, U-20685; apoptosis antagonist (e.g., troloxamine, TCH-346 (N-methyl-N-propargyl-10-aminomethyl-dibenzo(b,f)oxepin); and caspase inhibitors (e.g., PF-5901 (benzenemethanol, alpha-pentyl-3-(2-quinolinylmethoxy)-), and JNK inhibitor (e.g., AS-602801 ).

In another aspect, the composition may further include an antibiotic (e.g., amoxicillin, trimethoprim-sulfamethoxazole, azithromycin, clarithromycin, amoxicillin-clavulanate, cefprozil, cefuroxime, cefpodoxime, or cefd i n i r).
In certain aspects, a polymeric composition comprising a fibrosis-inhibiting agent is combined with an agent that can modify metabolism of the agent in vivo to enhance efficacy of the fibrosis-inhibiting agent. One class of therapeutic agents that can be used to alter drug metabolism includes agents capable of inhibiting oxidation of the anti-scarring agent by cytochrome P450 (CYP). In one embodiment, compositions are provided that include a fibrosis-inhibiting agent (e.g., paclitaxel, rapamycin, everolimus) and a CYP
inhibitor, which may be combined (e.g., coated) with any of the devices described herein, including, without limitation, stents, grafts, patches, valves, wraps, and films.
Representative examples of CYP inhibitors include flavones, azole antifungals, macrolide antibiotics, HIV protease inhibitors, and anti-sense oligomers.
Devices comprising a combination of a fibrosis-inhibiting agent and a CYP
inhibitor may be used to treat a variety of proliferative conditions that can lead to undesired scarring of tissue, including intimal hyperplasia, surgical adhesions, and tumor growth.
In another aspect, a polymeric composition comprising an anti-infective agent (e.g., anthracyclines (e.g., doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists (e.g., methotrexate and/or podophylotoxins (e.g., etoposide)) can be combined with traditional antibiotic and/or antifungal agents to enhance efficacy. The anti-infective agent may be further combined with anti-thrombotic and/or antiplatelet agents (for example, heparin, dextran sulfate, danaparoid, lepirudin, hirudin, AMP, adenosine, 2-chloroadenosine, aspirin, phenylbutazone, indomethacin, meclofenamate, hydrochloroquine, dipyridamole, iloprost, ticlopidine, clopidogrel, abcixamab, eptifibatide, tirofiban, streptokinase, and/or tissue plasminogen activator) to enhance efficacy.

Although the above therapeutic agents have been provided for the purposes of illustration, it should be understood that the present invention is not so limited. For example, although agents are specifically referred to above, the present invention should be understood to include analogues, derivatives and conjugates of such agents. As an illustration, paclitaxel should be understood to refer to not only the common chemically available form of paclitaxel, but analogues (e.g., TAXOTERE, as noted above) and paclitaxel conjugates (e.g., paclitaxel-PEG, paclitaxel-dextran, or paclitaxel-xylos). In addition, as will be evident to one of skill in the art, although the agents set forth above may be noted within the context of one class, many of the agents listed in fact have multiple biological activities. Further, more than one therapeutic agent may be utilized at a time (i.e., in combination), or delivered sequentially.
H. Compositions and Methods for Generating Compositions Which Comprise a Therapeutic Agent The present invention provides various compositions which can be used to inhibit fibrosis and/or infection of tissue in the vicinity of a treatment site (e.g., a surgical site). Within various embodiments, fibrosis and/or infection is inhibited by local or systemic release of specific pharmacological agents that become localized at the site or intervention. Within other embodiments, fibrosis and/or infection can be inhibited by local or systemic release of specific pharmacological agents that become localized adjacent to a device or implant that has been introduced into a host. In certain embodiments, compositions are provided which inhibit fibrosis in and around an implanted device, or prevent "stenosis" of a device/implant in situ, thus enhancing the efficacy. In other embodiments, anti-infective compositions are provided which inhibit or prevent infection in and around an implanted device.
There are numerous methods available for optimizing delivery of the therapeutic agent to the site of the intervention. Several of these are described below.

1 ) Systemic, Regional and Local Delivery of Therapeutic Agents A variety of drug-delivery technologies are available for systemic, regional and local delivery of anti-infective and/or anti-fibrosis therapeutic agents.
For systemic delivery of therapeutic agents, several routes of administration would be suitable to provide systemic exposure of the therapeutic agent, including: (a) intravenous, (b) oral, (c) subcutaneous, (d) intraperitoneal, (e) intrathecal, (f) inhaled and intranasal, (g) sublingual or transbuccal, (h) rectal, (i) intravaginal, (j) intra-arterial, (k) intracardiac, (I) transdermal, (m) intra-ocular and (n) intramuscular. The therapeutic agent may be administered as a sustained low dose therapy to prevent disease progression, prolong disease remission, or decrease symptoms in active disease. Alternatively, the therapeutic agent may be administered in higher doses as a "pulse" therapy to induce remission in acutely active disease. The minimum dose capable of achieving these endpoints can be used and can vary according to patient, severity of disease, formulation of the administered agent, potency and tolerability of. the therapeutic agent, and route of administration.
For regional and local delivery of therapeutic agents, several techniques would be suitable to achieve preferentially elevated levels of therapeutic agents in the vicinity of the area to be treated. These include:
(a) using drug-delivery catheters and/or a syringe and needle for local, regional or systemic delivery of fibrosis-inhibiting agents to the tissue surrounding the device or implant (typically, drug delivery catheters are advanced through the circulation or inserted directly into tissues under radiological guidance until they reach the desired anatomical location; the fibrosis-inhibiting agent can then be released from the catheter lumen in high local concentrations in order to deliver therapeutic doses of the drug to the tissue surrounding the device or implant);
(b) drug localization techniques such as magnetic, ultrasonic or MRI-guided drug delivery; (c) chemical modification of the therapeutic drug or formulation designed to increase uptake of the agent into damaged tissues (e.g., antibodies directed against damaged or healing tissue components such as macrophages, neutrophils, smooth muscle cells, fibroblasts, extracellular matrix components, neovascular tissue); (d) chemical modification of the therapeutic drug or formulation designed to localize the drug to areas of bleeding or disrupted vasculature; and/or (e) direct injection, for example subcutaneous, intramuscular, intra-articular, etc, of the therapeutic agent, for example, under normal or endoscopic vision.
2) Infiltration of Therapeutic Agents into the Tissue Surrounding a Device or Implant Alternatively, the tissue cavity or surgical pocket into which a device or implant is placed can be treated with an anti-infective and/or fibrosis-inhibiting therapeutic agent prior to, during, or after the procedure. This can be accomplished in several ways including: (a) topical application of the agent into the anatomical space or surface where the device will be placed (particularly useful for this embodiment is the use of polymeric carriers which release the agent over a period ranging from several hours to several weeks.
Compositions that can be used for this application include, e.g., fluids, microspheres, pastes, gels, microparticulates, sprays, aerosols, solid implants and other formulations which release a therapeutic agent into the region where the device or implant will be implanted); (b) microparticulate forms of the therapeutic agent are also useful for directed delivery into the implantation site;
(c) sprayable collagen-containing formulations such as COSTASIS and crosslinked derivatized polyethylene glycol) -collagen compositions (described, e.g., in U.S. Patent Nos. 5,874,500 and 5,565,519 and referred to herein as "CT3" (both from Angiotech Pharmaceuticals, Inc., Canada), either alone, or loaded with a therapeutic agent, applied to the implantation site (or the implantldevice surface); (d) sprayable PEG-containing formulations such as COSEAL or ADHIBIT (Angiotech Pharmaceuticals, Inc.), SPRAYGEL or DURASEAL (both from Confluent Surgical, Inc., Boston, MA), either alone, or loaded with a therapeutic agent, applied to the implantation site (or the implant/device surface); (e) fibrin-containing formulations such as FLOSEAL or TISSEEL (both from Baxter Healthcare Corporation, Fremont, CA), applied to the implantation site (or the implantldevice surface); (f) hyaluronic acid-s containing formulations such as RESTYLANE or PERLANE (both from Q-Med AB, Sweden), HYLAFORM (Inamed Corporation (Santa Barbara, CA)), SYNVISC (Biomatrix, Inc., Ridgefield, NJ), SEPRAFILM or SEPRACOAT (both from Genzyme Corporation, Cambridge, MA) loaded with a therapeutic agent applied to the implantation site (or the implant/device surface); (g) polymeric gels for surgical implantation such as REPEL (Life Medical Sciences, Inc., Princeton, NJ) or FLOGEL (Baxter Healthcare Corporation) loaded with a therapeutic agent applied to the implantation site (or the implant/device surface); (h) orthopedic "cements" used to hold prostheses and tissues in place with a therapeutic agent applied to the implantation site (or the implant/device surface); (i) surgical adhesives containing cyanoacrylates such as DERMABOND (Johnson & Johnson, Inc., New Brunswick, NJ), INDERMIL
(U.S. Surgical Company, Norwalk, CT), GLUSTITCH (Blacklock Medical Products Inc., Canada), TISSUMEND If (Veterniary Products Laboratories"
Phoenix, AZ), VETBOND (3M Company, St. Paul, MN), HISTOACRYL BLUE
(Davis & Geck, St. Louis, MO) and ORABASE SMOOTHE-N-SEAL Liquid Protectant (Colgate-Palmolive Company, New York, NY) loaded with a therapeutic agent, applied to the implantation site (or the implant/device surface); andlor (j) protein-based sealants or adhesives such as BIOGLUE
(Cryolife, Inc.) and TISSUEBOND (TissueMed, Ltd.) loaded with a therapeutic agent, applied to the implantation site (or the implant/device surface).
A preferred polymeric matrix which can be used to help prevent the formation of fibrous tissue, either alone or in combination with a fibrosis inhibiting agent/composition, is formed from reactants comprising either one or both of pentaerythritol polyethylene glycol)ether tetra-sulfhydryl] (4-armed thiol PEG, which includes structures having a linking groups) between a sulfhydryl groups) and the terminus of the polyethylene glycol backbone) and pentaerythritol polyethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG, which again includes structures having a linking groups) between a NHS groups) and the terminus of the polyethylene glycol backbone) as reactive reagents. Another preferred composition comprises either one or both of pentaerythritol polyethylene glycol)ether tetra-amino] (4-armed amino PEG, which includes structures having a linking groups) between an amino groups) and the terminus of the polyethylene glycol backbone) and pentaerythritol polyethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG, which again includes structures having a linking groups) between a NHS
groups) and the terminus of the polyethylene glycol backbone) as reactive reagents. Chemical structures for these reactants are shown in, e.g., U.S.
Patent 5,874,500. Optionally, collagen or a collagen derivative (e.g., methylated collagen) is added to the polyethylene glycol)-containing reactants) to form a preferred crosslinked matrix that can serve as a polymeric carrier for a therapeutic agent or a stand-alone composition to help prevent the formation of fibrous tissue.
3) Sustained-Release Preparations of Therapeutic Agents As described previously, desired therapeutic agents may be admixed with, blended with, conjugated to, or, otherwise modified to contain a polymer composition (which may be either biodegradable or non-biodegradable) or a non-polymeric composition in order to release the therapeutic agent over a prolonged period of time. For many of the aforementioned embodiments, localized delivery as well as localized sustained delivery of the fibrosis-inhibiting and/or anti-infective agent may be required.
For example, a desired therapeutic agent may be admixed with, blended with, conjugated to, or, otherwise modified to contain a polymeric composition (which may be either biodegradable or non-biodegradable) or non-polymeric composition in order to release the therapeutic agent over a period of time.

Representative examples of biodegradable polymers suitable for the delivery of the aforementioned therapeutic agents include albumin, collagen, gelatin, hyaluronic acid, starch, cellulose and cellulose derivatives (e.g., regenerated cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropylmethylcellulose phthalate), casein, dextrans, polysaccharides, fibrinogen, poly(ether ester) multiblock copolymers, based on polyethylene glycol) and poly(butylene terephthalate), tyrosine-derived polycarbonates (e.g., U.S. Patent No. 6,120,491), poly(hydroxyl acids), poly(D,L-lactide), poly(D,L-lactide-co-glycolide), poly(glycolide), poly(hydroxybutyrate), polydioxanone, poly(alkylcarbonate) and poly(orthoesters), polyesters, poly(hydroxyvaleric acid), polydioxanone, polyesters, poly(malic acid), poly(tartronic acid), poly(acrylamides), polyanhydrides, polyphosphazenes, poly(amino acids), poly(alkylene oxide)-polyester) block copolymers (e.g., X-Y, X-Y-X, Y-X-Y, R-(Y-X)", or R-(X-Y)", where X is a polyalkylene oxide (e.g., poly(ethylene glycol, polypropylene glycol) and block copolymers of polyethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF
Corporation, Mount Olive, NJ) and Y is a polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, y-decanolactone, ~-decanolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-Zone (e.g., PLGA, PLA, PCL, polydioxanone and copolymers thereof) and R is a multifunctional initiator), and the copolymers as well as blends thereof (see generally, Illum, L., Davids, S.S. (eds.) "Polymers in Controlled Drug Delivery" Wright, Bristol, 1987;
Arshady, J. Controlled Release 7 7:1-22, 1991; Pitt, Int. J. Phar. 59:173-196, 1990; Holland et al., J. Controlled Release 4:155-0180, 1986).

Representative examples of non-degradable polymers suitable for the delivery of the aforementioned therapeutic agents include polyethylene-co-vinyl acetate) ("EVA") copolymers, aromatic polyesters, such as polyethylene terephthalate), silicone rubber, acrylic polymers (polyacrylate, polyacrylic acid, polymethylacrylic acid, polymethylmethacrylate, poly(butyl methacrylate)), poly(alkylcynoacrylate) (e.g., poly(ethylcyanoacrylate), poly(butyicyanoacrylate) poly(hexylcyanoacrylate) poly(octylcyanoacrylate)), acrylic resin, polyethylene, polypropylene, polyamides (nylon 6,6), polyurethanes (e.g., CHRONOFLEX AL
and CHRONOFLEX AR (both from CardioTech International, Inc., Woburn, MA), TECOFLEX, and BIONATE (Polymer Technology Group, Inc., Emeryville, CA))" polyester urethanes), poly(ether urethanes), polyester-urea), polyethers (poly(ethylene oxide), polypropylene oxide), polyoxyalkylene ether block copolymers based on ethylene oxide and propylene oxide such as the PLURONIC polymers (e.g., F-127 or F87) from BASF Corporation (Mount Olive, NJ), and poly(tetramethylene glycol), styrene-based polymers (polystyrene, polystyrene sulfonic acid), poly(styrene)-block-poly(isobutylene)-block-poly(styrene), poly(styrene)-poly(isoprene) block copolymers), and vinyl polymers (polyvinylpyrrolidone, polyvinyl alcohol), polyvinyl acetate phthalate) as well as copolymers and blends thereof. Polymers may also be developed which are either anionic (e.g., alginate, carrageenan, carboxymethyl cellulose, poly(acrylamido-2-methyl propane sulfonic acid) and copolymers thereof, poly(methacrylic acid and copolymers thereof and poly(acrylic acid) and copolymers thereof, as well as blends thereof, or cationic (e.g., chitosan, poly-L-lysine, polyethylenimine, and poly(allyl amine)) and blends thereof (see generally, Dunn et al., J. Applied Polymer Sci. 50:353-365, 1993; Cascone et al., J. Materials Sci.: Materials in Medicine 5:770-774, 1994; Shiraishi et al., Biol. Pharm. Bull. 16(11 ):1164-1168, 1993; Thacharodi and Rao, Int'I J.
Pharm.
120:115-118, 1995; Miyazaki et al., Int'I J. Pharm. 115:257-263, 1995).
Some examples of preferred polymeric carriers for the practice of this invention include polyethylene-co-vinyl acetate), polyurethanes, poly (D,L-lactic acid) oligomers and polymers, poly (L-lactic acid) oligomers and polymers, poly (glycolic acid), copolymers of lactic acid and glycolic acid, copolymers of lactide and glycolide, poly (caprolactone), poly (valerolactone), polyanhydrides, copolymers of poly (caprolactone) or poly (lactic acid) with a polyethylene glycol (e.g., MePEG), block copolymers of the form X-Y, X-Y-X, Y-X-Y, R-(Y-X)", or R-(X-Y)", where X is a polyalkylene oxide (e.g., poly(ethylene glycol, polypropylene glycol) and block copolymers of polyethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, y-decanolactone, ~-decanolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-Zone and R is a multifunctional initiator), silicone rubbers, poly(styrene)block-poly(isobutylene)-block-poly(styrene), poly(acrylate) polymers and blends, admixtures, or co-polymers of any of the above. Other preferred polymers include collagen, poly(alkylene oxide)-based polymers, polysaccharides such as hyaluronic acid, chitosan and fucans, and copolymers of polysaccharides with degradable polymers.
Other representative polymers capable of sustained localized delivery of anti-infective andlor fibrosis-inhibiting therapeutic agents include carboxylic polymers, polyacetates, polycarbonates, polyethers, polyethylenes, polyvinylbutyrals, polysilanes, polyureas, polyoxides, polystyrenes, polysulfides, polysulfones, polysulfonides, polyvinylhalides, pyrrolidones, rubbers, thermal-setting polymers, cross-linkable acrylic and methacrylic polymers, ethylene acrylic acid copolymers, styrene acrylic copolymers, vinyl acetate polymers and copolymers, vinyl acetal polymers and copolymers, epoxies, melamines, other amino resins, phenolic polymers, and copolymers thereof, water-insoluble cellulose ester polymers (including cellulose acetate propionate, cellulose 14~

acetate, cellulose acetate butyrate, cellulose nitrate, cellulose acetate phthalate, and mixtures thereof), polyvinylpyrrolidone, polyethylene glycols, polyethylene oxide, polyvinyl alcohol, polyethers, polysaccharides, hydrophilic polyurethane, polyhydroxyacrylate, dextran, xanthan, hydroxypropyl cellulose, and homopolymers and copolymers of N-vinylpyrrolidone, N-vinyllactam, N-vinyl butyrolactam, N-vinyl caprolactam, other vinyl compounds having polar pendant groups, acrylate and methacrylate having hydrophilic esterifying groups, hydroxyacrylate, and acrylic acid, and combinations thereof; cellulose esters and ethers, ethyl cellulose, hydroxyethyl cellulose, cellulose nitrate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, natural and synthetic elastomers, rubber, acetal, styrene polybutadiene, acrylic resin, polyvinylidene chloride, polycarbonate, homopolymers and copolymers of vinyl compounds, polyvinylchloride, and polyvinylchloride acetate.
Representative examples of patents relating to drug-delivery polymers and their preparation include PCT Publication Nos. WO 98/19713, WO 01/17575, WO 01/41821, WO 01/41822, and WO 01/15526 (as well as the corresponding U.S. applications), U.S. Patent Nos. 4,500,676, 4,582,865, 4,629,623, 4,636,524, 4,713,448, 4,795,741, 4,913,743, 5,069,899, 5,099,013, 5,128,326, 5,143,724, 5,153,174, 5,246,698, 5,266,563, 5,399,351, 5,525,348, 5,800,412, 5,837,226, 5,942,555, 5,997,517, 6,007,833, 6,071,447, 6,090,995, 6,106,473, 6,110,483, 6,121,027, 6,156,345, 6,214,901, 6,368,611 6,630,155, 6,528,080, RE37,950, 6,46,1631, 6,143,314, 5,990,194, 5,792,469, 5,780,044, 5,759,563, 5,744,153, 5,739,176, 5,733,950, 5,681,873, 5,599,552, 5,340,849, 5,278,202, 5,278,201, 6,589,549, 6,287,588, 6,201,072, 6,117,949, 6,004,573, 5,702,717, 6,413,539, 5,714,159, 5,612,052, and U.S. Patent Application Publication Nos. 2003/0068377, 2002/0192286, 2002/0076441, and 2002/0090398.
It should be obvious to one of skill in the art that the polymers as described herein can also be blended or copolymerized in various compositions as required to deliver therapeutic doses of biologically active agents.

Polymeric carriers for anti-infective and/or fibrosis-inhibiting therapeutic agents can be fashioned in a variety of forms, with desired release characteristics and/or with specific properties depending upon the composition being utilized. For example, polymeric carriers may be fashioned to release a therapeutic agent upon exposure to a specific triggering event such as pH
(see, e.g., Heller et al., "Chemically Self-Regulated Drug Delivery Systems," in Polymers in Medicine 111, Elsevier Science Publishers B.V., Amsterdam, 1988, pp. 175-188; Kang et al., J. Applied Polymer Sci. 48:343-354, 1993; Dong et al., J. Controlled Release 19:171-178, 1992; Dong and Hoffman, J. Controlled Release 15:141-152, 1991; Kim et al., J. Controlled Release 28:143-152, 1994;
Cornejo-Bravo et al., J. Controlled Release 33:223-229, 1995; Wu and Lee, Pharm. Res. 10(10):1544-1547, 1993; Serres et al., Pharm. Res. 13(2):196-201, 1996; Peppas, "Fundamentals of pH- and Temperature-Sensitive Delivery Systems," in Gurny et al. (eds.), Pulsatile Drug Delivery, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1993, pp. 41-55; Doelker, "Cellulose Derivatives," 1993, in Peppas and Langer (eds.), Biopolymers I, Springer-Verlag, Berlin). Representative examples of pH-sensitive polymers include poly (acrylic acid) and its derivatives (including for example, homopolymers such as poly(aminocarboxylic acid); poly(acrylic acid); poly(methyl acrylic acid), copolymers of such homopolymers, and copolymers of poly(acrylic acid) and/or acrylate or acrylamide (monomers such as those discussed above. Other pH
sensitive polymers include polysaccharides such as cellulose acetate phthalate;
hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose acetate succinate; cellulose acetate trimellilate; and chitosan. Yet other pH
sensitive polymers include any mixture of a pH sensitive polymer and a water-soluble polymer.
Likewise, ant-infective and/or fibrosis-inhibiting therapeutic agents can be delivered via polymeric carriers which are temperature sensitive (see, e.g., Chen et al., "Novel Hydrogels of a Temperature-Sensitive PLURONIC
Grafted to a Bioadhesive Polyacrylic Acid Backbone for Vaginal Drug Delivery,"

in Proceed. Intern. Symp. Control. Rel. Bioact. Mater. 22:167-168, Controlled Release Society, Inc., 1995; Okano, "Molecular Design of Stimuli-Responsive Hydrogels for Temporal Controlled Drug Delivery," in Proceed. Intern. Symp.
Control. Rel. Bioact. Mater. 22:111-112, Controlled Release Society, Inc., 1995;
Johnston et al., Pharm. Res. 9(3):425-433, 1992; Tung, Int'I J. Pharm. 107:85-90, 1994; Harsh and Gehrke, J. Controlled Release 17:175-186, 1991; Bae et al., Pharm. Res. 8(4):531-537, 1991; Dinarvand and D'Emanuele, J. Controlled Release 36:221-227, 1995; Yu and Grainger, "Novel Thermo-sensitive Amphiphilic Gels: Poly N-isopropylacrylamide-co-sodium acrylate-co-n-N-alkylacrylamide Network Synthesis and Physicochemical Characterization,"
Dept. of Chemical & Biological Sci., Oregon Graduate Institute of Science &
Technology, Beaverton, OR, pp. 820-821; ~hou and Smid, "Physical Hydrogels of Associative Star Polymers," Polymer Research Institute, Dept. of Chemistry, College of Environmental Science and Forestry, State Univ. of New York, Syracuse, NY, pp. 822-823; Hoffman et al., "Characterizing Pore Sizes and Water 'Structure' in Stimuli-Responsive Hydrogels," Center for Bioengineering, Univ. of Washington, Seattle, WA, p. 828; Yu and Grainger, "Thermo-sensitive Swelling Behavior in Crosslinked N-isopropylacrylamide Networks: Cationic, Anionic and Ampholytic Hydrogels," Dept. of Chemical & Biological Sci., Oregon Graduate Institute of Science & Technology, Beaverton, OR, pp. 829-830; Kim et al., Pharm. Res. 9(3):283-290, 1992; Bae et al., Pharm. Res.
8(5):624-628,' 1991; Kono et al., J. Controlled Release 30:69-75, 1994;
Yoshida et al., J. Controlled Release 32:97-102, 1994; Okano et al., J. Controlled Release 36:125-133, 1995; Chun and Kim, J. Controlled Release 38:39-47, 1996; D'Emanuele and Dinarvand, Int'I J. Pharm. 118:237-242, 1995; Katono et al., J. Controlled Release 16:215-228, 1991; Hoffman, "Thermally Reversible Hydrogels Containing Biologically Active Species," in Migliaresi et al.
(eds.), Polymers in Medicine III, Elsevier Science Publishers B.V., Amsterdam, 1988, pp. 161-167; Hoffman, "Applications of Thermally Reversible Polymers and Hydrogels in Therapeutics and Diagnostics," in Third International Symposium on Recent Advances in Drug Delivery Systems, Salt Lake City, UT, Feb. 24-27, 1987, pp. 297-305; Gutowska et al., J. Controlled Release 22:95-104, 1992;
Palasis and Gehrke, J. Controlled Release 18:1-12, 1992; Paavola et al., Pharm. Res. 12(12):1997-2002, 1995).
Representative examples of thermogelling polymers, and the gelatin temperature (LCST (°C)) include homopolymers such as poly(N-methyl-N-n-propylacrylamide), 19.8; poly(N-n-propylacrylamide), 21.5;
poly(N-methyl-N-isopropylacrylamide), 22.3; poly(N-n-propylmethacrylamide), 28.0; poly(N-isopropylacrylamide), 30.9; poly(N, n-diethylacrylamide), 32.0;
poly(N-isopropylmethacrylamide), 44.0; poly(N-cyclopropylacrylamide), 45.5;
poly(N-ethylmethyacrylamide), 50.0; poly(N-methyl-N-ethylacrylamide), 56.0;
poly(N-cyclopropylmethacrylamide), 59.0; poly(N-ethylacrylamide), 72Ø
Moreover thermogelling polymers may be made by preparing copolymers between (among) monomers of the above, or by combining such homopolymers with other water-soluble polymers such as acrylmonomers (e.g., acrylic acid and derivatives thereof, such as methylacrylic acid, acrylate monomers and derivatives thereof, such as butyl methacrylate, butyl acrylate, lauryl acrylate, and acrylamide monomers and derivatives thereof, such as N-butyl acrylamide and acrylamide).
Other representative examples of thermogelling polymers include cellulose ether derivatives such as hydroxypropyl cellulose, 41 °C;
methyl cellulose, 55°C; hydroxypropylmethyl cellulose, 66°C; and ethylhydroxyethyl cellulose, polyalkylene oxide-polyester block copolymers of the structure X-Y, Y-X-Y and X-Y-X where X in a polyalkylene oxide and Y is a biodegradable polyester (e.g., PLG-PEG-PLG) and PLURONICs such as F-127, 10 - 15°C;
L-122, 19°C; L-92, 26°C; L-81, 20°C; and L-61, 24°C.
Representative examples of patents relating to thermally gelling polymers and the preparation include U.S. Patent Nos. 6,451,346; 6,201,072;
6,117,949; 6,004,573; 5,702,717; and 5,484,610; and PCT Publication Nos.

WO 99/07343; WO 99/18142; WO 03/17972; WO 01/82970; WO 00/18821;
WO 97/15287; WO 01/41735; WO 00/00222 and WO 00/38651.
Anti-infective and/or fibrosis-inhibiting therapeutic agents may be linked by occlusion in the polymer, dissolution in the polymer, bound by covalent linkages, bound by ionic interactions, or encapsulated in microcapsules. Within certain embodiments of the invention, therapeutic compositions are provided in non-capsular formulations such as microspheres (ranging from nanometers to micrometers in size), pastes, threads of various size, films, or sprays. In one aspect, the anti-scarring agent may be incorporated into biodegradable magnetic nanospheres. The nanospheres may be used, for example, to replenish an anti-scarring agent into an implanted intravascular device, such as a stent containing a weak magnetic alloy (see, e.g., Z. Forties, B. B. Yellen, G. Friedman, K. Barbee. "An approach to targeted drug delivery based on uniform magnetic fields," IEEE Trans. Magn. 39(5):
3372-3377 (2003)).
Within certain aspects of the present invention, therapeutic compositions of anti-infective and/or fibrosis-inhibiting agents may be fashioned in the form of microspheres, microparticles and/or nanoparticles having any size ranging from 50 nm to 500 Vim, depending upon the particular use. These compositions can be. These compositions can be formed by spray-drying methods, milling methods, coacervation methods, W/O emulsion methods, W/O/W emulsion methods, and solvent evaporation methods. In other aspects, these compositions can include microemulsions, emulsions, liposomes and micelles. Alternatively, such compositions may also be readily applied as a "spray", which solidifies into a film or coating for use as a device/implant surface coating or to line the tissues of the implantation site. Such sprays may be prepared from microspheres of a wide array of sizes, including for example, from 0.1 pm to 3 Vim, from 10 ~m to 30 p,m, and from 30 pm to 100 p.m.
Therapeutic compositions that include anti-infective and/or anti-fibrosis agents may also be prepared in a variety of "paste" or gel forms. For example, within one embodiment of the invention, therapeutic compositions are provided which are liquid at one temperature (e.g., temperature greater than 37°C, such as 40°C, 45°C, 50°C, 55°C or 60°C), and solid or semi-solid at another temperature (e.g., ambient body temperature, or any temperature lower than 37°C). Such "thermopastes" may be readily made utilizing a variety of techniques (see, e.g., PCT Publication WO 98/24427). Other pastes may be applied as a liquid, which solidify in vivo due to dissolution of a water-soluble component of the paste and precipitation of encapsulated drug into the aqueous body environment. These "pastes" and "gels" containing therapeutic agents are particularly useful for application to the surface of tissues that will be in contact with the implant or device.
Within further aspects of the present invention, polymeric carriers are provided which are adapted to contain and release a hydrophobic ant-infective and/or fibrosis-inhibiting compound, and/or the carrier containing the hydrophobic compound in combination with a carbohydrate, protein or polypeptide. Within certain embodiments, the polymeric carrier contains or comprises regions, pockets, or granules of one or more hydrophobic compounds. For example, within one embodiment of the invention, hydrophobic compounds may be incorporated within a matrix which contains the hydrophobic therapeutic compound, followed by incorporation of the matrix within the polymeric carrier. A variety of matrices can be utilized in this regard, including for example, carbohydrates and polysaccharides such as starch, cellulose, dextran, methylcellulose, sodium alginate, heparin, chitosan and hyaluronic acid, proteins or polypeptides such as albumin, collagen and gelatin.
Within alternative embodiments, hydrophobic compounds may be contained within' a hydrophobic core, and this core contained within a hydrophilic shell.
The anti-infective and/or fibrosis-inhibiting therapeutic agent may be delivered as a solution. The therapeutic agent can be incorporated directly into the solution to provide a homogeneous solution or dispersion. In certain embodiments, the solution is an aqueous solution. The aqueous solution may further include buffer salts, as well as viscosity modifying agents (e.g., hyaluronic acid, alginates, carboxymethylcellulose (CMG), and the like). In another aspect of the invention, the solution can include a biocompatible solvent or liquid oligomers and/or polymers, such as ethanol, DMSO, glycerol, PEG-200, PEG-300 or NMP. These compositions may further comprise a polymer such a degradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, y-decanolactone, ~-decanolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-Zone, or block copolymers of the form X-Y, Y-X-Y, R-(Y-X)", R-(X-Y)" and X-Y-X (where X in a polyalkylene oxide (e.g., polyethylene glycol, polypropylene glycol) and block copolymers of polyethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, y-decanolactone, b-decanolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-Zone (e.g., PLG-PEG-PLG) and R is a multifunctional initiator).
Within another aspect of the invention, the therapeutic anti-infective and/or fibrosis-inhibiting agent can further comprise a secondary carrier. The secondary carrier can be in the form of microspheres (e.g., PLGA, PLLA, PDLLA, PCL, gelatin, polydioxanone, poly(alkylcyanoacrylate)), nanospheres (PLGA, PLLA, PDLLA, PCL, gelatin, polydioxanone, poly(alkylcyanoacrylate)), liposomes, emulsions, microemulsions, micelles (SDS, block copolymers of the form X-Y, Y-X-Y, R-(Y-X)", R-(X-Y)~ and X-Y-X
(where X in a polyalkylene oxide (e.g., poly(ethylene glycol, polypropylene glycol) and block copolymers of polyethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF
Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, y-decanolactone, b-decanolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-2one (e.g., PLG-PEG-PLG) and R is a multifunctional initiator), zeolites or cyclodextrins.
Other carriers that may likewise be utilized to contain and deliver anti-infective and/or fibrosis-inhibiting therapeutic agents described herein include: hydroxypropyl cyclodextrin (Cserhati and Hollo, Int. J. Pharm. 108:69-75, 1994), liposomes (see, e.g., Sharma et al., Cancer Res. 53:5877-5881, 1993; Sharma and Straubinger, Pharm. Res. 11(60):889-896, 1994; WO
93/18751; U.S. Patent No. 5,242,073), liposomelgel (WO 94/26254), nanocapsules (Bartoli et al., J. Microencapsulation 7(2):191-197, 1990), micelles (Alkan-Onyuksel et al., Pharm. Res. 11(2):206-212, 1994), implants (Jampel et al., Invest. Ophthalm. Vis. Science 34(11 ):3076-3083, 1993; Walter et al., Cancer Res. 54:22017-2212, 1994), nanoparticles (Violante and Lanzafame PAACR), nanoparticles - modified (U.S. Patent No. 5,145,684), nanoparticles (surface modified) (U.S. Patent No. 5,399,363), micelle (surfactant) (U.S. Patent No. 5,403,858), synthetic phospholipid compounds (U.S. Patent No. 4,534,899), gas borne dispersion (U.S. Patent No. 5,301,664), liquid emulsions, foam, spray, gel, lotion, cream, ointment, dispersed vesicles, particles or droplets solid- or liquid- aerosols, microemulsions (U.S. Patent No.
5,330,756), polymeric shell (nano- and micro- capsule) (U.S. Patent No.
5,439,686), emulsion (Tarr et al., Pharm Res. 4: 62-165, 1987), nanospheres (Hagan et al., Proc. Intern. Symp. Control Rel. Bioact. Mater. 22, 1995; Kwon et al., Pharm Res. 12(2):192-195; Kwon et al., Pharm Res. 10(7):970-974;

Yokoyama et al., J. Contr. Rel. 32:269-277, 1994; Gref et al., Science 263:1600-1603, 1994; Bazile et al., J. Pharm. Sci. 84:493-498, 1994) and implants (U.S. Patent No. 4,882,168).
Within another aspect of the present invention, polymeric carriers can be materials that are formed in situ. In one embodiment, the precursors can be monomers or macromers that contain unsaturated groups that can be polymerized and/or cross-linked. The monomers or macromers can then, for example, be injected into the treatment area or onto the surface of the treatment area and polymerized in situ using a radiation source (e.g., visible or UV light) or a free radical system (e.g., potassium persulfate and ascorbic acid or iron and hydrogen peroxide). The polymerization step can be performed immediately prior to, simultaneously to or post injection of the reagents into the treatment site. Representative examples of compositions that undergo free radical polymerization reactions are described in WO 01/44307, WO 01/68720, WO 02/072166, WO 03/043552, WO 93/17669, WO 00/64977; U.S. Patent Nos. 5,900,245, 6,051,248, 6,083,524, 6,177,095, 6,201,065, 6,217,894, 6,639,014, 6,352,710, 6,410,645, 6,531,147, 5,567,435, 5,986,043, 6,602,975;
U.S. Patent Application Publication Nos. 2002/012796A1, 2002/0127266A1, 2002/0151650A1, 2003/0104032A1, 2002/0091229A1, and 2003/0059906A1.
In certain aspects, it is desirable to use compositions that can be administered as liquids, but subsequently form hydrogels at the site of administration. Such in situ hydrogel forming compositions can be administered as liquids from a variety of different devices, and are more adaptable for administration to any site, since they are not preformed.
Examples of in situ forming hydrogels include photoactivatable mixtures of water-soluble co-polyester prepolymers and polyethylene glycol to create hydrogel barriers. Block copolymers of polyalkylene oxide polymers (e.g., PLURONIC compounds from BASF Corporation, Mount Olive, NJ) and poloxamers have been designed that are soluble in cold water, but form insoluble hydrogels that adhere to tissues at body temperature (Leach, et al., Am. J. Obstet. Gynecol. 162:1317-1319 (1990)).
As mentioned elsewhere herein, the present invention provides for polymeric crosslinked matrices, and polymeric carriers, that may be used to assist in the prevention of the formation or growth of fibrous connective tissue.
The composition may contain and deliver fibrosis-inhibiting agents in the vicinity of the implanted device. The following compositions are particularly useful when it is desired to infiltrate around the device, with or without a fibrosis-inhibiting agent. Such polymeric materials may be prepared from, e.g., (a) synthetic materials, (b) naturally-occurring materials, or (c) mixtures of synthetic and naturally occurring materials. The matrix may be prepared from, e.g., (a) a one-component; i.e., self-reactive, compound, or (b) two or more compounds that are reactive with one another. Typically, these materials are fluid prior to delivery, and thus can be sprayed or otherwise extruded from a delivery device (e.g., a syringe) in order to deliver the composition. After delivery, the component materials react with each other, andlor with the body, to provide the desired affect. In some instances, materials that are reactive with one another must be kept separated prior to delivery to the patient, and are mixed together just prior to being delivered to the patient, in order that they maintain a fluid form prior to delivery. In a preferred aspect of the invention, the components of the matrix are delivered in a liquid state to the desired site in the body, whereupon in situ polymerization occurs.
First and Second Synthetic Polymers In one embodiment, crosslinked polymer compositions (in other words, crosslinked matrices) are prepared by reacting a first synthetic polymer containing two or more nucleophilic groups with a second synthetic polymer containing two or more electrophilic groups, where the electrophilic groups are capable of covalently binding with the nucleophilic groups. In one embodiment, the first and second polymers are each non-immunogenic. In another embodiment, the matrices are not susceptible to enzymatic cleavage by, e.g., a matrix metalloproteinase (e.g., collagenase) and are therefore expected to have greater long-term persistence in vivo than collagen-based compositions.
As used herein, the term "polymer" refers inter alia to polyalkyls, polyamino acids, polyalkyleneoxides and polysaccharides. Additionally, for external or oral use, the polymer may be polyacrylic acid or carbopol. As used herein, the term "synthetic polymer" refers to polymers that are not naturally occurring and that are produced via chemical synthesis. As such, naturally occurring proteins such as collagen and naturally occurring polysaccharides such as hyaluronic acid are specifically excluded. Synthetic collagen, and synthetic hyaluronic acid, and their derivatives, are included. Synthetic polymers containing either nucleophilic or electrophilic groups are also referred to herein as "multifunctionally activated synthetic polymers." The term "multifunctionally activated" (or, simply, "activated") refers to synthetic polymers which have, or have been chemically modified to have, two or more nucleophilic or electrophilic groups which are capable of reacting with one another (i.e., the nucleophilic groups react with the electrophilic groups) to form covalent bonds.
Types of multifunctionally activated synthetic polymers include difunctionally activated, tetrafunctionally activated, and star-branched polymers.
Multifunctionally activated synthetic polymers for use in the present invention must contain at least two, more preferably, at least three, functional groups in order to form a three-dimensional crosslinked network with synthetic polymers containing multiple nucleophilic groups (i.e., "multi-nucleophilic polymers"). In other words, they must be at least difunctionally activated, and are more preferably trifunctionally or tetrafunctionally activated.
If the first synthetic polymer is a difunctionally activated synthetic polymer, the second synthetic polymer must contain three or more functional groups in order to obtain a three-dimensional crosslinked network. Most preferably, both the first and the second synthetic polymer contain at least three functional groups.

Synthetic polymers containing multiple nucleophilic groups are also referred to generically herein as "multi-nucleophilic polymers." For use in the present invention, multi-nucleophilic polymers must contain at least two, more preferably, at least three, nucleophilic groups. If a synthetic polymer containing only two nucleophilic groups is used, a synthetic polymer containing three or more electrophilic groups must be used in order to obtain a three-dimensional crosslinked network.
Preferred multi-nucleophilic polymers for use in the compositions and methods of the present invention include synthetic polymers that contain, or have been modified to contain, multiple nucleophilic groups such as primary amino groups and thiol groups. Preferred multi-nucleophilic polymers include:
(i) synthetic polypeptides that have been synthesized to contain two or more primary amino groups or thiol groups; and (ii) polyethylene glycols that have been modified to contain two or more primary amino groups or thiol groups. In general, reaction of a thiol group with an electrophilic group tends to proceed more slowly than reaction of a primary amino group with an electrophilic group.
In one embodiment, the multi-nucleophilic polypeptide is a synthetic polypeptide that has been synthesized to incorporate amino acid residues containing primary amino groups (such as lysine) and/or amino acids containing thiol groups (such as cysteine). Poly(lysine), a synthetically produced polymer of the amino acid lysine (145 MW), is particularly preferred.
Poly(lysine)s have been prepared having anywhere from 6 to about 4,000 primary amino groups, corresponding to molecular weights of about 870 to about 580,000.
Poly(lysine)s for use in the present invention preferably have a molecular weight within the range of about 1,000 to about 300,000; more preferably, within the range of about 5,000 to about 100,000; most preferably, within the range of about 8,000 to about 15,000. Poly(lysine)s of varying molecular weights are commercially available from Peninsula Laboratories, Inc.
(Belmont, Calif.) and Aldrich Chemical (Milwaukee, WI).

Polyethylene glycol can be chemically modified to contain multiple primary amino or thiol groups according to methods set forth, for example, in Chapter 22 of Polyethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, J. Milton Harris, ed., Plenum Press, N.Y. (1992). Polyethylene glycols which have been modified to contain two or more primary amino groups are referred to herein as "multi-amino PEGs." Polyethylene glycols which have been modified to contain two or more thiol groups are referred to herein as "multi-thiol PEGs." As used herein, the term "polyethylene glycol(s)" includes modified and or derivatized polyethylene glycol(s).
Various forms of multi-amino PEG are commercially available from Shearwater Polymers (Huntsville, Ala.) and from Huntsman Chemical Company (Utah) under the name "Jeffamine." Multi-amino PEGs useful in the present invention include Huntsman's Jeffamine diamines ("D" series) and triamines ("T" series), which contain two and three primary amino groups per molecule, respectively.
Polyamines such as ethylenediamine (H2N-CH2-CH2-NH2), tetramethylenediamine (H2N-(CH2)4-NH2), pentamethylenediamine (cadaverine) (H2N-(CH2)5-NH2), hexamethylenediamine (H2N-(CH~)6-NH2), di(2-aminoethyl)amine (HN-(CH2-CH2-NH2)2), and tris(2-aminoethyl)amine (N-(CH2-CH2-NH2)3) may also be used as the synthetic polymer containing multiple nucleophilic groups.
Synthetic polymers containing multiple electrophilic groups are also referred to herein as "multi-electrophilic polymers." For use in the present invention, the multifunctionally activated synthetic polymers must contain at least two, more preferably, at least three, electrophilic groups in order to form a three-dimensional crosslinked network with multi-nucleophilic polymers.
Preferred multi-electrophilic polymers for use in the compositions of the invention are polymers which contain two or more succinimidyl groups capable of forming covalent bonds with nucleophilic groups on other molecules.
Succinimidyl groups are highly reactive with materials containing primary amino (NH2) groups, such as multi-amino PEG, poly(lysine), or collagen. Succinimidyl groups are slightly less reactive with materials containing thiol (SH) groups, such as multi-thiol PEG or synthetic polypeptides containing multiple cysteine residues.
As used herein, the term "containing two or more succinimidyl groups" is meant to encompass polymers which are preferably commercially available containing two or more succinimidyl groups, as well as those that must be chemically derivatized to contain two or more succinimidyl groups. As used herein, the term "succinimidyl group" is intended to encompass sulfosuccinimidyl groups and other such variations of the "generic"
succinimidyl group. The presence of the sodium sulfite moiety on the sulfosuccinimidyl group serves to increase the solubility of the polymer.
Hydrophilic polymers and, in particular, various derivatized polyethylene glycols, are preferred for use in the compositions of the present invention. As used herein, the term "PEG" refers to polymers having the repeating structure (OCH2-CH2)~. Structures for some specific, tetrafunctionally activated forms of PEG are shown in FIGS. 4 to 13 of U.S. Patent 5,874,500, incorporated herein by reference. Examples of suitable PEGS include PEG
succinimidyl propionate (SE-PEG), PEG succinimidyl succinamide (SSA-PEG), and PEG succinimidyl carbonate (SC-PEG). In one aspect of the invention, the crosslinked matrix is formed in situ by reacting pentaerythritol polyethylene glycol)ether tetra-sulfhydryl] (4-armed thiol PEG) and pentaerythritol polyethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG) as reactive reagents. Structures for these reactants are shown in U.S. Patent 5,874,500. Each of these materials has a core with a structure that may be seen by adding ethylene oxide-derived residues to each of the hydroxyl groups in pentaerythritol, and then derivatizing the terminal hydroxyl groups (derived from the ethylene oxide) to contain either thiol groups (so as to form 4-armed thiol PEG) or N-hydroxysuccinimydyl groups (so as to form 4-armed NHS
PEG), optionally with a linker group present between the ethylene oxide derived backbone and the reactive functional group, where this product is commercially available as COSEAL from Angiotech Pharmaceuticals Inc. Optionally, a group "D" may be present in one or both of these molecules, as discussed in more detail below.
As discussed above, preferred activated polyethylene glycol derivatives for use in the invention contain succinimidyl groups as the reactive group. However, different activating groups can be attached at sites along the length of the PEG molecule. For example, PEG can be derivatized to form functionally activated PEG propionaldehyde (A-PEG), or functionally activated PEG glycidyl ether (E-PEG), or functionally activated PEG-isocyanate (I-PEG), or functionally activated PEG-vinylsulfone (V-PEG).
Hydrophobic polymers can also be used to prepare the compositions of the present invention. Hydrophobic polymers for use in the present invention preferably contain, or can be derivatized to contain, two or more electrophilic groups, such as succinimidyl groups, most preferably, two, three, or four electrophilic groups. As used herein, the term "hydrophobic polymer" refers to polymers which contain a relatively small proportion of oxygen or nitrogen atoms.
Hydrophobic polymers which already contain two or more succinimidyl groups include, without limitation, disuccinimidyl suberate (DSS), bis(sulfosuccinimidyl) suberate (BS3), dithiobis(succinimidylpropionate) (DSP), bis(2-succinimidooxycarbonyloxy) ethyl sulfone (BSOCOES), and 3,3'--dithiobis(sulfosuccinimidylpropionate (DTSPP), and their analogs and derivatives. The above-referenced polymers are commercially available from Pierce (Rockford, IIL), under catalog Nos. 21555, 21579, 22585, 21554, and 21577, respectively.
Preferred hydrophobic polymers for use in the invention generally have a carbon chain that is no longer than about 14 carbons. Polymers having carbon chains substantially longer than 14 carbons generally have very poor solubility in aqueous solutions and, as such, have very long reaction times when mixed with aqueous solutions of synthetic polymers containing multiple nucleophilic groups.
Certain polymers, such as polyacids, can be derivatized to contain two or more functional groups, such as succinimidyl groups. Polyacids for use in the present invention include, without limitation, trimethylolpropane-based tricarboxylic acid, di(trimethylol propane)-based tetracarboxylic acid, heptanedioic acid, octanedioic acid (suberic acid), and hexadecanedioic acid (thapsic acid). Many of these polyacids are commercially available from DuPont Chemical Company (Wilmington, DE). According to a general method, polyacids can be chemically derivatized to contain two or more succinimidyl groups by reaction with an appropriate molar amount of N-hydroxysuccinimide (NHS) in the presence of N,N'-dicyclohexylcarbodiimide (DCC).
Polyalcohols such as trimethylolpropane and di(trimethylol propane) can be converted to carboxylic acid form using various methods, then further derivatized by reaction with NHS in the presence of DCC to produce trifunctionally and tetrafunctionally activated polymers, respectively, as described in U.S. application Ser. No. 08/403,358. Polyacids such as heptanedioic acid (HOOC-(CH2)5-COOH), octanedioic acid (HOOC-(CH2)s-COOH), and hexadecanedioic acid (HOOC-(CH2)~4-COOH) are derivatized by the addition of succinimidyl groups to produce difunctionally activated polymers.
Polyamines such as ethylenediamine, tetramethylenediamine, pentamethylenediamine (cadaverine), hexamethylenediamine, bis (2-aminoethyl)amine, and tris(2-aminoethyl)amine can be chemically derivatized to polyacids, which can then be derivatized to contain two or more succinimidyl groups by reacting with the appropriate molar amounts of N-hydroxysuccinimide in the presence of DCC, as described in U.S. application Ser. No. 08/403,358. Many of these polyamines are commercially available from DuPont Chemical Company.
In a preferred embodiment, the first synthetic polymer will contain multiple nucleophilic groups (represented below as "X") and it will react with the second synthetic polymer containing multiple electrophilic groups (represented below as "Y"), resulting in a covalently bound polymer network, as follows:
Polymer-Xm + Polymer-Y" -~ Polymer-Z-Polymer wherein m <_2, n <_2, and m + n _<5;
where exemplary X groups include -NH2, -SH, -OH, -PH2, CO-NH-NHS, etc., where the X groups may be the same or different in polymer-Xm;
where exemplary Y groups include -C02-N(COCH2)2, -CO2H, -CHO, -CHOCH~ (epoxide), -N=C=O, -S02-CH=CH2, -N(COCH)2 (i.e., a five-membered heterocyclic ring with a double bond present between the two CH
groups), -S-S-(C5H4N), etc., where the Y groups may be the same or different in polymer-Y~; and where Z is the functional group resulting from the union of a nucleophilic group (X) and an electrophilic group (Y).
As noted above, it is also contemplated by the present invention that X and Y may be the same or different, i.e., a synthetic polymer may have two different electrophilic groups, or two different nucleophilic groups, such as with glutathione.
In one embodiment, the backbone of at least one of the synthetic polymers comprises alkylene oxide residues, e.g., residues from ethylene oxide, propylene oxide, and mixtures thereof. The term 'backbone' refers to a significant portion of the polymer.
For example, the synthetic polymer containing alkylene oxide residues may be described by the formula X-polymer-X or Y-polymer-Y, wherein X and Y are as defined above, and the term "polymer" represents -(CH2CH2 O)"- or -(CH(CH3)CH2 O)n or -(CH2-CH2-O)"-(CH(CH3)CH2-O)n . In these cases the synthetic polymer would be difunctional.
The required functional group X or Y is commonly coupled to the polymer backbone by a linking group (represented below as "Q"), many of which are known or possible. There are many ways to prepare the various functionalized polymers, some of which are listed below:

Polymer-Q~-X + Polymer-Q2-Y --> Polymer-Q~-Z-Q2-Polymer Exemplary Q groups include -O-(GH~)~ ; -S-(CH2)~ ; -NH-(CH2)n ;
-02C-NH-(CH2)n ; -02C-(CH2)n ; -02C-(CR~H)n ; and -O-R2-CO-NH-, which provide synthetic polymers of the partial structures: polymer-O-(CH2)n (X or Y);
polymer-S-(CH2)n (X or Y); polymer-NH-(CH2)"(X or Y); polymer-02C-NH-(CH2)~ (X or Y); polymer-02C-(CH~)~ (X or Y); polymer-02C-(CR~H)"-(X or Y);
and polymer-O-R2-CO-NH-(X or Y), respectively. In these structures, n = 1-10, R~ = H or alkyl (i.e., CH3, C2H5, etc.); R~ = CH2, or CO-NH-CH~CH2; and Q~ and Q2 may be the same or different.
For example, when Q2 = OCH2CH~ (there is no Q~ in this case); Y
- -C02-N(COCH2)2; and X = -NH2, -SH, or -OH, the resulting reactions and Z
groups would be as follows:
Polymer-NHS + Polymer-O-CH2-CH2-C02-N(COCH~)~
Polymer-NH-CO-CHI-CHI-O-Polymer;
Polymer-SH + Polymer-O-CHI-CH2-C02-N(COCH2)2 -Polymer-S-COCH2CH2-O-Polymer; and Polymer-OH + Polymer-O-CH2-CH2-C02-N(COCH2)2 Polymer-O-COCH2CH2-O-Polymer.
An additional group, represented below as "D", can be inserted between the polymer and the linking group, if present. One purpose of such a D group is to affect the degradation rate of the crosslinked polymer composition in vivo, for example, to increase the degradation rate, or to decrease the degradation rate. This may be useful in many instances, for example, when drug has been incorporated into the matrix, and it is desired to increase or decrease polymer degradation rate so as to influence a drug delivery profile in the desired direction. An illustration of a crosslinking reaction involving first and second synthetic polymers each having D and Q groups is shown below.
Polymer-D-Q-X + Polymer-D-Q-Y -~ Polymer-D-Q-Z-Q-D-Polymer Some useful biodegradable groups "D" include polymers formed from one or more a-hydroxy acids, e.g., lactic acid, glycolic acid, and the cyclization products thereof (e.g., lactide, glycolide), E-caprolactone, and amino acids. The polymers may be referred to as polylactide, polyglycolide, poly(co-lactide-glycolide); poly-~-caprolactone, polypeptide (also known as poly amino acid, for example, various di- or tri-peptides) and poly(anhydride)s.
In a general method for preparing the crosslinked polymer compositions used in the context of the present invention, a first synthetic polymer containing multiple nucleophilic groups is mixed with a second synthetic polymer containing multiple electrophilic groups. Formation of a three-dimensional crosslinked network occurs as a result of the reaction between the nucleophilic groups on the first synthetic polymer and the electrophilic groups on the second synthetic polymer.
The concentrations of the first synthetic polymer and the second synthetic polymer used to prepare the compositions of the present invention will vary depending upon a number of factors, including the types and molecular weights of the particular synthetic polymers used and the desired end use application. In general, when using multi-amino PEG as the first synthetic polymer, it is preferably used at a concentration in the range of about 0.5 to about 20 percent by weight of the final composition, while the second synthetic polymer is used at a concentration in the range of about 0.5 to about 20 percent by weight of the final composition. For example, a final composition having a total weight of 1 gram (1000 milligrams) would contain between about 5 to about 200 milligrams of multi-amino PEG, and between about 5 to about 200 milligrams of the second synthetic polymer.
Use of higher concentrations of both first and second synthetic polymers will result in the formation of a more tightly crosslinked network, producing a stiffer, more robust gel. Compositions intended for use in tissue augmentation will generally employ concentrations of first and second synthetic polymer that fall toward the higher end of the preferred concentration range.
Compositions intended for use as bioadhesives or in adhesion prevention do not need to be as firm and may therefore contain lower polymer concentrations.

Because polymers containing multiple electrophilic groups will also react with water, the second synthetic polymer is generally stored and used in sterile, dry form to prevent the loss of crosslinking ability due to hydrolysis which typically occurs upon exposure of such electrophilic groups to aqueous media. Processes for preparing synthetic hydrophilic polymers containing multiple electrophylic groups in sterile, dry form are set forth in U.S.
Patent 5,643,464. For example, the dry synthetic polymer may be compression molded into a thin sheet or membrane, which can then be sterilized using gamma or, preferably, e-beam irradiation. The resulting dry membrane or sheet can be cut to the desired size or chopped into smaller size particulates.
In contrast, polymers containing multiple nucleophilic groups are generally not water-reactive and can therefore be stored in aqueous solution.
In certain embodiments, one or both of the electrophilic- or nucleophilic-terminated polymers described above can be combined with a synthetic or naturally occurring polymer. The presence of the synthetic or naturally occurring polymer may enhance the mechanical and/or adhesive properties of the in situ forming compositions. Naturally occurring polymers, and polymers derived from naturally occurring polymer that may be included in in situ forming materials include naturally occurring proteins, such as collagen, collagen derivatives (such as methylated collagen), fibrinogen, thrombin, albumin, fibrin, and derivatives of and naturally occurring polysaccharides, such as glycosaminoglycans, including deacetylated and desulfated glycosaminoglycan derivatives.
In one aspect, a composition comprising naturally-occurring protein and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising collagen and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising methylated collagen and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising fibrinogen and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a ~ composition comprising thrombin and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising albumin and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising fibrin and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising naturally occurring polysaccharide and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
In one aspect, a composition comprising glycosaminoglycan and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising deacetylated glycosaminoglycan and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising desulfated glycosaminoglycan and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
In one aspect, a composition comprising naturally-occurring protein and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising collagen and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
In one aspect, a composition comprising methylated collagen and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising fibrinogen and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising thrombin and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
In one aspect, a composition comprising albumin and the first synthetic polymer as described above is used fo form the crosslinked matrix according to the present invention. In one aspect, a composition comprising fibrin and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising naturally occurring polysaccharide and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
In one aspect, a composition comprising glycosaminoglycan and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising deacetylated glycosaminoglycan and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
In one aspect, a composition comprising desulfated glycosaminoglycan and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
In one aspect, a composition comprising naturally-occurring protein and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising collagen and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising methylated collagen and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising fibrinogen and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising thrombin and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising albumin and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising fibrin and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
In one aspect, a composition comprising naturally occurring polysaccharide and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising glycosaminoglycan and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising deacetylated glycosaminoglycan and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising desulfated glycosaminoglycan and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.
The presence of protein or polysaccharide components which contain functional groups that can react with the functional groups on multiple activated synthetic polymers can result in formation of a crosslinked synthetic polymer-naturally occurring polymer matrix upon mixing and/or crosslinking of the synthetic polymer(s). In particular, when the naturally occurring polymer (protein or polysaccharide) also contains nucleophilic groups such as primary amino groups, the electrophilic groups on the second synthetic polymer will react with the primary amino groups on these components, as well as the nucleophilic groups on the first synthetic polymer, to cause these other components to become part of the polymer matrix. For example, lysine-rich proteins such as collagen may be especially reactive with electrophilic groups on synthetic polymers.

In one aspect, the naturally occurring protein is polymer may be collagen. As used herein, the term "collagen" or "collagen material" refers to all forms of collagen, including those which have been processed or otherwise modified and is intended to encompass collagen of any type, from any source, including, but not limited to, collagen extracted from tissue or produced recombinantly, collagen analogues, collagen derivatives, modified collagens, and denatured collagens, such as gelatin.
In general, collagen from any source may be included in the compositions of the invention; for example, collagen may be extracted and purified from human or other mammalian source, such as bovine or porcine corium and human placenta, or may be recombinantly or otherwise produced.
The preparation of purified, substantially non-antigenic collagen in solution from bovine skin is well known in the art. U.S. Patent No. 5,428,022 discloses methods of extracting and purifying collagen from the human placenta. U.S.
Patent No. 5,667,839, discloses methods of producing recombinant human collagen in the milk of transgenic animals, including transgenic cows.
Collagen of any type, including, but not limited to, types I, II, III, IV, or any combination thereof, may be used in the compositions of the invention, although type I is generally preferred. Either atelopeptide or telopeptide-containing collagen may be used; however, when collagen from a xenogeneic source, such as bovine collagen, is used, atelopeptide collagen is generally preferred, because of its reduced immunogenicity compared to telopeptide-containing collagen.
Collagen that has not been previously crosslinked by methods such as heat, irradiation, or chemical crosslinking agents is preferred for use in the compositions of the invention, although previously crosslinked collagen may be used. Non-crosslinked atelopeptide fibrillar collagen is commercially available from Inamed Aesthetics (Santa Barbara, CA) at collagen concentrations of 35 mg/ml and 65 mg/ml under the trademarks ZYDERM I
Collagen and ZYDERM II Collagen, respectively. Glutaraldehyde crosslinked atelopeptide fibrillar collagen is commercially available from Inamed Corporation (Santa Barbara, CA) at a collagen concentration of 35 mg/ml under the trademark ZYPLAST Collagen.
Collagens for use in the present invention are generally in aqueous suspension at a concentration between about 20 mg/ml to about 120 mg/ml; preferably, between about 30 mg/ml to about 90 mg/ml.
Because of its tacky consistency, nonfibrillar collagen may be preferred for use in compositions that are intended for use as bioadhesives.
The term "nonfibrillar collagen" refers to any modified or unmodified collagen material that is in substantially nonfibrillar form at pH 7, as indicated by optical clarity of an aqueous suspension of the collagen.
Collagen that is already in nonfibrillar form may be used in the compositions of the invention. As used herein, the term "nonfibrillar collagen" is intended to encompass collagen types that are nonfibrillar in native form, as well as collagens that have been chemically modified such that they are in nonfibrillar form at or around neutral pH. Collagen types that are nonfibrillar (or microfibrillar) in native form include types IV, VI, and VII.
Chemically modified collagens that are in nonfibrillar form at neutral pH include succinylated collagen and methylated collagen, both of which can be prepared according to the methods described in U.S. Pat. No.
4,164,559, issued Aug. 14, 1979, to Miyata et al., which is hereby incorporated by reference in its entirety. Due to its inherent tackiness, methylated collagen is particularly preferred for use in bioadhesive compositions, as disclosed in U.S.
application Ser. No. 08/476,825.
Collagens for use in the crosslinked polymer compositions of the present invention may start out in fibrillar form, then be rendered nonfibrillar by the addition of one or more fiber disassembly agent. The fiber disassembly agent must be present in an amount sufficient to render the collagen substantially nonfibrillar at pH 7, as described above. Fiber disassembly agents for use in the present invention include, without limitation, various biocompatible alcohols, amino acids (e.g., arginine), inorganic salts (e.g., sodium chloride and potassium chloride), and carbohydrates (e.g., various sugars including sucrose).
In one aspect, the polymer may be collagen or a collagen derivative, for example methylated collagen. An example of an in situ forming composition uses pentaerythritol polyethylene glycol)ether tetra-sulfhydryl]
(4-armed thiol PEG), pentaerythritol polyethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG) and methylated collagen as the reactive reagents. This composition, when mixed with the appropriate buffers can produce a crosslinked hydrogel. (See, e.g., U.S. Patent Nos. 5,874,500;
6,051,648; 6,166,130; 5,565,519 and 6,312,725).
In another aspect, the naturally occurring polymer may be a glycosaminoglycan. Glycosaminoglycans, e.g., hyaluronic acid, contain both anionic and cationic functional groups along each polymeric chain, which can form intramolecular and/or intermolecular ionic crosslinks, and are responsible for the thixotropic (or shear thinning) nature of hyaluronic acid.
In certain aspects, the glycosaminoglycan may be derivatized.
For example, glycosaminoglycans can be chemically derivatized by, e.g., deacetylation, desulfation, or both in order to contain primary amino groups available for reaction with electrophilic groups on synthetic polymer molecules.
Glycosaminoglycans that can be derivatized according to either or both of the aforementioned methods include the following: hyaluronic acid, chondroitin sulfate A, chondroitin sulfate B (dermatan sulfate), chondroitin sulfate C, chitin (can be derivatized to chitosan), keratan sulfate, keratosulfate, and heparin.
Derivatization of glycosaminoglycans by deacetylation and/or desulfation and covalent binding of the resulting glycosaminoglycan derivatives with synthetic hydrophilic polymers is described in further detail in commonly assigned, allowed U.S. patent application Ser. No. 08/146,843, filed Nov. 3, 1993.
In general, the collagen is added to the first synthetic polymer, then the collagen and first synthetic polymer are mixed thoroughly to achieve a homogeneous composition. The second synthetic polymer is then added and mixed into the collagen/first synthetic polymer mixture, where it will covalently bind to primary amino groups or thiol groups on the first synthetic polymer and primary amino groups on the collagen, resulting in the formation of a homogeneous crosslinked network. Various deacetylated and/or desulfated glycosaminoglycan derivatives can be incorporated into the composition in a similar manner as that described above for collagen. In addition, the iritroduction of hydrocolloids such as carboxymethylcellulose may promote tissue adhesion and/or swellability.
Administration of the Crosslinked Synthetic Polymer Compositions The compositions of the present invention having two synthetic polymers may be administered before, during or after crosslinking of the first and second synthetic polymer. Certain uses, which are discussed in greater detail below, such as tissue augmentation, may require the compositions to be crosslinked before administration, whereas other applications, such as tissue adhesion, require the compositions to be administered before crosslinking has reached "equilibrium." The point at which crosslinking has reached equilibrium is defined herein as the point at which the composition no longer feels tacky or sticky to the touch.
In order to administer the composition prior to crosslinking, the first synthetic polymer and second synthetic polymer may be contained within separate barrels of a dual-compartment syringe. In this case, the two synthetic polymers do not actually mix until the point at which the two polymers are extruded from the tip of the syringe needle into the patient's tissue. This allows the vast majority of the crosslinking reaction to occur in situ, avoiding the problem of needle blockage which commonly occurs if the two synthetic polymers are mixed too early and crosslinking between the two components is already too advanced prior to delivery from the syringe needle. The use of a dual-compartment syringe, as described above, allows for the use of smaller diameter needles, which is advantageous when performing soft tissue augmentation in delicate facial tissue, such as that surrounding the eyes.
Alternatively, the first synthetic polymer and second synthetic polymer may be mixed according to the methods described above prior to delivery to the tissue site, then injected to the desired tissue site immediately (preferably, within about 60 seconds) following mixing.
In another embodiment of the invention, the first synthetic polymer and second synthetic polymer are mixed, then extruded and allowed to crosslink into a sheet or other solid form. The crosslinked solid is then dehydrated to remove substantially all unbound water. The resulting dried solid may be ground or comminuted into particulates, then suspended in a nonaqueous fluid carrier, including, without limitation, hyaluronic acid, dextran sulfate, dextran, succinylated noncrosslinked collagen, methylated noncrosslinked collagen, glycogen, glycerol, dextrose, maltose, triglycerides of fatty acids (such as corn oil, soybean oil, and sesame oil), and egg yolk phospholipid. The suspension of particulates can be injected through a small-gauge needle to a tissue site. Once inside the tissue, the crosslinked polymer particulates will rehydrate and swell in size at least five-fold.
Hydrophilic Polymer + Plurality of Crosslinkable Components As mentioned above, the first and/or second synthetic polymers may be combined with a hydrophilic polymer, e.g., collagen or methylated collagen, to form a composition useful in the present invention. In one general embodiment, the compositions useful in the present invention include a hydrophilic polymer in combination with two or more crosslinkable components.
This embodiment is described in further detail in this section.
The Hydrophilic Polymer Component:
The hydrophilic polymer component may be a synthetic or naturally occurring hydrophilic polymer. Naturally occurring hydrophilic polymers include, but are not limited to: proteins such as collagen and derivatives thereof, fibronectin, albumins, globulins, fibrinogen, and fibrin, with collagen particularly preferred; carboxylated polysaccharides such as polymannuronic acid and polygalacturonic acid; aminated polysaccharides, particularly the glycosaminoglycans, e.g., hyaluronic acid, chitin, chondroitin sulfate A, B, or C, keratin sulfate, keratosulfate and heparin; and activated polysaccharides such as dextran and starch derivatives. Collagen (e.g., methylated collagen) and glycosaminoglycans are preferred naturally occurring hydrophilic polymers for use herein.
In general, collagen from any source may be used in the composition of the method; for example, collagen may be extracted and purified from human or other mammalian source, such as bovine or porcine corium and human placenta, or may be recombinantly or otherwise produced. The preparation of purified, substantially non-antigenic collagen in solution from bovine skin is well known in the art. See, e.g., U.S. Pat. No. 5,428,022, to Palefsky et al., which discloses methods of extracting and purifying collagen from the human placenta. See also U.S. Patent No. 5,667,839, to Berg, which discloses methods of producing recombinant human collagen in the milk of transgenic animals, including transgenic cows. Unless otherwise specified, the term "collagen" or "collagen material" as used herein refers to all forms of collagen, including those that have been processed or otherwise modified.
Collagen of any type, including, but not limited to, types I, II, III, IV, or any combination thereof, may be used in the compositions of the invention, although type I is generally preferred. Either atelopeptide or telopeptide-containing collagen may be used; however, when collagen from a source, such as bovine collagen, is used, atelopeptide collagen is generally preferred, because of its reduced immunogenicity compared to telopeptide-containing collagen.
Collagen that has not been previously crosslinked by methods such as heat, irradiation, or chemical crosslinking agents is preferred for use in the compositions of the invention, although previously crosslinked collagen may be used. Non-crosslinked atelopeptide fibrillar collagen is commercially available from McGhan Medical Corporation (Santa Barbara, Calif.) at collagen concentrations of 35 mg/ml and 65 mg/ml under the trademarks ZYDERM~ I
Collagen and ZYDERM~ II Collagen, respectively. Glutaraldehyde-crosslinked atelopeptide fibrillar collagen is commercially available from McGhan Medical Corporation at a collagen concentration of 35 mg/ml under the trademark ZYPLAST~
Collagens for use in the present invention are generally, although not necessarily, in aqueous suspension at a concentration between about 20 mg/ml to about 120 mg/ml, preferably between about 30 mg/ml to about 90 mg/ml.
Although intact collagen is preferred, denatured collagen, commonly known as gelatin, can also be used in the compositions of the invention. Gelatin may have the added benefit of being degradable faster than collagen.
Because of its greater surface area and greater concentration of reactive groups, nonfibrillar collagen is generally preferred. The term "nonfibrillar collagen" refers to any modified or unmodified collagen material that is in substantially nonfibrillar form at pH 7, as indicated by optical clarity of an aqueous suspension of the collagen.
Collagen that is already in nonfibrillar form may be used in the compositions of the invention. As used herein, the term "nonfibrillar collagen" is intended to encompass collagen types that are nonfibrillar in native form, as well as collagens that have been chemically modified such that they are in nonfibrillar form at or around neutral pH. Collagen types that are nonfibrillar (or microfibrillar) in native form include types IV, VI, and VII.
Chemically modified collagens that are in nonfibrillar form at neutral pH include succinylated collagen, propylated collagen, ethylated collagen, methylated collagen, and the like, both of which can be prepared according to the methods described in U.S. Pat. No. 4,164,559, to Miyata et al., which is hereby incorporated by reference in its entirety. Due to its inherent tackiness, methylated collagen is particularly preferred, as disclosed in U.S.
Patent No. 5,614,587 to Rhee et al.
Collagens for use in the crosslinkable compositions of the present invention may start out in fibrillar form, then be rendered nonfibrillar by the addition of one or more fiber disassembly agents. The fiber disassembly agent must be present in an amount sufficient to render the collagen substantially nonfibrillar at pH 7, as described above. Fiber disassembly agents for use in the present invention include, without limitation, various biocompatible alcohols, amino acids, inorganic salts, and carbohydrates, with biocompatible alcohols being particularly preferred. Preferred biocompatible alcohols include glycerol and propylene glycol. Non-biocompatible alcohols, such as ethanol, methanol, and isopropanol, are not preferred for use in the present invention, due to their potentially deleterious effects on the body of the patient receiving them.
Preferred amino acids include arginine. Preferred inorganic salts include sodium chloride and potassium chloride. Although carbohydrates, such as various sugars including sucrose, may be used in the practice of the present invention, they are not as preferred as other types of fiber disassembly agents because they can have cytotoxic effects in vivo.
As fibrillar collagen has less surface area and a lower concentration of reactive groups than nonfibrillar, fibrillar collagen is less preferred. However, as disclosed in U.S. Patent 5,614,587, fibrillar collagen, or mixtures of nonfibrillar and fibrillar collagen, may be preferred for use in compositions intended for long-term persistence in vivo, if optical clarity is not a requirement.
Synthetic hydrophilic polymers may also be used in the present invention. Useful synthetic hydrophilic polymers include, but are not limited to:
polyalkylene oxides, particularly polyethylene glycol and polyethylene oxide)-polypropylene oxide) copolymers, including block and random copolymers;

polyols such as glycerol, polyglycerol (particularly highly branched polyglycerol), propylene glycol and trimethylene glycol substituted with one or more polyalkylene oxides, e.g., mono-, di- and tri-polyoxyethylated glycerol, mono- and di-polyoxyethylated propylene glycol, and mono- and di-polyoxyethylated trimethylene glycol; polyoxyethylated sorbitol, polyoxyethylated glucose; acrylic acid polymers and analogs and copolymers thereof, such as polyacrylic acid per se, polymethacrylic acid, poly(hydroxyethyl-methacrylate), poly(hydroxyethylacrylate), poly(methylalkylsulfoxide methacrylate), poly(methylalkylsulfoxide acrylate) and copolymers of any of the foregoing, and/or with additional acrylate species such as aminoethyl acrylate and mono-2-(acryloxy)-ethyl succinate; polymaleic acid;
poly(acrylamides) such as polyacrylamide per se, poly(methacrylamide), poly(dimethylacrylamide), and poly(N-isopropyl-acrylamide); poly(olefinic alcohol)s such as polyvinyl alcohol); poly(N-vinyl lactams) such as polyvinyl pyrrolidone), poly(N-vinyl caprolactam), and copolymers thereof;
polyoxazolines, including poly(methyloxazoline) and poly(ethyloxazoline); and polyvinylamines. It must be emphasized that the aforementioned list of polymers is not exhaustive, and a variety of other synthetic hydrophilic polymers may be used, as will be appreciated by those skilled in the art.
The Crosslinkable Components:
The compositions of the invention also comprise a plurality of crosslinkable components. Each of the crosslinkable components participates in a reaction that results in a crosslinked matrix. Prior to completion of the crosslinking reaction, the crosslinkable components provide the necessary adhesive qualities that enable the methods of the invention.
The crosslinkable components are selected so that crosslinking gives rise to a biocompatible, nonimmunogenic matrix useful in a variety of contexts including adhesion prevention, biologically active agent delivery, tissue augmentation, and other applications. The crosslinkable components of the invention comprise: a component A, which has m nucleophilic groups, wherein m > 2 and a component B, which has n electrophilic groups capable of reaction with the m nucleophilic groups, wherein n > 2 and m + n > 4. An optional third component, optional component C, which has at least one functional group that is either electrophilic and capable of reaction with the nucleophilic groups of component A, or nucleophilic and capable of reaction with the electrophilic groups of component B may also be present. Thus, the total number of functional groups present on components A, B and C, when present, in combination is > 5; that is, the total functional groups given by m + n + p must be > 5, where p is the number of functional groups on component C and, as indicated, is > 1. Each of the components is biocompatible and nonimmunogenic, and at least one component is comprised of a hydrophilic polymer. Also, as will be appreciated, the composition may contain additional crosslinkable components D, E, F, etc., having one or more reactive nucleophilic or electrophilic groups and thereby participate in formation of the crosslinked biomaterial via covalent bonding to other components.
The m nucleophilic groups on component A may all be the same, or, alternatively, A may contain two or more different nucleophilic groups.
Similarly, the n electrophilic groups on component B may all be the same, or two or more different electrophilic groups may be present. The functional groups) on optional component C, if nucleophilic, may or may not be the same as the nucleophilic groups on component A, and, conversely, if electrophilic, the functional groups) on optional component C may or may not be the same as the electrophilic groups on component B.
Accordingly, the components may be represented by the structural formulae (I) R~(-[Q~]q-X)m (component A), (II) R2(-[Q2]rY)" (component B), and (III) R3(-[Q3]S Fn)P (optional component C), wherein:

R~, R~ and R3 are independently selected from the group consisting of C2 to C~4 hydrocarbyl, heteroatom-containing C~ to C~4 hydrocarbyl, hydrophilic polymers, and hydrophobic polymers, providing that at least one of R~, R2 and R3 is a hydrophilic polymer, preferably a synthetic hydrophilic polymer;
X represents one of the m nucleophilic groups of component A, and the various X moieties on A may be the same or different;
Y represents one of the n electrophilic groups of component B, and the various Y moieties on A may be the same or different;
Fn represents a functional group on optional component C;
Q~, Q2 and Q3 are linking groups;
m >2, n >2, m + n is >_4, q, and r are independently zero or 1, and when optional component C is present, p >_1, and s is independently zero or 1.
Reactive Groups:
X may be virtually any nucleophilic group, so long as reaction can occur with the electrophilic group Y. Analogously, Y may be virtually any electrophilic group, so long as reaction can take place with X. The only limitation is a practical one, in that reaction between X and Y should be fairly rapid and take place automatically upon admixture with an aqueous medium, without need for heat or potentially toxic or non-biodegradable reaction catalysts or other chemical reagents. It is also preferred although not essential that reaction occur without need for ultraviolet or other radiation. Ideally, the reactions between X and Y should be complete in under 60 minutes, preferably under 30 minutes. Most preferably, the reaction occurs in about 5 to 15 minutes or less.
Examples of nucleophilic groups suitable as X include, but are not limited to, -NH2, -NHR~, -N(R4)2, -SH, -OH, -COOH, -C6H4-OH, -PH2, -PHRS, -P(R5)2, -NH-NH2, -CO-NH-NH2, -C5H4N, etc. wherein R4 and R5 are hydrocarbyl, typically alkyl or monocyclic aryl, preferably alkyl, and most preferably lower alkyl. Organometallic moieties are also useful nucleophilic groups for the purposes of the invention, particularly those that act as carbanion donors. Organometallic nucleophiles are not, however, preferred. Examples of organometallic moieties include: Grignard functionalities -R6MgHal wherein R6 is a carbon atom (substituted or unsubstituted), and Hal is halo, typically bromo, iodo or chloro, preferably bromo; and lithium-containing functionalities, typically alkyllithium groups; sodium-containing functionalities.
It will be appreciated by those of ordinary skill in the art that certain nucleophilic groups must be activated with a base so as to be capable of reaction with an electrophile. For example, when there are nucleophilic sulfhydryl and hydroxyl groups in the crosslinkable composition, the composition must be admixed with an aqueous base in order to remove a proton and provide an -S- or -O' species to enable reaction with an electrophile.
Unless it is desirable for the base to participate in the crosslinking reaction, a nonnucleophilic base is preferred. In some embodiments, the base may be present as a component of a buffer solution. Suitable bases and corresponding crosslinking reactions are described infra in Section E.
The selection of electrophilic groups provided within the crosslinkable composition, i.e., on component B, must be made so that reaction is possible with the specific nucleophilic groups. Thus, when the X moieties are amino groups, the Y groups are selected so as to react with amino groups.
Analogously, when the X moieties are sulfhydryl moieties, the corresponding electrophilic groups are sulfhydryl-reactive groups, and the like.
By way of example, when X is amino (generally although not necessarily primary amino), the electrophilic groups present on Y are amino reactive groups such as, but not limited to: (1 ) carboxylic acid esters, including cyclic esters and "activated" esters; (2) acid chloride groups (-CO-CI); (3) anhydrides (-(CO)-O-(CO)-R); (4) ketones and aldehydes, including a,(3-unsaturated aldehydes and ketones such as -CH=CH-CH=O and -CH=CH-C(CH3)=O; (5) halides; (6) isocyanate (-N=C=O); (7) isothiocyanate (-N=C=S);
(8) epoxides; (9} activated hydroxyl groups (e.g., activated with conventional activating agents such as carbonyldiimidazole or sulfonyl chloride); and (10) olefins, including conjugated olefins, such as ethenesulfonyl (-S02CH=CH2) and analogous functional groups, including acrylate (-C02-C=CH2), methacrylate (-C02-C(CH3)=CH2)), ethyl acrylate (-C02-C(CH2CH3)=CH2), and ethyleneimino (-CH=CH-C=NH). Since a carboxylic acid group per se is not susceptible to reaction with a nucleophilic amine, components containing carboxylic acid groups must be activated so as to be amine-reactive.
Activation may be accomplished in a variety of ways, but often involves reaction with a suitable hydroxyl-containing compound in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or dicyclohexylurea (DHU). For example, a carboxylic acid can be reacted with an alkoxy-substituted N-hydroxy-succinimide or N-hydroxysulfosuccinimide in the presence of DCC to form reactive electrophilic groups, the N-hydroxysuccinimide ester and the N-hydroxysulfosuccinimide ester, respectively. Carboxylic acids may also be activated by reaction with an acyl halide such as an acyl chloride (e.g., acetyl chloride), to provide a reactive anhydride group. In a further example, a carboxylic acid may be converted to an acid chloride group using, e.g., thionyl chloride or an acyl chloride capable of an exchange reaction. Specific reagents and procedures used to carry out such activation reactions will be known to those of ordinary skill in the art and are described in the pertinent texts and literature.
Analogously, when X is sulfhydryl, the electrophilic groups present on Y are groups that react with a sulfhydryl moiety. Such reactive groups include those that form thioester linkages upon reaction with a sulfhydryl group, such as those described in PCT Publication No. WO 00/62827 to Wallace et al.
As explained in detail therein, such "sulfhydryl reactive" groups include, but are not limited to: mixed anhydrides; ester derivatives of phosphorus; ester derivatives of p-nitrophenol, p-nitrothiophenol and pentafluorophenol; esters of substituted hydroxylamines, including N-hydroxyphthalimide esters, N-hydroxysuccinimide esters, N-hydroxysulfosuccinimide esters, and N-hydroxygfutarimide esters; esters of 1-hydroxybenzotriazole; 3-hydroxy-3,4-dihydro-benzotriazin-4-one; 3-hydroxy-3,4-dihydro-quinazoline-4-one;
carbonylimidazole derivatives; acid chlorides; ketenes; and isocyanates. With these sulfhydryl reactive groups, auxiliary reagents can also be used to facilitate bond formation, e.g., 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide can be used to facilitate coupling of sulfhydryl groups to carboxyl-containing groups.
In addition to the sulfhydryl reactive groups that form thioester linkages, various other sulfhydryl reactive functionalities can be utilized that form other types of linkages. For example, compounds that contain methyl imidate derivatives form imido-thioester linkages with sulfhydryl groups.
Alternatively, sulfhydryl reactive groups can be employed that form disulfide bonds with sulfhydryl groups; such groups generally have the structure -S-S-Ar where Ar is a substituted or unsubstituted nitrogen-containing heteroaromatic moiety or a non-heterocyclic aromatic group substituted with an electron-withdrawing moiety, such that Ar may be, for example, 4-pyridinyl, o-nitrophenyl, m-nitrophenyl, p-nitrophenyl, 2,4-dinitrophenyl, 2-nitro-4-benzoic acid, 2-nitro-4-pyridinyl, etc. In such instances, auxiliary reagents, i.e., mild oxidizing agents such as hydrogen peroxide, can be used to facilitate disulfide bond formation.
Yet another class of sulfhydryl reactive groups forms thioether bonds with sulfhydryl groups. Such groups include, inter alia, maleimido, substituted maleimido, haloalkyl, epoxy, imino, and aziridino, as well as olefins (including conjugated olefins) such as ethenesulfonyl, etheneimino, acrylate, methacrylate, and a,(3-unsaturated aldehydes and ketones. This class of sulfhydryl reactive groups are particularly preferred as the thioether bonds may provide faster crosslinking and longer in vivo stability.

When X is -OH, the electrophilic functional groups on the remaining components) must react with hydroxyl groups. The hydroxyl group may be activated as described above with respect to carboxylic acid groups, or it may react directly in the presence of base with a sufficiently reactive electrophile such as an epoxide group, an aziridine group, an acyl halide, or an anhydride.
When X is an organometallic nucleophile such as a Grignard functionality or an alkyllithium group, suitable electrophilic functional groups for reaction therewith are those containing carbonyl groups, including, by way of example, ketones and aldehydes.
It will also be appreciated that certain functional groups can react as nucleophiles or as electrophiles, depending on the selected reaction partner and/or the reaction conditions. For example, a carboxylic acid group can act as a nucleophile in the presence of a fairly strong base, but generally acts as an electrophile allowing nucleophilic attack at the carbonyl carbon and concomitant replacement of the hydroxyl group with the incoming nucleophile.
The covalent linkages in the crosslinked structure that result upon covalent binding of specific nucleophilic components to specific electrophilic components in the crosslinkable composition include, solely by way of example, the following (the optional linking groups Q~ and Q~ are omitted for clarity):
TABLE
REPRESENTATIVE

NUCLEOPHILIC REPRESENTATIVE

COMPONENT ELECTROPHILIC

COMPONENT RESULTING LINI~CAGE

(A, optional component C (B, FNE~) element FNNU) R~-NH2 R2-O-(CO)-O-N(COCH2) R~-NH-(CO)-O-R2 (succinimidyl carbonate terminus) 1~6 REPRESENTATIVE

NUCLEOPHILIC REPRESENTATIVE

COMPONENT ELECTROPHILIC

(A, optional COMPONENT RESULTING LINKAGE

component C (B, FNE~) element FNNU) R~-SH R2-O-(CO)-O-N(COCH2) R~-S-(CO)-O-R~

R~-OH R~-O-(CO)-O-N(COCH~) R~-O-(CO)-R2 R~-NH2 R2-O(CO)-CH=CH2 R~-NH-CH~CH~-(CO)-O-R2 (acrylate terminus) R~-SH R2-O-(CO)-CH=CH2 R~-S-CH2CH2-(CO)-O-R2 R~-OH R2-O-(CO)-CH=CH2 R~-O-CH2CH2-(CO)-O-R~

R~-NH2 R2-O(CO)-(CH2)3-CO~- R~-NH-(CO)-(CH2)3-(CO)-N(COCH2) ORS

(succinimidyl glutarate terminus) R~-SH R2-O(CO)-(CH2)3-C02- R~-S-(CO)-(CH~)3-(CO)-N(COCH2) OR2 R~-OH R2-O(CO)-(CH2)3-C02- R~-O-(CO)-(CH2)3-(CO)-N(COCH2) OR2 R~-NH2 R2-O-CH2-C02-N(COCH~) R'-NH-(CO)-CH2-OR2 (succinimidyl acetate terminus) R~-SH R2-O-CH2-CO2-N(COCH2) R~-S-(CO)-CH2-OR2 R~-OH R2-O-CH2-CO2-N(COCH2) R~-O-(CO)-CH2-OR2 R~-NH2 R2-O-NH(CO)-(CH2)2-C02-R~-NH-~CO)-(CH2)2-(CO)-N(COCH2) NH-OR

(succinimidyl succinamide terminus) R~-SH R2-O-NH(CO)-(CH2)2-C02-R~-S-(CO)-(CH2)2-(CO)-N(COCH2) NH-OR2 R~-OH R2-O-NH(CO)-(CH2)2-C02-R~-O-(CO)-(CH2)2-(CO)-N(COCH2) NH-OR2 R~-NH2 R2-O- (CH2)2-CHO R~-NH-(CO)-(CH2)2-OR2 (propionaldehyde terminus) REPRESENTATIVE

NUCLEOPHILIC REPRESENTATIVE

COMPONENT ELECTROPHILIC

RESULTING LINKAGE
(A, optional COMPONENT

component C (B, FNE~) element FNNU) R~-NH2 j ~ R~-NH-CH2-CH(OH)-CH~-2 OR and R -O-CH2=CH-CH2 R~-N[CH2-CH(OH)-CH2-(glycidyl ether terminus)~R~12 R~-NH2 R2-O-(CH2)~-N=C=O R~-NH-(CO)-NH-CH2-OR2 (isocyanate terminus) R~-NH2 R~-NH-CH2CH2-S02-R~

R2-S02-CH=CH2 (vinyl sulfone terminus) R~-SH R~-S02-CH=CH2 R~-S-CH~CH~-S02-R2 Linking Groups:
The functional groups X and Y and FN on optional component C
may be directly attached to the compound core (R~, R2 or R3 on optional component C, respectively), or they may be indirectly attached through a linking group, with longer linking groups also termed "chain extenders." In structural formulae (I), (II) and (III), the optional linking groups are represented by Q~, Q2 and Q3, wherein the linking groups are present when q, r and s are equal to 1 (with R, X, Y, Fn, m n and p as defined previously).
Suitable linking groups are well known in the art. See, for example, International Patent Publication No. WO 97/22371. Linking groups are useful to avoid steric hindrance problems that are sometimes associated with the formation of direct linkages between molecules. Linking groups may additionally be used to link several multifunctionally activated compounds together to make larger molecules. In a preferred embodiment, a linking group can be used to alter the degradative properties of the compositions after administration and resultant gel formation. For example, linking groups can be incorporated into components A, B, or optional component C to promote hydrolysis, to discourage hydrolysis, or to provide a site for enzymatic degradation.
Examples of linking groups that provide hydrolyzable sites, include, inter alias ester linkages; anhydride linkages, such as obtained by incorporation of glutarate and succinate; ortho ester linkages; ortho carbonate linkages such as trimethylene carbonate; amide linkages; phosphoester linkages; a-hydroxy acid linkages, such as may be obtained by incorporation of lactic acid and glycolic acid; lactone-based linkages, such as may be obtained by incorporation of caprolactone, valerolactone, y-butyrolactone and p-dioxanone; and amide linkages such as in a dimeric, oligomeric, or poly(amino acid) segment. Examples of non-degradable linking groups include succinimide, propionic acid and carboxymethylate linkages. See, for example, PCT WO 99/07417. Examples of enzymatically degradable linkages include Leu-Gly-Pro-Ala, which is degraded by collagenase; and Gly-Pro-Lys, which is degraded by plasmin.
Linking groups can also enhance or suppress the reactivity of the various nucleophilic and electrophilic groups. For example, electron-withdrawing groups within one or two carbons of a sulfhydryl group would be expected to diminish its effectiveness in coupling, due to a lowering of nucleophilicity. Carbon-carbon double bonds and carbonyl groups will also have such an effect. Conversely, electron-withdrawing groups adjacent to a carbonyl group (e.g., the reactive carbonyl of glutaryl-N-hydroxysuccinimidyl) would increase the reactivity of the carbonyl carbon with respect to an incoming nucleophile. By contrast, sterically bulky groups in the vicinity of a functional group can be used to diminish reactivity and thus coupling rate as a result of steric hindrance.
By way of example, particular linking groups and corresponding component structure are indicated in the following Table:

TABLE
LINKING GROUP COMPONENT STRUCTURE

-O-(CH2)n- Component A: R~-O-(CH2)n-X

Component B: R~-O-(CH2)n Y

Optional Component C: R3-O-(CH2)n-Z

-S-(CH2)n Component A: R~-S-(CH2)n X

Component B: R2-S-(CH2)~ Y

Optional Component C: R3-S-(CH~)n Z

-NH-(CH2)~ Component A: R~-NH-(CH2)n-X

Component B: R2-NH-(CH2)n-Y

Optional Component C: R3-NH-(CH~)n-Z

-O-(CO)-NH-(CH2)n- Component A: 'R~-O-(CO)-NH-(CH2)n X

Component B: R2-O-(CO)-NH-(CH2)~ Y

Optional Component C: R3-O-(CO)-NH-(CH2)n-Z

-NH-(CO)-O-(CH2)n- Component A: R~-NH-(CO)-O-(CH2)n X

Component B: R~-NH-(CO)-O-(CH2)n-Y

Optional Component C: R3-NH-(CO)-O-(CH2)n-Z

-O-(CO)-(CH2)n- Component A: R~-O-(CO)-(CH2)n-X

Component B: R2-O-(CO)-(CH2)n Y

Optional Component C: R3-O-(CO)-(CH2)n-Z

-(CO)-O-(CH2)n Component A: R~-(CO)-O-(CH2)n-X

Component B: R2-(CO)-O-(CH2)"Y

Optional Component C: R3-(CO)-O-(CH2)n Z

-O-(CO)-O-(CHZ)~ Component A: R~-O-(CO)-O-(CH2)n X

Component B: R2-O-(CO)-O-(CH2)n Y

Optional Component C: R3-O-(CO)-O-(CH2)n-Z

-O-(CO)-CHR~- Component A: R~-O-(CO)-CHR~-X

Component B: R2-O-(CO)-CHR~-Y

Optional Component C: R3-O-(CO)-CHR7-Z

-O-R$-(CO)-NH- Component A: R~-O-R$-(CO)-NH-X

Component B: R2- O-R$-(CO)-NH-Y

Optional Component C: R3- O-R$-(CO)-NH-Z

In the above Table, n is generally in the range of 1 to about 10, R' is generally hydrocarbyl, typically alkyl or aryl, preferably alkyl, and most preferably lower alkyl, and R$ is hydrocarbylene, heteroatom-containing hydrocarbylene, substituted hydrocarbylene, or substituted heteroatom-containing hydrocarbylene) typically alkylene or arylene (again, optionally substituted and/or containing a heteroatom), preferably lower alkylene (e.g., methylene, ethylene, n-propylene, n-butylene, etc.), phenylene, or amidoalkylene (e.g., -(CO)-NH-CH2).
Other general principles that should be considered with respect to linking groups are as follows: If higher molecular weight components are to be used, they preferably have biodegradable linkages as described above, so that fragments larger than 20,000 mol. wt. are not generated during resorption in the body. In addition, to promote water miscibility and/or solubility, it may be desired to add sufficient electric charge or hydrophilicity. Hydrophilic groups can be easily introduced using known chemical synthesis, so long as they do not give rise to unwanted swelling or an undesirable decrease in compressive strength. In particular, polyalkoxy segments may weaken gel strength.
The Component Core:
The "core" of each crosslinkable component is comprised of the molecular structure to which the nucleophilic or electrophilic groups are bound.
Using the formulae (I) R~-[Q~]q-X)m, for component A, (II) R2(-[Q2]r-Y)" for component B, and (III) R3(-[Q3]S Fn)p for optional component C, the "core" groups are R~, R2 and R3. Each molecular core of the reactive components of the crosslinkable composition is generally selected from synthetic and naturally occurring hydrophilic polymers, hydrophobic polymers, and C2-C~4 hydrocarbyl groups zero to 2 heteroatoms selected from N, O and S, with the proviso that at least one of the crosslinkable components A, B, and optionally C, comprises a molecular core of a synthetic hydrophilic polymer. In a preferred embodiment, at least one of A and B comprises a molecular core of a synthetic hydrophilic polymer.
Hydrophilic Crosslinkable Components In one aspect, the crosslinkable components) is (are) hydrophilic polymers. The term "hydrophilic polymer" as used herein refers to a synthetic polymer having an average molecular weight and composition effective to render the polymer "hydrophilic" as defined above. As discussed above, synthetic crosslinkable hydrophilic polymers useful herein include, but are not limited to: polyalkylene oxides, particularly polyethylene glycol and polyethylene oxide)-polypropylene oxide) copolymers, including block and random copolymers; polyols such as glycerol, polyglycerol (particularly highly branched polyglycerol), propylene glycol and trimethylene glycol substituted with one or more polyalkylene oxides, e.g., mono-, di- and tri-polyoxyethylated glycerol, mono- and di-polyoxyethylated propylene glycol, and mono- and di-polyoxyethylated trimethylene glycol; polyoxyethylated sorbitol, polyoxyethylated glucose; acrylic acid polymers and analogs and copolymers thereof, such as polyacrylic acid per se, polymethacrylic acid, poly(hydroxyethyl-methacrylate), poly(hydroxyethylacrylate), poly(methylalkylsulfoxide methacrylate), poly(methylalkylsulfoxide acrylate) and copolymers of any of the foregoing, and/or with additional acrylate species such as aminoethyl acrylate and mono-2-(acryloxy)-ethyl succinate; polymaleic acid;
poly(acrylamides) such as polyacrylamide per se, poly(methacrylamide), poly(dimethylacrylamide), and poly(N-isopropyl-acrylamide); poly(olefinic alcohol)s such as polyvinyl alcohol); poly(N-vinyl lactams) such as polyvinyl pyrrolidone), poly(N-vinyl caprolactam), and copolymers thereof;
polyoxazolines, including poly(methyloxazoline) and poly(ethyloxazoline); and polyvinylamines. It must be emphasized that the aforementioned list of polymers is not exhaustive, and a variety of other synthetic hydrophilic polymers may be used, as will be appreciated by those skilled in the art.
The synthetic crosslinkable hydrophilic polymer may be a homopolymer, a block copolymer, a random copolymer, or a graft copolymer.
In addition, the polymer may be linear or branched, and if branched, may be minimally to highly branched, dendrimeric, hyperbranched, or a star polymer.
The polymer may include biodegradable segments and blocks, either distributed throughout the polymer's molecular structure or present as a single block, as in a block copolymer. Biodegradable segments are those that degrade so as to break covalent bonds. Typically, biodegradable segments are segments that are hydrolyzed in the presence of water and/or enzymatically cleaved in situ. Biodegradable segments may be composed of small molecular segments such as ester linkages, anhydride linkages, ortho ester linkages, ortho carbonate linkages, amide linkages, phosphonate linkages, etc. Larger biodegradable "blocks" will generally be composed of oligomeric or polymeric segments incorporated within the hydrophilic polymer. Illustrative oligomeric and polymeric segments that are biodegradable include, by way of example, poly(amino acid) segments, poly(orthoester) segments, poly(orthocarbonate) segments, and the like.
Other suitable synthetic crosslinkable hydrophilic polymers include chemically synthesized polypeptides, particularly polynucleophilic polypeptides that have been synthesized to incorporate amino acids containing primary amino groups (such as lysine) and/or amino acids containing thiol groups (such as cysteine). Poly(lysine), a synthetically produced polymer of the amino acid lysine (145 MW), is particularly preferred. Poly(lysine)s have been prepared having anywhere from 6 to about 4,000 primary amino groups, corresponding to molecular weights of about 870 to about 580,000.
Poly(lysine)s for use in the present invention preferably have a molecular weight within the range of about 1,000 to about 300,000, more preferably within the range of about 5,000 to about 100,000, and most preferably, within the range of about 8,000 to about 15,000. Poly(lysine)s of varying molecular weights are commercially available from Peninsula Laboratories, Inc. (Belmont, Calif.).
The synthetic crosslinkable hydrophilic polymer may be a homopolymer, a block copolymer, a random copolymer, or a graft copolymer.
In addition, the polymer may be linear or branched, and if branched, may be minimally to highly branched, dendrimeric, hyperbranched, or a star polymer.
The polymer may include biodegradable segments and blocks, either distributed throughout the polymer's molecular structure or present as a single block, as in a block copolymer. Biodegradable segments are those that degrade so as to break covalent bonds. Typically, biodegradable segments are segments that are hydrolyzed in the presence of water and/or enzymatically cleaved in situ. Biodegradable segments may be composed of small molecular segments such as ester linkages, anhydride linkages, ortho ester linkages, ortho carbonate linkages, amide linkages, phosphonate linkages, etc. Larger biodegradable "blocks" will generally be composed of oligomeric or polymeric segments incorporated within the hydrophilic polymer. Illustrative oligomeric and polymeric segments that are biodegradable include, by way of example, poly(amino acid) segments, poly(orthoester) segments, poly(orthocarbonate) segments, and the like.
Although a variety of different synthetic crosslinkable hydrophilic polymers can be used in the present compositions, as indicated above, preferred synthetic crosslinkable hydrophilic polymers are polyethylene glycol (PEG) and polyglycerol (PG), particularly highly branched polyglycerol.
Various forms of PEG are extensively used in the modification of biologically active molecules because PEG lacks toxicity, antigenicity, and immunogenicity (i.e., is biocompatible), can be formulated so as to have a wide range of solubilities, and do not typically interfere with the enzymatic activities and/or conformations of peptides. A particularly preferred synthetic crosslinkable hydrophilic polymer for certain applications is a polyethylene glycol (PEG) having a molecular weight within the range of about 100 to about 100,000 mol. wt., although for highly branched PEG, far higher molecular weight polymers can be employed --up to 1,000,000 or more -- providing that biodegradable sites are incorporated ensuring that all degradation products will have a molecular weight of less than about 30,000. For most PEGs, however, the preferred molecular weight is about 1,000 to about 20,000 mol. wt., more preferably within the range of about 7,500 to about 20,000 mol. wt. Most preferably, the polyethylene glycol has a molecular weight of approximately 10,000 mol. wt.
Naturally occurring crosslinkable hydrophilic polymers include, but are not limited to: proteins such as collagen, fibronectin, albumins, globulins, fibrinogen, and fibrin, with collagen particularly preferred; carboxylated polysaccharides such as polymannuronic acid and polygalacturonic acid;
aminated polysaccharides, particularly the glycosaminoglycans, e.g., hyaluronic acid, chitin, chondroitin sulfate A, B, or C, keratin sulfate, keratosulfate and heparin; and activated polysaccharides such as dextran and starch derivatives.
Collagen and glycosaminoglycans are examples of naturally occurring hydrophilic polymers for use herein, with methylated collagen being a preferred hydrophilic polymer.
Any of the hydrophilic polymers herein must contain, or be activated to contain, functional groups, i.e., nucleophilic or electrophilic groups, which enable crosslinking. Activation of PEG is discussed below; it is to be understood, however, that the following discussion is for purposes of illustration and analogous techniques may be employed with other polymers.
With respect to PEG, first of all, various functionalized polyethylene glycols have been used effectively in fields such as protein modification (see Abuchowski et al., Enzymes as Drugs, John Wiley & Sons:
New York, N.Y. (1981 ) pp. 367-383; and Dreborg et al., Crit. Rev. Therap.
Drug Carrier Syst. (1990) 6:315), peptide chemistry (see Mutter et al., The Peptides, Academic: New York, N.Y. 2:285-332; and Zalipsky et al., Int. J. Peptide Protein Res. (1987) 30:740), and the synthesis of polymeric drugs (see Zalipsky et al., Eur. Polym. J. (1983) 19:1177; and Ouchi et al., J. Macromol. Sci. Chem.
(1987) A24:1011 ).
Activated forms of PEG, including multifunctionally activated PEG, are commercially available, and are also easily prepared using known methods.
For example, see Chapter 22 of Polyethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, J. Milton Harris, ed., Plenum Press, NY (1992);
and Shearwater Polymers, Inc. Catalog, Polyethylene Glycol Derivatives, Huntsville, Alabama (1997-1998).
Structures for some specific, tetrafunctionally activated forms of PEG are shown in FIGS. 1 to 10 of U.S. Patent 5,874,500, as are generalized reaction products obtained by reacting the activated PEGs with multi-amino PEGs, i.e., a PEG with two or more primary amino groups. The activated PEGs illustrated have a pentaerythritol (2,2-bis(hydroxymethyl)-1,3-propanediol) core.
Such activated PEGs, as will be appreciated by those in the art, are readily prepared by conversion of the exposed hydroxyl groups in the PEGylated polyol (i.e., the terminal hydroxyl groups on the PEG chains) to carboxylic acid groups (typically by reaction with an anhydride in the presence of a nitrogenous base), followed by esterification with N-hydroxysuccinimide, N-hydroxysulfosuccinimide, or the like, to give the polyfunctionally activated PEG.
Hydrophobic Polymers:
The crosslinkable compositions of the invention can also include hydrophobic polymers, although for most uses hydrophilic polymers are preferred. Polylactic acid and polyglycolic acid are examples of two hydrophobic polymers that can be used. With other hydrophobic polymers, only short-chain oligomers should be used, containing at most about 14 carbon atoms, to avoid solubility-related problems during reaction.

Low Molecular Weight Components:
As indicated above, the molecular core of one or more of the crosslinkable components can also be a low molecular weight compound, i.e., a C2-C~4 hydrocarbyl group containing zero to 2 heteroatoms selected from N, O, S and combinations thereof. Such a molecular core can be substituted with nucleophilic groups or with electrophilic groups.
When the low molecular weight molecular core is substituted with primary amino groups, the component may be, for example, ethylenediamine (H2N-CH2CH~-NH2), tetramethylenediamine (H2N-(CH4)-NHS), pentamethylenediamine (cadaverine) (H2N-(CH5)-NH2), hexamethylenediamine (H2N-(CH6)-NH2), bis(2-aminoethyl)amine (HN-[CH2CH2-NH2]2), or tris(2-aminoethyl)amine (N-[CH2CH2-NH~~3).
Low molecular weight diols and polyols include trimethylolpropane, di(trimethylol propane), pentaerythritol, and diglycerol, all of which require activation with a base in order to facilitate their reaction as nucleophiles. Such diols and polyols may also be functionalized to provide di-and poly-carboxylic acids, functional groups that are, as noted earlier herein, also useful as nucleophiles under certain conditions. Polyacids for use in the present compositions include, without limitation, trimethylolpropane-based tricarboxylic acid, di(trimethylol propane)-based tetracarboxylic acid, heptanedioic acid, octanedioic acid (suberic acid), and hexadecanedioic acid (thapsic acid), all of which are commercially available and/or readily synthesized using known techniques.
Low molecular weight di- and poly-electrophiles include, for example, disuccinimidyl suberate (DSS), bis(sulfosuccinimidyl) suberate (BS3), dithiobis(succinimidylpropionate) (DSP), bis(2-succinimidooxycarbonyloxy) ethyl sulfone (BSOCOES), and 3,3'-dithiobis(sulfosuccinimidylpropionate (DTSPP), and their analogs and derivatives. The aforementioned compounds are commercially available from Pierce (Rockford, IIL). Such di- and poly-electrophiles can also be synthesized from di- and polyacids, for example by reaction with an appropriate molar amount of N-hydroxysuccinimide in the presence of DCC. Polyols such as trimethylolpropane and di(trimethylol propane) can be converted to carboxylic acid form using various known techniques, then further derivatized by reaction with NHS in the presence of DCC to produce trifunctionally and tetrafunctionally activated polymers.
Delivery Systems:
Suitable delivery systems for the homogeneous dry powder composition (containing at least two crosslinkable polymers) and the two buffer solutions may involve a multi-compartment spray device, where one or more compartments contains the powder and one or more compartments contain the buffer solutions needed to provide for the aqueous environment, so that the composition is exposed to the aqueous environment as it leaves the compartment. Many devices that are adapted for delivery of multi-component tissue sealants/hemostatic agents are well known in the art and can also be used in the practice of the present invention. Alternatively, the composition can be delivered using any type of controllable extrusion system, or it can be delivered manually in the form of a dry powder, and exposed to the aqueous environment at the site of administration.
The homogeneous dry powder composition and the two buffer solutions may be conveniently formed under aseptic conditions by placing each of the three ingredients (dry powder, acidic buffer solution and basic buffer solution) into separate syringe barrels. For example, the composition, first buffer solution and second buffer solution can be housed separately in a multiple-compartment syringe system having a multiple barrels, a mixing head, and an exit orifice. The first buffer solution can be added to the barrel housing the composition to dissolve the composition and form a homogeneous solution, which is then extruded into the mixing head. The second buffer solution can be simultaneously extruded into the mixing head. Finally, the resulting composition can then be extruded through the orifice onto a surface.

For example, the syringe barrels holding the dry powder and.the basic buffer may be part of a dual-syringe system, e.g., a double barrel syringe as described in U.S. Patent 4,359,049 to Redl et al. In this embodiment, the acid buffer can be added to the syringe barrel that also holds the dry powder, so as to produce the homogeneous solution. In other words, the acid buffer may be added (e.g., injected) into the syringe barrel holding the dry powder to thereby produce a homogeneous solution of the first and second components.
This homogeneous solution can then be extruded into a mixing head, while the basic buffer is simultaneously extruded into the mixing head. Within the mixing head, the homogeneous solution and the basic buffer are mixed together to thereby form a reactive mixture. Thereafter, the reactive mixture is extruded through an orifice and onto a surface (e.g., tissue), where a film is formed, which can function as a sealant or a barrier, or the like. The reactive mixture begins forming a three-dimensional matrix immediately upon being formed by the mixing of the homogeneous solution and the basic buffer in the mixing head. Accordingly, the reactive mixture is preferably extruded from the mixing head onto the tissue very quickly after it is formed so that the three-dimensional matrix forms on, and is able to adhere to, the tissue.
Other systems for combining two reactive liquids are well known in the art, and include the systems described in U.S. Patent Nos. 6,454,786 to Holm et al.; 6,461,325 to Delmotte et al.; 5,585,007 to Antanavich et al.;
5,116,315 to Capozzi et al.; and 4,631,055 to Redl et al.
Storage and Handling:
Because crosslinkable components containing electrophilic groups react with water, the electrophilic component or components are generally stored and used in sterile, dry form to prevent hydrolysis.
Processes for preparing synthetic hydrophilic polymers containing multiple electrophilic groups in sterile, dry form are set forth in commonly assigned U.S. Patent No.
5,643,464 to Rhee et al. For example, the dry synthetic polymer may be compression molded into a thin sheet or membrane, which can then be sterilized using gamma or, preferably, e-beam irradiation. The resulting dry membrane or sheet can be cut to the desired size or chopped into smaller size particulates.
Components containing multiple nucleophilic groups are generally not water-reactive and can therefore be stored either dry or in aqueous solution.
If stored as a dry, particulate, solid, the various components of the crosslinkable composition may be blended and stored in a single container. Admixture of all components with water, saline, or other aqueous media should not occur until immediately prior to use.
In an alternative embodiment, the crosslinking components can be mixed together in a single aqueous medium in which they are both unreactive, i.e., such as in a low pH buffer. Thereafter, they can be sprayed onto the targeted tissue site along with a high pH buffer, after which they will rapidly react and form a gel.
Suitable liquid media for storage of crosslinleable compositions include aqueous buffer solutions such as monobasic sodium phosphateldibasic sodium phosphate, sodium carbonatelsodium bicarbonate, glutamate or acetate, at a concentration of 0.5 to 300 mM. In general, a sulfhydryl-reactive component such as PEG substituted with maleimido groups or succinimidyl esters is prepared in water or a dilute buffer, with a pH of between around 5 to 6. Buffers with pKs between about 8 and 10.5 for preparing a polysulfhydryl component such as sulfhydryl-PEG are useful to achieve fast gelation time of compositions containing mixtures of sulfhydryl-PEG and SG-PEG. These include carbonate, borate and AMPSO (3-[(1,1-dimethyl-2-hydroxyethyl)amino]2-hydroxy-propane-sulfonic acid). In contrast, using a combination of maleimidyl PEG and sulfhydryl-PEG, a pH of around 5 to 9 is preferred for the liquid medium used to prepare the sulfhydryl PEG.

Collagen + Fibrinogen and/or Thrombin (e.e~., Costasis) In yet another aspect, the polymer composition may include collagen in combination with fibrinogen and/or thrombin. (See, e.g., U.S.
Patent Nos. 5,290,552; 6,096,309; and 5,997,811 ). For example, an aqueous composition may include a fibrinogen and FXIII, particularly plasma, collagen in an amount sufficient to thicken the composition, thrombin in an amount sufficient to catalyze polymerization of fibrinogen present in the composition, and Ca2+ and, optionally, an antifibrinolytic agent in amount sufficient to retard degradation of the resulting adhesive clot. The composition may be formulated as a two-part composition that may be mixed together just prior to use, in which fibrinogen/FXIII and collagen constitute the first component, and thrombin together with an antifibrinolytic agent, and Ca2+ constitute the second component.
Plasma, which provides a source of fibrinogen, may be obtained from the patient for which the composition is to be delivered. The plasma can be used "as is" after standard preparation which includes centrifuging out cellular components of blood. Alternatively, the plasma can be further processed to concentrate the fibrinogen to prepare a plasma cryoprecipitate.
The plasma cryoprecipitate can be prepared by freezing the plasma for at least about an hour at about -20 °C., and then storing the frozen plasma overnight at about 4 °C. to slowly thaw. The thawed plasma is centrifuged and the plasma cryoprecipitate is harvested by removing approximately four-fifths of the plasma to provide a cryoprecipitate comprising the remaining one-fifth of the plasma.
Other fibrinogen/FXIII preparations may be used, such as cryoprecipitate, patient autologous fibrin sealant, fibrinogen analogs or other single donor or commercial fibrin sealant materials. Approximately 0.5 ml to about 1.0 ml of either the plasma or the plasma-cryoprecipitate provides about 1 to 2 ml of adhesive composition which is sufficient for use in middle ear surgery. Other plasma proteins (e.g., albumin, plasminogen, von Willebrands factor, Factor VIII, etc.) may or may not be present in the fibrinogen/FXII separation due to wide variations in the formulations and methods to derive them.
Collagen, preferably hypoallergenic collagen, is present in the composition in an amount sufficient to thicken the composition and augment the cohesive properties of the preparation. The collagen may be atelopeptide collagen or telopeptide collagen, e.g., native collagen. In addition to thickening the composition, the collagen augments the fibrin by acting as a macromolecular lattice work or scaffold to which the fibrin network adsorbs.
This gives more strength and durability to the resulting glue clot with a relatively low concentration of fibrinogen in comparison to the various concentrated autogenous fibrinogen glue formulations (i.e., AFGs).
The form of collagen which is employed may be described as at least "near native" in its structural characteristics. It may be further characterized as resulting in insoluble fibers at a pH above 5; unless crosslinked or as part of a complex composition, e.g., bone, it will generally consist of a minor amount by weight of fibers with diameters greater than 50 nm, usually from about 1 to 25 volume % and there will be substantially little, if any, change in the helical structure of the fibrils. In addition, the collagen composition must be able to enhance gelation in the surgical adhesion composition.
A number of commercially available collagen preparations may be used. ZYDERM Collagen Implant (ZCI) has a fibrillar diameter distribution consisting of 5 to 10 nm diameter fibers at 90% volume content and the remaining 10% with greater than about 50 nm diameter fibers. ZCI is available as a fibrillar slurry and solution in phosphate buffered isotonic saline, pH
7.2, and is injectable with fine gauge needles. As distinct from ZCI, cross-linked collagen available as ZYPLAST may be employed. ZYPLAST is essentially an exogenously crosslinked (glutaraldehyde) version of ZCI. The material has a somewhat higher content of greater than about 50 nm diameter fibrils and remains insoluble over a wide pH range. Crosslinking has the effect of mimicking in vivo endogenous crosslinking found in many tissues.
Thrombin acts as a catalyst for fibrinogen to provide fibrin, an insoluble polymer and is present in the composition in an amount sufficient to catalyze polymerization of fibrinogen present in the patient plasma. Thrombin also activates FXIII, a plasma protein that catalyzes covalent crosslinks in fibrin, rendering the resultant clot insoluble. Usually the thrombin is present in the adhesive composition in concentration of from about 0.01 to about 1000 or greater NIH units (NIHu) of activity, usually about i to about 500 NIHu, most usually about 200 to about 500 NIHu. The thrombin can be from a variety of host animal sources, conveniently bovine. Thrombin is commercially available from a variety of sources including Parke-Davis, usually lyophilized with buffer salts and stabilizers in vials which provide thrombin activity ranging from about 1000 NIHu to 10,000 NIHu. The thrombin is usually prepared by reconstituting the powder by the addition of either sterile distilled water or isotonic saline.
Alternately, thrombin analogs or reptile-sourced coagulants may be used.
The composition may additionally comprise an effective amount of an antifibrinolytic agent to enhance the integrity of the glue clot as the healing processes occur. A number of antifibrinolytic agents are well known and include aprotinin, C1-esterase inhibitor and s-amino-n-caproic acid (EACA). s-amino-n-caproic acid, the only antifibrinolytic agent approved by the FDA, is effective at a concentration of from about ~ mg/ml to about 40 mg/ml of the final adhesive composition, more usually from about 20 to about 30 mg/ml. EACA is commercially available as a solution having a concentration of about 250 mg/ml. Conveniently, the commercial solution is diluted with distilled water to provide a solution of the desired concentration. That solution is desirably used to reconstitute lyophilized thrombin to the desired thrombin concentration.
Other examples of in situ forming materials based on the crosslinking of proteins are described, e.g., in U.S. Patent Nos. RE38158;
4,839,345; 5,514,379, 5,583,114; 6,458,147; 6,371,975; 5,290,552; 6,096,309;

U.S. Patent Application Publication Nos. 2002/0161399; 2001 /0018598 and PCT Publication Nos. WO 03/090683; WO 01/45761; WO 99/66964 and WO
96/03159). ' Self-Reactive Compounds In one aspect, the therapeutic agent is released from a crosslinked matrix formed, at least in part, from a self-reactive compound. As used herein, a self-reactive compound comprises a core substituted with a minimum of three reactive groups. The reactive groups may be directed attached to the core of the compound, or the reactive groups may be indirectly attached to the compound's core, e.g., the reactive groups are joined to the core through one or more linking groups.
Each of the three reactive groups that are necessarily present in a self-reactive compound can undergo a bond-forming reaction with at least one of the remaining two reactive groups. For clarity it is mentioned that when these compounds react to form a crosslinked matrix, it will most often happen that reactive groups on one compound will reactive with reactive groups on another compound. That is, the term "self-reactive" is not intended to mean that each self-reactive compound necessarily reacts with itself, but rather that when a plurality of identical self-reactive compounds are in combination and undergo a crosslinking reaction, then these compounds will react with one another to form the matrix. The compounds are "self-reactive" in the sense that they can react with other compounds having the identical chemical structure as themselves.
The self-reactive compound comprises at least four components:
a core and three reactive groups. In one embodiment, the self-reactive compound can be characterized by the formula (I), where R is the core, the reactive groups are represented by X~, X2 and X3, and a linker (L) is optionally present between the core and a functional group.

(L2)q (1 ) X1-(L1)p R-(Ls)r Xs The core R is a polyvalent moiety having attachment to at least three groups (i.e., it is at least trivalent) and may be, or may contain, for example, a hydrophilic polymer, a hydrophobic polymer, an amphiphilic polymer, a C2_~4 hydrocarbyl, or a C~_~4 hydrocarbyl which is heteroatom-containing. The linking groups L~, L2, and L3 may be the same or different.
The designators p, q and r are either 0 (when no linker is present) or 1 (when a linker is present). The reactive groups X~, X2 and X3 may be the same or different. Each of these reactive groups reacts with at least one other reactive group to form a three-dimensional matrix. Therefore X~ can react with X2 and/or X3, X2 can react with X~ and/or X3, X3 can react with X~ and/or X2 and so forth. A trivalent core will be directly or indirectly bonded to three functional groups, a tetravalent core will be directly or indirectly bonded to four functional groups, etc.
Each side chain typically has one reactive group. However, the invention also encompasses self-reactive compounds where the side chains contain more than one reactive group. Thus, in another embodiment of the invention, the self-reactive compound has the formula (II):
L X~ - (~4)a - '~~ ' (L5)b l c where: a and b are integers from 0-1; c is an integer from 3-12; R' is selected from hydrophilic polymers, hydrophobic polymers, amphiphilic polymers, C2_~4 hydrocarbyls, and heteroatom-containing C~_~4 hydrocarbyls; X' and Y' are reactive groups and can be the same or different; and L4 and L5 are linking groups. Each reactive group inter-reacts with the other reactive group to form a three-dimensional matrix. The compound is essentially non-reactive in an initial environment but is rendered reactive upon exposure to a modification in the initial environment that provides a modified environment such that a plurality of the self-reactive compounds inter-react in the modified environment to form a three-dimensional matrix. In one preferred embodiment, R is a hydrophilic polymer. In another preferred embodiment, X' is a nucleophilic group and Y' is an electrophilic group.
The following self-reactive compound is one example of a compound of formula (II):
where R4 has the formula:

H2N p-N
x O
Thus, in formula (II), a and b are 1; c is 4; the core R' is the hydrophilic polymer, tefirafunctionally activated polyethylene glycol, (C(CH2-O-)4; X' is the electrophilic reactive group, succinimidyl; Y' is the nucleophilic reactive group -CH-NH2; L4 is -C(O)-O-; and L5 is -(CH2- CH2-O-CH2)x CH2-O-C(O)-(CH2)2-.
The self-reactive compounds of the invention are readily synthesized by techniques that are well known in the art. An exemplary synthesis is set forth below:

O
HO
O
HN O
O
O
Mitsunobo or DCC
o o o O HN O
x O
RaO O

H2, Pd/C

O
Mitsunobo or HO DCC
o The reactive groups are selected so that the compound is essentially non-reactive in an initial environment. Upon exposure to a specific modification in the initial environment, providing a modified environment, the compound is rendered reactive and a plurality of self-reactive compounds are then able to inter-react in the modified environment to form a three-dimensional matrix. Examples of modification in the initial environment are detailed below, but include the addition of an aqueous medium, a change in pH, exposure to ultraviolet radiation, a change in temperature, or contact with a redox initiator.
The core and reactive groups can also be selected so as to provide a compound that has one of more of the following features: are biocompatible, are non-immunogenic, and do not leave any toxic, inflammatory or immunogenic reaction products at the site of administration. Similarly, the core and reactive groups can also be selected so as to provide a resulting matrix that has one or more of these features.
In one embodiment of the invention, substantially immediately or immediately upon exposure to the modified environment, the self-reactive compounds inter-react form a three-dimensional matrix. The term "substantially immediately" is intended to mean within less than five minutes, preferably within less than two minutes, and the term "immediately" is intended to mean within less than one minute, preferably within less than 30 seconds.
In one embodiment, the self-reactive compound and resulting matrix are not subject to enzymatic cleavage by matrix metalloproteinases such as collagenase, and are therefore not readily degradable in vivo. Further, the self-reactive compound may be readily tailored, in terms of the selection and quantity of each component, to enhance certain properties, e.g., compression strength, swellability, tack, hydrophilicity, optical clarity, and the like.
In one preferred embodiment, R is a hydrophilic polymer. In another preferred embodiment, X is a nucleophilic group, Y is an electrophilic group and Z is either an electrophilic or a nucleophilic group. Additional embodiments are detailed below.
A higher degree of inter-reaction, e.g., crosslinking, may be useful when a less swellable matrix is desired or increased compressive strength is desired. In those embodiments, it may be desirable to have n be an integer from 2-12. In addition, when a plurality of self-reactive compounds are utilized, the compounds may be the same or different.
A. Reactive Groups Prior to use, the self-reactive compound is stored in an initial environment that insures that the compound remain essentially non-reactive until use. Upon modification of this environment, the compound is rendered reactive and a plurality of compounds will then inter-react to form the desired matrix. The initial environment, as well as the modified environment, is thus determined by the nature of the reactive groups involved.
The number of reactive groups can be the same or different.
However, in one embodiment of the invention, the number of reactive groups are approximately equal. As used in this context, the term "approximately"
refers to a 2:1 to 1:2 ratio of moles of one reactive group to moles of a different reactive groups. A 1:1:1 molar ratio of reactive groups is generally preferred.
In general, the concentration of the self-reactive compounds in the modified environment, when liquid in nature, will be in the range of about 1 to 50 wt%, generally about 2 to 40 wt%. The preferred concentration of the compound in the liquid will depend on a number of factors, including the type of compound (i.e., type of molecular core and reactive groups), its molecular weight, and the end use of the resulting three-dimensional matrix. For example, use of higher concentrations of the compounds, or using highly functionalized compounds, will result in the formation of a more tightly crosslinked network, producing a stiffer, more robust gel. As such, compositions intended for use in tissue augmentation will generally employ concentrations of self-reactive compounds that fall toward the higher end of the preferred concentration range. Compositions intended for use as bioadhesives or in adhesion prevention do not need to be as firm and may therefore contain lower concentrations of the self-reactive compounds.
1 ) Electrophilic and Nucleophilic Reactive Groups In one embodiment of the invention, the reactive groups are electrophilic and nucleophilic groups, which undergo a nucleophilic substitution reaction, a nucleophilic addition reaction, or both. The term "electrophilic"
refers to a reactive group that is susceptible to nucleophilic attack, i.e., susceptible to reaction with an incoming nucleophilic group. Electrophilic groups herein are positively charged or electron-deficient, typically electron-deficient. The term "nucleophilic" refers to a reactive group that is electron rich, has an unshared pair of electrons acting as a reactive site, and reacts with a positively charged or electron-deficient site. For such reactive groups, the modification in the initial environment comprises the addition of an aqueous medium and/or a change in pH.
In one embodiment of the invention, X1 (also referred to herein as X) can be a nucleophilic group and X2 (also referred to herein as Y) can be an electrophilic group or vice versa, and X3 (also referred to herein as Z) can be either an electrophilic or a nucleophilic group.
X may be virtually any nucleophilic group, so long as reaction can occur with the electrophilic group Y and also with Z, when Z is electrophilic (~EL)~ Analogously, Y may be virtually any electrophilic group, so long as reaction can take place with X and also with Z when Z is nucleophilic (ZNU).
The only limitation is a practical one, in that reaction between X and Y, and X
and ZED, or Y and ZNU should be fairly rapid and take place automatically upon admixture with an aqueous medium, without need for heat or potentially toxic or non-biodegradable reaction catalysts or other chemical reagents. It is also preferred although not essential that reaction occur without need for ultraviolet or other radiation. In one embodiment, the reactions between X and Y, and between either X and ZED or Y and ZNU, are complete in under 60 minutes, preferably under 30 minutes. Most preferably, the reaction occurs in about 5 to 15 minutes or less.
Examples of nucleophilic groups suitable as X or FnNU include, but are not limited to: -NH2, -NHR~, -N(R~)2, -SH, -OH, -COOH, -C6H4-OH, -H, -PH2, -PHR~, -P(R~)2, -NH-NH2, -CO-NH-NH2, -C5H4N, etc. wherein R~ is a hydrocarbyl group and each R1 may be the same or different. R~ is typically alkyl or monocyclic aryl, preferably alkyl, and most preferably lower alkyl.
Organometallic moieties are also useful nucleophilic groups for the purposes of the invention, particularly those that act as carbanion donors. Examples of organometallic moieties include: Grignard functionalities -R2MgHal wherein R2 is a carbon atom (substituted or unsubstituted), and Hal is halo, typically bromo, iodo or chloro, preferably bromo; and lithium-containing functionalities, typically alkyllithium groups; sodium-containing functionalities.
It will be appreciated by those of ordinary skill in the art that certain nucleophilic groups must be activated with a base so as to be capable of reaction with an electrophilic group. For example, when there are nucleophilic sulfhydryl and hydroxyl groups in the self-reactive compound, the compound must be admixed with an aqueous base in order to remove a proton and provide an -S- or -O- species to enable reaction with the electrophilic group.
Unless it is desirable for the base to participate in the reaction, a non-nucleophilic base is preferred. In some embodiments, the base may be present as a component of a buffer solution. Suitable bases and corresponding crosslinking reactions are described herein.
The selection of electrophilic groups provided on the self-reactive compound, must be made so that reaction is possible with the specific nucleophilic groups. Thus, when the X reactive groups are amino groups, the Y
and any ZED groups are selected so as to react with amino groups.
Analogously, when the X reactive groups are sulfhydryl moieties, the corresponding electrophilic groups are sulfhydryl-reactive groups, and the like.
In general, examples of electrophilic groups suitable as Y or ZED include, but are not limited to, -CO-CI, -(CO)-O-(CO)-R (where R is an alkyl group), -CH=CH-CH=O and -CH=CH-C(CH3)=O, halo, -N=C=O, -N=C=S, -S02CH=CH2, -O(CO)-C=CH2, -O(CO)-C(CH3)=CH2, -S-S-(C5H4N), -O(CO)-C(CH2CH3)=CH2, -CH=CH-C=NH, -COOH, -(CO)O-N(COCH2)2, -CHO, -(CO)O-N(COCH2)2-S(O)20H, and -N(COCH)2.
When X is amino (generally although not necessarily primary amino), the electrophilic groups present on Y and ZED are amine-reactive groups. Exemplary amine-reactive groups include, by way of example and not limitation, the following groups, or radicals thereof: (1 ) carboxylic acid esters, including cyclic esters and "activated" esters; (2) acid chloride groups (-CO-CI);

(3) anhydrides (-(CO)-O-(CO)-R, where R is an alkyl group); (4) ketones and aldehydes, including a,~i-unsaturated aldehydes and ketones such as -CH=CH-CH=O and -CH=CH-C(CH3)=O; (5) halo groups; (6) isocyanate group (-N=C=O); (7) thioisocyanato group (-N=C=S); (8) epoxides; (9) activated hydroxyl groups (e.g., activated with conventional activating agents such as carbonyldiimidazole or sulfonyl chloride); and (10) olefins, including conjugated olefins, such as ethenesulfonyl (-S02CH=CH2) and analogous functional groups, including acrylate (-O(CO)-C=CH2), methacrylate (-O(CO)-C(CH3)=CH2), ethyl acrylate (-O(CO)-C(CH2CH3)=CHI), and ethyleneimino (-CH=CH-C=NH).
In one embodiment the amine-reactive groups contain an electrophilically reactive carbonyl group susceptible to nucleophilic attack by a primary or secondary amine, for example the carboxylic acid esters and aldehydes noted above, as well as carboxyl groups (-COOH).
Since a carboxylic acid group per se is not susceptible to reaction with a nucleophilic amine, components containing,carboxylic acid groups must be activated so as to be amine-reactive. Activation may be accomplished in a variety of ways, but often involves reaction with a suitable hydroxyl-containing compound in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or dicyclohexylurea (DHU). For example, a carboxylic acid can be reacted with an alkoxy-substituted N-hydroxy-succinimide'or N-hydroxysulfosuccinimide in the presence of DCC to form reactive electrophilic groups, the N-hydroxysuccinimide ester and the N-hydroxysulfosuccinimide ester, respectively. Carboxylic acids may also be activated by reaction with an acyl halide such as an acyl chloride (e.g., acetyl chloride), to provide a reactive anhydride group. In a further example, a carboxylic acid may be converted to an acid chloride group using, e.g., thionyl chloride or an acyl chloride capable of an exchange reaction. Specific reagents and procedures used to carry out such activation reactions will be known to those of ordinary skill in the art and are described in the pertinent texts and literature.
Accordingly, in one embodiment, the amine-reactive groups are selected from succinimidyl ester (-O(CO)-N(COCH2)2), sulfosuccinimidyl ester (-O(CO)-N(COCH2)2-S(O)20H), maleimido (-N(COCH)2), epoxy, isocyanato, thioisocyanato, and ethenesulfonyl.
Analogously, when X is sulfhydryl, the electrophilic groups present on Y and ZED are groups that react with a sulfhydryl moiety. Such reactive groups include those that form thioester linkages upon reaction with a sulfhydryl group, such as those described in WO 00/62827 to Wallace et al. As explained in detail therein, sulfhydryl reactive groups include, but are not limited to:
mixed anhydrides; ester derivatives of phosphorus; ester derivatives of p-nitrophenol, p-nitrothiophenol and pentafluorophenol; esters of substituted hydroxylamines, including N-hydroxyphthalimide esters, N-hydroxysuccinimide esters, N-hydroxysulfosuccinimide esters, and N-hydroxyglutarimide esters; esters of 1-hydroxybenzotriazole; 3-hydroxy-3,4-dihydro-benzotriazin-4-one; 3-hydroxy-3,4-dihydro-quinazoline-4-one; carbonylimidazole derivatives; acid chlorides;
ketenes; and isocyanates. With these sulfhydryl reactive groups, auxiliary reagents can also be used to facilitate bond formation, e.g., 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide can be used to facilitate coupling of sulfhydryl groups to carboxyl-containing groups.
In addition to the sulfhydryl reactive groups that form thioester linkages, various other sulfhydryl reactive functionalities can be utilized that form other types of linkages. For example, compounds that contain methyl imidate derivatives form imido-thioester linkages with sulfhydryl groups.
Alternatively, sulfhydryl reactive groups can be employed that form disulfide bonds with sulfhydryl groups; such groups generally have the structure -S-S-Ar where Ar is a substituted or unsubstituted nitrogen-containing heteroaromatic moiety or a non-heterocyclic aromatic group substituted with an electron-withdrawing moiety, such that Ar may be, for example, 4-pyridinyl, o-nitrophenyl, m-nitrophenyl, p-nitrophenyl, 2,4-dinitrophenyl, 2-nitro-4-benzoic acid, 2-nitro-4-pyridinyl, etc. In such instances, auxiliary reagents, i.e., mild oxidizing agents such as hydrogen peroxide, can be used to facilitate disulfide bond formation.
Yet another class of sulfhydryl reactive groups forms thioether bonds with sulfhydryl groups. Such groups include, inter alia, maleimido, substituted maleimido, haloalkyl, epoxy, imino, and aziridino, as well as olefins (including conjugated olefins) such as ethenesulfonyl, etheneimino, acrylate, methacrylate, and a,(3-unsaturated aldehydes and ketones.
When X is -OH, the electrophilic functional groups on the remaining components) must react with hydroxyl groups. The hydroxyl group may be activated as described above with respect to carboxylic acid groups, or it may react directly in the presence of base with a sufficiently reactive electrophilic group such as an epoxide group, an aziridine group, an acyl halide, an anhydride, and so forth.
When X is an organometallic nucleophilic group such as a Grignard functionality or an alkyllithium group, suitable electrophilic functional groups for reaction therewith are those containing carbonyl groups, including, by way of example, ketones and aldehydes.
It will also be appreciated that certain functional groups can react as nucleophilic or as electrophilic groups, depending on the selected reaction partner andlor the reaction conditions. For example, a carboxylic acid group can act as a nucleophilic group in the presence of a fairly strong base, but generally acts as an electrophilic group allowing nucleophilic attack at the carbonyl carbon and concomitant replacement of the hydroxyl group with the incoming nucleophilic group.
These, as well as other embodiments are illustrated below, where the covalent linkages in the matrix that result upon covalent binding of specific nucleophilic reactive groups to specific electrophilic reactive groups on the self-reactive compound include, solely by way of example, the following Table:

Table Representative Nucleophilic Representative Electrophilic Group (?C, Group (Y, ZED) Resulting Linkage GNU) -NH2 -O-(CO)-O-N(COCH~)a -NH-(CO)-O-succinimidyl carbonate terminus -SH -O-(CO)-O-N(COCH~)2 -S-(CO)-O--OH -O-(CO)-O-N(COCH~)2 -O-(CO)--NH2 -O(CO)-CH=CH2 -NH-CH2CH2-(CO)-O-acrylate terminus -S H -O-(CO)-CH=CH2 -S-CH2CH2-(CO)-O--OH -O-(CO)-CH=CH2 -O-CH2CH2-(CO)-O--NH~ -O(CO)-(CH2)3-C02-N(COCH2)2-NH-(CO)-(CH2)3-(CO)-O-succinimidyl glutarate terminus -SH -O(CO)-(CH2)3-C02-N(COCH2)2-S-(CO)-(CH2)3-(CO)-O--OH -O(CO)-(CH2)3-C02-N(COCH2)2-O-(CO)-(CH2)3-(CO)-O--N H2 -O-CH2-C02-N(COCH2)2 -N H-( CO)-CH2-O-succinimidyl acetate terminus -S H -O-CH2-C02-N(COC H2)2 -S-(CO)-C H2-O--OH -O-CH2-CO~-N(COCH2)2 -O-(CO)-CH2-O--NH2 -O-NH(CO)-(CH2)2-C02- -NH-(CO)-(CH2)2-(CO)-N(COCH2)2 NH-O-succinimidyl succinamide terminus -SH -O-NH(CO)-(CH2)2-C02- -S-(CO)-(CH2)2-(CO)-NH-N(COCH2)2 O-OH -O-NH(CO)-(CH2)2-C02- -O-(CO)-(CH2)2-(CO)-NH-N(COCH2)2 O--NH2 -O- (CH2)2-CHO -NH-(CO)-(CH2)2-O-propionaldehyde terminus -NH2 % ~ -NH-CH2-CH(OH)-CH2-O--O-CH2-CH CH2 and glycidyl ether terminus -N[CH2-CH(OH)-CH2-O-J2 Representative Nucleophilic Representative Electrophilic Group (X, Group (Y, ZED) Resulting Linkage ~N~) -NH2 -O-(CH2)2-N=C=O -NH-(CO)-NH-CH2-O-(isocyanate terminus) -NH2 -S02-CH=CH2 -NH-CH~CH2-S02-vinyl sulfone terminus -SH -S02-CH=CH2 -S-CH2CH2-S02-For self-reactive compounds containing electrophilic and nucleophilic reactive groups, the initial environment typically can be dry and sterile. Since electrophilic groups react with water, storage in sterile, dry form will prevent hydrolysis. The dry synthetic polymer may be compression molded into a thin sheet or membrane, which can then be sterilized using gamma or e-beam irradiation. The resulting dry membrane or sheet can be cut to the desired size or chopped into smaller size particulates. The modification of a dry initial environment will typically comprise the addition of an aqueous medium.
In one embodiment, the initial environment can be an aqueous medium such as in a low pH bufFer, i.e., having a pH less than about 6.0, in which both electrophilic and nucleophilic groups are non-reactive. Suitable liquid media for storage of such compounds include aqueous buffer solutions such as monobasic sodium phosphate/dibasic sodium phosphate, sodium carbonate/sodium bicarbonate, glutamate or acetate, at a concentration of 0.5 to 300 mM. Modification of an initial low pH aqueous environment will typically comprise increasing the pH to at least pH 7.0, more preferably increasing the pH to at least pH 9.5.
In another embodiment the modification of a dry initial environment comprises dissolving the self-reactive compound in a first buffer solution having a pH within the range of about 1.0 to 5.5 to form a homogeneous solution, and (ii) adding a second buffer solution having a pH
within the range of about 6.0 to 11.0 to the homogeneous solution. The buffer solutions are aqueous and can be any pharmaceutically acceptable basic or acid composition. The term "buffer" is used in a general sense to refer to an acidic or basic aqueous solution, where the solution may or may not be functioning to provide a buffering effect (i.e., resistance to change in pH
upon addition of acid or base) in the compositions of the present invention. For example, the self-reactive compound-can be in the form of a homogeneous dry powder. This powder is then combined with a buffer solution having a pH within the range of about 1.0 to 5.5 to form a homogeneous acidic aqueous solution, and this solution is then combined with a buffer solution having a pH within the range of about 6.0 to 11.0 to form a reactive solution. For example, 0.375 grams of the dry powder can be combined with 0.75 grams of the acid buffer to provide, after mixing, a homogeneous solution, where this solution is combined with 1.1 grams of the basic buffer to provide a reactive mixture that substantially immediately forms a three-dimensional matrix.
Acidic buffer solutions having a pH within the range of about 1.0 to 5.5, include by way of illustration and not limitation, solutions of:
citric acid, hydrochloric acid, phosphoric acid, sulfuric acid, AMPSO (3-[(1,1-dimethyl-2-hydroxyethyl)aminoJ2-hydroxy-propane-sulfonic acid), acetic acid, lactic acid, and combinations thereof. In a preferred embodiment, the acidic buffer solution, is a solution of citric acid, hydrochloric acid, phosphoric acid, sulfuric acid, and combinations thereof. Regardless of the precise acidifying agent, the acidic buffer preferably has a pH such that it retards the reactivity of the nucleophilic groups on the core. For example, a pH of 2.1 is generally sufficient to retard the nucleophilicity of thiol groups. A lower pH is typically preferred when the core contains amine groups as the nucleophilic groups. In general, the acidic buffer is an acidic solution that, when contacted with nucleophilic groups, renders those nucleophilic groups relatively non-nucleophilic.
An exemplary acidic buffer is a solution of hydrochloric acid, having a concentration of about 6.3 mM, and a pH in the range of 2.1 to 2.3.
This buffer may be prepared by combining concentrated hydrochloric acid with water, i.e., by diluting concentrated hydrochloric acid with water. Similarly, this buffer A may also be conveniently prepared by diluting 1.23 grams of concentrated hydrochloric acid to a volume of 2 liters, or diluting 1.84 grams of concentrated hydrochloric acid to a volume to 3 liters, or diluting 2.45 grams of concentrated hydrochloric acid to a volume of 4 liters, or diluting 3.07 grams concentrated hydrochloric acid to a volume of 5 liters, or diluting 3.68 grams of concentrated hydrochloric acid to a volume to 6 liters. For safety reasons, the concentrated acid is preferably added to water.
Basic buffer solutions having a pH within the range of about 6.0 to 11.0, include by way of illustration and not limitation, solutions of:
glutamate, acetate, carbonate and carbonate salts (e.g., sodium carbonate, sodium carbonate monohydrate and sodium bicarbonate), borate, phosphate and phosphate salts (e.g., monobasic sodium phosphate monohydrate and dibasic sodium phosphate), and combinations thereof. In a preferred embodiment, the basic buffer solution is a solution of carbonate salts, phosphate salts, and combinations thereof.
In general, the basic buffer is an aqueous solution that neutralizes the effect of the acidic buffer, when it is added to the homogeneous solution of the compound and first buffer, so that the nucleophilic groups on the core regain their nucleophilic character (that has been masked by the action of the acidic buffer), thus allowing the nucleophilic groups to inter-react with the electrophilic groups on the core.
An exemplary basic buffer is an aqueous solution of carbonate and phosphate salts. This buffer may be prepared by combining a base solution with a salt solution. The salt solution may be prepared by combining 34.7 g of monobasic sodium phosphate monohydrate, 49.3 g of sodium carbonate monohydrate, and sufficient water to provide a solution volume of 2 liter. Similarly, a 6 liter solution may be prepared by combining 104.0 g of monobasic sodium phosphate monohydrate, 147.94 g of sodium carbonate monohydrate, and sufficient water to provide 6 liter of the salt solution. The basic buffer may be prepared by combining 7.2 g of sodium hydroxide with 180.0 g of water. The basic buffer is typically prepared by adding the base solution as needed to the salt solution, ultimately to provide a mixture having the desired pH, e.g., a pH of 9.65 to 9.75.
In general, the basic species present in the basic buffer should be sufficiently basic to neutralize the acidity provided by the acidic buffer, but should not be so nucleophilic itself that it will react substantially with the electrophilic groups'on the core. For this reason, relatively "soft" bases such as carbonate and phosphate are preferred in this embodiment of the invention.
To illustrate the preparation of a three-dimensional matrix of the present invention, one may combine an admixture of the self-reactive compound with a first, acidic, buffer (e.g., an acid solution, e.g., a dilute hydrochloric acid solution) to form a homogeneous solution. This homogeneous solution is mixed with a second, basic, buffer (e.g., a basic solution, e.g., an aqueous solution containing phosphate and carbonate salts) whereupon the reactive groups on the core of the self-reactive compound substantially immediately inter-react with one another to form a three-dimensional matrix.
2) Redox Reactive Groups In one embodiment of the invention, the reactive groups are vinyl groups such as styrene derivatives, which undergo a radical polymerization upon initiation with a redox initiator. The term "redox" refers to a reactive group that is susceptible to oxidation-reduction activation. The term "vinyl" refers to a reactive group that is activated by a redox initiator, and forms a radical upon reaction. X, Y and Z can be the same or different vinyl groups, for example, methacrylic groups.
For self-reactive compounds containing vinyl reactive groups, the initial environment typically will be an aqueous environment. The modification of the initial environment involves the addition of a redox initiator.

3) Oxidative Coupling Reactive Groups In one embodiment of the invention, the reactive groups undergo an oxidative coupling reaction. For example, X, Y and Z can be a halo group such as chloro, with an adjacent electron-withdrawing group on the halogen-bearing carbon (e.g., on the "L" linking group). Exemplary electron-withdrawing groups include nitro, aryl, and so forth.
For such reactive groups, the modification in the initial environment comprises a change in pH. For example, in the presence of a base such as KOH, the self-reactive compounds then undergo a de-hydro, chloro coupling reaction, forming a double bond between the carbon atoms, as illustrated below:
c1 c-Ar c1 -Ar Ar-C- ~ -C-Ar CI I KOH Ar-C-R-C-Ar CI ~ CI
C-Ar CI
-Ar Ar-C-R-CI+Ar Ar-C-R-C-Ar CI CI
CI CI
For self reactive compounds containing oxidative coupling reactive groups, the initial environment typically can be can be dry and sterile, or a non-basic medium. The modification of the initial environment will typically comprise the addition of a base.
4) Photoinitiated Reactive Groups In one embodiment of the invention, the reactive groups are photoinitiated groups. For such reactive groups, the modification in the initial environment comprises exposure to ultraviolet radiation.
In one embodiment of the invention, X can be an azide (-N3) group and Y can be an alkyl group such as -CH(CH3)2 or vice versa. Exposure to ultraviolet radiation will then form a bond between the groups to provide for the following linkage: -NH-C(CH3)2-CH2-. In another embodiment of the invention, X can be a benzophenone (-(C6H4)-C(O)-(C6H5)) group and Y can be an alkyl group such as -CH(CH3)2 or vice versa. Exposure to ultraviolet radiation will then form a bond between the groups to provide for the following linkage:
OH
~ ~ ~ HsC~CHs~
For self-reactive compounds containing photoinitiated reactive groups, the initial environment typically will be in an ultraviolet radiation-shielded environment. This can be for example, storage within a container that is impermeable to ultraviolet radiation.
The modification of the initial environment will typically comprise exposure to ultraviolet radiation.
5) Temperature-sensitive Reactive Groins In one embodiment of the invention, the reactive groups are temperature-sensitive groups, which undergo a thermochemical reaction. For such reactive groups, the modification in the initial environment thus comprises a change in temperature. The term "temperature-sensitive" refers to a reactive group that is chemically inert at one temperature or temperature range and reactive at a different temperature or temperature range.
In one embodiment of the invention, X, Y, and Z are the same or different vinyl groups.
For self-reactive compounds containing reactive groups that are temperature-sensitive, the initial environment typically will be within the range of about 10 to 30°C.
The modification of the initial environment will typically comprise changing the temperature to within the range of about 20 to 40°C.

B. Linking Groups The reactive groups may be directly attached to the core, or they may be indirectly attached through a linking group, with longer linking groups also termed "chain extenders." In the formula (I) shown above, the optional linker groups are represented by L~, L2, and L3, wherein the linking groups are present when p, q and r are equal to 1.
Suitable linking groups are well known in the art. See, for example, WO 97/22371 to Rhee et al. Linking groups are useful to avoid steric hindrance problems that can sometimes associated with the formation of direct linkages between molecules. Linking groups may additionally be used to link several self-reactive compounds together to make larger molecules. In one embodiment, a linking group can be used to alter the degradative properties of the compositions after administration and resultant gel formation. For example, linking groups can be used to promote hydrolysis, to discourage hydrolysis, or to provide a site for enzymatic degradation.
Examples of linking groups that provide hydrolyzable sites, include, inter alias ester linkages; anhydride linkages, such as those obtained by incorporation of glutarate and succinate; ortho ester linkages; ortho carbonate linkages such as trimethylene carbonate; amide linkages; phosphoester linkages; a-hydroxy acid linkages, such as those obtained by incorporation of lactic acid and glycolic acid; lactone-based linkages, such as those obtained by incorporation of caprolactone, valerolactone, y-butyrolactone and p-dioxanone;
and amide linkages such as in a dimeric, oligomeric, or poly(amino acid) segment. Examples of non-degradable linking groups include succinimide, propionic acid and carboxymethylate linkages. See, for example, WO 99/07417 to Coury et al. Examples of enzymatically degradable linkages include Leu-Gly-Pro-Ala, which is degraded by collagenase; and Gly-Pro-Lys, which is degraded by plasmin.
Linking groups can also be included to enhance or suppress the reactivity of the various reactive groups. For example, electron-withdrawing groups within one or two carbons of a sulfhydryl group would be expected to diminish its effectiveness in coupling, due to a lowering of nucleophilicity.
Carbon-carbon double bonds and carbonyl groups will also have such an effect.
Conversely, electron-withdrawing groups adjacent to a carbonyl group (e.g., the reactive carbonyl of glutaryl-N-hydroxysuccinimidyl) would increase the reactivity of the carbonyl carbon with respect to an incoming nucleophilic group.
By contrast, sterically bulky groups in the vicinity of a reactive group can be used to diminish reactivity and thus reduce the coupling rate as a result of steric hindrance.
By way of example, particular linking groups and corresponding formulas are indicated in the following Table:
Table Linking group Component structure -O-(CH2),~ -O-(CH2)X X

-O-(CH2)X Y

-O-(CH2)X Z

-S-(CH2)X -S-(CH2)X X

-S-(CH2),~ Y

-S-(CH2)x Z

-NH-(CH2)X -NH-(CH2)X X

-NH-(CH2),~ Y

-NH-(CH2)x Z

-O-(CO)-NH-(CH2)X -O-(CO)-NH-(CH2)x X

-O-(CO)-NH-(CH2)X Y

-O-(CO)-NH-(CH2)x Z

-NH-(CO)-O-(CH2)x -NH-(CO)-O-(CH2)X X

-NH-(CO)-O-(CH2)x Y

-NH-(CO)-O-(CH2)X Z

Linking group Component structure -O-(CO)-(CH2)X -O-(CO)-(CH2)x X

-O-(CO)-(CH~)X Y

-O-(CO)-(CH2),~ Z

-(CO)-O-(CH2)X -(CO)-O-(CH2)~-X

-(CO)-O-(CH2)n-Y

-(CO)-O-(CH2)" Z

-O-(CO)-O-(CH2),~ -O-(CO)-O-(CH~),~ X

-O-(CO)-O-(CH2)X Y

-O-(CO)-O-(CH2)x Z

-O-( CO )-C H R2- -O-( CO )-C H R2-X

-O-(CO)-CH R2-Y

-O-(CO)-CH R~-Z

-O-R3-( C O )-N H- -O-R3-( CO )-N H-X

- O-R3-(CO)-NH-Y

- O-R3-(CO)-NH-Z

In the above Table, x is generally in the range of 1 to about 10; R2 is generally hydrocarbyl, typically alkyl or aryl, preferably alkyl, and most preferably lower alkyl; and R3 is hydrocarbylene, heteroatom-containing hydrocarbylene, substituted hydrocarbylene, or substituted heteroatom-containing hydrocarbylene) typically alkylene or arylene (again, optionally substituted and/or containing a heteroatom), preferably lower alkylene (e.g., methylene, ethylene, n-propylene, n-butylene, etc.), phenylene, or amidoalkylene (e.g., -(CO)-NH-CH2).
Other general principles that should be considered with respect to linking groups are as follows. If a higher molecular weight self-reactive compound is to be used, it will preferably have biodegradable linkages as described above, so that fragments larger than 20,000 mol. wt. are not generated during resorption in the body. In addition, to promote water miscibility and/or solubility, it may be desired to add sufficient electric charge or hydrophilicity. Hydrophilic groups can be easily introduced using known chemical synthesis, so long as they do not give rise to unwanted swelling or an undesirable decrease in compressive strength. In particular, polyalkoxy segments may weaken gel strength.
C. The Core The "core" of each self-reactive compound is comprised of the molecular structure to which the reactive groups are bound. The molecular core can a polymer, which includes synthetic polymers and naturally occurring polymers. In one embodiment, the core is a polymer containing repeating monomer units. The polymers can be hydrophilic, hydrophobic, or amphiphilic.
The molecular core can also be a low molecular weight components such as a C2_~4 hydrocarbyl or a heteroatom-containing C2_~4 hydrocarbyl. The heteroatom-containing C2_~4 hydrocarbyl can have 1 or 2 heteroatoms selected from N, O and S. In a preferred embodiment, the self-reactive compound comprises a molecular core of a synthetic hydrophilic polymer.
1 ) Hydrophilic Polymers As mentioned above, the term "hydrophilic polymer" as used herein refers to a polymer having an average molecular weight and composition that naturally renders, or is selected to render the polymer as a whole "hydrophilic." Preferred polymers are highly pure or are purified to a highly pure state such that the polymer is or is treated to become pharmaceutically pure.
Most hydrophilic polymers can be rendered water soluble by incorporating a sufficient number of oxygen (or less frequently nitrogen) atoms available for forming hydrogen bonds in aqueous solutions.
Synthetic hydrophilic polymers may be homopolymers, block copolymers including di-block and tri-block copolymers, random copolymers, or graft copolymers. In addition, the polymer may be linear or branched, and if branched, may be minimally to highly branched, dendrimeric, hyperbranched, or a star polymer. The polymer may include biodegradable segments and blocks, either distributed throughout the polymer's molecular structure or present as a single block, as in a block copolymer. Biodegradable segments preferably degrade so as to break covalent bonds. Typically, biodegradable segments are segments that are hydrolyzed in the presence of water and/or enzymatically cleaved in situ. Biodegradable segments may be composed of small molecular segments such as ester linkages, anhydride linkages, ortho ester linkages, ortho carbonate linkages, amide linkages, phosphonate linkages, etc. Larger biodegradable "blocks" will generally be composed of ,oligomeric or polymeric segments incorporated within the hydrophilic polymer.
Illustrative oligomeric and polymeric segments that are biodegradable include, by way of example, poly(amino acid) segments, poly(orthoester) segments, poly(orthocarbonate) segments, and the like. ~ther biodegradable segments that may form part of the hydrophilic polymer core include polyesters such as polylactide, polyethers such as polyalkylene oxide, polyamides such as a protein, and polyurethanes. For example, the core of the self-reactive compound can be a diblock copolymer of tetrafunctionally activated polyethylene glycol and polylactide.
Synthetic hydrophilic polymers that are useful herein include, but are not limited to: polyalkylene oxides, particularly polyethylene glycol (PEG) and polyethylene oxide)-polypropylene oxide) copolymers, including block and random copolymers; polyols such as glycerol, polyglycerol (PG) and particularly highly branched polyglycerol, propylene glycol; poly(oxyalkylene)-substituted diols, and poly(oxyalkylene)-substituted polyols such as mono-, dl- and tri-polyoxyethylated glycerol, mono- and di-polyoxyethylated propylene glycol, and mono- and di-polyoxyethylated trimethylene glycol; polyoxyethylated sorbitol, polyoxyethylated glucose; poly(acrylic acids) and analogs and copolymers thereof, such as polyacrylic acid per se, polymethacrylic acid, poly(hydroxyethylmethacrylate), poly(hydroxyethylacrylate), poly(methylalkylsulfoxide methacrylates), poly(methylalkylsulfoxide acrylates) and copolymers of any of the foregoing, and/or with additional acrylate species such as aminoethyl acrylate and mono-2-(acryloxy)-ethyl succinate; polymaleic acid; poly(acrylamides) such as polyacrylamide per se, poly(methacrylamide), poly(dimethylacrylamide), poly(N-isopropyl-acrylamide), and copolymers thereof; poly(olefinic alcohols) such as polyvinyl alcohols) and copolymers thereof; poly(N-vinyl lactams) such as polyvinyl pyrrolidones), poly(N-vinyl caprolactams), and copolymers thereof; polyoxazolines, including poly(methyloxazoline) and poly(ethyloxazoline); and polyvinylamines; as well as copolymers of any of the foregoing. It must be emphasized that the aforementioned list of polymers is not exhaustive, and a variety of other synthetic hydrophilic polymers may be used, as will be appreciated by those skilled in the art.
Those of ordinary skill in the art will appreciate that synthetic polymers such as polyethylene glycol cannot be prepared practically to have exact molecular weights, and that the term "molecular weight" as used herein refers to the weight average molecular weight of a number of molecules in any given sample, as commonly used in the art. Thus, a sample of PEG 2,000 might contain a statistical mixture of polymer molecules ranging in weight from, for example, 1,500 to 2,500 daltons with one molecule differing slightly from the next over a range. Specification of a range of molecular weights indicates that the average molecular weight may be any value between the limits specified, and may include molecules outside those limits. Thus, a molecular weight range of about 800 to about 20,000 indicates an average molecular weight of at least about 800, ranging up to about 20 kDa.
Other suitable synthetic hydrophilic polymers include chemically synthesized polypeptides, particularly polynucleophilic polypeptides that have been synthesized to incorporate amino acids containing primary amino groups (such as lysine) and/or amino acids containing thiol groups (such as cysteine).
Poly(lysine), a synthetically produced polymer of the amino acid lysine (145 MW), is particularly preferred. Poly(lysine)s have been prepared having anywhere from 6 to about 4,000 primary amino groups, corresponding to molecular weights of about 870 to about 580,000. Poly(lysine)s for use in the present invention preferably have a molecular weight within the range of about 1,000 to about 300,000, more preferably within the range of about 5,000 to about 100,000, and most preferably, within the range of about 8,000 to about 15,000. Poly(lysine)s of varying molecular weights are commercially available from Peninsula Laboratories, Inc. (Belmont, Calif.).
Although a variety of different synthetic hydrophilic polymers can be used in the present compounds, preferred synthetic hydrophilic polymers are PEG and PG, particularly highly branched PG. Various forms of PEG are extensively used in the modification of biologically active molecules because PEG lacks toxicity, antigenicity, and immunogenicity (i.e., is biocompatible), can be formulated so as to have a wide range of solubilities, and does not typically interfere with the enzymatic activities and/or conformations of peptides. A
particularly preferred synthetic hydrophilic polymer for certain applications is a PEG having a molecular weight within the range of about 100 to about 100,000, although for highly branched PEG, far higher molecular weight polymers can be employed, up to 1,000,000 or more, providing that biodegradable sites are incorporated ensuring that all degradation products will have a molecular weight of less than about 30,000. For most PEGs, however, the preferred molecular weight is about 1,000 to about 20,000, more preferably within the range of about 7,500 to about 20,000. Most preferably, the polyethylene glycol has a molecular weight of approximately 10,000.
Naturally occurring hydrophilic polymers include, but are not limited to: proteins such as collagen, fibronectin, albumins, globulins, fibrinogen, fibrin and thrombin, with collagen particularly preferred; carboxylated polysaccharides such as polymannuronic acid and polygalacturonic acid;
aminated polysaccharides, particularly the glycosaminoglycans, e.g., hyaluronic acid, chitin, chondroitin sulfate A, B, or C, keratin sulfate, keratosulfate and heparin; and activated polysaccharides such as dextran and starch derivatives.
Collagen and glycosaminoglycans are preferred naturally occurring hydrophilic polymers for use herein.
Unless otherwise specified, the term "collagen" as used herein refers to all forms of collagen, including those, which have been processed or otherwise modified. Thus, collagen from any source may be used in the compounds of the invention; for example, collagen may be extracted and purified from human or other mammalian source, such as bovine or porcine corium and human placenta, or may be recombinantly or otherwise produced.
The preparation of purified, substantially non-antigenic collagen in solution from bovine skin is well known in the art. For example, U.S. Patent No. 5,428,022 to Palefsky et al. discloses methods of extracting and purifying collagen from the human placenta, and U.S. Patent No. 5,667,839 to Berg discloses methods of producing recombinant human collagen in the milk of transgenic animals, including transgenic cows. Non-transgenic, recombinant collagen expression in yeast and other cell lines) is described in U.S. Patent No. 6,413,742 to Olsen et al., 6,428,978 to Olsen et al., and 6,653,450 to Berg et al.
Collagen of any type, including, but not limited to, types I, II, III, IV, or any combination thereof, may be used in the compounds of the invention, although type I is generally preferred. Either atelopeptide or telopeptide-containing collagen may be used; however, when collagen from a natural source, such as bovine collagen, is used, atelopeptide collagen is generally preferred, because of its reduced immunogenicity compared to telopeptide-containing collagen.
Collagen that has not been previously crosslinked by methods such as heat, irradiation, or chemical crosslinking agents is preferred for use in the invention, although previously crosslinked collagen may be used.
Collagens for use in the present invention are generally, although not necessarily, in aqueous suspension at a concentration between about 20 mg/ml to about 120 mg/ml, preferably between about 30 mg/ml to about 90 mglml. Although intact collagen is preferred, denatured collagen, commonly known as gelatin, can also be used. Gelatin may have the added benefit of being degradable faster than collagen.
Nonfibrillar collagen is generally preferred for use in compounds of the invention, although fibrillar collagens may also be used. The term "nonfibrillar collagen" refers to any modified or unmodified collagen material that is in substantially nonfibrillar form, i.e., molecular collagen that is not tightly associated with other collagen molecules so as to form fibers. Typically, a solution of nonfibrillar collagen is more transparent than is a solution of fibrillar collagen. Collagen types that are nonfibrillar (or microfibrillar) in native form include types IV, VI, and VII.
Chemically modified collagens that are in nonfibrillar form at neutral pH include succinylated collagen and methylated collagen, both of which can be prepared according to the methods described in U.S. Patent No.
4,164,559 to Miyata et al. Methylated collagen, which contains reactive amine groups, is a preferred nucleophile-containing component in the compositions of the present invention. In another aspect, methylated collagen is a component that is present in addition to first and second components in the matrix-forming reaction of the present invention. Methylated collagen is described in, for example, in U.S. Patent No. 5,614,587 to Rhee et al.
Collagens for use in the compositions of the present invention may start out in fibrillar form, then can be rendered nonfibrillar by the addition of one or more fiber disassembly agent. The fiber disassembly agent must be present in an amount sufficient to render the collagen substantially nonfibrillar at pH 7, as described above. Fiber disassembly agents for use in the present invention include, without limitation, various biocompatible alcohols, amino acids, inorganic salts, and carbohydrates, with biocompatible alcohols being particularly preferred. Preferred biocompatible alcohols include glycerol and propylene glycol. Non-biocompatible alcohols, such as ethanol, methanol, and isopropanol, are not preferred for use in the present invention, due to their potentially deleterious effects on the body of the patient receiving them.
Preferred amino acids include arginine. Preferred inorganic salts include sodium chloride and potassium chloride. Although carbohydrates, such as various sugars including sucrose, may be used in the practice of the present invention, they are not as preferred as other types of fiber disassembly agents because they can have cytotoxic effects in vivo.
Fibrillar collagen is less preferred for use in the compounds of the invention. However, as disclosed in U.S. Patent No. 5,614,587 to Rhee et al., fibrillar collagen, or mixtures of nonfibrillar and fibrillar collagen, may be preferred for use in compounds intended for long-term persistence in vivo.
2) Hydrophobic Polymers The core of the self-reactive compound may also comprise a hydrophobic polymer, including low molecular weight polyfunctional species, although for most uses hydrophilic polymers are preferred. Generally, "hydrophobic polymers" herein contain a relatively small proportion of oxygen andlor nitrogen atoms. Preferred hydrophobic polymers for use in the invention generally have a carbon chain that is no longer than about 14 carbons.
Polymers having carbon chains substantially longer than 1'4 carbons generally have very poor solubility in aqueous solutions and, as such, have very long reaction times when mixed with aqueous solutions of synthetic polymers containing, for example, multiple nucleophilic groups. Thus, use of short-chain oligomers can avoid solubility-related problems during reaction. Polylactic acid and polyglycolic acid are examples of two particularly suitable hydrophobic .
polymers.
3) Amphiphilic Polymers Generally, amphiphilic polymers have a hydrophilic portion and a hydrophobic (or lipophilic) portion. The hydrophilic portion can be at one end of the core and the hydrophobic portion at the opposite end, or the hydrophilic and hydrophobic portions may be distributed randomly (random copolymer) or in the form of sequences or grafts (block copolymer) to form the amphiphilic polymer core of the self-reactive compound. The hydrophilic and hydrophobic portions may include any of the aforementioned hydrophilic and hydrophobic polymers.
Alternately, the amphiphilic polymer core can be a hydrophilic polymer that has been modified with hydrophobic moieties (e.g., alkylated PEG
or a hydrophilic polymer modified with one or more fatty chains ), or a hydrophobic polymer that has been modified with hydrophilic moieties (e.g., "PEGylated" phospholipids such as polyethylene glycolated phospholipids).
4) Low Molecular Weight Components As indicated above, the molecular core of the self-reactive compound can also be a low molecular weight compound, defined herein as being a C2_~4 hydrocarbyl or a heteroatom-containing C~_~4 hydrocarbyl, which contains 1 to 2 heteroatoms selected from N, O, S and combinations thereof.
Such a molecular core can be substituted with any of the reactive groups described herein.
Alkanes are suitable Cg_q4 hydrocarbyl molecular cores.
Exemplary alkanes, for substituted with a nucleophilic primary amino group and a Y electrophilic group, include, ethyleneamine (H2N-CH2CH2-Y), tetramethyleneamine (H2N-(CH4)-Y), pentamethyleneamine (H2N-(CH5)-Y), and hexamethyleneamine (H2N-(CH6)-Y).
Low molecular weight diols and polyols are also suitable C~_14 hydrocarbyls and include trimethylolpropane, di(trimethylol propane), pentaerythritol, and diglycerol. Polyacids are also suitable C2_~4 hydrocarbyls, and include trimethylolpropane-based tricarboxylic acid, di(trimethylol propane)-based tetracarboxylic acid, heptanedioic acid, octanedioic acid (suberic acid), and hexadecanedioic acid (thapsic acid).
Low molecular weight di- and poly-electrophiles are suitable heteroatom-containing C2_~4 hydrocarbyl molecular cores. These include, for example, disuccinimidyl suberate (DSS), bis(sulfosuccinimidyl) suberate (BS3), dithiobis(succinimidylpropionate) (DSP), bis(2-succinimidooxycarbonyloxy) ethyl sulfone (BSOCOES), and 3,3'-dithiobis(sulfosuccinimidylpropionate (DTSPP), and their analogs and derivatives.
In one embodiment of the invention, the self-reactive compound of the invention comprises a low-molecular weight material core, with a plurality of acrylate moieties and a plurality of thiol groups.
D. Preparation The self-reactive compounds are readily synthesized to contain a hydrophilic, hydrophobic or amphiphilic polymer core or a low molecular weight core, functionalized with the desired functional groups, i.e., nucleophilic and electrophilic groups, which enable crosslinking. For example, preparation of a self-reactive compound having a polyethylene glycol (PEG) core is discussed below. However, it is to be understood that the following discussion is for purposes of illustration and analogous techniques may be employed with other polymers.
With respect to PEG, first of all, various functionalized PEGs have been used effectively in fields such as protein modification (see Abuchowski et al., Enzymes as Drugs, John Wiley & Sons: New York, N.Y. (1981 ) pp. 367-383; and Dreborg et al. (1990) Crit. Rev. Therap. Drug Carrier Syst. 6:315), peptide chemistry (see Mutter et al., The Peptides, Academic: New York, N.Y.
2:285-332; and Zalipsky et al. (1987) Int. J. Peptide Protein Res. 30:740), and the synthesis of polymeric drugs (see Zalipsky et al. (1983) Eur. Polym. J.
19:1177; and Ouchi et al. (1987) J. Maeromol. Sci. Cflem. A24:1011 ).
Functionalized forms of PEG, including multi-functionalized PEG, are commercially available, and are also easily prepared using known methods.
For example, see Chapter 22 of Polyethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, J. Milton Harris, ed., Plenum Press, NY (1992).

Multi-functionalized forms of PEG are of particular interest and include, PEG succinimidyl glutarate, PEG succinimidyl propionate, succinimidyl butylate, PEG succinimidyl acetate, PEG succinimidyl succinamide, PEG
succinimidyl carbonate, PEG propionaldehyde, PEG glycidyl ether, PEG-isocyanate, and PEG-vinylsulfone. Many such forms of PEG are described in U.S. Patent No. 5,328,955 and 6,534,591, both to Rhee et al. Similarly, various forms of multi-amino PEG are commercially available from sources such as PEG Shop, a division of SunBio of South Korea (www.sunbio.com), Nippon Oil and Fats (Yebisu Garden Place Tower, 20-3 Ebisu 4-chome, Shibuya-ku, Tokyo), Nektar Therapeutics (San Carlos, California, formerly Shearwater Polymers, Huntsville, Alabama) and from Huntsman's Performance Chemicals Group (Houston, Texas) under the name Jeffamine~ polyoxyalkyleneamines.
Multi-amino PEGs useful in the present invention include the Jeffamine diamines ("D" series) and triamines ("T" series), which contain two and three primary amino groups per molecule. Analogous poly(sulfhydryl) PEGs are also available from Nektar Therapeutics, e.g., in the form of pentaerythritol polyethylene glycol) ether tetra-sulfhydryl (molecular weight 10,000). These multi-functionalized forms of PEG can then be modified to include the other desired reactive groups.
Reaction with succinimidyl groups to convert terminal hydroxyl groups to reactive esters is one technique for preparing a core with electrophilic groups. This core can then be modified include nucleophilic groups such as primary amines, thiols, and hydroxyl groups. Other agents to convert hydroxyl groups include carbonyldiimidazole and sulfonyl chloride. However, as discussed herein, a wide variety of electrophilic groups may be advantageously employed for reaction with corresponding nucleophilic groups. Examples of such electrophilic groups include acid chloride groups; anhydrides, ketones, aldehydes, isocyanate, isothiocyanate, epoxides, and olefins, including conjugated olefins such as ethenesulfonyl (-S02CH=CH2) and analogous functional groups.

Other in situ Crosslinkina Materials Numerous other types of in situ forming materials have been described which may be used in combination with an anti-scarring agent in accordance with the invention. The in situ forming material may be a biocompatible crosslinked polymer that is formed from water soluble precursors having electrophilic and nucleophilic groups capable of reacting and crosslinking in situ (see, e.g., U.S. Patent No. 6,566,406). The in situ forming material may be hydrogel that may be formed through a combination of physical and chemical crosslinking processes, where physical crosslinking is mediated by one or more natural or synthetic components that stabilize the hydrogel-forming precursor solution at a deposition site for a period of time sufficient for more resilient chemical crosslinks to form (see, e.g., U.S. Patent No.
6,818,018). The in situ forming material may be formed upon exposure to an aqueous fluid from a physiological environment from dry hydrogel precursors (see, e.g., U.S. Patent No. 6,703,047). The in situ forming material may be a hydrogel matrix that provides controlled release of relatively low molecular weight therapeutic species by first dispersing or dissolving the therapeutic species within relatively hydrophobic rate modifying agents to form a mixture;
the mixture is formed into microparticles that are dispersed within bioabsorbable hydrogels, so as to release the water soluble therapeutic agents in a controlled fashion (see, e.g., 6,632,457). The in situ forming material may be a multi-component hydrogel system (see, e.g., U.S. Patent No. 6,379, 373).
The in situ forming material may be a multi-arm block copolymer that includes a central core molecule, such as a residue of a polyol, and at least three copolymer arms covalently attached to the central core molecule, each copolymer arm comprising an inner hydrophobic polymer segment covalently attached to the central core molecule and an outer hydrophilic polymer segment covalently attached to the hydrophobic polymer segment, wherein the central core molecule and the hydrophobic polymer segment define a hydrophobic core region (see, e.g., 6,730,334). The in situ forming material may include a gel-forming macromer that includes at least four polymeric blocks, at feast two of which are hydrophobic and at least one of which is hydrophilic, and including a crosslinkable group (see, e.g., 6,639,014). The in situ forming material may be a water-soluble macromer that includes at least one hydrolysable linkage formed from carbonate or dioxanone groups, at least one water-soluble polymeric block, and at least one polymerizable group (see, e.g., U.S. Patent No. 6,177,095). The in situ forming material may comprise polyoxyalkylene block copolymers that form weak physical crosslinks to provide gels having a paste-like consistency at physiological temperatures. (see, e.g., U.S. Patent No.
4,911,926). The in situ forming material may be a thermo-irreversible gel made from polyoxyalkylene polymers and ionic polysaccharides (see, e.g., U.S.
Patent No. 5,126,141 ). The in situ forming material may be a gel forming composition that includes chitin derivatives (see, e.g., U.S. Patent No.
5,093,319), chitosan-coagulum (see, e.g., U.S. Patent No. 4,532,134), or hyaluronic acid (see, e.g., U.S. Patent No. 4,141,973). The in situ forming material may be an in situ modification of alginate (see, e.g., U.S. Patent No.
5,266,326 ). The in situ forming material may be formed from ethylenically unsaturated water soluble macromers that can be crosslinked in contact with tissues, cells, and bioactive molecules to form gels (see, e.g., U.S. Patent No.
5,573,934). The in situ forming material may include urethane prepolymers used in combination with an unsaturated cyano compound containing a cyano group attached to a carbon atom, such as cyano(meth)acrylic acids and esters thereof (see, e.g., U.S. Patent No. 4,740,534). The in situ forming material may be a biodegradable hydrogel that polymerizes by a photoinitiated free radical polymerization from water soluble macromers (see, e.g., U.S. Patent No.
5,410,016). The in situ forming material may be formed from a two component mixture including a first part comprising a serum albumin protein in an aqueous buffer having a pH in a range of about 8.0-11.0, and a second part comprising a water-compatible or water-soluble bifunctional crosslinking agent. (see, e.g., U.S. Patent No. 5,583,114).

In another aspect, in situ forming materials that can be used include those based on the crosslinking of proteins. For example, the in situ forming material may be a biodegradable hydrogel composed of a recombinant or natural human serum albumin and polyethylene) glycol polymer solution whereby upon mixing the solution cross-links to form a mechanical non-liquid covering structure which acts as a sealant. See e.g., U.S. Patent No.
6,458,147 and 6,371,975. The in situ forming material may be composed of two separate mixtures based on fibrinogen and thrombin which are dispensed together to form a biological adhesive when intermixed either prior to or on the application site to form a fibrin sealant. See e.g., U.S. Patent No. 6,764,467. The in situ forming material may be composed of ultrasonically treated collagen and albumin which form a viscous material that develops adhesive properties when crosslinked chemically with glutaraldehyde and amino acids or peptides. See e.g., U.S. Patent No. 6,310,036. The in situ forming material may be a hydrated adhesive gel composed of an aqueous solution consisting essentially of a protein having amino groups at the side chains (e.g., gelatin, albumin) which is crosslinked with an N-hydroxyimidoester compound. See e.g., U.S.
Patent No. 4,839,345. The in situ forming material may be a hydrogel prepared from a protein or polysaccharide backbone (e.g., albumin or polymannuronic acid) bonded to a cross-linking agent (e.g., polyvalent derivatives of polyethylene or polyalkylene glycol). See e.g., U.S. Patent No. 5,514,379. The in situ forming material may be composed of a polymerizable collagen composition that is applied to the tissue and then exposed to an initiator to polymerize the collagen to form a seal over a wound opening in the tissue. See e.g., U.S. Patent No. 5,874,537. The in situ forming material may be a two component mixture composed of a protein (e.g., serum albumin) in an aqueous bufFer having a pH in the range of about 8.0-11.0 and a water-soluble bifunctional polyethylene oxide type crosslinking agent, which transforms from a liquid to a strong, flexible bonding composition to seal tissue in situ. See e.g., U.S. Patents 5,583,114 and RE38158 and PCT Publication No. WO 96/03159.

The in situ forming material may be composed of a protein, a surfactant, and a lipid in a liquid carrier, which is crosslinked by adding a crosslinker and used as a sealant or bonding agent in situ. See e.g., U.S. Patent Application No.
2004/0063613A1 and PCT Publication Nos. WO 01/45761 and WO 03/090683.
The in situ forming material may be composed of two enzyme-free liquid components that are mixed by dispensing the components into a catheter tube deployed at the vascular puncture site, wherein, upon mixing, the two liquid components chemically cross-link to form a mechanical non-liquid matrix that seals a vascular puncture site. See e.g., U.S. Patent Application Nos.
2002/0161399A1 and 2001/0018598A1. The in situ forming material may be a cross-linked albumin composition composed of an albumin preparation and a carbodiimide preparation which are mixed under conditions that permit crosslinking of the albumin for use as a bioadhesive or sealant. See e.g., PCT
Publication No. WO 99/66964. The in situ forming material may be composed of collagen and a peroxidase and hydrogen peroxide, such that the collagen is crosslinked to from a semi-solid gel that seals a wound. See e.g., PCT
Publication No. WO 01/35882.
In another aspect, in situ forming materials that can be used include those based on isocyanate or isothiocyanate capped polymers. For example, the in situ forming material may be composed of isocyanate-capped polymers that are liquid compositions which form into a solid adhesive coating by in situ polymerization and crosslinking upon contact with body fluid or tissue.
See e.g., PCT Publication No. WO 04/021983. The in situ forming material may be a moisture-curing sealant composition composed of an active isocyanato-terminated isocyanate prepolymer containing a polyol component with a molecular weight of 2,000 to 20,000 and an isocyanurating catalyst agent. See e.g., U.S. Patent No. 5,206,331.
In another embodiment, the reagents can undergo an electrophilic-nucleophilic reaction to produce a crosslinked matrix. Polymers containing and/or terminated with nucleophilic groups such as amine, sulfhydryl, hydroxyl, -PH2 or C~-NH-NH2 can be used as the nucleophilic reagents and polymers containing and/or terminated with electrophilic groups such as succinimidyl, carboxylic acid, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(C5H4N) or activated esters, such as are used in peptide synthesis can be used as the electrophilic reagents. For example, a 4-armed thiol derivatized polyethylene glycol) (e.g., pentaerythritol polyethylene glycol)ether tetra-sulfhydryl) can be reacted with a 4 armed NHS-derivatized polyethylene glycol (e.g., pentaerythritol polyethylene glycol)ether tetra-succinimidyl glutarate) under basic conditions (pH > about 8). Representative examples of compositions that undergo such electrophilic-nucleophilic crosslinking reactions are described, for example, in U.S. Patent. Nos.
5,752,974; 5,807,581; 5,874,500; 5,936,035; 6,051,648; 6,165,489; 6,312,725;
6,458,889; 6,495,127; 6,534,591; 6,624,245; 6,566,406; 6,610,033; 6,632,457;
and PCT Application Publication Nos. WO 04/060405 and WO 04/060346.
In another embodiment, the electrophilic- or nucleophilic-terminated polymers can further comprise a polymer that can enhance the mechanical and/or adhesive properties of the in situ forming compositions.
This polymer can be a degradable or non-degradable polymer. For example, the polymer may be collagen or a collagen derivative, for example methylated collagen. An example of an in situ forming composition uses pentaerythritol polyethylene glycol)ether tetra-sulfhydryl) (4-armed thiol PEG), pentaerythritol polyethylene glycol)ether tetra-succinimidyl glutarate) (4-armed NHS PEG) and methylated collagen as the reactive reagents. This composition, when mixed with the appropriate buffers can produce a crosslinked hydrogel. (See, e.g., U.S. Patent Nos. 5,874,500; 6,051,648; 6,166,130; 5,565,519 and 6,312,725).
In another embodiment, the reagents that can form a covalent bond with the tissue to which it is applied may be used. Polymers containing and/or terminated with electrophilic groups such as succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(C5H4N) or activated esters, such as are used in peptide synthesis may be used as the reagents.

For example, a 4 armed NHS-derivatized polyethylene glycol (e.g., pentaerythritol polyethylene glycol)ether tetra-succinimidyl glutarate) may be applied to the tissue in the solid form or in a solution form. In the preferred embodiment, the 4 armed NHS-derivatized polyethylene glycol is applied to the tissue under basic conditions (pH > about 8). Other representative examples of compositions of this nature that may be used are disclosed in PCT Application Publication No. WO 04/060405 and WO 04/060346, and U.S. Patent Application No. 10/749,123.
In another embodiment, the in situ forming material polymer can be a polyester. Polyesters that can be used in in situ forming compositions include poly(hydroxyesters). In another embodiment, the polyester can comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-bufyrolactone, gamma-butyrolactone, gamma-valerolactone, y-decanolactone, b-decanolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-Zone.
Representative examples of these types of compositions are described in U.S.
Patent. Nos. 5,874,500; 5,936,035; 6,312,725; 6,495,127 and PCT Publication Nos. WO 2004/028547.
In another embodiment, the electrophilic-terminated polymer can be partially or completely replaced by a small molecule or oligomer that comprises an electrophilic group (e.g., disuccinimidyl glutarate).
In another embodiment, the nucleophilic-terminated polymer can be partially or completely replaced by a small molecule or oligomer that comprises a nucleophilic group (e.g., dicysteine, dilysine, trilysine, etc.).
Other examples of in situ forming materials that can be used include those based on the crosslinking of proteins (described in, for example, U.S. Patent Nos. RE38158; 4,839,345; 5,514,379, 5,583,114; 6,310,036;
6,458,147; 6,371,975; US Patent Application Publication Nos.
2004/0063613A1, 2002/0161399A1, and 2001 /0018598A1, and PCT

Publication Nos. WO 03/090683, WO 01/45761, WO 99/66964, and WO
96/03159) and those based on isocyanate or isothiocyanate capped polymers (see, e.g., PCT Publication No. WO 04/021983).
Other examples of in situ forming materials can include reagents that comprise one or more cyanoacrylate groups. These reagents can be used to prepare a poly(alkylcyanoacrylate) or poly(carboxyalkylcyanoacrylate) (e.g., poly(ethylcyanoacrylate), poly(butylcyanoacrylate), poly(isobutylcyanoacrylate), poly(hexylcyanoacrylate), poly(methoxypropylcyanoacrylate), and poly(octylcyanoacrylate)).
Examples of commercially available cyanoacrylates that can be used in the present invention include DERMABOND, INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL, TISSUMEND, HISTOACRYL BLUE and ORABASE
SOOTHE-N-SEAL LIQUID PROTECTANT.
In another embodiment, the cyanoacrylate compositions may further comprise additives to stabilize the reagents and/or alter the rate of reaction of the cyanoacrylate, and/or plasticize the poly(cyanoacrylate), and/or alter the rate of degradation of the poly(cyanoacrylate). For example, a trimethylene carbonate based polymer or an oxalate polymer of polyethylene glycol) or a s-caprolactone based copolymer may be mixed with a 2-alkoxyalkylcyanoacrylate (e.g., 2-methoxypropylcyanoacrylate). Representative examples of these compositions are described in U.S. Patent Nos. 5,350,798 and 6,299,631.
In another embodiment, the cyanoacrylate composition can be prepared by capping heterochain polymers with a cyanoacrylate group. The cyanoacrylate-capped heterochain polymer preferably has at least two cyanoacrylate ester groups per chain. The heterochain polymer can comprise an absorbable poly(ester), polyester-carbonate), poly(ether-carbonate) and poly(ether-ester). The poly(ether-esters described in U.S. Patent Nos.
5,653,992 and 5,714,159 can also be used as the heterochain polymers. A
triaxial poly(s-caprolactone-co-trimethylene carbonate) is an example of a polyester-carbonate) that can be used. The heterochain polymer may be a polyether. Examples of polyethers that can be used include polyethylene glycol), polypropylene glycol) and block copolymers of polyethylene glycol) and polypropylene glycol) (e.g., PLURONICS group of polymers including but not limited to PLURONIC F127 or F63). Representative examples of these compositions are described in U.S. Patent No. 6,699,940.
Within another aspect of the invention, the biologically active ant-infective and/or fibrosis-inhibiting agent can be delivered with a non-polymeric compound (e.g., a carrier). These non-polymeric carriers can include sucrose derivatives (e.g., sucrose acetate isobutyrate, sucrose oleate), sterols such as cholesterol, stigmasterol, (3-sitosterol, and estradiol; cholesteryl esters such as cholesteryl stearate; C~2 -C24 fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, and lignoceric acid; C~$
-C36 mono-, di- and triacylglycerides such as glyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate, glyceryl monodocosanoate, glyceryl monomyristate, glyceryl monodicenoate, glyceryl dipalmitate, glyceryl didocosanoate, glyceryl dimyristate, glyceryl didecenoate, glyceryl tridocosanoate, glyceryl trimyristate, glyceryl tridecenoate, glycerol tristearate and mixtures thereof; sucrose fatty acid esters such as sucrose distearate and sucrose palmitate; sorbitan fatty acid esters such as sorbitan monostearate, sorbitan monopalmitate and sorbitan tristearate; C~6 -C~$ fatty alcohols such as cetyl alcohol, myristyl alcohol, stearyl alcohol, and cetostearyl alcohol;
esters of fatty alcohols and fatty acids such as cetyl palmitate and cetearyl palmitate;
anhydrides of fatty acids such as stearic anhydride; phospholipids including phosphatidylcholine (lecithin), phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, and lysoderivatives thereof; sphingosine and derivatives thereof; spingomyelins such as stearyl, palmitoyl, and tricosanyl spingomyelins;
ceramides such as stearyl and palmitoyl ceramides; glycosphingolipids; lanolin and lanolin alcohols, calcium phosphate, sinfiered and unscintered hydoxyapatite, zeolites; and combinations and mixtures thereof.

Representative examples of patents relating to non-polymeric delivery systems and the preparation include U.S. Patent Nos. 5,736,152;
5,888,533; 6,120,789; 5,968,542; and 5,747,058.
Within certain embodiments of the invention, the therapeutic compositions are provided that include (i) a fibrosis-inhibiting agent and/or (ii) an anti-infective agent. The therapeutic compositions may include one or more additional therapeutic agents (such as described above), for example, anti-inflammatory agents, anti-thrombotic agents, and/ or anti-platelet agents.
Other agents that may be combined with the therapeutic compositions include, e.g., additional ingredients such as surfactants (e.g., PLURONICS, such as F-127, L-122, L-101, L-92, L-81, and L-61 ), preservatives, anti-oxidants.
In one aspect, the present invention provides compositions comprising i) an anti-fibrotic agent and ii) a polymer or a compound that forms a polymer in situ. The following are some, but by no means all, of the preferred anti-fibrotic agents and classes of anti-fibrotic agents that may be included in the inventive compositions:
1 a. An anti-fibrotic agent that inhibits cell regeneration.
2a. An anti-fibrotic agent that inhibits angiogenesis.
3a. An anti-fibrotic agent that inhibits fibroblast migration.
4a. An anti-fibrotic agent that inhibits fibroblast proliferation.
5a. An anti-fibrotic agent that inhibits deposition of extracellular matrix.
6a. An anti-fibrotic agent inhibits tissue remodeling.
7a. An anti-fibrotic agent that is an angiogenesis inhibitor.

8a. An anti-fibrotic agent that is a 5-lipoxygenase inhibitor or antagonist.
9a. An anti-fibrotic agent that is a chemokine receptor antagonist.
1 Oa. An anti-fibrotic agent that is a cell cycle inhibitor.
11 a. An anti-fibrotic agent that is a taxane.
12a. An anti-fibrotic agent that is an anti-microtubule agent.
13a. An anti-fibrotic agent that is paclitaxel.
14a. An anti-fibrotic agent that is a cathepsin inhibitor.
15a. An anti-fibrotic agent that is an analogue or derivative of paclitaxel.
16a. An anti-fibrotic agent that is a vinca alkaloid.
17a. An anti-fibrotic agent that is camptothecin or an analogue or derivative thereof.
18a. An anti-fibrotic agent that is a podophyllotoxin.
19a. An anti-fibrotic agent that is etoposide or an analogue or derivative thereof.
20a. An anti-fibrotic agent that is an anthracycline.
21 a. An anti-fibrotic agent that is doxorubicin or an analogue or derivative thereof.
22a. An anti-fibrotic agent that mitoxantrone or an analogue or derivative thereof.

23a. An anti-fibrotic agent that is a platinum compound.
24a. An anti-fibrotic agent that is a nitrosourea.
25a. An anti-fibrotic agent that is a nitroimidazole.
26a. An anti-fibrotic agent that is a folic acid antagonist.
27a. An anti-fibrotic agent that is a cytidine analogue.
28a. An anti-fibrotic agent that is a pyrimidine analogue.
29a. An anti-fibrotic agent that is a fluoropyrimidine analogue.
30a. An anti-fibrotic agent that is a purine analogue.
31 a. An anti-fibrotic agent that is a nitrogen mustard or an analogue or derivative thereof.
32a. An anti-fibrotic agent that is a hydroxyurea.
33a. An anti-fibrotic agent that is a mytomicin or an analogue or derivative thereof.
34a. An anti-fibrotic agent that is an alkyl sulfonate.
35a. An anti-fibrotic agent that is a benzamide or an analogue or derivative thereof.
36a. An anti-fibrotic agent that is a nicotinamide or an analogue or derivative thereof.
37a. An anti-fibrotic agent that is a halogenated sugar or an analogue or derivative thereof.
38a. An anti-fibrotic agent that is a DNA alkylating agent.

39a. An anti-fibrotic agent that is an anti-microtubule agent.
40a. An anti-fibrotic agent that is a topoisomerase inhibitor.
41 a. An anti-fibrotic agent that is a DNA cleaving agent.
42a. An anti-fibrotic agent that is an antimetabolite.
43a. An anti-fibrotic agent inhibits adenosine deaminase.
44a. An anti-fibrotic agent inhibits purine ring synthesis.
45a. An anti-fibrotic agent that is a nucleotide interconversion inhibitor.
46a. An anti-fibrotic agent inhibits dihydrofolate reduction.
47a. An anti-fibrotic agent blocks thymidine monophosphate.
48a. An anti-fibrotic agent causes DNA damage.
49a. An anti-fibrotic agent that is a DNA intercalation agent.
50a. An anti-fibrotic agent that is a RNA synthesis inhibitor.
51 a. An anti-fibrotic agent that is a pyrimidine synthesis inhibitor.
52a. An anti-fibrotic agent that inhibits ribonucleotide synthesis or function.
53a. An anti-fibrotic agent that inhibits thymidine monophosphate synthesis or function.
54a. An anti-fibrotic agent that inhibits DNA synthesis.
55a. An anti-fibrotic agent that causes DNA adduct formation.
56a. An anti-fibrotic agent that inhibits protein synthesis.

57a. An anti-fibrotic agent that inhibits microtubule function.
58a. - An anti-fibrotic agent that is a cyclin dependent protein kinase inhibitor.
59a. An anti-fibrotic agent that is an epidermal growth factor kinase inhibitor.
60a. An anti-fibrotic agent that is an elastase inhibitor.
61 a. An anti-fibrotic agent that is a factor Xa inhibitor.
62a. An anti-fibrotic agent that is a farnesyltransferase inhibitor.
63a. An anti-fibrotic agent that is a fibrinogen antagonist.
64a. An anti-fibrotic agent that is a guanylate cyclase stimulant.
65a. An anti-fibrotic agent that is a heat shock protein 90 antagonist.
66a. An anti-fibrotic agent that is geldanamycin or an analogue or derivative thereof.
67a. An anti-fibrotic agent that is a guanylate cyclase stimulant.
68a. An anti-fibrotic agent that is a HMGCoA reductase inhibitor.
69a. An anti-fibrotic agent that is simvastatin or an analogue or derivative thereof.
70a. An anti-fibrotic agent that is a hydroorotate dehydrogenase inhibitor.
71 a. An anti-fibrotic agent that is an IKK2 inhibitor.
72a. An anti-fibrotic agent that is an IL-1 antagonist.

73a. An anti-fibrotic agent that is an ICE antagonist.
74a. An anti-fibrotic agent that is an IRAK antagonist.
75a. An anti-fibrotic agent that is an IL-4 agonist.
76a. An anti-fibrotic agent that is an immunomodulatory agent.
77a. An anti-fibrotic agent that is sirolimus or an analogue or derivative thereof.
78a. An anti-fibrotic agent that is a nitric oxide inhibitor.
79a. An anti-fibrotic agent that is everolimus or an analogue or derivative thereof.
80a. An anti-fibrotic agent that is tacrolimus or an analogue or derivative thereof.
81a. An anti-fibrotic agent that is a TNF alpha inhibitor.
82a. An anti-fibrotic agent that is biolmus or an analogue or derivative thereof.
83a. An anti-fibrotic agent that is tresperimus or an analogue or derivative thereof.
84a. An anti-fibrotic agent that is auranofin or an analogue or derivative thereof.
85a. An anti-fibrotic agent that is 27-0-demethylrapamycin or an analogue or derivative thereof.
86a. An anti-fibrotic agent that is gusperimus or an analogue or derivative thereof.

87a. An anti-fibrotic agent that is pimecrolimus or an analogue or derivative thereof.
88a. An anti-fibrotic agent that is ABT-578 or an analogue or derivative thereof.
89a. An anti-fibrotic agent that is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.
90a. An anti-fibrotic agent that is mycophenolic acid or an analogue or derivative thereof.
91 a. An anti-fibrotic agent that is 1-alpha-25 dihydroxy vitamin D3 or an analogue or derivative thereof.
92a. An anti-fibrotic agent that is a leukotriene inhibitor.
93a. An anti-fibrotic agent that is a MCP-1 antagonist.
94a. An anti-fibrotic agent that is a MMP inhibitor.
95a. An anti-fibrotic agent that is an NF kappa B inhibitor.
96a. An anti-fibrotic agent that is an NF kappa B inhibitor, wherein the NF kappa B inhibitor is Bay 11-7082.
97a. An anti-fibrotic agent that is an NO antagonist.
98a. An anti-fibrotic agent that is a p38 MAP kinase inhibitor.
99a. An anti-fibrotic agent that is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB 202190.
100a. An anti-fibrotic agent that is a phosphodiesterase inhibitor.
101 a. An anti-fibrotic agent that is a TGF beta inhibitor.

102x. An anti-fibrotic agent that is a thromboxane A2 antagonist.
103a. An anti-fibrotic agent that is a TNF alpha antagonist.
104a. An anti-fibrotic agent that is a TACE inhibitor.
105a. An anti-fibrotic agent that is a tyrosine kinase inhibitor.
106a. An anti-fibrotic agent that is a vitronectin inhibitor.
107a. An anti-fibrotic agent that is a fibroblast growth factor inhibitor.
108a. An anti-fibrotic agent that is a protein kinase inhibitor.
109a. An anti-fibrotic agent that is a PDGF receptor kinase inhibitor.
110a. An anti-fibrotic agent that is an endothelial growth factor receptor kinase inhibitor.
111 a. An anti-fibrotic agent that is a retinoic acid receptor antagonist.
112a. An anti-fibrotic agent that is a platelet derived growth factor receptor kinase inhibitor.
113a. An anti-fibrotic agent that is a fibrinogen antagonist.
114a. An anti-fibrotic agent that is an antimycotic agent.
115a. An anti-fibrotic agent that is an antimycotic agent, wherein the antimycotic agent that is sulconizole.
116a. An anti-fibrotic agent that is a bisphosphonate.
117a. An anti-fibrotic agent that is a phospholipase A1 inhibitor.

118a. An anti-fibrotic agent that is a histamine H1/H2/H3 receptor antagonist.
119a. An anti-fibrotic agent that is a macrolide antibiotic.
120a. An anti-fibrotic agent that is a GPllb/Illa receptor antagonist.
121 a. An anti-fibrotic agent that is an endothelin receptor antagonist.
122a. An anti-fibrotic agent that is a peroxisome proliferator-activated receptor agonist.
123a. An anti-fibrotic agent that is an estrogen receptor agent.
124a. An anti-fibrotic agent that is a somastostatin analogue.
125a. An anti-fibrotic agent that is a neurokinin 1 antagonist.
126a. An anti-fibrotic agent that is a neurokinin 3 antagonist.
127a. An anti-fibrotic agent that is a VLA-4 antagonist.
128a. An anti-fibrotic agent that is an osteoclast inhibitor.
129a. An anti-fibrotic agent that is a DNA topoisomerase ATP
hydrolyzing inhibitor.
130a. An anti-fibrotic agent that is an angiotensin I converting enzyme inhibitor.
131 a. An anti-fibrotic agent that is an angiotensin II antagonist.
132a. An anti-fibrotic agent that is an enkephalinase inhibitor.

133a. An anti-fibrotic agent that is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer.
134a. An anti-fibrotic agent that is a protein kinase C inhibitor.
135a. An anti-fibrotic agent that is a ROCK (rho-associated kinase) inhibitor.
136a. An anti-fibrotic agent that is a CXCR3 inhibitor.
137a. An anti-fibrotic agent that is an Itk inhibitor.
138a. An anti-fibrotic agent that is a cytosolic phospholipase A2-alpha inhibitor.
139a. An anti-fibrotic agent that is a PPAR agonist.
140a. An anti-fibrotic agent that is an immunosuppressant.
141 a. An anti-fibrotic agent that is an Erb inhibitor.
142a. An anti-fibrotic agent that is an apoptosis agonist.
143a. An anti-fibrotic agent that is a lipocortin agonist.
144a. An anti-fibrotic agent that is a VCAM-1 antagonist.
145a. An anti-fibrotic agent that is a collagen antagonist.
As mentioned above, the present invention provides compositions comprising each of the foregoing 146 (i.e., 1 a through 145a) listed anti-fibrotic agents or classes of anti-fibrotic agents, with each of the following 98 (i.e., 1 b through 97b) polymers and compounds:
1 b. A crosslinked polymer.
2b. A polymer that reacts with mammalian tissue.

3b. A polymer that is a naturally occurring polymer.

4b. A polymer that is a protein.

5b. A polymer that is a carbohydrate.

6b. A polymer that is biodegradable.

7b. A polymer that is crosslinked and biodegradable.

8b. A polymer that nonbiodegradable.

9b. Collagen.
10b. Methylated collagen.
11 b. Fibrinogen.
12b. Thrombin.
13b. Albumin.
14b. Plasminogen.
15b. von Willebrands factor.
16b. Factor VIII.
17b. Hypoallergenic collagen.
18b. Atelopeptidic collagen.
19b. Telopeptide collagen.
20b. Crosslinked collagen.
21 b. Aprotinin.
22b. Gelatin.
23b. A protein conjugate.

24b. A gelatin conjugate.
25b. Hyaluronic acid.
26b. A hyaluronic acid derivative.
27b. A synthetic polymer.
28b. A polymer formed from reactants comprising a synthetic isocyanate-containing compound.
29b. A synthetic isocyanate-containing compound.
30b. A polymer formed from reactants comprising a synthetic thiol-containing compound.
31 b. A synthetic thiol-containing compound.
32b. A polymer formed from reactants comprising a synthetic compound containing at least two thiol groups.
33b. A synthetic compound containing at least two thiol groups.
34b. A polymer formed from reactants comprising a synthetic compound containing at least three thiol groups.
35b. A synthetic compound containing at least three thiol groups.
36b. A polymer formed from reactants comprising a synthetic compound containing at least four thiol groups.
37b. A synthetic compound containing at least four thiol groups.
38b. A polymer formed from reactants comprising a synthetic amino-containing compound.
39b. A synthetic amino-containing compound.

40b. A polymer formed from reactants comprising a synthetic compound containing at least two amino groups.
41 b. A synthetic compound containing at least two amino groups.
42b. A polymer formed from reactants comprising a synthetic compound containing at least three amino groups.
43b. A synthetic compound containing at least three amino groups.
44b. A polymer formed from reactants comprising a synthetic compound containing at least four amino groups.
45b. A synthetic compound containing at least four amino groups.
46b. A polymer formed from reactants comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group.
47b. A synthetic compound comprising a carbonyl-oxygen-succinimidyl group.
48b. A polymer formed from reactants comprising a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups.
49b. A synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups.
50b. A polymer formed from reactants comprising a synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.
51 b. A synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.
52b. A polymer formed from reactants comprising a synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.

53b. A synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.
54b. A polymer formed from from reactants comprising a synthetic polyalkylene oxide-containing compound.
55b. A synthetic polyalkylene oxide-containing compound.
56b. A polymer formed from reactants comprising a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.
57b. A synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.
58b. A polymer formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive amino groups.
59b. A synthetic polyalkylene oxide-containing compound having reactive amino groups.
60b. A polymer formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive thiol groups.
61 b. A synthetic polyalkylene oxide-containing compound having reactive thiol groups.
62b. A polymer formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups.
63b. A synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups.
64b. A polymer formed from reactants comprising a synthetic compound comprising a biodegradable polyester block.

65b. A synthetic compound comprising a biodegradable polyester block.
66b. A polymer formed from reactants comprising a synthetic polymer formed in whole or part from lactic acid or lactide.
67b. A synthetic polymer formed in whole or part from lactic acid or lactide.
68b. A polymer formed from reactants comprising a synthetic polymer formed in whole or part from glycolic acid or glycolide.
69b. A synthetic polymer formed in whole or part from glycolic acid or glycolide.
70b. A polymer formed from reactants comprising polylysine.
71 b. Polylysine.
72b. A polymer formed from reactants comprising (a) protein and (b) a compound comprising a polyalkylene oxide portion.
73b. A polymer formed from reactants comprising (a) protein and (b) polylysine.
74b. A polymer formed from reactants comprising (a) protein and (b) a compound having at least four thiol groups.
75b. A polymer formed from reactants comprising (a) protein and (b) a compound having at least four amino groups.
76b. A polymer formed from reactants comprising (a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.
77b. A polymer formed from reactants comprising (a) protein and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epsilon-caprolactone.

78b. A polymer formed from reactants comprising (a) collagen and (b) a compound comprising a polyalkylene oxide portion.
79b. A polymer formed from reactants comprising (a) collagen and (b) polylysine.
80b. A polymer formed from reactants comprising (a) collagen and (b) a compound having at least four thiol groups.
81 b. A polymer formed from reactants comprising (a) collagen and (b) a compound having at least four amino groups.
82b. A polymer formed from reactants comprising (a) collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.
83b. A polymer formed from reactants comprising (a) collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epsilon-caprolactone.
84b. A polymer formed from reactants comprising (a) methylated collagen and (b) a compound comprising a polyalkylene oxide portion.
85b. A polymer formed from reactants comprising (a) methylated collagen and (b) polylysine.
86b. A polymer formed from reactants comprising (a) methylated collagen and (b) a compound having at least four thiol groups.
87b. A polymer formed from reactants comprising (a) methylated collagen and (b) a compound having at least four amino groups.
88b. A polymer formed from reactants comprising (a) methylated collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

89b. A polymer formed from reactants comprising (a) methylated collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epsilon-caprolactone.
90b. A polymer formed from reactants comprising hyaluronic acid.
91 b. A polymer formed from reactants comprising a hyaluronic acid derivative.
92b. A polymer formed from reactants comprising pentaerythritol polyethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.
93b. Pentaerythritol polyethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.
94b. A polymer formed from reactants comprising pentaerythritol polyethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.
95b. Pentaerythritol polyethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.
96b. A polymer formed from reactants comprising (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.
97b. A mixture of (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalleylene oxide region and multiple electrophilic groups.
As mentioned above, the present invention provides compositions comprising each of the foregoing 146 (1 a through 145a) listed anti-fibrotic agents or classes of anti-fibrotic agents, with each of the foregoing 98 (1 b through 97b) polymers and compounds: Thus, in separate aspects, the invention provides 146 times 98 = 14,308 described compositions. In other words, each of the following is a distinct aspect of the present invention:
1 a+1 b; 1 a + 2b; 1 a + 3b; 1 a+4b; 1 a+5b; 1 a+6b; 1 a+7b; 1 a+8b; 1 a+9b; 1 a+1 Ob;
1 a+11 b; 1 a+12b; 1 a+13b; 1 a+14b; 1 a+15b; 1 a+16b; 1 a+17b; 1 a+18b; 1 a+19b;
1 a+20b; 1 a+21 b; 1 a+22b; 1 a+23b; 1 a+24b; 1 a+25b; 1 a+26b; 1 a+27b; 1 a+28b;
1 a+29b; 1 a+30b; 1 a+31 b; 1 a+32b; 1 a+33b; 1 a+34b; 1 a+35b; 1 a+36b; 1 a+37b;
1 a+38b; 1 a+39b; 1 a+40b; 1 a+41 b; 1 a+42b; 1 a+43b; 1 a+44b; 1 a+45b; 1 a+46b;
1 a+47b; 1 a+48b; 1 a+49b; 1 a+50b; 1 a+51 b; 1 a+52b; 1 a+53b; 1 a+54b; 1 a+55b;
1 a+55b; 1 a+57b; 1 a+58b; 1 a+59b; 1 a+60b; 1 a+61 b; 1 a+62b; 1 a+63b; 1 a+64b;
1 a+65b; 1 a+66b; 1 a+67b; 1 a+68b; 1 a+69b; 1 a+70b; 1 a+71 b; 1 a+72b; 1 a+73b;
1 a+74b; 1 a+75b; 1 a+76b; 1 a+77b; 1 a+78b; 1 a+79b; 1 a+80b; 1 a+81 b; 1 a+82b;
1 a+83b; 1 a+84b; 1 a+85b; 1 a+86b; 1 a+87b; 1 a+88b; 1 a+89b; 1 a+90b; 1 a+91 b;
1 a+92b; 1 a+93b; 1 a+94b; 1 a+95b; 1 a+96b; 1 a+97b; 2a+1 b; 2a + 2b; 2a +
3b;
2a+4b; 2a+5b; 2a+6b; 2a+7b; 2a+8b; 2a+9b; 2a+1 Ob; 2a+11 b; 2a+12b;
2a+13b; 2a+14b; 2a+15b; 2a+16b; 2a+17b; 2a+18b; 2a+19b; 2a+20b; 2a+21 b;
2a+22b; 2a+23b; 2a+24b; 2a+25b; 2a+26b; 2a+27b; 2a+28b; 2a+29b; 2a+30b;
2a+31 b; 2a+32b; 2a+33b; 2a+34b; 2a+35b; 2a+36b; 2a+37b; 2a+38b; 2a+39b;
2a+40b; 2a+41 b; 2a+42b; 2a+43b; 2a+44b; 2a+45b; 2a+46b; 2a+47b; 2a+48b;
2a+49b; 2a+50b; 2a+51 b; 2a+52b; 2a+53b; 2a+54b; 2a+55b; 2a+55b; 2a+57b;
2a+58b; 2a+59b; 2a+60b; 2a+61 b; 2a+62b; 2a+63b; 2a+64b; 2a+65b; 2a+66b;
2a+67b; 2a+68b; 2a+69b; 2a+70b; 2a+71 b; 2a+72b; 2a+73b; 2a+74b; 2a+75b;
2a+76b; 2a+77b; 2a+78b; 2a+79b; 2a+80b; 2a+81 b; 2a+82b; 2a+83b; 2a+84b;
2a+85b; 2a+86b; 2a+87b; 2a+88b; 2a+89b; 2a+90b; 2a+91 b; 2a+92b; 2a+93b;
2a+94b; 2a+95b; 2a+96b; 2a+97b; 3a+22b; 3a+23b; 3a+24b; 3a+25b; 3a+26b;

3a+27b; 3a+28b; 3a+29b; 3a+30b; 3a+31 b; 3a+32b; 3a+33b; 3a+34b; 3a+35b;
3a+36b; 3a+37b; 3a+38b; 3a+39b; 3a+40b; 3a+41 b; 3a+42b; 3a+43b; 3a+44b;
3a+45b; 3a+46b; 3a+47b; 3a+48b; 3a+49b; 3a+50b; 3a+51 b; 3a+52b; 3a+53b;
3a+54b; 3a+55b; 3a+55b; 3a+57b; 3a+58b; 3a+59b; 3a+60b; 3a+61 b; 3a+62b;
3a+63b; 3a+64b; 3a+65b; 3a+66b; 3a+67b; 3a+68b; 3a+69b; 3a+70b; 3a+71 b;
3a+72b; 3a+73b; 3a+74b; 3a+75b; 3a+76b; 3a+77b; 3a+78b; 3a+79b; 3a+80b;
3a+81 b; 3a+82b; 3a+83b; 3a+84b; 3a+85b; 3a+86b; 3a+87b; 3a+88b; 3a+89b;
3a+90b; 3a+91 b; 3a+92b; 3a+93b; 3a+94b; 3a+95b; 3a+96b; 3a+97b; 4a+12b;
4a+13b; 4a+14b; 4a+15b; 4a+16b; 4a+17b; 4a+18b; 4a+19b; 4a+20b; 4a+21 b;
4a+22b; 4a+23b; 4a+24b; 4a+25b; 4a+26b; 4a+27b; 4a+28b; 4a+29b; 4a+30b;
4a+31 b; 4a+32b; 4a+33b; 4a+34b; 4a+35b; 4a+36b; 4a+37b; 4a+38b; 4a+39b;
4a+40b; 4a+41 b; 4a+42b; 4a+43b; 4a+44b; 4a+45b; 4a+46b; 4a+47b; 4a+48b;
4a+49b; 4a+50b; 4a+51 b; 4a+52b; 4a+53b; 4a+54b; 4a+55b; 4a+55b; 4a+57b;
4a+58b; 4a+59b; 4a+60b; 4a+61 b; 4a+62b; 4a+63b; 4a+64b; 4a+65b; 4a+66b;
4a+67b; 4a+68b; 4a+69b; 4a+70b; 4a+71 b; 4a+72b; 4a+73b; 4a+74b; 4a+75b;
4a+76b; 4a+77b; 4a+78b; 4a+79b; 4a+80b; 4a+81 b; 4a+82b; 4a+83b; 4a+84b;
4a+85b; 4a+86b; 4a+87b; 4a+88b; 4a+89b; 4a+90b; 4a+91 b; 4a+92b; 4a+93b;
4a+94b; 4a+95b; 4a+96b; 4a+97b; 5a+12b; 5a+13b; 5a+14b; 5a+15b; 5a+16b;
5a+17b; 5a+18b; 5a+19b; 5a+20b; 5a+21 b; 5a+22b; 5a+23b; 5a+24b; 5a+25b;
5a+26b; 5a+27b; 5a+28b; 5a+29b; 5a+30b; 5a+31 b; 5a+32b; 5a+33b; 5a+34b;
5a+35b; 5a+36b; 5a+37b; 5a+38b; 5a+39b; 5a+40b; 5a+41 b; 5a+42b; 5a+43b;
5a+44b; 5a+45b; 5a+46b; 5a+47b; 5a+48b; 5a+49b; 5a+50b; 5a+51 b; 5a+52b;
5a+53b; 5a+54b; 5a+55b; 5a+55b; 5a+57b; 5a+58b; 5a+59b; 5a+60b; 5a+61 b;
5a+62b; 5a+63b; 5a+64b; 5a+65b; 5a+66b; 5a+67b; 5a+68b; 5a+69b; 5a+70b;
5a+71 b; 5a+72b; 5a+73b; 5a+74b; 5a+75b; 5a+76b; 5a+77b; 5a+78b; 5a+79b;
5a+80b; 5a+81 b; 5a+82b; 5a+83b; 5a+84b; 5a+85b; 5a+86b; 5a+87b; 5a+88b;
5a+89b; 5a+90b; 5a+91 b; 5a+92b; 5a+93b; 5a+94b; 5a+95b; 5a+96b; 5a+97b;
6a+1 b; 6a + 2b; 6a + 3b; 6a+4b; 6a+5b; 6a+6b; 6a+7b; 6a+8b; 6a+9b; 6a+1 Ob;
6a+11 b; 6a+12b; 6a+13b; 6a+14b; 6a+15b; 6a+16b; 6a+17b; 6a+18b; 6a+19b;
6a+20b; 6a+21 b; 6a+22b; 6a+23b; 6a+24b; 6a+25b; 6a+26b; 6a+27b; 6a+28b;

6a+29b; 6a+30b; 6a+31 b; 6a+32b; 6a+33b; 6a+34b; 6a+35b; 6a+36b; 6a+37b;
6a+38b; 6a+39b; 6a+40b; 6a+41 b; 6a+42b; 6a+43b; 6a+44b; 6a+45b; 6a+46b;
6a+47b; 6a+48b; 6a+49b; 6a+50b; 6a+51 b; 6a+52b; 6a+53b; 6a+54b; 6a+55b;
6a+55b; 6a+57b; 6a+58b; 6a+59b; 6a+60b; 6a+61 b; 6a+62b; 6a+63b; 6a+64b;
6a+65b; 6a+66b; 6a+67b; 6a+68b; 6a+69b; 6a+70b; 6a+71 b; 6a+72b; 6a+73b;
6a+74b; 6a+75b; 6a+76b; 6a+77b; 6a+78b; 6a+79b; 6a+80b; 6a+81 b; 6a+82b;
6a+83b; 6a+84b; 6a+85b; 6a+86b; 6a+87b; 6a+88b; 6a+89b; 6a+90b; 6a+91 b;
6a+92b; 6a+93b; 6a+94b; 6a+95b; 6a+96b; 6a+97b; 7a+1 b; 7a + 2b; 7a + 3b;
7a+4b; 7a+5b; 7a+6b; 7a+7b; 7a+8b; 7a+9b; 7a+1 Ob; 7a+11 b; 7a+12b;
7a+13b; 7a+14b; 7a+15b; 7a+16b; 7a+17b; 7a+18b; 7a+19b; 7a+20b; 7a+21 b;
7a+22b; 7a+23b; 7a+24b; 7a+25b; 7a+26b; 7a+27b; 7a+28b; 7a+29b; 7a+30b;
7a+31 b; 7a+32b; 7a+33b; 7a+34b; 7a+35b; 7a+36b; 7a+37b; 7a+38b; 7a+39b;
7a+40b; 7a+41 b; 7a+42b; 7a+43b; 7a+44b; 7a+45b; 7a+46b; 7a+47b; 7a+48b;
7a+49b; 7a+50b; 7a+51 b; 7a+52b; 7a+53b; 7a+54b; 7a+55b; 7a+55b; 7a+57b;
7a+58b; 7a+59b; 7a+60b; 7a+61 b; 7a+62b; 7a+63b; 7a+64b; 7a+65b; 7a+66b;
7a+67b; 7a+68b; 7a+69b; 7a+70b; 7a+71 b; 7a+72b; 7a+73b; 7a+74b; 7a+75b;
7a+76b; 7a+77b; 7a+78b; 7a+79b; 7a+80b; 7a+81 b; 7a+82b; 7a+83b; 7a+84b;
7a+85b; 7a+86b; 7a+87b; 7a+88b; 7a+89b; 7a+90b; 7a+91 b; 7a+92b; 7a+93b;
7a+94b; 7a+95b; 7a+96b; 7a+97b; 8a+12b; 8a+13b; 8a+14b; 8a+15b; 8a+16b;
8a+17b; 8a+18b; 8a+19b; 8a+20b; 8a+21 b; 8a+22b; 8a+23b; 8a+24b; 8a+25b;
8a+26b; 8a+27b; 8a+28b; 8a+29b; 8a+30b; 8a+31 b; 8a+32b; 8a+33b; 8a+34b;
8a+35b; 8a+36b; 8a+37b; 8a+38b; 8a+39b; 8a+40b; 8a+41 b; 8a+42b; 8a+43b;
8a+44b; 8a+45b; 8a+46b; 8a+47b; 8a+48b; 8a+49b; 8a+50b; 8a+51 b; 8a+52b;
8a+53b; 8a+54b; 8a+55b; 8a+55b; 8a+57b; 8a+58b; 8a+59b; 8a+60b; 8a+61 b;
8a+62b; 8a+63b; 8a+64b; 8a+65b; 8a+66b; 8a+67b; 8a+68b; 8a+69b; 8a+70b;
8a+71 b; 8a+72b; 8a+73b; 8a+74b; 8a+75b; 8a+76b; 8a+77b; 8a+78b; 8a+79b;
8a+80b; 8a+81 b; 8a+82b; 8a+83b; 8a+84b; 8a+85b; 8a+86b; 8a+87b; 8a+88b;
8a+89b; 8a+90b; 8a+91 b; 8a+92b; 8a+93b; 8a+94b; 8a+95b; 8a+96b; 8a+97b;
9a+1 b; 9a + 2b; 9a + 3b; 9a+4b; 9a+5b; 9a+6b; 9a+7b; 9a+8b; 9a+9b; 9a+1 Ob;
9a+11 b; 9a+12b; 9a+13b; 9a+14b; 9a+15b; 9a+16b; 9a+17b; 9a+18b; 9a+19b;

9a+20b; 9a+21 b; 9a+22b; 9a+23b; 9a+24b; 9a+25b; 9a+26b; 9a+27b; 9a+28b;
9a+29b; 9a+30b; 9a+31 b; 9a+32b; 9a+33b; 9a+34b; 9a+35b; 9a+36b; 9a+37b;
9a+38b; 9a+39b; 9a+40b; 9a+41 b; 9a+42b; 9a+43b; 9a+44b; 9a+45b; 9a+46b;
9a+47b; 9a+48b; 9a+49b; 9a+50b; 9a+51 b; 9a+52b; 9a+53b; 9a+54b; 9a+55b;
9a+55b; 9a+57b; 9a+58b; 9a+59b; 9a+60b; 9a+61 b; 9a+62b; 9a+63b; 9a+64b;
9a+65b; 9a+66b; 9a+67b; 9a+68b; 9a+69b; 9a+70b; 9a+71 b; 9a+72b; 9a+73b;
9a+74b; 9a+75b; 9a+76b; 9a+77b; 9a+78b; 9a+79b; 9a+80b; 9a+81 b; 9a+82b;
9a+83b; 9a+84b; 9a+85b; 9a+86b; 9a+87b; 9a+88b; 9a+89b; 9a+90b; 9a+91 b;
9a+92b; 9a+93b; 9a+94b; 9a+95b; 9a+96b; 9a+97b; 1 Oa+1 b; 1 Oa + 2b; 1 Oa +
3b; 1 Oa+4b; 10a+5b; 10a+6b; 10a+7b; 1 Oa+8b; 10a+9b; 10a+1 Ob; 1 Oa+11 b;
10a+12b; 10a+13b; 10a+14b; 10a+15b; 10a+16b; 10a+17b; 10a+18b;
10a+19b; 1 Oa+20b; 10a+21 b; 1 Oa+22b; 10a+23b; 1 Oa+24b; 10a+25b;
1 Oa+26b; 10a+27b; 1 Oa+28b; 10a+29b; 10a+30b; 10a+31 b; 10a+32b;
10a+33b;10a+34b;10a+35b;10a+36b;10a+37b;10a+38b;10a+39b;
10a+40b; 1 Oa+41 b; 1 Oa+42b; 1 Oa+43b; 10a+44b; 10a+45b; 10a+46b;
1 Oa+47b; 1 Oa+48b; 1 Oa+49b; 1 Oa+50b; 1 Oa+51 b; 1 Oa+52b; 1 Oa+53b;
10a+54b; 10a+55b; 10a+55b; 10a+57b; 10a+58b; 10a+59b; 10a+60b;
1 Oa+61 b; 1 Oa+62b; 10a+63b; 1 Oa+64b; 10a+65b; 1 Oa+66b; 1 Oa+67b;
1 Oa+68b; 10a+69b; 1 Oa+70b; 10a+71 b; 10a+72b; 10a+73b; 10a+74b;
10a+75b; 1 Oa+76b; 10a+77b; 1 Oa+78b; 10a+79b; 10a+80b; 1 Oa+81 b;
10a+82b; 10a+83b; 10a+84b; 10a+85b; 10a+86b; 10a+87b; 10a+88b;
1 Oa+89b; 10a+90b; 1 Oa+91 b; 10a+92b; 1 Oa+93b; 1 Oa+94b; 10a+95b;
1 Oa+96b; 1 Oa+97b; 11 a+1 b; 11 a + 2b; 11 a + 3b; 11 a+4b; 11 a+5b; 11 a+6b;
11 a+7b; 11 a+8b; 11 a+9b; 11 a+1 Ob; 11 a+11 b; 11 a+12b; 11 a+13b; 11 a+14b;
11 a+15b; 11 a+16b; 11 a+17b; 11 a+18b; 11 a+19b; 11 a+20b; 11 a+21 b;
11 a+22b; 11 a+23b; 11 a+24b; 11 a+25b; 11 a+26b; 11 a+27b; 11 a+28b;
11 a+29b; 11 a+30b; 11 a+31 b; 11 a+32b; 11 a+33b; 11 a+34b; 11 a+35b;
11 a+36b; 11 a+37b; 11 a+38b; 11 a+39b; 11 a+40b; 11 a+41 b; 11 a+42b;
11 a+43b; 11 a+44b; 11 a+45b; 11 a+46b; 11 a+47b; 11 a+48b; 11 a+49b;
11 a+50b; 11 a+51 b; 11 a+52b; 11 a+53b; 11 a+54b; 11 a+55b; 11 a+55b;

11 a+57b; 11 a+58b; 11 a+59b; 11 a+60b; 11 a+61 b; 11 a+62b; 11 a+63b;
11a+64b;11a+65b;11a+66b;11a+67b;11a+68b;11a+69b;11a+70b;
11 a+71 b; 11 a+72b; 11 a+73b; 11 a+74b; 11 a+75b; 11 a+76b; 11 a+77b;
11 a+78b; 11 a+79b; 11 a+80b; 11 a+81 b; 11 a+82b; 11 a+83b; 11 a+84b;
11 a+85b; 11 a+86b; 11 a+87b; 11 a+88b; 11 a+89b; 11 a+90b; 11 a+91 b;
11 a+92b; 11 a+93b; 11 a+94b; 11 a+95b; 11 a+96b; 11 a+97b; 12a+1 b; 12a + 2b;
12a + 3b; 12a+4b; 12a+5b; 12a+6b; 12a+7b; 12a+8b; 12a+9b; 12a+10b;
12a+11 b; 12a+12b; 12a+13b; 12a+14b; 12a+15b; 12a+16b; 12a+17b;
12a+18b; 12a+19b; 12a+20b; 12a+21 b; 12a+22b; 12a+23b; 12a+24b;
12a+25b; 12a+26b; 12a+27b; 12a+28b; 12a+29b; 12a+30b; 12a+31 b;
12a+32b;12a+33b;12a+34b;12a+35b;12a+36b;12a+37b;12a+38b;
12a+39b; 12a+40b; 12a+41 b; 12a+42b; 12a+43b; 12a+44b; 12a+45b;
12a+46b; 12a+47b; 12a+48b; 12a+49b; 12a+50b; 12a+51 b; 12a+52b;
12a+53b;12a+54b;12a+55b;12a+55b;12a+57b;12a+58b;12a+59b;
12a+60b; 12a+61 b; 12a+62b; 12a+63b; 12a+64b; 12a+65b; 12a+66b;
12a+67b; 12a+68b; 12a+69b; 12a+70b; 12a+71 b; 12a+72b; 12a+73b;
12a+74b;12a+75b;12a+76b;12a+77b;12a+78b;12a+79b;12a+80b;
12a+81 b; 12a+82b; 12a+83b; 12a+84b; 12a+85b; 12a+86b; 12a+87b;
12a+88b; 12a+89b; 12a+90b; 12a+91 b; 12a+92b; 12a+93b; 12a+94b;
12a+95b; 12a+96b; 12a+97b; 13a+1 b; 13a + 2b; 13a + 3b; 13a+4b; 13a+5b;
13a+6b; 13a+7b; 13a+8b; 13a+9b; 13a+10b; 13a+11 b; 13a+12b; 13a+13b;
13a+14b; 13a+15b; 13a+16b; 13a+17b; 13a+18b; 13a+19b; 13a+20b;
13a+21 b; 13a+22b; 13a+23b; 13a+24b; 13a+25b; 13a+26b; 13a+27b;
13a+28b; 13a+29b; 13a+30b; 13a+31 b; 13a+32b; 13a+33b; 13a+34b;
13a+35b; 13a+36b; 13a+37b; 13a+38b; 13a+39b; 13a+40b; 13a+41 b;
13a+42b; 13a+43b; 13a+44b; 13a+45b; 13a+46b; 13a+47b; 13a+48b;
13a+49b; 13a+50b; 13a+51 b; 13a+52b; 13a+53b; 13a+54b; 13a+55b;
13a+55b; 13a+57b; 13a+58b; 13a+59b; 13a+60b; 13a+61 b; 13a+62b;
13a+63b; 13a+64b; 13a+65b; 13a+66b; 13a+67b; 13a+68b; 13a+6gb;
13a+70b; 13a+71 b; 13a+72b; 13a+73b; 13a+74b; 13a+75b; 13a+76b;

13a+77b; 13a+78b; 13a+79b; 13a+80b; 13a+81 b; 13a+82b; 13a+83b;
13a+84b;13a+85b;13a+86b;13a+87b;13a+88b;13a+89b;13a+90b;
13a+91 b; 13a+92b; 13a+93b; 13a+94b; 13a+95b; 13a+96b; 13a+97b; 14a+1 b;
14a + 2b; 14a + 3b; 14a+4b; 14a+5b; 14a+6b; 14a+7b; 14a+8b; 14a+9b;
14a+1 Ob; 14a+11 b; 14a+12b; 14a+13b; 14a+14b; 14a+15b; 14a+16b;
14a+17b; 14a+18b; 14a+19b; 14a+20b; 14a+21 b; 14a+22b; 14a+23b;
14a+24b;14a+25b;14a+26b;14a+27b;14a+28b;14a+29b;14a+30b;
14a+31 b; 14a+32b; 14a+33b; 14a+34b; 14a+35b; 14a+36b; 14a+37b;
14a+38b; 14a+39b; 14a+40b; 14a+41 b; 14a+42b; 14a+43b; 14a+44b;
14a+45b; 14a+46b; 14a+47b; 14a+48b; 14a+49b; 14a+50b; 14a+51 b;
14a+52b;14a+53b;14a+54b;14a+55b;14a+55b;14a+57b;14a+58b;
14a+59b; 14a+60b; 14a+61 b; 14a+62b; 14a+63b; 14a+64b; 14a+65b;
14a+66b; 14a+67b; 14a+68b; 14a+69b; 14a+70b; 14a+71 b; 14a+72b;
14a+73b; 14a+74b; 14a+75b; 14a+76b; 14a+77b; 14a+78b; 14a+79b;
14a+80b; 14a+81 b; 14a+82b; 14a+83b; 14a+84b; 14a+85b; 14a+86b;
14a+87b; 14a+88b; 14a+89b; 14a+90b; 14a+91 b; 14a+92b; 14a+93b;
14a+94b; 14a+95b; 14a+96b; 14a+97b; 15a+1 b; 15a + 2b; 15a + 3b; 15a+4b;
15a+5b; 15a+6b; 15a+7b; 15a+8b; 15a+9b; 15a+1 Ob; 15a+11 b; 15a+12b;
15a+13b; 15a+14b; 15a+15b; 15a+16b; 15a+17b; 15a+18b; 15a+19b;
15a+20b; 15a+21 b; 15a+22b; 15a+23b; 15a+24b; 15a+25b; 15a+26b;
15a+27b; 15a+28b; 15a+29b; 15a+30b; 15a+31 b; 15a+32b; 15a+33b;
15a+34b; 15a+35b; 15a+36b; 15a+37b; 15a+38b; 15a+39b; 15a+40b;
15a+41 b; 15a+42b; 15a+43b; 15a+44b; 15a+45b; 15a+46b; 15a+47b;
15a+48b; 15a+49b; 15a+50b; 15a+51 b; 15a+52b; 15a+53b; 15a+54b;
15a+55b; 15a+55b; 15a+57b; 15a+58b; 15a+59b; 15a+60b; 15a+61 b;
15a+62b; 15a+63b; 15a+64b; 15a+65b; 15a+66b; 15a+67b; 15a+68b;
15a+69b; 15a+70b; 15a+71 b; 15a+72b; 15a+73b; 15a+74b; 15a+75b;
15a+76b; 15a+77b; 15a+78b; 15a+79b; 15a+80b; 15a+81 b; 15a+82b;
15a+83b; 15a+84b; 15a+85b; 15a+86b; 15a+87b; 15a+88b; 15a+89b;
15a+90b; 15a+91 b; 15a+92b; 15a+93b; 15a+94b; 15a+95b; 15a+96b;

15a+97b; 16a+1 b; 16a + 2b; 16a + 3b; 16a+4b; 16a+5b; 16a+6b; 16a+7b;
16a+8b; 16a+9b; 16a+1 Ob; 16a+11 b; 16a+12b; 16a+13b; 16a+14b; 16a+15b;
16a+16b; 16a+17b; 16a+18b; 16a+19b; 16a+20b; 16a+21 b; 16a+22b;
16a+23b; 16a+24b; 16a+25b; 16a+26b; 16a+27b; 16a+28b; 16a+29b;
16a+30b; 16a+31 b; 16a+32b; 16a+33b; 16a+34b; 16a+35b; 16a+36b;
16a+37b; 16a+38b; 16a+39b; 16a+40b; 16a+41 b; 16a+42b; 16a+43b;
16a+44b; 16a+45b; 16a+46b; 16a+47b; 16a+48b; 16a+49b; 16a+50b;
16a+51 b; 16a+52b; 16a+53b; 16a+54b; 16a+55b; 16a+55b; 16a+57b;
16a+58b; 16a+59b; 16a+60b; 16a+61 b; 16a+62b; 16a+63b; 16a+64b;
16a+65b; 16a+66b; 16a+67b; 16a+68b; 16a+69b; 16a+70b; 16a+71 b;
16a+72b; 16a+73b; 16a+74b; 16a+75b; 16a+76b; 16a+77b; 16a+78b;
16a+79b; 16a+80b; 16a+81 b; 16a+82b; 16a+83b; 16a+84b; 16a+85b;
16a+86b; 16a+87b; 16a+88b; 16a+89b; 16a+90b; 16a+91 b; 16a+92b;
16a+93b; 16a+94b; 16a+95b; 16a+96b; 16a+97b; 17a+1 b; 17a + 2b; 17a + 3b;
17a+4b; 17a+5b; 17a+6b; 17a+7b; 17a+8b; 17a+9b; 17a+1 Ob; 17a+11 b;
17a+12b; 17a+13b; 17a+14b; 17a+15b; 17a+16b; 17a+17b; 17a+18b;
17a+19b; 17a+20b; 17a+21 b; 17a+22b; 17a+23b; 17a+24b; 17a+25b;
17a+26b; 17a+27b; 17a+28b; 17a+29b; 17a+30b; 17a+31 b; 17a+32b;
17a+33b; 17a+34b; 17a+35b; 17a+36b; 17a+37b; 17a+38b; 17a+39b;
17a+40b; 17a+41 b; 17a+42b; 17a+43b; 17a+44b; 17a+45b; 17a+46b;
17a+47b; 17a+48b; 17a+49b; 17a+50b; 17a+51 b; 17a+52b; 17a+53b;
17a+54b; 17a+55b; 17a+55b; 17a+57b; 17a+58b; 17a+59b; 17a+60b;
17a+61 b; 17a+62b; 17a+63b; 17a+64b; 17a+65b; 17a+66b; 17a+67b;
17a+68b; 17a+69b; 17a+70b; 17a+71 b; 17a+72b; 17a+73b; 17a+74b;
17a+75b; 17a+76b; 17a+77b; 17a+78b; 17a+79b; 17a+80b; 17a+81 b;
17a+82b; 17a+83b; 17a+84b; 17a+85b; 17a+86b; 17a+87b; 17a+88b;
17a+89b; 17a+90b; 17a+91 b; 17a+92b; 17a+93b; 17a+94b; 17a+95b;
17a+96b; 17a+97b; 18a+1 b; 18a + 2b; 18a + 3b; 18a+4b; 18a+5b; 18a+6b;
18a+7b; 18a+8b; 18a+9b; 18a+10b; 18a+11 b; 18a+12b; 18a+13b; 18a+14b;
18a+15b; 18a+16b; 18a+17b; 18a+18b; 18a+19b; 18a+20b; 18a+21 b;

18a+22b;18a+23b;18a+24b;18a+25b;18a+26b;18a+27b;18a+28b;
18a+29b; 18a+30b; 18a+31 b; 18a+32b; 18a+33b; 18a+34b; 18a+35b;
18a+36b; 18a+37b; 18a+38b; 18a+39b; 18a+40b; 18a+41 b; 18a+42b;
18a+43b; 18a+44b; 18a+45b; 18a+46b; 18a+47b; 18a+48b; 18a+49b;
18a+50b; 18a+51 b; 18a+52b; 18a+53b; 18a+54b; 18a+55b; 18a+55b;
18a+57b; 18a+58b; 18a+59b; 18a+60b; 18a+61 b; 18a+62b; 18a+63b;
18a+64b;18a+65b;18a+66b;18a+67b;18a+68b;18a+69b;18a+70b;
18a+71 b; 18a+72b; 18a+73b; 18a+74b; 18a+75b; 18a+76b; 18a+77b;
18a+78b; 18a+79b; 18a+80b; 18a+81 b; 18a+82b; 18a+83b; 18a+84b;
18a+85b; 18a+86b; 18a+87b; 18a+88b; 18a+89b; 18a+90b; 18a+91 b;
18a+92b; 18a+93b; 18a+94b; 18a+95b; 18a+96b; 18a+97b; 19a+1 b; 19a + 2b;
19a + 3b; 19a+4b; 19a+5b; 19a+6b; 19a+7b; 19a+8b; 19a+9b; 19a+10b;
19a+11 b; 19a+12b; 19a+13b; 19a+14b; 19a+15b; 19a+16b; 19a+17b;
19a+18b; 19a+19b; 19a+20b; 19a+21 b; 19a+22b; 19a+23b; 19a+24b;
19a+25b; 19a+26b; 19a~27b; 19a+28b; 19a+29b; 19a+30b; 19a+31 b;
19a+32b;19a+33b;19a+34b;19a+35b;19a+36b;19a+37b;19a+38b;
19a+39b; 19a+40b; 19a+41 b; 19a+42b; 19a+43b; 19a+44b; 19a+45b;
19a+46b; 19a+47b; 19a+48b; 19a+49b; 19a+50b; 19a+51 b; 19a+52b;
19a+53b;19a+54b;19a+55b;19a+55b;19a+57b;19a+58b;19a+59b;
19a+60b; 19a+61 b; 19a+62b; 19a+63b; 19a+64b; 19a+65b; 19a+66b;
19a+67b; 19a+68b; 19a+69b; 19a+70b; 19a+71 b; 19a+72b; 19a+73b;
19a+74b;19a+75b;19a+76b;19a+77b;19a+78b;19a+79b;19a+80b;
19a+81 b; 19a+82b; 19a+83b; 19a+84b; 19a+85b; 19a+86b; 19a+87b;
19a+88b; 19a+89b; 19a+90b; 19a+91 b; 19a+92b; 19a+93b; 19a+94b;
19a+95b; 19a+96b; 19a+97b; 20a+1 b; 20a + 2b; 20a + 3b; 20a+4b; 20a+5b;
20a+6b; 20a+7b; 20a+8b; 20a+9b; 20a+10b; 20a+11 b; 20a+12b; 20a+13b;
20a+14b; 20a+15b; 20a+16b; 20a+17b; 20a+18b; 20a+19b; 20a+20b;
20a+21 b; 20a+22b; 20a+23b; 20a+24b; 20a+25b; 20a+26b; 20a+27b;
20a+28b; 20a+29b; 20a+30b; 20a+31 b; 20a+32b; 20a+33b; 20a+34b;
20a+35b; 20a+36b; 20a+37b; 20a+38b; 20a+39b; 20a+40b; 20a+41 b;

20a+42b; 20a+43b; 20a+44b; 20a+45b; 20a+46b; 20a+47b; 20a+48b;
20a+49b; 20a+50b; 20a+51 b; 20a+52b; 20a+53b; 20a+54b; 20a+55b;
20a+55b; 20a+57b; 20a+58b; 20a+59b; 20a+60b; 20a+61 b; 20a+62b;
20a+63b; 20a+64b; 20a+65b; 20a+66b; 20a+67b; 20a+68b; 20a+69b;
20a+70b; 20a+71 b; 20a+72b; 20a+73b; 20a+74b; 20a+75b; 20a+76b;
20a+77b; 20a+78b; 20a+79b; 20a+80b; 20a+81 b; 20a+82b; 20a+83b;
20a+84b; 20a+85b; 20a+86b; 20a+87b; 20a+88b; 20a+89b; 20a+90b;
20a+91 b; 20a+92b; 20a+93b; 20a+94b; 20a+95b; 20a+96b; 20a+97b; 21 a+1 b;
21 a + 2b; 21 a + 3b; 21 a+4b; 21 a+5b; 21 a+6b; 21 a+7b; 21 a+8b; 21 a+9b;
21 a+1 Ob; 21 a+11 b; 21 a+12b; 21 a+13b; 21 a+14b; 21 a+15b; 21 a+16b;
21 a+17b; 21 a+18b; 21 a+19b; 21 a+20b; 21 a+21 b; 21 a+22b; 21 a+23b;
21 a+24b; 21 a+25b; 21 a+26b; 21 a+27b; 21 a+28b; 21 a+29b; 21 a+30b;
21 a+31 b; 21 a+32b; 21 a+33b; 21 a+34b; 21 a+35b; 21 a+36b; 21 a+37b;
21 a+38b; 21 a+39b; 21 a+40b; 21 a+41 b; 21 a+42b; 21 a+43b; 21 a+44b;
21 a+45b; 21 a+46b; 21 a+47b; 21 a+48b; 21 a+49b; 21 a+50b; 21 a+51 b;
21 a+52b; 21 a+53b; 21 a+54b; 21 a+55b; 21 a+55b; 21 a+57b; 21 a+58b;
21 a+59b; 21 a+60b; 21 a+61 b; 21 a+62b; 21 a+63b; 21 a+64b; 21 a+65b;
21 a+66b; 21 a+67b; 21 a+68b; 21 a+69b; 21 a+70b; 21 a+71 b; 21 a+72b;
21 a+73b; 21 a+74b; 21 a+75b; 21 a+76b; 21 a+77b; 21 a+78b; 21 a+79b;
21 a+80b; 21 a+81 b; 21 a+82b; 21 a+83b; 21 a+84b; 21 a+85b; 21 a+86b;
21 a+87b; 21 a+88b; 21 a+89b; 21 a+90b; 21 a+91 b; 21 a+92b; 21 a+93b;
21 a+94b; 21 a+95b; 21 a+96b; 21 a+97b; 22a+1 b; 22a + 2b; 22a + 3b; 22a+4b;
22a+5b; 22a+6b; 22a+7b; 22a+8b; 22a+9b; 22a+1 Ob; 22a+11 b; 22a+12b;
22a+13b; 22a+14b; 22a+15b; 22a+16b; 22a+17b; 22a+18b; 22a+19b;
22a+20b; 22a+21 b; 22a+22b; 22a+23b; 22a+24b; 22a+25b; 22a+26b;
22a+27b; 22a+28b; 22a+29b; 22a+30b; 22a+31 b; 22a+32b; 22a+33b;
22a+34b; 22a+35b; 22a+36b; 22a+37b; 22a+38b; 22a+39b; 22a+40b;
22a+41 b; 22a+42b; 22a+43b; 22a+44b; 22a+45b; 22a+46b; 22a+47b;
22a+48b; 22a+49b; 22a+50b; 22a+51 b; 22a+52b; 22a+53b; 22a+54b;
22a+55b; 22a+55b; 22a+57b; 22a+58b; 22a+59b; 22a+60b; 22a+61 b;

22a+62b; 22a+63b; 22a+64b; 22a+65b; 22a+66b; 22a+67b; 22a+68b;
22a+69b; 22a+70b; 22a+71 b; 22a+72b; 22a+73b; 22a+74b; 22a+75b;
22a+76b; 22a+77b; 22a+78b; 22a+79b; 22a+80b; 22a+81 b; 22a+82b;

22a+83b; 22a+84b; 22a+85b; 22a+86b; 22a+87b; 22a+88b; 22a+89b;
22a+90b; 22a+91 b; 22a+92b; 22a+93b; 22a+94b; 22a+95b; 22a+96b;
22a+97b; 23a+1 b; 23a + 2b; 23a + 3b; 23a+4b; 23a+5b; 23a+6b; 23a+7b;
23a+8b; 23a+9b; 23a+10b; 23a+11 b; 23a+12b; 23a+13b; 23a+14b; 23a+15b;
23a+16b; 23a+17b; 23a+18b; 23a+19b; 23a+20b; 23a+21 b; 23a+22b;
23a+23b; 23a+24b; 23a+25b; 23a+26b; 23a+27b; 23a+28b; 23a+29b;
23a+30b; 23a+31 b; 23a+32b; 23a+33b; 23a+34b; 23a+35b; 23a+36b;
23a+37b; 23a+38b; 23a+39b; 23a+40b; 23a+41 b; 23a+42b; 23a+43b;
23a+44b; 23a+45b; 23a+46b; 23a+47b; 23a+48b; 23a+49b; 23a+50b;
23a+51 b; 23a+52b; 23a+53b; 23a+54b; 23a+55b; 23a+55b; 23a+57b;
23a+58b; 23a+59b; 23a+60b; 23a+61 b; 23a+62b; 23a+63b; 23a+64b;
23a+65b; 23a+66b; 23a+67b; 23a+68b; 23a+69b; 23a+70b; 23a+71 b;
23a+72b; 23a+73b; 23a+74b; 23a+75b; 23a+76b; 23a+77b; 23a+78b;
23a+79b; 23a+80b; 23a+81 b; 23a+82b; 23a+83b; 23a+84b; 23a+85b;
23a+86b; 23a+87b; 23a+88b; 23a+89b; 23a+90b; 23a+91 b; 23a+92b;
23a+93b; 23a+94b; 23a+95b; 23a+96b; 23a+97b; 24a+1 b; 24a + 2b; 24a + 3b;
24a+4b; 24a+5b; 24a+6b; 24a+7b; 24a+8b; 24a+9b; 24a+1 Ob; 24a+11 b;
24a+12b; 24a+13b; 24a+14b; 24a+15b; 24a+16b; 24a+17b; 24a+18b; ' 24a+19b; 24a+20b; 24a+21 b; 24a+22b; 24a+23b; 24a+24b; 24a+25b;
24a+26b; 24a+27b; 24a+28b; 24a+29b; 24a+30b; 24a+31 b; 24a+32b;
24a+33b; 24a+34b; 24a+35b; 24a+36b; 24a+37b; 24a+38b; 24a+39b;
24a+40b; 24a+41 b; 24a+42b; 24a+43b; 24a+44b; 24a+45b; 24a+46b;
24a+47b; 24a+48b; 24a+49b; 24a+50b; 24a+51 b; 24a+52b; 24a+53b;
24a+54b; 24a+55b; 24a+55b; 24a+57b; 24a+58b; 24a+59b; 24a+60b;
24a+61 b; 24a+62b; 24a+63b; 24a+64b; 24a+65b; 24a+66b; 24a+67b;
24a+68b; 24a+69b; 24a+70b; 24a+71 b; 24a+72b; 24a+73b; 24a+74b;
24a+75b; 24a+76b; 24a+77b; 24a+78b; 24a+79b; 24a+80b; 24a+81 b;

24a+82b; 24a+83b; 24a+84b; 24a+85b; 24a+86b; 24a+87b; 24a+88b;
24a+89b; 24a+90b; 24a+91 b; 24a+92b; 24a+93b; 24a+94b; 24a+95b;
24a+96b; 24a+97b; 25a+1 b; 25a + 2b; 25a + 3b; 25a+4b; 25a+5b; 25a+6b;
25a+7b; 25a+8b; 25a+9b; 25a+10b; 25a+11 b; 25a+12b; 25a+13b; 25a+14b;
25a+15b; 25a+16b; 25a+17b; 25a+18b; 25a+19b; 25a+20b; 25a+21 b;
25a+22b; 25a+23b; 25a+24b; 25a+25b; 25a+26b; 25a+27b; 25a+28b;
25a+29b; 25a+30b; 25a+31 b; 25a+32b; 25a+33b; 25a+34b; 25a+35b;
25a+36b; 25a+37b; 25a+38b; 25a+39b; 25a+40b; 25a+41 b; 25a+42b;
25a+43b; 25a+44b; 25a+45b; 25a+46b; 25a+47b; 25a+48b; 25a+49b;
25a+50b; 25a+51 b; 25a+52b; 25a+53b; 25a+54b; 25a+55b; 25a+55b;
25a+57b; 25a+58b; 25a+59b; 25a+60b; 25a+61 b; 25a+62b; 25a+63b;
25a+64b; 25a+65b; 25a+66b; 25a+67b; 25a+68b; 25a+69b; 25a+70b;
25a+71 b; 25a+72b; 25a+73b; 25a+74b; 25a+75b; 25a+76b; 25a+77b;
25a+78b; 25a+79b; 25a+80b; 25a+81 b; 25a+82b; 25a+83b; 25a+84b;
25a+85b; 25a+86b; 25a+87b; 25a+88b; 25a+89b; 25a+90b; 25a+91 b;
25a+92b; 25a+93b; 25a+94b; 25a+95b; 25a+96b; 25a+97b; 26a+1 b; 26a + 2b;
26a + 3b; 26a+4b; 26a+5b; 26a+6b; 26a+7b; 26a+8b; 26a+9b; 26a+10b;
26a+11 b; 26a+12b; 26a+13b; 26a+14b; 26a+15b; 26a+16b; 26a+17b;
26a+18b; 26a+19b; 26a+20b; 26a+21 b; 26a+22b; 26a+23b; 26a+24b;
26a+25b; 26a+26b; 26a+27b; 26a+28b; 26a+29b; 26a+30b; 26a+31 b;
26a+32b; 26a+33b; 26a+34b; 26a+35b; 26a+36b; 26a+37b; 26a+38b;
26a+39b; 26a+40b; 26a+41 b; 26a+42b; 26a+43b; 26a+44b; 26a+45b;
26a+46b; 26a+47b; 26a+48b; 26a+49b; 26a+50b; 26a+51 b; 26a+52b;
26a+53b; 26a+54b; 26a+55b; 26a+55b; 26a+57b; 26a+58b; 26a+59b;
26a+60b; 26a+61 b; 26a+62b; 26a+63b; 26a+64b; 26a+65b; 26a+66b;
26a+67b; 26a+68b; 26a+69b; 26a+70b; 26a+71 b; 26a+72b; 26a+73b;
26a+74b; 26a+75b; 26a+76b; 26a+77b; 26a+78b; 26a+79b; 26a+80b;
26a+81 b; 26a+82b; 26a+83b; 26a+84b; 26a+85b; 26a+86b; 26a+87b;
26a+88b; 26a+89b; 26a+90b; 26a+91 b; 26a+92b; 26a+93b; 26a+94b;
26a+95b; 26a+96b; 26a+97b; 27a+1 b; 27a + 2b; 27a + 3b; 27a+4b; 27a+5b;

27a+6b; 27a+7b; 27a+8b; 27a+9b; 27a+1 Ob; 27a+11 b; 27a+12b; 27a+13b;
27a+14b; 27a+15b; 27a+16b; 27a+17b; 27a+18b; 27a+19b; 27a+20b;
27a+21 b; 27a+22b; 27a+23b; 27a+24b; 27a+25b; 27a+26b; 27a+27b;
27a+28b; 27a+29b; 27a+30b; 27a+31 b; 27a+32b; 27a+33b; 27a+34b;
27a+35b; 27a+36b; 27a+37b; 27a+38b; 27a+39b; 27a+40b; 27a+41 b;
27a+42b; 27a+43b; 27a+44b; 27a+45b; 27a+46b; 27a+47b; 27a+48b;
27a+49b; 27a+50b; 27a+51 b; 27a+52b; 27a+53b; 27a+54b; 27a+55b;
27a+55b; 27a+57b; 27a+58b; 27a+59b; 27a+60b; 27a+61 b; 27a+62b;
27a+63b; 27a+64b; 27a+65b; 27a+66b; 27a+67b; 27a+68b; 27a+69b;
27a+70b; 27a+71 b; 27a+72b; 27a+73b; 27a+74b; 27a+75b; 27a+76b;
27a+77b; 27a+78b; 27a+79b; 27a+80b; 27a+81 b; 27a+82b; 27a+83b;
27a+84b; 27a+85b; 27a+86b; 27a+87b; 27a+88b; 27a+89b; 27a+90b;
27a+91 b; 27a+92b; 27a+93b; 27a+94b; 27a+95b; 27a+96b; 27a+97b; 28a+1 b;
28a + 2b; 28a + 3b; 28a+4b; 28a+5b; 28a+6b; 28a+7b; 28a+8b; 28a+9b;
28a+1 Ob; 28a+11 b; 28a+12b; 28a+13b; 28a+14b; 28a+15b; 28a+16b;
28a+17b; 28a+18b; 28a+19b; 28a+20b; 28a+21 b; 28a+22b; 28a+23b;
28a+24b; 28a+25b; 28a+26b; 28a+27b; 28a+28b; 28a+29b; 28a+30b;
28a+31 b; 28a+32b; 28a+33b; 28a+34b; 28a+35b; 28a+36b; 28a+37b;
28a+38b; 28a+39b; 28a+40b; 28a+41 b; 28a+42b; 28a+43b; 28a+44b;
28a+45b; 28a+46b; 28a+47b; 28a+48b; 28a+49b; 28a+50b; 28a+51 b;
28a+52b; 28a+53b; 28a+54b; 28a+55b; 28a+55b; 28a+57b; 28a+58b;
28a+59b; 28a+60b; 28a+61 b; 28a+62b; 28a+63b; 28a+64b; 28a+65b;
28a+66b; 28a+67b; 28a+68b; 28a+69b; 28a+70b; 28a+71 b; 28a+72b;
28a+73b; 28a+74b; 28a+75b; 28a+76b; 28a+77b; 28a+78b; 28a+79b;
28a+80b; 28a+81 b; 28a+82b; 28a+83b; 28a+84b; 28a+85b; 28a+86b;
28a+87b; 28a+88b; 28a+89b; 28a+90b; 28a+91 b; 28a+92b; 28a+93b;
28a+94b; 28a+95b; 28a+96b; 28a+97b; 29a+1 b; 29a + 2b; 29a + 3b; 29a+4b;
29a+5b; 29a+6b; 29a+7b; 29a+8b; 29a+9b; 29a+1 Ob; 29a+11 b; 29a+12b;
29a+13b; 29a+14b; 29a+15b; 29a+16b; 29a+17b; 29a+18b; 29a+19b;
29a+20b; 29a+21 b; 29a+22b; 29a+23b; 29a+24b; 29a+25b; 29a+26b;

29a+27b; 29a+28b; 29a+29b; 29a+30b; 29a+31 b; 29a+32b; 29a+33b;
29a+34b; 29a+35b; 29a+36b; 29a+37b; 29a+38b; 29a+39b; 29a+40b;
29a+41 b; 29a+42b; 29a+43b; 29a+44b; 29a+45b; 29a+46b; 29a+47b;
29a+48b; 29a+49b; 29a+50b; 29a+51 b; 29a+52b; 29a+53b; 29a+54b;
29a+55b; 29a+55b; 29a+57b; 29a+58b; 29a+59b; 29a+60b; 29a+61 b;
29a+62b; 29a+63b; 29a+64b; 29a+65b; 29a+66b; 29a+67b; 29a+68b;
29a+69b; 29a+70b; 29a+71 b; 29a+72b; 29a+73b; 29a+74b; 29a+75b;
29a+76b; 29a+77b; 29a+78b; 29a+79b; 29a+80b; 29a+81 b; 29a+82b;
29a+83b; 29a+84b; 29a+85b; 29a+86b; 29a+87b; 29a+88b; 29a+89b;
29a+90b; 29a+91 b; 29a+92b; 29a+93b; 29a+94b; 29a+95b; 29a+96b;
29a+97b; 30a+1 b; 30a + 2b; 30a + 3b; 30a+4b; 30a+5b; 30a+6b; 30a+7b;
30a+8b; 30a+9b; 30a+1 Ob; 30a+11 b; 30a+12b; 30a+13b; 30a+14b; 30a+15b;
30a+16b; 30a+17b; 30a+18b; 30a+19b; 30a+20b; 30a+21 b; 30a+22b;
30a+23b; 30a+24b; 30a+25b; 30a+26b; 30a+27b; 30a+28b; 30a+29b;
30a+30b; 30a+31 b; 30a+32b; 30a+33b; 30a+34b; 30a+35b; 30a+36b;
30a+37b; 30a+38b; 30a+39b; 30a+40b; 30a+41 b; 30a+42b; 30a+43b;
30a+44b; 30a+45b; 30a+46b; 30a+47b; 30a+48b; 30a+49b; 30a+50b;
30a+51 b; 30a+52b; 30a+53b; 30a+54b; 30a+55b; 30a+55b; 30a+57b;
30a+58b; 30a+59b; 30a+60b; 30a+61 b; 30a+62b; 30a+63b; 30a+64b;
30a+65b; 30a+66b; 30a+67b; 30a+68b; 30a+69b; 30a+70b; 30a+71 b;
30a+72b; 30a+73b; 30a+74b; 30a+75b; 30a+76b; 30a+77b; 30a+78b;
30a+79b; 30a+80b; 30a+81 b; 30a+82b; 30a+83b; 30a+84b; 30a+85b;
30a+86b; 30a+87b; 30a+88b; 30a+89b; 30a+90b; 30a+91 b; 30a+92b;
30a+93b; 30a+94b; 30a+95b; 30a+96b; 30a+97b; 31 a+1 b; 31 a + 2b; 31 a + 3b;
31 a+4b; 31 a+5b; 31 a+6b; 31 a+7b; 31 a+8b; 31 a+9b; 31 a+1 Ob; 31 a+11 b;
31 a+12b; 31 a+13b; 31 a+14b; 31 a+15b; 31 a+16b; 31 a+17b; 31 a+18b;
31 a+19b; 31 a+20b; 31 a+21 b; 31 a+22b; 31 a+23b; 31 a+24b; 31 a+25b;
31 a+26b; 31 a+27b; 31 a+28b; 31 a+29b; 31 a+30b; 31 a+31 b; 31 a+32b;
31 a+33b; 31 a+34b; 31 a+35b; 31 a+36b; 31 a+37b; 31 a+38b; 31 a+39b;
31 a+40b; 31 a+41 b; 31 a+42b; 31 a+43b; 31 a+44b; 31 a+45b; 31 a+46b;

31 a+47b; 31 a+48b; 31 a+49b; 31 a+50b; 31 a+51 b; 31 a+52b; 31 a+53b;
31 a+54b; 31 a+55b; 31 a+55b; 31 a+57b; 31 a+58b; 31 a+59b; 31 a+60b;
31 a+61 b; 31 a+62b; 31 a+63b; 31 a+64b; 31 a+65b; 31 a+66b; 31 a+67b;
31 a+68b; 31 a+69b; 31 a+70b; 31 a+71 b; 31 a+72b; 31 a+73b; 31 a+74b;
31 a+75b; 31 a+76b; 31 a+77b; 31 a+78b; 31 a+79b; 31 a+80b; 31 a+81 b;
31 a+82b; 31 a+83b; 31 a+84b; 31 a+85b; 31 a+86b; 31 a+87b; 31 a+88b;
31 a+89b; 31 a+90b; 31 a+91 b; 31 a+92b; 31 a+93b; 31 a+94b; 31 a+95b;
31 a+96b; 31 a+97b; 32a+1 b; 32a + 2b; 32a + 3b; 32a+4b; 32a+5b; 32a+6b;
32a+7b; 32a+8b; 32a+9b; 32a+10b; 32a+11 b; 32a+12b; 32a+13b; 32a+14b;
32a+15b; 32a+16b; 32a+17b; 32a+18b; 32a+19b; 32a+20b; 32a+21 b;
32a+22b; 32a+23b; 32a+24b; 32a+25b; 32a+26b; 32a+27b; 32a+28b;
32a+29b; 32a+30b; 32a+31 b; 32a+32b; 32a+33b; 32a+34b; 32a+35b;
32a+36b; 32a+37b; 32a+38b; 32a+39b; 32a+40b; 32a+41 b; 32a+42b;
32a+43b; 32a+44b; 32a+45b; 32a+46b; 32a+47b; 32a+48b; 32a+49b;
32a+50b; 32a+51 b; 32a+52b; 32a+53b; 32a+54b; 32a+55b; 32a+55b;
32a+57b; 32a+58b; 32a+59b; 32a+60b; 32a+61 b; 32a+62b; 32a+63b;
32a+64b; 32a+65b; 32a+66b; 32a+67b; 32a+68b; 32a+69b; 32a+70b;
32a+71 b; 32a+72b; 32a+73b; 32a+74b; 32a+75b; 32a+76b; 32a+77b;
32a+78b; 32a+79b; 32a+80b; 32a+81 b; 32a+82b; 32a+83b; 32a+84b;
32a+85b; 32a+86b; 32a+87b; 32a+88b; 32a+89b; 32a+90b; 32a+91 b;
32a+92b; 32a+93b; 32a+94b; 32a+95b; 32a+96b; 32a+97b; 33a+1 b; 33a + 2b;
33a + 3b; 33a+4b; 33a+5b; 33a+6b; 33a+7b; 33a+8b; 33a+9b; 33a+10b;
33a+11 b; 33a+12b; 33a+13b; 33a+14b; 33a+15b; 33a+16b; 33a+17b;
33a+18b; 33a+19b; 33a+20b; 33a+21 b; 33a+22b; 33a+23b; 33a+24b;
33a+25b; 33a+26b; 33a+27b; 33a+28b; 33a+29b; 33a+30b; 33a+31 b;
33a+32b; 33a+33b; 33a+34b; 33a+35b; 33a+36b; 33a+37b; 33a+38b;
33a+39b; 33a+40b; 33a+41 b; 33a+42b; 33a+43b; 33a+44b; 33a+45b;
33a+46b; 33a+47b; 33a+48b; 33a+49b; 33a+50b; 33a+51 b; 33a+52b;
33a+53b; 33a+54b; 33a+55b; 33a+55b; 33a+57b; 33a+58b; 33a+59b;
33a+60b; 33a+61 b; 33a+62b; 33a+63b; 33a+64b; 33a+65b; 33a+66b;

33a+67b; 33a+68b; 33a+69b; 33a+70b; 33a+71 b; 33a+72b; 33a+73b;
33a+74b; 33a+75b; 33a+76b; 33a+77b; 33a+78b; 33a+79b; 33a+80b;
33a+81 b; 33a+82b; 33a+83b; 33a+84b; 33a+85b; 33a+86b; 33a+87b;
33a+88b; 33a+89b; 33a+90b; 33a+91 b; 33a+92b; 33a+93b; 33a+94b;
33a+95b; 33a+96b; 33a+97b; 34a+1 b; 34a + 2b; 34a + 3b; 34a+4b; 34a+5b;
34a+6b; 34a+7b; 34a+8b; 34a+9b; 34a+10b; 34a+11 b; 34a+12b; 34a+13b;
34a+14b; 34a+15b; 34a+16b; 34a+17b; 34a+18b; 34a+19b; 34a+20b;
34a+21 b; 34a+22b; 34a+23b; 34a+24b; 34a+25b; 34a+26b; 34a+27b;
34a+28b; 34a+29b; 34a+30b; 34a+31 b; 34a+32b; 34a+33b; 34a+34b;
34a+35b; 34a+36b; 34a+37b; 34a+38b; 34a+39b; 34a+40b; 34a+41 b;
34a+42b; 34a+43b; 34a+44b; 34a+45b; 34a+46b; 34a+47b; 34a+48b;
34a+49b; 34a+50b; 34a+51 b; 34a+52b; 34a+53b; 34a+54b; 34a+55b;
34a+55b; 34a+57b; 34a+58b; 34a+59b; 34a+60b; 34a+61 b; 34a+62b;
34a+63b; 34a+64b; 34a+65b; 34a+66b; 34a+67b; 34a+68b; 34a+69b;
34a+70b; 34a+71 b; 34a+72b; 34a+73b; 34a+74b; 34a+75b; 34a+76b;
34a+77b; 34a+78b; 34a+79b; 34a+80b; 34a+81 b; 34a+82b; 34a+83b;
34a+84b; 34a+85b; 34a+86b; 34a+87b; 34a+88b; 34a+89b; 34a+90b;
34a+91 b; 34a+92b; 34a+93b; 34a+94b; 34a+95b; 34a+96b; 34a+97b; 35a+1 b;
35a + 2b; 35a + 3b; 35a+4b; 35a+5b; 35a+6b; 35a+7b; 35a+8b; 35a+9b;
35a+1 Ob; 35a+11 b; 35a+12b; 35a+13b; 35a+14b; 35a+15b; 35a+16b;
35a+17b; 35a+18b; 35a+19b; 35a+20b; 35a+21 b; 35a+22b; 35a+23b;
35a+24b; 35a+25b; 35a+26b; 35a+27b; 35a+28b; 35a+29b; 35a+30b;
35a+31 b; 35a+32b; 35a+33b; 35a+34b; 35a+35b; 35a+36b; 35a+37b;
35a+38b; 35a+39b; 35a+40b; 35a+41 b; 35a+42b; 35a+43b; 35a+44b;
35a+45b; 35a+46b; 35a+47b; 35a+48b; 35a+49b; 35a+50b; 35a+51 b;
35a+52b; 35a+53b; 35a+54b; 35a+55b; 35a+55b; 35a+57b; 35a+58b;
35a+59b; 35a+60b; 35a+61 b; 35a+62b; 35a+63b; 35a+64b; 35a+65b;
35a+66b; 35a+67b; 35a+68b; 35a+69b; 35a+70b; 35a+71 b; 35a+72b;
35a+73b; 35a+74b; 35a+75b; 35a+76b; 35a+77b; 35a+78b; 35a+79b;
35a+80b; 35a+81 b; 35a+82b; 35a+83b; 35a+84b; 35a+85b; 35a+86b;

35a+87b; 35a+88b; 35a+89b; 35a+90b; 35a+91 b; 35a+92b; 35a+93b;
35a+94b; 35a+95b; 35a+96b; 35a+97b; 36a+1 b; 36a + 2b; 36a + 3b; 36a+4b;
36a+5b; 36a+6b; 36a+7b; 36a+8b; 36a+9b; 36a+1 Ob; 36a+11 b; 36a+12b;
36a+13b; 36a+14b; 36a+15b; 36a+16b; 36a+17b; 36a+18b; 36a+19b;
36a+20b; 36a+21 b; 36a+22b; 36a+23b; 36a+24b; 36a+25b; 36a+26b;
36a+27b; 36a+28b; 36a+29b; 36a+30b; 36a+31 b; 36a+32b; 36a+33b;
36a+34b; 36a+35b; 36a+36b; 36a+37b; 36a+38b; 36a+39b; 36a+40b;
36a+41 b; 36a+42b; 36a+43b; 36a+44b; 36a+45b; 36a+46b; 36a+47b;
36a+48b; 36a+49b; 36a+50b; 36a+51 b; 36a+52b; 36a+53b; 36a+54b;
36a+55b; 36a+55b; 36a+57b; 36a+58b; 36a+59b; 36a+60b; 36a+61 b;
36a+62b; 36a+63b; 36a+64b; 36a+65b; 36a+66b; 36a+67b; 36a+68b;
36a+69b; 36a+70b; 36a+71 b; 36a+72b; 36a+73b; 36a+74b; 36a+75b;
36a+76b; 36a+77b; 36a+78b; 36a+79b; 36a+80b; 36a+81 b; 36a+82b;
36a+83b; 36a+84b; 36a+85b; 36a+86b; 36a+87b; 36a+88b; 36a+89b;
36a+90b; 36a+91 b; 36a+92b; 36a+93b; 36a+94b; 36a+95b; 36a+96b;
36a+97b; 37a+1 b; 37a + 2b; 37a + 3b; 37a+4b; 37a+5b; 37a+6b; 37a+7b;
37a+8b; 37a+9b; 37a+1 Ob; 37a+11 b; 37a+12b; 37a+13b; 37a+14b; 37a+15b;
37a+16b; 37a+17b; 37a+18b; 37a+19b; 37a+20b; 37a+21 b; 37a+22b;
37a+23b; 37a+24b; 37a+25b; 37a+26b; 37a+27b; 37a+28b; 37a+29b;
37a+30b; 37a+31 b; 37a+32b; 37a+33b; 37a+34b; 37a+35b; 37a+36b;
37a+37b; 37a+38b; 37a+39b; 37a+40b; 37a+41 b; 37a+42b; 37a+43b;
37a+44b; 37a+45b; 37a+46b; 37a+47b; 37a+48b; 37a+49b; 37a+50b;
37a+51 b; 37a+52b; 37a+53b; 37a+54b; 37a+55b; 37a+55b; 37a+57b;
37a+58b; 37a+59b; 37a+60b; 37a+61 b; 37a+62b; 37a+63b; 37a+64b;
37a+65b; 37a+66b; 37a+67b; 37a+68b; 37a+69b; 37a+70b; 37a+71 b;
37a+72b; 37a+73b; 37a+74b; 37a+75b; 37a+76b; 37a+77b; 37a+78b;
37a+79b; 37a+80b; 37a+81 b; 37a+82b; 37a+83b; 37a+84b; 37a+85b;
37a+86b; 37a+87b; 37a+88b; 37a+89b; 37a+90b; 37a+91 b; 37a+92b;
37a+93b; 37a+94b; 37a+95b; 37a+96b; 37a+97b; 38a+1 b; 38a + 2b; 38a + 3b;
38a+4b; 38a+5b; 38a+6b; 38a+7b; 38a+8b; 38a+9b; 38a+1 Ob; 38a+11 b;

38a+12b; 38a+13b; 38a+14b; 38a+15b; 38a+16b; 38a+17b; 38a+18b;
38a+19b; 38a+20b; 38a+21 b; 38a+22b; 38a+23b; 38a+24b; 38a+25b;
38a+26b; 38a+27b; 38a+28b; 38a+29b; 38a+30b; 38a+31 b; 38a+32b;
38a+33b; 38a+34b; 38a+35b; 38a+36b; 38a+37b; 38a+38b; 38a+39b;
38a+40b; 38a+41 b; 38a+42b; 38a+43b; 38a+44b; 38a+45b; 38a+46b;
38a+47b; 38a+48b; 38a+49b; 38a+50b; 38a+51 b; 38a+52b; 38a+53b;
38a+54b; 38a+55b; 38a+55b; 38a+57b; 38a+58b; 38a+59b; 38a+60b;
38a+61 b; 38a+62b; 38a+63b; 38a+64b; 38a+65b; 38a+66b; 38a+67b;
38a+68b; 38a+69b; 38a+70b; 38a+71 b; 38a+72b; 38a+73b; 38a+74b;
38a+75b; 38a+76b; 38a+77b; 38a+78b; 38a+79b; 38a+80b; 38a+81 b;
38a+82b; 38a+83b; 38a+84b; 38a+85b; 38a+86b; 38a+87b; 38a+88b;
38a+89b; 38a+90b; 38a+91 b; 38a+92b; 38a+93b; 38a+94b; 38a+95b;
38a+96b; 38a+97b; 39a+1 b; 39a + 2b; 39a + 3b; 39a+4b; 39a+5b; 39a+6b;
39a+7b; 39a+8b; 39a+9b; 39a+1 Ob; 39a+11 b; 39a+12b; 39a+13b; 39a+14b;
39a+15b; 39a+16b; 39a+17b; 39a+18b; 39a+19b; 39a+20b; 39a+21 b;
39a+22b; 39a+23b; 39a+24b; 39a+25b; 39a+26b; 39a+27b; 39a+28b;
39a+29b; 39a+30b; 39a+31 b; 39a+32b; 39a+33b; 39a+34b; 39a+35b;
39a+36b; 39a+37b; 39a+38b; 39a+39b; 39a+40b; 39a+41 b; 39a+42b;
39a+43b; 39a+44b; 39a+45b; 39a+46b; 39a+47b; 39a+48b; 39a+49b;
39a+50b; 39a+51 b; 39a+52b; 39a+53b; 39a+54b; 39a+55b; 39a+55b;
39a+57b; 39a+58b; 39a+59b; 39a+60b; 39a+61 b; 39a+62b; 39a+63b;
39a+64b; 39a+65b; 39a+66b; 39a+67b; 39a+68b; 39a+69b; 39a+70b;
39a+71 b; 39a+72b; 39a+73b; 39a+74b; 39a+75b; 39a+76b; 39a+77b;
39a+78b; 39a+79b; 39a+80b; 39a+81 b; 39a+82b; 39a+83b; 39a+84b;
39a+85b; 39a+86b; 39a+87b; 39a+88b; 39a+89b; 39a+90b; 39a+91 b;
39a+92b; 39a+93b; 39a+94b; 39a+95b; 39a+96b; 39a+97b; 40a+1 b; 40a + 2b;
40a + 3b; 40a+4b; 40a+5b; 40a+6b; 40a+7b; 40a+8b; 40a+9b; 40a+10b;
40a+11 b; 40a+12b; 40a+13b; 40a+14b; 40a+15b; 40a+16b; 40a+17b;
40a+18b; 40a+19b; 40a+20b; 40a+21 b; 40a+22b; 40a+23b; 40a+24b;
40a+25b; 40a+26b; 40a+27b; 40a+28b; 40a+29b; 40a+30b; 40a+31 b;

40a+32b; 40a+33b; 40a+34b; 40a+35b; 40a+36b; 40a+37b; 40a+38b;
40a+39b; 40a+40b; 40a+41 b; 40a+42b; 40a+43b; 40a+44b; 40a+45b;
40a+46b; 40a+47b; 40a+48b; 40a+49b; 40a+50b; 40a+51 b; 40a+52b;
40a+53b; 40a+54b; 40a+55b; 40a+55b; 40a+57b; 40a+58b; 40a+59b;
40a+60b; 40a+61 b; 40a+62b; 40a+63b; 40a+64b; 40a+65b; 40a+66b;
40a+67b; 40a+68b; 40a+69b; 40a+70b; 40a+71 b; 40a+72b; 40a+73b;
40a+74b; 40a+75b; 40a+76b; 40a+77b; 40a+78b; 40a+79b; 40a+80b;
40a+81 b; 40a+82b; 40a+83b; 40a+84b; 40a+85b; 40a+86b; 40a+87b;
40a+88b; 40a+89b; 40a+90b; 40a+91 b; 40a+92b; 40a+93b; 40a+94b;
40a+95b; 40a+96b; 40a+97b; 41 a+1 b; 41 a + 2b; 41 a + 3b; 41 a+4b; 41 a+5b;
41 a+6b; 41 a+7b; 41 a+8b; 41 a+9b; 41 a+1 Ob; 41 a+11 b; 41 a+12b; 41 a+13b;
41 a+14b; 41 a+15b; 41 a+16b; 41 a+17b; 41 a+18b; 41 a+19b; 41 a+20b;
41 a+21 b; 41 a+22b; 41 a+23b; 41 a+24b; 41 a+25b; 41 a+26b; 41 a+27b;
41 a+28b; 41 a+29b; 41 a+30b; 41 a+31 b; 41 a+32b; 41 a+33b; 41 a+34b;
41 a+35b; 41 a+36b; 41 a+37b; 41 a+38b; 41 a+39b; 41 a+40b; 41 a+41 b;
41 a+42b; 41 a+43b; 41 a+44b; 41 a+45b; 41 a+46b; 41 a+47b; 41 a+48b;
41 a+49b; 41 a+50b; 41 a+51 b; 41 a+52b; 41 a+53b; 41 a+54b; 41 a+55b;
41 a+55b; 41 a+57b; 41 a+58b; 41 a+59b; 41 a+60b; 41 a+61 b; 41 a+62b;
41 a+63b; 41 a+64b; 41 a+65b; 41 a+66b; 41 a+67b; 41 a+68b; 41 a+69b;
41 a+70b; 41 a+71 b; 41 a+72b; 41 a+73b; 41 a+74b; 41 a+75b; 41 a+76b;
41 a+77b; 41 a+78b; 41 a+79b; 41 a+80b; 41 a+81 b; 41 a+82b; 41 a+83b;
41 a+84b; 41 a+85b; 41 a+86b; 41 a+87b; 41 a+88b; 41 a+89b; 41 a+90b;
41 a+91 b; 41 a+92b; 41 a+93b; 41 a+94b; 41 a+95b; 41 a+96b; 41 a+97b; 42a+1 b;
42a + 2b; 42a + 3b; 42a+4b; 42a+5b; 42a+6b; 42a+7b; 42a+8b; 42a+9b;
42a+1 Ob; 42a+11 b; 42a+12b; 42a+13b; 42a+14b; 42a+15b; 42a+16b;
42a+17b; 42a+18b; 42a+19b; 42a+20b; 42a+21 b; 42a+22b; 42a+23b;
42a+24b; 42a+25b; 42a+26b; 42a+27b; 42a+28b; 42a+29b; 42a+30b;
42a+31 b; 42a+32b; 42a+33b; 42a+34b; 42a+35b; 42a+36b; 42a+37b;
42a+38b; 42a+39b; 42a+40b; 42a+41 b; 42a+42b; 42a+43b; 42a+44b;
42a+45b; 42a+46b; 42a+47b; 42a+48b; 42a+49b; 42a+50b; 42a+51 b;

42a+52b; 42a+53b; 42a+54b; 42a+55b; 42a+55b; 42a+57b; 42a+58b;
42a+59b; 42a+60b; 42a+61 b; 42a+62b; 42a+63b; 42a+64b; 42a+65b;
42a+66b; 42a+67b; 42a+68b; 42a+69b; 42a+70b; 42a+71 b; 42a+72b;
42a+73b; 42a+74b; 42a+75b; 42a+76b; 42a+77b; 42a+78b; 42a+79b;
42a+80b; 42a+81 b; 42a+82b; 42a+83b; 42a+84b; 42a+85b; 42a+86b;
42a+87b; 42a+88b; 42a+89b; 42a+90b; 42a+91 b; 42a+92b; 42a+93b;
42a+94b; 42a+95b; 42a+96b; 42a+97b; 43a+1 b; 43a + 2b; 43a + 3b; 43a+4b;
43a+5b; 43a+6b; 43a+7b; 43a+8b; 43a+9b; 43a+1 Ob; 43a+11 b; 43a+12b;
43a+13b; 43a+14b; 43a+15b; 43a+16b; 43a+17b; 43a+18b; 43a+19b;
43a+20b; 43a+21 b; 43a+22b; 43a+23b; 43a+24b; 43a+25b; 43a+26b;
43a+27b; 43a+28b; 43a+29b; 43a+30b; 43a+31 b; 43a+32b; 43a+33b;
43a+34b; 43a+35b; 43a+36b; 43a+37b; 43a+38b; 43a+39b; 43a+40b;
43a+41 b; 43a+42b; 43a+43b; 43a+44b; 43a+45b; 43a+46b; 43a+47b;
43a+48b; 43a+49b; 43a+50b; 43a+51 b; 43a+52b; 43a+53b; 43a+54b;
43a+55b; 43a+55b; 43a+57b; 43a+58b; 43a+59b; 43a+60b; 43a+61 b;
43a+62b; 43a+63b; 43a+64b; 43a+65b; 43a+66b; 43a+67b; 43a+68b;
43a+69b; 43a+70b; 43a+71 b; 43a+72b; 43a+73b; 43a+74b; 43a+75b;
43a+76b; 43a+77b; 43a+78b; 43a+79b; 43a+80b; 43a+81 b; 43a+82b;
43a+83b; 43a+84b; 43a+85b; 43a+86b; 43a+87b; 43a+88b; 43a+89b;
43a+90b; 43a+91 b; 43a+92b; 43a+93b; 43a+94b; 43a+95b; 43a+96b;
43a+97b; 44a+1 b; 44a + 2b; 44a + 3b; 44a+4b; 44a+5b; 44a+6b; 44a+7b;
44a+8b; 44a+9b; 44a+1 Ob; 44a+11 b; 44a+12b; 44a+13b; 44a+14b; 44a+15b;
44a+16b; 44a+17b; 44a+18b; 44a+19b; 44a+20b; 44a+21 b; 44a+22b;
44a+23b; 44a+24b; 44a+25b; 44a+26b; 44a+27b; 44a+28b; 44a+29b;
44a+30b; 44a+31 b; 44a+32b; 44a+33b; 44a+34b; 44a+35b; 44a+36b;
44a+37b; 44a+38b; 44a+39b; 44a+40b; 44a+41 b; 44a+42b; 44a+43b;
44a+44b; 44a+45b; 44a+46b; 44a+47b; 44a+48b; 44a+49b; 44a+50b;
44a+51 b; 44a+52b; 44a+53b; 44a+54b; 44a+55b; 44a+55b; 44a+57b;
44a+58b; 44a+59b; 44a+60b; 44a+61 b; 44a+62b; 44a+63b; 44a+64b;
44a+65b; 44a+66b; 44a+67b; 44a+68b; 44a+69b; 44a+70b; 44a+71 b;

44a+72b; 44a+73b; 44a+74b; 44a+75b; 44a+76b; 44a+77b; 44a+78b;
44a+79b; 44a+80b; 44a+81 b; 44a+82b; 44a+83b; 44a+84b; 44a+85b;
44a+86b; 44a+87b; 44a+88b; 44a+89b; 44a+90b; 44a+91 b; 44a+92b;
44a+93b; 44a+94b; 44a+95b; 44a+96b; 44a+97b; 45a+1 b; 45a + 2b; 45a + 3b;
45a+4b; 45a+5b; 45a+6b; 45a+7b; 45a+8b; 45a+9b; 45a+1 Ob; 45a+11 b;
45a+12b; 45a+13b; 45a+14b; 45a+15b; 45a+16b; 45a+17b; 45a+18b;
45a+19b; 45a+20b; 45a+21 b; 45a+22b; 45a+23b; 45a+24b; 45a+25b;
45a+26b; 45a+27b; 45a+28b; 45a+29b; 45a+30b; 45a+31 b; 45a+32b;
45a+33b; 45a+34b; 45a+35b; 45a+36b; 45a+37b; 45a+38b; 45a+39b;
45a+40b; 45a+41 b; 45a+42b; 45a+43b; 45a+44b; 45a+45b; 45a+46b;
45a+47b; 45a+48b; 45a+49b; 45a+50b; 45a+51 b; 45a+52b; 45a+53b;
45a+54b; 45a+55b; 45a+55b; 45a+57b; 45a+58b; 45a+59b; 45a+60b;
45a+61 b; 45a+62b; 45a+63b; 45a+64b; 45a+65b; 45a+66b; 45a+67b;
45a+68b; 45a+69b; 45a+70b; 45a+71 b; 45a+72b; 45a+73b; 45a+74b;
45a+75b; 45a+76b; 45a+77b; 45a+78b; 45a+79b; 45a+80b; 45a+81 b;
45a+82b; 45a+83b; 45a+84b; 45a+85b; 45a+86b; 45a+87b; 45a+88b;
45a+89b; 45a+90b; 45a+91 b; 45a+92b; 45a+93b; 45a+94b; 45a+95b;
45a+96b; 45a+97b; 46a+1 b; 46a + 2b; 46a + 3b; 46a+4b; 46a+5b; 46a+6b;
46a+7b; 46a+8b; 46a+9b; 46a+1 Ob; 46a+11 b; 46a+12b; 46a+13b; 46a+14b;
46a+15b; 46a+16b; 46a+17b; 46a+18b; 46a+19b; 46a+20b; 46a+21 b;
46a+22b; 46a+23b; 46a+24b; 46a+25b; 46a+26b; 46a+27b; 46a+28b;
46a+29b; 46a+30b; 46a+31 b; 46a+32b; 46a+33b; 46a+34b; 46a+35b;
46a+36b; 46a+37b; 46a+38b; 46a+39b; 46a+40b; 46a+41 b; 46a+42b;
46a+43b; 46a+44b; 46a+45b; 46a+46b; 46a+47b; 46a+48b; 46a+49b;
46a+50b; 46a+51 b; 46a+52b; 46a+53b; 46a+54b; 46a+55b; 46a+55b;
46a+57b; 46a+58b; 46a+59b; 46a+60b; 46a+61 b; 46a+62b; 46a+63b;
46a+64b; 46a+65b; 46a+66b; 46a+67b; 46a+68b; 46a+69b; 46a+70b;
46a+71 b; 46a+72b; 46a+73b; 46a+74b; 46a+75b; 46a+76b; 46a+77b;
46a+78b; 46a+79b; 46a+80b; 46a+81 b; 46a+82b; 46a+83b; 46a+84b;
46a+85b; 46a+86b; 46a+87b; 46a+88b; 46a+89b; 46a+90b; 46a+91 b;

46a+92b; 46a+93b; 46a+94b; 46a+95b; 46a+96b; 46a+97b; 47a+1 b; 47a + 2b;
47a + 3b; 47a+4b; 47a+5b; 47a+6b; 47a+7b; 47a+8b; 47a+9b; 47a+10b;
47a+11 b; 47a+12b; 47a+13b; 47a+14b; 47a+15b; 47a+16b; 47a+17b;
47a+18b; 47a+19b; 47a+20b; 47a+21 b; 47a+22b; 47a+23b; 47a+24b;
47a+25b; 47a+26b; 47a+27b; 47a+28b; 47a+29b; 47a+30b; 47a+31 b;
47a+32b; 47a+33b; 47a+34b; 47a+35b; 47a+36b; 47a+37b; 47a+38b;
47a+39b; 47a+40b; 47a+41 b; 47a+42b; 47a+43b; 47a+44b; 47a+45b;
47a+46b; 47a+47b; 47a+48b; 47a+49b; 47a+50b; 47a+51 b; 47a+52b;
47a+53b; 47a+54b; 47a+55b; 47a+55b; 47a+57b; 47a+58b; 47a+59b;
47a+60b; 47a+61 b; 47a+62b; 47a+63b; 47a+64b; 47a+65b; 47a+66b;
47a+67b; 47a+68b; 47a+69b; 47a+70b; 47a+71 b; 47a+72b; 47a+73b;
47a+74b; 47a+75b; 47a+76b; 47a+77b; 47a+78b; 47a+79b; 47a+80b;
47a+81 b; 47a+82b; 47a+83b; 47a+84b; 47a+85b; 47a+86b; 47a+87b;
47a+88b; 47a+89b; 47a+90b; 47a+91 b; 47a+92b; 47a+93b; 47a+94b;
47a+95b; 47a+96b; 47a+97b; 48a+1 b; 48a + 2b; 48a + 3b; 48a+4b; 48a+5b;
48a+6b; 48a+7b; 48a+8b; 48a+9b; 48a+10b; 48a+11 b; 48a+12b; 48a+13b;
48a+14b; 48a+15b; 48a+16b; 48a+17b; 48a+18b; 48a+19b; 48a+20b;
48a+21 b; 48a+22b; 48a+23b; 48a+24b; 48a+25b; 48a+26b; 48a+27b;
48a+28b; 48a+29b; 48a+30b; 48a+31 b; 48a+32b; 48a+33b; 48a+34b;
48a+35b; 48a+36b; 48a+37b; 48a+38b; 48a+39b; 48a+40b; 48a+41 b;
48a+42b; 48a+43b; 48a+44b; 48a+45b; 48a+46b; 48a+47b; 48a+48b;
48a+49b; 48a+50b; 48a+51 b; 48a+52b; 48a+53b; 48a+54b; 48a+55b;
48a+55b; 48a+57b; 48a+58b; 48a+59b; 48a+60b; 48a+61 b; 48a+62b;
48a+63b; 48a+64b; 48a+65b; 48a+66b; 48a+67b; 48a+68b; 48a+69b;
48a+70b; 48a+71 b; 48a+72b; 48a+73b; 48a+74b; 48a+75b; 48a+76b;
48a+77b; 48a+78b; 48a+79b; 48a+80b; 48a+81 b; 48a+82b; 48a+83b;
48a+84b; 48a+85b; 48a+86b; 48a+87b; 48a+88b; 48a+89b; 48a+90b;
48a+91 b; 48a+92b; 48a+93b; 48a+94b; 48a+95b; 48a+96b; 48a+97b; 49a+1 b;
49a + 2b; 49a + 3b; 49a+4b; 49a+5b; 49a+6b; 49a+7b; 49a+8b; 49a+9b;
49a+1 Ob; 49a+11 b; 49a+12b; 49a+13b; 49a+14b; 49a+15b; 49a+16b;

49a+17b; 49a+18b; 49a+19b; 49a+20b; 49a+21 b; 49a+22b; 49a+23b;
49a+24b; 49a+25b; 49a+26b; 49a+27b; 49a+28b; 49a+29b; 49a+30b;
49a+31 b; 49a+32b; 49a+33b; 49a+34b; 49a+35b; 49a+36b; 49a+37b;
49a+38b; 49a+39b; 49a+40b; 49a+41 b; 49a+42b; 49a+43b; 49a+44b;
49a+45b; 49a+46b; 49a+47b; 49a+48b; 49a+49b; 49a+50b; 49a+51 b;
49a+52b; 49a+53b; 49a+54b; 49a+55b; 49a+55b; 49a+57b; 49a+58b;
49a+59b; 49a+60b; 49a+61 b; 49a+62b; 49a+63b; 49a+64b; 49a+65b;
49a+66b; 49a+67b; 49a+68b; 49a+69b; 49a+70b; 49a+71 b; 49a+72b;
49a+73b; 49a+74b; 49a+75b; 49a+76b; 49a+77b; 49a+78b; 49a+79b;
49a+80b; 49a+81 b; 49a+82b; 49a+83b; 49a+84b; 49a+85b; 49a+86b;
49a+87b; 49a+88b; 49a+89b; 49a+90b; 49a+91 b; 49a+92b; 49a+93b;
49a+94b; 49a+95b; 49a+96b; 49a+97b; 50a+1 b; 50a + 2b; 50a + 3b; 50a+4b;
50a+5b; 50a+6b; 50a+7b; 50a+8b; 50a+9b; 50a+1 Ob; 50a+11 b; 50a+12b;
50a+13b; 50a+14b; 50a+15b; 50a+16b; 50a+17b; 50a+18b; 50a+19b;
50a+20b; 50a+21 b; 50a+22b; 50a+23b; 50a+24b; 50a+25b; 50a+26b;
50a+27b; 50a+28b; 50a+29b; 50a+30b; 50a+31 b; 50a+32b; 50a+33b;
50a+34b; 50a+35b; 50a+36b; 50a+37b; 50a+38b; 50a+39b; 50a+40b;
50a+41 b; 50a+42b; 50a+43b; 50a+44b; 50a+45b; 50a+46b; 50a+47b;
50a+48b; 50a+49b; 50a+50b; 50a+51 b; 50a+52b; 50a+53b; 50a+54b;
50a+55b; 50a+55b; 50a+57b; 50a+58b; 50a+59b; 50a+60b; 50a+61 b;
50a+62b; 50a+63b; 50a+64b; 50a+65b; 50a+66b; 50a+67b; 50a+68b;
50a+69b; 50a+70b; 50a+71 b; 50a+72b; 50a+73b; 50a+74b; 50a+75b;
50a+76b; 50a+77b; 50a+78b; 50a+79b; 50a+80b; 50a+81 b; 50a+82b;
50a+83b; 50a+84b; 50a+85b; 50a+86b; 50a+87b; 50a+88b; 50a+89b;
50a+90b; 50a+91 b; 50a+92b; 50a+93b; 50a+94b; 50a+95b; 50a+96b;
50a+97b; 51 a+1 b; 51 a + 2b; 51 a + 3b; 51 a+4b; 51 a+5b; 51 a+6b; 51 a+7b;
51 a+8b; 51 a+9b; 51 a+1 Ob; 51 a+11 b; 51 a+12b; 51 a+13b; 51 a+14b; 51 a+15b;
51 a+16b; 51 a+17b; 51 a+18b; 51 a+19b; 51 a+20b; 51 a+21 b; 51 a+22b;
51 a+23b; 51 a+24b; 51 a+25b; 51 a+26b; 51 a+27b; 51 a+28b; 51 a+29b;
51 a+30b; 51 a+31 b; 51 a+32b; 51 a+33b; 51 a+34b; 51 a+35b; 51 a+36b;

51 a+37b; 51 a+38b; 51 a+39b; 51 a+40b; 51 a+41 b; 51 a+42b; 51 a+43b;
51 a+44b; 51 a+45b; 51 a+46b; 51 a+47b; 51 a+48b; 51 a+49b; 51 a+50b;
51 a+51 b; 51 a+52b; 51 a+53b; 51 a+54b; 51 a+55b; 51 a+55b; 51 a+57b;
51 a+58b; 51 a+59b; 51 a+60b; 51 a+61 b; 51 a+62b; 51 a+63b; 51 a+64b;
51 a+65b; 51 a+66b; 51 a+67b; 51 a+68b; 51 a+69b; 51 a+70b; 51 a+71 b;
51 a+72b; 51 a+73b; 51 a+74b; 51 a+75b; 51 a+76b; 51 a+77b; 51 a+78b;
51 a+79b; 51 a+80b; 51 a+81 b; 51 a+82b; 51 a+83b; 51 a+84b; 51 a+85b;
51 a+86b; 51 a+87b; 51 a+88b; 51 a+89b; 51 a+90b; 51 a+91 b; 51 a+92b;
51 a+93b; 51 a+94b; 51 a+95b; 51 a+96b; 51 a+97b; 52a+1 b; 52a + 2b; 52a + 3b;
52a+4b; 52a+5b; 52a+6b; 52a+7b; 52a+8b; 52a+9b; 52a+1 Ob; 52a+11 b;
52a+12b; 52a+13b; 52a+14b; 52a+15b; 52a+16b; 52a+17b; 52a+18b;
52a+19b; 52a+20b; 52a+21 b; 52a+22b; 52a+23b; 52a+24b; 52a+25b;
52a+26b; 52a+27b; 52a+28b; 52a+29b; 52a+30b; 52a+31 b; 52a+32b;
52a+33b; 52a+34b; 52a+35b; 52a+36b; 52a+37b; 52a+38b; 52a+39b;
52a+40b; 52a+41 b; 52a+42b; 52a+43b; 52a+44b; 52a+45b; 52a+46b;
52a+47b; 52a+48b; 52a+49b; 52a+50b; 52a+51 b; 52a+52b; 52a+53b;
52a+54b; 52a+55b; 52a+55b; 52a+57b; 52a+58b; 52a+59b; 52a+60b;
52a+61 b; 52a+62b; 52a+63b; 52a+64b; 52a+65b; 52a+66b; 52a+67b;
52a+68b; 52a+69b; 52a+70b; 52a+71 b; 52a+72b; 52a+73b; 52a+74b;
52a+75b; 52a+76b; 52a+77b; 52a+78b; 52a+79b; 52a+80b; 52a+81 b;
52a+82b; 52a+83b; 52a+84b; 52a+85b; 52a+86b; 52a+87b; 52a+88b;
52a+89b; 52a+90b; 52a+91 b; 52a+92b; 52a+93b; 52a+94b; 52a+95b;
52a+96b; 52a+97b; 53a+1 b; 53a + 2b; 53a + 3b; 53a+4b; 53a+5b; 53a+6b;
53a+7b; 53a+8b; 53a+9b; 53a+10b; 53a+11 b; 53a+12b; 53a+13b; 53a+14b;
53a+15b; 53a+16b; 53a+17b; 53a+18b; 53a+19b; 53a+20b; 53a+21 b;
53a+22b; 53a+23b; 53a+24b; 53a+25b; 53a+26b; 53a+27b; 53a+28b;
53a+29b; 53a+30b; 53a+31 b; 53a+32b; 53a+33b; 53a+34b; 53a+35b;
53a+36b; 53a+37b; 53a+38b; 53a+39b; 53a+40b; 53a+41 b; 53a+42b;
53a+43b; 53a+44b; 53a+45b; 53a+46b; 53a+47b; 53a+48b; 53a+49b;
53a+50b; 53a+51 b; 53a+52b; 53a+53b; 53a+54b; 53a+55b; 53a+55b;

53a+57b; 53a+58b; 53a+59b; 53a+60b; 53a+61 b; 53a+62b; 53a+63b;
53a+64b; 53a+65b; 53a+66b; 53a+67b; 53a+68b; 53a+69b; 53a+70b;
53a+71 b; 53a+72b; 53a+73b; 53a+74b; 53a+75b; 53a+76b; 53a+77b;
53a+78b; 53a+79b; 53a+80b; 53a+81 b; 53a+82b; 53a+83b; 53a+84b;
53a+85b; 53a+86b; 53a+87b; 53a+88b; 53a+89b; 53a+90b; 53a+91 b;
53a+92b; 53a+93b; 53a+94b; 53a+95b; 53a+96b; 53a+97b; 54a+1 b; 54a + 2b;
54a + 3b; 54a+4b; 54a+5b; 54a+6b; 54a+7b; 54a+8b; 54a+9b; 54a+10b;
54a+11 b; 54a+12b; 54a+13b; 54a+14b; 54a+15b; 54a+16b; 54a+17b;
54a+18b; 54a+19b; 54a+20b; 54a+21 b; 54a+22b; 54a+23b; 54a+24b;
54a+25b; 54a+26b; 54a+27b; 54a+28b; 54a+29b; 54a+30b; 54a+31 b;
54a+32b; 54a+33b; 54a+34b; 54a+35b; 54a+36b; 54a+37b; 54a+38b;
54a+39b; 54a+40b; 54a+41 b; 54a+42b; 54a+43b; 54a+44b; 54a+45b;
54a+46b; 54a+47b; 54a+48b; 54a+49b; 54a+50b; 54a+51 b; 54a+52b;
54a+53b; 54a+54b; 54a+55b; 54a+55b; 54a+57b; 54a+58b; 54a+59b;
54a+60b; 54a+61 b; 54a+62b; 54a+63b; 54a+64b; 54a+65b; 54a+66b;
54a+67b; 54a+68b; 54a+69b; 54a+70b; 54a+71 b; 54a+72b; 54a+73b;
54a+74b; 54a+75b; 54a+76b; 54a+77b; 54a+78b; 54a+79b; 54a+80b;
54a+81 b; 54a+82b; 54a+83b; 54a+84b; 54a+85b; 54a+86b; 54a+87b;
54a+88b; 54a+89b; 54a+90b; 54a+91 b; 54a+92b; 54a+93b; 54a+94b;
54a+95b; 54a+96b; 54a+97b; 55a+1 b; 55a + 2b; 55a + 3b; 55a+4b; 55a+5b;
55a+6b; 55a+7b; 55a+8b; 55a+9b; 55a+1 Ob; 55a+11 b; 55a+12b; 55a+13b;
55a+14b; 55a+15b; 55a+16b; 55a+17b; 55a+18b; 55a+19b; 55a+20b;
55a+21 b; 55a+22b; 55a+23b; 55a+24b; 55a+25b; 55a+26b; 55a+27b;
55a+28b; 55a+29b; 55a+30b; 55a+31 b; 55a+32b; 55a+33b; 55a+34b;
55a+35b; 55a+36b; 55a+37b; 55a+38b; 55a+39b; 55a+40b; 55a+41 b;
55a+42b; 55a+43b; 55a+44b; 55a+45b; 55a+46b; 55a+47b; 55a+48b;
55a+49b; 55a+50b; 55a+51 b; 55a+52b; 55a+53b; 55a+54b; 55a+55b;
55a+55b; 55a+57b; 55a+58b; 55a+59b; 55a+60b; 55a+61 b; 55a+62b;
55a+63b; 55a+64b; 55a+65b; 55a+66b; 55a+67b; 55a+68b; 55a+69b;
55a+70b; 55a+71 b; 55a+72b; 55a+73b; 55a+74b; 55a+75b; 55a+76b;

55a+77b; 55a+78b; 55a+79b; 55a+80b; 55a+81 b; 55a+82b; 55a+83b;
55a+84b; 55a+85b; 55a+86b; 55a+87b; 55a+88b; 55a+89b; 55a+90b;
55a+91 b; 55a+92b; 55a+93b; 55a+94b; 55a+95b; 55a+96b; 55a+97b; 56a+1 b;
56a + 2b; 56a + 3b; 56a+4b; 56a+5b; 56a+6b; 56a+7b; 56a+8b; 56a+9b;
56a+1 Ob; 56a+11 b; 56a+12b; 56a+13b; 56a+14b; 56a+15b; 56a+16b;
56a+17b; 56a+18b; 56a+19b; 56a+20b; 56a+21 b; 56a+22b; 56a+23b;
56a+24b; 56a+25b; 56a+26b; 56a+27b; 56a+28b; 56a+29b; 56a+30b;
56a+31 b; 56a+32b; 56a+33b; 56a+34b; 56a+35b; 56a+36b; 56a+37b;
56a+38b; 56a+39b; 56a+40b; 56a+41 b; 56a+42b; 56a+43b; 56a+44b;
56a+45b; 56a+46b; 56a+47b; 56a+48b; 56a+49b; 56a+50b; 56a+51 b;
56a+52b; 56a+53b; 56a+54b; 56a+55b; 56a+55b; 56a+57b; 56a+58b;
56a+59b; 56a+60b; 56a+61 b; 56a+62b; 56a+63b; 56a+64b; 56a+65b;
56a+66b; 56a+67b; 56a+68b; 56a+69b; 56a+70b; 56a+71 b; 56a+72b;
56a+73b; 56a+74b; 56a+75b; 56a+76b; 56a+77b; 56a+78b; 56a+79b;
56a+80b; 56a+81 b; 56a+82b; 56a+83b; 56a+84b; 56a+85b; 56a+86b;
56a+87b; 56a+88b; 56a+89b; 56a+90b; 56a+91 b; 56a+92b; 56a+93b;
56a+94b; 56a+95b; 56a+96b; 56a+97b; 57a+1 b; 57a + 2b; 57a + 3b; 57a+4b;
57a+5b; 57a+6b; 57a+7b; 57a+8b; 57a+9b; 57a+1 Ob; 57a+11 b; 57a+12b;
57a+13b; 57a+14b; 57a+15b; 57a+16b; 57a+17b; 57a+18b; 57a+19b;
57a+20b; 57a+21 b; 57a+22b; 57a+23b; 57a+24b; 57a+25b; 57a+26b;
57a+27b; 57a+28b; 57a+29b; 57a+30b; 57a+31 b; 57a+32b; 57a+33b;
57a+34b; 57a+35b; 57a+36b; 57a+37b; 57a+38b; 57a+39b; 57a+40b;
57a+41 b; 57a+42b; 57a+43b; 57a+44b; 57a+45b; 57a+46b; 57a+47b;
57a+48b; 57a+49b; 57a+50b; 57a+51 b; 57a+52b; 57a+53b; 57a+54b;
57a+55b; 57a+55b; 57a+57b; 57a+58b; 57a+59b; 57a+60b; 57a+61 b;
57a+62b; 57a+63b; 57a+64b; 57a+65b; 57a+66b; 57a+67b; 57a+68b;
57a+69b; 57a+70b; 57a+71 b; 57a+72b; 57a+73b; 57a+74b; 57a+75b;
57a+76b; 57a+77b; 57a+78b; 57a+79b; 57a+80b; 57a+81 b; 57a+82b;
57a+83b; 57a+84b; 57a+85b; 57a+86b; 57a+87b; 57a+88b; 57a+89b;
57a+90b; 57a+91 b; 57a+92b; 57a+93b; 57a+94b; 57a+95b; 57a+96b;

57a+97b; 58a+1 b; 58a + 2b; 58a + 3b; 58a+4b; 58a+5b; 58a+6b; 58a+7b;
58a+8b; 58a+9b; 58a+1 Ob; 58a+11 b; 58a+12b; 58a+13b; 58a+14b; 58a+15b;
58a+16b; 58a+17b; 58a+18b; 58a+19b; 58a+20b; 58a+21 b; 58a+22b;
58a+23b; 58a+24b; 58a+25b; 58a+26b; 58a+27b; 58a+28b; 58a+29b;
58a+30b; 58a+31 b; 58a+32b; 58a+33b; 58a+34b; 58a+35b; 58a+36b;
58a+37b; 58a+38b; 58a+39b; 58a+40b; 58a+41 b; 58a+42b; 58a+43b;
58a+44b; 58a+45b; 58a+46b; 58a+47b; 58a+48b; 58a+49b; 58a+50b;
58a+51 b; 58a+52b; 58a+53b; 58a+54b; 58a+55b; 58a+55b; 58a+57b;
58a+58b; 58a+59b; 58a+60b; 58a+61 b; 58a+62b; 58a+63b; 58a+64b;
58a+65b; 58a+66b; 58a+67b; 58a+68b; 58a+69b; 58a+70b; 58a+71 b;
58a+72b; 58a+73b; 58a+74b; 58a+75b; 58a+76b; 58a+77b; 58a+78b;
58a+79b; 58a+80b; 58a+81 b; 58a+82b; 58a+83b; 58a+84b; 58a+85b;
58a+86b; 58a+87b; 58a+88b; 58a+89b; 58a+90b; 58a+91 b; 58a+92b;
58a+93b; 58a+94b; 58a+95b; 58a+96b; 58a+97b; 59a+1 b; 59a + 2b; 59a + 3b;
59a+4b; 59a+5b; 59a+6b; 59a+7b; 59a+8b; 59a+9b; 59a+1 Ob; 59a+11 b;
59a+12b; 59a+13b; 59a+14b; 59a+15b; 59a+16b; 59a+17b; 59a+18b;
59a+19b; 59a+20b; 59a+21 b; 59a+22b; 59a+23b; 59a+24b; 59a+25b;
59a+26b; 59a+27b; 59a+28b; 59a+29b; 59a+30b; 59a+31 b; 59a+32b;
59a+33b; 59a+34b; 59a+35b; 59a+36b; 59a+37b; 59a+38b; 59a+39b;
59a+40b; 59a+41 b; 59a+42b; 59a+43b; 59a+44b; 59a+45b; 59a+46b;
59a+47b; 59a+48b; 59a+49b; 59a+50b; 59a+51 b; 59a+52b; 59a+53b;
59a+54b; 59a+55b; 59a+55b; 59a+57b; 59a+58b; 59a+59b; 59a+60b;
59a+61 b; 59a+62b; 59a+63b; 59a+64b; 59a+65b; 59a+66b; 59a+67b;
59a+68b; 59a+69b; 59a+70b; 59a+71 b; 59a+72b; 59a+73b; 59a+74b;
59a+75b; 59a+76b; 59a+77b; 59a+78b; 59a+79b; 59a+80b; 59a+81 b;
59a+82b; 59a+83b; 59a+84b; 59a+85b; 59a+86b; 59a+87b; 59a+88b;
59a+89b; 59a+90b; 59a+91 b; 59a+92b; 59a+93b; 59a+94b; 59a+95b;
59a+96b; 59a+97b; 60a+1 b; 60a + 2b; 60a + 3b; 60a+4b; 60a+5b; 60a+6b;
60a+7b; 60a+8b; 60a+9b; 60a+10b; 60a+11 b; 60a+12b; 60a+13b; 60a+14b;
60a+15b; 60a+16b; 60a+17b; 60a+18b; 60a+19b; 60a+20b; 60a+21 b;

60a+22b; 60a+23b; 60a+24b; 60a+25b; 60a+26b; 60a+27b; 60a+28b;
60a+29b; 60a+30b; 60a+31 b; 60a+32b; 60a+33b; 60a+34b; 60a+35b;
60a+36b; 60a+37b; 60a+38b; 60a+39b; 60a+40b; 60a+41 b; 60a+42b;
60a+43b; 60a+44b; 60a+45b; 60a+46b; 60a+47b; 60a+48b; 60a+49b;
60a+50b; 60a+51 b; 60a+52b; 60a+53b; 60a+54b; 60a+55b; 60a+55b;
60a+57b; 60a+58b; 60a+59b; 60a+60b; 60a+61 b; 60a+62b; 60a+63b;
60a+64b; 60a+65b; 60a+66b; 60a+67b; 60a+68b; 60a+69b; 60a+70b;
60a+71 b; 60a+72b; 60a+73b; 60a+74b; 60a+75b; 60a+76b; 60a+77b;
60a+78b; 60a+79b; 60a+80b; 60a+81 b; 60a+82b; 60a+83b; 60a+84b;
60a+85b; 60a+86b; 60a+87b; 60a+88b; 60a+89b; 60a+90b; 60a+91 b;
60a+92b; 60a+93b; 60a+94b; 60a+95b; 60a+96b; 60a+97b; etc.
Within certain embodiments of the invention, the therapeutic composition can also comprise radio-opaque, echogenic materials and magnetic resonance imaging (MRI) responsive materials (i.e., MRI contrast agents) to aid in visualization of the composition under ultrasound, fluoroscopy and/or MRI. For example, a composition may be echogenic or radiopaque (e.g., made with echogenic or radiopaque with materials such as powdered tantalum, tungsten, barium carbonate, bismuth oxide, barium sulfate, metrazimide, iopamidol, iohexol, iopromide, iobitridol, iomeprol, iopentol, ioversol, ioxilan, iodixanol, iotrolan, acetrizoic acid derivatives, diatrizoic acid derivatives, iothalamic acid derivatives, ioxithalamic acid derivatives, metrizoic acid derivatives, iodamide, lypophylic agents, iodipamide and ioglycamic acid or, by the addition of microspheres or bubbles which present an acoustic interface). For visualization under MRI, contrast agents (e.g., gadolinium (III) chelates or iron oxide compounds) may be incorporated into the composition..
The compositions may, alternatively, or in addition, be visualized under visible light, using fluorescence, or by other spectroscopic means.
Visualization agents that can be included for this purpose include dyes, pigments, and other colored agents. In one aspect, the composition may further include a colorant to improve visualization of the composition in vivo andlor ex vivo. Frequently, compositions can be difficult to visualize upon delivery into a host, especially at the margins of an implant or tissue. A
coloring agent can be incorporated into a composition to reduce or eliminate the incidence or severity of this problem. The coloring agent provides a unique color, increased contrast, or unique fluorescence characteristics to the composition. In one aspect, a composition is provided that includes a colorant such that it is readily visible (under visible light or using a fluorescence technique) and easily differentiated from its implant site. In another aspect, a colorant can be included in a liquid or semi-solid composition. For example, a single component of a two component mixture may be colored, such that when combined ex-vivo or in-vivo, the mixture is sufficiently colored.
The coloring agent may be, for example, an endogenous compound (e.g., an amino acid or vitamin) or a nutrient or food material and may be a hydrophobic or a hydrophilic compound. Preferably, the colorant has a very low or no toxicity at the concentration used. Also preferred are colorants that are safe and normally enter the body through absorption such as ~-carotene. Representative examples of colored nutrients (under visible light) include fat soluble vitamins such as Vitamin A (yellow); water soluble vitamins such as Vitamin B12 (pink-red) and folic acid (yellow-orange); carotenoids such as ~3-carotene (yellow-purple) and lycopene (red). Other examples of coloring agents include natural product (berry and fruit) extracts such as anthrocyanin (purple) and saffron extract (dark red). The coloring agent may be a fluorescent or phosphorescent compound such as a-tocopherolquinol (a Vitamin E
derivative) or L-tryptophan.
In one aspect, the compositions of the present invention include one or more coloring agents, also referred to as dyestuffs, which will be present in an effective amount to impart observable coloration to the composition, e.g., the gel. Examples of coloring agents include dyes suitable for food such as those known as F. D. & C. dyes and natural coloring agents such as grape skin extract, beet red powder, beta carotene, annato, carmine, turmeric, paprika, and so forth. Derivatives, analogues, and isomers of any of the above colored compound also may be used. The method for incorporating a colorant into an implant or therapeutic composition may be varied depending on the properties of and the desired location for the colorant. For example, a hydrophobic colorant may be selected for hydrophobic matrices. The colorant may be incorporated into a carrier matrix, such as micelles. Further, the pH of the environment may be controlled to further control the color and intensity.
In one aspect, the compositions of the present invention include one or more preservatives or bacteriostatic agents present in an effective amount to preserve the composition and/or inhibit bacterial growth in the composition, for example, bismuth tribromophenate, methyl hydroxybenzoate, bacitracin, ethyl hydroxybenzoate, propyl hydroxybenzoate, erythromycin, chlorocresol, benzalkonium chlorides, and the like. Examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzylalcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc. In one aspect, the compositions of the present invention include one or more bactericidal (also known as bacteriacidal) agents. , In one aspect, the compositions of the present invention include one or more antioxidants, present in an effective amount. Examples of the antioxidant include sulfites, alpha-tocopherol, beta-carotene and ascorbic acid.
Further, therapeutic compositions of the present invention should preferably be have a stable shelf-life of at least several months and capable of being produced and maintained under sterile conditions. The composition may be sterile either by preparing them under aseptic environment and/or they may be terminally sterilized using methods known in the art. A combination of both of these methods may also be used to prepare the composition in the sterile form. Sterilization may also occur by terminally using gamma radiation or electron beam sterilization methods.

In one aspect, the compounds and compositions of the present invention are sterile. Many pharmaceuticals are manufactured to be sterile and this criterion is defined by the USP XXII <1211 >. The term "USP" refers to U.S.
Pharmacopeia (see www.usp.org, Rockville, MD). Sterilization in this embodiment may be accomplished by a number of means accepted in the industry and listed in the USP XXII <1211 >, including gas sterilization, ionizing radiation or, when appropriate, filtration. Sterilization may be maintained by what is termed asceptic processing, defined also in USP XXII <1211 >.
Acceptable gases used for gas sterilization include ethylene oxide. Acceptable radiation types used for ionizing radiation methods include gamma, for instance from a cobalt 60 source and electron beam. A typical dose of gamma radiation is 2.5 MRad. Filtration may be accomplished using a filter with suitable pore size, for example 0.22 ~,m and of a suitable material, for instance polytetrafluoroethylene (e.g., TEFLON from E. I. DuPont De Nemours and Company, Wilmington, DE).
In another aspect, the compositions of the present invention are contained in a container that allows them to be used for their intended purpose, i.e., as a pharmaceutical composition. Properties of the container that are important are a volume of empty space to allow for the addition of a constitution medium, such as water or other aqueous medium, e.g., saline, acceptable light transmission characteristics in order to prevent light energy from damaging the composition in the container (refer to USP XXI I <661 >), an acceptable limit of extractables within the container material (refer to USP XXII), an acceptable barrier capacity for moisture (refer to USP XXI I <671 >) or oxygen. In the case of oxygen penetration, this may be controlled by including in the container, a positive pressure of an inert gas, such as high purity nitrogen, or a noble gas, such as argon.
Typical materials used to make containers for pharmaceuticals include USP Type I through III and Type NP glass (refer to USP XXII <661 >), polyethylene, TEFLON, silicone, and gray-butyl rubber. For parenterals, USP
Types I to III glass and polyethylene are preferred.
E. Methods for Utilizing Compositions The compositions of the present invention can be used in a variety of different applications. For example, the compositions may be used for (a) preventing tissue adhesions; (b) treating or preventing inflammatory arthritis; (c) prevention of cartilage loss; (d) treating or preventing hypertrophic scars/keloids; (e) treating or preventing vascular disease; and (f) coating medical implants and devices. A more detailed description of several specific applications is given below.
Adhesion Prevention The present invention provides compositions for use in the prevention of adhesions (e.g., surgical adhesions). The polymeric compositions may include one or more therapeutically active agents (e.g., anti-scarring agents), which provide pharmacological alteration of cellular and/ or non-cellular processes involved in the development and/or progression of surgical adhesions. Therapeutically active agents are described that can reduce surgical adhesions by inhibiting the formation of fibrous or scar tissue. In another aspect, the present invention provides surgical adhesion barriers that include an anti-scarring agent or a composition that includes an anti-scarring agent.
Surgical adhesions are abnormal, fibrous bands of scar tissue that can form inside the body as a result of the healing process that follows any open or minimally invasive surgical procedure including abdominal, gynecologic, cardiothoracic, spinal, plastic, vascular, ENT, ophthalmologic, urologic, neuro, or orthopedic surgery. Surgical adhesions are typically connective tissue structures that form between adjacent injured areas within the body. Briefly, localized areas of injury trigger an inflammatory and healing response that culminates in healing and scar tissue formation. If scarring results in the formation of fibrous tissue bands or adherence of adjacent anatomical structures (that should be separate), surgical adhesion formation is said to have occurred. Adhesions can range from flimsy, easily separable structures to dense, tenacious fibrous structures that can only be separated by surgical dissection. While many adhesions are benign, some can cause significant clinical problems and are a leading cause of repeat surgical intervention. Surgery to breakdown adhesions (adhesiolysis) often results in failure and recurrence because the surgical trauma involved in breaking down the adhesion triggers the entire process to repeat itself. Surgical breakdown of adhesions is a significant clinical problem and it is estimated that there were 473,000 adhesiolysis procedures in the US in 2002. According to the Diagnosis-Related Groups (DRGs), the total hospital charges for these procedures is likely to be at least US $10 billion annually.
Since all interventions involve a certain degree of trauma to the operative tissues, virtually any procedure (no matter how well executed) has the potential to result in the formation of clinically significant adhesion formation.
Adhesions can be triggered by surgical trauma such as cutting, manipulation, retraction or suturing, as well as from inflammation, infection (e.g., fungal or mycobacterium), bleeding or the presence of a foreign body. Surgical trauma may also result from tissue drying, ischemia, or thermal injury. Due to the diverse etiology of surgical adhesions, the potential for formation exists regardless of whether the surgery is done in a so-called minimally invasive fashion (e.g., catheter-based therapies, laparoscopy) or in a standard open technique involving one or more relatively large incisions. Although a potential complication of any surgical intervention, surgical adhesions are particularly problematic in GI surgery (causing bowel obstruction), gynecological surgery (causing pain and/or infertility), tendon repairs (causing shortening and flexion deformities), joint capsule procedures (causing capsular contractures), and nerve and muscle repair procedures (causing diminished or lost function).

Surgical adhesions may cause various, often serious and unpredictable clinical complications; some of which manifest themselves only years after the original procedure was completed. Complications from surgical adhesions are a major cause of failed surgical therapy and are the leading cause of bowel obstruction and infertility. Other adhesion-related complications include chronic back or pelvic pain, intestinal obstruction, urethral obstruction and voiding dysfunction. Relieving the post-surgical complications caused by adhesions generally requires another surgery. However, the subsequent surgery is further complicated by adhesions formed as a result of the previous surgery. In addition, the second surgery is likely to result in further adhesions and a continuing cycle of additional surgical complications.
The placement of medical devices and implants also increases the risk that surgical adhesions will occur. In addition to the above mechanisms, an implanted device can trigger a "foreign body" response where the immune system recognizes the implant as foreign and triggers an inflammatory reaction that ultimately leads to scar tissue formation. A
specific form of foreign body reaction in response to medical device placement is complete enclosure ("walling off') of the implant in a capsule of scar tissue (encapsulation). Fibrous encapsulation of implanted devices and implants can complicate any procedure, but breast augmentation and reconstruction surgery, joint replacement surgery, hernia repair surgery, artificial vascular graft surgery, stent placement, and neurosurgery are particularly prone to this complication.
In each case, the implant becomes encapsulated by a fibrous connective tissue capsule which compromises or impairs the function of the surgical implant (e.g., breast implant, artificial joint, surgical mesh, vascular graft, stent or dural patch).
Adhesions generally begin to form within the first several days after surgery. Generally, adhesion formation is an inflammatory reaction in which factors are released, increasing vascular permeability and resulting in fibrinogen influx and fibrin deposition. This deposition forms a matrix that bridges the abutting tissues. Fibroblasts accumulate, attach to the matrix, deposit collagen and induce angiogenesis. If this cascade of events can be prevented within 4 to 5 days following surgery, then adhesion formation may be inhibited.
Various modes of adhesion prevention have been examined, including (1 ) prevention of fibrin deposition, (2) reduction of local tissue inflammation and (3) removal of fibrin deposits. Fibrin deposition is prevented through the use of physical barriers that are either mechanical or comprised of viscous solutions. Barriers have the added advantage of physically preventing adjacent tissues from contacting each other and thereby reducing the probability that they will scar together. Although many investigators and commercial products utilize adhesion prevention barriers, a number of technical difficulties exist and significant failure rates have been reported.
Inflammation is reduced by the administration of drugs such as corticosteroids and non-steroidal anti-inflammatory drugs. However, the results from the use of these drugs in animal models have not been encouraging due to the extent of the inflammatory response and dose restriction due to systemic side effects.
Finally, the removal of fibrin deposits has been investigated using proteolytic and fibrinolytic enzymes. A potential complication to the clinical use of these enzymes is the possibility for post-surgical excessive bleeding (surgical hemostasis is critical for procedural success).
Numerous polymeric compositions for use in the prevention of surgical adhesions (e.g., surgical adhesion barriers) may be used in the practice of the invention, either alone, or in combination with one or more anti-scarring agents. It should be noted that certain polymeric compositions can themselves help prevent the formation of fibrous tissue at a surgical site. In certain embodiments, the polymer composition can form a barrier between the tissue surfaces or organs.
For example, the surgical adhesion barrier may be coated onto tissue surfaces and may be composed of an aqueous solution of a hydrophilic, polymeric material (e.g., polypeptides or polysaccharide) having greater than 50,000 molecular weight and a concentration range of 0.01 % to 15% by weight.
See e.g., U.S. Patent No. 6,464,970. The surgical adhesion barrier may be a crosslinkable system with at least three reactive compounds each having a polymeric molecular core with at least one functional group. See e.g., U.S.
Patent No. 6,458,889. The surgical adhesions barrier may be composed of a non-gelling polyoxyalkylene composition with or without a therapeutic agent.
See e.g., U.S. Patent No. 6,436,425. The surgical adhesions barrier may be composed of an anionic polymer having an acid sulfate and sulfur content greater than 5% which acts to inhibit monocyte or macrophage invasion. See e.g., U.S. Patent No. 6,417,173. The surgical adhesions barrier may be an aqueous composition including a surfactant, pentoxifylline and a polyoxyalkylene polyether. See e.g., U.S. Patent No. 6,399,624. The surgical adhesions barrier may be composed by crosslinking two synthetic polymers, one having nucleophilic groups and the other having electrophilic groups, such that they form a matrix that may be used to incorporate a biologically active compound. See e.g., U.S. Patent Nos. 6,323,278; 6,166,130; 6,051,648 and 5,874,500. The surgical adhesion barrier may be composed of hyaluronic acid compositions such as those described in U.S. Patents Nos. 6,723,709;
6,531,147; and 6,464,970. The surgical adhesions barrier may be a polymeric tissue coating which is formed by applying a polymerization initiator to the tissue and then covering it with a water-soluble macromer that is polymerizable using free radical initiators under the influence of UV light. See e.g., U.S.
Patent Nos. 6,177,095 and 6,083,524. The surgical adhesions barrier may be composed of fluent prepolymeric material that is emitted to the tissue surface and then exposed to activating energy in situ to initiate conversion of the applied material to non-fluent polymeric form. See e.g., U.S. Patent Nos.
6,004,547 and 5,612,050. The surgical adhesions barrier may be a hydrogel-forming, self-solvating, absorbable polyester copolymers capable of selective, segmental association into compliant hydrogels mass upon contact with an aqueous environment. See e.g., U.S. Patent No. 5,612,052. The surgical adhesions barrier may be an anionic polymer effective to inhibit cell invasion or fibrosis (e.g., dermatan sulfate, dextran sulfate, pentosan polysulfate, or alginate), and a pharmaceutically effective carrier, in which the carrier may be semi-solid. See e.g., U.S. Patent Nos. 6,756,362; 6,127,348 and 5,994,325.
The surgical adhesions barrier may be an acidified hydrogel comprising a carboxypolysaccharide and a polyether having a pH in the range of about 2.0 to about 6Ø See e.g., U.S. Patent No. 6,017,301. The surgical adhesions barrier may be composed of dextran sulfate having a molecular weight about 40,000 to 500,000 Daltons which is used to inhibit neurite outgrowth. See e.g., U.S.
Patent No. 5,705,178. The surgical adhesions barrier may be a fragmented biocompatible hydrogel which is at least partially hydrated and is substantially free from an aqueous phase, wherein said hydrogel comprises gelatin and will absorb water when delivered to a moist tissue target site. See e.g., U.S.
Patent No. 6,066,325. The surgical adhesions barrier may be a water-soluble, degradable macromer that is composed of at least two-crosslinkable substituents that may crosslink to other macromers at a localized site when under the influence of a polymerization initiator. See e.g., U.S. Patent No.
6,465,001. The surgical adhesions barrier may be a biocompatible adhesive composition comprising at least one alkyl ester cyanoacrylate monomer and a polymerization initiator or accelerator. See e.g., U.S. Patent No. 6,620,846.
In one embodiment, the polymers that can form a covalent bond with the tissue to which it is applied may be used. Polymers containing and/or terminated with electrophilic groups such as succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(C5H4N) or activated esters, such as are used in peptide synthesis may be used as the reagents. For example, a 4 armed NHS-derivatized polyethylene glycol (e.g., pentaerythritol polyethylene glycol)ether tetra-succinimidyl glutarate) may be applied to the tissue in the solid form or in a solution form. In this embodiment, the 4 armed NHS-derivatized polyethylene glycol is dissolved in an acidic solution (pH
about 2-3) and is then co-applied to the tissue using a basic buffer (pH > about 8).
The fibrosis-inhibiting agents) may be incorporated directly into either the 4 armed NHS-derivatized polyethylene glycol, the acidic solution or the basic buffer. In another embodiment, the fibrosis-inhibiting agent may be incorporated into a secondary carrier that may then be incorporated into the 4 armed NHS-derivatized polyethylene glycol, the acidic solution and/or the basic buffer.
Secondary carriers may include microparticles and/or microspheres which are made from degradable polymers. Degradable polymers may include polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, y-decanolactone, ~-decanolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-Zone, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)", R-(X-Y)" and X-Y-X (where X in a polyalkylene oxide (e.g., poly(ethylene glycol, polypropylene glycol) and block copolymers of polyethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, y-decanolactone, ~-decanolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-Zone (e.g., PLG-PEG-PLG) and R is a multifunctional initiator).
In another embodiment, the tissue reactive polymer may be applied initially and then the fibrosis-inhibiting agent may then be applied to the coated tissue. The fibrosis-inhibiting agent may be applied directly to the tissue or it may be incorporated into a secondary carrier. Secondary carriers may include microspheres (as described above), microparticles (as described above), gels (e.g., hyaluronic acid, carboxymethyl cellulose, dextran, polyethylene oxide) - polypropylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof) and films (degradable polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, y-decanolactone, ~-decanolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-Zone, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)~, R-(X-Y)" and X-Y-X (where X in a polyalkylene oxide (e.g., poly(ethylene glycol, polypropylene glycol) and block copolymers of polyethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, y-decanolactone, b-decanolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-Zone (e.g., PLG-PEG-PLG) and R is a multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, dextran, polyethylene oxide) -polypropylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof.
A preferred polymeric matrix which can be used to help prevent the formation of fibrous tissue, either alone or in combination with a fibrosis inhibiting agent/composition, is formed from reactants comprising either one or both of pentaerythritol polyethylene glycol)ether tetra-sulfhydryl] (4-armed thiol PEG, which includes structures having a linking groups) between a sulfhydryl groups) and the terminus of the polyethylene glycol backbone) and pentaerythritol polyethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG, which again includes structures having a linking groups) between a NHS groups) and the terminus of the polyethylene glycol backbone) as reactive reagents. Another preferred composition comprises either one or both of pentaerythritol polyethylene glycol)ether tetra-amino] (4-armed amino PEG, which includes structures having a linking groups) between an amino groups) and the terminus of the polyethylene glycol backbone) and pentaerythritol polyethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG, which again includes structures having a linking groups) between a NHS
groups) and the terminus of the polyethylene glycol backbone) as reactive reagents. Chemical structures for these reactants are shown in, e.g., U.S.
Patent 5,874,500. Optionally, collagen or a collagen derivative (e.g., methylated collagen) is added to the polyethylene glycol)-containing reactants) to form a preferred crosslinked matrix that can serve as a polymeric carrier for a therapeutic agent or a stand-alone composition to help prevent the formation of fibrous tissue.
Surgical adhesion barriers, which may be combined with one or more anti-scarring agents according to the present invention, also include commercially available products. Examples of surgical adhesion barrier compositions into which a fibrosis agent can be incorporated include: (a) sprayable collagen-containing formulations such as COSTASIS or CT3 (Angiotech Pharmaceuticals, Inc., Canada); (b) sprayable PEG-containing formulations such as COSEAL or ADHIBIT (Angiotech Pharmaceuticals, Inc.), SPRAYGEL or DURASEAL (both from Confluent Surgical, Inc., Boston, MA) or FOCALSEAL (Genzyme Corporation, Cambridge, MA); (c) hyaluronic acid-containing formulations such as RESTYLANE or PERLANE (both from Q-Med AB, Sweden), HYLAFORM (Inamed Corporation, Santa Barbara, CA), SYNVISC (Biomatrix, Inc., Ridgefield, NJ), SEPRAFILM or SEPRACOAT (both from Genzyme Corporation), (d) fibrinogen-containing formulations such as FLOSEAL or TISSEAL (both from Baxter Healthcare Corporation, Fremont, CA); (e) polymeric gels such as REPEL (Life Medical Sciences, Inc., Princeton, NJ) or FLOWGEL (Baxter Healthcare Corporation, Deerfield, IL), (f) surgical adhesives containing cyanoacrylates such as DERMABOND (Johnson &

Johnson, Inc., New Brunswick, NJ), INDERMIL (U.S. Surgical Company, Norwalk, CT), GLUSTITCH (Blacklock Medical Products Inc., Canada), TISSUMEND (Veterinary Products Laboratories, Phoenix, AZ), VETBOND (3M
Company, St. Paul, MN), HISTOACRYL BLUE (Davis & Geck, St. Louis, MO) and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT (Colgate-Palmolive Company, New York, NY); (g) dextran sulfate gels such as the ADCON range of products (available from Wright Medical Technology, Inc. Arlington, TN), (h) lipid based compositions such as ADSURF (Britannia Pharmaceuticals Ltd., United Kingdom) and (j) film compositions such as INTERCEED (Ethicon, Inc., Somerville, NJ) and HYDROSORB (MacroPore Biosurgery, Inc., San Diego, CA /Medtronic Sofamor Danek, Memphis, TN).
For greater clarity, several specific applications and treatments will be described in greater detail including:
i) Adhesion Prevention in Spinal and Neurosurgical Procedures Back pain is the number one cause of healthcare expenditures in the United States and accounts for over $50 billion in costs annually ($100 billion worldwide). Over 12 million people in the U.S. have some form of degenerative disc disease (DDD) and 10% of them (1.2 million) will require surgery to correct their problem.
In healthy individuals, the vertebral column is composed of vertebral bone plates separated by intervertebral discs that form strong joints and absorb spinal compression during movement. The intervertebral disc is comprised of an inner gel-like substance called the nucleus pulposus which is surrounded by a tough fibrocartilagenous capsule called the annulus fibrosis.
The nucleus pulposus is composed of a loose framework of collagen fibrils and connective tissue cells (resembling fibroblasts and chondrocytes) embedded in a gelatinous matrix of glycosaminoglycans and water. The annulus fibrosus is composed of numerous concentric rings of fibrocartilage that anchor into the vertebral bodies. The most common cause of DDD occurs when tears in the annulus fibrosis create an area of localized weakness that allow bulging, herniation or sequestration of the nucleus pulposis and annulus fibrosis into the spinal canal and/or spinal foramena. The bulging or herniated disc often compresses nerve tissue such as spinal cord fibers or spinal cord nerve root fibers. Pressure on the spinal cord or nerve roots from the damaged intervertebral disc results in neuronal dysfunction (numbness, weakness, tingling), crippling pain, bowel or bladder disturbances and can frequently cause long-term disability. Although many cases of DDD will spontaneously resolve, a significant number of patients will require surgical intervention in the form of minimally invasive procedures, microdiscectomy, major surgical resection of the disc, spinal fusion (fusion of adjacent vertebral bone plates using various techniques and devices), and/or implantation of an artificial disc. The present invention provides for the application of an anti-adhesion or anti-fibrosis agent in the surgical management of DDD.
Spinal disc removal is mandatory and urgent in cauda equine syndrome when there is a significant neurological deficit; particularly bowel or bladder dysfunction. It is also performed electively to relieve pain and eliminate lesser neurological symptoms. The spinal nerve roots exit the spinal canal through bony spinal foramena (a bony opening between the vertebra above and the vertebra below) that is a common site of nerve entrapment. To gain access to the spinal foramen during back surgeries, vertebral bone tissue is often resected; a process known as laminectomy.
In open surgical resection of a ruptured lumbar disc or entrapped spinal nerve root (laminectomy) the patient is placed in a modified kneeling position under general anesthesia. An incision is made in the posterior midline and the tissue is dissected away to expose the appropriate interspace; the ligamentum flavum is dissected and in some cases portions of the bony lamina are removed to allow adequate visualization. The nerve root is carefully retracted away to expose the herniated fragment and the defect in the annulus.

Typically, the cavity of the disc is entered from the tear in the annulus and the loose fragments of the nucleus pulposus are removed with pituitary forceps.
Any additional fragments of disc sequestered inside or outside of the disc space are also carefully removed and the disc space is forcefully irrigated to remove to remove any residual fragments. If tears are present in the dura, the dura is closed with sutures that are often augmented with fibrin glue. The tissue is then closed with absorbable sutures.
Microlumbar disc excision (microdiscectomy) can be performed as an outpatient procedure and has largely replaced laminectomy as the intervention of choice for herniated discs or root entrapment. A one inch incision is made from the spinous process above the disc affected to the spinous process below. Using an operating microscope, the tissue is dissected down to the ligamentum flavum and bone is removed from the lamina until the nerve root can be clearly identified. The nerve root is carefully retracted and the tears in the annulus are visualized under magnification. Microdisc forceps are used to remove disc fragments through the annular tear and any sequestered disc fragments are also removed. As with laminectomy, the disc space is irrigated to remove any disc fragments, any dural tears are repaired and the tissue is closed with absorbable sutures. It should be noted that anterior (abdominal) approaches can also be used for both open and endoscopic lumbar disc excision. Cervical and thoracic disc excisions are similar to lumbar procedures and can also be performed from a posterior approach (with laminectomy) or as an anterior discectomy with fusion.
Back surgeries, such as laminectomies, discectomies and microdiscectomies, often leave the spinal dura exposed and unprotected. As a result, scar tissue frequently forms between the dura and the surrounding tissue. This scar is formed from the damaged erector spinae muscles that overlay the laminectomy site. The result is adhesion development between the muscle tissue and the fragile dura, thereby, reducing mobility of the spine and the nerve roots that exit from it, leading to pain, persistent neurological symptoms and slow post-operative recovery. Similarly, adhesions that occur in the epidural and dural tissue cause complications in spinal injury (e.g., compression and crush injuries) cases. In addition, scar and adhesion formation within the dura and around nerve roots has been implicated in rendering subsequent (revision and repeat) spine operations technically more difficult to perform.
To circumvent adhesion development, a scar-reducing barrier may be inserted between the dural sleeve and the paravertebral musculature post-laminectomy. Alternatively (or in addition to this), the adhesion barrier, either alone or containing a fibrosis-inhibiting agent, can be coated on (or infiltrated into the tissues around) the spinal nerve as it exits the spinal canal and traverses the space between the bony vertebra (i.e., the laminectomy site).
This reduces cellular and vascular invasion into the epidural space from the overlying muscle and exposed cancellous bone and thus, reduces the complications associated with scarring of the canal housing, spinal chord and/or nerve roots. In microdiscectomy procedures it is important that the barrier be deliverable as a spray, gel or fluid material that can be administered via the delivery port of an endoscope. Once again, the adhesion barrier, either alone or containing a fibrosis-inhibiting agent, can be sprayed onto the spinal nerve (or infiltrated into the tissues~around it) as it exits the spinal canal and traverses the space between the bony vertebra (i.e., the laminectomy site). The present invention discloses barrier compositions, used either alone or combined with a fibrosis-inhibiting agent, that can be delivered during surgical disc resection and microdiscectomy either directly, using specialized delivery catheters, via an endoscope, or through a needle or other applicator. When dural defects are present, the fibrosis-inhibiting agent will assist in the healing of the dura and prevent complications such as blockage of CSF flow.
In another aspect, adhesion formation may be associated with a neurosurgical (brain) procedure. Neurosurgical procedures are fraught with potentially severe post-operative complications that are often attributed to surgical trauma and unwanted fibrosis or gliosis (gliosis is scar tissue formation in the brain as a result of glial cell activity). Increased intracranial bleeding, infection, cerebrospinal fluid leakage and pain are but some complications resulting from adhesions following neurosurgery. For example, if scar tissue interrupts the normal circulation of cerebrospinal fluid (CSF) following brain or spinal surgery, the fluid can accumulate and exert pressure on surrounding tissues (causing increased intracranial pressure) leading to severe complications (such as uncal herneation, brain damage and/or death). Here the adhesion barrier alone, or combined with a fibrosis-inhibiting agent, can be used to prevent excessive dural scarring and adhesion formation in a variety of neurosurgical procedures.
There are numerous compositions that may be used alone or loaded with a therapeutic agent (e.g., a fibrosis-inhibiting agent or an anti-infective agent), applied to a spinal or neurosurgical site (or to an implant surface placed in the spine - such as an artificial disc, rods, screws, spinal cages, drug-delivery pumps, neurostimulation devices; or to an implant placed in the brain - such as drains, shunts, drug-delivery pumps, neurostimulation devices) for the prevention of surgical adhesions in neurosurgical procedures.
It should be noted that certain polymeric compositions can themselves help prevent the formation of fibrous tissue at a spinal or neurosurgical site.
These compositions are particularly useful for the practice of this embodiment, either alone, or in combination with a fibrosis-inhibiting composition.
Various polymeric compositions can be infiltrated into the spinal or neurosurgical site (e.g., onto tissue at the surgical site or in the vicinity of the implant-tissue interface) with or without an additional therapeutic agent for the prevention of surgical adhesions.
In one embodiment, the polymers that can form a covalent bond with the tissue to which it is applied may be used. Polymers containing and/or terminated with electrophilic groups such as succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(C5H4N) or activated esters, such as are used in peptide synthesis may be used as the reagents. For example, a 4 armed NHS-derivatized polyethylene glycol (e.g., pentaerythritol polyethylene glycol)ether tetra-succinimidyl glutarate) may be applied to the tissue in the solid form or in a solution form. In this embodiment, the 4 armed NHS-derivatized polyethylene glycol is dissolved in an acidic solution (pH
about 2-3) and is then co-applied to the tissue using a basic buffer (pH > about 8).
The antifibrosisfibrosis-inhibiting agents) may be incorporated directly into either the 4 armed NHS-derivatized polyethylene glycol, the acidic solution or the basic buffer.
In another embodiment, the fibrosis-inhibiting agent may be incorporated into a secondary carrier that may then be incorporated into the 4 armed NHS-derivatized polyethylene glycol, the acidic solution and/or the basic buffer. The secondary carriers may include microparticles and/or microspheres which are made from degradable polymers. The degradable polymers may include polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, y-decanolactone, b-decanolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-Zone, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)", R-(X-Y)" and X-Y-X (where X in a polyalkylene oxide (e.g., poly(ethylene glycol, polypropylene glycol) and block copolymers of polyethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, y-decanolactone, ~-decanolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-Zone (e.g., PLG-PEG-PLG) and R is a multifunctional initiator).

In another embodiment, the tissue reactive polymer may be applied initially and then the fibrosis-inhibiting agent may then be applied to the coated tissue. The fibrosis-inhibiting agent may be applied directly to the tissue or it may be incorporated into a secondary carrier. The secondary carriers may include microspheres (as described above), microparticles (as described above), gels (e.g., hyaluronic acid, carboxymethyl cellulose, dextran, polyethylene oxide) - polypropylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof) and films (degradable polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, y-decanolactone, ~-decanolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-Zone, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)", R-(X-Y)" and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, polypropylene glycol) and block copolymers of polyethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from SASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, y-decanolactone, ~-decanolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-Zone (e.g., PLG-PEG-PLG) and R is a multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, dextran, polyethylene oxide) -poly(propylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof.
A preferred polymeric matrix which can be used to help prevent the formation of fibrous tissue that leads to surgical adhesions, either alone or in combination with a fibrosis inhibiting agent/composition, is formed from reactants comprising either one or both of pentaerythritol polyethylene glycol)ether tetra-sulfhydryl] (4-armed thiol PEG, which includes structures having a linking groups) between a sulfhydryl groups) and the terminus of the polyethylene glycol backbone) and pentaerythritol polyethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG, which again includes structures having a linking groups) between a NHS groups) and the terminus of the polyethylene glycol backbone) as reactive reagents. Another preferred composition comprises either one or both of pentaerythritol polyethylene glycol)ether tetra-amino] (4-armed amino PEG, which includes structures having a linking groups) between an amino groups) and the terminus of the polyethylene glycol backbone) and pentaerythritol polyethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG, which again includes structures having a linking groups) between a NHS groups) and the terminus of the polyethylene glycol backbone) as reactive reagents. Chemical structures for these reactants are shown in, e.g., U.S. Patent 5,874,500. Optionally, collagen or a collagen derivative (e.g., methylated collagen) is added to the polyethylene glycol)-containing reactants) to form a preferred crosslinked matrix that can serve as a polymeric carrier for a therapeutic agent or a stand-alone composition to help prevent the formation of fibrous tissue.
Other examples of polymeric compositions that can be infiltrated into the spinal or neurosurgical site (e.g., onto tissue at the surgical site or in the vicinity of the implant-tissue interface) with or without an additional fibrosis-inhibiting (and/or an anti-infective) therapeutic agent for the prevention of surgical adhesions, include a variety of commercial products. For example, Confluent Surgical, Inc. makes their DURASEAL which is a synthetic hydrogel designed to augment sutured dura closures following cranial surgical procedures. Products that are being developed by Confluent Surgical, Inc. are described in, for example, U.S. Patent No. 6,379,373. FzioMed, Inc. (San Luis Obispo, CA) makes OXIPLEX/SP Gel which is being sold as an adhesion barrier for spine surgery. OXIPLEXISP Gel is being used for the reduction of pain and radiculopathy in laminectomy, laminotomy and discectomy surgeries.
Products being developed by FzioMed, Inc, are described in, for example, U.S.
Patent Nos. 6,566,345 and 6,017,301. Anika Therapeutics, Inc. (Woburn, MA) is developing INCERT-S for the prevention of internal adhesions or scarring following spinal surgery. INCERT-S is part of a potential family of bioabsorbable, chemically modified hyaluronic acid therapies. Products being developed by Anika Therapeutics, Inc. are described in, for example, U.S.
Patent Nos. 6,548,081; 6,537,979; 6,096,727; 6,013,679; 5,502,081 and 5,356,883. Life Medical Sciences, Inc. (Little Silver, NJ) is developing RELIEVE as a bio-resorbable polymer designed to prevent or reduce the formation of adhesions that can follow spinal surgery. Products being developed by Life Medical Sciences, Inc. are described in, for example, U.S.
Patent Nos. 6,696,499; 6,399,624; 6,211,249; 6,136,333 and 5,711,958.
Wright Medical Technology, Inc. is selling the ADCON range of products which are dextran sulfate gels originally developed by Gliatech, Inc. (Beachwood, OH) to inhibit postsurgical peridural fibrosis that occurs in posterior lumbar laminectomy or laminotomy procedures where nerve routes are exposed.
ADCON provides a barrier between the spinal cord and nerve roots and the surrounding muscle and bone following lumbar spine surgeries. The ADCON
range of products may be described in, for example, U.S. Patent Nos.
6,417,173; 6,127,348; 6,083,930; 5,994,325 and 5,705,178.
Other commercially available materials that may be used alone or loaded with a therapeutic agent (e.g., a fibrosis-inhibiting agent and/or an anti infective agent), applied to or infiltrated into a spinal or neurosurgical site (or to an implant surface) for the prevention of adhesions include: (a) sprayable collagen-containing formulations such as COSTASIS or CT3; (b) sprayable PEG-containing formulations such as COSEAL, ADHIBIT, FOCALSEAL, or SPRAYGEL; (c) fibrinogen-containing formulations such as FLOSEAL or TISSEAL (both from Baxter Healthcare Corporation, Fremont, CA); (d) hyaluronic acid-containing formulations such as RESTYLANE, PERLANE, HYLAFORM, SYNVISC, SEPRAFILM or SEPRACOAT; (e) polymeric gels for surgical implantation such as REPEL or FLOWGEL; (f) surgical adhesives containing cyanoacrylates such as DERMABOND, INDERMIL, GLUSTITCH, TISSUMEND, VETBOND, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT; (h) lipid based compositions such as ADSURF, and (j) film compositions such as INTERCEED (Ethicon, Inc., Somerville, NJ) and HYDROSORB (MacroPore Biosurgery, Inc., San Diego, CA /Medtronic Sofamor Danek, Memphis, TN). It should be obvious to one of skill in the art that commercial compositions not specifically cited above as well as next-generation and/or subsequently-developed commercial products are to be anticipated and are suitable for use under the present invention.
As described above, the compositions for the prevention of surgical adhesions can be applied directly or indirectly to the tissue in a spinal or neurosurgical site. The polymeric compositions (either with or without a therapeutic agent) can be administered in any manner described herein.
Exemplary methods include either direct application at the time of surgery, with endoscopic, ultrasound, CT, MRI, or fluoroscopic guidance, and/or in conjunction with the placement of a device or implant at the surgical site.
Representative examples of devices or implants for use in spinal and neurosurgical procedures includes, without limitation, dural patches, spinal prostheses (e.g., artificial discs, injectable filling or bulking agents for discs, spinal grafts, spinal nucleus implants, intervertebral disc spacers), fusion cages, neurostimulation devices, implantable drug-delivery pumps, shunts, drains, electrodes, and bone fixation devices (e.g., anchoring plates and bone screws).
The polymeric composition, with or without a fibrosis-inhibiting agent, may be applied during open or endoscopic procedures: (a) to the surface of the operative site (e.g., as an injectable, solution, paste, gel, in situ forming gel or mesh) before, during, or after the surgical procedure; (b) to the surface of the tissue surrounding the operative site (e.g., as an injectable, solution, paste, gel, in situ forming gel or mesh) before, during or after the surgical procedure;

(c) by topical application of the composition into an anatomical space (such as the subdural space or intrathecally) at the surgical site (particularly useful for this embodiment is the use of polymeric carriers which release the fibrosis-inhibiting agent over a period ranging from several hours to several weeks -fluids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticulates, sprays, aerosols, solid implants and other formulations which release the agent and can be delivered into the region where the device will be inserted); (d) via percutaneous injection into the tissue in and around the operative site as a solution, as an infusate, or as a sustained release preparation; and/or (e) by any combination of the aforementioned methods.
Combination therapies (i.e., combinations of therapeutic agents and combinations with antithrombotic, anti-infective, and/or antiplatelet agents) can also be used.
In certain applications involving the placement of a medical device or implant, it may be desirable to apply the anti-fibrosis (and/or anti-infective) composition at a site that is adjacent to an implant (preferably near the implant-tissue interface). This can be accomplished during open or endoscopic procedures by applying the polymeric composition, with or without a fibrosis-inhibiting agent: (a) to the implant surface (e.g., as an injectable, solution, paste, gel, in situ forming gel, or mesh) before, during, or after the implantation procedure; (b) to the surface of the adjacent tissue (e.g., as an injectable, solution, paste, gel, in situ forming gel, or mesh) immediately prior to, during, or after implantation of the implant; (c) to the surface of the implant and the tissue surrounding the implant (e.g., as an injectable, solution, paste, gel, in situ forming gel or mesh) before, during, or after implantation of the implant; (d) by topical application of the composition into the anatomical space (such as the sudural space or intrathecally) where the implant will be placed (particularly useful for this embodiment is the use of polymeric carriers which release the fibrosis-inhibiting agent over a period ranging from several hours to several weeks - fluids, suspensions, emulsions, microemulsions, microspheres, pastes, DEMANDE OU BREVET VOLUMINEUX
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Claims (4907)

1. A method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with i) an anti-fibrotic agent, ii) an anti-infective agent, iii) a polymer;
iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

2. The method for implanting a medical device according to claim 1 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-fibrotic agent, and (b) implanting the medical device into the host.

3. The method for implanting a medical device according to claim 1 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-infective agent, and (b) implanting the medical device into the host.

4. The method for implanting a medical device according to claim 1 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a polymer; and (b) implanting the medical device into the host.

5. The method for implanting a medical device according to claim 1 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent and a polymer, and (b) implanting the medical device into the host.

6. The method for implanting a medical device according to claim 1 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

7. The method for implanting a medical device according to claim 1 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

8. The method of any one of claims 1-7 wherein the device is an intravascular device.

9. The method of any one of claims 1-7 wherein the device is a gastrointestinal stent.

10. The method of any one of claims 1-7 wherein the device is a tracheal and bronchial stent.

11. The method of any one of claims 1-7 wherein the device is a genital urinary stent.

12. The method of any one of claims 1-7 wherein the device is an ear and nose stent.

13. The method of any one of claims 1-7 wherein the device is an ear ventilation device.

14. The method of any one of claims 1-7 wherein the device is an intraocular implant.

15. The method of any one of claims 1-7 wherein the device is a vascular graft.

16. The method of any one of claims 1-7 wherein the device comprises a film or a mesh.

17. The method of any one of claims 1-7 wherein the device is a glaucoma drainage device.

18. The method of any one of claims 1-7 wherein the device is a prosthetic heart valve or a component thereof.

19. The method of any one of claims 1-7 wherein the device is a penile implant.

20. The method of any one of claims 1-7 wherein the device is an endotracheal or tracheostomy tube.

21. The method of any one of claims 1-7 wherein the device is a peritoneal dialysis catheter.

22. The method of any one of claims 1-7 wherein the device is a central nervous system shunt or a pressure monitoring device.

23. The method of any one of claims 1-7 wherein the device is an inferior vena cava filter.

24. The method of any one of claims 1-7 wherein the device is a gastrointestinal device.

25. The method of any one of claims 1-7 wherein the device is a central venous catheter.

26. The method of any one of claims 1-7 wherein the device is a ventricular assist device.

27. The method of any one of claims 1-7 wherein the device is a spinal implant.

28. The method of any one of claims 1-7 wherein the device is an implantable electrical device.

29. The method of any one of claims 1-7 wherein the device is an implantable sensor.

30. The method of any one of claims 1-7 wherein the device is an implantable pump.

31. The method of any one of claims 1-7 wherein the device is a soft tissue implant.

32. The method of claim 1 wherein the anti-fibrotic agent inhibits cell regeneration.

33. The method of claim 1 wherein the anti-fibrotic agent inhibits angiogenesis.

34. The method of claim 1 wherein the anti-fibrotic agent inhibits fibroblast migration.

35. The method of claim 1 wherein the anti-fibrotic agent inhibits fibroblast proliferation.

36. The method of claim 1 wherein the anti-fibrotic agent inhibits deposition of extracellular matrix.

37. The method of claim 1 wherein the anti-fibrotic agent inhibits tissue remodeling.

38. The method of claim 1 wherein the anti-fibrotic agent is an angiogenesis inhibitor.

39. The method of claim 1 wherein the anti-fibrotic agent is a 5-lipoxygenase inhibitor or antagonist.

40. The method of claim 1 wherein the anti-fibrotic agent is a chemokine receptor antagonist.

41. The method of claim 1 wherein the anti-fibrotic agent is a cell cycle inhibitor.

42. The method of claim 1 wherein the anti-fibrotic agent is a taxane.

43. The method of claim 1 wherein the anti-fibrotic agent is an anti-microtubule agent.

44. The method of claim 1 wherein the anti-fibrotic agent is paclitaxel.

45. The method of claim 1 wherein the anti-fibrotic agent is not paclitaxel.

46. The method of claim 1 wherein the anti-fibrotic agent is an analogue or derivative of paclitaxel.

47. The method of claim 1 wherein the anti-fibrotic agent is a vinca alkaloid.

48. The method of claim 1 wherein the anti-fibrotic agent is camptothecin or an analogue or derivative thereof.

49. The method of claim 1 wherein the anti-fibrotic agent is a podophyllotoxin.

50. The method of claim 1 wherein the anti-fibrotic agent is a podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof.

51. The method of claim 1 wherein the anti-fibrotic agent is an anthracycline.

52. The method of claim 1 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof.

53. The method of claim 1 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof.

54. The method of claim 1 wherein the anti-fibrotic agent is a platinum compound.

55. The method of claim 1 wherein the anti-fibrotic agent is a nitrosourea.

56. The method of claim 1 wherein the anti-fibrotic agent is a nitroimidazole.

57. The method of claim 1 wherein the anti-fibrotic agent is a folic acid antagonist.

58. The method of claim 1 wherein the anti-fibrotic agent is a cytidine analogue.

59. The method of claim 1 wherein the anti-fibrotic agent is a pyrimidine analogue.

60. The method of claim 1 wherein the anti-fibrotic agent is a fluoropyrimidine analogue.

61. The method of claim 1 wherein the anti-fibrotic agent is a purine analogue.

62. The method of claim 1 wherein the anti-fibrotic agent is a nitrogen mustard or an analogue or derivative thereof.

63. The method of claim 1 wherein the anti-fibrotic agent is a hydroxyurea.

64. The method of claim 1 wherein the anti-fibrotic agent is a mytomicin or an analogue or derivative thereof.

65. The method of claim 1 wherein the anti-fibrotic agent is an alkyl sulfonate.

66. The method of claim 1 wherein the anti-fibrotic agent is a benzamide or an analogue or derivative thereof.

67. The method of claim 1 wherein the anti-fibrotic agent is a nicotinamide or an analogue or derivative thereof.

68. The method of claim 1 wherein the anti-fibrotic agent is a halogenated sugar or an analogue or derivative thereof.

69. The method of claim 1 wherein the anti-fibrotic agent is a DNA alkylating agent.

70. The method of claim 1 wherein the anti-fibrotic agent is an anti-microtubule agent.

71. The method of claim 1 wherein the anti-fibrotic agent is a topoisomerase inhibitor.

72. The method of claim 1 wherein the anti-fibrotic agent is a DNA cleaving agent.

73. The method of claim 1 wherein the anti-fibrotic agent is an antimetabolite.

74. The method of claim 1 wherein the anti-fibrotic agent inhibits adenosine deaminase.

75. The method of claim 1 wherein the anti-fibrotic agent, inhibits purine ring synthesis.

76. The method of claim 1 wherein the anti-fibrotic agent is a nucleotide interconversion inhibitor.

77. The method of claim 1 wherein the anti-fibrotic agent inhibits dihydrofolate reduction.

78. The method of claim 1 wherein the anti-fibrotic agent blocks thymidine monophosphate.

79. The method of claim 1 wherein the anti-fibrotic agent causes DNA damage.

80. The method of claim 1 wherein the anti-fibrotic agent is a DNA intercalation agent.

81. The method of claim 1 wherein the anti-fibrotic agent is a RNA synthesis inhibitor.

82. The method of claim 1 wherein the anti-fibrotic agent is a pyrimidine synthesis inhibitor.

83. The method of claim 1 wherein the anti-fibrotic agent inhibits ribonucleotide synthesis or function.

84. The method of claim 1 wherein the anti-fibrotic agent inhibits thymidine monophosphate synthesis or function.

85. The method of claim 1 wherein the anti-fibrotic agent inhibits DNA synthesis.

86. The method of claim 1 wherein the anti-fibrotic agent causes DNA adduct formation.

87. The method of claim 1 wherein the anti-fibrotic agent inhibits protein synthesis.

88. The method of claim 1 wherein the anti-fibrotic agent inhibits microtubule function.

89. The method of claim 1 wherein the anti-fibrotic agent is a cyclin dependent protein kinase inhibitor.

90. The method of claim 1 wherein the anti-fibrotic agent is an epidermal growth factor kinase inhibitor.

91. The method of claim 1 wherein the anti-fibrotic agent is an elastase inhibitor.

92. The method of claim 1 wherein the anti-fibrotic agent is a factor Xa inhibitor.

93. The method of claim 1 wherein the anti-fibrotic agent is a farnesyltransferase inhibitor.

94. The method of claim 1 wherein the anti-fibrotic agent is a fibrinogen antagonist.

95. The method of claim 1 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

96. The method of claim 1 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist.

97. The method of claim 1 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof.

98. The method of claim 1 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

99. The method of claim 1 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor.

100. The method of claim 1 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof.

101. The method of claim 1 wherein the anti-fibrotic agent is a hydroorotate dehydrogenase inhibitor.

102. The method of claim 1 wherein the anti-fibrotic agent is an IKK2 inhibitor.

103. The method of claim 1 wherein the anti-fibrotic agent is an IL-1 antagonist.

104. The method of claim 1 wherein the anti-fibrotic agent is an ICE antagonist.

105. The method of claim 1 wherein the anti-fibrotic agent is an IRAK antagonist.

106. The method of claim 1 wherein the anti-fibrotic agent is an IL-4 agonist.

107. The method of claim 1 wherein the anti-fibrotic agent is an immunomodulatory agent.

108. The method of claim 1 wherein the anti-fibrotic agent is sirolimus or an analogue or derivative thereof.

109. The method of claim 1 wherein the anti-fibrotic agent is not sirolimus.

110. The method of claim 1 wherein the anti-fibrotic agent is everolimus or an analogue or derivative thereof.

111. The method of claim 1 wherein the anti-fibrotic agent is tacrolimus or an analogue or derivative thereof.

112. The method of claim 1 wherein the anti-fibrotic agent is not tacrolimus.

113. The method of claim 1 wherein the anti-fibrotic agent is biolmus or an analogue or derivative thereof.

114. The method of claim 1 wherein the anti-fibrotic agent is tresperimus or an analogue or derivative thereof.

115. The method of claim 1 wherein the anti-fibrotic agent is auranofin or an analogue or derivative thereof.

116. The method of claim 1 wherein the anti-fibrotic agent is 27-0-demethylrapamycin or an analogue or derivative thereof.

117. The method of claim 1 wherein the anti-fibrotic agent is gusperimus or an analogue or derivative thereof.

118. The method of claim 1 wherein the anti-fibrotic agent is pimecrolimus or an analogue or derivative thereof.

119. The method of claim 1 wherein the anti-fibrotic agent is ABT-578 or an analogue or derivative thereof.

120. The method of claim 1 wherein the anti-fibrotic agent is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.

121. The method of claim 1 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof.

122. The method of claim 1 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-alpha-25 dihydroxy vitamin D3 or an analogue or derivative thereof.

123. The method of claim 1 wherein the anti-fibrotic agent is a leukotriene inhibitor.

124. The method of claim 1 wherein the anti-fibrotic agent is a MCP-1 antagonist.

125. The method of claim 1 wherein the anti-fibrotic agent is a MMP inhibitor.

126. The method of claim 1 wherein the anti-fibrotic agent is an NF kappa B inhibitor.

127. The method of claim 1 wherein the anti-fibrotic agent is an NF kappa B inhibitor, wherein the NF kappa B inhibitor is Bay 11-7082.

128. The method of claim 1 wherein the anti-fibrotic agent is an NO antagonist.

129. The method of claim 1 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor.

130. The method of claim 1 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB 202190.

131. The method of claim 1 wherein the anti-fibrotic agent is a phosphodiesterase inhibitor.

132. The method of claim 1 wherein the anti-fibrotic agent is a TGF beta inhibitor.

133. The method of claim 1 wherein the anti-fibrotic agent is a thromboxane A2 antagonist.

134. The method of claim 1 wherein the anti-fibrotic agent is a TNF alpha antagonist.

135. The method of claim 1 wherein the anti-fibrotic agent is a TACE inhibitor.

136. The method of claim 1 wherein the anti-fibrotic agent is a tyrosine kinase inhibitor.

137. The method of claim 1 wherein the anti-fibrotic agent is a vitronectin inhibitor.

133. The method of claim 1 wherein the anti-fibrotic agent is a fibroblast growth factor inhibitor.

139. The method of claim 1 wherein the anti-fibrotic agent is a protein kinase inhibitor.

140. The method of claim 1 wherein the anti-fibrotic agent is a PDGF receptor kinase inhibitor.

141. The method of claim 1 wherein the anti-fibrotic agent is an endothelial growth factor receptor kinase inhibitor.

142. The method of claim 1 wherein the anti-fibrotic agent is a retinoic acid receptor antagonist.

143. The method of claim 1 wherein the anti-fibrotic agent is a platelet derived growth factor receptor kinase inhibitor.

144. The method of claim 1 wherein the anti-fibrotic agent is a fibrinogen antagonist.

145. The method of claim 1 wherein the anti-fibrotic agent is an antimycotic agent.

146. The method of claim 1 wherein the anti-fibrotic agent is an antimycotic agent, wherein the antimycotic agent is sulconizole.

147. The method of claim 1 wherein the anti-fibrotic agent is a bisphosphonate.

148. The method of claim 1 wherein the anti-fibrotic agent is a phospholipase A1 inhibitor.

149. The method of claim 1 wherein the anti-fibrotic agent is a histamine H1/H2/H3 receptor antagonist.

150. The method of claim 1 wherein the anti-fibrotic agent is a macrolide antibiotic.

151. The method of claim 1 wherein the anti-fibrotic agent is a GPIIb/IIIa receptor antagonist.

152. The method of claim 1 wherein the anti-fibrotic agent is an endothelin receptor antagonist.

153. The method of claim 1 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor agonist.

154. The method of claim 1 wherein the anti-fibrotic agent is an estrogen receptor agent.

155. The method of claim 1 wherein the anti-fibrotic agent is a somastostatin analogue.

156. The method of claim 1 wherein the anti-fibrotic agent is a neurokinin 1 antagonist.

157. The method of claim 1 wherein the anti-fibrotic agent is a neurokinin 3 antagonist.

158. The method of claim 1 wherein the anti-fibrotic agent is a VLA-4 antagonist.

159. The method of claim 1 wherein the anti-fibrotic agent is an osteoclast inhibitor.

160. The method of claim 1 wherein the anti-fibrotic agent is a DNA topoisomerase ATP hydrolyzing inhibitor.

161. The method of claim 1 wherein the anti-fibrotic agent is an angiotensin I converting enzyme inhibitor.

162. The method of claim 1 wherein the anti-fibrotic agent is an angiotensin II antagonist.

163. The method of claim 1 wherein the anti-fibrotic agent is an enkephalinase inhibitor.

164. The method of claim 1 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer.

165. The method of claim 1 wherein the anti-fibrotic agent is a protein kinase C inhibitor.

166. The method of claim 1 wherein the anti-fibrotic agent is a ROCK (rho-associated kinase) inhibitor.

167. The method of claim 1 wherein the anti-fibrotic agent is a CXCR3 inhibitor.

168. The method of claim 1 wherein the anti-fibrotic agent is an Itk inhibitor.

169. The method of claim 1 wherein the anti-fibrotic agent is a cytosolic phospholipase A2-alpha inhibitor.

170. The method of claim 1 wherein the anti-fibrotic agent is a PPAR agonist.

171. The method of claim 1 wherein the anti-fibrotic agent is an immunosuppressant.

172. The method of claim 1 wherein the anti-fibrotic agent is an Erb inhibitor.

173. The method of claim 1 wherein the anti-fibrotic agent is an apoptosis agonist.

174. The method of claim 1 wherein the anti-fibrotic agent is a lipocortin agonist.

175. The method of claim 1 wherein the anti-fibrotic agent is a VCAM-1 antagonist.

176. The method of claim 1 wherein the anti-fibrotic agent is a collagen antagonist.

177. The method of claim 1 wherein the anti-fibrotic agent is an alpha 2 integrin antagonist.

178. The method of claim 1 wherein the anti-fibrotic agent is a TNF alpha inhibitor.

179. The method of claim 1 wherein the anti-fibrotic agent is a nitric oxide inhibitor

180. The method of claim 1 wherein the anti-fibrotic agent is a cathepsin inhibitor.

181. The method of claim 1 wherein the anti-fibrotic agent is not an anti-inflammatory agent.

182. The method of claim 1 wherein the anti-fibrotic agent is not a steroid.

183. The method of claim 1 wherein the anti-fibrotic agent is not a glucocorticosteroid.

184. The method of claim 1 wherein the anti-fibrotic agent is not dexamethasone.

185. The method of claim 1 wherein the anti-fibrotic agent is not beclomethasone.

186. The method of claim 1 wherein the anti-fibrotic agent is not dipropionate.

187. The method of claim 1 wherein the anti-fibrotic agent is not an anti-infective agent.

188. The method of claim 1 wherein the anti-fibrotic agent is not an antibiotic.

189. The method of claim 1 wherein the anti-fibrotic agent is not an anti-fungal agent.

190. The method of claim 1 wherein the anti-infective agent isan anthracycline.

191. The method of claim 1 wherein the anti-infective agent isdoxorubicin.

192. The method of claim 1 wherein the anti-infective agent is ismitoxantrone.

193. The method of claim 1 wherein the anti-infective agent is a fluoropyrimidine.

194. The method of claim 1 wherein the anti-infective agent is 5-fluorouracil (5-FU).

195. The method of claim 1 wherein the anti-infective agent is a folic acid antagonist.

196. The method of claim 1 wherein the anti-infective agent is methotrexate.

197. The method of claim 1 wherein the anti-infective agent is a podophylotoxin.

198. The method of claim 1 wherein the anti-infective agent is etoposide.

199. The method of claim 1 wherein the anti-infective agent is camptothecin.

200. The method of claim 1 wherein the anti-infective agent is a hydroxyurea.

201. The method of claim 1 wherein the anti-infective agent is a platinum complex.

202. The method of claim 1 wherein the anti-infective agent is cisplatin.

203. The method of claim 1 wherein the composition comprises an anti-thrombotic agent.

204. The method of claim 1 wherein the polymer is formed from reactants comprising a naturally occurring polymer.

205. The method of claim 1 wherein the polymer is formed from reactants comprising protein.

206. The method of claim 1 wherein the polymer is formed from reactants comprising carbohydrate.

207. The method of claim 1 wherein the polymer is formed from reactants comprising biodegradable polymer.

208. The method of claim 1 wherein the polymer is formed from reactants comprising nonbiodegradable polymer.

209. The method of claim 1 wherein the polymer is formed from reactants comprising collagen.

210. The method of claim 1 wherein the polymer is formed from reactants comprising methylated collagen.

211. The method of claim 1 wherein the polymer is formed from reactants comprising fibrinogen.

212. The method of claim 1 wherein the polymer is formed from reactants comprising thrombin.

213. The method of claim 1 wherein the polymer is formed from reactants comprising blood plasma.

214. The method of claim 1 wherein the polymer is formed from reactants comprising calcium salt.

215. The method of claim 1 wherein the polymer is formed from reactants comprising an antifibronolytic agent.

216. The method of claim 1 wherein the polymer is formed from reactants comprising fibrinogen analog.

217. The method of claim 1 wherein the polymer is formed from reactants comprising albumin.

218. The method of claim 1 wherein the polymer is formed from reactants comprising plasminogen.

219. The method of claim 1 wherein the polymer is formed from reactants comprising von Willebrands factor.

220. The method of claim 1 wherein the polymer is formed from reactants comprising Factor VIII.

221. The method of claim 1 wherein the polymer is formed from reactants comprising hypoallergenic collagen.

222. The method of claim 1 wherein the polymer is formed from reactants comprising atelopeptidic collagen.

223. The method of claim 1 wherein the polymer is formed from reactants comprising telopeptide collagen.

224. The method of claim 1 wherein the polymer is formed from reactants comprising crosslinked collagen.

225. The method of claim 1 wherein the polymer is formed from reactants comprising aprotinin.

226. The method of claim 1 wherein the polymer is formed from reactants comprising epsilon-amino-n-caproic acid.

227. The method of claim 1 wherein the polymer is formed from reactants comprising gelatin.

228. The method of claim 1 wherein the polymer is formed from reactants comprising protein conjugates.

229. The method of claim 1 wherein the polymer is formed from reactants comprising gelatin conjugates.

230. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic polymer.

231. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic isocyanate-containing compound.

232. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic thiol-containing compound.

233. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two thiol groups.

234. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three thiol groups.

235. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four thiol groups.

236. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic amino-containing compound.

237. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two amino groups.

238. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three amino groups.

239. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four amino groups.

240. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group.

241. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups.

242. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.

243. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.

244. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound.

245. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.

246. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive amino groups.

247. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive thiol groups.

248. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups.

249. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic compound comprising a biodegradable polyester block.

250. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from lactic acid or lactide.

251. The method of claim 1 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from glycolic acid or glycolide.

252. The method of claim 1 wherein the polymer is formed from reactants comprising polylysine.

253. The method of claim 1 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound comprising a polyalkylene oxide portion.

254. The method of claim 1 wherein the polymer is formed from reactants comprising (a) protein and (b) polylysine.

255. The method of claim 1 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four thiol groups.

256. The method of claim 1 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four amino groups.

257. The method of claim 1 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

258. The method of claim 1 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

259. The method of claim 1 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound comprising a polyalkylene oxide portion.

260. The method of claim 1 wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine.

261. The method of claim 1 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four thiol groups.

262. The method of claim 1 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four amino groups.

263. The method of claim 1 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

264. The method of claim 1 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

265. The method of claim 1 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound comprising a polyalkylene oxide portion.

266. The method of claim 1 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine.

267. The method of claim 1 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four thiol groups.

263. The method of claim 1 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four amino groups.

269. The method of claim 1 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

270. The method of claim 1 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

271. The method of claim 1 wherein the polymer is formed from reactants comprising hyaluronic acid.

272. The method of claim 1 wherein the polymer is formed from reactants comprising a hyaluronic acid derivative.

273. The method of claim 1 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.

274. The method of claim 1 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.

275. The method of claim 1 wherein the polymer is formed from reactants comprising (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.

276. The method of claim 1 wherein the composition comprises a colorant.

277. The method of claim 1 wherein the composition is sterile.

278. A method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with i) an anti-fibrotic agent, ii) an anti-infective agent, iii) a polymer;
iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host, wherein the medical device is an intravascular device.

279. The method for implanting a medical device according to claim 278 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-fibrotic agent, and (b) implanting the medical device into the host.

280. The method for implanting a medical device according to claim 278 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-infective agent, and (b) implanting the medical device into the host.

281. The method for implanting a medical device according to claim 278 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a polymer; and (b) implanting the medical device into the host.

282. The method for implanting a medical device according to claim 278 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent and a polymer, and (b) implanting the medical device into the host.

283. The method for implanting a medical device according to claim 278 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

284. The method for implanting a medical device according to claim 278 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

285. The method of claim 278 wherein the medical device is a catheter.

286. The method of claim 278 wherein the medical device is a balloon catheter.

287. The method of claim 278 wherein the medical device is a balloon.

288. The method of claim 278 wherein the medical device is a stent graft.

289. The method of claim 278 wherein the medical device is a guidewire.

290. The method of claim 278 wherein the medical device is a stent.

291. The method of claim 278 wherein the medical device is an intravascular stent.

292. The method of claim 278 wherein the medical device is a metallic stent.

293. The method of claim 278 wherein the medical device is a polymeric stent.

294. The method of claim 278 wherein the medical device is a biodegradable stent.

295. The method of claim 278 wherein the medical device is a non-biodegradable stent.

296. The method of claim 278 wherein the medical device is a self expandable stent.

297. The method of claim 278 wherein the medical device is a balloon expandable stent.

298. The method of claim 278 wherein the medical device is a covered stent.

299. The method of claim 278 wherein the medical device is a drug eluting stent.

300. The method of claim 278 wherein the medical device is a stent that comprises a radio-opaque material.

301. The method of claim 278 wherein the medical device is a stent that comprises an echogenic material.

302. The method of claim 278 wherein the medical device is a stent that comprise an MRI responsive material.

303. The method of claim 278 wherein the medical device is an anastomotic connector device.

304. The method of claim 278 wherein the medical device is an artery to artery anastomotic connector device.

305. The method of claim 278 wherein the medical device is a vein to artery anastomotic connector device.

306. The method of claim 278 wherein the medical device is an artery to vein anastomotic connector device.

307. The method of claim 278 wherein the medical device is an artery to synthetic graft anastomotic connector device.

308. The method of claim 278 wherein the medical device is a synthetic graft to artery anastomotic conncector device.

309. The method of claim 278 wherein the medical device is a vein to synthetic graft anastomotic connector device.

310. The method of claim 278 wherein the medical device is a synthetic graft to vein anastomotic connector device.

311. The method of claim 278 wherein the medical device is a vascular clip.

312. The method of claim 278 wherein the medical device is a vascular suture.

313. The method of claim 278 wherein the medical device is a vascular clamp.

314. The method of claim 278 wherein the medical device is a suturing device.

315. The method of claim 278 wherein the medical device is an anastomotic coupler.

316. The method of claim 278 wherein the medical device is an automated or modified suture device.

317. The method of claim 278 wherein the medical device is a micromehical anastomotic connector device.

318. The method of claim 278 wherein the medical device is an anastomotic coupling device that facilitates automated attachement of a graft or vessel to an aperture or orifice in a target vessel without the use of sutures or staples.

319. The method of claim 278 wherein the medical device is an anastomotic coupling device that comprises a tubular graft conduit and may be placed in a side wall of a target vessel so that the tubular graft conduit may be extended from the target vessel.

320. The method of claim 278 wherein the medical device is an anastomotic coupler in the form of a frame.

321. The method of claim 278 wherein the medical device is an anastomotic coupler in a ring-like form.

322. The method of claim 278 wherein the medical device is a resorbable anastomotic coupler.

323. The method of claim 278 wherein the medical device is an anastomotic coupler that comprises a bioabsorbable and elastomeric material.

324. The method of claim 278 wherein the medical device is an anastomotic coupler adapted to connect a first blood vessel with a second blood vessel with a graft vessel.

325. The method of claim 278 wherein the medical device is an anastomotic coupler adapted to connect a first blood vessel with a second blood vessel without a graft vessel.

326. The method of claim 278 wherein the medical device is an anastomotic coupler that is incorporated in the design of a vascular graft.

327. The method of claim 278 wherein the medical device is an anastomotic coupler that comprises a graft that incorporates a fixation mechanism.

328. The method of claim 278 wherein the medical device is an anastomotic coupler that comprises a compressible, expandable fitting for securing the ends of a bypass graft to two vessels.

329. The method of claim 278 wherein the medical device is an anastomotic coupler that comprises a pair of coupling disc members for joining two vessels in an end to end or end to side fashion.

330. The method of claim 278 wherein the medical device is a proximal aortic connector.

331. The method of claim 278 wherein the medical device is a distal coronary connector.

332. The method of claim 278 wherein the medical device is a bypass device made of a biocompatible material.

333. The method of claim 278 wherein the medical device is a bypass device made of at least partially a metal or metal alloy.

334. The method of claim 278 wherein the medical device is a bypass device made of at least partially a synthetic polymer.

335. The method of claim 278 wherein the medical device is a bypass device made of at least partially naturally derived polymer.

336. The method of claim 278 wherein the medical device is a tubular anastomotic coupler that comprises a tubular structure that may be attached directly to a proximal blood vessel.

337. The method of claim 278 wherein the medical device is a tubular anastomotic coupler that comprises a tubular structure that may be attached directly to a distal blood vessel.

338. The method of claim 278 wherein the medical device is a tubular anastomotic coupler that has a proximal end attachable to a proximal vessel and a distal end attachable to a bypass graft.

339. The method of claim 278 wherein the medical device is a tubular anastomotic coupler that has a proximal end attachable to a graft vessel that is secured to a proximal blood vessel and a distal end attachable to a distal blood vessel.

340. The method of claim 278 wherein the medical device is an anastomotic connector device adapted for end to end anastomosis procedures.

341. The method of claim 278 wherein the medical device is an anastomotic stent.

342. The method of claim 278 wherein the medical device is anastomotic sleeve.

343. The method of claim 278 wherein the medical device is an anastomotic connector device adapted for end to side anastomosis procedures.

344. The method of claim 278 wherein the medical device is a single lumen bypass device.

345. The method of claim 278 wherein the medical device is a multi-lumen bypass device.

346. The method of claim 278 wherein the medical device is an anastomotic coupling device that comprises a single tubular portion that may be used as a shunt to divert blood from a source vessel to a graft vessel.

347. The method of claim 278 wherein the medical device is anastomotic coupling device that comprises more than one tubular portion, and wherein at least one tubular portion may be used as a shunt for diverting blood between a source vessel and a target vessel.

348. The method of claim 278 wherein the medical device is an anastomotic connector device that comprises a tubular portion, and wherein one or more ends of the tubular portion may be inserted into the end or into the side of one or more blood vessels.

349. The method of claim 278 wherein the medical device is a multi-lumen anastomotic connector device that at least one arm of the device may be attached to a graft vessel.

350. The method of claim 278 wherein the medical device is an anastomotic connector device that includes three or more tubular arms that extend from a junction site.

351. The method of claim 278 wherein the medical device is a multi-lumen anastomotic connector device is generally T-shaped.

352. The method of claim 278 wherein the medical device is a multi-lumen anastomotic connector device is generally Y shaped.

353. The method of claim 278 wherein the medical device is an anastomotic connector device that comprises a tube for bypassing blood flow directly from a portion of the heart to a coronary artery.

354. The method of claim 278 wherein the medical device is an anastomotic connector device that comprises a network of interconnected tubular conduits.

355. The method of claim 278 wherein the medical device is an anastomotic connector device that is configured with two or more termini that provide a vessel interface without the need for sutures and a fluid communication through an intersecting lumen.

356. The method of claim 278 wherein the anti-fibrotic agent inhibits cell regeneration.

357. The method of claim 278 wherein the anti-fibrotic agent inhibits angiogenesis.

358. The method of claim 278 wherein the anti-fibrotic agent inhibits fibroblast migration.

359. The method of claim 278 wherein the anti-fibrotic agent inhibits fibroblast proliferation.

360. The method of claim 278 wherein the anti-fibrotic agent inhibits deposition of extracellular matrix.

361. The method of claim 278 wherein the anti-fibrotic agent inhibits tissue remodeling.

362. The method of claim 278 wherein the anti-fibrotic agent is an angiogenesis inhibitor.

363. The method of claim 278 wherein the anti-fibrotic agent is a 5-lipoxygenase inhibitor or antagonist.

364. The method of claim 278 wherein the anti-fibrotic agent is a chemokine receptor antagonist.

365. The method of claim 278 wherein the anti-fibrotic agent is a cell cycle inhibitor.

366. The method of claim 278 wherein the anti-fibrotic agent is a taxane.

367. The method of claim 278 wherein the anti-fibrotic agent is an anti-microtubule agent.

368. The method of claim 278 wherein the anti-fibrotic agent is paclitaxel.

369. The method of claim 278 wherein the anti-fibrotic agent is not paclitaxel.

370. The method of claim 278 wherein the anti-fibrotic agent is an analogue or derivative of paclitaxel.

371. The method of claim 278 wherein the anti-fibrotic agent is a vinca alkaloid.

372. The method of claim 278 wherein the anti-fibrotic agent is camptothecin or an analogue or derivative thereof.

373. The method of claim 278 wherein the anti-fibrotic agent is a podophyllotoxin.

374. The method of claim 278 wherein the anti-fibrotic agent is a podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof.

375. The method of claim 278 wherein the anti-fibrotic agent is an anthracycline.

376. The method of claim 278 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof.

377. The method of claim 278 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof.

378. The method of claim 278 wherein the anti-fibrotic agent is a platinum compound.

379. The method of claim 278 wherein the anti-fibrotic agent is a nitrosourea.

380. The method of claim 278 wherein the anti-fibrotic agent is a nitroimidazole.

381. The method of claim 278 wherein the anti-fibrotic agent is a folic acid antagonist.

382. The method of claim 278 wherein the anti-fibrotic agent is a cytidine analogue.

383. The method of claim 278 wherein the anti-fibrotic agent is a pyrimidine analogue.

384. The method of claim 278 wherein the anti-fibrotic agent is a fluoropyrimidine analogue.

385. The method of claim 278 wherein the anti-fibrotic agent is a purine analogue.

386. The method of claim 278 wherein the anti-fibrotic agent is a nitrogen mustard or an analogue or derivative thereof.

387. The method of claim 278 wherein the anti-fibrotic agent is a hydroxyurea.

388. The method of claim 278 wherein the anti-fibrotic agent is a mytomicin or an analogue or derivative thereof.

389. The method of claim 278 wherein the anti-fibrotic agent is an alkyl sulfonate.

390. The method of claim 278 wherein the anti-fibrotic agent is a benzamide or an analogue or derivative thereof.

391. The method of claim 278 wherein the anti-fibrotic agent is a nicotinamide or an analogue or derivative thereof.

392. The method of claim 278 wherein the anti-fibrotic agent is a halogenated sugar or an analogue or derivative thereof.

393. The method of claim 278 wherein the anti-fibrotic agent is a DNA alkylating agent.

394. The method of claim 278 wherein the anti-fibrotic agent is an anti-microtubule agent.

395. The method of claim 278 wherein the anti-fibrotic agent is a topoisomerase inhibitor.

396. The method of claim 278 wherein the anti-fibrotic agent is a DNA cleaving agent.

397. The method of claim 278 wherein the anti-fibrotic agent is an antimetabolite.

398. The method of claim 278 wherein the anti-fibrotic agent inhibits adenosine deaminase.

399. The method of claim 278 wherein the anti-fibrotic agent inhibits purine ring synthesis.

400. The method of claim 278 wherein the anti-fibrotic agent is a nucleotide interconversion inhibitor.

401. The method of claim 278 wherein the anti-fibrotic agent inhibits dihydrofolate reduction.

402. The method of claim 278 wherein the anti-fibrotic agent blocks thymidine monophosphate.

403. The method of claim 278 wherein the anti-fibrotic agent causes DNA damage.

404. The method of claim 278 wherein the anti-fibrotic agent is a DNA intercalation agent.

405. The method of claim 278 wherein the anti-fibrotic agent is a RNA synthesis inhibitor.

406. The method of claim 278 wherein the anti-fibrotic agent is a pyrimidine synthesis inhibitor.

407. The method of claim 278 wherein the anti-fibrotic agent inhibits ribonucleotide synthesis or function.

408. The method of claim 278 wherein the anti-fibrotic agent inhibits thymidine monophosphate synthesis or function.

409. The method of claim 278 wherein the anti-fibrotic agent inhibits DNA synthesis.

410. The method of claim 278 wherein the anti-fibrotic agent causes DNA adduct formation.

411. The method of claim 278 wherein the anti-fibrotic agent inhibits protein synthesis.

412. The method of claim 278 wherein the anti-fibrotic agent inhibits microtubule function.

413. The method of claim 278 wherein the anti-fibrotic agent is a cyclin dependent protein kinase inhibitor.

414. The method of claim 278 wherein the anti-fibrotic agent is an epidermal growth factor kinase inhibitor.

415. The method of claim 278 wherein the anti-fibrotic agent is an elastase inhibitor.

416. The method of claim 278 wherein the anti-fibrotic agent is a factor Xa inhibitor.

417. The method of claim 278 wherein the anti-fibrotic agent is a farnesyltransferase inhibitor.

418. The method of claim 278 wherein the anti-fibrotic agent is a fibrinogen antagonist.

419. The method of claim 278 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

420. The method of claim 278 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist.

421. The method of claim 278 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof.

422. The method of claim 278 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

423. The method of claim 278 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor.

424. The method of claim 278 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof.

425. The method of claim 278 wherein the anti-fibrotic agent is a hydroorotate dehydrogenase inhibitor.

426. The method of claim 278 wherein the anti-fibrotic agent is an IKK2 inhibitor.

427. The method of claim 278 wherein the anti-fibrotic agent is an IL-1 antagonist.

428. The method of claim 278 wherein the anti-fibrotic agent is an ICE antagonist.

429. The method of claim 278 wherein the anti-fibrotic agent is an IRAK antagonist.

430. The method of claim 278 wherein the anti-fibrotic agent is an IL-4 agonist.

431. The method of claim 278 wherein the anti-fibrotic agent is an immunomodulatory agent.

432. The method of claim 278 wherein the anti-fibrotic agent is sirolimus or an analogue or derivative thereof.

433. The method of claim 278 wherein the anti-fibrotic agent is not sirolimus.

434. The method of claim 278 wherein the anti-fibrotic agent is everolimus or an analogue or derivative thereof.

435. The method of claim 278 wherein the anti-fibrotic agent is tacrolimus or an analogue or derivative thereof.

436. The method of claim 278 wherein the anti-fibrotic agent is not tacrolimus.

437. The method of claim 278 wherein the anti-fibrotic agent is biolmus or an analogue or derivative thereof.

438. The method of claim 278 wherein the anti-fibrotic agent is tresperimus or an analogue or derivative thereof.

439. The method of claim 278 wherein the anti-fibrotic agent is auranofin or an analogue or derivative thereof.

440. The method of claim 278 wherein the anti-fibrotic agent is 27-0-demethylrapamycin or an analogue or derivative thereof.

441. The method of claim 278 wherein the anti-fibrotic agent is gusperimus or an analogue or derivative thereof.

442. The method of claim 278 wherein the anti-fibrotic agent is pimecrolimus or an analogue or derivative thereof.

443. The method of claim 278 wherein the anti-fibrotic agent is ABT-578 or an analogue or derivative thereof.

444. The method of claim 278 wherein the anti-fibrotic agent is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.

445. The method of claim 278 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof.

446. The method of claim 278 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-alpha-25 dihydroxy vitamin D3 or an analogue or derivative thereof.

447. The method of claim 278 wherein the anti-fibrotic agent is a leukotriene inhibitor.

448. The method of claim 278 wherein the anti-fibrotic agent is a MCP-1 antagonist.

449. The method of claim 278 wherein the anti-fibrotic agent is a MMP inhibitor.

450. The method of claim 278 wherein the anti-fibrotic agent is an NF kappa B inhibitor.

451. The method of claim 278 wherein the anti-fibrotic agent is an NF kappa B inhibitor, wherein the NF kappa B inhibitor is Bay 11-7082.

452. The method of claim 278 wherein the anti-fibrotic agent is an NO antagonist.

453. The method of claim 278 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor.

454. The method of claim 278 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB 202190.

455. The method of claim 278 wherein the anti-fibrotic agent is a phosphodiesterase inhibitor.

456. The method of claim 278 wherein the anti-fibrotic agent is a TGF beta inhibitor.

457. The method of claim 278 wherein the anti-fibrotic agent is a thromboxane A2 antagonist.

458. The method of claim 278 wherein the anti-fibrotic agent is a TNF alpha antagonist.

459. The method of claim 278 wherein the anti-fibrotic agent is a TACE inhibitor.

460. The method of claim 278 wherein the anti-fibrotic agent is a tyrosine kinase inhibitor.

461. The method of claim 278 wherein the anti-fibrotic agent is a vitronectin inhibitor.

462. The method of claim 278 wherein the anti-fibrotic agent is a fibroblast growth factor inhibitor.

463. The method of claim 278 wherein the anti-fibrotic agent is a protein kinase inhibitor.

464. The method of claim 278 wherein the anti-fibrotic agent is a PDGF receptor kinase inhibitor.

465. The method of claim 278 wherein the anti-fibrotic agent is an endothelial growth factor receptor kinase inhibitor.

466. The method of claim 278 wherein the anti-fibrotic agent is a retinoic acid receptor antagonist.

467. The method of claim 278 wherein the anti-fibrotic agent is a platelet derived growth factor receptor kinase inhibitor.

468. The method of claim 278 wherein the anti-fibrotic agent is a fibrinogen antagonist.

469. The method of claim 278 wherein the anti-fibrotic agent is an antimycotic agent.

470. The method of claim 278 wherein the anti-fibrotic agent is an antimycotic agent, wherein the antimycotic agent is sulconizole.

471. The method of claim 278 wherein the anti-fibrotic agent is a bisphosphonate.

472. The method of claim 278 wherein the anti-fibrotic agent is a phospholipase A1 inhibitor.

473. The method of claim 278 wherein the anti-fibrotic agent is a histamine H1/H2/H3 receptor antagonist.

474. The method of claim 278 wherein the anti-fibrotic agent is a macrolide antibiotic.

475. The method of claim 278 wherein the anti-fibrotic agent is a GPIIb/IIIa receptor antagonist.

476. The method of claim 278 wherein the anti-fibrotic agent is an endothelin receptor antagonist.

477. The method of claim 278 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor agonist.

478. The method of claim 278 wherein the anti-fibrotic agent is an estrogen receptor agent.

479. The method of claim 278 wherein the anti-fibrotic agent is a somastostatin analogue.

480. The method of claim 278 wherein the anti-fibrotic agent is a neurokinin 1 antagonist.

481. The method of claim 278 wherein the anti-fibrotic agent is a neurokinin 3 antagonist.

482. The method of claim 278 wherein the anti-fibrotic agent is a VLA-4 antagonist.

483. The method of claim 278 wherein the anti-fibrotic agent is an osteoclast inhibitor.

484. The method of claim 278 wherein the anti-fibrotic agent is a DNA topoisomerase ATP hydrolyzing inhibitor.

485. The method of claim 278 wherein the anti-fibrotic agent is an angiotensin I converting enzyme inhibitor.

486. The method of claim 278 wherein the anti-fibrotic agent is an angiotensin II antagonist.

487. The method of claim 278 wherein the anti-fibrotic agent is an enkephalinase inhibitor.

488. The method of claim 278 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer.

489. The method of claim 278 wherein the anti-fibrotic agent is a protein kinase C inhibitor.

490. The method of claim 278 wherein the anti-fibrotic agent is a ROCK (rho-associated kinase) inhibitor.

491. The method of claim 278 wherein the anti-fibrotic agent is a CXCR3 inhibitor.

492. The method of claim 278 wherein the anti-fibrotic agent is an Itk inhibitor.

493. The method of claim 278 wherein the anti-fibrotic agent is a cytosolic phospholipase A2-alpha inhibitor.

494. The method of claim 278 wherein the anti-fibrotic agent is a PPAR agonist.

495. The method of claim 278 wherein the anti-fibrotic agent is an immunosuppressant.

496. The method of claim 278 wherein the anti-fibrotic agent is an Erb inhibitor.

47. The method of claim 278 wherein the anti-fibrotic agent is an apoptosis agonist.

498. The method of claim 278 wherein the anti-fibrotic agent is a lipocortin agonist.

499. The method of claim 278 wherein the anti-fibrotic agent is a VCAM-1 antagonist.

500. The method of claim 278 wherein the anti-fibrotic agent is a collagen antagonist.

501. The method of claim 278 wherein the anti-fibrotic agent is an alpha 2 integrin antagonist.

502. The method of claim 278 wherein the anti-fibrotic agent is a TNF alpha inhibitor.

503. The method of claim 278 wherein the anti-fibrotic agent is a nitric oxide inhibitor

504. The method of claim 278 wherein the anti-fibrotic agent is a cathepsin inhibitor.

505. The method of claim 278 wherein the anti-fibrotic agent is not an anti-inflammatory agent.

506. The method of claim 278 wherein the anti-fibrotic agent is not a steroid.

507. The method of claim 278 wherein the anti-fibrotic agent is not a glucocorticosteroid.

508. The method of claim 278 wherein the anti-fibrotic agent is not dexamethasone.

509. The method of claim 278 wherein the anti-fibrotic agent is not beclomethasone.

510. The method of claim 278 wherein the anti-fibrotic agent is not dipropionate.

511. The method of claim 278 wherein the anti-fibrotic agent is not an anti-infective agent.

512. The method of claim 278 wherein the anti-fibrotic agent is not an antibiotic.

513. The method of claim 278 wherein the anti-fibrotic agent is not an anti-fungal agent.

514. The method of claim 278 wherein the anti-infective agent isan anthracycline.

515. The method of claim 278 wherein the anti-infective agent isdoxorubicin.

516. The method of claim 278 wherein the anti-infective agent is ismitoxantrone.

517. The method of claim 278 wherein the anti-infective agent is a fluoropyrimidine.

518. The method of claim 278 wherein the anti-infective agent is 5-fluorouracil (5-FU).

519. The method of claim 278 wherein the anti-infective agent is a folic acid antagonist.

520. The method of claim 278 wherein the anti-infective agent is methotrexate.

521. The method of claim 278 wherein the anti-infective agent is a podophylotoxin.

522. The method of claim 278 wherein the anti-infective agent is etoposide.

523. The method of claim 278 wherein the anti-infective agent is camptothecin.

524. The method of claim 278 wherein the anti-infective agent is a hydroxyurea.

525. The method of claim 278 wherein the anti-infective agent is a platinum complex.

526. The method of claim 278 wherein the anti-infective agent is cisplatin.

527. The method of claim 278 wherein the composition comprises an anti-thrombotic agent.

528. The method of claim 278 wherein the polymer is formed from reactants comprising a naturally occurring polymer.

529. The method of claim 278 wherein the polymer is formed from reactants comprising protein.

530. The method of claim 278 wherein the polymer is formed from reactants comprising carbohydrate.

531. The method of claim 278 wherein the polymer is formed from reactants comprising biodegradable polymer.

532. The method of claim 278 wherein the polymer is formed from reactants comprising nonbiodegradable polymer.

533. The method of claim 278 wherein the polymer is formed from reactants comprising collagen.

534. The method of claim 278 wherein the polymer is formed from reactants comprising methylated collagen.

535. The method of claim 278 wherein the polymer is formed from reactants comprising fibrinogen.

536. The method of claim 278 wherein the polymer is formed from reactants comprising thrombin.

537. The method of claim 278 wherein the polymer is formed from reactants comprising blood plasma.

538. The method of claim 278 wherein the polymer is formed from reactants comprising calcium salt.

539. The method of claim 278 wherein the polymer is formed from reactants comprising an antifibronolytic agent.

540. The method of claim 278 wherein the polymer is formed from reactants comprising fibrinogen analog.

541. The method of claim 278 wherein the polymer is formed from reactants comprising albumin.

542. The method of claim 278 wherein the polymer is formed from reactants comprising plasminogen.

543. The method of claim 278 wherein the polymer is formed from reactants comprising von Willebrands factor.

544. The method of claim 278 wherein the polymer is formed from reactants comprising Factor VIII.

545. The method of claim 278 wherein the polymer is formed from reactants comprising hypoallergenic collagen.

546. The method of claim 278 wherein the polymer is formed from reactants comprising atelopeptidic collagen.

547. The method of claim 278 wherein the polymer is formed from reactants comprising telopeptide collagen.

548. The method of claim 278 wherein the polymer is formed from reactants comprising crosslinked collagen.

549. The method of claim 278 wherein the polymer is formed from reactants comprising aprotinin.

550. The method of claim 278 wherein the polymer is formed from reactants comprising epsilon-amino-n-caproic acid.

551. The method of claim 278 wherein the polymer is formed from reactants comprising gelatin.

552. The method of claim 278 wherein the polymer is formed from reactants comprising protein conjugates.

553. The method of claim 278 wherein the polymer is formed from reactants comprising gelatin conjugates.

554. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic polymer.

555. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic isocyanate-containing compound.

556. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic thiol-containing compound.

557. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two thiol groups.

558. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three thiol groups.

559. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four thiol groups.

560. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic amino-containing compound.

561. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two amino groups.

562. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three amino groups.

563. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four amino groups.

564. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group.

565. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups.

566. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.

567. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.

568. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound.

569. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.

570. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive amino groups.

571. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive thiol groups.

572. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups.

573. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic compound comprising a biodegradable polyester block.

574. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from lactic acid or lactide.

575. The method of claim 278 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from glycolic acid or glycolide.

576. The method of claim 278 wherein the polymer is formed from reactants comprising polylysine.

577. The method of claim 278 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound comprising a polyalkylene oxide portion.

578. The method of claim 278 wherein the polymer is formed from reactants comprising (a) protein and (b) polylysine.

579. The method of claim 278 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four thiol groups.

580. The method of claim 278 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four amino groups.

581. The method of claim 278 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

582. The method of claim 278 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

583. The method of claim 278 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound comprising a polyalkylene oxide portion.

584. The method of claim 278 wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine.

585. The method of claim 278 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four thiol groups.

586. The method of claim 278 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four amino groups.

587. The method of claim 278 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

588. The method of claim 278 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

589. The method of claim 278 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound comprising a polyalkylene oxide portion.

590. The method of claim 278 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine.

591. The method of claim 278 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four thiol groups.

592. The method of claim 278 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four amino groups.

593. The method of claim 278 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

594. The method of claim 278 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

595. The method of claim 278 wherein the polymer is formed from reactants comprising hyaluronic acid.

596. The method of claim 278 wherein the polymer is formed from reactants comprising a hyaluronic acid derivative.

597. The method of claim 278 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.

598. The method of claim 278 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.

599. The method of claim 278 wherein the polymer is formed from reactants comprising (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.

600. The method of claim 278 wherein the composition comprises a colorant.

601. The method of claim 278 wherein the composition is sterile.

602. A method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with i) an anti-fibrotic agent, ii) an anti-infective agent, iii) a polymer;
iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host, where the medical device is a gastrointestinal stent.

603. The method for implanting a medical device according to claim 602 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-fibrotic agent, and (b) implanting the medical device into the host.

604. The method for implanting a medical device according to claim 602 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-infective agent, and (b) implanting the medical device into the host.

605. The method for implanting a medical device according to claim 602 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a polymer; and (b) implanting the medical device into the host.

606. The method for implanting a medical device according to claim 602 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent and a polymer, and (b) implanting the medical device into the host.

607. The method for implanting a medical device according to claim 602 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

608. The method for implanting a medical device according to claim 602 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

609. The method of claim 602 wherein the medical device is an esophageal stent.

610. The method of claim 602 wherein the medical device is a billary stent.

611. The method of claim 602 wherein the medical device is a colonic stent.

612. The method of claim 602 wherein the medical device is a pancreatic stent.

613. The method of claim 602 wherein the anti-fibrotic agent inhibits cell regeneration.

614. The method of claim 602 wherein the anti-fibrotic agent inhibits angiogenesis.

615. The method of claim 602 wherein the anti-fibrotic agent inhibits fibroblast migration.

616. The method of claim 602 wherein the anti-fibrotic agent inhibits fibroblast proliferation.

617. The method of claim 602 wherein the anti-fibrotic agent inhibits deposition of extracellular matrix.

618. The method of claim 602 wherein the anti-fibrotic agent inhibits tissue remodeling.

619. The method of claim 602 wherein the anti-fibrotic agent is an angiogenesis inhibitor.

620. The method of claim 602 wherein the anti-fibrotic agent is a 5-lipoxygenase inhibitor or antagonist.

621. The method of claim 602 wherein the anti-fibrotic agent is a chemokine receptor antagonist.

622. The method of claim 602 wherein the anti-fibrotic agent is a cell cycle inhibitor.

623. The method of claim 602 wherein the anti-fibrotic agent is a taxane.

624. The method of claim 602 wherein the anti-fibrotic agent is an anti-microtubule agent.

625. The method of claim 602 wherein the anti-fibrotic agent is paclitaxel.

626. The method of claim 602 wherein the anti-fibrotic agent is not paclitaxel.

627. The method of claim 602 wherein the anti-fibrotic agent is an analogue or derivative of paclitaxel.

628. The method of claim 602 wherein the anti-fibrotic agent is a vinca alkaloid.

629. The method of claim 602 wherein the anti-fibrotic agent is camptothecin or an analogue or derivative thereof.

630. The method of claim 602 wherein the anti-fibrotic agent is a podophyllotoxin.

631. The method of claim 602 wherein the anti-fibrotic agent is a podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof.

632. The method of claim 602 wherein the anti-fibrotic agent is an anthracycline.

633. The method of claim 602 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof.

634. The method of claim 602 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof.

635. The method of claim 602 wherein the anti-fibrotic agent is a platinum compound.

636. The method of claim 602 wherein the anti-fibrotic agent is a nitrosourea.

637. The method of claim 602 wherein the anti-fibrotic agent is a nitroimidazole.

638. The method of claim 602 wherein the anti-fibrotic agent is a folic acid antagonist.

639. The method of claim 602 wherein the anti-fibrotic agent is a cytidine analogue.

640. The method of claim 602 wherein the anti-fibrotic agent is a pyrimidine analogue.

641. The method of claim 602 wherein the anti-fibrotic agent is a fluoropyrimidine analogue.

642. The method of claim 602 wherein the anti-fibrotic agent is a purine analogue.

643. The method of claim 602 wherein the anti-fibrotic agent is a nitrogen mustard or an analogue or derivative thereof.

644. The method of claim 602 wherein the anti-fibrotic agent is a hydroxyurea.

645. The method of claim 602 wherein the anti-fibrotic agent is a mytomicin or an analogue or derivative thereof.

646. The method of claim 602 wherein the anti-fibrotic agent is an alkyl sulfonate.

647. The method of claim 602 wherein the anti-fibrotic agent is a benzamide or an analogue or derivative thereof.

648. The method of claim 602 wherein the anti-fibrotic agent is a nicotinamide or an analogue or derivative thereof.

649. The method of claim 602 wherein the anti-fibrotic agent is a halogenated sugar or an analogue or derivative thereof.

650. The method of claim 602 wherein the anti-fibrotic agent is a DNA alkylating agent.

651. The method of claim 602 wherein the anti-fibrotic agent is an anti-microtubule agent.

652. The method of claim 602 wherein the anti-fibrotic agent is a topoisomerase inhibitor.

653. The method of claim 602 wherein the anti-fibrotic agent is a DNA cleaving agent.

654. The method of claim 602 wherein the anti-fibrotic agent is an antimetabolite.

655. The method of claim 602 wherein the anti-fibrotic agent inhibits adenosine deaminase.

656. The method of claim 602 wherein the anti-fibrotic agent inhibits purine ring synthesis.

657. The method of claim 602 wherein the anti-fibrotic agent is a nucleotide interconversion inhibitor.

658. The method of claim 602 wherein the anti-fibrotic agent inhibits dihydrofolate reduction.

659. The method of claim 602 wherein the anti-fibrotic agent blocks thymidine monophosphate.

660. The method of claim 602 wherein the anti-fibrotic agent causes DNA damage.

661. The method of claim 602 wherein the anti-fibrotic agent is a DNA intercalation agent.

662. The method of claim 602 wherein the anti-fibrotic agent is a RNA synthesis inhibitor.

663. The method of claim 602 wherein the anti-fibrotic agent is a pyrimidine synthesis inhibitor.

664. The method of claim 602 wherein the anti-fibrotic agent inhibits ribonucleotide synthesis or function.

665. The method of claim 602 wherein the anti-fibrotic agent inhibits thymidine monophosphate synthesis or function.

666. The method of claim 602 wherein the anti-fibrotic agent inhibits DNA synthesis.

667. The method of claim 602 wherein the anti-fibrotic agent causes DNA adduct formation.

668. The method of claim 602 wherein the anti-fibrotic agent inhibits protein synthesis.

669. The method of claim 602 wherein the anti-fibrotic agent inhibits microtubule function.

670. The method of claim 602 wherein the anti-fibrotic agent is a cyclin dependent protein kinase inhibitor.

671. The method of claim 602 wherein the anti-fibrotic agent is an epidermal growth factor kinase inhibitor.

672. The method of claim 602 wherein the anti-fibrotic agent is an elastase inhibitor.

673. The method of claim 602 wherein the anti-fibrotic agent is a factor Xa inhibitor.

674. The method of claim 602 wherein the anti-fibrotic agent is a farnesyltransferase inhibitor.

675. The method of claim 602 wherein the anti-fibrotic agent is a fibrinogen antagonist.

676. The method of claim 602 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

677. The method of claim 602 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist.

678. The method of claim 602 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof.

679. The method of claim 602 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

680. The method of claim 602 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor.

681. The method of claim 602 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof.

682. The method of claim 602 wherein the anti-fibrotic agent is a hydroorotate dehydrogenase inhibitor.

683. The method of claim 602 wherein the anti-fibrotic agent is an IKK2 inhibitor.

684. The method of claim 602 wherein the anti-fibrotic agent is an IL-1 antagonist.

685. The method of claim 602 wherein the anti-fibrotic agent is an ICE antagonist.

686. The method of claim 602 wherein the anti-fibrotic agent is an IRAK antagonist.

687. The method of claim 602 wherein the anti-fibrotic agent is an IL-4 agonist.

688. The method of claim 602 wherein the anti-fibrotic agent is an immunomodulatory agent.

689. The method of claim 602 wherein the anti-fibrotic agent is sirolimus or an analogue or derivative thereof.

690. The method of claim 602 wherein the anti-fibrotic agent is not sirolimus.

691. The method of claim 602 wherein the anti-fibrotic agent is everolimus or an analogue or derivative thereof.

692. The method of claim 602 wherein the anti-fibrotic agent is tacrolimus or an analogue or derivative thereof.

693. The method of claim 602 wherein the anti-fibrotic agent is not tacrolimus.

694. The method of claim 602 wherein the anti-fibrotic agent is biolmus or an analogue or derivative thereof.

695. The method of claim 602 wherein the anti-fibrotic agent is tresperimus or an analogue or derivative thereof.

696. The method of claim 602 wherein the anti-fibrotic agent is auranofin or an analogue or derivative thereof.

697. The method of claim 602 wherein the anti-fibrotic agent is 27-0-demethylrapamycin or an analogue or derivative thereof.

698. The method of claim 602 wherein the anti-fibrotic agent is gusperimus or an analogue or derivative thereof.

699. The method of claim 602 wherein the anti-fibrotic agent is pimecrolimus or an analogue or derivative thereof.

700. The method of claim 602 wherein the anti-fibrotic agent is ABT-578 or an analogue or derivative thereof.

701. The method of claim 602 wherein the anti-fibrotic agent is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.

702. The method of claim 602 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof.

703. The method of claim 602 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-alpha-25 dihydroxy vitamin D3 or an analogue or derivative thereof.

704. The method of claim 602 wherein the anti-fibrotic agent is a leukotriene inhibitor.

705. The method of claim 602 wherein the anti-fibrotic agent is a MCP-1 antagonist.

706. The method of claim 602 wherein the anti-fibrotic agent is a MMP inhibitor.

707. The method of claim 602 wherein the anti-fibrotic agent is an NF kappa B inhibitor.

708. The method of claim 602 wherein the anti-fibrotic agent is an NF kappa B inhibitor, wherein the NF kappa B inhibitor is Bay 11-7082.

709. The method of claim 602 wherein the anti-fibrotic agent is an NO antagonist.

710. The method of claim 602 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor.

711. The method of claim 602 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB 202190.

712. The method of claim 602 wherein the anti-fibrotic agent is a phosphodiesterase inhibitor.

713. The method of claim 602 wherein the anti-fibrotic agent is a TGF beta inhibitor.

714. The method of claim 602 wherein the anti-fibrotic agent is a thromboxane A2 antagonist.

715. The method of claim 602 wherein the anti-fibrotic agent is a TNF alpha antagonist.

716. The method of claim 602 wherein the anti-fibrotic agent is a TACE inhibitor.

717. The method of claim 602 wherein the anti-fibrotic agent is a tyrosine kinase inhibitor.

718. The method of claim 602 wherein the anti-fibrotic agent is a vitronectin inhibitor.

719. The method of claim 602 wherein the anti-fibrotic agent is a fibroblast growth factor inhibitor.

720. The method of claim 602 wherein the anti-fibrotic agent is a protein kinase inhibitor.

721. The method of claim 602 wherein the anti-fibrotic agent is a PDGF receptor kinase inhibitor.

722. The method of claim 602 wherein the anti-fibrotic agent is an endothelial growth factor receptor kinase inhibitor.

723. The method of claim 602 wherein the anti-fibrotic agent is a retinoic acid receptor antagonist.

724. The method of claim 602 wherein the anti-fibrotic agent is a platelet derived growth factor receptor kinase inhibitor.

725. The method of claim 602 wherein the anti-fibrotic agent is a fibrinogen antagonist.

726. The method of claim 602 wherein the anti-fibrotic agent is an antimycotic agent.

727. The method of claim 602 wherein the anti-fibrotic agent is an antimycotic agent, wherein the antimycotic agent is sulconizole.

728. The method of claim 602 wherein the anti-fibrotic agent is a bisphosphonate.

729. The method of claim 602 wherein the anti-fibrotic agent is a phospholipase A1 inhibitor.

730. The method of claim 602 wherein the anti-fibrotic agent is a histamine H1/H2/H3 receptor antagonist.

731. The method of claim 602 wherein the anti-fibrotic agent is a macrolide antibiotic.

732. The method of claim 602 wherein the anti-fibrotic agent is a GPIIb/IIIa receptor antagonist.

733. The method of claim 602 wherein the anti-fibrotic agent is an endothelin receptor antagonist.

734. The method of claim 602 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor agonist.

735. The method of claim 602 wherein the anti-fibrotic agent is an estrogen receptor agent.

736. The method of claim 602 wherein the anti-fibrotic agent is a somastostatin analogue.

737. The method of claim 602 wherein the anti-fibrotic agent is a neurokinin 1 antagonist.

738. The method of claim 602 wherein the anti-fibrotic agent is a neurokinin 3 antagonist.

739. The method of claim 602 wherein the anti-fibrotic agent is a VLA-4 antagonist.

740. The method of claim 602 wherein the anti-fibrotic agent is an osteoclast inhibitor.

741. The method of claim 602 wherein the anti-fibrotic agent is a DNA topoisomerase ATP hydrolyzing inhibitor.

742. The method of claim 602 wherein the anti-fibrotic agent is an angiotensin I converting enzyme inhibitor.

743. The method of claim 602 wherein the anti-fibrotic agent is an angiotensin II antagonist.

744. The method of claim 602 wherein the anti-fibrotic agent is an enkephalinase inhibitor.

745. The method of claim 602 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer.

746. The method of claim 602 wherein the anti-fibrotic agent is a protein kinase C inhibitor.

747. The method of claim 602 wherein the anti-fibrotic agent is a ROCK (rho-associated kinase) inhibitor.

748. The method of claim 602 wherein the anti-fibrotic agent is a CXCR3 inhibitor.

749. The method of claim 602 wherein the anti-fibrotic agent is an Itk inhibitor.

750. The method of claim 602 wherein the anti-fibrotic agent is a cytosolic phospholipase A2-alpha inhibitor.

751. The method of claim 602 wherein the anti-fibrotic agent is a PPAR agonist.

752. The method of claim 602 wherein the anti-fibrotic agent is an immunosuppressant.

753. The method of claim 602 wherein the anti-fibrotic agent is an Erb inhibitor.

754. The method of claim 602 wherein the anti-fibrotic agent is an apoptosis agonist.

755. The method of claim 602 wherein the anti-fibrotic agent is a lipocortin agonist.

756. The method of claim 602 wherein the anti-fibrotic agent is a VCAM-1 antagonist.

757. The method of claim 602 wherein the anti-fibrotic agent is a collagen antagonist.

758. The method of claim 602 wherein the anti-fibrotic agent is an alpha 2 integrin antagonist.

759. The method of claim 602 wherein the anti-fibrotic agent is a TNF alpha inhibitor.

760. The method of claim 602 wherein the anti-fibrotic agent is a nitric oxide inhibitor

761. The method of claim 602 wherein the anti-fibrotic agent is a cathepsin inhibitor.

762. The method of claim 602 wherein the anti-fibrotic agent is not an anti-inflammatory agent.

763. The method of claim 602 wherein the anti-fibrotic agent is not a steroid.

764. The method of claim 602 wherein the anti-fibrotic agent is not a glucocorticosteroid.

765. The method of claim 602 wherein the anti-fibrotic agent is not dexamethasone.

766. The method of claim 602 wherein the anti-fibrotic agent is not beclomethasone.

767. The method of claim 602 wherein the anti-fibrotic agent is not dipropionate.

768. The method of claim 602 wherein the anti-fibrotic agent is not an anti-infective agent.

769. The method of claim 602 wherein the anti-fibrotic agent is not an antibiotic.

770. The method of claim 602 wherein the anti-fibrotic agent is not an anti-fungal agent.

771. The method of claim 602 wherein the anti-infective agent isan anthracycline.

772. The method of claim 602 wherein the anti-infective agent isdoxorubicin.

773. The method of claim 602 wherein the anti-infective agent is ismitoxantrone.

774. The method of claim 602 wherein the anti-infective agent is a fluoropyrimidine.

775. The method of claim 602 wherein the anti-infective agent is 5-fluorouracil (5-FU).

776. The method of claim 602 wherein the anti-infective agent is a folic acid antagonist.

777. The method of claim 602 wherein the anti-infective agent is methotrexate.

778. The method of claim 602 wherein the anti-infective agent is a podophylotoxin.

779. The method of claim 602 wherein the anti-infective agent is etoposide.

780. The method of claim 602 wherein the anti-infective agent is camptothecin.

781. The method of claim 602 wherein the anti-infective agent is a hydroxyurea.

782. The method of claim 602 wherein the anti-infective agent is a platinum complex.

783. The method of claim 602 wherein the anti-infective agent is cisplatin.

784. The method of claim 602 wherein the composition comprises an anti-thrombotic agent.

785. The method of claim 602 wherein the polymer is formed from reactants comprising a naturally occurring polymer.

786. The method of claim 602 wherein the polymer is formed from reactants comprising protein.

787. The method of claim 602 wherein the polymer is formed from reactants comprising carbohydrate.

788. The method of claim 602 wherein the polymer is formed from reactants comprising biodegradable polymer.

789. The method of claim 602 wherein the polymer is formed from reactants comprising nonbiodegradable polymer.

790. The method of claim 602 wherein the polymer is formed from reactants comprising collagen.

791. The method of claim 602 wherein the polymer is formed from reactants comprising methylated collagen.

792. The method of claim 602 wherein the polymer is formed from reactants comprising fibrinogen.

793. The method of claim 602 wherein the polymer is formed from reactants comprising thrombin.

794. The method of claim 602 wherein the polymer is formed from reactants comprising blood plasma.

795. The method of claim 602 wherein the polymer is formed from reactants comprising calcium salt.

796. The method of claim 602 wherein the polymer is formed from reactants comprising an antifibronolytic agent.

797. The method of claim 602 wherein the polymer is formed from reactants comprising fibrinogen analog.

798. The method of claim 602 wherein the polymer is formed from reactants comprising albumin.

799. The method of claim 602 wherein the polymer is formed from reactants comprising plasminogen.

800. The method of claim 602 wherein the polymer is formed from reactants comprising von Willebrands factor.

801. The method of claim 602 wherein the polymer is formed from reactants comprising Factor VIII.

802. The method of claim 602 wherein the polymer is formed from reactants comprising hypoallergenic collagen.

803. The method of claim 602 wherein the polymer is formed from reactants comprising atelopeptidic collagen.

804. The method of claim 602 wherein the polymer is formed from reactants comprising telopeptide collagen.

805. The method of claim 602 wherein the polymer is formed from reactants comprising crosslinked collagen.

806. The method of claim 602 wherein the polymer is formed from reactants comprising aprotinin.

807. The method of claim 602 wherein the polymer is formed from reactants comprising epsilon-amino-n-caproic acid.

808. The method of claim 602 wherein the polymer is formed from reactants comprising gelatin.

809. The method of claim 602 wherein the polymer is formed from reactants comprising protein conjugates.

810. The method of claim 602 wherein the polymer is formed from reactants comprising gelatin conjugates.

811. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic polymer.

812. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic isocyanate-containing compound.

813. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic thiol-containing compound.

814. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two thiol groups.

815. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three thiol groups.

816. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four thiol groups.

817. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic amino-containing compound.

818. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two amino groups.

819. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three amino groups.

820. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four amino groups.

821. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group.

822. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups.

823. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.

824. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.

825. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound.

826. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.

827. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive amino groups.

828. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive thiol groups.

829. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups.

830. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic compound comprising a biodegradable polyester block.

831. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from lactic acid or lactide.

832. The method of claim 602 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from glycolic acid or glycolide.

833. The method of claim 602 wherein the polymer is formed from reactants comprising polylysine.

834. The method of claim 602 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound comprising a polyalkylene oxide portion.

835. The method of claim 602 wherein the polymer is formed from reactants comprising (a) protein and (b) polylysine.

836. The method of claim 602 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four thiol groups.

837. The method of claim 602 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four amino groups.

838. The method of claim 602 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

839. The method of claim 602 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

840. The method of claim 602 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound comprising a polyalkylene oxide portion.

841. The method of claim 602 wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine.

842. The method of claim 602 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four thiol groups.

843. The method of claim 602 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four amino groups.

844. The method of claim 602 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

845. The method of claim 602 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

846. The method of claim 602 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound comprising a polyalkylene oxide portion.

847. The method of claim 602 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine.

848. The method of claim 602 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four thiol groups.

849. The method of claim 602 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four amino groups.

850. The method of claim 602 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

851. The method of claim 602 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

852. The method of claim 602 wherein the polymer is formed from reactants comprising hyaluronic acid.

853. The method of claim 602 wherein the polymer is formed from reactants comprising a hyaluronic acid derivative.

854. The method of claim 602 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.

855. The method of claim 602 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.

856. The method of claim 602 wherein the polymer is formed from reactants comprising (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.

857. The method of claim 602 wherein the composition comprises a colorant.

858. The method of claim 602 wherein the composition is sterile.

859. A method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with i) an anti-fibrotic agent, ii) an anti-infective agent, iii) a polymer;
iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host, where the medical device is a tracheal or bronchial stent.

860. The method for implanting a medical device according to claim 859 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-fibrotic agent, and (b) implanting the medical device into the host.

861. The method for implanting a medical device according to claim 859 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-infective agent, and (b) implanting the medical device into the host.

862. The method for implanting a medical device according to claim 859 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a polymer; and (b) implanting the medical device into the host.

863. The method for implanting a medical device according to claim 859 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent and a polymer, and (b) implanting the medical device into the host.

864. The method for implanting a medical device according to claim 859 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

865. The method for implanting a medical device according to claim 859 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

866. The method of claim 859 wherein the medical device is a tracheal stent.

867. The method of claim 859 wherein the medical device is a bronchial stent.

868. The method of claim 859 wherein the medical device is a metallic tracheal stent.

869. The method of claim 859 wherein the medical device is a metallic bronchial stent.

870. The method of claim 859 wherein the medical device is a polymeric tracheal stent.

871. The method of claim 859 wherein the medical device is a polymeric bronchial stent.

872. The method of claim 859 wherein the anti-fibrotic agent inhibits cell regeneration.

873. The method of claim 859 wherein the anti-fibrotic agent inhibits angiogenesis.

874. The method of claim 859 wherein the anti-fibrotic agent inhibits fibroblast migration.

875. The method of claim 859 wherein the anti-fibrotic agent inhibits fibroblast proliferation.

876. The method of claim 859 wherein the anti-fibrotic agent inhibits deposition of extracellular matrix.

877. The method of claim 859 wherein the anti-fibrotic agent inhibits tissue remodeling.

878. The method of claim 859 wherein the anti-fibrotic agent is an angiogenesis inhibitor.

879. The method of claim 859 wherein the anti-fibrotic agent is a 5-lipoxygenase inhibitor or antagonist.

880. The method of claim 859 wherein the anti-fibrotic agent is a chemokine receptor antagonist.

881. The method of claim 859 wherein the anti-fibrotic agent is a cell cycle inhibitor.

882. The method of claim 859 wherein the anti-fibrotic agent is a taxane.

883. The method of claim 859 wherein the anti-fibrotic agent is an anti-microtubule agent.

884. The method of claim 859 wherein the anti-fibrotic agent is paclitaxel.

885. The method of claim 859 wherein the anti-fibrotic agent is not paclitaxel.

886. The method of claim 859 wherein the anti-fibrotic agent is an analogue or derivative of paclitaxel.

887. The method of claim 859 wherein the anti-fibrotic agent is a vinca alkaloid.

888. The method of claim 859 wherein the anti-fibrotic agent is camptothecin or an analogue or derivative thereof.

889. The method of claim 859 wherein the anti-fibrotic agent is a podophyllotoxin.

890. The method of claim 859 wherein the anti-fibrotic agent is a podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof.

891. The method of claim 859 wherein the anti-fibrotic agent is an anthracycline.

892. The method of claim 859 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof.

893. The method of claim 859 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof.

894. The method of claim 859 wherein the anti-fibrotic agent is a platinum compound.

895. The method of claim 859 wherein the anti-fibrotic agent is a nitrosourea.

896. The method of claim 859 wherein the anti-fibrotic agent is a nitroimidazole.

897. The method of claim 859 wherein the anti-fibrotic agent is a folic acid antagonist.

898. The method of claim 859 wherein the anti-fibrotic agent is a cytidine analogue.

899. The method of claim 859 wherein the anti-fibrotic agent is a pyrimidine analogue.

900. The method of claim 859 wherein the anti-fibrotic agent is a fluoropyrimidine analogue.

901. The method of claim 859 wherein the anti-fibrotic agent is a purine analogue.

902. The method of claim 859 wherein the anti-fibrotic agent is a nitrogen mustard or an analogue or derivative thereof.

903. The method of claim 859 wherein the anti-fibrotic agent is a hydroxyurea.

904. The method of claim 859 wherein the anti-fibrotic agent is a mytomicin or an analogue or derivative thereof.

905. The method of claim 859 wherein the anti-fibrotic agent is an alkyl sulfonate.

906. The method of claim 859 wherein the anti-fibrotic agent is a benzamide or an analogue or derivative thereof.

907. The method of claim 859 wherein the anti-fibrotic agent is a nicotinamide or an analogue or derivative thereof.

908. The method of claim 859 wherein the anti-fibrotic agent is a halogenated sugar or an analogue or derivative thereof.~

909. The method of claim 859 wherein the anti-fibrotic agent is a DNA alkylating agent.

910. The method of claim 859 wherein the anti-fibrotic agent is an anti-microtubule agent.

911. The method of claim 859 wherein the anti-fibrotic agent is a topoisomerase inhibitor.

912. The method of claim 859 wherein the anti-fibrotic agent is a DNA cleaving agent.

913. The method of claim 859 wherein the anti-fibrotic agent is an antimetabolite.

914. The method of claim 859 wherein the anti-fibrotic agent inhibits adenosine deaminase.

915. The method of claim 859 wherein the anti-fibrotic agent inhibits purine ring synthesis.

916. The method of claim 859 wherein the anti-fibrotic agent is a nucleotide interconversion inhibitor.

917. The method of claim 859 wherein the anti-fibrotic agent inhibits dihydrofolate reduction.

918. The method of claim 859 wherein the anti-fibrotic agent blocks thymidine monophosphate.

919. The method of claim 859 wherein the anti-fibrotic agent causes DNA damage.

920. The method of claim 859 wherein the anti-fibrotic agent is a DNA intercalation agent.

921. The method of claim 859 wherein the anti-fibrotic agent is a RNA synthesis inhibitor.

922. The method of claim 859 wherein the anti-fibrotic agent is a pyrimidine synthesis inhibitor.

923. The method of claim 859 wherein the anti-fibrotic agent inhibits ribonucleotide synthesis or function.

924. The method of claim 859 wherein the anti-fibrotic agent inhibits thymidine monophosphate synthesis or function.

925. The method of claim 859 wherein the anti-fibrotic agent inhibits DNA synthesis.

926. The method of claim 859 wherein the anti-fibrotic agent causes DNA adduct formation.

927. The method of claim 859 wherein the anti-fibrotic agent inhibits protein synthesis.

928. The method of claim 859 wherein the anti-fibrotic agent inhibits microtubule function.

929. The method of claim 859 wherein the anti-fibrotic agent is a cyclin dependent protein kinase inhibitor.

930. The method of claim 859 wherein the anti-fibrotic agent is an epidermal growth factor kinase inhibitor.

931. The method of claim 859 wherein the anti-fibrotic agent is an elastase inhibitor.

932. The method of claim 859 wherein the anti-fibrotic agent is a factor Xa inhibitor.

933. The method of claim 859 wherein the anti-fibrotic agent is a farnesyltransferase inhibitor.

934. The method of claim 859 wherein the anti-fibrotic agent is a fibrinogen antagonist.

935. The method of claim 859 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

936. The method of claim 859 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist.

937. The method of claim 859 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof.

938. The method of claim 859 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

939. The method of claim 859 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor.

940. The method of claim 859 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof.

941. The method of claim 859 wherein the anti-fibrotic agent is a hydroorotate dehydrogenase inhibitor.

942. The method of claim 859 wherein the anti-fibrotic agent is an IKK2 inhibitor.

943. The method of claim 859 wherein the anti-fibrotic agent is an IL-1 antagonist.

944. The method of claim 859 wherein the anti-fibrotic agent is an ICE antagonist.

945. The method of claim 859 wherein the anti-fibrotic agent is an IRAK antagonist.

946. The method of claim 859 wherein the anti-fibrotic agent is an IL-4 agonist.

947. The method of claim 859 wherein the anti-fibrotic agent is an immunomodulatory agent.

948. The method of claim 859 wherein the anti-fibrotic agent is sirolimus or an analogue or derivative thereof.

949. The method of claim 859 wherein the anti-fibrotic agent is not sirolimus.

950. The method of claim 859 wherein the anti-fibrotic agent is everolimus or an analogue or derivative thereof.

951. The method of claim 859 wherein the anti-fibrotic agent is tacrolimus or an analogue or derivative thereof.

952. The method of claim 859 wherein the anti-fibrotic agent is not tacrolimus.

953. The method of claim 859 wherein the anti-fibrotic agent is biolmus or an analogue or derivative thereof.

954. The method of claim 859 wherein the anti-fibrotic agent is tresperimus or an analogue or derivative thereof.

955. The method of claim 859 wherein the anti-fibrotic agent is auranofin or an analogue or derivative thereof.

956. The method of claim 859 wherein the anti-fibrotic agent is 27-0-demethylrapamycin or an analogue or derivative thereof.

957. The method of claim 859 wherein the anti-fibrotic agent is gusperimus or an analogue or derivative thereof.

958. The method of claim 859 wherein the anti-fibrotic agent is pimecrolimus or an analogue or derivative thereof.

959. The method of claim 859 wherein the anti-fibrotic agent is ABT-578 or an analogue or derivative thereof.

960. The method of claim 859 wherein the anti-fibrotic agent is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.

961. The method of claim 859 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof.

962. The method of claim 859 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-alpha-25 dihydroxy vitamin D3 or an analogue or derivative thereof.

963. The method of claim 859 wherein the anti-fibrotic agent is a leukotriene inhibitor.

964. The method of claim 859 wherein the anti-fibrotic agent is a MCP-1 antagonist.

965. The method of claim 859 wherein the anti-fibrotic agent is a MMP inhibitor.

966. The method of claim 859 wherein the anti-fibrotic agent is an NF kappa B inhibitor.

967. The method of claim 859 wherein the anti-fibrotic agent is an NF kappa B inhibitor, wherein the NF kappa B inhibitor is Bay 11-7082.

968. The method of claim 859 wherein the anti-fibrotic agent is an NO antagonist.

969. The method of claim 859 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor.

970. The method of claim 859 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB 202190.

971. The method of claim 859 wherein the anti-fibrotic agent is a phosphodiesterase inhibitor.

972. The method of claim 859 wherein the anti-fibrotic agent is a TGF beta inhibitor.

973. The method of claim 859 wherein the anti-fibrotic agent is a thromboxane A2 antagonist.

974. The method of claim 859 wherein the anti-fibrotic agent is a TNF alpha antagonist.

975. The method of claim 859 wherein the anti-fibrotic agent is a TACE inhibitor.

976. The method of claim 859 wherein the anti-fibrotic agent is a tyrosine kinase inhibitor.

977. The method of claim 859 wherein the anti-fibrotic agent is a vitronectin inhibitor.

978. The method of claim 859 wherein the anti-fibrotic agent is a fibroblast growth factor inhibitor.

979. The method of claim 859 wherein the anti-fibrotic agent is a protein kinase inhibitor.

980. The method of claim 859 wherein the anti-fibrotic agent is a PDGF receptor kinase inhibitor.

981. The method of claim 859 wherein the anti-fibrotic agent is an endothelial growth factor receptor kinase inhibitor.

982. The method of claim 859 wherein the anti-fibrotic agent is a retinoic acid receptor antagonist.

983. The method of claim 859 wherein the anti-fibrotic agent is a platelet derived growth factor receptor kinase inhibitor.

984. The method of claim 859 wherein the anti-fibrotic agent is a fibrinogen antagonist.

985. The method of claim 859 wherein the anti-fibrotic agent is an antimycotic agent.

986. The method of claim 859 wherein the anti-fibrotic agent is an antimycotic agent, wherein the antimycotic agent is sulconizole.

987. The method of claim 859 wherein the anti-fibrotic agent is a bisphosphonate.

988. The method of claim 859 wherein the anti-fibrotic agent is a phospholipase A1 inhibitor.

989. The method of claim 859 wherein the anti-fibrotic agent is a histamine H1/H2/H3 receptor antagonist.

990. The method of claim 859 wherein the anti-fibrotic agent is a macrolide antibiotic.

991. The method of claim 859 wherein the anti-fibrotic agent is a GPIIb/IIIa receptor antagonist.

992. The method of claim 859 wherein the anti-fibrotic agent is an endothelin receptor antagonist.

993. The method of claim 859 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor agonist.

994. The method of claim 859 wherein the anti-fibrotic agent is an estrogen receptor agent.

995. The method of claim 859 wherein the anti-fibrotic agent is a somastostatin analogue.

996. The method of claim 859 wherein the anti-fibrotic agent is a neurokinin 1 antagonist.

997. The method of claim 859 wherein the anti-fibrotic agent is a neurokinin 3 antagonist.

998. The method of claim 859 wherein the anti-fibrotic agent is a VLA-4 antagonist.

999. The method of claim 859 wherein the anti-fibrotic agent is an osteoclast inhibitor.

1000. The method of claim 859 wherein the anti-fibrotic agent is a DNA topoisomerase ATP hydrolyzing inhibitor.

1001. The method of claim 859 wherein the anti-fibrotic agent is an angiotensin I converting enzyme inhibitor.

1002. The method of claim 859 wherein the anti-fibrotic agent is an angiotensin II antagonist.

1003. The method of claim 859 wherein the anti-fibrotic agent is an enkephalinase inhibitor.

1004. The method of claim 859 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer.

1005. The method of claim 859 wherein the anti-fibrotic agent is a protein kinase C inhibitor.

1006. The method of claim 859 wherein the anti-fibrotic agent is a ROCK (rho-associated kinase) inhibitor.

1007. The method of claim 859 wherein the anti-fibrotic agent is a CXCR3 inhibitor.

1008. The method of claim 859 wherein the anti-fibrotic agent is an Itk inhibitor.

1009. The method of claim 859 wherein the anti-fibrotic agent is a cytosolic phospholipase A2-alpha inhibitor.

1010. The method of claim 859 wherein the anti-fibrotic agent is a PPAR agonist.

1011. The method of claim 859 wherein the anti-fibrotic agent is an immunosuppressant.

1012. The method of claim 859 wherein the anti-fibrotic agent is an Erb inhibitor.

1013. The method of claim 859 wherein the anti-fibrotic agent is an apoptosis agonist.

1014. The method of claim 859 wherein the anti-fibrotic agent is a lipocortin agonist.

1015. The method of claim 859 wherein the anti-fibrotic agent is a VCAM-1 antagonist.

1016. The method of claim 859 wherein the anti-fibrotic agent is a collagen antagonist.

1017. The method of claim 859 wherein the anti-fibrotic agent is an alpha 2 integrin antagonist.

1018. The method of claim 859 wherein the anti-fibrotic agent is a TNF alpha inhibitor.

1019. The method of claim 859 wherein the anti-fibrotic agent is a nitric oxide inhibitor

1020. The method of claim 859 wherein the anti-fibrotic agent is a cathepsin inhibitor.

1021. The method of claim 859 wherein the anti-fibrotic agent is not an anti-inflammatory agent.

1022. The method of claim 859 wherein the anti-fibrotic agent is not a steroid.

1023. The method of claim 859 wherein the anti-fibrotic agent is not a glucocorticosteroid.

1024. The method of claim 859 wherein the anti-fibrotic agent is not dexamethasone.

1025. The method of claim 859 wherein the anti-fibrotic agent is not beclomethasone.

1026. The method of claim 859 wherein the anti-fibrotic agent is not dipropionate.

1027. The method of claim 859 wherein the anti-fibrotic agent is not an anti-infective agent.

1028. The method of claim 859 wherein the anti-fibrotic agent is not an antibiotic.

1029. The method of claim 859 wherein the anti-fibrotic agent is not an anti-fungal agent.

1030. The method of claim 859 wherein the anti-infective agent isan anthracycline.

1031. The method of claim 859 wherein the anti-infective agent isdoxorubicin.

1032. The method of claim 859 wherein the anti-infective agent is ismitoxantrone.

1033. The method of claim 859 wherein the anti-infective agent is a fluoropyrimidine.

1034. The method of claim 859 wherein the anti-infective agent is 5-fluorouracil (5-FU).

1035. The method of claim 859 wherein the anti-infective agent is a folic acid antagonist.

1036. The method of claim 859 wherein the anti-infective agent is methotrexate.

1037. The method of claim 859 wherein the anti-infective agent is a podophylotoxin.

1038. The method of claim 859 wherein the anti-infective agent is etoposide.

1039. The method of claim 859 wherein the anti-infective agent is camptothecin.

1040. The method of claim 859 wherein the anti-infective agent is a hydroxyurea.

1041. The method of claim 859 wherein the anti-infective agent is a platinum complex.

1042. The method of claim 859 wherein the anti-infective agent is cisplatin.

1043. The method of claim 859 wherein the composition comprises an anti-thrombotic agent.

1044. The method of claim 859 wherein the polymer is formed from reactants comprising a naturally occurring polymer.

1045. The method of claim 859 wherein the polymer is formed from reactants comprising protein.

1046. The method of claim 859 wherein the polymer is formed from reactants comprising carbohydrate.

1047. The method of claim 859 wherein the polymer is formed from reactants comprising biodegradable polymer.

1048. The method of claim 859 wherein the polymer is formed from reactants comprising nonbiodegradable polymer.

1049. The method of claim 859 wherein the polymer is formed from reactants comprising collagen.

1050. The method of claim 859 wherein the polymer is formed from reactants comprising methylated collagen.

1051. The method of claim 859 wherein the polymer is formed from reactants comprising fibrinogen.

1052. The method of claim 859 wherein the polymer is formed from reactants comprising thrombin.

1053. The method of claim 859 wherein the polymer is formed from reactants comprising blood plasma.

1054. The method of claim 859 wherein the polymer is formed from reactants comprising calcium salt.

1055. The method of claim 859 wherein the polymer is formed from reactants comprising an antifibronolytic agent.

1056. The method of claim 859 wherein the polymer is formed from reactants comprising fibrinogen analog.

1057. The method of claim 859 wherein the polymer is formed from reactants comprising albumin.

1058. The method of claim 859 wherein the polymer is formed from reactants comprising plasminogen.

1059. The method of claim 859 wherein the polymer is formed from reactants comprising von Willebrands factor.

1060. The method of claim 859 wherein the polymer is formed from reactants comprising Factor VIII.

1061. The method of claim 859 wherein the polymer is formed from reactants comprising hypoallergenic collagen.

1062. The method of claim 859 wherein the polymer is formed from reactants comprising atelopeptidic collagen.

1063. The method of claim 859 wherein the polymer is formed from reactants comprising telopeptide collagen.

1064. The method of claim 859 wherein the polymer is formed from reactants comprising crosslinked collagen.

1065. The method of claim 859 wherein the polymer is formed from reactants comprising aprotinin.

1066. The method of claim 859 wherein the polymer is formed from reactants comprising epsilon-amino-n-caproic acid.

1067. The method of claim 859 wherein the polymer is formed from reactants comprising gelatin.

1068. The method of claim 859 wherein the polymer is formed from reactants comprising protein conjugates.

1069. The method of claim 859 wherein the polymer is formed from reactants comprising gelatin conjugates.

1070. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic polymer.

1071. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic isocyanate-containing compound.

1072. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic thiol-containing compound.

1073. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two thiol groups.

1074. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three thiol groups.

1075. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four thiol groups.

1076. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic amino-containing compound.

1077. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two amino groups.

1078. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three amino groups.

1079. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four amino groups.

1080. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group.

1081. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups.

1082. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.

1083. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.

1084. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound.

1085. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.

1086. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive amino groups.

1087. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive thiol groups.

1088. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups.

1089. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic compound comprising a biodegradable polyester block.

1090. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from lactic acid or lactide.

1091. The method of claim 859 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from glycolic acid or glycolide.

1092. The method of claim 859 wherein the polymer is formed from reactants comprising polylysine.

1093. The method of claim 859 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound comprising a polyalkylene oxide portion.

1094. The method of claim 859 wherein the polymer is formed from reactants comprising (a) protein and (b) polylysine.

1095. The method of claim 859 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four thiol groups.

1096. The method of claim 859 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four amino groups.

1097. The method of claim 859 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

1098. The method of claim 859 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

1099. The method of claim 859 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound comprising a polyalkylene oxide portion.

1100. The method of claim 859 wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine.

1101. The method of claim 859 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four thiol groups.

1102. The method of claim 859 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four amino groups.

1103. The method of claim 859 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

1104. The method of claim 859 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

1105. The method of claim 859 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound comprising a polyalkylene oxide portion.

1106. The method of claim 859 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine.

1107. The method of claim 859 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four thiol groups.

1108. The method of claim 859 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four amino groups.

1109. The method of claim 859 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

1110. The method of claim 859 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

1111. The method of claim 859 wherein the polymer is formed from reactants comprising hyaluronic acid.

1112. The method of claim 859 wherein the polymer is formed from reactants comprising a hyaluronic acid derivative.

1113. The method of claim 859 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.

1114. The method of claim 859 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.

1115. The method of claim 859 wherein the polymer is formed from reactants comprising (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.

1116. The method of claim 859 wherein the composition comprises a colorant.

1117. The method of claim 859 wherein the composition is sterile.

1118. A method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with i) an anti-fibrotic agent, ii) an anti-infective agent, iii) a polymer;
iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host, where the medical device is a genital urinary stent.

1119. The method for implanting a medical device according to claim 1118 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-fibrotic agent, and (b) implanting the medical device into the host.

1120. The method for implanting a medical device according to claim 1118 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-infective agent, and (b) implanting the medical device into the host.

1121. The method for implanting a medical device according to claim 1118 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a polymer; and (b) implanting the medical device into the host.

1122. The method for implanting a medical device according to claim 1118 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent and a polymer, and (b) implanting the medical device into the host.

1123. The method for implanting a medical device according to claim 1118 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

1124. The method for implanting a medical device according to claim 1118 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

1125. The method of claim 1118 wherein the medical device is a ureteric stent.

1126. The method of claim 1118 wherein the medical device is aurethral stent.

1127. The method of claim 1118 wherein the medical device is a fallopian tube stent.

1128. The method of claim 1118 wherein the medical device is a prostate stent.

1129. The method of claim 1118 wherein the medical device is a metallic genital urinary stent.

1130. The method of claim 1118 wherein the medical device is a polymeric genital urinary stent.

1131. The method of claim 1118 wherein the anti-fibrotic agent inhibits cell regeneration.

1132. The method of claim 1118 wherein the anti-fibrotic agent inhibits angiogenesis.

1133. The method of claim 1118 wherein the anti-fibrotic agent inhibits fibroblast migration.

1134. The method of claim 1118 wherein the anti-fibrotic agent inhibits fibroblast proliferation.

1135. The method of claim 1118 wherein the anti-fibrotic agent inhibits deposition of extracellular matrix.

1136. The method of claim 1118 wherein the anti-fibrotic agent inhibits tissue remodeling.

1137. The method of claim 1118 wherein the anti-fibrotic agent is an angiogenesis inhibitor.

1138. The method of claim 1118 wherein the anti-fibrotic agent is a 5-lipoxygenase inhibitor or antagonist.

1139. The method of claim 1118 wherein the anti-fibrotic agent is a chemokine receptor antagonist.

1140. The method of claim 1118 wherein the anti-fibrotic agent is a cell cycle inhibitor.

1141. The method of claim 1118 wherein the anti-fibrotic agent is a taxane.

1142. The method of claim 1118 wherein the anti-fibrotic agent is an anti-microtubule agent.

1143. The method of claim 1118 wherein the anti-fibrotic agent is paclitaxel.

1144. The method of claim 1118 wherein the anti-fibrotic agent is not paclitaxel.

1145. The method of claim 1118 wherein the anti-fibrotic agent is an analogue or derivative of paclitaxel.

1146. The method of claim 1118 wherein the anti-fibrotic agent is a vinca alkaloid.

1147. The method of claim 1118 wherein the anti-fibrotic agent is camptothecin or an analogue or derivative thereof.

1148. The method of claim 1118 wherein the anti-fibrotic agent is a podophyllotoxin.

1149. The method of claim 1118 wherein the anti-fibrotic agent is a podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof.

1150. The method of claim 1118 wherein the anti-fibrotic agent is an anthracycline.

1151. The method of claim 1118 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof.

1152. The method of claim 1118 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof.

1153. The method of claim 1118 wherein the anti-fibrotic agent is a platinum compound.

1154. The method of claim 1118 wherein the anti-fibrotic agent is a nitrosourea.

1155. The method of claim 1118 wherein the anti-fibrotic agent is a nitroimidazole.

1156. The method of claim 1118 wherein the anti-fibrotic agent is a folic acid antagonist.

1157. The method of claim 1118 wherein the anti-fibrotic agent is a cytidine analogue.

1158. The method of claim 1118 wherein the anti-fibrotic agent is a pyrimidine analogue.

1159. The method of claim 1118 wherein the anti-fibrotic agent is a fluoropyrimidine analogue.

1160. The method of claim 1118 wherein the anti-fibrotic agent is a purine analogue.

1161. The method of claim 1118 wherein the anti-fibrotic agent is a nitrogen mustard or an analogue or derivative thereof.

1162. The method of claim 1118 wherein the anti-fibrotic agent is a hydroxyurea.

1163. The method of claim 1118 wherein the anti-fibrotic agent is a mytomicin or an analogue or derivative thereof.

1164. The method of claim 1118 wherein the anti-fibrotic agent is an alkyl sulfonate.

1165. The method of claim 1118 wherein the anti-fibrotic agent is a benzamide or an analogue or derivative thereof.

1166. The method of claim 1118 wherein the anti-fibrotic agent is a nicotinamide or an analogue or derivative thereof.

1126~

1167. The method of claim 1118 wherein the anti-fibrotic agent is a halogenated sugar or an analogue or derivative thereof.

1168. The method of claim 1118 wherein the anti-fibrotic agent is a DNA alkylating agent.

1169. The method of claim 1118 wherein the anti-fibrotic agent is an anti-microtubule agent.

1170. The method of claim 1118 wherein the anti-fibrotic agent is a topoisomerase inhibitor.

1171. The method of claim 1118 wherein the anti-fibrotic agent is a DNA cleaving agent.

1172. The method of claim 1118 wherein the anti-fibrotic agent is an antimetabolite.

1173. The method of claim 1118 wherein the anti-fibrotic agent inhibits adenosine deaminase.

1174. The method of claim 1118 wherein the anti-fibrotic agent inhibits purine ring synthesis.

1175. The method of claim 1118 wherein the anti-fibrotic agent is a nucleotide interconversion inhibitor.

1176. The method of claim 1118 wherein the anti-fibrotic agent inhibits dihydrofolate reduction.

1177. The method of claim 1118 wherein the anti-fibrotic agent blocks thymidine monophosphate.

1178. The method of claim 1118 wherein the anti-fibrotic agent causes DNA damage.

1179. The method of claim 1118 wherein the anti-fibrotic agent is a DNA intercalation agent.

1180. The method of claim 1118 wherein the anti-fibrotic agent is a RNA synthesis inhibitor.

1181. The method of claim 1118 wherein the anti-fibrotic agent is a pyrimidine synthesis inhibitor.

1182. The method of claim 1118 wherein the anti-fibrotic agent inhibits ribonucleotide synthesis or function.

1183. The method of claim 1118 wherein the anti-fibrotic agent inhibits thymidine monophosphate synthesis or function.

1184. The method of claim 1118 wherein the anti-fibrotic agent inhibits DNA synthesis.

1185. The method of claim 1118 wherein the anti-fibrotic agent causes DNA adduct formation.

1186. The method of claim 1118 wherein the anti-fibrotic agent inhibits protein synthesis.

1187. The method of claim 1118 wherein the anti-fibrotic agent inhibits microtubule function.

1188. The method of claim 1118 wherein the anti-fibrotic agent is a cyclin dependent protein kinase inhibitor.

1189. The method of claim 1118 wherein the anti-fibrotic agent is an epidermal growth factor kinase inhibitor.

1190. The method of claim 1118 wherein the anti-fibrotic agent is an elastase inhibitor.

1191. The method of claim 1118 wherein the anti-fibrotic agent is a factor Xa inhibitor.

1192. The method of claim 1118 wherein the anti-fibrotic agent is a farnesyltransferase inhibitor.

1193. The method of claim 1118 wherein the anti-fibrotic agent is a fibrinogen antagonist.

1194. The method of claim 1118 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

1195. The method of claim 1118 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist.

1196. The method of claim 1118 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof.

1197. The method of claim 1118 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

1198. The method of claim 1118 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor.

1199. The method of claim 1118 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof.

1200. The method of claim 1118 wherein the anti-fibrotic agent is a hydroorotate dehydrogenase inhibitor.

1201. The method of claim 1118 wherein the anti-fibrotic agent is an IKK2 inhibitor.

1202. The method of claim 1118 wherein the anti-fibrotic agent is an IL-1 antagonist.

1203. The method of claim 1118 wherein the anti-fibrotic agent is an ICE antagonist.

1204. The method of claim 1118 wherein the anti-fibrotic agent is an IRAK antagonist.

1205. The method of claim 1118 wherein the anti-fibrotic agent is an IL-4 agonist.

1206. The method of claim 1118 wherein the anti-fibrotic agent is an immunomodulatory agent.

1207. The method of claim 1118 wherein the anti-fibrotic agent is sirolimus or an analogue or derivative thereof.

1208. The method of claim 1118 wherein the anti-fibrotic agent is not sirolimus.

1209. The method of claim 1118 wherein the anti-fibrotic agent is everolimus or an analogue or derivative thereof.

1210. The method of claim 1118 wherein the anti-fibrotic agent is tacrolimus or an analogue or derivative thereof.

1211. The method of claim 1118 wherein the anti-fibrotic agent is not tacrolimus.

1212. The method of claim 1118 wherein the anti-fibrotic agent is biolmus or an analogue or derivative thereof.

1213. The method of claim 1118 wherein the anti-fibrotic agent is tresperimus or an analogue or derivative thereof.

1214. The method of claim 1118 wherein the anti-fibrotic agent is auranofin or an analogue or derivative thereof.

1215. The method of claim 1118 wherein the anti-fibrotic agent is 27-0-demethylrapamycin or an analogue or derivative thereof.

1216. The method of claim 1118 wherein the anti-fibrotic agent is gusperimus or an analogue or derivative thereof.

1217. The method of claim 1118 wherein the anti-fibrotic agent is pimecrolimus or an analogue or derivative thereof.

1218. The method of claim 1118 wherein the anti-fibrotic agent is ABT-578 or an analogue or derivative thereof.

1219. The method of claim 1118 wherein the anti-fibrotic agent is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.

1220. The method of claim 1118 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof.

1221. The method of claim 1118 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-alpha-25 dihydroxy vitamin D3 or an analogue or derivative thereof.

1222. The method of claim 1118 wherein the anti-fibrotic agent is a leukotriene inhibitor.

1223. The method of claim 1118 wherein the anti-fibrotic agent is a MCP-1 antagonist.

1224. The method of claim 1118 wherein the anti-fibrotic agent is a MMP inhibitor.

1225. The method of claim 1118 wherein the anti-fibrotic agent is an NF kappa B inhibitor.

1226. The method of claim 1118 wherein the anti-fibrotic agent is an NF kappa B inhibitor, wherein the NF kappa B inhibitor is Bay 11-7082.

1227. The method of claim 1118 wherein the anti-fibrotic agent is an NO antagonist.

1228. The method of claim 1118 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor.

1229. The method of claim 1118 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB
202190.

1230. The method of claim 1118 wherein the anti-fibrotic agent is a phosphodiesterase inhibitor.

1231. The method of claim 1118 wherein the anti-fibrotic agent is a TGF beta inhibitor.

1232. The method of claim 1118 wherein the anti-fibrotic agent is a thromboxane A2 antagonist.

1233. The method of claim 1118 wherein the anti-fibrotic agent is a TNF alpha antagonist.

1234. The method of claim 1118 wherein the anti-fibrotic agent is a TACE inhibitor.

1235. The method of claim 1118 wherein the anti-fibrotic agent is a tyrosine kinase inhibitor.

1236. The method of claim 1118 wherein the anti-fibrotic agent is a vitronectin inhibitor.

1237. The method of claim 1118 wherein the anti-fibrotic agent is a fibroblast growth factor inhibitor.

1238. The method of claim 1118 wherein the anti-fibrotic agent is a protein kinase inhibitor.

1239. The method of claim 1118 wherein the anti-fibrotic agent is a PDGF receptor kinase inhibitor.

1240. The method of claim 1118 wherein the anti-fibrotic agent is an endothelial growth factor receptor kinase inhibitor.

1241. The method of claim 1118 wherein the anti-fibrotic agent is a retinoic acid receptor antagonist.

1242. The method of claim 1118 wherein the anti-fibrotic agent is a platelet derived growth factor receptor kinase inhibitor.

1243. The method of claim 1118 wherein the anti-fibrotic agent is a fibrinogen antagonist.

1244. The method of claim 1118 wherein the anti-fibrotic agent is an antimycotic agent.

1245. The method of claim 1118 wherein the anti-fibrotic agent is an antimycotic agent, wherein the antimycotic agent is sulconizole.

1246. The method of claim 1118 wherein the anti-fibrotic agent is a bisphosphonate.

1247. The method of claim 1118 wherein the anti-fibrotic agent is a phospholipase A1 inhibitor.

1248. The method of claim 1118 wherein the anti-fibrotic agent is a histamine H1/H2/H3 receptor antagonist.

1249. The method of claim 1118 wherein the anti-fibrotic agent is a macrolide antibiotic.

1250. The method of claim 1118 wherein the anti-fibrotic agent is a GPIIb/IIIa receptor antagonist.

1251. The method of claim 1118 wherein the anti-fibrotic agent is an endothelin receptor antagonist.

1252. The method of claim 1118 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor agonist.

1253. The method of claim 1118 wherein the anti-fibrotic agent is an estrogen receptor agent.

1254. The method of claim 1118 wherein the anti-fibrotic agent is a somastostatin analogue.

1255. The method of claim 1118 wherein the anti-fibrotic agent is a neurokinin 1 antagonist.

1256. The method of claim 1118 wherein the anti-fibrotic agent is a neurokinin 3 antagonist.

1257. The method of claim 1118 wherein the anti-fibrotic agent is a VLA-4 antagonist.

1258. The method of claim 1118 wherein the anti-fibrotic agent is an osteoclast inhibitor.

1259. The method of claim 1118 wherein the anti-fibrotic agent is a DNA topoisomerase ATP hydrolyzing inhibitor.

1260. The method of claim 1118 wherein the anti-fibrotic agent is an angiotensin I converting enzyme inhibitor.

1261. The method of claim 1118 wherein the anti-fibrotic agent is an angiotensin II antagonist.

1262. The method of claim 1118 wherein the anti-fibrotic agent is an enkephalinase inhibitor.

1263. The method of claim 1118 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer.

1264. The method of claim 1118 wherein the anti-fibrotic agent is a protein kinase C inhibitor.

1265. The method of claim 1118 wherein the anti-fibrotic agent is a ROCK (rho-associated kinase) inhibitor.

1266. The method of claim 1118 wherein the anti-fibrotic agent is a CXCR3 inhibitor.

1267. The method of claim 1118 wherein the anti-fibrotic agent is an Itk inhibitor.

1268. The method of claim 1118 wherein the anti-fibrotic agent is a cytosolic phospholipase A2-alpha inhibitor.

1269. The method of claim 1118 wherein the anti-fibrotic agent is a PPAR agonist.

1270. The method of claim 1118 wherein the anti-fibrotic agent is an immunosuppressant.

1271. The method of claim 1118 wherein the anti-fibrotic agent is an Erb inhibitor.

1272. The method of claim 1118 wherein the anti-fibrotic agent is an apoptosis agonist.

1273. The method of claim 1118 wherein the anti-fibrotic agent is a lipocortin agonist.

1274. The method of claim 1118 wherein the anti-fibrotic agent is a VCAM-1 antagonist.

1275. The method of claim 1118 wherein the anti-fibrotic agent is a collagen antagonist.

1276. The method of claim 1118 wherein the anti-fibrotic agent is an alpha 2 integrin antagonist.

1277. The method of claim 1118 wherein the anti-fibrotic agent is a TNF alpha inhibitor.

1278. The method of claim 1118 wherein the anti-fibrotic agent is a nitric oxide inhibitor

1279. The method of claim 1118 wherein the anti-fibrotic agent is a cathepsin inhibitor.

1280. The method of claim 1118 wherein the anti-fibrotic agent is not an anti-inflammatory agent.

1281. The method of claim 1118 wherein the anti-fibrotic agent is not a steroid.

1282. The method of claim 1118 wherein the anti-fibrotic agent is not a glucocorticosteroid.

1283. The method of claim 1118 wherein the anti-fibrotic agent is not dexamethasone.

1284. The method of claim 1118 wherein the anti-fibrotic agent is not beclomethasone.

1285. The method of claim 1118 wherein the anti-fibrotic agent is not dipropionate.

1286. The method of claim 1118 wherein the anti-fibrotic agent is not an anti-infective agent.

1287. The method of claim 1118 wherein the anti-fibrotic agent is not an antibiotic.

1288. The method of claim 1118 wherein the anti-fibrotic agent is not an anti-fungal agent.

1289. The method of claim 1118 wherein the anti-infective agent isan anthracycline.

1290. The method of claim 1118 wherein the anti-infective agent isdoxorubicin.

1291. The method of claim 1118 wherein the anti-infective agent is ismitoxantrone.

1292. The method of claim 1118 wherein the anti-infective agent is a fluoropyrimidine.

1293. The method of claim 1118 wherein the anti-infective agent is 5-fluorouracil (5-FU).

1294. The method of claim 1118 wherein the anti-infective agent is a folic acid antagonist.

1295. The method of claim 1118 wherein the anti-infective agent is methotrexate.

1296. The method of claim 1118 wherein the anti-infective agent is a podophylotoxin.

1297. The method of claim 1118 wherein the anti-infective agent is etoposide.

1298. The method of claim 1118 wherein the anti-infective agent is camptothecin.

1299. The method of claim 1118 wherein the anti-infective agent is a hydroxyurea.

1300. The method of claim 1118 wherein the anti-infective agent is a platinum complex.

1301. The method of claim 1118 wherein the anti-infective agent is cisplatin.

1302. The method of claim 1118 wherein the composition comprises an anti-thrombotic agent.

1303. The method of claim 1118 wherein the polymer is formed from reactants comprising a naturally occurring polymer.

1304. The method of claim 1118 wherein the polymer is formed from reactants comprising protein.

1305. The method of claim 1118 wherein the polymer is formed from reactants comprising carbohydrate.

1306. The method of claim 1118 wherein the polymer is formed from reactants comprising biodegradable polymer.

1307. The method of claim 1118 wherein the polymer is formed from reactants comprising nonbiodegradable polymer.

1308. The method of claim 1118 wherein the polymer is formed from reactants comprising collagen.

1309. The method of claim 1118 wherein the polymer is formed from reactants comprising methylated collagen.

1310. The method of claim 1118 wherein the polymer is formed from reactants comprising fibrinogen.

1311. The method of claim 1118 wherein the polymer is formed from reactants comprising thrombin.

1312. The method of claim 1118 wherein the polymer is formed from reactants comprising blood plasma.

1313. The method of claim 1118 wherein the polymer is formed from reactants comprising calcium salt.

1314. The method of claim 1118 wherein the polymer is formed from reactants comprising an antifibronolytic agent.

1315. The method of claim 1118 wherein the polymer is formed from reactants comprising fibrinogen analog.

1316. The method of claim 1118 wherein the polymer is formed from reactants comprising albumin.

1317. The method of claim 1118 wherein the polymer is formed from reactants comprising plasminogen.

1318. The method of claim 1118 wherein the polymer is formed from reactants comprising von Willebrands factor.

1319. The method of claim 1118 wherein the polymer is formed from reactants comprising Factor VIII.

1320. The method of claim 1118 wherein the polymer is formed from reactants comprising hypoallergenic collagen.

1321. The method of claim 1118 wherein the polymer is formed from reactants comprising atelopeptidic collagen.

1322. The method of claim 1118 wherein the polymer is formed from reactants comprising telopeptide collagen.

1323. The method of claim 1118 wherein the polymer is formed from reactants comprising crosslinked collagen.

1324. The method of claim 1118 wherein the polymer is formed from reactants comprising aprotinin.

1325. The method of claim 1118 wherein the polymer is formed from reactants comprising epsilon-amino-n-caproic acid.

1326. The method of claim 1118 wherein the polymer is formed from reactants comprising gelatin.

1327. The method of claim 1118 wherein the polymer is formed from reactants comprising protein conjugates.

1328. The method of claim 1118 wherein the polymer is formed from reactants comprising gelatin conjugates.

1329. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic polymer.

1330. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic isocyanate-containing compound.

1331. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic thiol-containing compound.

1332. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two thiol groups.

1333. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three thiol groups.

1334. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four thiol groups.

1335. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic amino-containing compound.

1336. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two amino groups.

1337. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three amino groups.

1338. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four amino groups.

1339. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group.

1340. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups.

1341. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.

1342. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.

1343. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound.

1344. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.

1345. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive amino groups.

1346. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive thiol groups.

1347. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups.

1348. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic compound comprising a biodegradable polyester block.

1349. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from lactic acid or lactide.

1350. The method of claim 1118 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from glycolic acid or glycolide.

1351. The method of claim 1118 wherein the polymer is formed from reactants comprising polylysine.

1352. The method of claim 1118 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound comprising a polyalkylene oxide portion.

1353. The method of claim 1118 wherein the polymer is formed from reactants comprising (a) protein and (b) polylysine.

1354. The method of claim 1118 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four thiol groups.

1355. The method of claim 1118 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four amino groups.

1356. The method of claim 1118 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

1357. The method of claim 1118 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

1358. The method of claim 1118 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound comprising a polyalkylene oxide portion.

1359. The method of claim 1118 wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine.

1360. The method of claim 1118 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four thiol groups.

1361. The method of claim 1118 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four amino groups.

1362. The method of claim 1118 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

1363. The method of claim 1118 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

1364. The method of claim 1118 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound comprising a polyalkylene oxide portion.

1365. The method of claim 1118 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine.

1366. The method of claim 1118 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four thiol groups.

1367. The method of claim 1118 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four amino groups.

1368. The method of claim 1118 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

1369. The method of claim 1118 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

1370. The method of claim 1118 wherein the polymer is formed from reactants comprising hyaluronic acid.

1371. The method of claim 1118 wherein the polymer is formed from reactants comprising a hyaluronic acid derivative.

1372. The method of claim 1118 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.

1373. The method of claim 1118 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.

1374. The method of claim 1118 wherein the polymer is formed from reactants comprising (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.

1375. The method of claim 1118 wherein the composition comprises a colorant.

1376. The method of claim 1118 wherein the composition is sterile.

1377. A method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with i) an anti-fibrotic agent, ii) an anti-infective agent, iii) a polymer;
iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host, where the medical device is an ear or nose stent.

1378. The method for implanting a medical device according to claim 1377 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-fibrotic agent, and (b) implanting the medical device into the host.

1379. The method for implanting a medical device according to claim 1377 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-infective agent, and (b) implanting the medical device into the host.

1380. The method for implanting a medical device according to claim 1377 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a polymer; and (b) implanting the medical device into the host.

1381. The method for implanting a medical device according to claim 1377 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent and a polymer, and (b) implanting the medical device into the host.

1382. The method for implanting a medical device according to claim 1377 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

1383. The method for implanting a medical device according to claim 1377 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

1384. The method of claim 1377 wherein the medical device is a lacrimal duct stent.

1385. The method of claim 1377 wherein the medical device is an Eustachian tube stent.

1386. The method of claim 1377 wherein the medical device is a nasal stent.

1387. The method of claim 1377 wherein the medical device is a sinus stent.

1388. The method of claim 1377 wherein the anti-fibrotic agent inhibits cell regeneration.

1389. The method of claim 1377 wherein the anti-fibrotic agent inhibits angiogenesis.

1390. The method of claim 1377 wherein the anti-fibrotic agent inhibits fibroblast migration.

1391. The method of claim 1377 wherein the anti-fibrotic agent inhibits fibroblast proliferation.

1392. The method of claim 1377 wherein the anti-fibrotic agent inhibits deposition of extracellular matrix.

1393. The method of claim 1377 wherein the anti-fibrotic agent inhibits tissue remodeling.

1394. The method of claim 1377 wherein the anti-fibrotic agent is an angiogenesis inhibitor.

1395. The method of claim 1377 wherein the anti-fibrotic agent is a 5-lipoxygenase inhibitor or antagonist.

1396. The method of claim 1377 wherein the anti-fibrotic agent is a chemokine receptor antagonist.

1397. The method of claim 1377 wherein the anti-fibrotic agent is a cell cycle inhibitor.

1398. The method of claim 1377 wherein the anti-fibrotic agent is a taxane.

1399. The method of claim 1377 wherein the anti-fibrotic agent is an anti-microtubule agent.

1400. The method of claim 1377 wherein the anti-fibrotic agent is paclitaxel.

1401. The method of claim 1377 wherein the anti-fibrotic agent is not paclitaxel.

1402. The method of claim 1377 wherein the anti-fibrotic agent is an analogue or derivative of paclitaxel.

1403. The method of claim 1377 wherein the anti-fibrotic agent is a vinca alkaloid.

1404. The method of claim 1377 wherein the anti-fibrotic agent is camptothecin or an analogue or derivative thereof.

1405. The method of claim 1377 wherein the anti-fibrotic agent is a podophyllotoxin.

1406. The method of claim 1377 wherein the anti-fibrotic agent is a podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof.

1407. The method of claim 1377 wherein the anti-fibrotic agent is an anthracycline.

1408. The method of claim 1377 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof.

1409. The method of claim 1377 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof.

1410. The method of claim 1377 wherein the anti-fibrotic agent is a platinum compound.

1411. The method of claim 1377 wherein the anti-fibrotic agent is a nitrosourea.

1412. The method of claim 1377 wherein the anti-fibrotic agent is a nitroimidazole.

1413. The method of claim 1377 wherein the anti-fibrotic agent is a folic acid antagonist.

1414. The method of claim 1377 wherein the anti-fibrotic agent is a cytidine analogue.

1415. The method of claim 1377 wherein the anti-fibrotic agent is a pyrimidine analogue.

1416. The method of claim 1377 wherein the anti-fibrotic agent is a fluoropyrimidine analogue.

1417. The method of claim 1377 wherein the anti-fibrotic agent is a purine analogue.

1418. The method of claim 1377 wherein the anti-fibrotic agent is a nitrogen mustard or an analogue or derivative thereof.

1419. The method of claim 1377 wherein the anti-fibrotic agent is a hydroxyurea.

1420. The method of claim 1377 wherein the anti-fibrotic agent is a mytomicin or an analogue or derivative thereof.

1421. The method of claim 1377 wherein the anti-fibrotic agent is an alkyl sulfonate.

1422. The method of claim 1377 wherein the anti-fibrotic agent is a benzamide or an analogue or derivative thereof.

1423. The method of claim 1377 wherein the anti-fibrotic agent is a nicotinamide or an analogue or derivative thereof.

1424. The method of claim 1377 wherein the anti-fibrotic agent is a halogenated sugar or an analogue or derivative thereof.

1425. The method of claim 1377 wherein the anti-fibrotic agent is a DNA alkylating agent.

1426. The method of claim 1377 wherein the anti-fibrotic agent is an anti-microtubule agent.

1427. The method of claim 1377 wherein the anti-fibrotic agent is a topoisomerase inhibitor.

1428. The method of claim 1377 wherein the anti-fibrotic agent is a DNA cleaving agent.

1429. The method of claim 1377 wherein the anti-fibrotic agent is an antimetabolite.

1430. The method of claim 1377 wherein the anti-fibrotic agent inhibits adenosine deaminase.

1431. The method of claim 1377 wherein the anti-fibrotic agent inhibits purine ring synthesis.

1432. The method of claim 1377 wherein the anti-fibrotic agent is a nucleotide interconversion inhibitor.

1433. The method of claim 1377 wherein the anti-fibrotic agent inhibits dihydrofolate reduction.

1434. The method of claim 1377 wherein the anti-fibrotic agent blocks thymidine monophosphate.

1435. The method of claim 1377 wherein the anti-fibrotic agent causes DNA damage.

1436. The method of claim 1377 wherein the anti-fibrotic agent is a DNA intercalation agent.

1437. The method of claim 1377 wherein the anti-fibrotic agent is a RNA synthesis inhibitor.

1438. The method of claim 1377 wherein the anti-fibrotic agent is a pyrimidine synthesis inhibitor.

1439. The method of claim 1377 wherein the anti-fibrotic agent inhibits ribonucleotide synthesis or function.

1440. The method of claim 1377 wherein the anti-fibrotic agent inhibits thymidine monophosphate synthesis or function.

1441. The method of claim 1377 wherein the anti-fibrotic agent inhibits DNA synthesis.

1442. The method of claim 1377 wherein the anti-fibrotic agent causes DNA adduct formation.

1443. The method of claim 1377 wherein the anti-fibrotic agent inhibits protein synthesis.

1444. The method of claim 1377 wherein the anti-fibrotic agent inhibits microtubule function.

1445. The method of claim 1377 wherein the anti-fibrotic agent is a cyclin dependent protein kinase inhibitor.

1446. The method of claim 1377 wherein the anti-fibrotic agent is an epidermal growth factor kinase inhibitor.

1447. The method of claim 1377 wherein the anti-fibrotic agent is an elastase inhibitor.

1448. The method of claim 1377 wherein the anti-fibrotic agent is a factor Xa inhibitor.

1449. The method of claim 1377 wherein the anti-fibrotic agent is a farnesyltransferase inhibitor.

1450. The method of claim 1377 wherein the anti-fibrotic agent is a fibrinogen antagonist.

1451. The method of claim 1377 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

1452. The method of claim 1377 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist.

1453. The method of claim 1377 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof.

1454. The method of claim 1377 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

1455. The method of claim 1377 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor.

1456. The method of claim 1377 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof.

1457. The method of claim 1377 wherein the anti-fibrotic agent is a hydroorotate dehydrogenase inhibitor.

1458. The method of claim 1377 wherein the anti-fibrotic agent is an IKK2 inhibitor.

1459. The method of claim 1377 wherein the anti-fibrotic agent is an IL-1 antagonist.

1460. The method of claim 1377 wherein the anti-fibrotic agent is an ICE antagonist.

1461. The method of claim 1377 wherein the anti-fibrotic agent is an IRAK antagonist.

1462. The method of claim 1377 wherein the anti-fibrotic agent is an IL-4 agonist.

1463. The method of claim 1377 wherein the anti-fibrotic agent is an immunomodulatory agent.

1464. The method of claim 1377 wherein the anti-fibrotic agent is sirolimus or an analogue or derivative thereof.

1465. The method of claim 1377 wherein the anti-fibrotic agent is not sirolimus.

1466. The method of claim 1377 wherein the anti-fibrotic agent is everolimus or an analogue or derivative thereof.

1467. The method of claim 1377 wherein the anti-fibrotic agent is tacrolimus or an analogue or derivative thereof.

1468. The method of claim 1377 wherein the anti-fibrotic agent is not tacrolimus.

1469. The method of claim 1377 wherein the anti-fibrotic agent is biolmus or an analogue or derivative thereof.

1470. The method of claim 1377 wherein the anti-fibrotic agent is tresperimus or an analogue or derivative thereof.

1471. The method of claim 1377 wherein the anti-fibrotic agent is auranofin or an analogue or derivative thereof.

1472. The method of claim 1377 wherein the anti-fibrotic agent is 27-0-demethylrapamycin or an analogue or derivative thereof.

1473. The method of claim 1377 wherein the anti-fibrotic agent is gusperimus or an analogue or derivative thereof.

1474. The method of claim 1377 wherein the anti-fibrotic agent is pimecrolimus or an analogue or derivative thereof.

1475. The method of claim 1377 wherein the anti-fibrotic agent is ABT-578 or an analogue or derivative thereof.

1476. The method of claim 1377 wherein the anti-fibrotic agent is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.

1477. The method of claim 1377 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof.

1478. The method of claim 1377 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-alpha-25 dihydroxy vitamin D3 or an analogue or derivative thereof.

1479. The method of claim 1377 wherein the anti-fibrotic agent is a leukotriene inhibitor.

1480. The method of claim 1377 wherein the anti-fibrotic agent is a MCP-1 antagonist.

1481. The method of claim 1377 wherein the anti-fibrotic agent is a MMP inhibitor.

1482. The method of claim 1377 wherein the anti-fibrotic agent is an NF kappa B inhibitor.

1483. The method of claim 1377 wherein the anti-fibrotic agent is an NF kappa B inhibitor, wherein the NF kappa B inhibitor is Bay 11-7082.

1484. The method of claim 1377 wherein the anti-fibrotic agent is an NO antagonist.

1485. The method of claim 1377 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor.

1486. The method of claim 1377 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB
202190.

1487. The method of claim 1377 wherein the anti-fibrotic agent is a phosphodiesterase inhibitor.

1488. The method of claim 1377 wherein the anti-fibrotic agent is a TGF beta inhibitor.

1489. The method of claim 1377 wherein the anti-fibrotic agent is a thromboxane A2 antagonist.

1490. The method of claim 1377 wherein the anti-fibrotic agent is a TNF alpha antagonist.

1491. The method of claim 1377 wherein the anti-fibrotic agent is a TACE inhibitor.

1492. The method of claim 1377 wherein the anti-fibrotic agent is a tyrosine kinase inhibitor.

1493. The method of claim 1377 wherein the anti-fibrotic agent is a vitronectin inhibitor.

1494. The method of claim 1377 wherein the anti-fibrotic agent is a fibroblast growth factor inhibitor.

1495. The method of claim 1377 wherein the anti-fibrotic agent is a protein kinase inhibitor.

1496. The method of claim 1377 wherein the anti-fibrotic agent is a PDGF receptor kinase inhibitor.

1497. The method of claim 1377 wherein the anti-fibrotic agent is an endothelial growth factor receptor kinase inhibitor.

1498. The method of claim 1377 wherein the anti-fibrotic agent is a retinoic acid receptor antagonist.

1499. The method of claim 1377 wherein the anti-fibrotic agent is a platelet derived growth factor receptor kinase inhibitor.

1500. The method of claim 1377 wherein the anti-fibrotic agent is a fibrinogen antagonist.

1501. The method of claim 1377 wherein the anti-fibrotic agent is an antimycotic agent.

1502. The method of claim 1377 wherein the anti-fibrotic agent is an antimycotic agent, wherein the antimycotic agent is sulconizole.

1503. The method of claim 1377 wherein the anti-fibrotic agent is a bisphosphonate.

1504. The method of claim 1377 wherein the anti-fibrotic agent is a phospholipase A1 inhibitor.

1505. The method of claim 1377 wherein the anti-fibrotic agent is a histamine H1/H2/H3 receptor antagonist.

1506. The method of claim 1377 wherein the anti-fibrotic agent is a macrolide antibiotic.

1507. The method of claim 1377 wherein the anti-fibrotic agent is a GPIIb/IIIa receptor antagonist.

1508. The method of claim 1377 wherein the anti-fibrotic agent is an endothelin receptor antagonist.

1509. The method of claim 1377 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor agonist.

1510. The method of claim 1377 wherein the anti-fibrotic agent is an estrogen receptor agent.

1511. The method of claim 1377 wherein the anti-fibrotic agent is a somastostatin analogue.

1512. The method of claim 1377 wherein the anti-fibrotic agent is a neurokinin 1 antagonist.

1513. The method of claim 1377 wherein the anti-fibrotic agent is a neurokinin 3 antagonist.

1514. The method of claim 1377 wherein the anti-fibrotic agent is a VLA-4 antagonist.

1515. The method of claim 1377 wherein the anti-fibrotic agent is an osteoclast inhibitor.

1516. The method of claim 1377 wherein the anti-fibrotic agent is a DNA topoisomerase ATP hydrolyzing inhibitor.

1517. The method of claim 1377 wherein the anti-fibrotic agent is an angiotensin I converting enzyme inhibitor.

1518. The method of claim 1377 wherein the anti-fibrotic agent is an angiotensin II antagonist.

1519. The method of claim 1377 wherein the anti-fibrotic agent is an enkephalinase inhibitor.

1520. The method of claim 1377 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer.

1521. The method of claim 1377 wherein the anti-fibrotic agent is a protein kinase C inhibitor.

1522. The method of claim 1377 wherein the anti-fibrotic agent is a ROCK (rho-associated kinase) inhibitor.

1523. The method of claim 1377 wherein the anti-fibrotic agent is a CXCR3 inhibitor.

1524. The method of claim 1377 wherein the anti-fibrotic agent is an Itk inhibitor.

1525. The method of claim 1377 wherein the anti-fibrotic agent is a cytosolic phospholipase A2-alpha inhibitor.

1526. The method of claim 1377 wherein the anti-fibrotic agent is a PPAR agonist.

1527. The method of claim 1377 wherein the anti-fibrotic agent is an immunosuppressant.

1528. The method of claim 1377 wherein the anti-fibrotic agent is an Erb inhibitor.

1529. The method of claim 1377 wherein the anti-fibrotic agent is an apoptosis agonist.

1530. The method of claim 1377 wherein the anti-fibrotic agent is a lipocortin agonist.

1531. The method of claim 1377 wherein the anti-fibrotic agent is a VCAM-1 antagonist.

1532. The method of claim 1377 wherein the anti-fibrotic agent is a collagen antagonist.

1533. The method of claim 1377 wherein the anti-fibrotic agent is an alpha 2 integrin antagonist.

1534. The method of claim 1377 wherein the anti-fibrotic agent is a TNF alpha inhibitor.

1535. The method of claim 1377 wherein the anti-fibrotic agent is a nitric oxide inhibitor

1536. The method of claim 1377 wherein the anti-fibrotic agent is a cathepsin inhibitor.

1537. The method of claim 1377 wherein the anti-fibrotic agent is not an anti-inflammatory agent.

1538. The method of claim 1377 wherein the anti-fibrotic agent is not a steroid.

1539. The method of claim 1377 wherein the anti-fibrotic agent is not a glucocorticosteroid.

1540. The method of claim 1377 wherein the anti-fibrotic agent is not dexamethasone.

1541. The method of claim 1377 wherein the anti-fibrotic agent is not beclomethasone.

1542. The method of claim 1377 wherein the anti-fibrotic agent is not dipropionate.

1543. The method of claim 1377 wherein the anti-fibrotic agent is not an anti-infective agent.

1544. The method of claim 1377 wherein the anti-fibrotic agent is not an antibiotic.

1545. The method of claim 1377 wherein the anti-fibrotic agent is not an anti-fungal agent.

1546. The method of claim 1377 wherein the anti-infective agent isan anthracycline.

1547. The method of claim 1377 wherein the anti-infective agent isdoxorubicin.

1548. The method of claim 1377 wherein the anti-infective agent is ismitoxantrone.

1549. The method of claim 1377 wherein the anti-infective agent is a fluoropyrimidine.

1550. The method of claim 1377 wherein the anti-infective agent is 5-fluorouracil (5-FU).

1551. The method of claim 1377 wherein the anti-infective agent is a folic acid antagonist.

1552. The method of claim 1377 wherein the anti-infective agent is methotrexate.

1553. The method of claim 1377 wherein the anti-infective agent is a podophylotoxin.

1554. The method of claim 1377 wherein the anti-infective agent is etoposide.

1555. The method of claim 1377 wherein the anti-infective agent is camptothecin.

1556. The method of claim 1377 wherein the anti-infective agent is a hydroxyurea.

1557. The method of claim 1377 wherein the anti-infective agent is a platinum complex.

1558. The method of claim 1377 wherein the anti-infective agent is cisplatin.

1559. The method of claim 1377 wherein the composition comprises an anti-thrombotic agent.

1560. The method of claim 1377 wherein the polymer is formed from reactants comprising a naturally occurring polymer.

1561. The method of claim 1377 wherein the polymer is formed from reactants comprising protein.

1562. The method of claim 1377 wherein the polymer is formed from reactants comprising carbohydrate.

1563. The method of claim 1377 wherein the polymer is formed from reactants comprising biodegradable polymer.

1564. The method of claim 1377 wherein the polymer is formed from reactants comprising nonbiodegradable polymer.

1565. The method of claim 1377 wherein the polymer is formed from reactants comprising collagen.

1566. The method of claim 1377 wherein the polymer is formed from reactants comprising methylated collagen.

1567. The method of claim 1377 wherein the polymer is formed from reactants comprising fibrinogen.

1568. The method of claim 1377 wherein the polymer is formed from reactants comprising thrombin.

1569. The method of claim 1377 wherein the polymer is formed from reactants comprising blood plasma.

1570. The method of claim 1377 wherein the polymer is formed from reactants comprising calcium salt.

1571. The method of claim 1377 wherein the polymer is formed from reactants comprising an antifibronolytic agent.

1572. The method of claim 1377 wherein the polymer is formed from reactants comprising fibrinogen analog.

1573. The method of claim 1377 wherein the polymer is formed from reactants comprising albumin.

1574. The method of claim 1377 wherein the polymer is formed from reactants comprising plasminogen.

1575. The method of claim 1377 wherein the polymer is formed from reactants comprising von Willebrands factor.

1576. The method of claim 1377 wherein the polymer is formed from reactants comprising Factor VIII.

1577. The method of claim 1377 wherein the polymer is formed from reactants comprising hypoallergenic collagen.

1578. The method of claim 1377 wherein the polymer is formed from reactants comprising atelopeptidic collagen.

1579. The method of claim 1377 wherein the polymer is formed from reactants comprising telopeptide collagen.

1580. The method of claim 1377 wherein the polymer is formed from reactants comprising crosslinked collagen.

1581. The method of claim 1377 wherein the polymer is formed from reactants comprising aprotinin.

1582. The method of claim 1377 wherein the polymer is formed from reactants comprising epsilon-amino-n-caproic acid.

1583. The method of claim 1377 wherein the polymer is formed from reactants comprising gelatin.

1584. The method of claim 1377 wherein the polymer is formed from reactants comprising protein conjugates.

1585. The method of claim 1377 wherein the polymer is formed from reactants comprising gelatin conjugates.

1586. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic polymer.

1587. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic isocyanate-containing compound.

1588. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic thiol-containing compound.

1589. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two thiol groups.

1590. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three thiol groups.

1591. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four thiol groups.

1592. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic amino-containing compound.

1593. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two amino groups.

1594. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three amino groups.

1595. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four amino groups.

1596. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group.

1597. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups.

1598. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.

1599. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.

1600. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound.

1601. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.

1602. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive amino groups.

1603. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive thiol groups.

1604. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups.

1605. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic compound comprising a biodegradable polyester block.

1606. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from lactic acid or lactide.

1607. The method of claim 1377 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from glycolic acid or glycolide.

1608. The method of claim 1377 wherein the polymer is formed from reactants comprising polylysine.

1609. The method of claim 1377 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound comprising a polyalkylene oxide portion.

1610. The method of claim 1377 wherein the polymer is formed from reactants comprising (a) protein and (b) polylysine.

1611. The method of claim 1377 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four thiol groups.

1612. The method of claim 1377 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four amino groups.

1613. The method of claim 1377 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

1614. The method of claim 1377 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

1615. The method of claim 1377 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound comprising a polyalkylene oxide portion.

1616. The method of claim 1377 wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine.

1617. The method of claim 1377 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four thiol groups.

1618. The method of claim 1377 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four amino groups.

1619. The method of claim 1377 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

1620. The method of claim 1377 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

1621. The method of claim 1377 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound comprising a polyalkylene oxide portion.

1622. The method of claim 1377 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine.

1623. The method of claim 1377 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four thiol groups.

1624. The method of claim 1377 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four amino groups.

1625. The method of claim 1377 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

1626. The method of claim 1377 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

1627. The method of claim 1377 wherein the polymer is formed from reactants comprising hyaluronic acid.

1628. The method of claim 1377 wherein the polymer is formed from reactants comprising a hyaluronic acid derivative.

1629. The method of claim 1377 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.

1630. The method of claim 1377 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.

1631. The method of claim 1377 wherein the polymer is formed from reactants comprising (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.

1632. The method of claim 1377 wherein the composition comprises a colorant.

1633. The method of claim 1377 wherein the composition is sterile.

1634. A method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with i) an anti-fibrotic agent, ii) an anti-infective agent, iii) a polymer;
iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host, where the medical device is an ear ventilation tube.

1635. The method for implanting a medical device according to claim 1634 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-fibrotic agent, and (b) implanting the medical device into the host.

1636. The method for implanting a medical device according to claim 1634 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-infective agent, and (b) implanting the medical device into the host.

1637. The method for implanting a medical device according to claim 1634 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a polymer; and (b) implanting the medical device into the host.

1638. The method for implanting a medical device according to claim 1634 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent and a polymer, and (b) implanting the medical device into the host.

1639. The method for implanting a medical device according to claim 1634 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

1640. The method for implanting a medical device according to claim 1634 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

1641. The method of claim 1634 wherein the medical device is a grommet shaped tube.

1642. The method of claim 1634 wherein the medical device is a T-tube.

1643. The method of claim 1634 wherein the medical device is a tympanostomy tube.

1644. The method of claim 1634 wherein the medical device is a drain tube.

1645. The method of claim 1634 wherein the medical device is a tympanic tube.

1646. The method of claim 1634 wherein the medical device is an otological tube.

1647. The method of claim 1634 wherein the medical device is a myringotomy tube.

1648. The method of claim 1634 wherein the medical device is an artifical Eustachian tube.

1649. The method of claim 1634 wherein the medical device is an Eustachian tube prosthesis.

1650. The method of claim 1634 wherein the medical device is an Eustachian stent.

1651. The method of claim 1634 wherein the anti-fibrotic agent inhibits cell regeneration.

1652. The method of claim 1634 wherein the anti-fibrotic agent inhibits angiogenesis.

1653. The method of claim 1634 wherein the anti-fibrotic agent inhibits fibroblast migration.

1654. The method of claim 1634 wherein the anti-fibrotic agent inhibits fibroblast proliferation.

1655. The method of claim 1634 wherein the anti-fibrotic agent inhibits deposition of extracellular matrix.

1656. The method of claim 1634 wherein the anti-fibrotic agent inhibits tissue remodeling.

1657. The method of claim 1634 wherein the anti-fibrotic agent is an angiogenesis inhibitor.

1658. The method of claim 1634 wherein the anti-fibrotic agent is a 5-lipoxygenase inhibitor or antagonist.

1659. The method of claim 1634 wherein the anti-fibrotic agent is a chemokine receptor antagonist.

1660. The method of claim 1634 wherein the anti-fibrotic agent is a cell cycle inhibitor.

1661. The method of claim 1634 wherein the anti-fibrotic agent is a taxane.

1662. The method of claim 1634 wherein the anti-fibrotic agent is an anti-microtubule agent.

1663. The method of claim 1634 wherein the anti-fibrotic agent is paclitaxel.

1664. The method of claim 1634 wherein the anti-fibrotic agent is not paclitaxel.

1665. The method of claim 1634 wherein the anti-fibrotic agent is an analogue or derivative of paclitaxel.

1666. The method of claim 1634 wherein the anti-fibrotic agent is a vinca alkaloid.

1667. The method of claim 1634 wherein the anti-fibrotic agent is camptothecin or an analogue or derivative thereof.

1668. The method of claim 1634 wherein the anti-fibrotic agent is a podophyllotoxin.

1669. The method of claim 1634 wherein the anti-fibrotic agent is a podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof.

1670. The method of claim 1634 wherein the anti-fibrotic agent is an anthracycline.

1671. The method of claim 1634 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof.

1672. The method of claim 1634 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof.

1673. The method of claim 1634 wherein the anti-fibrotic agent is a platinum compound.

1674. The method of claim 1634 wherein the anti-fibrotic agent is a nitrosourea.

1675. The method of claim 1634 wherein the anti-fibrotic agent is a nitroimidazole.

1676. The method of claim 1634 wherein the anti-fibrotic agent is a folic acid antagonist.

1677. The method of claim 1634 wherein the anti-fibrotic agent is a cytidine analogue.

1678. The method of claim 1634 wherein the anti-fibrotic agent is a pyrimidine analogue.

1679. The method of claim 1634 wherein the anti-fibrotic agent is a fluoropyrimidine analogue.

1680. The method of claim 1634 wherein the anti-fibrotic agent is a purine analogue.

1681. The method of claim 1634 wherein the anti-fibrotic agent is a nitrogen mustard or an analogue or derivative thereof.

1682. The method of claim 1634 wherein the anti-fibrotic agent is a hydroxyurea.

1683. The method of claim 1634 wherein the anti-fibrotic agent is a mytomicin or an analogue or derivative thereof.

1684. The method of claim 1634 wherein the anti-fibrotic agent is an alkyl sulfonate.

1685. The method of claim 1634 wherein the anti-fibrotic agent is a benzamide or an analogue or derivative thereof.

1686. The method of claim 1634 wherein the anti-fibrotic agent is a nicotinamide or an analogue or derivative thereof.

1687. The method of claim 1634 wherein the anti-fibrotic agent is a halogenated sugar or an analogue or derivative thereof.

1688. The method of claim 1634 wherein the anti-fibrotic agent is a DNA alkylating agent.

1689. The method of claim 1634 wherein the anti-fibrotic agent is an anti-microtubule agent.

1690. The method of claim 1634 wherein the anti-fibrotic agent is a topoisomerase inhibitor.

1691. The method of claim 1634 wherein the anti-fibrotic agent is a DNA cleaving agent.

1692. The method of claim 1634 wherein the anti-fibrotic agent is an antimetabolite.

1693. The method of claim 1634 wherein the anti-fibrotic agent inhibits adenosine deaminase.

1694. The method of claim 1634 wherein the anti-fibrotic agent inhibits purine ring synthesis.

1695. The method of claim 1634 wherein the anti-fibrotic agent is a nucleotide interconversion inhibitor.

1696. The method of claim 1634 wherein the anti-fibrotic agent inhibits dihydrofolate reduction.

1697. The method of claim 1634 wherein the anti-fibrotic agent blocks thymidine monophosphate.

1698. The method of claim 1634 wherein the anti-fibrotic agent causes DNA damage.

1699. The method of claim 1634 wherein the anti-fibrotic agent is a DNA intercalation agent.

1700. The method of claim 1634 wherein the anti-fibrotic agent is a RNA synthesis inhibitor.

1701. The method of claim 1634 wherein the anti-fibrotic agent is a pyrimidine synthesis inhibitor.

1702. The method of claim 1634 wherein the anti-fibrotic agent inhibits ribonucleotide synthesis or function.

1703. The method of claim 1634 wherein the anti-fibrotic agent inhibits thymidine monophosphate synthesis or function.

1704. The method of claim 1634 wherein the anti-fibrotic agent inhibits DNA synthesis.

1705. The method of claim 1634 wherein the anti-fibrotic agent causes DNA adduct formation.

1706. The method of claim 1634 wherein the anti-fibrotic agent inhibits protein synthesis.

1707. The method of claim 1634 wherein the anti-fibrotic agent inhibits microtubule function.

1708. The method of claim 1634 wherein the anti-fibrotic agent is a cyclin dependent protein kinase inhibitor.

1709. The method of claim 1634 wherein the anti-fibrotic agent is an epidermal growth factor kinase inhibitor.

1710. The method of claim 1634 wherein the anti-fibrotic agent is an elastase inhibitor.

1711. The method of claim 1634 wherein the anti-fibrotic agent is a factor Xa inhibitor.

1712. The method of claim 1634 wherein the anti-fibrotic agent is a farnesyltransferase inhibitor.

1713. The method of claim 1634 wherein the anti-fibrotic agent is a fibrinogen antagonist.

1714. The method of claim 1634 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

1715. The method of claim 1634 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist.

1716. The method of claim 1634 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof.

1717. The method of claim 1634 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

1718. The method of claim 1634 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor.

1719. The method of claim 1634 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof.

1720. The method of claim 1634 wherein the anti-fibrotic agent is a hydroorotate dehydrogenase inhibitor.

1721. The method of claim 1634 wherein the anti-fibrotic agent is an IKK2 inhibitor.

1722. The method of claim 1634 wherein the anti-fibrotic agent is an IL-1 antagonist.

1723. The method of claim 1634 wherein the anti-fibrotic agent is an ICE antagonist.

1724. The method of claim 1634 wherein the anti-fibrotic agent is an IRAK antagonist.

1725. The method of claim 1634 wherein the anti-fibrotic agent is an IL-4 agonist.

1726. The method of claim 1634 wherein the anti-fibrotic agent is an immunomodulatory agent.

1727. The method of claim 1634 wherein the anti-fibrotic agent is sirolimus or an analogue or derivative thereof.

1728. The method of claim 1634 wherein the anti-fibrotic agent is 1 not sirolimus.

1729. The method of claim 1634 wherein the anti-fibrotic agent is everolimus or an analogue or derivative thereof.

1730. The method of claim 1634 wherein the anti-fibrotic agent is tacrolimus or an analogue or derivative thereof.

1731. The method of claim 1634 wherein the anti-fibrotic agent is not tacrolimus.

1732. The method of claim 1634 wherein the anti-fibrotic agent is biolmus or an analogue or derivative thereof.

1733. The method of claim 1634 wherein the anti-fibrotic agent is tresperimus or an analogue or derivative thereof.

1734. The method of claim 1634 wherein the anti-fibrotic agent is auranofin or an analogue or derivative thereof.

1735. The method of claim 1634 wherein the anti-fibrotic agent is 27-0-demethylrapamycin or an analogue or derivative thereof.

1736. The method of claim 1634 wherein the anti-fibrotic agent is gusperimus or an analogue or derivative thereof.

1737. The method of claim 1634 wherein the anti-fibrotic agent is pimecrolimus or an analogue or derivative thereof.

1738. The method of claim 1634 wherein the anti-fibrotic agent is ABT-578 or an analogue or derivative thereof.

1739. The method of claim 1634 wherein the anti-fibrotic agent is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.

1740. The method of claim 1634 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof.

1741. The method of claim 1634 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-alpha-25 dihydroxy vitamin D3 or an analogue or derivative thereof.

1742. The method of claim 1634 wherein the anti-fibrotic agent is a leukotriene inhibitor.

1743. The method of claim 1634 wherein the anti-fibrotic agent is a MCP-1 antagonist.

1744. The method of claim 1634 wherein the anti-fibrotic agent is a MMP inhibitor.

1745. The method of claim 1634 wherein the anti-fibrotic agent is an NF kappa B inhibitor.

1746. The method of claim 1634 wherein the anti-fibrotic agent is an NF kappa B inhibitor, wherein the NF kappa B inhibitor is Bay 11-7082.

1747. The method of claim 1634 wherein the anti-fibrotic agent is an NO antagonist.

1748. The method of claim 1634 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor.

1749. The method of claim 1634 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB
202190.

1750. The method of claim 1634 wherein the anti-fibrotic agent is a phosphodiesterase inhibitor.

1751. The method of claim 1634 wherein the anti-fibrotic agent is a TGF beta inhibitor.

1752. The method of claim 1634 wherein the anti-fibrotic agent is a thromboxane A2 antagonist.

1753. The method of claim 1634 wherein the anti-fibrotic agent is a TNF alpha antagonist.

1754. The method of claim 1634 wherein the anti-fibrotic agent is a TACE inhibitor.

1755. The method of claim 1634 wherein the anti-fibrotic agent is a tyrosine kinase inhibitor.

1756. The method of claim 1634 wherein the anti-fibrotic agent is a vitronectin inhibitor.

1757. The method of claim 1634 wherein the anti-fibrotic agent is a fibroblast growth factor inhibitor.

1758. The method of claim 1634 wherein the anti-fibrotic agent is a protein kinase inhibitor.

1759. The method of claim 1634 wherein the anti-fibrotic agent is a PDGF receptor kinase inhibitor.

1760. The method of claim 1634 wherein the anti-fibrotic agent is an endothelial growth factor receptor kinase inhibitor.

1761. The method of claim 1634 wherein the anti-fibrotic agent is a retinoic acid receptor antagonist.

1762. The method of claim 1634 wherein the anti-fibrotic agent is a platelet derived growth factor receptor kinase inhibitor.

1763. The method of claim 1634 wherein the anti-fibrotic agent is a fibrinogen antagonist.

1764. The method of claim 1634 wherein the anti-fibrotic agent is an antimycotic agent.

1765. The method of claim 1634 wherein the anti-fibrotic agent is an antimycotic agent, wherein the antimycotic agent is sulconizole.

1766. The method of claim 1634 wherein the anti-fibrotic agent is a bisphosphonate.

1767. The method of claim 1634 wherein the anti-fibrotic agent is a phospholipase A1 inhibitor.

1768. The method of claim 1634 wherein the anti-fibrotic agent is a histamine H1/H2/H3 receptor antagonist.

1769. The method of claim 1634 wherein the anti-fibrotic agent is a macrolide antibiotic.

1770. The method of claim 1634 wherein the anti-fibrotic agent is a GPIIb/IIIa receptor antagonist.

1771. The method of claim 1634 wherein the anti-fibrotic agent is an endothelin receptor antagonist.

1772. The method of claim 1634 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor agonist.

1773. The method of claim 1634 wherein the anti-fibrotic agent is an estrogen receptor agent.

1774. The method of claim 1634 wherein the anti-fibrotic agent is a somastostatin analogue.

1775. The method of claim 1634 wherein the anti-fibrotic agent is a neurokinin 1 antagonist.

1776. The method of claim 1634 wherein the anti-fibrotic agent is a neurokinin 3 antagonist.

1777. The method of claim 1634 wherein the anti-fibrotic agent is a VLA-4 antagonist.

1778. The method of claim 1634 wherein the anti-fibrotic agent is an osteoclast inhibitor.

1779. The method of claim 1634 wherein the anti-fibrotic agent is a DNA topoisomerase ATP hydrolyzing inhibitor.

1780. The method of claim 1634 wherein the anti-fibrotic agent is an angiotensin I converting enzyme inhibitor.

1781. The method of claim 1634 wherein the anti-fibrotic agent is an angiotensin II antagonist.

1782. The method of claim 1634 wherein the anti-fibrotic agent is an enkephalinase inhibitor.

1783. The method of claim 1634 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer.

1784. The method of claim 1634 wherein the anti-fibrotic agent is a protein kinase C inhibitor.

1785. The method of claim 1634 wherein the anti-fibrotic agent is a ROCK (rho-associated kinase) inhibitor.

1786. The method of claim 1634 wherein the anti-fibrotic agent is a CXCR3 inhibitor.

1787. The method of claim 1634 wherein the anti-fibrotic agent is an Itk inhibitor.

1788. The method of claim 1634 wherein the anti-fibrotic agent is a cytosolic phospholipase A2-alpha inhibitor.

1789. The method of claim 1634 wherein the anti-fibrotic agent is a PPAR agonist.

1790. The method of claim 1634 wherein the anti-fibrotic agent is an immunosuppressant.

1791. The method of claim 1634 wherein the anti-fibrotic agent is an Erb inhibitor.

1792. The method of claim 1634 wherein the anti-fibrotic agent is an apoptosis agonist.

1793. The method of claim 1634 wherein the anti-fibrotic agent is a lipocortin agonist.

1794. The method of claim 1634 wherein the anti-fibrotic agent is a VCAM-1 antagonist.

1795. The method of claim 1634 wherein the anti-fibrotic agent is a collagen antagonist.

1796. The method of claim 1634 wherein the anti-fibrotic agent is an alpha 2 integrin antagonist.

1797. The method of claim 1634 wherein the anti-fibrotic agent is a TNF alpha inhibitor.

1798. The method of claim 1634 wherein the anti-fibrotic agent is a nitric oxide inhibitor

1799. The method of claim 1634 wherein the anti-fibrotic agent is a cathepsin inhibitor.

1800. The method of claim 1634 wherein the anti-fibrotic agent is not an anti-inflammatory agent.

1801. The method of claim 1634 wherein the anti-fibrotic agent is not a steroid.

1802. The method of claim 1634 wherein the anti-fibrotic agent is not a glucocorticosteroid.

1803. The method of claim 1634 wherein the anti-fibrotic agent is not dexamethasone.

1804. The method of claim 1634 wherein the anti-fibrotic agent is not beclomethasone.

1805. The method of claim 1634 wherein the anti-fibrotic agent is not dipropionate.

1806. The method of claim 1634 wherein the anti-fibrotic agent is not an anti-infective agent.

1807. The method of claim 1634 wherein the anti-fibrotic agent is not an antibiotic.

1808. The method of claim 1634 wherein the anti-fibrotic agent is not an anti-fungal agent.

1809. The method of claim 1634 wherein the anti-infective agent isan anthracycline.

1810. The method of claim 1634 wherein the anti-infective agent isdoxorubicin.

1811. The method of claim 1634 wherein the anti-infective agent is ismitoxantrone.

1812. The method of claim 1634 wherein the anti-infective agent is a fluoropyrimidine.

1813. The method of claim 1634 wherein the anti-infective agent is 5-fluorouracil (5-FU).

1814. The method of claim 1634 wherein the anti-infective agent is a folic acid antagonist.

1815. The method of claim 1634 wherein the anti-infective agent is methotrexate.

1816. The method of claim 1634 wherein the anti-infective agent is a podophylotoxin.

1817. The method of claim 1634 wherein the anti-infective agent is etoposide.

1818. The method of claim 1634 wherein the anti-infective agent is camptothecin.

1819. The method of claim 1634 wherein the anti-infective agent is a hydroxyurea.

1820. The method of claim 1634 wherein the anti-infective agent is a platinum complex.

1821. The method of claim 1634 wherein the anti-infective agent is cisplatin.

1822. The method of claim 1634 wherein the composition comprises an anti-thrombotic agent.

1823. The method of claim 1634 wherein the polymer is formed from reactants comprising a naturally occurring polymer.

1824. The method of claim 1634 wherein the polymer is formed from reactants comprising protein.

1825. The method of claim 1634 wherein the polymer is formed from reactants comprising carbohydrate.

1826. The method of claim 1634 wherein the polymer is formed from reactants comprising biodegradable polymer.

1827. The method of claim 1634 wherein the polymer is formed from reactants comprising nonbiodegradable polymer.

1828. The method of claim 1634 wherein the polymer is formed from reactants comprising collagen.

1829. The method of claim 1634 wherein the polymer is formed from reactants comprising methylated collagen.

1830. The method of claim 1634 wherein the polymer is formed from reactants comprising fibrinogen.

1831. The method of claim 1634 wherein the polymer is formed from reactants comprising thrombin.

1832. The method of claim 1634 wherein the polymer is formed from reactants comprising blood plasma.

1833. The method of claim 1634 wherein the polymer is formed from reactants comprising calcium salt.

1834. The method of claim 1634 wherein the polymer is formed from reactants comprising an antifibronolytic agent.

1835. The method of claim 1634 wherein the polymer is formed from reactants comprising fibrinogen analog.

1836. The method of claim 1634 wherein the polymer is formed from reactants comprising albumin.

1837. The method of claim 1634 wherein the polymer is formed from reactants comprising plasminogen.

1838. The method of claim 1634 wherein the polymer is formed from reactants comprising von Willebrands factor.

1839. The method of claim 1634 wherein the polymer is formed from reactants comprising Factor VIII.

1840. The method of claim 1634 wherein the polymer is formed from reactants comprising hypoallergenic collagen.

1841. The method of claim 1634 wherein the polymer is formed from reactants comprising atelopeptidic collagen.

1842. The method of claim 1634 wherein the polymer is formed from reactants comprising telopeptide collagen.

1843. The method of claim 1634 wherein the polymer is formed from reactants comprising crosslinked collagen.

1844. The method of claim 1634 wherein the polymer is formed from reactants comprising aprotinin.

1845. The method of claim 1634 wherein the polymer is formed from reactants comprising epsilon-amino-n-caproic acid.

1846. The method of claim 1634 wherein the polymer is formed from reactants comprising gelatin.

1847. The method of claim 1634 wherein the polymer is formed from reactants comprising protein conjugates.

1848. The method of claim 1634 wherein the polymer is formed from reactants comprising gelatin conjugates.

1849. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic polymer.

1850. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic isocyanate-containing compound.

1851. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic thiol-containing compound.

1852. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two thiol groups.

1853. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three thiol groups.

1854. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four thiol groups.

1855. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic amino-containing compound.

1856. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two amino groups.

1857. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three amino groups.

1858. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four amino groups.

1859. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group.

1860. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups.

1861. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.

1862. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.

1863. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound.

1864. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.

1865. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive amino groups.

1866. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive thiol groups.

1867. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups.

1868. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic compound comprising a biodegradable polyester block.

1869. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from lactic acid or lactide.

1870. The method of claim 1634 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from glycolic acid or glycolide.

1871. The method of claim 1634 wherein the polymer is formed from reactants comprising polylysine.

1872. The method of claim 1634 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound comprising a polyalkylene oxide portion.

1873. The method of claim 1634 wherein the polymer is formed from reactants comprising (a) protein and (b) polylysine.

1874. The method of claim 1634 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four thiol groups.

1875. The method of claim 1634 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four amino groups.

1876. The method of claim 1634 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

1877. The method of claim 1634 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

1878. The method of claim 1634 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound comprising a polyalkylene oxide portion.

1879. The method of claim 1634 wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine.

1880. The method of claim 1634 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four thiol groups.

1881. The method of claim 1634 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four amino groups.

1882. The method of claim 1634 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

1883. The method of claim 1634 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having a biodegradable region formed from reactants selected from tactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

1884. The method of claim 1634 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound comprising a polyalkylene oxide portion.

1885. The method of claim 1634 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine.

1886. The method of claim 1634 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four thiol groups.

1887. The method of claim 1634 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four amino groups.

1888. The method of claim 1634 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

1889. The method of claim 1634 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

1890. The method of claim 1634 wherein the polymer is formed from reactants comprising hyaluronic acid.

1891. The method of claim 1634 wherein the polymer is formed from reactants comprising a hyaluronic acid derivative.

1892. The method of claim 1634 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.

1893. The method of claim 1634 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.

1894. The method of claim 1634 wherein the polymer is formed from reactants comprising (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.

1895. The method of claim 1634 wherein the composition comprises a colorant.

1896. The method of claim 1634 wherein the composition is sterile.

1897. A method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with i) an anti-fibrotic agent, ii) an anti-infective agent, iii) a polymer;
iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host, where the medical device is an intraocular implant.

1898. The method for implanting a medical device according to claim 1897 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-fibrotic agent, and (b) implanting the medical device into the host.

1899. The method for implanting a medical device according to claim 1897 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-infective agent, and (b) implanting the medical device into the host.

1900. The method for implanting a medical device according to claim 1897 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a polymer; and (b) implanting the medical device into the host.

1901. The method for implanting a medical device according to claim 1897 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent and a polymer, and (b) implanting the medical device into the host.

1902. The method for implanting a medical device according to claim 1897 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

1903. The method for implanting a medical device according to claim 1897 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

1904. The method of claim 1897 wherein the medical device is an intraocular lens device for preventing lens opacification.

1905. The method of claim 1897 wherein the medical device is a polymethylmethacrylate intraocular lense.

1906. The method of claim 1897 wherein the medical device is a silicone intraocular lens.

1907. The method of claim 1897 wherein the medical device is an achromatic lens.

1908. The method of claim 1897 wherein the medical device is a pseudophako.

1909. The method of claim 1897 wherein the medical device is a phakic lens.

1910. The method of claim 1897 wherein the medical device is aaphakic lens.

1911. The method of claim 1897 wherein the medical device is a multi-focal intraocular lens.

1912. The method of claim 1897 wherein the medical device is a hydrophilic and hydrophobic acrylic intraocular lens.

1913. The method of claim 1897 wherein the medical device is an intraocular implant.

1914. The method of claim 1897 wherein the medical device is an optic lens.

1915. The method of claim 1897 wherein the medical device is a rigid gas permeable lens.

1916. The method of claim 1897 wherein the medical device is a foldable intraocular lens.

1917. The method of claim 1897 wherein the medical device is a rigid intraocular lens.

1918. The method of claim 1897 wherein the medical device is a corrective implant for vision impairment.

1919. The method of claim 1897 wherein the medical device is an intraocular implant adapted for being used in conjunction with a transplant for the cornea.

1920. The method of claim 1897 wherein the medical device is an intraocular implant adapted for being used in conjunction with treatment of secondary cataract after extracapsular cataract extraction.

1921. The method of claim 1897 wherein the anti-fibrotic agent inhibits cell regeneration.

1922. The method of claim 1897 wherein the anti-fibrotic agent inhibits angiogenesis.

1923. The method of claim 1897 wherein the anti-fibrotic agent inhibits fibroblast migration.

1924. The method of claim 1897 wherein the anti-fibrotic agent inhibits fibroblast proliferation.

1925. The method of claim 1897 wherein the anti-fibrotic agent inhibits deposition of extracellular matrix.

1926. The method of claim 1897 wherein the anti-fibrotic agent inhibits tissue remodeling.

1927. The method of claim 1897 wherein the anti-fibrotic agent is an angiogenesis inhibitor.

1928. The method of claim 1897 wherein the anti-fibrotic agent is a 5-lipoxygenase inhibitor or antagonist.

1929. The method of claim 1897 wherein the anti-fibrotic agent is a chemokine receptor antagonist.

1930. The method of claim 1897 wherein the anti-fibrotic agent is a cell cycle inhibitor.

1931. The method of claim 1897 wherein the anti-fibrotic agent is a taxane.

1932. The method of claim 1897 wherein the anti-fibrotic agent is an anti-microtubule agent.

1933. The method of claim 1897 wherein the anti-fibrotic agent is paclitaxel.

1934. The method of claim 1897 wherein the anti-fibrotic agent is not paclitaxel.

1935. The method of claim 1897 wherein the anti-fibrotic agent is an analogue or derivative of paclitaxel.

1936. The method of claim 1897 wherein the anti-fibrotic agent is a vinca alkaloid.

1937. The method of claim 1897 wherein the anti-fibrotic agent is camptothecin or an analogue or derivative thereof.

1938. The method of claim 1897 wherein the anti-fibrotic agent is a podophyllotoxin.

1939. The method of claim 1897 wherein the anti-fibrotic agent is a podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof.

1940. The method of claim 1897 wherein the anti-fibrotic agent is an anthracycline.

1941. The method of claim 1897 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof.

1942. The method of claim 1897 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof.

1943. The method of claim 1897 wherein the anti-fibrotic agent is a platinum compound.

1944. The method of claim 1897 wherein the anti-fibrotic agent is a nitrosourea.

1945. The method of claim 1897 wherein the anti-fibrotic agent is a nitroimidazole.

1946. The method of claim 1897 wherein the anti-fibrotic agent is a folic acid antagonist.

1947. The method of claim 1897 wherein the anti-fibrotic agent is a cytidine analogue.

1948. The method of claim 1897 wherein the anti-fibrotic agent is a pyrimidine analogue.

1949. The method of claim 1897 wherein the anti-fibrotic agent is a fluoropyrimidine analogue.

1950. The method of claim 1897 wherein the anti-fibrotic agent is a purine analogue.

1951. The method of claim 1897 wherein the anti-fibrotic agent is a nitrogen mustard or an analogue or derivative thereof.

1952. The method of claim 1897 wherein the anti-fibrotic agent is a hydroxyurea.

1953. The method of claim 1897 wherein the anti-fibrotic agent is a mytomicin or an analogue or derivative thereof.

1954. The method of claim 1897 wherein the anti-fibrotic agent is an alkyl sulfonate.

1955. The method of claim 1897 wherein the anti-fibrotic agent is a benzamide or an analogue or derivative thereof.

1956. The method of claim 1897 wherein the anti-fibrotic agent is a nicotinamide or an analogue or derivative thereof.

1957. The method of claim 1897 wherein the anti-fibrotic agent is a halogenated sugar or an analogue or derivative thereof.

1958. The method of claim 1897 wherein the anti-fibrotic agent is a DNA alkylating agent.

1959. The method of claim 1897 wherein the anti-fibrotic agent is an anti-microtubule agent.

1960. The method of claim 1897 wherein the anti-fibrotic agent is a topoisomerase inhibitor.

1961. The method of claim 1897 wherein the anti-fibrotic agent is a DNA cleaving agent.

1962. The method of claim 1897 wherein the anti-fibrotic agent is an antimetabolite.

1963. The method of claim 1897 wherein the anti-fibrotic agent inhibits adenosine deaminase.

1964. The method of claim 1897 wherein the anti-fibrotic agent inhibits purine ring synthesis.

1965. The method of claim 1897 wherein the anti-fibrotic agent is a nucleotide interconversion inhibitor.

1966. The method of claim 1897 wherein the anti-fibrotic agent inhibits dihydrofolate reduction.

1967. The method of claim 1897 wherein the anti-fibrotic agent blocks thymidine monophosphate.

1968. The method of claim 1897 wherein the anti-fibrotic agent causes DNA damage.

1969. The method of claim 1897 wherein the anti-fibrotic agent is a DNA intercalation agent.

1970. The method of claim 1897 wherein the anti-fibrotic agent is a RNA synthesis inhibitor.

1971. The method of claim 1897 wherein the anti-fibrotic agent is a pyrimidine synthesis inhibitor.

1972. The method of claim 1897 wherein the anti-fibrotic agent inhibits ribonucleotide synthesis or function.

1973. The method of claim 1897 wherein the anti-fibrotic agent inhibits thymidine monophosphate synthesis or function.

1974. The method of claim 1897 wherein the anti-fibrotic agent inhibits DNA synthesis.

1975. The method of claim 1897 wherein the anti-fibrotic agent causes DNA adduct formation.

1976. The method of claim 1897 wherein the anti-fibrotic agent inhibits protein synthesis.

1977. The method of claim 1897 wherein the anti-fibrotic agent inhibits microtubule function.

1978. The method of claim 1897 wherein the anti-fibrotic agent is a cyclin dependent protein kinase inhibitor.

1979. The method of claim 1897 wherein the anti-fibrotic agent is an epidermal growth factor kinase inhibitor.

1980. The method of claim 1897 wherein the anti-fibrotic agent is an elastase inhibitor.

1981. The method of claim 1897 wherein the anti-fibrotic agent is a factor Xa inhibitor.

1982. The method of claim 1897 wherein the anti-fibrotic agent is a famesyltransferase inhibitor.

1983. The method of claim 1897 wherein the anti-fibrotic agent is a fibrinogen antagonist.

1984. The method of claim 1897 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

1985. The method of claim 1897 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist.

1986. The method of claim 1897 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof.

1987. The method of claim 1897 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

1988. The method of claim 1897 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor.

1989. The method of claim 1897 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof.

1990. The method of claim 1897 wherein the anti-fibrotic agent is a hydroorotate dehydrogenase inhibitor.

1991. The method of claim 1897 wherein the anti-fibrotic agent is an IKK2 inhibitor.

1992. The method of claim 1897 wherein the anti-fibrotic agent is an IL-1 antagonist.

1993. The method of claim 1897 wherein the anti-fibrotic agent is an ICE antagonist.

1994. The method of claim 1897 wherein the anti-fibrotic agent is an IRAK antagonist.

1995. The method of claim 1897 wherein the anti-fibrotic agent is an IL-4 agonist.

1996. The method of claim 1897 wherein the anti-fibrotic agent is an immunomodulatory agent.

1997. The method of claim 1897 wherein the anti-fibrotic agent is sirolimus or an analogue or derivative thereof.

1998. The method of claim 1897 wherein the anti-fibrotic agent is not sirolimus.

1999. The method of claim 1897 wherein the anti-fibrotic agent is everolimus or an analogue or derivative thereof.

2000. The method of claim 1897 wherein the anti-fibrotic agent is tacrolimus or an analogue or derivative thereof.

2001. The method of claim 1897 wherein the anti-fibrotic agent is not tacrolimus.

2002. The method of claim 1897 wherein the anti-fibrotic agent is biolmus or an analogue or derivative thereof.

2003. The method of claim 1897 wherein the anti-fibrotic agent is tresperimus or an analogue or derivative thereof.

2004. The method of claim 1897 wherein the anti-fibrotic agent is auranofin or an analogue or derivative thereof.

2005. The method of claim 1897 wherein the anti-fibrotic agent is 27-0-demethylrapamycin or an analogue or derivative thereof.

2006. The method of claim 1897 wherein the anti-fibrotic agent is gusperimus or an analogue or derivative thereof.

2007. The method of claim 1897 wherein the anti-fibrotic agent is pimecrolimus or an analogue or derivative thereof.

2008. The method of claim 1897 wherein the anti-fibrotic agent is ABT-578 or an analogue or derivative thereof.

2009. The method of claim 1897 wherein the anti-fibrotic agent is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.

2010. The method of claim 1897 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof.

2011. The method of claim 1897 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-alpha-25 dihydroxy vitamin D3 or an analogue or derivative thereof.

2012. The method of claim 1897 wherein the anti-fibrotic agent is a leukotriene inhibitor.

2013. The method of claim 1897 wherein the anti-fibrotic agent is a MCP-1 antagonist.

2014. The method of claim 1897 wherein the anti-fibrotic agent is a MMP inhibitor.

2015. The method of claim 1897 wherein the anti-fibrotic agent is an NF kappa B inhibitor.

2016. The method of claim 1897 wherein the anti-fibrotic agent is an NF kappa B inhibitor, wherein the NF kappa B inhibitor is Bay 11-7082.

2017. The method of claim 1897 wherein the anti-fibrotic agent is an NO antagonist.

2018. The method of claim 1897 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor.

2019. The method of claim 1897 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB
202190.

2020. The method of claim 1897 wherein the anti-fibrotic agent is a phosphodiesterase inhibitor.

2021. The method of claim 1897 wherein the anti-fibrotic agent is a TGF beta inhibitor.

2022. The method of claim 1897 wherein the anti-fibrotic agent is a thromboxane A2 antagonist.

2023. The method of claim 1897 wherein the anti-fibrotic agent is a TNF alpha antagonist.

2024. The method of claim 1897 wherein the anti-fibrotic agent is a TACE inhibitor.

2025. The method of claim 1897 wherein the anti-fibrotic agent is a tyrosine kinase inhibitor.

2026. The method of claim 1897 wherein the anti-fibrotic agent is a vitronectin inhibitor.

2027. The method of claim 1897 wherein the anti-fibrotic agent is a fibroblast growth factor inhibitor.

2028. The method of claim 1897 wherein the anti-fibrotic agent is a protein kinase inhibitor.

2029. The method of claim 1897 wherein the anti-fibrotic agent is a PDGF receptor kinase inhibitor.

2030. The method of claim 1897 wherein the anti-fibrotic agent is an endothelial growth factor receptor kinase inhibitor.

2031. The method of claim 1897 wherein the anti-fibrotic agent is a retinoic acid receptor antagonist.

2032. The method of claim 1897 wherein the anti-fibrotic agent is a platelet derived growth factor receptor kinase inhibitor.

2033. The method of claim 1897 wherein the anti-fibrotic agent is a fibrinogen antagonist.

2034. The method of claim 1897 wherein the anti-fibrotic agent is an antimycotic agent.

2035. The method of claim 1897 wherein the anti-fibrotic agent is an antimycotic agent, wherein the antimycotic agent is sulconizole.

2036. The method of claim 1897 wherein the anti-fibrotic agent is a bisphosphonate.

2037. The method of claim 1897 wherein the anti-fibrotic agent is a phospholipase A1 inhibitor.

2038. The method of claim 1897 wherein the anti-fibrotic agent is a histamine H1/H2/H3 receptor antagonist.

2039. The method of claim 1897 wherein the anti-fibrotic agent is a macrolide antibiotic.

2040. The method of claim 1897 wherein the anti-fibrotic agent is a GPIIb/IIIa receptor antagonist.

2041. The method of claim 1897 wherein the anti-fibrotic agent is an endothelin receptor antagonist.

2042. The method of claim 1897 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor agonist.

2043. The method of claim 1897 wherein the anti-fibrotic agent is an estrogen receptor agent.

2044. The method of claim 1897 wherein the anti-fibrotic agent is a somastostatin analogue.

2045. The method of claim 1897 wherein the anti-fibrotic agent is a neurokinin 1 antagonist.

2046. The method of claim 1897 wherein the anti-fibrotic agent is a neurokinin 3 antagonist.

2047. The method of claim 1897 wherein the anti-fibrotic agent is a VLA-4 antagonist.

2048. The method of claim 1897 wherein the anti-fibrotic agent is an osteoclast inhibitor.

2049. The method of claim 1897 wherein the anti-fibrotic agent is a DNA topoisomerase ATP hydrolyzing inhibitor.

2050. The method of claim 1897 wherein the anti-fibrotic agent is an angiotensin I converting enzyme inhibitor.

2051. The method of claim 1897 wherein the anti-fibrotic agent is an angiotensin II antagonist.

2052. The method of claim 1897 wherein the anti-fibrotic agent is an enkephalinase inhibitor.

2053. The method of claim 1897 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer.

2054. The method of claim 1897 wherein the anti-fibrotic agent is a protein kinase C inhibitor.

2055. The method of claim 1897 wherein the anti-fibrotic agent is a ROCK (rho-associated kinase) inhibitor.

2056. The method of claim 1897 wherein the anti-fibrotic agent is a CXCR3 inhibitor.

2057. The method of claim 1897 wherein the anti-fibrotic agent is an Itk inhibitor.

2058. The method of claim 1897 wherein the anti-fibrotic agent is a cytosolic phospholipase A2-alpha inhibitor.

2059. The method of claim 1897 wherein the anti-fibrotic agent is a PPAR agonist.

2060. The method of claim 1897 wherein the anti-fibrotic agent is an immunosuppressant.

2061. The method of claim 1897 wherein the anti-fibrotic agent is an Erb inhibitor.

2062. The method of claim 1897 wherein the anti-fibrotic agent is an apoptosis agonist.

2063. The method of claim 1897 wherein the anti-fibrotic agent is a lipocortin agonist.

2064. The method of claim 1897 wherein the anti-fibrotic agent is a VCAM-1 antagonist.

2065. The method of claim 1897 wherein the anti-fibrotic agent is a collagen antagonist.

2066. The method of claim 1897 wherein the anti-fibrotic agent is an alpha 2 integrin antagonist.

2067. The method of claim 1897 wherein the anti-fibrotic agent is a TNF alpha inhibitor.

2068. The method of claim 1897 wherein the anti-fibrotic agent is a nitric oxide inhibitor

2069. The method of claim 1897 wherein the anti-fibrotic agent is a cathepsin inhibitor.

2070. The method of claim 1897 wherein the anti-fibrotic agent is not an anti-inflammatory agent.

2071. The method of claim 1897 wherein the anti-fibrotic agent is not a steroid.

2072. The method of claim 1897 wherein the anti-fibrotic agent is not a glucocorticosteroid.

2073. The method of claim 1897 wherein the anti-fibrotic agent is not dexamethasone.

2074. The method of claim 1897 wherein the anti-fibrotic agent is not beclomethasone.

2075. The method of claim 1897 wherein the anti-fibrotic agent is not dipropionate.

2076. The method of claim 1897 wherein the anti-fibrotic agent is not an anti-infective agent.

2077. The method of claim 1897 wherein the anti-fibrotic agent is not an antibiotic.

2078. The method of claim 1897 wherein the anti-fibrotic agent is not an anti-fuhgal agent.

2079. The method of claim 1897 wherein the anti-infective agent isan anthracycline.

2080. The method of claim 1897 wherein the anti-infective agent isdoxorubicin.

2081. The method of claim 1897 wherein the anti-infective agent is ismitoxantrone.

2082. The method of claim 1897 wherein the anti-infective agent is a fluoropyrimidine.

2083. The method of claim 1897 wherein the anti-infective agent is 5-fluorouracil (5-FU).

2084. The method of claim 1897 wherein the anti-infective agent is a folic acid antagonist.

2085. The method of claim 1897 wherein the anti-infective agent is methotrexate.

2086. The method of claim 1897 wherein the anti-infective agent is a podophylotoxin.

2087. The method of claim 1897 wherein the anti-infective agent is etoposide.

2088. The method of claim 1897 wherein the anti-infective agent is camptothecin.

2089. The method of claim 1897 wherein the anti-infective agent is a hydroxyurea.

2090. The method of claim 1897 wherein the anti-infective agent is a platinum complex.

2091. The method of claim 1897 wherein the anti-infective agent is cisplatin.

2092. The method of claim 1897 wherein the composition comprises an anti-thrombotic agent.

2093. The method of claim 1897 wherein the polymer is formed from reactants comprising a naturally occurring polymer.

2094. The method of claim 1897 wherein the polymer is formed from reactants comprising protein.

2095. The method of claim 1897 wherein the polymer is formed from reactants comprising carbohydrate.

2096. The method of claim 1897 wherein the polymer is formed from reactants comprising biodegradable polymer.

2097. The method of claim 1897 wherein the polymer is formed from reactants comprising nonbiodegradable polymer.

2098. The method of claim 1897 wherein the polymer is formed from reactants comprising collagen.

2099. The method of claim 1897 wherein the polymer is formed from reactants comprising methylated collagen.

2100. The method of claim 1897 wherein the polymer is formed from reactants comprising fibrinogen.

2101. The method of claim 1897 wherein the polymer is formed from reactants comprising thrombin.

2102. The method of claim 1897 wherein the polymer is formed from reactants comprising blood plasma.

2103. The method of claim 1897 wherein the polymer is formed from reactants comprising calcium salt.

2104. The method of claim 1897 wherein the polymer is formed from reactants comprising an antifibronolytic agent.

2105. The method of claim 1897 wherein the polymer is formed from reactants comprising fibrinogen analog.

2106. The method of claim 1897 wherein the polymer is formed from reactants comprising albumin.

2107. The method of claim 1897 wherein the polymer is formed from reactants comprising plasminogen.

2108. The method of claim 1897 wherein the polymer is formed from reactants comprising von Willebrands factor.

2109. The method of claim 1897 wherein the polymer is formed from reactants comprising Factor VIII.

2110. The method of claim 1897 wherein the polymer is formed from reactants comprising hypoallergenic collagen.

2111. The method of claim 1897 wherein the polymer is formed from reactants comprising atelopeptidic collagen.

2112. The method of claim 1897 wherein the polymer is formed from reactants comprising telopeptide collagen.

2113. The method of claim 1897 wherein the polymer is formed from reactants comprising crosslinked collagen.

2114. The method of claim 1897 wherein the polymer is formed from reactants comprising aprotinin.

2115. The method of claim 1897 wherein the polymer is formed from reactants comprising epsilon-amino-n-caproic acid.

2116. The method of claim 1897 wherein the polymer is formed from reactants comprising gelatin.

2117. The method of claim 1897 wherein the polymer is formed from reactants comprising protein conjugates.

2118. The method of claim 1897 wherein the polymer is formed from reactants comprising gelatin conjugates.

2119. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic polymer.

2120. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic isocyanate-containing compound.

2121. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic thiol-containing compound.

2122. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two thiol groups.

2123. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three thiol groups.

2124. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four thiol groups.

2125. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic amino-containing compound.

2126. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two amino groups.

2127. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three amino groups.

2128. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four amino groups.

2129. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group.

2130. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups.

2131. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.

2132. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.

2133. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound.

2134. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.

2135. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive amino groups.

2136. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive thiol groups.

2137. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups.

2138. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic compound comprising a biodegradable polyester block.

2139. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from lactic acid or lactide.

2140. The method of claim 1897 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from glycolic acid or glycolide.

2141. The method of claim 1897 wherein the polymer is formed from reactants comprising polylysine.

2142. The method of claim 1897 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound comprising a polyalkylene oxide portion.

2143. The method of claim 1897 wherein the polymer is formed from reactants comprising (a) protein and (b) polylysine.

2144. The method of claim 1897 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four thiol groups.

2145. The method of claim 1897 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four amino groups.

2146. The method of claim 1897 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

2147. The method of claim 1897 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

2148. The method of claim 1897 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound comprising a polyalkylene oxide portion.

2149. The method of claim 1897 wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine.

2150. The method of claim 1897 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four thiol groups.

2151. The method of claim 1897 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four amino groups.

2152. The method of claim 1897 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

2153. The method of claim 1897 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

2154. The method of claim 1897 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound comprising a polyalkylene oxide portion.

2155. The method of claim 1897 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine.

2156. The method of claim 1897 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four thiol groups.

2157. The method of claim 1897 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four amino groups.

2158. The method of claim 1897 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

2159. The method of claim 1897 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

2160. The method of claim 1897 wherein the polymer is formed from reactants comprising hyaluronic acid.

2161. The method of claim 1897 wherein the polymer is formed from reactants comprising a hyaluronic acid derivative.

2162. The method of claim 1897 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.

2163. The method of claim 1897 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.

2164. The method of claim 1897 wherein the polymer is formed from reactants comprising (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.

2165. The method of claim 1897 wherein the composition comprises a colorant.

2166. The method of claim 1897 wherein the composition is sterile.

2167. A method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with i) an anti-fibrotic agent, ii) an anti-infective agent, iii) a polymer;
iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host, where the medical device is a medical device for treating hypertropic scar or keloid.

2168. The method for implanting a medical device according to claim 2167 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-fibrotic agent, and (b) implanting the medical device into the host.

2169. The method for implanting a medical device according to claim 2167 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-infective agent, and (b) implanting the medical device into the host.

2170. The method for implanting a medical device according to claim 2167 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a polymer; and (b) implanting the medical device into the host.

2171. The method for implanting a medical device according to claim 2167 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent and a polymer, and (b) implanting the medical device into the host.

2172. The method for implanting a medical device according to claim 2167 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

2173. The method for implanting a medical device according to claim 2167 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

2174. The method of claim 2167 wherein the medical device is a device for treating hypertropic scar or keloid that comprises an external tissue expansion device.

2175. The method of claim 2167 wherein the medical device is a device for treating hypertropic scar or keloid that comprises a masking element, and wherein the masking element may be pressed onto the scar tissue.

2176. The method of claim 2167 wherein the medical device is a device for treating hypertropic scar or keloid that comprises a locking element and a grasping structure so that the dermal and epidermal layers of a skin wound can be pushed together.

2177. The method of claim 2167 wherein the anti-fibrotic agent inhibits cell regeneration.

2178. The method of claim 2167 wherein the anti-fibrotic agent inhibits angiogenesis.

2179. The method of claim 2167 wherein the anti-fibrotic agent inhibits fibroblast migration.

2180. The method of claim 2167 wherein the anti-fibrotic agent inhibits fibroblast proliferation.

2181. The method of claim 2167 wherein the anti-fibrotic agent inhibits deposition of extracellular matrix.

2182. The method of claim 2167 wherein the anti-fibrotic agent inhibits tissue remodeling.

2183. The method of claim 2167 wherein the anti-fibrotic agent is an angiogenesis inhibitor.

2184. The method of claim 2167 wherein the anti-fibrotic agent is a 5-lipoxygenase inhibitor or antagonist.

2185. The method of claim 2167 wherein the anti-fibrotic agent is a chemokine receptor antagonist.

2186. The method of claim 2167 wherein the anti-fibrotic agent is a cell cycle inhibitor.

2187. The method of claim 2167 wherein the anti-fibrotic agent is a taxane.

2188. The method of claim 2167 wherein the anti-fibrotic agent is an anti-microtubule agent.

2189. The method of claim 2167 wherein the anti-fibrotic agent is paclitaxel.

2190. The method of claim 2167 wherein the anti-fibrotic agent is not paclitaxel.

2191. The method of claim 2167 wherein the anti-fibrotic agent is an analogue or derivative of paclitaxel.

2192. The method of claim 2167 wherein the anti-fibrotic agent is a vinca alkaloid.

2193. The method of claim 2167 wherein the anti-fibrotic agent is camptothecin or an analogue or derivative thereof.

2194. The method of claim 2167 wherein the anti-fibrotic agent is a podophyllotoxin.

2195. The method of claim 2167 wherein the anti-fibrotic agent is a podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof.

2196. The method of claim 2167 wherein the anti-fibrotic agent is an anthracycline.

2197. The method of claim 2167 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof.

2198. The method of claim 2167 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof.

2199. The method of claim 2167 wherein the anti-fibrotic agent is a platinum compound.

2200. The method of claim 2167 wherein the anti-fibrotic agent is a nitrosourea.

2201. The method of claim 2167 wherein the anti-fibrotic agent is a nitroimidazole.

2202. The method of claim 2167 wherein the anti-fibrotic agent is a folic acid antagonist.

2203. The method of claim 2167 wherein the anti-fibrotic agent is a cytidine analogue.

2204. The method of claim 2167 wherein the anti-fibrotic agent is a pyrimidine analogue.

2205. The method of claim 2167 wherein the anti-fibrotic agent is a fluoropyrimidine analogue.

2206. The method of claim 2167 wherein the anti-fibrotic agent is a purine analogue.

2207. The method of claim 2167 wherein the anti-fibrotic agent is a nitrogen mustard or an analogue or derivative thereof.

2208. The method of claim 2167 wherein the anti-fibrotic agent is a hydroxyurea.

2209. The method of claim 2167 wherein the anti-fibrotic agent is a mytomicin or an analogue or derivative thereof.

2210. The method of claim 2167 wherein the anti-fibrotic agent is an alkyl sulfonate.

2211. The method of claim 2167 wherein the anti-fibrotic agent is a benzamide or an analogue or derivative thereof.

2212. The method of claim 2167 wherein the anti-fibrotic agent is a nicotinamide or an analogue or derivative thereof.

2213. The method of claim 2167 wherein the anti-fibrotic agent is a halogenated sugar or an analogue or derivative thereof.

2214. The method of claim 2167 wherein the anti-fibrotic agent is a DNA alkylating agent.

2215. The method of claim 2167 wherein the anti-fibrotic agent is an anti-microtubule agent.

2216. The method of claim 2167 wherein the anti-fibrotic agent is a topoisomerase inhibitor.

2217. The method of claim 2167 wherein the anti-fibrotic agent is a DNA cleaving agent.

2218. The method of claim 2167 wherein the anti-fibrotic agent is an antimetabolite.

2219. The method of claim 2167 wherein the anti-fibrotic agent inhibits adenosine deaminase.

2220. The method of claim 2167 wherein the anti-fibrotic agent inhibits purine ring synthesis.

2221. The method of claim 2167 wherein the anti-fibrotic agent is a nucleotide interconversion inhibitor.

2222. The method of claim 2167 wherein the anti-fibrotic agent inhibits dihydrofolate reduction.

2223. The method of claim 2167 wherein the anti-fibrotic agent blocks thymidine monophosphate.

2224. The method of claim 2167 wherein the anti-fibrotic agent causes DNA damage.

2225. The method of claim 2167 wherein the anti-fibrotic agent is a DNA intercalation agent.

2226. The method of claim 2167 wherein the anti-fibrotic agent is a RNA synthesis inhibitor.

2227. The method of claim 2167 wherein the anti-fibrotic agent is a pyrimidine synthesis inhibitor.

2228. The method of claim 2167 wherein the anti-fibrotic agent inhibits ribonucleotide synthesis or function.

2229. The method of claim 2167 wherein the anti-fibrotic agent inhibits thymidine monophosphate synthesis or function.

2230. The method of claim 2167 wherein the anti-fibrotic agent inhibits DNA synthesis.

2231. The method of claim 2167 wherein the anti-fibrotic agent causes DNA adduct formation.

2232. The method of claim 2167 wherein the anti-fibrotic agent inhibits protein synthesis.

2233. The method of claim 2167 wherein the anti-fibrotic agent inhibits microtubule function.

2234. The method of claim 2167 wherein the anti-fibrotic agent is a cyclin dependent protein kinase inhibitor.

2235. The method of claim 2167 wherein the anti-fibrotic agent is an epidermal growth factor kinase inhibitor.

2236. The method of claim 2167 wherein the anti-fibrotic agent is an elastase inhibitor.

2237. The method of claim 2167 wherein the anti-fibrotic agent is a factor Xa inhibitor.

2233. The method of claim 2167 wherein the anti-fibrotic agent is a farnesyltransferase inhibitor.

2239. The method of claim 2167 wherein the anti-fibrotic agent is a fibrinogen antagonist.

2240. The method of claim 2167 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

2241. The method of claim 2167 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist.

2242. The method of claim 2167 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof.

2243. The method of claim 2167 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

2244. The method of claim 2167 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor.

2245. The method of claim 2167 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof.

2246. The method of claim 2167 wherein the anti-fibrotic agent is a hydroorotate dehydrogenase inhibitor.

2247. The method of claim 2167 wherein the anti-fibrotic agent is an IKK2 inhibitor.

2248. The method of claim 2167 wherein the anti-fibrotic agent is an IL-1 antagonist.

2249. The method of claim 2167 wherein the anti-fibrotic agent is an ICE antagonist.

2250. The method of claim 2167 wherein the anti-fibrotic agent is an IRAK antagonist.

2251. The method of claim 2167 wherein the anti-fibrotic agent is an IL-4 agonist.

2252. The method of claim 2167 wherein the anti-fibrotic agent is an immunomodulatory agent.

2253. The method of claim 2167 wherein the anti-fibrotic agent is sirolimus or an analogue or derivative thereof.

2254. The method of claim 2167 wherein the anti-fibrotic agent is not sirolimus.

2255. The method of claim 2167 wherein the anti-fibrotic agent is everolimus or an analogue or derivative thereof.

2256. The method of claim 2167 wherein the anti-fibrotic agent is tacrolimus or an analogue or derivative thereof.

2257. The method of claim 2167 wherein the anti-fibrotic agent is not tacrolimus.

2258. The method of claim 2167 wherein the anti-fibrotic agent is biolmus or an analogue or derivative thereof.

2259. The method of claim 2167 wherein the anti-fibrotic agent is tresperimus or an analogue or derivative thereof.

2260. The method of claim 2167 wherein the anti-fibrotic agent is auranofin or an analogue or derivative thereof.

2261. The method of claim 2167 wherein the anti-fibrotic agent is 27-0-demethylrapamycin or an analogue or derivative thereof.

2262. The method of claim 2167 wherein the anti-fibrotic agent is gusperimus or an analogue or derivative thereof.

2263. The method of claim 2167 wherein the anti-fibrotic agent is pimecrolimus or an analogue or derivative thereof.

2264. The method of claim 2167 wherein the anti-fibrotic agent is ABT-578 or an analogue or derivative thereof.

2265. The method of claim 2167 wherein the anti-fibrotic agent is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.

2266. The method of claim 2167 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof.

2267. The method of claim 2167 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-alpha-25 dihydroxy vitamin D3 or an analogue or derivative thereof.

2268. The method of claim 2167 wherein the anti-fibrotic agent is a leukotriene inhibitor.

2269. The method of claim 2167 wherein the anti-fibrotic agent is a MCP-1 antagonist.

2270. The method of claim 2167 wherein the anti-fibrotic agent is a MMP inhibitor.

2271. The method of claim 2167 wherein the anti-fibrotic agent is an NF kappa B inhibitor.

2272. The method of claim 2167 wherein the anti-fibrotic agent is an NF kappa B inhibitor, wherein the NF kappa B inhibitor is Bay 11-7082.

2273. The method of claim 2167 wherein the anti-fibrotic agent is an NO antagonist.

2274. The method of claim 2167 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor.

2275. The method of claim 2167 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB
202190.

2276. The method of claim 2167 wherein the anti-fibrotic agent is a phosphodiesterase inhibitor.

2277. The method of claim 2167 wherein the anti-fibrotic agent is a TGF beta inhibitor.

2278. The method of claim 2167 wherein the anti-fibrotic agent is a thromboxane A2 antagonist.

2279. The method of claim 2167 wherein the anti-fibrotic agent is a TNF alpha antagonist.

2280. The method of claim 2167 wherein the anti-fibrotic agent is a TACE inhibitor.

2281. The method of claim 2167 wherein the anti-fibrotic agent is a tyrosine kinase inhibitor.

2282. The method of claim 2167 wherein the anti-fibrotic agent is a vitronectin inhibitor.

2283. The method of claim 2167 wherein the anti-fibrotic agent is a fibroblast growth factor inhibitor.

2284. The method of claim 2167 wherein the anti-fibrotic agent is a protein kinase inhibitor.

2285. The method of claim 2167 wherein the anti-fibrotic agent is a PDGF receptor kinase inhibitor.

2286. The method of claim 2167 wherein the anti-fibrotic agent is an endothelial growth factor receptor kinase inhibitor.

2287. The method of claim 2167 wherein the anti-fibrotic agent is a retinoic acid receptor antagonist.

2288. The method of claim 2167 wherein the anti-fibrotic agent is a platelet derived growth factor receptor kinase inhibitor.

2289. The method of claim 2167 wherein the anti-fibrotic agent is a fibrinogen antagonist.

2290. The method of claim 2167 wherein the anti-fibrotic agent is an antimycotic agent.

2291. The method of claim 2167 wherein the anti-fibrotic agent is an antimycotic agent, wherein the antimycotic agent is sulconizole.

2292. The method of claim 2167 wherein the anti-fibrotic agent is a bisphosphonate.

2293. The method of claim 2167 wherein the anti-fibrotic agent is a phospholipase A1 inhibitor.

2294. The method of claim 2167 wherein the anti-fibrotic agent is a histamine H1/H2/H3 receptor antagonist.

2295. The method of claim 2167 wherein the anti-fibrotic agent is a macrolide antibiotic.

2296. The method of claim 2167 wherein the anti-fibrotic agent is a GPIIb/IIIa receptor antagonist.

2297. The method of claim 2167 wherein the anti-fibrotic agent is an endothelin receptor antagonist.

2298. The method of claim 2167 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor agonist.

2299. The method of claim 2167 wherein the anti-fibrotic agent is an estrogen receptor agent.

2300. The method of claim 2167 wherein the anti-fibrotic agent is a somastostatin analogue.

2301. The method of claim 2167 wherein the anti-fibrotic agent is a neurokinin 1 antagonist.

2302. The method of claim 2167 wherein the anti-fibrotic agent is a neurokinin 3 antagonist.

2303. The method of claim 2167 wherein the anti-fibrotic agent is a VLA-4 antagonist.

2304. The method of claim 2167 wherein the anti-fibrotic agent is an osteoclast inhibitor.

2305. The method of claim 2167 wherein the anti-fibrotic agent is a DNA topoisomerase ATP hydrolyzing inhibitor.

2306. The method of claim 2167 wherein the anti-fibrotic agent is an angiotensin I converting enzyme inhibitor.

2307. The method of claim 2167 wherein the anti-fibrotic agent is an angiotensin II antagonist.

2308. The method of claim 2167 wherein the anti-fibrotic agent is an enkephalinase inhibitor.

2309. The method of claim 2167 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer.

2310. The method of claim 2167 wherein the anti-fibrotic agent is a protein kinase C inhibitor.

2311. The method of claim 2167 wherein the anti-fibrotic agent is a ROCK (rho-associated kinase) inhibitor.

2312. The method of claim 2167 wherein the anti-fibrotic agent is a CXCR3 inhibitor.

2313. The method of claim 2167 wherein the anti-fibrotic agent is an Itk inhibitor.

2314. The method of claim 2167 wherein the anti-fibrotic agent is a cytosolic phospholipase A2-alpha inhibitor.

2315. The method of claim 2167 wherein the anti-fibrotic agent is a PPAR agonist.

2316. The method of claim 2167 wherein the anti-fibrotic agent is an immunosuppressant.

2317. The method of claim 2167 wherein the anti-fibrotic agent is an Erb inhibitor.

2318. The method of claim 2167 wherein the anti-fibrotic agent is an apoptosis agonist.

2319. The method of claim 2167 wherein the anti-fibrotic agent is a lipocortin agonist.

2320. The method of claim 2167 wherein the anti-fibrotic agent is a VCAM-1 antagonist.

2321. The method of claim 2167 wherein the anti-fibrotic agent is a collagen antagonist.

2322. The method of claim 2167 wherein the anti-fibrotic agent is an alpha 2 integrin antagonist.

2323. The method of claim 2167 wherein the anti-fibrotic agent is a TNF alpha inhibitor.

2324. The method of claim 2167 wherein the anti-fibrotic agent is a nitric oxide inhibitor

2325. The method of claim 2167 wherein the anti-fibrotic agent is a cathepsin inhibitor.

2326. The method of claim 2167 wherein the anti-fibrotic agent is not an anti-inflammatory agent.

2327. The method of claim 2167 wherein the anti-fibrotic agent is not a steroid.

2328. The method of claim 2167 wherein the anti-fibrotic agent is not a glucocorticosteroid.

2329. The method of claim 2167 wherein the anti-fibrotic agent is not dexamethasone.

2330. The method of claim 2167 wherein the anti-fibrotic agent is not beclomethasone.

2331. The method of claim 2167 wherein the anti-fibrotic agent is not dipropionate.

2332. The method of claim 2167 wherein the anti-fibrotic agent is not an anti-infective agent.

2333. The method of claim 2167 wherein the anti-fibrotic agent is not an antibiotic.

2334. The method of claim 2167 wherein the anti-fibrotic agent is not an anti-fungal agent.

2335. The method of claim 2167 wherein the anti-infective agent isan anthracycline.

2336. The method of claim 2167 wherein the anti-infective agent isdoxorubicin.

2337. The method of claim 2167 wherein the anti-infective agent is ismitoxantrone.

2338. The method of claim 2167 wherein the anti-infective agent is a fluoropyrimidine.

2339. The method of claim 2167 wherein the anti-infective agent is 5-fluorouracil (5-FU).

2340. The method of claim 2167 wherein the anti-infective agent is a folic acid antagonist.

2341. The method of claim 2167 wherein the anti-infective agent is methotrexate.

2342. The method of claim 2167 wherein the anti-infective agent is a podophylotoxin.

2343. The method of claim 2167 wherein the anti-infective agent is etoposide.

2344. The method of claim 2167 wherein the anti-infective agent is camptothecin.

2345. The method of claim 2167 wherein the anti-infective agent is a hydroxyurea.

2346. The method of claim 2167 wherein the anti-infective agent is a platinum complex.

2347. The method of claim 2167 wherein the anti-infective agent is cisplatin.

2348. The method of claim 2167 wherein the composition comprises an anti-thrombotic agent.

2349. The method of claim 2167 wherein the polymer is formed from reactants comprising a naturally occurring polymer.

2350. The method of claim 2167 wherein the polymer is formed from reactants comprising protein.

2351. The method of claim 2167 wherein the polymer is formed from reactants comprising carbohydrate.

2352. The method of claim 2167 wherein the polymer is formed from reactants comprising biodegradable polymer.

2353. The method of claim 2167 wherein the polymer is formed from reactants comprising nonbiodegradable polymer.

2354. The method of claim 2167 wherein the polymer is formed from reactants comprising collagen.

2355. The method of claim 2167 wherein the polymer is formed from reactants comprising methylated collagen.

2356. The method of claim 2167 wherein the polymer is formed from reactants comprising fibrinogen.

2357. The method of claim 2167 wherein the polymer is formed from reactants comprising thrombin.

2358. The method of claim 2167 wherein the polymer is formed from reactants comprising blood plasma.

2359. The method of claim 2167 wherein the polymer is formed from reactants comprising calcium salt.

2360. The method of claim 2167 wherein the polymer is formed from reactants comprising an antifibronolytic agent.

2361. The method of claim 2167 wherein the polymer is formed from reactants comprising fibrinogen analog.

2362. The method of claim 2167 wherein the polymer is formed from reactants comprising albumin.

2363. The method of claim 2167 wherein the polymer is formed from reactants comprising plasminogen.

2364. The method of claim 2167 wherein the polymer is formed from reactants comprising von Willebrands factor.

2365. The method of claim 2167 wherein the polymer is formed from reactants comprising Factor VIII.

2366. The method of claim 2167 wherein the polymer is formed from reactants comprising hypoallergenic collagen.

2367. The method of claim 2167 wherein the polymer is formed from reactants comprising atelopeptidic collagen.

2368. The method of claim 2167 wherein the polymer is formed from reactants comprising telopeptide collagen.

2369. The method of claim 2167 wherein the polymer is formed from reactants comprising crosslinked collagen.

2370. The method of claim 2167 wherein the polymer is formed from reactants comprising aprotinin.

2371. The method of claim 2167 wherein the polymer is formed from reactants comprising epsilon-amino-n-caproic acid.

2372. The method of claim 2167 wherein the polymer is formed from reactants comprising gelatin.

2373. The method of claim 2167 wherein the polymer is formed from reactants comprising protein conjugates.

2374. The method of claim 2167 wherein the polymer is formed from reactants comprising gelatin conjugates.

2375. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic polymer.

2376. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic isocyanate-containing compound.

2377. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic thiol-containing compound.

2378. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two thiol groups.

2379. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three thiol groups.

2380. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four thiol groups.

2381. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic amino-containing compound.

2382. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two amino groups.

2383. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three amino groups.

2384. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four amino groups.

2385. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group.

2386. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups.

2387. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.

2388. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.

2389. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound.

2390. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.

2391. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive amino groups.

2392. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive thiol groups.

2393. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups.

2394. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic compound comprising a biodegradable polyester block.

2395. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from lactic acid or lactide.

2396. The method of claim 2167 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from glycolic acid or glycolide.

2397. The method of claim 2167 wherein the polymer is formed from reactants comprising polylysine.

2398. The method of claim 2167 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound comprising a polyalkylene oxide portion.

2399. The method of claim 2167 wherein the polymer is formed from reactants comprising (a) protein and (b) polylysine.

2400. The method of claim 2167 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four thiol groups.

2401. The method of claim 2167 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four amino groups.

2402. The method of claim 2167 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

2403. The method of claim 2167 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

2404. The method of claim 2167 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound comprising a polyalkylene oxide portion.

2405. The method of claim 2167 wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine.

2406. The method of claim 2167 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four thiol groups.

2407. The method of claim 2167 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four amino groups.

2408. The method of claim 2167 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

2409. The method of claim 2167 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

2410. The method of claim 2167 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound comprising a polyalkylene oxide portion.

2411. The method of claim 2167 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine.

2412. The method of claim 2167 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four thiol groups.

2413. The method of claim 2167 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four amino groups.

2414. The method of claim 2167 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

2415. The method of claim 2167 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

2416. The method of claim 2167 wherein the polymer is formed from reactants comprising hyaluronic acid.

2417. The method of claim 2167 wherein the polymer is formed from reactants comprising a hyaluronic acid derivative.

2418. The method of claim 2167 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.

2419. The method of claim 2167 wherein the polymer is formed from reactants comprising pentaerythritol polyethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.

2420. The method of claim 2167 wherein the polymer is formed from reactants comprising (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.

2421. The method of claim 2167 wherein the composition comprises a colorant.

2422. The method of claim 2167 wherein the composition is sterile.

2423. A method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with i) an anti-fibrotic agent, ii) an anti-infective agent, iii) a polymer;
iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host, wherein the medical device is a vascular graft.

2424. The method for implanting a medical device according to claim 2423 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-fibrotic agent, and (b) implanting the medical device into the host.

2425. The method for implanting a medical device according to claim 2423 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-infective agent, and (b) implanting the medical device into the host.

2426. The method for implanting a medical device according to claim 2423 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a polymer; and (b) implanting the medical device info the host.

2427. The method for implanting a medical device according to claim 2423 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent and a polymer, and (b) implanting the medical device into the host.

2428. The method for implanting a medical device according to claim 2423 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

2429. The method for implanting a medical device according to claim 2423 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

2430. The method of claim 2423 wherein the medical device is an extravascular graft.

2431. The method of claim 2423 wherein the medical device is an intravascular graft.

2432. The method of claim 2423 wherein the medical device is a vascular graft adapted for replacing a blood vessel damaged by aneurysm.

2433. The method of claim 2423 wherein the medical device is a vascular graft adapted for replacing a blood vessel damaged by intimal.
hyperplasia.

2434. The method of claim 2423 wherein the medical device is a vascular graft adapted for replacing a blood vessel damaged by thrombosis.

2435. The method of claim 2423 wherein the medical device is a vascular graft adapted for providing access to blood vessel.

2436. The method of claim 2423 wherein the medical device is a vascular graft adapted for providing an alternative conduit for blood flow through a damaged or diseased area in a vein.

2437. The method of claim 2423 wherein the medical device is a vascular graft adapted for providing an alternative conduit for blood flow through a damaged or diseased area in an artery.

2438. The method of claim 2423 wherein the medical device is a synthetic bypass graft.

2439. The method of claim 2423 wherein the medical device is a femoral-popliteal bypass graft.

2440. The method of claim 2423 wherein the medical device is a femoral-femoral bypass graft.

2441. The method of claim 2423 wherein the medical device is an axillary-femoral bypass graft.

2442. The method of claim 2423 wherein the medical device is a vein graft.

2443. The method of claim 2423 wherein the medical device is a peripheral vein graft.

2444. The method of claim 2423 wherein the medical device is a coronary vein graft.

2445. The method of claim 2423 wherein the medical device is an internal mammary graft.

2446. The method of claim 2423 wherein the medical device is a bifurcated vascular graft.

2447. The method of claim 2423 wherein the medical device is an intraluminal graft.

2448. The method of claim 2423 wherein the medical device is a prosthetic vascular graft.

2449. The method of claim 2423 wherein the anti-fibrotic agent inhibits cell regeneration.

2450. The method of claim 2423 wherein the anti-fibrotic agent inhibits angiogenesis.

2451. The method of claim 2423 wherein the anti-fibrotic agent inhibits fibroblast migration.

2452. The method of claim 2423 wherein the anti-fibrotic agent inhibits fibroblast proliferation.

2453. The method of claim 2423 wherein the anti-fibrotic agent inhibits deposition of extracellular matrix.

2454. The method of claim 2423 wherein the anti-fibrotic agent inhibits tissue remodeling.

2455. The method of claim 2423 wherein the anti-fibrotic agent is an angiogenesis inhibitor.

2456. The method of claim 2423 wherein the anti-fibrotic agent is a 5-lipoxygenase inhibitor or antagonist.

2457. The method of claim 2423 wherein the anti-fibrotic agent is a chemokine receptor antagonist.

2458. The method of claim 2423 wherein the anti-fibrotic agent is a cell cycle inhibitor.

2459. The method of claim 2423 wherein the anti-fibrotic agent is a taxane.

2460. The method of claim 2423 wherein the anti-fibrotic agent is an anti-microtubule agent.

2461. The method of claim 2423 wherein the anti-fibrotic agent is paclitaxel.

2462. The method of claim 2423 wherein the anti-fibrotic agent is not paclitaxel.

2463. The method of claim 2423 wherein the anti-fibrotic agent is an analogue or derivative of paclitaxel.

2464. The method of claim 2423 wherein the anti-fibrotic agent is a vinca alkaloid.

2465. The method of claim 2423 wherein the anti-fibrotic agent is camptothecin or an analogue or derivative thereof.

2466. The method of claim 2423 wherein the anti-fibrotic agent is a podophyllotoxin.

2467. The method of claim 2423 wherein the anti-fibrotic agent is a podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof.

2468. The method of claim 2423 wherein the anti-fibrotic agent is an anthracycline.

2469. The method of claim 2423 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof.

2470. The method of claim 2423 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof.

2471. The method of claim 2423 wherein the anti-fibrotic agent is a platinum compound.

2472. The method of claim 2423 wherein the anti-fibrotic agent is a nitrosourea.

2473. The method of claim 2423 wherein the anti-fibrotic agent is a nitroimidazole.

2474. The method of claim 2423 wherein the anti-fibrotic agent is a folic acid antagonist.

2475. The method of claim 2423 wherein the anti-fibrotic agent is a cytidine analogue.

2476. The method of claim 2423 wherein the anti-fibrotic agent is a pyrimidine analogue.

2477. The method of claim 2423 wherein the anti-fibrotic agent is a fluoropyrimidine analogue.

2478. The method of claim 2423 wherein the anti-fibrotic agent is a purine analogue.

2479. The method of claim 2423 wherein the anti-fibrotic agent is a nitrogen mustard or an analogue or derivative thereof.

2480. The method of claim 2423 wherein the anti-fibrotic agent is a hydroxyurea.

2481. The method of claim 2423 wherein the anti-fibrotic agent is a mytomicin or an analogue or derivative thereof.

2482. The method of claim 2423 wherein the anti-fibrotic agent is an alkyl sulfonate.

2483. The method of claim 2423 wherein the anti-fibrotic agent is a benzamide or an analogue or derivative thereof.

2484. The method of claim 2423 wherein the anti-fibrotic agent is a nicotinamide or an analogue or derivative thereof.

2485. The method of claim 2423 wherein the anti-fibrotic agent is a halogenated sugar or an analogue or derivative thereof.

2486. The method of claim 2423 wherein the anti-fibrotic agent is a DNA alkylating agent.

2487. The method of claim 2423 wherein the anti-fibrotic agent is an anti-microtubule agent.

2488. The method of claim 2423 wherein the anti-fibrotic agent is a topoisomerase inhibitor.

2489. The method of claim 2423 wherein the anti-fibrotic agent is a DNA cleaving agent.

2490. The method of claim 2423 wherein the anti-fibrotic agent is an antimetabolite.

2491. The method of claim 2423 wherein the anti-fibrotic agent inhibits adenosine deaminase.

2492. The method of claim 2423 wherein the anti-fibrotic agent inhibits purine ring synthesis.

2493. The method of claim 2423 wherein the anti-fibrotic agent is a nucleotide interconversion inhibitor.

2494. The method of claim 2423 wherein the anti-fibrotic agent inhibits dihydrofolate reduction.

2495. The method of claim 2423 wherein the anti-fibrotic agent blocks thymidine monophosphate.

2496. The method of claim 2423 wherein the anti-fibrotic agent causes DNA damage.

2497. The method of claim 2423 wherein the anti-fibrotic agent is a DNA intercalation agent.

2498. The method of claim 2423 wherein the anti-fibrotic agent is a RNA synthesis inhibitor.

2499. The method of claim 2423 wherein the anti-fibrotic agent is a pyrimidine synthesis inhibitor.

2500. The method of claim 2423 wherein the anti-fibrotic agent inhibits ribonucleotide synthesis or function.

2501. The method of claim 2423 wherein the anti-fibrotic agent inhibits thymidine monophosphate synthesis or function.

2502. The method of claim 2423 wherein the anti-fibrotic agent inhibits DNA synthesis.

2503. The method of claim 2423 wherein the anti-fibrotic agent causes DNA adduct formation.

2504. The method of claim 2423 wherein the anti-fibrotic agent inhibits protein synthesis.

2505. The method of claim 2423 wherein the anti-fibrotic agent inhibits microtubule function.

2506. The method of claim 2423 wherein the anti-fibrotic agent is a cyclin dependent protein kinase inhibitor.

2507. The method of claim 2423 wherein the anti-fibrotic agent is an epidermal growth factor kinase inhibitor.

2508. The method of claim 2423 wherein the anti-fibrotic agent is an elastase inhibitor.

2509. The method of claim 2423 wherein the anti-fibrotic agent is a factor Xa inhibitor.

2510. The method of claim 2423 wherein the anti-fibrotic agent is a farnesyltransferase inhibitor.

2511. The method of claim 2423 wherein the anti-fibrotic agent is a fibrinogen antagonist.

2512. The method of claim 2423 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

2513. The method of claim 2423 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist.

2514. The method of claim 2423 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof.

2515. The method of claim 2423 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

2516. The method of claim 2423 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor.

2517. The method of claim 2423 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof.

2518. The method of claim 2423 wherein the anti-fibrotic agent is a hydroorotate dehydrogenase inhibitor.

2519. The method of claim 2423 wherein the anti-fibrotic agent is an IKK2 inhibitor.

2520. The method of claim 2423 wherein the anti-fibrotic agent is an IL-1 antagonist.

2521. The method of claim 2423 wherein the anti-fibrotic agent is an ICE antagonist.

2522. The method of claim 2423 wherein the anti-fibrotic agent is an IRAK antagonist.

2523. The method of claim 2423 wherein the anti-fibrotic agent is an IL-4 agonist.

2524. The method of claim 2423 wherein the anti-fibrotic agent is an immunomodulatory agent.

2525. The method of claim 2423 wherein the anti-fibrotic agent is sirolimus or an analogue or derivative thereof.

2526. The method of claim 2423 wherein the anti-fibrotic agent is not sirolimus.

2527. The method of claim 2423 wherein the anti-fibrotic agent is everolimus or an analogue or derivative thereof.

2528. The method of claim 2423 wherein the anti-fibrotic agent is tacrolimus or an analogue or derivative thereof.

2529. The method of claim 2423 wherein the anti-fibrotic agent is not tacrolimus.

2530. The method of claim 2423 wherein the anti-fibrotic agent is biolmus or an analogue or derivative thereof.

2531. The method of claim 2423 wherein the anti-fibrotic agent is tresperimus or an analogue or derivative thereof.

2532. The method of claim 2423 wherein the anti-fibrotic agent is auranofin or an analogue or derivative thereof.

2533. The method of claim 2423 wherein the anti-fibrotic agent is 27-0-demethylrapamycin or an analogue or derivative thereof.

2534. The method of claim 2423 wherein the anti-fibrotic agent is gusperimus or an analogue or derivative thereof.

2535. The method of claim 2423 wherein the anti-fibrotic agent is pimecrolimus or an analogue or derivative thereof.

2536. The method of claim 2423 wherein the anti-fibrotic agent is ABT-578 or an analogue or derivative thereof.

2537. The method of claim 2423 wherein the anti-fibrotic agent is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.

2538. The method of claim 2423 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof.

2539. The method of claim 2423 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-alpha-25 dihydroxy vitamin D3 or an analogue or derivative thereof.

2540. The method of claim 2423 wherein the anti-fibrotic agent is a leukotriene inhibitor.

2541. The method of claim 2423 wherein the anti-fibrotic agent is a MCP-1 antagonist.

2542. The method of claim 2423 wherein the anti-fibrotic agent is a MMP inhibitor.

2543. The method of claim 2423 wherein the anti-fibrotic agent is an NF kappa B inhibitor.

2544. The method of claim 2423 wherein the anti-fibrotic agent is an NF kappa B inhibitor, wherein the NF kappa B inhibitor is Bay 11-7082.

2545. The method of claim 2423 wherein the anti-fibrotic agent is an NO antagonist.

2546. The method of claim 2423 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor.

2547. The method of claim 2423 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB
202190.

2548. The method of claim 2423 wherein the anti-fibrotic agent is a phosphodiesterase inhibitor.

2549. The method of claim 2423 wherein the anti-fibrotic agent is a TGF beta inhibitor.

2550. The method of claim 2423 wherein the anti-fibrotic agent is a thromboxane A2 antagonist.

2551. The method of claim 2423 wherein the anti-fibrotic agent is a TNF alpha antagonist.

2552. The method of claim 2423 wherein the anti-fibrotic agent is a TACE inhibitor.

2553. The method of claim 2423 wherein the anti-fibrotic agent is a tyrosine kinase inhibitor.

2554. The method of claim 2423 wherein the anti-fibrotic agent is a vitronectin inhibitor.

2555. The method of claim 2423 wherein the anti-fibrotic agent is a fibroblast growth factor inhibitor.

2556. The method of claim 2423 wherein the anti-fibrotic agent is a protein kinase inhibitor.

2557. The method of claim 2423 wherein the anti-fibrotic agent is a PDGF receptor kinase inhibitor.

2558. The method of claim 2423 wherein the anti-fibrotic agent is an endothelial growth factor receptor kinase inhibitor.

2559. The method of claim 2423 wherein the anti-fibrotic agent is a retinoic acid receptor antagonist.

2560. The method of claim 2423 wherein the anti-fibrotic agent is a platelet derived growth factor receptor kinase inhibitor.

2561. The method of claim 2423 wherein the anti-fibrotic agent is a fibrinogen antagonist.

2562. The method of claim 2423 wherein the anti-fibrotic agent is an antimycotic agent.

2563. The method of claim 2423 wherein the anti-fibrotic agent is an antimycotic agent, wherein the antimycotic agent is sulconizole.

2564. The method of claim 2423 wherein the anti-fibrotic agent is a bisphosphonate.

2565. The method of claim 2423 wherein the anti-fibrotic agent is a phospholipase A1 inhibitor.

2566. The method of claim 2423 wherein the anti-fibrotic agent is a histamine H1/H2/H3 receptor antagonist.

2567. The method of claim 2423 wherein the anti-fibrotic agent is a macrolide antibiotic.

2568. The method of claim 2423 wherein the anti-fibrotic agent is a GPIIb/IIIa receptor antagonist.

2569. The method of claim 2423 wherein the anti-fibrotic agent is an endothelin receptor antagonist.

2570. The method of claim 2423 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor agonist.

2571. The method of claim 2423 wherein the anti-fibrotic agent is an estrogen receptor agent.

2572. The method of claim 2423 wherein the anti-fibrotic agent is a somastostatin analogue.

2573. The method of claim 2423 wherein the anti-fibrotic agent is a neurokinin 1 antagonist.

2574. The method of claim 2423 wherein the anti-fibrotic agent is a neurokinin 3 antagonist.

2575. The method of claim 2423 wherein the anti-fibrotic agent is a VLA-4 antagonist.

2576. The method of claim 2423 wherein the anti-fibrotic agent is an osteoclast inhibitor.

2577. The method of claim 2423 wherein the anti-fibrotic agent is a DNA topoisomerase ATP hydrolyzing inhibitor.

2578. The method of claim 2423 wherein the anti-fibrotic agent is an angiotensin I converting enzyme inhibitor.

2579. The method of claim 2423 wherein the anti-fibrotic agent is an angiotensin II antagonist.

2580. The method of claim 2423 wherein the anti-fibrotic agent is an enkephalinase inhibitor.

2581. The method of claim 2423 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer.

2582. The method of claim 2423 wherein the anti-fibrotic agent is a protein kinase C inhibitor.

2583. The method of claim 2423 wherein the anti-fibrotic agent is a ROCK (rho-associated kinase) inhibitor.

2584. The method of claim 2423 wherein the anti-fibrotic agent is a CXCR3 inhibitor.

2585. The method of claim 2423 wherein the anti-fibrotic agent is an Itk inhibitor.

2586. The method of claim 2423 wherein the anti-fibrotic agent is a cytosolic phospholipase A2-alpha inhibitor.

2587. The method of claim 2423 wherein the anti-fibrotic agent is a PPAR agonist.

2588. The method of claim 2423 wherein the anti-fibrotic agent is an immunosuppressant.

2589. The method of claim 2423 wherein the anti-fibrotic agent is an Erb inhibitor.

2590. The method of claim 2423 wherein the anti-fibrotic agent is an apoptosis agonist.

2591. The method of claim 2423 wherein the anti-fibrotic agent is a lipocortin agonist.

2592. The method of claim 2423 wherein the anti-fibrotic agent is a VCAM-1 antagonist.

2593. The method of claim 2423 wherein the anti-fibrotic agent is a collagen antagonist.

2594. The method of claim 2423 wherein the anti-fibrotic agent is an alpha 2 integrin antagonist.

2595. The method of claim 2423 wherein the anti-fibrotic agent is a TNF alpha inhibitor.

2596. The method of claim 2423 wherein the anti-fibrotic agent is a nitric oxide inhibitor

2597. The method of claim 2423 wherein the anti-fibrotic agent is a cathepsin inhibitor.

2598. The method of claim 2423 wherein the anti-fibrotic agent is not an anti-inflammatory agent.

2599. The method of claim 2423 wherein the anti-fibrotic agent is not a steroid.

2600. The method of claim 2423 wherein the anti-fibrotic agent is not a glucocorticosteroid.

2601. The method of claim 2423 wherein the anti-fibrotic agent is not dexamethasone.

2602. The method of claim 2423 wherein the anti-fibrotic agent is not beclomethasone.

2603. The method of claim 2423 wherein the anti-fibrotic agent is not dipropionate.

2604. The method of claim 2423 wherein the anti-fibrotic agent is not an anti-infective agent.

2605. The method of claim 2423 wherein the anti-fibrotic agent is not an antibiotic.

2606. The method of claim 2423 wherein the anti-fibrotic agent is not an anti-fungal agent.

2607. The method of claim 2423 wherein the anti-infective agent isan anthracycline.

2603. The method of claim 2423 wherein the anti-infective agent isdoxorubicin.

2609. The method of claim 2423 wherein the anti-infective agent is ismitoxantrone.

2610. The method of claim 2423 wherein the anti-infective agent is a fluoropyrimidine.

2611. The method of claim 2423 wherein the anti-infective agent is 5-fluorouracil (5-FU).

2612. The method of claim 2423 wherein the anti-infective agent is a folic acid antagonist.

2613. The method of claim 2423 wherein the anti-infective agent is methotrexate.

2614. The method of claim 2423 wherein the anti-infective agent is a podophylotoxin.

2615. The method of claim 2423 wherein the anti-infective agent is etoposide.

2616. The method of claim 2423 wherein the anti-infective agent is camptothecin.

2617. The method of claim 2423 wherein the anti-infective agent is a hydroxyurea.

2618. The method of claim 2423 wherein the anti-infective agent is a platinum complex.

2619. The method of claim 2423 wherein the anti-infective agent is cisplatin.

2620. The method of claim 2423 wherein the composition comprises an anti-thrombotic agent.

2621. The method of claim 2423 wherein the polymer is formed from reactants comprising a naturally occurring polymer.

2622. The method of claim 2423 wherein the polymer is formed from reactants comprising protein.

2623. The method of claim 2423 wherein the polymer is formed from reactants comprising carbohydrate.

2624. The method of claim 2423 wherein the polymer is formed from reactants comprising biodegradable polymer.

2625. The method of claim 2423 wherein the polymer is formed from reactants comprising nonbiodegradable polymer.

2626. The method of claim 2423 wherein the polymer is formed from reactants comprising collagen.

2627. The method of claim 2423 wherein the polymer is formed from reactants comprising methylated collagen.

2628. The method of claim 2423 wherein the polymer is formed from reactants comprising fibrinogen.

2629. The method of claim 2423 wherein the polymer is formed from reactants comprising thrombin.

2630. The method of claim 2423 wherein the polymer is formed from reactants comprising blood plasma.

2631. The method of claim 2423 wherein the polymer is formed from reactants comprising calcium salt.

2632. The method of claim 2423 wherein the polymer is formed from reactants comprising an antifibronolytic agent.

2633. The method of claim 2423 wherein the polymer is formed from reactants comprising fibrinogen analog.

2634. The method of claim 2423 wherein the polymer is formed from reactants comprising albumin.

2635. The method of claim 2423 wherein the polymer is formed from reactants comprising plasminogen.

2636. The method of claim 2423 wherein the polymer is formed from reactants comprising von Willebrands factor.

2637. The method of claim 2423 wherein the polymer is formed from reactants comprising Factor VIII.

2638. The method of claim 2423 wherein the polymer is formed from reactants comprising hypoallergenic collagen.

2639. The method of claim 2423 wherein the polymer is formed from reactants comprising atelopeptidic collagen.

2640. The method of claim 2423 wherein the polymer is formed from reactants comprising telopeptide collagen.

2641. The method of claim 2423 wherein the polymer is formed from reactants comprising crosslinked collagen.

2642. The method of claim 2423 wherein the polymer is formed from reactants comprising aprotinin.

2643. The method of claim 2423 wherein the polymer is formed from reactants comprising epsilon-amino-n-caproic acid.

2644. The method of claim 2423 wherein the polymer is formed from reactants comprising gelatin.

2645. The method of claim 2423 wherein the polymer is formed from reactants comprising protein conjugates.

2646. The method of claim 2423 wherein the polymer is formed from reactants comprising gelatin conjugates.

2647. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic polymer.

1275 2643. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic isocyanate-containing compound.

2649. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic thiol-containing compound.

2650. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two thiol groups.

2651. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three thiol groups.

2652. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four thiol groups.

2653. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic amino-containing compound.

2654. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two amino groups.

2655. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three amino groups.

2656. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four amino groups.

2657. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group.

2658. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups.

2659. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.

2660. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.

2661. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound.

2662. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.

2663. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive amino groups.

2664. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive thiol groups.

2665. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups.

2666. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic compound comprising a biodegradable polyester block.

2667. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from lactic acid or lactide.

2668. The method of claim 2423 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from glycolic acid or glycolide.

2669. The method of claim 2423 wherein the polymer is formed from reactants comprising polylysine.

2670. The method of claim 2423 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound comprising a polyalkylene oxide portion.

2671. The method of claim 2423 wherein the polymer is formed from reactants comprising (a) protein and (b) polylysine.

2672. The method of claim 2423 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four thiol groups.

2673. The method of claim 2423 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four amino groups.

2674. The method of claim 2423 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

2675. The method of claim 2423 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

2676. The method of claim 2423 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound comprising a polyalkylene oxide portion.

2677. The method of claim 2423 wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine.

2678. The method of claim 2423 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four thiol groups.

2679. The method of claim 2423 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four amino groups.

2680. The method of claim 2423 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

2681. The method of claim 2423 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

2682. The method of claim 2423 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound comprising a polyalkylene oxide portion.

2683. The method of claim 2423 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine.

2684. The method of claim 2423 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four thiol groups.

2685. The method of claim 2423 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four amino groups.

2686. The method of claim 2423 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

2687. The method of claim 2423 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

2688. The method of claim 2423 wherein the polymer is formed from reactants comprising hyaluronic acid.~

2689. The method of claim 2423 wherein the polymer is formed from reactants comprising a hyaluronic acid derivative.

2690. The method of claim 2423 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.

2691. The method of claim 2423 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.

2692. The method of claim 2423 wherein the polymer is formed from reactants comprising (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.

2693. The method of claim 2423 wherein the composition comprises a colorant.

2694. The method of claim 2423 wherein the composition is sterile.

2695. A method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with i) an anti-fibrotic agent, ii) an anti-infective agent, iii) a polymer;
iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host, wherein the medical device is a hemodialysis access device.

2696. The method for implanting a medical device according to claim 2695 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-fibrotic agent, and (b) implanting the medical device into the host.

2697. The method for implanting a medical device according to claim 2695 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-infective agent, and (b) implanting the medical device into the host.

2698. The method for implanting a medical device according to claim 2695 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a polymer; and (b) implanting the medical device into the host.

2699. The method for implanting a medical device according to claim 2695 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent and a polymer, and (b) implanting the medical device into the host.

2700. The method for implanting a medical device according to claim 2695 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

2701. The method for implanting a medical device according to claim 2695 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

2702. The method of claim 2695 wherein the medical device is an AV fistula graft.

2703. The method of claim 2695 wherein the medical device is an AV access graft.

2704. The method of claim 2695 wherein the medical device is a venous catheter.

2705. The method of claim 2695 wherein the medical device is a vascular graft.

2706. The method of claim 2695 wherein the medical device is an implantable port.

2707. The method of claim 2695 wherein the medical device is an AV shunt.

2708. The method of claim 2695 wherein the anti-fibrotic agent inhibits cell regeneration.

2709. The method of claim 2695 wherein the anti-fibrotic agent inhibits angiogenesis.

2710. The method of claim 2695 wherein the anti-fibrotic agent inhibits fibroblast migration.

2711. The method of claim 2695 wherein the anti-fibrotic agent inhibits fibroblast proliferation.

2712. The method of claim 2695 wherein the anti-fibrotic agent inhibits deposition of extracellular matrix.

2713. The method of claim 2695 wherein the anti-fibrotic agent inhibits tissue remodeling.

2714. The method of claim 2695 wherein the anti-fibrotic agent is an angiogenesis inhibitor.

2715. The method of claim 2695 wherein the anti-fibrotic agent is a 5-lipoxygenase inhibitor or antagonist.

2716. The method of claim 2695 wherein the anti-fibrotic agent is a chemokine receptor antagonist.

2717. The method of claim 2695 wherein the anti-fibrotic agent is a cell cycle inhibitor.

2718. The method of claim 2695 wherein the anti-fibrotic agent is a taxane.

2719. The method of claim 2695 wherein the anti-fibrotic agent is an anti-microtubule agent.

2720. The method of claim 2695 wherein the anti-fibrotic agent is paclitaxel.

2721. The method of claim 2695 wherein the anti-fibrotic agent is not paclitaxel.

2722. The method of claim 2695 wherein the anti-fibrotic agent is an analogue or derivative of paclitaxel.

2723. The method of claim 2695 wherein the anti-fibrotic agent is a vinca alkaloid.

2724. The method of claim 2695 wherein the anti-fibrotic agent is camptothecin or an analogue or derivative thereof.

2725. The method of claim 2695 wherein the anti-fibrotic agent is a podophyllotoxin.

2726. The method of claim 2695 wherein the anti-fibrotic agent is a podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof.

2727. The method of claim 2695 wherein the anti-fibrotic agent is an anthracycline.

2728. The method of claim 2695 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof.

2729. The method of claim 2695 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof.

2730. The method of claim 2695 wherein the anti-fibrotic agent is a platinum compound.

2731. The method of claim 2695 wherein the anti-fibrotic agent is a nitrosourea.

2732. The method of claim 2695 wherein the anti-fibrotic agent is a nitroimidazole.

2733. The method of claim 2695 wherein the anti-fibrotic agent is a folic acid antagonist.

2734. The method of claim 2695 wherein the anti-fibrotic agent is a cytidine analogue.

2735. The method of claim 2695 wherein the anti-fibrotic agent is a pyrimidine analogue.

2736. The method of claim 2695 wherein the anti-fibrotic agent is a fluoropyrimidine analogue.

2737. The method of claim 2695 wherein the anti-fibrotic agent is a purine analogue.

2738. The method of claim 2695 wherein the anti-fibrotic agent is a nitrogen mustard or an analogue or derivative thereof.

2739. The method of claim 2695 wherein the anti-fibrotic agent is a hydroxyurea.

2740. The method of claim 2695 wherein the anti-fibrotic agent is a mytomicin or an analogue or derivative thereof.

2741. The method of claim 2695 wherein the anti-fibrotic agent is an alkyl sulfonate.

2742. The method of claim 2695 wherein the anti-fibrotic agent is a benzamide or an analogue or derivative thereof.~

2743. The method of claim 2695 wherein the anti-fibrotic agent is a nicotinamide or an analogue or derivative thereof.

2744. The method of claim 2695 wherein the anti-fibrotic agent is a halogenated sugar or an analogue or derivative thereof.

2745. The method of claim 2695 wherein the anti-fibrotic agent is a DNA alkylating agent.

2746. The method of claim 2695 wherein the anti-fibrotic agent is an anti-microtubule agent.

2747. The method of claim 2695 wherein the anti-fibrotic agent is a topoisomerase inhibitor.

2748. The method of claim 2695 wherein the anti-fibrotic agent is a DNA cleaving agent.

2749. The method of claim 2695 wherein the anti-fibrotic agent is an antimetabolite.

2750. The method of claim 2695 wherein the anti-fibrotic agent inhibits adenosine deaminase.

2751. The method of claim 2695 wherein the anti-fibrotic agent inhibits purine ring synthesis.

2752. The method of claim 2695 wherein the anti-fibrotic agent is a nucleotide interconversion inhibitor.

2753. The method of claim 2695 wherein the anti-fibrotic agent inhibits dihydrofolate reduction.~

2754. The method of claim 2695 wherein the anti-fibrotic agent blocks thymidine monophosphate.

2755. The method of claim 2695 wherein the anti-fibrotic agent causes DNA damage.

2756. The method of claim 2695 wherein the anti-fibrotic agent is a DNA intercalation agent.

2757. The method of claim 2695 wherein the anti-fibrotic agent is a RNA synthesis inhibitor.

2758. The method of claim 2695 wherein the anti-fibrotic agent is a pyrimidine synthesis inhibitor.

2759. The method of claim 2695 wherein the anti-fibrotic agent inhibits ribonucleotide synthesis or function.

2760. The method of claim 2695 wherein the anti-fibrotic agent inhibits thymidine monophosphate synthesis or function.

2761. The method of claim 2695 wherein the anti-fibrotic agent inhibits DNA synthesis.

2762. The method of claim 2695 wherein the anti-fibrotic agent causes DNA adduct formation.

2763. The method of claim 2695 wherein the anti-fibrotic agent inhibits protein synthesis.

2764. The method of claim 2695 wherein the anti-fibrotic agent inhibits microtubule function.

2765. The method of claim 2695 wherein the anti-fibrotic agent is a cyclin dependent protein kinase inhibitor.

2766. The method of claim 2695 wherein the anti-fibrotic agent is an epidermal growth factor kinase inhibitor.

2767. The method of claim 2695 wherein the anti-fibrotic agent is an elastase inhibitor.

2768. The method of claim 2695 wherein the anti-fibrotic agent is a factor Xa inhibitor.

2769. The method of claim 2695 wherein the anti-fibrotic agent is a farnesyltransferase inhibitor.

2770. The method of claim 2695 wherein the anti-fibrotic agent is a fibrinogen antagonist.

2771. The method of claim 2695 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

2772. The method of claim 2695 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist.

2773. The method of claim 2695 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof.

2774. The method of claim 2695 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

2775. The method of claim 2695 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor.

2776. The method of claim 2695 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof.

2777. The method of claim 2695 wherein the anti-fibrotic agent is a hydroorotate dehydrogenase inhibitor.

2778. The method of claim 2695 wherein the anti-fibrotic agent is an IKK2 inhibitor.

2779. The method of claim 2695 wherein the anti-fibrotic agent is an IL-1 antagonist.

2780. The method of claim 2695 wherein the anti-fibrotic agent is an ICE antagonist.

2781. The method of claim 2695 wherein the anti-fibrotic agent is an IRAK antagonist.

2782. The method of claim 2695 wherein the anti-fibrotic agent is an IL-4 agonist.

2783. The method of claim 2695 wherein the anti-fibrotic agent is an immunomodulatory agent.

2784. The method of claim 2695 wherein the anti-fibrotic agent is sirolimus or an analogue or derivative thereof.

2785. The method of claim 2695 wherein the anti-fibrotic agent is not sirolimus.

2786. The method of claim 2695 wherein the anti-fibrotic agent is everolimus or an analogue or derivative thereof.

2787. The method of claim 2695 wherein the anti-fibrotic agent is tacrolimus or an analogue or derivative thereof.

2788. The method of claim 2695 wherein the anti-fibrotic agent is not tacrolimus.

2789. The method of claim 2695 wherein the anti-fibrotic agent is biolmus or an analogue or derivative thereof.

2790. The method of claim 2695 wherein the anti-fibrotic agent is tresperimus or an analogue or derivative thereof.

2791. The method of claim 2695 wherein the anti-fibrotic agent is auranofin or an analogue or derivative thereof.

2792. The method of claim 2695 wherein the anti-fibrotic agent is 27-0-demethylrapamycin or an analogue or derivative thereof.

2793. The method of claim 2695 wherein the anti-fibrotic agent is gusperimus or an analogue or derivative thereof.

2794. The method of claim 2695 wherein the anti-fibrotic agent is pimecrolimus or an analogue or derivative thereof.

2795. The method of claim 2695 wherein the anti-fibrotic agent is ABT-578 or an analogue or derivative thereof.

2796. The method of claim 2695 wherein the anti-fibrotic agent is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.

2797. The method of claim 2695 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof.

2798. The method of claim 2695 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-alpha-25 dihydroxy vitamin D3 or an analogue or derivative thereof.

2799. The method of claim 2695 wherein the anti-fibrotic agent is a leukotriene inhibitor.

2800. The method of claim 2695 wherein the anti-fibrotic agent is a MCP-1 antagonist.

2801. The method of claim 2695 wherein the anti-fibrotic agent is a MMP inhibitor.

2802. The method of claim 2695 wherein the anti-fibrotic agent is an NF kappa B inhibitor.

2803. The method of claim 2695 wherein the anti-fibrotic agent is an NF kappa B inhibitor, wherein the NF kappa B inhibitor is Bay 11-7082.

2804. The method of claim 2695 wherein the anti-fibrotic agent is an NO antagonist.

2805. The method of claim 2695 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor.

2806. The method of claim 2695 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB
202190.

2807. The method of claim 2695 wherein the anti-fibrotic agent is a phosphodiesterase inhibitor.

2808. The method of claim 2695 wherein the anti-fibrotic agent is a TGF beta inhibitor.

2809. The method of claim 2695 wherein the anti-fibrotic agent is a thromboxane A2 antagonist.

2810. The method of claim 2695 wherein the anti-fibrotic agent is a TNF alpha antagonist.

2811. The method of claim 2695 wherein the anti-fibrotic agent is a TACE inhibitor.

2812. The method of claim 2695 wherein the anti-fibrotic agent is a tyrosine kinase inhibitor.

2813. The method of claim 2695 wherein the anti-fibrotic agent is a vitronectin inhibitor.

2814. The method of claim 2695 wherein the anti-fibrotic agent is a fibroblast growth factor inhibitor.

2815. The method of claim 2695 wherein the anti-fibrotic agent is a protein kinase inhibitor.

2816. The method of claim 2695 wherein the anti-fibrotic agent is a PDGF receptor kinase inhibitor.

2817. The method of claim 2695 wherein the anti-fibrotic agent is an endothelial growth factor receptor kinase inhibitor.

2818. The method of claim 2695 wherein the anti-fibrotic agent is a retinoic acid receptor antagonist.

2819. The method of claim 2695 wherein the anti-fibrotic agent is a platelet derived growth factor receptor kinase inhibitor.

2820. The method of claim 2695 wherein the anti-fibrotic agent is a fibrinogen antagonist.

2821. The method of claim 2695 wherein the anti-fibrotic agent is an antimycotic agent.

2822. The method of claim 2695 wherein the anti-fibrotic agent is an antimycotic agent, wherein the antimycotic agent is sulconizole.

2823. The method of claim 2695 wherein the anti-fibrotic agent is a bisphosphonate.

2824. The method of claim 2695 wherein the anti-fibrotic agent is a phospholipase A1 inhibitor.

2825. The method of claim 2695 wherein the anti-fibrotic agent is a histamine H1/H2/H3 receptor antagonist.

2826. The method of claim 2695 wherein the anti-fibrotic agent is a macrolide antibiotic.

2827. The method of claim 2695 wherein the anti-fibrotic agent is a GPIIb/IIIa receptor antagonist.

2828. The method of claim 2695 wherein the anti-fibrotic agent is an endothelin receptor antagonist.

2829. The method of claim 2695 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor agonist.

2830. The method of claim 2695 wherein the anti-fibrotic agent is an estrogen receptor agent.

2831. The method of claim 2695 wherein the anti-fibrotic agent is a somastostatin analogue.

2832. The method of claim 2695 wherein the anti-fibrotic agent is a neurokinin 1 antagonist.

2833. The method of claim 2695 wherein the anti-fibrotic agent is a neurokinin 3 antagonist.

2834. The method of claim 2695 wherein the anti-fibrotic agent is a VLA-4 antagonist.

2835. The method of claim 2695 wherein the anti-fibrotic agent is an osteoclast inhibitor.

2836. The method of claim 2695 wherein the anti-fibrotic agent is a DNA topoisomerase ATP hydrolyzing inhibitor.

2837. The method of claim 2695 wherein the anti-fibrotic agent is an angiotensin I converting enzyme inhibitor.

2838. The method of claim 2695 wherein the anti-fibrotic agent is an angiotensin II antagonist.

2839. The method of claim 2695 wherein the anti-fibrotic agent is an enkephalinase inhibitor.

2840. The method of claim 2695 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer.

2841. The method of claim 2695 wherein the anti-fibrotic agent is a protein kinase C inhibitor.

2842. The method of claim 2695 wherein the anti-fibrotic agent is a ROCK (rho-associated kinase) inhibitor.

2843. The method of claim 2695 wherein the anti-fibrotic agent is a CXCR3 inhibitor.

2844. The method of claim 2695 wherein the anti-fibrotic agent is an Itk inhibitor.

2845. The method of claim 2695 wherein the anti-fibrotic agent is a cytosolic phospholipase A2-alpha inhibitor.

2846. The method of claim 2695 wherein the anti-fibrotic agent is a PPAR agonist.

2847. The method of claim 2695 wherein the anti-fibrotic agent is an immunosuppressant.

2848. The method of claim 2695 wherein the anti-fibrotic agent is an Erb inhibitor.

2849. The method of claim 2695 wherein the anti-fibrotic agent is an apoptosis agonist.

2850. The method of claim 2695 wherein the anti-fibrotic agent is a lipocortin agonist.

2851. The method of claim 2695 wherein the anti-fibrotic agent is a VCAM-1 antagonist.

2852. The method of claim 2695 wherein the anti-fibrotic agent is a collagen antagonist.

2853. The method of claim 2695 wherein the anti-fibrotic agent is an alpha 2 integrin antagonist.

2854. The method of claim 2695 wherein the anti-fibrotic agent is a TNF alpha inhibitor.

2855. The method of claim 2695 wherein the anti-fibrotic agent is a nitric oxide inhibitor

2856. The method of claim 2695 wherein the anti-fibrotic agent is a cathepsin inhibitor.

2857. The method of claim 2695 wherein the anti-fibrotic agent is not an anti-inflammatory agent.

2858. The method of claim 2695 wherein the anti-fibrotic agent is not a steroid.

2859. The method of claim 2695 wherein the anti-fibrotic agent is not a glucocorticosteroid.

2860. The method of claim 2695 wherein the anti-fibrotic agent is not dexamethasone.

2861. The method of claim 2695 wherein the anti-fibrotic agent is not beclomethasone.

2862. The method of claim 2695 wherein the anti-fibrotic agent is not dipropionate.

2863. The method of claim 2695 wherein the anti-fibrotic agent is not an anti-infective agent.

2864. The method of claim 2695 wherein the anti-fibrotic agent is not an antibiotic.

2865. The method of claim 2695 wherein the anti-fibrotic agent is not an anti-fungal agent.

2866. The method of claim 2695 wherein the anti-infective agent isan anthracycline.

2867. The method of claim 2695 wherein the anti-infective agent isdoxorubicin.

2868. The method of claim 2695 wherein the anti-infective agent is ismitoxantrone.

2869. The method of claim 2695 wherein the anti-infective agent is a fluoropyrimidine.

2870. The method of claim 2695 wherein the anti-infective agent is 5-fluorouracil (5-FU).

2871. The method of claim 2695 wherein the anti-infective agent is a folic acid antagonist.

2872. The method of claim 2695 wherein the anti-infective agent is methotrexate.

2873. The method of claim 2695 wherein the anti-infective agent is a podophylotoxin.

2874. The method of claim 2695 wherein the anti-infective agent is etoposide.

2875. The method of claim 2695 wherein the anti-infective agent is camptothecin.

2876. The method of claim 2695 wherein the anti-infective agent is a hydroxyurea.

2877. The method of claim 2695 wherein the anti-infective agent is a platinum complex.

2878. The method of claim 2695 wherein the anti-infective agent is cisplatin.

2879. The method of claim 2695 wherein the composition comprises an anti-thrombotic agent.

2880. The method of claim 2695 wherein the polymer is formed from reactants comprising a naturally occurring polymer.

2881. The method of claim 2695 wherein the polymer is formed from reactants comprising protein.

2882. The method of claim 2695 wherein the polymer is formed from reactants comprising carbohydrate.

2883. The method of claim 2695 wherein the polymer is formed from reactants comprising biodegradable polymer.

2884. The method of claim 2695 wherein the polymer is formed from reactants comprising nonbiodegradable polymer.

2885. The method of claim 2695 wherein the polymer is formed from reactants comprising collagen.

2886. The method of claim 2695 wherein the polymer is formed from reactants comprising methylated collagen.

2887. The method of claim 2695 wherein the polymer is formed from reactants comprising fibrinogen.

2888. The method of claim 2695 wherein the polymer is formed from reactants comprising thrombin.

2889. The method of claim 2695 wherein the polymer is formed from reactants comprising blood plasma.

2890. The method of claim 2695 wherein the polymer is formed from reactants comprising calcium salt.

2891. The method of claim 2695 wherein the polymer is formed from reactants comprising an antifibronolytic agent.

2892. The method of claim 2695 wherein the polymer is formed from reactants comprising fibrinogen analog.

2893. The method of claim 2695 wherein the polymer is formed from reactants comprising albumin.

2894. The method of claim 2695 wherein the polymer is formed from reactants comprising plasminogen.

2895. The method of claim 2695 wherein the polymer is formed from reactants comprising von Willebrands factor.

2896. The method of claim 2695 wherein the polymer is formed from reactants comprising Factor VIII.

2897. The method of claim 2695 wherein the polymer is formed from reactants comprising hypoallergenic collagen.

2898. The method of claim 2695 wherein the polymer is formed from reactants comprising atelopeptidic collagen.

2899. The method of claim 2695 wherein the polymer is formed from reactants comprising telopeptide collagen.

2900. The method of claim 2695 wherein the polymer is formed from reactants comprising crosslinked collagen.

2901. The method of claim 2695 wherein the polymer is formed from reactants comprising aprotinin.

2902. The method of claim 2695 wherein the polymer is formed from reactants comprising epsilon-amino-n-caproic acid.

2903. The method of claim 2695 wherein the polymer is formed from reactants comprising gelatin.

2904. The method of claim 2695 wherein the polymer is formed from reactants comprising protein conjugates.

2905. The method of claim 2695 wherein the polymer is formed from reactants comprising gelatin conjugates.

2906. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic polymer.

2907. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic isocyanate-containing compound.

2908. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic thiol-containing compound.

2909. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two thiol groups.

2910. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three thiol groups.

2911. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four thiol groups.

2912. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic amino-containing compound.

2913. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two amino groups.

2914. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three amino groups.

2915. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four amino groups.

2916. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group.

2917. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups.

2918. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.

2919. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.

2920. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound.

2921. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.

2922. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive amino groups.

2923. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive thiol groups.

2924. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups.

2925. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic compound comprising a biodegradable polyester block.

2926. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from lactic acid or lactide.

2927. The method of claim 2695 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from glycolic acid or glycolide.

2928. The method of claim 2695 wherein the polymer is formed from reactants comprising polylysine.

2929. The method of claim 2695 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound comprising a polyalkylene oxide portion.

2930. The method of claim 2695 wherein the polymer is formed from reactants comprising (a) protein and (b) polylysine.

2931. The method of claim 2695 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four thiol groups.

2932. The method of claim 2695 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four amino groups.

2933. The method of claim 2695 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

2934. The method of claim 2695 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

2935. The method of claim 2695 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound comprising a polyalkylene oxide portion.

2936. The method of claim 2695 wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine.

2937. The method of claim 2695 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four thiol groups.

2938. The method of claim 2695 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four amino groups.

2939. The method of claim 2695 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

2940. The method of claim 2695 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

2941. The method of claim 2695 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound comprising a polyalkylene oxide portion.

2942. The method of claim 2695 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine.

2943. The method of claim 2695 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four thiol groups.

2944. The method of claim 2695 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four amino groups.

2945. The method of claim 2695 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

2946. The method of claim 2695 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

2947. The method of claim 2695 wherein the polymer is formed from reactants comprising hyaluronic acid.

2948. The method of claim 2695 wherein the polymer is formed from reactants comprising a hyaluronic acid derivative.

2949. The method of claim 2695 wherein the polymer is formed from reactants comprising pentaerythritol polyethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.

2950. The method of claim 2695 wherein the polymer is formed from reactants comprising pentaerythritol polyethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.

2951. The method of claim 2695 wherein the polymer is formed from reactants comprising (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.

2952. The method of claim 2695 wherein the composition comprises a colorant.

2953. The method of claim 2695 wherein the composition is sterile.

2954. A method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with i) an anti-fibrotic agent, ii) an anti-infective agent, iii) a polymer;
iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host, wherein the medical device is a device that comprises a film or a mesh.

2955. The method for implanting a medical device according to claim 2954 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-fibrotic agent, and (b) implanting the medical device into the host.

2956. The method for implanting a medical device according to claim 2954 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-infective agent, and (b) implanting the medical device into the host.

2957. The method for implanting a medical device according to claim 2954 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a polymer; and (b) implanting the medical device into the host.

2958. The method for implanting a medical device according to claim 2954 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent and a polymer, and (b) implanting the medical device into the host.

2959. The method for implanting a medical device according to claim 2954 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

2960. The method for implanting a medical device according to claim 2954 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

2961. The method of claim 2954 wherein the medical device is a surgical barrier.

2962. The method of claim 2954 wherein the medical device is a surgical adhesion barrier.

2963. The method of claim 2954 wherein the medical device is a surgical sheet.

2964. The method of claim 2954 wherein the medical device is a surgical patch.

2965. The method of claim 2954 wherein the medical device is a surgical wrap.

2966. The method of claim 2954 wherein the medical device is a vascular wrap.

2967. The method of claim 2954 wherein the medical device is a perivascular wrap.

2968. The method of claim 2954 wherein the medical device is an, adventitial wrap.

2969. The method of claim 2954 wherein the medical device is a periadventitital wrap.

2970. The method of claim 2954 wherein the medical device is an adventitial sheet.

2971. The method of claim 2954 wherein the medical device is a perivascular mesh.

2972. The method of claim 2954 wherein the medical device is a bandage.

2973. The method of claim 2954 wherein the medical device is a liquid bandage.

2974. The method of claim 2954 wherein the medical device is a surgical dressing.

2975. The method of claim 2954 wherein the medical device is a gauze.

2976. The method of claim 2954 wherein the medical device is a fabric.

2977. The method of claim 2954 wherein the medical device is a tape.

2978. The method of claim 2954 wherein the medical device is a surgical membrane.

2979. The method of claim 2954 wherein the medical device is a polymer matrix.

2980. The method of claim 2954 wherein the medical device is a tissue covering.

2981. The method of claim 2954 wherein the medical device is a surgical matrix.

2982. The method of claim 2954 wherein the medical device is an envelope.

2983. The method of claim 2954 wherein the medical device is a tissue covering.

2984. The method of claim 2954 wherein the anti-fibrotic agent inhibits cell regeneration.

2985. The method of claim 2954 wherein the anti-fibrotic agent inhibits angiogenesis.

2986. The method of claim 2954 wherein the anti-fibrotic agent inhibits fibroblast migration.

2987. The method of claim 2954 wherein the anti-fibrotic agent inhibits fibroblast proliferation.

2988. The method of claim 2954 wherein the anti-fibrotic agent inhibits deposition of extracellular matrix.

2989. The method of claim 2954 wherein the anti-fibrotic agent inhibits tissue remodeling.

2990. The method of claim 2954 wherein the anti-fibrotic agent is an angiogenesis inhibitor.

2991. The method of claim 2954 wherein the anti-fibrotic agent is a 5-lipoxygenase inhibitor or antagonist.

2992. The method of claim 2954 wherein the anti-fibrotic agent is a chemokine receptor antagonist.

2993. The method of claim 2954 wherein the anti-fibrotic agent is a cell cycle inhibitor.

2994. The method of claim 2954 wherein the anti-fibrotic agent is a taxane.

2995. The method of claim 2954 wherein the anti-fibrotic agent is an anti-microtubule agent.

2996. The method of claim 2954 wherein the anti-fibrotic agent is paclitaxel.

2997. The method of claim 2954 wherein the anti-fibrotic agent is not paclitaxel.

2998. The method of claim 2954 wherein the anti-fibrotic agent is an analogue or derivative of paclitaxel.

2999. The method of claim 2954 wherein the anti-fibrotic agent is a vinca alkaloid.

3000. The method of claim 2954 wherein the anti-fibrotic agent is camptothecin or an analogue or derivative thereof.

3001. The method of claim 2954 wherein the anti-fibrotic agent is a podophyllotoxin.

3002. The method of claim 2954 wherein the anti-fibrotic agent is a podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof.

3003. The method of claim 2954 wherein the anti-fibrotic agent is an anthracycline.

3004. The method of claim 2954 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof.

3005. The method of claim 2954 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof.

3006. The method of claim 2954 wherein the anti-fibrotic agent is a platinum compound.

3007. The method of claim 2954 wherein the anti-fibrotic agent is a nitrosourea.

3008. The method of claim 2954 wherein the anti-fibrotic agent is a nitroimidazole.

3009. The method of claim 2954 wherein the anti-fibrotic agent is a folic acid antagonist.

3010. The method of claim 2954 wherein the anti-fibrotic agent is a cytidine analogue.

3011. The method of claim 2954 wherein the anti-fibrotic agent is a pyrimidine analogue.

3012. The method of claim 2954 wherein the anti-fibrotic agent is a fluoropyrimidine analogue.

3013. The method of claim 2954 wherein the anti-fibrotic agent is a purine analogue.

3014. The method of claim 2954 wherein the anti-fibrotic agent is a nitrogen mustard or an analogue or derivative thereof.

3015. The method of claim 2954 wherein the anti-fibrotic agent is a hydroxyurea.

3016. The method of claim 2954 wherein the anti-fibrotic agent is a mytomicin or an analogue or derivative thereof.

3017. The method of claim 2954 wherein the anti-fibrotic agent is an alkyl sulfonate.

3018. The method of claim 2954 wherein the anti-fibrotic agent is a benzamide or an analogue or derivative thereof.

3019. The method of claim 2954 wherein the anti-fibrotic agent is a nicotinamide or an analogue or derivative thereof.

3020. The method of claim 2954 wherein the anti-fibrotic agent is a halogenated sugar or an analogue or derivative thereof.

3021. The method of claim 2954 wherein the anti-fibrotic agent is a DNA alkylating agent.

3022. The method of claim 2954 wherein the anti-fibrotic agent is an anti-microtubule agent.

3023. The method of claim 2954 wherein the anti-fibrotic agent is a topoisomerase inhibitor.

3024. The method of claim 2954 wherein the anti-fibrotic agent is a DNA cleaving agent.

3025. The method of claim 2954 wherein the anti-fibrotic agent is an antimetabolite.

3026. The method of claim 2954 wherein the anti-fibrotic agent inhibits adenosine deaminase.

3027. The method of claim 2954 wherein the anti-fibrotic agent inhibits purine ring synthesis.

3028. The method of claim 2954 wherein the anti-fibrotic agent is a nucleotide interconversion inhibitor.

3029. The method of claim 2954 wherein the anti-fibrotic agent inhibits dihydrofolate reduction.

3030. The method of claim 2954 wherein the anti-fibrotic agent blocks thymidine monophosphate.

3031. The method of claim 2954 wherein the anti-fibrotic agent causes DNA damage.

3032. The method of claim 2954 wherein the anti-fibrotic agent is a DNA intercalation agent.

3033. The method of claim 2954 wherein the anti-fibrotic agent is a RNA synthesis inhibitor.

3034. The method of claim 2954 wherein the anti-fibrotic agent is a pyrimidine synthesis inhibitor.

3035. The method of claim 2954 wherein the anti-fibrotic agent inhibits ribonucleotide synthesis or function.

3036. The method of claim 2954 wherein the anti-fibrotic agent inhibits thymidine monophosphate synthesis or function.

3037. The method of claim 2954 wherein the anti-fibrotic agent inhibits DNA synthesis.

3038. The method of claim 2954 wherein the anti-fibrotic agent causes DNA adduct formation.

3039. The method of claim 2954 wherein the anti-fibrotic agent inhibits protein synthesis.

3040. The method of claim 2954 wherein the anti-fibrotic agent inhibits microtubule function.

3041. The method of claim 2954 wherein the anti-fibrotic agent is a cyclin dependent protein kinase inhibitor.

3042. The method of claim 2954 wherein the anti-fibrotic agent is an epidermal growth factor kinase inhibitor.

3043. The method of claim 2954 wherein the anti-fibrotic agent is an elastase inhibitor.

3044. The method of claim 2954 wherein the anti-fibrotic agent is a factor Xa inhibitor.

3045. The method of claim 2954 wherein the anti-fibrotic agent is a farnesyltransferase inhibitor.

3046. The method of claim 2954 wherein the anti-fibrotic agent is a fibrinogen antagonist.

3047. The method of claim 2954 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

3043. The method of claim 2954 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist.

3049. The method of claim 2954 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof.

3050. The method of claim 2954 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

3051. The method of claim 2954 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor.

3052. The method of claim 2954 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof.

3053. The method of claim 2954 wherein the anti-fibrotic agent is a hydroorotate dehydrogenase inhibitor.

3054. The method of claim 2954 wherein the anti-fibrotic agent is an IKK2 inhibitor.

3055. The method of claim 2954 wherein the anti-fibrotic agent is an IL-1 antagonist.

3056. The method of claim 2954 wherein the anti-fibrotic agent is an ICE antagonist.

3057. The method of claim 2954 wherein the anti-fibrotic agent is an IRAK antagonist.

3058. The method of claim 2954 wherein the anti-fibrotic agent is an IL-4 agonist.

3059. The method of claim 2954 wherein the anti-fibrotic agent is an immunomodulatory agent.

3060. The method of claim 2954 wherein the anti-fibrotic agent is sirolimus or an analogue or derivative thereof.

3061. The method of claim 2954 wherein the anti-fibrotic agent is not sirolimus.

3062. The method of claim 2954 wherein the anti-fibrotic agent is everolimus or an analogue or derivative thereof.

3063. The method of claim 2954 wherein the anti-fibrotic agent is tacrolimus or an analogue or derivative thereof.

3064. The method of claim 2954 wherein the anti-fibrotic agent is not tacrolimus.

3065. The method of claim 2954 wherein the anti-fibrotic agent is biolmus or an analogue or derivative thereof.

3066. The method of claim 2954 wherein the anti-fibrotic agent is tresperimus or an analogue or derivative thereof.

3067. The method of claim 2954 wherein the anti-fibrotic agent is auranofin or an analogue or derivative thereof.

3068. The method of claim 2954 wherein the anti-fibrotic agent is 27-0-demethylrapamycin or an analogue or derivative thereof.

3069. The method of claim 2954 wherein the anti-fibrotic agent is gusperimus or an analogue or derivative thereof.

3070. The method of claim 2954 wherein the anti-fibrotic agent is pimecrolimus or an analogue or derivative thereof.

3071. The method of claim 2954 wherein the anti-fibrotic agent is ABT-578 or an analogue or derivative thereof.

3072. The method of claim 2954 wherein the anti-fibrotic agent is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.

3073. The method of claim 2954 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof.

3074. The method of claim 2954 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-alpha-25 dihydroxy vitamin D3 or an analogue or derivative thereof.

3075. The method of claim 2954 wherein the anti-fibrotic agent is a leukotriene inhibitor.

3076. The method of claim 2954 wherein the anti-fibrotic agent is a MCP-1 antagonist.

3077. The method of claim 2954 wherein the anti-fibrotic agent is a MMP inhibitor.

3078. The method of claim 2954 wherein the anti-fibrotic agent is an NF kappa B inhibitor.

3079. The method of claim 2954 wherein the anti-fibrotic agent is an NF kappa B inhibitor, wherein the NF kappa B inhibitor is Bay 11-7082.

3080. The method of claim 2954 wherein the anti-fibrotic agent is an NO antagonist.

3081. The method of claim 2954 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor.

3082. The method of claim 2954 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB
202190.

3083. The method of claim 2954 wherein the anti-fibrotic agent is a phosphodiesterase inhibitor.

3084. The method of claim 2954 wherein the anti-fibrotic agent is a TGF beta inhibitor.

3085. The method of claim 2954 wherein the anti-fibrotic agent is a thromboxane A2 antagonist.

3086. The method of claim 2954 wherein the anti-fibrotic agent is a TNF alpha antagonist.

3087. The method of claim 2954 wherein the anti-fibrotic agent is a TACE inhibitor.

3088. The method of claim 2954 wherein the anti-fibrotic agent is a tyrosine kinase inhibitor.

3089. The method of claim 2954 wherein the anti-fibrotic agent is a vitronectin inhibitor.

3090. The method of claim 2954 wherein the anti-fibrotic agent is a fibroblast growth factor inhibitor.

3091. The method of claim 2954 wherein the anti-fibrotic agent is a protein kinase inhibitor.

3092. The method of claim 2954 wherein the anti-fibrotic agent is a PDGF receptor kinase inhibitor.

3093. The method of claim 2954 wherein the anti-fibrotic agent is an endothelial growth factor receptor kinase inhibitor.

3094. The method of claim 2954 wherein the anti-fibrotic agent is a retinoic acid receptor antagonist.

3095. The method of claim 2954 wherein the anti-fibrotic agent is a platelet derived growth factor receptor kinase inhibitor.

3096. The method of claim 2954 wherein the anti-fibrotic agent is a fibrinogen antagonist.

3097. The method of claim 2954 wherein the anti-fibrotic agent is an antimycotic agent.

3098. The method of claim 2954 wherein the anti-fibrotic agent is an antimycotic agent, wherein the antimycotic agent is sulconizole.

3099. The method of claim 2954 wherein the anti-fibrotic agent is a bisphosphonate.

3100. The method of claim 2954 wherein the anti-fibrotic agent is a phospholipase A1 inhibitor.

3101. The method of claim 2954 wherein the anti-fibrotic agent is a histamine H1/H2/H3 receptor antagonist.

3102. The method of claim 2954 wherein the anti-fibrotic agent is a macrolide antibiotic.

3103. The method of claim 2954 wherein the anti-fibrotic agent is a GPIIb/IIIa receptor antagonist.

3104. The method of claim 2954 wherein the anti-fibrotic agent is an endothelin receptor antagonist.

3105. The method of claim 2954 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor agonist.

3106. The method of claim 2954 wherein the anti-fibrotic agent is an estrogen receptor agent.

3107. The method of claim 2954 wherein the anti-fibrotic agent is a somastostatin analogue.

3108. The method of claim 2954 wherein the anti-fibrotic agent is a neurokinin 1 antagonist.

3109. The method of claim 2954 wherein the anti-fibrotic agent is a neurokinin 3 antagonist.

3110. The method of claim 2954 wherein the anti-fibrotic agent is a VLA-4 antagonist.

3111. The method of claim 2954 wherein the anti-fibrotic agent is an osteoclast inhibitor.

3112. The method of claim 2954 wherein the anti-fibrotic agent is a DNA topoisomerase ATP hydrolyzing inhibitor.

3113. The method of claim 2954 wherein the anti-fibrotic agent is an angiotensin I converting enzyme inhibitor.

3114. The method of claim 2954 wherein the anti-fibrotic agent is an angiotensin II antagonist.

3115. The method of claim 2954 wherein the anti-fibrotic agent is an enkephalinase inhibitor.

3116. The method of claim 2954 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer.

3117. The method of claim 2954 wherein the anti-fibrotic agent is a protein kinase C inhibitor.

3118. The method of claim 2954 wherein the anti-fibrotic agent is a ROCK (rho-associated kinase) inhibitor.

3119. The method of claim 2954 wherein the anti-fibrotic agent is a CXCR3 inhibitor.

3120. The method of claim 2954 wherein the anti-fibrotic agent is an Itk inhibitor.

3121. The method of claim 2954 wherein the anti-fibrotic agent is a cytosolic phospholipase A2-alpha inhibitor.

3122. The method of claim 2954 wherein the anti-fibrotic agent is a PPAR agonist.

3123. The method of claim 2954 wherein the anti-fibrotic agent is an immunosuppressant.

3124. The method of claim 2954 wherein the anti-fibrotic agent is an Erb inhibitor.

3125. The method of claim 2954 wherein the anti-fibrotic agent is an apoptosis agonist.

3126. The method of claim 2954 wherein the anti-fibrotic agent is a lipocortin agonist.

3127. The method of claim 2954 wherein the anti-fibrotic agent is a VCAM-1 antagonist.

3128. The method of claim 2954 wherein the anti-fibrotic agent is a collagen antagonist.

3129. The method of claim 2954 wherein the anti-fibrotic agent is an alpha 2 integrin antagonist.

3130. The method of claim 2954 wherein the anti-fibrotic agent is a TNF alpha inhibitor.

3131. The method of claim 2954 wherein the anti-fibrotic agent is a nitric oxide inhibitor

3132. The method of claim 2954 wherein the anti-fibrotic agent is a cathepsin inhibitor.

3133. The method of claim 2954 wherein the anti-fibrotic agent is not an anti-inflammatory agent.

3134. The method of claim 2954 wherein the anti-fibrotic agent is not a steroid.

3135. The method of claim 2954 wherein the anti-fibrotic agent is not a glucocorticosteroid.

3136. The method of claim 2954 wherein the anti-fibrotic agent is not dexamethasone.

3137. The method of claim 2954 wherein the anti-fibrotic agent is not beclomethasone.

3138. The method of claim 2954 wherein the anti-fibrotic agent is not dipropionate.

3139. The method of claim 2954 wherein the anti-fibrotic agent is not an anti-infective agent.

3140. The method of claim 2954 wherein the anti-fibrotic agent is not an antibiotic.

3141. The method of claim 2954 wherein the anti-fibrotic agent is not an anti-fungal agent.

3142. The method of claim 2954 wherein the anti-infective agent isan anthracycline.

3143. The method of claim 2954 wherein the anti-infective agent isdoxorubicin.

3144. The method of claim 2954 wherein the anti-infective agent is ismitoxantrone.

3145. The method of claim 2954 wherein the anti-infective agent is a fluoropyrimidine.

3146. The method of claim 2954 wherein the anti-infective agent is 5-fluorouracil (5-FU).

3147. The method of claim 2954 wherein the anti-infective agent is a folic acid antagonist.

3143. The method of claim 2954 wherein the anti-infective agent is methotrexate.

3149. The method of claim 2954 wherein the anti-infective agent is a podophylotoxin.

3150. The method of claim 2954 wherein the anti-infective agent is etoposide.

3151. The method of claim 2954 wherein the anti-infective agent is camptothecin.

3152. The method of claim 2954 wherein the anti-infective agent is a hydroxyurea.

3153. The method of claim 2954 wherein the anti-infective agent is a platinum complex.

3154. The method of claim 2954 wherein the anti-infective agent is cisplatin.

3155. The method of claim 2954 wherein the composition comprises an anti-thrombotic agent.

3156. The method of claim 2954 wherein the polymer is formed from reactants comprising a naturally occurring polymer.

3157. The method of claim 2954 wherein the polymer is formed from reactants comprising protein.

3158. The method of claim 2954 wherein the polymer is formed from reactants comprising carbohydrate.

3159. The method of claim 2954 wherein the polymer is formed from reactants comprising biodegradable polymer.

3160. The method of claim 2954 wherein the polymer is formed from reactants comprising nonbiodegradable polymer.

3161. The method of claim 2954 wherein the polymer is formed from reactants comprising collagen.

3162. The method of claim 2954 wherein the polymer is formed from reactants comprising methylated collagen.

3163. The method of claim 2954 wherein the polymer is formed from reactants comprising fibrinogen.

3164. The method of claim 2954 wherein the polymer is formed from reactants comprising thrombin.

3165. The method of claim 2954 wherein the polymer is formed from reactants comprising blood plasma.

3166. The method of claim 2954 wherein the polymer is formed from reactants comprising calcium salt.

3167. The method of claim 2954 wherein the polymer is formed from reactants comprising an antifibronolytic agent.

3168. The method of claim 2954 wherein the polymer is formed from reactants comprising fibrinogen analog.

3169. The method of claim 2954 wherein the polymer is formed from reactants comprising albumin.

3170. The method of claim 2954 wherein the polymer is formed from reactants comprising plasminogen.

3171. The method of claim 2954 wherein the polymer is formed from reactants comprising von Willebrands factor.

3172. The method of claim 2954 wherein the polymer is formed from reactants comprising Factor VIII.

3173. The method of claim 2954 wherein the polymer is formed from reactants comprising hypoallergenic collagen.

3174. The method of claim 2954 wherein the polymer is formed from reactants comprising atelopeptidic collagen.

3175. The method of claim 2954 wherein the polymer is formed from reactants comprising telopeptide collagen.

3176. The method of claim 2954 wherein the polymer is formed from reactants comprising crosslinked collagen.

3177. The method of claim 2954 wherein the polymer is formed from reactants comprising aprotinin.

3178. The method of claim 2954 wherein the polymer is formed from reactants comprising epsilon-amino-n-caproic acid.

3179. The method of claim 2954 wherein the polymer is formed from reactants comprising gelatin.

3180. The method of claim 2954 wherein the polymer is formed from reactants comprising protein conjugates.

3181. The method of claim 2954 wherein the polymer is formed from reactants comprising gelatin conjugates.

3182. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic polymer.

3183. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic isocyanate-containing compound.

3184. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic thiol-containing compound.

3185. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two thiol groups.

3186. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three thiol groups.

3187. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four thiol groups.

3188. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic amino-containing compound.

3189. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two amino groups.

3190. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three amino groups.

3191. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four amino groups.

3192. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group.

3193. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups.

3194. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.

3195. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.

3196. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound.

3197. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.

3198. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive amino groups.

3199. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive thiol groups.

3200. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups.

3201. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic compound comprising a biodegradable polyester block.

3202. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from lactic acid or lactide.

3203. The method of claim 2954 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from glycolic acid or glycolide.

3204. The method of claim 2954 wherein the polymer is formed from reactants comprising polylysine.

3205. The method of claim 2954 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound comprising a polyalkylene oxide portion.

3206. The method of claim 2954 wherein the polymer is formed from reactants comprising (a) protein and (b) polylysine.

3207. The method of claim 2954 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four thiol groups.

3208. The method of claim 2954 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four amino groups.

3209. The method of claim 2954 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

3210. The method of claim 2954 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

3211. The method of claim 2954 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound comprising a polyalkylene oxide portion.

3212. The method of claim 2954 wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine.

3213. The method of claim 2954 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four thiol groups.

3214. The method of claim 2954 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at feast four amino groups.

3215. The method of claim 2954 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

3216. The method of claim 2954 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

3217. The method of claim 2954 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound comprising a polyalkylene oxide portion.

3218. The method of claim 2954 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine.~

3219. The method of claim 2954 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four thiol groups.

3220. The method of claim 2954 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four amino groups.

3221. The method of claim 2954 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

3222. The method of claim 2954 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

3223. The method of claim 2954 wherein the polymer is formed from reactants comprising hyaluronic acid.

3224. The method of claim 2954 wherein the polymer is formed from reactants comprising a hyaluronic acid derivative.

3225. The method of claim 2954 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.

3226. The method of claim 2954 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.

3227. The method of claim 2954 wherein the polymer is formed from reactants comprising (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.

3228. The method of claim 2954 wherein the composition comprises a colorant.

3229. The method of claim 2954 wherein the composition is sterile.

3230. A method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with i) an anti-fibrotic agent, ii) an anti-infective agent, iii) a polymer;
iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host, wherein the medical device is a glaucoma drainage device.

3231. The method for implanting a medical device according to claim 3230 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-fibrotic agent, and (b) implanting the medical device into the host.

3232. The method for implanting a medical device according to claim 3230 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-infective agent, and (b) implanting the medical device into the host.

3233. The method for implanting a medical device according to claim 3230 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a polymer; and (b) implanting the medical device into the host.

3234. The method for implanting a medical device according to claim 3230 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent and a polymer, and (b) implanting the medical device into the host.

3235. The method for implanting a medical device according to claim 3230 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

3236. The method for implanting a medical device according to claim 3230 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

3237. The method of claim 3230 wherein the medical device is a glaucoma drainage device comprising a plate and a tube.

3238. The method of claim 3230 wherein the anti-fibrotic agent inhibits cell regeneration.

3239. The method of claim 3230 wherein the anti-fibrotic agent inhibits angiogenesis.

3240. The method of claim 3230 wherein the anti-fibrotic agent inhibits fibroblast migration.

3241. The method of claim 3230 wherein the anti-fibrotic agent inhibits fibroblast proliferation.

3242. The method of claim 3230 wherein the anti-fibrotic agent inhibits deposition of extracellular matrix.

3243. The method of claim 3230 wherein the anti-fibrotic agent inhibits tissue remodeling.

3244. The method of claim 3230 wherein the anti-fibrotic agent is an angiogenesis inhibitor.

3245. The method of claim 3230 wherein the anti-fibrotic agent is a 5-lipoxygenase inhibitor or antagonist.

3246. The method of claim 3230 wherein the anti-fibrotic agent is a chemokine receptor antagonist.

3247. The method of claim 3230 wherein the anti-fibrotic agent is a cell cycle inhibitor.

3248. The method of claim 3230 wherein the anti-fibrotic agent is a taxane.

3249. The method of claim 3230 wherein the anti-fibrotic agent is an anti-microtubule agent.

3250. The method of claim 3230 wherein the anti-fibrotic agent is paclitaxel.

3251. The method of claim 3230 wherein the anti-fibrotic agent is not paclitaxel.

3252. The method of claim 3230 wherein the anti-fibrotic agent is an analogue or derivative of paclitaxel.

3253. The method of claim 3230 wherein the anti-fibrotic agent is a vinca alkaloid.

3254. The method of claim 3230 wherein the anti-fibrotic agent is camptothecin or an analogue or derivative thereof.

3255. The method of claim 3230 wherein the anti-fibrotic agent is a podophyllotoxin.

3256. The method of claim 3230 wherein the anti-fibrotic agent is a podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof.

3257. The method of claim 3230 wherein the anti-fibrotic agent is an anthracycline.

3258. The method of claim 3230 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof.

3259. The method of claim 3230 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof.

3260. The method of claim 3230 wherein the anti-fibrotic agent is a platinum compound.

3261. The method of claim 3230 wherein the anti-fibrotic agent is a nitrosourea.

3262. The method of claim 3230 wherein the anti-fibrotic agent is a nitroimidazole.

3263. The method of claim 3230 wherein the anti-fibrotic agent is a folic acid antagonist.

3264. The method of claim 3230 wherein the anti-fibrotic agent is a cytidine analogue.

3265. The method of claim 3230 wherein the anti-fibrotic agent is a pyrimidine analogue.

3266. The method of claim 3230 wherein the anti-fibrotic agent is a fluoropyrimidine analogue.

3267. The method of claim 3230 wherein the anti-fibrotic agent is a purine analogue.~

3268. The method of claim 3230 wherein the anti-fibrotic agent is a nitrogen mustard or an analogue or derivative thereof.

3269. The method of claim 3230 wherein the anti-fibrotic agent is a hydroxyurea.

3270. The method of claim 3230 wherein the anti-fibrotic agent is a mytomicin or an analogue or derivative thereof.

3271. The method of claim 3230 wherein the anti-fibrotic agent is an alkyl sulfonate.

3272. The method of claim 3230 wherein the anti-fibrotic agent is a benzamide or an analogue or derivative thereof.

3273. The method of claim 3230 wherein the anti-fibrotic agent is a nicotinamide or an analogue or derivative thereof.

3274. The method of claim 3230 wherein the anti-fibrotic agent is a halogenated sugar or an analogue or derivative thereof.

3275. The method of claim 3230 wherein the anti-fibrotic agent is a DNA alkylating agent.

3276. The method of claim 3230 wherein the anti-fibrotic agent is an anti-microtubule agent.

3277. The method of claim 3230 wherein the anti-fibrotic agent is a topoisomerase inhibitor.

3278. The method of claim 3230 wherein the anti-fibrotic agent is a DNA cleaving agent.

3279. The method of claim 3230 wherein the anti-fibrotic agent is an antimetabolite.

3280. The method of claim 3230 wherein the anti-fibrotic agent inhibits adenosine deaminase.

3281. The method of claim 3230 wherein the anti-fibrotic agent inhibits purine ring synthesis.

3282. The method of claim 3230 wherein the anti-fibrotic agent is a nucleotide interconversion inhibitor.

3283. The method of claim 3230 wherein the anti-fibrotic agent inhibits dihydrofolate reduction.

3284. The method of claim 3230 wherein the anti-fibrotic agent blocks thymidine monophosphate.

3285. The method of claim 3230 wherein the anti-fibrotic agent causes DNA damage.

3286. The method of claim 3230 wherein the anti-fibrotic agent is a DNA intercalation agent.

3287. The method of claim 3230 wherein the anti-fibrotic agent is a RNA synthesis inhibitor.

3288. The method of claim 3230 wherein the anti-fibrotic agent is a pyrimidine synthesis inhibitor.

3289. The method of claim 3230 wherein the anti-fibrotic agent inhibits ribonucleotide synthesis or function.

3290. The method of claim 3230 wherein the anti-fibrotic agent inhibits thymidine monophosphate synthesis or function.

3291. The method of claim 3230 wherein the anti-fibrotic agent inhibits DNA synthesis.

3292. The method of claim 3230 wherein the anti-fibrotic agent causes DNA adduct formation.

3293. The method of claim 3230 wherein the anti-fibrotic agent inhibits protein synthesis.

3294. The method of claim 3230 wherein the anti-fibrotic agent inhibits microtubule function.

3295. The method of claim 3230 wherein the anti-fibrotic agent is a cyclin dependent protein kinase inhibitor.

3296. The method of claim 3230 wherein the anti-fibrotic agent is an epidermal growth factor kinase inhibitor.

3297. The method of claim 3230 wherein the anti-fibrotic agent is an elastase inhibitor.

3298. The method of claim 3230 wherein the anti-fibrotic agent is a factor Xa inhibitor.

3299. The method of claim 3230 wherein the anti-fibrotic agent is a farnesyltransferase inhibitor.

3300. The method of claim 3230 wherein the anti-fibrotic agent is a fibrinogen antagonist.

3301. The method of claim 3230 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

3302. The method of claim 3230 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist.

3303. The method of claim 3230 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof.

3304. The method of claim 3230 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

3305. The method of claim 3230 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor.

3306. The method of claim 3230 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof.

3307. The method of claim 3230 wherein the anti-fibrotic agent is a hydroorotate dehydrogenase inhibitor.

3308. The method of claim 3230 wherein the anti-fibrotic agent is an IKK2 inhibitor.

3309. The method of claim 3230 wherein the anti-fibrotic agent is an IL-1 antagonist.

3310. The method of claim 3230 wherein the anti-fibrotic agent is an ICE antagonist.

3311. The method of claim 3230 wherein the anti-fibrotic agent is an IRAK antagonist.

3312. The method of claim 3230 wherein the anti-fibrotic agent is an IL-4 agonist.

3313. The method of claim 3230 wherein the anti-fibrotic agent is an immunomodulatory agent.~

3314. The method of claim 3230 wherein the anti-fibrotic agent is sirolimus or an analogue or derivative thereof.

3315. The method of claim 3230 wherein the anti-fibrotic agent is not sirolimus.

3316. The method of claim 3230 wherein the anti-fibrotic agent is everolimus or an analogue or derivative thereof.

3317. The method of claim 3230 wherein the anti-fibrotic agent is tacrolimus or an analogue or derivative thereof.

3318. The method of claim 3230 wherein the anti-fibrotic agent is not tacrolimus.

3319. The method of claim 3230 wherein the anti-fibrotic agent is biolmus or an analogue or derivative thereof.

3320. The method of claim 3230 wherein the anti-fibrotic agent is tresperimus or an analogue or derivative thereof.

3321. The method of claim 3230 wherein the anti-fibrotic agent is auranofin or an analogue or derivative thereof.

3322. The method of claim 3230 wherein the anti-fibrotic agent is 27-0-demethylrapamycin or an analogue or derivative thereof.

3323. The method of claim 3230 wherein the anti-fibrotic agent is gusperimus or an analogue or derivative thereof.

3324. The method of claim 3230 wherein the anti-fibrotic agent is pimecrolimus or an analogue or derivative thereof.

3325. The method of claim 3230 wherein the anti-fibrotic agent is ABT-578 or an analogue or derivative thereof.

3326. The method of claim 3230 wherein the anti-fibrotic agent is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.

3327. The method of claim 3230 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof.

3328. The method of claim 3230 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-alpha-25 dihydroxy vitamin D3 or an analogue or derivative thereof.

3329. The method of claim 3230 wherein the anti-fibrotic agent is a leukotriene inhibitor.

3330. The method of claim 3230 wherein the anti-fibrotic agent is a MCP-1 antagonist.

3331. The method of claim 3230 wherein the anti-fibrotic agent is a MMP inhibitor.

3332. The method of claim 3230 wherein the anti-fibrotic agent is an NF kappa B inhibitor.

3333. The method of claim 3230 wherein the anti-fibrotic agent is an NF kappa B inhibitor, wherein the NF kappa B inhibitor is Bay 11-7082.

3334. The method of claim 3230 wherein the anti-fibrotic agent is an NO antagonist.

3335. The method of claim 3230 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor.

3336. The method of claim 3230 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB
202190.

3337. The method of claim 3230 wherein the anti-fibrotic agent is a phosphodiesterase inhibitor.

3338. The method of claim 3230 wherein the anti-fibrotic agent is a TGF beta inhibitor.

3339. The method of claim 3230 wherein the anti-fibrotic agent is a thromboxane A2 antagonist.

3340. The method of claim 3230 wherein the anti-fibrotic agent is a TNF alpha antagonist.

3341. The method of claim 3230 wherein the anti-fibrotic agent is a TACE inhibitor.

3342. The method of claim 3230 wherein the anti-fibrotic agent is a tyrosine kinase inhibitor.

3343. The method of claim 3230 wherein the anti-fibrotic agent is a vitronectin inhibitor.

3344. The method of claim 3230 wherein the anti-fibrotic agent is a fibroblast growth factor inhibitor.

3345. The method of claim 3230 wherein the anti-fibrotic agent is a protein kinase inhibitor.

3346. The method of claim 3230 wherein the anti-fibrotic agent is a PDGF receptor kinase inhibitor.

3347. The method of claim 3230 wherein the anti-fibrotic agent is an endothelial growth factor receptor kinase inhibitor.

3348. The method of claim 3230 wherein the anti-fibrotic agent is a retinoic acid receptor antagonist.

3349. The method of claim 3230 wherein the anti-fibrotic agent is a platelet derived growth factor receptor kinase inhibitor.

3350. The method of claim 3230 wherein the anti-fibrotic agent is a fibrinogen antagonist.

3351. The method of claim 3230 wherein the anti-fibrotic agent is an antimycotic agent.

3352. The method of claim 3230 wherein the anti-fibrotic agent is an antimycotic agent, wherein the antimycotic agent is sulconizole.

3353. The method of claim 3230 wherein the anti-fibrotic agent is a bisphosphonate.

3354. The method of claim 3230 wherein the anti-fibrotic agent is a phospholipase A1 inhibitor.

3355. The method of claim 3230 wherein the anti-fibrotic agent is a histamine H1/H2/H3 receptor antagonist.

3356. The method of claim 3230 wherein the anti-fibrotic agent is a macrolide antibiotic.

3357. The method of claim 3230 wherein the anti-fibrotic agent is a GPIIb/IIIa receptor antagonist.

3358. The method of claim 3230 wherein the anti-fibrotic agent is an endothelin receptor antagonist.

3359. The method of claim 3230 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor agonist.

3360. The method of claim 3230 wherein the anti-fibrotic agent is an estrogen receptor agent.

3361. The method of claim 3230 wherein the anti-fibrotic agent is a somastostatin analogue.

3362. The method of claim 3230 wherein the anti-fibrotic agent is a neurokinin 1 antagonist.

3363. The method of claim 3230 wherein the anti-fibrotic agent is a neurokinin 3 antagonist.

3364. The method of claim 3230 wherein the anti-fibrotic agent is a VLA-4 antagonist.

3365. The method of claim 3230 wherein the anti-fibrotic agent is an osteoclast inhibitor.

3366. The method of claim 3230 wherein the anti-fibrotic agent is a DNA topoisomerase ATP hydrolyzing inhibitor.

3367. The method of claim 3230 wherein the anti-fibrotic agent is an angiotensin I converting enzyme inhibitor.

3368. The method of claim 3230 wherein the anti-fibrotic agent is an angiotensin II antagonist.

3369. The method of claim 3230 wherein the anti-fibrotic agent is an enkephalinase inhibitor.

3370. The method of claim 3230 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer.

3371. The method of claim 3230 wherein the anti-fibrotic agent is a protein kinase C inhibitor.

3372. The method of claim 3230 wherein the anti-fibrotic agent is a ROCK (rho-associated kinase) inhibitor.

3373. The method of claim 3230 wherein the anti-fibrotic agent is a CXCR3 inhibitor.

3374. The method of claim 3230 wherein the anti-fibrotic agent is an Itk inhibitor.

3375. The method of claim 3230 wherein the anti-fibrotic agent is a cytosolic phospholipase A2-alpha inhibitor.

3376. The method of claim 3230 wherein the anti-fibrotic agent is a PPAR agonist.

3377. The method of claim 3230 wherein the anti-fibrotic agent is an immunosuppressant.

3378. The method of claim 3230 wherein the anti-fibrotic agent is an Erb inhibitor.

3379. The method of claim 3230 wherein the anti-fibrotic agent is an apoptosis agonist.

3380. The method of claim 3230 wherein the anti-fibrotic agent is a lipocortin agonist.

3381. The method of claim 3230 wherein the anti-fibrotic agent is a VCAM-1 antagonist.

3382. The method of claim 3230 wherein the anti-fibrotic agent is a collagen antagonist.

3383. The method of claim 3230 wherein the anti-fibrotic agent is an alpha 2 integrin antagonist.

3384. The method of claim 3230 wherein the anti-fibrotic agent is a TNF alpha inhibitor.

3385. The method of claim 3230 wherein the anti-fibrotic agent is a nitric oxide inhibitor.

3386. The method of claim 3230 wherein the anti-fibrotic agent is a cathepsin inhibitor.

3387. The method of claim 3230 wherein the anti-fibrotic agent is not an anti-inflammatory agent.

3388. The method of claim 3230 wherein the anti-fibrotic agent is not a steroid.

3389. The method of claim 3230 wherein the anti-fibrotic agent is not a glucocorticosteroid.

3390. The method of claim 3230 wherein the anti-fibrotic agent is not dexamethasone.

3391. The method of claim 3230 wherein the anti-fibrotic agent is not beclomethasone.

3392. The method of claim 3230 wherein the anti-fibrotic agent is not dipropionate.

3393. The method of claim 3230 wherein the anti-fibrotic agent is not an anti-infective agent.

3394. The method of claim 3230 wherein the anti-fibrotic agent is not an antibiotic.

3395. The method of claim 3230 wherein the anti-fibrotic agent is not an anti-fungal agent.

3396. The method of claim 3230 wherein the anti-infective agent isan anthracycline.

3397. The method of claim 3230 wherein the anti-infective agent isdoxorubicin.

3398. The method of claim 3230 wherein the anti-infective agent is ismitoxantrone.

3399. The method of claim 3230 wherein the anti-infective agent is a fluoropyrimidine.

3400. The method of claim 3230 wherein the anti-infective agent is 5-fluorouracil (5-FU).

3401. The method of claim 3230 wherein the anti-infective agent is a folic acid antagonist.

3402. The method of claim 3230 wherein the anti-infective agent is methotrexate.

3403. The method of claim 3230 wherein the anti-infective agent is a podophylotoxin.

3404. The method of claim 3230 wherein the anti-infective agent is etoposide.

3405. The method of claim 3230 wherein the anti-infective agent is camptothecin.

3406. The method of claim 3230 wherein the anti-infective agent is a hydroxyurea.

3407. The method of claim 3230 wherein the anti-infective agent is a platinum complex.

3403. The method of claim 3230 wherein the anti-infective agent is cisplatin.

3409. The method of claim 3230 wherein the composition comprises an anti-thrombotic agent.

3410. The method of claim 3230 wherein the polymer is formed from reactants comprising a naturally occurring polymer.

3411. The method of claim 3230 wherein the polymer is formed from reactants comprising protein.

3412. The method of claim 3230 wherein the polymer is formed from reactants comprising carbohydrate.

3413. The method of claim 3230 wherein the polymer is formed from reactants comprising biodegradable polymer.

3414. The method of claim 3230 wherein the polymer is formed from reactants comprising nonbiodegradable polymer.

3415. The method of claim 3230 wherein the polymer is formed from reactants comprising collagen.

3416. The method of claim 3230 wherein the polymer is formed from reactants comprising methylated collagen.

3417. The method of claim 3230 wherein the polymer is formed from reactants comprising fibrinogen.

3418. The method of claim 3230 wherein the polymer is formed from reactants comprising thrombin.

3419. The method of claim 3230 wherein the polymer is formed from reactants comprising blood plasma.

3420. The method of claim 3230 wherein the polymer is formed from reactants comprising calcium salt.

3421. The method of claim 3230 wherein the polymer is formed from reactants comprising an antifibronolytic agent.

3422. The method of claim 3230 wherein the polymer is formed from reactants comprising fibrinogen analog.

3423. The method of claim 3230 wherein the polymer is formed from reactants comprising albumin.

3424. The method of claim 3230 wherein the polymer is formed from reactants comprising plasminogen.

3425. The method of claim 3230 wherein the polymer is formed from reactants comprising von Willebrands factor.

3426. The method of claim 3230 wherein the polymer is formed from reactants comprising Factor VIII.

3427. The method of claim 3230 wherein the polymer is formed from reactants comprising hypoallergenic collagen.

3428. The method of claim 3230 wherein the polymer is formed from reactants comprising atelopeptidic collagen.

3429. The method of claim 3230 wherein the polymer is formed from reactants comprising telopeptide collagen.

3430. The method of claim 3230 wherein the polymer is formed from reactants comprising crosslinked collagen.

3431. The method of claim 3230 wherein the polymer is formed from reactants comprising aprotinin.

3432. The method of claim 3230 wherein the polymer is formed from reactants comprising epsilon-amino-n-caproic acid.

3433. The method of claim 3230 wherein the polymer is formed from reactants comprising gelatin.

1355~

3434. The method of claim 3230 wherein the polymer is formed from reactants comprising protein conjugates.

3435. The method of claim 3230 wherein the polymer is formed from reactants comprising gelatin conjugates.

3436. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic polymer.

3437. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic isocyanate-containing compound.

3438. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic thiol-containing compound.

3439. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two thiol groups.

3440. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three thiol groups.

3441. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four thiol groups.

3442. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic amino-containing compound.

3443. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two amino groups.

3444. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three amino groups.

3445. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four amino groups.

3446. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group.

3447. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups.

3448. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.

3449. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.

3450. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound.

3451. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.

3452. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive amino groups.

3453. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive thiol groups.

3454. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups.

3455. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic compound comprising a biodegradable polyester block.

3456. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from lactic acid or lactide.

3457. The method of claim 3230 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from glycolic acid or glycolide.

3458. The method of claim 3230 wherein the polymer is formed from reactants comprising polylysine.~

3459. The method of claim 3230 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound comprising a polyalkylene oxide portion.

3460. The method of claim 3230 wherein the polymer is formed from reactants comprising (a) protein and (b) polylysine.

3461. The method of claim 3230 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four thiol groups.

3462. The method of claim 3230 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four amino groups.

3463. The method of claim 3230 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

3464. The method of claim 3230 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

3465. The method of claim 3230 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound comprising a polyalkylene oxide portion.

3466. The method of claim 3230 wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine.

3467. The method of claim 3230 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four thiol groups.

3468. The method of claim 3230 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four amino groups.

3469. The method of claim 3230 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

3470. The method of claim 3230 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

3471. The method of claim 3230 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound comprising a polyalkylene oxide portion.

3472. The method of claim 3230 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine.

3473. The method of claim 3230 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four thiol groups.

3474. The method of claim 3230 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four amino groups.

3475. The method of claim 3230 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

3476. The method of claim 3230 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

3477. The method of claim 3230 wherein the polymer is formed from reactants comprising hyaluronic acid.

3478. The method of claim 3230 wherein the polymer is formed from reactants comprising a hyaluronic acid derivative.

3479. The method of claim 3230 wherein the polymer is formed from reactants comprising pentaerythritol polyethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.

3480. The method of claim 3230 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.

3481. The method of claim 3230 wherein the polymer is formed from reactants comprising (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.

3482. The method of claim 3230 wherein the composition comprises a colorant.

3483. The method of claim 3230 wherein the composition is sterile.

3484. A method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with i) an anti-fibrotic agent, ii) an anti-infective agent, iii) a polymer;
iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host, wherein the medical device is a prosthetic heart valve or a component thereof.

3485. The method for implanting a medical device according to claim 3484 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-fibrotic agent, and (b) implanting the medical device into the host.

3486. The method for implanting a medical device according to claim 3484 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-infective agent, and (b) implanting the medical device into the host.

3487. The method for implanting a medical device according to claim 3484 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a polymer; and (b) implanting the medical device into the host.

3488. The method for implanting a medical device according to claim 3484 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent and a polymer, and (b) implanting the medical device into the host.

3489. The method for implanting a medical device according to claim 3484 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

3490. The method for implanting a medical device according to claim 3484 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

3491. The method of claim 3484 wherein the medical device is a mechanical prosthetic heart valve.

3492. The method of claim 3484 wherein the medical device is a bioprosthetic heart valve.

3493. The method of claim 3484 wherein the medical device is an implantable annular ring for receiving a prosthetic heart valve.

3494. The method of claim 3484 wherein the medical device is a suture ring having an outer peripheral tapered thread for attaching a heart valve prosthesis.

3495. The method of claim 3484 wherein the medical device is a suture ring for a mechanical heart valve.

3496. The method of claim 3484 wherein the anti-fibrotic agent inhibits cell regeneration.

3497. The method of claim 3484 wherein the anti-fibrotic agent inhibits angiogenesis.

3498. The method of claim 3484 wherein the anti-fibrotic agent inhibits fibroblast migration.

3499. The method of claim 3484 wherein the anti-fibrotic agent inhibits fibroblast proliferation.

3500. The method of claim 3484 wherein the anti-fibrotic agent inhibits deposition of extracellular matrix.

3501. The method of claim 3484 wherein the anti-fibrotic agent inhibits tissue remodeling.

3502. The method of claim 3484 wherein the anti-fibrotic agent is an angiogenesis inhibitor.

3503. The method of claim 3484 wherein the anti-fibrotic agent is a 5-lipoxygenase inhibitor or antagonist.

3504. The method of claim 3484 wherein the anti-fibrotic agent is a chemokine receptor antagonist.~

3505. The method of claim 3484 wherein the anti-fibrotic agent is a cell cycle inhibitor.

3506. The method of claim 3484 wherein the anti-fibrotic agent is a taxane.

3507. The method of claim 3484 wherein the anti-fibrotic agent is an anti-microtubule agent.

3508. The method of claim 3484 wherein the anti-fibrotic agent is paclitaxel.

3509. The method of claim 3484 wherein the anti-fibrotic agent is not paclitaxel.

3510. The method of claim 3484 wherein the anti-fibrotic agent is an analogue or derivative of paclitaxel.

3511. The method of claim 3484 wherein the anti-fibrotic agent is a vinca alkaloid.

3512. The method of claim 3484 wherein the anti-fibrotic agent is camptothecin or an analogue or derivative thereof.

3513. The method of claim 3484 wherein the anti-fibrotic agent is a podophyllotoxin.

3514. The method of claim 3484 wherein the anti-fibrotic agent is a podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof.

3515. The method of claim 3484 wherein the anti-fibrotic agent is an anthracycline.

3516. The method of claim 3484 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof.

3517. The method of claim 3484 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof.

3518. The method of claim 3484 wherein the anti-fibrotic agent is a platinum compound.

3519. The method of claim 3484 wherein the anti-fibrotic agent is a nitrosourea.

3520. The method of claim 3484 wherein the anti-fibrotic agent is a nitroimidazole.

3521. The method of claim 3484 wherein the anti-fibrotic agent is a folic acid antagonist.

3522. The method of claim 3484 wherein the anti-fibrotic agent is a cytidine analogue.

3523. The method of claim 3484 wherein the anti-fibrotic agent is a pyrimidine analogue.

3524. The method of claim 3484 wherein the anti-fibrotic agent is a fluoropyrimidine analogue.

3525. The method of claim 3484 wherein the anti-fibrotic agent is a purine analogue.

3526. The method of claim 3484 wherein the anti-fibrotic agent is a nitrogen mustard or an analogue or derivative thereof.

3527. The method of claim 3484 wherein the anti-fibrotic agent is a hydroxyurea.

3528. The method of claim 3484 wherein the anti-fibrotic agent is a mytomicin or an analogue or derivative thereof.

3529. The method of claim 3484 wherein the anti-fibrotic agent is an alkyl sulfonate.

3530. The method of claim 3484 wherein the anti-fibrotic agent is a benzamide or an analogue or derivative thereof.

3531. The method of claim 3484 wherein the anti-fibrotic agent is a nicotinamide or an analogue or derivative thereof.

3532. The method of claim 3484 wherein the anti-fibrotic agent is a halogenated sugar or an analogue or derivative thereof.

3533. The method of claim 3484 wherein the anti-fibrotic agent is a DNA alkylating agent.

3534. The method of claim 3484 wherein the anti-fibrotic agent is an anti-microtubule agent.

3535. The method of claim 3484 wherein the anti-fibrotic agent is a topoisomerase inhibitor.

3536. The method of claim 3484 wherein the anti-fibrotic agent is a DNA cleaving agent.

3537. The method of claim 3484 wherein the anti-fibrotic agent is an antimetabolite.

3538. The method of claim 3484 wherein the anti-fibrotic agent inhibits adenosine deaminase.

3539. The method of claim 3484 wherein the anti-fibrotic agent inhibits purine ring synthesis.

3540. The method of claim 3484 wherein the anti-fibrotic agent is a nucleotide interconversion inhibitor.

3541. The method of claim 3484 wherein the anti-fibrotic agent inhibits dihydrofolate reduction.

3542. The method of claim 3484 wherein the anti-fibrotic agent blocks thymidine monophosphate.

3543. The method of claim 3484 wherein the anti-fibrotic agent causes DNA damage.

3544. The method of claim 3484 wherein the anti-fibrotic agent is a DNA intercalation agent.

3545. The method of claim 3484 wherein the anti-fibrotic agent is a RNA synthesis inhibitor.

3546. The method of claim 3484 wherein the anti-fibrotic agent is a pyrimidine synthesis inhibitor.

3547. The method of claim 3484 wherein the anti-fibrotic agent inhibits ribonucleotide synthesis or function.

3548. The method of claim 3484 wherein the anti-fibrotic agent inhibits thymidine monophosphate synthesis or function.

3549. The method of claim 3484 wherein the anti-fibrotic agent inhibits DNA synthesis.

3550. The method of claim 3484 wherein the anti-fibrotic agent causes DNA adduct formation.

3551. The method of claim 3484 wherein the anti-fibrotic agent inhibits protein synthesis.

3552. The method of claim 3484 wherein the anti-fibrotic agent inhibits microtubule function.

3553. The method of claim 3484 wherein the anti-fibrotic agent is a cyclin dependent protein kinase inhibitor.

3554. The method of claim 3484 wherein the anti-fibrotic agent is an epidermal growth factor kinase inhibitor.

3555. The method of claim 3484 wherein the anti-fibrotic agent is an elastase inhibitor.

3556. The method of claim 3484 wherein the anti-fibrotic agent is a factor Xa inhibitor.

3557. The method of claim 3484 wherein the anti-fibrotic agent is a farnesyltransferase inhibitor.

3558. The method of claim 3484 wherein the anti-fibrotic agent is a fibrinogen antagonist.

3559. The method of claim 3484 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

3560. The method of claim 3484 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist.

3561. The method of claim 3484 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof.

3562. The method of claim 3484 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

3563. The method of claim 3484 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor.

3564. The method of claim 3484 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof.

3565. The method of claim 3484 wherein the anti-fibrotic agent is a hydroorotate dehydrogenase inhibitor.

3566. The method of claim 3484 wherein the anti-fibrotic agent is an IKK2 inhibitor.

3567. The method of claim 3484 wherein the anti-fibrotic agent is an IL-1 antagonist.

3568. The method of claim 3484 wherein the anti-fibrotic agent is an ICE antagonist.

3569. The method of claim 3484 wherein the anti-fibrotic agent is an IRAK antagonist.

3570. The method of claim 3484 wherein the anti-fibrotic agent is an IL-4 agonist.

3571. The method of claim 3484 wherein the anti-fibrotic agent is an immunomodulatory agent.

3572. The method of claim 3484 wherein the anti-fibrotic agent is sirolimus or an analogue or derivative thereof.

3573. The method of claim 3484 wherein the anti-fibrotic agent is not sirolimus.

3574. The method of claim 3484 wherein the anti-fibrotic agent is everolimus or an analogue or derivative thereof.

3575. The method of claim 3484 wherein the anti-fibrotic agent is tacrolimus or an analogue or derivative thereof.

3576. The method of claim 3484 wherein the anti-fibrotic agent is not tacrolimus.

3577. The method of claim 3484 wherein the anti-fibrotic agent is biolmus or an analogue or derivative thereof.

3578. The method of claim 3484 wherein the anti-fibrotic agent is tresperimus or an analogue or derivative thereof.

3579. The method of claim 3484 wherein the anti-fibrotic agent is auranofin or an analogue or derivative thereof.

3580. The method of claim 3484 wherein the anti-fibrotic agent is 27-0-demethylrapamycin or an analogue or derivative thereof.

3581. The method of claim 3484 wherein the anti-fibrotic agent is gusperimus or an analogue or derivative thereof.

3582. The method of claim 3484 wherein the anti-fibrotic agent is pimecrolimus or an analogue or derivative thereof.

3583. The method of claim 3484 wherein the anti-fibrotic agent is ABT-578 or an analogue or derivative thereof.

3584. The method of claim 3484 wherein the anti-fibrotic agent is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.

3585. The method of claim 3484 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof.

3586. The method of claim 3484 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-alpha-25 dihydroxy vitamin D3 or an analogue or derivative thereof.

3587. The method of claim 3484 wherein the anti-fibrotic agent is a leukotriene inhibitor.

3588. The method of claim 3484 wherein the anti-fibrotic agent is a MCP-1 antagonist.

3589. The method of claim 3484 wherein the anti-fibrotic agent is a MMP inhibitor.

3590. The method of claim 3484 wherein the anti-fibrotic agent is an NF kappa B inhibitor.

3591. The method of claim 3484 wherein the anti-fibrotic agent is an NF kappa B inhibitor, wherein the NF kappa B inhibitor is Bay 11-7082.

3592. The method of claim 3484 wherein the anti-fibrotic agent is an NO antagonist.

3593. The method of claim 3484 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor.

3594. The method of claim 3484 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB
202190.

3595. The method of claim 3484 wherein the anti-fibrotic agent is a phosphodiesterase inhibitor.

3596. The method of claim 3484 wherein the anti-fibrotic agent is a TGF beta inhibitor.

3597. The method of claim 3484 wherein the anti-fibrotic agent is a thromboxane A2 antagonist.

3598. The method of claim 3484 wherein the anti-fibrotic agent is a TNF alpha antagonist.

3599. The method of claim 3484 wherein the anti-fibrotic agent is a TACE inhibitor.

3600. The method of claim 3484 wherein the anti-fibrotic agent is a tyrosine kinase inhibitor.

3601. The method of claim 3484 wherein the anti-fibrotic agent is a vitronectin inhibitor.

3602. The method of claim 3484 wherein the anti-fibrotic agent is a fibroblast growth factor inhibitor,

3603. The method of claim 3484 wherein the anti-fibrotic agent is a protein kinase inhibitor.

3604. The method of claim 3484 wherein the anti-fibrotic agent is a PDGF receptor kinase inhibitor.

3605. The method of claim 3484 wherein the anti-fibrotic agent is an endothelial growth factor receptor kinase inhibitor.

3606. The method of claim 3484 wherein the anti-fibrotic agent is a retinoic acid receptor antagonist.

3607. The method of claim 3484 wherein the anti-fibrotic agent is a platelet derived growth factor receptor kinase inhibitor.

3608. The method of claim 3484 wherein the anti-fibrotic agent is a fibrinogen antagonist.

3609. The method of claim 3484 wherein the anti-fibrotic agent is an antimycotic agent.

3610. The method of claim 3484 wherein the anti-fibrotic agent is an antimycotic agent, wherein the antimycotic agent is sulconizole.

3611. The method of claim 3484 wherein the anti-fibrotic agent is a bisphosphonate.

3612. The method of claim 3484 wherein the anti-fibrotic agent is a phospholipase A1 inhibitor.

3613. The method of claim 3484 wherein the anti-fibrotic agent is a histamine H1/H2/H3 receptor antagonist.

3614. The method of claim 3484 wherein the anti-fibrotic agent is a macrolide antibiotic.

3615. The method of claim 3484 wherein the anti-fibrotic agent is a GPIIb/IIIa receptor antagonist.

3616. The method of claim 3484 wherein the anti-fibrotic agent is an endothelin receptor antagonist.

3617. The method of claim 3484 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor agonist.

3618. The method of claim 3484 wherein the anti-fibrotic agent is an estrogen receptor agent.

3619. The method of claim 3484 wherein the anti-fibrotic agent is a somastostatin analogue.

3620. The method of claim 3484 wherein the anti-fibrotic agent is a neurokinin 1 antagonist.

3621. The method of claim 3484 wherein the anti-fibrotic agent is a neurokinin 3 antagonist.

3622. The method of claim 3484 wherein the anti-fibrotic agent is a VLA-4 antagonist.

3623. The method of claim 3484 wherein the anti-fibrotic agent is an osteoclast inhibitor.

3624. The method of claim 3484 wherein the anti-fibrotic agent is a DNA topoisomerase ATP hydrolyzing inhibitor.

3625. The method of claim 3484 wherein the anti-fibrotic agent is an angiotensin I converting enzyme inhibitor.

3626. The method of claim 3484 wherein the anti-fibrotic agent is an angiotensin II antagonist.

3627. The method of claim 3484 wherein the anti-fibrotic agent is an enkephalinase inhibitor.

3628. The method of claim 3484 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer.

3629. The method of claim 3484 wherein the anti-fibrotic agent is a protein kinase C inhibitor.

3630. The method of claim 3484 wherein the anti-fibrotic agent is a ROCK (rho-associated kinase) inhibitor.

3631. The method of claim 3484 wherein the anti-fibrotic agent is a CXCR3 inhibitor.

3632. The method of claim 3484 wherein the anti-fibrotic agent is an Itk inhibitor.

3633. The method of claim 3484 wherein the anti-fibrotic agent is a cytosolic phospholipase A2-alpha inhibitor.

3634. The method of claim 3484 wherein the anti-fibrotic agent is a PPAR agonist.

3635. The method of claim 3484 wherein the anti-fibrotic agent is an immunosuppressant.

3636. The method of claim 3484 wherein the anti-fibrotic agent is an Erb inhibitor.

3637. The method of claim 3484 wherein the anti-fibrotic agent is an apoptosis agonist.

3638. The method of claim 3484 wherein the anti-fibrotic agent is a lipocortin agonist.

3639. The method of claim 3484 wherein the anti-fibrotic agent is a VCAM-1 antagonist.

3640. The method of claim 3484 wherein the anti-fibrotic agent is a collagen antagonist.

3641. The method of claim 3484 wherein the anti-fibrotic agent is an alpha 2 integrin antagonist.

3642. The method of claim 3484 wherein the anti-fibrotic agent is a TNF alpha inhibitor.

3643. The method of claim 3484 wherein the anti-fibrotic agent is a nitric oxide inhibitor

3644. The method of claim 3484 wherein the anti-fibrotic agent is a cathepsin inhibitor.

3645. The method of claim 3484 wherein the anti-fibrotic agent is not an anti-inflammatory agent.

3646. The method of claim 3484 wherein the anti-fibrotic agent is not a steroid.

3647. The method of claim 3484 wherein the anti-fibrotic agent is not a glucocorticosteroid.

3648. The method of claim 3484 wherein the anti-fibrotic agent is not dexamethasone.

3649. The method of claim 3484 wherein the anti-fibrotic agent is not beclomethasone.

3650. The method of claim 3484 wherein the anti-fibrotic agent is not dipropionate.

3651. The method of claim 3484 wherein the anti-fibrotic agent is not an anti-infective agent.

3652. The method of claim 3484 wherein the anti-fibrotic agent is not an antibiotic.

3653. The method of claim 3484 wherein the anti-fibrotic agent is not an anti-fungal agent.

3654. The method of claim 3484 wherein the anti-infective agent isan anthracycline.

3655. The method of claim 3484 wherein the anti-infective agent isdoxorubicin.

3656. The method of claim 3484 wherein the anti-infective agent is ismitoxantrone.

3657. The method of claim 3484 wherein the anti-infective agent is a fluoropyrimidine.

3658. The method of claim 3484 wherein the anti-infective agent is 5-fluorouracil (5-FU).

3659. The method of claim 3484 wherein the anti-infective agent is a folic acid antagonist.

3660. The method of claim 3484 wherein the anti-infective agent is methotrexate.

3661. The method of claim 3484 wherein the anti-infective agent is a podophylotoxin.

3662. The method of claim 3484 wherein the anti-infective agent is etoposide.

3663. The method of claim 3484 wherein the anti-infective agent is camptothecin.

3664. The method of claim 3484 wherein the anti-infective agent is a hydroxyurea.

3665. The method of claim 3484 wherein the anti-infective agent is a platinum complex.

3666. The method of claim 3484 wherein the anti-infective agent is cisplatin.

3667. The method of claim 3484 wherein the composition comprises an anti-thrombotic agent.

3668. The method of claim 3484 wherein the polymer is formed from reactants comprising a naturally occurring polymer.

3669. The method of claim 3484 wherein the polymer is formed from reactants comprising protein.

3670. The method of claim 3484 wherein the polymer is formed from reactants comprising carbohydrate.

3671. The method of claim 3484 wherein the polymer is formed from reactants comprising biodegradable polymer.

3672. The method of claim 3484 wherein the polymer is formed from reactants comprising nonbiodegradable polymer.

3673. The method of claim 3484 wherein the polymer is formed from reactants comprising collagen.

3674. The method of claim 3484 wherein the polymer is formed from reactants comprising methylated collagen.

3675. The method of claim 3484 wherein the polymer is formed from reactants comprising fibrinogen.

3676. The method of claim 3484 wherein the polymer is formed from reactants comprising thrombin.

3677. The method of claim 3484 wherein the polymer is formed from reactants comprising blood plasma.

3678. The method of claim 3484 wherein the polymer is formed from reactants comprising calcium salt.

3679. The method of claim 3484 wherein the polymer is formed from reactants comprising an antifibronolytic agent.

3680. The method of claim 3484 wherein the polymer is formed from reactants comprising fibrinogen analog.

3681. The method of claim 3484 wherein the polymer is formed from reactants comprising albumin.

3682. The method of claim 3484 wherein the polymer is formed from reactants comprising plasminogen.

3683. The method of claim 3484 wherein the polymer is formed from reactants comprising von Willebrands factor.

3684. The method of claim 3484 wherein the polymer is formed from reactants comprising Factor VIII.

3685. The method of claim 3484 wherein the polymer is formed from reactants comprising hypoallergenic collagen.

3686. The method of claim 3484 wherein the polymer is formed from reactants comprising atelopeptidic collagen.

3687. The method of claim 3484 wherein the polymer is formed from reactants comprising telopeptide collagen.

3688. The method of claim 3484 wherein the polymer is formed from reactants comprising crosslinked collagen.

3689. The method of claim 3484 wherein the polymer is formed from reactants comprising aprotinin.

3690. The method of claim 3484 wherein the polymer is formed from reactants comprising epsilon-amino-n-caproic acid.

3691. The method of claim 3484 wherein the polymer is formed from reactants comprising gelatin.

3692. The method of claim 3484 wherein the polymer is formed from reactants comprising protein conjugates.

3693. The method of claim 3484 wherein the polymer is formed from reactants comprising gelatin conjugates.

3694. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic polymer.

3695. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic isocyanate-containing compound.

3696. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic thiol-containing compound.

3697. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two thiol groups.

3698. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three thiol groups.

3699. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four thiol groups.

3700. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic amino-containing compound.

3701. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two amino groups.

3702. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three amino groups.

3703. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four amino groups.

3704. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group.

3705. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups.

3706. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.

3707. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.

3708. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound.

3709. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.

3710. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive amino groups.

3711. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive thiol groups.

3712. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups.

3713. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic compound comprising a biodegradable polyester block.

3714. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from lactic acid or lactide.

3715. The method of claim 3484 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from glycolic acid or glycolide.

3716. The method of claim 3484 wherein the polymer is formed from reactants comprising polylysine.

3717. The method of claim 3484 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound comprising a polyalkylene oxide portion.

3718. The method of claim 3484 wherein the polymer is formed from reactants comprising (a) protein and (b) polylysine.

3719. The method of claim 3484 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four thiol groups.

3720. The method of claim 3484 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four amino groups.

3721. The method of claim 3484 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

3722. The method of claim 3484 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

3723. The method of claim 3484 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound comprising a polyalkylene oxide portion.

3724. The method of claim 3484 wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine.

3725. The method of claim 3484 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four thiol groups.

3726. The method of claim 3484 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four amino groups.

3727. The method of claim 3484 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

3728. The method of claim 3484 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

3729. The method of claim 3484 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound comprising a polyalkylene oxide portion.

3730. The method of claim 3484 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine.

3731. The method of claim 3484 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four thiol groups.

3732. The method of claim 3484 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four amino groups.

3733. The method of claim 3484 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

3734. The method of claim 3484 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

3735. The method of claim 3484 wherein the polymer is formed from reactants comprising hyaluronic acid.

3736. The method of claim 3484 wherein the polymer is formed from reactants comprising a hyaluronic acid derivative.

3737. The method of claim 3484 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.

3738. The method of claim 3484 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.

3739. The method of claim 3484 wherein the polymer is formed from reactants comprising (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.

3740. The method of claim 3484 wherein the composition comprises a colorant.

3741. The method of claim 3484 wherein the composition is sterile.

3742. A method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with i) an anti-fibrotic agent, ii) an anti-infective agent, iii) a polymer;
iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host, wherein the medical device is a penile implant.

3743. The method for implanting a medical device according to claim 3742 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-fibrotic agent, and (b) implanting the medical device into the host.

3744. The method for implanting a medical device according to claim 3742 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-infective agent, and (b) implanting the medical device into the host.

3745. The method for implanting a medical device according to claim 3742 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a polymer; and (b) implanting the medical device into the host.

3746. The method for implanting a medical device according to claim 3742 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent and a polymer, and (b) implanting the medical device into the host.

3747. The method for implanting a medical device according to claim 3742 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

3748. The method for implanting a medical device according to claim 3742 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

3749. The method of claim 3742 wherein the medical device is a penile implant that is a flexible rod.

3750. The method of claim 3742 wherein the medical device is a penile implant that is a hinged rod.

3751. The method of claim 3742 wherein the medical device is a penile implant that is an inflatable device with a pump.

3752. The method of claim 3742 wherein the anti-fibrotic agent inhibits cell regeneration.

3753. The method of claim 3742 wherein the anti-fibrotic agent inhibits angiogenesis.

3754. The method of claim 3742 wherein the anti-fibrotic agent inhibits fibroblast migration.

3755. The method of claim 3742 wherein the anti-fibrotic agent inhibits fibroblast proliferation.

3756. The method of claim 3742 wherein the anti-fibrotic agent inhibits deposition of extracellular matrix.

3757. The method of claim 3742 wherein the anti-fibrotic agent inhibits tissue remodeling.

3758. The method of claim 3742 wherein the anti-fibrotic agent is an angiogenesis inhibitor.

3759. The method of claim 3742 wherein the anti-fibrotic agent is a 5-lipoxygenase inhibitor or antagonist.

3760. The method of claim 3742 wherein the anti-fibrotic agent is a chemokine receptor antagonist.

3761. The method of claim 3742 wherein the anti-fibrotic agent is a cell cycle inhibitor.

3762. The method of claim 3742 wherein the anti-fibrotic agent is a taxane.

3763. The method of claim 3742 wherein the anti-fibrotic agent is an anti-microtubule agent.

3764. The method of claim 3742 wherein the anti-fibrotic agent is paclitaxel.

3765. The method of claim 3742 wherein the anti-fibrotic agent is not paclitaxel.

3766. The method of claim 3742 wherein the anti-fibrotic agent is an analogue or derivative of paclitaxel.

3767. The method of claim 3742 wherein the anti-fibrotic agent is a vinca alkaloid.

3768. The method of claim 3742 wherein the anti-fibrotic agent is camptothecin or an analogue or derivative thereof.

3769. The method of claim 3742 wherein the anti-fibrotic agent is a podophyllotoxin.

3770. The method of claim 3742 wherein the anti-fibrotic agent is a podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof.

3771. The method of claim 3742 wherein the anti-fibrotic agent is an anthracycline.

3772. The method of claim 3742 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof.

3773. The method of claim 3742 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof.

3774. The method of claim 3742 wherein the anti-fibrotic agent is a platinum compound.

3775. The method of claim 3742 wherein the anti-fibrotic agent is a nitrosourea.

3776. The method of claim 3742 wherein the anti-fibrotic agent is a nitroimidazole.

3777. The method of claim 3742 wherein the anti-fibrotic agent is a folic acid antagonist.

3778. The method of claim 3742 wherein the anti-fibrotic agent is a cytidine analogue.

3779. The method of claim 3742 wherein the anti-fibrotic agent is a pyrimidine analogue.

3780. The method of claim 3742 wherein the anti-fibrotic agent is a fluoropyrimidine analogue.

3781. The method of claim 3742 wherein the anti-fibrotic agent is a purine analogue.

3782. The method of claim 3742 wherein the anti-fibrotic agent is a nitrogen mustard or an analogue or derivative thereof.

3783. The method of claim 3742 wherein the anti-fibrotic agent is a hydroxyurea.

3784. The method of claim 3742 wherein the anti-fibrotic agent is a mytomicin or an analogue or derivative thereof.

3785. The method of claim 3742 wherein the anti-fibrotic agent is an alkyl sulfonate.

3786. The method of claim 3742 wherein the anti-fibrotic agent is a benzamide or an analogue or derivative thereof.

3787. The method of claim 3742 wherein the anti-fibrotic agent is a nicotinamide or an analogue or derivative thereof.

3788. The method of claim 3742 wherein the anti-fibrotic agent is a halogenated sugar or an analogue or derivative thereof.

3789. The method of claim 3742 wherein the anti-fibrotic agent is a DNA alkylating agent.

3790. The method of claim 3742 wherein the anti-fibrotic agent is an anti-microtubule agent.

3791. The method of claim 3742 wherein the anti-fibrotic agent is a topoisomerase inhibitor.

3792. The method of claim 3742 wherein the anti-fibrotic agent is a DNA cleaving agent.

3793. The method of claim 3742 wherein the anti-fibrotic agent is an antimetabolite.

3794. The method of claim 3742 wherein the anti-fibrotic agent inhibits adenosine deaminase.

3795. The method of claim 3742 wherein the anti-fibrotic agent inhibits purine ring synthesis.

3796. The method of claim 3742 wherein the anti-fibrotic agent is a nucleotide interconversion inhibitor.

3797. The method of claim 3742 wherein the anti-fibrotic agent inhibits dihydrofolate reduction.

3798. The method of claim 3742 wherein the anti-fibrotic agent blocks thymidine monophosphate.

3799. The method of claim 3742 wherein the anti-fibrotic agent causes DNA damage.

3800. The method of claim 3742 wherein the anti-fibrotic agent is a DNA intercalation agent.

3801. The method of claim 3742 wherein the anti-fibrotic agent is a RNA synthesis inhibitor.

3802. The method of claim 3742 wherein the anti-fibrotic agent is a pyrimidine synthesis inhibitor.

3803. The method of claim 3742 wherein the anti-fibrotic agent inhibits ribonucleotide synthesis or function.

3804. The method of claim 3742 wherein the anti-fibrotic agent inhibits thymidine monophosphate synthesis or function.

3805. The method of claim 3742 wherein the anti-fibrotic agent inhibits DNA synthesis.

3806. The method of claim 3742 wherein the anti-fibrotic agent causes DNA adduct formation.

3807. The method of claim 3742 wherein the anti-fibrotic agent inhibits protein synthesis.

3808. The method of claim 3742 wherein the anti-fibrotic agent inhibits microtubule function.

3809. The method of claim 3742 wherein the anti-fibrotic agent is a cyclin dependent protein kinase inhibitor.

3810. The method of claim 3742 wherein the anti-fibrotic agent is an epidermal growth factor kinase inhibitor.

3811. The method of claim 3742 wherein the anti-fibrotic agent is an elastase inhibitor.

3812. The method of claim 3742 wherein the anti-fibrotic agent is a factor Xa inhibitor.

3813. The method of claim 3742 wherein the anti-fibrotic agent is a farnesyltransferase inhibitor.

3814. The method of claim 3742 wherein the anti-fibrotic agent is a fibrinogen antagonist.

3815. The method of claim 3742 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

3816. The method of claim 3742 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist.

3817. The method of claim 3742 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof.

3818. The method of claim 3742 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

3819. The method of claim 3742 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor.

3820. The method of claim 3742 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof.

3821. The method of claim 3742 wherein the anti-fibrotic agent is a hydroorotate dehydrogenase inhibitor.

3822. The method of claim 3742 wherein the anti-fibrotic agent is an IKK2 inhibitor.

3823. The method of claim 3742 wherein the anti-fibrotic agent is an IL-1 antagonist.

3824. The method of claim 3742 wherein the anti-fibrotic agent is an ICE antagonist.

3825. The method of claim 3742 wherein the anti-fibrotic agent is an IRAK antagonist.

3826. The method of claim 3742 wherein the anti-fibrotic agent is an IL-4 agonist.

3827. The method of claim 3742 wherein the anti-fibrotic agent is an immunomodulatory agent.

3828. The method of claim 3742 wherein the anti-fibrotic agent is sirolimus or an analogue or derivative thereof.

3829. The method of claim 3742 wherein the anti-fibrotic agent is not sirolimus.

3830. The method of claim 3742 wherein the anti-fibrotic agent is everolimus or an analogue or derivative thereof.

3831. The method of claim 3742 wherein the anti-fibrotic agent is tacrolimus or an analogue or derivative thereof.

3832. The method of claim 3742 wherein the anti-fibrotic agent is not tacrolimus.

3833. The method of claim 3742 wherein the anti-fibrotic agent is biolmus or an analogue or derivative thereof.

3834. The method of claim 3742 wherein the anti-fibrotic agent is tresperimus or an analogue or derivative thereof.

3835. The method of claim 3742 wherein the anti-fibrotic agent is auranofin or an analogue or derivative thereof.

3836. The method of claim 3742 wherein the anti-fibrotic agent is 27-0-demethylrapamycin or an analogue or derivative thereof.

3837. The method of claim 3742 wherein the anti-fibrotic agent is gusperimus or an analogue or derivative thereof.

3838. The method of claim 3742 wherein the anti-fibrotic agent is pimecrolimus or an analogue or derivative thereof.

3839. The method of claim 3742 wherein the anti-fibrotic agent is ABT-578 or an analogue or derivative thereof.

3840. The method of claim 3742 wherein the anti-fibrotic agent is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.

3841. The method of claim 3742 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof.

3842. The method of claim 3742 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-alpha-25 dihydroxy vitamin D3 or an analogue or derivative thereof.

3843. The method of claim 3742 wherein the anti-fibrotic agent is a leukotriene inhibitor.

3844. The method of claim 3742 wherein the anti-fibrotic agent is a MCP-1 antagonist.

3845. The method of claim 3742 wherein the anti-fibrotic agent is a MMP inhibitor.

3846. The method of claim 3742 wherein the anti-fibrotic agent is an NF kappa B inhibitor.

3847. The method of claim 3742 wherein the anti-fibrotic agent is an NF kappa B inhibitor, wherein the NF kappa B inhibitor is Bay 11-7082.

3848. The method of claim 3742 wherein the anti-fibrotic agent is an NO antagonist.

3849. The method of claim 3742 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor.

3850. The method of claim 3742 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB
202190.

3851. The method of claim 3742 wherein the anti-fibrotic agent is a phosphodiesterase inhibitor.

3852. The method of claim 3742 wherein the anti-fibrotic agent is a TGF beta inhibitor.

3853. The method of claim 3742 wherein the anti-fibrotic agent is a thromboxane A2 antagonist.

3854. The method of claim 3742 wherein the anti-fibrotic agent is a TNF alpha antagonist.

3855. The method of claim 3742 wherein the anti-fibrotic agent is a TACE inhibitor.

3856. The method of claim 3742 wherein the anti-fibrotic agent is a tyrosine kinase inhibitor.

3857. The method of claim 3742 wherein the anti-fibrotic agent is a vitronectin inhibitor.

3858. The method of claim 3742 wherein the anti-fibrotic agent is a fibroblast growth factor inhibitor.

3859. The method of claim 3742 wherein the anti-fibrotic agent is a protein kinase inhibitor.

3860. The method of claim 3742 wherein the anti-fibrotic agent is a PDGF receptor kinase inhibitor.

3861. The method of claim 3742 wherein the anti-fibrotic agent is an endothelial growth factor receptor kinase inhibitor.

3862. The method of claim 3742 wherein the anti-fibrotic agent is a retinoic acid receptor antagonist.

3863. The method of claim 3742 wherein the anti-fibrotic agent is a platelet derived growth factor receptor kinase inhibitor.

3864. The method of claim 3742 wherein the anti-fibrotic agent is a fibrinogen antagonist.

3865. The method of claim 3742 wherein the anti-fibrotic agent is an antimycotic agent.

3866. The method of claim 3742 wherein the anti-fibrotic agent is an antimycotic agent, wherein the antimycotic agent is sulconizole.

3867. The method of claim 3742 wherein the anti-fibrotic agent is a bisphosphonate.

3868. The method of claim 3742 wherein the anti-fibrotic agent is a phospholipase A1 inhibitor.

3869. The method of claim 3742 wherein the anti-fibrotic agent is a histamine H1/H2/H3 receptor antagonist.

3870. The method of claim 3742 wherein the anti-fibrotic agent is a macrolide antibiotic.

3871. The method of claim 3742 wherein the anti-fibrotic agent is a GPIIb/IIIa receptor antagonist.

3872. The method of claim 3742 wherein the anti-fibrotic agent is an endothelin receptor antagonist.

3873. The method of claim 3742 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor agonist.

3874. The method of claim 3742 wherein the anti-fibrotic agent is an estrogen receptor agent.

3875. The method of claim 3742 wherein the anti-fibrotic agent is a somastostatin analogue.

3876. The method of claim 3742 wherein the anti-fibrotic agent is a neurokinin 1 antagonist.

3877. The method of claim 3742 wherein the anti-fibrotic agent is a neurokinin 3 antagonist.

3878. The method of claim 3742 wherein the anti-fibrotic agent is a VLA-4 antagonist.

3879. The method of claim 3742 wherein the anti-fibrotic agent is an osteoclast inhibitor.

3880. The method of claim 3742 wherein the anti-fibrotic agent is a DNA topoisomerase ATP hydrolyzing inhibitor.

3881. The method of claim 3742 wherein the anti-fibrotic agent is an angiotensin I converting enzyme inhibitor.

3882. The method of claim 3742 wherein the anti-fibrotic agent is an angiotensin II antagonist.

3883. The method of claim 3742 wherein the anti-fibrotic agent is an enkephalinase inhibitor.

3884. The method of claim 3742 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer.

3885. The method of claim 3742 wherein the anti-fibrotic agent is a protein kinase C inhibitor.

3886. The method of claim 3742 wherein the anti-fibrotic agent is a ROCK (rho-associated kinase) inhibitor.

3887. The method of claim 3742 wherein the anti-fibrotic agent is a CXCR3 inhibitor.

3888. The method of claim 3742 wherein the anti-fibrotic agent is an Itk inhibitor.

3889. The method of claim 3742 wherein the anti-fibrotic agent is a cytosolic phospholipase A2-alpha inhibitor.

3890. The method of claim 3742 wherein the anti-fibrotic agent is a PPAR agonist.

3891. The method of claim 3742 wherein the anti-fibrotic agent is an immunosuppressant.

3892. The method of claim 3742 wherein the anti-fibrotic agent is an Erb inhibitor.

3893. The method of claim 3742 wherein the anti-fibrotic agent is an apoptosis agonist.

3894. The method of claim 3742 wherein the anti-fibrotic agent is a lipocortin agonist.

3895. The method of claim 3742 wherein the anti-fibrotic agent is a VCAM-1 antagonist.

3896. The method of claim 3742 wherein the anti-fibrotic agent is a collagen antagonist.

3897. The method of claim 3742 wherein the anti-fibrotic agent is an alpha 2 integrin antagonist.

3898. The method of claim 3742 wherein the anti-fibrotic agent is a TNF alpha inhibitor.

3899. The method of claim 3742 wherein the anti-fibrotic agent is a nitric oxide inhibitor

3900. The method of claim 3742 wherein the anti-fibrotic agent is a cathepsin inhibitor.

3901. The method of claim 3742 wherein the anti-fibrotic agent is not an anti-inflammatory agent.

3902. The method of claim 3742 wherein the anti-fibrotic agent is not a steroid.

3903. The method of claim 3742 wherein the anti-fibrotic agent is not a glucocorticosteroid.

3904. The method of claim 3742 wherein the anti-fibrotic agent is not dexamethasone.

3905. The method of claim 3742 wherein the anti-fibrotic agent is not beclomethasone.

3906. The method of claim 3742 wherein the anti-fibrotic agent is not dipropionate.

3907. The method of claim 3742 wherein the anti-fibrotic agent is not an anti-infective agent.

3908. The method of claim 3742 wherein the anti-fibrotic agent is not an antibiotic.

3909. The method of claim 3742 wherein the anti-fibrotic agent is not an anti-fungal agent.

3910. The method of claim 3742 wherein the anti-infective agent isan anthracycline.

3911. The method of claim 3742 wherein the anti-infective agent isdoxorubicin.

3912. The method of claim 3742 wherein the anti-infective agent is ismitoxantrone.

3913. The method of claim 3742 wherein the anti-infective agent is a fluoropyrimidine.

3914. The method of claim 3742 wherein the anti-infective agent is 5-fluorouracil (5-FU),

3915. The method of claim 3742 wherein the anti-infective agent is a folic acid antagonist.

3916. The method of claim 3742 wherein the anti-infective agent is methotrexate.

3917. The method of claim 3742 wherein the anti-infective agent is a podophylotoxin.

3918. The method of claim 3742 wherein the anti-infective agent is etoposide.

3919. The method of claim 3742 wherein the anti-infective agent is camptothecin.

3920. The method of claim 3742 wherein the anti-infective agent is a hydroxyurea.

3921. The method of claim 3742 wherein the anti-infective agent is a platinum complex.

3922. The method of claim 3742 wherein the anti-infective agent is cisplatin.

3923. The method of claim 3742 wherein the composition comprises an anti-thrombotic agent.

3924. The method of claim 3742 wherein the polymer is formed from reactants comprising a naturally occurring polymer.

3925. The method of claim 3742 wherein the polymer is formed from reactants comprising protein.

3926. The method of claim 3742 wherein the polymer is formed from reactants comprising carbohydrate.

3927. The method of claim 3742 wherein the polymer is formed from reactants comprising biodegradable polymer.

3928. The method of claim 3742 wherein the polymer is formed from reactants comprising nonbiodegradable polymer.

3929. The method of claim 3742 wherein the polymer is formed from reactants comprising collagen.

3930. The method of claim 3742 wherein the polymer is formed from reactants comprising methylated collagen.

3931. The method of claim 3742 wherein the polymer is formed from reactants comprising fibrinogen.

3932. The method of claim 3742 wherein the polymer is formed from reactants comprising thrombin.

3933. The method of claim 3742 wherein the polymer is formed from reactants comprising blood plasma.

3934. The method of claim 3742 wherein the polymer is formed from reactants comprising calcium salt.

3935. The method of claim 3742 wherein the polymer is formed from reactants comprising an antifibronolytic agent.

3936. The method of claim 3742 wherein the polymer is formed from reactants comprising fibrinogen analog.

3937. The method of claim 3742 wherein the polymer is formed from reactants comprising albumin.

3938. The method of claim 3742 wherein the polymer is formed from reactants comprising plasminogen.

3939. The method of claim 3742 wherein the polymer is formed from reactants comprising von Willebrands factor.

3940. The method of claim 3742 wherein the polymer is formed from reactants comprising Factor VIII.

3941. The method of claim 3742 wherein the polymer is formed from reactants comprising hypoallergenic collagen.

3942. The method of claim 3742 wherein the polymer is formed from reactants comprising atelopeptidic collagen.

3943. The method of claim 3742 wherein the polymer is formed from reactants comprising telopeptide collagen.

3944. The method of claim 3742 wherein the polymer is formed from reactants comprising crosslinked collagen.

3945. The method of claim 3742 wherein the polymer is formed from reactants comprising aprotinin.

3946. The method of claim 3742 wherein the polymer is formed from reactants comprising epsilon-amino-n-caproic acid.

3947. The method of claim 3742 wherein the polymer is formed from reactants comprising gelatin.

3948. The method of claim 3742 wherein the polymer is formed from reactants comprising protein conjugates.

3949. The method of claim 3742 wherein the polymer is formed from reactants comprising gelatin conjugates.

3950. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic polymer.

3951. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic isocyanate-containing compound.

3952. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic thiol-containing compound.

3953. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two thiol groups.

3954. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three thiol groups.

3955. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four thiol groups.

3956. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic amino-containing compound.

3957. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two amino groups.

3953. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three amino groups.

3959. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four amino groups.

3960. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group.

3961. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups.

3962. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.

3963. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.

3964. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound.

3965. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.

3966. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive amino groups.

3967. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive thiol groups.

3968. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups.

3969. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic compound comprising a biodegradable polyester block.

3970. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from lactic acid or lactide.

3971. The method of claim 3742 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from glycolic acid or glycolide.

3972. The method of claim 3742 wherein the polymer is formed from reactants comprising polylysine.

3973. The method of claim 3742 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound comprising a polyalkylene oxide portion.

3974. The method of claim 3742 wherein the polymer is formed from reactants comprising (a) protein and (b) polylysine.

3975. The method of claim 3742 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four thiol groups.

3976. The method of claim 3742 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four amino groups.

3977. The method of claim 3742 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

3978. The method of claim 3742 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having a biodegradable region formed from reactants selected from tactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

3979. The method of claim 3742 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound comprising a polyalkylene oxide portion.

3980. The method of claim 3742 wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine.

3981. The method of claim 3742 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four thiol groups.

3982. The method of claim 3742 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four amino groups.

3983. The method of claim 3742 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

3984. The method of claim 3742 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

3985. The method of claim 3742 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound comprising a polyalkylene oxide portion.

3986. The method of claim 3742 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine.

3987. The method of claim 3742 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four thiol groups.

3988. The method of claim 3742 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four amino groups.

3989. The method of claim 3742 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

3990. The method of claim 3742 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

3991. The method of claim 3742 wherein the polymer is formed from reactants comprising hyaluronic acid.

3992. The method of claim 3742 wherein the polymer is formed from reactants comprising a hyaluronic acid derivative.

3993. The method of claim 3742 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.

3994. The method of claim 3742 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.

3995. The method of claim 3742 wherein the polymer is formed from reactants comprising (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.

3996. The method of claim 3742 wherein the composition comprises a colorant.

3997. The method of claim 3742 wherein the composition is sterile.

3998. A method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with i) an anti-fibrotic agent, ii) an anti-infective agent, iii) a polymer;
iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host, wherein the medical device is an endotracheal or tracheostomy tube.

3999. The method for implanting a medical device according to claim 3998 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-fibrotic agent, and (b) implanting the medical device into the host.

4000. The method for implanting a medical device according to claim 3998 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-infective agent, and (b) implanting the medical device into the host.

4001. The method for implanting a medical device according to claim 3998 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a polymer; and (b) implanting the medical device into the host.

4002. The method for implanting a medical device according to claim 3998 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent and a polymer, and (b) implanting the medical device into the host.

4003. The method for implanting a medical device according to claim 3998 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

4004. The method for implanting a medical device according to claim 3998 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

4005. The method of claim 3998 wherein the medical device is an endotracheal tube.

4006. The method of claim 3998 wherein the medical device is an endotracheal tube with a single lumen.

4007. The method of claim 3998 wherein the medical device is an endotracheal tube with double lumens.

4008. The method of claim 3998 wherein the medical device is a tracheostomy tube.

4009. The method of claim 3998 wherein the anti-fibrotic agent inhibits cell regeneration.

4010. The method of claim 3998 wherein the anti-fibrotic agent inhibits angiogenesis.

4011. The method of claim 3998 wherein the anti-fibrotic agent inhibits fibroblast migration.

4012. The method of claim 3998 wherein the anti-fibrotic agent inhibits fibroblast proliferation.

4013. The method of claim 3998 wherein the anti-fibrotic agent inhibits deposition of extracellular matrix.

4014. The method of claim 3998 wherein the anti-fibrotic agent inhibits tissue remodeling.

4015. The method of claim 3998 wherein the anti-fibrotic agent is an angiogenesis inhibitor.

4016. The method of claim 3998 wherein the anti-fibrotic agent is a 5-lipoxygenase inhibitor or antagonist.

4017. The method of claim 3998 wherein the anti-fibrotic agent is a chemokine receptor antagonist.

4018. The method of claim 3998 wherein the anti-fibrotic agent is a cell cycle inhibitor.

4019. The method of claim 3998 wherein the anti-fibrotic agent is a taxane.

4020. The method of claim 3998 wherein the anti-fibrotic agent is an anti-microtubule agent.

4021. The method of claim 3998 wherein the anti-fibrotic agent is paclitaxel.

4022. The method of claim 3998 wherein the anti-fibrotic agent is not paclitaxel.

4023. The method of claim 3998 wherein the anti-fibrotic agent is an analogue or derivative of paclitaxel.

4024. The method of claim 3998 wherein the anti-fibrotic agent is a vinca alkaloid.

4025. The method of claim 3998 wherein the anti-fibrotic agent is camptothecin or an analogue or derivative thereof.

4026. The method of claim 3998 wherein the anti-fibrotic agent is a podophyllotoxin.

4027. The method of claim 3998 wherein the anti-fibrotic agent is a podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof.

4028. The method of claim 3998 wherein the anti-fibrotic agent is an anthracycline.

4029. The method of claim 3998 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof.

4030. The method of claim 3998 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof.

4031. The method of claim 3998 wherein the anti-fibrotic agent is a platinum compound.

4032. The method of claim 3998 wherein the anti-fibrotic agent is a nitrosourea.

4033. The method of claim 3998 wherein the anti-fibrotic agent is a nitroimidazole.

4034. The method of claim 3998 wherein the anti-fibrotic agent is a folic acid antagonist.

4035. The method of claim 3998 wherein the anti-fibrotic agent is a cytidine analogue.

4036. The method of claim 3998 wherein the anti-fibrotic agent is a pyrimidine analogue.

4037. The method of claim 3998 wherein the anti-fibrotic agent is a fluoropyrimidine analogue.

4038. The method of claim 3998 wherein the anti-fibrotic agent is a purine analogue.

4039. The method of claim 3998 wherein the anti-fibrotic agent is a nitrogen mustard or an analogue or derivative thereof.

4040. The method of claim 3998 wherein the anti-fibrotic agent is a hydroxyurea.

4041. The method of claim 3998 wherein the anti-fibrotic agent is a mytomicin or an analogue or derivative thereof.

4042. The method of claim 3998 wherein the anti-fibrotic agent is an alkyl sulfonate.

4043. The method of claim 3998 wherein the anti-fibrotic agent is a benzamide or an analogue or derivative thereof.

4044. The method of claim 3998 wherein the anti-fibrotic agent is a nicotinamide or an analogue or derivative thereof.

4045. The method of claim 3998 wherein the anti-fibrotic agent is a halogenated sugar or an analogue or derivative thereof.

4046. The method of claim 3998 wherein the anti-fibrotic agent is a DNA alkylating agent.

4047. The method of claim 3998 wherein the anti-fibrotic agent is an anti-microtubule agent.

4048. The method of claim 3998 wherein the anti-fibrotic agent is a topoisomerase inhibitor.

4049. The method of claim 3998 wherein the anti-fibrotic agent is a DNA cleaving agent.

4050. The method of claim 3998 wherein the anti-fibrotic agent is an antimetabolite.

4051. The method of claim 3998 wherein the anti-fibrotic agent inhibits adenosine deaminase.

4052. The method of claim 3998 wherein the anti-fibrotic agent inhibits purine ring synthesis.

4053. The method of claim 3998 wherein the anti-fibrotic agent is a nucleotide interconversion inhibitor.

4054. The method of claim 3998 wherein the anti-fibrotic agent inhibits dihydrofolate reduction.

4055. The method of claim 3998 wherein the anti-fibrotic agent blocks thymidine monophosphate.

4056. The method of claim 3998 wherein the anti-fibrotic agent causes DNA damage.

4057. The method of claim 3998 wherein the anti-fibrotic agent is a DNA intercalation agent.

4058. The method of claim 3998 wherein the anti-fibrotic agent is a RNA synthesis inhibitor.

4059. The method of claim 3998 wherein the anti-fibrotic agent is a pyrimidine synthesis inhibitor.

4060. The method of claim 3998 wherein the anti-fibrotic agent inhibits ribonucleotide synthesis or function.

4061. The method of claim 3998 wherein the anti-fibrotic agent inhibits thymidine monophosphate synthesis or function.

4062. The method of claim 3998 wherein the anti-fibrotic agent inhibits DNA synthesis.

4063. The method of claim 3998 wherein the anti-fibrotic agent causes DNA adduct formation.

4064. The method of claim 3998 wherein the anti-fibrotic agent inhibits protein synthesis.

4065. The method of claim 3998 wherein the anti-fibrotic agent inhibits microtubule function.

4066. The method of claim 3998 wherein the anti-fibrotic agent is a cyclin dependent protein kinase inhibitor.

4067. The method of claim 3998 wherein the anti-fibrotic agent is an epidermal growth factor kinase inhibitor.

4068. The method of claim 3998 wherein the anti-fibrotic agent is an elastase inhibitor.

4069. The method of claim 3998 wherein the anti-fibrotic agent is a factor Xa inhibitor.

4070. The method of claim 3998 wherein the anti-fibrotic agent is a farnesyltransferase inhibitor.

4071. The method of claim 3998 wherein the anti-fibrotic agent is a fibrinogen antagonist.

4072. The method of claim 3998 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

4073. The method of claim 3998 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist.

4074. The method of claim 3998 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof.

4075. The method of claim 3998 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

4076. The method of claim 3998 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor.

4077. The method of claim 3998 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof.

4078. The method of claim 3998 wherein the anti-fibrotic agent is a hydroorotate dehydrogenase inhibitor.

4079. The method of claim 3998 wherein the anti-fibrotic agent is an IKK2 inhibitor.

4080. The method of claim 3998 wherein the anti-fibrotic agent is an IL-1 antagonist.

4081. The method of claim 3998 wherein the anti-fibrotic agent is an ICE antagonist.

4082. The method of claim 3998 wherein the anti-fibrotic agent is an IRAK antagonist.

4083. The method of claim 3998 wherein the anti-fibrotic agent is an IL-4 agonist.

4084. The method of claim 3998 wherein the anti-fibrotic agent is an immunomodulatory agent.

4085. The method of claim 3998 wherein the anti-fibrotic agent is sirolimus or an analogue or derivative thereof.

4086. The method of claim 3998 wherein the anti-fibrotic agent is not sirolimus.

4087. The method of claim 3998 wherein the anti-fibrotic agent is everolimus or an analogue or derivative thereof.

4088. The method of claim 3998 wherein the anti-fibrotic agent is tacrolimus or an analogue or derivative thereof.

4089. The method of claim 3998 wherein the anti-fibrotic agent is not tacrolimus.

4090. The method of claim 3998 wherein the anti-fibrotic agent is biolmus or an analogue or derivative thereof.

4091. The method of claim 3998 wherein the anti-fibrotic agent is tresperimus or an analogue or derivative thereof.

4092. The method of claim 3998 wherein the anti-fibrotic agent is auranofin or an analogue or derivative thereof.

4093. The method of claim 3998 wherein the anti-fibrotic agent is 27-0-demethylrapamycin or an analogue or derivative thereof.

4094. The method of claim 3998 wherein the anti-fibrotic agent is gusperimus or an analogue or derivative thereof.

4095. The method of claim 3998 wherein the anti-fibrotic agent is pimecrolimus or an analogue or derivative thereof.

4096. The method of claim 3998 wherein the anti-fibrotic agent is ABT-578 or an analogue or derivative thereof.

4097. The method of claim 3998 wherein the anti-fibrotic agent is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.

4098. The method of claim 3998 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof.

4099. The method of claim 3998 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-alpha-25 dihydroxy vitamin D3 or an analogue or derivative thereof.

4100. The method of claim 3998 wherein the anti-fibrotic agent is a leukotriene inhibitor.

4101. The method of claim 3998 wherein the anti-fibrotic agent is a MCP-1 antagonist.

4102. The method of claim 3998 wherein the anti-fibrotic agent is a MMP inhibitor.

4103. The method of claim 3998 wherein the anti-fibrotic agent is an NF kappa B inhibitor.

4104. The method of claim 3998 wherein the anti-fibrotic agent is an NF kappa B inhibitor, wherein the NF kappa B inhibitor is Bay 11-7082.

4105. The method of claim 3998 wherein the anti-fibrotic agent is an NO antagonist.

4106. The method of claim 3998 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor.

4107. The method of claim 3998 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB
202190.

4108. The method of claim 3998 wherein the anti-fibrotic agent is a phosphodiesterase inhibitor.

4109. The method of claim 3998 wherein the anti-fibrotic agent is a TGF beta inhibitor.

4110. The method of claim 3998 wherein the anti-fibrotic agent is a thromboxane A2 antagonist.

4111. The method of claim 3998 wherein the anti-fibrotic agent is a TNF alpha antagonist.

4112. The method of claim 3998 wherein the anti-fibrotic agent is a TACE inhibitor.

4113. The method of claim 3998 wherein the anti-fibrotic agent is a tyrosine kinase inhibitor.

4114. The method of claim 3998 wherein the anti-fibrotic agent is a vitronectin inhibitor.

4115. The method of claim 3998 wherein the anti-fibrotic agent is a fibroblast growth factor inhibitor.

4116. The method of claim 3998 wherein the anti-fibrotic agent is a protein kinase inhibitor.

4117. The method of claim 3998 wherein the anti-fibrotic agent is a PDGF receptor kinase inhibitor.

4118. The method of claim 3998 wherein the anti-fibrotic agent is an endothelial growth factor receptor kinase inhibitor.

4119. The method of claim 3998 wherein the anti-fibrotic agent is a retinoic acid receptor antagonist.

4120. The method of claim 3998 wherein the anti-fibrotic agent is a platelet derived growth factor receptor kinase inhibitor.

4121. The method of claim 3998 wherein the anti-fibrotic agent is a fibrinogen antagonist.

4122. The method of claim 3998 wherein the anti-fibrotic agent is an antimycotic agent.

4123. The method of claim 3998 wherein the anti-fibrotic agent is an antimycotic agent, wherein the antimycotic agent is sulconizole.

4124. The method of claim 3998 wherein the anti-fibrotic agent is a bisphosphonate.

4125. The method of claim 3998 wherein the anti-fibrotic agent is a phospholipase A1 inhibitor.

4126. The method of claim 3998 wherein the anti-fibrotic agent is a histamine H1/H2/H3 receptor antagonist.

4127. The method of claim 3998 wherein the anti-fibrotic agent is a macrolide antibiotic.

4128. The method of claim 3998 wherein the anti-fibrotic agent is a GPIIb/IIIa receptor antagonist.

4129. The method of claim 3998 wherein the anti-fibrotic agent is an endothelin receptor antagonist.

4130. The method of claim 3998 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor agonist.

4131. The method of claim 3998 wherein the anti-fibrotic agent is an estrogen receptor agent.

4132. The method of claim 3998 wherein the anti-fibrotic agent is a somastostatin analogue.

4133. The method of claim 3998 wherein the anti-fibrotic agent is a neurokinin 1 antagonist.

4134. The method of claim 3998 wherein the anti-fibrotic agent is a neurokinin 3 antagonist.

4135. The method of claim 3998 wherein the anti-fibrotic agent is a VLA-4 antagonist.

4136. The method of claim 3998 wherein the anti-fibrotic agent is an osteoclast inhibitor.

4137. The method of claim 3998 wherein the anti-fibrotic agent is a DNA topoisomerase ATP hydrolyzing inhibitor.

4138. The method of claim 3998 wherein the anti-fibrotic agent is an angiotensin I converting enzyme inhibitor.

4139. The method of claim 3998 wherein the anti-fibrotic agent is an angiotensin II antagonist.

4140. The method of claim 3998 wherein the anti-fibrotic agent is an enkephalinase inhibitor.

4141. The method of claim 3998 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer.

4142. The method of claim 3998 wherein the anti-fibrotic agent is a protein kinase C inhibitor.

4143. The method of claim 3998 wherein the anti-fibrotic agent is a ROCK (rho-associated kinase) inhibitor.

4144. The method of claim 3998 wherein the anti-fibrotic agent is a CXCR3 inhibitor.

4145. The method of claim 3998 wherein the anti-fibrotic agent is an Itk inhibitor.

4146. The method of claim 3998 wherein the anti-fibrotic agent is a cytosolic phospholipase A2-alpha inhibitor.

4147. The method of claim 3998 wherein the anti-fibrotic agent is a PPAR agonist.

4148. The method of claim 3998 wherein the anti-fibrotic agent is an immunosuppressant.

4149. The method of claim 3998 wherein the anti-fibrotic agent is an Erb inhibitor.

4150. The method of claim 3998 wherein the anti-fibrotic agent is an apoptosis agonist.

4151. The method of claim 3998 wherein the anti-fibrotic agent is a lipocortin agonist.

4152. The method of claim 3998 wherein the anti-fibrotic agent is a VCAM-1 antagonist.

4153. The method of claim 3998 wherein the anti-fibrotic agent is a collagen antagonist.

4154. The method of claim 3998 wherein the anti-fibrotic agent is an alpha 2 integrin antagonist.

4155. The method of claim 3998 wherein the anti-fibrotic agent is a TNF alpha inhibitor.

4156. The method of claim 3998 wherein the anti-fibrotic agent is a nitric oxide inhibitor

4157. The method of claim 3998 wherein the anti-fibrotic agent is a cathepsin inhibitor.

4158. The method of claim 3998 wherein the anti-fibrotic agent is not an anti-inflammatory agent.

4159. The method of claim 3998 wherein the anti-fibrotic agent is not a steroid.

4160. The method of claim 3998 wherein the anti-fibrotic agent is not a glucocorticosteroid.

4161. The method of claim 3998 wherein the anti-fibrotic agent is not dexamethasone.

4162. The method of claim 3998 wherein the anti-fibrotic agent is not beclomethasone.

4163. The method of claim 3998 wherein the anti-fibrotic agent is not dipropionate.

4164. The method of claim 3998 wherein the anti-fibrotic agent is not an anti-infective agent.

4165. The method of claim 3998 wherein the anti-fibrotic agent is not an antibiotic.

4166. The method of claim 3998 wherein the anti-fibrotic agent is not an anti-fungal agent.

4167. The method of claim 3998 wherein the anti-infective agent isan anthracycline.

4168. The method of claim 3998 wherein the anti-infective agent isdoxorubicin.

4169. The method of claim 3998 wherein the anti-infective agent is ismitoxantrone.

4170. The method of claim 3998 wherein the anti-infective agent is a fluoropyrimidine.

4171. The method of claim 3998 wherein the anti-infective agent is 5-fluorouracil (5-FU).

4172. The method of claim 3998 wherein the anti-infective agent is a folic acid antagonist.

4173. The method of claim 3998 wherein the anti-infective agent is methotrexate.

4174. The method of claim 3998 wherein the anti-infective agent is a podophylotoxin.

4175. The method of claim 3998 wherein the anti-infective agent is etoposide.

4176. The method of claim 3998 wherein the anti-infective agent is camptothecin.

4177. The method of claim 3998 wherein the anti-infective agent is a hydroxyurea.

4178. The method of claim 3998 wherein the anti-infective agent is a platinum complex.

4179. The method of claim 3998 wherein the anti-infective agent is cisplatin.

4180. The method of claim 3998 wherein the composition comprises an anti-thrombotic agent.

4181. The method of claim 3998 wherein the polymer is formed from reactants comprising a naturally occurring polymer.

4182. The method of claim 3998 wherein the polymer is formed from reactants comprising protein.

4183. The method of claim 3998 wherein the polymer is formed from reactants comprising carbohydrate.

4184. The method of claim 3998 wherein the polymer is formed from reactants comprising biodegradable polymer.

4185. The method of claim 3998 wherein the polymer is formed from reactants comprising nonbiodegradable polymer.

4186. The method of claim 3998 wherein the polymer is formed from reactants comprising collagen.

4187. The method of claim 3998 wherein the polymer is formed from reactants comprising methylated collagen.

4188. The method of claim 3998 wherein the polymer is formed from reactants comprising fibrinogen.

4189. The method of claim 3998 wherein the polymer is formed from reactants comprising thrombin.

4190. The method of claim 3998 wherein the polymer is formed from reactants comprising blood plasma.

4191. The method of claim 3998 wherein the polymer is formed from reactants comprising calcium salt.

4192. The method of claim 3998 wherein the polymer is formed from reactants comprising an antifibronolytic agent.

4193. The method of claim 3998 wherein the polymer is formed from reactants comprising fibrinogen analog.

4194. The method of claim 3998 wherein the polymer is formed from reactants comprising albumin.

4195. The method of claim 3998 wherein the polymer is formed from reactants comprising plasminogen.

4196. The method of claim 3998 wherein the polymer is formed from reactants comprising von Willebrands factor.

4197. The method of claim 3998 wherein the polymer is formed from reactants comprising Factor VIII.

4198. The method of claim 3998 wherein the polymer is formed from reactants comprising hypoallergenic collagen.

4199. The method of claim 3998 wherein the polymer is formed from reactants comprising atelopeptidic collagen.

4200. The method of claim 3998 wherein the polymer is formed from reactants comprising telopeptide collagen.

4201. The method of claim 3998 wherein the polymer is formed from reactants comprising crosslinked collagen.

4202. The method of claim 3998 wherein the polymer is formed from reactants comprising aprotinin.

4203. The method of claim 3998 wherein the polymer is formed from reactants comprising epsilon-amino-n-caproic acid.

4204. The method of claim 3998 wherein the polymer is formed from reactants comprising gelatin.

4205. The method of claim 3998 wherein the polymer is formed from reactants comprising protein conjugates.

4206. The method of claim 3998 wherein the polymer is formed from reactants comprising gelatin conjugates.

4207. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic polymer.

4208. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic isocyanate-containing compound.

4209. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic thiol-containing compound.

4210. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two thiol groups.

4211. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three thiol groups.

4212. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four thiol groups.

4213. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic amino-containing compound.

4214. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two amino groups.

4215. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three amino groups.

4216. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four amino groups.

4217. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group.

4218. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups.

4219. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.

4220. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.

4221. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound.

4222. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.

4223. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive amino groups.

4224. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive thiol groups.

4225. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups.

4226. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic compound comprising a biodegradable polyester block.

4227. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from lactic acid or lactide.

4228. The method of claim 3998 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from glycolic acid or glycolide.

4229. The method of claim 3998 wherein the polymer is formed from reactants comprising polylysine.

4230. The method of claim 3998 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound comprising a polyalkylene oxide portion.

4231. The method of claim 3998 wherein the polymer is formed from reactants comprising (a) protein and (b) polylysine.

4232. The method of claim 3998 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four thiol groups.

4233. The method of claim 3998 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four amino groups.

4234. The method of claim 3998 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

4235. The method of claim 3998 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

4236. The method of claim 3998 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound comprising a polyalkylene oxide portion.

4237. The method of claim 3998 wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine.

4238. The method of claim 3998 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four thiol groups.

4239. The method of claim 3998 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four amino groups.

4240. The method of claim 3998 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

4241. The method of claim 3998 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

4242. The method of claim 3998 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound comprising a polyalkylene oxide portion.

4243. The method of claim 3998 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine.

4244. The method of claim 3998 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four thiol groups.

4245. The method of claim 3998 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four amino groups.

4246. The method of claim 3998 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

4247. The method of claim 3998 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

4248. The method of claim 3998 wherein the polymer is formed from reactants comprising hyaluronic acid.

4249. The method of claim 3998 wherein the polymer is formed from reactants comprising a hyaluronic acid derivative.

4250. The method of claim 3998 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.

4251. The method of claim 3998 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.

4252. The method of claim 3998 wherein the polymer is formed from reactants comprising (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.

4253. The method of claim 3998 wherein the composition comprises a colorant.

4254. The method of claim 3998 wherein the composition is sterile.

4255. A method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with i) an anti-fibrotic agent, ii) an anti-infective agent, iii) a polymer;
iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host, wherein the medical device is a peritoneal dialysis catheter.

4256. The method for implanting a medical device according to claim 4255 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-fibrotic agent, and (b) implanting the medical device into the host.

4257. The method for implanting a medical device according to claim 4255 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-infective agent, and (b) implanting the medical device into the host.

4258. The method for implanting a medical device according to claim 4255 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a polymer; and (b) implanting the medical device into the host.

4259. The method for implanting a medical device according to claim 4255 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent and a polymer, and (b) implanting the medical device into the host.

4260. The method for implanting a medical device according to claim 4255 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

4261. The method for implanting a medical device according to claim 4255 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

4262. The method of claim 4255 wherein the medical device is a peritoneal dialysis catheter is adapted for delivering a drug to the peritoneum.

4263. The method of claim 4255 wherein the anti-fibrotic agent inhibits cell regeneration.

4264. The method of claim 4255 wherein the anti-fibrotic agent inhibits angiogenesis.

4265. The method of claim 4255 wherein the anti-fibrotic agent inhibits fibroblast migration.

4266. The method of claim 4255 wherein the anti-fibrotic agent inhibits fibroblast proliferation.

4267. The method of claim 4255 wherein the anti-fibrotic agent inhibits deposition of extracellular matrix.

4268. The method of claim 4255 wherein the anti-fibrotic agent inhibits tissue remodeling.

4269. The method of claim 4255 wherein the anti-fibrotic agent is an angiogenesis inhibitor.

4270. The method of claim 4255 wherein the anti-fibrotic agent is a 5-lipoxygenase inhibitor or antagonist.

4271. The method of claim 4255 wherein the anti-fibrotic agent is a chemokine receptor antagonist.

4272. The method of claim 4255 wherein the anti-fibrotic agent is a cell cycle inhibitor.

4273. The method of claim 4255 wherein the anti-fibrotic agent is a taxane.

4274. The method of claim 4255 wherein the anti-fibrotic agent is an anti-microtubule agent.

4275. The method of claim 4255 wherein the anti-fibrotic agent is paclitaxel.

4276. The method of claim 4255 wherein the anti-fibrotic agent is not paclitaxel.

4277. The method of claim 4255 wherein the anti-fibrotic agent is an analogue or derivative of paclitaxel.

4278. The method of claim 4255 wherein the anti-fibrotic agent is a vinca alkaloid.

4279. The method of claim 4255 wherein the anti-fibrotic agent is camptothecin or an analogue or derivative thereof.

4280. The method of claim 4255 wherein the anti-fibrotic agent is a podophyllotoxin.

4281. The method of claim 4255 wherein the anti-fibrotic agent is a podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof.

4282. The method of claim 4255 wherein the anti-fibrotic agent is an anthracycline.

4283. The method of claim 4255 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof.

4284. The method of claim 4255 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof.

4285. The method of claim 4255 wherein the anti-fibrotic agent is a platinum compound.

4286. The method of claim 4255 wherein the anti-fibrotic agent is a nitrosourea.

4287. The method of claim 4255 wherein the anti-fibrotic agent is a nitroimidazole.

4288. The method of claim 4255 wherein the anti-fibrotic agent is a folic acid antagonist.

4289. The method of claim 4255 wherein the anti-fibrotic agent is a cytidine analogue.

4290. The method of claim 4255 wherein the anti-fibrotic agent is a pyrimidine analogue.

4291. The method of claim 4255 wherein the anti-fibrotic agent is a fluoropyrimidine analogue.

4292. The method of claim 4255 wherein the anti-fibrotic agent is a purine analogue.

4293. The method of claim 4255 wherein the anti-fibrotic agent is a nitrogen mustard or an analogue or derivative thereof.

4294. The method of claim 4255 wherein the anti-fibrotic agent is a hydroxyurea.

4295. The method of claim 4255 wherein the anti-fibrotic agent is a mytomicin or an analogue or derivative thereof.

4296. The method of claim 4255 wherein the anti-fibrotic agent is an alkyl sulfonate.

4297. The method of claim 4255 wherein the anti-fibrotic agent is a benzamide or an analogue or derivative thereof.

4293. The method of claim 4255 wherein the anti-fibrotic agent is a nicotinamide or an analogue or derivative thereof.

4299. The method of claim 4255 wherein the anti-fibrotic agent is a halogenated sugar or an analogue or derivative thereof.

4300. The method of claim 4255 wherein the anti-fibrotic agent is a DNA alkylating agent.

4301. The method of claim 4255 wherein the anti-fibrotic agent is an anti-microtubule agent.

4302. The method of claim 4255 wherein the anti-fibrotic agent is a topoisomerase inhibitor.

4303. The method of claim 4255 wherein the anti-fibrotic agent is a DNA cleaving agent.

4304. The method of claim 4255 wherein the anti-fibrotic agent is an antimetabolite.

4305. The method of claim 4255 wherein the anti-fibrotic agent inhibits adenosine deaminase.

4306. The method of claim 4255 wherein the anti-fibrotic agent inhibits purine ring synthesis.

4307. The method of claim 4255 wherein the anti-fibrotic agent is a nucleotide interconversion inhibitor.

4308. The method of claim 4255 wherein the anti-fibrotic agent inhibits dihydrofolate reduction.

4309. The method of claim 4255 wherein the anti-fibrotic agent blocks thymidine monophosphate.

4310. The method of claim 4255 wherein the anti-fibrotic agent causes DNA damage.

4311. The method of claim 4255 wherein the anti-fibrotic agent is a DNA intercalation agent.

4312. The method of claim 4255 wherein the anti-fibrotic agent is a RNA synthesis inhibitor.

4313. The method of claim 4255 wherein the anti-fibrotic agent is a pyrimidine synthesis inhibitor.

4314. The method of claim 4255 wherein the anti-fibrotic agent inhibits ribonucleotide synthesis or function.

4315. The method of claim 4255 wherein the anti-fibrotic agent inhibits thymidine monophosphate synthesis or function.

4316. The method of claim 4255 wherein the anti-fibrotic agent inhibits DNA synthesis.

4317. The method of claim 4255 wherein the anti-fibrotic agent causes DNA adduct formation.

4313. The method of claim 4255 wherein the anti-fibrotic agent inhibits protein synthesis.

4319. The method of claim 4255 wherein the anti-fibrotic agent inhibits microtubule function.

4320. The method of claim 4255 wherein the anti-fibrotic agent is a cyclin dependent protein kinase inhibitor.

4321. The method of claim 4255 wherein the anti-fibrotic agent is an epidermal growth factor kinase inhibitor.

4322. The method of claim 4255 wherein the anti-fibrotic agent is an elastase inhibitor.

4323. The method of claim 4255 wherein the anti-fibrotic agent is a factor Xa inhibitor.

4324. The method of claim 4255 wherein the anti-fibrotic agent is a farnesyltransferase inhibitor.

4325. The method of claim 4255 wherein the anti-fibrotic agent is a fibrinogen antagonist.

4326. The method of claim 4255 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

4327. The method of claim 4255 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist.

4328. The method of claim 4255 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof.

4329. The method of claim 4255 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

4330. The method of claim 4255 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor.

4331. The method of claim 4255 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof.

4332. The method of claim 4255 wherein the anti-fibrotic agent is a hydroorotate dehydrogenase inhibitor.

4333. The method of claim 4255 wherein the anti-fibrotic agent is an IKK2 inhibitor.

4334. The method of claim 4255 wherein the anti-fibrotic agent is an IL-1 antagonist.

4335. The method of claim 4255 wherein the anti-fibrotic agent is an ICE antagonist.

4336. The method of claim 4255 wherein the anti-fibrotic agent is an IRAK antagonist.

4337. The method of claim 4255 wherein the anti-fibrotic agent is an IL-4 agonist.

4338. The method of claim 4255 wherein the anti-fibrotic agent is an immunomodulatory agent.

4339. The method of claim 4255 wherein the anti-fibrotic agent is sirolimus or an analogue or derivative thereof.

4340. The method of claim 4255 wherein the anti-fibrotic agent is not sirolimus.

4341. The method of claim 4255 wherein the anti-fibrotic agent is everolimus or an analogue or derivative thereof.

4342. The method of claim 4255 wherein the anti-fibrotic agent is tacrolimus or an analogue or derivative thereof.

4343. The method of claim 4255 wherein the anti-fibrotic agent is not tacrolimus.

4344. The method of claim 4255 wherein the anti-fibrotic agent is biolmus or an analogue or derivative thereof.

4345. The method of claim 4255 wherein the anti-fibrotic agent is tresperimus or an analogue or derivative thereof.

4346. The method of claim 4255 wherein the anti-fibrotic agent is auranofin or an analogue or derivative thereof.

4347. The method of claim 4255 wherein the anti-fibrotic agent is 27-0-demethylrapamycin or an analogue or derivative thereof.

4348. The method of claim 4255 wherein the anti-fibrotic agent is gusperimus or an analogue or derivative thereof.

4349. The method of claim 4255 wherein the anti-fibrotic agent is pimecrolimus or an analogue or derivative thereof.

4350. The method of claim 4255 wherein the anti-fibrotic agent is ABT-578 or an analogue or derivative thereof.

4351. The method of claim 4255 wherein the anti-fibrotic agent is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.

4352. The method of claim 4255 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof.

4353. The method of claim 4255 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-alpha-25 dihydroxy vitamin D3 or an analogue or derivative thereof.

4354. The method of claim 4255 wherein the anti-fibrotic agent is a leukotriene inhibitor.

4355. The method of claim 4255 wherein the anti-fibrotic agent is a MCP-1 antagonist.

4356. The method of claim 4255 wherein the anti-fibrotic agent is a MMP inhibitor.

4357. The method of claim 4255 wherein the anti-fibrotic agent is an NF kappa B inhibitor.

4358. The method of claim 4255 wherein the anti-fibrotic agent is an NF kappa B inhibitor, wherein the NF kappa B inhibitor is Bay 11-7082.

4359. The method of claim 4255 wherein the anti-fibrotic agent is an NO antagonist.

4360. The method of claim 4255 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor.

4361. The method of claim 4255 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB
202190.

4362. The method of claim 4255 wherein the anti-fibrotic agent is a phosphodiesterase inhibitor.

4363. The method of claim 4255 wherein the anti-fibrotic agent is a TGF beta inhibitor.

4364. The method of claim 4255 wherein the anti-fibrotic agent is a thromboxane A2 antagonist.

4365. The method of claim 4255 wherein the anti-fibrotic agent is a TNF alpha antagonist.

4366. The method of claim 4255 wherein the anti-fibrotic agent is a TACE inhibitor.

4367. The method of claim 4255 wherein the anti-fibrotic agent is a tyrosine kinase inhibitor.

4368. The method of claim 4255 wherein the anti-fibrotic agent is a vitronectin inhibitor.

4369. The method of claim 4255 wherein the anti-fibrotic agent is a fibroblast growth factor inhibitor.

4370. The method of claim 4255 wherein the anti-fibrotic agent is a protein kinase inhibitor.

4371. The method of claim 4255 wherein the anti-fibrotic agent is a PDGF receptor kinase inhibitor.

4372. The method of claim 4255 wherein the anti-fibrotic agent is an endothelial growth factor receptor kinase inhibitor.

4373. The method of claim 4255 wherein the anti-fibrotic agent is a retinoic acid receptor antagonist.

4374. The method of claim 4255 wherein the anti-fibrotic agent is a platelet derived growth factor receptor kinase inhibitor.

4375. The method of claim 4255 wherein the anti-fibrotic agent is a fibrinogen antagonist.

4376. The method of claim 4255 wherein the anti-fibrotic agent is an antimycotic agent.

4377. The method of claim 4255 wherein the anti-fibrotic agent is an antimycotic agent, wherein the antimycotic agent is sulconizole.

4378. The method of claim 4255 wherein the anti-fibrotic agent is a bisphosphonate.

4379. The method of claim 4255 wherein the anti-fibrotic agent is a phospholipase A1 inhibitor.

4380. The method of claim 4255 wherein the anti-fibrotic agent is a histamine H1/H2/H3 receptor antagonist.

4381. The method of claim 4255 wherein the anti-fibrotic agent is a macrolide antibiotic.

4382. The method of claim 4255 wherein the anti-fibrotic agent is a GPIIb/IIIa receptor antagonist.

4383. The method of claim 4255 wherein the anti-fibrotic agent is an endothelin receptor antagonist.

4384. The method of claim 4255 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor agonist.

4385. The method of claim 4255 wherein the anti-fibrotic agent is an estrogen receptor agent.

4386. The method of claim 4255 wherein the anti-fibrotic agent is a somastostatin analogue.

4387. The method of claim 4255 wherein the anti-fibrotic agent is a neurokinin 1 antagonist.

4388. The method of claim 4255 wherein the anti-fibrotic agent is a neurokinin 3 antagonist.

4389. The method of claim 4255 wherein the anti-fibrotic agent is a VLA-4 antagonist.

4390. The method of claim 4255 wherein the anti-fibrotic agent is an osteoclast inhibitor.

4391. The method of claim 4255 wherein the anti-fibrotic agent is a DNA topoisomerase ATP hydrolyzing inhibitor.

4392. The method of claim 4255 wherein the anti-fibrotic agent is an angiotensin I converting enzyme inhibitor.

4393. The method of claim 4255 wherein the anti-fibrotic agent is an angiotensin II antagonist.

4394. The method of claim 4255 wherein the anti-fibrotic agent is an enkephalinase inhibitor.

4395. The method of claim 4255 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer.

4396. The method of claim 4255 wherein the anti-fibrotic agent is a protein kinase C inhibitor.

4397. The method of claim 4255 wherein the anti-fibrotic agent is a ROCK (rho-associated kinase) inhibitor.

4398. The method of claim 4255 wherein the anti-fibrotic agent is a CXCR3 inhibitor.

4399. The method of claim 4255 wherein the anti-fibrotic agent is an Itk inhibitor.

4400. The method of claim 4255 wherein the anti-fibrotic agent is a cytosolic phospholipase A2-alpha inhibitor.

4401. The method of claim 4255 wherein the anti-fibrotic agent is a PPAR agonist.

4402. The method of claim 4255 wherein the anti-fibrotic agent is an immunosuppressant.

4403. The method of claim 4255 wherein the anti-fibrotic agent is an Erb inhibitor.

4404. The method of claim 4255 wherein the anti-fibrotic agent is an apoptosis agonist.

4405. The method of claim 4255 wherein the anti-fibrotic agent is a lipocortin agonist.

4406. The method of claim 4255 wherein the anti-fibrotic agent is a VCAM-1 antagonist.

4407. The method of claim 4255 wherein the anti-fibrotic agent is a collagen antagonist.

4408. The method of claim 4255 wherein the anti-fibrotic agent is an alpha 2 integrin antagonist.

4409. The method of claim 4255 wherein the anti-fibrotic agent is a TNF alpha inhibitor.

4410. The method of claim 4255 wherein the anti-fibrotic agent is a nitric oxide inhibitor

4411. The method of claim 4255 wherein the anti-fibrotic agent is a cathepsin inhibitor.

4412. The method of claim 4255 wherein the anti-fibrotic agent is not an anti-inflammatory agent.

4413. The method of claim 4255 wherein the anti-fibrotic agent is not a steroid.

4414. The method of claim 4255 wherein the anti-fibrotic agent is not a glucocorticosteroid.

4415. The method of claim 4255 wherein the anti-fibrotic agent is not dexamethasone.

4416. The method of claim 4255 wherein the anti-fibrotic agent is not beclomethasone.

4417. The method of claim 4255 wherein the anti-fibrotic agent is not dipropionate.

4418. The method of claim 4255 wherein the anti-fibrotic agent is not an anti-infective agent.

4419. The method of claim 4255 wherein the anti-fibrotic agent is not an antibiotic.

4420. The method of claim 4255 wherein the anti-fibrotic agent is not an anti-fungal agent.

4421. The method of claim 4255 wherein the anti-infective agent isan anthracycline.

4422. The method of claim 4255 wherein the anti-infective agent isdoxorubicin.

4423. The method of claim 4255 wherein the anti-infective agent is ismitoxantrone.

4424. The method of claim 4255 wherein the anti-infective agent is a fluoropyrimidine.

4425. The method of claim 4255 wherein the anti-infective agent is 5-fluorouracil (5-FU).

4426. The method of claim 4255 wherein the anti-infective agent is a folic acid antagonist.

4427. The method of claim 4255 wherein the anti-infective agent is methotrexate.

4428. The method of claim 4255 wherein the anti-infective agent is a podophylotoxin.

4429. The method of claim 4255 wherein the anti-infective agent is etoposide.

4430. The method of claim 4255 wherein the anti-infective agent is camptothecin.

4431. The method of claim 4255 wherein the anti-infective agent is a hydroxyurea.

4432. The method of claim 4255 wherein the anti-infective agent is a platinum complex.

4433. The method of claim 4255 wherein the anti-infective agent is cisplatin.

4434. The method of claim 4255 wherein the composition comprises an anti-thrombotic agent.

4435. The method of claim 4255 wherein the polymer is formed from reactants comprising a naturally occurring polymer.

4436. The method of claim 4255 wherein the polymer is formed from reactants comprising protein.

4437. The method of claim 4255 wherein the polymer is formed from reactants comprising carbohydrate.

4438. The method of claim 4255 wherein the polymer is formed from reactants comprising biodegradable polymer.

4439. The method of claim 4255 wherein the polymer is formed from reactants comprising nonbiodegradable polymer.

4440. The method of claim 4255 wherein the polymer is formed from reactants comprising collagen.

4441. The method of claim 4255 wherein the polymer is formed from reactants comprising methylated collagen.

4442. The method of claim 4255 wherein the polymer is formed from reactants comprising fibrinogen.

4443. The method of claim 4255 wherein the polymer is formed from reactants comprising thrombin.

4444. The method of claim 4255 wherein the polymer is formed from reactants comprising blood plasma.

4445. The method of claim 4255 wherein the polymer is formed from reactants comprising calcium salt.

4446. The method of claim 4255 wherein the polymer is formed from reactants comprising an antifibronolytic agent.

4447. The method of claim 4255 wherein the polymer is formed from reactants comprising fibrinogen analog.

4448. The method of claim 4255 wherein the polymer is formed from reactants comprising albumin.

4449. The method of claim 4255 wherein the polymer is formed from reactants comprising plasminogen.

4450. The method of claim 4255 wherein the polymer is formed from reactants comprising von Willebrands factor.

4451. The method of claim 4255 wherein the polymer is formed from reactants comprising Factor VIII.

4452. The method of claim 4255 wherein the polymer is formed from reactants comprising hypoallergenic collagen.

4453. The method of claim 4255 wherein the polymer is formed from reactants comprising atelopeptidic collagen.

4454. The method of claim 4255 wherein the polymer is formed from reactants comprising telopeptide collagen.

4455. The method of claim 4255 wherein the polymer is formed from reactants comprising crosslinked collagen.

4456. The method of claim 4255 wherein the polymer is formed from reactants comprising aprotinin.

4457. The method of claim 4255 wherein the polymer is formed from reactants comprising epsilon-amino-n-caproic acid.

4458. The method of claim 4255 wherein the polymer is formed from reactants comprising gelatin.

4459. The method of claim 4255 wherein the polymer is formed from reactants comprising protein conjugates.

4460. The method of claim 4255 wherein the polymer is formed from reactants comprising gelatin conjugates.

4461. The method of claim 4255 wherein the polymer is formed from reactants comprising a synthetic polymer.

4462. The method of claim 4255 wherein the polymer is formed from reactants comprising a synthetic isocyanate-containing compound.

4463. The method of claim 4255 wherein the polymer is formed from reactants comprising a synthetic thiol-containing compound.

4464. The method of claim 4255 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two thiol groups.

4465. The method of claim 4255 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three thiol groups.

4466. The method of claim 4255 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four thiol groups.

4467. The method of claim 4255 wherein the polymer is formed from reactants comprising a synthetic amino-containing compound.

4468. The method of claim 4255 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two amino groups.

4469. The method of, claim 4255 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three amino groups.

4470. The method of claim 4255 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four amino groups.

4471. The method of claim 4255 wherein the polymer is formed from reactants comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group.

4472. The method of claim 4255 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups.

4473. The method of claim 4255 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.

4474. The method of claim 4255 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.

4475. The method of claim 4255 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound.

4476. The method of claim 4255 wherein the polymer is formed from reactants comprising a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.

4477. The method of claim 4255 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive amino groups.

4478. The method of claim 4255 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive thiol groups.

4479. The method of claim 4255 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups.

4480. The method of claim 4255 wherein the polymer is formed from reactants comprising a synthetic compound comprising a biodegradable polyester block.

4481. The method of claim 4255 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from lactic acid or lactide.

4482. The method of claim 4255 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from glycolic acid or glycolide.

4483. The method of claim 4255 wherein the polymer is formed from reactants comprising polylysine.

4484. The method of claim 4255 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound comprising a polyalkylene oxide portion.

4485. The method of claim 4255 wherein the polymer is formed from reactants comprising (a) protein and (b) polylysine.

4486. The method of claim 4255 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four thiol groups.

4487. The method of claim 4255 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four amino groups.

4488. The method of claim 4255 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

4489. The method of claim 4255 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

4490. The method of claim 4255 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound comprising a polyalkylene oxide portion.

4491. The method of claim 4255 wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine.

4492. The method of claim 4255 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four thiol groups.

4493. The method of claim 4255 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four amino groups.

4494. The method of claim 4255 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

4495. The method of claim 4255 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

4496. The method of claim 4255 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound comprising a polyalkylene oxide portion.

4497. The method of claim 4255 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine.

4493. The method of claim 4255 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four thiol groups.

4499. The method of claim 4255 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four amino groups.

4500. The method of claim 4255 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

4501. The method of claim 4255 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

4502. The method of claim 4255 wherein the polymer is formed from reactants comprising hyaluronic acid.

4503. The method of claim 4255 wherein the polymer is formed from reactants comprising a hyaluronic acid derivative.

4504. The method of claim 4255 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.

4505. The method of claim 4255 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.

4506. The method of claim 4255 wherein the polymer is formed from reactants comprising (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.

4507. The method of claim 4255 wherein the composition comprises a colorant.

4503. The method of claim 4255 wherein the composition is sterile.

4509. A method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with i) an anti-fibrotic agent, ii) an anti-infective agent, iii) a polymer;
iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host, wherein the medical device is a central nervous system shunt or a pressure monitoring.

4510. The method for implanting a medical device according to claim 4509 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-fibrotic agent, and (b) implanting the medical device into the host.

4511. The method for implanting a medical device according to claim 4509 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-infective agent, and (b) implanting the medical device into the host.

4512. The method for implanting a medical device according to claim 4509 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a polymer; and (b) implanting the medical device into the host.

4513. The method for implanting a medical device according to claim 4509 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent and a polymer, and (b) implanting the medical device into the host.

4514. The method for implanting a medical device according to claim 4509 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

4515. The method for implanting a medical device according to claim 4509 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

4516. The method of claim 4509 wherein the medical device is a ventriculopleural shunt.

4517. The method of claim 4509 wherein the medical device is a jugular vein shunt.

4518. The method of claim 4509 wherein the medical device is a vena cava shunt.

4519. The method of claim 4509 wherein the medical device is a ventriculoperitoneal shunt.

4520. The method of claim 4509 wherein the medical device is a gallbladder shunt.

4521. The method of claim 4509 wherein the medical device is a peritoneum shunt.

4522. The method of claim 4509 wherein the medical device is an external ventricular drainage device.

4523. The method of claim 4509 wherein the medical device is an intracranial pressure monitoring device.

4524. The method of claim 4509 wherein the medical device is a dural patch.

4525. The method of claim 4509 wherein the medical device is an implant to prevent epidural fibrosis post-laminectomy.

4526. The method of claim 4509 wherein the medical device is a device for continuous subarachnoid infusion.

4527. The method of claim 4509 wherein the medical device is a drainage shunt useful for draining fluids in the brain.

4528. The method of claim 4509 wherein the medical device is a pressure monitoring device.

4529. The method of claim 4509 wherein the anti-fibrotic agent inhibits cell regeneration.

4530. The method of claim 4509 wherein the anti-fibrotic agent inhibits angiogenesis.

4531. The method of claim 4509 wherein the anti-fibrotic agent inhibits fibroblast migration.

4532. The method of claim 4509 wherein the anti-fibrotic agent inhibits fibroblast proliferation.

4533. The method of claim 4509 wherein the anti-fibrotic agent inhibits deposition of extracellular matrix.

4534. The method of claim 4509 wherein the anti-fibrotic agent inhibits tissue remodeling.

4535. The method of claim 4509 wherein the anti-fibrotic agent is an angiogenesis inhibitor.

4536. The method of claim 4509 wherein the anti-fibrotic agent is a 5-lipoxygenase inhibitor or antagonist.

4537. The method of claim 4509 wherein the anti-fibrotic agent is a chemokine receptor antagonist.

4538. The method of claim 4509 wherein the anti-fibrotic agent is a cell cycle inhibitor.

4539. The method of claim 4509 wherein the anti-fibrotic agent is a taxane.

4540. The method of claim 4509 wherein the anti-fibrotic agent is an anti-microtubule agent.

4541. The method of claim 4509 wherein the anti-fibrotic agent is paclitaxel.

4542. The method of claim 4509 wherein the anti-fibrotic agent is not paclitaxel.

4543. The method of claim 4509 wherein the anti-fibrotic agent is an analogue or derivative of paclitaxel.

4544. The method of claim 4509 wherein the anti-fibrotic agent is a vinca alkaloid.

4545. The method of claim 4509 wherein the anti-fibrotic agent is camptothecin or an analogue or derivative thereof.

4546. The method of claim 4509 wherein the anti-fibrotic agent is a podophyllotoxin.

4547. The method of claim 4509 wherein the anti-fibrotic agent is a podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof.

4548. The method of claim 4509 wherein the anti-fibrotic agent is an anthracycline.

4549. The method of claim 4509 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof.

4550. The method of claim 4509 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof.

4551. The method of claim 4509 wherein the anti-fibrotic agent is a platinum compound.

4552. The method of claim 4509 wherein the anti-fibrotic agent is a nitrosourea.

4553. The method of claim 4509 wherein the anti-fibrotic agent is a nitroimidazole.

4554. The method of claim 4509 wherein the anti-fibrotic agent is a folic acid antagonist.

4555. The method of claim 4509 wherein the anti-fibrotic agent is a cytidine analogue.

4556. The method of claim 4509 wherein the anti-fibrotic agent is a pyrimidine analogue.

4557. The method of claim 4509 wherein the anti-fibrotic agent is a fluoropyrimidine analogue.

4558. The method of claim 4509 wherein the anti-fibrotic agent is a purine analogue.

4559. The method of claim 4509 wherein the anti-fibrotic agent is a nitrogen mustard or an analogue or derivative thereof.

4560. The method of claim 4509 wherein the anti-fibrotic agent is a hydroxyurea.

4561. The method of claim 4509 wherein the anti-fibrotic agent is a mytomicin or an analogue or derivative thereof.

4562. The method of claim 4509 wherein the anti-fibrotic agent is an alkyl sulfonate.

4563. The method of claim 4509 wherein the anti-fibrotic agent is a benzamide or an analogue or derivative thereof.

4564. The method of claim 4509 wherein the anti-fibrotic agent is a nicotinamide or an analogue or derivative thereof.

4565. The method of claim 4509 wherein the anti-fibrotic agent is a halogenated sugar or an analogue or derivative thereof.

4566. The method of claim 4509 wherein the anti-fibrotic agent is a DNA alkylating agent.

4567. The method of claim 4509 wherein the anti-fibrotic agent is an anti-microtubule agent.

4568. The method of claim 4509 wherein the anti-fibrotic agent is a topoisomerase inhibitor.

4569. The method of claim 4509 wherein the anti-fibrotic agent is a DNA cleaving agent.

4570. The method of claim 4509 wherein the anti-fibrotic agent is an antimetabolite.

4571. The method of claim 4509 wherein the anti-fibrotic agent inhibits adenosine deaminase.

4572. The method of claim 4509 wherein the anti-fibrotic agent inhibits purine ring synthesis.

4573. The method of claim 4509 wherein the anti-fibrotic agent is a nucleotide interconversion inhibitor.

4574. The method of claim 4509 wherein the anti-fibrotic agent inhibits dihydrofolate reduction.

4575. The method of claim 4509 wherein the anti-fibrotic agent blocks thymidine monophosphate.

4576. The method of claim 4509 wherein the anti-fibrotic agent causes DNA damage.

4577. The method of claim 4509 wherein the anti-fibrotic agent is a DNA intercalation agent.

4578. The method of claim 4509 wherein the anti-fibrotic agent is a RNA synthesis inhibitor.

4579. The method of claim 4509 wherein the anti-fibrotic agent is a pyrimidine synthesis inhibitor.

4580. The method of claim 4509 wherein the anti-fibrotic agent inhibits ribonucleotide synthesis or function.

4581. The method of claim 4509 wherein the anti-fibrotic agent inhibits thymidine monophosphate synthesis or function.

4582. The method of claim 4509 wherein the anti-fibrotic agent inhibits DNA synthesis.

4583. The method of claim 4509 wherein the anti-fibrotic agent causes DNA adduct formation.

4584. The method of claim 4509 wherein the anti-fibrotic agent inhibits protein synthesis.

4585. The method of claim 4509 wherein the anti-fibrotic agent inhibits microtubule function.

4586. The method of claim 4509 wherein the anti-fibrotic agent is a cyclin dependent protein kinase inhibitor.

4587. The method of claim 4509 wherein the anti-fibrotic agent is an epidermal growth factor kinase inhibitor.

4588. The method of claim 4509 wherein the anti-fibrotic agent is an elastase inhibitor.

4589. The method of claim 4509 wherein the anti-fibrotic agent is a factor Xa inhibitor.

4590. The method of claim 4509 wherein the anti-fibrotic agent is a farnesyltransferase inhibitor.

4591. The method of claim 4509 wherein the anti-fibrotic agent is a fibrinogen antagonist.

4592. The method of claim 4509 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

4593. The method of claim 4509 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist.

4594. The method of claim 4509 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof.

4595. The method of claim 4509 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

4596. The method of claim 4509 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor.

4597. The method of claim 4509 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof.

4598. The method of claim 4509 wherein the anti-fibrotic agent is a hydroorotate dehydrogenase inhibitor.

4599. The method of claim 4509 wherein the anti-fibrotic agent is an IKK2 inhibitor.

4600. The method of claim 4509 wherein the anti-fibrotic agent is an IL-1 antagonist.

4601. The method of claim 4509 wherein the anti-fibrotic agent is an ICE antagonist.

4602. The method of claim 4509 wherein the anti-fibrotic agent is an IRAK antagonist.

4603. The method of claim 4509 wherein the anti-fibrotic agent is an IL-4 agonist.

4604. The method of claim 4509 wherein the anti-fibrotic agent is an immunomodulatory agent.

4605. The method of claim 4509 wherein the anti-fibrotic agent is sirolimus or an analogue or derivative thereof.

4606. The method of claim 4509 wherein the anti-fibrotic agent is not sirolimus.

4607. The method of claim 4509 wherein the anti-fibrotic agent is everolimus or an analogue or derivative thereof.

4608. The method of claim 4509 wherein the anti-fibrotic agent is tacrolimus or an analogue or derivative thereof.

4609. The method of claim 4509 wherein the anti-fibrotic agent is not tacrolimus.

4610. The method of claim 4509 wherein the anti-fibrotic agent is biolmus or an analogue or derivative thereof.

4611. The method of claim 4509 wherein the anti-fibrotic agent is tresperimus or an analogue or derivative thereof.

4612. The method of claim 4509 wherein the anti-fibrotic agent is auranofin or an analogue or derivative thereof.

4613. The method of claim 4509 wherein the anti-fibrotic agent is 27-0-demethylrapamycin or an analogue or derivative thereof.

4614. The method of claim 4509 wherein the anti-fibrotic agent is gusperimus or an analogue or derivative thereof.

4615. The method of claim 4509 wherein the anti-fibrotic agent is pimecrolimus or an analogue or derivative thereof.

4616. The method of claim 4509 wherein the anti-fibrotic agent is ABT-578 or an analogue or derivative thereof.

4617. The method of claim 4509 wherein the anti-fibrotic agent is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.

4618. The method of claim 4509 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof.

4619. The method of claim 4509 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-alpha-25 dihydroxy vitamin D3 or an analogue or derivative thereof.

4620. The method of claim 4509 wherein the anti-fibrotic agent is a leukotriene inhibitor.

4621. The method of claim 4509 wherein the anti-fibrotic agent is a MCP-1 antagonist.

4622. The method of claim 4509 wherein the anti-fibrotic agent is a MMP inhibitor.

4623. The method of claim 4509 wherein the anti-fibrotic agent is an NF kappa B inhibitor.

4624. The method of claim 4509 wherein the anti-fibrotic agent is an NF kappa B inhibitor, wherein the NF kappa B inhibitor is Bay 11-7082.

4625. The method of claim 4509 wherein the anti-fibrotic agent is an NO antagonist.

4626. The method of claim 4509 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor.

4627. The method of claim 4509 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB
202190.

4628. The method of claim 4509 wherein the anti-fibrotic agent is a phosphodiesterase inhibitor.

4629. The method of claim 4509 wherein the anti-fibrotic agent is a TGF beta inhibitor.

4630. The method of claim 4509 wherein the anti-fibrotic agent is a thromboxane A2 antagonist.

4631. The method of claim 4509 wherein the anti-fibrotic agent is a TNF alpha antagonist.

4632. The method of claim 4509 wherein the anti-fibrotic agent is a TACE inhibitor.

4633. The method of claim 4509 wherein the anti-fibrotic agent is a tyrosine kinase inhibitor.

4634. The method of claim 4509 wherein the anti-fibrotic agent is a vitronectin inhibitor.

4635. The method of claim 4509 wherein the anti-fibrotic agent is a fibroblast growth factor inhibitor.

4636. The method of claim 4509 wherein the anti-fibrotic agent is a protein kinase inhibitor.

4637. The method of claim 4509 wherein the anti-fibrotic agent is a PDGF receptor kinase inhibitor.

4638. The method of claim 4509 wherein the anti-fibrotic agent is an endothelial growth factor receptor kinase inhibitor.

4639. The method of claim 4509 wherein the anti-fibrotic agent is a retinoic acid receptor antagonist.

4640. The method of claim 4509 wherein the anti-fibrotic agent is a platelet derived growth factor receptor kinase inhibitor.

4641. The method of claim 4509 wherein the anti-fibrotic agent is a fibrinogen antagonist.

4642. The method of claim 4509 wherein the anti-fibrotic agent is an antimycotic agent.

4643. The method of claim 4509 wherein the anti-fibrotic agent is an antimycotic agent, wherein the antimycotic agent is sulconizole.

4644. The method of claim 4509 wherein the anti-fibrotic agent is a bisphosphonate.

4645. The method of claim 4509 wherein the anti-fibrotic agent is a phospholipase A1 inhibitor.

4646. The method of claim 4509 wherein the anti-fibrotic agent is a histamine H1/H2/H3 receptor antagonist.

4647. The method of claim 4509 wherein the anti-fibrotic agent is a macrolide antibiotic.

4648. The method of claim 4509 wherein the anti-fibrotic agent is a GPIIb/IIIa receptor antagonist.

4649. The method of claim 4509 wherein the anti-fibrotic agent is an endothelin receptor antagonist.

4650. The method of claim 4509 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor agonist.

4651. The method of claim 4509 wherein the anti-fibrotic agent is an estrogen receptor agent.

4652. The method of claim 4509 wherein the anti-fibrotic agent is a somastostatin analogue.

4653. The method of claim 4509 wherein the anti-fibrotic agent is a neurokinin 1 antagonist.

4654. The method of claim 4509 wherein the anti-fibrotic agent is a neurokinin 3 antagonist.

4655. The method of claim 4509 wherein the anti-fibrotic agent is a VLA-4 antagonist.

4656. The method of claim 4509 wherein the anti-fibrotic agent is an osteoclast inhibitor.

4657. The method of claim 4509 wherein the anti-fibrotic agent is a DNA topoisomerase ATP hydrolyzing inhibitor.

4658. The method of claim 4509 wherein the anti-fibrotic agent is an angiotensin I converting enzyme inhibitor.

4659. The method of claim 4509 wherein the anti-fibrotic agent is an angiotensin II antagonist.

4660. The method of claim 4509 wherein the anti-fibrotic agent is an enkephalinase inhibitor.

4661. The method of claim 4509 wherein the anti-fibrotic agent is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer.

4662. The method of claim 4509 wherein the anti-fibrotic agent is a protein kinase C inhibitor.

4663. The method of claim 4509 wherein the anti-fibrotic agent is a ROCK (rho-associated kinase) inhibitor.

4664. The method of claim 4509 wherein the anti-fibrotic agent is a CXCR3 inhibitor.

4665. The method of claim 4509 wherein the anti-fibrotic agent is an Itk inhibitor.

4666. The method of claim 4509 wherein the anti-fibrotic agent is a cytosolic phospholipase A2-alpha inhibitor.

4667. The method of claim 4509 wherein the anti-fibrotic agent is a PPAR agonist.

4668. The method of claim 4509 wherein the anti-fibrotic agent is an immunosuppressant.

4669. The method of claim 4509 wherein the anti-fibrotic agent is an Erb inhibitor.

4670. The method of claim 4509 wherein the anti-fibrotic agent is an apoptosis agonist.

4671. The method of claim 4509 wherein the anti-fibrotic agent is a lipocortin agonist.

4672. The method of claim 4509 wherein the anti-fibrotic agent is a VCAM-1 antagonist.

4673. The method of claim 4509 wherein the anti-fibrotic agent is a collagen antagonist.

4674. The method of claim 4509 wherein the anti-fibrotic agent is an alpha 2 integrin antagonist.

4675. The method of claim 4509 wherein the anti-fibrotic agent is a TNF alpha inhibitor.

4676. The method of claim 4509 wherein the anti-fibrotic agent is a nitric oxide inhibitor

4677. The method of claim 4509 wherein the anti-fibrotic agent is a cathepsin inhibitor.

4678. The method of claim 4509 wherein the anti-fibrotic agent is not an anti-inflammatory agent.

4679. The method of claim 4509 wherein the anti-fibrotic agent is not a steroid.

4680. The method of claim 4509 wherein the anti-fibrotic agent is not a glucocorticosteroid.

4681. The method of claim 4509 wherein the anti-fibrotic agent is not dexamethasone.

4682. The method of claim 4509 wherein the anti-fibrotic agent is not beclomethasone.

4683. The method of claim 4509 wherein the anti-fibrotic agent is not dipropionate.

4684. The method of claim 4509 wherein the anti-fibrotic agent is not an anti-infective agent.

4685. The method of claim 4509 wherein the anti-fibrotic agent is not an antibiotic.

4686. The method of claim 4509 wherein the anti-fibrotic agent is not an anti-fungal agent.

4687. The method of claim 4509 wherein the anti-infective agent isan anthracycline.

4688. The method of claim 4509 wherein the anti-infective agent isdoxorubicin.

4689. The method of claim 4509 wherein the anti-infective agent is ismitoxantrone.

4690. The method of claim 4509 wherein the anti-infective agent is a fluoropyrimidine.

4691. The method of claim 4509 wherein the anti-infective agent is 5-fluorouracil (5-FU).

4692. The method of claim 4509 wherein the anti-infective agent is a folic acid antagonist.

4693. The method of claim 4509 wherein the anti-infective agent is methotrexate.

4694. The method of claim 4509 wherein the anti-infective agent is a podophylotoxin.

4695. The method of claim 4509 wherein the anti-infective agent is etoposide.

4696. The method of claim 4509 wherein the anti-infective agent is camptothecin.

4697. The method of claim 4509 wherein the anti-infective agent is a hydroxyurea.

4698. The method of claim 4509 wherein the anti-infective agent is a platinum complex.

4699. The method of claim 4509 wherein the anti-infective agent is cisplatin.

4700. The method of claim 4509 wherein the composition comprises an anti-thrombotic agent.

4701. The method of claim 4509 wherein the polymer is formed from reactants comprising a naturally occurring polymer.

4702. The method of claim 4509 wherein the polymer is formed from reactants comprising protein.

4703. The method of claim 4509 wherein the polymer is formed from reactants comprising carbohydrate.

4704. The method of claim 4509 wherein the polymer is formed from reactants comprising biodegradable polymer.

4705. The method of claim 4509 wherein the polymer is formed from reactants comprising nonbiodegradable polymer.

4706. The method of claim 4509 wherein the polymer is formed from reactants comprising collagen.

4707. The method of claim 4509 wherein the polymer is formed from reactants comprising methylated collagen.

4708. The method of claim 4509 wherein the polymer is formed from reactants comprising fibrinogen.

4709. The method of claim 4509 wherein the polymer is formed from reactants comprising thrombin.

4710. The method of claim 4509 wherein the polymer is formed from reactants comprising blood plasma.

4711. The method of claim 4509 wherein the polymer is formed from reactants comprising calcium salt.

4712. The method of claim 4509 wherein the polymer is formed from reactants comprising an antifibronolytic agent.

4713. The method of claim 4509 wherein the polymer is formed from reactants comprising fibrinogen analog.

4714. The method of claim 4509 wherein the polymer is formed from reactants comprising albumin.

4715. The method of claim 4509 wherein the polymer is formed from reactants comprising plasminogen.

4716. The method of claim 4509 wherein the polymer is formed from reactants comprising von Willebrands factor.

4717. The method of claim 4509 wherein the polymer is formed from reactants comprising Factor VIII.

4718. The method of claim 4509 wherein the polymer is formed from reactants comprising hypoallergenic collagen.

4719. The method of claim 4509 wherein the polymer is formed from reactants comprising atelopeptidic collagen.

4720. The method of claim 4509 wherein the polymer is formed from reactants comprising telopeptide collagen.

4721. The method of claim 4509 wherein the polymer is formed from reactants comprising crosslinked collagen.

4722. The method of claim 4509 wherein the polymer is formed from reactants comprising aprotinin.

4723. The method of claim 4509 wherein the polymer is formed from reactants comprising epsilon-amino-n-caproic acid.

4724. The method of claim 4509 wherein the polymer is formed from reactants comprising gelatin.

4725. The method of claim 4509 wherein the polymer is formed from reactants comprising protein conjugates.

4726. The method of claim 4509 wherein the polymer is formed from reactants comprising gelatin conjugates.

4727. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic polymer.

4728. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic isocyanate-containing compound.

4729. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic thiol-containing compound.

4730. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two thiol groups.

4731. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three thiol groups.

4732. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four thiol groups.

4733. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic amino-containing compound.

4734. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic compound containing at least two amino groups.

4735. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic compound containing at least three amino groups.

4736. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic compound containing at least four amino groups.

4737. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group.

4738. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups.

4739. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.

4740. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.

4741. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound.

4742. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.

4743. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive amino groups.

4744. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive thiol groups.

4745. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups.

4746. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic compound comprising a biodegradable polyester block.

4747. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from lactic acid or lactide.

4748. The method of claim 4509 wherein the polymer is formed from reactants comprising a synthetic polymer formed in whole or part from glycolic acid or glycolide.

4749. The method of claim 4509 wherein the polymer is formed from reactants comprising polylysine.

4750. The method of claim 4509 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound comprising a polyalkylene oxide portion.

4751. The method of claim 4509 wherein the polymer is formed from reactants comprising (a) protein and (b) polylysine.

4752. The method of claim 4509 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four thiol groups.

4753. The method of claim 4509 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four amino groups.

4754. The method of claim 4509 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

4755. The method of claim 4509 wherein the polymer is formed from reactants comprising (a) protein and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

4756. The method of claim 4509 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound comprising a polyalkylene oxide portion.

4757. The method of claim 4509 wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine.

4758. The method of claim 4509 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four thiol groups.

4759. The method of claim 4509 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four amino groups.

4760. The method of claim 4509 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

4761. The method of claim 4509 wherein the polymer is formed from reactants comprising (a) collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

4762. The method of claim 4509 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound comprising a polyalkylene oxide portion.

4763. The method of claim 4509 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine.

4764. The method of claim 4509 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four thiol groups.

4765. The method of claim 4509 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four amino groups.

4766. The method of claim 4509 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

4767. The method of claim 4509 wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epison-caprolactone.

4768. The method of claim 4509 wherein the polymer is formed from reactants comprising hyaluronic acid.

4769. The method of claim 4509 wherein the polymer is formed from reactants comprising a hyaluronic acid derivative.

4770. The method of claim 4509 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.

4771. The method of claim 4509 wherein the polymer is formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.

4772. The method of claim 4509 wherein the polymer is formed from reactants comprising (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.

4773. The method of claim 4509 wherein the composition comprises a colorant.

4774. The method of claim 4509 wherein the composition is sterile.

4775. A method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with i) an anti-fibrotic agent, ii) an anti-infective agent, iii) a polymer;
iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host, wherein the medical device is an inferior vena cava filter.

4776. The method for implanting a medical device according to claim 4775 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-fibrotic agent, and (b) implanting the medical device into the host.

4777. The method for implanting a medical device according to claim 4775 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-infective agent, and (b) implanting the medical device into the host.

4778. The method for implanting a medical device according to claim 4775 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a polymer; and (b) implanting the medical device into the host.

4779. The method for implanting a medical device according to claim 4775 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent and a polymer, and (b) implanting the medical device into the host.

4780. The method for implanting a medical device according to claim 4775 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

4781. The method for implanting a medical device according to claim 4775 comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

4782. The method of claim 4775 wherein the medical device is a vascular filter.

4783. The method of claim 4775 wherein the medical device is a blood filter.

4784. The method of claim 4775 wherein the medical device is a caval filter.

4785. The method of claim 4775 wherein the medical device is a vena cava filter.

4786. The method of claim 4775 wherein the medical device is a thrombus filter.

4787. The method of claim 4775 wherein the medical device is an antimigration filter.

4788. The method of claim 4775 wherein the medical device is a percutaneous filter system.

4789. The method of claim 4775 wherein the medical device is an intravascular trap.

4790. The method of claim 4775 wherein the medical device is an intravascular filter.

4791. The method of claim 4775 wherein the medical device is a clot filter.

4792. The method of claim 4775 wherein the medical device is a vein filter.

4793. The method of claim 4775 wherein the medical device is a body vessel filter.

4794. The method of claim 4775 wherein the anti-fibrotic agent inhibits cell regeneration.

4795. The method of claim 4775 wherein the anti-fibrotic agent inhibits angiogenesis.

4796. The method of claim 4775 wherein the anti-fibrotic agent inhibits fibroblast migration.

4797. The method of claim 4775 wherein the anti-fibrotic agent inhibits fibroblast proliferation.

4798. The method of claim 4775 wherein the anti-fibrotic agent inhibits deposition of extracellular matrix.

4799. The method of claim 4775 wherein the anti-fibrotic agent inhibits tissue remodeling.

4800. The method of claim 4775 wherein the anti-fibrotic agent is an angiogenesis inhibitor.

4801. The method of claim 4775 wherein the anti-fibrotic agent is a 5-lipoxygenase inhibitor or antagonist.

4802. The method of claim 4775 wherein the anti-fibrotic agent is a chemokine receptor antagonist.

4803. The method of claim 4775 wherein the anti-fibrotic agent is a cell cycle inhibitor.

4804. The method of claim 4775 wherein the anti-fibrotic agent is a taxane.

4805. The method of claim 4775 wherein the anti-fibrotic agent is an anti-microtubule agent.

4806. The method of claim 4775 wherein the anti-fibrotic agent is paclitaxel.

4807. The method of claim 4775 wherein the anti-fibrotic agent is not paclitaxel.

4808. The method of claim 4775 wherein the anti-fibrotic agent is an analogue or derivative of paclitaxel.

4809. The method of claim 4775 wherein the anti-fibrotic agent is a vinca alkaloid.

4810. The method of claim 4775 wherein the anti-fibrotic agent is camptothecin or an analogue or derivative thereof.

4811. The method of claim 4775 wherein the anti-fibrotic agent is a podophyllotoxin.

4812. The method of claim 4775 wherein the anti-fibrotic agent is a podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof.

4813. The method of claim 4775 wherein the anti-fibrotic agent is an anthracycline.

4814. The method of claim 4775 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof.

4815. The method of claim 4775 wherein the anti-fibrotic agent is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof.

4816. The method of claim 4775 wherein the anti-fibrotic agent is a platinum compound.

4817. The method of claim 4775 wherein the anti-fibrotic agent is a nitrosourea.

4818. The method of claim 4775 wherein the anti-fibrotic agent is a nitroimidazole.

4819. The method of claim 4775 wherein the anti-fibrotic agent is a folic acid antagonist.

4820. The method of claim 4775 wherein the anti-fibrotic agent is a cytidine analogue.

4821. The method of claim 4775 wherein the anti-fibrotic agent is a pyrimidine analogue.

4822. The method of claim 4775 wherein the anti-fibrotic agent is a fluoropyrimidine analogue.

4823. The method of claim 4775 wherein the anti-fibrotic agent is a purine analogue.

4824. The method of claim 4775 wherein the anti-fibrotic agent is a nitrogen mustard or an analogue or derivative thereof.

4825. The method of claim 4775 wherein the anti-fibrotic agent is a hydroxyurea.

4826. The method of claim 4775 wherein the anti-fibrotic agent is a mytomicin or an analogue or derivative thereof.

4827. The method of claim 4775 wherein the anti-fibrotic agent is an alkyl sulfonate.

4828. The method of claim 4775 wherein the anti-fibrotic agent is a benzamide or an analogue or derivative thereof.

4829. The method of claim 4775 wherein the anti-fibrotic agent is a nicotinamide or an analogue or derivative thereof.

4830. The method of claim 4775 wherein the anti-fibrotic agent is a halogenated sugar or an analogue or derivative thereof.

4831. The method of claim 4775 wherein the anti-fibrotic agent is a DNA alkylating agent.

4832. The method of claim 4775 wherein the anti-fibrotic agent is an anti-microtubule agent.

4833. The method of claim 4775 wherein the anti-fibrotic agent is a topoisomerase inhibitor.

4834. The method of claim 4775 wherein the anti-fibrotic agent is a DNA cleaving agent.

4835. The method of claim 4775 wherein the anti-fibrotic agent is an antimetabolite.

4836. The method of claim 4775 wherein the anti-fibrotic agent inhibits adenosine deaminase.

4837. The method of claim 4775 wherein the anti-fibrotic agent inhibits purine ring synthesis.

4838. The method of claim 4775 wherein the anti-fibrotic agent is a nucleotide interconversion inhibitor.

4839. The method of claim 4775 wherein the anti-fibrotic agent inhibits dihydrofolate reduction.

4840. The method of claim 4775 wherein the anti-fibrotic agent blocks thymidine monophosphate.

4841. The method of claim 4775 wherein the anti-fibrotic agent causes DNA damage.

4842. The method of claim 4775 wherein the anti-fibrotic agent is a DNA intercalation agent.

4843. The method of claim 4775 wherein the anti-fibrotic agent is a RNA synthesis inhibitor.

4844. The method of claim 4775 wherein the anti-fibrotic agent is a pyrimidine synthesis inhibitor.

4845. The method of claim 4775 wherein the anti-fibrotic agent inhibits ribonucleotide synthesis or function.

4846. The method of claim 4775 wherein the anti-fibrotic agent inhibits thymidine monophosphate synthesis or function.

4847. The method of claim 4775 wherein the anti-fibrotic agent inhibits DNA synthesis.

4848. The method of claim 4775 wherein the anti-fibrotic agent causes DNA adduct formation.

4849. The method of claim 4775 wherein the anti-fibrotic agent inhibits protein synthesis.

4850. The method of claim 4775 wherein the anti-fibrotic agent inhibits microtubule function.

4851. The method of claim 4775 wherein the anti-fibrotic agent is a cyclin dependent protein kinase inhibitor.

4852. The method of claim 4775 wherein the anti-fibrotic agent is an epidermal growth factor kinase inhibitor.

4853. The method of claim 4775 wherein the anti-fibrotic agent is an elastase inhibitor.

4854. The method of claim 4775 wherein the anti-fibrotic agent is a factor Xa inhibitor.

4855. The method of claim 4775 wherein the anti-fibrotic agent is a farnesyltransferase inhibitor.

4856. The method of claim 4775 wherein the anti-fibrotic agent is a fibrinogen antagonist.

4857. The method of claim 4775 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

4858. The method of claim 4775 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist.

4859. The method of claim 4775 wherein the anti-fibrotic agent is a heat shock protein 90 antagonist, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof.

4860. The method of claim 4775 wherein the anti-fibrotic agent is a guanylate cyclase stimulant.

4861. The method of claim 4775 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor.

4862. The method of claim 4775 wherein the anti-fibrotic agent is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof.

4863. The method of claim 4775 wherein the anti-fibrotic agent is a hydroorotate dehydrogenase inhibitor.

4864. The method of claim 4775 wherein the anti-fibrotic agent is an IKK2 inhibitor.

4865. The method of claim 4775 wherein the anti-fibrotic agent is an IL-1 antagonist.

4866. The method of claim 4775 wherein the anti-fibrotic agent is an ICE antagonist.

4867. The method of claim 4775 wherein the anti-fibrotic agent is an IRAK antagonist.

4868. The method of claim 4775 wherein the anti-fibrotic agent is an IL-4 agonist.

4869. The method of claim 4775 wherein the anti-fibrotic agent is an immunomodulatory agent.

4870. The method of claim 4775 wherein the anti-fibrotic agent is sirolimus or an analogue or derivative thereof.

4871. The method of claim 4775 wherein the anti-fibrotic agent is not sirolimus.

4872. The method of claim 4775 wherein the anti-fibrotic agent is everolimus or an analogue or derivative thereof.

4873. The method of claim 4775 wherein the anti-fibrotic agent is tacrolimus or an analogue or derivative thereof.

4874. The method of claim 4775 wherein the anti-fibrotic agent is not tacrolimus.

4875. The method of claim 4775 wherein the anti-fibrotic agent is biolmus or an analogue or derivative thereof.

4876. The method of claim 4775 wherein the anti-fibrotic agent is tresperimus or an analogue or derivative thereof.

4877. The method of claim 4775 wherein the anti-fibrotic agent is auranofin or an analogue or derivative thereof.

4878. The method of claim 4775 wherein the anti-fibrotic agent is 27-0-demethylrapamycin or an analogue or derivative thereof.

4879. The method of claim 4775 wherein the anti-fibrotic agent is gusperimus or an analogue or derivative thereof.

4880. The method of claim 4775 wherein the anti-fibrotic agent is pimecrolimus or an analogue or derivative thereof.

4881. The method of claim 4775 wherein the anti-fibrotic agent is ABT-578 or an analogue or derivative thereof.

4882. The method of claim 4775 wherein the anti-fibrotic agent is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.

4883. The method of claim 4775 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof.

4884. The method of claim 4775 wherein the anti-fibrotic agent is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-alpha-25 dihydroxy vitamin D3 or an analogue or derivative thereof.

4885. The method of claim 4775 wherein the anti-fibrotic agent is a leukotriene inhibitor.

4886. The method of claim 4775 wherein the anti-fibrotic agent is a MCP-1 antagonist.

4887. The method of claim 4775 wherein the anti-fibrotic agent is a MMP inhibitor.

4888. The method of claim 4775 wherein the anti-fibrotic agent is an NF kappa B inhibitor.

4889. The method of claim 4775 wherein the anti-fibrotic agent is an NF kappa B inhibitor, wherein the NF kappa B inhibitor is Bay 11-7082.

4890. The method of claim 4775 wherein the anti-fibrotic agent is an NO antagonist.

4891. The method of claim 4775 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor.

4892. The method of claim 4775 wherein the anti-fibrotic agent is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB
202190.

4893. The method of claim 4775 wherein the anti-fibrotic agent is a phosphodiesterase inhibitor.

4894. The method of claim 4775 wherein the anti-fibrotic agent is a TGF beta inhibitor.

4895. The method of claim 4775 wherein the anti-fibrotic agent is a thromboxane A2 antagonist.

4896. The method of claim 4775 wherein the anti-fibrotic agent is a TNF alpha antagonist.

4897. The method of claim 4775 wherein the anti-fibrotic agent is a TACE inhibitor.

4898. The method of claim 4775 wherein the anti-fibrotic agent is a tyrosine kinase inhibitor.

4899. The method of claim 4775 wherein the anti-fibrotic agent is a vitronectin inhibitor.

4900. The method of claim 4775 wherein the anti-fibrotic agent is a fibroblast growth factor inhibitor.

4901. The method of claim 4775 wherein the anti-fibrotic agent is a protein kinase inhibitor.

4902. The method of claim 4775 wherein the anti-fibrotic agent is a PDGF receptor kinase inhibitor.

4903. The method of claim 4775 wherein the anti-fibrotic agent is an endothelial growth factor receptor kinase inhibitor.

4904. The method of claim 4775 wherein the anti-fibrotic agent is a retinoic acid receptor antagonist.

4905. The method of claim 4775 wherein the anti-fibrotic agent is a platelet derived growth factor receptor kinase inhibitor.

4906. The method of claim 4775 wherein the anti-fibrotic agent is a fibrinogen antagonist.

4907. The method of claim 4775 wherein the anti-fibrotic agent is an antimycotic agent.