AU770519B2 - DHA-pharmaceutical agent conjugates - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANT: Protarga, Inc.

ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street Melbourne, 3000.

IP Australia

CD

Documents received on: 0 1 7 JAN 2001 Batch No: Batch No: INVENTION TITLE: "DHA-pharmaceutical agent conjugates" The following statement is a full description of this invention, including the best method of performing it known to us: P:'OPER\MKR\SPECI\31425-97-divdoc-17/01/01 -1- DHA-PHARMACEUTICAL AGENT CONJUGATES This is a divisional of Australian patent application No. 31425/97, the disclosure of which is included herein in its entirety by way of reference.

Background of the Invention Improving drug selectivity for target tissue is an established goal in the medical arts. In general, it is desirable to deliver a drug selectively to its target, so that dosage and, consequently, side effects can be reduced. This is particularly the case for toxic agents such as anti-cancer agents because achieving therapeutic doses effective for treating cancer is often limited by the toxic side effects of the anti-cancer agent on normal, healthy tissue.

The problems relating to lack of drug selectivity can be exemplified by Taxol®.

Taxol® (paclitaxel) was first isolated in 1971 from the bark of Taxus brevifolia and was approved in 1992 by the US Food and Drug Administration for treatment of metastatic ovarian cancer and later for breast cancer. Its mechanism of action is believed to involve promoting formation and hyperstabilization of microtubules, thereby preventing the disassembly of microtubules necessary for completion of cell division. It also has been reported that Taxol induces expression of cytokines, affects the activity of kinases and blocks processes essential for metastasis, in as yet uncharacterized mechanisms of action.

Taxol has attracted unusually strong scientific attention, not only because of its unique antiproliferative mechanism of action, but also because it is active against nearly all cancers against which it has been tested and because it has been discovered to be an analog of numerous closely related compounds occurring naturally. These compounds, taxanes, are now recognized as a new class of anticancer compounds.

Taxol's strength against cancers of diverse tissue origin also represents a significant drawback. An ideal anticancer agent has tissue specificity, thereby reducing side-effects on normal (dividing) cells. Taxol analogs with tissue specificity therefore are desired.

Another drawback of Taxol is its extreme insolubility. Taxol can be administered effectively in a solvent including cremophor, which combination can provoke severe hypersensitive immune responses. As a result of these drawbacks, and also as a result of P:'OPER\MKR\SPECI\31425-97-div.doc-17/01/01 -1Athe potential for modifying Taxol at numerous sites as demonstrated by other naturallyoccurring taxanes with anticancer activity, a search for more selective taxanes was launched.

To date, more than 200 taxanes have been synthesized (or isolated) and tested in vitro or in vivo for anticancer activity. The results, however, have been so disappointing that the National Cancer Institute (NCI) generally no longer is interested in testing Taxol analogs. In general with Taxol analogs, the solubility problems remain, and/or potency is sharply reduced, and/or selectivity o *o ooooo *oo -2is not improved, and/or the ratio of the median toxic dose to the median effective dose ("therapeutic index") is unacceptably reduced.

Taxol has the following formula: i H AcO 0 OH )^H0Y^Bc 52'

OHH

OH HO A P Ac PhCO 2 Taxanes have the basic three ring structure B and substituted or unsubstituted.

Taxol's carbons are numbered conventionally as follows: is io 9 0 9 7 16; 13 09 P"-H 4 14 1 2 Based upon the taxanes tested to date, as many questions have been raised as have been answered, and general rules have not been fashioned easily in predicting selectivity, activity and solubility. Firstly, no rules have emerged regarding selectivity. Those taxanes that are strongly active appear to have activity as broad as Taxol's activity, and no headway appears to have been made in terms of developing a more selective Taxol analog.

20 Some information about activity'has emerged. Numerous substitutions have been made at C7, C9, C 10, C19, R, and combinations thereof while retaining significant, but usually reduced, oeeoo* activity. Substitutions at C2, C4 and 2'OI-I, however, are generally not tolerated. These conclusions are only generalities, for example, because some substitutions at C9-C 10 (cyclic derivatives) are not tolerated and some substitutions at C2 (meta substitutions on the phenyl) arc tolerated. Likewise, the C13 side chain and, in particular, the 2'OH are required, although the minimum structviral 6. requirements of the side chain have not been determined for therapeutic efficacy.

Attempts to improve Taxol's solubility have not resulted in successful clinical products. One approach has been to manulfacture prodrugs of Taxol, which prodrugs undergo in vivo transformation into Taxol and some other product. Attempts were made to esterify the C7 hydroxy and 2' hydroxy groups, with the hope that the bond would be stable in solution (to permit preferred administration modes over at least 24 hours) but would cleave readily in vivo. The groups tested were all hydrophilic and included amines, short carboxylic acids (using e.g. succinic anhydride and glutaric anhydride), sulfonic acids, amino acids and phosphates. Generally, activity was reduced although some success was obtained with certain derivatives. Again, no particular pattern emerged permitting one to predict reliably which groups could be substituted on Taxol to yield a therapeutically useful product, although it was suggested that the 2' OH derivatives may cleave more easily than the C7 O1 derivatives.

Several other factors add to the problem of predicting which Taxol analogs will be effective.

Multiple mechanisms of action have been proposed in the literature, and a change in one position may have no effect on activity on one such mechanism but may eliminate activity on another mechanism. In addition, changes that favorably influence activity may unfavorably influence bioavailability. For example, Taxol affects microtubule formation inside a cell, but a change in structure that increases intracellular activity may adversely affect the ability of Taxol to gain entry into a cell. Taxol also is known to bind to proteins, and the effect on activity that results from a change in Taxol's binding to protein (in terms of conformation, cellular absorption and solubility) is unknown.

It has been reported that Taxol does not get into the brain, apparently excluded by the blood brain barrier. It is not known why this is so, as Taxol is lipophilic, gets into cells and might be expected to cross the blood brain barrier.

Among the most promising of the two hundred analogs tested is Taxotere (docetaxel), because of its slightly increased activity and solubility. Oddly, however, Taxotere differs from 20 Taxol at sites which typically do not have a strong influence on activity, and one would not predict the improvements in Taxotere from these differences, even in hindsight.

Taxotere has the following formula: HO 0 OH 0 O NH 0 0 P k PhHO 6 O H J OAc 0 Ph DHA (docosahexaenoic acid) is a 22 carbon naturally-occurring, unbranchced fatty acid that previously has been attached to drugs to help deliver them across the blood brain barrier. DI-IA is attached via the acid group to hydrophilic drugs and renders these drugs more hydrophobic (lipophilic). DHA is an important constituent of the brain and recently has been approved in Europe -4as an additive to infant formula. It is present in the milk of lactating women. The mechanism of action by which DHA helps drugs conjugated to it cross the blood brain barrier is unknown.

Summary of the Invention The present invention involves the unexpected finding that conjugates of pharmaceutical agents and a highly lipophilic group, a C22 unbranched carbon chain, have a different selectivity relative to the unconjugated pharmaceutical agents. The conjugates, in general, render the activity of these compounds selective for colon tissue, breast tissue and central nervous system tissue ("targeted tissues"). The conjugates, also unexpectedly, restrict the activity of these compounds to cell types within these tissue categories relative to that of the unconjugated pharmaceutical agents.

The conjugates, further unexpectedly, reduce sharply the activity of these compounds relative to that of the unconjugated pharmaceutical agents in most cell lines of tissue types other than colon, breast, and central nervous system, thereby reducing potential side effects of the conjugates versus those of the unconjugated pharmaceutical agents. The therapeutic index of the conjugates may be improved, versus that of the unconjugated pharmaceutical agents.

According to one aspect of the invention, a method is provided for targeting a pharmaceutical agent to a noncentral nervous system tissue to treat a noncentral nervous system condition. A covalent conjugate of cis-docosahcxaenoic acid and a pharmaceutical agent effective for treating said condition is administered to a subject in need of such treatment. Preferably, the conjugate consists S 20 only of cis-docosahexaenoic acid and the pharmaceutical agent, wherein the cis-docosahexaenoic acid is conjugated directly to the pharmaceutical agent, fi'ee of linker, for example via the carboxylic acid group of the cis-docosahcxaenoic acid and a reactive group such as a free amino or hydroxyl group of the pharmaceutical agent. In preferred embodiments, the tissue is breast tissue, gastrointestinal tissue and ovarian tissue and the condition calls for treatment of breast tissue, gastrointestinal tissue or ovarian tissue, respectively.

The conjugates of the invention can be isolated conjugates. An isolated conjugate is one which is separated from other different docosahexaenoic acid-pharmaceutical agent conjugates.

The pharmaceutical agent may be any pharmacological compound or diagnostic agent, as desired. The pharmaceutical agent, of course, has an activity outside of the central nervous system.

Examples of catagorics of pharmaceutical agents include: adrenergic agent; adrenocortical steroid; adrenocortical suppressant; alcohol deterrent; aldosterone antagonist; amino acid; ammonia detoxicant; anabolic; analeptic; analgesic; androgen; anesthesia, adjunct to; anesthetic; anorectic; antagonist; anterior pituitary suppressant; anthelmintic; anti-acne agent; anti-adrenergic; anti-allergic; anti-amebic; anti-androgen; anti-anemic; anti-anginal; anti-anxiety; anti-arthritic; anti-asthmatic; anti-atherosclerotic; antibacterial; anticholelithic; anticholelithogenic; anticholinergic; anticoagulant; anticoccidal; anticonvulsant; antidepressant; antidiabetic; antidiarrheal; antidiuretic; antidote; anti-emetic; anti-epileptic; anti-estrogen; antifibrinolytic; antifungal; antiglaucoma agent; antihemophilic; antihemorrhagic; antihistamine; antihyperlipidemia; antihyperlipoproteinemic; antihypertensive; antihypotensive; anti-infective; anti-infective, topical; anti-inflammatory; antikeratinizing agent; antimalarial; antimicrobial; antimigraine; antimitotic; antimycotic, antinauseant, antineoplastic, antineutropenic, antiobessional agent; antiparasitic; antiparkinsonian; antiperistaltic, antipneumocystic; antiproliferative; antiprostatic hypertrophy; antiprotozoal; antipruritic; antipsychotic; antirheumatic; antischistosomal; antiseborrheic; antisecretory; antispasmodic; antithrombotic; antitussive; anti-ulcerative; anti-urolithic; antiviral; appetite suppressant; benign prostatic hyperplasia therapy agent; blood glucose regulator; bone resorption inhibitor; bronchodilator; carbonic anhydrase inhibitor; cardiac depressant; cardioprotectant; cardiotonic; cardiovascular agent; choleretic; cholinergic; cholinergic agonist; cholinesterase deactivator; coccidiostat; cognition adjuvant; cognition enhancer; depressant; diagnostic aid; diuretic; dopaminergic agent; ectoparasiticide; emetic; enzyme inhibitor; estrogen; fibrinolytic; fluorescent agent; free oxygen radical scavenger; gastrointestinal motility effector; .i glucocorticoid; gonad-stimulating principle; hair growth stimulant: hemostatic; histamine H2 receptor antagonists; hormone; hypocholesterolemic; hypoglycemic; hypolipidemic; hypotensive; imaging agent; immunizing agent; immunomrnodulator; immnunoregulator; immunostimulant; iimunosuppressant; impotence therapy adjunct; inhibitor; keratolyic; LNRI-1 agonist; liver disorder ~treatment; luteolysin; memory adjuvant; mental performance enhancer; mood regulator; mucolytic; mucosal protective agent; mydriatic; nasal decongestant; neuromuscular blocking agent; neuroprotective; NMDA antagonist; non-hormonal sterol derivative; oxytocic; plasminogen activator; platelet activating factor antagonist; platelet aggregation inhibitor; post-stroke and post-head trauma treatment; potentiator; progestin; prostaglandin; prostate growth inhibitor; prothyrotropin; psychotropic; pulmonary surface; radioactiv agent; regulator; relaxant; repartitioning agent; scabicide; sclcrosing agent; sedative; scdativc-hypnotic; selective adenosine Al antagonist; serotonin antagonist; serotonin inhibitor; serotonin receptor antagonist; steroid; stimulant; suppressant; symptomatic multiple sclerosis; syncrgist; thyroid hormone; thyroid inhibitor; thyromimctic; tranquilizer; treatment of arnyotrophic lateral sclerosis; treatment of cerebral ischemia; treatment of Paget's disease; treatment of unstable angina; uricosuric; vasoconstrictor; vasodilator; vulnerary; wound healing agent; xanthine oxidase inhibitor.

In important embodiments of the invention, the pharmaceutical agent is a non anti-cancer agent. In another embodiment of the invention, the pharmaceutical agent is an anti-cancer agent.

Examples of anti-cancer agents are described in greater detail in the specification. Included specifically are the taxanes Taxol and Taxotere). Conjugates ofcis-docosahexaenoic acid and taxoids also are embraced by the invention.

Cis-docosahexaenoic acid previously has been conjugated to drugs that are active in the central nervous system. The present invention contemplates the use ofcis-docosahexaenoic acid in the manufacture of a medicament for treating a noncentral nervous system condition. The invention further contemplates compositions of matter that are covalent conjugates of cis-docosahexaenoic acid and noncentral nervous system active pharmaceutical agents. A noncentral nervous system active pharmaceutical agent is one that has no function or use in the central nervous system. Its only therapeutic use is outside of the central nervous system. Examples of such agents include, but are not limited to: Blood glucose regulators, such as tolazamide, tolbutamide, chlorpropamide, acetohexamide, and, glipizide; HMGcoA reductase inhibitors, such as Lovastatin (Mevacor), Simvastatin (Zocor), Pravastatin (Pravachol), and, Fluvstatin (Lescol); Muscosal Protectives, such as Misoprostol (Cytotec); Gastrointestinal motility affectors, such as Cisapride (Propulsid), .Metoclopramide (Reglan), and, Hyoscyamine (Levsin); Antidiarrheals, such as Diphenoxylate 20 hydrochloride (Lomotil), Metronidazolc (Flagyl), Methylprednisolone (Medrol), and, Sulfasalazine .:..'(Azulfidine); and Hormones for treating, inter alia, ovarian conditions, such as Progesterone, Norgestrel, Norethynodrel. Norethindrone, Levonorgestrel, Ethyndiol, Mestranol, Estrone, Equilin, 17 alpha dihydroequilin, equilenin, 17 alpha dihydroequilenin, 17 alpha esradiol, 27 bea estradiol, Leuprolide (Lupron), Tcstolactone, Climiphene, urofollitropin, bromocriptinc. gonadorelin, danazol, dehydroepiandrosterone, androstenedione, dihydrotestosterone, Relaxin, folliculostatin, Follicle regulatory protein, Gonadocrinins, Oocyte maturation inhibitor, and, Insulin growth factor. Other compounds are detailed below.

The methods and/or products of the invention are useful for treating a variety of medical conditions including conditions involving abnormal mammalian-cell proliferation. They further arc useful in treating diabetes and its complications, excess acid secretion, cardiovascular conditions involving cholesterol hyperlipidemia and hypercholcsterolcmia), diarrhea, ovarian diseases endometriosis, ovarian cysts, etc.) and as contraceptive agents. Other conditions treatable P:OPER\MKR\SPECI\31425-97-div.doc-17/01/01 -7according to the invention will be apparent to those skilled in the art based upon the disclosure and lists of compounds provided.

The methods and/or products of the invention also are useful in treating conditions specific to noncentral nervous system tissue. Such conditions can be specific to breast tissue, gastrointestinal tissue and ovarian tissue. The tissue also may be other noncentral nervous system tissues. Noncentral nervous system tissue includes tissue of the: Blood and Blood Forming system: including platelets, blood vessel wall, and bone marrow; Cardiovascular system; including heart and vascular system; Digestive and excretory system: including alimentary tract, biliary tract, kidney, liver, pancreas and urinary tract; Endocrine system: including adrenal gland, kidney, ovary, pituitary gland, renal gland, salivary gland, sebaceous gland, testis, thymus gland and thyroid gland; Muscular system: including muscles that move the body. Reproductive System: including breast, ovary, penis and uterus; Respiratory system: including bronchus, lung and trachea; Skeletal system: including bones and joints; Tissue, fiber and integumentary system: including adipose tissue, cartilage, connective tissue, cuticle, dermis, epidermis, epithelium, fascia, hair follicle, ligament, bone marrow, melanin, melanocyte, mucous membrane, skin, soft tissue, synovial capsule and tendon.

In a preferred embodiment of the invention there is provided a method for targeting a pharmaceutical agent to a noncentral nervous system tissue to treat a noncentral nervous system condition comprising: administering to a subject in need of such treatment a covalent conjugate of cisdocosahexaenoic acid and a pharmaceutical agent effective for treating said condition.

In another preferred embodiment of the invention there is provided a pharmaceutical preparation comprising: 25 a covalent conjugate of cis-docosahexaenoic acid and a noncentral nervous system active agent, and a pharmaceutically acceptable carrier.

P:\OPER\MKR\SPEC[31425-97-div.doc-17/01/01 -7A- Brief Description of the Drawings Figure 1 is a graph plotting concentration of conjugate 1 leukemia cells.

Figure 2 is a graph plotting concentration of conjugate 1 non-small cell lung cancer cells.

Figure 3 is a graph plotting concentration of conjugate 1 colon cancer cells.

Figure 4 is a graph plotting concentration of conjugate 1 CNS cancel cells.

Figure 5 is a graph plotting concentration of conjugate 1 melanoma cells.

Figure 6 is a graph plotting concentration of conjugate 1 ovarian cancer cells.

Figure 7 is a graph plotting concentration of conjugate 1 renal cancer cells.

Figure 8 is a graph plotting concentration of conjugate prostate versus percent growth of versus percent growth of versus percent growth of versus percent growth of versus percent growth of versus percent growth of versus percent growth of 1 versus percent growth of i

S

cancer cells.

Figure 9 is a graph plotting concentration of conjugate I versus percent growth of breast cancer cells.

Figure 10 is a graph plotting concentration of conjugate 2 versus percent growth of leukemia cells.

Figure 11 is a graph plotting concentration of conjugate 2 versus percent growth of non-small cell lung cancer cells.

Figure 12 is a graph plotting concentration of conjugate 2 versus percent growth of colon cancer cells.

Figure 13 is a graph plotting concentration of conjugate 2 versus percent growth of CNS cancer cells.

Figure 14 is a graph plotting concentration of conjugate 2 versus percent growth of melanoma cells.

Figure 15 is a graph plotting concentration of conjugate 2 versus percent growth of ovarian cancer cells.

Figure 16 is a graph plotting concentration of conjugate 2 versus percent growth of renal cancer eel Is.

Figure 17 is a graph plotting concentration of conjugate 2 versus percent growth of prostate cancer cells.

Figure 18 is a graph plotting concentration of conjugate 2 versus percent growth of breast cancer cells.

Figure 19 is a graph plotting concentration of Taxol versus percent growth of leukemia cells.

:Fi igure 20 is a graph plotting concentration ofTaxol versus percent growth of non-small cell lung cancer cells.

6* O Figure 21 is a graph plotting concentration ofTaxol versus percent growth of colon canccr l'g: cells.

Figure 22 is a graph plotting concentration of Taxol versus percent growth of CNS cancer cells.

Figure 23 is a graph plotting concentration of Taxol versus percent growth of melanoma 30 cells.

Figure 24 is a graph plotting concentration ofTaxol versus percent growth of ovarian cancer cells.

-9- Figure 25 is a graph plotting concentration of Taxol versus percent growth of renal cancer cells.

Figure 26 is a graph plotting concentration of Taxol versus percent growth of prostate cancer cells.

Figure 27 is a graph plotting concentration of Taxol versus percent growth of breast cancer cells.

Detailed Description of the Invention Cis-docosahexaenoic acid (DHA) is a naturally occurring fatty acid. It is an unbranched chain fatty acid with six double bonds, all cis. Its structure is as follows: 0 DHA can be isolated, for example, from fish oil or can be chemically synthesized. These methods, however, can generate trans isomers, which are difficult and expensive to separate and which may present safety problems in humans. The preferred method of production is biological synthesis to produce the all cis isomer. The preferred source of DHA is from Martek Biosciences Corporation of Columbia, Maryland. Martek has a patented system for manufacturing DHA using microalgac which synthesize only a single isomer of DHA, the all cis isomer. Martek's patents 20 include U.S. Pat. Nos. 5,374,657, 5,492,938, 5,407,957 and 5,397,591.

DHA also is present in the milk of lactating women, and Martck's licensee has obtained approval in Europe of DIA as a nutritional supplement for infant formula.

It is known that DHA can be unstable in the presence of oxygen. To stablizie DH-A and its conjugates it is important to add anti-oxidants to the material after it is synthesized. One method of 25 stablization is to make-up the newly synthesized material in the following solution: 100 g neat DIIA-taxol plus 100 g of vehicle (100ml propylcne glycol, 70 mg alph-tocopherol, 5 mg dialaurylthiodipropionic acid, 50 mg ascorbic acid) prepared and held under argon in amber, sealed vials and stored at four degrees centigrade. The following anti-oxidants may also be employed: ascorbic acid, ascorbyl palmitate, dilauryl ascorbate, hydroquinone, butyated hydroxyanisole, .4 30 sodium meta bisulfitc, I-pI carotenc and ca-tocophcrol. A heavy metal chelator such as ethylenediamine tetra-acetic acid (EDTA) may also be used.

Paclitaxcl was first isolated from the bark of Taxu brcvifolia (Wani ct al., J. Anm Chem.

So,93, 2325, 197 Its isolation and synthesis have been reported extensively in the literature.

Applicants obtained paclitaxcl from a commercial source. Hauser Laboratories, of Boulder, Colorado.

TAXOL

A

OH

Ph'L NH 0 0 HO 0 S A0 OAc 0 0 Ph conjugate 1 A solution of Taxol (41 l tmol) in methylene chloride (2.5mL) under argon was mixed with 4-dimethylaminopyridine (41 pinol), dicyclohexylcarbodiimide (82.irnol), and DH-A (41 pmol) and the reaction mixture was stirred at ambient temperature for two hours. Following dilution with ether, the reaction mixture was washed with 5% hydrochloric acid, water, saturated aqueous sodium chloride, dried, and concentrated. Radial chromatography of thie residue produced 45mg of crystalline Taxol-D-A conjugate 1.

Exanp-le 2 AGO 0 OH TAXOL _4'N 0 HI 0 OSi0 3 HO 6 0~1. Ph 25 0 A 0 o* 0 Ph NH 0 -H B O 0 AcO 00 0 Ph NH 0 Ph 0C 0 conjugatec2 6H

HOD

OAC

0 Ph -11 The production of analog 2 involves several steps including a number of protection-acylation-deprotection steps. A solution of Taxol (59grmol) in methylene chloride was mixed at aribient temperature under argon with imidazole (147gamol) and triethylsilyl chloride (147mniol). The reaction mixture was stirred for thirty minutes, diluted with additional methylene chloride, washed with water, saturated aqueous sodium chloride, dried, and concentrated.

Chromatography of the residue produced 50mg of intermediate A plus 5mg of the 2', 7-di(triethylsilyl) ether derivative. A solution of intermediate A (52pmol) in methylene chloride (3mL) was mixed at ambient temperature under argon with 4-dimethylaminopyridine (52ptmol), dicyclohexylcarbodiimide (104[mol), and DHA (52pmol). The reaction mixture was stirred for ten hours, diluted with ether, passed through celite, and concentrated. Chromatography of the residue produced 65.9mg of intermediate B. A solution of intermediate B (51 mol) in acetonitrile (2mL) at 0°C under argon was mixed with 49% aqueous -IF (0.2rL) and the reaction mixture was stirred for one hour. After dilution with ether, the reaction mixture was washed with water, saturated aqueous sodium chloride, dried, and concentrated. Radial chromatography of the residue produced 44.6mg of Taxol-DHA conjugate 2.

Example 3 Conjugates 1 and 2 were sent to the United States National Cancer Institute (NCI) for screening in the NCI's anticancer screening program. The conjugates were provided in ethanol 20 (approximately 40mg analog/2ml ethanol). The conjugates were sealed in vials under argon to avoid exposure of the conjugates to oxygen because the conjugates were believed to be sensitive to oxygen. Instructions were provided to store at 4*C and to open the vials only when ready for immediate experimental use. Instructions also were provided to use the cthanol solutions containing the conjugates directly or to dissolve the analogs further in DMSO (dimethylsulfoxidc) at 25 appropriate concentrations, with vortexing if necessary for adequate dispersal.

The activities of conjugates I and 2 were tested against 57 cancer cell lines. The results are presented in Figs. 1-9 for conjugate 1, Figs. 10-18 for conjugate 2 and Figs 19-27 for Taxol. To understand the data, reference is made to the guides provided by the NCI, excerpted as follows: -12 The Calculated Measurement of Effect: Percentage Growth (PG) The measured effect of the compound on a cell line is currently calculated according to one or the other of the following two exprcssions: If (Mean -Mean 2 0, then PG 100 x (Mean OD,, -Mean ODc,,, -Mean Od,,ro) If (Mean -Mean 0, then PG 100 x (Mean -Mean Od,,,,)/Mean Od,,,o Where: Mean OD,,, Mean OD,,, Mean The average of optical density measurements of SRB*-derived color just before exposure of cells to the text compound.

S The average of optical density measurements of SRB*-derived color after 48 hours exposure of cells to the test compound.

S The average of optical density measurements of SRB*-derived color after 48 hours with no exposure of cells to the test compound.

*where SRB is an abbreviation for sulforhodamine B.

Experimental data was collected against each cell line. Each concentration is expressed as the logto (molar or pg/ml). The response parameters GI50, TGI (Total Growth Inhibition), and LC50 are interpolated values representing the concentrations at which the PG is +50, 0 and -50, respectively. Sometimes these response parameters cannot be obtained by interpolation. If, for instance, all of the PGs in a given row exceed +50, then none of the three parameters can be obtained by interpolation. In such a case, the value given for each response parameter is the highest concentration tested. This practice is extended similarly to the other possible situations where a response parameter cannot be "obtained by interpolation.

-13- Dose-Response Curves: The dose-response curve page of the data package is created by plotting the PGs against the log, 0 of the corresponding concentration for every cell line. The cell line curves are grouped by subpanel.

Horizontal lines are provided at the PG values of +50, 0, and -50. The concentrations corresponding to points where the curves cross these lines are the G150, TGI and LC50, respectively.

Several important distinctions are apparent from the data. Most important, the patterns of anticancer actively for conjugates 1 and 2 differ from that of Taxol. In one sense, conjugates I and 2 are effective anticancer agents against a more restricted set of cancer cell lines. For example, conjugates 1 and 2 were not very effective against any of the six leukemia cancer cell lines tested, whereas Taxol was somewhat effective against all four leukemia cell lines against which Taxol was tested. (See Figs. 1, 10 and 19.) The relative activity against members within a class of cancers also was altered. For example, at TGI (horizontal line at zero in the graphs), Taxol was more effective against non-small cell lung cancer line H522 than against H460 (by about 3 logs), whereas conjugates 1 and 2 were slightly more effective against 1-1460 than H522. As another example, Taxol was least effective at TGI against CNSU251, whereas conjugate 1 was most effective against CNSU251 and conjugates 2 was also very effective against CNSU251 (relative to other CNS cell lines). As a further example, 20 Taxol was equivalent in activity toward'MDA-N and MDA-MB-435 breast cancer cell lines at all concentrations tested, whereas conjugates I and 2 were more effective against MDA-N than S MDA-MB-435 at all concentrations tested.

To further illustrate the diffcrenccs in the activity of conjugates I and 2 versus that of Taxol, the NCI subjected the data to a statistical analysis designed by the NCI to reflect differences in the 25 pattern of activity of anticancer agents. Conjugate I and conjugate 2 were determined top be statistically different in their pattern of activity versus Taxol in this unique measurement by the NC1.

It also is to be noted that, in general, conjugates I and 2 were one thousand to ten thousand times less potent than Taxol for many cell lines tested. This reduction in activity is important, 30 especially since conjugates 1 and 2 maintained strong activity against some cell lines. Conjugates I and 2 will be sufficiently active against certain cell lines, but will have, on average, a substantially and disproportionately lower activity against other cell lines, reducing potential side effects. For -14example, the TGI for Taxol against CNS SF-539 is -6.95, and the TGI for conjugate 1 against this cell line is -5.13 and for conjugate 2 is -5.53. (In other words, the activity of the conjugates was reduced versus that of Taxol by less than 2 logs). The GI50 for Taxol against CNS SF 539 is -7.52, whereas the GI50s for conjugates 1 and 2 are -6.22 and -5.56, respectively (again less than 2 logs difference). In contrast, Taxol has a GI50 for cell line CNSSF 268 of less than -10.0, whereas conjugates 1 and 2 have GI50s for CNSSF 268 of 5.36 and 5.28, respectively. This represents a reduction of activity in the conjugates vs. that of Taxol by at least about 5 logs activity! On average, the GI50 for Taxol across all cell lines tested is at least -9.19. (It is probably much higher since concentrations less than -10 were not tested, and if Taxol was active at -10.0, -10 (instead of the to actual lower value) was used in calculating the average of -9.19. There were 27 instances when this occurred.) The average GIS0s for conjugates 1 and 2 on the other hand, were 5.49 and 5.22, respectively. Therefore, the average difference in activity for Taxol vs. the conjugates is at least between 3 and 4 logs. Thus, the sharp reduction in the activity of the conjugates against many cell lines vs. a lesser reduction for other cell lines is expected to reduce the potential side effects of the conjugates versus those of Taxol at effective doses.

Cancers other than CNS, breast and colon cancer can be treated. For example, there was activity against non-small cell lung cancer cells, melanoma cells and ovarian cancer cells. However, the activity was relatively reduced and was extremely specific, limiting the utility of the conjugates for treating generally such cancers. In any event, cancer patients could be evaluated to determine 20 if a conjugate is strongly active against the patient's cancer prior to selecting the conjugate as the anti-cancer agent of choice for that patient.

The foregoing experiments establish that DH-A analogs have altered specificity versus that of Taxol for cancer cell lines. Because of this altered specificity, it also is clear that the conjugates themselves are gaining access into the target cells (as opposed to simply releasing Taxol into the 25 environment outside o' the cell). Thus, the DHA moiety appears to selectively target certain cell types as opposed to others. The ability of the conjugates to gain entry into the cells was unknown prior to the invention, and the ability of the DI-IA moiety to selectively target certain cell types was Sunexpected.

The same is true of DHA-Taxotere covalent conjugates, examples of which are presented S 30 below. Taxotere's synthesis has been reported extensively in the literature. One example is IKanazawa. A. ct al., Organic Chem. 1994, Vol. 59, pp. 1238-1240.

Examplc 4I

TAXOTERE

DHAl/dicycko .4-dimethy ~hexycadbodiirde 0Q 0 NH 0 'Laminopyndine P 0 0 HO 0 Ph conjugate 3 A solution of Taxotere in methylene chloride under argon is mixed with 4-dimethylaminopyridifle, dicyclohexylcarbod iirnidc, and DI-A. Thle reaction mixture is stirred at ambient tcmperature. Radial chromatography of the residue is performed to produce Taxotere-DFIA conIJUgate 3.

Examplc TAXOTERE I~riethylsilyl chloride H ~(HH) TAXOTERE iamidazole,0 N 0 20 Ph~i'-JO 0

(CH

3 CH,7)si6 HO 6 C

OAC

DHA dicyclohexylc-arbodiimide 25 4 .dimneihylamninopyndine aqueous HF 0 0 OS7i(CH 2 CHa)3 0 Ph'" 0 M D (CH 3

CH

2 3 S10 O 0 QAc 0 HO! P 0 0 0 OH 0LNH 0 Ph' 0 Co nju gate 4 6HHO OAc 0 1 Ph

S..

S

16- A solution of Taxotere, in dimethylformamide is mixed at ambient temperature under argon with irnidazole and triethylsilyl chloride. The reaction mixture is stirred at ambient temperature, diluted with mnethylene chloride, washed with water, saturated acqueous sodium chloride, dricd, and concentrated. Radial chromatography of the residue is performed to produce intermediate C. A solution of intermediate C in methylene chloride is mixed at ambient temperature under argon with 4 dimethylaminopyridine, dicyclohexylcarbodiimide, and DHA. The reaction mixture is stirred at ambient temperature, diluted with ether, passed through celite, and concentrated. Radial chromatography of the residue is performed to produce intermediate D. A solution of intermediate D in acctonitrile at 0 0 C under argon is mixed with 49% aqueous I-IF and thle reaction mixture is i0 stirred at the same temperature. After dilution with ether, the reaction mixture is washed with water, saturated aqueous sodium chloride, dried, and concentrated Radial chromaitography of the residue is performed to produce Taxotere-DHA conjugate 4.

Exa mpl 6 f~~~erf-butyldimethylsilyl chloride X O~H o H O TAXOTERE N imidazole ItI-C 4

H

9

(CH

3 2 SiO HO 0

OAC

E 0 Ph 200 1 equivalent OHA O H dicyclohiexytcarbodiimide :4 -dimethylaminopyridine 0~o NHO0 f trC 4 Hi 9

(CH

3 2 SiO HO 6OAc Ph o0 O aqueous HF .0 0 0O H 0O HOc conjugate 4 0 Ph -17- A solution of Taxotere in dimethylforman-ide is mixed at ambient tcmpcrature under argon with imidazole and tort-butylydimnethylsilyl chloride. The reaction mixture is stirred at ambient temperature, diluted with methylene chloride, washed with water, saturated aqueous sodium chloride, dried, and concentrated. Radial chromatography of the residue is performed to produce s intermediate E. A solution of intermediate E in methylene chloride is mixed at ambient temperature under argon with 4-dimethylaminopyridine, dicyr-lohiexylcarbodiimide, and I equivalent of DHA.

The reaction mixture is stirred at ambient temperature, diluted with ether, passed through celite, and concentrated. Radial chromatography of the residue is performed to produce intermediate F.

(Intermediate H also is obtained and used in Example 8 below.) A solution of intermediate F in i o acetonitrile at 0 0 C under argon is mixed with aqucous.HF and the reaction mixture is stirred at the same temperature. After dilution with ether, the reaction mixture is washed with water. saturated aqueous sodium chloride, dried, and concentrated Radial chromatography of the residLIc is performed to produce Taxotere-DHA conjugate 4.

Exaruplc 7 lenlbulyldimethylsilyt chloride TAXOTERE imidazoic 0 HO 0 OH 1crf-CH(CH);SiO HO 0

A

0 '-Ph1 S. *.S

S

OHA i dicyclohexyica 25 4-dimethylaminop S30 aqueous HF 0 rb-odiidc 0> J NHO0 indine Ph 0

HO:

fen-C'RJ(CH.') 2 Si0 b Ac G 0, Ph 0 Ph O

HO

OH 0 OAc conjugate 0 1 Ph 18- A solution of Taxotere in dimethylformamide is mixed at ambient temperature under argon with imidazole and tert-butylydimethylsilyl chloride. The reaction mixture is stirred at ambient temperature, diluted with methylene chloride, washed with water, saturated aqueous sodium chloride, dried, and concentrated. Radial chromatography of the residue is performed to produce intermediate E. A solution of intermediate E in methylene chloride is mixed at ambient temperature under argon with 4-dimethylaminopyridine, dicyclohexylcarbodiimide, and DHA. The reaction mixture is stirred at ambient temperature, diluted with ether, passed through celite, and concentrated.

Radial chromatography of the residue is performed to produce intermediate G. A solution of intermediate G in acetonitrile at 0°C under argon is mixed with aqueous HF and the reaction mixture is stirred at the same temperature. After dilution with ether, the reaction mixture is washed with water, saturated aqueous sodium chloride, dried, and concentrated. Radial chromatography of the residue is performed to produce Taxotere-DHA conjugate Example 8 1 equivalent DHA dicydohexylarbodiimide 4-dimehylaminopyudine a a a 0 0 NH 01 PHO 11 rernlCH (CH) 2 SiO HO A O OAc O0P P h

H

0 0 HO 0 OH HOO SOAc 0 Ph aqueous HF 1 conjugate 6 -19- A solution oftaxotere in dimethylformamide is mixed at ambient temperature under argon with imidazole and tert-butylydimethylsilyl chloride. The reaction mixture is stirred at ambient temperature, diluted with methylene chloride, washed with water, saturated aqueous sodium chloride, dried, and concentrated. Radial chromatography of the residue is performed to produce intermediate E. A solution of intermediate E in methylene chloride is mixed at ambient temperature under argon with 4-dimethylaminopyridine, dicyclohexylcarbodiimide, and 1 equivalent of DHA.

The reaction mixture is stirred at ambient temperature, diluted with ether, passed through celite, and concentrated. Radial chromatography of the residue is performed to produce intermediate H (and intermediate F which was used above on Example 6. A solution of intermediate H in acetonitrite lo at 0°C under argon is mixed with aqueous HF and the reaction mixture is stirred at the same temperature. After dilution with ether, the reaction mixture is washed with water, saturated aqueous sodium chloride, dried, and concentrated. Radial chromatography of the residue is performed to produce Taxotere-DHA conjugate 6.

DHA may be conjugated to virtually any drug compound or diagnostic agent and used according to the methods of the present invention so long as the pharmaceutical agent has a use outside of the central nervous system. Pharmaceutical agents include the following categories and specific examples. It is not intended that the category be limited by the specific examples. Those of ordinary skill in the art will be able to identify readily those pharmaceutical agents that have utility outside of the central nervous system. Those of ordinary skill in the art will recognize also 20 numerous other compounds that fall within the categories and that are useful according to the invention.

Adrcnergic: Adrenalone; Amidcphrine Mesylate; Apraclonidine Hydrochloride; Brimonidine Tartrate; Dapiprazole Hydrochloride; Deterenol Hydrochloride; Dipivefrin; Dopamine 25 Hydrochloride; Ephcdrine Sulfate; Epinephrinc; Epincphrine Bitartratc; Epinephryl Boratc; Esproquin Hydrochloride; Etafedrine Hydrochloride; Hydroxyamphetamine Hydrobromide; Levonordefrin; Mephentermine Sulfate; Metaraminol Bitartrate; Metizoline H-ydrochloride; Naphazoline Hydrochloride; Norepincphrine Bitartrate; Oxidopamine; Oxymetazoline Hydrochloride; Phenylcphrine Hydrochloride; Phenylpropanolaminc Hydrochloride; Phenylpropanolamine Polistirex; Prenalterol l-Iydrochloride; Propylhexedrine; Pscudocphedrine Hydrochloride; Tctrahydrozoline Hydrochloride; Tramazoline lydrochloridc; Xylomctazoline Hydrochloride.

20 Adrenocortical steroid: Ciprocinonide; Desoxycorticosterone Acetate; Desoxycorticosterone Pivalate; Dexamethasone Acetate; Fludrocortisone Acetate; Fl urnoxonide; Hydrocortisone Hemisuccinate; Methyiprednisolone Hemisuccinate; Naflocort; Procinonide; Tirnobesone Acetate; Tipredanc.

Adrenocortical suppressant: Aminoglutethimide; Trilostane.

Alcohol deterrent: Disulfiram.

j o Aldosterone antagonist: Canrenoate Potassium; Canrenone; Dicirenone; Mexrenoate Potassium; Prorenoate Potassium; Spironolactone.

Amino acid: Alanine; Aspartic Acid; Cysteine Hydrochloride; Cystine; Histidine; lsoleucine; Leucine; Lysine; Lysine Acetate; Lysine Hydrochloride; Methionine; Phenylalanine; Prolinc; Serine; Threonine; Tryptophan; Tyrosine; Valine.

Ammonia detoxicant: Arginine: Arginine Glutamate; Arginine Hydrochloride.

Anabol ic: Bolandiol Dipropionate; Bolastcronc; IBoldcnone U ndecy leniate; Bolenol; Bolmantalate; Ethylestrcnol; Methenolone Acetate;, Metlicnolone Enianthate; Mibo lerone; Nandrolone Cyclotatc, Nor bolethonc; Pizotylinc; Quinbolonc; Stciibolonc Acctatc; ibolone, Zeranlol.

Anl.tc 99ainl 25 Anlesc 9ctmnpin letnlHdohoie;AioezacPtsim mnbno Soim 9ndxm;Aieiie nlrdn yrchoie nlpmHdohoie nrlc Anai: Hctmnpc' letn -ydrochloride;condln aet; Amiocnoac Poasium; Aminoenoathc Syodum;oAidoe; Anilerine; Aniiridine Hydorochlor; Ailorpham Hydtrtchlord;Anioac; Carbaspirin Calcium; Carbiphcne H-ydrochloride; Carfentanil Citratc; Ciprefadol Succinate; Ciraniadol; Ci ramadol l-lydrocilloridc; Clonixeril; Clonixiin; Codeinc Codcinec Phosphate; Codeine Sul fate-. Conorphone H-ydrochloride; Cyclazocine; Djexoxadrol H-ydrochloride; Dexpemcdolac; -21 Dezocine; IDi flunisal;, Di hydrocodeine Bitartrate; Dimefadane; Dipyrone; Doxpicomnine Hydrochloride; Drinidene; Enadoline Hydrochloride; Epirizole; Ergotaminc Tartrate; Ethoxazene Hydrochloride; Etofenamate; Eugenol; Fenoprofen;, Fenoprofen Calcium; Fentanyl Citrate; Floctafenine; Flufenisal; Flunixin; Flunixin Meglumine; Flupirtine Maleate; Fluproquazone; Fluradoline Hydrochloride; Flurbiprofen; Hydromorphone Hydrochloride; Ibufenac; Indoprofen; Ketazocine; Ketorfanol; Ketorolac Tronietharnine; Letimide Hydrochloride; Levomnetbadyl Acetate; Levomethadyl Acetate H-ydrochloride; Levonantradol Hydrochloride; Levorphanol Tartrate; Lofemizole Hydrochloride; Lofentanil Oxalate; Lorcinadol; Lornoxicarn; Magnesium Salicylate; Mefenarnic Acid; Menabitan Hydrochloride; Meperidine Hydrochloride; Meptazinol Hydrochloride; i o Methadone Hydrochloride; Methadyl Acetate; Methopholine; Methotrimeprazine; Metkephamid Acetate; Mimbane 1lydrochloridc; Mirfentanil Hlydrochiloride; Molinazone; Morphine Sulfate, Moxazocine; Nabitan H-ydrochloride; Nalbuphine H-ydrochloride; Nalmexone Hydrochloride Namoxyrate-; Nantradol Hydrochloride; Naproxcn Naproxen Sodium Naproxol; Nefoparn Hydrochloride; Nexeridine Hydrochloride; Noracymethadol Hydrochloride; Ocfentani I H-ydrochloride; Octazamide; Olvanil; Oxetorone Fumarate; Oxycodotie; Oxycodone Hydrochloride;.

Oxycodone Terephthalate; Oxymorphone Hydrochloride; Pemedolac; Pentamorphone; Pentazocine; Pentazocine H-ydrochloride; Pentazocine Lactate; Phenazopyridine Hydrochloride; Phenyrarnidol Hydrochloride; Picenadol Hydrochloridc; Pinadoline; Pirfenidone; Piroxicani Olamine; Pravadoline Malcate; Prod ilIidi ne Hydrochloride; Profadol Hydrochloride; Propiram Fuumarate; Propoxyphene 2o H-ydrochloride. Propoxyphcne Napsylate; Proxazole ,Proxazole Citrate Proxorphan Tartrate; Os Pyrrol i plenc H-ydrochloride. Rcmi fentan i H -ydrochiloride; Salcolcx Salctharn idc Malcatc; V0690Salicylamide; Salicylate Mglumine; Salsalute Sodium Salicylat; Spiradolinc Mesylate; Sufentanil; Sufentanil Citrate; Talmetacin Talniflurnate Talosalate Tazadolene Succinate; 0 Tebufelone Tctrydaminc Tifurac Sodium; Tilidiinc H-ydrochloride; Tiopinac; Tonazocine *0600 25 Mesylate; Traniadol Hlydrochloride; Trefentanil Hlydrochloride; Trolarnine. Veradoine IHydrochloride; Verilopam Hydrochloride; Volazocinc; Xorphanol Mesylate; Xylazine H-ydrochloride; Zenazocine Mesylatc; Zornepirac Sodium Zuicapsaicin.

0* 0 *90600 Androgen: FluoxymesIcronc*; Mestcroloue; Methylicstostcronc;, Nandrolone Dccanoatc; Nandrolone 00 4 30 Phenpropionate;, Nisterime Acetate; Oxandrolonc; Oxymectholone; Silandrone; Stanozolol; Testosterone; Testosterone Cypionatc, i'cstostcratie Fnanthaic.; rcstosicrone K1'etolaurate; 0 0 'Testosterone 13hcny lacclate; Testosterone Propionatc; Trestolone Acetate.

-22 Anesthesia, adjunct to: Sodium- Oxybate.

Anesthetic: Aliflurane; Benoxinate Hydrochloride; Benzocaine; Biphenamine Hydrochloride Bupivacaine Hydrochloride; Butambcn; Butariben Picrate; Chloroprocaine Hydrochloride; Cocaine; Cocaine Hydrochloride; Cyclopropane; Desfiurane; Dexivacaine; Diamocaine Cyclamate; Dibucaine; Dibucaine Hydrochloride; Dyclonine Hydrochloride; Enflurane; Ether; Ethyl Chloride; Etidocaine; Etoxadrol Hydrochloride; Euprocin Hydrochloride; Fluroxene; H-alothane; Isobutamben; Isoflurane; Ketamine Hydrochloride; Levoxadrol Hydrochloride Lidocaine; Lidocaine *Hydrochloride; Mepivacaine Hydrochloride; Methohexital Sodium; Methoxyflurane; Midazolamn i0 H-ydrochloride; Midazolam Maleate; Minaxoloric; Nitrous Oxide; Norfiurane; Octodrine; Oxethazaine; Phencyclidine Hydrochloride; Pramoxine Hydrochloride; Prilocaine Hydrochloride; Procaine Hydrochloride; Propanidid; Proparacaine H-ydrochloride; Propotbl;. Propoxycaine Hydrochloride; Pyrrocaine; Risocaine; Rodocaine; Roflurane; Salicyl Alcohol; Sevoflurane; Teflurane; Tetracaine; Tetracaine Hydrocloridc; Tb inmylal; Thiamylal Sodium; Thiopental Sodium Tiletamine Hydrochloride; Zolamnine Hydrochloride.

Anorectic compounds including dexfenflurarnine.

Anorexic: Aminorex; Amphecloral; Chlorphentermine Hydrochloride; Clominorex; Clortermine 20 H-ydrochloride; Diethyipropion Hydrochloride; Fcnfluram inc 1-1 ydrochloridc; Fenisorex; Fl udorcx; Flurninorcx; Levan-ifctarninc Succinate; Mazindol; Mc fenorex H-ydrochloride; Phenmetrazine H-Iyd rochloride: Phientcrii-inc; Sibutramine Hydrochloride.

*Antagonist: Atipamiezoic, Atosiban; Bosenltan; Cimectidine; Cimictidinc I lydrochloridc; Ciciutiazeml Maleate; Detirelix Acetate; Devazepide; Donetidine; Etintidine Hydrochloride Famnotid~ne; Fenmetozole Hydrochloride ;Flumazenil; Icatibant Acetite; icotidine; Isradipine; Metiarnide; Nadide; Nalmefene; Nalmexone H-ydrochloride Naloxone Hydrochloride; Naltrexone; Nilvadipine; Oxilorphan; Oxmectidine Hydrochloride Oxmcteidinc Mesylite Quadazocine Mesylate; Ranitidinc; Ranitidine Bismuth Citrate Ranitidine 1lydrochloridc Sufotidine; Teludipine H-ydrochloride; -3o Tiaparnil H-ydrochloride; Tiotidine; Vapiprost Hydrochloride; Zallidine Hydrochloride.

Anterior pituitary activator: Epi mestrol.

23 Anterior pituitary suppressant: Danazol.

Anthelmintic: Albendazole; Anthelmycin; Bromnoxanide; Bunamidine Hydrochloride; Butonate; Cambendazole; Carbantel Lauryl Sulfate; Clioxanide; Closantel; Cyclobendazole; Dichiorvos; Diethylcarbarnazine Citrate; Dribendazole; Dymanthine Hydrochloride; Etibendazole; Fenbendazole; Furodazole; Kexyiresorcinol; Mebendazole; Morantel Tartrate; Niclosamide; Nitramnisole Hydrochloride, Nitrodani; Oxantel Pamnoate: Oxfendazole; Oxibendazole; Parbendazole; Piperamide Maleate; Piperazine; Piperazine Citrate; Piperazine Edetate Calcium; Proclonol; Pyrantel Pamoate; Pyrantel Tartrate; Pyrviniurn Pamoate; Rafoxanide; Stilbaziumn Iodide; Tetramisole, to Hydrochloride; Thiabendazole; Ticarbodine; Tioxidazole. Triclofenol Piperazine; Vincofos; Zilantel.

Anti-acne: Adapalene; Erythromycin Salnaced in; Inocoteroie Acetate.

Anti-adrenergic: Acebutolol; Aiprenolol Hydrochloride; Atenolol; Bretylium Tosylate; B unolol H -ydrochloridc; Carteolol Hydrochloride; Cel iprolol 1 lydrochloride; Cetamolol Hydrochloride; Cicloprolol Hydrochloride; Dexpropranolol Hydrochloride; Diacetolol Hydrochloride; Dihydroergotamine Mesy late; Dilevalol Hydrochloride; Esmolol Hydrochloride; Exaprolol Hydrochloride; Fenspiride Hydrochloride; Flestolol Sulfate; Labetalol Hydrochloride **Levobetaxolol Hydrochloride; Levobunolol Hydrochloride; Metalol Hydrochloride; Metoprolol; Metoprolol Tartrate; Nadolol; Pamatol'ol Sulfate; Penbutolol Sulfate; Phentolamine Mesylate; Practolol; Propranolol Hlydrochloride; Proroxan llydrochloridc, Solyp'crtinc 1'artrate; Sotalol Hlydrochloride; Timolol;, Titnolol Malcate; Tipreiiol ol Hlydrochloride; Tolaniolol; Zolertine H-ydrochloride.

Anti-allergic: Amlexanox; Astemizole; Azclastinc H-ydrochloride; Eclazolast Minocroml Nedocroniil ;Nedocromil Calcium Ncdocrornil Sodium Nivimedone Sodium; Pcnmirolast Potassium l1'entigetide; Pirquinozol; Poisonoak Extract; Probicromil Calcium; Proxicromil; Repirinast Tetrazolast Meglumine; Thiazinamium Chloride; Tiacrilast; Tiacrilast Sodium; Tiprinast Mveglurnine; Tixaniox.

Anti-amebic Berythrornycin lBialarnicol lIydrochloridc; Chloroquine; Chloroquine Hydrochloride; Chloroquine Phosphate ,Clarnoxyquin H-ydrochloride; Clioquinol Emetinc Hydrochloride; 24 lodoquinol; Paromomycin Sulfate; Quinfamide;- Symeti ne Hydrochloride; Teclozan; Tetracycline; Tetracycline Hydrochloride.

Anti-androgen: Bcnorterone; Cioleronel; Cyproterone Acetate; Delmadinone Acetate Oxendolone; Topterone; Zanoterone.

Anti-anemic: Epoetin Alfa; Epoetin Beta; Ferrous Sulfate, Dried; Leucovorin Calcium.

Anti-anginal: Amlodipine Besylate; Amnlodipine Maleate; IBetaxolol Hydrochloride Bevantolol io H-ydrochloride; Butoprozinc Hydrochloride; Carvedilol Ciniepazet Malcate; Metoprolol Succinate Molsidomine ;Monatepil Malcate; Primidolol Ranolazine Hydrochloride; Tosifen; Verapamil Hydrochloride.

Anti-anxiety agent: Adatanserin Hydrochloride; Alpidem; Binospirone Mesylate; Bretazenil; is Glemanserin; Ipsapirone H-ydrochloride; Mirisetron Maleate; Ocinaplon; Ondansetron Hydrochloride Panadiplon; Pancopride Pazinaclone; Serazapinc Hydrochloride; Tandospirone Citrate; Zalospirone Hydrochloride.

Anti -arthritic: Lodelaben.

V 20 Anti-asthmiatic: Ablukast; Ablukast Sodium; Azelastine Hydrochloride ;Bunaprolast; Cinalukast; Crornitrilc Sodium; Cromnolyn Sodiurn; Enofelast. Isanoxoic; Kcioti fcn Fumnaratc; Levcromakalim; Lodoxarnide Ethyl Lodoxamidc T1romcthaminc; Montelukast Sodium; Ontazolast; Oxarbazole; Oxatomidc; Piriprost; Piriprost Potassium; Pirolate; Pobilukast Edamiine; Quazolast Repirinast; Ritolukast;..Sulukast; Tetrazolast Meglumine Tiaramidc H-ydrochloride-, Tibenelast Sodium; Tornclukast; Trani last; Verlukast; Verofyiliioc Zarirlukast.

Anti-athcrosclcrotic: Mi fobatc; Tinicfuronc.

00: Antibacterial: Acedapsone; Acciosul fone Sodium; Alarnccin; Alexidinc; Ardinociinii; Amidinocillin Pivoxil; Amicycline; Amifloxacin; Amifloxaciin Mesylate; Amikacin; Amikacin Sulfate; Arninosalicylic acid; Anminosalicylate sodiuml; Amioxici iiii; Amphomlycin; Amipicillin; Ampicillin Sodium; Apalcillin Sodium; Apramycin; Aspartociin; Astromnicin Sulfate; Avilamycin; Avoparcin; Azithromyci n; Azlocillin; Azioci Ilin Sodium; Bacampicill in Hydrochloride; Bacitracin; Bacitracin Mcthylene Disalicylatc, B acitracin Zinc; Banibermycins; Benzoylpas Calcium; Berythromycin Betamicin Sulfate; Biapenem; Biniramycin; Biphenamine Hydrochloride; Bispyrithione Magsulfex; Butikacin; Butirosin Sulfate; Capreomnycin Sulfate; Carbadox; Carbenicillin Disodium; Carbenicillin Indanyl Sodium; Carbenicillin Phenyl Sodium; Carbenicillin Potassium; Carumonam Sodium; Cefaclor; Cefadroxil; Cefamnandolc; Cefamando Ic Nafiatc; Cefamnandole Sodiurn; Cefaparole; Cefatrizine; Cefazaflur Sodium; Cefazolin; Cefazolin Sodium; Cefbuperazone; Cefdinir; Cefepime; Cefepime Hydrochloride; Cefetecol; Cefixime; Ccfmenoxime Hydrochloride; Cefmnetazole; Cefinetazole Sodium; Cefonicid, Monosodiumn; Cefonicid Sodium; Ccfoperazone Sodium; Ceforanide; Cefotaxime Sodium; Cefotetan; Cefotetan Disodiurn; Cefotiamn Hydrochloride; Cefoxitin; Cefoxitin Sodium; Cefpiniizole; Cefpimizole Sodium; Cefpiramide; Cefpiramidc Sodium; Cefpiromc Sulfate, Cefpodoxiime Proxetil; Cefprozi 1; Cefroxadine; Cefsulod in Sodium; Ceftazidimc; Ceftibuten; Ccftizoxime Sodium; Ccftriaxonie Sodium; Ce furoxirne; Cefuroxinie Axetil; Cefuroxime Pivoxeti I; Cefuroxime Sodium; Cephacetrile Sodium; Cephalexin; Ccphalexin Hydrochloride; Ccphaloglycin; Ccphaloridine; Ccphalothin Sodium; Cephapirin Sodium; Cephradinc; Cctocycline Hydrochloride; Cetophenicol; Chioramphenicol; Chloramphenicol Palmitate; Chloramphenicol I'antotlicnatc Complex Chloranicnicol Sodium Succinatc; Chiorhexidine Phosphanilate; Chioroxylenol; Chlortetracycline B~isulfate; Chlortetracycline Hydrochloride; Cinoxacin; Ciprofloxacin; Ciprofloxacin H-ydrochloride; Ciroleniycin Clarithromycin; Clinafloxacin oo: 20 H-ydrochloride; Clindamycin; Clindamycin H-ydrochloride; Clindamycin Pairnitate 1-lydrochloride; oooo:Clindarnycin Phosphatc; Clofazimine Cloxacil liii Benzathinc; C loxaci Ilin Sodium; Cloxyquin; Colistinmethate Sodium; Colistin Sulfate; Coumermycin; Cournermycin Sodium; Cyclacillin; o: Cycloscrine; Dalfopristin; Dapsone Daptomycin; Demeclocycline; Dcmeclocycline Hydrochloride; Deeylne eoungin Diaveridine; Dicloxaci Ilin; Dicloxacillin Sodium; Dihydrostreptomycin Sulfate; Dipyrithione; Dirithromycin; Doxycycline;. Doxycycline Calcium Doxycycline Fosfaex; Doxycycline Flyclate; Droxacin Sodium; Enoxacin; Epicillin; Epitetracycline Hydrochloride; e~ooErythromycin; Erythromycin Acistrate; Erythromnycin Estolatc; Erythromnyci n Ethylsuccinatc; VeoooErythromycin G luceptate; Erythromycin Lactobionate; Erythromycin Propionate; Erythromycin Stearate; Ethanibutol H-ydrochloride; Ethionamidc; Fleroxacin; Floxacil lin; Fludalaninc; Flumequine, Fosfomycin; Fosfomnycini Trometharninc; Furnoxicillin; Furazolium Chloride; Furazol iurn Tartratc; Fusidate Sodium; Fusidic, Acid; Gentamicin Sul fate-, G loximionam;, Gramicidin; 1laloprogin; I-Ictacillin; 1-Itacillin Potassium; 1lcxccine; lbafloxacin; linipenem; Isoconazoic; 26 Isepamiciri; Isoniazid; Josamycin; Kanamyci n Sulfate; Kitasamyci n; Levofural tadone; Levopropylcillin Potassium; Lexithromycin; Lincornycin; Lincomycin H-ydrochloride; Lomnefloxacin; Lomefloxaci n H-ydrochloride, Lomefloxacin Mesylate; Loracarbef;, Mafenide; Meclocycline; Meclocycline Sulfosalicylate; Megalomiciii Potassium Phosphate; Mequidox; Meropencm; Methacycline; Methacycline Hydrochloride; Mvethenamine; Methenamine Hippurate; Methenamnine Mandelate; MethicillIin Sodium; Metioprim; Metronidazole Hydrochloride; Metronidazole Phosphate; Meziocillin; Meziocillin Sodium; Minocycline; Minocycline Hydrochloride; Mirincamycin Hydrochloride Monensin Monensin Sodium Nafillin Sodium; Nalidixate Sodium; Nalidixic Acid; Natamycin; Ncbrarnycin; Neomycin Palmitatc; Neomycin Sulfate; Neomycin Undecylenate Netilmicin Sulfate; Neutramycin; Nifuradene; Nifuraldezone; Nifuratel Nifuratrone; Nifurdazil; Nifurimide; Nifurpirinol; Nifurquinazol; Nifurthiazole; N itrocycline; Nitrofurantoin; N itromide; Norfioxacin; Novobiocin Sodium; Ofloxacin; Ormetoprim;, Oxacillin Sodium; Oxinionam, Oximonarn Sodium; Oxolinic Acid; Oxytetracycline;, Oxytetracycline Calcium; Oxytetracyci ine Hydrochloride; Paldimycin; Parachlorophenol; is Paulomycin; Pefloxacin; Pefloxacin Mesylate; Penamecillin; Penicillin G Benzathine; Penicillin G Potassium; Penicillin G Procaine;, Penicillin G Sodium; Penicillin V; Penicillin V Benzathine; Penicillin V Hydrabamine; Penicillin V Potassium; Pentizidone Sodium; Phenyl Aminosalicylate; Piperacillin Sodium; Pirbenicillin Sodium; Piridicill in Sodium; Pirlimycin Hydrochloride; Pivampicillin Hvdrochloridc; Pivamipicillin Pamnoate; Pivampicillin Probenate; Polyrnyxin B Sulfate; 20 Porfirornycin Propikacin; Pyrazinamide; Pyrithione Zinc; Quindecarnine Acetate; Quinupristin; Racephenico I; Ramoplani a; Ranimycin;, Relomyci n; Reprornicin; Rifabutin; Rifainictanle; Rifamexi I; Ri fanide; Ri fampin; Rifapentinec; Ri laximin; Rolitetracycline; Rolitetracyclinc Nitrate; Rosaramicin; Rosaramicin Butyrate- Rosaramicin Propionate; Rosaramicin Sodiumn Phosphate; Rosaramicin Stearatc; Rosoxacin; Roxarsone; Roxithromycin; Sancycline; Sanfetrinem Sodium; Sarmoxicillin; Sarpicillin; Scopafungin Sisomicin; Sisomnicin Sulfate; Sparfloxacin; Spectinoniycin 1-Hydrochloride; Spiramycin; Stallirnycin Hydrochloride-. Steffimycin; Streptomycin SUlfatc; Streptonicozid; Sulfabenz. Sulfabcnizamnide; Sulfacetarnide; Sulfacetarnide Sodium; Sulfacytine; Sul fadiazine; Sulfadiazinc Sodium; Sulfadoxinc; Sulfalcnic; SUlffamcrizinc; Sulfarneter; Sulfamethazine; Sulfamethizole; Sul faniethoxazolc; Sul fanionomethoxine; Sulfamoxolc; Sulfanilatc Zinc; Sulf-anitran Sulfasalazine; Sulfasonlizole; Sulfathiazole; Sulfazarnet; Sulfisoxazole; Sulfisoxazole Acetyl; Sultisoxazole Diolamine; Sulfomyxin; Sulopenem; Sultamicillin; Suncillin Sodium; Talampicillin Flydrochloride; Teicoplailin; Temafioxacin 1lydrochioride; Teniocillin; 27 Tetracycline; Tetracycline Hydrochloride Tetracycline Phosphate Complex; Tetroxoprim; Thiamphenicol; Thiphencillin Potassium; Ticarcillin Cresy 1 Sodium; Ticarcillin Disodium Ticarcill in Monosodium; Ticlatone; Tiodoniumn Chloride; Tobramycin; Tobramycin Sulfate; Tosufloxacin; Trimethoprini; Trimethoprim Sulfate; Trisulfapyrirnidines; Troleandomycin; Trospectornycin Sulfate; Tyrothricin; Vancornycin; Vancomycin Hydrochloride; Virginiamycin; Zorbarnycin.

Anticholelithic: Monoctanoin.

Anticholelithogenic: Chenodiol; Ursodiol.

Anti cholIinergic: Alverine Citrate; Anisotropine Methyibrornide; Atropine; Atropine Oxide Hydrochloride; Atropine Sulfate; Belladonna; Benapryzi ne Hydrochloride; Benzetimide H-ydrochloride; Benzi lonium Bromide; B iperiden Biperiden 1-lydrochloride; Biperiden Lactate;, 1 5 Cl idiniumn Bromide; Cyclopentolate Hydrochloride; Dexetimide; Dicyclomine Hydrochloride; Di hexyvcri ne I lydrochloridc; Domazol ine Fumiaratc; Elantrine; Elucainc; Ethybcnztropinc; Eucatropine H-ydrochloride; Glycopyrrolate; H-eteronium Bromide; Homnatropine Hydrobromide; Homatropine Methyibromide; Il1yoscyarnine; Hyoscyamine Hydrobromide; 1lyoscyaminc Sulfate; Isopropamide Iodide; Mepcnzolate Bromide; Methylatropine Nitrate; Metoquizine; Oxybutynin 20 Chloride;, Parapenzolatc Bromide; Plentapiperium Methylsulfatc, Phencarbamide;, Poldine Methylsulfate;, Proglurnide; Propanthicline Bromide; Propenzolatc, lydrochloridc; Scopolamine 1lydrobrornidc; Ternatropium Mcthylsul atc; Tiquinamide Hlydrochloride; Tofeniacin 1-ydrochloridc; Toquizine; Triampyzinc Sulfate; Trihexyphenidyl H-ydrochloride; Tropicarnide.

Anticoagulant: Ancrod; Anticoagulant Citrate Dextrose Solution ;Anticoagulant Citrate Phosphate *..Dextrose Adenine Solution; Anticoagulant Citrate Phosphate Dextrose Solution; Anticoagulant I1-lparin Solution; Anticoagulant Sodium Citrate Solution; Ardcparin Sodium; Bivalirudin lBrornindionc; Daltcparin Sodium Dcsirudin; Dicumawrol; l-leparinl Calcium; Ileparin. Sodium; *:Lyapolate Sodium; Nafarnostat Mesylate Phenprocoumnon; Tinzaparin Sodium Warfarin Sodium.

Anticoccidal: Maduramicih.

AilcoIVuLIsant: Albutoin: .Arneltol idc; Atolide: Burainiatc: Carbamazii,,cpinc Ciiroiidc; Citeniamiidc; -28- Clonazepam; Cyheptamide; Dczinarnide; Dimcthad jone; Divaiproex Sodium; Eterobarb; Ethosuximide; Ethotoin; Flurazepamn Hydrochloride Fluzinamide; Fosphenytoin, Sodium; Gabapentin; lepcimide; Lamnotrigine;, Magnesium Sulfate Mephenytoin; Mephobarbital Methetoin; Methsuximide; Mi lacemide Hydrochloride Nabazenil; Nafimidone Hydrochloride; Nitrazeparn Phenacemnide; Phenobarbital Phenobarbital Sodium Phensuximidc; Phenytoin; Phenytoiri Sodium; Primidone; Progabide; Ralitoline; Remacemidc Hydrochloride; Ropizine; Sabeluzole Stiripentol; Suithiame; Thiopental Sodium Tiletarnine Hydrochloride Topiramate; Triniethadione; Valproate Sodium; Vaiproic Acid; Vigabatrin; Zoniclezole Hydrochloride; Zonisamide.

Antidepressant: Adatanserin H-ydrochloride; Adinazolam Adinazolamn Mesylate; Alaproclate; Aletarnine Hydrochloride; Arnedalin Hydrochloridc; Aniitriptyline Hydrochloride; Amnoxapine; Aptazapine Maleate; Azaloxan Fumarate; Azepindole;, Azipramine Hydrochloride; Bipenamol Hydrochloride; Bupropion Hydrochloride; Butacetin; Butriptyline Hydrochloride; Caroxazone; Cartazolate; Ciclazindol; Cidoxepin Hydrochloride; Cilobamine Mesylate; Clodazon Hydrochloride; Clomipramine Hydrochloride; Cotinine Fumarate; Cyclindole; Cypenamine Hydrochloride; Cyprolidol H-ydrochloride; Cyproximidc; Daledalin Tosylate; Dapoxetine Hydrochloride; Dazadrol Maleate; Dazepinil Hydrochloride; Desipramine H-ydrochloride; Dexamisole; Deximafen; Dibenzepin H-ydrochloride, Dioxadrol Hydrochloride; Dothiepin Hydrochloride; Doxepin Hydrochloride; Duloxetine Hydrochibride; Eclanamnine Malcate; Encypratc; Etoperidone Hydrochloride; Fantridone Hydrochloride;, Fenmetozole Hydrochloride Fenmetramide; Fezolaniinc Fumarate; Fluotracen H-ydrochloride Fluoxetine; Fluoxetine Hydrochloride; Fluparoxan Hydrochloride; Gamfexine; Guanoxyfen Sulfate; Imafen Hydrochloride; Imiloxan Hydrochloride; *I mipramine Hydrochloride; Indeloxazine Hydrochloride; Intriptyline Hydrochloride; Iprindole; Isocarboxazid; Ketipramine Fumnarate; Lofepramine Hydrochloride; Lortalamine; Maprotiflne; Maprotilinc H~ydrochloride; Melitraccn lIydrochloridc; Milacemide Hlydrochloride; Minaprine Hydrochloride; Mirtazapine; Moclobeniidc; Modaline Sulfate; Napactadine Hydrochloride; Napamezole H-ydrochloride; Nefazodone Hydrochloride; Nisoxetine; Nitrafudami Hydrochloride; Nomifensine Maleate; Nortriptylinc Hydrochloride; Octriptyline Phosphate; Opipramol Hydrochloride; Oxaprotiline Hydrochloride; Oxypertine;, Paroxetine;, Phenelzinc Sulfate; Pirandamine H-ydrochloride; Pizotyline Pridefine H-ydrochloride; Prolintane H-ydrochloride; Protri ptyl inc Hydrochloride; Quipazine Maleate Rolicyprine; Seproxetine Hydrochloride; -29- Sertraline Hiydrochloride; Sibutramine Hydrochloride Sulpiride; Suritozoic; Tametraline Hydrochloride; Tampramine Fumarate; Tandamine Hydrochloride; Thiazesim H-ydrochloride; Thozalinone; Tomnoxetine Hydrochloride; Trazodone Hydrochloride; Trebenzomine Hydrochloride; Trimipramine; Trimipramnine Maleate; Venlafaxine Hydrochloride; V iloxazine Hydrochloride; Zimeldine Hydrochloride; Zometapine.

Antidiabetic: Acetohexamide; Buformin; Butoxamine Hydrochloride Camigh bose; Chiorpropamide; Ciglitazone; Englitazone Sodium; Etoformin Hydrochloride; Gliamilide; Glibornuride; Glicetanile Sodium; Gliflumide; Glipizide; Glucagon; Glyburide; Glyhexamide; t0 Glymidine Sodium; Glyoctamide; Glyparamide; Insulin; Insulin, Dalanated; Insulin Human; Insulin Human, Isophane; Insulin 1lurnan Zinc; Insulin Human Zinc, Extended; Insulin, Isophane; Insulin Lispro; Insulin, Neutral; Insulin Zinc; Insulin Zinc, Extended; Insulin Zinc, Prompt; Linogliride; Linogl iride Fumarate; Metformin; Methyl Palmoxirate; Palmoxirate Sodium; Piogi itazone Hydrochloride; Pirogliride Tartrate; Proinsulin Human; Seglitide Acetate; Tolazamide; Tolbutamide; Troglitazone; Zopoirestat.

Antidiarrheal: Rolgamidine, Diphenoxylate hydrochloride (Lomoti Metronidazole (Flagyl), Methyl predniso lone (Medrol), Sulfasalazine (Azul fidine).

20 Antidiuretic: Argipressin Tannate; Desnhopressin Acetate; Lypressin.

"too:Antidote: Dimercaprol; Edrophoniumn Chloride; Fornepizole; Leucovorin Calcium Levoleucovorin Calcium; Methylene Blue Protamine Sulfate.

Antidyskinetic: Selegi line Hydrochloride.

Anti-emetic: Alosetron Hydrochloride; Batanopride Hydrochloride; Bemnesetron; Benzquinamide; Chlorpromazine Chlorpromazine Hydrochloride Clebopride; Cyclizi ne Hydrochloride; Dimenhydrinate; Diphenidol; Diphenidol Hydrochloride; Diphenidol Pamoate; Dolasetron Mesylate Domperidofle; Dronabi nol; Fludorex; Flumeridone; Galdansetron H-ydrochloride; Granisetron; 3oGranisetron Hydrochloride; Luirosetron Mesylate; Meclizine Hydrochloride; Metoclopraniide Hydrochloride; Metopiniazine; Ondansetron Hydrochloride Pancopride; Prochlorperazine; Prochiorperazine r-disylatc, Prochlorperazine Maleate Promethazinc Hydrochloride 30 Thiethylperazine; Thiethy lpcrazine Malate; Thiethyl perazi ne Maleate; Trimnethohenzamide Hydrochloride; Zacopride Hydrochloride.

Anti-epileptic: Felbamnate; Loreclezole; Tolgabide.

Anti-estrogen: Clomectherone; Delrnadinone Acetate ;Nafoxidine Hydrochloride; Nitromifene Citrate; Raloxifene Hydrochloride; Tarnoxifen Citrate; Toremnifene Citrate ;Trioxifene Mesylate.

Anti fi brinolyti c: Nafamnostat Mesylate Antifungal: Acrisorcin; Amnbruticin; Amphotericin B; Azaconazole; Azaserine;. Basifungin; Bifonazole; Biphecnamine Hydrochloride Bispyrithione Magsulfex; Butoconazole Nitrate;, Calcium Undecylenatc; Candicidin; Carbol-Fuclisin; Chlordantoin; Ciclopirox; Ciclopirox Olamine; Ci lofungin; C isconazole; Clotrimazole; Cuprimyxin; Denofungin Dip yrithione; Doconazole; is Econazole; Econazole Nitrate; Enilconazole; Ethonamn Nitrate; Fenticonazole Nitrate; Filipin; Fluconazole; Flucytosine; Fungimnycin; Griseofulvin; Hamycin; Isoconazole Itraconazole; KalafUngin; Ketoconazole; Lornofiingin; Lydimycin; Mepartricin Miconazole; Miconazole Nitrate; -Monensin Monensin Sodium Naftifine Hydrochloride; Neomnycin Undecylenate Nifuratel .4 .Nifurmerone; Nitralamine Hydrochloride;, Nystatin; Octanoic Acid; Orconazole Nitrate; Oxiconazole 20 Nitrate; Oxifungin Hydrochloride; Parconazole Hydrochloride; Pirtricin Potassium Iodide Proclonol Pyrithione Zinc Pyrrolnitrin: Rutornycin; Sanguinariurn Chloride Saperconazole; Scopafungin Selenium Sulfidc Sincfungin; Sulconazolc Nitratc; Tcrbinafinc; Tcrconazole; Thiramn; Ticlatone Tioconazole; Tolciclate; Tolindate; Tolnaftate; Triacetin; Triafungin; Undecy lenic Acid; Viridofulvin; Zinc Undecylenate; Zinoconazole Hydrochloride.

0 Antiglaucomna agent :Alprenoxime Hydrochloride Colforsin; Dapiprazole Hydrochloride Dipivefrin Hydrochloride Naboctate Hydrochloride; Pilocarpirie; Pimabine.

0 0 Antihemophilic: Antihemnophilic Factor.

Antihemorrhagic: Poliglusarn.

-31 Antihistamninic: Acrivastine; Antazoline Phosphate; Astemizole Azatadine Malcate; Barmastine; Bromod iphenhydramine Hydrochloride; Brompheni ramine Maleatc; Carbinoxarnine Maleate; Cetirizine Hydrochloride; Chiorpheniramine Maleate; Chiorpheniramine Polistirex; Cinnarizine; Clemastine; Clemastine Fumarate; Closiramine Aceturate;, Cycliramine Maleate; Cyclizine; Cyproheptadine Hydrochloride Dexbrompheniramine Maleate; Dexchlorpheniramninc Maleate; Dimethindend Maleate; Diphenhydramine Citrate; D iphenhydram inc Hydrochloride; Dorastine Hydrochloride; Doxy lamine Succinate; Ebastine; Levocabastine Hydrochloride; Loratadine; Mianserin H-ydrochloride Noberastine; Orphenadririe Citrate Pyrabrom; Pyrilamine Maleate; Pyroxamine Maleate; Rocastine Hydrochloride; Rotoxamine; Tazifylline Hydrochloridc; Temelastine; Terfenadine; Tripelennamine Citrate; Tripelennamine Hydrochloride; Triprolidine Hydrochloride; Zolamine Hydrochloride.

Antihyperlipidenlic: Cholestyramine Resin .Clofibrate; Colestipol Hydrochloride; Crilvastatin; Dalvastatin; Dextrothyroxine Sodium; Fluvastatin Sodium; Gemfibrozil; Lecimibide; Lovastatin; Niacin Pravastatin Sodium; Probucol; Simvastatin; Tiqueside; Xenbucin.

Antihyperlipoproteinemic: Aci-fran; Beloxamide; Bezafibrate; B oxidine; Butoxarnine Hydrochloride; Cetaben Sodium; Ciprofibrate; Gemcadiol; Halofenate Lifibratc; Meglutol; Nafenopin; Pimetine lHydrochloride; Theofibrate;, Tibric Acid; Treloxinate.

Antihypertcnsive: Alfuzosin Hydrochloride; Alipamide Aithiazide; Arniquinsiri Hydrochloride; Amlodipine Besylate Anilodipine Maleate Anaritide Acetate Atiprosin Maleate; Belfosdil; Bemitradine; Bendacalol Mesylate; Bendroflurnethiazide Benzthiazide Betaxolol Hydrochloride Bethanidine Sulfate; Bevantolol Hydrochloride Biclodil Hydrochloride; Biioprolol; lBisoprolol .000Furnaraic; Bucindolol Hydrochloride; Bupicomide; Buthiazide: Candoxatril; Candoxatrilat; *0000: 25 Captopril Carvedilol Ceronapril; Chlorothiazide Sodium Cicletanine; Cilazapril; Clonidoie; Clonidine Hydrochloride; Clopamide Cyclopenthiazide; Cyclothiazide Darodipine Debrisoquin Sulfate; Delapril Hydrochloride; Diapamide Diazoxide; Dilevalol H-ydrochloride Diltiazem :eooooMalate; Ditekiren; Doxazosin Mesylate; Ecadotril; Enalapril NMaleate; Enalaprilat; Enalkiren; 0 ~Endralazine Mesylate; Epithiazide Eprosartan; Eprosartan. Mesylate;, Fenoldoparn Mesylate Flavodilol Malcatc; Flordipine; Floscquinan; Fosinopril Sodium Posinoprilat; Guanabcnz; Guanabcnz Acetate; Guanacline Sulfatc; Guanadrel S ulfate; Guancydinc; G uanethidine Monosullfaic; Guanethidine Sulfatc-, Guanfacinc l-ydrochlloridc; Guanisoquin Sulfate; Guanoclor 32 Sulfatc; Guanoctine Hydrochloride; Guanoxabenz; Giuanoxan Sulfate; Guanoxyfen Sulfate Hydralazine Hydrochloride; Hydralazine Polistirex; Hydroflumethiazide; Indacrinone; Indapamide Indolapril H-ydrochloride; Indorarnin; Indoramin Hydrochloride; Indorenaic Hydrochloride; Lacidipine; Leniquinsin; Lcvcromakalim Lisinopril; Lofexidine Hydrochloride; Losartan Potassium; Losulazine H-ydrochloride; Mcbutamatc; Niccamy lamine H-ydrochloridc; Medroxalol; Medroxalol Hydrochloride; Methalihiazide ;Methyclothiazide Methyldopa; Methyldopate Hydrochloride; Metipranolol; Metolazone ;Metoprolol Fumnarate; Metoprolol Succiriate; Metyrosine; Minoxidil Monatepil Maleate ;Muzolirnine Nebivolol; Nitrendipine; Ofornine; Pargyline Hydrochloride; Pazoxide; Pelanserin Hydrochloride ;Perindlopril Erbumine; i o Phenoxybenzamine Hydrochloride; Pinacidil; Pivopril; Polythiazide ;Prazosin Hydrochloride; Primidolol Prizidilol Hydrochloride; Quinapril Hydrochloride Quinaprilat Quinazosin H-ydrochloride; Quinelorane Hydrochloride Quiripirole Hydrochloride, Quinuclium Bromide; Ramipril Rauwolfia Serpentina; Reserpine; Saprisartan Potassium; Saralasin Acetate; Sodium Nitroprusside; Sulfinalol Hydrochloride; Tasosartan; Teludipine Hydrochloride Temocapril i s Hydrochloride; Terazosin Hydrochloride; Terlakiren; Tiamenidine; Tiamenidine Hydrochloride; Ticrynafen -,Tinabinol; Tiodazosin; Tipentosin Hydrochloride; Trichlormethiazide Trimazosin Hydrochloride; Trimethaphan Camsylate; Trimoxarrine Hydrochloride, Tripamnide; Xipamide :Zankiren Hydrochloride; Zofenoprilat Arginine.

20 Antihypotensive: Ciclafrine Hydrochloride; Midodrine Hydrochloride.

Anti-infective: Difloxacin H-ydrochloride; Lauryl lsoqui noliniumn Bromide; Moxalactamn Disodiumn; Ornidazole; Pentisomicin; Sarafloxacin Hydrochloride; Protease inhibitors of HIM and other retroviruses; Integrase Inhibitors of H-IV and other rctroviruscs; Ccfaclor (Ceclor); Acyclovir 25 (Zovirax); Norfioxacin (Noroxin); Cefoxitin (Mefoxin); Cefuroxime axetil (Ceftin); Ciprofloxacin (Cipro).

V Anti-infective, topical: Alcohol; Aminacrine Hydrochloride; Benzethonium Chloride Bithionolate Sodium; Bromchlorenone; Carbamide Peroxide; Cetalkoniumn Chloride, Cetylpyridinium Chloride Chiorhcxidine Hydrochloride; Clioquinol, Dorniphen Bromide; Fenticlor; Fludazoniurn Chloride; Fuchsin, Basic; Furazolidone; Gentian Violet; Haiquinols; Hexachlorophene: Hydrogen Peroxide; Ichitharnmol; Imidecyl Iodine; Iodine, Isopropyl Alcohol; Mafecnide Acetate; Meralein Sodium; 33 Mercufenol Chloride; Mcrcury, Ammoniated; Methylbenzethoniuni Chloride; Nitrofurazone; Nitromersol; Octenidine Hydrochloride; Oxychiorosene; Oxychioroscne Sodium; Parachiorophenol, Camphorated; Potassium Permanganate; Povidone-lodi ne; Sepazonium Chloride; Silver Nitrate; Sulfadiazine, Silver; Symclosene; Thimerfonate Sodium; Tliirerosal: Troclosene Potassium.

Anti -inflammatory: Aiclofenac; Alclometasorie Dipropionate; Algcstone Acetonide; Alpha Amylase; Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac, Anitrazafen; Apazone; Balsalazide Disodiurn; Bendazac; Benoxaprofen Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen; Cicloprofen; C intazone; Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate; Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide; Desoximetasone; Dexamethasonc Dipropionate; Diclofenac. Potassium; Diclofenac Sodium; Di florasone Diacetate; Di flumidone Sodium; Diflunisal Difluprednate; Diftalone; Dimethyl Sulfoxide; Drocinonide; Endrysone; Enlimornab; Enolicam Sodium Epirizole Etodolac; Etofenarnatc Felbinac; Fenamole; Fenbufen; Fenclofenac; Fenclorac; Fendosal; Fenpipalone; Fentiazac; Flazalone; Fluazacort; Flufenamnic. Acid; Flumnizole; Flunisolide Acctatc; Flunixin Flunixin Meglurnine Fluocortin Butyl; Fluoromctholone Acetate; Fluquazone; Flurbiprofen Fluretofen;.Fluticasone Propionate; Furaprofen; Furobufen; :Halcinonide; Halobetasol Propionate; Halopredone Acetate; Ibufenac Ibuprofecn; Ibuprofen Aluminum; Ibuprofen Piconol; Ilonidap; Indomethacin; Indomethacin Sodium; Indoprofen 20 Indoxole Intrazole; Isoflupredone 'Acetate, Isoxepac; Isoxicarn; Ketoprofen; Lofemizole Hydrochloride Lomnoxicam Loteprednol Etabonate; Meclofenamate Sodium; Meclofenamic Acid; Meclorisone Dibutyrate; Mefenamic, Acid Mesalarnine; Meseclazone; Methylprednisolone Suleptanate; Morniflumate; Nabumetone; Naproxen Naproxen Sodium Naproxol Nimazonc; .00 Olsalazine Sodium; Orgotein; Orpanoxin; Oxaprozin; Oxyphenbutazone; Paranyline Hydrochloride; 0 25 Pentosan Polysulfate Sodium; Phenbutazone Sodium Glycerate; Pirfenidone Piroxicam; Piroxiram .0.00.Cinnamate; Piroxicam Olamine; Pirprofen; Prednazate; Pri felone; Prodolic Acid; Proquazonc; Proxazole; Proxazole Citrate Rimexolone; Romazarit Salcolex Salnacedin; Salsalate :ooeo.Sanguinariumn Chloride Seclazonc Sermetacin; Sudoxicam; Sulindac; Suprofen; Talmetacin; Talniflumate Talosalate.; Tebufelone Tenidap; Tcnidap Sodium; 'renoxicanm; Tesicarn; Tesimide; 3 0 Tetrydamine Tiopinac; Tixocortol Pivalate; Tolmetin; Tolmetin Sodium; Triclonide; Triflumidate; Zidometacin; Zornepirac Sodium.

-34- Antikeratinizing agent: Doretinel; Linarotene; Peiretin.

Antimalarial Acecdapsonc Arnodiaquinic FHydrochlIo ride Arniquinatc; Arteficric; Chioroquinc Chioroquine Hydrochloride Chioroquine Phosphate Cycloguanil Pamoate; Enpiroline Phosphate; Halofantrine Hydrochloride Hydroxychioroquine Sulfate Mefloquine Hydrochloride; Menoctone; Mirincarnycin Hydrochloride Primaquine Phosphate; Pyrimethamine; Quinine Sulfate; Tebuquine.

Antimicrobial: Aztreonam; Chlorhexidine Gluconate; Imidurea; Lycetamine; Nibroxane; Pirazmonam Sodium; Propionic Acid Pyrithione Sodium; Sanguinarium Chloride Tigemonamn to Dicholine.

Antimigraine: Dolasetron Mesylate ;Naratriptan Hydrochloride; Sergolexole Maleate, Sumatriptan Succinatc; Zatosetron Maleate.

Antirnitotic: Podofilox.

Antimycotic: Arnorolfine.

Antinatiseant Buclizine Hydrochloride; Cyclizine Lactate; Naboctate Hydrochloride.

*Antineoplastic: Acivicin; Aclarubicini; Acodazole I-ydrochiloride; Acroninc; Adozelesin; Aldesleukin Altretamine; Ambomycin; Amnetaritrone Acetate; Amninoglutethimide Amsacrine; Anastrozole; Anthraniycin; Asparaginase; Asperlin Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisaritrene Hydrochloride; Bisnafide Diniesylate; Bizelesin; Bleoniycin Sulfate; Brequinar Sodium; Bropirimine Busulfan; Cactinomycin; Calusterone; Caraccmi4c; Carbetirner; Carboplatin; Carmustine; Carubicin Hydrochloride; Carzelesin; Cedefingol; Chloramnbucil; Cirolemycin Cisplatin; Cladribine; Crisnatol Mesylate; Cyclophosphamide Cytarabine Dacarbazine; Dactinomycin; Daunorubicin Hydrochloride; Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine Mesylate; Diaziquone; Docetaxel; Doxorubicin; Doxorubicin Hydrochloride; Droloxifene; Droloxifenle Citrate; Dromostanolone Propionate; Duazomycin; Edatrexate; Eflornithine Hydrochloride Elsamnitrucin; Enloplatin; Enpromate; Epipropidine; Epirubicin Hydrochloride;' Erbulozole; Esorubicin Hydrochloride; Estrarnustine; Estran-ustine Phosphate Sodium; Etanidazole; Ethiodized Oil 1 131, Etoposide; Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride; Pazarabine; Fenretinidc; Floxuridine Fludarabine Phosphate; Fluorouracil; Flurocitabine; Fosquidorie; Fostriecin Sodium; Gemcitabine; Gerncitabinc Hydrochloride; Gold Au 198 Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide; Ilmofosine; s Interferon Alfa-2a Interferon Alfa-2b Interferon Alfa-n 1; Interferon Alfa-n3; Interferon Beta-I a ;Interferon Gamma-I b; Iproplatin; Irinotecan Hydrochloride Lanreotide Acetate; Letrozole; Leuprolide Acetate Liarozole Hydrochloride; Lometrexol Sodium; Lomustine; Losoxantrone Hydrochloride; Masoprocol; Maytansine; Mechloretharnine H-ydrochloride; Megestrol Acetate; Melengestrol Acetate; Meiphalan; Menogaril; Mercaptopurinc; Methotrexate; Methotrexate Sodium; o Metoprine; Meturedepa; Mitindomide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole; Nogalamycin; Ormaplatin; Oxisuran; Paclitaxel; Pcgaspargase; Peliomycin; Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipobroman; Piposulfan; P iroxantrone H-ydrochloride; Plicamycin; Plomestane; Porfimer Sodium; Porfiromycin Predniniustine; Procarbazine H-ydrochloride; Puromycin Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Safingol Safingol Hydrochloride ;Semustine; Simtrazene; Sparfosate Sodiurn; Sparsornycin; Spirogermanium Hydrochloride; Spirornustine; Spiroplatin; Streptonigrin; Streptozocin; Strontium Chloride Sr 89; Sulofenur; :Talisomycin; Taxane; Taxoid; Tecogalan Sodium; Tegafur; Teloxantrone Hydrochloride; Temoporfin; Teniposide; Teroxirone; Testolactone; Thiamiprine; Thioguanine, Thiiotepa; Tiazofurin; Tirapazamine; Topotecan Hydrochloride; Toremifene Citrate; Trestolone Acetate; Triciribine Phosphate; Trimetrexatc; Trimetrexate, Glucuronate; Triptorelin; Tubulozole Hydrochloride; Uracil Mustard; Uredepa; Vapreotide; Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Vindesine; Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; Vinrosidine, Sulfate; Vinzol idine Sulfate; Vorozole; Zeniplatin; Zinostatin; Zorubicin 25 Hydrochloride.

Other anti-neoplastic compounds include: 20-epi-1,25 dihydroxyvitamin D3; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsal izing morphogenetic protein- I; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaniinase; asulacrine; atamestane; 36 atrirnustine; axinastatin 1; axinastatin 2; axinastatin 3; azasctron; azatoxin; azatyrosine; baccatin Ill derivatives; balanol; batimastat; BCRIABL antagonists; benzochlorins; benzoylstaurosporine; beta lactamn derivatives; beta-alethine; betaclarnycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrenc; bisaziridinvi sperm-ine; bisnafidc; bistratene A; bizelesin; breflate; bropirirnine; budotitane; buthionine sulfoximine; calcipotriol; caiphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chioroquinoxalime sulfonamide; cicaprost; cis-porphyrin; cladribine; clomnifene, analogues; clotrimazole; collismycin A; collisniycin B; combretastatin AM; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatarn; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexifosfarnide; dexrazoxane; dexverapaniil; diaziquone; didemnin B; didox; diethylnorspermine;, dihydrotaxol, dioxamycin; diphenyl. spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emnitefur; epirubicin; cpristcrid,e;, estramusti ne analogue; estrogen agonists; estrogen antagonists; etanidazolc; etoposidc phosphate; exemestane; fadrozole; fazarabine; :fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone:, fludarabine; V. fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecini; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine ganire lix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hcxamethylenc bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; i imofosine; ilomastat; imidazoacridones; imiquimod; imi-nunostimnlant peptidcs; insulin-like growth factor-I receptor inhibitor; intcrfcron agonists; interferons; interleukins; iobenguanle; iododoxorubicin; ipomeanol, irinotecan; iroplact; 0 25 irsogladine; isobengazole; isohiomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamnellatin- N triacetate; lanreotide; leinamycin; lenograstirn; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; Icuprolide estrogen progesterone; leuprorelin; levarnisole; liarozole; linear polyarninc analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotccan; lutetium tcxaphiyrin; lysol'yllinc; lytic pcptides; maitansine; mannostatin A; marimastat; niasoprocol; niaspin; matrilysin inhibitors; matrix metal loproteinase nhibitors; mcnogaril;, mcrbarone; ineterelin; rnethioninasc; mietoclopramide; MWF inhibitor; 37 mifepristone; miltefosinc; ruirimostim; mismatched double stranded RNA; rnitoguazone; mitolactol; mitomycin analogues; mitonafi de; mitotoxin fibroblast growth factor-saporin, mitoxantrone; inofarotene; moigrarnostim; monoclonal antibody, human chorionic gonadotrophin;, monophosphoryl lipid A myobactcriuni cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumnor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nernorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrul lyn; 06-benzylguanine; octreotide; okicenonc; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; pad itaxe I analogues; pad itaxel derivatives; palauanine; palmitoylrhizoxin; parnidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflUbron; perfosfamide; perillyl alcohol; phenazinomyci n; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamnine complex; porfimner sodium; porfiromycin; propyl bisacridone; prostaglandin J2; proteasorne inhibitors; protein A-based immune modulator; protein :kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxycthiylcnc conjugate, raf antagonists; raltitrexed; ramrosetron; ras farnesyl protein transferase inhibitors; ras inhibitors: ras-GAIP inhibitor; retelliptine dernethylated; rhenium Re 1 86 etidronate; rhizoxin; ribozyrnes; RII retinarnide; rogletimide; rohitukinc; romnurtide; roquinimex: rubiginone B 1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sirgramostim; Sdi I mimetics; semiustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators;, single chain antigen binding protein; sizofiran; sobuzoxane; sodiom borocaptate; sodium phcenylacctatc; solverol; somatomedin binding protein; sonermin; sparrosic acid; spicarnycin D; spirornustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactivc vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosarninoglycans; talliniustinc; tamnoxi fen methiod ide; tauromustinc; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerasc inhibitors; ternoporfin; temozolomide; teniposidc; tctrachilorodecaoxide; tctrazominc; thaliblastine: thalidomnide: thiocoraline, thrombopoictin; thrombopoictin mimetic; thymalfasin; 38 thymopoietin receptor agonist; thyrnotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirap azamine; titanocene dichloride; topotecan; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenirnex; urogenital sinusderived growth inhibitory factor; urokinase receptor antagonists; vapreotidc; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoteronc; zeniplatin; zi lascorb; zinostatin stimalamer.

Anti-cancer Supplementary Potentiating Agents: Tricyclic anti-depressant drugs imipramine, desipramine, amitryptyline, clom ipramine, trimiprarnine, doxepin, nortriptyline, io protriptyline, amoxapine and maprotiline); non-tricyclic anti-depressant drugs sertraiine, trazodonc and citaloprarn); Ca** antagonists verapamil, nifedipine, nitrendipine and caroverine); Calmodulin inhibitors prenylamine, trifluoroperazine and clomipramine); Amphotericin 13; Triparanol analogues tarnoxifen); antiarrhythmic drugs quinidine); anti hypertensive drugs reserpine); Thiol depleters buthionine and sulfoximine) and Multiple Drug Resistance reducing agents such as Cremaphor EL. The compounds of the invention also can be administered with cytokines such as granulocyte colony stimulating factor.

0 .0 ::Antinheutropenic: Fi Igrastim; Lcnograstim; Mlrmsi;Rgaotm agaotm 20 Antiobsessional agent: Fluvoxamine Mdleate.

Antiparasitic: Abamectin;, Clorsulon; Ivermectin.

*.o Se* Antiparkinsonian: Bcnztropinc Mcsylate; lBiperidcn; lBipcridcn Ilydrocioride; Biperiden Lactate; Carmantadine; Ciladopa H-ydrochloridc; Dopamantine; Ethopropazine Hydrochloride; Lazabemide; Levodopa; Lomctral inc Hydrochloride; MofegilIinc 1lydrocliloridc; Naxagol ide H-ydrochloride; Pareptide Sulfatc; Procyclidine H-ydrochloride; Quinclorane Hydrochloride; Ropinirole 0 ~Hydrochloride; Selcgiline H4ydrochloride; Tolcapoac; Trihexyphcn idyl H-ydrochloride.

Antiperistaltic: Difenoximide H-ydrochloride; Difenoxin;, Diphenoxylate Hydrochloride; Fluperamide; Lidamidine Hydrochloride; Loperamide H-ydrochloride; Maletharner; Nufcnoxole; Paregoric.

39- Anti preurnocystic: Atovaquone.

Antiproliferative agent: Piritrexim Isethionate.

3 Antiprostatic hypertrophy: Sitogluside.

Antiprotozoal: Amodiaquine; Azanidazole; IBamnidazole; Camidazole; Chlortetracycline Bisulfate Chlortetracycline Hydrochloride; Flubendazole; Flunidazole; Halofuginone Hydrobromide; Imidocarb Hydrochloride; Ipronidazole; Metronidazole; Misonidazole; Moxnidazole; Nitarsone; Partricin; Purornycin; Puromycin Hydrochloride; Ronidazole; Sulnidazole; Tinidazole.

Antipruritic: Cyproheptadi ne, Hydrochloride Methdilazi ne; Mcthd ilazine Hydrochloride; Trimeprazine Tartrate.

Antipsoriatic: Acitretin; Anthralin; Azaribine; Calcipotriene; Cycloheximide; Enazadrern Phosphate; Etretinate; Liarozoic Fumaratc; Lonapalene; Tepoxalin.

:Antiosychotic: Acetophenazine Maleate; Alentemol Hydrobrornide; Alpertine; Azaperone; Batelapine Maleate; Benperidol; Benzindopyrinc Hydrochloride; Brofoxine; Bromperidol; 0 Bromlrperidol Dccanoatc; [3utaclrnol hlydrochloride; Butapcrazinc; Butapcrazine Malcaic; Carphenazine Maleate; Carvotroline Hydrochloride; Chlorpromazine; Chiorpromazine Hydrochloride; Chiorprothixcnc; Cinperene; Cintriarnide; Clomacran Phosphate; Clopenithixol; Clopirnozide; Clopipazan Mesylate; Cloroperone Hydrochloride; Clothiapine; Clothixamide Malcate; Clozapine; Cyclophenazine H-ydrochloridc; Droperidol; Etazolate H-ydrochloride; Fenirnide; Flucindole; Flurnezapine; Fluphienazine Dccanoatc; Fluphenazine Enanthate; Fluphenazine Hydrochloride; Fluspiperone; Fluspirilene; Flutrolinc; Gevotroline Hydrochloride; l-alopcmidc; Haloperidol; Haloperidol Decanoate; lioperidone; I midoline Hlydrochloride; Lenperone; Mazapertine Succinate; Mesoridazinc; Mesoridazine Besylate; Metiapine; Milenperone; Milipertine; Molindone H-ydrochloride; Naranol H-ydrochloride; Neflurnozide Hydrochloride; Ocapcridonc; Olanzapine, Oxipcromide; PenfIuridol; Pentiipinc Malcatc: Perplicnazi ne; P imozide; Pinoxcpin Hydrochloride, Piparnpcronc; Piperacciazinc, Pipotiazine Palmitatc; Piquindone I Iydrochloridc; Prochiorperazine Edisylatc; Prochiorperazine Maleatc; Promazinc Hlydrochloride; Remoxipride:, Remoxipride Hydrochloride; Rimcazole 1lydrochloride; Seperidol Hydrochloride; Sertindole Setoperone; Spiperone; Thioridazirie Thiioridazine Hydrochloride; Thiothixene; Thiothixene Hydrochloride; Tioperidone Hydrochloride; Tiospirorie Hydrochloride; Trifluoperazine H-ydrochloride; Trifluperidol; Triflupromazine; Triflupromazine Hydrochloride; Ziprasidone Hydrochloride.

Antirheumatic: Auranofin; Aurothioglucose; Bindarit; Loberizarit Sodium; Phenylbutazone; Pirazolac; Prinomide Tromethamine; Seprilose.

Anti schistosomal; Becanthone Hydrochloride; Hycanthone; Lucarithone Hydrochloride; Niridazole; Oxamniquifle; Pararosaniline Pamoatc; Teroxalene Hydrochloride.

Arfliseborrheic: ChIOroxine; Piroctone; Piroctone Olamnine; Resorcinol Monoacetate.

Antisecretory: Arbaprostil; Deprostil; Fenoctimine Sulfate; Octreotide;, Octreotide Acetate; Omeprazolc Sodium-. Rioprosti I; Trimoprostil.

Antispasmodic: Stiloniurn Iodide; Tizanidine Hydrochloride.

20 Antithrombotic: Anagrelide Hydrochloride; Bivalirudin Daltcparin Sodium ;Danaparoid Sodium; Dazoxiben Hydrochloride; Efegatran Sulfate; Enoxaparin Sodium; Ifetroban; Ifetroban Sodium; Tinzaparin Sodium ;T'ri fcnagrcl.

Antitussive: Benzoflatatc; Butamirate Citrate; Chlophedianol Hydrochloride; Codeine Polistirex; Codoxime; Dextroniethorphan; Dextromethorphan Ilydrobromide; Dextroinethorphan Polistinex; Ethyl Dibunate; Guaiapate; 1-ydrocodonc Bitartratc; H-ydrocodone Polistirex; Levopropoxyphene Napsylate; Noscapine; Pernerid Nitrate; Pipazethate; Suxemerid Sulfate.

Anti-ulcerative: Aceglutamide Aluminum. Cadexorner Iodine; Cetraxate H-ydrochloride; Enisoprost; Isotiquimide; Lansoprazoic; Lavoltidine Succinate; Misoprostol; Nizatidinc; Noliniurn Bromide Pantoprazole; Pifarnine; Pirenzepinc H-ydrochloride; Rabeprazole Sodium; Rcmiprostol; Roxatidine Acetate H-ydrochloride; Sucral fate; Sucrosofate Potassium; Troliniidone.

-41- Anti-urolithic: Gystearnine; Cysteamine Hydrochloride; Tricitrates.

Antiviral: Acemannan; Acyclovir; Acyclovir Sodium; Adefovir; Alovudine; AlVircept Sudotox; Amantadine H-ydrochloride; Aranotin; Arildonc; Atevirdine Mesylate; Avridine; Cidofovir; Cytarabine Hydrochloride; Delavirdine Mesylate; Desciclovir; Didanosine; Disoxaril; Edoxudine; Enviradene; Enviroxime; Famciclovir; Famotine Hydrochloride; Fiacitabine; Fialuridine; Fosari late. Foscarnet Sodium; Fosfonet Sodium; Ganciclovir; Ganciclovir Sodium; Idoxuridine; Kethoxal; Lamivudine; Lobucavir; Memotine Hydrochloride; Methisazone; Nevirapine; Penciclovir; Pirodavir; Ribavirin; Rimantadine Hydrochloride; Saquinavir Mesylate; Somantadine i o H-ydrochloride; Son vudinc; Statolon; Stavudine; Tilorone Hydrochloride; Trifluridine; Valacyclovir H-ydrochloride; Vidarabine; Vidarabinc Phosphate; Vidarabine Sodium Phosphate; Viroxime; Zalcitabine; Zidovudine; Zinviroxime.

Appetite suppressant: Dexfenfluramine Hydrochloride; Phendimetrazine Tartrate; Phentermine 1 5 -lydrochloride.

Benign prostatic hyperplasia therapy agent: Tamsulosin Hydrochloride.

Blood glucose regulators: Human insulin; Glucagon; Tolazamide; Tolbutamidc; Chioropropamide; Acctohcxamide and Glipizidc.

Bone resorption inhibitor: Alcndronate Sodium; Etid ronaic Disod iurn; Pamidronate Disodium.

0000 0 *go*Mesylatc; Doxaprost; Doxofylline; Dyphyllinc; Enprofyllinc; Ephedrine; Ephedrine Hydrochloride; V60*0Fenoterol; Fenprinast Hydrochloride; Guaithylline; Hexoprenaline Sulfate Hoquizil Hydrochloride; a Ipratropiurn Bromide; Isoetharine; Isoetharine Hydrochloride; Isoetharine Mesylatc; I soproterenol 0 Hlydrochloride; lsoprotcrenol Sulfatc; Metaproterenol Polistirex; Mictaprotcrcnol Sulfate; Nisbuterol Mesylate;, Oxtriphyll inci; Picumictcrol Fumaratc; Piquizil H -ydrochloride; Pi rbuterol Aetate; P irbutcrol H-Iydrochloride; Procatcrol H-ydrochloride: PSCudCocphedri nc Sul fate; Quazodinec Qu intcrcn() Sulhiutc;.Racepi cplirinc; Racepincphrinc H-ydrochloride; Rcprotcrol Hydrochloride; 42 Rimiterol Hydrobromide; Salmeterol; Salmeterol Xinafoate; Soterenol Hydrochloride; S ulfonterol Hydrochloride; Suloxifen Oxalate; Tcrbutaline Sul fate; Theophyl line; Xanoxatc Sodium; Zindotrine; Zinterol Hydrochloride.

Carbonic anhydrase inhibitor: Acetazolamnide; Acctazolamide Sodium; Dichlorphenainide; Dorzolamnidc Hydrochloride; Methazolamide; Sezolarnide Hydrochloride.

Cardiac depressant: Acecainide Hydrochloride; Acetylcholine Chloride; Actisomide; Adenosine; Amiodarone; Aprindine; Aprindine Hydrochloride; Artilide Furnarate; Azimil ide Dihydrochioride; Bidisomide; Bucainide Malcate; Bucromarone; Butoprozine Hydrochloride Capobenate Sodium; Capoberiic Acid; Cifenline; Cifenline Succinate; Clofiliurn Phosphate; Disobutamide; Disopyrarnide; Disopyramide Phosphate; Dofetilide; Drobuline; Edifolone Acetate; Emilium Tosylatc; Encainide Hydrochiloride; Ficcainide Acetatc; Ibutilide Fumarate; Indecainide Hydrochloride; Ipazilide Fumaratc; Lorajmine Hydrochloride; Lorcainide Hydrochloride; Meobentine Sulfate; Mexiletine Hydrochloride; Modecainide; Moricizine;, Oxiramide; Pirmenol Hydrochloride; Pirolazamnide; Pranolium Chloride; Procainarnide Hydrochloride; Propafenone Hydrochloride; Pyrinoline; Quindonium Bromide; Quinidine Gluconlate; Quinidine Sulfate; Recainamn Hydrochloride; Recainam Tosylate; Risotilide Hydrochloridc; Ropitoin Hydrochloride; Sematilide Hydrochloride; Suricainide Maleate; Tocainide;'Tocainide Hydrochloride; Transcai nidc.

Card ioprotectant: Dexrazoxane; Draflazine.

Cardiotonic: Actodigin; Arnrinonc; Bemiloradan; Butopanlinc; Carbazeran; Carsatrin Succinatc; Deslanoside; Digitalis; Digitoxin; Digoxin; Dobutamine; Dobutamine Hydrochloride; Dobutamine Lactobionate; Dobutamninc Tartratc; Enoximonc; Imazodan H-ydrochloride; Indolidan; lsomaz~ole Hydrochloride; Lcvdobutarnine Lactobionate; Lixazinone Sulfate; Medorinone; Milrinone; Peirinone l-ydrochloridc; Pimnobendan; Piroximonc; Prinoxodan; Proscillaridin; Quazinonc; Tazolol H-ydrochloride; Vesnarinone.

Cardiovascular agent: Dopexamine; Dopexamine Hydrochloride.

Choleretic; Dehydrocholic Acid; Fenicibutirol; 1lyrnecrornone; Piprozolin; Sincalide; Tocamphyl.

-43- Cholinergic: Aceclidine; Bethanechol Chloride; Carbachol; Demcecarium Bromide; Dexpanthenol; Echothiophate Iodide; I soflurophate; Methacholine Chloride; Neostigmine Bromide; Neostigrnine Methylsulfate; Physostigmine; Physostigmine Salicylate; Physostigmine Sulfate; Pilocarpine Pilocarpine Hydrochloride; Pilocarpine Nitrate; Pyridostigmi ne Bromide.

Cholinergic agonist: Xanomeline; Xanomeline Tartrate.

Cholinesterase Deactivator: Obidoximne Chloride; Pralidoxi me Chloride; Pralidoxime Iodide; Pralidoxime Mesylate.

Coccidiostat: Arprinocid; Narasin Semrduramnicin; Semduramici n Sodium.

Cognition adj uvant: Ergoloid Mesylates; Piracetam; Praniiracctami Hydrochloride; Pramiracctam Sulfate; Tacrine Hydrochloride.

Cognition enhancer: Besipirdine Hydrochloride; Linopirdine; Sibopirdine.

:Depressant: Omeprazo Ic.

2 Diagnostic aid: Aminohippurate Sodium;' Anazolene Sodium; Arciofenin; Arginine Bentiromide; Benzylpenicilloyl Polylysine; Butedronate Tetrasodium; Butilfenin; Coccidioidin; Corticorelin Ovi ne Tri flutate ;Corti cotropin, Repository Corticotropin Zinc H-ydroxide; Diatrizoate Megluniine; Diatrizoate Sodium; Diatrizoic Acid; Diphtheria Toxin for Schick Test; Disofenin; Edrophonium Chloride; Ethiodized Oil; Etifenin; Exametazime; Ferristenc; Ferumoxides; Ferumoxsil; Fluorescein; 25 I'luorescein Sodium; Gadobenate Dimeglumine; Gadoteridol; Gadodiamide; Gadopcntetate OV Dimegiumine; Gadovcrsetamide; Histoplasmin; Impromidine Hydrochloride; nd igoti ndisul fonate Sodium; Indocyanine Green lobenguane Sulfate 1 123; lobenzamic Acid; locarmate Meglurnine; locarmic Acid; locctamic Acid; lodarnide; lodaniide Mcgiuminc; lodipamidc Megluinen; lodixanol; lodoxamate Megluniine; lodoxamic Acid; loglicic Acid; loglucol; loglucomide; Ioglycamic Acid; 3 0 logularnide;, lohcxol; lomeprol; lopamidol; lopanoic Acid; lopentol; lophendylaLe; lprofcnin; lopronic Acid; loprocemic Acid; lopydol; lopydonc; losefamnic Acid; loscric Acid;, losulamide Meglutmine; Iosumcetic Acid; lotasul;, lotetric Acid; lothalamnatc Megluminc; lothalamate Sodium; 44 lothalamic Acid; lotrolan; lotroxic Acid; loversol; loxaglate Meglumine; loxagiate Sodium; loxaglic Acid; loxilan; loxotrizoic Acid; Ipodate Calcium; Ipodate Sodium; Isosulfan Blue; Leukocytc Typing Serum; Lidofenin; Mebrofenin; Meglumine; Metrizamide; Metrizoate Sodium; Metyrapone; Metyrapone'Tartratc; Mumps Skin Tcst Antigen; Pentetic Acid; Propyliodone; Quinaldine Blue; Schick Test Control; Serrnorelin Acetate Sodiumn lodide 123; Sprodiamide; Stannous P1yrophosphate; Stannous Sulfur Colloid; Succimer; Teriparatide Acetate; Tetrofosmin; Tolbutamnide Sodium; Tuberculin; Tyropanoate Sodium; Xylose.

Diuretic: Amrbuphylline Ambuside; Amiloride Hydrochloride; Azolimine; Azosemide; Brocrinat; Bumctanide; Chiorothiazide; Chiorthalidone; Clazolimine; Clorexolone; Ethacrynate Sodium; Ethacrynic Acid-, Etozolin; Fenquizone; Furosemide; Hydrochlorothiazide; Isosorbidc; Mannitol; Mefruside; Ozolitione; Piretanidc, Spiroxasone; Torscrnidc; Triamierene; Triflocin; Urea.

Dopaminergic agent: lbopaminc.

Ectoparasiticide: Nifluridide; Permethrin.

Emetic: Apomorphine Hydrochloride.

20 Enzyme inhibitor: Acetohydroxainic Acid; Airestatin Sodium; Aprotinin: Benazepril Hydrochloride; lBcnazcprilat;, Benurestat; Bromocriptine; Bromocriptine Mesylate; Cilastatin Sodium; Flurofainidc; Lergotri Ic; Lergotrile Mesy late; Lcvcycloserine; Libenzapril; Pentopri 1; Pepstati n; Perindopri I; Polignatc Sodiumn; Sodium Amlylosulltec Sorbinil; Spirapril Hydrochloride; Spiraprilat; Taleranol; Teprotide; Tolfamide; Zofenopril Calcium.

Estrogen: Chiorotrianisenie; Dienestrol; Diethyistilbestrol; Dicthy Istilbestrol Diphosphate; Equijin; Estradiol; Estradiol Cypionate; Estradiol Enanthate; Estradiol Undecylate; Estradiol Valerate; Estrazinol Hydrobromide; Estriol; Estrofurate; Estrogens, Conijugated;, Estrogens, Esterified; Estrone; Estropipate; Ethinyl Estradiol; Fenestrel; Mestranol; Nylestriol; Quinestrol.

Fibrinolytic: Anistreplase; Bisobrin Lactate; Brinolase.

Free oxygen radical scavenger: Pegorgoicin.

Gastrointestinal Motility agents: Cisapride (Propulsid); Metoclopramicic (Reglan); Hyoscyamine (Levsin).

Glucocorticoid: Amcinonidc; Beclomethasone Dipropionate; Betamethasone; Betamethasone Betamethasofle Benzoate; Betamethasone Dipropionate; IBetamethasone Sodium Phosphate; Betarnethasone Valerate; Carbenoxolone Sodium; Clocortolonc Acetate; Clocortolone Pivalate; C loprednol; Corticotropin; Corticotropin, Repository; Corticotropi n Zinc Hydroxide; Cortisone Acetate; Cortivazol; Descinolone Acetonide; Dexcamethasone; Dexamethasone Sodium Phosphate; Diflucortolone; Diflucortolone Pivalate; Flucloronide; Flumethasone; Flumethasone Pivalate; Flunisolide; -Fluocinolone Acetonide; Fluocinonide; Fluocortolone; Fluocortolone Caproate; Fluoronietho lone; Fluperolone Acetate; Fluprednisolone; Flupredniso lone Valerate; Flurandrenolide; Formocortal; I-Iydrocortisonc;, H-ydrocortisone Acetate; 1-lydrocortisone Buteprate; Hydrocortisone Butyrate; Hydrocortisonle Sodium Phosphate; Hydrocortison e Sodium Succinatc; H-ydrocortisone Valerate; Medrysone; Methyiprednisolone; Methyipredni so lone Acetate; Methyiprednisolone Sodium Phosphatc, Methylprednisoloiie Sodium Succinate; Nivazol; Paramcthasone Acetate; Prcdnicarbatc; Prednisolonc; Prednisolone Acetate; Prcdnisolonc Hemnisuccinate; Prednisolone Sodium Phosphatc; Prednisolonc Sodium Succinatc; Prednisolonc Tebutate; Prednisone; Prednival; Ticabesonc Propionatc; 1'ralonide; Triarncinolone; rriancinolone Acetonidc; Triamcinolone Acetonide Sodium; Triamcinolonc Diacetate; Triamcinolone -lexacetonide.

Gonad-stimulating principle: Buserelin Acetate. Clomniphene Citrate; Ganirel ix Acetate; Gonadorelin Acetatc; 0 onadorclin I-I ydrochloridc; Gonadotropin. Chorionic; Menotropi ns.

Ilair growth stimulant: Minoxidil.

Hemostatic: Atninocaproic Acid; Oxaniarin Hydrochloridc; Sulmarin; Thrombin; Tranexamic, Acid.

H-istamine 1-12 reccptor antagonists: Ranitidine (Zantac); Frimotidine (Pcpcid); Cirnetidine (Tagamet); Nizatidinc (Axid).

H-ormone: DiethylstilIbestr-ol; 1Progesteronc;, 17 hydroxy progcstcronc, MedroxyprogsteroflC N orgestrcl; N orethynodlrcl Estrad ici; Mcgcstrol (Megace); Norethindronc; Levonlorgestrel; -46- Ethyndiol; Ethinyl estradiol; Mestranol; Estrone; Equilin; 17 alpha dihydroequilin; equilenin; 17 alpha dihydroequilenin; 17 alpha estradiol; 17 beta estradiol; Leuprolide (lupron); Glucagon; Testolactone; Clomiphene; Han memopausal gonadotropins; Human chorionic gonadotropin; Urofollitropin; Bromocriptine; Gonadorelin; Luteinizing hormone releasing hormone and analogs; Gonadotropins; Danazol; Testosterone; Dehydroepiandrosterone; Androstenedione; Dihydroestosterone; Relaxin; Oxytocin; Vasopressin; Folliculostatin; Follicle regulatory protein; Gonadoctrinins; Oocyte maturation inhibitor; Insulin growth factor; Follicle Stimulating Hormone; Luteinizing hormone; Tamoxifen.; Corticorelin Ovine Triflutate; Cosyntropin; Metogest; Pituitary, Posterior; Seractide Acetate; Somalapor; Somatrem; Somatropin; Somenopor; Somidobove.

Hypocholesterolemic: Lifibrol.

Hypoglycemic: Darglitazone Sodium: Glimepiride.

Hypolipidemic: Azalanstat Dihydrochloride; Colestolone; Surfomer; Xenalipin.

Hypotensive: Viprostol.

HMGCoA reductase inhibitors: Lovastatin (Mevacor); Simvastatin (Zocor); Pravastatin (Pravachol); Fluvasatin (Lescol).

S* Immunizing agent: Antirabics Serum; Antivenin (Latrodectus mactans); Antivenin (Micrurus Fulvius); Antivenin (Crotalidae) Polyvalent; BCG Vaccine; Botulism Antitoxin; Cholera Vaccine; Diphtheria Antitoxin; Diphtheria Toxoid; Diphtheria Toxoid Adsorbed; Globulin, Immune; Hepatitis B Immune Globulin; Hepatitis B Virus Vaccine Inactivated; Influenza Virus Vaccine; Measles Virus S 25 Vaccine Live; Meningococcal Polysaccharide Vaccine Group A; Meningococcal Polysaccharide Vaccine Group C; Mumps Virus Vaccine Live; Pertussis Immune Globulin; Pertussis Vaccine; Pertussis Vaccine Adsorbed; Plague Vaccine; Poliovirus Vaccine Inactivated; Poliovirus Vaccine Live Oral; Rabies Immune Globulin; Rabies Vaccine; Rho(D) Immune Globulin; Rubella Virus ***Vaccine Live; Smallpox Vaccine; Tetanus Antitoxin; Tetanus immune Globulin; Tetanus Toxoid; Tetanus Toxoid Adsorbed; Typhoid Vaccine; Yellow Fever vaccine; Vaccinia Immune Globulin;.

Varicella-Zoster Immune Globulin.

47 immunomodulator: Dimepranol Acedoben; Imiquimod; Interferon Beta-Ib; Lisofylline; Mycophenolate Mofetil; Prczatide Copper Acetate.

Immunoregulator: Azarole; Fanetizole Mesylate; Frentizole; Oxamisolc Hydrochloride; Ristianol Phosphate; Thymopentin; Tilomisole.

Immunostimulant: Loxoribine Teceleukin.

Immunosuppressalt: Azathioprine; Azathioprine Sodium; Cyclosporine; Daltroban; Gusperimus Trihydrochioride; Sirolimus-, Tacrolirnus.

Impote nce therapy adjunct: Delequarnine Hydrochloride.

Inhibitor: Acarbose; Atorvastatin Calcium; Benserazide Brocresine; Carbidopa; Clavulanate Potassium; Dazmcgrcl; Doccbcnonc; Epoprostenol; Epoprostenol Sodium; Epristeridc; Finastcride; Flurbiprofcni Sodium; Furcgrclatc Sodium; Lufironil; Miglitol; Orlistit; Pimagcdinc Hydrochloride; Pirmagrel; Ponalrestat; Ridogrel; Sulbactam Benzathine Sulbactam Pivoxil Sulbactam Sodium Suronacrine Maleate; Tazobactam; Tazobactam Sod iuin; Ticlopidine H-ydrochloride; Tirilazad Mesylate; Toirestat; Velnacrine Maleate; Zifrosilone; Zileuton.

2o Keratolytic: Aicloxa Aldioxa Benzoyyl Peroxide; Dibenzothiophene; Etarotene; Isotretinoin; Motretinide; Plicotrin Diolaminc; Resorcinol; Resorcinol Monoacetate; Salicylic Acid; Sumarotene; Tazarotene; Tetroquinone; Tretinoin.

LHRI-I agonist: Desloreli Goserelin; Histrclin; Lutrelin Acetate; Nafarclin Acetate.

Liver disorder treatment: Maloti late.

Luteolysin: Fenprostalene.

3 0 Memory adjuvant: Dimoxamine Hydrochloride; Ribaminol.

Mental performance enhancer: Aniracetarn.

48 Mood regulator: Fengabine.

Mucolytic: Acetylcysteine; Carbocysteine; Domiodol.

s Mucosal Protcctivc agents: Misoprostol (Cytotec).

Mydriatic: Berefrine.

Nasal decongestant: Nemazoline Hydrochloride; Pseudoephedririe Po] istirex.

Neuroleptic: Duoperone Fumaratc; Risperidone.

S S

S

S S

C

Neuromuscular blocking agent: Atracurium Besylate; Cisatracurium Besylate; Doxacuriun Chloride; Gallaniine Triethiodide; Metocurine Iodide; Mivacurium Chloride; Pancuronium Bromide; Pipecuronium Bromide; Rocuronium Bromide; Succiny Icholine Chloride; Tubocurarine Chloride; Vecurorijum Bromide.

Neuroprotcctivc: Dizocilpine Maleate.

20 NMDA antagonist: Scifotel.

Non-hormonal sterol1 derivative: Prcgncnolonc Succinate.

Oxytocic: Carboprost; Carboprost Methyl; Carboprost Tromethamine; Dinoprost Dinoprost Tromcthamninc Dinoprostone Ergonovine Maleate; Mctcnepros. Methylergonovine Maleqte; Oxytocin; Spartcine Sulfate.

Plasminogcn activator: Altcplasc; Urokinase.

Platelet activating factor antagonist: Lexipafant.

Platelct aggregation inhibitor: Acadesine; Beraprost; lBcraprost Sodium; Ciprostcne Calcium; liazigrel; Liflarizine, Oxagrclatc.

49 Post-stroke and post-head trauma treatment: Citicoline Sodium.

Potentiator: Pentostati n; Talopramn Hydrochloride.

Progestin: Algestone Acetophenide; Amadinone Acetate; Anagestone Acetate; Chiormadinone Acetalte; Cingestol; Clogestonie Acetate; Clomegestone Acetate; Desogestrcl; Dimcthisterone; Dydrogesterone; Ethynerone; Ethynodiol Diacetate; Etonogestrel; Flurogestonc Acetate; Gestaclone; Gestodene; Gestoriorone Caproatc-; Gestrinonc; I-laloprogcsteronc; 1-ydroxyprogesterone Caproate; Levonorgestrel; Lynestrenol; Medrogestone; Medroxyprogesterone Acetate; Methynodiol Diacetate; Norethindrone; Norethindrone Acetate; Norethynodrel; Norgestimate; Norgestomet; Norgestrel; Oxogestone Phenpropionate; Progesterone; Qui ngestanol Acetate; Quingestrone; Tigestol.

Prostaglandini: Cloprostcnol Sodium; Fl uprostenol Sodiurn; Gcrncprost; Prostalene; Suiprostone.

Prostate growth inhibitor: 1Pentornonc, Prothyrotropin: Protirelin.

*Psyc hotropic: Minaprine.

Pulmonary surface: Beractant; Colibscril Palmitate.

Radioactive agent: Fibrinogen 1 125 Fludeoxyglucosc F 8 ;Fluorodopa F 18 ;Insulin 1 125; Insulin 1 13 1; lobenguane 1 123; Iodiparnide Sodium 1 131 Iodoantipyrine 1 131 lodocholesterol 1 131 lodohippurate Sodium 1 123 lodohippuratc Sodium 1 125 lodohippurate Sodium I I *0*lodopyracct 1125 lodopyracct 1 131 Iofetaininc H-ydrochloride 1 123 lomecthin 1 125 lornethin 1131I lothalamate Sodium 1 125 lothalaniate Sodium 1131 lotyrosirie 1 13 1; Liothyronline 1 125; Liothyroninc 1 13 1; Mcrisoprol Acetate Fig 197; Mcrisoprol Acetatc H~g 203; Mcrisoprol Fig 197 Selenomncthioninc Se 75 Tchnctium 1c 99m Awniony Trisullide Colloid, rcchrictium Te 99m Bicisate Tcclinctiurn Tc 99m Disofenin ;Technetiumn Tc 99m Etidronate Technctiurn Tc 99mi 1Lxanctazinie Technctium 'UC 9911 FUril'osmin Tcchnctium, 'c 99m GlUCCPtatc Tcchnctiurn Tc 99ni Lidofeniin TFechnetium Toc 99m Mebrofenin T-cchinctium Tce 99rn Medronate Technetium 50 Tc 99m Medronate Disodium; Technetium Tc 99m Mertiatide Technetium Tc 99m Oxidronate Tech netiumn Tc 99m Pentetate; Tcchnetium Tc 99m Pentetate Calcium Trisodium; Technetium Tc 99m Sestarnibi Technetium To 99m Siboroxime Technetiumn To 99m Succimer Technetium Tc 99m Sulfuir Colloid Technetium Tc, 99m Teboroxine Technetium Tc 99m letrofosmin Technetium Tc 99m Tiatidc; Thyroxine 1 125; Thyroxine 1 13 1; Tolpovidone 1 131 Triolein 1 125; Triolein 1 131.

Regulator: Calci fediol; Calcitonin; Calcitriol; Clodronic Acid; Dihydrotachysterol; Etidronic Acid; Oxidronic Acid; Piridronate Sodium; Risedronate Sodium; Secalciferol.

to Relaxant: Adiphenine Hydrochloride; Alcuronium Chloride-, Aminophylline; Azumolene Sodium; Baclofen; Benzoctamine Hydrochloride; Carisoprodol; Chlorphenesin Carbamate; Chlorzoxazonc; Cinflumide; Cinnaniedrine; Clodanolene; Cyclobenzaprine Hydrochloride; Dantrolene; Dantrolene Sodium; Fenalamide; Fenyripol H-ydrochloride; Fetoxylate Hydrochloride; Flavoxate Hydrochloride; Fletazepam; Flumetramide; Flurazepamn Hydrochloride; Hexafluorenium Bromide; Isomylamine H-ydrochloride; Lorbaniate; Mcbcverine Hydrochiloridc; Mesuprine H-ydrochloride Metaxalone; Methocarbaniol; Methixenc Hydrochloride; Nafomine NMalate; Nelezaprine Mal eate; Papaverine 1lydrochloride; Pipoxolan H-ydrochloride; Quinctolaic; Ritodrine; Ritodrine Hydrochloride; Rolodine, Theophylline Sodium Glycinate; Thiphenarnil H-ydrochloride; Xilobam.

Repartitioning, agent: C iraterol.

Scabicide; Amitraz; Crotamiton.

Sclerosing agcnt: Ethanolamine Oleate; Morrhuate Sodium; Tribenoside.

Sedative: Propiomazine.

Sedative-hypnotic: Allobarbital; Alonimid; Aiprazolamn; Arnobarbital Sodium; Bentazepam; 13rotizolam; BLuiabarbital; Butabarbital Sodium; lButal bital; Capuride; Carbocloral; Chloral Betaine; Chloral llydratc; Chloi'dia7.cpoxidc I-lydrochloride; Cloperidone Ilydrochloridc; Clorethate; Cyprazepam; Dexciamol Hydrochloride; Diazepam; Dichloralphenazonc; Estazolam; Ethchlorvynol; -51 Etomidate; Fenobam; Flunitrazepamn; Fosazepam; G lutethimide; H-alazepam; Lormetazeparn; Mecloqualone; Meprobamate; Methaqualone; Midaflur: Paraldehydc; Pentobarbital; Pentobarbital Sodium; Perlapine; Prazepam; Quazepam; Rcclazcpamn; Roletamide; Secobarbital; Secobarbital Sodium; Suproclone; Thalidomide; Tracazolate; Trepipam Maleate; Triazolam; Tricetamide; Triclofos Sodium; Trimetozine; Uldazepam; Zaleplon; Zolazepamn Hydrochloride; Zolpidem Tartrate.

Selective adenosine Al antagonist: Apaxifylline.

Serotonin antagonist: Altanserin Tartrate; Amnesergide; Ketanserin; Ritanserin.

Serotonin inhibitor: Cinanserin Hydrochloride; Fenclonine; Fonazine Mcsylate; Xylamidine Tosylatc.

Serotonin receptor antagonist: Tropanserin H-ydrochloride.

Steroid: Dexaniethiasone Acefurate; Momnetasone Furoate.

**Stimulant: Amifonelic Acid; Amphetamine Sulfate; Ampyzine: Sulfate; Arbutarnine H-ydrochloride; 20 Azabon; Caffeine; Ccrulctide; Ccrukltidc Diefihylaniine; Cisapride; Dazopride Fumnarate; Dextroamphetaniinc;. Dextroarnplctaniine Sulfatc; Difluaninc Hydrochloride; Dimmcfl m l-lydrochiloridc; Doxaprani H-ydrochiloride; lEtryptamine Acetate; Etharnivan; Fenethyll inc Hlydrochloride; Flubanilate: Hydrochloride; IPlurothyl; Ilistaiic Phosphate; Indriline H-ydrochloride; Mefexamide; Niethamphetamine Hydrochloride; Mcthylphicnidlate Hydrochloride; lPeroline, Pyrovalerone H-ydrochloride; Xaniotcrol; Xainoterol Fumlarate.

Supprcssant: AMfiutZOle; Colchicic; T-azofcelonc.

Symnptonmatic multiple sclcrosis: Famnpridine.

Sy nergist: Proadifcn [lydrochloridc.

-52- Thyroid hormone: Levothyroxine Sodiumn; Liothyronine Sodium; Liotrix.

Thyroid inhibitor: Methimazoic; Propylthiouracil.

Thyromimetic: Thyromedan Hydrochloride.

Tranquilizer: Bromazepam; lBuspirone Hydrochloride; Chiordiazepoxide; Clazolarn; Clobazam; C lorazepate Dipotassium; Clorazepate Monopotassiumn; Demoxepamn; Dexmedetom idine; Enciprazine Hydrochloride; Gepirone Hydrochloride; Hydroxyphenamate; Hydroxyzine H-1ydrochloride; Hydroxyzine Pamnoate; Ketazolamn; Lorazepamn; Lorzafone; Loxapine; Loxapine Succinate; Medazepam H-ydrochloride; Nabilone; Nisobamate Oxazeparn; Pentabamate; Pirenperone; Ripazepam; Rolipram; Sulazepamn; Tacianiine l-ydrochloridc; Temazepam; Triflubazamn; Tybaniate; Valnoctamide.

Amnyotrophic. lateral sclerosis agents: Riluzole.

Cerebral isehemnia agents: Dextrorphan Hydrochloride.

Paget's disease agents: Tiludronate Disodiuni.

Unstable angina agents: Tirofiban H-ydrochloride, Uricosuric: Benzbromarone; I rtemazolc; Probenecid; Sulfinpyrazone.

Vasoconstrictor: Angiotensin Amnide; Felypressin; Mcthysergide; Methysergide Maleate.

Vasodilator: Alprostadil; Azaclorzine Hydrochloridc; Bamiethan Sulfate; lBepridil Hydrochloride; Buterizinc; Cetiedil Citrate; Chromonar H-ydrochloride; Clonitrate; Diltiazemn H-ydrochloride; Dipyridamole; Droprenilamine; Erythrityl Tetranitrate;, Felodipine; Flunarizine Hydrochloride; Fostedil; llecxobendinc; Inositol Niacinate; Iproxamine Hydrochloride;. Isosorbide Dinitrate; I sosorbide Mononitratc; lsoxsuprinc Hlydrochloride, Lidofhizinc; Mcfenidi I; Mefeniidil Furnaratc; Mibel'radil Dihydrochioridc; Mioflazine Ilydrochioride; Mixidine; Nafronvi Oxalate; N icardipi ne 53 Hydrochloride; Nicergolitie; Nicorandil; Nicotinyl Alcohol; Nifedipine; Nirnodipine; Nisoldipine; Oxfenicine; Oxprenolol Hydrochloride; Pentacrythritol Tetranitrate; Pentoxifylline; Pentrinitrol; Perhexiline Maleate; Pindolol; Pirsidomine; Prenylarnine; Propatyl Nitratc; Suloctidil; Terodiline Hydrochloride; Tipropidil H-ydrochloride; Tolazoline Hydrochloride; Xanthinol Niacinate.

Vulnerary: Allantoin.

Wound healing agent: Ersoferrnin.

Xanthine oxidase inhibitor: Allopurinol; Oxypurinol Other pharmaceutical agents include: I -decpyrrolidinone; I -dodecpyrrolidinone; 16-alpha fluoroestradiol; 16-epiestriol; 16alphia-gitoxin; I7alpha estradiol; l7beta estradiol; ]lphahydroxyvitamin D2, 2'-nor-cGMP; 20-epi-1,25 dihydroxyvitam-in D3; 22-oxacalcitriol; 2CVV; 3isobuty I GAI3A; 6-FUDCA; 7-mellhoxytacrine; abamectiin; abanoqui 1; abecarnil; abiraterone; acadesine; acamprosate; acarbosc; accclofenac; acemannan; acetomepregenol; acetyl-L-carnitine; acetylcysteine, acctylmethadol; acifran; acipimox; acitemate; acitretin; aclarubicin; aclatoniurn; napadisilatc; aconiazide; acrivastinet; adafenoxate; adapalene; adatanscrin; adecypenol; adefovir 0O S dipivoxil; adelmidrol; ademetionine; adinazolam; adiposin; adozelesin; adrafinil; alacepril; ,***aladapein; alaptide; albendazole; albolabrin; aldecalmycin; aldeslcukin; alendronic acid; alentemol; too. 20 alfacalcidlol-; alfuzosin; alglucerase; aliiistinc; alosetron; alpha idosonc; alprostadil. ahtrctamine; altrornycin B; ambamustine; amelornetasone; amesergide; amezinium meti Isulfate; amfebutarnone, amidox; amifloxacin; amifostine; arniodarone;, amnisulpride; amlexanox; amlodipine; amlodipine; ampiroxicam; amrinonc; amrubic in; amnsacrine; amyl in; amythi amicin; anagrelide; anakinra; vote ananain;, anaritide; pnastrozolc; andrographolidc; anordrin; apadoline; apafant; apaxifyllinc; 25 aphidicolin glycinate; apraclonidinc; aprosulate sodium; aptiganel; apurinic acid; aranidipinie; *0:00 *see% arbekacin; arbidol; arbutamine; ardeparin sodium; arecatannin B3I; argatroban; aripiprazol; 0000 arotinolol; asirnadoline; aspalatone; aspcrfuran; aspoxicillin; aslcmizolc; asulacrine; atamestane; atenolol, atevirdine;, atosiban; atovaquone; atpein B3; atrimustinc; atrinositol; aurcobasidin A; azadirachitine; azasetron; azatyrosinc; azelaic acid; azelastine; azelnidipinc; azimilide; azithromycin; azosernide; azireonani; baccatin 1l1; bacoside A; bacoside B; bactobolaminc; balazipone; baihirnycin;,. balofloxaciri; balsalazide; bamibuterol; baohiuoside 1; barnidipine; basifungin; batebulast; batimastat; bcauvericin; becaplermin; becliconazole; bcfloxatone: belfosdil; -54 bellenamine; benflurnetol; benidipine; benzisoxazole; benzochiorins; benzoidazoxan; benzoylstaurosporine; bcnztropine; bepridi I; beractant; beraprost; berlafenone; bertosamni besipirdine;. beta-alethine; betaclamycin B; betamipron; betaxolol; betulinic acid; bevantolol; bicalutarnide; bifemnelane., bimakalim; bimithil; binospirone; bioxalomycin alpha2; biriperone; bisbenzimidazole A; bis-benzimidazole B; bisanltrene; bisaramil; bisaziridinyispermine; bisnafide; bisoprolol; bistramide D; bistramide K; bistratenc A; boldine; bopindolol; brefeldin; breflate; brimonidinc; bromfenac; bromperidol; bropiritnine; bucindolol; budesonide; budipine; budotitane; bunaprolast; bunazosin; butenafine; buthionine sulfoximine; butixocort propionate; cadexomer iodine; calanolide A; calcipotriol; caiphostin C; camonagrel; candesartan; candesartan cilexetil; candoxatril; candoxatrilat; capccitabine; caprornab; capsaicin; captopril; carbazomycin C; carbetocin; carbovir; carboxarnide-amino-triazole; carboxyamidotriazole; carboxymnethyl ated beta- I ,3-glucan; carperitide; carteolol; carumonani; carvedilol;, carvotroline; carzelesin; castariospen-mine; cebaracetam; cecropin B; cefcapene pivoxil; cefdaloxime pentexil tosilate; ccfdinir; cefditoren pivoxil; cefepime; cefetamrct; ccfetamrct pivoxil; cefixirne; cefluprenam; cefmetazole; cefmninox; cefodizime; cefoselis; ccfotctan; cefotiamn; cefotiamn hexetil; cefozopran; cefpimizole; cefpiramide; cefpirome; ccfpodoxime proxctil; ccfprozil; ccfsulodin; cefterarn; ceftibuten; ceftriaxone; cefuroxime axetil; cclastrol; elikalimi; celiprolol; cepacidine A; cericlaminc; ccrivastatin; ceronapril; certoparin sodium; ectiedil; cetirizine; chioroorienticin A; chioroorienticin B; chioroquinoxaline sulfonamide; cibenzoline; cicaprost; ciclesonide; cicletanine; cicloprolol; 20 -cidofovir; cilansetron; cilazapril; cilnidipinc; cilobradine; cilostazol;. cimetropium bromide; citapridc; cinolazepam;: ciotcroncl; ci profi braic; ciprofioxaciin; ciprosicnc; cis-porphyri n; cisapridc; cisatracurium bc'silate; cistinexinc; citalopram; citicoline; citreamicin alpha; cladribine; clar-ithrornycin; clausenarnide; clebopride; clinafloxacin; clobazarn; clobetasone butyrate; clodronic acid; clomethiazole; clopidogrcl; clotrimazole; colestimide; colfosceril palmitate; collismycin A; 25 collismycin B; combrctastatin A4; complestatin; conagcnin; contignasterol; contortrost~tin; cosalane; costatolide; cotinine; cournerraycin AlI; cucumariosid; curacin A; curdlan sulfate; curiosin; cyclazosin; cyclic I-IPMPC; cyclobenzaprinc; cyclobut A; cyclobUt G; cyclocapron; cycloplatam; cyclosin; cyclothial idine; cyciotliiazomycin; cypemycin; cyproterone; cytarabine ocfosfate; cytochalasin B; daclixirnab;, dactimicin; daidzcin; daidzin; dalfopristini; dalteparin sodium; danaparoid; daphnodorin A; dapiprazole; dapitant; darifenacin; darlucin A; darsidomine; ddUTP; decitabinc; cefcriprone; deflazacort; dehydrodidcmnin dchydrocpiandrosteronc; delapril; delcquarniinc; dcl faprazine; delmopinol; del phinidi n; deoxypyridino Ii ne deprodone; depsi dornycin; derarnciclane; dermatan sulfate; desflurane; desirudin; deslorelin; desmopressin; desogestrel; desoxoarniodarofle; detajmium bitarirate; dexifosfamide; dexketoprofen; dexioxiglumide; dexmcdetomidine; dexpemedolac; dexrazoxane; dexsotalol; dextrin 2-sulphate; dexverapami 1; dezinamide; dezocine; diaziquone; diclofenac digolil; diclofenac potassium; dicranin; didemnnin B; didox; dienogest;, diethyihomospermifle; diethylnorsperrninc; dihydrexidine; di dimethyl prostaglandin Al; dimethyihornospermifle; dimniracetam; dioxamycin; diphencyprone; diphenyl spirornustine; diprafenone; dipropylnorspermine; dirithromycin; discoidermolide; disulfiram; ditekiren; docarpamine; docosanol, dofetilide; dolasetron; domitroban; dopexamine; dorzolarnide; dosmalfate; dotarizine; doxacurium chloride; doxazosin; doxifluridine; doxofylline; draculin; draflazine; droloxifene; dronabinol; drosperidone; drotaverine acephyllinate; droxicam; ebiratide; ebrotidine; ebselen; ecabapidc; ecabet; ecadotril; ecdisteron; echicetin; echistatin; ecomusline; ecteinascidin 722; ecteinascidin 729; ecteinascidin 743; edaravone; edelfosine; edobacomab; edrecolomab; efegatran; eflornithine; efonidipine; egualen; elcatonin; eletriptan; elgodipine; eliprodil; eitenac; emakalim; emedastine; emniglitate; emitefur; ernoctakin; enadoline hydrochloride; enalapril; cnazadrcm; cnglitazone; cnlinmornab; cnoxacin;. cnoxaparin sodium; enoximone; entacapone; enterostatin; epoprostenol; epoxyniexrenone; epristeride; eprosartan; eptastigmilC; erdosteine; ersentilide; ersofermin; erythritol; esuprone; etanidazole; ctanterol; ethacizin; ethinylestradiol; etizolam; etodolac; etoposide phosphatc; etrabamine; everninomnicin; exarnorel in; cxemcstanc; fadrozoic; facriefungin; faniciclovir; famnpridinc;, fakitofaronc; faropcnem; fasidotril; fasud ii; fazarabine; fedototine; felbamate; fenofi brate; fenoldopam; fenretinide; fcnspiridc; f'enticonazole; flepradinol; fcrpifosate sodium; fcrristcne;, ferrixan; ferumoxsil; fexofenadine; flavopiridol; ficcainide; ficrobuterol; fieroxacin; flcsinoxan; flezelastine; flobufen; flomoxef; florfenicol; florifenine; flosatidil; fluasteronc; fluconazole; fludarabine; flumazenil; flumeci nol; flumcquinc; flunarizine; fluocalcitriol; fluorodaunorunicin hydrochloride; fluoxetine, fluoxetine, fluparoxan; flupirtine; flurbiprofen axetil; flurithromycin; fluticasone propionate; flutrimazole; fluvastatin; fluvoxaminc; forasartan; forfcnirnex; formestane; formoterol; formotcrol, fosfomycin; trometamol; fosinopril; fosphcnytoin; fostriecin; foternustinc; gabapentin; gadobenic acid; gadobutrol; gadodiamide; gadodiamide-EOB-DTPA; gadolinium tcxaphyrin; gadoteric acid; gadoter idol; gadovcrsctainidc; galantamine; galdansetron; galloparni galocitabine; garnolenic acid; ganirelix; gepirone; gestrinonc; girisoparn; glaspirnod; glaucocalyxinl A; glutapyrone; glycopine; glycopril; granisetron; grepafloxacin; halichondrin B; halofantrine; haiomon; hialopredone; hatornamicin; hatomarubigin A; hatornarubigin B; hatomarubigin C; 56hatomarubigin D, ibogainc; ibopamine; ibudilast; illimaquinone; ilmnofosine; ilornastat; ioeioc iloprost; imidapril; imidazenil; indinavir; indolidan; indornetacin farnesil; indometacin; tropine ester; indorami n; inocoteronc; i nogatran;- i nol inornab; intcrfcronl at fa; interferon al fa-2d, intcrfcron alfa-2b; interferon alfa-N 1; interferon alfa-n3; interferon beta; interferon beta- 1 al; interferon beta- I b; interferon gamma- I a; interferon gamma- I b; interferon omega; interferon, consensus; interleukin- 1; interleukin- I alpha; interleukin- 1 beta; interleukin- 10; interleukin- 1I; interleukin- 12; interleukin- 12; interleukin- 15; interieukin-2; interleukin-3; interleukin-4; interleukin-5; interleukin-7; interieukin-8; iobenguane; iobitridol; iodoamiloride; jododoxorubicin; iofratol; iomeprol; iopentol; ioprornide; iopyrol; iotriside; ioversol; ioxilan; ipazilide; IpdR; ipenoxazone; ipidacrine; ipomeanol, 4-; i o ipriflavone; ipsapirone; irbesartan; irinotecan; irloxacin; irsogladine; irtemazole; isaisteine; isbogrel; iseparnicin; isobengazole; isofloxythepin; isohomohalicondrin B; isopropyl unoprosione; isradipine; itarneline; itasetron; itopride; itraconazole; ketoprofen. ketoprofen, ketorolac; lacidipine; lactitol; lactivicin; Iaennec; lafutidine; Iamellarin-N triacetate; lamnifiban; lamivudine; lamotrigine; lanoconazole; lanperisone; lanreotide; lansoprazoic; latanoprost; lateritin; laurocapram; lazabemide; lemefloxacin; lemildipine; leminoprazole; lenercept; lenograstirn; lentinan sulfate; leptin; leptoistatin; lercanidipinc; lerisetron; lesopitron; letrazuril; letrozoic; leucomyzin; leuprorelin; levcromakalim; levetiracetam; levobetaxolol; levobunolol; levobupivacaine; levocabastine; levocarnitine;- levodropropizine; levofloxacin;, levomoprolol; lcvoilorgcstrel; levormeloxifene; levosimendan; levosulpiride; linotroban; linsidomine; lintitript; lintopride;, liothyronine sodium; 20 lirexapridc; lisinopriL; lobaplatin; lobucavir; lodoxamiide; lombricinc:, Iorncfloxacin; lornerizinc; lometrexol; lonazolac; lonidamine; loracarbef; loratadine; lorglurnide;, lornoxicam; losartan; losigamone; losoxantronc; loteprednol; loviridc; loxoribine; luibeluzole; lurtotecan; luteinizing hormone; lutetium; luzindole; lydicamycin; iysofy'lline; lysostaphin; niagainin 2 amide; rnagnolol; mallotochromcne; mallotojaponin; malotilatc; inangafodipir; manidipine; maniwalycin A; 25 mannostatin A; manumycin E; manumycin F; rnapiniastine; marimastat; Martek 8708; Ma~ek 92211; masoprocol; maspin; massetolide; meterelin; mcthioxalonc; methyihistamirie, R-alpha; methylinosine monophosphate; methyiprednisolone aceponate; methyl prednisolone suleptanate; metiparnide; metoclopramide; rnetoprolol, metrifonatc; inibefradil; niichiellarnine microcolin A; midodrine; mifepristone; miglitol; milaccmide; milaamcline, rnildronate; itnacipran; rnilrinonc; rniktfosinc; mninaprine; miokainycin; iiipragosidc; inirficnianil; mirirnostini; miirtazapinc; misoprostol; mnitoguazone; mitolactol; mitonafide; mitoxantrone; mnivacurium chloride; mivazerol; mnixanpril;, mizolastine; nmizoribinc; moclobemide; modafinil; mnoexipri I; mnofarotene; mnofezolac; 57 moigramostim; momelasone; miontirelin; mopidarnol; rnoracizine; mosapramine; rnosapride; motiIi de; moxiraprine; moxonidine; nadifloxacin; nadroparin calcium; nafadotride; nafamostat; nafarelin; naftopidi 1; naglivan; nagrestip; nalmefene; naphterpin; napsagatran; naratriptan; nartograstim; nasaruplase; nateplase; niperotidine; niravoline; nisamycin; nisin; nisoldipine; nitazoxanide; nitecapone; nitrendipine; riitrendipine, nitrofurantoin mionohydrate; nitrullyn; nizatidine; ofloxacin; okicenone; olanzapine; olopatadine; olprinonc; olsalazine; omeprazole; onapristone; ondansetron; ondansetron, ontazolast; oraciin; otenzepad; oxaliplatin; oxamisoic; oxandrolone; oxaprozin; oxaunomycin; oxcarbazepine; oxiconazole; oxiracetam; oxodipine; ozagrel; palauaminc; pal inavir; palrnitoylrhizoxin; parnaqueside; parnicogrcl; pamnidronic acid; panamesine; i0 panaxytriol; panipenem; panipenum; pannorlin; panomifene; pantethine; pantoprazole; parabactin; parnaparin sodium; paroxetinc; parthenolide; pazell iptinc; pazufloxacin; pefloxacin; pegaspargase; peldesine; pemedolac; pcmirolast; penciclovir; pentafuside; pentamidine; pcntarnorphone; pentigetide; pentosan; pentostatin; pentrozole; perfiubron; perfosfamide; pergolide; perindoprilat; perospirone; phenaridine, phenazinoniycin; plicnserine; phensuccinal; phentolamine mesi late; phenylacetatc; phenylalanyl ketoconazoic; picenadol; picibanil; picroliv; picumeterol; pidotimod; pilocarpine hydrochloride; pi Isicainide; pimagedine; pimilprost; piniobendan; pinacidi 1; pinocebri n; pioglitazone; pipecuronium bromide; pirarubicin; piretanide; pirfenidone; piritrexim; pirlindole; pirmggrcl; pirmenol; pirodavir; pirodoniast; piroxicam cinnamite: propagermnanium; propentofyl line; propionylcarnitine, propirarn; propirarn paracclaniol; propiverine; propyl bis-acridonc; prostaglandin J2; prostratin; protegrili; protosufloxacin; prttlifloxaein; pyrazoloacridine; quazepai; quetiapinc; quiflapon; quinagolidc; quinapril; quinfarnidc; quinupristin; raloxifenc; raltitrexed; ramatroban; ranipril; ramosetron; ranelic acid; ranitidine bismuth citrate; ranolazine; rccainarn; regavirumab; relaxin; repirinast; resinferatoxi n; reticulon; revipari n sodium; rcvizi none; ricasctron; ridogrel; ri fabutin; rifapentine; rifaximin; ri lopirox; riluzole; rimantad inIe; rimexolone; ri moprogin; riodipinc; ripisartan; risedronic acid; rispenzcpinc; rispcridonc; ritanscrin;, ritipcnem; ritipciwin acoxil; ritolukast; ritonavir; rizatriptan bcnzoatc; rohititki ne; rokitamy cin; ropinirole; ropivacaine; roquiuimcx; roxatidine; roxi ndole; roxithromycin; rubiginonle B 1; ruboxyl; rufloxaciin; rupatidine; ruzadolane; safingol; safironil; saintopin; salbutaniol. salmeiiterol; salmeterol, R-salnaccdin; sanicridine, samipatri lat; san lctrincm:i saprisartan; saproptcrin; saquinavir; SarCNU; sarcophytol A sargraniostim; sarpogrelate; saruplase; saterinone; satigrel; saturnomab pendetidc; sciegiline; seleni um thiosemicarbazone; scniatil idc; serndurarniciii; scniotiadil; semustine, sermorelin; scrtacoilazolc; scrtindoic; scrtraline; sctiptilinc; sevirurnib; scvothirane; sezolarnide; silipide; -58silteplasc; simendan; simvastatin; sinitrodil; sinnabidol; sipatrigine; sirolimus; sizofiran; sornatomedin B; somatornedin C; somatrem; somatropin; sonerrnin; sotalol; staurosporine; stavudine; stepronin; stipiamide; stiripentol; stobadine; succibun; sucralfate; sulfasalazine; sulfinosine; sulfoxamine; sulopenem; sultaniicillin; sultopride; sulukast; sumatriptan: symakalim; tandospirone; tapgen; taprostene; tasosartan; tazanolast; tazarotene; teicoplanin; telenzepine; tellurapyrylium; telmesteine; telmisartan; temocapril; temoporfin; temozolomide; tenidap; teniposide; tenosal; tenoxicamn; tepirindole; tepoxal in; terazosin; terbinafine; terfenadine; terfiavoxate; terguride; terlakiren; terlipressin; terod ifim; tertatolol; testosterone buciclate; tetrachllorodccaoxide; tetrazomine; thaliblastine; thalidomide; thiocoraline; tliiofedrine; thiomarinol; i0 thioperarnide; thyroid stimulating hormone; tiagabine; tianeptine; tiapafant; tibolone; ticlopidine; tienoxolol; tilisolol; tilnoprofen arbamel; tiludronic acid; tinzaparin sodium; tiotropium bromide; tipredane; tiqueside; tirandalydigin; tirapazamine; tirilazad; tirofiban; tiropramide; topsentin; torasemide; toremifene, tosufloxacin; traferrnin; t randolapril; traxanox;, tretirioin; tretinoin tocoferil; triacetyluridine; tricaprilin; trichohyalin; trichosanthin, alpha; triciribine; trientine; triflavin; trimegestone; triptorel in; troglitazone; trombod ipine; tropisetron; trospectomyci n; trovafloxacin; trovirdine; tucaresol; tulobutcrol; tylogenin; ui-apidil; uridinc triphiosphate; valaciclovir; vaiproate magnesium; valproate semisodium; valsartan; vamicamide; vanadeine; vaninolol; vapreotide; variolin B; velaresol; vcnlafaxine; veramine; vcraparnil, vcrdins; veroxan; vcrteporfin; vesnarinone; vexibinol; vigabatrin; vinburnine citrate; vinburnine resinate; vinconate; vinorelbine; vinpocctinc; vinpoetinc citrate; vintopcrol; vinxalti; voriconazole; vorozolc; voxergolidc; xcmilofiban; xinioprofien; yangambin; zabicipril; zacopride; zacopridc, zafirlukast; zalcitabine; zaleplon; zalospirone; zaltoprofen; zanamivir; zankiren; zanoterone; zatebradine; zatosetron; zenarcstat; zeniplatin; zifrosi lone; zilascorb; zileuton; zi nostatin1 stimalamcr; ziprasidone; zolcdronic acid; zolmitriptan; zolpidem; zonisamide; zopiclone; zopiclone, zopoirestat; zotepine.

275 Trhc invention also embraces novel compositions of mater that arc covalcnt conjugatc of' DI-IA and pharmaceutical agents that are noncentral nervous system active agents. Noncentral nervous system active agents have no function or usc within the central nervous system. Their only use is outside of thc central ncrvous system. Such agents include all drugs within certain of the foregoing categories and only some drugs within othcr of the foregoing catagorics. For example, the cnLirc catagory of blood glucose regulators have no itse or lbnction within the central ncrVOLIs system. In contrast, certain anti-cancer agents are useful in the central nervous system whereas others are not. For example, ccntral nervous systcmn cancers are not hormone dependent, and, -59therefore, an anti-cancer agent such as Tamoxifen which treats certain hormone dependent cancers is not useful in the central nervous system. Those skilled in the art will be able to identify readily those catagories and/or members of a catagory which are noncentral nervous system active agents.

Among the foregoing compounds, the following catagorics and/or members of the following catagorics are noncentral nervous system active agents: adrenocortical steroid; adrenocortical suppressant; aldosterone antagonist; amino acid; anabolic; androgen; antagonist; anthelmintic; anti-acne agent; anti-adrenergic; anti-allergic; anti-amebic; anti-androgen; anti-anemic; anti-anginal; anti-arthritic; anti-asthmatic; anti-atherosclerotic; antibacterial; anticholelithic; anticholelithogenic; anticholinergic; anticoagulant; anticoccidal; antidiabetic; antidiarrheal; antidiuretic; antidote; anti-estrogen; antifibrinolytic; antifungal; antiglaucoma agent; antihemophilic; antihemorrhagic; antihistamine; antihyperlipidemia; antihyperlipoproteinemic; antihypertensive; antilypotensive; anti-infective; anti-infective, topical; anti-inflammatory; antikeratinizing agent; antimalarial; antimicrobial; antimitotic; antimycotic, antincoplastic, antineutropenic, antiparasitic; antiperistaltic, antipneumocystic; antiproliferativc; antiprostatic hypertrophy; antiprotozoal; antipruritic; antipsoriatic; antirheumatic; antischistosomal; antiseborrheic; antisecretory; antispasmodic; antithrombotic; antitussive; anti-ulcerative; anti-urolithic; antiviral; appetite suppressant; benign prostatic hyperplasia therapy agent; bone Sresorption inhibitor; bronchodilator; carbonic anhydrase inhibitor; cardiac depressant; cardioprotectant; cardiotonic; cardiovascular agent; choleretic; cholinergic; cholinergic agonist; cholinesterase deactivator; coccidiostat; diagnostic aid; diuretic; cctoparasiticide; enzyme inhibitor; estrogen; fibrinolytic; free oxygen radical scavenger; glucocorticoid; gonad-stimulating principle; hair growth stimulant; hemostatic; hormone; hypocholesterolemic; hypoglycemic; hypolipidemic; hypotensive; immunizing agent; immunomodulator; immunoregulator; immunostimulant; immunosuppressant; impotence therapy adjunct; inhibitor; keratolytic; LI-RI- agonist; liver disorder 25 treatment; lutcolysin; mucolytic; mydriatic; nasal decongestant; neuromuscular blocking agQnt; non-hormonal sterol derivative; oxytocic; plasminogcn activator; platelet activating factor antagonist; platelet aggregation inhibitor; potentiator; progestin; prostaglandin; prostate growth inhibitor; prothyrotropin; pulmonary surface; radioactive agent; regulator; relaxant; repartitioning agent; scabicide; sclerosing agent; selective adenosine Al antagonist; steroid: suppressant; symptomatic multiple sclerosis; synergist; thyroid hormone; thyroid inhibitor; thyromimetic; amyotrophic lateral sclerosis agents; Paget's disease agents; unstable angina agents; uricosuric; vasoconstrictor; vasodilator; vulnerary; wound healing agent: xanthine oxidase inhibitor.

As used herein, a taxane is a molecule that possesses the following tricyclic carbon-atom connectivity network, which may incorporate carbon-carbon multiple bonds, and which through the involvement of carbon-atom-noncarbon-atom bonds may include substituents, functional groups, and additional rings.

.8 10 9 19 8 7 12 1 1 6 3 1 4 1 2 A taxoid is a molecule structurally related to a taxane in which the above taxane carbon-atom connectivity network is altered, for example, by cleavage of one or more of the carbocyclic rings, by deletion or addition of carbon substituents, by connection of carbon atoms normally not bonded to each other, by disconnection of carbon atoms normally bonded to each other, or by some other reorganization of or adjustment to the taxane carbon-atom connectivity network, but in which one or more structural features characteristic of the taxane carbon-atom connectivity network are conserved.

The compounds useful in the invention may be delivered in the form of anti-cancer cocktails.

S An anti-cancer cocktail is a mixture of any one of the compounds useful with this invention with another anti-cancer agent such as an anti-cancer drug, a cytokine, and/or supplementary potentiating agent(s). The use of cocktails in the treatinent of cancer is routine. In this embodiment, a common administration vehicle pill, tablet, implant, injectable solution, etc.) would contain both the conjugate useful in this invention and the anti-cancer drug and/or supplementary potentiating agent.

The compounds of the invention, when used in cocktails, arc administered in therapeutically .oIo effective amounts. A therapeutically effective amount will be determined by the parameters discussed below; but, in any event, is that amount which establishes a level of the drug(s) in the area of the tumor which is effective in inhibiting the tumor growth.

When administered, the formulations of the invention are applied in pharmaceutically acceptable amounts and in pharmaceutically acceptable compositions. Such preparations may routinely contain salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic ingredients. When used in medicine the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof and are not excluded from the scope of the invention. Such -61 pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic. sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulfonic, tartaric, citric, methane sulfonic, formic, malonic, succinic, naphthalene-2-sulfonic, and benzene sulfonic. Also, pharmaceutically acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts.

Suitable buffering agents include: acetic acid and a salt WN); citric acid and a salt boric acid and a salt WN); and phosphoric acid and a salt W/V).

Suitable preservatives include benzalkonium chloride (0.003-0.03% WN); chlorobutanol WN); parabens (0.01-0.25% W/V) and thimerosal (0.004-0.02% WN).

The active compounds of the present invention may be a pharmaceutical composition having a therapeutically effective amount of a conjugate of the invention optionally included in a pharmaceutically-acceptable carrier. The term "pharmaccutically-acceptable carrier" as used herein means one or more compatible solid or liquid filler, dilutants or encapsulating substances which are suitable for administration to a human or other animal. The term "carrier" denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions are capable of being S. commingled with the molecules of the present invention, and with each other, in a manner such that S there is no interaction which would substantially impair the desired pharmaceutical efficacy.

Compositions suitable for parenteral administration conveniently comprise a sterile preparation of the conjugates of the invention. This preparation may be formulated according to known methods. Formulations for taxanes can be found in Chapter 9 of Taxol: Science and Applications, CRC Press, Inc., 2000 Corporate Boulevard, Boca Raton, FL 33431. In general, Taxol has been formulated as a 6 mg/ml cremophor EL (polyoxyethylated castor oil)/ethanol mixture, which is diluted to final volume with normal saline or 5% dextrose. A 15mg/ml solution of taxotere has been formulated in polysorbate 80 (polyoxycthylene sorbitanmonooleate)/ethanol mixture, diluted with 5% dextrose.

The sterile preparation thus may be a sterile solution or suspension in a non-toxic parenterally-acceptable diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono ordi-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectablcs. Carrier formulations suitable for oral, subcutaneous, intravenous, intramuscular, etc. can be found in Remington's Pharmaceutical Sciences, Mack -62- Publishing Company, Easton, PA.

A subject as used herein means humans, primates, horses, cows, pigs, sheep, goats, dogs, cats and rodents.

The conjugates of the invention are administered in effective amounts. An effective amount means that amount necessary to delay the onset of, inhibit the progression of, halt altogether the onset or progression of or diagnose the particular condition being treated. In general, an effective amount for treating cancer will be that amount necessary to inhibit mammalian cancer cell proliferation in-situ. When administered to a subject, effective amounts will depend, of course, on the particular condition being treated; the severity of the condition; individual patient parameters to including age, physical condition, size and weight; concurrent treatment; frequency of treatment; and the mode of administration. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is preferred generally that a maximum dose be used, that is, the highest safe dose according to sound medical judgment.

Dosage may be adjusted appropriately to achieve desired drug levels, locally or systemically.

Generally, daily oral doses of active compounds will be from about 0.01 mg/kg per day to 1000 mg/kg per day. It is expected that IV doses in the range of about 1 to 1000 mg/mn per day will be effective. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Continuous IV dosing over, for example 24 hours or multiple doses per day are contemplated to achie'e appropriate systemic levels of compounds.

A variety of administration routes are available. The particular mode selected will depend of course, upon the particular drug selected, the severity of the disease state being treated and the dosage required for therapeutic efficacy. The methods of this invention, generally speaking, may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects. Such modes of administration include oral, rectal, sublingual, topical, nasal, transdermal or parenteral routes. The term "parenteral" includes subcutaneous, intravenous, intramuscular, or infusion. Intravenous routes are preferred.

The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the conjugates of the invention into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions arc prepared by uniformly and intimately -63bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.

Compositions suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active compound. Other compositions include suspensions in aqueous liquors or non-aqueous liquids such as a syrup, an elixir, or an emulsion.

Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of the active compounds of the invention, increasing convenience to the subject and the physician. Many types of release delivery systems are to available and known to those of ordinary skill in the art. They include polymer based systems such as polylactic and polyglycolic acid, polyanhydrides and polycaprolactone; nonpolymer systems that are lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-, di and triglycerides; hydrogel release systems; silastic systems; peptide based systems; wax coatings, compressed tablets using conventional binders and excipients, partially fused implants and the like. In addition, a pump-based hardware delivery system can be used, some of which are adapted for implantation.

A long-term sustained release implant also may be used. "Long-term" release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active S ingredient for at least 30 days, and preferably 60 days. Long-term sustained release implants are well known to those of ordinary skill in the art and include some of the release systems described above. Such implants can be particularly useful in treating solid tumors by placing the implant near or directly within the tumor, thereby affecting localized, high-doses of the compounds of the invention.

The conjugates of the invention also are useful, in general, for treating mammalian cell proliferative disorders other than cancer, including psoriasis, actinic keratosis, etc. They further are S.useful in treating diabetes and its complications, excess acid secretion, cardiovascular conditions involving cholesterol hyperlipidemia and hypercholcsterolemia), diarrhea, ovarian diseases endometriosis, ovarian cysts, etc.) and as contraceptive agents.

Those skilled in the art will be able to recognize with no more than routine experimentation 30 numerous equivalents to the specific products and processes described above. Such equivalents are intended to be included within the scope of the appended claims.

P\OPERMKR\SPECI 1423-9V7.234.loc-2110 I 63A Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

Claims (6)

1. 06-01-'04 15:23 FROM-DCC +61392542770 T-894 P09/28 U-896 -64- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A method for targeting a pharmaceutical agent to a noncentral nervous system tissue to treat a noncentral nervous system condition comprising: administering to a subject in need of such treatment a covalent conjugate of cis- docosahexaenoic acid and a pharmaceutical agent effective for treating said condition; wherein the pharmaceutical agent is not a peptide antiproliferative agent. 2. The method of claim 1, wherein the cis-docosahexaenoic acid is conjugated directly to the pharmaceutical agent. 99 9 9 3. The method of claim 2, wherein the tissue is breast tissue and wherein the subject has a condition calling for treatment of breast tissue with the pharmaceutical agent. 9
2. 9. 15 4. The method of claim 2, wherein the tissue is gastrointestinal tissue and wherein the subject has a condition calling for treatment of gastrointestinal tissue with the pharmaceutical agent. 5. The method of claim 2, wherein the tissue is ovarian tissue and wherein the subject 20 has a condition calling for treatment of ovarian tissue with the pharmaceutical agent, eeo9 6. The method of claim 2, wherein the pharmaceutical agent is a noncentral nervous :o system active agent that is nonactive within the central nervous system. 7. The method of claim 2, wherein the pharmaceutical agent is an anti-cancer agent. 8. The method of claim 7, wherein the pharmaceutical agent is Taxol. COMS ID No: SMBI-00558085 Received by IP Australia: Time 15:20 Date 2004-01-06 06-01-'04 15:23 FROM-DCC FOPBR't\ mlSrCM632 <l *Wd.dKoSol/9 +61392542770 T-894 P10/28 U-896 9. The method of claim 8, wherein the conjugate is The method of claim 8, wherein the conjugate is 0 S S S S PANH
3. 11. The method of claim 7, wherein the pharmaceutical agent is Taxotere.
4. 12. The method of claim 11, wherein the conjugate is H O 0 OH Ph H OAc 0 O Ph
5. 13. The method of claim 11, wherein the conjugate is o O OH COMS ID No: SMBI-00558085 Received by IP Australia: Time 15:20 Date 2004-01-06 06-01-'04 15:24 FROM-DCC 61392542770 T-894 P11/28 U-896
6. 66- 14. The method of claim 11, wherein the conjugate is -N 0 The method of claim 11, wherein the conjugate is 0 a@ 0 0 0 00 00 0 *4~ 9 OS 0 0 9 0 S 0 0 0 9 asne 0 00(00. 9 0000 s000 0 0*00 0 flS0 50&0 0 .0 00 OS *009 0*@0 0 0 0000 16. The method of any one of claims 1, 2, 3, 6, 7, 8, 9, 10, the condition is breast cancer. 10 17. The method of any one of claims 1, 2, 3, 6, 7, 8, 9, 10, the condition is colon cancer. 18. The method of any one of claims 1, 2, 3, 6, 7, 8, 9, 10, the condition is ovarian cancer. 11, 12, 13, 14 or 15, wherein 11, 12, 13, 14 or 15, wherein 11, 12, 13, 14 or 15, wherein 19. A pharmaceutical preparation comprising: a covalent conjugate of cis-docosahexaenoic acid and a noncentral nervous system active agent, and a pharmaceutically acceptable carrier; wherein the active agent is not a peptide antiproliferative agent. COMS ID No: SMBI-00558085 Received by IP Australia: Time 15:20 Date 2004-01-06 06-01-'04 15:24 FROM-DCC +61392542770 T-894 P12/28 U-896 -67- The pharmaceutical preparation of claim 19, wherein the cis-docosahexaenoic acid is conjugated directly to the active agent. 21. The pharmaceutical preparation as claimed in claim 20, wherein the noncentral nervous system active agent is active on a tissue selected from the group consisting of: Blood and Blood Forming tissue; Cardiovascular system tissue; Digestive and excretory system tissue; Endocrine system tissue; Muscular system tissue; Reproductive System tissue; Respiratory system tissue; Skeletal system tissue; and Fiber and integumentary system tissue. 10 .9 22. Use of a covalent conjugate of cis-docosahexaenoic acid and a pharmaceutical agent effective for treating a noncentral nervous system condition in preparation of 9 a medicament for targeting the pharmaceutical agent to a noncentral nervous system tissue. 23. A method according to claim 1 or a pharmaceutical preparation according to claim 19 substantially as hereinbefore described with reference to the examples. DATED this 6th day of January, 2004 Protarga, Inc. By DAVIES COLLISON CAVE Patent Attorneys for the Applicant COMS ID No: SMBI-00558085 Received by IP Australia: Time 15:20 Date 2004-01-06