AU1632801A - 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.

INVENTION TITLE: "DHA-pharmaceutical agent conjugates" IP Australia Documents received on: 0 1 7 JAN 2001 Batch No: The following statement is a full description of this invention, including the best method of performing it known to us: P:\OPER\MKR\SPEC'31425-97-div.doc-17101/01 -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 S* 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:VOPER\MKR\SPECI31425-97-div.do-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 is 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: AcO 0 OH P NH0B C Ph 2'0" 0-H OH HO OAc PhC0 2 Taxanes have the basic three ring structure B and substituted or unsubstituted.

to Taxol's carbons are numbered conventionally as follows: 10O9 19 7 13 47J>--HI 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 I0, C19, R, and combinations thereof while retaining significant, but usually reduced, activity. Substitutions at C2, C4 and 2'01-I, however, are generally not tolerated. These conclusions are only generalities, for example, because some substitutions at C9-C10 (cyclic derivatives) arc not tolerated and some substitutions at C2 (mecta substitutions on the phenyl) arc tolerated. Likewise, the C13 side chain and, in particular, the 2'OH are required, although the minimum structiral requirements of the side chain have not been determined lor therapeutic efficacy.

Attempts to improve Taxol's solubility have not resulted in successful clinical products. One approach has been to manufIcturc 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 therapcutically useful product, although it was suggested that the 2' OH derivatives may cleave more easily than the C7 OH 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 (docctaxel), 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 O OH

O

25 "O NH 0 Ph'^ 0 SPh OH HO OH HO OAc OAc 0 Ph DHA (docosahexaenoic acid) is a 22 carbon naturally-occurring, unbranclid 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 ofthe nvcntion 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 0o 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-docosahexaenoic acid and a pharmaceutical agent effective for treating said condition is administered to a subject in need of such treatment. Preferably, the conjugate consists 20 only of cis-docosahexaenoic acid and the pharmaceutical agent, wherein the cis-docosahexaenoic acid is conjugated directly to the pharmaceutical agent, free 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 catagories of pharmaceutical agents include: adrenergic agent; adrenocortical steroid; adrenocortical suppressant; alcohol deterrent; aldosterone antagonist; amino acid; ammonia detoxicant; anabolic; analcptic; 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-cpileptic; 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 to 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; ectoparasiticidc; emetic; enzyme inhibitor; estrogen; fibrinolytic; fluorescent agent; free oxygen radical scavenger; gastrointestinal motility effector; .glucocorticoid; gonad-stimulating principle; hair growth stimulant; hemostatic; histamine 1-12 receptor antagonists; hormone; hypocholesterolemic; hypoglycemic; hypolipidemic; hypotensive; imaging agent; immunizing agent; immunomodulator; immunoregulator; immunostimulant; immunosuppressant; impotence therapy adjuwct; inhibitor; keratolytic; LNRIl 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; radioactive agent; regulator; relaxant; repartitioning agent; scabicidc; sclcrosing agent; sedative; sedative-hypnotic; selective adcnosine Al antagonist; serotonin antagonist; serotonin inhibitor; serotonin receptor antagonist; steroid; stimulant; suppressant; symptomatic multiple sclerosis; syncrgist; thyroid hormone; thyroid inhibitor; thyrominimetic; tranquilizer; treatment of amyotrophic 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 of cis-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), Metronidazole (Flagyl), Methylprednisolone (Mcdrol), 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), Testolactone, Climiphcne, urofollitropin, bromocriptinc. gonadorclin, danazol, dehydroepiandrosterone, androstenedione, dihydrotestosterone, Relaxin, folliculostatin, Follicle :***.regulatory protein, Gonadocrinins, Oocyte maturation inhibitor, and, Insulin growth factor. Other compounds arc detailed below.

The methods and/or products of the invention are useful for treating a variety of medical conditions including conditions involving abnormal mammalian-ccll 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\SPECR31425-97-div.doc-1 7/01/01 -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 S* tissue, synovial capsule and tendon.

SIn 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 S 20 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: 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 versus percent growth of leukemia cells.

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

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

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

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

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

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

Figure 8 is a graph plotting concentration of conjugate 1 versus percent growth of prostate -8cancer 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 cells.

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

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

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

Figure 20 is a graph plotting concentration ofTaxol versus percent growth of non-small cell 0 lung cancer cells.

Figure 21 is a graph plotting concentration ofTaxol versus percent growth of colon cancer 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 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: o 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.

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

It is known that DHA can be unstable in the presence of oxygen. To stablizie DHA and its o:..oo 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 DIA-taxol plus 100 g of vehicle (100ml propylene 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, 30 sodium meta bisulfitc, 1-[1 carotenc and ca-tocophcrol. A heavy metal chclator such as oo..

ethylenediamine tetra-acetic acid (EDTA) may also be used.

S

Paclitaxcl was lirst isolated from the bark ofTaxus brevilblia (Wani ct al., J. Am. Chm.

So., 93, 2325, 1971). Its isolation and synthesis have been reported extensively in the literature.

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

Example 1

TAXOL

A c O O H Ph NH 0 Ph O O 0 HO O0 OAc o 0 Ph conjugate 1 A solution of Taxol (41 1tmol) in methylene chloride (2.5mL) under argon was mixed with 4-dimethylaminopyridine (41 Cuol), dicyclohexylcarbodiimide (82pmol), and DHA (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 the residue produced 45mg of crystalline Taxol-DI-IA conjugate 1.

Example 2 0 AcO OH TAXOL Ph NH 0 PhH 0 OSiEt 3 HO 6 OAc 0 Ph 25 A 2 Ph 0 Ph OE A AcO

O

Ph NH 0 .H

B

*cPh nugH t SOSiE 3 HO 0 O OS3OAc 0 Pit 0 30 AcO 0O :Ph ANH 0 Ph O 0o conjugate 2 OH HO 0 1 The production of analog 2 involves several steps including a number of protection-acylation-deprotection steps. A solution of Taxol (59imol) in methylene chloride was mixed at amrbient temperature under argon with imidazole (147gmol) and triethylsilyl chloride (147pmol). The reaction mixture was stirred for thirty minutes, diluted with additional mcthylene 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 (52p.mol), dicyclohexylcarbodiimide (104pmol), 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 pmol) in acetonitrile (2mL) at 0°C under argon was mixed with 49% aqueous HF (0.2mL) 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-DIA 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 ethanol 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 1 and 2 were tested against 57 cancer cell lines. The results are presented in Figs. 1-9 for conjugate I, 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: 3 -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 -Mean -Mean OdJ,,o) If (Mean -Mean 0, then PG 100 x (Mean -Mean Odzo)/Mean Od,,ro Where: Mean The average of optical density measurements of SRB*-derived color just before exposure of cells to the text compound.

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

Mean 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 loglo (molar or pg/ml). The response parameters GISO, 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 -,btained by interpolation.

13- Dose-Response Curves: The dose-response curve page of the data package is created by plotting the PGs against the logi 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 GI50, TGI and LC50, respectively.

Several important distinctions are apparent from the data. Most important, the patterns of anticancer actively for conjugates I and 2 differ from that of Taxol. In one sense, conjugates 1 and 2 are effective anticancer agents against a more restricted set of cancer cell lines. For example, conjugates I 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 (rclative 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 MDA-MB-435 at all concentrations tested.

To lirther illustrate the differences 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 to 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, especially since conjugates 1 and 2 maintained strong activity against some cell lines. Conjugates Sand 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 G150s 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 0o actual lower value) was used in calculating the average of -9.19. There were 27 instances when this occurred.) The average GISOs 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 DHA analogs have altered specificity versus that ofTaxol 'or cancer cell lines. Because of this altered specificity, it also is clear that the conjugates themselves arc gaining access into the target cells (as opposed to simply releasing Taxol into the 25 environment outside of 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 unexpected.

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

15 Exam ple 4

TAXOTERE

OHAl/dicyclo 4-dimethy HO 0 OH hexylcarbodiirnie taminopyridine 0 N Ph :H 0 ~0 Ph conjugate 3 A solution of Taxoterc in methylene chloride under argon is mixed with 4-dimethylaminopyridine, dicyclohcxylcarbodiirnidc. and DI-IA. The reaction mixture is stirred at ambient temperature. Radial chromatography of the residue is performed to produce Taxotere-DHA conJugate 3.

Example 'ri~hlsiylchlrie0 HO 0 OSi(CH 2

CH

3 3 R imidazole .O J 0 O* H6

(CH

3

CH)

3 Si6 HO 6~ 0 Ph OSi(CH 2

CH

3 3 DHA dicyclohexylcarbodiimnide 25 4 .cimethyamninopyndine aqueous

HF_

(UI

3

UI

2

OAC

0IJ Ph 0 0 0OH 'V lNH 0 OH HOI conjugatc 4 0 OAc 041Ph 9 30 -16- A solution of Taxotere in dimethylformamide is mixed at ambient temperature under argon with imidazole and triethylsilyl chloride. The reaction mixture is stirred at ambient temperature, diluted with methylene chloride, washed with water, saturated acqueous sodium chloride, dried, 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 0C under argon is mixed with 49% aqueous HF and the reaction mixture is to 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 4.

Example 6 ter-bulyldimelhylslyl chloride imidazole

TAXOTERE

HO 0 OH O NH O Ph OAc te^-C 4 Hg(CH 3 2 SiO HO Ph O Ph 1 equivalenl OHA dicyclohexylcarbodiimide 4-dimelhylaminopyridine aqueous HF

O

0 0 OH o-kNH 0 I Ph -O O OH HO O OAc conj Ph conjugate 4 -17- 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 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 F.

(Intermediate H also is obtained and used in Example 8 below.) A solution of intermediate F in to acetonitrile at O°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 residue is performed to produce Taxotere-DHA conjugate 4.

Example 7 lent-bulyldimelhylsilyl chloride TAXOTERE imidaC imidazole o HO 0 OH O NH 0 Ph O C 0 tcrt-C 4 H(CH) SiO HO O 0 PI 0O O 0 p OHA I dicyclohexylcarbodiimidc NH 0 4 -dimethylaminopyridine Ph tentC,H.(CH,)?SiO HO O G SOAc G 0 Ph 30 0 o aqueous HF "ON O NH 0

H..H

Phl H O OH

HO

OH o OAc conjugate 0 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 I-IF 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 dicydohexylcarbodiimide 4-dimethylaminopyridine 0 HO 0 ter.Ca4H(CH 3 )Si HO I O OAc

H

0 Ph 0 O HO OO 0" NH 0 Ph K O 0 H OH HO 0

OAC

0 Ph aqueous HF 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 at 0°C under argon is mixed with aqueous H-F 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 chromatbgraphy of the residue is performed to produce Taxotere-D-IA conjugate 6.

DHA may be conjugated to virtually any drug compound or diagnostic agent and used s1 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; Apraclonidinc I-Hydrochloride; Brimonidine Tartrate; Dapiprazole I-lydrochloride; Deterenol Hydrochloride; Dipivefrin; Dopamine 25 -lydrochloridc; Ephedrine Sulfatc; Epincphrinc; Epincphrinc Bitartratc; Epincphryl Borate; Esproquin 1-lydrochloride; Etafedrine Hydrochloridc; H-ydroxyamphetamine Hydrobromide; Levonordefrin; Mephentermine Sulfate; Metaraminol Bitartrate; Metizoline -lydrochloride; Naphazoline H-ydrochloridc; Norepincphrine Bitartratc; Oxidopamine; Oxymetazoline 1-lydrochloride; Phenylcphrine Hydrochloride; Phcnylpropanolaminc Hydrochloride; Phenylpropanolamine Polistirex; Prenalterol H-ydrochloride; Propylhexedrine; lscudoephcdrinc Hydrochloride; Tetrahydrozoline Ilydrochloridc; Tramazoline Iydrochloridc; Xylomctazoline Ilydrochloride.

20 Adrenocortical steroid: Ciprocitionide; Desoxycorticosterone Acetate; Desoxycorticosterone Pivalate; Dexamethasonc Acetate; Fludrocortisone Acetate; Flurnoxonide; Hydrocortisone Hemisuccinate; Methyiprednisolone Hemisuccinate; Naflocort; Procinonide; Tirnobesone Acetate; Tipredanc.

Adrenocortical suppressant: Aminoglutethim ide; Trilostane.

Alcohol deterrent: Disulfiram.

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

Amino acid: Alanine; Aspartic Acid; Cysteine Hydrochloride; Cystine; Histidine; Isoleucine; Leucine; Lysine; Lysine Acetate;, Lysinie Hydrochloride; Methionine; Phenylalanine; Praline; Serine; Threonine; Tryptophan; Tyrosine; Valine.

Ammonia detoxicant: Arginine: Arginine Glutamate; Arginine Hydrochloride.

Anabolic: Bolandiol Dipropionate; Bolastcronc; Boldcnone Undecylenate; Bolenol; Bolmantalate; 20 Ethylestrenol; Methenolone Acetate, Methcnolone Enanthatc; Mibolerone; Nandrolone Cyclotate; Norbolcthone; PiZOtylinIc; QUinbolonc; Stenbolonc Acctatc; Tiholoiie; Zeranol.

Analeptic: Modulinil.

25 Analgesic: Acctamlinophefl; Alfentani Il Hydrochloride; Amninobenzoato Potassium; Am inobcnzoate Sodium; Anidoxime; Anileridine; Anileridine Hydrochloride; Anilopam Hydrochloride; Anirolac; Antipyrine; Aspirin; lBenoxaprofen; lBenzydarninc H-Iydrochloride; B icifadine Hydrochloride; Brifentanil H-ydrochloride; Bromadoline Maleate; lBromfenac Sodium; Buprenorphine Hlydrochloride-. Butacetin; BLutiXiratc, Butorphanol; Butorphanol Tartratc; Carbarnazepitie; :9 30 Carbaspirin Calcium, Carbiphcne H-ydrochloride; Carfentanil Citrate; Ciprefadol Succinate; Cir-amadol; Ciramadol Hydrochloride; Clonixeril; Clonixin; Codeine Codeine Phosphate; Codeine Sulfatc;, Conorphone H-ydrochloride; Cyclazocine; Dexoxadrol Ilydrochiloridc; Dexpemnedolac; -21 Dezocine; Diflunisal; Dihydrocodeine Bitartrate; Dirnefadane; Dipyrone; Doxpicomine Hydrochloride; Drinidene; Enadoline Hydrochloride; Epirizole; Ergotaminc Tartrate; Ethoxazene Hydrochloride; Etofenarnate; Eugenol; Fenoprofen; Fenoprofen Calcium; Fentanyl Citrate; Floctafenine; Flufenisal; Flunixin; Flunixin Meglumine; Flupirtine Maleate; Fluproquazone; Fluradoline Hydrochloride; Flurbiprofen; Hydromorphorie Hydrochloride; Ibufenac; Indoprofen; Ketazocine; Ketorfanol; Ketorolac. Trornethaniine; Letimide Hydrochloride; Levomethadyl Acetate; Levomethadyl Acetate H-ydrochloride; Levonantradol Hydrochloride; Levorphano] Tartrate; Lofemizole Hydrochloride; Lofentanil Oxalate; Lorcinadol; Lornoxicam; Magnesium Salicylate; Mefenarnic Acid; Menabitari Hydrochloride; Meperidine Hydrochloride; Meptazinol Hydrochloride; i o Methadone Hydrochloride; Methadyl Acetate; Methopholine; Methotrimeprazine; Metkephamid Acetate; Mimbane Hlydrochloridc; Mirfentanil H-ydrochloride; Molinazone; Morphine Sulfate, Moxazocine; Nabitan H-ydrochloride; Nalbuphinc H-Iydrochloride; Nalmexone Hydrochloride Namoxyrate; Nantradol H-ydrochloride; Naproxcn Naproxen Sodium Naproxol; Nefopam Hydrochloride; Nexeridine Hydrochloride; Noracymethadol Hydrochloride; Ocfentani I H-ydrochloride; Octa7zamide; Olvanil; Oxetoronc Fumarate; Oxycodone; Oxycodone Hydrochloride-, Oxycodone Terephthalate; Oxyrnorphone Hydrochloride; Pemedolac; Pentamorphone; Pentazocine; Pentazocine H-ydrochloride; Pentazocine Lactate; Phenazopyridime Hydrochloride; Phcnyramidol Hiydrochloride; Picenadol Hydrochloride; Pinadoline; Pirfenidone; Piroxicam Olamine; Pravadoline NMalcatc; Prodilidine Hydrochloride; Profadol Hydrochloride; Propiram Fuarate; Propoxyphene s 20 H-ydrochloride: Propoxyphcne Napsylate; Proxazolc Proxazolc Citrate Proxorphan Tartrate; ~pyrrolipliene Hydrochloridec: Rciniifentanil H-ydrochloride; Salcolex Salctharnidc Malcatc; Salicylamidc; Salicylate Mcgluminc; Salsalate Sodiumi Salicylatc; Spiradolinc Mesylate; Sufntail;S~ientni Cirat; Tlmeaci ;Talniflumate Talosalate Tazadolene Succinate; Tebufelone ,Tctrydaminc Tifurac Sodium; Tilidinc Hydrochloride; Tiopitiac; Tonazocine *fee*: 25 Mesy late; Traniadol H-1ydrochloridc; Trcentanil Hydrochloridc; Trrolaminc; Veradoline H-ydrochloride; Verilopami H-ydrochloride; Volazocinc; Xorphanol Mesylate; Xylazine H-ydrochloride; Zcnazocine Mcsylatc; Zorncpirac, Sodium. Zuicapsaicin.

000 Androgen: Fluoxymcstcroinc: Mestcrolone; Mcthyltcstostcronc, Nandrololoc Dccanoatc; Nandrolonc Phenpropionate; Nisterime Acetate; Oxandrolonc; Oxyrncitholone; Silandrone; Stanozolol; Testostcronc;, Testosterone Cypionatec: Testostcronc [inanthate&: Tcstostcronc K'eto laurate; *:se:Tcstostcrone Phcny lacctate; Testostc rone Propionatc; Trcstol one Acetate.

22 Anesthesia, adjunct to: Sodium Oxybate.

Anesthetic: Alifluranc; Benoxinate Hydrochloride; Benzocaine; Biphenamine Hydrochloride Bupivacaine Hydrochloride; Butamnbcn; Butaniben Picrate; Chioroprocaine Hydrochloride; Cocaine; Cocaine Hydrochloride; Cyclopropane; Desfiurane; Dexivacaine; Diamocaine Cyclamate; Dibucaine; Dibucaine Hydrochloride; Dyclonine Hydrochloride; Enflurane; Ether; Ethyl Chloride; lEtidocaine; Etoxadrol H-ydrochloride; Euprocin Hydrochloride; Fluroxene; Halothane; Isobutamben; Isoflurane; Ketamine Hydrochloride; Levoxadrol Hydrochloride Lidocaine; Lidocaine Hydrochloride; Mepivacaine Hydrochloride; Methohexital Sodium; Methoxyflurane; Midazolamn io Hydrochloride; Midazolamn Maleate; Minaxolone; Nitrous Oxide; Norfiurane; Octodrine; Oxethazaine; Phencyclidine Hydrochloride; Pramoxine Hydrochloride; Prilocaine Hydrochloride; Procaine Hydrochloride; Propanidid; Proparacai ne Hydrochloride; Propofol; Propoxycaine Hydrochloride; Pyrrocaine; Risocaine; Rodocaine; Roflurane; Salicyl Alcohol; Sevoflurane; Tcflurane; Tctracaine; Totracaine Hydrochloride; Thiamylal; Thiarnylal Sodium; Thiopental Sodium Tiletamine Hydrochloride; Zolamine Hydrochloride.

Anorectic compounds including dexfenfluramine.

Anorexic: Aniinorex; Amphecloral; Chlorphentermine Hydrochloride; Clominorex; Clortermine 20 H-ydrochloride; Diethy Ipropion Hydrochloride; Fcnfl uraiuci H-ydrochloride; Fenisorex; Fl udorex; Flurninormx Levainfetamine Succinate; Mazindol; Mcfenorex H-ydrochloridc; lPhenmetrazine H-ydrochloride; Phecntermine; Sibutramine Hydrochloride.

*Antagonist: Atipameczoic; Atosiban; Bosciltan; Cimictidie Cimectidinc I lydrochioride; CIcntiazem Maleate; Detirelix Acetate; Devazepide; Donetidine; 2Etintidine Hydrochloride Famotidie; Fenmetozole Hydrochloride ,Flumazenil; Icatibant Acetate; Icotidine; Isradipine; Metiamide; Nadide; Nalmefene; Nalmexone H-ydrochloride Naloxone H-ydrochloride; Naltrexone; Nilvadipine; Oxilorphan; Oxmnctidine Hlydrochloride Oxmctdic Mcsylatc Quadazocine Mcsylatc; Ranitidinc; Ranitidine Bismuth Citratc Ranitidine HIydrochloride Sufotidinc; Tcluidipinc H-ydrochloride; Taparil -lydrochioride; Tiotidine; Vapiprost H-yd rochl oride; Zaltidine1ldohoie Anterior pituitary activator: 13,pi mestrol.

23 Anterior pituitary suppressant: Danazol.

Anthelmintic: Albendazoic; Anthclmycin; Bromoxanide; Bunamidine Hydrochloride; Butonate; Cambendazoje; Carbantel Lauryl Sulfate; Clioxanide; Clasantel; Cyclobendazole; Dichiorvos; Diethylcarbamazine Citrate; Dribendazole; Dymanthine Hydrochloride; Etibendazole; Fenbendazole; Furodazole; Hexylresorcinol; Mebendazole; Morantel Tartrate; Niclosamide; Nitrarnisole Hydrochloride. Nitrodan; Oxantel Parnoate; Oxfcndazole; Oxibendazole; Parbendazole; Piperamide Maleate; Piperazine; Piperazirie Citrate; Piperazine Edetate Calcium; Proclonol; Pyrantel Pamoate; Pyrantel Tartrate; Pyrviniurn Pamoate; Rafoxanide; Stilbazium Iodide; Tetramisole Hydrochloride; Thiabendazole; Ticarbodine; Tioxidazole. Triclofenol Piperazine; Vincofos; Zilantel.

Anti -acnc: Adapalene; Erythromycin Salnaced in; Inocoterone Acetate.

Anti -adrenerg ic: Acebutolol; Alprenolol Hydrochloride; Atenolol; Bretylium Tosylate; Bunolol Iiydrochloridc; Carteolol Hiydrochloridc; Celiprolol Hlydrochloride; Cetamnolol H-ydrochloride; Cicloprolol Hydrochloride; Dexpropranolol Hydrochloride; Diacetolol Hydrochloride; Di hydroergotamine Mesylate; Dilevalol H-ydrochloride; Esmolol Hydrochloride; Exaprolol Hydrochloride; -Fenspiride Hydrochloride; Flestolol Sulfate; Labetalol H-ydrochloride Levobetaxolo] Hydrochloride; Levobunolol Hydrochloride; Mctalol Hydrochloride; Metoprolol; Metoprolol Tartrate; Nadolol; Pamatolol Sulfate; Pcnbutolol Sulfate; Phentolamine Mesylate; Practolol; Propranoiol I-ydrochlofidc; Proroxan llydrochloridc; Soiypcrtinc Tartratc; Sotalol Hlydrochloride; Timolol; 1'imolol Malcate; Tiprenolol Hlydrochloride; Tolamolol; Zolertine H-ydrochloride.

Anti-allergic: Amnlexanox; Asternizolc; Azclastinc l-ydrochloridc; Eclazolast Minocroml Nedocroniil Ncdocromil Calcium Ncdocrornil Sodium Nivimiedone Sodium; Pcmirolast Potassium Pcntigetide; Pirquinozol; Poisonoak Extract; Probicrornil Calcium; Proxicromil;, Repirinast Tetrazol ast Meglumine; Thiazinamium Chiloride; Tiacrilast; Tiacrilast Sodium; Tiprinast Meglumine; Tixanox.

Anti-amebic Bcrythromycin; lBialornicol l-ydrochloridc; Chloroquinc; Chloroquinc Hydrochloride; Chloroquinc: Phosphatc ,Clarnoxyquin H-ydrochloride; Clioqtiinol Emictinc Hlydrochloride; 24 lodoquinol; Paromomycin Sulfate; Quinfamide;- Symetine Hydrochloride; Teclozan; Tetracycline; Tetracycline Hydrochloride.

Anti-androgen: Benorterone; Cioleronel; Cyprotcrone Acetate; Dclniadinone Acetatc Oxendolone; Topterone; Zanoterone.

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

Anti-anginal: Amlodipinc Besylate; Amnlodipine Maleate; IBetaxolol Hydrochloride Bevantolol to H-ydrochloride; Butoprozine Hydrochloride; Carvedilol Cinepazet Maleate; Metoprolol Succinate Molsidomnine Monatepil Malcatc; Primidolol Ranolazine Hydrochloride; Tosifen; Verapamil Hydrochloride.

Anti-anxiety agent: Adatanserin HIydrochloride; Al pidem; Binospirone Mesy late; Bretazeni I; Glemanseri n; Ipsapirone H-Iydrochloride; Mirisetron Mal eate; Oci naplon; Ondansetron Hydrochloridc Panadiplon;, Pancopride Pazinaclone; Serazapine Hydrochloride; Tandospirone Citrate; Zalospirone Hydrochloride.

Anti-arthritic: Lodelaben.

*20 Anti-asthmatic: Ablukast; Ablukast Sodium; Azelastine Hydrochloride ;Buriaprolast; Cinalukast; Cronmitrile Sodium; Cromnolyn Sodium; Enofelast: Isarnoxolc; Kctotiflci Fumaratc; Levcromakalim; Lodoxamnide Ethyl Lodoxam idc Tromethamine; Montelukast Sodium; Ontazolast; Oxarbazole; Oxatomidc; Piriprost; Piriprost Potassium; Pirolatc, Pobilukast Edamnine; Quazolast Repirinast; Ritolukast;. Sulukast; Tctrazolast Meglumine Tiaramide H-ydrochloridc, Tibenclast Sodium; Tomclukast; Trani last; VerlUkast; Vcrofyilline Zarirlukast.

Anti-athcrosolcrotic: Mifobatc; Tiniefuronc.

~Antibacterial: Acedapsonc; Acctosul fone Sodium; Alamcci n; A lcxidinc; Aid inoci I lin; Aid i nocilIli n Pivoxil; Ainicycline; Amifloxacin; Amifloxaciin Mesylate; Arnikacin; Amikacin Sulfate; Arninosalicylic acid; Aninosalicy late sodium; Anioxicillin; Amphomycin; Anipici Ilin; Ainpicillin Sodium; Apalcillin Sodium; Apramycin; Aspartociii; Astrornicin Sulfate; Avilamnycin; Avoparcin; Azithromycin; Azlocillin;, Aziocillin Sodium; Bacampicillin Hydrochloride; Bacitracin; Bacitracin Mcethylcne Disalicylate; Bacitracin Zinc, Bambermycins; Benzoylpas Calcium; Berythromycin Betamicin Sulfate; Biapenern; Binirarnycin; Biphenamine Hydrochloride Bispyrithione Magsulfex; Butikacin; Butirosin Sulfate; Capreomycin Sulfate; Carbadox; Carbenicillin Disodium; Carbenicillin Indanyl Sodium; Carbenicillin. Phenyl Sodium; Carbenicillin Potassium; Carumonam Sodium; Cefaclor; Cefadroxil; Cefamandoic; Cefamandole Nafatc; Ccfamandole Sodium; Cefaparole; Cefatrizine; Cefazaflur Sodium; Cefazolin; Cefazolin Sodium; Cefbuperazone; Cefdinir; Cefepime; Cefepime Hydrochloride; Cefetecol; Cefixime; Ccfmenoxime Hydrochloride; Cefmfetazole; Cefrnetazole Sodium; Cefonicid, Monosodium; Cefonicid Sodium; Cefoperazone Sodium; Ceforanide; Cefotaxirne Sodium; Cefotetan; Cefotetan Disodium; Cefotiam H-ydrochloride; Cefoxitin; Cefoxitin Sodium; Cefpiniizole; Cefpimizole Sodium; Cefpiramide; Cefpiramide Sodium; Cefpiromc Sulfate; Cefpodoxir-ne Proxetil; Cefprozi 1: Cefroxadine; Cefsulod in Sodium-, Ceftazidime; Ceftibuten; Ccftizoxime Sodium; Ceftriaxone Sodium; Cefuroxime;, Cefuroxinie Axetil; Cefuroxime Pivoxetil; Cefuroxime Sodium; Cephacetrile Sodium; Cephalexin; Cephalexin Hydrochloride; Cephaloglycin; Ccphaloridine; Ccphalothin Sodium; Cephapirin Sodium; Cephradine; Cetocycline Hydrochloride; Cetophenicol; Chloramphenicol; Chloramphenicol Palmitate; Chioramphenicol I'antothenate Complex Chloramphcnicol Sodium Succinatc; Chiorhexidine Phosphanilate; Chioroxylenol; Chlortetracycline Bisulfate; Chlortetracycline H-ydrochloride; Cinoxacin; Cipr ofloxacin; Ciprofloxacin H-ydrochiloride; Cirolernycin Clarithromycin; Clinafloxacin 20 H-ydrochloride; Clindamycin; Clindamnydin H-ydrochloride; Clindamycin Palmitate H-ydrochloride; C lindamycin Phosphatc; Clofazimninc Cloxacil lin Benzathinc, Cloxaci Ilin Sodium;, Cloxyquin;, Colistiicthatc Sodium; Colistin Sulfate; Coumermycin; Coumnermycin Sodium; Cyclacillin; Cycloserinc; Dalfopristin; Dapsonc; Daptomycin; Demeclocycline; Demeclocycline Hydrochloride; ****Demecycline; Denofungin Diaveridine; DicloxacilIlin;, Dicloxacill in Sodium; Dihydrostreptomycin Sulfate; Dipyrithione; Dirithromycin; Doxycycline; Doxycycline Calcium Doxycycline Fosfa~ex; Doxycycline 1lyclate; Droxacin Sodium; Enoxacin; Epicillin; Epitetracycline Hydrochloridc; Erythromycin; Erythromycin Acistrate;, Erythiromycin IEstolatc; Erythromycin Ethylsuccinate; Erythromnycin G luceptatc; Erythromycin Lactobi onatc; Erythromycin Propionate; Erythromycin Stearate; Ethambutol Hydrochloride; Ethionamidc; Fleroxacin; Floxacillin; Fludulaninc; Flumequinc, Fosfornycin; Fosfomnycin, Trometharninc; Fumnoxicillin; Furazolium Chloride; Furazolium Tartratc; Fusidate Sodium; Fusidic Acid; Gcatamnicin, Sulfate, Gloximionam;: Gramiceidin: I-laoprogin; I-ltacillin; FHctacil lin Potassium leIxcdinc; Ibafloxacin; limipencri; Isoconazolc; 26 Isepamicin; Isoniazid; Josamycin; Kanamycin Sulfate; Kitasamycin; Levofuraltadone; Levopropylcillin Potassium; Lexithromycin; Lincomlycin; Lincomycin Hydrochloride; Lornefloxcacin; Lomefloxacin Hydrochloride; Loniefloxacin Mcsylate; Loracarbef; Mafenide; Meclocycline; Meclocycline Sul fosalicylate; Megalomnicin Potassium Phosphate; Mequidox; Meropencm; Methacycline; Methacycline Hydrochloride; Methenamine; Metbenamine Hippurate; Methenamine Mandelate; Methicil [in Sodium; Metioprim; Metronidazole Hydrochloride; Metronidazole Phosphate; Mezlocillin; Meziocillin Sodium; Minocycline; Minocycline Hydrochloride; Mirincamycin Hydrochloride Monensin Monensin Sodium Naffillin Sodiumf; Nalidixate Sodium; Nalidixie Acid; Natamycin; Nebramnycin; Neomycin Palmitatc; Neomycin i0 Sulfate; Neomycin Undecylenate Netilmicin Sulfate; Neutramycin; Nifuradene; Nifuraldezone; Nifuratel Nifuratrone; Nifurdazil; Nifurimide; Nifurpirinol; Nifurquinazol; Nifurthiazole; Nitrocycline; Nitrofurantoin; N itromide; Norfloxaci n; Novobiocin Sodium; Ofloxacin; Ormetoprim; Oxacillin Sodium; Oximonam, Oximonam Sodium; Oxolinic Acid; Oxytetracycline; Oxytetracycline Calcium; Oxytetracycline Hydrochloride; Paldimycin; Parachiorophenol; Paulomycin; Pefloxacin; Pefloxacin Mesylate; Penamecillin; Penicillin G Benzathine; Penicillin G Potassium; Penicillin G Procaine;, Penicillin G Sodium; Penicillin V; Penicillin V Benzathine; Peni cillin V Hydrabaniine; Penicillin V Potassium; Pentizidone Sodium; Phenyl Aminosal icy late; Pipefacillin Sodium; Pirbenicillin Sodium; Piridicillin Sodium; Pirlimycin Hydrochloride; Pivamnpicillin Hydrochloride; Pivampicillin Parnoate; Pivampicillin Probenate; Polymyxin B Sulfate; Porfironiycin Propikacin; Pyrazinamide; Pyrithione Zinc; Quindccamine Acetate; Quinupristin; Racephenicol; Ramoplanin; Ranimycin; Relomyciri; Repromicin; Rifabutin; Rifarnetane; Rifamexil; Ri famide; Ri fampin; Rifapcntinc; Ri faxiimiin; Rolitetricycline; Rolitetracycline Nitrate; Rosaramicin; Rosaramicin Butyrate: Rosaramicin Propionate; Rosaramnicin Sodium Phosphate; Rosaramicin Stearatc; Rosoxacin; Roxarsone; Roxithromycin; Sancyclinc; Sanfetrinemn Sodium; Sarmoxicillin; Sarpicillin; Scopafungin; Sisomicin; Sisomicin Sulfate; Sparfloxacin; Spectinomycin I-lydrochloride; Spiramycin; Stallirnycin Hydrochloride-. Steffirnycin; Streptomycin Sulfate; Strcptonicozid; Sulfabenz: Sulfabcnzamide; Sulfacetarnide; Sulfacetamnide Sodium; Sulfacytine; Sul fadiazine; Sulfadiazine Sodium; Sulfadoxinc; Sulfalcne; Sulfamicrazinc; Sulfamecter; Sulfamethazine; Sulfamnethizoke; Sulfamethoxazolc; Sulfamonomethioxinc; Sulfamoxolc; Sulfani late Zinc; Sulf-anitran Sulfasalazinc; Sul fasomizole; Sulfathiazole; Sul fazamet; Sulfisoxazolc; Sulfisoxazole Acetyl; Sulfisoxazole Diolamine; Sulfomnyxin; Sulopenem; Sultamicillin; Suncillin Sodium; Talanipicill in H-ydrochloride; Teicoplanin; Tcmifloxacin -lydrochloride; Tcmocillin; -27- Tetracycline; Tetracycline H-ydrochloride Tetracycline Phosphate Complex; Tetroxoprim; Thiamphenicol; Thiphencillin Potassium; Ticarcillin Cresyl Sodium; Ticarcillin Disodium;- Ticarcillin Monosodium; Ticlatone; Tiodoniumn Chloride; Tobramycin; Tobramycin Sulfate; Tosufloxacin; Trimethoprim; Trimethoprim Sulfate; Trisulfapyriniidines; Troleandomycin; Trospectornycin Sulfate; Tyrothricin; Vancornycin; Vancomycin Hydrochloride; Virginiamycin; Zorbamycin.

Anticholelithic: Monoctanoin.

Anticholelithogenic: Chenodiol; Ursodiol.

Anticholinergic: Alverinc Citrate; Anisotropine Methylbromide; Atropine; Atropine Oxide Hydrochloride; Atropine Sulfate; Belladonna; Benapryzine Hydrochloride; Benzetimide Hydrochloride; Benziloniuin Bromide; Biperiden Biperiden Hydrochloride; Biperiden Lactate Clidiniumn Bromide; Cyclopentolate Hydrochloride; Dexetimide; Dicyclomnine Hydrochloride; Dihcxyverinc H ydrochloride; Domazoline Fumiarate; Elantrine; Elucainc; Ethiybcnztropinc; Eucatropine H-ydrochloride; Glycopyrrolate; H-eteroniumn Bromide; Homatropine Hydrobroniide; Honiatropine Mcthiylbromidc; Ilyoscyamine; 1-yoscyamine Hydrobromide; 1lyoscyamine Sulfate; Isopropamide Iodide; Mepcnzolate Bromide; Methylatropine Nitrate; Metoquizine; Oxybutynin *20 Chloride; Parapenzolatc Bromide; Pentapiperium NMethylsulfatc; Phecncarbamnide, Poldine *.Methy Isulfate;. Proglurnide; Propanthicline Bromide; Propcnzolatc llydrochloridc; Scopolamnine 1-ydrobroinidc; Tcinatropium Mcthylsul fatc; Tiquinamide Hlydrochloride; Tofunaci n H-ydrochloride; Toquizinc; Triampyzi ne Sulfate; Trihoxyphenidyl H-ydrochloride; Tropicamide.

Anticoagulant: Ancrod; Anticoagulant Citrate Dextrose Solution ;Anticoagulant Citrate Phosphate Dextrose Adenine Solution; Anticoagulant Citrate Phosphate Dextrose Solution; Anticoagulant l-lcparin Solution; Anticoagulant Sodium Citrate Solution; Ardeparin Sodium11; Bivalirudin :0 l3roniindionc; Dalteparin Sodium Desirudin; Dicumarol; 1leparin Calcium; I leparin Sodium; Lyapolate Sodium; Nafamnostat Mcsylatc Phenprocournon; Tinzaparin Sodium Warfarin Sodium.

Anticoccidal: Maduramicin.

Anticon1VUlsant: Albutoi n: Amcl lol ide;, Atol ide; Burainatc: Carbaniazepine Cinromidc; Citenamide; -28- Clonazepam; Cyhieptamide; Dczinamide; Dimcthadione; Di vaiproex Sodium; Eterobarb; Ethosuximide; Ethotoin; Flurazeparn Hydrochloride Fluzinamide; Fosphenytoin Sodium; Gabapentin;, liepcimidc; Lamotri gine; Magnesiurn Sulfate Mephenytoin; Mephobarbital Methetoin; Methsuximide; Mi lacemide Hydrochloride Nabazenil; Nafiniidone Hydrochloride; Nitrazeparn Phenacemide; Phenobarbital Phenobarbital Sodium Phensuximide; Phenytoin; Phenytoiri Sodium; Pri midone; Progabide; Ralitoline; Remacemide H-ydrochloride; Ropizine; Sabeluzole Stiripentol; Sulthiamne; Thiopental Sodium Tiletaine Hydrochloride Topiramnate; Triniethadione; Vaiproate Sodium; Vaiproic Acid; V igabatrin; Zoniclezole Hydrochloride; Zonisamide.

Antidepressant: Adatanserin H-ydrochloride; Adinazolarn Adinazolam Mesylate; Alaproclate; Aletaniine Hydrochloride; Arnedalin Hydrochloride; Anitriptyline Hydrochloride; Amoxapine; Aptazapine NMaleate; Azaloxan Fumarate; Azepindole; Azipramine Hydrochloride; Bipenamol Hydrochloride; Bupropi on Hydrochloride; Butacetin; B utriptyli ne Hydrochloride; Caroxazone; Cartazolate; Ciclazindol; Cidoxepin Hydrochloride; Cilobamine Mesylate; Clodazon Hydrochloride; Clomipramine. Hydrochloride; Cotinine Fumarate; Cyclindole; Cypenamine Hydrochloride; Cyprolidol H-ydrochloride; Cyproximidc; Daledalin Tosylate; Dapoxetine, H-ydrochloride; Dazadrol Mal eate; Dazepinil Hydrochloride; Desipramine, Hydrochloride; Dexamisole; Dexi mafen; Dibcnzepin Hydrochloride; Dioxadrol Hydrochloride; Dothiepin Hydrochloride; Doxepin 20 Hydrochloride; Duloxetine Hydrochloride; Eclanamine Maleate; Encypratc; Etoperidone Hydrochloride; Fantridone Hydrochloride; Fernetozole Hydrochloride; Fenmetraniidc; Fezolaniinc Fumarate; Fluotracen H-ydrochloride Fluoxetine; Fluoxetine H-Iydrochloride, Fluparoxan Hydrochloride; Gamfexine; Guanoxyfen Sulfate; Imafen Hydrochloride; Imiloxan Hydrochloride; I mipramine Hydrochloride; Indeloxazine, Hydrochloride; Intriptyline Hydrochloride; Iprindole; I socarboxazid; Ketipramine Fumarate; Lofeprarnine Hydrochloridc; Lortalarnine; Maprotiline; Niaprotilinc Hlydrochloride; Meitracen l-lydrochloridc; Milacemide Hlydrochloride; Minaprinc Hydrochloride; Mirtazapine; Moclobemide; Modaline Sulfate; Napactadine Hydrochloride; Naparnezole H-ydrochloride; Nefazodone Hydrochloride; Nisoxetine; Nitrafudam Hydrochloride; Nomnifensine Maleate; Nortriptyl inc Hydrochloride; Octriptyline Phosphate; Opipramol 3o H-ydrochloride; Oxaprotiline Hydrochloride; Oxypertinc;, Paroxetine; Phenelzine Sulfate; P irandamine H-ydrochloride; P izotyline Pridefine H-ydrochloride; Prolintane H-ydrochloride; Protriptylinc H-ydrochloride; Quipazinc, Maleate Rolicyprine; Seproxctinc Hydrochloride; -29- Sertralinc liydrochloridc; Sibutramine Hydrochloride Sulpiride; Suritozole; Tameitraline Hydrochloride; Tampramine Fumarate; Thndamine Hydrochloride;, Thiazesim Hydrochloride; Thozalinone; Tornoxetine Hydrochloride; Trazodone Hydrochloride; Trebenzomine Hydrochloride; Trimipramine; Trimipramine Maleate; Venlafaxine Hydrochloride; Viloxazine Hydrochloride; Zimeldine Hydrochloride; Zometapine.

Antidiabetic: Acetohexaniide; Buformin; Butoxamine Hydrochloride Camiglibose; Chiorpropamide; Ciglitazone; Englitazone Sodium; Etoformin Hydrochloride; Gliamilide; Glibornuride; Glicetanile Sodium; Gliflumide; Glipizide; Glucagon; Glyburide; Glyhexamide; to Glymidine Sodium; Glyoctaniide; Glyparamide; Insulin; Insulin, Dalanated; Insulin Human; Insulin Human, Isophane; Insulin H-umnan Zinc; Insulin H-uman Zinc, Extended; Insulin, Isophane; Insulin Lispro; Insulin, Neutral; Insulin Zinc; Insulin Zinc, Extended; Insulin Zinc, Prompt; Linogliride; Linogliride Fumarate; Metformin; Methyl Palmoxirate; Palmoxirate Sodium; Piogl itazone Hydrochloride; Pirogliride Tartrate; Proinsulin Human; Seglitide Acetate; Tolazamide; Tolbutamide; Tolpyrramide;, Troglitazone; Zopolrestat.

Antidiarrheal: Rolgamidine, Diphenoxylate hydrochloride (Lomoti Metronidazole (Flagyl), Methylprednisolone (Medrol), Sulfasalazine (Azulfidine).

20 Antidiuretic: Argipressin Tannate; Desrtopressin Acetate; Lypressin.

Antidote: Dimercaprol; Edrophonium Chloride; Fornepizole; Leucovorin Calcium ;Levoleucovorin Calcium; Methylene Blue Protamnine Sulfate.

*...Antidyskinetic: Selegi line Hydrochloride.

Anti-emetic: Alosetron Hydrochloride; Batanopride Hydrochloride; Bemnesetron; Benzquinamide, Chlorpromazine Chlorpromazine Hlydrochloride Cleboprid e; Cyclizine Hydrochloride; Dimenhydrinate; Diphenidol; Diphenidol Hydrochloride; Diphenidol Pamnoate; Dolasetron Mesylate Domperidone; Dronabinol; Fludorex; Flumeridone; Galdansetron 1lydrochloride; Granisetron; Granisctron H-ydrochloride; Lurosetron Mesylate; Meclizine Hydrochloride; Metoclopramide Hydrochloride; Metopirnazine; Ondansetrori Hydrochloride Pancopridc; Prochlorperazine; Prochlorpcrazine Edisylatc; Prochlorperazine Maleate Promethazine Hydrochloride 30 Thiethylperazine; Thicthylpcrazine Malate; Thi ethyl perazi ne Maleate; Trimethobenzamide H-ydrochloride; Zacopride Hydrochloride.

Anti-epileptic: Felbamate; Loreclezole; Tolgabide.

Anti-estrogen: Clometherone; Delmadinone Acetate Nafoxidine Hydrochloride; Nitromifene Citrate; Raloxifene Hydrochloride; Tarnoxifen Citrate; Toremifene Citrate Trioxifene Mesylate.

Anti fi brinolyti c: Nafamostat Mesylate Antifungal; Acrisorcin; Ambruticin; Arnphotericin B; Azaconazole; Azaserine;. Basifungin; Bifonazole; Biphenarnine Hydrochloride Bispyrithione Magsulfex Butoconazole Nitrate; Calcium Undecylenatc; Candicidin; Carbol-Fuchisin; Chiordantoin; Ciclopirox; Ciclopirox Olamnine; Cilofungin; Cisconazole; Clotrimazole; Cuprimyxin; Denofungin Dip yrithione; Doconazole; Econazole; Econazole Nitrate; Enilconazole; Ethonamn Nitrate; Fenticonazole Nitrate; Filipin; Fluconazoic; Flucytosine; Fungimycin; Griseofulvin; Hamycin; Isoconazole Itraconazole; Kalafungin; Ketoconazole; Lornoflingin; Lydimyciri; Mepartricin Miconazole; Miconazole Nitrate; 6 Modensin Monensin Sodium Naftifine H-ydrochloride; Neomycin Undecylenate Nifuratel 6* 6.Nifurmerone; Nitralamine Hydrochloride; Nystatin; Octanoic Acid; Orconazole Nitrate; Oxiconazole 20 Nitrate;, Oxifungin Hydrochloride; Paitonazole Hydrochloride; Partricin Potassium Iodide Procloriol Pyrithione Zinc Pyrrolnitrin; Rutarnycin; Sanguinariurn Chloride Saperconazole; Scopafungin Scleniurn Sulfide Sincf'Ungin; Sulconazolc Nitratc; Tcrbinafinc; Tcrconazoic; Thiram; Ticlatone Tioconazole; Tolciclate; Tolindate; Tolnaftate; Triacetin; Triafungin; 66:66Undecylenic Acid; Viridofulvin; Zinc Undecylenate; Zinoconazole H-ydrochloride.

S...Antiglaucomna agent Alprenoxime Hydrochloride Colforsin; Dapiprazole Hydrochloride Dipivefrin Hydrochloride Naboctate Hydrochloride; Pilocarpine; Pimabine.

Anieohlc AniempilcFatr 03 Antihemorrhagic: Poliglusam.

-31 Anti histani ni c: Acrivastine; Antazoline Phosphate; Asternizole Azatadine Maleate; Barmastine; Bromod iphenhydrarnine Hydrochloride; Brompheniramine Maleate; Carbinoxamine Maleate; Cetirizine Hydrochloride; Chlorphenirarnine Maleate; Chiorphcnirarnine Polistirex;- Cinnarizine; Clemastine; Clemastine Fumarate; Closiramine Aceturate; Cycliramine Maleate; Cyclizine; Cyproheptadine Hydrochloride Dexbromphenirani Maleate; Dexchlorpheriiraminc Maleate; Dimethindene Maleate; Diphenhydramine Citrate; D iphenhydramine Hydrochloride; Dorastine Hydrochloride; Doxylarnine Succinate: Ebastine; Levocabastine Hydrochloride; Loratadine; Mianserin Hydrochloride Noberastine; Orphenadrine Citrate Pyrabrom; Pyrilamine Maleate; Pyroxamine Maleate; Rocastine Hydrochloride; Rotoxaminc; Tazifylline H-ydrochloridc; Temelastine; Terfenadine; Tripelennamine Citrate; Tripelennamine Hydrochloride; Triprolidine Hydrochloride; Zolamine Hydrochloride Antihyperlipidemic: Cholestyramine Resin Clofibrate;- Colestipol Hydrochloride; Crilvastatin; Dalvastatin; Dextrothyroxine Sodium; Fluvastatin Sodium Gemfibrozil; Lecimibide; Lovastatin; Niacin Pravastatin Sodium; Probucol; Simvastatin; Tiqueside; Xenbucin.

Antihyperlipoproteinemic: Aci-fran; IBeloxarnide; Bezafi brate; B oxidine; Butoxamine Hydrochloride; Cetaben Sodium; Ciprofibrate; Gemcadiol; Halofenate Lifibratc; Meglutol; Nafenopin; Pimnetine l-lydtochloride; Theofibrate; Tibric Acid; Treloxinate.

*20 Antihypertensive: Alfuzosin Hydrochloride; Alipamide Aithiazide; Arniquinsiri Hydrochloride; Amlodipine Besylate Amlodipine Maleate Anaritide Acetate Atiprosin Maleate; Belfosdil; Bemnitradine; Bendacalol Mesylate; Bendroflurnethiazide Benzthiazide Betaxolol Hydrochloride Betbanidine Sulfate; lBevantolol Hydrochloride Biclodil Hlydrochloride; Bis'oprolol; IBisoprolol Fumaratc; Bucindolol H-ydrochloride; Bupicornide; Buthiazide: Candoxatril; Candoxatrilat; 25 Captopril Carvedilol Ceronapril; Chiorothiazide Sodium Cicletanine; Cilazapril; Clonidjine; Clonidine Hydrochloride; Clopamide; Cyclopenthiazide; Cyclothiazide Darodipine Debrisoquin Sulfate; Delapril Hydrochloride; Diapamide Diazoxide; Dilevalol Hydrochloride Diltiazemn Malate; Ditekiren; Doxazosin Mesylate; Ecadotril; Enalapril NMaleate; Enalaprilat; Enalkiren; Endralazine Msylate; Epithiazide Eprosartan; Eprosartan Mesylate; Fenoldoparn Mesylate Flavodilol Malcatc; Flordipinc; Floscquinan; Fosinopril Sodium Posinoprilat; Guanabcnz; Guanabenz Acetate-, Guanacl ine Sulfate; Guanadrel S ul fate; Guancydine; Guanethidine Monosulfatc; Guanethidine Sul fftc;, Guanfacine I-ydrochioridc; Guanisoquin Sulfate; Guanoclor -32- Sul fatc; Guanoctine Hydrochloride; Guanoxabenz; Guanoxan Sulfate; Guanoxyfen Sulfate Hydralazine Hydrochloride; Hydralazine Polistirex; 1-ydroflumethiazide Indacrinone Indapamide Indolapril H-ydrochloride; Indoramin; Indoramnin Hydrochloride; lndorenatc Hydrochloride; Lacidipine; Leniquinsin; Levcromakalirn Lisinopril; Lofexidirie Hydrochloride; Losartan Potassium; Losulazinc Hydrochloride; Mebutaniatc; Mecamy larnine H-ydrochloride; Medroxalol; Medroxalol Hydrochloride; Methalthiazide ;Methyclothiazide Methyldopa; Methyldopate Hydrochloride; Metipranolol; Metolazone ;Metoprolol Fumarate; Metoprolol Succinate; Mctyrosine; Minoxidil Monatepil Maleate ;Muzolirnine Nebivolol; Nitrendipine; Ofornine; Pargyline Hydrochloride; Pazoxide; Pelanserin Hydrochloride ;Perindopril Erbumine; i o Phenoxybenzamnine Hydrochloride; Pinacidi I; Pivopri I; Polythiazide ;Prazosin Hydrochloride;, Primidolol Prizidilol H-ydrochloride; Quinapril Hydrochloride Quinaprilat Quinazosin Hydrochloride; Quinelorane Hydrochloride Quinpirole Hydrochloride, Quinuclium Bromide; Ramipril Rauwolfia Serpentina; Reserpine; Saprisartan Potassium; Saralasin Acetate; Sodium Nitroprusside; Sulfinalol Hydrochloride; Tasosartan; Teludipine Hydrochloride Temocapri I Hydrochloride; Terazosin Hydrochloride; Terlakiren; Tiamenidine; Tiamenidinc H-ydrochloride; Ticrynafen Tinabinol; Tiodazosin; Tipentosin Hydrochloride; Triclilormethiazide Trimazosin Hydrochloride; Trimethaphan Camsylate; Trimoxamine H-ydrochloride; Tripamide; Xipamide :Zankircn Hydrochloride; Zofenoprilat Arginine.

0 Antihypotensive: Ciclafrine Hydrochloride; Midodrine Hydrochloride.

Anti-infective: Di floxacin H-ydrochloride Lauryl Isoquinolinium Bromide; Moxalactarn Disodium; Ornidazole; Pentisomicin; Sarafloxacin Hydrochloride; Protease inhibitors of IV and other retroviruses; Integrase Inhibitors of l-IIV and other retroviruses; Ccfaclor (Ceclor); Acyclovir 25 (Zovirax); Norfioxacin (Noroxin); Cefoxitin (Mefoxin); Cefuroxime axetil (Ceftin); Ciprofloxztin (Cipro).

Anti-infective, topical: Alcohol; Aminacrine Hydrochloride; lBenzethonium Chloride: Bithionolate Sodium; Bromchlorenone; Carbamide Peroxide; Cetalkonium Chloride. Cetylpyridinium Chloride :Chlorhecxidine Hydrochloride; Clioquinol ;Domiphen Bromide; Fenticlor; Fludazoniurm Chloride; Fuchsin, Basic; Furazolidone Gentian Violet; Halquinols; H-exachlorophene: Hydrogen Peroxide; Ichtharnmol; Imidecyl Iodine; Iodine, Isopropyl Alcohol; Mafcnide Acetate; Meralein Sodium; 33 Mercutenol Chloride; Mcrcury, Ammoniated; Methvlbenzethonium Chloride; Nitrof-urazone; Nitromcrsol; Octenidine Hydrochloride; Oxychiorosene; Oxychilorosene Sodium; Parachiorophenol, Camphorated; Potassium Permanganate; Povidone-lodine; Sepazonium Chloride; Silver Nitrate; Sulfadiazine, Silver; Symclosene; Thimerfoniate Sodium; Thirnerosal :Troclosene Potassium.

Anti -inflammatory: Aiclofenac; Aiclometasone Dipropionate; Algestone Acetonide; Alpha Amylase; Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac; Anitrazafen; Apazonc; Balsalazide Disodium; Bendazac; Benoxaprofen Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen; Cicloprofen; Cintazone; i0 Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate; Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide; Desoximetasone; Dexamethasone Dipropionate; Diclofenac Potassium; Diclofenac Sodium; Diflorasone Diacetate; Diflumidone Sodium; Diflunisal Difluprednate; Diftalone; Dimethyl Sulfoxidc; Drocinonide; Endrysone; Enlirnomab; Enolicam Sodium Epirizole Etodolac; Etofenamatc Felbinac; Fenamole; Fenbuflen; Fenclofenac; Fenclorac; Fendosal; Fenpipalone; Fent iazac; Flazalonc; Fluazacort; Flufenamic Acid, Flumizoic; Flunisolide Acctate; Flunixin Flunixin Meglurnc; Fluocortin Butyl; Fluorometholone Acctate; Fluquazone; Flurbiprofen Fluretofen;. Fluticasone Propionate; Furaprofen; Furobu fen; :Halcinonide; Halobetasol Propionate; Halopredone Acetate; Ibufenac Ibuprofen; lbuprofen Aluminum; Ibuprofen Piconol; llonidap; Indornethacin; Indomethacin Sodium; Indoprofen 0 Indoxole Intrazoie; Isoflupredone -Acetate; Isoxepac; Isoxicam; Ketoprofen; Lofemizole Hydrochloride Lornoxicam Loteprednol Etabonate; Meclofenamate Sodium; Meclofenarnic Acid; Meclorisone Dibutyrate; Mefenamic Acid ;Mesalaminc; Meseclazone; Methyiprednisolone Suleptanate; Morniflumate; Nabumetone; Naproxen Naproxen Sodium Naproxol Nimazonic; Olsalazine Sodium; Orgotein; Orpanoxin; Oxaprozin; Oxyphenbutazone; Paranyline Hydrochloride; Pentosan Polysulfate Sodium; Phenbutazone Sodium Glycerate; Pirfenidone Piroxicam; Piroxicam :ooo* Cinnamate; Piroxicamn Olamine; Pirprofen; Prednazate; Prifelone; Prodolic Acid; Proquazonc; Proxazole; Proxazole Citrate Rimexolone; Romazarit Salcolex Salnacedin; Salsalate Sanguinariumn Chloride Seclazonc Sermetacin; Sudoxicam; Sulindac; Suprofen; Talmetacin; Talniflumatc Talosalate.; Tebufelone Tenidap; Tenidap Sodium; Tenoxicanm; Tesicam; Tesimide; Tetrydarnine Tiopinac; Tixocortol Pivalate; Tolmetin; Tolmetin Sodium; Triclonide; Triflumidate; Zidometacin; Zomepirac Sodium.

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

Antimialarial :Acedapsoric Arnodiaquiinc Hydrochloride Arnquijiatc; Artcflcnc; Chioroquinc Chioroquine Hydrochloride Chioroquine Phosphate Cycloguanil Pamoate; Enpiroline Phosphate; 1-alofantrine Hydrochloride 1-ydroxychloroquine Sulfate; Mefloquine Hydrochloride; Menoctone; NMirincaniycin Hydrochloride Primaquine Phosphate; Pyrimetharnine; Quinine Sulfate; Tebuquine.

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

i o Dicholine.

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

Antimitotic: Podofilox.

Antimiycotic: Arnorolfine.

Antinauseant: Buclizine Hydrochloride; Cyclizine Lactate; Naboctate H-ydrochloride Antineoplastic: Acivicin; Aclarubicin; Acodazolc H-ydrochloride; Acronine; Adozelesin; Aldesleukin Altretamine; Amnbomycin; Ametantrone Acetate; Aminoglutethimide Amsacrine; Anastrozole; Anthrarnycin; Asparaginase; Asperlini; Azacitidiiie; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamnide; Bisantrene Hydrochloride; Bisnafide Dirniesylate; Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Bropirimine ;Busulfan; Cactinornycin; Calusterone; Caracemile; :::*Carbetimer; Carboplatin; Carmustine; Carubicin Hydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cirolemycin Cisplatin; Cladribine; Crisnatol Mesylate; Cyclophospharnide Cytarabine Dacarbazine; Dactinomycin; Daunorubicin Hydrochloride; Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine Mesylate; D iaziq uone; Docetaxel; Doxorubicin; Doxorubicin H-ydrochloride; Droloxifene; Droloxifene Citrate; Dromostanolone Propionate; Duazomycin; Edatrexate; Eflomnithine Hydrochloride Elsamitrucin; Enloplatin; Enpromate; Epipropidine; Epirubicin Hydrochloride;' Erbulozole; Esonibicin Hydrochloride; fistramustine; Estramustine Phosphate Sodium; Etanidazole; Ethiodized Oil 1 131, Etoposide; Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride; Fazarabine; Fenretinidc; Floxuridine Fludarabine Phosphate; Fluorouracil; Flurocitabine; Fosquidone; Fostriecin Sodium; Gemcitabine; Gemcitabinc Hydrochloride; Gold Au 198 Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide; Ilmofosine; Interferon Alfa-2a Interferon Alfa-2b Interferon Alfa-ni1; Interferon Alfa-n3; Interferon Beta-I a ;Interferon Gamma-I b; 1proplatin; Irinotecan Hydrochloride Lanreotide Acetate; Letrozole; Leuprolide Acetate Liarozole Hydrochloride; Lometrexol Sodium; Lomustine; Losoxantrone Hydrochloride; Masoprocol; Maytansine; Mechiorethamine Hydrochloride; Megestrol Acetate; Melengestrol Acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate Sodium; a0 Metoprine; Meturedepa; Mitindomide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole; Nogalamycin; Ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Peliomycin; Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipobroman; P iposulfan; P iroxantrorie Hydrochloride; Plicamycin; Plomestane; Porfimer Sodium; Porfiromycin Predniniustine; Procarbazine H-ydrochloride; Puromycin 1 5 Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Safingol Safingol Hydrochloride ;Semustine; Simtrazene; Sparfosate Sod iurn; Sparsornycin; Spirogermanium Hlydrochloride; Spirornustine; Spiroplatin; Streptonigrin; Streptozocin; Strontium Chloride Sr 89; Sulofenur; Talisomycin; Taxane; Taxoid; Tecogalan Sodium; Tegafur; Teloxantrone Hydrochloride; Temroporlin; Teniposide; Teroxirone; Testolactone;, Thiamiprine; Thioguanine, -Thiotepa; Tiazofurin; Tirapazamine; Topotecan Hydrochloride; Toremifene Citrate; Trestolone Acetate; Triciribine Phosphate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin;, Tubulozole Hydrochloride, Uracil Mustard; Uredepa; Vapreotide; Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; V indesine; Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; Vinrosidine Sulfate; Vinzoiidine Sulfate; Vorozole; Zeniplatin; Zinostatin; Zorubicin 25 Hydrochloride.

Other anti-neoplastic compounds include: 20-epi-l,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-dorsalizing morphogenetic protein-I1; antiandrogen, prostatic carcinioma; antiestrogen; antineoplaston; antisense ol igonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; 36 atrinmustine; axinastatin 1; axinastatin 2; axinastatin 3; azasctron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCRIABL antagonists; benzochlorins; benzoylstaurosporine; beta lactain derivatives; beta-alethine; betaclamycin B; betulinic acid; bPGF inhibitor; bicalutamide; bisantrenc; bisazi rid iny Isperinine; bisnafidc; bistratene bizelesin; breflate; bropiriniine; budotitane; buthionine sulfoximine; caicipotriol; caiphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyarnidotriazole; CaRest M3; CARI'. 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; collismycin B; combretastatin AM; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentazithraquinones; cycloplatarn, cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabirie; dehydrodidemnin B; deslorelin; dexifosfarnide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydrotaxol, dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emnitefur, epirubicin; epristeride; estramustine analogue; estrogcn agonists; estrogen antagonists; etanidazoic; ctoposidc phosphate; exemestane; fadrozole; fazarabine; :fenretinide; filgrastirn; finnsteride; flavopiridol; flezelastine; fluasterone, fludarabine; fluorodaunorunicin hydrochloride; forfenimex; forniestane; fostriecin; fotemustine; gadolinium 20 texaphyrin; galliumn nitrate; galocitabine, ganirelix; gelatinase inhibitors; gemeitabine; glutathione inhibitors; hepsul fain; heregulin; hcxarnethylenc bisacctnrnide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomnastat; imidazoacridones; imiquimnod; immunoslimulint pcptidcs; insulin-likc growth factor-I rccvptor inhibitor; intcrfcron agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, irinotecon; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasctron; jasplakinolide; kahalalide F; lamellatin- N triacetate; lanreotide; leinamycin; lenograstirn; lentinan sulfate; Icptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; Icuprolide estrogen progesterone; leuprorelin; levamisole; liarozole; linear polyainen analogue; lipophilic disaccharide peptide; lipophilic platinum compounds, lissoclinamide 7; lobaplatin, lombricine; lornetrexol; lonidamine; losoxantronc; lovastatin; loxoribinc; lUrtotecan; lutctium tcxaphyrin; Iysofyllinc; lytic peptides; maitansine; mannostatin A; marirnastat; masoprocol; maspin; rnatrilysin inhibitors; matrix metal loprotei nase inhibitors; mcnogaril;, mcrbarone; meterelin; methioninase; iinetociopramidc; MIF inhibitor; 37 mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; rnitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin, mitoxantrone; mnofarotene; moigrarnostim; monoclonalI antibody, human chorionic gonadotrophinlmonophosphoryl lipid A myobacteriumn cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumnor suppressor 1-based therapy; mustard anticancer agent; rnycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzaniides; nafarelin; nagrestip; naloxone pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrul lyn; 06-benzyl guanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel analogues; paclitaxel derivatives; palauarnine; palmitoylrhizoxin; parnidronic acid; panaxytriol; panomifene; pirabactin; pazelliptine; pegaspargase; peldesine; pcntosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfarnide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porimer sodium; porfiromycin; propyl bisacridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein :kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucicoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hcmoglobin polyoxycthylcnc conjugate; raf antagonists; raltitrexed; ramosctron; ras farnecsyl protein transferase inhibitors; ras inhibitors: ras-GAP inhibitor; retelliptine demnethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII rctinamidc; rogletimide; rohitukinc; romnurtide; roquinimex: rubiginone B 1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargrarnostim; Sdi I miructics; semnustine; senescence derived inhibitor 1 sense oligonucicotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran; sobuzoxane; sodiim borocaptate; sodium plienylacctate; solverol; somatornedin binding protein; sonermin; sparfosic acid; spicamnycin D; spirornustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinlosine; superactive vasoactive intestinal 'etde antagns;s.dit;srmn swainsonine; synthetic glycosarninoglycans; tallimustinc; tanioxiton niethiodidec; tauromnustine; tazarotene; tecogalan sodiumn; tegafur; tellurapyrylium; telomerase inhibitors; ternoporfin; ternozolomide; teniposide; tctrachlorodecaoxide; tctrazominc; thali blastine;, thalidomnide:- thiocoraline, thirombopoictin; thrombopoictin mimetic; thymal fasin; 38 thymopoietin receptor agonist; thyniotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirap azamine; titanocene dichloride; topotecan; topsentin; toremi fene; totipotent stem cell factor; translation inhibitors; tretinoin; tri acetyl uri dine; triciribine; trirnetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphosti ns; UBC inhibitors; ubenirnex; urogenital sinusderived growth inhibitory factor; urokinase receptor antagonists; vapreotidc; variolin B; vector system, erythrocyte gene therapy; velaresol; veramnine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer.

Anti-cancer Supplementary Potentiating Agents: Tricyclic anti-depressant drugs imipramine, desipramine, amitryptyline, clom ipramine, triniiprarnine, doxepin, nortriptyline, protriptyline, amoxapine and maprotiline); non-tricyclic anti-depressant drugs sertraline, trazodonc and citalopramn); Ca** antagonists verapamil, nifedipine, nitrendipine and carovcrine); Calmodulin inhibitors prenylamine, trifluoroperazine and clomipramine); Amphotericin B; Triparanol analogues tamoxifen); 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 tile invention also can be administcred with cytokines such as granulocyte colony stimulating factor.

:Antinheutropen ic: Filgrastim; Lcnograstirn; Molgraniostim; Regramostim; Sargramostim.

Antiobsessional agent: Fluvoxamine Maileate.

Antiparasitic: Abaniectin;. Clorsulon; Ivermectin.

Antiparkinsonian: Bcnztropinc Mcsylate; lBipcridcn; Bllipridcn Hlydrochloride; B iperiden Lactate; Carmantadine; Ciladopa H-ydrochloride; Dopamantinc; Ethopropazine Hydrochloride; Lazabemnide; Levodlopa; Lomctralinc Hydrochloride; Mofegiline H-ydrochloridc; Naxagolidc Hlydrochloride; Pareptide Sulfate; Procyclidine Hydrochloride; Quinclorane Hydrochloride; Ropinirole Hydrochloride; Selegiline 1lydrochloride; Tolcaponc; Trihexyphenidyl H-ydrochloride.

Antiperistaltic: Difenoxirnide H-ydrochloride; Difenoxin;, Diphenoxylate Hydrochloride; Fluperamide; Lidarnidine Hydrochloride; Loperamide H-ydrochioride; Malethamer; Nufenoxole; Paregoric.

39.

Antiprieur-nocystic: Atovaquone.

Antiproliferative agent: Piritrexim Isethionate.

Antiprostatic hypertrophy: Sitogluside.

Antiprotozoal: Amodiaquine; Azanidazole; Bamnidazole; Camidazoic; Chlortetracycline Bisulfate Chlortetracycline Hydrochloride; Flubendazole; Fluiiidazole; Halofuginone Hydrobromide; Imidocarb Hydrochloride; Ipronidazole; Metronidazole; Misonidazole; Moxnidazo le; Nitarsone; Partricin; Puromycin; Puromycin Hydrochloride; Roriidazole; Sulnidazole; Tinidazole.

Antipruritic: Cyproheptadi ne Hydrochloride Methdilazi nc; Mcthid ilazine Hydrochloride; Trimeprazine Tartrate.

Antipsoriatic: Acitretin; Anthralin; Azaribine; Cakipotriene; Cycloheximide; Enazadrern Phosphate; Etretinate; Liarozoic Fumaratc; Lonapalene; Tepoxal in.

:Antipsychotic: Acetophenazine Maleate; Alentemol Hydrobrornide; Alpertine; Azaperone; Bateiapine Maleate; Benperidol; Benzindopyrinc Hydrochloride; Brofoxine; Bromperidol; 0 Broinpcridol Dccanoalc; Butaclrniol' 'Ilydrochiloridc; Butipcrazinc; Butapcrazine Maleatc; Carphenazine Maleate; Carvotroline Hydrochloride; Chlorpromazine; Chlorpromazine 1-ydrochioridc; Chiorprothixcnc; Cinpcrcne; Cintriarnide; Clomacran Phosphate; Clopenthixol; Clopimozide; Clopipazan Mesylate; Cloroperone Hydrochloride; Clothiapine; Clothixamide Maleate; Clozapine; Cyclophenazine l-lydrocliloridc; Droperidol; Etazolate H-ydrochloride; Fenimide; Flucindole; Flurnezapine; Fluphenazine Dccanoatc; Fluphenazine Enanthate; Fluphenazine Hydrochloride; Fluspiperone; Fluspirilene; Flutroline; Gevotroline H-ydrochloride; -lalopemidc; Haloperidol; Haloperidol Decanoate; Iloperidonc; Imidoline Hydrochloride; Lenperone; Mazapertine Succinate; Mesoridazinc; Niesoridazine Besylatc; Metiapine; Milenperone; Milipertinc; Molindone H-ydrochloride; Naranol 1lydrochioridc; Neflurnozide H-ydrochloride; Ocapcridonc; Olanzapine; Oxiperomide; Pen fluridol; Pentinpine Maleatc: Perphecnazine; P imozide; Pinoxepin Hydrochloride; Piparnpcronc; P liperacciazinc.: Pipotiazinc Palmitatc; Piquindone I lydrochioridc; Prochiorperazine Edisy late; Prochiorperazine Maleate; Promazine Hlydrochloride; Remnoxipride:, Remoxipride Hydrochloride; Rimcazole Hydrochloride; Seperidol Hydrochloride; Sertindole Setoperone; Spiperonc; Thioridazine Thioridazine Hydrochloride; Thiothixene; Thiothixene Hydrochloride; Tioperidone Hydrochloride; Tiospirone Hydrochloride; Trifluoperazine Hydrochloride; Trifluperidol; Triflupromazine; Triflpromazine Hydrochloride; Ziprasidone Hydrochloride.

Antirheumatic: Auranofin; Aurothioglucose; B indarit; Lobenzarit Sodium; Phenylbutazone; Pirazolac; Prinomide Tromethamine; Seprilose.

Anti schistosomal: Becanthone Hydrochloride; Hycanthone; Lucanithone Hydrochloride; Niridazole; Oxamniquine; Pararosaniline Pamoatc; Teroxalene Hydrochloride.

Antiseborrheic: Chioroxine; Piroctone; Piroctone Olamirie; Resorcinol Monoacetate.

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

:Antispasmodic: Stiloniurn Iodide; Tizanidine Hydrochloridc.

20 Anti thrombotic: Anagrelide H-ydrochloride; Bivalirudiii; Daltcparin Sodium Danaparoid Sodium; Dazoxihen Hydrochloride;, Efegatran Sulfate; Enoxaparin Sodium; lfetroban; Ifetroban Sodium; Tinzapari n Sodium ;T'rificnagrcl.

Antitussive: Benzonatatc; Butamnirate Citrate; Ch lophcdianol Hydrochloride; Codeine Pol istirex; Codoxime; Dextromethorphan; Dextromethorphan H-ydrobrornide; Dextromethorphan Polistinex; Ethyl Dibunatc; Guaiapate; 1lydrocodone, B itartratc; I-lydrocodone Pol istirex; Levopropoxyphene Napsylate; Noscapine; Pcererd Nitrate; Pipazethate; Suxemerid Sulfate.

Anti-ulcerative: Aceglutamide Aluminum. Cadexomeir lodine; Cetraxate H-ydrochloride; Enisoprost; Isotiquimide; Lansoprazoic, Lavoltidine, Succinate; Miso~prostol; Nizatidinc; Noliniurn Bromide; Pantoprazolc; Pifarnine; Pirenzcpinc H-Iydrochloride; Rabcprazolc Sodium Rcniiprostol; Roxatidinc Acetate IHIydrochloride; Sucral fate; Sucrosofate Potassium; TolIiniidone.

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

Antiviral: Acernannan; Acyclovir; Acyclovir Sodium; Adefovir; Alovudine; Alvirccpt Sudotox; Arnantadine H-ydrochloride; Aranotiri; Arildonc: Atevirdine Mesylate; Avridine; Cidofovir; s Cipamfylline; Cytarabine Hydrochloride; Delavirdine Mesylatc; Desciclovir; Didanosine; Disoxaril; Edoxudine; Enviradene; Enviroxime; Famciclovir; Famoti ne Hydrochloride; Fiacitabine; Fialuridine; Fosari iate, Foscarnet Sodium; Fosfonet Sodium; Ganciclovir; Ganciclovir Sodium; Idoxuridine; Kethoxal; Lamnivudine; Lobucavir; Memnotine Hydrochloride; Methisazone; Nevirapine; Penciclovir; Pirodavir; Ribavirin; Rimantadine Hydrochloride; Saqui navir Mesylate. Somantadine t o Hydrochloride; Sorivudinc; Statolon; Stavudine; Tilorone Hiydrochloridc; Trifluridine; Valacyclovir H-ydrochloride; Vidarabine; Vidarabinc Phosphate; Vidarabine Sodiumn Phosphate; Viroxime; Zalcitabine; Zidovudine; Zinviroxime.

Appetite suppressant: Dexfenfluramine H-ydrochloride; Phendimetrazine Tartrate; Phentermine i s H-ydrochloride.

Benign prostatic hyperplasia therapy agent: Tamsulosin Hydrochloride.

Blood glucose regulators: Human insulin; Glucagon; Tolazamide; Tolbutarnide; Chloropropamide; 20 Acetohexarnide and Glipizidc.

Bone resorption inhibitor: Alcildronate Sodium; Etidronaic Disodiurn; Panmidronate Disodium.

Bronchodilator: Albutcrol; Albutcrol Sulfate; Azanator Malcatc; Bariffyllinc Hydrochloride; .:25 B itolterol Mesylate; Butaprost; Carbuterol Hydrochloride; Clorprenal inc Hydrochloride; Colterol Mesylatc; Doxaprost; Doxofylline; Dyphylline; Enprofyllinc; Ephedrine; Ephedrine Hydrochloride; Fenoterol; Fenprinast Hydrochloride; Guaithyl line; Hexoprenaline Sulfate H-oquizil Hydrochloride; I pratropium Bromide; Isoetharine; Isoethnrine Hydrochloride; Isoctharine M esylatc; Isoprotereno I 0 Hydrochloride; Isoproicrenol Sulfate; Metaprotcrenol Polistirex; Metaprotcrcnol Sulfate; Nisbuterol Mesylatc-, Oxtriphyllinc; Picumnctcrol Fumnarate; Piquizil Hlydrochloride; Pirbuterol Acetate; P irbutcrol H-Iydrochloride; Procatcrol Hydrochloride: Pscudocphedri ne Sulfate; Quazodinc Quintcrcnol Sulfate; Raccpiricphrinc; Racepinephrinc H-ydrochloridc; R1cprotcrol Hydrochloride; -42- Rimiterol 1-ydrobrornide; Salmeterol; Salmeterol Xinafoate;.Soterenol Hydrochloride; Sulfonterol Hydrochloride; Suloxifen Oxalate; Tcrbutaline Sulfate; Theophylli ne; Xanoxatc Sodium; Zindotrine; Zinterol Hydrochloride.

Carbonic anhydrase inhibitor: Acetazolamide; Acctazolamnide Sodium; Dichiorphenamide; DOrzo lamide H-ydrochloride; Mcthazolamide; Sezolarnide, Hydrochloride.

Cardiac depressant: Acecainide Hydrochloride; Acetylcholine Chloride; Actisomide; Adenosine; Amiodarone; Aprindine; Aprindine Hydrochloride; Artilide Fumarate; Azimil ide Dihydrochioride; Bidisomide; Bucainide Maleate; Bucromarone; Butoprozirie Hydrochloride Capobenate Sodium; Capobenic Acid: Cifenline; Cifenline Succinate; Clofiliurn Phosphate; Disobutai-ide; Disopyrarnide; Disopyramide Phosphate; Dofetilide; Drobuline; Edifolone Acetate; Emiliumn Tosylatc; Encainide Hydrochloride; Flecainide Acetatc; Ibutilide Fumnarate; Indecainide Hydrochloride; Ipazilide Fumaratc; Lorajmine Hydrochloride; Lorcainide Hydrochloride; Meobentine Sulfate; Mexiletine Hydrochloride; Modecainide; Moricizine; Oxiramide; Pirmenol Hydrochloride; Pirolazamide; Pranoliumn ChlJoride; Procainaniidc Hydrochloride; Propafenone H-ydrochloride; Pyrinoline; Quindonium Bromide; Quinidine Gluconate; Quinidine Sulfate; Recainam H-ydrochloride; Recainam Tosylate; Risotilide Hydrochloride; Ropitoin Hydrochloride; Sematilide Hydrochloride; Suricainide NMaleate; Tocainide; Tocainidc Hydrochiloride; Transcaiide.

.**.Card ioprotectant: Dexrazoxane; Draflazine.

Cardiotonic: Actodigin; Arnrinoinc; B~cnoradan; Butopnininc; Carba-tcran; Carsatrin Succinatc; Deslanoside; Digitalis; Digitoxin; Digoxin; Dobutanc; Dobutamine Hydrochloride; Dobutamine Lactobionate; Dobutaminc Tartratc; Enoximone; Imazodan Hydrochloride; I ndolidan; lsornaz~le Hydrochloride; Levdobutai-nine Lactobionate; Lixazinone Sulfate; Mcdorinone; Milrinone; Pelrinonc Hydrochloridc; Pimobendan; Piroximione; Prinoxodan; Proscillaridin; Quazinone; Tazolol Hydrochloride; Vesnarinone.

Cardiovascular agent: Dopexamine; Dopexamine Hydrochloride.

Choleretic: Dehydrochol ic, Acid; rencibutirol; 1lynecromone; Piprozolin; Sincalide; Tocamphyl.

-43- Cholinergic: Aceclidine; Bethanechol Chloride; Carbachol; Demecarium Bromide; Dexpanthenol; Echothiophate Iodide; Isoflurophate; M~ethacholine Chloride; Neostigmine Bromide; Neostigmine Methylsulfate; Physostigmine; Physostigmine Salicylate; Physostigmine Sulfate; Pilocarpine Pilocarpine Hydrochloride; Pilocarpine Nitrate; Pyridostigmine Bromide.

Cholinergic agonist: Xanomeiine; Xanomeline Tartrate.

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

Coccidiostat: Arprinocid; Narasin Sernduramicin; Scmduramicin Sodium.

Cognition adj uvant: Ergoloid Mesylates; Piracetamn; Pram iracetarn Hydrochloride; Pramniracetan Sulfate; Tacrine Hydrochloride.

Cognition enhancer: Besipirdine Hydrochloride; Linopirdine; Sibopirdine.

:Depiessant: Omneprazoic.

V 2 Diagnostic aid: Aminohippurate Sodiurn;'Anazolene Sodium; Arclofenin; Arginine Bentiromide; Benzylpenicilloyl Polylysine; Butedronate Tetrasodium; Butilfenin; Coccidioidin; Corticorelin Ovine Triflutate; Corticotropin, Repository Corticotropin Zinc -lydroxide; Diatrizoate Meglunmine; Diatrizoate Sodium; Diatrizoic Acid-, Diphtheria Toxin for Schick Tcst; Disofenin; Edrophonium Chloride; Ethiodized Oil; Etiflenin; Exametazirne; Ferristenc; Ferumoxides; Ferumoxsil; Fluorescein; 25 Fluorescein Sodium; Gadobenate Dimeglumine; Gadoteridol; Gadodiamide; Gadopcntetaite Dimegiumine; Gadovcrsetamide; H-istoplasmin; Impromidine Hydrochloride; Indigotindisulfonate Sodium; Indocyanine Green lobenguane Sulfate 1 123; lobenzamic Acid; locarmate Megluniine; Voooo locarmic Acid; locetamnic Acid; lodamidc; lodamide Mcgiuminc; lodipamide Megluminc; lodixonol; lodoxamnatc Meglurnine; lodoxamic Acid; loglicic Acid; loglucol; loglucomide; loglycarnic Acid; logularnide; lohexol; lomeprol; lopamidol; lopanoic Acid; lopentol; lophendylate; Iprofecnin; lopronic Acid; loprocemic Acid; lopydol; lopydonc; losefamic Acid;. loscric Acid; losulamide Meglumine; losuiletic Acid; lotasul; lotetric Acid; lothalamate Megluminc; lothialamate Sodium; 44 lothalanie Acid, Iotrolan; lotroxic Acid; loversol; loxaglate Meglumine; loxagiate Sodium; Joxaglic Acid; Joxilan; loxotrizoic Acid; Ipodate Calcium; Ipodate Sodium; Isosulfan Blue; Leukocyte Typing Serum; Lidofenin; Mebrofenin; Meglumine; Metrizamide; Metrizoate Sodium; Metyrapone; Metyrapone'artrate; Mumps Skin Test Antigen; Pentetic, Acid; Propyliodone; Quinaldine Blue; Schick Test Control; Sermorelin Acctate Sodium Iodide 1 123; Sprodiamiide; Stannous Plyrophosphate; Stannous Sulfur Colloid; Succimer; Teriparatide Acetate; Tetrofosmin; Tolbutamide Sodium; Tuberculin; Tyropanoatc Sodium; Xylose.

Diuretic: Ambuphylline Ambuside; Amiloridc Hydrochloride; Azolimine; Azosemide; Brocrinat; Bumetanide; Chiorothiazide; Chiorthalidone; Clazolimine; Clorexolone; Ethacrynate Sodium; Ethacrynie Acid; Etozolin; Fenquizone; Furosemide; Hydrochiorothiazide; Isosorbide; Mannitol; Mefruside; Ozolinone; Piretanidc; Spiroxasone; Torscmidc; Triamrierene; Triflocin; U rca.

Dopaminergic agent: Ibopamine.

Ectoparasiticide: Nifluridide; Permethrin.

Emetic: Apornorphine Hydrochloride.

20 Enzyme inhibitor: Acetohydroxamic Acid; Airestatin Sodium; Aprotinin. Benazepril Hydrochloride; lBcnazcprilat; Bcnurestat; Bromocriptine; Bromnocriptine Mcsylatc; Cilastatin Sodium; Flurofarnidc; Lergotrile; Lergotrile Mesylate; Lcvcycloserine; Libenzapril; Pentopril; Pepstatin; Perindopril; Polignate: Sodium; Sodium Amlylosulfhic;, Sorbinil; Spirapril Hydrochloride; Spiraprilat; Taleranol; Teprotide; To! famide; Zofenopril Calcium.

Estrogen: Chlorotrianisenec; Dienestrol; Diethylstilbestrol; Dicthylstilbestrol Diphosphiate; Equi4in; *Estradiol; Estradiol Cypionatc; Estradiol Enanthate; Estradiol Undecylate; Estradiol Valerate; Estrazi no! Hydrobromide; Estrio I; Estrof'urate; Estrogens, Conjugated; Estrogens, Esterified; Estrone; Estropipate; Ethinyl Estradiol; Fenestrel; Mestranol; Nylestriol; Quinestrol.

Fibrinolytic: Anistreplase; Bisobrin Lactate; Brinolase.

Free oxygen radical scavcnger: Pegorgotein, Gastrointestinal Motility agents: Cisapride (Propulsid); Metoclopramidc (Reglan);- Hyoscyamine (Levsin).

Glucocorticoid: Amcinonidc; Beclomethasone Dipropionate; Betamnethasone; Betamethasone Acetate; Betarnethasone Benzoate; Betamethasone Dipropionate; Betamethasone Sodium Phosphate; Betamethasone Valerate; Carbenoxolone Sodium; Clocortolone Acetate; Clocortolone Pivalate; Cloprednol; Corticotropin; Corticotropin, Repository; Corticotropin Zinc Hydroxide; Cortisone Acetate; Cortivazol; Descinolone Acetonide; Dexcamethasone; Dexaniethasone Sodium Phosphate; Diflucortolone; Diflucortolone Pivalate; Flucloronide; Flumethasone; Flumethasone Pivalate; Flunisolide; -fluocinolone Acetonide; Fluocinonide; Fluoc-ortolone; Fluocortolone Caproate; Fluorornetho lone; Fluperolone Acetate; Fluprednisolone; Fluprednisolone Valerate; Flurandrenolide; Formocortal; H-ydrocortisonc, 1-ydrocortisone Acetate; Hydrocortisone Buteprate; Hydrocortisone Butyrate; Hydrocortisone Sodium Phosphate; Hydrocortisonc Sodium Succinate; Hydrocortisone Valerate; Medrysone; Methyiprednisolone; Methyiprednisolone Acetate; Methyiprednisolone Sodium Phosphate-, Methylprednisolonie Sodium Succinate; Nivazol; PUarachasone Acetate; Prednicarbatc; Prednisolone; P1rcdnisolone Acetate; Prcdnisolonc Hemisuccinate; Prednisolone Sodium Phosphate; Prednisolone Sodium Succinatc; Prcdniisolonc Tebutate; Prcdnisone; Prednival; Tricabesonc Propionatc; Tralonide; rriamncinolone; Trianicinolonc Acetonide; Triameinolone Acetonide Sodium; Triamcinolonc Diacetate; Triameinolone Hexacetonide.

Gonad-stimulating principle: Buserelin Acetate: Clomiphene Citrate; Ganirelix Acetate; Gonadorelini Acetate; Gonadorelin H-ydrochloride; Gonadotropin. Chiorionic; Menotropins.

o Ilair growth stimulant: Minoxidil.

:o~oo Hemostatic: Arninocaproic Acid; Oxamarin Hydrochlloride; Sulmnarin; Thrombin; Tranexamic Acid.

:0 Histamine 1-12 receptor antagonists: Ranitidine (Zantac); Famnotidine (Pepeid); Cimetidinc (Tagamet); Nizatidinc (Axid).

H-ormone: Diethyistilbestrol;, 11rogestcronc; 17 hydroxy progcstcrone; Medi-oxyprogcsterone; Norgesircl; Norethynodrel; Estradiol, Mcgcstrol (Mcgace); Norcthindronc, 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).

Immunizing agent: Antirabies Serum; Antivenin (Latrodcctus 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 25 Vaccine Live; Meningococcal Polysaccharide Vaccine Group A; Meningococcal Polysacchaide 0:00.: 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: Dimnepranol Acedoben; Imiquimiod; Interferon Beta-ib; Lisofylline; Mycophenolate Mofetil; Prczatide Copper Acetate.

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

Immunostimulant: Loxoribine Teceleukin.

Immunosuppressant: Azathioprine; Azathioprine Sodium; Cyclosporine; Daltroban; Gusperimus Trihydrochioride; Sirolimus; Tacrolimus.

Impote nce therapy adjunct: Delequamine Hydrochloride.

Inhibitor: Acarbose; Atorvastatin Calcium; Benserazide Brocresine; Carbidopa; Clavulanate Potassium; Dazmegrcl; Docebenoace; Epoprostenol; Epoprostcnol Sodium; Epristcridc; Finastcridc; Flurbiprofcin Sodium; Furcgrclatc Sodium; Lufironil; Miglitol; Orlistnt; Pimagedine Hydrochloride; Pirmagrel; Ponairestat; Ridogrel; Sulbactam Benzathine Sulbactam Pivoxil Sulbactamn Sodium Suronacri ne Maleate; Tazobactam; Tazobactamn Sodium; Ticlopidine Hydrochloride; Tirilazad Mesylate; Toirestat; Velnacrine Maleate;- Zifrosilone; Zileuton.

2o Keratolytic: Alcioxa Aldioxa Benzoyl Peroxide; Dibenzothiophene; Etarotene; Isotretinoin; Motretinide; Picotrin Eholarninc; Rcsorcinol; Resorcinol Monoacctatc Salicylic Acid; Sumarotene; Tazarotene; Tetroqu inone; Tretinoin.

LHRH- agonist: Dcslorclin; Goserelin; 1-istrclin; Lutrclin Acetate; Nafarclin Acetatc.

Liver disorder treatiment: Malotilate.

Luteolysin: Fcnprostalene.

Memory adjuvant: Dirnoxami ne H-ydrochloride; Ribarninol.

Mentail performance enhancer: Aniracetamn.

48 Mood regulator: Fengabine.

Mucolytic: Acetylcysteine; Carbocysteine; Domiodol.

Mucosal Protective agents: Misoprostol (Cytotcc).

Mydriatic: Berefine.

Nasal decongestant: Nemazoline Hydrochloridc; Pseudoephedrine Pol istirex.

Neuroleptic: Duoperone Fumaratc; Risperidone.

Neuromuscular blocking agent: Atracurium Besylate; Cisatracurium Besylate; Doxacurium Chloride; Gallamine Triethiodide; Metocurine Iodide; Mivacurium Chloride; Pancuronium Bromide; Pipecuronium~ Bromide; Rocuronium Bromide; Succinyicholine Chloridc; Tubocurarine Chloride; Vecuroniumn Bromide.

Neuroprotectivc: Dizocilpine Maleate.

,20 NMDA antagonist: Sclfotel.

Non-hormonal sterol derivative: Prcgncnolonc Succinate.

Oxytocic: Carboprost; Carboprost Methyl; Carboprost Tromethamine; Dinoprost Dinoprost Trornctharninc Dinoprostone Ergonovine Maleate; Mcteneprost Methylergonovine Male~te; Oxytocin; Spartcinc Sulfate.

Plasminogen activator: Altcplasc; Urokinase.

Platelet activating factor antagonist: Lcxipafant.

Platelct aggregation inhibitor: Acadesine; Beraprost; Beraprost Sodium; Ciprostcnc Calcium; Ilazigrcl; Lifarizine. Oxagrelatc.

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

Potentiator: Pentostatin; Talopram Hydrochloride.

Progestin: Algestone Acetophienide; Amadinone Acetate; Anagestone Acetate; Chiormad inone Acetate; Cingestol; Clogestone Acetate; Clomegestone Acetate', Dcsogestrcl; Dimcthisterone; Dydrogesterone; Ethynerone; Ethynodiol, Diacetate-, Etonogestrel; Flurogestonc Acetate; Gestaclone; Gestodene; Gestonorone Caproatc; Gestrinonc; I-Ialoprogcsteronc; Hydroxyprogesterone Caproate; Levonorgestrel; Lynestrenol; Medrogestone; Medroxyprogesterone Acetate; Methynodiol Diacetate; 1o Norethindrone; Norethindrone Acetate; Norethynodrel; Norgestimate; Norgestomet; Norgestrel; Oxogestone Phenpropionate; Progesterone; Quingestanol Acetate; Quingestrone; Tigestol.

Prostaglandin: Cloprostcnol Sodium; Fluprostenol Sodium; Gcrncprost; Prostalene; Suiprostone.

Prostate growth inhibitor: Pentonionc.

Prothyrotropin: Protirelin.

*Psyc hotropic: Minaprine.

Pulmonary surface: fBeractant; Colfosceril Palmitate.

Radioactivc agent: Fibrinogen 1 125 Fludcoxyglucosc F 18 ;Fluorodopa F 18 ;Insulin 1 125; Insulin 1 13 1; lobenguane 1 123;- lodipamide Sodium 1131 lodoantipyrinc 1 131 Iodocholestcrol 1 13 1; lodohippuratc Sodium 1 123 lodohippuratc Sodium 1 125 lodohippurate Sodium I1 1; *lodopyracet 1125 lodopyracct 1 131 lofelaiic H-ydrochloride 1 123 lomicthin 1 125 lomnethin 1 131 ;lothalamate Sodium 1 125 lothalarnatc Sodium 1131 lotyrosine 1 13 1; Liothyronlinc 1 125; Liothyroinet 1 131; Mcrisoprol Aetate H-g 197; Merisoprol Acetate Fig 203; Mcrisoprol l-Ig 197; Scenoincthioninc Se 75 Technectium Tc 99m Antimony Trisullidc Colloid, rcchriciium Tc 99mi Bicisatc Tcchinctiumn Tc 99m Disofenin Technletiumn Tc 99rn Etidronate Technetium Tc 99mn Lixametazinic T echnectium, rc 9911 F"Urifosmnin Techinetium Tc 99ni GILuccptate Technietium Te 99m Lidofenin Technietium Tc 99m Mebrofeniri Tcchnictium Tc 99nm Medronate Technetium 50 Tc 99m Medronate Disodium; Tehnetium Tc 99m Mertiatide Technetium To 99m Oxidronate; Technetiumn Tc 99m Pentetate; Tcchnetium Tc 99m Pentetate Calcium Trisodium; Technetiumn Tc 99 m Sestamibi Technetium Tc 99m Siboroxime Technetiumn Tc, 99m Succimer Tcchnetjum Tc 99m Sulfur Colloid Technetium Tc 99m Teboroxirne Technetium Tc 99m Tetrofosmin Technetium Tc 99m Tiatidc; Thyroxine 1 125; Thyroxine 1 13 1; Tolpovidone 1 131 Triolein 1 125; Triolein 1 13 1.

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

I0 Relaxant: Adiphenine Hydrochloride; Alcuronium Chloride; Amiriophylline; Azumnolene Sodium; Baclofen; Benzoctamine Hydrochloride; Carisoprodol; Chiorphenesin Carbamate; Chlorzoxazonc; Cinflumnide; Cinnamedrine; Clodanolene; Cyclobenzaprine Hydrochloride; Dantrolene; Dantrolene Sodium; Fenalarnide; Fenyripol H-ydrochloride; Fetoxylate Hydrochloride; Flavoxate Hydrochloride; Fletazeparn; Flumetramide; Flurazeparn Hydrochloride; Hexafluoreniumn Bromide; Isomylamine 1-ydrochloridc; Lorbamnatc; Mebeverine H-ydrochloride; Mcsupri ne H-ydrochloride Metaxalone; Methocarbarnol; Methixene Hydrochloride; Nafomnine Malate; Nelezaprine Maleate; Papaverine 1-lydeochioride; Pipoxolan H-ydrochloride; Quinctolatc; Ritodrinc; Ritodrine Hydrochloride; Rolodine; Theophylline Sodium Glycinate; Thiphenarnil Hydrochloride; Xilobam.

Repartitioning agent: Cimaterol.

Scabicide: AmItraz; Crotamiton.

Sclerosing agent: Ethanolamnine Oleate; Morrhuate Sodium; Tribenoside.

Sedative: Propiomazine.

Sedative-hypnotic: Allobarbital; Alonimid; Aiprazolam-; Arnobarbital Sodium; Bentazepam; l3rotiy7olan; BL~tabarbital; Butabarbital Sodium; Butalbital; Capuridc; Carbocloral; Chloral Betaine; Chloral Hlydrate; Chilordiazepoxide Hlydrochloride; Clopcridonc Ilydrochloride; Clorethate; Cyprazepam, Dexclamol H-ydrochloride; Diazepam; Dicioraiphenazonec; E~stazolam; Ethchlorvyno I; -51 Etomidate; Fenobam; Flunitrazepam; Fosazeparn; G lutethimide; 1-alazepam; Lormetazeparn; Mecloqualone; Meprobamate; Methaqualone; Midaflur; Paraldehlyde; Pentobarbital; Pentobarbital Sodium; Perlapine; Prazepam; Quazepam; Rcclazepani; Roletamide; Secobarbital; Secobarbital Sodium; Suproclone; Thalidomide; Tracazolate; Trepipam Maleate; Triazolam; Tricetamide; Triclofos Sodium; Trimetozine; Uldazepamn; Zaleplon; Zolazepam Hydrochloride;, Zolpidem Tartratc.

Selective adenosine Al antagonist: Apaxi fylline.

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

Serotonin inhibitor: Cinanserin Hydrochloride; Fenclonine; Fonazine Mcsylate; Xylamidirie Tosy latc.

Serotoni n receptor antagonist: Tropanserin Hydrochloride.

Steroid: Dexarnethasone Acefuratc; Mometasone Furoate.

Stimulant: Amifonelic. Acid; Amphetamine Sulfatc; Ampyzinc Sulfate; Arbutamine H-ydrochloride; 20 Azabon; Caffeine; Ceruictide; Ccrulitidc Diethylainine; Cisapride; Dazopride Fumarate; Dextroamplictarnine; Dextroamphiclaminc Sulfatec; Difl uainc H-ydrochloride; Dimceflime H-ydrochloride; Doxaprarn H-ydrochloride; Etryptamine Acctate; Ethainivan; Fcnethylline I -ydrochloridc; Flubani late: Hydrochloride; I'lurothly IHIIislanlinc IPhospliatc; I odriline H-ydrochloride; Mefexarnide; Methamnphetamnine Hydrochloride; Mcthylphcnidate Hydrochloride; Pernoline-; Pyrovalerone HyIdrochloride; Xamiotcrol; Xarnoterol Fumiaratc.

Suppircssant: AnmftiZOlc; Colchicine; Tamioklonc.

Symplonatic 111uliple sclerosis: Famnpridine.

Synergist: lProadi fcr Hlydrochloride.

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

Thyroid inhibitor: Methimazole; Propylthiouracil.

Thyromi metic: Thyromedan Hydrochloride.

Tranquilizer: Bromazepamn; Buspirone Hydrochloride; Cliordiazepoxide; Clazolani; Clobazamn; C lorazepate Dipotassium; Clorazepate Monopotassium; -Demoxepam; Dexrnedetom idine; Enciprazine Hydrochloride; Gepirone Hydrochloride; Hydroxyphenamate; Hydroxyzine to H-ydrochloride; Hydroxyzine Pamoate; Ketazolam;, Lorazepam; Lorzafone; Loxapine, Loxapine Succinate; Mcdazepam Hydrochloride; Nabilone; Nisobamate Oxazeparn; Pentabamate; Pireriperone; Ripazepam; Rolipram; Sulazepamn; Tacianiine H-ydrochloride; Temazepam; Triflubazam; Tybarnate; Valnoctamide.

Amyotrophic lateral sclerosis agents: Riluzole.

Cerebral isehemia, agents: Dextrorphan Hydrochloride.

Paget's disease agents: Tiludronate Disodiuni.

Unstable angina agents: Tirofiban H-ydrochloride.

Uricosuric: Benzbromarone; Irtemazolc; Probeneid; Sulfinpyrazone.

Vasoconstrictor Angiotensin Amide; Felypressin; Mcthysergide; Methyscrgide Maleate.

Vasod ilator: Aiprostadi I; Azaclorzine H-ydrochloride; Bamethan Sulfate; Bepridil H-ydrochloride; Buterizinc; Cetiedil Citrate; Chromonar H-ydrochloride; Clonitrate; Diltiazern Hydrochloride; Dipyridamoic; Droprenilamnine; Erythrityl Tetranitrate;, Fclodipinc;, Flunarizine Hydrochloride; Fostedi 1; I-lexobcndinc; I nositol N jacinate; I proxarnine Hlydrochloride, Isosorbide Dinitratc; I sosorbidc Mononitrate, I soxsuprinc I ydrochlloride; Lidollazinc; Melenid i Mefcnidil Fumarate; Mibcfradil Dihydrocliloridc; Mioflazine Hydrochloride; Mixidine; Nafronvi Oxalate; Nicardipine 53 Hydrochloride; Nicergolitic; Nicorandil; Nicotinyl Alcohol; Nifedipine;, Nimodipine; Nisoldipine; Oxfenicine; Oxprenolol Hydrochloride; Pentacrythritol Tetranitrate; Pentoxifyl line; Pentrinitrol; Perhexiline Maleate; Pindolol; Pirsidomine; Prenylarnine; Propatyl Nitrate; Suloctidil; Terodiline Hydrochloride; Tipropidil H-ydrochloride; Tolazoline Hydrochloride;, Xanthinol Niacinate.

Vulnerary: Allantoin.

Wound healing agent: Ersofermin.

Xanthine oxidase inhibitor: Allopurinol; Oxypurinol Other pharmaceutical agents include: I -decpyrrolidinone; I -dodecpyrrolidinone; 16-alpha fluoroestradiol; I 6-epiestriol; 1 6alpha-gitoxin; I 7alpha estradiol; I 7beta. estradiol; 1 alphahydroxyvitamnin D2; 2'-nor-cGMP; 20-epi-I,25 dihydroxyvitarnin DI, 22-oxacalcitriol; 2CVV; 3isobutyl GABA; 6-FUDCA; 7-methoxytacrine; abamcctin; abanoqui 1; abecarnil; abiraterone; acadcsi ne; acamprosate; acarbosc; aceclo Cenac; acemnannan; acetoniepregenol; acetyl-L-carnitine; acetylcysteine, acetylmethadol; acifran; acipimox; acitemnate; acitretin; aclarubicin; aclatoniuni; napadisi latc; aconiazide; acrivastinet; adafenoxate; adapalene; adatanserin; adecypenol; adefovi r dipivoxil; adelniidrol; ademnetionine; adinazolam; adiposin; idozeiesin; adrafinil; alacepril; aladapcin; alaptide; albendazole; albolabrin; aldecalmycin; aldeslcukin; alendronic acid; alentemol; 20 alfacalcidol; alfuzosin; alglucerase; aliiistine; alosetron; alpha idosonc; alprostadil. altretamnine; **':altrornycin B; amnbamustine; arnelornetasone; aiesergide; amezinium meti Isulfate; amfebutamone; amidox; amifloxacin; amifostine; amniodaronc; arnisulpride; amlexanox; amilodipine; amlodipine; ampiroxicam; amrinonc; amrubicin; amnsacrine; amylin; amythiamicin; anagrelide; anakinra; ananain; anaritide; qnastrozoic; andrographiolidc; anordrin; apadolinc; apofant; apaxify~firc; aphidicolin glycinate; apraclonidine; aprosulate sodium; aptiganel; apurinic acid; aranidipinle; arbckacin; arbidol; arbutamine; ardeparin sodium; arecatannin 131; argatroban; aripiprazol; arotinolol; asirnadolinc; aspalatonc; asperFuran; aspoxicillin; ustemnizolc; asulacrine; atarnestane; atenolol, atcvirdine:, atosiban; atovaquonc; atpcnin 1B; atrirnUstinc; atrinositol; aurcobasidin A; azadirachtine; azasetron; azatyrosine; azelaic acid; azelastine; azelnidipine; azimilide; azithrornycin; azosemide; oztronam; baccatin 111, bacosidc A; bacosidc B; bactobolaminc; balazipone; baihirnycin;. balofloxacin; balsalazidc; bambuterol; baohiuoside 1; barnidipine; basifungin; batebulast; batirnastat, beauvericin; becaplermiin; beeliconazol C; befloxatone:, belfosdil; -54bellenarnine; benflumetol; benidipine; benzisoxazole; benzodhlorins; benzoidazoxan; benzoylstaurosporine; bcnztropine; bcpridi I; beractant; beraprost; berlafenone; bertosami I; besipirdine; beta-alethine; betaclamycin B; betamnipron; betaxolol; betulinic acid; bevantolol; bicalutamide; bifemnelane; bimakalim; bimithil; binospirone; bioxalomycin alpha2; biriperone; bisbenzimidazole A; bis-benzimidazolc B; bisantrene; bisaramil; bisaziridinyispermine; bisnafide; bisoprolol; bistraniide D; bistramide K; bistratcec A; boldine; bopindolol; brefeldin; breflate; brimonidinc; bromfenac; bromperidol; bropirimine; bucindolol; budesonide; budipine; budotitane; bunaprolast; bunazosin; butenafine; buthionine sul foximine; butixocort propionate; cadexomner iodine; calanolide A; calcipotriol; caiphostin C; camonagrel; candesartan; candesartan cilexetil; candoxatril; candoxatrilat; capccitabine; capromab; capsaicin; captopril; carbazomycin C; carbetocin; carbovir; carboxaniide-amino-triazole, carboxyamidotriazole; carboxymethyl ated beta- I ,3-gl ucan; carperitide; carteolol; carurnonam; carvedilol; carvotroline; carzelesin;, castanospermnine; cebaracetamn; cecropin B; cefcapene pivoxil; cefdaloxime pentexil tosilate; cefdinir; cefditoren pivoxil; cefepimne; cefetamct; ccfetamct pivoxil; cefixirne; cefluprenam; cefmetazole; cefminox; cefodizime; cefoselis; ccfotctan; cefotiam; cefotiam hexetil; cefozopran; cefpimnizole; cefpiramnide; cefpirome; ccfpodoxirne proxctji; cefprozil; cefsulodin; cefterarn; ceftibuten; ceftriaxonc; cefuroxime axetil; cclastroL; cclikalimi; celiprolol; cepacidine A; cericlaminc; ccrivastatin; *ccro,.napril; certoparin sodium; cctiedil; cetirizine; chioroorienticin A; chioroorienticin B; chioroquinoxaline sulfonamide; cibenzoi me; cicaprost; ciclesonidc; cicletanine; cicloprolol; 20 cidofovir; cilansetron; cilazapril; cilnidipine; cilobradine; cilostazol;. cimetropium bromide; cinilapridle; cinolazcparn; ciotcroncl; ciprolibratc; ciprofloxacin; ciprosicnc; cis-porphyrin; cisapridc; cisatracurium be'silate; cistinexinc; citalopram;, citicoline; citreamicin alpha; cladribine; clarithrornycin; clausenarnide; clebopride; clinafloxacin; clobazarn; clobetasone butyrate; clodronic acid; clomethiazole; clopidogrel; clotrimazole; colestimide; colfosceril palmitate; collismycin A; 25 collismycin B; combrctastatin AM; complestatin; conagenin; contignasterol; contortrostalin; cosalane; costatolide; cotinine; courncrrnycin Al1; cucumnariosid; curacin A; curdlan sulfate; curiosin; V cyclazosin; cyclic I-IPMPC; cyclobcnzaprinc; cyclobUt A, cyclobut G; cyclocapron; cyclopilam; cyclosin; cyclothialidine; cyciothiiazomycin; cypemycin; cyproterone; cytarabine ocfosfatc; cytoclialasin B; daclixim-ab; dactiniicin; daidzcin; daidzin; dal ropristin; clalteparin sodium; danaparoid; daphnodorin dapiprazole; dapitant; darifcnacin; darlucin A; darsidomine; ddUTP; decitabine; dcfcripronc; delkacort; dehydrodidcrnnin dchydrocpiandrosterone; delapril; deicquamiiuc; dclaprazinc; dchmopinol; deiphinidin; deoxypyridinlolinc; dcprodonc; depsidornycin; 55 deramciclane; dermatan sulfate; desflurane; desirud in; deslorelin; desmopressin; desogestrel; desoxoamiodarone; detajmium bitarirate; dexifosfamide; dexketoprofen; dexioxigi umide; dexmcdetomidine; dexpemedolac; dexrazoxane; dexsotalol; dextrin 2-sulphate; dexverapami I; dezinamide; dezocine; diaziquone; diclofenac digolil; diclofenac potassium; dicranin; didemnin B; didox; dienogest;, diethiyihornosperMire; diethylniorsperminc; dihydrexidi ne; d i dimethyl prostaglandi n Al; dimethylhomospermifle dimiracetam; dioxamycin; diphencyprone; diphenyl spiromustine; diprafenone; dipropylnorspermine; dirithroniycin; discodermolidc; disulfirarn; ditekiren; docarpamine; docosanol, dofetilide; dolasetron; domitroban; dopexamine; dorzolamide; dosmal fate; dotarizine; doxacurium chloride; doxazosin; doxifluridine; doxofylline; draculin; draflazine; droloxifene; dronabinol; drosperidone; drotaverine acephyl linate; droxicam; ebiratide; ebrotidine; ebselen; ecabapidc; ecabet; ecadotril; ecdisteron; echicetin; echistatin; ecomustine; ecteinascidin 722; ecteinascidin 729; ecteinascidin 743; edaravone; edelfosine; edobacomab; edrecolomab; efegatran; eflornithine; efonidipine; egualen; elcatonin; eletriptan; elgodipine; eliprodil; eltenac; emakalim; emedastine; emiglitate; emitefur; emoctakin; enadoline hydrochloride; enalapril; cnazadrcm; englitazone; cnlimioniab; enoxacin;. cnoxaparin sodium; enoximone; entacaponc; enterostatin; epoprostenol; epoxymexrenone; epristeride; eprosartan; eptastigminc; erdosteine; ersentilide; ersofermin; erythritol; esuprone; etanidazole; ctanterol; ethacizin; ethinylestradiol; etizolam; etodolac; etoposide phosphatc; etrabamine; everninoniicin; cxarnorel in; cxemcstailc; fadrozole; facricfungin; farneiclovir; fampridinc; faiflofaronc; faropenem; fasidotri I; fasud ii; fazarabine; fedotozine; felbamate; fenofi bratc; fenoldoparn; fenretinide; fcnspiridc; f'enticonazole; flepradinol; ferpifosate sodium; fcrristcne; ferrixan; ferumoxsil;.

fexofenadine; flavopiridol; ficcainide; flcrobuterol; fleroxacin; tIcsinoxan; flezelastine; flobufen; flomoxef; florfenicol; florifenine; flosatidil; fluasteronc; fluconazolc; fludarabine; flumazenil; tiumecinol; flumcquinc; flunarizine; fluocalcitriol; fluorodaunorunicin hydrochloride; fluoxetine, fluoxetine, fluparoxan; flupirtine; flurbiprofen axetil; flurithromycin; fluticasone propionate; :0 flutrirnazoic; fluvastatin; fluvoxamine; forasartan; forfeni mex; formestanc; formoterol; formotcrol, 0 fosfornycin; trometamol; fosinopril; fosphicnyto in; fostriccin; fotemustinc; gabapentini; gadobenic acid; gadobutrol; gadodiamide; gadodiamlide-EOB3-DTPA; gadoliniumi tcxaphyrin; gadoteric acid; gadoteridol; gadovcrsctarnidc; galantamine; galdansetron; galloparnil; galocitabine; gamiolenic acid; ganirclix; gepironc; gestrinonc; girisoparn; glaspimod; glaucocalyxin A; glutapyrone; glycopine; glycopril; granisetron; grepa floxacini; hal ichondrin B; hialofantrine; halomon; lialopredonc; hatomamici n; hatomarubigin A; hatornarubi gin B; hatomarubigin C; -56liatomarubigin D, ibogainc; ibopamnine; ibudilast; illimaquinone;, ilmofosine; ilomastat; iloperidonc; iloprost; imidapril; imidazenil;, indinavir; indolidan; indornetacin farnesil; indometacin; tropine ester; indoramnin; inocotcronc; inogatran; inoliniomnab; interfecron alfa; interferon alfa-2u; interferon 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 ailha; interleukin- 1 beta; interleukin- 10; interleukin- I I interleukin- 12; interleukin- 12; interlcukin- 15; interleukin-2; intcrleukin-3; interleukin-4; interleuki n-5; interleukin-7; interieukin-8; iobenguane; iobitridol; iodoamniloride; iododoxorubicin; iofratol; iomeprol; iopentol; lopromide; iopyrol; jotriside; ioversol; ioxilan; ipazilide; IpdR; ipenoxazone; ipidacrine; ipomeanol, 4-; 0o ipriflavone; ipsapirone; irbesartan; irinotecan; iloxacin; irsogladine; irtemnazole; isaisteine; isbogrel; isepamicin; isobengazole; isofioxythepin; isohomohalicondri n B; isopropyl unoprostone; isradipine; itarneline; itasetron; itopride; itraconazole; ketoprofen. ketoprofen, ketorolac; lacidipine; lactitol; lactivicin; laennec; lafutidine; Iamnellarin-N triacetate; lamnifiban; lamivudine; lamotrigine; lanoconazol e; lanperisone; lanreotide; lansoprazoic; latanoprost; lateritin; laurocapram; lazabemide; lemefloxacin;, lemildipine; leminoprazoic; lenercept; lenograstini; lentinan sulfate; leptin; leptoistatin; Iecanidipinc; lerisetron; lesopitron; letrazuril; letrozole; leucomyzin; leuprorelin; levcromakalim; levetiracetam; levobetaxolol; levobunolol; Ievobupivacaine; levocabastine; levocarnitine; levodropropizine; levofloxacin, levomoprolol; lcvoniorgcstrel; levormeloxifene; levosimendan; levosulpiride; linotroban; linsidomine; lintitript; lintopride; liothyronine sodium; 20 lirexapride; lisinopri; lobaplatin; lobucavir; lodoxamlide; lombricinc: lomefloxacin; lomnerizine; lometrexol; lonazolac; lonidarnine; loracarbef; loratadine; lorgiurnide; lornoxicam; losartan; losigarnone; losoxantronc; loteprednol; loviridc; loxoribine; lubeluzole; Itirtotccan; luteinizing hormone; lutetium; luzindole; lydicamycin; lysofyrline; lysostaphlin; magainin 2 amide; magnolol; mallotochromcnc; mnallotojaponin; malotilatc; mnangafodipir; manidipinc; maniwarnycin A; 25 mannostatin A; inanumycin E; manumycin F; rnapinastine, marimastat; Martek 8708; Maitek 92211; masoprocol; maspin; massetolide; meterelin; mcthoxatonc; methylhistamine, R-alpha; methyli nosi ne mono phosphate; ruethy Ipredni solone aceponate; methyl prednisol one suleptanate; metipamide; metoclopramide; metoprolol, metrifonate; mibefradil; mnichellarnine microcolin A; midodrine; mifepristone; miglo101 iiacemide; milaiel inc', mildronatc; ilinacipran; rni Iinone; nilitcfosinc; rninaprine; rniokamycin; mipragosidc; nmirfentanil; mirimogti in; mirtazapine; misoprostol;, mitoguazone;- mitolactol; mitonafide; mitoxantrone; mivacurium chloride; rnivazerol; mnixanpril;, mizolastinc; inizoribinc; moclobernide; modafinil; mioexipri I; mofarotene; mrofezolac; 57 moigramnostini; mometasone; miontirelin; mopidamol; moracizine; mosapramnine; mosapride; moti lide; moxirapririe; mioxonidine; nadifloxacin; nadroparin calcium; nafadotride; nafamostat; nafarel in; naftopidi I; naglivan; nagrestip; nalmefene; naphterpin; napsagatran; naratriptan; nartograstim; nasaruplase; nateplase; niperotidine; niravoline; nisamycin; nisin; nisoidipine; nitazoxanide; nitecapone; nitrendipine; nitrendipine, nitrofurantoin monohydrate; nitrullyn; nizatidine; ofloxacin; okicenone;, olanzapine; olopatadine; olprinonc; olsalazine; omeprazole; onapri stone; ondansetron; ondansetron, ontazolast; oraci n; otenzepad; oxal iplatin; oxami sole; oxandrolone; oxaprozin; oxaunornycin; oxcarbazepine; oxiconazole; oxiracetam; oxodipine; ozagrel; palauaminc; palinavir; palmitoylrhizoxiin; parnaqueside; pamicogrcl; pamidronic acid; panamesine; i o panaxytriol; panipenemn; panipenum; pannorin; panoniifene; pantethine; pantoprazole; parabactin; pamraparin sodim; paroxetine; parthenol ide; pazelliptine; pazufloxacin; pefloxacin; pegaspargase; peldesine; pemedolac; pemirolast; penciclovir; pentafuside; pentarnidine; pentamorphone; pentigetide; pentosan; pentostatin; pentrozole; perfiubron; perfos famide; pergolide; perindopri hit; perospirone; phenaridine; phenazinornycin; phecnserine; phensuccinal; phentolarnine mesi late; plienylacctate; phenylalanyl ketoconazoic; picenadol; picibanil; picroliv; picumneterol; pidotimod; pi locarpine hydrochloride; pi Isicainide; pimagedine; pimilprost; pimobendan; pi nacidi I; pinocebri n; pioglitazone; pipecuronium bromide; pirarubicin; piretanide; pirfenidone; piritrexim; pirlindole; pirmggrel; pirmenol; pirodavir; pirodoniast; piroxicamn cinnamate. propagermanium; propentofylline; propionylcarnitine, propirarn; propirarn paracclaamol; propivcrine; propyl bis-acridonc; prostaglandin J2; prostratin; protegrin; protosufloxacin; pruilifloxacin; pyrazoloacridine; quazepail; qluetiapinc; qui flapon; quinagolidc; quinapri I; quinfamidc; qtinupristin; raloxifenc; raltitrexed; ramatroban; ramipril; ramnosetron; ranelic acid; ranitidine bismuth citrate; raniolazine; rccainamn; regavirurnab; relaxin; repirinast; resinferatoxin; reticulon; rcviparin sodiuim; rcvizinonc; ricasetron, ridogrel; rifabutin; rifapcntine; rifoximnin; rilopirox; riluzole; rimantadine; rimexolone; rimoprogin; 2 roiie;rpsrtn isdoi ai;rspcnzcpinc; rispcridonc; ritanscrin; ritipenemn; ritipcivim acoxil; ritolukast; ritonavir; rizatriptan benzoate; rohittukine; rokitamycin; ropinirole; ropivacaine; roquinimcx; roxatidinc; roxindoke; roxithroinycin; rubiginonc B I; ruboxyl; rufloxacin; rupatidine; ruzadolane; safingol; safironil; saintopin; salbutamnol, salmetcrol; salmeterol, R-salnacedin; sanicridinc; sampatri hit; san fetrincm;, saprisartan; s-,proptcn; saquinavir; SarCNU; sarcophytol A sargraniostim; sarpogrelate; saruplase; saterinone; sati grel; satumomab pendetidc; sciegiline; seleniumi thiosemnicarbazone; srnatil idc; semduramicin; scmnotiadil; semustine; scrmorclin; sertaconazoic; scrtindolc; scrtralinc; sctipti linc; sevirurnab; sevotflurane; sezolarnide; si lipide; 58 silteplase; simendan; simvastatin; sinitrodil; sinnabidol; sipatrigine; sirolimus; sizofiran; sornatomedin B; somatomedin C; somatrem; somatropin; sonermin; sotalol; staurosporine; stavudine; stepronin; stipiamide; stiripentol; stobadine; succibun; sucralfate, sulfasalazine; sulfinosine; sulfoxamine; sulopenem; sultarnicillin; sultopride; sulukast; sumatriptan; symakalim; tandospirone; tapgcn; taprostene; tasosartan; tazanolast, tazarotene; teicoplanin; telenzepine; tellurapyrylium; tclmesteine; telmisartan; temocapril; temoporfin; temozolomide; tenidap; teniposide; tenosal; tenoxicam; tepirindole; tepoxal in; terazosin; terbinafine; terfenadine; terflavoxate; terguride; terlakiren; terlipressiri; terod ii me; tertatolol; testosterone buciclate; tctrachlorodecaoxide; tetrazomine; thaliblastine; thalidom-ide; thiocoraline; thiofedrine: thiomarinol; to thioperarnide; thyroid stimulating hormone; tiagabine; tiancptine; tiapafant; tibolone; ticlopidine; tienoxolol; tilisolol; tilnoprofen arbamel; tiludronic acid; tinzaparin sodium; tiotropium bromide; tipredane; tiqueside; tirandalydigin; tirapazamine; tirilazad; tirofiban; tiropramide; topsentin; torasemide; toremnifene;- tosufloxacin; trafermin; trandolapril; traxanox; tretinoin; tretinoin tocoferi I; triacetyluridine; tricaprilin; trichohyalin; trichosainhin, alpha; triciribine; trientine; triflavin; trimegestone; triptorel in; troglitazone; trombod ipine; tropisetron; trospectornyci n; trovafloxacin; trovirdine; tucaresol; tulobuterol; tylogenin; urapidil; uridinc triphosphatc; valaciclovir; vaiproate magnesium; valproate semisodium; valsartan; vamnicamide; vanadeine; vaninolol; vapreotide; variolin B; velaresol;- vcnlafaxine; veramine; vcrapaniil, vcrdins; veroxan; vcrteporfin; yesnarinone; vexibinol; vigabatrin; vinburnine citratc; vinburnine resinate; vinconate; vinorelbine; vinpoceti ne; vinpocetinc citratc; vintopcrol; vinxaltinc; voriconazolc; vorozoic; voxergolide; xcmiloliban; xinmopro1len; yangamnbin; zabicipril; zacopride; zacopriclc, zafirlukast: zalcitabine; zaleplon; zalospirone; zaltoprofen; zanamivir; zankiren; zanoteronc; zatebradine; zatosetron; zenarestat; zeniplatin; zifrosilonc; zilascorb; zileuton; zinostatin stimalamer; ziprasidone; zolcdronic acid; zolmitriptan; zolpidcm; zonisamnide; zopiclone; zopiclone, zopolrestat; zotepine.

25 'rhc invention also emnbraccs novcl compositions of mautcr that arc covalent conjugatc of DI-A and pharmaceutical agents that are noncentral nervous system active agents. Nonccntral nervous system active agents have no function or use within thle ccntral nervous system. Thcir only usc is outside of the ccntral nervous systcm. Such agents include all drugs within certain of thle Foregoing categories and only some drugs withiin othecr of tile foregoing catagorics. For example, thle entire catagory ol'blood glucosc regulators have nio use or function within thle central nerIvouIs system. In contrast, certain anti-cancer agents are uscful in thc ccntral nervous system whereas others are not. For example, central nervous systcn~ cancers arc 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 catagories 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; antibypotensive; 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; .i 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; ectoparasiticide; enzyme inhibitor; estrogen; fibrinolytic; free oxygen radical scavenger; glucocorticoid; gonad-stimulating principle; S hair growth stimulant; hemostatic; hormone; hypocholesterolemic; hypoglycemic; hypolipidemic; hypotensive; immunizing agent; immunomodulator; immunoregulator; immunostimulant; immunosuppressant; impotence therapy adjunct; inhibitor; keratolytic; L-HRH agonist; liver disorder 25 treatment; lutcolysin; mucolytic; mydriatic; nasal decongestant; neuromuscular blocking agent; 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; scabicidc; 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.

10 9 19 S8 7 8 51 1 6 3 13 17 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.

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 effective amounts. A therapeutically effective amount will be determined by the parameters S 25 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 30 therapeutic ingredients. When used in medicine the salts should be phannaceutically 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 WIV); 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% chlorobutanol parabens (0.01-0.25% W/V) and thimerosal (0.004-0.02% W/V).

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 "pharmaceutically-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 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 invdntion. 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 injcctablcs. Carrier formulations suitable for oral, subcutaneous, intravenous, intramuscular. etc. can be found in Rcmington'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 i 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 achiee 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 parentcral routes. The term "parenteral" includes subcutaneous, intravenous, intramuscular, or infusion. Intravenous routes arc 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 ingredient for at least 30 days, and preferably 60 days. Long-term sustained release implants are well known to those of ordinary skill in Ihe 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 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.

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.OPERk\MIR\SPEC 3l142 S-9713.dtoc.21 1 -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.

eo

Claims (22)

1. A method for targeting a pharmaceutical agent to a noncentral nervous system tissue to treat a nonccntral 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.

2. The method of claim 1, wherein the cis-docosahcxacnoic acid is conjugated directly to the pharmaceutical agent.

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.

4. The method of claim 2, wherein the tissue is gastrointestinal tissue and wherein the subject 15 has a condition calling for treatment of gastrointestinal tissue with the pharmaceutical agent. S*

5. The method of claim 2, wherein the tissue is ovarian tissue and wherein the subject has a d condition calling for treatment of ovarian tissue with the pharmaceutical agent. 20

6. The method of claim 2, whcrcin'the pharmaceutical agent is a noncentral nervous system active agent that is nonactive within the central nervous system. .f

7. The method of claim 2, wherein the drug is an anti-cancer agent. 25

8. The method of claim 7, wherein the drug is Taxol.

9. The method of claim 8, wherein the conjugate is o Aco OH Ph NH 0 Ph 0 H 0 OAc 65

1 0. Thle method of claim 8, wherein the conjugate is 0 ~AcO 0 Ph NH 0 0.* Ph 0 H= OH HOO0 OAC 0 Ph ii.

The method of claim 7, wherein the drug is Taxotere.

12. The method of claimn 11, wherein the conjugate is HO 0OH 0 NHO0 h iH 0 6HO o OAc Ph

.13. The method of claim 11, wherein thle conjugate is 00 0~H 0 HO: 0 OAc 0 1 Ph -66-

14. The method of claim 11, wherein the conjugate is O o XO NH 0 OH HO OAc oAOAc 0 Ph The method of claim 11, wherein the conjugate is 0 HO 0 0 O;"NH 0 H Ph 0 H H OH HO O H OAc

15 O Ph

16. The method of claim 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, wherein the condition is breast cancer.

17. The method of claim 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, wherein the condition is colon cancer. S

18. The method of claim 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, wherein the condition is ovarian cancer. 25

19. A pharmaceutical preparation comprising: a covalent conjugate of cis-docosahexaenoic acid and a noncentral nervous system active agent, and a pharmaceutically acceptable carrier.

20. The pharmaceutical preparation of claim 19, wherein the cis-docosahcxacnoic acid is conjugated directly to the active agent. P:<OPER\MKRSPECI\31425-97-div.doc- 17/01/01 -67-

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.

22. 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 17th day of January, 2001 Protarga, Inc. 15 By DAVIES COLLISON CAVE Patent Attorneys for the Applicant oo*