CA2255614C - Dha-pharmaceutical agent conjugates - Google Patents
Dha-pharmaceutical agent conjugates Download PDFInfo
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- CA2255614C CA2255614C CA002255614A CA2255614A CA2255614C CA 2255614 C CA2255614 C CA 2255614C CA 002255614 A CA002255614 A CA 002255614A CA 2255614 A CA2255614 A CA 2255614A CA 2255614 C CA2255614 C CA 2255614C
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- hydrochloride
- tissue
- sodium
- taxane
- conjugate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention provides conjugates of cis-docosahexaenoic acid and pharmaceutical agents useful in treating noncentral nervous system conditions. Methods for selectively targeting pharmaceutical agents to desired tissues are provided.
Description
DHA-PHARMACEUTICAL AGENT CONJUGATES
I3ackground of the Invcntion 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 the 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 TaxolO.
TaxolO (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 hynerstabilization of microtuhulcs, thereby preventing the disassembly of inicrotubules necessary for completion of cell division. It also has been reported that Taxol induces -5 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 lias been discovered to be an analog of numerous closely 2o 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 lias tissue specificitv, thereby reducing side-effects on normal (dividing) cells. Taxol analogs witli tissue specificity tlierefore are desired. Anotlier drawback of 25 Taxol is its extreme insolubility. Taxol can be administered effectively in a solvent including cremophor, whicii combination can provoke severe hypersensitive immune responses. As a re'sult of these drawbacks, and also as a result of the potential for modifying Taxol at numerous sites as demonstrated by otlier naturally-occurring taxancs with anticancer activity, a search for more selective taxancs was iaLuiched.
30 To date, more than 200 taxanes have been synthesized (or isolated) and tested in vilro or in vivo 1or anticancer activity. The rcsults, however, llave been so disappointing that the National Cancer institute (NCI) generally no longer is interested in testing Taxol analogs. In general with Taxol analogs, the solubilitv problcnis reniain, and/or potency is sliarply 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:
Ri o AcO o OH
P' N H O B C
===H
Ph 3. :2. O F( Do OH HO OAc PhCO2 Taxanes have the basic three ring structure (A, B and C), substituted or unsubstituted.
Taxol's carbons are numbered conventionally as follows:
1o 9 19 1 11 ~ a 6 ~ 16 3C
S
Based upon the taxanes testcd 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 seiectivity. 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 analol;.
Some information about activity'has emerged. Numerous substitutions have been made at C7, C9, C10, C19, R, and combinations tliereof wliile retaining significant, but usually reduced, activity. Substitutions at C2, C4 and 2'Ol-I, however, are l;enerally not tolerated. Tliese conclusions are oniy generaiities, for example, because some substitutions at C9-C 10 (cyclic derivatives) are not toleratcd and some substitutions at C2 (meta substitutions on the phenyl) are tolerated. Likewise, the C13 side chain and, in particular, the 2'OH are required, although the minimum structtlral requiremcnts of the side chain have not been determined for therapeutic efficacy.
Attempts to improve Taxol's solubility have not resulted in successful clinical products. One approach lias been to manulacturc prodrugs of 'l'axol, wliich prodrugs undergo in vivo transformation into Taxol and some other product. Attempts were made to esterify the C7 hydroxy and 2' liydroxy groups, with the liope that the bond would be stable in solution (to permit preferred administration modes -i.v. over at least 24 hours) but would cleave readily in vivo. The groups tested wcre all hvcirophilic and included amines, sliort 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 whicli groups could be substituted on Taxol to yield a therapeutically useful product, although it was suggested that the 2' OH derivatives may cleave more easily than the C7 OH derivatives.
Several other factors add to the problem of predicting which Taxol analogs will be effective.
Multiple nlechanisms 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 1o bioavailability. For example, Taxol affects nlicrotubule 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 cliange 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 wliy 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 liundred analogs tested is Taxotere (docetaxel), because of its slightly increased activity and solubility. Oddly, however, Taxotere differs from 'I'axol at sites wliich typically do not llave a strong influence on activity, and one would not predict the iniprovenients in Taxotere from these differences, even in hindsiglit.
'I'axotere has the (ollowinl; formula:
HO O OH
O
OA, NH 0 ....f..{
Ph' O H 0 OH HO O
OAc O Ph DHA (docosahexaenoic acid) is a 22 carbon naturally-occurring, unbranclied 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 liydrophilic drugs and renders these drugs niore hydrophobic (lipophilic). DHA is an important constituent of the brain and recently has been approved in Europe as an additive to infant formula. It is present in the milk of lactating women. The mechanism of action by which DHA helps drugs conjugated to it cross the blood brain barrier is unknown.
Summary of the Invention The present invention involves the unexpected finding that conjugates of pharniaceutical 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 i o 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 pliarmaceutical agents in most cell lines of tissue types other than colon, breast, and central nervous system, tliereby reducing potential side effects of the conjugates versus those of the unconjugated pharmaceutical agents. The therapcutic 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 pharmaccutical agent effective for treating said condition is administered to a subject in need of sucli treatment. Preferably, the conjugate consists only of cis-docosahexacnoic acid and tht pharmaceutical agent, wherein the cis-docosahexaenoic acid is conjugated directly to the pharmaceuticai agent, free of linker, for example via the carboxylic acid grotip of the cis-docosahexaenoic acid and a reactive group suc11 as a free amino or hydroxyl group of the pharmaccutical agent. In preferred cmbodiments, the tissue is breast tissue, gastrointestinal tissuc and ovarian tissue and the condition calls for treatment of breast tissue, gastrointestinal tissue or ovarian tissue, respectively.
'I'ile conjubatcs of tlie invention can bc isolated conjugates. An isolated conjubate is one which is separated from otller different docosahexaenoic acid-pharmaceutical agent conjugates.
The pharmaceutical agent may be any pliarmacolobical compound or diagnostic agent, as desired. '1'he pliarmaceutical agent, of course, has an activity outside of the central nervous system.
Examples of catagories of pharmaceutical agents include: adrcnergic agent;
adrenocortical steroid; adrenocortical stippressant; alcohol deterrent; aldostcrone antagonist; amino acid; ammonia dctoxicant; anabolic; analeptic; analgesic; androgen; anesthesia, adjunct to;
anesthetic;
I3ackground of the Invcntion 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 the 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 TaxolO.
TaxolO (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 hynerstabilization of microtuhulcs, thereby preventing the disassembly of inicrotubules necessary for completion of cell division. It also has been reported that Taxol induces -5 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 lias been discovered to be an analog of numerous closely 2o 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 lias tissue specificitv, thereby reducing side-effects on normal (dividing) cells. Taxol analogs witli tissue specificity tlierefore are desired. Anotlier drawback of 25 Taxol is its extreme insolubility. Taxol can be administered effectively in a solvent including cremophor, whicii combination can provoke severe hypersensitive immune responses. As a re'sult of these drawbacks, and also as a result of the potential for modifying Taxol at numerous sites as demonstrated by otlier naturally-occurring taxancs with anticancer activity, a search for more selective taxancs was iaLuiched.
30 To date, more than 200 taxanes have been synthesized (or isolated) and tested in vilro or in vivo 1or anticancer activity. The rcsults, however, llave been so disappointing that the National Cancer institute (NCI) generally no longer is interested in testing Taxol analogs. In general with Taxol analogs, the solubilitv problcnis reniain, and/or potency is sliarply 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:
Ri o AcO o OH
P' N H O B C
===H
Ph 3. :2. O F( Do OH HO OAc PhCO2 Taxanes have the basic three ring structure (A, B and C), substituted or unsubstituted.
Taxol's carbons are numbered conventionally as follows:
1o 9 19 1 11 ~ a 6 ~ 16 3C
S
Based upon the taxanes testcd 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 seiectivity. 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 analol;.
Some information about activity'has emerged. Numerous substitutions have been made at C7, C9, C10, C19, R, and combinations tliereof wliile retaining significant, but usually reduced, activity. Substitutions at C2, C4 and 2'Ol-I, however, are l;enerally not tolerated. Tliese conclusions are oniy generaiities, for example, because some substitutions at C9-C 10 (cyclic derivatives) are not toleratcd and some substitutions at C2 (meta substitutions on the phenyl) are tolerated. Likewise, the C13 side chain and, in particular, the 2'OH are required, although the minimum structtlral requiremcnts of the side chain have not been determined for therapeutic efficacy.
Attempts to improve Taxol's solubility have not resulted in successful clinical products. One approach lias been to manulacturc prodrugs of 'l'axol, wliich prodrugs undergo in vivo transformation into Taxol and some other product. Attempts were made to esterify the C7 hydroxy and 2' liydroxy groups, with the liope that the bond would be stable in solution (to permit preferred administration modes -i.v. over at least 24 hours) but would cleave readily in vivo. The groups tested wcre all hvcirophilic and included amines, sliort 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 whicli groups could be substituted on Taxol to yield a therapeutically useful product, although it was suggested that the 2' OH derivatives may cleave more easily than the C7 OH derivatives.
Several other factors add to the problem of predicting which Taxol analogs will be effective.
Multiple nlechanisms 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 1o bioavailability. For example, Taxol affects nlicrotubule 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 cliange 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 wliy 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 liundred analogs tested is Taxotere (docetaxel), because of its slightly increased activity and solubility. Oddly, however, Taxotere differs from 'I'axol at sites wliich typically do not llave a strong influence on activity, and one would not predict the iniprovenients in Taxotere from these differences, even in hindsiglit.
'I'axotere has the (ollowinl; formula:
HO O OH
O
OA, NH 0 ....f..{
Ph' O H 0 OH HO O
OAc O Ph DHA (docosahexaenoic acid) is a 22 carbon naturally-occurring, unbranclied 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 liydrophilic drugs and renders these drugs niore hydrophobic (lipophilic). DHA is an important constituent of the brain and recently has been approved in Europe as an additive to infant formula. It is present in the milk of lactating women. The mechanism of action by which DHA helps drugs conjugated to it cross the blood brain barrier is unknown.
Summary of the Invention The present invention involves the unexpected finding that conjugates of pharniaceutical 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 i o 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 pliarmaceutical agents in most cell lines of tissue types other than colon, breast, and central nervous system, tliereby reducing potential side effects of the conjugates versus those of the unconjugated pharmaceutical agents. The therapcutic 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 pharmaccutical agent effective for treating said condition is administered to a subject in need of sucli treatment. Preferably, the conjugate consists only of cis-docosahexacnoic acid and tht pharmaceutical agent, wherein the cis-docosahexaenoic acid is conjugated directly to the pharmaceuticai agent, free of linker, for example via the carboxylic acid grotip of the cis-docosahexaenoic acid and a reactive group suc11 as a free amino or hydroxyl group of the pharmaccutical agent. In preferred cmbodiments, the tissue is breast tissue, gastrointestinal tissuc and ovarian tissue and the condition calls for treatment of breast tissue, gastrointestinal tissue or ovarian tissue, respectively.
'I'ile conjubatcs of tlie invention can bc isolated conjugates. An isolated conjubate is one which is separated from otller different docosahexaenoic acid-pharmaceutical agent conjugates.
The pharmaceutical agent may be any pliarmacolobical compound or diagnostic agent, as desired. '1'he pliarmaceutical agent, of course, has an activity outside of the central nervous system.
Examples of catagories of pharmaceutical agents include: adrcnergic agent;
adrenocortical steroid; adrenocortical stippressant; alcohol deterrent; aldostcrone antagonist; amino acid; ammonia dctoxicant; anabolic; analeptic; analgesic; androgen; anesthesia, adjunct to;
anesthetic;
anorectic; antagonist; anterior pituitary suppressant; antheimintic; anti-acne agent;
anti-adrenergic; anti-allergic; anti-amebic; anti-androgen; anti-anemic; anti-anginal; anti-anxiety;
anti-arthritic; anti-asthmatic; anti -atherosclerotic; antibacterial;
anticholelithic;
anticholelithogenic; anticholinergic; anticoagulant; anticoccidal;
anticonvulsant; antidepressant;
antidiabetic; antidiarrheal; antidiuretic; antidote; anti-emetic; anti-epileptic; anti-estrogen;
antifibrinolytic; antifungal; antiglaucoma agent; antihemophilic;
antihemorrhagic; antihistamine;
antihyperlipidemia; antihyperlipoproteinemic; antihypertensive;
antihypotensive; anti-infective;
anti-infective, topical; anti-inflammatory; antikeratinizing agent;
antimalarial; antimicrobial;
antimigraine; antimitotic; antimycotic, antinauseant, antineoplastic, antineutropenic, antiobessional agent; antiparasitic; antiparkinsonian; antiperistaltic, antipneumocystic;
antiproliferative;
antiprostatic hypertrophy; antiprotozoal; antipruritic; antipsychotic;
antirheumatic; antischistosomal;
antiseborrheic; antisecretory; antispasmodic; antithrombotic; antitussive;
anti-ulcerative;
anti-urolithic; antiviral; appetite suppressant; benign prostatic hyperplasia therapy agent; blood glucose regulator; bone resorption inhibitor; bronchodilator; carbonic anhydrase inhibitor; cardiac depressant; cardioprotectant; cardiotonic; cardiovascular agent; clloleretic;
cholinergic; cholinergic agonist; cholinesterase deactivator; coccidiostat; cognition adjuvant;
cognition enhancer; depressant;
diagnostic aid; diuretic; dopaminergic agent; ectoparasiticide; emetic; enzyme inliibitor; estrogen;
fibrinolytic; fluorescent agent; free oxygen radical scavenger;
gastrointestinal motility effector;
glucocorticoid; gonad-stiirnilating principle; hair l;rowth stiniulant;
lieniostatic; liistamine 1-12 receptor antagonists; hormone; hypochoj esterolemic; hypoglycemic;
hypolipidemic; hypotensive;
imaging agent; imtnunizinl; agent; immunoniodulator; immunoregulator;
immunostimulant;
immunosuppressant; impotence tlierapy adjunct: inhibitor; keratolytic; LNRl-I
agonist; liver disorder treatment; luteolysin; memory adjuvant; mental performance enhancer; mood regulator; mucolytic;
niucosal 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; pulinonary surtace; radioactive abent;
regulator; relaxant;
repartitioning agent; scabicide; sclerosing abent; sedative; sedative-hypnotic; selective adenosine Al antagonist; serotonin antagonist; serotonin lnhlbitor; serotonin receptor antagonist; steroid;
stimulant; suppressant; symptoniatic multiple sclerosis; syner6ist; thyroid liormone; thyroid inhibitor; thyromimetic; tranquiiizer; treatment of amyotrophic lateral sclerosis; treatment of cerebral ischemia; trcatment of Paget's disease; treatment of unstable angina;
uricosuric; vasoconstrictor;
vasodilator; vulnerary; wound healing agent; xanthine oxidasc inhibitor.
In important embodiments of the invention, the pharmaceutical agent is a non anti-cancer agent. ln 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 (e.g., TaxolTM and TaxotereTM). 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 of cis-docosahexaenoic acid in t o 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 pliarrnaceutical 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 (lviev'aoa'T"), Simvastatin (Z,ococTM),Pravastatin (PravacholTM), and, Fluvstatin(Lesco1TM);
Muscosal Protectives, such as Misoprostol (C.`ytotecTM); Gastrointestinal motility affectors, such as Cisapride (PropulsidT"'), Metoclopramide (ReglanTM), and, I-lyoscyamine (LevsinTM}; Antidiarrlieals, stich as Diphcnoxylate liydrochloride (LanotilTM~ Metronidazolc (F1agy11M),Methylprednisolonc (Medro1TM), and, Sulfasatazinc i(AsulfidineTM); and Hormones for treating, inter alia, ovarian conditions, such as Progesterone, Norgestrel, Norethynodrel, Norethindrone, Levonorgcstrel, Ethyndiol, Mestranol, Estrone, Equilin, 17 alpha dihydroequilin, equilenin, 17 alpha dihydroequilenin, 17 alpha esradiol, 27 bea estradiol, l.euprolide qAVWM),Tcstolactone, Climiphcne, urofollitropin, brornocriptine, bonadorclin, danazol, dehydrocpiandrosterone, 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 involvinb abnormal mammalian-cdl pro.lifcration. 'I7icy further arc useful in treating diabetes and its complications, excess acid secretion, cardiovascular conditions involving cholestcrol (e.g., hyperlipidcnua and hypcrcholesterolemiu), diarrlica, ovarian diseases (e.g. cndometriosis, ovarian cysts, etc.) and as contraceptive agents. Other conditions treatable according 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 tl1e: 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 io gland, renal gland, salivary gland, sebaceous gland, testis, thymus gland and tliyroid gland; Musclar 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; Tissuc, fiber, and integumentary system: including adipose tissue, cartilage, connective tissue, cuticle, dermis, epidermis, epitheliuni, fascia, hair follicle, ligament, bone marrow, melanin, melanocyte, mucous membrane, skin, soft tissue, synovial capsule and tendon.
Brief Description of the Drawi~gs Figure 1 is a graph plotting concentration of conjugate I versus pereent growth of leukemia cells.
Figure 2 is a graph plotting concentration of conjugate I versus percent growth of non-small cell lung canccr cclls.
Figure 3 is a graph plotting concentration of conjugate I versus percent growth of colon cancer cells.
Figurc 4 is a graph plotting concentration of conjugate i vcrsus percent growth of CNS
cancer cells.
Figure 5 is a graph plotting concentration of conjugate I versus percent growth of melanoma cells.
= Figure 6 is a t;rapli plotting conecntration of conjugate I versus percent growth of ovarian cancer ceils.
l"it;ure 7 is a graph plotting conceiitration of conjugate I versus percent growtll of renal canccr eclls.
Figure 8 is a graph plotting concentration ofconjugate 1 versus perecnt growth of prostate cancer cells.
Figure 9 is a graph plotting concentration of conjugate I versus percent growth of breast cancer cells.
Figure 10 is a graph plotting concentration of conjugate 2 versus percent growth of leukemia cells.
Figure 11 is a graph plotting concentration of conjugate 2 versus percent growth of non-small cell lung cancer cells.
Figure 12 is a graph plotting concentration of conjugate 2 versus percent growth of colon cancer cells.
Figure 13 is a graph plotting concentration of conjugate 2 versus percent growth of CNS
cancer cells.
Figure 14 is a graph plotting concentration of conjugate 2 versus percent growth of inelanoma cells.
Figure 15 is a graph plotting concentration of conjugate 2 versus percent growth of ovarian cancer cells.
Figure 16 is a graph plotting coneentration 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 cancer cells.
Figure 18 is a graph plotting concentration of conjugate 2 versus percent growth of breast cancer cells.
Figure 19 is a graph plotting concentration of Taxol versus percent growth of leukemia cclls.
I'igure 20 is a graph plotting concentration of Taxol versus percent growth of' non-small cell lung cancer cells.
Figure 21 is a grapli plotting concentration of Taxol vcrsus percent growth of colon caiicer 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 inelanoma cells.
Figure 24 is a graph plotting conccntration of Taxol versus percent growtil of ovarian cancer cells.
anti-adrenergic; anti-allergic; anti-amebic; anti-androgen; anti-anemic; anti-anginal; anti-anxiety;
anti-arthritic; anti-asthmatic; anti -atherosclerotic; antibacterial;
anticholelithic;
anticholelithogenic; anticholinergic; anticoagulant; anticoccidal;
anticonvulsant; antidepressant;
antidiabetic; antidiarrheal; antidiuretic; antidote; anti-emetic; anti-epileptic; anti-estrogen;
antifibrinolytic; antifungal; antiglaucoma agent; antihemophilic;
antihemorrhagic; antihistamine;
antihyperlipidemia; antihyperlipoproteinemic; antihypertensive;
antihypotensive; anti-infective;
anti-infective, topical; anti-inflammatory; antikeratinizing agent;
antimalarial; antimicrobial;
antimigraine; antimitotic; antimycotic, antinauseant, antineoplastic, antineutropenic, antiobessional agent; antiparasitic; antiparkinsonian; antiperistaltic, antipneumocystic;
antiproliferative;
antiprostatic hypertrophy; antiprotozoal; antipruritic; antipsychotic;
antirheumatic; antischistosomal;
antiseborrheic; antisecretory; antispasmodic; antithrombotic; antitussive;
anti-ulcerative;
anti-urolithic; antiviral; appetite suppressant; benign prostatic hyperplasia therapy agent; blood glucose regulator; bone resorption inhibitor; bronchodilator; carbonic anhydrase inhibitor; cardiac depressant; cardioprotectant; cardiotonic; cardiovascular agent; clloleretic;
cholinergic; cholinergic agonist; cholinesterase deactivator; coccidiostat; cognition adjuvant;
cognition enhancer; depressant;
diagnostic aid; diuretic; dopaminergic agent; ectoparasiticide; emetic; enzyme inliibitor; estrogen;
fibrinolytic; fluorescent agent; free oxygen radical scavenger;
gastrointestinal motility effector;
glucocorticoid; gonad-stiirnilating principle; hair l;rowth stiniulant;
lieniostatic; liistamine 1-12 receptor antagonists; hormone; hypochoj esterolemic; hypoglycemic;
hypolipidemic; hypotensive;
imaging agent; imtnunizinl; agent; immunoniodulator; immunoregulator;
immunostimulant;
immunosuppressant; impotence tlierapy adjunct: inhibitor; keratolytic; LNRl-I
agonist; liver disorder treatment; luteolysin; memory adjuvant; mental performance enhancer; mood regulator; mucolytic;
niucosal 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; pulinonary surtace; radioactive abent;
regulator; relaxant;
repartitioning agent; scabicide; sclerosing abent; sedative; sedative-hypnotic; selective adenosine Al antagonist; serotonin antagonist; serotonin lnhlbitor; serotonin receptor antagonist; steroid;
stimulant; suppressant; symptoniatic multiple sclerosis; syner6ist; thyroid liormone; thyroid inhibitor; thyromimetic; tranquiiizer; treatment of amyotrophic lateral sclerosis; treatment of cerebral ischemia; trcatment of Paget's disease; treatment of unstable angina;
uricosuric; vasoconstrictor;
vasodilator; vulnerary; wound healing agent; xanthine oxidasc inhibitor.
In important embodiments of the invention, the pharmaceutical agent is a non anti-cancer agent. ln 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 (e.g., TaxolTM and TaxotereTM). 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 of cis-docosahexaenoic acid in t o 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 pliarrnaceutical 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 (lviev'aoa'T"), Simvastatin (Z,ococTM),Pravastatin (PravacholTM), and, Fluvstatin(Lesco1TM);
Muscosal Protectives, such as Misoprostol (C.`ytotecTM); Gastrointestinal motility affectors, such as Cisapride (PropulsidT"'), Metoclopramide (ReglanTM), and, I-lyoscyamine (LevsinTM}; Antidiarrlieals, stich as Diphcnoxylate liydrochloride (LanotilTM~ Metronidazolc (F1agy11M),Methylprednisolonc (Medro1TM), and, Sulfasatazinc i(AsulfidineTM); and Hormones for treating, inter alia, ovarian conditions, such as Progesterone, Norgestrel, Norethynodrel, Norethindrone, Levonorgcstrel, Ethyndiol, Mestranol, Estrone, Equilin, 17 alpha dihydroequilin, equilenin, 17 alpha dihydroequilenin, 17 alpha esradiol, 27 bea estradiol, l.euprolide qAVWM),Tcstolactone, Climiphcne, urofollitropin, brornocriptine, bonadorclin, danazol, dehydrocpiandrosterone, 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 involvinb abnormal mammalian-cdl pro.lifcration. 'I7icy further arc useful in treating diabetes and its complications, excess acid secretion, cardiovascular conditions involving cholestcrol (e.g., hyperlipidcnua and hypcrcholesterolemiu), diarrlica, ovarian diseases (e.g. cndometriosis, ovarian cysts, etc.) and as contraceptive agents. Other conditions treatable according 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 tl1e: 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 io gland, renal gland, salivary gland, sebaceous gland, testis, thymus gland and tliyroid gland; Musclar 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; Tissuc, fiber, and integumentary system: including adipose tissue, cartilage, connective tissue, cuticle, dermis, epidermis, epitheliuni, fascia, hair follicle, ligament, bone marrow, melanin, melanocyte, mucous membrane, skin, soft tissue, synovial capsule and tendon.
Brief Description of the Drawi~gs Figure 1 is a graph plotting concentration of conjugate I versus pereent growth of leukemia cells.
Figure 2 is a graph plotting concentration of conjugate I versus percent growth of non-small cell lung canccr cclls.
Figure 3 is a graph plotting concentration of conjugate I versus percent growth of colon cancer cells.
Figurc 4 is a graph plotting concentration of conjugate i vcrsus percent growth of CNS
cancer cells.
Figure 5 is a graph plotting concentration of conjugate I versus percent growth of melanoma cells.
= Figure 6 is a t;rapli plotting conecntration of conjugate I versus percent growth of ovarian cancer ceils.
l"it;ure 7 is a graph plotting conceiitration of conjugate I versus percent growtll of renal canccr eclls.
Figure 8 is a graph plotting concentration ofconjugate 1 versus perecnt growth of prostate cancer cells.
Figure 9 is a graph plotting concentration of conjugate I versus percent growth of breast cancer cells.
Figure 10 is a graph plotting concentration of conjugate 2 versus percent growth of leukemia cells.
Figure 11 is a graph plotting concentration of conjugate 2 versus percent growth of non-small cell lung cancer cells.
Figure 12 is a graph plotting concentration of conjugate 2 versus percent growth of colon cancer cells.
Figure 13 is a graph plotting concentration of conjugate 2 versus percent growth of CNS
cancer cells.
Figure 14 is a graph plotting concentration of conjugate 2 versus percent growth of inelanoma cells.
Figure 15 is a graph plotting concentration of conjugate 2 versus percent growth of ovarian cancer cells.
Figure 16 is a graph plotting coneentration 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 cancer cells.
Figure 18 is a graph plotting concentration of conjugate 2 versus percent growth of breast cancer cells.
Figure 19 is a graph plotting concentration of Taxol versus percent growth of leukemia cclls.
I'igure 20 is a graph plotting concentration of Taxol versus percent growth of' non-small cell lung cancer cells.
Figure 21 is a grapli plotting concentration of Taxol vcrsus percent growth of colon caiicer 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 inelanoma cells.
Figure 24 is a graph plotting conccntration of Taxol versus percent growtil of ovarian cancer cells.
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 Io cllain fatty acid with six double bonds, all cis. Its structure is as follows:
pH
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 microalgae which syntliesize only a single isomer of DI-IA, the all cis isomer. Mat-tek's patents include U.S. Pat. Nos. 5,374,657, 5,492;938, 5,407,957 and 5,397,591.
DHA also is present in the milk of lactating women, and Martek's licensee has obtained approval in Europe of DI-IA as a nutritional supplcmcnt for inlant Iormula.
It is known that DI-IA can be unstable in the presence of oxygen. To stablizie DI-IA and its conjugates it is important to add anti-oxidants to the material after it is synthesized. One method of stablization is to inake-up the newly synthesized niaterial in the following solution:
100 g neat DI IA-taxol plus 100 g of vchicle (100m1 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 followinb anti-oxidants may also be employcd:
ascorbic acid, ascorbyl palmitate, dilauryl ascorbatc, hydroduinone, butyated hydroxyanisole, = 30 sodium nieta bisulfite, 1-(i carotene and a.-tocoplicrol. A heavy metal chclator such as ethylenediamine tetra-acetic acid (EDTA) may also be used.
Paclitaxel was lirst isolatcd 1i"om thc bark of "I'axus brevilolia (Wani et al., J. Am. Chem.
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 Io cllain fatty acid with six double bonds, all cis. Its structure is as follows:
pH
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 microalgae which syntliesize only a single isomer of DI-IA, the all cis isomer. Mat-tek's patents include U.S. Pat. Nos. 5,374,657, 5,492;938, 5,407,957 and 5,397,591.
DHA also is present in the milk of lactating women, and Martek's licensee has obtained approval in Europe of DI-IA as a nutritional supplcmcnt for inlant Iormula.
It is known that DI-IA can be unstable in the presence of oxygen. To stablizie DI-IA and its conjugates it is important to add anti-oxidants to the material after it is synthesized. One method of stablization is to inake-up the newly synthesized niaterial in the following solution:
100 g neat DI IA-taxol plus 100 g of vchicle (100m1 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 followinb anti-oxidants may also be employcd:
ascorbic acid, ascorbyl palmitate, dilauryl ascorbatc, hydroduinone, butyated hydroxyanisole, = 30 sodium nieta bisulfite, 1-(i carotene and a.-tocoplicrol. A heavy metal chclator such as ethylenediamine tetra-acetic acid (EDTA) may also be used.
Paclitaxel was lirst isolatcd 1i"om thc bark of "I'axus brevilolia (Wani et al., J. Am. Chem.
Soc. 93, 2325, 1971). Its isolation and synthesis have been reported extensively in the literature.
Applicants obtained paclitaxel from a commercial source, Hauser Laboratories, of Boulder, Colorado.
Example 1 TAXOL
AcO OH
PhNH O
k-1 Ph" v O H O
HO O
IJI OAc 0 0 Ph conjugate 1 A solution of Taxol (41 mol) in methylene chloride (2.5mL) under argon was mixed with 4-dimethylaminopyridine (41 mol), dicyclohexylcarbodiimide (824rnol), and DHA
(41 mol) 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 cllromatography of the residue produced 45mg (94%) of crystalline Taxol-DHA conjugate 1.
I:xample 2 0 AcO O Of.{
TAXOL Ph ~ NH 0 Ph O = = H O
OSiEt3 HO
OAc 0 Ph O Ac0 0 O - - - - - -Phlul NH 0 H B
Ph" v O : H O
O.SiEt3 HO O
OAc 0 0 Pr' 30 O Ac0 O O -- - - - - -PhNH 0 H
Ph' = N O conjugate 2 OH HO O
OAc O~ Ph WO 97144063 CA 02255614 2004-09-23 pCT/[j$97/08867 -ll-The production of analog 2 involves several steps including a number of protection-acylation-deprotection steps. A solution of Taxol (59 mol) in methylcne cliloride ' (2.5mL) was mixed at ambient temperature under argon with imidazole (147 mol) and triethylsilyl chloride (147 mol). The reaction mixture was stirred for thirty minutes, diluted with additional methylene chloride, washed with water, saturated aqueous sodium chloride, dried, and concentrated.
Chromatography of the residue produced 50mg (88%) of intermediate A plus 5mg of the 2', 7-di(triethylsilyl) ether derivative. A solution of intermediate A(52 mol) in methylene chloride (3mL) was mixed at ambient temperature under argon with 4-dimetliylaminopyridinc (52 mo1), dicyclohexylcarbodiimide (104 mol), and DHA (52 mol). The reaction mixture was stirred for tcn lo hours, diluted with ether, passed through celiteTM, 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 (75%) of Taxol-DI=IA conjugate 2.
E e3 Conjugates I and 2 were sent to the United States National Cancer Institute-(NCI) for screcning in the NCI's anticancer screcninb program. The conjugates were provided in ethanol (approximately 40mg analog/2ml ethanol). The conjugates were sealed in vials widcr argon to avoid exposure of the cotijugatcs to oxybcn because the conjugates were believed to be sensitive to oxygen. Insttvctions were provided to store at 4 C and to open the vials only when ready for immediate experimental usc. Instructions also were provided to use the cthanol solutions containing thc conjubatcs dircctly or to dissolvc the analogs liirthcr in DMSO
(dimcthylsull'oxide) at 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 presentcd in Figs. 1-9 for conjugate 1, Figs. 10-18 for conjugate 2 and Figs 19-27 for Taxol. To undcrstand the data, rcfcrence is made to the buides provided by thc NCI, excerpted as follows:
The Calculated Measurement of Effect: Percentaee 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 expressions:
If (Mean OD,,,, -Mean OD,j > 0, then PG = 100 x (Mean OD,,,, -Mean OD,Z,TO)/(Mean ODCW -Mean Odzc,o) If (Mean OD1C5, -Mean ODz,:,o) < 0, then PG = 100 x (Mean OD,,,, -Mean Od,Z,,.)/Mean Odt,CFo Where:
Mean OD,Z o = The average of optical density measurements of SRB-derived color just before exposure of cells to the test compound.
Mean ODt.s, = The average of optical density measurements of SRB-derived color aiter 48 hours exposure of cells to the test compound.
Mean OD,,,, = The average of optical density nieasurements of SRB-derived color after 48 hours witli no exposure of cells to the tcst coinpound.
Experimental data was collected against each cell line. ... Each concentration is expressed as the log,o (inolar or g/ml). ... The response parameters G150, TGI, and LC50 are interpolated values representing the concentrations at wliicli the I'G 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, thcn none of thc three paramcters can he obtained by interpoiation. In such a case, the value given for each response parameter is the higliest concentration tested. ... This practice is extendcd similarly to the other possible situations whcre a response parametcr cannot be obtained by iiiterpolation.
Dose-Response Curves:
The dose-response curve page of the data package is created by plotting the PGs against the log,o 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. Tlie concentrations corresponding to points where the curves cross these lines are the G150, TGI and LC50, respectively.
Several important distinctions are apparent from the data. Most important, the patterns of anticancer actively for conjugates 1 and 2 differ from that of Taxoi. In one sense, conjugates 1 and -o 2 are effective anticancer agents against a niore 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 somcwhat 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-sniall cell lung cancer line H522 than against H460 (by about 3 logs), whereas conjugates 1 and 2 were sliglltly more effective against 1-1460 than H522. As anotlier example, Taxol was least effective at TGI against CNSU25 1, wliereas 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, 2o 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 ef'fective against MDA-N than MDA-MB-435 at all concentrations tested.
To further illustrate the differences in the activity of conjubatcs 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 pattern of activity of anticancer agents. Conjugate I and conjugate 2 were determined tc~ be statistically different in their pattern of activity versus T'axol in this unique measurement by the NCI.
It also is to be noted that, in general, conjugates 1 and 2 were one tliousand to ten thousand times less potent than Taxol for many cell lines tested. This reduction in activity is iniportant, 3o especially since conjugates 1 and 2 maintained strong activity against some cell lines. Conjugates I and 2 will be sufficicntly active against ccrtain cell lines, but will have, on average, a substantially and disproportionately lower activity against other cell lines, reducing potential side effects. For example, 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 G150 for Taxol against CNS SF 539 is -7.52, whereas the G150s for conjugates 1 and 2 are -6.22 and -5.56, respectively (again less than 2 logs difference). In contrast, Taxol has a G150 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 G150 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 1 o actual lower value) was used in calculating the average of -9.19. There were 27 instances when this occurred.) The average G150s for conjugates I 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 otlier 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 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 DI-IA analogs have altered specificity versus that of Taxol for cancer ccll lines. I3ccause of tliis altered spccilicity, it also is clear that the conjugates themselves arc gaining access into the target cells (as opposed to simply releasing Taxol into the environment outside of the cell). 'I'hus, the DHA moiety appears to selectively target certain eell types as opposed to others. Tlic ability of thc conjugatcs to l;ain cntry into the cells was unknown prior to the invention, vid the ability of the DI-IA moiety to selectively target certain cell types was unexpected.
The same is true of DI-IA-Taxotere covalent conjugates, examples of wliich are presented below. 'faxotcre's svnthesis lias bcen reported extensively in the literature.
One example is Kanazawa, A. et al., .1. Organic Chcm. 1994, Vol. 59, pp. 1238-1240.
Exampie 4 TAXOTERE
HO O OH
. 5 O
DHA / dicyclohexylcarbodiimide O~NH 0 4-dimethylaminopyridine m H
PhO O
p OAc 0 O1~1 Ph conjugate 3 A solution of Taxotere in methylene chloride under argon is mixed with 4-dimethyiaminopyridine, dicyclohexylcarbodiimide, and DI-IA. 1'he reaction niixture is stirred at ambient temperature. Radial chromatography of the residue is performed to produce Taxotere-DHA
conjugate 3.
ExampLeS
0 HO 0 OSI(CH?CH3)3 triethylsiiyl chloride TAXOTERE O14, NH O
imidazole,..H
ph~
O H O
(CH3CH?)3SiO HO 0 =
OAc 0 Ph V~% - - - O
O O OSi(CHZCHa)3 DHA / dicyc{ohexylcarbodiimide O-k NH 0 -' ,===H
4-dimethylaminopyridine Ph~O" hi O
(CH3CH2)3Si0 HO
D p OAc O1~1 Ph - - - - - O
aqueous HF 0 O 0 OH
)~OAI NH O
}-i Ph~O Ft conjugate 4 OH HO O OAc O'~, Ph 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 witli 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 etlier, passed throufili celite, and concentrated. Radial cllromatography of the residue is performed to produce intermediate D. A
solution of intermediate D in acctonitrile at 0 C under argon is mixed witli 49% aqueous FIF and the reaction mixture is i o 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.
I;xaniple 6 O HO O OH
fert={)ulyldimethyisilyl chloride TAXOTERE O~NH O ~
imidazole ^ ~ = = '+~
Ph' v O== H- o terl-C.4H9(CH3)2SiO HO O OAc E O Ph O
1 equivalent DHA 0 0 OH
O
dicyclotiexylcarbodi imide 4-dimethylaminopyridine O~NH 0 ~
H
Ph' v O= _ H O
F HO lCri-CqHg(CH3)2SIO 0 OAc 0 Ph - O
O O O OH
aqueous HF
>cANH 0 =H
Ph' v O' F{ O
OH HO
p OAc O~Ph conjugate 4 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, dicyclollexylcarbodiimide, and I
equivalent of DHA.
The reaction mixture is stirred at ambient temperature, diluted with etller, passed through celite, and concentrated. Radial cliromatography of the residue is performed to produce intermediate F.
(Intermediate H also is obtained and used in Example 8 below.) A solution of intermediate F in I o acetonitrile at 0 C under argon is niixed with aqueous HF and the reaction mixture is stirred at the same temperature. After dilution witli ether, the reaction mixture is washed with water, saturated aqueous sodium chloride, dried, and concentrated Radial cliromatograpliy of the residuc is performed to produce Taxotere-DI-IA conjugate 4.
Ex:tmple 7 O HO OH
lerr=bLnyldimethytsilyl chloride ~
O NH O
TAXOTERE imidazole oN
Ph' v O' H
tert-C.Ha(CH3)2SiO HO O OAc O~PIi E
O O
OHA/dicyclohexylcarbodiimide -~"OJ~NH O
....H
4=dimethylaminopyridine Ph' O" O
ternL4H,(CH,)?SiO HO G
p OAc ~
O Pti O O
O O O - _ - - - -O
aqueous HF
O'.111 NH 0 ,,,H
Ph" ~' O H O
OH HO '= =
p OAc conjttgate 5 0 'j, Ph A solution of Taxotere in dimethvlformamide is rnixed 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 witli 4-dimetliylaminopyridine, 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 lo 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 5.
Example 8 HO O O - - - - - -1 equivalent DHA ~ ONH O
~ ....{.~
dicydohexykxrbodiimide Ph'^v'O' 4-dimethylaminopyridine HO
teri-C4H9(CH3)2SiO p OAc H
0 Ph O
aqueous HF
Ph' v 'O' : H O
OH HO O
OAc 0 Pli conjugate 6 A solution of taxotere in dimcthylformamide is mixed at atnbient temperature under argon with imidazole and tert-butylydimethylsilyl cliloride. The reaction mixture is stirred at ambient temperature, diluted with methylene chloride, washed with water, saturated aqueous sodium chloride, dried, and coiicentrated. Radial chromatography of the residue is performed to produce intermediate E. A solution of intermediate E in niethylene chloride is mixed at ambient temperature under argon with 4-dimethylaininopyridine, dicyclohexylcarbodiimide, and I
eqttivalent of DHA.
The reaction niixture is stirred at ambient temperature, diluted witli 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 HF and the reaction mixture is stirred at the same temperature. After diiution with ether, the reaction mixture is washed with water, saturated aqueous sodium cltloride, dried, and concetitrated. Radial chromatography of tlie residue is performed to produce Taxotere-DHA conjugate 6.
DHA may be conjugated to virtually any drug conipound or diagnostic agent and used according to the methods of the present invention so long as the pllarmaceutical agent has a use outside of the central nervous system. I'harmaceutical 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 ncrvous system. Those of ordinary skill in the art will rccognize also 2o numerous other compounds that fall wlthin the categories and that are useful accordinb to the invcntion.
Adrenergic: Adrenalone; Amidcplirinc Mesylate; Apraclonidinc I-lydrochloride;
Brimonidine Tartrate; Dapiprazole I-Iydrochloride; Deterenol t-Iydrochloride; Dipivefrin;
Dopamine 1lydrochloride; I_:phedrinc Sulfate; E-pinephrinc; l:pincphrine I3itartratc;
[:pincpliryl I3orKte;
Esproquin I-lydrochloride; Etafedrine Hydrochloride; I-Iydroxyamphctamine Hydrobromide;
Levonordefrin; Mephenterminc Sulfatc; Metaraminol Bitartratc; Metizoline I-lydrocllloridc;
Naphazoline I-lydrochloride; Norepinephrine I3itartratc; Oxidopamine;
Oxymetazoline I-Iydrochloridc; Phenyiephrinc 1-tydrochloridc; Phenylpropanolaminc I-Iydrocliloride;
Pllenylpropanolamine Polistirex; Prenalterol I-lydrochloride; Pt-opylhexedrinc; Pseudocnhedrinc Hydrochloride; Tetrahydrozolinc I Iydrochloridc; Tramazolinc I tydrochloride;
Xyionictazoline I lydrochioridc.
Adrenocortical steroid: Ciprocinonide; Desoxycorticosterone Acetate;
Desoxycorticosterone Pivalate; Dexamethasone Acetate; Fludrocortisone Acetate; Flumoxonide; I-Hydrocortisone Hemisuccinate; Methylprednisolone Hemisuccinate; Naflocort; Procinonide;
Timobesone Acetate;
Tipredanc.
Adrenocortical suppressant: Aminoglutethimide; Trilostane.
Alcohol deterrent: Disulfiram.
io 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; Lysine Hydrochloride; Methionine;
Phenylalanine; Proline; Serine;
Threonine; Tryptophan; Tyrosine; Valine.
Ammonia detoxicant: Arginine: Arginine Glutamate; Arginine Hydrochloride.
Anabolic: Bolandiol Dipropionate; Bolasteronc; Boldenone Undecylenate;
Bolenol; Bolmantalate;
I;thylestrenol; Metlienolone Acetate; Methcnolone Cnantiiatc; Mibolerone;
Nandrolone Cyclotate;
Norbolctlionc; Pizotyline; Quinbolonc; Stcnbolonc Acctate; 'ribolonc; Zcranol.
Analeptic: Modalinil.
Analgesic: Acctaminophcn; Alfentanii I-lydrochioride; Aminobcnzoatc Potassium;
Aminobenz4atc Sodium; Anidoxime; Anileridine; Anileridine Hydrochloride; Anilopam Hydrochloride; Anirolac;
Antipyrine; Aspirin; Benoxaprofen; Benzydaminc I-lydrocliloride; Bicifadine I-Iydrochloride;
Brifentanil 1-Iydrochioride; Bromadoline Maleate; Bromfenac Sodium;
Buprenorphinc I-lydrochloridc; Butacctin; Butixiratc; Butorpilanol; Butorplianol Tartratc;
Carbamazcpinc;
Carbaspirin Calcium; Carbiphcne I-lydrochloride; Carfentanil Citrate;
Ciprefadol Succinate;
Ciraniadol: Ciramadol liydrochloridc; Clonixeril; Clonixin; Codcinc ; Codeinc Phospliatc; Codeinc Sulfatc; Conorpiione I-lydrocliloridc; Cyclazocinc; Dcxoxadrol I-lydrochloride; Dexpemedolac;
Dezocine; Diflunisal; Dillydrocodeine Bitartrate; Dimefadane; Dipyrone;
Doxpicomine Hydrochloride; Drinidene; Enadoline Hydrochloride; Epirizole; Ergotamine Tartrate; Ethoxazene Hydrochloride; Etofenamate; Eugenol; Fenoprofen; Fenoprofen Calcium; Fentanyl Citrate;
Floctafenine; Flufenisal; Flunixin; Flunixin Meglumine; Flupirtine Maleate;
Fluproquazone;
Fluradoline Hydrochloride; Flurbiprofen ; Hydromorphone Hydrochloride;
Ibufenac; Indoprofen;
Ketazocine; Ketorfanol; Ketorolac Tromethamine; Letimide Hydrochloride;
Levomethadyl Acetate;
Levomethadyl Acetate Hydrocllloride; Levonantradol I-Iydrochloride;
Levorphanol Tartrate;
Lofemizole Hydrochloride; Lofentanil Oxalate; Lorcinadol; Lornoxicam;
Magnesium Salicylate;
Mefenamic Acid; Menabitan Hydrochloride; Meperidine Hydrochloride; Meptazinol Hydrochloride;
I o Methadone Hydrochloride; Metlladyl Acetate; Methopholine;
Methotrimeprazine; Metkephamid Acetate; Mimbane I-Iydrochloridc; Mirfentanil I-Iydrocllloride; Molinazone;
Morphine Sulfate;
Moxazocine; Nabitan Hydrochloride; Nalbuphine 1-Iydrochloride; Nalmexone Hydrocliloride ;
Namoxyrate; Nantradol I-Iydrochloride; Naproxen ; Naproxen Sodium ; Naproxol;
Nefopanl Hydrochloride; Nexeridine Hydrocllloride; Noracymetlladol Hydrochloride;
Ocfentanil I-lydrochloride; Octazamide; Olvanil; Oxetorone Fumarate; Oxycodone; Oxycodone Hydrochloride;
Oxycodone Terephthalate; Oxynlorphone Hydrochloride; Pemedolac; Pentamorphone;
Pentazocine;
Pentazocine Hydrochloride; Pentazocine Lactate; Phenazopyridine Hydrochloride;
Phenyraniidol 1-Iydrochloride; Picenadol Hydrochloride; Pinadoline; Pirfenidone; Piroxicam Olamine; Pravadoline Maleate; Prodilidine Hydrochloride; Profadol Hydrocllloride; Propiram Funlarate; Propoxypllene I-lydrocllloride; Propoxyphene Napsylate; Proxazole ; Proxazole Citrate ;
Proxorphan Tartrate;
Pyrroliphene 1-Iydrocllloridc; Renlifentanil I-Iydrocllloride; Salcolex Salethanlide Maleatc;
Salicylamidc; Salicylatc Meblunline; Salsalate ; Sodiunl Salicylatc;
Spiradoline Mesylate;
Sufentanil; Sufentanil Citrate; Talmetacin ; Talniflumate ; Talosalate ;
Tazadolene Succinate;
Tebufeione ; Tetrydanline ; Tifurac Sodiunl; Tilidine I-lydrochloridc;
Tiopinac; 'ronazocine Mesylate; Traniadol I-lydrochloride; Trefentanil Hydrochloride; 'rrolamine;
Veradokne I-lydrochloride; Verilopanl I-Iydrochloride; Volazocinc; Xorphanol Mesylate;
Xylazine 1-Iydrochloride; Zetlazocitle Mesylate; Zomepirac Sodlunl ;"Lucapsaicin.
Androgen: Fluoxymcsteronc; Mestcrolonc; Metllyltestosterotlc; Nandrolone Decanoate; Nandrolone Phenpropionate; Nisterime Acetate; Oxandrolone; Oxymetholone; Silandrone;
Stanozolol;
Tcstosterone; Tcstosteronc Cypionate; 'fcstosterone i;nanthatc: Tcstostcrone 1Cctolauratc;
'f'estosterone l'llcnylacetate; Testostcrone Propionatc;l'restolone Acctate.
- 22_ Anestllesia, adjunct to: Sodium Oxybate.
Anesthetic: Aliflurane; Benoxinate Hydrochloride; Benzocaine; Biphenamine Hydrochloride Bupivacaine Hydrochloride; Butamben; Butamben Picrate; Chloroprocaine Hydrochloride; Cocaine;
Cocaine Hydrochloride; Cyclopropane; Desflurane; Dexivacaine; Diamocaine Cyclamate;
Dibucaine; Dibucaine Hydrochloride; Dyclonine Hydrochloride; Enflurane; Ether;
Ethyl Cllloride;
Etidocaine; Etoxadrol Hydrochloride; Euprocin Hydrochloride; Fluroxene;
Halothane; Isobutamben;
Isoflurane; Ketamine Hydrochloride; Levoxadrol Hydrochloride ; Lidocaine;
Lidocaine Hydrochloride; Mepivacaine Hydrochloride; Methohexital Sodium; Methoxyflurane;
Midazolam i o Hydrochloride; Midazolam Maleate; Minaxolone; Nitrous Oxide; Norflurane;
Octodrine;
Oxethazaine; Phencyclidine Hydrochloride; Pramoxine Hydrochloride; Prilocaine Hydrochloride;
Procaine Hydrochloride; Propanidid; Proparacaine Hydrochloride; Propofol;
Propoxycaine Hydrochloride; Pyrrocaine; Risocaine; Rodocaine; Roflurane; Salicyl Alcohol;
Sevoflurane;
Teflurane; Tctracaine; Tetracaine Hydrochloride; Tllianlylal; Tliiamylal Sodium; Thiopental Sodium ; Tiletamine Hydrocllloride; Zolamine Hydrochloride.
Anorectic coinpounds including dexfenfluramine.
Anorexic: Aminorex; Ampllecloral; Chlorphentermine Hydrocllloride; Clominorex;
Clortermine I-Iydrocllloride; Dietllyipropion Hydroclltoride; Fenfluranline I-lydrocllloride; Fenisorex; Fludorex;
Fluminorcx; Levamfetanlinc Succinate; Mazindol; Mefcnorex I Iydrochloride;
Pllenmetrazine I-lydrochioride; Pllentcrmine; Sibutramine Hydrocllloride.
Antagonist: Atipamezolc; Atosiban; Boscntan; Cinletidinc; Cinletidinc I
lydrochloride; ClcnUazenl Maleate; Detirelix Acetate; Devazepide; Donetidine; Etintidine Hydrochloride ;
Famotid'}ne;
Fenmetozole Hydrocllloride ; Flumazenil; Icatibant Acetate; Icotidine;
lsradipine; Metiamide;
Nadide; Nalmefene; Nalmexone I-Iydrochloride ; Naloxone Hydrochloride;
Naltrexone; Nilvadipine;
Oxiloiphan; Oxmctidine I-Iycirocllloride ; Oxmetidine Mesylatc ; Quadazocinc Mcsylatc; Ranitidinc;
Ranitidine Bismuth Citrate ; Ranitidine Ilydrochloridc ; Sufotidine;
Tcludipine I-Iydrocilloride;
3o Tiapamil I-Iydrocliloride; Tiotidine; Vapiprost Hydrocllloride; Zaltidine Hydrochloride.
Anterior pituitary activator: Epimestrol.
Anterior pituitary suppressant: Danazol.
Anthelmintic: Albendazole; Anthelmycin; Bromoxanide; Bunamidine Hydrochloride;
Butonate;
Cambendazole; Carbantel Lauryl Sulfate; Clioxanide; Closantel; Cyclobendazole;
Dichlorvos;
Diethylcarbamazine Citrate; Dribendazole; Dymanthine Hydrochloride;
Etibendazole;
Fenbendazole; Furodazoie; Hexylresorcinol; Mebendazole; Morantel Tartrate;
Niclosamide;
Nitramisole Hydrochloride; Nitrodan; Oxantel Pamoate; Oxfendazole;
Oxibendazole; Parbendazole;
Piperamide Maleate; Piperazine; Piperazine Citrate; Piperazine Edetate Calcium; Proclonol; Pyrantel Pamoate; Pyrantel Tartrate; Pyrvinium Pamoate; Rafoxanide; Stilbazium Iodide;
Tetramisole 1o Hydrochloride; Thiabendazole; Ticarbodine; Tioxidazole; Triclofenol Piperazine; Vincofos; Zilantel.
Anti-acne: Adapalene; Ervthromycin Sa(nacedin; Inocoterone Acetate.
Anti-adrenergic: Acebutolol; Aiprenolol Hydrochloride; Atenolol; Bretylium Tosylate; Bunolol I-Iydrochloride; Carteolol I-lydrochloride; Celiprolol I Iydrocliloride;
Cetamolol I-Iydrochloride;
Cicloprolol Hydrochloride; Dexpropranolol Hydrochloride; Diacetolol Hydrochloride;
Diliydroerbotamine Mesyiatc; Dilevalol 1-Iydrochloride; Esmolol I-lydrochloride; Exaprolol Hydrocliloride; Fenspiride Hydrochloride; Flestolol Sulfate; Labetalol Hydrochloride Levobetaxolol Hydrochloride; Levobunolol Hydrochloride; Metalol Hydrprhloride;
Metoprolol;
Metoprolol Tartrate; Nadolol; Pamatolol Sulfate; Penbutolol Sulfate;
Phentolamine Mesylate;
Practolol; I'ropranolol I-Ivdrochloridc; Proroxan Ilydrocliloricic;
Solypcrtinc Tartratc; Sotalol 1lydrochloridc; Timolol; 1'imolol Maleate; Tiprenolol Ilydrochloridc;
'I'olamolol; Zolertinc Hydrochloride.
Anti-allergic: Amlexanox; Astemizole; Azelastine Hydrochloride; Eclazolast ;
Minocro"l Nedocrornil ; Nedocromil Calcium ; Ncdocromil Sodium ; Nivimedone Sodiunl;
Pemirolast Potassium ; Pentigetide; Pirquinozol; Poisonoak Extract; Probicromil Calciuni;
Proxicromil;
Repirinast ; Tetrazolast Meglumine; Thiazinamium Cliloride; Tiacrilast;
Tiacrilast Sodiuni; Tiprinast Meglumine; Tixanox.
Anti-amebic : Berythromycin ; Bialamicol I-Iydrochloridc; Chloroquinc;
Chloroquinc I Iydrocllloridc;
Cliloroquinc 1'liospliate ; Clamoxyquin I-Iydrochloridc; Clioquinol ; Emctinc 1{ydrochloridc;
Iodoquinol; Paromomycin Sulfate; Quinfamide; Symetine Hydrochloride; Teclozan;
Tetracycline;
Tetracycline Hydrochloride.
Anti-androgen: Benorterone; Cioteronel; Cyproterone Acetate; Delmadinone Acetate ; Oxendolone;
Topterone; Zanoterone.
Anti-anemic: Epoetin Alfa; Epoetin Beta ; Ferrous Sulfate, Dried; Leucovorin Calcium.
Anti-anginal: Amlodipine Besylate; Amlodipine Maleate; Betaxolol Hydrochloride ; Bevantolol io I-lydrochloride ; Butoprozine Hydrochloride; Carvedilol ; Cinepazet Maleate; Metoprolol Succinate ; Molsidomine ; Monatepil Maleate; Primidolol ; Ranolazine Hydrochloride;
Tosifen; Verapamil Hydrocliloride.
Anti-anxiety agent: Adatanserin Hydrochloride; Alpidem; Binospirone Mesylate;
Bretazenil;
Glemanserin; Ipsapirone I-Iydrochioride; Mirisetron Maleate; Ocinaplon;
Ondansetron Hydrochloride ; Panadiplon; Pancopride ; Pazinaclone; Serazapine Hydrochloride; Tandospirone Citrate; Zalospirone Hydrochloride.
Anti-arthritic: Lodelaben .
2o Anti-asthniatic: Ablukast; Ablukast Sodlum; Azelastine Hydrocliloride ;
Bunaprolast; Cinalukast;
Cronlitrile Sodium; Cromolyn Sodium; Cnofelast; Isamoxole; Ketotifcn Fumaratc;
Levcromakalim;
Lodoxamide Cthyl ; Lodoxamidc Tromethaminc; Montelukast Sodium; Ontazolast;
Oxarbazole;
Oxatomidc; Piriprost; Piriprost Potassium; Pirolate; I'obilukast Ldaniine;
Quazolast ; Repirinast;
Ritolukast; Sulukast; Tetrazolast Meglumine ; Tiaramide I-Iydrochloride;
Tibenefast Sodium;
Tomelukast; '1'ranilast; Verlukast; Verofylline ; Zarirlukast.
Anti-atherosclcrotic: Mifobate; Timefuronc.
Antibacterial: Acedapsonc; Acetosulfone Sodium; Alamccin; Alexidinc;
Amdinocillin; Amdinocillin Pivoxii; Amicycline; Amifloxacin; Amifloxacin Mesylate; Amikacin; Amikacin Sulfate;
Anllnotiallcyllc acid; Aminosalicylatc sociiiun; Amoxicillin; Amphomycin;
Anipiciliin; Ampicillin Sodium; Apalcillin Sodium; Apramycin; Aspartocin; Astromicin Sulfate;
Avilamycin; Avoparcin;
Azithromycin; Azlocillin; Aztocillin Sodium; Bacampicillin Hydrocliloride;
Bacitracin; Bacitracin Methylene Disalicylate; Bacitracin Zinc; Bambermycins; Benzoylpas Calciuni;
Berythromycin Betamicin Sulfate; Biapenem; Biniraniycin; 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 Nafate; Ccfamandole Sodium;
Cefaparole;
Cefatrizine; Cefazaflur Sodium; Cefazolin; Cefazolin Sodium; Cefbuperazone;
Cefdinir; Cefepime;
Cefepime Hydrochloride; Cefetecol; Cefixime; Cefmenoxime Hydrochloride;
Cefmetazole;
Cefnietazole Sodium; Cefonicid Monosodium; Cefonicid Sodium; Cefoperazone Sodium;
t o Ceforanide; Cefotaxime Sodium; Cefotetan; Cefotetan Disodium; Cefotiam Hydrochloride;
Cefoxitin; Cefoxitin Sodium; Cefpimizole; Cefpimizole Sodium; Cefpiramide;
Cefpiramide Sodiuni;
Cefpirome Sulfate; Cefpodoxiine Proxetil; Cefprozil; Cefroxadine; Cefsulodin Sodium; Ceftazidime;
Ceitibuten; Ceftizoxime Sodium; Ceftriaxone Sodium; Cefuroxime; Cefuroxime Axetil; Cefuroxime Pivoxetil; Cefuroxime Sodium; Cephacetrile Sodium; Cephalexin; Cephalexin Hydrochloride;
Cephalol;lycin; Cephaloridine; Cephalothin Sodium; Cephapirin Sodium;
Cephradine; Cetocycline Hydrochloride; Cetophenicol; Chloramphenicol; Chloramphenicol Palmitate;
Chloramphenicol 1'antotllenate C.omplcx ; Cliloramphcnicol Sodiuni Succinatc; Chlorhexidine Phosphanilate;
Chloroxylenol; Chlortetracycline Bisulfate; Chlortetracycline Hydrochloride;
Cinoxacin;
Ciprofloxacin; Ciprofloxacin Hydrocllloride; Cirolemycin ; Clarithromycin;
Clinafloxacin 2o Hydrocliioride; Clindamycin; Clindamycin I-lydrochloride; Clindamycin Palmitate Hydrochloride;
Clindamvcin Phosphatc; Clofaziminc ; Cloxacillin Bcnzathinc; Cloxacillin Sodium; Cloxyquin;
Colistimethate Sodium; Colistin Sulfate; Coumermycin; Coumermycin Sodiuwn;
Cyclacillin;
Cycloserine; Dalfopristin; Dapsonc ; Daptomycin; Dcmeclocycline;
Denieclocycline Hydrochloride;
Demecycline; Denofungin ; Diaveridine; Dicloxacillin; Dicloxacillin Sodium;
Dihydrostreptomycin Sulfate; Dipyrithione; Dirithromycin; Doxycycline; Doxycycline Calciuni ;
Doxycycline FosfaFex;
Doxycycline Hyclate; Droxacin Sodium; Enoxacin; Epicillin; Epitetracycline Hydrochloride;
Erythromycin; Erythromycin Acistrate; Erythromycin Estolate; Erythroinycin Ethylsuccinate;
Erythromycin Gluceptate; Erythronlycin Lactobionate; Erythromycin Propionate;
Erythromycin Stearate; Ethambutol I-lydrochloride; L'=thionamide; Fleroxacin; Floxacillin;
Fludalaninc;
3o Flumequine; Fosfomycin; Fosfomycin Tromethaminc; Fumoxicillin; Furazoliuni Chloridc;
Furazoliuni Tartratc; Fusidatc Sodium; Fusidic Acid; Gcntamicin Sulfate;
Gloximonam; Gramicidin;
I-Ialoprogin; I-Ietacillin; I-letacillin Potassium; Hexedine; Ibafloxacin;
lmipenem; Isoconazole;
Isepamicin; Isoniazid; Josamycin; Kanamycin Sulfate; Kitasamycin;
Levofuraltadone;
Levopropylcillin Potassium; Lexithromycin; Lincomycin; Lincomycin Hydrochioride;
Lomefloxacin; Lomefloxacin Hydrochloride; Lomefloxacin Mesylate; Loracarbef;
Mafenide;
Meclocycline; Meclocycline Sulfosalicylate; Megalomicin Potassium Phospliate;
Mequidox;
Meropenem; Methacycline; Methacycline Hydrochloride; Methenamine; Methenamine Hippurate;
Methenamine Mandelate; Methicillin Sodium; Metioprim; Metronidazole Hydrochloride;
Metronidazole Phosphate; Mezlocillin; Mezlocillin Sodium; Minocycline;
Minocycline Hydrochloride; Mirincamycin Hydrochloride ; Monensin ; Monensin Sodium ;
Nafcillin Sodium;
Nalidixate Sodium; Nalidixic Acid; Natatnycin; Nebramycin; Neomycin Palmitate;
Neomycin lo Sulfate; Neomycin Undecylenate ; Netilmicin Sulfate; Neutramycin;
Nifuradene; Nifuraldezone;
Nifuratcl ; Nifuratrone; Nifurdazil; Nifurimide; Nifurpirinol; Nifurquinazol;
Nifurthiazole;
Nitrocycline; Nitrofurantoin; Nitromide; Norfloxacin; Novobiocin Sodium;
Ofloxacin; Ormetoprim;
Oxaciliin Sodium; Oximonam; Oximonam Sodium; Oxolinic Acid; Oxytetracycline;
Oxytetracycline Calcium; Oxytetracycline Hydrochloride; Paldimycin;
Paraclilorophenol;
Paulomycin; Pefloxacin; Pefloxacin Mesylate; Penamecillin; Penicillin G
Benzathine; Penicillin G
Potassium; Peniciilin G Procaine; Penicillin G Sodium; Penicillin V;
Penicillin V Benzathine;
Penicillin V Hydrabamine; Penicillin V Potassium; Pentizidone Sodium; Phenyl Aminosalicylate;
Piperacillin Sodium; Pirbenicillin Sodium; Piridicillin Sodium; Pirlimycin Hydrochloride;
Pivampicillin Hydrochloride; Pivanipicillin Pamoate; Pivampicillin Probenate;Polyniyxin B Sulfate;
Poriiromycin ; Propikacin; Pyrazinamide; Pyrithione Zinc; Quindecamine Acetate; Quinupristin;
Racephenicol; Ranioplanin; Raniniycin; Relomyciti; Repromicin; Rifabutin;
Rifametane; Rifainexil;
Rifanlide; Rifampin; Rifapentinc; Rltaxlnlln; Rolitetracyclinc;
Rolitetracycline Nitrate;
Rosarainicin; Rosaramicin Butyrate; Rosaramicin Propionate; Rosaramicin Sodium Phosphate;
Rosaramicin Stearate; Rosoxacin; Roxarsone; Roxithromycin; Sancycline;
Sanfetrinem Sodium;
Sarnioxicillin; Sarpicillin; Scopafungin ; Sisomicin; Sisomicin Sulfate;
Sparfloxacin; Spectinomycin I-lydrocliloride; Spiramycin; Stallimycin I-lydrocliloride; Steffimycin;
Streptomycin Sulfatc;
Streptonicozid; Sulfabenz ; Sulfabenzamide; Sulfacetamide; Sulfacetainide Sodium; Sulfacytine;
Sulfadiazine; Sulfadiazinc Sodium; Sulfadoxine; Sulfalene; Sulfamerazine;
Sulfameter;
Sulfamethazine; Sulfamethizole; Sulfaniethoxazole; Sulfamonomethoxine;
Sulfamoxole; Sulfanilate Zinc; Sulfanitran ; Sulfasalazinc; Sulfasomizole; Sulfatliiazole; Sulfazamet;
Sulfisoxazole;
Sulfisoxazole Acetyl; Sulfisoxazole Diolamine; Sulfomyxin; Sulopenem;
Sultamicillin; Suncillin Sodium; Talampicillin I-Ivdrochloride; Teicoplanin; Temafloxacin 1-iydrochloride; Temocillin;
Tetracycline; Tetracycline Hydrochloride ; Tetracycline Phosphate Complex;
Tetroxoprim;
Thiamphenicol; Thiphencillin Potassium; Ticarcillin Cresyl Sodium; Ticarcillin Disodium;
Ticarcillin Monosodium; Ticlatone; Tiodonium Chloride; Tobramycin; Tobramycin Sulfate;
Tosufloxacin; Trimethoprinl; Trimethoprim Sulfate; Trisulfapyrimidines;
Troleandomycin;
Trospectomycin Sulfate; Tyrothricin; Vancomycin; Vancomycin Hydrochloride;
Virginiamycin;
Zorbanlycin.
Anticholelithic: Monoctanoin.
1o Anticholelithogenic: Chenodiol; Ursodiol.
Anticholinergic: Alverinc Citrate; Anisotropine Methylbromide; Atropine;
Atropine Oxide Hydrochioride; Atropine Sulfate; Belladonna; Benapryzine Hydrocliloride;
Benzetimide Hydrocllloride; Benzilonium Bromide; Biperiden ; Biperiden I-Iydrochloride;
Biperiden Lactate ;
Clidinium Bromide; Cyclopentolate Hydrochloride; Dexetimide; Dicyclomine Hydrochloride;
Dihexyverinc llydrocllloridc; Domazolinc Funiaratc; Elantrine; Elucainc;
L=:thybcnztropinc;
Eucatropine I-Iydrochloride; Glycopyrrolate; Heteronium Bromide; Homatropine Hydrobromide;
Homatropine Metliylbromide; I lyoscyamine; I-Iyoscyamine Hydrobromide; I-Iyoscyamine Sulfate;
Isopropamide Iodide; Mepenzolate Bromide; Methylatropine Nitrate; Metoquizine;
Oxybutynin Chloridc; Parapenzolate Brornide; P'entapiperium Methylsulfatc;
Pliencarbamide; Poidine Metliylsulfate; Prol;lumide; Propanthcline Broniide; Propenzolate flydrochloride; Scopolamine I-lydrobromide; Tcinatropiuni Methylsulfate; Tiquinamide I lydrochloride;
Tofcnacin I-Iydrochloridc;
Toquizinc; Triampyzine Sulfate; Trihexyphenidyl I-Iydrocliloride; Tropicamide.
Anticoagulant: Ancrod; Anticoagulant Citrate Dextrose Solution ; Anticoagulant Citrate Phosphate Dextrose Adeiiine Solution; Anticoagulant Citrate Phosphate Dextrose Solution;
Anticoagulant I-Icparin Solution; Anticoagulant Sodiuni Citrate Solution; Ardepat=in Sodiuin; Bivalirudin ;
I3roniindionc; Dalteparin Sodium ; Desirudin; Dicuinarol; I-leparin Calcium;
Ileparin Sodium;
Lyapolate Sodium; Nafainostat Mesylate ; I'henprocounion; Tinzaparin Sodium ;
Warfarin Sodium.
Anticoccidal: Maduramicin.
Anticonvulsant: Albutoin; Amcltolidc; Atolide; Buramatc; Carbaniazepine ;
Cinronlidc; C.itcnaniide;
Clonazepam; Cyheptamide; Dezinamide; Dimethadione; Divalproex Sodium;
Eterobarb;
Ethosuximide; Ethotoin; Flurazepam Hydrochloride ; Fluzinamide; Fosphenytoin Sodium;
Gabapentin; Ilepcimide; Lamotrigine; Magnesium Sulfate ; Mephenytoin;
Mephobarbital ;
Methetoin; Methsuximide; Milacemide Hydrochloride ; Nabazenil; Nafimidone Hydrochloride;
Nitrazepam ; Phenacemide; Phenobarbital ; Phenobarbital Sodium ; Phensuximide;
Phenytoin;
Phenytoin Sodiuin; Primidone; Progabide; Ralitoline; Remacemide Hydrochloride;
Ropizine;
Sabeluzole ; Stiripentol; Sulthiame; Thiopental Sodium ; Tiletamine Hydrochloride ; Topiramate;
Trimethadione; Valproate Sodium; Valproic Acid; Vigabatrin; Zoniclezole Hydrochloride;
Zonisamide.
Antidepressant: Adatanserin I-Iydrochloride; Adinazolam ; Adinazolam Mesylate;
Alaproclate;
Aletaniine Hydrochloride; Amedalin Hydrochloride; Aniitriptyline Hydrochloride; Amoxapine;
Aptazapine Maleate; Azaloxan Fumarate; Azepindole; Azipramine Hydrochloride;
Bipenamol I-Iydrochloride; Bupropion Hydrochloride; Butacetin; Butriptyline Hydrochloride; Caroxazone;
Cartazolate; Ciclazindol; Cidoxepin Hydrochloride; Cilobamine Mesylate;
Clodazon Hydrochloride;
Clomipramine Hydrochloride; Cotinine Fumarate; Cyclindole; Cypenamine Hydrochloride;
Cyprolidol Hydrochloride; Cyproximide ; Daledalin Tosylate; Dapoxetine Hydrochloride; Dazadrol Maleate; Dazepinil Hydrochloride; Desipramine Hydrochloride; Dexamisole;
Deximafen;
Dibenzepin I-lydrochloride; Dioxadrol Hydrochloride; Dothiepin Hydrochloride;
Doxepin Hydrochloride; Duloxetine Hydroclilbride; Eclanamine Maleate; Encypratc;
Etoperidone 1-Iydrochloride; Fantridone Hydrochloride; Fenmetozole Hydrochloride ;
Fenmetramide; Fezolamine Fumarate; Fluotracen I-lydrochloride ; Fluoxetine; Fluoxetine I-lydrocliloride; Fluparoxan Hydrochloride; Gamfexine; Guanoxyfen Sulfate ; Imafen Hydrochloride; Imiloxan Hydrochloride;
Imipramine Hydrochloride; Indeioxazine Hydrochloride; Intriptyline Hydrochloride; Iprindole;
Isocarboxazid; Ketipramine Fumarate; Lofepramine Hydrochloride; Lortalamine;
Maprotilale;
Maprotilinc Ilydrocliloridc; Mclitraccn I-Iydrochloridc; Milacemide I-Iydrocliloridc; Minaprinc Hydrochloride; Mirtazapine; Moclobemide; Modaline Sulfate; Napactadine Hydrochloride;
Napamezole I-lydrochloride; Nefazodone Hydrochloride; Nisoxetine; Nitrafudam Hydrochloride;
Nomifensine Maleate; Nortriptyline Hydrochloride; Octriptyiine Phosphate;
Opipramol Hydrochloride; Oxaprotiline Hydrochloride; Oxypertine; Paroxetine; Phenelzine Sulfate;
Pirandamine I-Iydrochioride; Pizotyline ; Pridefine Hydrochloride; Prolintane I-Iydrochloride;
Protriptyline Hydrochloride; Quipazine Maleate ; Rolicyprine; Seproxetine I-Iydrochloride;
Sertraline Hydrochloride; Sibutramine Hydrochloride ; Sulpiride; Suritozole;
Tametraline Hydrochloride; Tampramine Fumarate; Tandamine Hydrochloride: Thiazesim Hydrochloride;
Tliozalinone; Tomoxetine Hydrochloride; Trazodone Hydrochloride; Trebenzomine Hydrochloride;
Trimipramine; Trimipramine Maleate; Venlafaxine Hydrochloride; Viloxazine Hydrochloride;
Zimeldine Hydrochloride; Zometapine.
Antidiabetic: Acetohexamide; Buformin; Butoxamine Hydrochloride ; Camiglibose;
Chiorpropamide; Ciglitazone; Englitazone Sodium; Etoformin Hydrochloride;
Gliamilide;
Glibornuride; Glicetanile Sodium; Gliflumide; Glipizide; Glucagon; Glyburide;
Glyhexamide;
io Glymidine Sodium; Glyoctamide; Glyparamide; Insulin; Insulin, Dalanated;
Insulin Human; Insulin Human, Isophane; Insulin I-Iuman Zinc; Insulin Human Zinc, Extended; Insulin, Isophane; Insulin Lispro; Insulin, Neutral; Insulin Zinc; Insulin Zinc, Extended; Insulin Zinc, Prompt; Linogliride;
Linogliride Fumarate; Metformin; Methyl Palmoxirate; Palmoxirate Sodium;
Pioglitazone Hydrochloride; Pirogliride Tartrate; I'roinsulin Human; Seglitide Acetate;
Tolazamide; Tolbutamide;
Tolpyrramide; Troglitazone; Zopoirestat.
Antidiarrheal: Rolgamidine, Diphenoxylate hydrochloride (Lomotil), Metronidazole (Flagyl), Methylprednisolone (Medrol), Sulfasalazine (Azulfidine).
2o Antidiuretic: Argipressin Tannate; Desrtiopressin Acetate; Lypressin .
Antidote: Dimercaprol; Edrophonium Chloride; Fomepizole; Leucovorin Calcium ;
Levoleucovorin Calcium; Metliylene Blue ; Protamine Sulfate.
Antidyskinetic: Seiegiline Hydrochloride .
Anti-emetic: Alosetron Hydrocliloride; Batanopride Hydrochloride; Bemesetron;
Benzquinamide;
Chlorpromazine ; Chlorpromazine Hydrochloride ; Clebopride; Cyclizine Hydrochloride;
Dimenhydrinate; Diphenidol; Diphenidol Hydrochloride; Diphenidol Pamoate;
Dolasetron Mesylate ; Domperidone; Dronabinol; Fludorex; Tlumeridone; Galdansetron I-lydrochioride; Granisetron;
3o Granisetron I-lydrochloride; Lurosetron Mesylate; Mcclizine Hydrochloride;
Metoclopramide Hydrochloride; Metopimazine; Ondansetron Hydrochloride ; Pancopride;
Prochlorperazine;
Prochlorperazine Edisylate; Prochlorperazine Maleate ; Promethazine Hydrochloride Thiethylperazine; Thiethylperazine Malate; Thiethylperazine Maleate;
Trimethobenzamide Hydrochloride; Zacopride Hydrochloride.
Anti-epileptic: Felbamate; Loreclezole; Tolgabide.
Anti-estrogen: Clometherone; Delmadinone Acetate ; Nafoxidine Hydrochloride;
Nitromifene Citrate; Raloxifene Hydrochloride; Tamoxifen Citrate; Toremifene Citrate ;
Trioxifene Mesylate.
Antifibrinolytic: Nafamostat Mesylate .
Antifungal: Acrisorcin; Ambruticin; Amphotericin B; Azaconazole; Azaserine;
Basifungin;
Bifonazole; Biphenaniine Hydrochloride ; Bispyrithione Magsulfex ;
Butoconazole Nitrate; Calcium Undecylenate; Candicidin; Carbol-Fuchsin; Chiordantoin; Ciclopirox; Ciclopirox Olamine;
Cilofungin; Cisconazole; Clotrimazole; Cuprimyxin; Denofungin ; Dipyrithione;
Doconazole;
Econazole; Econazole Nitrate; Enilconazole; Ethonam Nitrate; Fenticonazole Nitrate; Filipin;
Fluconazole; Flucytosine; Fungimycin; Griseofulvin; Hamycin; Isoconazole ;
Itraconazole;
Kalafungin; Ketoconazole; Lomofungin; Lydimycin; Mepartricin ; Miconazole;
Miconazole Nitrate;
Monensin ; Monensin Sodium ; Naftifine Hydrochloride; Neomycin Undecylenate ;
Nifuratel Nifutmerone; Nitralamine Hydrochloride; Nystatin; Octanoic Acid; Orconazole Nitrate; Oxiconazole 2o Nitrate; Oxifungin Hydrochloride; ParConazole Hydrochloride; Partricin ;
Potassium Iodide I'rocloiiol ; Pyrithione Zinc ; Pyrrolnitrin; Rutamycin; Sanguinariuni Chloride ; Saperconazoic;
Scopatungin ; Scleniuni Sulfide ; Sinetungin; Sulconazole Nitrate;
"I'erbinaGne; Terconazole;
Thiram; Ticlatone ; Tioconazole; Tolciclate; Tolindate; Tolnaftate; Triacetin;
Triafungin;
Undecylenic Acid; Viridofulvin; Zinc Undecylenate; Zinoconazole Hydrochloride.
Antiglaucoma agent : Alprcnoxime Hydrocliloride ; Colforsin; Dapiprazole Hydrochloride Dipivefrin Hydrochloride ; Naboctate Hydrochloride ; Pilocarpine; Pimabine.
Antihemophilic: Antihemophilic Factor.
Antihemorrhagic: Poliglusam.
Antihistaniinic: Acrivastine; Antazoline Phosphate; Astemizole ; Azatadine Maleate; Barmastine;
Bromodiphenhydramine Hydrochloride; Brompheniramine Maleate; Carbinoxamine Maleate;
Cetirizine Hydrochloride; Clilorpheniramine Maleate; Chlorpheniramine Polistirex; Cinnarizine;
Clemastine; Clemastine Fumarate; Closiramine Aceturate; Cycliramine Maleate;
Cyclizine;
Cyproheptadine Hydrochloride ; Dexbrompheniramine Maleate; Dexchlorpheniramine Maleate;
Dimethindene Maleate; Diphenhydramine Citrate; Diphenhydramine Hydrochloride;
Dorastine Hydrochloride; Doxylamine Succinate; Ebastine; Levocabastine Hydrochloride;
Loratadine;
Mianserin I-lydrochloride ; Noberastine; Orphenadrine Citrate ; Pyrabrom;
Pyrilamine Maleate;
Pyroxamine Maleate; Rocastine Hydrocliloride; Rotoxaniine; Tazifylline Hydrochloride;
lo Temelastine; Terfenadine; Tripelennamine Citrate; Tripelennamine Hydrochloride; Triprolidine Hydrochloride; Zolamine Hydrochloride .
Antihyperlipidemic: Cholestyramine Resin ; Clofibrate; Colestipol Hydrochloride; Crilvastatin;
Dalvastatin; Dextrothvroxine Sodium; Fluvastatin Sodium ; Gemfibrozil;
Lecimibide; Lovastatin;
Niacin ; Pravastatin Sodium; Probucol; Simvastatin; Tiqueside; Xenbucin.
Antihyperlipoproteinemic: Acifran; Beloxamide; Bezafibrate; Boxidine;
Butoxanmine Hydrocllloride;
Cetaben Sodium; Ciprofibrate; Gemcadiol; Halofenate ; Lifibrate; Meglutol;
Nafenopin; Pimetine I-Iydrochloride; Theofibrate; Tibric Acid; Treloxinate.
2o Antihypertensive: Alfuzosin Hydrochloride; Alipamide ; Althiazide;
Amiquinsin Hydrochloride;
Amlodipine Besylate ; Anilodipine Maleate ; Anaritide Acetate ; Atiprosin Maleate; Belfosdil;
Bemitradine; Bendacalol Mesylate; Bendrofluniethiazide ; Benzthiazide ;
Betaxolol Hydrochloride ; Bethanidine Sulfate; Bevantolol 1-Iydrochloride ; Biclodil I-Iydrochloride;
Bisoprolol; Bisoprolol Fumaratc; Bucindolol Hydrochloride; Bupicomide; Buthiazide: Candoxatril;
Candoxatrilat;
Captopril ; Carvedilol ; Ceronapril; Chlorothiazide Sodium ; Cicletanine;
Cilazapril; Clonidiie;
Clonidine Hydrochloride; Clopamide ; Cyclopenthiazide; Cyclothiazide ;
Darodipine ; Debrisoquin Sulfate; Delapril Hydrocliloride; Diapamide ; Diazoxide; Dilevalol I-Iydrochloride ; Diltiazem Malate; Ditekiren; Doxazosin Mesylate; Ecadotril; Enalapril Maleate;
Enalaprilat; Enalkiren;
Endralazinc Mesylate; Epithiazide ; Eprosartan; Eprosartan Mesylate;
Fenoldopam Mesylate ;
Flavodilol Malcate; Flordipinc; Flosequinan; Fosinopril Sodium ; f osinoprilat; Guanabcnz;
Guanabenz Acetate; Guanaciine Sulfate; Guanadrel Sulfate; Guancydine;
Guanethidine Monosulfate; Guanethiciine Sulfate; Guanfacine Hydrochloride; Guanisoquin Sulfate; Guanoclor Sulfatc; Guanoctinc Hydrochloride; Guanoxabenz; Guanoxan Sulfate; Guanoxyfcn Sulfate Hydralazine Hydrochloride; Hydralazine Polistirex; Hydroflumethiazide ;
Indacrinone ; Indapamide;
Indolapril I-Iydrochloride; Indoramin; Indoramin Hydrochloride; Indorenate Hydrochloride;
Lacidipine; Leniquinsin; Levcromakalim ; Lisinopril; Lofexidine Hydrochloride;
Losartan S 1'otassium; Losulazinc Hydrochloridc; Mebutamate; Mecamylamine 1-lydroehloridc; Medroxalol;
Medroxalol Hydrochloride; Methaithiazide ; Methyclothiazide ; Methyldopa;
Methyldopate Hydrocliloride; Metipranolol; Metolazone ; Metoprolol Fumarate; Metoprolol Succinate Metyrosine; Minoxidil ; Monatepil Maleate ; Muzolimine ; Nebivolol;
Nitrendipine; Ofomine;
Pargyline Hydrochloride; Pazoxide; Pelanserin Hydrochloride ; Perindopril Erbumine;
jo Phenoxybenzamine Hydrochloride; Pinacidil; Pivopril; Polythiazide ;
Prazosin Hydrochloride;
Primidolol ; Prizidilol Hydrochloride; Quinapril Hydrochloride ; Quinaprilat ;
Quinazosin 1-lydrochloridc; Quinelorane Hydrochloride ; Quinpirole I-Iydrochloride;
Quinuclium Bromide;
Ramipril ; Rauwolfia Serpentina; Reserpine; Saprisartan Potassium; Saralasin Acetate; Sodium Nitroprusside; Sulfinalol Hydrochloride; Tasosartan; Teludipine Hydrochloride ; Temocapril 15 Hydrochloride; Terazosin I-lydrochloride; Terlakiren; Tiamenidine;
Tiamenidine Hydrochloride;
Ticrynafen ; Tinabinol; Tiodazosin; Tipentosin Hydrochloride;
Trichlorniethiazide ; Trimazosin Hydrochloride; Trimethaphan Camsylate; Trimoxamine Hydrochloride; Tripamide;
Xipamide Zankircn Hydrochloride; Zofenoprilat Arginine.
20 Antihypotensive: Ciclafrine I-Iydrochloride; Midodrine Hydrochloride.
Anti-infective: Difloxacin Hydrochloridc ; Lauryl Isoquinoliniutn Bromide;
Moxalactam Disodium;
Ornidazole; Pentisomicin; Sarafloxacin Hydrochloride; Protease inhibitors of I-IIV and other retroviruses; Integrase Inhibitors of HIV and other retroviruses; Cefaclor (CeclorTM); Acyclovir 25 (ZoviraxTM); Norfloxacin (NoroxinTM); Cefoxitin (MefoxinTM); Cefuroxime axetil (CeftinTM);
Ciprofloxacin (CiproTM).
Anti-infective, topical: Alcohol; Aminacrine Hydrochloride; Benzethonium Chloride : Bithionolate Sodium; Bromchlorenone; Carbamide Peroxide; Cetalkonium Chloride;
Cetylpyridinium Chloride:
30 Chlorhexidine Hydrochloride; Clioquinol ; Domiphen Bromide; Fenticlor;
Fludazonium Chloride;
Fuchsin, Basic; Furazolidone ; Gentian Violet; Halquinols; Hexachlorophene:
Hydrogen Peroxide;
Ichthammol; Imidecyl Iodine; Iodine; Isopropyl Alcohol; Mafenide Acetate;
Meralein Sodium;
1. i. '', .~~- lq.u~11..1,~ , ~
Mercufenol Cliloride; Mercury, Ammoniated; Methvibenzethonium Chloride;
Nitrofurazone;
Nitromersol; Octenidine Hydrochloride; Oxychlorosene; Oxychlorosene Sodium;
Parachlorophenol, Camphorated; Potassium Permanganate; Povidone-Iodine; Sepazonium Cliloride;
Silver Nitrate;
Sulfadiazine, Silver; Symclosene; Thimerfonate Sodium; Thimerosal : Troclosene Potassium.
Anti-inflammatory: Alclofenac; Alclometasone Dipropionate; Algestone Acetonide; Alpha Amylase;
Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose Hydrochloride; Anakinra;
Anirolac Anitrazafen; Apazone; Balsalazide Disodium; Bendazac; Benoxaprofen ;
Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen; Cicloprofen;
Cintazone;
1 o Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac;
Cloticasone Propionate;
Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide; Desoximetasone;
Dexamethasone Dipropionate; Diclofenac Potassiunl; Diciofenac Sodium; Diflorasone Diacetate;
Diflumidone Sodium; Diflunisal ; Difluprednate; Diftalone; Dimethyl Sulfoxide;
Drocinonide; Endrysone;
Enliniomab ; Cnolicam Sodium ; Epirizole ; Etodolac; Etofenamate ; Felbinac;
Fenamole; Fenbufen;
Fenclofenac; Fenclorac; Fendosal; Fenpipalone; Fentiazac; Flazalone;
Fluazacort; Flufenamic Acid;
Flumizole; Flunisolide Acetate; Flunixin ; Flunixin Meglunline ; Fluocortin Butyl; Fluorometholone Acetate; Fluquazone; Flurbiprofen ; Fluretofen; Fluticasone Propionate;
Furaprofen; Furobufen;
Halcinonide; Halobetasol Propionate; Halopredone Acetate; Ibufenac ;
Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol; Ilonidap; Indometliacin; Indomethacin Sodium;
Indoprofen Indoxole ; Intrazole; Isoflupredone -Acetate; Isoxepac; Isoxicam; Ketoprofen;
Lofemizole Hydrochloride ; Lomoxicam ; Loteprednol Etabonate; Meclofenamate Sodium;
Meclofenamic Acid;
Meclorisone Dibutyrate; Mefenamic Acid ; Mesalamine; Meseclazone;
Methylprednisolone Suleptanate; Morniflumate; Nabumetone; Naproxen ; Naproxen Sodium ; Naproxol ;
Nimazone;
Olsalazine Sodium; Orgotein ; Orpanoxin; Oxaprozin; Oxyphenbutazone;
Paranyline Hydrochioride;
Pentosan Polysulfate Sodium; Plienbutazone Sodium Glycerate; Pirfenidone ;
Piroxicam; Piroxic,am Cinnamate; Piroxicam Olamine; Pirprofen; Prednazate; Prifelone; Prodolic Acid;
Proquazone;
Proxazole; Proxazole Citrate ; Rimexolone; Romazarit ; Salcolex ; Salnacedin;
Salsalate Sanguinarium Chloride ; Seclazone ; Sermetacin; Sudoxicam; Sulindac; Suprofen;
Talmetacin;
Talniflumate ; Talosalate ; Tebufelone ; Tenidap; Tenidap Sodium; Tenoxicam;
Tesicam; Tesimide;
Tetrydamine ; Tiopinac; Tixocortol Pivalate; Tolmetin; Tolnietin Sodium;
Triclonide; Triflumidate;
Zidometacin; Zomepirac Sodium.
- - ------- - -- -------Antikeratinizing agent: Doretinel; Linarotene; Pelretin.
Antimalarial : Acedapsonc ; Amodiaquine I-Iydrochloriclc ; Amquinatc;
Artellcnc; Cliloroquinc Chloroquine Hydrochloride ; Chloroquine Phosphate ; Cycloguanil Pamoate;
Enpiroline Phosphate;
Halofantrine Hydrocliloride ; Hydroxychloroquine Sulfate ; Mefloquine Hydrochloride; Menoctone;
Mirincamycin Hydrochloride ; Primaquine Phosphate; Pyrimethamine; Quinine Sulfate; Tebuquine.
Antimicrobial: Aztreonam; Chlorhexidine Gluconate; Imidurea; Lycetamine;
Nibroxane;
Pirazmonam Sodium; Propionic Acid ; Pyrithione Sodium; Sanguinarium Chloride ;
Tigemonam t o Dicholine.
Antimigraine: Dolasetron Mesylate ; Naratriptan Hydrochloride; Sergolexole Maleate; Sumatriptan Succinate; Zatosetron Maleate.
Antimitotic: Podofilox.
Antiniycotic: Amorolfine.
Antinauseant : Buclizine Hydrochloride ; Cyclizine Lactate; Naboctate Hydrochloride.
Antineoplastic: Acivicin; Aciarubicin; Acodazole 1-Iydrochloride; Acronine;
Adozelesin;
Aldesleukin ; Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutethimide ;
Amsacrine;
Anastrozole; Anthraniycin; Asparaginase; Asperlin ; Azacitidine; Azetepa;
Azotomycin; Batimastat;
Benzodepa; Bicalutamide; Bisantrene Hydrochloride; Bisnafide Dimesylate;
Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Bropirimine ; Busulfan; Cactinomycin; Calusterone;
Caracemiide;
Carbetimer; Carboplatin; Carmustine; Carubicin Hydrochloride; Carzelesin;
Cedefingol;
Chlorambucil; Cirolemycin ; Cisplatin; Cladribine; Crisnatol Mesylate;
Cyclophosphamide ;
Cytarabine ; Dacarbazine; Dactinomycin; Daunorubicin Hydrochloride;
Decitabine; Dexormaplatin;
Dezaguanine; Dezaguanine Mesylate; Diaziquone; Docetaxel; Doxorubicin;
Doxorubicin 3o Hydrochloride; Droloxifene; Droloxifene Citrate; Dromostanolone Propionate;
Duazomycin;
Edatrexate; Eflornithine Hydrochloride ; Elsamitrucin; Enloplatin; Enpromate;
Epipropidine;
Epirubicin Hydrochloride; Erbulozole; Esorubicin Hydrochloride; Estranlustine;
Estramustine Phosphate Sodium; Etanidazole; Ethiodized Oil I 131; Etoposide; Etoposide Phosphate; Etoprine;
Fadrozole Hydrochloride; Fazarabine; Fenretinide; Floxuridine ; Fludarabine Phosphate;
Fluorouracil; Flurocitabine; Fosquidone; Fostriecin Sodium; Gemcitabine;
Gemcitabine Hydrochloride; Gold Au 198 ; Hydroxyurea; Idarubicin Hydrochloride;
Ifosfamide; Ilmofosine;
Interferon Alfa-2a ; Interferon Alfa-2b ; Interferon Alfa-n1; Interferon Alfa-n3; Interferon Beta-I a ; Interferon Gamma-I b; Iproplatin; Irinotecan Hydrochloride ; Lanreotide Acetate; Letrozole;
Leuprolide Acetate ; Liarozole Hydrochloride; Lometrexol Sodium; Lomustine;
Losoxantrone [-Iydrochloride; Masoprocol; Maytansine; Meclilorethamine 1-Iydrochloride;
Megestrol Acetate;
Melengestrol Acetate; Meiphalan; Menogaril; Mercaptopurine; Methotrexate;
Methotrexate Sodium;
i o 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; Piposulfan; Piroxantrone Hydrochloride; Plicamycin;
Plomestane;
Porfimer Sodium; Porfiromycin ; Prednimustine; Procarbazine I-Iydrochloride;
Puromycin ;
Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Safingol ;
Safingol Hydrochloride ; Semustine; Simtrazene; Sparfosate Sodiuni; Sparsomycin; Spirogermanium 1-Iydrochloride;
Spiromustine; Spiroplatin; Streptonigrin; Streptozocin; Strontium Chloride Sr 89; Sulofenur;
Talisomycin; Taxane; Taxoid; Tecogalan Sodium; Tegafur; Teloxantrone Hydrochloride;
Temoporfin; Teniposide; Teroxirone; Testolactone; Thiamiprine; Thioguanine;
Thiotepa; Tiazofurin;
2o Tirapazamine; Topotecan Hydrochloride; Toremifene Citrate; Trestolone Acetate; Triciribine Phosphate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin; Tubulozole Hydrochloride; Uracil Mustard; Uredepa; Vapreotide; Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Vindesine;
Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; Vinrosidine Sulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin;
Zinostatin; Zorubicin Hydrochloride.
Other anti-neoplastic compounds include: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil;
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;
3o antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen;
antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators;
apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase;
asulacrine; atamestane;
atriniustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron;
azatoxin; azatyrosine; baccatin III
derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins;
benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF
inhibitor; bicalutamide;
bisantrene; bisaziridinvlspertnine; bisnafidc; bistratene A; bizelesin;
breflate; bropirimine;
budotitane; buthionine sttlfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700;
cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS);
castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;
clomifene analogues; clotrimazole; collismycin A; collismycin B;
combretastatin A4; combretastatin i o analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives;
curacin A; cyclopentanthraquinones; cycloplatanl; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexifosfamide; dexrazoxane;
dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;
dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docosanol; dolasetron;
doxifluridine;
droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine;
edrecolomab;
eflornithine; elemene; emitefur; epirubicin; epristeride; estratnustine analogue; estrogen agonists;
estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;
fazarabine;
fenretinidc; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone;
fludarabine;
fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin;
fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors;
gemcitabine; glutathione inhibitors; hepsuifam; het-egttlin; hexamethylene bisacetamide; hypericin;
ibandronic acid;
idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones;
imiquimod;
immunostimulant pcptidcs; insulin-like growth factor-I receptor inhibitor;
interferon agonists;
interferons; interleukins; iobenguatie; iododoxorubicin; ipomeanol, 4-;
irinotecan; iroplact;
irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;
kahalalide F; lamellatin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate;
leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide + estrogen +
progesterone; leuprorelin;
levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinuni compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine;
losoxantrone;
lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic pcptides; maitansine;
mannostatin A; marimastat; masoprocol; niaspin; matrilysin inhibitors; matrix nletalloproteinase inhibitors; menogaril; merbarone; meterelin; metliioninasc; metoclopramide;
MIF inhibitor;
mifepristone; miltefosine; niirimostim; mismatched double stranded RNA;
mitoguazone; mitolactol;
mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin;
mitoxantrone;
mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin;
monophosphoryl lipid A + myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based tlierapy; mustard anticancer agent; mycaperoxide B;
mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin;
nagrestip; naloxone + pentazocine; napavin; naphterpin; nartograstim;
nedaplatin: nemorubicin;
neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06-benzylguanine; octreotide; okicenone;
oligonucleotides; onapristone;
ondansetron; ondansetron; oracin; oral cytokine inducer; ormapiatin;
osaterone; oxaliplatin;
oxaunomycin; paclitaxel analogues; paclitaxel derivatives; palauamine;
palmitoylrhizoxin;
painidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;
pegaspargase; peldesine;
pentosan polysulfate sodiuni; pentostatin; pentrozole; perflubron;
perfosfamide; 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; porfimer sodium; porfiromycin;
propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inliibitor; protein kinase C i-iliibitors, microalgal; protein tyrosine phosphatase inhibitors;
purine nucleoside phospiiorylase inhibitors; purpurins; pyrazoloacridine;
pyridoxylated hemoglobin 30 polyoxycthylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAI' inhibitor; retelliptine demethylated;
rhenium Re 186 etidronate;
rhizoxin; ribozynies; RII rctinaniidc; robletimidc; roliitukinc; romurtide;
roquinimex: rubiginone B1;
ruboxyl; saluigol; saintopin; SarCNU; sarcophytol A; sargraniostim; Sdi 1 mimetics; semustine;
senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chaiii antigen binding protein; sizofiran;
sobuzoxane; sodium borocaptatc; sodium phenylacetate; solverol; somatomedin binding protein;
sonermin; sparfosic acid;
spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipianiide; stronielysin inhibitors; sulfinosine;
superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; syntlietic glycosaminoblycans; tallimustinc;
tanioxifen methiodide; tauromustinc; tazarotenc; tecogalan sodium; tegafur;
tellurapyrylitnn;
telomerase inhibitors; tenioporfin; temozolomide; tcniposide;
tetrachlorodecaoxide; tetrazomine;
thaliblastinc: tlialidomide; thiocoraline; thrombopoictin; thrombopoictin inimetic; tliymalfasin;
tliymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin;
tirapazamine; titanocene dichloride; topotecan; topsentin; toremifene;
totipotent stem cell factor;
translation inhibitors; tretinoin; triacetyluridine; triciribine;
trimetrexate; triptorelin; tropisetron;
turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors;
ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide;
variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin;
vinorelbine; vinxaltine;
vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer.
Anti-cancer Supplementary Potentiating Agents: Tricyclic anti-depressant drugs (e.g., imipramine, desipramine, amitryptyline, clomipramine, trimipramine, doxepin, nortriptyline, lo protriptyline, amoxapine and maprotiline); non-tricyclic anti-depressant drugs (e.g., sertraline, trazodone and citalopram); Ca++ antagonists (e.g., verapamil, nifedipine, nitrendipine and caroverine); Calmodulin inhibitors (e.g., prenvlamine, trifluoroperazine and clomipramine);
Amphotericin B; Triparanol analogues (e.g., tamoxifen); antiarrhythmic drugs (e.g., quinidine);
antihypertensive drugs (e.g., reserpine); Tliiol depleters (e.g., buthionine and sulfoximine) and Multiple Drug Resistance reducing agents such as Cremaphor EL. The compounds of the invention also can be administered with cytokines such as granulocyte colony stimulating factor.
Antiheutropenic: Pilgrastim; Lenograstim; Molgramostim; Regramostim;
Sargramostim.
2o Antiobsessional agent: Fluvoxamine Maleate.
Antiparasitic: Abamectin; Clorsulon; Ivermectin.
Antiparkinsonian: Bcnztropinc Mesylate; I3iperidcn; Bipcriden l lydrochloridc;
Biperiden Lactate;
Carmantadine; Ciladopa Hydrochloride; Dopamantine; Ethopropazine Hydrochloride; Lazabemide;
Levodopa; Lometraline Hydrochloride; Mofegiline Hydrochloride; Naxagolide I-lydrochloride;
Pareptide Sulfate; Procyclidine Hydrochloride; Quinelorane Hydrochloride;
Ropinirole Hydrochloride; Selegiline Hydrochloride; Tolcapone; Ti-ihexyplienidyl I-Iydrochloride.
3o Antiperistaltic: Difenoxicnide I-Iydrochloride; Difenoxin; Diplienoxylate Hydrochloride;
Pluperamide; Lidamidine Hydrochloride; Loperamide Hydrochloride; Malethamer;
Nufcnoxole;
Paregoric.
Antipneumocystic: Atovaquone.
Antiproliferative agent: Piritrexim Isethionate.
Antiprostatic hypertrophy: Sitogluside.
Antiprotozoal: Amodiaquine; Azanidazole; Bamnidazole; Carnidazole;
Chlortetracycline Bisulfate ; Chlortetracycline Hydrochloride; Flubendazole; Flunidazole; Halofuginone Hydrobromide;
Imidocarb Hydrochloride; Ipronidazole; Metronidazole; Misonidazole;
Moxnidazole; Nitarsone;
io Partricin; Puromycin; Puromycin Hydrochloride; Ronidazole; Sulnidazole;
Tinidazole.
Antipruritic: Cyproheptadine Hydrochloride ; Methdilazine; Methdilazine Hydrochloride;
Trimeprazine Tartrate.
Antipsoriatic: Acitretin; Anthralin; Azaribine; Calcipotriene; Cycloheximide;
Enazadrem Phosphate;
Etretinate; Liarozole Fumarate; Lonapalene; Tepoxalin.
Antipsychotic: Acetophenazine Maleate; Alentemol Hydrobrotnide; Alpertine;
Azaperone;
Batelapine Maleatc; Benperidol; Benzindopyrine Hydrochloride; Brofoxine;
Bromperidol;
2o Bromperidol Dccanoatc; I3utacianiol' 'I lydrochloride; Butaperazine;
Butapcrazine Maleate;
Carphenazine Maleate; Carvotroline Hydrochloride; Clilorpromazine;
Chlorpromazine I-Iydrocliloridc; Clllorprothixcne; Cinpercne; Cintriarnidc; Clomacran P11osp11ate; Clopenthixol;
Clopimozide; Clopipazan Mesylate; Cloroperone Ilydrochloride; Clothiapine;
Clothixamide Maleate; Clozapine; Cyclophenazine I-lydrochloride; Droperidol; Etazolate I-lydrocliloride;
Fenimide; Flucindole; Flumezapine; Fluplienazine Decanoate; Fluplienazine Enanthate;
Fluplienazine Hydrochloride; Fluspiperone; Fluspirilene; Flutroline;
Gevotroline Hydrocliloride;
1-Ialopcmide; Haloperidol; Haloperidol Decanoate; Iloperidonc; Imidoline I-lydrochloride;
Lenperone; Mazapertine Succinate; Mesoridazine; Mesoridazine Besylate;
Metiapine; Milenperone;
Milipertine; Molindone Hydrochloride; Naranol I-Iydrochloride; Ncf3umozide I-Iydrochloride;
Ocaperidonc; Olanzapine; Oxiperomide; Pcniluridol; Pentiapine Maleatc:
Applicants obtained paclitaxel from a commercial source, Hauser Laboratories, of Boulder, Colorado.
Example 1 TAXOL
AcO OH
PhNH O
k-1 Ph" v O H O
HO O
IJI OAc 0 0 Ph conjugate 1 A solution of Taxol (41 mol) in methylene chloride (2.5mL) under argon was mixed with 4-dimethylaminopyridine (41 mol), dicyclohexylcarbodiimide (824rnol), and DHA
(41 mol) 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 cllromatography of the residue produced 45mg (94%) of crystalline Taxol-DHA conjugate 1.
I:xample 2 0 AcO O Of.{
TAXOL Ph ~ NH 0 Ph O = = H O
OSiEt3 HO
OAc 0 Ph O Ac0 0 O - - - - - -Phlul NH 0 H B
Ph" v O : H O
O.SiEt3 HO O
OAc 0 0 Pr' 30 O Ac0 O O -- - - - - -PhNH 0 H
Ph' = N O conjugate 2 OH HO O
OAc O~ Ph WO 97144063 CA 02255614 2004-09-23 pCT/[j$97/08867 -ll-The production of analog 2 involves several steps including a number of protection-acylation-deprotection steps. A solution of Taxol (59 mol) in methylcne cliloride ' (2.5mL) was mixed at ambient temperature under argon with imidazole (147 mol) and triethylsilyl chloride (147 mol). The reaction mixture was stirred for thirty minutes, diluted with additional methylene chloride, washed with water, saturated aqueous sodium chloride, dried, and concentrated.
Chromatography of the residue produced 50mg (88%) of intermediate A plus 5mg of the 2', 7-di(triethylsilyl) ether derivative. A solution of intermediate A(52 mol) in methylene chloride (3mL) was mixed at ambient temperature under argon with 4-dimetliylaminopyridinc (52 mo1), dicyclohexylcarbodiimide (104 mol), and DHA (52 mol). The reaction mixture was stirred for tcn lo hours, diluted with ether, passed through celiteTM, 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 (75%) of Taxol-DI=IA conjugate 2.
E e3 Conjugates I and 2 were sent to the United States National Cancer Institute-(NCI) for screcning in the NCI's anticancer screcninb program. The conjugates were provided in ethanol (approximately 40mg analog/2ml ethanol). The conjugates were sealed in vials widcr argon to avoid exposure of the cotijugatcs to oxybcn because the conjugates were believed to be sensitive to oxygen. Insttvctions were provided to store at 4 C and to open the vials only when ready for immediate experimental usc. Instructions also were provided to use the cthanol solutions containing thc conjubatcs dircctly or to dissolvc the analogs liirthcr in DMSO
(dimcthylsull'oxide) at 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 presentcd in Figs. 1-9 for conjugate 1, Figs. 10-18 for conjugate 2 and Figs 19-27 for Taxol. To undcrstand the data, rcfcrence is made to the buides provided by thc NCI, excerpted as follows:
The Calculated Measurement of Effect: Percentaee 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 expressions:
If (Mean OD,,,, -Mean OD,j > 0, then PG = 100 x (Mean OD,,,, -Mean OD,Z,TO)/(Mean ODCW -Mean Odzc,o) If (Mean OD1C5, -Mean ODz,:,o) < 0, then PG = 100 x (Mean OD,,,, -Mean Od,Z,,.)/Mean Odt,CFo Where:
Mean OD,Z o = The average of optical density measurements of SRB-derived color just before exposure of cells to the test compound.
Mean ODt.s, = The average of optical density measurements of SRB-derived color aiter 48 hours exposure of cells to the test compound.
Mean OD,,,, = The average of optical density nieasurements of SRB-derived color after 48 hours witli no exposure of cells to the tcst coinpound.
Experimental data was collected against each cell line. ... Each concentration is expressed as the log,o (inolar or g/ml). ... The response parameters G150, TGI, and LC50 are interpolated values representing the concentrations at wliicli the I'G 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, thcn none of thc three paramcters can he obtained by interpoiation. In such a case, the value given for each response parameter is the higliest concentration tested. ... This practice is extendcd similarly to the other possible situations whcre a response parametcr cannot be obtained by iiiterpolation.
Dose-Response Curves:
The dose-response curve page of the data package is created by plotting the PGs against the log,o 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. Tlie concentrations corresponding to points where the curves cross these lines are the G150, TGI and LC50, respectively.
Several important distinctions are apparent from the data. Most important, the patterns of anticancer actively for conjugates 1 and 2 differ from that of Taxoi. In one sense, conjugates 1 and -o 2 are effective anticancer agents against a niore 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 somcwhat 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-sniall cell lung cancer line H522 than against H460 (by about 3 logs), whereas conjugates 1 and 2 were sliglltly more effective against 1-1460 than H522. As anotlier example, Taxol was least effective at TGI against CNSU25 1, wliereas 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, 2o 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 ef'fective against MDA-N than MDA-MB-435 at all concentrations tested.
To further illustrate the differences in the activity of conjubatcs 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 pattern of activity of anticancer agents. Conjugate I and conjugate 2 were determined tc~ be statistically different in their pattern of activity versus T'axol in this unique measurement by the NCI.
It also is to be noted that, in general, conjugates 1 and 2 were one tliousand to ten thousand times less potent than Taxol for many cell lines tested. This reduction in activity is iniportant, 3o especially since conjugates 1 and 2 maintained strong activity against some cell lines. Conjugates I and 2 will be sufficicntly active against ccrtain cell lines, but will have, on average, a substantially and disproportionately lower activity against other cell lines, reducing potential side effects. For example, 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 G150 for Taxol against CNS SF 539 is -7.52, whereas the G150s for conjugates 1 and 2 are -6.22 and -5.56, respectively (again less than 2 logs difference). In contrast, Taxol has a G150 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 G150 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 1 o actual lower value) was used in calculating the average of -9.19. There were 27 instances when this occurred.) The average G150s for conjugates I 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 otlier 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 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 DI-IA analogs have altered specificity versus that of Taxol for cancer ccll lines. I3ccause of tliis altered spccilicity, it also is clear that the conjugates themselves arc gaining access into the target cells (as opposed to simply releasing Taxol into the environment outside of the cell). 'I'hus, the DHA moiety appears to selectively target certain eell types as opposed to others. Tlic ability of thc conjugatcs to l;ain cntry into the cells was unknown prior to the invention, vid the ability of the DI-IA moiety to selectively target certain cell types was unexpected.
The same is true of DI-IA-Taxotere covalent conjugates, examples of wliich are presented below. 'faxotcre's svnthesis lias bcen reported extensively in the literature.
One example is Kanazawa, A. et al., .1. Organic Chcm. 1994, Vol. 59, pp. 1238-1240.
Exampie 4 TAXOTERE
HO O OH
. 5 O
DHA / dicyclohexylcarbodiimide O~NH 0 4-dimethylaminopyridine m H
PhO O
p OAc 0 O1~1 Ph conjugate 3 A solution of Taxotere in methylene chloride under argon is mixed with 4-dimethyiaminopyridine, dicyclohexylcarbodiimide, and DI-IA. 1'he reaction niixture is stirred at ambient temperature. Radial chromatography of the residue is performed to produce Taxotere-DHA
conjugate 3.
ExampLeS
0 HO 0 OSI(CH?CH3)3 triethylsiiyl chloride TAXOTERE O14, NH O
imidazole,..H
ph~
O H O
(CH3CH?)3SiO HO 0 =
OAc 0 Ph V~% - - - O
O O OSi(CHZCHa)3 DHA / dicyc{ohexylcarbodiimide O-k NH 0 -' ,===H
4-dimethylaminopyridine Ph~O" hi O
(CH3CH2)3Si0 HO
D p OAc O1~1 Ph - - - - - O
aqueous HF 0 O 0 OH
)~OAI NH O
}-i Ph~O Ft conjugate 4 OH HO O OAc O'~, Ph 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 witli 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 etlier, passed throufili celite, and concentrated. Radial cllromatography of the residue is performed to produce intermediate D. A
solution of intermediate D in acctonitrile at 0 C under argon is mixed witli 49% aqueous FIF and the reaction mixture is i o 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.
I;xaniple 6 O HO O OH
fert={)ulyldimethyisilyl chloride TAXOTERE O~NH O ~
imidazole ^ ~ = = '+~
Ph' v O== H- o terl-C.4H9(CH3)2SiO HO O OAc E O Ph O
1 equivalent DHA 0 0 OH
O
dicyclotiexylcarbodi imide 4-dimethylaminopyridine O~NH 0 ~
H
Ph' v O= _ H O
F HO lCri-CqHg(CH3)2SIO 0 OAc 0 Ph - O
O O O OH
aqueous HF
>cANH 0 =H
Ph' v O' F{ O
OH HO
p OAc O~Ph conjugate 4 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, dicyclollexylcarbodiimide, and I
equivalent of DHA.
The reaction mixture is stirred at ambient temperature, diluted with etller, passed through celite, and concentrated. Radial cliromatography of the residue is performed to produce intermediate F.
(Intermediate H also is obtained and used in Example 8 below.) A solution of intermediate F in I o acetonitrile at 0 C under argon is niixed with aqueous HF and the reaction mixture is stirred at the same temperature. After dilution witli ether, the reaction mixture is washed with water, saturated aqueous sodium chloride, dried, and concentrated Radial cliromatograpliy of the residuc is performed to produce Taxotere-DI-IA conjugate 4.
Ex:tmple 7 O HO OH
lerr=bLnyldimethytsilyl chloride ~
O NH O
TAXOTERE imidazole oN
Ph' v O' H
tert-C.Ha(CH3)2SiO HO O OAc O~PIi E
O O
OHA/dicyclohexylcarbodiimide -~"OJ~NH O
....H
4=dimethylaminopyridine Ph' O" O
ternL4H,(CH,)?SiO HO G
p OAc ~
O Pti O O
O O O - _ - - - -O
aqueous HF
O'.111 NH 0 ,,,H
Ph" ~' O H O
OH HO '= =
p OAc conjttgate 5 0 'j, Ph A solution of Taxotere in dimethvlformamide is rnixed 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 witli 4-dimetliylaminopyridine, 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 lo 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 5.
Example 8 HO O O - - - - - -1 equivalent DHA ~ ONH O
~ ....{.~
dicydohexykxrbodiimide Ph'^v'O' 4-dimethylaminopyridine HO
teri-C4H9(CH3)2SiO p OAc H
0 Ph O
aqueous HF
Ph' v 'O' : H O
OH HO O
OAc 0 Pli conjugate 6 A solution of taxotere in dimcthylformamide is mixed at atnbient temperature under argon with imidazole and tert-butylydimethylsilyl cliloride. The reaction mixture is stirred at ambient temperature, diluted with methylene chloride, washed with water, saturated aqueous sodium chloride, dried, and coiicentrated. Radial chromatography of the residue is performed to produce intermediate E. A solution of intermediate E in niethylene chloride is mixed at ambient temperature under argon with 4-dimethylaininopyridine, dicyclohexylcarbodiimide, and I
eqttivalent of DHA.
The reaction niixture is stirred at ambient temperature, diluted witli 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 HF and the reaction mixture is stirred at the same temperature. After diiution with ether, the reaction mixture is washed with water, saturated aqueous sodium cltloride, dried, and concetitrated. Radial chromatography of tlie residue is performed to produce Taxotere-DHA conjugate 6.
DHA may be conjugated to virtually any drug conipound or diagnostic agent and used according to the methods of the present invention so long as the pllarmaceutical agent has a use outside of the central nervous system. I'harmaceutical 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 ncrvous system. Those of ordinary skill in the art will rccognize also 2o numerous other compounds that fall wlthin the categories and that are useful accordinb to the invcntion.
Adrenergic: Adrenalone; Amidcplirinc Mesylate; Apraclonidinc I-lydrochloride;
Brimonidine Tartrate; Dapiprazole I-Iydrochloride; Deterenol t-Iydrochloride; Dipivefrin;
Dopamine 1lydrochloride; I_:phedrinc Sulfate; E-pinephrinc; l:pincphrine I3itartratc;
[:pincpliryl I3orKte;
Esproquin I-lydrochloride; Etafedrine Hydrochloride; I-Iydroxyamphctamine Hydrobromide;
Levonordefrin; Mephenterminc Sulfatc; Metaraminol Bitartratc; Metizoline I-lydrocllloridc;
Naphazoline I-lydrochloride; Norepinephrine I3itartratc; Oxidopamine;
Oxymetazoline I-Iydrochloridc; Phenyiephrinc 1-tydrochloridc; Phenylpropanolaminc I-Iydrocliloride;
Pllenylpropanolamine Polistirex; Prenalterol I-lydrochloride; Pt-opylhexedrinc; Pseudocnhedrinc Hydrochloride; Tetrahydrozolinc I Iydrochloridc; Tramazolinc I tydrochloride;
Xyionictazoline I lydrochioridc.
Adrenocortical steroid: Ciprocinonide; Desoxycorticosterone Acetate;
Desoxycorticosterone Pivalate; Dexamethasone Acetate; Fludrocortisone Acetate; Flumoxonide; I-Hydrocortisone Hemisuccinate; Methylprednisolone Hemisuccinate; Naflocort; Procinonide;
Timobesone Acetate;
Tipredanc.
Adrenocortical suppressant: Aminoglutethimide; Trilostane.
Alcohol deterrent: Disulfiram.
io 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; Lysine Hydrochloride; Methionine;
Phenylalanine; Proline; Serine;
Threonine; Tryptophan; Tyrosine; Valine.
Ammonia detoxicant: Arginine: Arginine Glutamate; Arginine Hydrochloride.
Anabolic: Bolandiol Dipropionate; Bolasteronc; Boldenone Undecylenate;
Bolenol; Bolmantalate;
I;thylestrenol; Metlienolone Acetate; Methcnolone Cnantiiatc; Mibolerone;
Nandrolone Cyclotate;
Norbolctlionc; Pizotyline; Quinbolonc; Stcnbolonc Acctate; 'ribolonc; Zcranol.
Analeptic: Modalinil.
Analgesic: Acctaminophcn; Alfentanii I-lydrochioride; Aminobcnzoatc Potassium;
Aminobenz4atc Sodium; Anidoxime; Anileridine; Anileridine Hydrochloride; Anilopam Hydrochloride; Anirolac;
Antipyrine; Aspirin; Benoxaprofen; Benzydaminc I-lydrocliloride; Bicifadine I-Iydrochloride;
Brifentanil 1-Iydrochioride; Bromadoline Maleate; Bromfenac Sodium;
Buprenorphinc I-lydrochloridc; Butacctin; Butixiratc; Butorpilanol; Butorplianol Tartratc;
Carbamazcpinc;
Carbaspirin Calcium; Carbiphcne I-lydrochloride; Carfentanil Citrate;
Ciprefadol Succinate;
Ciraniadol: Ciramadol liydrochloridc; Clonixeril; Clonixin; Codcinc ; Codeinc Phospliatc; Codeinc Sulfatc; Conorpiione I-lydrocliloridc; Cyclazocinc; Dcxoxadrol I-lydrochloride; Dexpemedolac;
Dezocine; Diflunisal; Dillydrocodeine Bitartrate; Dimefadane; Dipyrone;
Doxpicomine Hydrochloride; Drinidene; Enadoline Hydrochloride; Epirizole; Ergotamine Tartrate; Ethoxazene Hydrochloride; Etofenamate; Eugenol; Fenoprofen; Fenoprofen Calcium; Fentanyl Citrate;
Floctafenine; Flufenisal; Flunixin; Flunixin Meglumine; Flupirtine Maleate;
Fluproquazone;
Fluradoline Hydrochloride; Flurbiprofen ; Hydromorphone Hydrochloride;
Ibufenac; Indoprofen;
Ketazocine; Ketorfanol; Ketorolac Tromethamine; Letimide Hydrochloride;
Levomethadyl Acetate;
Levomethadyl Acetate Hydrocllloride; Levonantradol I-Iydrochloride;
Levorphanol Tartrate;
Lofemizole Hydrochloride; Lofentanil Oxalate; Lorcinadol; Lornoxicam;
Magnesium Salicylate;
Mefenamic Acid; Menabitan Hydrochloride; Meperidine Hydrochloride; Meptazinol Hydrochloride;
I o Methadone Hydrochloride; Metlladyl Acetate; Methopholine;
Methotrimeprazine; Metkephamid Acetate; Mimbane I-Iydrochloridc; Mirfentanil I-Iydrocllloride; Molinazone;
Morphine Sulfate;
Moxazocine; Nabitan Hydrochloride; Nalbuphine 1-Iydrochloride; Nalmexone Hydrocliloride ;
Namoxyrate; Nantradol I-Iydrochloride; Naproxen ; Naproxen Sodium ; Naproxol;
Nefopanl Hydrochloride; Nexeridine Hydrocllloride; Noracymetlladol Hydrochloride;
Ocfentanil I-lydrochloride; Octazamide; Olvanil; Oxetorone Fumarate; Oxycodone; Oxycodone Hydrochloride;
Oxycodone Terephthalate; Oxynlorphone Hydrochloride; Pemedolac; Pentamorphone;
Pentazocine;
Pentazocine Hydrochloride; Pentazocine Lactate; Phenazopyridine Hydrochloride;
Phenyraniidol 1-Iydrochloride; Picenadol Hydrochloride; Pinadoline; Pirfenidone; Piroxicam Olamine; Pravadoline Maleate; Prodilidine Hydrochloride; Profadol Hydrocllloride; Propiram Funlarate; Propoxypllene I-lydrocllloride; Propoxyphene Napsylate; Proxazole ; Proxazole Citrate ;
Proxorphan Tartrate;
Pyrroliphene 1-Iydrocllloridc; Renlifentanil I-Iydrocllloride; Salcolex Salethanlide Maleatc;
Salicylamidc; Salicylatc Meblunline; Salsalate ; Sodiunl Salicylatc;
Spiradoline Mesylate;
Sufentanil; Sufentanil Citrate; Talmetacin ; Talniflumate ; Talosalate ;
Tazadolene Succinate;
Tebufeione ; Tetrydanline ; Tifurac Sodiunl; Tilidine I-lydrochloridc;
Tiopinac; 'ronazocine Mesylate; Traniadol I-lydrochloride; Trefentanil Hydrochloride; 'rrolamine;
Veradokne I-lydrochloride; Verilopanl I-Iydrochloride; Volazocinc; Xorphanol Mesylate;
Xylazine 1-Iydrochloride; Zetlazocitle Mesylate; Zomepirac Sodlunl ;"Lucapsaicin.
Androgen: Fluoxymcsteronc; Mestcrolonc; Metllyltestosterotlc; Nandrolone Decanoate; Nandrolone Phenpropionate; Nisterime Acetate; Oxandrolone; Oxymetholone; Silandrone;
Stanozolol;
Tcstosterone; Tcstosteronc Cypionate; 'fcstosterone i;nanthatc: Tcstostcrone 1Cctolauratc;
'f'estosterone l'llcnylacetate; Testostcrone Propionatc;l'restolone Acctate.
- 22_ Anestllesia, adjunct to: Sodium Oxybate.
Anesthetic: Aliflurane; Benoxinate Hydrochloride; Benzocaine; Biphenamine Hydrochloride Bupivacaine Hydrochloride; Butamben; Butamben Picrate; Chloroprocaine Hydrochloride; Cocaine;
Cocaine Hydrochloride; Cyclopropane; Desflurane; Dexivacaine; Diamocaine Cyclamate;
Dibucaine; Dibucaine Hydrochloride; Dyclonine Hydrochloride; Enflurane; Ether;
Ethyl Cllloride;
Etidocaine; Etoxadrol Hydrochloride; Euprocin Hydrochloride; Fluroxene;
Halothane; Isobutamben;
Isoflurane; Ketamine Hydrochloride; Levoxadrol Hydrochloride ; Lidocaine;
Lidocaine Hydrochloride; Mepivacaine Hydrochloride; Methohexital Sodium; Methoxyflurane;
Midazolam i o Hydrochloride; Midazolam Maleate; Minaxolone; Nitrous Oxide; Norflurane;
Octodrine;
Oxethazaine; Phencyclidine Hydrochloride; Pramoxine Hydrochloride; Prilocaine Hydrochloride;
Procaine Hydrochloride; Propanidid; Proparacaine Hydrochloride; Propofol;
Propoxycaine Hydrochloride; Pyrrocaine; Risocaine; Rodocaine; Roflurane; Salicyl Alcohol;
Sevoflurane;
Teflurane; Tctracaine; Tetracaine Hydrochloride; Tllianlylal; Tliiamylal Sodium; Thiopental Sodium ; Tiletamine Hydrocllloride; Zolamine Hydrochloride.
Anorectic coinpounds including dexfenfluramine.
Anorexic: Aminorex; Ampllecloral; Chlorphentermine Hydrocllloride; Clominorex;
Clortermine I-Iydrocllloride; Dietllyipropion Hydroclltoride; Fenfluranline I-lydrocllloride; Fenisorex; Fludorex;
Fluminorcx; Levamfetanlinc Succinate; Mazindol; Mefcnorex I Iydrochloride;
Pllenmetrazine I-lydrochioride; Pllentcrmine; Sibutramine Hydrocllloride.
Antagonist: Atipamezolc; Atosiban; Boscntan; Cinletidinc; Cinletidinc I
lydrochloride; ClcnUazenl Maleate; Detirelix Acetate; Devazepide; Donetidine; Etintidine Hydrochloride ;
Famotid'}ne;
Fenmetozole Hydrocllloride ; Flumazenil; Icatibant Acetate; Icotidine;
lsradipine; Metiamide;
Nadide; Nalmefene; Nalmexone I-Iydrochloride ; Naloxone Hydrochloride;
Naltrexone; Nilvadipine;
Oxiloiphan; Oxmctidine I-Iycirocllloride ; Oxmetidine Mesylatc ; Quadazocinc Mcsylatc; Ranitidinc;
Ranitidine Bismuth Citrate ; Ranitidine Ilydrochloridc ; Sufotidine;
Tcludipine I-Iydrocilloride;
3o Tiapamil I-Iydrocliloride; Tiotidine; Vapiprost Hydrocllloride; Zaltidine Hydrochloride.
Anterior pituitary activator: Epimestrol.
Anterior pituitary suppressant: Danazol.
Anthelmintic: Albendazole; Anthelmycin; Bromoxanide; Bunamidine Hydrochloride;
Butonate;
Cambendazole; Carbantel Lauryl Sulfate; Clioxanide; Closantel; Cyclobendazole;
Dichlorvos;
Diethylcarbamazine Citrate; Dribendazole; Dymanthine Hydrochloride;
Etibendazole;
Fenbendazole; Furodazoie; Hexylresorcinol; Mebendazole; Morantel Tartrate;
Niclosamide;
Nitramisole Hydrochloride; Nitrodan; Oxantel Pamoate; Oxfendazole;
Oxibendazole; Parbendazole;
Piperamide Maleate; Piperazine; Piperazine Citrate; Piperazine Edetate Calcium; Proclonol; Pyrantel Pamoate; Pyrantel Tartrate; Pyrvinium Pamoate; Rafoxanide; Stilbazium Iodide;
Tetramisole 1o Hydrochloride; Thiabendazole; Ticarbodine; Tioxidazole; Triclofenol Piperazine; Vincofos; Zilantel.
Anti-acne: Adapalene; Ervthromycin Sa(nacedin; Inocoterone Acetate.
Anti-adrenergic: Acebutolol; Aiprenolol Hydrochloride; Atenolol; Bretylium Tosylate; Bunolol I-Iydrochloride; Carteolol I-lydrochloride; Celiprolol I Iydrocliloride;
Cetamolol I-Iydrochloride;
Cicloprolol Hydrochloride; Dexpropranolol Hydrochloride; Diacetolol Hydrochloride;
Diliydroerbotamine Mesyiatc; Dilevalol 1-Iydrochloride; Esmolol I-lydrochloride; Exaprolol Hydrocliloride; Fenspiride Hydrochloride; Flestolol Sulfate; Labetalol Hydrochloride Levobetaxolol Hydrochloride; Levobunolol Hydrochloride; Metalol Hydrprhloride;
Metoprolol;
Metoprolol Tartrate; Nadolol; Pamatolol Sulfate; Penbutolol Sulfate;
Phentolamine Mesylate;
Practolol; I'ropranolol I-Ivdrochloridc; Proroxan Ilydrocliloricic;
Solypcrtinc Tartratc; Sotalol 1lydrochloridc; Timolol; 1'imolol Maleate; Tiprenolol Ilydrochloridc;
'I'olamolol; Zolertinc Hydrochloride.
Anti-allergic: Amlexanox; Astemizole; Azelastine Hydrochloride; Eclazolast ;
Minocro"l Nedocrornil ; Nedocromil Calcium ; Ncdocromil Sodium ; Nivimedone Sodiunl;
Pemirolast Potassium ; Pentigetide; Pirquinozol; Poisonoak Extract; Probicromil Calciuni;
Proxicromil;
Repirinast ; Tetrazolast Meglumine; Thiazinamium Cliloride; Tiacrilast;
Tiacrilast Sodiuni; Tiprinast Meglumine; Tixanox.
Anti-amebic : Berythromycin ; Bialamicol I-Iydrochloridc; Chloroquinc;
Chloroquinc I Iydrocllloridc;
Cliloroquinc 1'liospliate ; Clamoxyquin I-Iydrochloridc; Clioquinol ; Emctinc 1{ydrochloridc;
Iodoquinol; Paromomycin Sulfate; Quinfamide; Symetine Hydrochloride; Teclozan;
Tetracycline;
Tetracycline Hydrochloride.
Anti-androgen: Benorterone; Cioteronel; Cyproterone Acetate; Delmadinone Acetate ; Oxendolone;
Topterone; Zanoterone.
Anti-anemic: Epoetin Alfa; Epoetin Beta ; Ferrous Sulfate, Dried; Leucovorin Calcium.
Anti-anginal: Amlodipine Besylate; Amlodipine Maleate; Betaxolol Hydrochloride ; Bevantolol io I-lydrochloride ; Butoprozine Hydrochloride; Carvedilol ; Cinepazet Maleate; Metoprolol Succinate ; Molsidomine ; Monatepil Maleate; Primidolol ; Ranolazine Hydrochloride;
Tosifen; Verapamil Hydrocliloride.
Anti-anxiety agent: Adatanserin Hydrochloride; Alpidem; Binospirone Mesylate;
Bretazenil;
Glemanserin; Ipsapirone I-Iydrochioride; Mirisetron Maleate; Ocinaplon;
Ondansetron Hydrochloride ; Panadiplon; Pancopride ; Pazinaclone; Serazapine Hydrochloride; Tandospirone Citrate; Zalospirone Hydrochloride.
Anti-arthritic: Lodelaben .
2o Anti-asthniatic: Ablukast; Ablukast Sodlum; Azelastine Hydrocliloride ;
Bunaprolast; Cinalukast;
Cronlitrile Sodium; Cromolyn Sodium; Cnofelast; Isamoxole; Ketotifcn Fumaratc;
Levcromakalim;
Lodoxamide Cthyl ; Lodoxamidc Tromethaminc; Montelukast Sodium; Ontazolast;
Oxarbazole;
Oxatomidc; Piriprost; Piriprost Potassium; Pirolate; I'obilukast Ldaniine;
Quazolast ; Repirinast;
Ritolukast; Sulukast; Tetrazolast Meglumine ; Tiaramide I-Iydrochloride;
Tibenefast Sodium;
Tomelukast; '1'ranilast; Verlukast; Verofylline ; Zarirlukast.
Anti-atherosclcrotic: Mifobate; Timefuronc.
Antibacterial: Acedapsonc; Acetosulfone Sodium; Alamccin; Alexidinc;
Amdinocillin; Amdinocillin Pivoxii; Amicycline; Amifloxacin; Amifloxacin Mesylate; Amikacin; Amikacin Sulfate;
Anllnotiallcyllc acid; Aminosalicylatc sociiiun; Amoxicillin; Amphomycin;
Anipiciliin; Ampicillin Sodium; Apalcillin Sodium; Apramycin; Aspartocin; Astromicin Sulfate;
Avilamycin; Avoparcin;
Azithromycin; Azlocillin; Aztocillin Sodium; Bacampicillin Hydrocliloride;
Bacitracin; Bacitracin Methylene Disalicylate; Bacitracin Zinc; Bambermycins; Benzoylpas Calciuni;
Berythromycin Betamicin Sulfate; Biapenem; Biniraniycin; 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 Nafate; Ccfamandole Sodium;
Cefaparole;
Cefatrizine; Cefazaflur Sodium; Cefazolin; Cefazolin Sodium; Cefbuperazone;
Cefdinir; Cefepime;
Cefepime Hydrochloride; Cefetecol; Cefixime; Cefmenoxime Hydrochloride;
Cefmetazole;
Cefnietazole Sodium; Cefonicid Monosodium; Cefonicid Sodium; Cefoperazone Sodium;
t o Ceforanide; Cefotaxime Sodium; Cefotetan; Cefotetan Disodium; Cefotiam Hydrochloride;
Cefoxitin; Cefoxitin Sodium; Cefpimizole; Cefpimizole Sodium; Cefpiramide;
Cefpiramide Sodiuni;
Cefpirome Sulfate; Cefpodoxiine Proxetil; Cefprozil; Cefroxadine; Cefsulodin Sodium; Ceftazidime;
Ceitibuten; Ceftizoxime Sodium; Ceftriaxone Sodium; Cefuroxime; Cefuroxime Axetil; Cefuroxime Pivoxetil; Cefuroxime Sodium; Cephacetrile Sodium; Cephalexin; Cephalexin Hydrochloride;
Cephalol;lycin; Cephaloridine; Cephalothin Sodium; Cephapirin Sodium;
Cephradine; Cetocycline Hydrochloride; Cetophenicol; Chloramphenicol; Chloramphenicol Palmitate;
Chloramphenicol 1'antotllenate C.omplcx ; Cliloramphcnicol Sodiuni Succinatc; Chlorhexidine Phosphanilate;
Chloroxylenol; Chlortetracycline Bisulfate; Chlortetracycline Hydrochloride;
Cinoxacin;
Ciprofloxacin; Ciprofloxacin Hydrocllloride; Cirolemycin ; Clarithromycin;
Clinafloxacin 2o Hydrocliioride; Clindamycin; Clindamycin I-lydrochloride; Clindamycin Palmitate Hydrochloride;
Clindamvcin Phosphatc; Clofaziminc ; Cloxacillin Bcnzathinc; Cloxacillin Sodium; Cloxyquin;
Colistimethate Sodium; Colistin Sulfate; Coumermycin; Coumermycin Sodiuwn;
Cyclacillin;
Cycloserine; Dalfopristin; Dapsonc ; Daptomycin; Dcmeclocycline;
Denieclocycline Hydrochloride;
Demecycline; Denofungin ; Diaveridine; Dicloxacillin; Dicloxacillin Sodium;
Dihydrostreptomycin Sulfate; Dipyrithione; Dirithromycin; Doxycycline; Doxycycline Calciuni ;
Doxycycline FosfaFex;
Doxycycline Hyclate; Droxacin Sodium; Enoxacin; Epicillin; Epitetracycline Hydrochloride;
Erythromycin; Erythromycin Acistrate; Erythromycin Estolate; Erythroinycin Ethylsuccinate;
Erythromycin Gluceptate; Erythronlycin Lactobionate; Erythromycin Propionate;
Erythromycin Stearate; Ethambutol I-lydrochloride; L'=thionamide; Fleroxacin; Floxacillin;
Fludalaninc;
3o Flumequine; Fosfomycin; Fosfomycin Tromethaminc; Fumoxicillin; Furazoliuni Chloridc;
Furazoliuni Tartratc; Fusidatc Sodium; Fusidic Acid; Gcntamicin Sulfate;
Gloximonam; Gramicidin;
I-Ialoprogin; I-Ietacillin; I-letacillin Potassium; Hexedine; Ibafloxacin;
lmipenem; Isoconazole;
Isepamicin; Isoniazid; Josamycin; Kanamycin Sulfate; Kitasamycin;
Levofuraltadone;
Levopropylcillin Potassium; Lexithromycin; Lincomycin; Lincomycin Hydrochioride;
Lomefloxacin; Lomefloxacin Hydrochloride; Lomefloxacin Mesylate; Loracarbef;
Mafenide;
Meclocycline; Meclocycline Sulfosalicylate; Megalomicin Potassium Phospliate;
Mequidox;
Meropenem; Methacycline; Methacycline Hydrochloride; Methenamine; Methenamine Hippurate;
Methenamine Mandelate; Methicillin Sodium; Metioprim; Metronidazole Hydrochloride;
Metronidazole Phosphate; Mezlocillin; Mezlocillin Sodium; Minocycline;
Minocycline Hydrochloride; Mirincamycin Hydrochloride ; Monensin ; Monensin Sodium ;
Nafcillin Sodium;
Nalidixate Sodium; Nalidixic Acid; Natatnycin; Nebramycin; Neomycin Palmitate;
Neomycin lo Sulfate; Neomycin Undecylenate ; Netilmicin Sulfate; Neutramycin;
Nifuradene; Nifuraldezone;
Nifuratcl ; Nifuratrone; Nifurdazil; Nifurimide; Nifurpirinol; Nifurquinazol;
Nifurthiazole;
Nitrocycline; Nitrofurantoin; Nitromide; Norfloxacin; Novobiocin Sodium;
Ofloxacin; Ormetoprim;
Oxaciliin Sodium; Oximonam; Oximonam Sodium; Oxolinic Acid; Oxytetracycline;
Oxytetracycline Calcium; Oxytetracycline Hydrochloride; Paldimycin;
Paraclilorophenol;
Paulomycin; Pefloxacin; Pefloxacin Mesylate; Penamecillin; Penicillin G
Benzathine; Penicillin G
Potassium; Peniciilin G Procaine; Penicillin G Sodium; Penicillin V;
Penicillin V Benzathine;
Penicillin V Hydrabamine; Penicillin V Potassium; Pentizidone Sodium; Phenyl Aminosalicylate;
Piperacillin Sodium; Pirbenicillin Sodium; Piridicillin Sodium; Pirlimycin Hydrochloride;
Pivampicillin Hydrochloride; Pivanipicillin Pamoate; Pivampicillin Probenate;Polyniyxin B Sulfate;
Poriiromycin ; Propikacin; Pyrazinamide; Pyrithione Zinc; Quindecamine Acetate; Quinupristin;
Racephenicol; Ranioplanin; Raniniycin; Relomyciti; Repromicin; Rifabutin;
Rifametane; Rifainexil;
Rifanlide; Rifampin; Rifapentinc; Rltaxlnlln; Rolitetracyclinc;
Rolitetracycline Nitrate;
Rosarainicin; Rosaramicin Butyrate; Rosaramicin Propionate; Rosaramicin Sodium Phosphate;
Rosaramicin Stearate; Rosoxacin; Roxarsone; Roxithromycin; Sancycline;
Sanfetrinem Sodium;
Sarnioxicillin; Sarpicillin; Scopafungin ; Sisomicin; Sisomicin Sulfate;
Sparfloxacin; Spectinomycin I-lydrocliloride; Spiramycin; Stallimycin I-lydrocliloride; Steffimycin;
Streptomycin Sulfatc;
Streptonicozid; Sulfabenz ; Sulfabenzamide; Sulfacetamide; Sulfacetainide Sodium; Sulfacytine;
Sulfadiazine; Sulfadiazinc Sodium; Sulfadoxine; Sulfalene; Sulfamerazine;
Sulfameter;
Sulfamethazine; Sulfamethizole; Sulfaniethoxazole; Sulfamonomethoxine;
Sulfamoxole; Sulfanilate Zinc; Sulfanitran ; Sulfasalazinc; Sulfasomizole; Sulfatliiazole; Sulfazamet;
Sulfisoxazole;
Sulfisoxazole Acetyl; Sulfisoxazole Diolamine; Sulfomyxin; Sulopenem;
Sultamicillin; Suncillin Sodium; Talampicillin I-Ivdrochloride; Teicoplanin; Temafloxacin 1-iydrochloride; Temocillin;
Tetracycline; Tetracycline Hydrochloride ; Tetracycline Phosphate Complex;
Tetroxoprim;
Thiamphenicol; Thiphencillin Potassium; Ticarcillin Cresyl Sodium; Ticarcillin Disodium;
Ticarcillin Monosodium; Ticlatone; Tiodonium Chloride; Tobramycin; Tobramycin Sulfate;
Tosufloxacin; Trimethoprinl; Trimethoprim Sulfate; Trisulfapyrimidines;
Troleandomycin;
Trospectomycin Sulfate; Tyrothricin; Vancomycin; Vancomycin Hydrochloride;
Virginiamycin;
Zorbanlycin.
Anticholelithic: Monoctanoin.
1o Anticholelithogenic: Chenodiol; Ursodiol.
Anticholinergic: Alverinc Citrate; Anisotropine Methylbromide; Atropine;
Atropine Oxide Hydrochioride; Atropine Sulfate; Belladonna; Benapryzine Hydrocliloride;
Benzetimide Hydrocllloride; Benzilonium Bromide; Biperiden ; Biperiden I-Iydrochloride;
Biperiden Lactate ;
Clidinium Bromide; Cyclopentolate Hydrochloride; Dexetimide; Dicyclomine Hydrochloride;
Dihexyverinc llydrocllloridc; Domazolinc Funiaratc; Elantrine; Elucainc;
L=:thybcnztropinc;
Eucatropine I-Iydrochloride; Glycopyrrolate; Heteronium Bromide; Homatropine Hydrobromide;
Homatropine Metliylbromide; I lyoscyamine; I-Iyoscyamine Hydrobromide; I-Iyoscyamine Sulfate;
Isopropamide Iodide; Mepenzolate Bromide; Methylatropine Nitrate; Metoquizine;
Oxybutynin Chloridc; Parapenzolate Brornide; P'entapiperium Methylsulfatc;
Pliencarbamide; Poidine Metliylsulfate; Prol;lumide; Propanthcline Broniide; Propenzolate flydrochloride; Scopolamine I-lydrobromide; Tcinatropiuni Methylsulfate; Tiquinamide I lydrochloride;
Tofcnacin I-Iydrochloridc;
Toquizinc; Triampyzine Sulfate; Trihexyphenidyl I-Iydrocliloride; Tropicamide.
Anticoagulant: Ancrod; Anticoagulant Citrate Dextrose Solution ; Anticoagulant Citrate Phosphate Dextrose Adeiiine Solution; Anticoagulant Citrate Phosphate Dextrose Solution;
Anticoagulant I-Icparin Solution; Anticoagulant Sodiuni Citrate Solution; Ardepat=in Sodiuin; Bivalirudin ;
I3roniindionc; Dalteparin Sodium ; Desirudin; Dicuinarol; I-leparin Calcium;
Ileparin Sodium;
Lyapolate Sodium; Nafainostat Mesylate ; I'henprocounion; Tinzaparin Sodium ;
Warfarin Sodium.
Anticoccidal: Maduramicin.
Anticonvulsant: Albutoin; Amcltolidc; Atolide; Buramatc; Carbaniazepine ;
Cinronlidc; C.itcnaniide;
Clonazepam; Cyheptamide; Dezinamide; Dimethadione; Divalproex Sodium;
Eterobarb;
Ethosuximide; Ethotoin; Flurazepam Hydrochloride ; Fluzinamide; Fosphenytoin Sodium;
Gabapentin; Ilepcimide; Lamotrigine; Magnesium Sulfate ; Mephenytoin;
Mephobarbital ;
Methetoin; Methsuximide; Milacemide Hydrochloride ; Nabazenil; Nafimidone Hydrochloride;
Nitrazepam ; Phenacemide; Phenobarbital ; Phenobarbital Sodium ; Phensuximide;
Phenytoin;
Phenytoin Sodiuin; Primidone; Progabide; Ralitoline; Remacemide Hydrochloride;
Ropizine;
Sabeluzole ; Stiripentol; Sulthiame; Thiopental Sodium ; Tiletamine Hydrochloride ; Topiramate;
Trimethadione; Valproate Sodium; Valproic Acid; Vigabatrin; Zoniclezole Hydrochloride;
Zonisamide.
Antidepressant: Adatanserin I-Iydrochloride; Adinazolam ; Adinazolam Mesylate;
Alaproclate;
Aletaniine Hydrochloride; Amedalin Hydrochloride; Aniitriptyline Hydrochloride; Amoxapine;
Aptazapine Maleate; Azaloxan Fumarate; Azepindole; Azipramine Hydrochloride;
Bipenamol I-Iydrochloride; Bupropion Hydrochloride; Butacetin; Butriptyline Hydrochloride; Caroxazone;
Cartazolate; Ciclazindol; Cidoxepin Hydrochloride; Cilobamine Mesylate;
Clodazon Hydrochloride;
Clomipramine Hydrochloride; Cotinine Fumarate; Cyclindole; Cypenamine Hydrochloride;
Cyprolidol Hydrochloride; Cyproximide ; Daledalin Tosylate; Dapoxetine Hydrochloride; Dazadrol Maleate; Dazepinil Hydrochloride; Desipramine Hydrochloride; Dexamisole;
Deximafen;
Dibenzepin I-lydrochloride; Dioxadrol Hydrochloride; Dothiepin Hydrochloride;
Doxepin Hydrochloride; Duloxetine Hydroclilbride; Eclanamine Maleate; Encypratc;
Etoperidone 1-Iydrochloride; Fantridone Hydrochloride; Fenmetozole Hydrochloride ;
Fenmetramide; Fezolamine Fumarate; Fluotracen I-lydrochloride ; Fluoxetine; Fluoxetine I-lydrocliloride; Fluparoxan Hydrochloride; Gamfexine; Guanoxyfen Sulfate ; Imafen Hydrochloride; Imiloxan Hydrochloride;
Imipramine Hydrochloride; Indeioxazine Hydrochloride; Intriptyline Hydrochloride; Iprindole;
Isocarboxazid; Ketipramine Fumarate; Lofepramine Hydrochloride; Lortalamine;
Maprotilale;
Maprotilinc Ilydrocliloridc; Mclitraccn I-Iydrochloridc; Milacemide I-Iydrocliloridc; Minaprinc Hydrochloride; Mirtazapine; Moclobemide; Modaline Sulfate; Napactadine Hydrochloride;
Napamezole I-lydrochloride; Nefazodone Hydrochloride; Nisoxetine; Nitrafudam Hydrochloride;
Nomifensine Maleate; Nortriptyline Hydrochloride; Octriptyiine Phosphate;
Opipramol Hydrochloride; Oxaprotiline Hydrochloride; Oxypertine; Paroxetine; Phenelzine Sulfate;
Pirandamine I-Iydrochioride; Pizotyline ; Pridefine Hydrochloride; Prolintane I-Iydrochloride;
Protriptyline Hydrochloride; Quipazine Maleate ; Rolicyprine; Seproxetine I-Iydrochloride;
Sertraline Hydrochloride; Sibutramine Hydrochloride ; Sulpiride; Suritozole;
Tametraline Hydrochloride; Tampramine Fumarate; Tandamine Hydrochloride: Thiazesim Hydrochloride;
Tliozalinone; Tomoxetine Hydrochloride; Trazodone Hydrochloride; Trebenzomine Hydrochloride;
Trimipramine; Trimipramine Maleate; Venlafaxine Hydrochloride; Viloxazine Hydrochloride;
Zimeldine Hydrochloride; Zometapine.
Antidiabetic: Acetohexamide; Buformin; Butoxamine Hydrochloride ; Camiglibose;
Chiorpropamide; Ciglitazone; Englitazone Sodium; Etoformin Hydrochloride;
Gliamilide;
Glibornuride; Glicetanile Sodium; Gliflumide; Glipizide; Glucagon; Glyburide;
Glyhexamide;
io Glymidine Sodium; Glyoctamide; Glyparamide; Insulin; Insulin, Dalanated;
Insulin Human; Insulin Human, Isophane; Insulin I-Iuman Zinc; Insulin Human Zinc, Extended; Insulin, Isophane; Insulin Lispro; Insulin, Neutral; Insulin Zinc; Insulin Zinc, Extended; Insulin Zinc, Prompt; Linogliride;
Linogliride Fumarate; Metformin; Methyl Palmoxirate; Palmoxirate Sodium;
Pioglitazone Hydrochloride; Pirogliride Tartrate; I'roinsulin Human; Seglitide Acetate;
Tolazamide; Tolbutamide;
Tolpyrramide; Troglitazone; Zopoirestat.
Antidiarrheal: Rolgamidine, Diphenoxylate hydrochloride (Lomotil), Metronidazole (Flagyl), Methylprednisolone (Medrol), Sulfasalazine (Azulfidine).
2o Antidiuretic: Argipressin Tannate; Desrtiopressin Acetate; Lypressin .
Antidote: Dimercaprol; Edrophonium Chloride; Fomepizole; Leucovorin Calcium ;
Levoleucovorin Calcium; Metliylene Blue ; Protamine Sulfate.
Antidyskinetic: Seiegiline Hydrochloride .
Anti-emetic: Alosetron Hydrocliloride; Batanopride Hydrochloride; Bemesetron;
Benzquinamide;
Chlorpromazine ; Chlorpromazine Hydrochloride ; Clebopride; Cyclizine Hydrochloride;
Dimenhydrinate; Diphenidol; Diphenidol Hydrochloride; Diphenidol Pamoate;
Dolasetron Mesylate ; Domperidone; Dronabinol; Fludorex; Tlumeridone; Galdansetron I-lydrochioride; Granisetron;
3o Granisetron I-lydrochloride; Lurosetron Mesylate; Mcclizine Hydrochloride;
Metoclopramide Hydrochloride; Metopimazine; Ondansetron Hydrochloride ; Pancopride;
Prochlorperazine;
Prochlorperazine Edisylate; Prochlorperazine Maleate ; Promethazine Hydrochloride Thiethylperazine; Thiethylperazine Malate; Thiethylperazine Maleate;
Trimethobenzamide Hydrochloride; Zacopride Hydrochloride.
Anti-epileptic: Felbamate; Loreclezole; Tolgabide.
Anti-estrogen: Clometherone; Delmadinone Acetate ; Nafoxidine Hydrochloride;
Nitromifene Citrate; Raloxifene Hydrochloride; Tamoxifen Citrate; Toremifene Citrate ;
Trioxifene Mesylate.
Antifibrinolytic: Nafamostat Mesylate .
Antifungal: Acrisorcin; Ambruticin; Amphotericin B; Azaconazole; Azaserine;
Basifungin;
Bifonazole; Biphenaniine Hydrochloride ; Bispyrithione Magsulfex ;
Butoconazole Nitrate; Calcium Undecylenate; Candicidin; Carbol-Fuchsin; Chiordantoin; Ciclopirox; Ciclopirox Olamine;
Cilofungin; Cisconazole; Clotrimazole; Cuprimyxin; Denofungin ; Dipyrithione;
Doconazole;
Econazole; Econazole Nitrate; Enilconazole; Ethonam Nitrate; Fenticonazole Nitrate; Filipin;
Fluconazole; Flucytosine; Fungimycin; Griseofulvin; Hamycin; Isoconazole ;
Itraconazole;
Kalafungin; Ketoconazole; Lomofungin; Lydimycin; Mepartricin ; Miconazole;
Miconazole Nitrate;
Monensin ; Monensin Sodium ; Naftifine Hydrochloride; Neomycin Undecylenate ;
Nifuratel Nifutmerone; Nitralamine Hydrochloride; Nystatin; Octanoic Acid; Orconazole Nitrate; Oxiconazole 2o Nitrate; Oxifungin Hydrochloride; ParConazole Hydrochloride; Partricin ;
Potassium Iodide I'rocloiiol ; Pyrithione Zinc ; Pyrrolnitrin; Rutamycin; Sanguinariuni Chloride ; Saperconazoic;
Scopatungin ; Scleniuni Sulfide ; Sinetungin; Sulconazole Nitrate;
"I'erbinaGne; Terconazole;
Thiram; Ticlatone ; Tioconazole; Tolciclate; Tolindate; Tolnaftate; Triacetin;
Triafungin;
Undecylenic Acid; Viridofulvin; Zinc Undecylenate; Zinoconazole Hydrochloride.
Antiglaucoma agent : Alprcnoxime Hydrocliloride ; Colforsin; Dapiprazole Hydrochloride Dipivefrin Hydrochloride ; Naboctate Hydrochloride ; Pilocarpine; Pimabine.
Antihemophilic: Antihemophilic Factor.
Antihemorrhagic: Poliglusam.
Antihistaniinic: Acrivastine; Antazoline Phosphate; Astemizole ; Azatadine Maleate; Barmastine;
Bromodiphenhydramine Hydrochloride; Brompheniramine Maleate; Carbinoxamine Maleate;
Cetirizine Hydrochloride; Clilorpheniramine Maleate; Chlorpheniramine Polistirex; Cinnarizine;
Clemastine; Clemastine Fumarate; Closiramine Aceturate; Cycliramine Maleate;
Cyclizine;
Cyproheptadine Hydrochloride ; Dexbrompheniramine Maleate; Dexchlorpheniramine Maleate;
Dimethindene Maleate; Diphenhydramine Citrate; Diphenhydramine Hydrochloride;
Dorastine Hydrochloride; Doxylamine Succinate; Ebastine; Levocabastine Hydrochloride;
Loratadine;
Mianserin I-lydrochloride ; Noberastine; Orphenadrine Citrate ; Pyrabrom;
Pyrilamine Maleate;
Pyroxamine Maleate; Rocastine Hydrocliloride; Rotoxaniine; Tazifylline Hydrochloride;
lo Temelastine; Terfenadine; Tripelennamine Citrate; Tripelennamine Hydrochloride; Triprolidine Hydrochloride; Zolamine Hydrochloride .
Antihyperlipidemic: Cholestyramine Resin ; Clofibrate; Colestipol Hydrochloride; Crilvastatin;
Dalvastatin; Dextrothvroxine Sodium; Fluvastatin Sodium ; Gemfibrozil;
Lecimibide; Lovastatin;
Niacin ; Pravastatin Sodium; Probucol; Simvastatin; Tiqueside; Xenbucin.
Antihyperlipoproteinemic: Acifran; Beloxamide; Bezafibrate; Boxidine;
Butoxanmine Hydrocllloride;
Cetaben Sodium; Ciprofibrate; Gemcadiol; Halofenate ; Lifibrate; Meglutol;
Nafenopin; Pimetine I-Iydrochloride; Theofibrate; Tibric Acid; Treloxinate.
2o Antihypertensive: Alfuzosin Hydrochloride; Alipamide ; Althiazide;
Amiquinsin Hydrochloride;
Amlodipine Besylate ; Anilodipine Maleate ; Anaritide Acetate ; Atiprosin Maleate; Belfosdil;
Bemitradine; Bendacalol Mesylate; Bendrofluniethiazide ; Benzthiazide ;
Betaxolol Hydrochloride ; Bethanidine Sulfate; Bevantolol 1-Iydrochloride ; Biclodil I-Iydrochloride;
Bisoprolol; Bisoprolol Fumaratc; Bucindolol Hydrochloride; Bupicomide; Buthiazide: Candoxatril;
Candoxatrilat;
Captopril ; Carvedilol ; Ceronapril; Chlorothiazide Sodium ; Cicletanine;
Cilazapril; Clonidiie;
Clonidine Hydrochloride; Clopamide ; Cyclopenthiazide; Cyclothiazide ;
Darodipine ; Debrisoquin Sulfate; Delapril Hydrocliloride; Diapamide ; Diazoxide; Dilevalol I-Iydrochloride ; Diltiazem Malate; Ditekiren; Doxazosin Mesylate; Ecadotril; Enalapril Maleate;
Enalaprilat; Enalkiren;
Endralazinc Mesylate; Epithiazide ; Eprosartan; Eprosartan Mesylate;
Fenoldopam Mesylate ;
Flavodilol Malcate; Flordipinc; Flosequinan; Fosinopril Sodium ; f osinoprilat; Guanabcnz;
Guanabenz Acetate; Guanaciine Sulfate; Guanadrel Sulfate; Guancydine;
Guanethidine Monosulfate; Guanethiciine Sulfate; Guanfacine Hydrochloride; Guanisoquin Sulfate; Guanoclor Sulfatc; Guanoctinc Hydrochloride; Guanoxabenz; Guanoxan Sulfate; Guanoxyfcn Sulfate Hydralazine Hydrochloride; Hydralazine Polistirex; Hydroflumethiazide ;
Indacrinone ; Indapamide;
Indolapril I-Iydrochloride; Indoramin; Indoramin Hydrochloride; Indorenate Hydrochloride;
Lacidipine; Leniquinsin; Levcromakalim ; Lisinopril; Lofexidine Hydrochloride;
Losartan S 1'otassium; Losulazinc Hydrochloridc; Mebutamate; Mecamylamine 1-lydroehloridc; Medroxalol;
Medroxalol Hydrochloride; Methaithiazide ; Methyclothiazide ; Methyldopa;
Methyldopate Hydrocliloride; Metipranolol; Metolazone ; Metoprolol Fumarate; Metoprolol Succinate Metyrosine; Minoxidil ; Monatepil Maleate ; Muzolimine ; Nebivolol;
Nitrendipine; Ofomine;
Pargyline Hydrochloride; Pazoxide; Pelanserin Hydrochloride ; Perindopril Erbumine;
jo Phenoxybenzamine Hydrochloride; Pinacidil; Pivopril; Polythiazide ;
Prazosin Hydrochloride;
Primidolol ; Prizidilol Hydrochloride; Quinapril Hydrochloride ; Quinaprilat ;
Quinazosin 1-lydrochloridc; Quinelorane Hydrochloride ; Quinpirole I-Iydrochloride;
Quinuclium Bromide;
Ramipril ; Rauwolfia Serpentina; Reserpine; Saprisartan Potassium; Saralasin Acetate; Sodium Nitroprusside; Sulfinalol Hydrochloride; Tasosartan; Teludipine Hydrochloride ; Temocapril 15 Hydrochloride; Terazosin I-lydrochloride; Terlakiren; Tiamenidine;
Tiamenidine Hydrochloride;
Ticrynafen ; Tinabinol; Tiodazosin; Tipentosin Hydrochloride;
Trichlorniethiazide ; Trimazosin Hydrochloride; Trimethaphan Camsylate; Trimoxamine Hydrochloride; Tripamide;
Xipamide Zankircn Hydrochloride; Zofenoprilat Arginine.
20 Antihypotensive: Ciclafrine I-Iydrochloride; Midodrine Hydrochloride.
Anti-infective: Difloxacin Hydrochloridc ; Lauryl Isoquinoliniutn Bromide;
Moxalactam Disodium;
Ornidazole; Pentisomicin; Sarafloxacin Hydrochloride; Protease inhibitors of I-IIV and other retroviruses; Integrase Inhibitors of HIV and other retroviruses; Cefaclor (CeclorTM); Acyclovir 25 (ZoviraxTM); Norfloxacin (NoroxinTM); Cefoxitin (MefoxinTM); Cefuroxime axetil (CeftinTM);
Ciprofloxacin (CiproTM).
Anti-infective, topical: Alcohol; Aminacrine Hydrochloride; Benzethonium Chloride : Bithionolate Sodium; Bromchlorenone; Carbamide Peroxide; Cetalkonium Chloride;
Cetylpyridinium Chloride:
30 Chlorhexidine Hydrochloride; Clioquinol ; Domiphen Bromide; Fenticlor;
Fludazonium Chloride;
Fuchsin, Basic; Furazolidone ; Gentian Violet; Halquinols; Hexachlorophene:
Hydrogen Peroxide;
Ichthammol; Imidecyl Iodine; Iodine; Isopropyl Alcohol; Mafenide Acetate;
Meralein Sodium;
1. i. '', .~~- lq.u~11..1,~ , ~
Mercufenol Cliloride; Mercury, Ammoniated; Methvibenzethonium Chloride;
Nitrofurazone;
Nitromersol; Octenidine Hydrochloride; Oxychlorosene; Oxychlorosene Sodium;
Parachlorophenol, Camphorated; Potassium Permanganate; Povidone-Iodine; Sepazonium Cliloride;
Silver Nitrate;
Sulfadiazine, Silver; Symclosene; Thimerfonate Sodium; Thimerosal : Troclosene Potassium.
Anti-inflammatory: Alclofenac; Alclometasone Dipropionate; Algestone Acetonide; Alpha Amylase;
Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose Hydrochloride; Anakinra;
Anirolac Anitrazafen; Apazone; Balsalazide Disodium; Bendazac; Benoxaprofen ;
Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen; Cicloprofen;
Cintazone;
1 o Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac;
Cloticasone Propionate;
Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide; Desoximetasone;
Dexamethasone Dipropionate; Diclofenac Potassiunl; Diciofenac Sodium; Diflorasone Diacetate;
Diflumidone Sodium; Diflunisal ; Difluprednate; Diftalone; Dimethyl Sulfoxide;
Drocinonide; Endrysone;
Enliniomab ; Cnolicam Sodium ; Epirizole ; Etodolac; Etofenamate ; Felbinac;
Fenamole; Fenbufen;
Fenclofenac; Fenclorac; Fendosal; Fenpipalone; Fentiazac; Flazalone;
Fluazacort; Flufenamic Acid;
Flumizole; Flunisolide Acetate; Flunixin ; Flunixin Meglunline ; Fluocortin Butyl; Fluorometholone Acetate; Fluquazone; Flurbiprofen ; Fluretofen; Fluticasone Propionate;
Furaprofen; Furobufen;
Halcinonide; Halobetasol Propionate; Halopredone Acetate; Ibufenac ;
Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol; Ilonidap; Indometliacin; Indomethacin Sodium;
Indoprofen Indoxole ; Intrazole; Isoflupredone -Acetate; Isoxepac; Isoxicam; Ketoprofen;
Lofemizole Hydrochloride ; Lomoxicam ; Loteprednol Etabonate; Meclofenamate Sodium;
Meclofenamic Acid;
Meclorisone Dibutyrate; Mefenamic Acid ; Mesalamine; Meseclazone;
Methylprednisolone Suleptanate; Morniflumate; Nabumetone; Naproxen ; Naproxen Sodium ; Naproxol ;
Nimazone;
Olsalazine Sodium; Orgotein ; Orpanoxin; Oxaprozin; Oxyphenbutazone;
Paranyline Hydrochioride;
Pentosan Polysulfate Sodium; Plienbutazone Sodium Glycerate; Pirfenidone ;
Piroxicam; Piroxic,am Cinnamate; Piroxicam Olamine; Pirprofen; Prednazate; Prifelone; Prodolic Acid;
Proquazone;
Proxazole; Proxazole Citrate ; Rimexolone; Romazarit ; Salcolex ; Salnacedin;
Salsalate Sanguinarium Chloride ; Seclazone ; Sermetacin; Sudoxicam; Sulindac; Suprofen;
Talmetacin;
Talniflumate ; Talosalate ; Tebufelone ; Tenidap; Tenidap Sodium; Tenoxicam;
Tesicam; Tesimide;
Tetrydamine ; Tiopinac; Tixocortol Pivalate; Tolmetin; Tolnietin Sodium;
Triclonide; Triflumidate;
Zidometacin; Zomepirac Sodium.
- - ------- - -- -------Antikeratinizing agent: Doretinel; Linarotene; Pelretin.
Antimalarial : Acedapsonc ; Amodiaquine I-Iydrochloriclc ; Amquinatc;
Artellcnc; Cliloroquinc Chloroquine Hydrochloride ; Chloroquine Phosphate ; Cycloguanil Pamoate;
Enpiroline Phosphate;
Halofantrine Hydrocliloride ; Hydroxychloroquine Sulfate ; Mefloquine Hydrochloride; Menoctone;
Mirincamycin Hydrochloride ; Primaquine Phosphate; Pyrimethamine; Quinine Sulfate; Tebuquine.
Antimicrobial: Aztreonam; Chlorhexidine Gluconate; Imidurea; Lycetamine;
Nibroxane;
Pirazmonam Sodium; Propionic Acid ; Pyrithione Sodium; Sanguinarium Chloride ;
Tigemonam t o Dicholine.
Antimigraine: Dolasetron Mesylate ; Naratriptan Hydrochloride; Sergolexole Maleate; Sumatriptan Succinate; Zatosetron Maleate.
Antimitotic: Podofilox.
Antiniycotic: Amorolfine.
Antinauseant : Buclizine Hydrochloride ; Cyclizine Lactate; Naboctate Hydrochloride.
Antineoplastic: Acivicin; Aciarubicin; Acodazole 1-Iydrochloride; Acronine;
Adozelesin;
Aldesleukin ; Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutethimide ;
Amsacrine;
Anastrozole; Anthraniycin; Asparaginase; Asperlin ; Azacitidine; Azetepa;
Azotomycin; Batimastat;
Benzodepa; Bicalutamide; Bisantrene Hydrochloride; Bisnafide Dimesylate;
Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Bropirimine ; Busulfan; Cactinomycin; Calusterone;
Caracemiide;
Carbetimer; Carboplatin; Carmustine; Carubicin Hydrochloride; Carzelesin;
Cedefingol;
Chlorambucil; Cirolemycin ; Cisplatin; Cladribine; Crisnatol Mesylate;
Cyclophosphamide ;
Cytarabine ; Dacarbazine; Dactinomycin; Daunorubicin Hydrochloride;
Decitabine; Dexormaplatin;
Dezaguanine; Dezaguanine Mesylate; Diaziquone; Docetaxel; Doxorubicin;
Doxorubicin 3o Hydrochloride; Droloxifene; Droloxifene Citrate; Dromostanolone Propionate;
Duazomycin;
Edatrexate; Eflornithine Hydrochloride ; Elsamitrucin; Enloplatin; Enpromate;
Epipropidine;
Epirubicin Hydrochloride; Erbulozole; Esorubicin Hydrochloride; Estranlustine;
Estramustine Phosphate Sodium; Etanidazole; Ethiodized Oil I 131; Etoposide; Etoposide Phosphate; Etoprine;
Fadrozole Hydrochloride; Fazarabine; Fenretinide; Floxuridine ; Fludarabine Phosphate;
Fluorouracil; Flurocitabine; Fosquidone; Fostriecin Sodium; Gemcitabine;
Gemcitabine Hydrochloride; Gold Au 198 ; Hydroxyurea; Idarubicin Hydrochloride;
Ifosfamide; Ilmofosine;
Interferon Alfa-2a ; Interferon Alfa-2b ; Interferon Alfa-n1; Interferon Alfa-n3; Interferon Beta-I a ; Interferon Gamma-I b; Iproplatin; Irinotecan Hydrochloride ; Lanreotide Acetate; Letrozole;
Leuprolide Acetate ; Liarozole Hydrochloride; Lometrexol Sodium; Lomustine;
Losoxantrone [-Iydrochloride; Masoprocol; Maytansine; Meclilorethamine 1-Iydrochloride;
Megestrol Acetate;
Melengestrol Acetate; Meiphalan; Menogaril; Mercaptopurine; Methotrexate;
Methotrexate Sodium;
i o 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; Piposulfan; Piroxantrone Hydrochloride; Plicamycin;
Plomestane;
Porfimer Sodium; Porfiromycin ; Prednimustine; Procarbazine I-Iydrochloride;
Puromycin ;
Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Safingol ;
Safingol Hydrochloride ; Semustine; Simtrazene; Sparfosate Sodiuni; Sparsomycin; Spirogermanium 1-Iydrochloride;
Spiromustine; Spiroplatin; Streptonigrin; Streptozocin; Strontium Chloride Sr 89; Sulofenur;
Talisomycin; Taxane; Taxoid; Tecogalan Sodium; Tegafur; Teloxantrone Hydrochloride;
Temoporfin; Teniposide; Teroxirone; Testolactone; Thiamiprine; Thioguanine;
Thiotepa; Tiazofurin;
2o Tirapazamine; Topotecan Hydrochloride; Toremifene Citrate; Trestolone Acetate; Triciribine Phosphate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin; Tubulozole Hydrochloride; Uracil Mustard; Uredepa; Vapreotide; Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Vindesine;
Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; Vinrosidine Sulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin;
Zinostatin; Zorubicin Hydrochloride.
Other anti-neoplastic compounds include: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil;
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;
3o antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen;
antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators;
apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase;
asulacrine; atamestane;
atriniustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron;
azatoxin; azatyrosine; baccatin III
derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins;
benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF
inhibitor; bicalutamide;
bisantrene; bisaziridinvlspertnine; bisnafidc; bistratene A; bizelesin;
breflate; bropirimine;
budotitane; buthionine sttlfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700;
cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS);
castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;
clomifene analogues; clotrimazole; collismycin A; collismycin B;
combretastatin A4; combretastatin i o analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives;
curacin A; cyclopentanthraquinones; cycloplatanl; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexifosfamide; dexrazoxane;
dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;
dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docosanol; dolasetron;
doxifluridine;
droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine;
edrecolomab;
eflornithine; elemene; emitefur; epirubicin; epristeride; estratnustine analogue; estrogen agonists;
estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;
fazarabine;
fenretinidc; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone;
fludarabine;
fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin;
fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors;
gemcitabine; glutathione inhibitors; hepsuifam; het-egttlin; hexamethylene bisacetamide; hypericin;
ibandronic acid;
idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones;
imiquimod;
immunostimulant pcptidcs; insulin-like growth factor-I receptor inhibitor;
interferon agonists;
interferons; interleukins; iobenguatie; iododoxorubicin; ipomeanol, 4-;
irinotecan; iroplact;
irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;
kahalalide F; lamellatin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate;
leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide + estrogen +
progesterone; leuprorelin;
levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinuni compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine;
losoxantrone;
lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic pcptides; maitansine;
mannostatin A; marimastat; masoprocol; niaspin; matrilysin inhibitors; matrix nletalloproteinase inhibitors; menogaril; merbarone; meterelin; metliioninasc; metoclopramide;
MIF inhibitor;
mifepristone; miltefosine; niirimostim; mismatched double stranded RNA;
mitoguazone; mitolactol;
mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin;
mitoxantrone;
mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin;
monophosphoryl lipid A + myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based tlierapy; mustard anticancer agent; mycaperoxide B;
mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin;
nagrestip; naloxone + pentazocine; napavin; naphterpin; nartograstim;
nedaplatin: nemorubicin;
neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06-benzylguanine; octreotide; okicenone;
oligonucleotides; onapristone;
ondansetron; ondansetron; oracin; oral cytokine inducer; ormapiatin;
osaterone; oxaliplatin;
oxaunomycin; paclitaxel analogues; paclitaxel derivatives; palauamine;
palmitoylrhizoxin;
painidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;
pegaspargase; peldesine;
pentosan polysulfate sodiuni; pentostatin; pentrozole; perflubron;
perfosfamide; 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; porfimer sodium; porfiromycin;
propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inliibitor; protein kinase C i-iliibitors, microalgal; protein tyrosine phosphatase inhibitors;
purine nucleoside phospiiorylase inhibitors; purpurins; pyrazoloacridine;
pyridoxylated hemoglobin 30 polyoxycthylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAI' inhibitor; retelliptine demethylated;
rhenium Re 186 etidronate;
rhizoxin; ribozynies; RII rctinaniidc; robletimidc; roliitukinc; romurtide;
roquinimex: rubiginone B1;
ruboxyl; saluigol; saintopin; SarCNU; sarcophytol A; sargraniostim; Sdi 1 mimetics; semustine;
senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chaiii antigen binding protein; sizofiran;
sobuzoxane; sodium borocaptatc; sodium phenylacetate; solverol; somatomedin binding protein;
sonermin; sparfosic acid;
spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipianiide; stronielysin inhibitors; sulfinosine;
superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; syntlietic glycosaminoblycans; tallimustinc;
tanioxifen methiodide; tauromustinc; tazarotenc; tecogalan sodium; tegafur;
tellurapyrylitnn;
telomerase inhibitors; tenioporfin; temozolomide; tcniposide;
tetrachlorodecaoxide; tetrazomine;
thaliblastinc: tlialidomide; thiocoraline; thrombopoictin; thrombopoictin inimetic; tliymalfasin;
tliymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin;
tirapazamine; titanocene dichloride; topotecan; topsentin; toremifene;
totipotent stem cell factor;
translation inhibitors; tretinoin; triacetyluridine; triciribine;
trimetrexate; triptorelin; tropisetron;
turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors;
ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide;
variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin;
vinorelbine; vinxaltine;
vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer.
Anti-cancer Supplementary Potentiating Agents: Tricyclic anti-depressant drugs (e.g., imipramine, desipramine, amitryptyline, clomipramine, trimipramine, doxepin, nortriptyline, lo protriptyline, amoxapine and maprotiline); non-tricyclic anti-depressant drugs (e.g., sertraline, trazodone and citalopram); Ca++ antagonists (e.g., verapamil, nifedipine, nitrendipine and caroverine); Calmodulin inhibitors (e.g., prenvlamine, trifluoroperazine and clomipramine);
Amphotericin B; Triparanol analogues (e.g., tamoxifen); antiarrhythmic drugs (e.g., quinidine);
antihypertensive drugs (e.g., reserpine); Tliiol depleters (e.g., buthionine and sulfoximine) and Multiple Drug Resistance reducing agents such as Cremaphor EL. The compounds of the invention also can be administered with cytokines such as granulocyte colony stimulating factor.
Antiheutropenic: Pilgrastim; Lenograstim; Molgramostim; Regramostim;
Sargramostim.
2o Antiobsessional agent: Fluvoxamine Maleate.
Antiparasitic: Abamectin; Clorsulon; Ivermectin.
Antiparkinsonian: Bcnztropinc Mesylate; I3iperidcn; Bipcriden l lydrochloridc;
Biperiden Lactate;
Carmantadine; Ciladopa Hydrochloride; Dopamantine; Ethopropazine Hydrochloride; Lazabemide;
Levodopa; Lometraline Hydrochloride; Mofegiline Hydrochloride; Naxagolide I-lydrochloride;
Pareptide Sulfate; Procyclidine Hydrochloride; Quinelorane Hydrochloride;
Ropinirole Hydrochloride; Selegiline Hydrochloride; Tolcapone; Ti-ihexyplienidyl I-Iydrochloride.
3o Antiperistaltic: Difenoxicnide I-Iydrochloride; Difenoxin; Diplienoxylate Hydrochloride;
Pluperamide; Lidamidine Hydrochloride; Loperamide Hydrochloride; Malethamer;
Nufcnoxole;
Paregoric.
Antipneumocystic: Atovaquone.
Antiproliferative agent: Piritrexim Isethionate.
Antiprostatic hypertrophy: Sitogluside.
Antiprotozoal: Amodiaquine; Azanidazole; Bamnidazole; Carnidazole;
Chlortetracycline Bisulfate ; Chlortetracycline Hydrochloride; Flubendazole; Flunidazole; Halofuginone Hydrobromide;
Imidocarb Hydrochloride; Ipronidazole; Metronidazole; Misonidazole;
Moxnidazole; Nitarsone;
io Partricin; Puromycin; Puromycin Hydrochloride; Ronidazole; Sulnidazole;
Tinidazole.
Antipruritic: Cyproheptadine Hydrochloride ; Methdilazine; Methdilazine Hydrochloride;
Trimeprazine Tartrate.
Antipsoriatic: Acitretin; Anthralin; Azaribine; Calcipotriene; Cycloheximide;
Enazadrem Phosphate;
Etretinate; Liarozole Fumarate; Lonapalene; Tepoxalin.
Antipsychotic: Acetophenazine Maleate; Alentemol Hydrobrotnide; Alpertine;
Azaperone;
Batelapine Maleatc; Benperidol; Benzindopyrine Hydrochloride; Brofoxine;
Bromperidol;
2o Bromperidol Dccanoatc; I3utacianiol' 'I lydrochloride; Butaperazine;
Butapcrazine Maleate;
Carphenazine Maleate; Carvotroline Hydrochloride; Clilorpromazine;
Chlorpromazine I-Iydrocliloridc; Clllorprothixcne; Cinpercne; Cintriarnidc; Clomacran P11osp11ate; Clopenthixol;
Clopimozide; Clopipazan Mesylate; Cloroperone Ilydrochloride; Clothiapine;
Clothixamide Maleate; Clozapine; Cyclophenazine I-lydrochloride; Droperidol; Etazolate I-lydrocliloride;
Fenimide; Flucindole; Flumezapine; Fluplienazine Decanoate; Fluplienazine Enanthate;
Fluplienazine Hydrochloride; Fluspiperone; Fluspirilene; Flutroline;
Gevotroline Hydrocliloride;
1-Ialopcmide; Haloperidol; Haloperidol Decanoate; Iloperidonc; Imidoline I-lydrochloride;
Lenperone; Mazapertine Succinate; Mesoridazine; Mesoridazine Besylate;
Metiapine; Milenperone;
Milipertine; Molindone Hydrochloride; Naranol I-Iydrochloride; Ncf3umozide I-Iydrochloride;
Ocaperidonc; Olanzapine; Oxiperomide; Pcniluridol; Pentiapine Maleatc:
11'erplienazine; Pimozide;
Pinoxepin I-lydrochloridc; Pipampcrone; Piperacetazinc: Pipotiazine Palniitatc; Piquindone llydrochloridc; Prochlorperarine Gdisylate; Prochlorperazinc Maleate;
l'romazine llydrocliloride;
Remoxipride; Remoxipride Hydrochloride; Rimcazole Hydrochloride; Seperidol Hydrocliloride;
Sertindole ; Setoperone; Spiperone; Thioridazine ; Tliioridazine Hydrochloride; Thiothixene;
Thiothixene Hydrochloride; Tioperidone I-lydrocliloride; Tiospirone Hydrochloride; Trifluoperazine I-Iydrochloride; Trifluperidol; Triflupromazine; Triflupromazine Hydrocliloride; Ziprasidone Hydrocliioride.
Antirheumatic: Auranofin; Aurothioglucose; Bindarit; Lobenzarit Sodium;
Phenylbutazone;
Pirazolac; Prinomide Tromethamine; Seprilose.
i o Antischistosomal: Becanthone Hydrochloride; Hycanthone; Lucanthone Hydrochloride; Niridazole;
Oxamniquine; Pararosaniline Pamoate; Teroxalene Hydrochloride.
Antiseborrheic: Chloroxine; Piroctone; Piroctone Olamine; Resorcinol Monoacetate.
Antisecretory: Arbaprostil; Deprostil; Fenoctimine Sulfate; Octreotide:
Octreotide Acetate;
Omeprazole Sodium; Rioprostil; Trimoprostil.
Antispasmodic: Stilonium Iodide; Tizanidine Hydrochloride.
2o Antithrombotic: Anagrelide I-Iydrochloride; Bivalirudin ; Dalteparin Sodium ; Danaparoid Sodium;
Dazoxiben Hydrochloride; Efegatran Sulfate; Enoxaparin Sodium; Ifetroban;
Ifetroban Sodium;
Tinzaparin Sodiuni ; Trifenagrel.
Antitussive: Benzonatate; Butamirate Citrate; Chlophedianol Hydrochloride;
Codeine Polistirex;
Codoxime; Dextromethorphan; Dextromethorphan Hydrobromide; Dextromethorphan Polistinex;
Etliyl Dibunate; Guaiapate; I-Iydrocodonc Bitartratc; 1-Iydrocodonc Polistirex; Levopropoxyphene Napsylate; Noscapine; Pemerid Nitrate; Pipazethate; Suxemerid Sulfate.
Anti-ulcerative: Aceglutamide Aluminum; Cadexomer Iodine ; Cetraxate I-Iydrochloride; Enisoprost;
Isotiquimide; Lansoprazole; Lavoltidine Succinate; Misoprostol; Nizatidine;
Noliniuni Bromide ;
Pantoprazolc; Pifarninc; I'irenzcpinc 1-Iydrocliloride; Rabeprazolc Sodium ;
Rcmiprostol; Roxatidinc Acetate Hydrocliloride; Sucralfatc; Sucrosofate Potassium; 'Tolimidone.
Anti-urolithic: Cysteamine; Cysteamine Hydrochloride; Tricitrates Antiviral: Acemannan; Acyclovir; Acyclovir Sodium; Adefovir; Alovudine;
Alvircept Sudotox;
Amantadine Hydrochloride; Aranotin; Arildone; Atevirdine Mesylate; Avridine;
Cidofovir;
Cipamfylline; Cytarabine Hydrochloride; Delavirdine Mesylate; Desciclovir;
Didanosine; Disoxaril;
Edoxudine; Enviradene; Enviroxime; Famciclovir; Famotine Hydrochloride;
Fiacitabine;
Fialuridine; Fosarilate; Foscarnet Sodium; Fosfonet Sodium; Ganciclovir;
Ganciclovir Sodium;
Idoxuridine; Ketlioxal; Lanlivudine; Lobucavir; Memotine Hydrochloride;
Methisazone; Nevirapine;
Penciclovir; Pirodavir; Ribavirin; Rimantadine Hydrochloride; Saquinavir Mesylate; Somantadine I o I-lydrochloride; Sorivtidinc; Statolon; Stavudine; Tilorone 1-Iydrochloridc; Trifluridine; Valacyclovir I-Iydrochloride; Vidarabine; Vidarabine Phospliatc; Vidarabine Sodium Phosphate; Viroxiine;
Zalcitabine; Zidovudine; Zinviroxime.
Appetite suppressant: Dexfenfluramine Hydrochloride; Phendimetrazine Tartrate;
Phentermine I-Iydrochloride.
Benign prostatic hyperplasia tlierapy agent: Tamsulosin Hydrochloride.
Blood glucose regulators: I-Iuman insulin; Glucagon; Tolazamide; Tolbutaniide;
Cllloropropamide;
2o Acetohexamide and Glipizidc.
13one resorption inhibitor: Alendronate Sodium; Etidronatc Disodiunl;
Pamidronate Disodium.
I3ronchodilator: Albutcrol; Albutcrol Sulfate; Azanator Maicate; I3aniifyliinc Ilydrochloride;
Bitolterol Mesylate; Butaprost; Carbuterol Hydrochloride; Clorprenaline Hydrochloride; Coltarol Mesylatc; Doxaprost; Doxofylline; Dyphylline; Enprofylline; Ephedrine;
Ephedrine Hydrochloride;
Fenoterol; Fenprinast Hydrochloride; Guaitliylline; Hexoprenaline Sulfate ;
Hoquizil Hydrochloride;
Ipratropium Bromide; Isoetharine; Isoetharine Hydrochloride; Isoetliarine Mesylatc; Isoproterenol Hydrocliloride; lsoproterenol Sulfatc; Metaprotcrenol Polistirex;
Metaproterenol Sulfatc; Nisbuterol Mcsylate; Oxtriphyllinc; PicunIctcrol Fumaratc; Piquizil I-lydrocliloridc;
Pirbuterol Acctatc;
Pirbuterol I-Iydrochloridc; Procatcrol Ilydrocliloride; Pscuciocpliedrine Sulfate; Quazodinc ;
Quintcrenol Sulfate; Raccpincphrinc; Racepinephrine I-lydrochloride;
Reproterol I-Iydrocliloride;
Rimiterol Hydrobroniide; Salmeterol; Salmeterol Xinafoate; Soterenol Hydrochloride; Sulfonterol Hydrochloride; Suloxifen Oxalate; Terbutaline Sulfate; Theopliylline; Xanoxate Sodium; Zindotrine;
Zinterol Hydrochloride.
Carbonic anhydrase inhibitor: Acetazolamide; Acetazolamide Sodium;
Dichlorphenamide;
Dorzolamide Hydrochloride; Methazolamide; Sezolamide Hydrochloride.
Cardiac depressant: Acecainide Hydrochloride; Acetylcholine Chloride;
Actisomide; Adenosine;
Amiodarone; Aprindine; Aprindine Hydrochloride; Artilide Fumarate; Azimilide Dihydrochloride;
io Bidisomide; Bucainide Maleate; Bucromarone; Butoprozine Hydrochloride ;
Capobenate Sodium;
Capobenic Acid; Cifenline; Cifenline Succinate; Clofiliuni Phosphate;
Disobutamide; Disopyramide;
Disopyramide Phosphate; Dofetilide; Drobuline; Edifolone Acetate; Emilium Tosylate; Encainide Hydrochloride; Flecainide Acetate; Ibutilide Fumarate; Indecainide Hydrochloride; Ipazilide Fumarate; Lorajmine Hydrochloride; Lorcainide I-Iydrochloride; Meobentine Sulfate; Mexiletine Hydrochloride; Modecainide; Moricizine; Oxiramide; Pirmenol Hydrochloride;
Pirolazamide;
Pranolium Chloride; Procainamide Hydrochloride; Propafenone Hydrochloride;
Pyrinoline;
Quindonium Bromide; Quinidine Gluconate; Quinidine Sulfate; Recainam Hydrochloride; Recainam Tosylate; Risotilide Hydrochloride; Ropitoin Hydrochloride; Sematilide Hydrochloride; Suricainide Maleate; Tocainidc; Tocainide I-Iydrocllloride; Transcainide.
Cardioprotectant: Dexrazoxane; Draflazine.
Cardiotonic: Actodigin; Anirinone; Bemoradan; Butopatnine; Carbazcran;
Carsatrin Succinatc;
Deslanoside; Digitalis; Digitoxin; Digoxin; Dobutamine; Dobutamine Hydrochloride; Dobutamine Lactobionate; Dobutamine Tartrate; Enoximonc; Imazodan I-Iydrochloride;
Indolidan; Isomaz,ole Hydrochloride; Levdobutarnine Lactobionate; Lixazinone Sulfate; Medorinone;
Milrinone; Pelrinone I-Iydrochloride; Pimobendan; Piroximonc; Prinoxodan; Proscillaridin;
Quazinone; Tazolol Hydrochloride; Vesnarinone.
Cardiovascular agent: Dopexamine; Dopexamine Hydrochloride.
Choleretic: Dehydrocholic Acid; Fencibutirol; I-Iymecromone; Piprozolin;
Sincalide; Tocamphyl.
Cholinergic: Aceclidine; Bethanechol Chloride; Carbachol; Demecarium Bromide;
Dexpanthenol;
Echothiophate Iodide; Isoflurophate; Methacholine Chloride; Neostigmine Bromide; Neostigmine Methylsulfate; Physostigmine; Physostigmine Salicylate; Pliysostigmine Sulfate; Pilocarpine Pilocarpine Hydroclzloride; Pilocarpine Nitrate; Pyridostigmine Bromide.
Cliolinergic agonist: Xanomeline; Xanomeline Tartrate.
Cholinesterase Deactivator: Obidoxime Chloride; Pralidoxime Chloride;
Pralidoxime Iodide;
Pralidoxime Mesylate.
to Coccidiostat: Arprinocid; Narasin ; Semduramicin; Semduramicin Sodium.
Cognition adjuvant: Ergoloid Mesylates; Piracetam; Pramiracetam Hydrochloride;
Pramiracetam Sulfate; Tacrine Hydrochloride.
Cognition enhancer: Besipirdine Hydrochloride; Linopirdine; Sibopirdine.
Depressant: Omeprazol c.
2o Diagnostic aid: Aminohippurate Sodium; Anazolene Sodium; Arclofenin;
Arginine ; Bentiromide;
Benzylpenicilloyl Polylysine; Butedronate Tetrasodium; Butilfenin;
Coccidioidin; Corticorelin Ovine Triflutate ; Corticotropin, Repository; Corticotropin Zinc I-lydroxide;
Diatrizoate Megluniine;
Diatrizoate Sodium; Diatrizoic Acid; Diplltheria Toxin for Schick Test;
Disofenin; Edrophonium Chloride; Ethiodized Oil; Etifenin; Exametazime; Ferristenc; Ferumoxides;
Ferumoxsil; Fluorescein;
Fluorescein Sodium; Gadobenate Dimeglumine; Gadoteridol; Gadodiamide;
Gadopcntetate Dimegiumine; Gadoversetamide; Histoplasmin; Impromidine Hydrochloride;
Indigotindisulfonate Sodium; Indocyanine Green ; lobenguane Sulfate I 123; Iobenzamic Acid;
locarmate Meglumine;
locarmic Acid; locetamic Acid; lodainide; lodamide Megiumine; lodipamide Meglumine; Iodixanol;
lodoxamate Meglumine; lodoxamic Acid; Iogiicic Acid; Ioblucol; Ioglucomide;
loglycamic Acid;
logulaniide; Ioliexol; lonieprol; lopaniidol; lopanoic Acid; lopentol;
lophendylate; lprofenin;
lopronic Acid; loprocemic Acid; lopydol; lopydone; losefamic Acid; loscric Acid; losulamide Meglumine; losumctic Acid; lotasul; lotetric Acid; lotlialamate Meglumine;
lothalamate Sodium;
Iothalamic Acid; lotrolan; lotroxic Acid; loversol; Ioxaglate Meglumine;
loxagiate Sodium; loxaglic Acid; loxilan; loxotrizoic Acid; Ipodate Calcium; Ipodate Sodium; Isosulfan Blue; Leukocyte Typing Serum; Lidofenin; Mebrofenin; Megiumine; Metrizamide; Metrizoate Sodium; Metyrapone;
Metyrapone Tartrate; Mumps Skin Test Antigen; I'entetic Acid; Propyliodone;
Quinaldine Blue;
Schick Test Control; Sermorelin Acetate ; Sodium Iodide 1 123; Sprodiamide;
Stannous Pyrophosphate; Stannous Sulfur Colloid; Succimer; Teriparatide Acetate;
Tetrofosmin; Tolbutamide Sodium; Tuberculin; Tyropanoate Sodium; Xylose.
Diuretic: Ambuphylline ; Ambuside; Amiloride Hydrochloride; Azolimine;
Azosemide; Brocrinat;
i o Bumctanide; Chlorothiazide; Clilorthalidone; Clazolimine; Clorexolone;
Ethacrynate Sodium;
Ethacrynic Acid; Etozolin; Fenquizone; Furosemide; Hvdrochlorothiazide;
Isosorbide; Mannitol ;
Mefruside; Ozolinone; Piretanide; Spiroxasone; Torsemide; Triamterene;
Triflocin; Urea.
Dopaminergic agent: ibopamine.
Ectoparasiticide: Nifluridide; Permethrin.
Emetic: Apomorphine Hydrocliloride.
Enzyme inhibitor: Acetohydroxamic Acid; Alrestatin Sodium; Aprotinin;
Benazepril Hydrochloride;
Benazcprilat; Bcnurcstat; Broniocriptinc; Bromocriptinc Mcsylate; Cilastatin Sodium; Flurofatnide;
Lergotrile; Lergotrile Mesylate; Lcvcycloserine; Libenzapril; Pentopril;
Pepstatin; Perindopril;
Polibnate Sodium; Sodiuni Amylosullate; Sorbinil; Spirapril I-lydrocliloride;
Spiraprilat; Taleranol;
Teprotide; Tolfamide; Zofenopril Calcium.
Estrogen: Chlorotrianisenc; Dienestrol; Diethylstilbestrol; Dicthylstilbestrol Diphosphate; Equidin;
Estradiol; Estradiol Cypionate; Estradiol Enanthate; Estradiol Undecvlate;
Estradiol Valerate;
Estrazinol Hydrobromide; Estriol; Estrofurate; Estrogens, Conjugated;
Estrogens, Esterified;
Estrone; Estropipate; Ethinyl Estradiol; Fenestrel; Mestranol; Nylestriol;
Quinestrol.
3o Fibrinolytic: Anistreplase; Bisobriii Lactate; Brinolase.
Free oxygen radical scavenger: Pegorgotcin.
Gastrointestinal Motility agents: Cisapride (PropulsidTM Metoclopramide (ReglanTM);
Hyoscyamine (LevsinTM).
Glucocorticoid: Amcinonide; Beclomethasone Dipropionate; Betamethasone;
Betamethasone Acetate; Betaniethasone Benzoate; Betamethasone Dipropionate; Betamethasone Sodium Phosphate;
Betaniethasone Valerate; Carbenoxolone Sodium; Clocortolone Acetate;
Clocortolone Pivalate;
Cloprednol; Corticotropin; Corticotropin, Repository; Corticotropin Zinc Hydroxide; Cortisone Acetate; Cortivazol; Descinolone Acetonide; Dexamethasone; Dexamethasone Sodium Phosphate;
Diflucortolone; Diflucortolone Pivalate; Flucloronide; Flumethasone;
Flumethasone Pivalate;
Flunisolide; Fluocinolonc Acctonide; Fluocinonidc; Fluocortolone;
Fluocortolone Caproate;
Fluoroinetholone; Fluperolone Acetate; Fluprednisolone; Fluprednisolone Valerate; Flurandrenolide;
Formocortal; Hydrocortisonc; I-lydrocortisone Acetate; Hydrocortisone Buteprate; Hydrocortisone Butyrate; IIydrocortisone Sodium Phosphate; Hydrocortisonc Sodium Succinatc; I-iydrocortisone Valerate; Medrysone; Methylprednisolone; Methyiprednisolone Acetate;
Methylprednisolone Sodium Phosphatc; Mcthylprednisolotie Sodium Succinate; Nivazol;
Paramctliasone Acetatc;
Prednicarbate; Prednisolonc; I'rednisolone Acetate; Prednisolonc Hemisuccinate; Prednisolone Sodiuni Phospliatc; Prednisolonc Sodium Succinate; Prcdnisolone Tebutate;
Prcdnisone; Prednival;
Ticabesonc Propionate; 1'ralonide; Triamcinolonc; Triamcinolone Acetonide;
Triamcinolone Acetonide Sodium; Triamcinolone Diacetate; Triamcinolone I-iexacetonide.
Gonad-stimulating principle: Buserelin Acetate; Clomiphene Citrate; Ganirelix Acetate; Gonadorelin Acetatc; Gonadorclin 1-lydrochloride; Gonadotropin. Chorionic; Menotropins.
Hair growth stimulant: Minoxidil .
Hemostatic: Aminocaproic Acid; Oxamarin 1-lydrochloridc; Sulmarin; Thrombin;
Trancxamic Acid.
Histamine H2 receptor antagonists: Ranitidine (ZantacTM); Famotidine (PepcidTM); Cimetidine (TagametTM); Nizatidine (AxidTM).
3() I-lorrnone: Diethylstilbestrol; Probesteronc; 17 liydroxy progestcronc;
Medroxyprobcstcronc;
Norgestrel; Norcthynoclrcl; E-stradiol; Mcgcstrol (MegaoeTm); Norcthindronc;
Levonorgestrcl;
Ethyndiol; Ethinyl estradiol; Mestranol; Estrone; Equilin; 17 aipha dihydroequilin; equilenin; 17 alpha dihydroequilenin; 17 alpha estradiol; 17 beta estradiol; Leuprolide (lupron); Glucagon;
Testolactone; Clomiphene; Han memopausal gonadotropins; Human cllorionic gonadotropin;
Urofollitropin; Bromocriptine; Gonadorelin; Luteinizing hormone releasing liormone 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 (Latrodectus mactans); Antivenin (Micrurus Fulvius); Antivenin (Crotalidae) Polyvalent; BCG Vaccine; Botulisnl Antitoxin;
Cholera Vaccine;
Diphtheria Antitoxin; Diphtheria Toxoid; Diplitheria Toxoid Adsorbed;
Globulin, Immune; Hepatitis B Immune Globulin; Hepatitis B Virus Vaccine Inactivated; Influenza Virus Vaccine; Measles Virus Vaccine Live; Meningococcal Polysaccharide Vaccine Group A; Meningococcal Polysaccha~de 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; Snialipox Vaccine; Tetanus Antitoxin; Tetanus Immune Globulin;
Tetanus Toxoid;
3fl Tetanus Toxoid Adsorbed; Typhoid Vaccine; Yellow Fever vaccine; Vaccinia Immune Globulin;
Varicella-Zoster Immune Globulin.
.Immunomodulator: Dimepranol Acedoben; Imiquimod; Iiiterferon Beta-lb;
Lisofylline;
Mycophenolate Mofetil; Prczatide Copper Acetate.
Immunoregulator: Azarole; Fanetizole Mesylate; Frentizole; Oxamisole Hydrochloride; Ristianol Phosphate; Thymopentin; Tilomisole.
Immunostimulant: Loxoribine ; Teceleukin.
Immunosuppressant: Azathioprine; Azathioprine Sodium; Cyclosporine; Daltroban;
Gusperimus Trihydrochloride; Sirolimus; Tacrolimus.
Impotence therapy adjunct: Delequamine Hydrochloride.
Inhibitor: Acarbose; Atorvastatin Calcium; Benserazide ; Brocresine;
Carbidopa; Clavulanate Potassium; Dazniegrcl; Docebenone; Epoprostenol; Epoprostenol Sodium;
Epristeridc; Finasteride;
Flurbiprofcn Sodium; Furegrelate Sodium; Lufironil; Miglitol; Orlistat;
Pimagedine Hydrochloride;
Pirmagrel; Ponalrestat; Ridogrel; Sulbactam Benzathine ; Sulbactam Pivoxil ;
Sulbactam Sodium ; Suronacrine Maleate; Tazobactam; Tazobactam Sodium; Ticlopidine I-Iydrocliloride; Tirilazad Mesylate; Toirestat; Veinacrine Maleate; Zifrosilone; Zileuton.
2o Keratolytic: Alcioxa ; Aldioxa ; Benzoyl Peroxide; Dibenzothiophene;
Etarotene; Isotretinoin;
Motretinide; I'icotrin Diolamine; Resorcinol; Resorcinol Monoacetate ;
Salicylic Acid; Sumarotene;
Tazarotene; Tetroquinone; Tretinoin.
LHRH agonist: Deslorelin; Goserelin; Histrclin; Lutrelin Acetate; Nafarelin Acetate.
Liver disorder treatment: Malotilate.
Luteolysin: Fenprostalene.
Memory adjuvant: Dimoxamine Hydrocllloride; Ribaminol.
Mental performance enhancer: Aniracetam.
Mood regulator: Fengabine.
Mucolytic: Acetylcysteine; Carbocysteine; Domiodol.
Mucosal Protective agents: Misoprostol (CytotecTM).
Mydriatic: Berefrine.
Nasal decongestant: Nemazoline Hydrochloride; Pseudoephedrine Polistirex.
to Neuroleptic: Duoperone Fumaratc; Risperidone.
Neuromuscular blocking agent: Atracurium Besylate; Cisatracurium Besylate;
Doxacurium Chloride; Gallamine Triethiodide; Metocurine Iodide; Mivacurium Chloride;
Pancuronium Bromide;
Pipecuroniuin Bromide; Rocuronium Bromide; Suecinylcholine Chloride;
Tubocurarine Chloride;
Vecuronium Bromide.
Neut'oprotective: Dizocilpine Maleate.
io NMDA antagonist: Sclfotel.
Non-hormonal sterol derivative: Pregnenolone Succinate.
Oxytocic: Carboprost; Carboprost Methyl; Carboprost Tromethamine; Dinoprost ;
Dinoprost Tromethaminc ; Dinoprostone ; Brgonovine Maleate; Mcteneprost ;
Methylergonovine Male*te;
Oxytocin; Spartcine Sulfatc.
Pltisminogcn activator: Alteplasc; Urokinase.
Platelet activating factor antagonist: Lcxipafant.
Platelet aggregation inhibitor: Acadesine; Beraprost; Bcraprost Sodium;
Ciprostene Calcium;
Itazigrcl; 1.ifarizinc; Oxagrclatc.
Post-stroke and post-head trauma treatment: Citicoline Sodium.
Potentiator: Pentostatin; Talopram Hydrochloride.
Progestin: Algestone Acetophenide; Amadinone Acetate; Anagestone Acetate;
Chlormadinone Acetate; Cingestol; Clogestone Acetate; Clonlegestone Acetate; Desogestrel;
Dimethisterone;
Dydrogesterone; Ethyncrone; Etllynodiol Diacetate; Etonogestrel; Flurogestone Acetate; Gestaclone;
Gestodene; Gestonorone Caproatc; Gestrinone; I Ialoprogcsteronc;
Hydroxyprogesterone Caproate;
Levonorgestrel; Lynestrenol; Medrogestone; Medroxyprogesterone Acetate;
Metllynodiol Diacetate;
i o Noretllindrone; Norethindrone Acetate; Noretllynodrel; Norgestimate;
Norgestomet; Norgestrel;
Oxogestone Phenpropionate; Progesterone; Quingestanol Acetate; Quingestrone;
Tigestol.
I'rostaglandin: Cloprostcnol Sodiunl; Fluprostenol Sodium; Gemeprost;
Prostalene; Sulprostone.
Prostate growth inhibitor: Pentonlone.
Protllyrotropin: Protirelin.
Psycllotropic: Minaprine.
I'ulnionary surface: Beractant; Colfosceril Palnlitate.
Radioactive agent: Fibrinogen 1 125 ; Fludeoxyglucose F 18 ; Fluorodopa F 18 ;
Insulin I 125;
Insulin 1 131; lobenguane 1 123; lodipamide Sodium I 131 ; Iodoantipyrine 1 131 ; lodocholesterol 1 131 ; lodohippurate Sodium 1 123 ; Iodollippurate Sodium I 125 ;
lodohippurate Sodium I 1~1 ;
lodopyracct I 125 ; Iodopyracet 1 131 ; tofetanline I-Iydrochloride I 123 ;
Ionlethin 1 125 ; lometllin I 131 ; Iotllalamatc Sodiunl1 125 ; Iotllalanlatc Sodium I 131 ; Iotyrosine 1 131; Liotllyroninc 1 125;
Liothyroninc 1 131; Mcrisoprol Acetate 1-lg 197; Mcrisoprol Acclatc 1 lg 203;
Mcrisoprol I Ig 197 ;
Sclenomctllioninc Se 75 ; Tcchnctium 'I'c 99111 Antimony "1'risultidc Colloid;
'Tcchnctiunl Tc 99m 3o Bicisatc ; Tcchnctium Tc 99111 Disofenin ; Technetium Tc 99n1 Etidronate ;
Technetiunl Tc 99111 L'xamCl'1'LI111C ; TCCI111Ct111111 1 C 99111 I'llrlfosnllil ; 1 CChnCtilinl I
c 99111 GJllceptate ; rl'ccllnCtlum Tc 99111 Lidofenin ;'I'echnetium "I'c 99m Mebrofenin ; Technetium "Tc 99rn Medronate ; Technetium Tc 99m Medronate Disodium; Technetiuni Tc 99m Mertiatide ; Technetium Tc 99m Oxidronate ;
Technetium Tc 99m Pentetate; Technetium Tc 99m Pentetate Calcium Trisodium;
Technetium Tc 99m Sestamibi ; Technetium Tc 99m Siboroxime ; Technetium Tc 99m Succimer ;
Technetium Tc 99m Sulfur Colloid ; Technetium Tc 99m Teboroxime ; Technetium Tc 99m Tetrofosmin ;
Technetium Tc 99m Tiatide; Thyroxine 1 125; Thyroxine 1 131; Tolpovidone 1 131 ; Triolein 1 125;
Triolein 1 131.
Regulator: Calcifediol; Calcitonin; Calcitriol; Clodronic Acid;
Dihydrotachysterol; Etidronic Acid;
Oxidronic Acid; Piridronate Sodium; Risedronate Sodium; Secalciferol.
io Relaxant: Adiphenine Hydrochloride; Alcuronium Chloride; Aminophylline;
Azumolene Sodium;
Baclofen; Benzoctaniine Hydrochloride; Carisoprodol; Chlorplienesin Carbamate;
Chlorzoxazone;
Cinflumide; Cinnamedrine; Clodanolene; Cyclobenzaprine Hydrochloride;
Dantrolene; Dantrolene Sodium; Fenalamide; Fenyripol Hydrochloride; Fetoxylate Hydrochloride;
Flavoxate Hydrocliloride;
Fletazepam; Flumetramide; Flurazepam Hydrochloride; Hexafluorenium Bromide;
Isomylamine I-iydrochloride; Lorbanlate; Mebeverine Hydrochloride; Mesuprine I-Iydrocliloride ; Metaxalone;
Methocarbamol; Methixene Hydrochloride; Nafomine Malate; Nelezaprine Maleate;
Papaverine flydi=ochloride; Pipoxolan Hydrochloride; Quinctolate; Ritodrine; Ritodrine Hydrocliloride;
Rolodine; Theophylline Sodium Glycinate; Thiphenamil Hydrochloride; Xilobam.
Repartitioning agent: Cimaterol.
Scabicide: Amitraz; Crotamiton.
Sclerosing agent: Ethanolamine Oleate; Morrhuate Sodium; Tribenoside.
Sedative: Propioniazine.
Sedative-hypnotic: Allobarbital; Alonimid; Alprazolam; Amobarbital Sodium;
Bentazepam;
13roti7olam; Butabarbital; Butabarbital Sodium; Butalbital; Capuride;
Carbocloral; Chloral IIetainc;
Chloral I-lydratc; Clilordiazepoxidc llydrochloridc; Cloperidone Ilydrochloridc; Clorethate;
Cyprazepam; Dcxclamol I-lydrochloride; Diazepam; Dichloralphenazone;
Estazolam; Ethchlorvynol;
Etomidate; Fenobam; Flunitrazepam; Fosazepam; Glutethimide; Halazepam;
Lornletazepam;
Mecloqualone; Meprobamate; Methaqualone; Midaflur; Paraldehyde; Pentobarbital;
Pentobarbital Sodium; Perlapine; Prazepam; Quazepam; Reclazepam; Roletamide; Secobarbital;
Secobarbital Sodium; Suproclone; Thalidomide; Tracazolate; Trepipam Maleate; Triazolam;
Tricetamide;
Triclofos Sodium; Trimetozine; Uldazepam; Zaleplon; Zolazepam Hydrochloride;
Zolpidem Tartrate.
Selective adenosine Al antagonist: Apaxifylline.
io Serotonin antagonist: Altanserin Tartrate; Amesergide; Ketanserin;
Ritanserin.
Serotonin iilhibitor: Cinanserin Hydrochloride; Fenclonine; Fonazine Mesylate;
Xylamidine Tosylate.
Serotonin receptor antagonist: Tropanserin Hydrochloride.
Steroid: Dexamethasone Acefuratc; Mometasone Furoate.
Stimulant: Anlfonelic Acid; Amphetamine Sulfate; Ampyzine Sulfate; Arbutaniine I-Iydrocliloride;
2o Azabon; Caffeine; Cerulctide; Ceruletide Diethylatnine; Cisapride;
Dazopride Fumarate;
Dextroamphctaminc; Dcxtroaniplictantine Sulfate; Dilluanine I-lydrochloridc;
Dimel7ine I-Iydrochloride; Doxapram I-lydrochloride; rtryptamine Acetate; Etliainivan;
Fenethylline I-lydrocliloride; Flubanilate i-lydrochloride; Flurothyl; Ilistaminc I'hosphatc; Indriline I-Iydrochloride; Mefexamide; Methamphetamine Hydrochloride; Methylpllenidate Hydrochloride;
1'emoline; Pyrovaleronc I-Iydrochloride; Xamotcroi; Xatnoterol Fumarate.
Suppressant: Amflutizolc; Colchicinc; Tazofclonc.
Symptomatic multiple sclerosi5: Fampridinc.
Syncrbist: I'roadifen I iydrochloridc.
Thyroid hormone: Levothyroxine Sodiuin; Liothyronine Sodium; Liotrix.
Thyroid inhibitor: Methimazole; Propylthiouracil.
Thyromimetic: Tliyromedan Hydrochloride.
Tranquilizer: Bromazepam; Buspirone Hydrocliloride; Chlordiazepoxide;
Clazolam; Clobazam;
Clorazepate Dipotassium; Clorazepate Monopotassium; Demoxepam;
Dexmedetomidine;
Enciprazine Hydrochloride; Gepirone Hydrochloride; Hydroxyphenamate;
Hydroxyzine t o I-lydrochloride; Hydroxyzine Pamoate; Ketazolam; Lorazepam; Lorzafone;
Loxapine; Loxapine Succinate; Medazepam Hydrochloride; Nabilone; Nisobamate ; Oxazepam;
Pentabamate;
Pirenperone; Ripazepam; Rolipram; Sulazepam; Taciamine I-lydrochloride;
Temazepam;
Tritlubazam; Tybamate; Valnoctamide.
Amyotrophic lateral sclerosis agents: Riluzole.
Cerebral ischemia agents: Dextrorphan Hydrochloride.
Paget's disease agents: Tiludronate Disodium.
Unstable angina agents: Tirofiban Hydrochloride.
Uricosuric: Benzbromarone; Irtemazole; Probenecid; Sulfinpyrazone.
Vasoconstrictor : Angiotensin Amide; Felypressin; Metliysergide; Methysergide Maleate.
Vasodilator: Alprostadil; Azaclorzine Hydrochloride; Bametlian Sulfate;
Bepridil Hydrochloride;
Buterizine; Cetiedil Citrate; Chromonar I-lydrochloride; Clonitrate; Diltiazem I-lydrochloride;
Dipyridamole; Droprenilamine; Erythrityl Tetranitrate; Felodipine; Flunarizine Hydrochioride;
Fostedil; liexobendinc; Inositol Niacinatc; Iproxaininc Ilydrocliloride;
Isosorbide Dinitratc;
Isosorbide Mononitratc; isoxsuprinc I-tydrochloride; Lidotlazinc; Me('enidil;
Mcl'enidil Fuinarate;
Mibcfradil Dillvdrochloride; Mioflazine f-lydrochloride; Mixidine; Nafronyl Oxalate; Nicardipine Hydrochloride; Nicergoiine; Nicorandil; Nicotinyl Alcohoi; Nifedipine;
Nimodipine; Nisoldipine;
Oxfenicine; Oxprenolol Hydrochloride; Pentaerythritol Tetranitrate;
Pentoxifylline; Pentrinitrol;
I'erhexiline Maleate; Pindolol; Pirsidomine; Prenylaniine; Propatyl Nitrate;
Suloctidil; Terodiline Hydrochloride; Tipropidil Hydrocliloride; Tolazoline Hydrochloride; Xanthinol Niacinate.
Vulnerary: Allantoin.
Wound liealing agent: Ersofermin.
Xanthine oxidase inhibitor: Allopurinol; Oxypurinol Other pharmaceutical agents include: 1-decpyrrolidinone; 1-dodecpyrrolidinone;
16-alpha fluoroestradiol; 16-epiestriol; 16alplia-gitoxin; l7alpha estradiol; 17beta estradiol; l alpha-hydroxyvitamin D2; 2'-nor-cGMP; 20-epi-1,25 dihydroxyvitamin D3; 22-oxacalcitriol; 2CVV; 3-isobutyl GABA; 6-FUDCA; 7-methoxytacrine; abamectin; abanoquil; abecarnil;
abiraterone;
acadesine; acamprosate; acarbose; aceclofenac; acemannan; acetomepregenol;
acetyl-L-carnitine;
acetylcysteine, N-; acetylmethadol; acifran; acipimox; acitemate; acitretin;
aclarubicin; aciatoniuni;
napadisilate; aconiazide; acrivastinet; adafenoxate; adapalene; adatanserin;
adecypenol; adefovir dipivoxil; adelmidrol; ademetionitie; adinazolam; adiposin; adozelesin;
adrafinil; alacepril;
aladapcin; alaptide; albendazole; albolabrin; aldecalmycin; aldesleukin;
alendronic acid; alentemol;
alfacalcidol; alfuzosin; alglucerase; alihastine; alosetron; alplia idosone;
alprostadil; altretamine;
altromycin B; ambamustine; amelometasone; amesergide; amezinium metilsulfate;
amfebutamone;
amidox; amifloxacin; amifostine; amiodarone; amisulpride; amlexanox;
amlodipine; amlodipine;
ampiroxicam; amrinone; amrubicin; amsacrine; amylin; amythiamicin; anagrelide;
anakinra;
ananain; anaritide; anastrozolc; andrographolidc; anordrin; apadolinc;
apafant; apaxifyllinc;
aphidicolin glycinate; apraclonidine; aprosulate sodium; aptiganel; apurinic acid; aranidipvne;
arbckacin; arbidol; arbutamine; ardeparin sodium; arecatannin BI; argatroban;
aripiprazol;
arotinolol; asimadoline; aspalatone; asperfuran; aspoxicillin; astcmizolc;
asulacrine; atamestane;
atenolol, S-; atevirdine; atosiban; atovaquone; atpenin I3; atrimustine;
atrinositol; aurcobasidin A;
azadiraclitine; azasetron; azatyrosinc; azelaic acid; azelastine;
azelnidipine; azimilide; azithrotnycin;
azosemide; aztrconam; baccatin III; bacoside A; bacosidc I3; bactobolaminc;
balaziponc;
balhimycin;. balofloxacin; balsalazide; banibuterol; baohuoside 1;
barnidipine; basifungin;
batebulast; batimastat; beauvericin; becapiermin; becliconazole; befloxatone;
belfosdil;
bellenamine; benflumetol; benidipine; benzisoxazole; benzochlorins;
benzoidazoxan;
benzoylstaurosporine; benztropine; bepridil; beractant; beraprost;
berlafenone; bertosamil;
besipirdine; beta-alethine; betaclamycin B; betamipron; betaxolol; betulinic acid; bevantolol;
bicalutamide; bifemelane; bimakalim; bimithil; binospirone; bioxalomycin alpha2; biriperone; bis-benzimidazole A; bis-benzimidazole B; bisantrene; bisaramil;
bisaziridinylspermine; bisnafide;
bisoprolol; bistramide D; bistramide K; bistratene A; boldine; bopindolol;
brefeldin; breflate;
brimonidine; bromfenac; bromperidol; bropirimine; bucindolol; budesonide;
budipine; budotitane;
bunaprolast; bunazosin; butenafine; buthionine sulfoximine; butixocort propionate; cadexomer iodine; calanolide A; calcipotriol; calphostin C; camonagrel; candesartan;
candesartan cilexetil;
t o candoxatril; candoxatrilat; capecitabine; capromab; capsaicin; captopril;
carbazomycin C;
carbetocin; carbovir; carboxamide-amino-triazole; carboxyamidotriazole;
carboxymethylated beta-1,3-glucan; carperitide; carteolol; carumonam; carvedilol; carvotroiine;
carzelesin; castanospermine;
cebaracetam; cecropin B; cefcapene pivoxil; cefdaloxime pentexil tosilate;
cefdinir; cefditoren pivoxil; cefepime; cefetamet; cefetamet pivoxil; cefixime; cefluprenam;
cefmetazole; cefminox;
cefodizime; cefoselis; cefotetan; cefotiam; cefotiam hexetil; cefozopran;
cefpimizole; cefpiramide;
cefpirome; cefpodoxime proxetil; cefprozil; cefsulodin; cefteram; ceftibuten;
ceftriaxone;
cefuroxime axetil; celastrol; eclikalim; celiprolol; cepacidine A;
cerielamine; cerivastatiti;
ceronapril; certoparin sodium; cetiedil; cetirizine; chloroorienticin A;
chloroorienticin B;
cliloroquinoxaline sulfonamide; cibenzoline; cicaprost; ciclesonide;
cicletanine; cicloprolol;
cidofovir; cilansetron; cilazapril; cilnldipine; cilobradine; cilostazol;.
cimetropium bromide;
cinitapride; cinolazepam; ciotcroncl; ciprolibrate; cipro(]oxacin; ciprostene;
cis-porphyrin; cisapride;
cisatracurium besilate; cistinexine; citalopram; citicoline; citreamicin alpha; cladribine;
clarithromycin; clausenamide; clebopride; clinafloxacin; clobazam; clobetasone butyrate; clodronic acid; clomethiazole; clopidogrel; clotrimazole; colestimide; colfosceril palmitate; collismycin A;
collismycin B; combrctastatin A4; complestatin; conagenin; contignasterol;
contortrosta,tin;
cosalane; costatolide; cotinine; coumermycin A 1; cucumariosid; curacin A;
curdlan sulfate; curiosin;
cyclazosin; cyclic I-IPMPC; cyclobcnzaprinc; cyclobut A; cyclobut G;
cyclocapron; cycloplatam;
cyclosin; cyclothialidine; cyclotliiazomycin; cypemycin; cyproterone;
cytarabine ocfosfate;
cytochalasin B; dacliximab; dactiniicin; daidzein; daidzin; dalfopristin;
dalteparin sodium;
3o danaparoid; daphnodorin A; dapiprazole; dapitant; darifenacin; darlucin A;
darsidomine; ddUTP;
decitabine; cleferipronc; dellazacort; dehydrodidemnin B;
dchydrocpiandrosterone; dclapril;
dclequaminc; dclfaprazinc; delmopinol; delphinidin; deoxypyridinolinc;
deprodone; depsidoniycin;
deramciclane; dermatan sulfate; desflurane; desirudin; deslorelin;
desmopressin; desogestrel;
desoxoamiodarone; detajmium bitartrate; dexifosfamide; dexketoprofen;
dexloxiglumide;
dexmedetomidine; dexpemedolac; dexrazoxane; dexsotalol; dextrin 2-sulphate;
dexverapamil;
dezinamide; dezocine; diaziquone; diclofenac digolil; diclofenac potassium;
dicranin; didemnin B;
didox; dienogest; diethylhomospermine; diethylnorspermine; dihydrexidine;
dihydro-5-azacytidine;
dimethyl prostaglandin A 1; dimethylhomospermine; dimiracetam; dioxamycin;
diphencyprone;
diphenyl spiromustine; diprafenone; dipropylnorspermine; diritliromycin;
discodermolide;
disulfiram; ditekiren; docarpamine; docosanol, 1-; dofetilide; dolasetron;
domitroban; dopexamine;
dorzolamide; dosmalfate; dotarizine; doxacurium chloride; doxazosin;
doxifluridine; doxofylline;
io draculin; draflazine; droloxifene; dronabinol; drosperidone; drotaverine acephyllinate; droxicam;
ebiratide; ebrotidine; ebselen; ecabapide; 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; cnalapril; enazadrem; englitazone; enlimonlab; enoxacin;
enoxaparin sodium;
enoximone; entacapone; enterostatin; epoprostenol; epoxymexrenone;
epristeride; eprosartan;
eptastigminc; erdosteine; ersentilide; ersoferinin; erythritol; esuprone;
etanidazole; etanterol;
ethacizin; ethinylestradiol; etizolam; etodolac; etoposide phosphate;
etrabamine; everninomicin;
examorelin; exemestane; fadrozole; faeriefungin; faniciclovir; fatnpridine;
fantofarone; faropenem;
fasidotril; fasudil; fazarabine; fedoto?,ine; felbamate; fenofibrate;
fenoldopam; fenretinide;
fenspiride; fenticonazole; f'epradinol; ferpifosate sodium; ferristene;
ferrixan; ferumoxsil;
fexofenadine; flavopiridol; flecainide; flerobuterol; fleroxacin; flesinoxan;
flezelastine; flobufen;
flomoxef; florfenicol; florifenine; flosatidil; fluasterone; fluconazole;
fludarabine; flumazenil;
flumecinol; flumequine; flunarizine; fluocalcitriol; fluorodaunorunicin hydrochloride; fluoxetine, R-; fluoxetine, S-; fluparoxan; flupirtine; flurbiprofen axetil;
flurithromycin; fluticasone propionate;
flutrimazolc; fluvastatin; fluvoxamine; forasartan; forfenimex; formestane;
formotcrol; formotcrol, R,R-; fosfomycin; trometamol; fosinopril; fosphenytoin; fostriecin;
foteniustine; gabapentin;
gadobenic acici; gadobutrol; gadodiamide; gadodiamide-L:OB-DTi'A; gadolinium texaphyrin;
gadoteric acid; gadoteridol; gadoversetamide; galantaniine; galdatlsetron;
gallopamil; galocitabine;
gamolenic acid; ganirelix; gepirone; gestrinone; girisopanz; glaspimod;
glaucocalyxin A;
glutapyrone; glycopine; glycopril; granisetron; grepafloxacin; halichondrin B;
halofantrine;
lialomon; halopredone; liatomamicin; hatomarubigin A; hatomarubigin B;
hatomarubigin C;
hatomarubigin D; ibogaine; ibopamine; ibudilast; illimaquinone; ilmofosine;
ilomastat; iloperidone;
iloprost; imidapril; imidazenil; indinavir; indolidan; indometacin farnesil;
indometacin; tropine ester;
indoramin; inocoteronc; inogatran; inolimomab; interferon alfa; interferon alfa-2a; interferon alfa-2b; interferon alfa-NI; interferon alfa-n3; interferon beta; interferon beta-lal; interferon beta-1 b;
interferon gamma-1 a; interferon gamma- I b; interferon omega; interferon, consensus; interleukin-1;
interieukin- I alpha; interleukin-1 beta; interleukin-10; interleukin-11;
interleukin-12; interleukin-12;
interleukin-15; interleukin-2; interleukin-3; interleukin-4; interleukin-5;
interleukin-7; interleukin-8;
iobenguane; iobitridol; iodoamiloride; iododoxorubicin; iofratol; iomeprol;
iopentol; iopromide;
iopyrol; iotriside; ioversol; ioxilan; ipazilide; IpdR; ipenoxazone;
ipidacrine; ipomeanol, 4-;
-o ipriflavone; ipsapirone; irbesartan; irinotecan; irloxacin; irsogladine;
irtemazole; isalsteine; isbogrel;
isepamicin; isobengazole; isofloxythepin; isohomohalicondrin B; isopropyl unoprostone; isradipine;
itameline; itasetron; itopride; itraconazole; ketoprofen, R-; ketoprofen, S-;
ketorolac; lacidipine;
lactitol; lactivicin; laennec; lafutidine; lamellarin-N triacetate; lamifiban;
lamivudine; lamotrigine;
lanoconazole; lanperisone; lanreotide; lansoprazole; latanoprost; lateritin;
laurocapram; lazabemide;
lemefloxacin; lemildipine; leminoprazole; lenercept; lenograstim; lentinan sulfate; leptin;
leptoistatin; lercanidipine; lerisetron; lesopitron; letrazuril; letrozole;
leucomyzin; leuprorelin;
levcromakalim; levetiracetam; levobetaxolol; levobunolol; levobupivacaine;
levocabastine;
levocarnitine; levodropropizine; levofloxacin; levomoprolol; levonorgestrel;
levormeloxifene;
levosimendan; levosulpiride; linotroban; linsidomine; lintitript; lintopride;
liothyronine sodium;
lirexapride; lisinopril; lobaplatin; lobucavir; lodoxamide; lombricine;
loniefloxacin; lomerizine;
lometrexol; lonazolac; lonidamine; loracarbef; loratadine; lorglumide;
lornoxicam; losartan;
losigamone; losoxantronc; loteprcdnol; loviride; loxoribine; lubeluzole;
lurtotecan; luteinizing hormone; lutetium; luzindole; lydicamycin; lysofylline; lysostaphin; magainin 2 amide; magnolol;
mallotochromene; mallotojaponin; malotilatc; mangafodipir; manidipine;
maniwamycin A;
mannostatin A; manumycin E; manumycin F; mapinastine; marimastat; Martek 8708;
Ma,rtek 92211; masoprocol; maspin; massetolide; ineterelin; metlloxatone;
inethylhistamine, R-alpha;
methylinosine monophosphate; methylprednisolone aceponate; methylprednisolone suleptanate;
metipainide; metoclopramide; metoprolol, S-; nletrifonatc; mibefradil;
michellamine B; microcolin A; midodrine; mifepristone; miglitol; milacemide; mllanleline; mildronate;
milnacipran; milrinone;
miltcfosinc; minaprine; miokamycin; mipragoside; mirfentanil; mirimostim;
mirtazapine;
misoprostol; mitoguazone; mitolactol; mitonafide; mitoxantrone; mivacurium chloride; mivazerol;
mixanpril; mizolastine; mizoribinc; moclobemide; modafinil; moexipril;
mofarotene; inofezolac.
niolgramostim; mometasone; inontirelin; mopidamol; moracizine; mosapramine;
mosapride;
motilide; moxiraprine; moxonidine; nadifloxacin; nadroparin calcium;
nafadotride; nafamostat;
nafarelin; naftopidil; naglivan; nagrestip; nalmefene; napliterpin;
napsagatran; naratriptan;
nartograstim; nasaruplase; nateplase; niperotidine; niravoline; nisamycin;
nisin; nisoldipine;
nitazoxanide; nitecapone; nitrendipine; nitrendipine, S-; nitrofurantoin monohydrate; nitrullyn;
nizatidine; ofloxacin; okicenone; olanzapine; olopatadine; olprinone;
olsalazine; omeprazole;
onapristone; ondansetron; ondansetron, R-; ontazolast; oracin; otenzepad;
oxaliplatin; oxamisole;
oxandrolone; oxaprozin; oxaunomycin; oxcarbazepine; oxiconazole; oxiracetam;
oxodipine; ozagrel;
palauamine; palinavir; palmitoyirhizoxin; paniaqueside; pamicogrel; pamidronic acid; panamesine;
i o panaxytriol; panipenem; panipenum; pannorin; panomifene; pantethine;
pantoprazole; parabactin;
pamaparin sodium; paroxetine; partlienolide; pazelliptine; pazufloxacin;
pefloxacin; pegaspargase;
peldesine; pemedolac; pemirolast; penciclovir; pentafuside; pentamidine;
pentamorphone;
pentigetide; pentosan; pentostatin; pentrozole; perflubron; perfosfamide;
pergolide; perindoprilat;
perospirone; phenaridine; phenazinomycin; pllenserine; phensuccinal;
phentolamine mesilate;
plienylacetate; phenylalanyl ketoconazole; picenadol; picibanil; picroliv;
picumeterol; pidotimod;
pilocarpine hydrocliloride; pilsicainide; piinagedine; pimilprost; pimobendan;
pinacidil; pinocebrin;
pioglitazone; pipecuronium bromide; pirarubicin; piretanide; pirfenidone;
piritrexim; pirlindole;
pirmagrel; pirmenol; pirodavir; pirodoniast; piroxicam cinnamate:
propagermanium; propentofylline;
propionylcarnitine, L-; propiram; propiram + paracetaniol; propivcrine; propyl bis-acridonc;
prostaglandin J2; prostratin; protegrin; prbtosufioxacin; prtilifloxacin;
pyrazoloacridine; quazepam;
cluetiapine; quiflapon; quinagolidc; quinapril; duinfiimidc; quinupristin;
raloxifene; raltitrexed;
ramatroban; raniipril; ramosetron; ranelic acid; ranitidine bismutli citrate;
ranolazine; recainam;
regavirumab; relaxin; repirinast; resinferatoxin; reticulon; reviparin sodiuni; revizinone; ricasetron;
ridogrel; rifabutin; rifapentine; rifaximin; rilopirox; riluzole; rimantadine;
rimexolone; rimoprogin;
riodipinc; ripisartan; risedronic acid; rispenzcpinc; i-ispcridonc;
ritanscrin; ritipcncm; ritipcrqem acoxil; ritolukast; ritonavir; rizatriptan benzoate; rohitukinc; rokitamycin;
ropinirole; ropivacaine;
roquinimcx; roxatidinc; roxindole; roxithromycin; rubiginonc [31; ruboxyl;
rufioxacin; rupatidine;
ruzadolane; safingol; safironil; saintopin; salbutamol, R-; salmeterol;
salmeterol, R-salnacedin;
sameridinc; sanipatrilat; sanfctrinem; saprisartan; saproptcrin; saquinavir;
SarCNU; sarcophytol A
sargramostim; sarpogrelate; saruplase; saterinone; satigrel; satumomab pendetide; selebiline;
selcnium thiosenlicarbazone; seniatilide; semduramicin; scmotiadil; semustine;
sermorelin;
sertaconazolc: sertindole; scrtralinc; setiptiline; sevirumab; sevotlurane;
sezolamide; silipide;
-5s-siiteplase; simendan; simvastatin; sinitrodil; sinnabidol; sipatrigine;
sirolimus; sizofiran;
somatomedin B; somatomedin C; somatrem; somatropin; sonermin; sotalol;
staurosporine;
stavudine; stepronin; stipianiide; stiripentol; stobadine; succibun;
sucralfate; sulfasalazine;
sulfinosine; sulfoxamine; stilopenem; sultaniicillin; sultopride; sulukast;
sumatriptan; symakalim;
tandospirone; tapgen; taprostene; tasosartan; tazanolast; tazarotene;
teicoplanin; telenzepine;
tellurapyrylium; telmesteine; telmisartan; temocapril; temoporfin;
temozolomide; tenidap;
teniposide; tenosal; tenoxicam; tepirindole; tepoxalin; terazosin;
terbinafine; terfenadine;
terflavoxate; terguride; terlakiren; terlipressin; terodiline; tertatolol;
testosterone buciclate;
tetrachlorodecaoxide; tetrazomine; thaliblastine; thalidoniide; thiocoraline;
thiofedrine; thiomarinol;
io thioperamide; thyroid stimulating hormone; tiagabine; tianeptine;
tiapafant; tibolone; ticlopidine;
tienoxolol; tilisolol; tilnoprofen arbamel; tiludronic acid; tinzaparin sodium; tiotropium bromide;
tipredane; tiqueside; tirandalydigin; tirapazamine; tirilazad; tirofiban;
tiropramide; topsentin;
torasemide; toremifene: tosufloxacin; trafermin; trandolapril; traxanox;
tretinoin; tretinoin tocoferil;
triacetyluridine; tricaprilin; trichohyalin; trichosanthiii, alpha;
triciribine; trientine; triflavin;
trimegestone; triptorelin; troglitazone; trombodipine; tropisetron;
trospectoniycin; trovafloxacin;
trovirdine; tucaresol; tulobuterol; tylogenin; urapidil; uridinc tripllosphate; valaciclovir; valproate magnesium; valproate semisodium; valsartan; vamicamide; vanadeine; vaninolol;
vapreotide;
variolin B; velaresol; venlafaxine; veramine; verapamil, (S); verdins;
veroxan; verteporfin;
vesnarinone; vexibinol; visabatrin; vinburnine citrate; vinburnine resinate;
vinconate; vinorelbine;
vinpocetine; vinpocetine citratc; vintoperol; vinxaltine; voriconazole;
vorozole; voxergolidc;
xcmilotiban; ximoprofen; yangambin; zabicipril; zacopride; zacopride, R-;
zafirlukast; zalcitabine;
zaleplon; zalospirone; zaltoprofen; zanamivir; zankiren; zanoterone;
zatebradine; zatosetron;
zenarestat; zeniplatin; zifrosilone; zilascorb; zileuton; zinostatin stimalamer; ziprasidone; zoledronic acid; zolmitriptan; zolpidem; zonisamide; zopiclone; zopicione, S-;
zopolrestat; zotepine.
'fhc invcntion also cmbraces novel compositions of matter that arc covalent conjugatc$ of' D1-IA and pharmaceutical agents that are noncentral nervous system active agents. Noncentral nervous system active agents have no tiinction or use within the central nervous svstem. Tlieir only use is outside of the central nervous system. Such agents include all drugs witllin certain of the foregoing categories and only sonie drugs within other of the foregoing catagorics. For example, thc cntire catagory ol' blood glucose regulators liave no use or liinction within the central nervous system. In contrast, certain anti-cancer agents are useful in the central nervous system whereas others are not. For exaniple, central nervous systcm cancers are not hornione dependent, and, therefore, 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 catagories are noncentral nervous system active agents: adrenocortical steroid; adrenocortical suppressant; aldosterone antagonist; amino acid; anabolic; androgen;
antagonist; anthelinintic;
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;
i o antidiuretic; antidote; anti-estrogen; antifibrinolytic; antifungal;
antiglaucoma agent;
antihemophilic; antihemorrhagic; antihistamine; antihyperlipidemia;
antihyperlipoproteinemic;
antihypertensive; antihypotensive; anti-infective; anti-infective, topical;
anti-inflammatory;
antikeratinizing agent; antimalarial; antimicrobial; antimitotic; antimycotic, antineoplastic, antineutropenic, antiparasitic; antiperistaltic, antipneuniocystic;
antiproliferativc; antiprostatic hypertrophy; antiprotozoal; antipruritic; antipsoriatic; antirheumatic;
antischistosomal;
antiseborrheic; antisecretory; antispasmodic; antithrombotic; antitussive;
anti-ulcerative;
anti-urolithic; antiviral; appetite suppressant; benign prostatic hyperplasia therapy agent; bone resorption inhibitor; broncliodilator; carbonic anliydrase inhibitor; cardiac depressant;
cardioprotectant; cardiotonic; cardiovascular agent; choleretic; cliolinergic;
cliolinergic agonist;
cholinesterase deactivator; coccidiostat; -diagnostic aid; diuretic;
ectoparasiticide; enzyme inliibitor;
estrogen; fibrinolytic; free oxygen radical scavenger; glucocorticoid; gonad-stimulating principle;
liair growtli stimulant; hemostatic; hormone; hypocholesterolemic;
hypoglycemic; hypolipideinic;
hypotensive; inimunizing agent; immunomodulator; immunoregulator;
immunostimulant;
immunosuppressant; impotence therapy adjunct; inhibitor; kcratolytic; LI-IRI I
agonist; liver disorder treatnient; lutcolysin; mucolytic; mydriatic; nasal decongestant;
neuromuscular blocking agqnt;
non-hormonal stcrol derivativc; oxytocic; plasminogen activator; platelet activating factor antagonist; platelet aggregation inhibitor; potentiator; progestln;
prostaglandiu; prostate growth inhibitor; prothyrotropin; pulmonary surface; radioactive agent; regulator;
relaxant; repartitioning agent; scabicidc; sclerosing agent; selective adenosinc Al antagonist;
steroid: suppressant;
syinptomatic multiple sclerosis; synergist; thyroid hormone; thyroid inhibitor; thyromimetic;
amyotropliic lateral sclerosis agents; Paget's disease agents; unstable angina agents; uricosuric;
vasoconstrictor; vasodilator; vulnerary; wound healing agent: xanthine oxidase inhibitor.
As used lierein, a taxane is a inolecule 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.
5 ~8 1 ~
~2 j A 6 43 ~17 , J~
10 A taxoid is a molecule structurally related to a taxane in wliich 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 15 or more structural features cliaracteristic of the taxane carbon-atom connectivity network are conserved.
The compounds useful in the invention may be delivered in the fonn of anti-cancer cocktails.
An anti-cancer cocktail is a mixture of any one of the compounds tiseful with this invention with another anti-cancer agent such as an anti-cancer drug, a cytokine, and/or supplementary potentiating 20 agent(s). The use of cocktails in the treatinent of cancer is routine. In this embodiment, a common administration vehicle (e.g., pill, tablet, implant, in,jectable solution, etc.) would contain both the conjugate useful in this invention and the anti-cancer drug and/or supplementary potentiating agent.
Thc compounds of thc invention, whcn uscd in cocktails, arc administered in tllcrapeutically effective amounts. A therapeutically effective amount will be determined by the parameters discussed below; but, in any event, is that amount which establishes a level of the drug(s) in the at'ea of the tutnor which is effective in inhibiting the tumor growth.
When administered, the 1'ormulations of the invention are applied in pharmaceutically acceptable amounts and in pharmaceutically acceptable coinpositions. Such preparations may routinely contain s-Its, bu[7'ering agents, preservativcs, compatibic carriers, and optionally othcr therapeutic ingredients. Wlien used in medicine the salts should be pharmaceutically acceptable, but non-pliarmaceutically acceptable salts may convenicntly be used to prepare pharmacetitically acceptable salts thereof and are not excluded from the scope of the invention.
Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrocllloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulfonic, tartaric, citric, methane sulfonic, formic, malonic, succinic, naphthalene-2-sulfonic, aiid 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 (1-2% WN); citric acid and a salt (1-3% W/V); boric acid and a salt (0.5-2.5% W/V); and phosphoric acid and a salt (0.8-2% WN).
Suitable preservatives include benzalkonium chloride (0.003-0.03% W/V);
chlorobutanol (0.3-0.9% WN); parabens (0.01-0.25% WN) and tllimerosal (0.004-0.02% WN).
The active compounds of the present invention niay be a phannaceutical cotiiposition having a tlierapeutically effective amount of a conjugate of the invention optionally included in a pliarmaceutically-acceptable carrier. 'I'he tenn "pharmaceutically-acceptable carrier" as used herein means one or more compatible solid or liquid filler, dilutants or encapsuiating 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 wliich the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions are capable of being commingled witli the molecules of the present invention, and witli each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.
Compositions suitable for parenteral administration convenientlv coniprisc a sterile preparation of the conjugates of tile invention. This preparation may be formulated according to known methods. Formulations for taxanes can be found in Chapter 9 of Taxol:
Science and Applications, CRC Press, Inc., 2000 Corporate Boulevard. N.W., 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/mi solution of taxotere has been formulated in polysorbate 80 (polyoxyethylenc sorbitanmonooleate)/ethanol mixture, diluted with 5% dextrose.
The sterile preparation tlius 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 mcdlunl. For this purpose any bland iixcd oil n,ay be 3o employed including synthetic mono ordi-glycerides. In addition, fatty acids such as oleic acid find use in tlic preparation of injectables. Carrier formulations suitable for oral, subcutaneous, intravenous, intraniuscular, etc. can be found in Reniington's Pharmaceutical Sciences, Mack I'ublisliing Coinpany, Caston, I'A.
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 -0 including age, physical condition, size and weight; concurrent treatment;
frequency of treatment; and the mode of adniinistration. Tliese factors are well known to those of ordinary skill in tiie art and can be addressed with no more than routine experimentation. It is preferred generally that a maximum dose be used, that is, the higliest 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/m2 per day will be effective. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Continuous IV dosing over, for example 24 hours or multiple 2o doses per day are contemplated to achieve appropriate systemic levels of compounds.
A variety of administration routes are available. The particular mode selected will depend of course, upon the particular drug selectcd, the severity of the disease state being treated and the dosage requircd for therapeutic efficacy. The inethods of this invention, generally speaking, may be practiced using any niode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects. Such modes of administration include oral, rectal, sublingual, topical, nasal, transdermal or parenteral routes. 7'he tcrm "parenteral" includes subcutancous, intravenous, intramuscular, or inhision. lntravenous routcs are preferred.
The conipositions may conveniently be presented in unit dosage form and may be preparcd 3o by any of the mcthods well known in the art of pliarmacy. All methods includc thc stcp ol'bringing the conjugates of the iirvention into association with a carricr wliich constitutes one or more accessory ingredients. In general, the compositions arc prcpared by uniformiy and intimately bringing 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 niav be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined aniount of the active compound. Other conipositiotis include suspensions in aqtteous 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 sttbject and the physician. Many types of release delivery systems are i o 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 cliolesterol, 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 wliicli are adapted for implantation.
A long-term sustained release implant also niay 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 tlie art and include some of the release systems described above. Such itnplants can be particularly useful in treating solid tumors by placing the implant near or directly within the lunlor, lhereby alTecting localized, liigh-doses of the compounds of the invention.
The conjugates of the invention also are useful, in general, for treating mammalian cell proliferative disorders otlier than cancer, including psoriasis, actinic keratosis, etc. They fut-ther nre useful in treating diabetes and its complications, excess acid secretion, cardiovascular conditions involving cholesterol (e.g., hyperlipidemia and hypercholesterolemia), diarrhea, ovarian diseases (e.g. endometriosis, ovarian cysts, etc.) and as contraceptive agents.
Those skilled in the art will be able to recognize with no more than routine experimentation numcrous cquivalents to the specific products and processcs described above.
Stich equivalents are intended to be included within the scope of the appended claims.
Pinoxepin I-lydrochloridc; Pipampcrone; Piperacetazinc: Pipotiazine Palniitatc; Piquindone llydrochloridc; Prochlorperarine Gdisylate; Prochlorperazinc Maleate;
l'romazine llydrocliloride;
Remoxipride; Remoxipride Hydrochloride; Rimcazole Hydrochloride; Seperidol Hydrocliloride;
Sertindole ; Setoperone; Spiperone; Thioridazine ; Tliioridazine Hydrochloride; Thiothixene;
Thiothixene Hydrochloride; Tioperidone I-lydrocliloride; Tiospirone Hydrochloride; Trifluoperazine I-Iydrochloride; Trifluperidol; Triflupromazine; Triflupromazine Hydrocliloride; Ziprasidone Hydrocliioride.
Antirheumatic: Auranofin; Aurothioglucose; Bindarit; Lobenzarit Sodium;
Phenylbutazone;
Pirazolac; Prinomide Tromethamine; Seprilose.
i o Antischistosomal: Becanthone Hydrochloride; Hycanthone; Lucanthone Hydrochloride; Niridazole;
Oxamniquine; Pararosaniline Pamoate; Teroxalene Hydrochloride.
Antiseborrheic: Chloroxine; Piroctone; Piroctone Olamine; Resorcinol Monoacetate.
Antisecretory: Arbaprostil; Deprostil; Fenoctimine Sulfate; Octreotide:
Octreotide Acetate;
Omeprazole Sodium; Rioprostil; Trimoprostil.
Antispasmodic: Stilonium Iodide; Tizanidine Hydrochloride.
2o Antithrombotic: Anagrelide I-Iydrochloride; Bivalirudin ; Dalteparin Sodium ; Danaparoid Sodium;
Dazoxiben Hydrochloride; Efegatran Sulfate; Enoxaparin Sodium; Ifetroban;
Ifetroban Sodium;
Tinzaparin Sodiuni ; Trifenagrel.
Antitussive: Benzonatate; Butamirate Citrate; Chlophedianol Hydrochloride;
Codeine Polistirex;
Codoxime; Dextromethorphan; Dextromethorphan Hydrobromide; Dextromethorphan Polistinex;
Etliyl Dibunate; Guaiapate; I-Iydrocodonc Bitartratc; 1-Iydrocodonc Polistirex; Levopropoxyphene Napsylate; Noscapine; Pemerid Nitrate; Pipazethate; Suxemerid Sulfate.
Anti-ulcerative: Aceglutamide Aluminum; Cadexomer Iodine ; Cetraxate I-Iydrochloride; Enisoprost;
Isotiquimide; Lansoprazole; Lavoltidine Succinate; Misoprostol; Nizatidine;
Noliniuni Bromide ;
Pantoprazolc; Pifarninc; I'irenzcpinc 1-Iydrocliloride; Rabeprazolc Sodium ;
Rcmiprostol; Roxatidinc Acetate Hydrocliloride; Sucralfatc; Sucrosofate Potassium; 'Tolimidone.
Anti-urolithic: Cysteamine; Cysteamine Hydrochloride; Tricitrates Antiviral: Acemannan; Acyclovir; Acyclovir Sodium; Adefovir; Alovudine;
Alvircept Sudotox;
Amantadine Hydrochloride; Aranotin; Arildone; Atevirdine Mesylate; Avridine;
Cidofovir;
Cipamfylline; Cytarabine Hydrochloride; Delavirdine Mesylate; Desciclovir;
Didanosine; Disoxaril;
Edoxudine; Enviradene; Enviroxime; Famciclovir; Famotine Hydrochloride;
Fiacitabine;
Fialuridine; Fosarilate; Foscarnet Sodium; Fosfonet Sodium; Ganciclovir;
Ganciclovir Sodium;
Idoxuridine; Ketlioxal; Lanlivudine; Lobucavir; Memotine Hydrochloride;
Methisazone; Nevirapine;
Penciclovir; Pirodavir; Ribavirin; Rimantadine Hydrochloride; Saquinavir Mesylate; Somantadine I o I-lydrochloride; Sorivtidinc; Statolon; Stavudine; Tilorone 1-Iydrochloridc; Trifluridine; Valacyclovir I-Iydrochloride; Vidarabine; Vidarabine Phospliatc; Vidarabine Sodium Phosphate; Viroxiine;
Zalcitabine; Zidovudine; Zinviroxime.
Appetite suppressant: Dexfenfluramine Hydrochloride; Phendimetrazine Tartrate;
Phentermine I-Iydrochloride.
Benign prostatic hyperplasia tlierapy agent: Tamsulosin Hydrochloride.
Blood glucose regulators: I-Iuman insulin; Glucagon; Tolazamide; Tolbutaniide;
Cllloropropamide;
2o Acetohexamide and Glipizidc.
13one resorption inhibitor: Alendronate Sodium; Etidronatc Disodiunl;
Pamidronate Disodium.
I3ronchodilator: Albutcrol; Albutcrol Sulfate; Azanator Maicate; I3aniifyliinc Ilydrochloride;
Bitolterol Mesylate; Butaprost; Carbuterol Hydrochloride; Clorprenaline Hydrochloride; Coltarol Mesylatc; Doxaprost; Doxofylline; Dyphylline; Enprofylline; Ephedrine;
Ephedrine Hydrochloride;
Fenoterol; Fenprinast Hydrochloride; Guaitliylline; Hexoprenaline Sulfate ;
Hoquizil Hydrochloride;
Ipratropium Bromide; Isoetharine; Isoetharine Hydrochloride; Isoetliarine Mesylatc; Isoproterenol Hydrocliloride; lsoproterenol Sulfatc; Metaprotcrenol Polistirex;
Metaproterenol Sulfatc; Nisbuterol Mcsylate; Oxtriphyllinc; PicunIctcrol Fumaratc; Piquizil I-lydrocliloridc;
Pirbuterol Acctatc;
Pirbuterol I-Iydrochloridc; Procatcrol Ilydrocliloride; Pscuciocpliedrine Sulfate; Quazodinc ;
Quintcrenol Sulfate; Raccpincphrinc; Racepinephrine I-lydrochloride;
Reproterol I-Iydrocliloride;
Rimiterol Hydrobroniide; Salmeterol; Salmeterol Xinafoate; Soterenol Hydrochloride; Sulfonterol Hydrochloride; Suloxifen Oxalate; Terbutaline Sulfate; Theopliylline; Xanoxate Sodium; Zindotrine;
Zinterol Hydrochloride.
Carbonic anhydrase inhibitor: Acetazolamide; Acetazolamide Sodium;
Dichlorphenamide;
Dorzolamide Hydrochloride; Methazolamide; Sezolamide Hydrochloride.
Cardiac depressant: Acecainide Hydrochloride; Acetylcholine Chloride;
Actisomide; Adenosine;
Amiodarone; Aprindine; Aprindine Hydrochloride; Artilide Fumarate; Azimilide Dihydrochloride;
io Bidisomide; Bucainide Maleate; Bucromarone; Butoprozine Hydrochloride ;
Capobenate Sodium;
Capobenic Acid; Cifenline; Cifenline Succinate; Clofiliuni Phosphate;
Disobutamide; Disopyramide;
Disopyramide Phosphate; Dofetilide; Drobuline; Edifolone Acetate; Emilium Tosylate; Encainide Hydrochloride; Flecainide Acetate; Ibutilide Fumarate; Indecainide Hydrochloride; Ipazilide Fumarate; Lorajmine Hydrochloride; Lorcainide I-Iydrochloride; Meobentine Sulfate; Mexiletine Hydrochloride; Modecainide; Moricizine; Oxiramide; Pirmenol Hydrochloride;
Pirolazamide;
Pranolium Chloride; Procainamide Hydrochloride; Propafenone Hydrochloride;
Pyrinoline;
Quindonium Bromide; Quinidine Gluconate; Quinidine Sulfate; Recainam Hydrochloride; Recainam Tosylate; Risotilide Hydrochloride; Ropitoin Hydrochloride; Sematilide Hydrochloride; Suricainide Maleate; Tocainidc; Tocainide I-Iydrocllloride; Transcainide.
Cardioprotectant: Dexrazoxane; Draflazine.
Cardiotonic: Actodigin; Anirinone; Bemoradan; Butopatnine; Carbazcran;
Carsatrin Succinatc;
Deslanoside; Digitalis; Digitoxin; Digoxin; Dobutamine; Dobutamine Hydrochloride; Dobutamine Lactobionate; Dobutamine Tartrate; Enoximonc; Imazodan I-Iydrochloride;
Indolidan; Isomaz,ole Hydrochloride; Levdobutarnine Lactobionate; Lixazinone Sulfate; Medorinone;
Milrinone; Pelrinone I-Iydrochloride; Pimobendan; Piroximonc; Prinoxodan; Proscillaridin;
Quazinone; Tazolol Hydrochloride; Vesnarinone.
Cardiovascular agent: Dopexamine; Dopexamine Hydrochloride.
Choleretic: Dehydrocholic Acid; Fencibutirol; I-Iymecromone; Piprozolin;
Sincalide; Tocamphyl.
Cholinergic: Aceclidine; Bethanechol Chloride; Carbachol; Demecarium Bromide;
Dexpanthenol;
Echothiophate Iodide; Isoflurophate; Methacholine Chloride; Neostigmine Bromide; Neostigmine Methylsulfate; Physostigmine; Physostigmine Salicylate; Pliysostigmine Sulfate; Pilocarpine Pilocarpine Hydroclzloride; Pilocarpine Nitrate; Pyridostigmine Bromide.
Cliolinergic agonist: Xanomeline; Xanomeline Tartrate.
Cholinesterase Deactivator: Obidoxime Chloride; Pralidoxime Chloride;
Pralidoxime Iodide;
Pralidoxime Mesylate.
to Coccidiostat: Arprinocid; Narasin ; Semduramicin; Semduramicin Sodium.
Cognition adjuvant: Ergoloid Mesylates; Piracetam; Pramiracetam Hydrochloride;
Pramiracetam Sulfate; Tacrine Hydrochloride.
Cognition enhancer: Besipirdine Hydrochloride; Linopirdine; Sibopirdine.
Depressant: Omeprazol c.
2o Diagnostic aid: Aminohippurate Sodium; Anazolene Sodium; Arclofenin;
Arginine ; Bentiromide;
Benzylpenicilloyl Polylysine; Butedronate Tetrasodium; Butilfenin;
Coccidioidin; Corticorelin Ovine Triflutate ; Corticotropin, Repository; Corticotropin Zinc I-lydroxide;
Diatrizoate Megluniine;
Diatrizoate Sodium; Diatrizoic Acid; Diplltheria Toxin for Schick Test;
Disofenin; Edrophonium Chloride; Ethiodized Oil; Etifenin; Exametazime; Ferristenc; Ferumoxides;
Ferumoxsil; Fluorescein;
Fluorescein Sodium; Gadobenate Dimeglumine; Gadoteridol; Gadodiamide;
Gadopcntetate Dimegiumine; Gadoversetamide; Histoplasmin; Impromidine Hydrochloride;
Indigotindisulfonate Sodium; Indocyanine Green ; lobenguane Sulfate I 123; Iobenzamic Acid;
locarmate Meglumine;
locarmic Acid; locetamic Acid; lodainide; lodamide Megiumine; lodipamide Meglumine; Iodixanol;
lodoxamate Meglumine; lodoxamic Acid; Iogiicic Acid; Ioblucol; Ioglucomide;
loglycamic Acid;
logulaniide; Ioliexol; lonieprol; lopaniidol; lopanoic Acid; lopentol;
lophendylate; lprofenin;
lopronic Acid; loprocemic Acid; lopydol; lopydone; losefamic Acid; loscric Acid; losulamide Meglumine; losumctic Acid; lotasul; lotetric Acid; lotlialamate Meglumine;
lothalamate Sodium;
Iothalamic Acid; lotrolan; lotroxic Acid; loversol; Ioxaglate Meglumine;
loxagiate Sodium; loxaglic Acid; loxilan; loxotrizoic Acid; Ipodate Calcium; Ipodate Sodium; Isosulfan Blue; Leukocyte Typing Serum; Lidofenin; Mebrofenin; Megiumine; Metrizamide; Metrizoate Sodium; Metyrapone;
Metyrapone Tartrate; Mumps Skin Test Antigen; I'entetic Acid; Propyliodone;
Quinaldine Blue;
Schick Test Control; Sermorelin Acetate ; Sodium Iodide 1 123; Sprodiamide;
Stannous Pyrophosphate; Stannous Sulfur Colloid; Succimer; Teriparatide Acetate;
Tetrofosmin; Tolbutamide Sodium; Tuberculin; Tyropanoate Sodium; Xylose.
Diuretic: Ambuphylline ; Ambuside; Amiloride Hydrochloride; Azolimine;
Azosemide; Brocrinat;
i o Bumctanide; Chlorothiazide; Clilorthalidone; Clazolimine; Clorexolone;
Ethacrynate Sodium;
Ethacrynic Acid; Etozolin; Fenquizone; Furosemide; Hvdrochlorothiazide;
Isosorbide; Mannitol ;
Mefruside; Ozolinone; Piretanide; Spiroxasone; Torsemide; Triamterene;
Triflocin; Urea.
Dopaminergic agent: ibopamine.
Ectoparasiticide: Nifluridide; Permethrin.
Emetic: Apomorphine Hydrocliloride.
Enzyme inhibitor: Acetohydroxamic Acid; Alrestatin Sodium; Aprotinin;
Benazepril Hydrochloride;
Benazcprilat; Bcnurcstat; Broniocriptinc; Bromocriptinc Mcsylate; Cilastatin Sodium; Flurofatnide;
Lergotrile; Lergotrile Mesylate; Lcvcycloserine; Libenzapril; Pentopril;
Pepstatin; Perindopril;
Polibnate Sodium; Sodiuni Amylosullate; Sorbinil; Spirapril I-lydrocliloride;
Spiraprilat; Taleranol;
Teprotide; Tolfamide; Zofenopril Calcium.
Estrogen: Chlorotrianisenc; Dienestrol; Diethylstilbestrol; Dicthylstilbestrol Diphosphate; Equidin;
Estradiol; Estradiol Cypionate; Estradiol Enanthate; Estradiol Undecvlate;
Estradiol Valerate;
Estrazinol Hydrobromide; Estriol; Estrofurate; Estrogens, Conjugated;
Estrogens, Esterified;
Estrone; Estropipate; Ethinyl Estradiol; Fenestrel; Mestranol; Nylestriol;
Quinestrol.
3o Fibrinolytic: Anistreplase; Bisobriii Lactate; Brinolase.
Free oxygen radical scavenger: Pegorgotcin.
Gastrointestinal Motility agents: Cisapride (PropulsidTM Metoclopramide (ReglanTM);
Hyoscyamine (LevsinTM).
Glucocorticoid: Amcinonide; Beclomethasone Dipropionate; Betamethasone;
Betamethasone Acetate; Betaniethasone Benzoate; Betamethasone Dipropionate; Betamethasone Sodium Phosphate;
Betaniethasone Valerate; Carbenoxolone Sodium; Clocortolone Acetate;
Clocortolone Pivalate;
Cloprednol; Corticotropin; Corticotropin, Repository; Corticotropin Zinc Hydroxide; Cortisone Acetate; Cortivazol; Descinolone Acetonide; Dexamethasone; Dexamethasone Sodium Phosphate;
Diflucortolone; Diflucortolone Pivalate; Flucloronide; Flumethasone;
Flumethasone Pivalate;
Flunisolide; Fluocinolonc Acctonide; Fluocinonidc; Fluocortolone;
Fluocortolone Caproate;
Fluoroinetholone; Fluperolone Acetate; Fluprednisolone; Fluprednisolone Valerate; Flurandrenolide;
Formocortal; Hydrocortisonc; I-lydrocortisone Acetate; Hydrocortisone Buteprate; Hydrocortisone Butyrate; IIydrocortisone Sodium Phosphate; Hydrocortisonc Sodium Succinatc; I-iydrocortisone Valerate; Medrysone; Methylprednisolone; Methyiprednisolone Acetate;
Methylprednisolone Sodium Phosphatc; Mcthylprednisolotie Sodium Succinate; Nivazol;
Paramctliasone Acetatc;
Prednicarbate; Prednisolonc; I'rednisolone Acetate; Prednisolonc Hemisuccinate; Prednisolone Sodiuni Phospliatc; Prednisolonc Sodium Succinate; Prcdnisolone Tebutate;
Prcdnisone; Prednival;
Ticabesonc Propionate; 1'ralonide; Triamcinolonc; Triamcinolone Acetonide;
Triamcinolone Acetonide Sodium; Triamcinolone Diacetate; Triamcinolone I-iexacetonide.
Gonad-stimulating principle: Buserelin Acetate; Clomiphene Citrate; Ganirelix Acetate; Gonadorelin Acetatc; Gonadorclin 1-lydrochloride; Gonadotropin. Chorionic; Menotropins.
Hair growth stimulant: Minoxidil .
Hemostatic: Aminocaproic Acid; Oxamarin 1-lydrochloridc; Sulmarin; Thrombin;
Trancxamic Acid.
Histamine H2 receptor antagonists: Ranitidine (ZantacTM); Famotidine (PepcidTM); Cimetidine (TagametTM); Nizatidine (AxidTM).
3() I-lorrnone: Diethylstilbestrol; Probesteronc; 17 liydroxy progestcronc;
Medroxyprobcstcronc;
Norgestrel; Norcthynoclrcl; E-stradiol; Mcgcstrol (MegaoeTm); Norcthindronc;
Levonorgestrcl;
Ethyndiol; Ethinyl estradiol; Mestranol; Estrone; Equilin; 17 aipha dihydroequilin; equilenin; 17 alpha dihydroequilenin; 17 alpha estradiol; 17 beta estradiol; Leuprolide (lupron); Glucagon;
Testolactone; Clomiphene; Han memopausal gonadotropins; Human cllorionic gonadotropin;
Urofollitropin; Bromocriptine; Gonadorelin; Luteinizing hormone releasing liormone 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 (Latrodectus mactans); Antivenin (Micrurus Fulvius); Antivenin (Crotalidae) Polyvalent; BCG Vaccine; Botulisnl Antitoxin;
Cholera Vaccine;
Diphtheria Antitoxin; Diphtheria Toxoid; Diplitheria Toxoid Adsorbed;
Globulin, Immune; Hepatitis B Immune Globulin; Hepatitis B Virus Vaccine Inactivated; Influenza Virus Vaccine; Measles Virus Vaccine Live; Meningococcal Polysaccharide Vaccine Group A; Meningococcal Polysaccha~de 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; Snialipox Vaccine; Tetanus Antitoxin; Tetanus Immune Globulin;
Tetanus Toxoid;
3fl Tetanus Toxoid Adsorbed; Typhoid Vaccine; Yellow Fever vaccine; Vaccinia Immune Globulin;
Varicella-Zoster Immune Globulin.
.Immunomodulator: Dimepranol Acedoben; Imiquimod; Iiiterferon Beta-lb;
Lisofylline;
Mycophenolate Mofetil; Prczatide Copper Acetate.
Immunoregulator: Azarole; Fanetizole Mesylate; Frentizole; Oxamisole Hydrochloride; Ristianol Phosphate; Thymopentin; Tilomisole.
Immunostimulant: Loxoribine ; Teceleukin.
Immunosuppressant: Azathioprine; Azathioprine Sodium; Cyclosporine; Daltroban;
Gusperimus Trihydrochloride; Sirolimus; Tacrolimus.
Impotence therapy adjunct: Delequamine Hydrochloride.
Inhibitor: Acarbose; Atorvastatin Calcium; Benserazide ; Brocresine;
Carbidopa; Clavulanate Potassium; Dazniegrcl; Docebenone; Epoprostenol; Epoprostenol Sodium;
Epristeridc; Finasteride;
Flurbiprofcn Sodium; Furegrelate Sodium; Lufironil; Miglitol; Orlistat;
Pimagedine Hydrochloride;
Pirmagrel; Ponalrestat; Ridogrel; Sulbactam Benzathine ; Sulbactam Pivoxil ;
Sulbactam Sodium ; Suronacrine Maleate; Tazobactam; Tazobactam Sodium; Ticlopidine I-Iydrocliloride; Tirilazad Mesylate; Toirestat; Veinacrine Maleate; Zifrosilone; Zileuton.
2o Keratolytic: Alcioxa ; Aldioxa ; Benzoyl Peroxide; Dibenzothiophene;
Etarotene; Isotretinoin;
Motretinide; I'icotrin Diolamine; Resorcinol; Resorcinol Monoacetate ;
Salicylic Acid; Sumarotene;
Tazarotene; Tetroquinone; Tretinoin.
LHRH agonist: Deslorelin; Goserelin; Histrclin; Lutrelin Acetate; Nafarelin Acetate.
Liver disorder treatment: Malotilate.
Luteolysin: Fenprostalene.
Memory adjuvant: Dimoxamine Hydrocllloride; Ribaminol.
Mental performance enhancer: Aniracetam.
Mood regulator: Fengabine.
Mucolytic: Acetylcysteine; Carbocysteine; Domiodol.
Mucosal Protective agents: Misoprostol (CytotecTM).
Mydriatic: Berefrine.
Nasal decongestant: Nemazoline Hydrochloride; Pseudoephedrine Polistirex.
to Neuroleptic: Duoperone Fumaratc; Risperidone.
Neuromuscular blocking agent: Atracurium Besylate; Cisatracurium Besylate;
Doxacurium Chloride; Gallamine Triethiodide; Metocurine Iodide; Mivacurium Chloride;
Pancuronium Bromide;
Pipecuroniuin Bromide; Rocuronium Bromide; Suecinylcholine Chloride;
Tubocurarine Chloride;
Vecuronium Bromide.
Neut'oprotective: Dizocilpine Maleate.
io NMDA antagonist: Sclfotel.
Non-hormonal sterol derivative: Pregnenolone Succinate.
Oxytocic: Carboprost; Carboprost Methyl; Carboprost Tromethamine; Dinoprost ;
Dinoprost Tromethaminc ; Dinoprostone ; Brgonovine Maleate; Mcteneprost ;
Methylergonovine Male*te;
Oxytocin; Spartcine Sulfatc.
Pltisminogcn activator: Alteplasc; Urokinase.
Platelet activating factor antagonist: Lcxipafant.
Platelet aggregation inhibitor: Acadesine; Beraprost; Bcraprost Sodium;
Ciprostene Calcium;
Itazigrcl; 1.ifarizinc; Oxagrclatc.
Post-stroke and post-head trauma treatment: Citicoline Sodium.
Potentiator: Pentostatin; Talopram Hydrochloride.
Progestin: Algestone Acetophenide; Amadinone Acetate; Anagestone Acetate;
Chlormadinone Acetate; Cingestol; Clogestone Acetate; Clonlegestone Acetate; Desogestrel;
Dimethisterone;
Dydrogesterone; Ethyncrone; Etllynodiol Diacetate; Etonogestrel; Flurogestone Acetate; Gestaclone;
Gestodene; Gestonorone Caproatc; Gestrinone; I Ialoprogcsteronc;
Hydroxyprogesterone Caproate;
Levonorgestrel; Lynestrenol; Medrogestone; Medroxyprogesterone Acetate;
Metllynodiol Diacetate;
i o Noretllindrone; Norethindrone Acetate; Noretllynodrel; Norgestimate;
Norgestomet; Norgestrel;
Oxogestone Phenpropionate; Progesterone; Quingestanol Acetate; Quingestrone;
Tigestol.
I'rostaglandin: Cloprostcnol Sodiunl; Fluprostenol Sodium; Gemeprost;
Prostalene; Sulprostone.
Prostate growth inhibitor: Pentonlone.
Protllyrotropin: Protirelin.
Psycllotropic: Minaprine.
I'ulnionary surface: Beractant; Colfosceril Palnlitate.
Radioactive agent: Fibrinogen 1 125 ; Fludeoxyglucose F 18 ; Fluorodopa F 18 ;
Insulin I 125;
Insulin 1 131; lobenguane 1 123; lodipamide Sodium I 131 ; Iodoantipyrine 1 131 ; lodocholesterol 1 131 ; lodohippurate Sodium 1 123 ; Iodollippurate Sodium I 125 ;
lodohippurate Sodium I 1~1 ;
lodopyracct I 125 ; Iodopyracet 1 131 ; tofetanline I-Iydrochloride I 123 ;
Ionlethin 1 125 ; lometllin I 131 ; Iotllalamatc Sodiunl1 125 ; Iotllalanlatc Sodium I 131 ; Iotyrosine 1 131; Liotllyroninc 1 125;
Liothyroninc 1 131; Mcrisoprol Acetate 1-lg 197; Mcrisoprol Acclatc 1 lg 203;
Mcrisoprol I Ig 197 ;
Sclenomctllioninc Se 75 ; Tcchnctium 'I'c 99111 Antimony "1'risultidc Colloid;
'Tcchnctiunl Tc 99m 3o Bicisatc ; Tcchnctium Tc 99111 Disofenin ; Technetium Tc 99n1 Etidronate ;
Technetiunl Tc 99111 L'xamCl'1'LI111C ; TCCI111Ct111111 1 C 99111 I'llrlfosnllil ; 1 CChnCtilinl I
c 99111 GJllceptate ; rl'ccllnCtlum Tc 99111 Lidofenin ;'I'echnetium "I'c 99m Mebrofenin ; Technetium "Tc 99rn Medronate ; Technetium Tc 99m Medronate Disodium; Technetiuni Tc 99m Mertiatide ; Technetium Tc 99m Oxidronate ;
Technetium Tc 99m Pentetate; Technetium Tc 99m Pentetate Calcium Trisodium;
Technetium Tc 99m Sestamibi ; Technetium Tc 99m Siboroxime ; Technetium Tc 99m Succimer ;
Technetium Tc 99m Sulfur Colloid ; Technetium Tc 99m Teboroxime ; Technetium Tc 99m Tetrofosmin ;
Technetium Tc 99m Tiatide; Thyroxine 1 125; Thyroxine 1 131; Tolpovidone 1 131 ; Triolein 1 125;
Triolein 1 131.
Regulator: Calcifediol; Calcitonin; Calcitriol; Clodronic Acid;
Dihydrotachysterol; Etidronic Acid;
Oxidronic Acid; Piridronate Sodium; Risedronate Sodium; Secalciferol.
io Relaxant: Adiphenine Hydrochloride; Alcuronium Chloride; Aminophylline;
Azumolene Sodium;
Baclofen; Benzoctaniine Hydrochloride; Carisoprodol; Chlorplienesin Carbamate;
Chlorzoxazone;
Cinflumide; Cinnamedrine; Clodanolene; Cyclobenzaprine Hydrochloride;
Dantrolene; Dantrolene Sodium; Fenalamide; Fenyripol Hydrochloride; Fetoxylate Hydrochloride;
Flavoxate Hydrocliloride;
Fletazepam; Flumetramide; Flurazepam Hydrochloride; Hexafluorenium Bromide;
Isomylamine I-iydrochloride; Lorbanlate; Mebeverine Hydrochloride; Mesuprine I-Iydrocliloride ; Metaxalone;
Methocarbamol; Methixene Hydrochloride; Nafomine Malate; Nelezaprine Maleate;
Papaverine flydi=ochloride; Pipoxolan Hydrochloride; Quinctolate; Ritodrine; Ritodrine Hydrocliloride;
Rolodine; Theophylline Sodium Glycinate; Thiphenamil Hydrochloride; Xilobam.
Repartitioning agent: Cimaterol.
Scabicide: Amitraz; Crotamiton.
Sclerosing agent: Ethanolamine Oleate; Morrhuate Sodium; Tribenoside.
Sedative: Propioniazine.
Sedative-hypnotic: Allobarbital; Alonimid; Alprazolam; Amobarbital Sodium;
Bentazepam;
13roti7olam; Butabarbital; Butabarbital Sodium; Butalbital; Capuride;
Carbocloral; Chloral IIetainc;
Chloral I-lydratc; Clilordiazepoxidc llydrochloridc; Cloperidone Ilydrochloridc; Clorethate;
Cyprazepam; Dcxclamol I-lydrochloride; Diazepam; Dichloralphenazone;
Estazolam; Ethchlorvynol;
Etomidate; Fenobam; Flunitrazepam; Fosazepam; Glutethimide; Halazepam;
Lornletazepam;
Mecloqualone; Meprobamate; Methaqualone; Midaflur; Paraldehyde; Pentobarbital;
Pentobarbital Sodium; Perlapine; Prazepam; Quazepam; Reclazepam; Roletamide; Secobarbital;
Secobarbital Sodium; Suproclone; Thalidomide; Tracazolate; Trepipam Maleate; Triazolam;
Tricetamide;
Triclofos Sodium; Trimetozine; Uldazepam; Zaleplon; Zolazepam Hydrochloride;
Zolpidem Tartrate.
Selective adenosine Al antagonist: Apaxifylline.
io Serotonin antagonist: Altanserin Tartrate; Amesergide; Ketanserin;
Ritanserin.
Serotonin iilhibitor: Cinanserin Hydrochloride; Fenclonine; Fonazine Mesylate;
Xylamidine Tosylate.
Serotonin receptor antagonist: Tropanserin Hydrochloride.
Steroid: Dexamethasone Acefuratc; Mometasone Furoate.
Stimulant: Anlfonelic Acid; Amphetamine Sulfate; Ampyzine Sulfate; Arbutaniine I-Iydrocliloride;
2o Azabon; Caffeine; Cerulctide; Ceruletide Diethylatnine; Cisapride;
Dazopride Fumarate;
Dextroamphctaminc; Dcxtroaniplictantine Sulfate; Dilluanine I-lydrochloridc;
Dimel7ine I-Iydrochloride; Doxapram I-lydrochloride; rtryptamine Acetate; Etliainivan;
Fenethylline I-lydrocliloride; Flubanilate i-lydrochloride; Flurothyl; Ilistaminc I'hosphatc; Indriline I-Iydrochloride; Mefexamide; Methamphetamine Hydrochloride; Methylpllenidate Hydrochloride;
1'emoline; Pyrovaleronc I-Iydrochloride; Xamotcroi; Xatnoterol Fumarate.
Suppressant: Amflutizolc; Colchicinc; Tazofclonc.
Symptomatic multiple sclerosi5: Fampridinc.
Syncrbist: I'roadifen I iydrochloridc.
Thyroid hormone: Levothyroxine Sodiuin; Liothyronine Sodium; Liotrix.
Thyroid inhibitor: Methimazole; Propylthiouracil.
Thyromimetic: Tliyromedan Hydrochloride.
Tranquilizer: Bromazepam; Buspirone Hydrocliloride; Chlordiazepoxide;
Clazolam; Clobazam;
Clorazepate Dipotassium; Clorazepate Monopotassium; Demoxepam;
Dexmedetomidine;
Enciprazine Hydrochloride; Gepirone Hydrochloride; Hydroxyphenamate;
Hydroxyzine t o I-lydrochloride; Hydroxyzine Pamoate; Ketazolam; Lorazepam; Lorzafone;
Loxapine; Loxapine Succinate; Medazepam Hydrochloride; Nabilone; Nisobamate ; Oxazepam;
Pentabamate;
Pirenperone; Ripazepam; Rolipram; Sulazepam; Taciamine I-lydrochloride;
Temazepam;
Tritlubazam; Tybamate; Valnoctamide.
Amyotrophic lateral sclerosis agents: Riluzole.
Cerebral ischemia agents: Dextrorphan Hydrochloride.
Paget's disease agents: Tiludronate Disodium.
Unstable angina agents: Tirofiban Hydrochloride.
Uricosuric: Benzbromarone; Irtemazole; Probenecid; Sulfinpyrazone.
Vasoconstrictor : Angiotensin Amide; Felypressin; Metliysergide; Methysergide Maleate.
Vasodilator: Alprostadil; Azaclorzine Hydrochloride; Bametlian Sulfate;
Bepridil Hydrochloride;
Buterizine; Cetiedil Citrate; Chromonar I-lydrochloride; Clonitrate; Diltiazem I-lydrochloride;
Dipyridamole; Droprenilamine; Erythrityl Tetranitrate; Felodipine; Flunarizine Hydrochioride;
Fostedil; liexobendinc; Inositol Niacinatc; Iproxaininc Ilydrocliloride;
Isosorbide Dinitratc;
Isosorbide Mononitratc; isoxsuprinc I-tydrochloride; Lidotlazinc; Me('enidil;
Mcl'enidil Fuinarate;
Mibcfradil Dillvdrochloride; Mioflazine f-lydrochloride; Mixidine; Nafronyl Oxalate; Nicardipine Hydrochloride; Nicergoiine; Nicorandil; Nicotinyl Alcohoi; Nifedipine;
Nimodipine; Nisoldipine;
Oxfenicine; Oxprenolol Hydrochloride; Pentaerythritol Tetranitrate;
Pentoxifylline; Pentrinitrol;
I'erhexiline Maleate; Pindolol; Pirsidomine; Prenylaniine; Propatyl Nitrate;
Suloctidil; Terodiline Hydrochloride; Tipropidil Hydrocliloride; Tolazoline Hydrochloride; Xanthinol Niacinate.
Vulnerary: Allantoin.
Wound liealing agent: Ersofermin.
Xanthine oxidase inhibitor: Allopurinol; Oxypurinol Other pharmaceutical agents include: 1-decpyrrolidinone; 1-dodecpyrrolidinone;
16-alpha fluoroestradiol; 16-epiestriol; 16alplia-gitoxin; l7alpha estradiol; 17beta estradiol; l alpha-hydroxyvitamin D2; 2'-nor-cGMP; 20-epi-1,25 dihydroxyvitamin D3; 22-oxacalcitriol; 2CVV; 3-isobutyl GABA; 6-FUDCA; 7-methoxytacrine; abamectin; abanoquil; abecarnil;
abiraterone;
acadesine; acamprosate; acarbose; aceclofenac; acemannan; acetomepregenol;
acetyl-L-carnitine;
acetylcysteine, N-; acetylmethadol; acifran; acipimox; acitemate; acitretin;
aclarubicin; aciatoniuni;
napadisilate; aconiazide; acrivastinet; adafenoxate; adapalene; adatanserin;
adecypenol; adefovir dipivoxil; adelmidrol; ademetionitie; adinazolam; adiposin; adozelesin;
adrafinil; alacepril;
aladapcin; alaptide; albendazole; albolabrin; aldecalmycin; aldesleukin;
alendronic acid; alentemol;
alfacalcidol; alfuzosin; alglucerase; alihastine; alosetron; alplia idosone;
alprostadil; altretamine;
altromycin B; ambamustine; amelometasone; amesergide; amezinium metilsulfate;
amfebutamone;
amidox; amifloxacin; amifostine; amiodarone; amisulpride; amlexanox;
amlodipine; amlodipine;
ampiroxicam; amrinone; amrubicin; amsacrine; amylin; amythiamicin; anagrelide;
anakinra;
ananain; anaritide; anastrozolc; andrographolidc; anordrin; apadolinc;
apafant; apaxifyllinc;
aphidicolin glycinate; apraclonidine; aprosulate sodium; aptiganel; apurinic acid; aranidipvne;
arbckacin; arbidol; arbutamine; ardeparin sodium; arecatannin BI; argatroban;
aripiprazol;
arotinolol; asimadoline; aspalatone; asperfuran; aspoxicillin; astcmizolc;
asulacrine; atamestane;
atenolol, S-; atevirdine; atosiban; atovaquone; atpenin I3; atrimustine;
atrinositol; aurcobasidin A;
azadiraclitine; azasetron; azatyrosinc; azelaic acid; azelastine;
azelnidipine; azimilide; azithrotnycin;
azosemide; aztrconam; baccatin III; bacoside A; bacosidc I3; bactobolaminc;
balaziponc;
balhimycin;. balofloxacin; balsalazide; banibuterol; baohuoside 1;
barnidipine; basifungin;
batebulast; batimastat; beauvericin; becapiermin; becliconazole; befloxatone;
belfosdil;
bellenamine; benflumetol; benidipine; benzisoxazole; benzochlorins;
benzoidazoxan;
benzoylstaurosporine; benztropine; bepridil; beractant; beraprost;
berlafenone; bertosamil;
besipirdine; beta-alethine; betaclamycin B; betamipron; betaxolol; betulinic acid; bevantolol;
bicalutamide; bifemelane; bimakalim; bimithil; binospirone; bioxalomycin alpha2; biriperone; bis-benzimidazole A; bis-benzimidazole B; bisantrene; bisaramil;
bisaziridinylspermine; bisnafide;
bisoprolol; bistramide D; bistramide K; bistratene A; boldine; bopindolol;
brefeldin; breflate;
brimonidine; bromfenac; bromperidol; bropirimine; bucindolol; budesonide;
budipine; budotitane;
bunaprolast; bunazosin; butenafine; buthionine sulfoximine; butixocort propionate; cadexomer iodine; calanolide A; calcipotriol; calphostin C; camonagrel; candesartan;
candesartan cilexetil;
t o candoxatril; candoxatrilat; capecitabine; capromab; capsaicin; captopril;
carbazomycin C;
carbetocin; carbovir; carboxamide-amino-triazole; carboxyamidotriazole;
carboxymethylated beta-1,3-glucan; carperitide; carteolol; carumonam; carvedilol; carvotroiine;
carzelesin; castanospermine;
cebaracetam; cecropin B; cefcapene pivoxil; cefdaloxime pentexil tosilate;
cefdinir; cefditoren pivoxil; cefepime; cefetamet; cefetamet pivoxil; cefixime; cefluprenam;
cefmetazole; cefminox;
cefodizime; cefoselis; cefotetan; cefotiam; cefotiam hexetil; cefozopran;
cefpimizole; cefpiramide;
cefpirome; cefpodoxime proxetil; cefprozil; cefsulodin; cefteram; ceftibuten;
ceftriaxone;
cefuroxime axetil; celastrol; eclikalim; celiprolol; cepacidine A;
cerielamine; cerivastatiti;
ceronapril; certoparin sodium; cetiedil; cetirizine; chloroorienticin A;
chloroorienticin B;
cliloroquinoxaline sulfonamide; cibenzoline; cicaprost; ciclesonide;
cicletanine; cicloprolol;
cidofovir; cilansetron; cilazapril; cilnldipine; cilobradine; cilostazol;.
cimetropium bromide;
cinitapride; cinolazepam; ciotcroncl; ciprolibrate; cipro(]oxacin; ciprostene;
cis-porphyrin; cisapride;
cisatracurium besilate; cistinexine; citalopram; citicoline; citreamicin alpha; cladribine;
clarithromycin; clausenamide; clebopride; clinafloxacin; clobazam; clobetasone butyrate; clodronic acid; clomethiazole; clopidogrel; clotrimazole; colestimide; colfosceril palmitate; collismycin A;
collismycin B; combrctastatin A4; complestatin; conagenin; contignasterol;
contortrosta,tin;
cosalane; costatolide; cotinine; coumermycin A 1; cucumariosid; curacin A;
curdlan sulfate; curiosin;
cyclazosin; cyclic I-IPMPC; cyclobcnzaprinc; cyclobut A; cyclobut G;
cyclocapron; cycloplatam;
cyclosin; cyclothialidine; cyclotliiazomycin; cypemycin; cyproterone;
cytarabine ocfosfate;
cytochalasin B; dacliximab; dactiniicin; daidzein; daidzin; dalfopristin;
dalteparin sodium;
3o danaparoid; daphnodorin A; dapiprazole; dapitant; darifenacin; darlucin A;
darsidomine; ddUTP;
decitabine; cleferipronc; dellazacort; dehydrodidemnin B;
dchydrocpiandrosterone; dclapril;
dclequaminc; dclfaprazinc; delmopinol; delphinidin; deoxypyridinolinc;
deprodone; depsidoniycin;
deramciclane; dermatan sulfate; desflurane; desirudin; deslorelin;
desmopressin; desogestrel;
desoxoamiodarone; detajmium bitartrate; dexifosfamide; dexketoprofen;
dexloxiglumide;
dexmedetomidine; dexpemedolac; dexrazoxane; dexsotalol; dextrin 2-sulphate;
dexverapamil;
dezinamide; dezocine; diaziquone; diclofenac digolil; diclofenac potassium;
dicranin; didemnin B;
didox; dienogest; diethylhomospermine; diethylnorspermine; dihydrexidine;
dihydro-5-azacytidine;
dimethyl prostaglandin A 1; dimethylhomospermine; dimiracetam; dioxamycin;
diphencyprone;
diphenyl spiromustine; diprafenone; dipropylnorspermine; diritliromycin;
discodermolide;
disulfiram; ditekiren; docarpamine; docosanol, 1-; dofetilide; dolasetron;
domitroban; dopexamine;
dorzolamide; dosmalfate; dotarizine; doxacurium chloride; doxazosin;
doxifluridine; doxofylline;
io draculin; draflazine; droloxifene; dronabinol; drosperidone; drotaverine acephyllinate; droxicam;
ebiratide; ebrotidine; ebselen; ecabapide; 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; cnalapril; enazadrem; englitazone; enlimonlab; enoxacin;
enoxaparin sodium;
enoximone; entacapone; enterostatin; epoprostenol; epoxymexrenone;
epristeride; eprosartan;
eptastigminc; erdosteine; ersentilide; ersoferinin; erythritol; esuprone;
etanidazole; etanterol;
ethacizin; ethinylestradiol; etizolam; etodolac; etoposide phosphate;
etrabamine; everninomicin;
examorelin; exemestane; fadrozole; faeriefungin; faniciclovir; fatnpridine;
fantofarone; faropenem;
fasidotril; fasudil; fazarabine; fedoto?,ine; felbamate; fenofibrate;
fenoldopam; fenretinide;
fenspiride; fenticonazole; f'epradinol; ferpifosate sodium; ferristene;
ferrixan; ferumoxsil;
fexofenadine; flavopiridol; flecainide; flerobuterol; fleroxacin; flesinoxan;
flezelastine; flobufen;
flomoxef; florfenicol; florifenine; flosatidil; fluasterone; fluconazole;
fludarabine; flumazenil;
flumecinol; flumequine; flunarizine; fluocalcitriol; fluorodaunorunicin hydrochloride; fluoxetine, R-; fluoxetine, S-; fluparoxan; flupirtine; flurbiprofen axetil;
flurithromycin; fluticasone propionate;
flutrimazolc; fluvastatin; fluvoxamine; forasartan; forfenimex; formestane;
formotcrol; formotcrol, R,R-; fosfomycin; trometamol; fosinopril; fosphenytoin; fostriecin;
foteniustine; gabapentin;
gadobenic acici; gadobutrol; gadodiamide; gadodiamide-L:OB-DTi'A; gadolinium texaphyrin;
gadoteric acid; gadoteridol; gadoversetamide; galantaniine; galdatlsetron;
gallopamil; galocitabine;
gamolenic acid; ganirelix; gepirone; gestrinone; girisopanz; glaspimod;
glaucocalyxin A;
glutapyrone; glycopine; glycopril; granisetron; grepafloxacin; halichondrin B;
halofantrine;
lialomon; halopredone; liatomamicin; hatomarubigin A; hatomarubigin B;
hatomarubigin C;
hatomarubigin D; ibogaine; ibopamine; ibudilast; illimaquinone; ilmofosine;
ilomastat; iloperidone;
iloprost; imidapril; imidazenil; indinavir; indolidan; indometacin farnesil;
indometacin; tropine ester;
indoramin; inocoteronc; inogatran; inolimomab; interferon alfa; interferon alfa-2a; interferon alfa-2b; interferon alfa-NI; interferon alfa-n3; interferon beta; interferon beta-lal; interferon beta-1 b;
interferon gamma-1 a; interferon gamma- I b; interferon omega; interferon, consensus; interleukin-1;
interieukin- I alpha; interleukin-1 beta; interleukin-10; interleukin-11;
interleukin-12; interleukin-12;
interleukin-15; interleukin-2; interleukin-3; interleukin-4; interleukin-5;
interleukin-7; interleukin-8;
iobenguane; iobitridol; iodoamiloride; iododoxorubicin; iofratol; iomeprol;
iopentol; iopromide;
iopyrol; iotriside; ioversol; ioxilan; ipazilide; IpdR; ipenoxazone;
ipidacrine; ipomeanol, 4-;
-o ipriflavone; ipsapirone; irbesartan; irinotecan; irloxacin; irsogladine;
irtemazole; isalsteine; isbogrel;
isepamicin; isobengazole; isofloxythepin; isohomohalicondrin B; isopropyl unoprostone; isradipine;
itameline; itasetron; itopride; itraconazole; ketoprofen, R-; ketoprofen, S-;
ketorolac; lacidipine;
lactitol; lactivicin; laennec; lafutidine; lamellarin-N triacetate; lamifiban;
lamivudine; lamotrigine;
lanoconazole; lanperisone; lanreotide; lansoprazole; latanoprost; lateritin;
laurocapram; lazabemide;
lemefloxacin; lemildipine; leminoprazole; lenercept; lenograstim; lentinan sulfate; leptin;
leptoistatin; lercanidipine; lerisetron; lesopitron; letrazuril; letrozole;
leucomyzin; leuprorelin;
levcromakalim; levetiracetam; levobetaxolol; levobunolol; levobupivacaine;
levocabastine;
levocarnitine; levodropropizine; levofloxacin; levomoprolol; levonorgestrel;
levormeloxifene;
levosimendan; levosulpiride; linotroban; linsidomine; lintitript; lintopride;
liothyronine sodium;
lirexapride; lisinopril; lobaplatin; lobucavir; lodoxamide; lombricine;
loniefloxacin; lomerizine;
lometrexol; lonazolac; lonidamine; loracarbef; loratadine; lorglumide;
lornoxicam; losartan;
losigamone; losoxantronc; loteprcdnol; loviride; loxoribine; lubeluzole;
lurtotecan; luteinizing hormone; lutetium; luzindole; lydicamycin; lysofylline; lysostaphin; magainin 2 amide; magnolol;
mallotochromene; mallotojaponin; malotilatc; mangafodipir; manidipine;
maniwamycin A;
mannostatin A; manumycin E; manumycin F; mapinastine; marimastat; Martek 8708;
Ma,rtek 92211; masoprocol; maspin; massetolide; ineterelin; metlloxatone;
inethylhistamine, R-alpha;
methylinosine monophosphate; methylprednisolone aceponate; methylprednisolone suleptanate;
metipainide; metoclopramide; metoprolol, S-; nletrifonatc; mibefradil;
michellamine B; microcolin A; midodrine; mifepristone; miglitol; milacemide; mllanleline; mildronate;
milnacipran; milrinone;
miltcfosinc; minaprine; miokamycin; mipragoside; mirfentanil; mirimostim;
mirtazapine;
misoprostol; mitoguazone; mitolactol; mitonafide; mitoxantrone; mivacurium chloride; mivazerol;
mixanpril; mizolastine; mizoribinc; moclobemide; modafinil; moexipril;
mofarotene; inofezolac.
niolgramostim; mometasone; inontirelin; mopidamol; moracizine; mosapramine;
mosapride;
motilide; moxiraprine; moxonidine; nadifloxacin; nadroparin calcium;
nafadotride; nafamostat;
nafarelin; naftopidil; naglivan; nagrestip; nalmefene; napliterpin;
napsagatran; naratriptan;
nartograstim; nasaruplase; nateplase; niperotidine; niravoline; nisamycin;
nisin; nisoldipine;
nitazoxanide; nitecapone; nitrendipine; nitrendipine, S-; nitrofurantoin monohydrate; nitrullyn;
nizatidine; ofloxacin; okicenone; olanzapine; olopatadine; olprinone;
olsalazine; omeprazole;
onapristone; ondansetron; ondansetron, R-; ontazolast; oracin; otenzepad;
oxaliplatin; oxamisole;
oxandrolone; oxaprozin; oxaunomycin; oxcarbazepine; oxiconazole; oxiracetam;
oxodipine; ozagrel;
palauamine; palinavir; palmitoyirhizoxin; paniaqueside; pamicogrel; pamidronic acid; panamesine;
i o panaxytriol; panipenem; panipenum; pannorin; panomifene; pantethine;
pantoprazole; parabactin;
pamaparin sodium; paroxetine; partlienolide; pazelliptine; pazufloxacin;
pefloxacin; pegaspargase;
peldesine; pemedolac; pemirolast; penciclovir; pentafuside; pentamidine;
pentamorphone;
pentigetide; pentosan; pentostatin; pentrozole; perflubron; perfosfamide;
pergolide; perindoprilat;
perospirone; phenaridine; phenazinomycin; pllenserine; phensuccinal;
phentolamine mesilate;
plienylacetate; phenylalanyl ketoconazole; picenadol; picibanil; picroliv;
picumeterol; pidotimod;
pilocarpine hydrocliloride; pilsicainide; piinagedine; pimilprost; pimobendan;
pinacidil; pinocebrin;
pioglitazone; pipecuronium bromide; pirarubicin; piretanide; pirfenidone;
piritrexim; pirlindole;
pirmagrel; pirmenol; pirodavir; pirodoniast; piroxicam cinnamate:
propagermanium; propentofylline;
propionylcarnitine, L-; propiram; propiram + paracetaniol; propivcrine; propyl bis-acridonc;
prostaglandin J2; prostratin; protegrin; prbtosufioxacin; prtilifloxacin;
pyrazoloacridine; quazepam;
cluetiapine; quiflapon; quinagolidc; quinapril; duinfiimidc; quinupristin;
raloxifene; raltitrexed;
ramatroban; raniipril; ramosetron; ranelic acid; ranitidine bismutli citrate;
ranolazine; recainam;
regavirumab; relaxin; repirinast; resinferatoxin; reticulon; reviparin sodiuni; revizinone; ricasetron;
ridogrel; rifabutin; rifapentine; rifaximin; rilopirox; riluzole; rimantadine;
rimexolone; rimoprogin;
riodipinc; ripisartan; risedronic acid; rispenzcpinc; i-ispcridonc;
ritanscrin; ritipcncm; ritipcrqem acoxil; ritolukast; ritonavir; rizatriptan benzoate; rohitukinc; rokitamycin;
ropinirole; ropivacaine;
roquinimcx; roxatidinc; roxindole; roxithromycin; rubiginonc [31; ruboxyl;
rufioxacin; rupatidine;
ruzadolane; safingol; safironil; saintopin; salbutamol, R-; salmeterol;
salmeterol, R-salnacedin;
sameridinc; sanipatrilat; sanfctrinem; saprisartan; saproptcrin; saquinavir;
SarCNU; sarcophytol A
sargramostim; sarpogrelate; saruplase; saterinone; satigrel; satumomab pendetide; selebiline;
selcnium thiosenlicarbazone; seniatilide; semduramicin; scmotiadil; semustine;
sermorelin;
sertaconazolc: sertindole; scrtralinc; setiptiline; sevirumab; sevotlurane;
sezolamide; silipide;
-5s-siiteplase; simendan; simvastatin; sinitrodil; sinnabidol; sipatrigine;
sirolimus; sizofiran;
somatomedin B; somatomedin C; somatrem; somatropin; sonermin; sotalol;
staurosporine;
stavudine; stepronin; stipianiide; stiripentol; stobadine; succibun;
sucralfate; sulfasalazine;
sulfinosine; sulfoxamine; stilopenem; sultaniicillin; sultopride; sulukast;
sumatriptan; symakalim;
tandospirone; tapgen; taprostene; tasosartan; tazanolast; tazarotene;
teicoplanin; telenzepine;
tellurapyrylium; telmesteine; telmisartan; temocapril; temoporfin;
temozolomide; tenidap;
teniposide; tenosal; tenoxicam; tepirindole; tepoxalin; terazosin;
terbinafine; terfenadine;
terflavoxate; terguride; terlakiren; terlipressin; terodiline; tertatolol;
testosterone buciclate;
tetrachlorodecaoxide; tetrazomine; thaliblastine; thalidoniide; thiocoraline;
thiofedrine; thiomarinol;
io thioperamide; thyroid stimulating hormone; tiagabine; tianeptine;
tiapafant; tibolone; ticlopidine;
tienoxolol; tilisolol; tilnoprofen arbamel; tiludronic acid; tinzaparin sodium; tiotropium bromide;
tipredane; tiqueside; tirandalydigin; tirapazamine; tirilazad; tirofiban;
tiropramide; topsentin;
torasemide; toremifene: tosufloxacin; trafermin; trandolapril; traxanox;
tretinoin; tretinoin tocoferil;
triacetyluridine; tricaprilin; trichohyalin; trichosanthiii, alpha;
triciribine; trientine; triflavin;
trimegestone; triptorelin; troglitazone; trombodipine; tropisetron;
trospectoniycin; trovafloxacin;
trovirdine; tucaresol; tulobuterol; tylogenin; urapidil; uridinc tripllosphate; valaciclovir; valproate magnesium; valproate semisodium; valsartan; vamicamide; vanadeine; vaninolol;
vapreotide;
variolin B; velaresol; venlafaxine; veramine; verapamil, (S); verdins;
veroxan; verteporfin;
vesnarinone; vexibinol; visabatrin; vinburnine citrate; vinburnine resinate;
vinconate; vinorelbine;
vinpocetine; vinpocetine citratc; vintoperol; vinxaltine; voriconazole;
vorozole; voxergolidc;
xcmilotiban; ximoprofen; yangambin; zabicipril; zacopride; zacopride, R-;
zafirlukast; zalcitabine;
zaleplon; zalospirone; zaltoprofen; zanamivir; zankiren; zanoterone;
zatebradine; zatosetron;
zenarestat; zeniplatin; zifrosilone; zilascorb; zileuton; zinostatin stimalamer; ziprasidone; zoledronic acid; zolmitriptan; zolpidem; zonisamide; zopiclone; zopicione, S-;
zopolrestat; zotepine.
'fhc invcntion also cmbraces novel compositions of matter that arc covalent conjugatc$ of' D1-IA and pharmaceutical agents that are noncentral nervous system active agents. Noncentral nervous system active agents have no tiinction or use within the central nervous svstem. Tlieir only use is outside of the central nervous system. Such agents include all drugs witllin certain of the foregoing categories and only sonie drugs within other of the foregoing catagorics. For example, thc cntire catagory ol' blood glucose regulators liave no use or liinction within the central nervous system. In contrast, certain anti-cancer agents are useful in the central nervous system whereas others are not. For exaniple, central nervous systcm cancers are not hornione dependent, and, therefore, 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 catagories are noncentral nervous system active agents: adrenocortical steroid; adrenocortical suppressant; aldosterone antagonist; amino acid; anabolic; androgen;
antagonist; anthelinintic;
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;
i o antidiuretic; antidote; anti-estrogen; antifibrinolytic; antifungal;
antiglaucoma agent;
antihemophilic; antihemorrhagic; antihistamine; antihyperlipidemia;
antihyperlipoproteinemic;
antihypertensive; antihypotensive; anti-infective; anti-infective, topical;
anti-inflammatory;
antikeratinizing agent; antimalarial; antimicrobial; antimitotic; antimycotic, antineoplastic, antineutropenic, antiparasitic; antiperistaltic, antipneuniocystic;
antiproliferativc; antiprostatic hypertrophy; antiprotozoal; antipruritic; antipsoriatic; antirheumatic;
antischistosomal;
antiseborrheic; antisecretory; antispasmodic; antithrombotic; antitussive;
anti-ulcerative;
anti-urolithic; antiviral; appetite suppressant; benign prostatic hyperplasia therapy agent; bone resorption inhibitor; broncliodilator; carbonic anliydrase inhibitor; cardiac depressant;
cardioprotectant; cardiotonic; cardiovascular agent; choleretic; cliolinergic;
cliolinergic agonist;
cholinesterase deactivator; coccidiostat; -diagnostic aid; diuretic;
ectoparasiticide; enzyme inliibitor;
estrogen; fibrinolytic; free oxygen radical scavenger; glucocorticoid; gonad-stimulating principle;
liair growtli stimulant; hemostatic; hormone; hypocholesterolemic;
hypoglycemic; hypolipideinic;
hypotensive; inimunizing agent; immunomodulator; immunoregulator;
immunostimulant;
immunosuppressant; impotence therapy adjunct; inhibitor; kcratolytic; LI-IRI I
agonist; liver disorder treatnient; lutcolysin; mucolytic; mydriatic; nasal decongestant;
neuromuscular blocking agqnt;
non-hormonal stcrol derivativc; oxytocic; plasminogen activator; platelet activating factor antagonist; platelet aggregation inhibitor; potentiator; progestln;
prostaglandiu; prostate growth inhibitor; prothyrotropin; pulmonary surface; radioactive agent; regulator;
relaxant; repartitioning agent; scabicidc; sclerosing agent; selective adenosinc Al antagonist;
steroid: suppressant;
syinptomatic multiple sclerosis; synergist; thyroid hormone; thyroid inhibitor; thyromimetic;
amyotropliic lateral sclerosis agents; Paget's disease agents; unstable angina agents; uricosuric;
vasoconstrictor; vasodilator; vulnerary; wound healing agent: xanthine oxidase inhibitor.
As used lierein, a taxane is a inolecule 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.
5 ~8 1 ~
~2 j A 6 43 ~17 , J~
10 A taxoid is a molecule structurally related to a taxane in wliich 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 15 or more structural features cliaracteristic of the taxane carbon-atom connectivity network are conserved.
The compounds useful in the invention may be delivered in the fonn of anti-cancer cocktails.
An anti-cancer cocktail is a mixture of any one of the compounds tiseful with this invention with another anti-cancer agent such as an anti-cancer drug, a cytokine, and/or supplementary potentiating 20 agent(s). The use of cocktails in the treatinent of cancer is routine. In this embodiment, a common administration vehicle (e.g., pill, tablet, implant, in,jectable solution, etc.) would contain both the conjugate useful in this invention and the anti-cancer drug and/or supplementary potentiating agent.
Thc compounds of thc invention, whcn uscd in cocktails, arc administered in tllcrapeutically effective amounts. A therapeutically effective amount will be determined by the parameters discussed below; but, in any event, is that amount which establishes a level of the drug(s) in the at'ea of the tutnor which is effective in inhibiting the tumor growth.
When administered, the 1'ormulations of the invention are applied in pharmaceutically acceptable amounts and in pharmaceutically acceptable coinpositions. Such preparations may routinely contain s-Its, bu[7'ering agents, preservativcs, compatibic carriers, and optionally othcr therapeutic ingredients. Wlien used in medicine the salts should be pharmaceutically acceptable, but non-pliarmaceutically acceptable salts may convenicntly be used to prepare pharmacetitically acceptable salts thereof and are not excluded from the scope of the invention.
Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared from the following acids: hydrocllloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulfonic, tartaric, citric, methane sulfonic, formic, malonic, succinic, naphthalene-2-sulfonic, aiid 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 (1-2% WN); citric acid and a salt (1-3% W/V); boric acid and a salt (0.5-2.5% W/V); and phosphoric acid and a salt (0.8-2% WN).
Suitable preservatives include benzalkonium chloride (0.003-0.03% W/V);
chlorobutanol (0.3-0.9% WN); parabens (0.01-0.25% WN) and tllimerosal (0.004-0.02% WN).
The active compounds of the present invention niay be a phannaceutical cotiiposition having a tlierapeutically effective amount of a conjugate of the invention optionally included in a pliarmaceutically-acceptable carrier. 'I'he tenn "pharmaceutically-acceptable carrier" as used herein means one or more compatible solid or liquid filler, dilutants or encapsuiating 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 wliich the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions are capable of being commingled witli the molecules of the present invention, and witli each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.
Compositions suitable for parenteral administration convenientlv coniprisc a sterile preparation of the conjugates of tile invention. This preparation may be formulated according to known methods. Formulations for taxanes can be found in Chapter 9 of Taxol:
Science and Applications, CRC Press, Inc., 2000 Corporate Boulevard. N.W., 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/mi solution of taxotere has been formulated in polysorbate 80 (polyoxyethylenc sorbitanmonooleate)/ethanol mixture, diluted with 5% dextrose.
The sterile preparation tlius 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 mcdlunl. For this purpose any bland iixcd oil n,ay be 3o employed including synthetic mono ordi-glycerides. In addition, fatty acids such as oleic acid find use in tlic preparation of injectables. Carrier formulations suitable for oral, subcutaneous, intravenous, intraniuscular, etc. can be found in Reniington's Pharmaceutical Sciences, Mack I'ublisliing Coinpany, Caston, I'A.
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 -0 including age, physical condition, size and weight; concurrent treatment;
frequency of treatment; and the mode of adniinistration. Tliese factors are well known to those of ordinary skill in tiie art and can be addressed with no more than routine experimentation. It is preferred generally that a maximum dose be used, that is, the higliest 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/m2 per day will be effective. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Continuous IV dosing over, for example 24 hours or multiple 2o doses per day are contemplated to achieve appropriate systemic levels of compounds.
A variety of administration routes are available. The particular mode selected will depend of course, upon the particular drug selectcd, the severity of the disease state being treated and the dosage requircd for therapeutic efficacy. The inethods of this invention, generally speaking, may be practiced using any niode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compounds without causing clinically unacceptable adverse effects. Such modes of administration include oral, rectal, sublingual, topical, nasal, transdermal or parenteral routes. 7'he tcrm "parenteral" includes subcutancous, intravenous, intramuscular, or inhision. lntravenous routcs are preferred.
The conipositions may conveniently be presented in unit dosage form and may be preparcd 3o by any of the mcthods well known in the art of pliarmacy. All methods includc thc stcp ol'bringing the conjugates of the iirvention into association with a carricr wliich constitutes one or more accessory ingredients. In general, the compositions arc prcpared by uniformiy and intimately bringing 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 niav be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined aniount of the active compound. Other conipositiotis include suspensions in aqtteous 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 sttbject and the physician. Many types of release delivery systems are i o 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 cliolesterol, 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 wliicli are adapted for implantation.
A long-term sustained release implant also niay 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 tlie art and include some of the release systems described above. Such itnplants can be particularly useful in treating solid tumors by placing the implant near or directly within the lunlor, lhereby alTecting localized, liigh-doses of the compounds of the invention.
The conjugates of the invention also are useful, in general, for treating mammalian cell proliferative disorders otlier than cancer, including psoriasis, actinic keratosis, etc. They fut-ther nre useful in treating diabetes and its complications, excess acid secretion, cardiovascular conditions involving cholesterol (e.g., hyperlipidemia and hypercholesterolemia), diarrhea, ovarian diseases (e.g. endometriosis, ovarian cysts, etc.) and as contraceptive agents.
Those skilled in the art will be able to recognize with no more than routine experimentation numcrous cquivalents to the specific products and processcs described above.
Stich equivalents are intended to be included within the scope of the appended claims.
Claims (47)
EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE
DEFINED AS FOLLOWS:
1. Use of a covalent conjugate of cis-docosahexaenoic acid and a taxane wherein said conjugate is effective for targeting a noncentral nervous system tissue to treat a noncentral nervous system condition, wherein the condition-n is a mammalian cell proliferation disorder.
2. The use of claim 1, wherein the disorder is a cancer.
3. The use of claim 1, wherein said cis-docosahexaenoic acid is conjugated directly to said taxane.
4. The use of claim 3, wherein said tissue is breast tissue.
5. The use of claim 3, wherein said tissue is gastrointestinal tissue.
6. The use of claim 3, wherein said tissue is ovarian tissue.
7. The use of claim 3, wherein said taxane is a noncentral nervous system active agent that is nonactive within the central nervous system.
8. The use of claim 3, wherein said taxane is an anti-cancer agent.
9. The use of claim 8, wherein said taxane is Taxol.TM.
10. The use of claim 9, wherein said conjugate is
11. The use of claim 9, wherein said conjugate is
12. The use of claim 8, wherein said taxane is Taxotere.TM.
13. The use of claim 12, wherein said conjugate is
14. The use of claim 12, wherein said conjugate is
15. The use of claim 12, wherein said conjugate is
16. The use of claim 12, wherein said conjugate is
17. The use of any one of claims 1, 2, 3, 4 or 7 through 16, wherein said condition is breast cancer.
18. The use of any one of claims 1, 2, 3, 5 or 7 through 16, wherein said condition is colon cancer.
19. The use of any one of claims 1, 2, 3, or 6 through 16, wherein said condition is ovarian cancer.
20. A pharmaceutical preparation, comprising:
a covalent conjugate of cis-docosahexaenoic acid and a taxane other than paclitaxel or Taxotere.TM.; and a pharmaceutically acceptable carrier.
a covalent conjugate of cis-docosahexaenoic acid and a taxane other than paclitaxel or Taxotere.TM.; and a pharmaceutically acceptable carrier.
21. The pharmaceutical preparation of claim 20, wherein the cis-docosahexaenoic acid is conjugated directly to said taxane.
22. The pharmaceutical preparation of claim 21, wherein said taxane 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.
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.
23. Use of a covalent conjugate of cis-docosahexaenoic acid and a taxane in the manufacture of a medicament, wherein the taxane is other than paclitaxel or Taxotere.TM.
24. The use as claimed in claim 23, wherein said medicament is for targeting a noncentral nervous system tissue for treating a noncentral nervous system condition.
25. The use of a covalent conjugate of cis-docosahexaenoic acid and a taxane in the manufacture of a medicament, wherein said medicament is for targeting a noncentral nervous system tissue for treating a noncentral nervous system condition, wherein the condition is a mammalian cell proliferation disorder.
26. The use of claim 25, wherein the disorder is a cancer.
27. The use of claim 23, wherein said cis-docosahexaenoic acid is conjugated directly to said taxane.
28. The use of claim 23, wherein said taxane 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.
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.
29. The use of claim 23, wherein said taxane is active on breast tissue.
30. The use of claim 23, wherein said taxane is active on gastrointestinal tissue.
31. The use of claim 23, wherein said taxane is active on ovarian tissue.
32. The use of claim 23, wherein said taxane is a noncentral nervous system active agent that is nonactive within the central nervous system.
33. The use of claim 25, wherein said taxane is an anti-cancer agent.
34. The use of claim 33, wherein said taxane is Taxol.TM.
35. The use of claim 34, wherein said conjugate is
36. The use of claim 34, wherein said conjugate is
37. The use of claim 33, wherein said taxane is Taxotere.TM.
38. The use of claim 37, wherein said conjugate is
39. The use of claim 37, wherein said conjugate is
40. The use of claim 37, wherein said conjugate is
41. The use of claim 37, wherein said conjugate is
42. The use of any one of claims 26, 27 or 33 through 41, wherein said condition is breast cancer.
43. The use of any one of claims 26, 27 or 33 through 41, wherein said condition is colon cancer.
44. The use of any one of claims 26, 27 or 33 through 41, wherein said condition is ovarian cancer.
45. Use of a covalent conjugate of cis-docosahexaenoic acid and a taxane wherein said conjugate is effective for targeting a noncentral nervous system tissue to treat a noncentral nervous system condition.
46. The use of claim 45, wherein said cis-docosahexaenoic acid is conjugated directly to said taxane.
47. The use of claim 45, wherein said taxane is nonactive within the central nervous system.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/651,312 US5795909A (en) | 1996-05-22 | 1996-05-22 | DHA-pharmaceutical agent conjugates of taxanes |
| US08/651,312 | 1996-05-22 | ||
| PCT/US1997/008867 WO1997044063A2 (en) | 1996-05-22 | 1997-05-22 | Dha-pharmaceutical agent conjugates |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2255614A1 CA2255614A1 (en) | 1997-11-27 |
| CA2255614C true CA2255614C (en) | 2009-12-15 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002255614A Expired - Fee Related CA2255614C (en) | 1996-05-22 | 1997-05-22 | Dha-pharmaceutical agent conjugates |
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|---|---|
| US (3) | US5795909A (en) |
| EP (2) | EP0909183B1 (en) |
| JP (1) | JP4402173B2 (en) |
| AT (1) | ATE273025T1 (en) |
| AU (1) | AU725759B2 (en) |
| CA (1) | CA2255614C (en) |
| DE (1) | DE69730217T2 (en) |
| DK (1) | DK0909183T3 (en) |
| ES (1) | ES2222514T3 (en) |
| WO (1) | WO1997044063A2 (en) |
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- 1997-05-22 DE DE69730217T patent/DE69730217T2/en not_active Expired - Lifetime
- 1997-05-22 ES ES97926723T patent/ES2222514T3/en not_active Expired - Lifetime
- 1997-05-22 WO PCT/US1997/008867 patent/WO1997044063A2/en active IP Right Grant
- 1997-05-22 EP EP97926723A patent/EP0909183B1/en not_active Expired - Lifetime
- 1997-05-22 AU AU31425/97A patent/AU725759B2/en not_active Ceased
- 1997-05-22 EP EP04015625A patent/EP1466628A1/en not_active Withdrawn
- 1997-05-22 JP JP54281197A patent/JP4402173B2/en not_active Expired - Fee Related
-
2001
- 2001-05-01 US US09/846,838 patent/US6602902B2/en not_active Expired - Lifetime
-
2003
- 2003-07-14 US US10/618,884 patent/US7199151B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| ATE273025T1 (en) | 2004-08-15 |
| AU3142597A (en) | 1997-12-09 |
| US5795909A (en) | 1998-08-18 |
| DK0909183T3 (en) | 2004-12-20 |
| EP1466628A1 (en) | 2004-10-13 |
| WO1997044063A3 (en) | 1998-02-26 |
| US7199151B2 (en) | 2007-04-03 |
| US20040180949A1 (en) | 2004-09-16 |
| JP4402173B2 (en) | 2010-01-20 |
| EP0909183A2 (en) | 1999-04-21 |
| EP0909183B1 (en) | 2004-08-11 |
| CA2255614A1 (en) | 1997-11-27 |
| AU725759B2 (en) | 2000-10-19 |
| DE69730217D1 (en) | 2004-09-16 |
| DE69730217T2 (en) | 2005-07-28 |
| JP2000514405A (en) | 2000-10-31 |
| ES2222514T3 (en) | 2005-02-01 |
| WO1997044063A2 (en) | 1997-11-27 |
| US20020010208A1 (en) | 2002-01-24 |
| US6602902B2 (en) | 2003-08-05 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20140522 |