US007 1991.51B2

(12) United States Patent (10) Patent No.: US 7,199,151 B2 Shashoua et al. (45) Date of Patent: *Apr. 3, 2007

(54) DHA-PHARMACEUTICAL AGENT 4,692,441 A 9, 1987 Alexander et al. CONUGATES OF TAXANES 4,704,393 A 11/1987 Wakabayashi et al. 4,729,989 A 3, 1988 Alexander (75) Inventors: Victor E. Shashoua, Brookline, MA 4,788,063 A 11/1988 Fisher et al. (US); Charles E. Swindell, Merion, PA is: A RE s al (US); Nigel L. Webb, Bryn Mawr, PA 4s68161. A 9, 1989 Roberts (US); Matthews O. Bradley, 4.902,505 A 2/1990 Pardridge et al. Laytonsville, MD (US) 4,933,324. A 6/1990 Shashoua 4,939,174 A 7, 1990 Shashoua (73) Assignee: Luitpold Pharmaceuticals, Inc., 4,943,579 A 7, 1990 Vishnuvajala et al. Shirley, NY (US) 4,968,672 A 1 1/1990 Jacobson et al. 5,059,699 A 10/1991 Kingston et al. (*) Notice: Subject to any disclaimer, the term of this 5,068,224. A 11/1991 Fryklund et al. patent is extended or adjusted under 35 5, 112,596 A 5/1992 Malfroy-Camine U.S.C. 154(b) by 81 days. 5, 112,863 A 5/1992 Hashimoto et al. 5,116,624 A 5/1992 Horrobin et al. This patent is Subject to a terminal dis- 5, 120,760 A 6/1992 Horrobin claimer. 5,141,958 A 8, 1992 Crozier-Willi et al. 5,169,762 A 12/1992 Grey et al. (21) Appl. No.: 10/618,884 5,169,764 A 12/1992 Shooter et al. 5,194,654 A 3, 1993 Hostetler et al. (22) Filed: Jul. 14, 2003 5,214,062 A 5/1993 Mark et al. 5,216,023 A 6/1993 Literati-Nagy et al. (65) Prior Publication Data 5,216,142 A 6/1993 Horribin et al. 5,223,263. A 6/1993 Hostetler et al. US 2004/O180949 A1 Sep. 16, 2004 5,246,726 A 9, 1993 Horribin et al. 5,250,722 A 10, 1993 Bombardelli et al. Related U.S. Application Data 5,276,020 A 1/1994 Horribin et al. (63) Continuation of application No. 09/846,838, filed on 5,278.324 A 1/1994 Kingston et al. 5,284,876 A 2, 1994 Shashoua et al. May 1, 2001, now Pat. No. 6,602,902, which is a 5,308,832 A 5/1994 Garleb et al. continuation of application No. 09/135,291, filed on 5.314.991 A 5/1994 Oka et all Aug. 17, 1998, now abandoned, which is a continu- 5,336,684 A 8/1994 Murray et al ation of application No. 08/651.312, filed on May 22, 5,352.596 A 10, 1994 Cheung et al. 1996, now Pat. No. 5,795,909. 5,356,928 A 10/1994 Murray et al. 5,362,831 A 11/1994 Mongelli et al. (51) Int. Cl. A 6LX 3/59 (2006.01) A 6LX 3/592 (2006.01) (Continued) A6 IK 9/42 (2006.01) FOREIGN PATENT DOCUMENTS A6 IK 47/48 (2006.01) A61 K 47/00 (2006.01) AU T46472 6, 1999 (52) U.S. Cl...... 514/449; 514/560; 514/558: 514/552; 514/549; 514/943 (Continued) (58) Field of Classification Search ...... 514/449, OTHER PUBLICATIONS 514/560, 558,552,549; 549/510 See application file for complete search history. Chen, et al. “Taxol Structure-Activity Relationships: Synthesis and Biological Evaluation of Taxol Analogs Modified at C-7.” (56) References Cited Bioorganic & Medicinal Chemistry Letters, vol. 4. No. 18, pp. 2223-2228, 1994. U.S. PATENT DOCUMENTS 3,539,573 A 11/1970 Schmutz (Continued) 3,621,048 A 11/1971 Bauman Primary Examiner Ardin H. Marschel 4,088.646 A 5, 1978 Ishida et al. Assistant Examiner—Donna Jagoe 4,097,597 A 6, 1978 Horrom et al. (74) Attorney, Agent, or Firm Wolf, Greenfield & Sacks, 4,185,095 A 1/1980 Young P.C. 4,218,234 A 8/1980 Nadasy et al. 4,287.184 A 9/1981 Young (57) ABSTRACT 4,346,085 A 8, 1982 Growdon et al. 4,351,831 A 9, 1982 Growden et al. 4,407,744 A 10/1983 Young The invention provides conjugates of cis-docosahexaenoic 4.550,109 A 10, 1985 Folkers et al. acid and pharmaceutical agents useful in treating noncentral 4,554,272 A 11, 1985 Bock et al. nervous system conditions. Methods for selectively target 4,558,049 A 12/1985 Bernardi et al. ing pharmaceutical agents to desired tissues are provided. 4,636,494. A 1, 1987 Growden et al. 4,684,646 A 8/1987 Chang et al. 12 Claims, 14 Drawing Sheets US 7,199,151 B2 Page 2

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9 -8 -7 -6 -5 -4 LOGO OF SAMPLE CONCENTRATION (MOLAR) COLO 205-O- HCT-116--O-- HCT-15- - -a- - - KM12- - ) -- SW-620---4--- HT29 ...... Fig. 3 1 OO CNS CANCER

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MELANOMA 100

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MELANOMA

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RENAL CANCER

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BREAST CANCER

-100 C.G.Y. Geese GalC O - 10 -9 -8 -7 -6 LOGo OF SAMPLE CONCENTRATION (MOLAR) MCF 7-O- MDA-N----- HS 578T.O. MDA-MB-435- - - - MDA-MB-231/ -- A - - T-47D---E- MCF 7/ADR-RE--&- BT-549-...-A-...- Fig. 27 US 7,199,151 B2 1. 2 DHA-PHARMACEUTICAL AGENT Taxol has the following formula: CONUGATES OF TAXANES

RELATED APPLICATIONS AcO O OH O This application is a continuation of U.S. patent applica - NH O tion Ser. No. 09/846,838 filed May 1, 2001, now U.S. Pat. E III IIH No. 6,602,902, which is a continuation of U.S. patent w application Ser. No. 09/135,291 filed Aug. 17, 1998, now Ph O E E O 10 3' E 2' abandoned, which is a continuation of U.S. patent applica OH HO E OAc tion Ser. No. 08/651,312, filed May 22, 1996, now U.S. Pat. PhCO, No. 5,795,909. Taxanes have the basic three ring structure (A, B and C), BACKGROUND OF THE INVENTION 15 substituted or unsubstituted. Taxols carbons are numbered conventionally as follows: Improving drug selectivity for target tissue is an estab lished 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 particu larly 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 25 TaxolR). Taxol.R (paclitaxel) was first isolated in 1971 from the Based upon the taxanes tested to date, as many questions bark of Taxus brevifolia and was approved in 1992 by the US have been raised as have been answered, and general rules Food and Drug Administration for treatment of metastatic 30 have not been fashioned easily in predicting selectivity, ovarian cancer and later for breast cancer. Its mechanism of activity and solubility. Firstly, no rules have emerged regard action is believed to involve promoting formation and ing selectivity. Those taxanes that are strongly active appear hyperstabilization of microtubules, thereby preventing the to have activity as broad as Taxol's activity, and no headway disassembly of microtubules necessary for completion of appears to have been made in terms of developing a more cell division. It also has been reported that Taxol induces 35 selective Taxol analog. expression of cytokines, affects the activity of kinases and Some information about activity has emerged. Numerous substitutions have been made at C7, C9, C10, C19, R and blocks processes essential for metastasis, in as yet unchar combinations thereof while retaining significant, but usually acterized mechanisms of action. reduced, activity. Substitutions at C2, C4 and 2'OH, how Taxol has attracted unusually strong scientific attention, 40 ever, are generally not tolerated. These conclusions are only not only because of its unique antiproliferative mechanism generalities, for example, because some Substitutions at of action, but also because it is active against nearly all C9–C10 (cyclic derivatives) are not tolerated and some cancers against which it has been tested and because it has substitutions at C2 (meta substitutions on the phenyl) are been discovered to be an analog of numerous closely related tolerated. Likewise, the C13 side chain and, in particular, the compounds occurring naturally. These compounds, taxanes, 45 2'OH are required although the minimum structural require are now recognized as a new class of anticancer compounds. ments of the side chain have not been determined for Taxol's strength against cancers of diverse tissue origin therapeutic efficacy. also represents a significant drawback. An ideal anticancer Attempts to improve Taxol's solubility have not resulted agent has tissue specificity, thereby reducing side-effects on in Successful clinical products. One approach has been to normal (dividing) cells. Taxol analogs with tissue specificity 50 manufacture prodrugs of Taxol, which prodrugs undergo in therefore are desired. Another drawback of Taxol is its Vivo transformation into Taxol and some other product. extreme insolubility. Taxol can be administered effectively Attempts were made to esterify the C7 hydroxy and 2 in a solvent including cremophor, which combination can hydroxy groups, with the hope that the bond would be stable provoke severe hypersensitive immune responses. As a in Solution (to permit preferred administration modes—i.V. result of these drawbacks, and also as a result of the potential 55 over at least 24 hours) but would cleave readily in vivo. The for modifying Taxol at numerous sites as demonstrated by groups tested were all hydrophilic and included amines, other naturally-occurring taxanes with anticancer activity, a short carboxylic acids (using e.g. Succinic anhydride and search for more selective taxanes was launched. glutaric anhydride), Sulfonic acids, amino acids and phos To date, more than 200 taxanes have been synthesized (or phates. Generally, activity was reduced although some Suc isolated) and tested in vitro or in vivo for anticancer activity. 60 cess was obtained with certain derivatives. Again, no par The results, however, have been so disappointing that the ticular pattern emerged permitting one to predict reliably National Cancer Institute (NCI) generally no longer is which groups could be substituted on Taxol to yield a interested in testing Taxol analogs. In general with Taxol therapeutically useful product, although it was suggested analogs, the solubility problems remain, and/or potency is that the 2' OH derivatives may cleave more easily than the sharply reduced, and/or selectivity is not improved, and/or 65 C7 OH derivatives. the ratio of the median toxic dose to the median effective Several other factors add to the problem of predicting dose (“therapeutic index') is unacceptably reduced. which Taxol analogs will be effective. Multiple mechanisms US 7,199,151 B2 3 4 of action have been proposed in the literature and a change According to one aspect of the invention, a method is in one position may have no effect on activity on one Such provided for targeting a pharmaceutical agent to a noncen mechanism but may eliminate activity on another mecha tral nervous system tissue to treat a noncentral nervous nism. In addition, changes that favorably influence activity system condition. A covalent conjugate of cis-docosahex may unfavorably influence bioavailability. For example, anoic acid and a pharmaceutical agent effective for treating Taxol affects microtubule formation inside a cell, but a said condition is administered to a Subject in need of Such change in structure that increases intracellular activity may treatment. In preferred embodiments, the tissue is breast adversely affect the ability of Taxol to gain entry into a cell. tissue, gastrointestinal tissue and ovarian tissue and the Taxol also is known to bind to proteins, and the effect on condition calls for treatment of breast tissue, gastrointestinal activity that results from a change in Taxol's binding to 10 tissue or ovarian tissue, respectively. protein (in terms of conformation. cellular absorption and The pharmaceutical agent may be any pharmacological solubility) is unknown. compound or diagnostic agent, as desired. The pharmaceu It has been reported that Taxol does not get into the brain, tical agent, of course, has an activity outside of the central apparently excluded by the blood brain barrier. It is not nervous system. known why this is so, as Taxol is lipophilic, gets into cells 15 Examples of categories of pharmaceutical agents include: and might be expected to cross the blood brain barrier. Among the most promising of the two hundred analogs adrenergic agent, adrenocortical steroid; adrenocortical Sup tested is Taxotere (docetaxel), because of its slightly pressant; alcohol deterrent; aldosterone antagonist; amino increased activity and solubility. Oddly, however, Taxotere acid; ammonia detoxicant; anabolic; analeptic; analgesic; differs from Taxol at sites which typically do not have a androgen; anesthesia, adjunct to; anesthetic; anorectic; strong influence on activity, and one would not predict the antagonist; anterior pituitary Suppressant; anthelmintic; anti improvements in Taxotere from these differences, even in acne agent; anti-adrenergic; anti-allergic; anti-amebic; anti hindsight. androgen; anti-anemic; anti-anginal; anti-anxiety; anti-ar thritic; anti-asthmatic; anti-atherosclerotic; antibacterial; Taxotere has the following formula: anticholelithic; anticholelithogenic; anticholinergic; antico 25 agulant; anticoccidal; anticonvulsant; antidepressant; antidiabetic; antidiarrheal; antidiuretic; antidote; anti emetic; anti-epileptic; anti-estrogen; antifibrinolytic; anti fungal; antiglaucoma agent; antihemophilic; antihemor rhagic; antihistamine; antihyperlipidemia; 30 antihyperlipoproteinemic; antihypertensive; antihypoten sive; anti-infective; anti-infective, topical; anti-inflamma tory; antikeratinizing agent; antimalarial; antimicrobial; antimigraine; antimitotic; antimycotic, antinauseant, antine oplastic, antineutropenic, antiobessional agent; antiparasitic; antiparkinsonian; antiperistaltic, antipneumocystic; antipro Ph liferative; antiprostatic hypertrophy; antiprotozoal; antipru ritic; antipsychotic; antirheumatic; antischistosomal; antise DHA (docosahexaenoic acid) is a 22 carbon naturally borrheic; antisecretory; antispasmodic; antithrombotic; occurring, unbranched fatty acid that previously has been antitussive; anti-ulcerative; anti-urolithic; antiviral; appetite attached to drugs to help deliver them across the blood brain 40 Suppressant; benign prostatic hyperplasia therapy agent; barrier. DHA is attached via the acid group to hydrophilic blood glucose regulator, bone resorption inhibitor; bron drugs and renders these drugs more hydrophobic (lipo chodilator, carbonic anhydrase inhibitor, cardiac depressant; philic). DHA is an important constituent of the brain and cardioprotectant; cardiotonic; cardiovascular agent; choler recently has been approved in Europe as an additive to infant etic; cholinergic; cholinergic agonist; cholinesterase deacti formula. It is present in the milk of lactating women. The 45 vator, coccidiostat; cognition adjuvant; cognition enhancer, mechanism of action by which DHA helps drugs conjugated depressant; diagnostic aid; diuretic: dopaminergic agent; to it cross the blood brain barrier is unknown. ectoparasiticide; emetic; enzyme inhibitor; estrogen; fibrin olytic; fluorescent agent; free oxygen radical scavenger; SUMMARY OF THE INVENTION gastrointestinal motility effector; glucocorticoid; gonad 50 The present invention involves the unexpected finding stimulating principle; hair growth stimulant; hemostatic; that conjugates of pharmaceutical agents and a highly lip histamine H2 receptor antagonists; hormone; hypocholes philic group, a C22 unbranched carbon chain, have a dif terolemic; hypoglycemic; hypolipidemic; hypotensive; ferent selectivity relative to the unconjugated pharmaceuti imaging agent; immunizing agent; immunomodulator; cal agents. The conjugates, in general, render the activity of immunoregulator; immunostimulant; immunosuppressant; these compounds selective for colon tissue, breast tissue and 55 impotence therapy adjunct; inhibitor, keratolytic; LNRH central nervous system tissue (“targeted tissues'). The con agonist, liver disorder treatment; luteolysin; memory adju jugates, also unexpectedly, restrict the activity of these vant; mental performance enhancer, mood regulator, muco compounds to cell types within these tissue categories lytic; mucosal protective agent; mydriatic; nasal deconges relative to that of the unconjugated pharmaceutical agents. tant; neuromuscular blocking agent; neuroprotective; The conjugates, further unexpectedly, reduce sharply the 60 NMDA antagonist; non-hormonal sterol derivative; oxyto activity of these compounds relative to that of the unconju cic; plasminogen activator, platelet activating factor antago gated pharmaceutical agents in most cell lines of tissue types nist, platelet aggregation inhibitor, post-stroke and post other than colon, breast, and central nervous system, thereby head trauma treatment; potentiator, progestin; reducing potential side effects of the conjugates versus those prostaglandin; prostate growth inhibitor, prothrotropin; psy of the unconjugated pharmaceutical agents. The therapeutic 65 chotropic; pulmonary Surface; radioactive agent; regulator; index of the conjugates may be improved, Versus that of the relaxant, repartitioning agent; Scabicide; sclerosing agent; unconjugated pharmaceutical agents. sedative; sedative-hypnotic; selective adenosine A1 antago US 7,199,151 B2 5 6 nist, serotonin antagonist; serotonin inhibitor, serotonin system tissue. Such conditions can be specific to breast receptor antagonist; Steroid; stimulant; Suppressant; Symp tissue, gastrointestinal tissue and ovarian tissue. The tissue tomatic multiple Sclerosis; synergist; thyroid hormone; thy also may be other noncentral nervous system tissues. Non roid inhibitor; thyromimetic; tranquilizer; treatment of central nervous system tissue includes tissue of the: Blood amyotrophic lateral sclerosis; treatment of cerebral 5 ischemia; treatment of Paget’s disease; treatment of unstable and Blood Forming system: including platelets, blood vessel angina; uricoSuric; vasoconstrictor, vasodilator, Vulnerary; wall, and bone marrow; Cardiovascular system: including wound healing agent; Xanthine oxidase inhibitor. heart and vascular system; Digestive and excretory system: In one particularly preferred embodiment of the inven including alimentary tract, biliary tract, kidney, liver, pan tion, the pharmaceutical agent is an anti-cancer agent. 10 creas and urinary tract; Endocrine system: including adrenal Examples of anti-cancer agents are described in greater gland, kidney, ovary, pituitary gland, renal gland, salivary detail in the specification. Included specifically are the gland, sebaceous gland, testis, thymus gland and thyroid taxanes (e.g., Taxol and Taxotere). Conjugates of cis gland; Muscular system: including muscles that move the docosahexanoic acid and taxoids also are embraced by the 15 body. Reproductive System: including breast, ovary, penis invention. and uterus; Respiratory system: including bronchus, lung Cis-docosahexanoic acid previously has been conjugated and trachea: Skeletal system: including bones and joints; to drugs that are active in the central nervous system. The Tissue, fiber, and integumentary system: including adipose present invention contemplates the use of cis-docosahex tissue, cartilage, connective tissue, cuticle, dermis, epider anoic acid in the manufacture of a medicament for treating mis, epithelium, fascia, hair follicle, ligament, bone marrow, a noncentral nervous system condition. The invention fur melanin, melanocyte, mucous membrane, skin, soft tissue, ther contemplates compositions of matter that are covalent synovial capsule and tendon. conjugates of cis-docosahexanoic acid and noncentral ner Vous system active pharmaceutical agents. A noncentral 25 BRIEF DESCRIPTION OF THE DRAWINGS nervous system active pharmaceutical agent is one that has no function or use in the central nervous system. Its only FIG. 1 is a graph plotting concentration of conjugate 1 therapeutic use is outside of the central nervous system. versus percent growth of leukemia cells. Examples of Such agents include, but are not limited to: Blood glucose regulators, such as tolaZamide, tolbutamide, 30 FIG. 2 is a graph plotting concentration of conjugate 1 chlorpropamide, acetohexamide, and, glipizide; HMGcoA versus percent growth of non-Small cell lung cancer cells. reductase inhibitors, such as Lovastatin (Mevacor), Simv FIG. 3 is a graph plotting concentration of conjugate 1 astatin (Zocor), Pravastatin (Pravachol), and, Fluvstatin (Le versus percent growth of colon cancer cells. scol); Muscosal Protectives, such as Misoprostol (Cytotec): 35 FIG. 4 is a graph plotting concentration of conjugate 1 Gastrointestinal motility affectors, such as Cisapride (Pro versus percent growth of CNS cancer cells. pulsid), Metoclopramide (Reglan), and, Hyoscyamine FIG. 5 is a graph plotting concentration of conjugate 1 (Levsin); Antidiarrheals, such as Diphenoxylate hydrochlo versus percent growth of melanoma cells. ride (Lomotil), Metronidazole (Flagyl), Methylprednisolone FIG. 6 is a graph plotting concentration of conjugate 1 (Medrol), and, Sulfasalazine (AZulfidine); and Hormones 40 versus percent growth of ovarian cancer cells. for treating, inter alia, ovarian conditions, such as Progest erone, Norgestrel, Norethynodrel, Norethindrone, FIG. 7 is a graph plotting concentration of conjugate 1 Levonorgestrel, Ethyndiol, Mestranol, Estrone, Equilin, 17 versus percent growth of renal cancer cells. alpha dihydroequilin, equilenin, 17 alpha dihydroequilenin, FIG. 8 is a graph plotting concentration of conjugate 1 17 alpha esradiol, 27 bea estradiol, Leuprolide (Lupron), 45 versus percent growth of prostate cancer cells. Testolactone, Climiphene, urofollitropin, bromocriptine, FIG. 9 is a graph plotting concentration of conjugate 1 gonadorelin, danazol, dehydroepiandrosterone, androstene versus percent growth of breast cancer cells. dione, dihydrotestosterone, Relaxin, folliculostatin, Follicle FIG. 10 is a graph plotting concentration of conjugate 2 regulatory protein, Gonadocrinins, Oocyte maturation 50 versus percent growth of leukemia cells. inhibitor, and, Insulin growth factor. Other compounds are FIG. 11 is a graph plotting concentration of conjugate 2 detailed below. versus percent growth of non-Small cell lung cancer cells. The methods and/or products of the invention are useful FIG. 12 is a graph plotting concentration of conjugate 2 for treating a variety of medical conditions including con 55 versus percent growth of colon cancer cells. ditions involving abnormal mammalian-cell proliferation. FIG. 13 is a graph plotting concentration of conjugate 2 They further are useful in treating diabetes and its compli versus percent growth of CNS cancer cells. cations, excess acid secretion, cardiovascular conditions involving cholesterol (e.g., hyperlipidemia and hypercho FIG. 14 is a graph plotting concentration of conjugate 2 lesterolemia), diarrhea, ovarian diseases (e.g. endometriosis, 60 versus percent growth of melanoma cells. ovarian cysts, etc.) and as contraceptive agents. Other con FIG. 15 is a graph plotting concentration of conjugate 2 ditions treatable according to the invention will be apparent versus percent growth of ovarian cancer cells. to those skilled in the art based upon the disclosure and lists FIG. 16 is a graph plotting concentration of conjugate 2 of compounds provided. 65 versus percent growth of renal cancer cells. The methods and/or products of the invention also are FIG. 17 is a graph plotting concentration of conjugate 2 useful in treating conditions specific to noncentral nervous versus percent growth of prostate cancer cells. US 7,199,151 B2 7 8 FIG. 18 is a graph plotting concentration of conjugate 2 DHA can be isolated, for example, from fish oil or can be versus percent growth of breast cancer cells. chemically synthesized. These methods, however, can gen FIG. 19 is a graph plotting concentration of Taxol versus erate trans isomers, which are difficult and expensive to percent growth of leukemia cells. separate and which may present safety problems in humans. FIG. 20 is a graph plotting concentration of Taxol versus The preferred method of production is biological synthesis percent growth of non-Small cell lung cancer cells. to produce the all cis isomer. The preferred source of DNA is from Martek Biosciences Corporation of Columbia, Md. FIG. 21 is a graph plotting concentration of Taxol versus Martek has a patented system for manufacturing DHA using percent growth of colon cancer cells. 10 microalgae which synthesize only a single isomer of DHA. FIG. 22 is a graph plotting concentration of Taxol versus the all cis isomer. Martek’s patents include U.S. Pat. Nos. percent growth of CNS cancer cells. 5,374,657, 5,492,938; 5.407,957 and 5,397,591. FIG. 23 is a graph plotting concentration of Taxol versus DHA also is present in the milk of lactating women, and percent growth of melanoma cells. Martek’s licensee has obtained approval in Europe of DHA FIG. 24 is a graph plotting concentration of Taxol versus 15 as a nutritional Supplement for infant formula. percent growth of ovarian cancer cells. It is known that DHA can be unstable in the presence of FIG. 25 is a graph plotting concentration of Taxol versus oxygen. To stabilize DHA and its conjugates it is important percent growth of renal cancer cells. to add anti-oxidants to the material after it is synthesized. FIG. 26 is a graph plotting concentration of Taxol versus One method of stabilization is to make-up the newly syn percent growth of prostate cancer cells. thesized material in the following solution: 100 g neat FIG. 27 is a graph plotting concentration of Taxol versus DHA-taxol plus 100 g of vehicle (100 ml propylene glycol, percent growth of breast cancer cells. 70 mg alph-tocopherol, 5 mg dialaurylthiodipropionic acid, 25 50 mg ascorbic acid) prepared and held under argon in DETAILED DESCRIPTION OF THE amber, sealed vials and stored at four degrees centigrade. INVENTION The following anti-oxidants may also be employed: ascorbic cis-docosahexaenoic acid (DHA) is a naturally occurring acid, ascorbyl palmitate, dilauryl ascorbate, hydroquinone, fatty acid. It is an unbranched chain fatty acid with six 30 butylated hydroxyanisole, sodium meta bisulfite, t-B caro double bonds, all cis. Its structure is as follows: tene and X-tocopherol. A heavy metal chelator Such as ethylenediamine tetra-acetic acid (EDTA) may also be used. Paclitaxel was first isolated from the bark of Taxus brevifolia (Wani et al., J. Am. Chem. Soc., 93, 2325, 1971). 35 Its isolation and synthesis have been reported extensively in OH the literature. Applicants obtained paclitaxel from a com mercial source, Hauser Laboratories, of Boulder, Colo.

EXAMPLE 1.

TAXOL

conjugate 1 US 7,199,151 B2 9 10 A solution of Taxol (41 umol) in methylene chloride (2.5 reaction mixture was stirred for thirty minutes, diluted with mL) under argon was mixed with 4-dimethylaminopyridine additional methylene chloride, washed with water, saturated (41 umol), dicyclohexylcarbodiimide (82 mol), and DHA aqueous sodium chloride, dried, and concentrated. Chroma (41 umol) and the reaction mixture was stirred at ambient tography of the residue produced 50 mg (88%) of interme temperature for two hours. Following dilution with ether, the diate A plus 5 mg of the 2, 7-di(triethylsilyl) ether deriva reaction mixture was washed with 5% hydrochloric acid, tive. A solution of intermediate A (52 umol) in methylene water, Saturated aqueous Sodium chloride, dried, and con chloride (3 mL) was mixed at ambient temperature under centrated. Radial chromatography of the residue produced argon with 4-dimethylaminopyridine (52 umol), dicyclo 45 mg (94%) of crystalline Taxol-DHA conjugate 1. 10 hexylcarbodiimide (104 umol), and DHA (52 umol). The reaction mixture was stirred for ten hours, diluted with ether, EXAMPLE 2 passed through celite, and concentrated. Chromatography of

TAXOL Ph

Ph

conjugate 2

The production of analog 2 involves several steps includ the residue produced 65.9 mg of intermediate B. A solution ing a number of protection-acylation-deprotection steps. A of intermediate B (51 umol) in acetonitrile (2 mL) at 0°C. solution of Taxol (59 umol) in methylene chloride (2.5 mol) is under argon was mixed with 49% aqueous HF (0.2 mL) and was mixed at ambient temperature under argon with imida the reaction mixture was stirred for one hour. After dilution Zole (147 umol) and triethylsilyl chloride (147 umol). The with ether, the reaction mixture was washed with water, US 7,199,151 B2 11 12 saturated aqueous sodium chloride, dried, and concentrated. lines are provided at the PG values of +50, 0, and -50. Radial chromatography of the residue produced 44.6 mg The concentrations corresponding to points where the (75%) of Taxol-DHA conjugate 2. curves cross these lines are the GI50, TGI and LC50, respectively. EXAMPLE 3 5 Several important distinctions are apparent from the data. Most important, the patterns of anticancer actively for Conjugates 1 and 2 were sent to the United States conjugates 1 and 2 differ from that of Taxol. In one sense, National Cancer Institute (NCI) for screening in the NCI's conjugates 1 and 2 are effective anticancer agents against a anticancer Screening program. The conjugates were pro more restricted set of cancer cell lines. For example, con vided in ethanol (approximately 40 mg analog/2 ml ethanol). 10 jugates 1 and 2 were not very effective against any of the six The conjugates were sealed in vials under argon to avoid leukemia cancer cell lines tested, whereas Taxol was some exposure of the conjugates to oxygen because the conjugates what effective against all four leukemia cell lines against were believed to be sensitive to oxygen. Instructions were which Taxol was tested. (See FIGS. 1, 10 and 19.) provided to store at 4° C. and to open the vials only when The relative activity against members within a class of ready for immediate experimental use. Instructions also 15 cancers also was altered. For example, at TGI (horizontal were provided to use the ethanol Solutions containing the line at Zero in the graphs), Taxol was more effective against conjugates directly or to dissolve the analogs further in non-small cell lung cancer line H522 than against H460 (by DMSO (dimethylsulfoxide) at appropriate concentrations, about 3 logs), whereas conjugates 1 and 2 were slightly more with Vortexing if necessary for adequate dispersal. effective against H460 than H522. As another example, The activities of conjugates 1 and 2 were tested against 57 Taxol was least effective at TGI against CNSU251, whereas cancer cell lines. The results are presented in FIGS. 1-9 for conjugate 1 was most effective against CNSU251 and con conjugate 1, FIGS. 10–18 for conjugate 2 and FIGS. 19–27 jugates 2 was also very effective against CNSU251 (relative for Taxol. To understand the data, reference is made to the to other CNS cell lines). As a further example, Taxol was guides provided by the NCI, excerpted as follows: equivalent in activity toward MDA-N and MDA-MB-435 The Calculated Measurement of Effect: Percentage 25 breast cancer cell lines at all concentrations tested, whereas Growth (PG) conjugates 1 and 2 were more effective against MDA-N than The measured effect of the compound on a cell line is MDA-MB-435 at all concentrations tested. currently calculated according to one or the other of the To further illustrate the differences in the activity of following two expressions: conjugates 1 and 2 versus that of Taxol, the NCI subjected 30 the data to a statistical analysis designed by the NCI to If (Mean OD-Mean OD)2O, then reflect differences in the pattern of activity of anticancer PG=100x(Mean OD-Mean OD)/(Mean agents. Conjugate 1 and conjugate 2 were determined to be OD-Mean Od. ero) statistically different in their pattern of activity versus Taxol in this unique measurement by the NCI. If (Mean OD-Mean OD)<0, then 35 It also is to be noted that, in general, conjugates 1 and 2 were one thousand to ten thousand times less potent than PG-100x (Mean OD-Mean Ode). Mean Od Taxol for many cell lines tested. This reduction in activity is important, especially since conjugates 1 and 2 maintained Where: strong activity against Some cell lines. Conjugates 1 and 2 Mean OD, The average of optical density measurements 40 will be sufficiently active against certain cell lines, but will of SRB-derived color just before exposure of cells to the have, on average, a Substantially and disproportionately test compound. lower activity against other cell lines, reducing potential side Mean OD, The average of optical density measurements effects. For example, the TGI for Taxol against CNS SF-539 of SRB-derived color after 48 hours exposure of cells to is -6.95, and the TGI for conjugate 1 against this cell line is the test compound. 45 -5.13 and for conjugate 2 is -5.53. (In other words, the Mean OD. The average of optical density measurements activity of the conjugates was reduced versus that of Taxol of SRB-derived color after 48 hours with no exposure of by less than 2 logs). The GI50 for Taxol against CNS SF 539 cells to the test compound. is -7.52, whereas the GI50s for conjugates 1 and 2 are -6.22 Experimental data was collected against each cell and -5.56, respectively (again less than 2 logs difference). In line . . . Each concentration is expressed as the logo 50 contrast, Taxol has a GI50 for cell line CNSSF 268 of less (molar or ug/ml) . . . The response parameters GI50, than -10.0, whereas conjugates 1 and 2 have GI50s for TGI, and LC50 are interpolated values representing the CNSSF 268 of 5.36 and 5.28, respectively. This represents concentrations at which the PG is +50, 0, and -50, a reduction of activity in the conjugates vs. that of Taxol by respectively. Sometimes these response parameters at least about 5 logs activity. On average, the GI50 for Taxol cannot be obtained by interpolation. If, for instance, all 55 across all cell lines tested is at least -9.19. (It is probably of the PGs in a given row exceed +50, then none of the much higher since concentrations less than -10 were not three parameters can be obtained by interpolation. In tested, and if Taxol was active at -10.0, -10 (instead of the Such a case, the value given for each response param actual lower value) was used in calculating the average of eter is the highest concentration tested ... This practice -9.19. There were 27 instances when this occurred.) The is extended similarly to the other possible situations 60 average GI50s for conjugates 1 and 2, on the other hand, where a response parameter cannot be obtained by were 5.49 and 5.22, respectively. Therefore, the average interpolation. difference in activity for Taxol vs. the conjugates is at least Dose-Response Curves: between 3 and 4 logs. Thus, the sharp reduction in the The dose-response curve page of the data package is activity of the conjugates against many cell lines vs. a lesser created by plotting the PGs against the logo of the 65 reduction for other cell lines is expected to reduce the corresponding concentration for every cell line. The potential side effects of the conjugates versus those of Taxol cell line curves are grouped by Subpanel. Horizontal at effective doses. US 7,199,151 B2 13 14 Cancers other than CNS, breast and colon cancer can be treated. For example, there was activity against non-small cell lung cancer cells, melanoma cells and ovarian cancer cells. However, the activity was relatively reduced and was extremely specific, limiting the utility of the conjugates for treating generally Such cancers. In any event, cancer patients could be evaluated to determine 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. 10 The foregoing experiments establish that DHA analogs have altered specificity versus that of Taxol for cancer cell lines. Because of this altered specificity, it also is clear that the conjugates themselves are gaining access into the target cells (as opposed to simply releasing Taxol into the envi 15 ronment outside of the cell). Thus, the DHA moiety appears to selectively target certain cell types as opposed to others. The ability of the conjugates to gain entry into the cells was unknown prior to the invention, and the ability of the DHA moiety to selectively target certain cell types was unex pected. The same is true of DHA-Taxotere covalent conjugates, examples of which are presented below. Taxotere’s synthesis has been reported extensively in the literature. One example is Kanazawa, A. et al., J. Organic Chem. 1994, Vol. 59, pp. 25 1238-1240. EXAMPLE 4

TAXOTERE HerDHA? dicyclohexylcarbodiimide 4-dimethylaminopyridine

conjugate 3

A solution of Taxotere in methylene chloride under argon is mixed with 4-dimethylaminopyridine, dicyclohexylcarbo diimide, and DHA. The reaction mixture is stirred at ambient temperature. Radial chromatography of the residue is per formed to produce Taxotere-DHA conjugate 3.

EXAMPLE 5

O triethylsilyl chloride X l DHA? dicyclohexylcarbodiimide TAXOTERE - -- O NH O He imidazole 4-dimethylaminopyridine US 7,199,151 B2 15 16

-continued

O

X O ul NH O Heraqueous HF

Ph O (CHCH.);Sió

D

o o o o o o O

conjugate 4

A solution of Taxotere in dimethylformamide is mixed at residue is performed to produce intermediate D. A solution ambient temperature under argon with imidazole and trieth 35 of intermediate D in acetonitrile at 0° C. under argon is ylsilyl chloride. The reaction mixture is stirred at ambient mixed with 49% aqueous HF and the reaction mixture is temperature, diluted with methylene chloride, washed with stirred at the same temperature. After dilution with ether, the water, Saturated aqueous sodium chloride, dried, and con reaction mixture is washed with water, Saturated aqueous centrated. Radial chromatography of the residue is per 40 Sodium chloride, dried, and concentrated Radial chromatog formed to produce intermediate C. A solution of intermedi raphy of the residue is performed to produce Taxotere-DHA ate C in methylene chloride is mixed at ambient temperature conjugate 4. under argon with 4 dimethylaminopyridine, dicyclohexyl carbodiimide, and DHA. The reaction mixture is stirred at ambient temperature, diluted with ether, passed through 45 celite, and concentrated. Radial chromatography of the EXAMPLE 6

O TAXOTERE tert-butyldimethylsilyl chloride X- NH 1 equivalent DHA imidazole dicyclohexylcarbodiimide 4-dimethylaminopyridine US 7,199,151 B2 17 18

-continued

H *'''aqueous HFF O w O H5 6 A. 1s Ph F

o o o O

X-1sO

Ph

conjugate 4

A solution of Taxotere in dimethylformamide is mixed at chromatography of the residue is performed to produce ambient temperature under argon with imidazole and tert intermediate F. (Intermediate H also is obtained and used in butylydimethylsilyl chloride. The reaction mixture is stirred 40 Example 8 below.) A solution of intermediate F in acetoni at ambient temperature, diluted with methylene chloride, trile at 0°C. under argon is mixed with aqueous HF and the washed with water, Saturated aqueous Sodium chloride, reaction mixture is stirred at the same temperature. After dried, and concentrated. Radial chromatography of the resi dilution with ether, the reaction mixture is washed with due is performed to produce intermediate E. A solution of 45 water, Saturated aqueous Sodium chloride, dried, and con intermediate E in methylene chloride is mixed at ambient centrated Radial chromatography of the residue is performed temperature under argon with 4-dimethylaminopyridine, to produce Taxotere-DHA conjugate 4. dicyclohexylcarbodiimide, and 1 equivalent of DHA. The reaction mixture is stirred at ambient temperature, diluted 50 with ether, passed through celite, and concentrated. Radial EXAMPLE 7

tert-butyldimethylsilyl chloride DHA? dicyclohexylcarbodiimide TAXOTERE He --- imidazole 4-dimethylaminopyridine US 7,199,151 B2 19 20

-continued

aqueous HF ---

conjugate 5

A solution of Taxotere in dimethylformamide is mixed at through celite, and concentrated. Radial chromatography of ambient temperature under argon with imidazole and tert 35 the residue is performed to produce intermediate G. A butylydimethylsilyl chloride. The reaction mixture is stirred solution of intermediate G in acetonitrile at 0° C. under at ambient temperature, diluted with methylene chloride, argon is mixed with aqueous HF and the reaction mixture is washed with water, Saturated aqueous Sodium chloride, stirred at the same temperature. After dilution with ether, the 40 reaction mixture is washed with water, Saturated aqueous dried, and concentrated. Radial chromatography of the resi Sodium chloride, dried, and concentrated. Radial chroma due is performed to produce intermediate E. A solution of tography of the residue is performed to produce Taxotere intermediate E in methlylene chloride is mixed at ambient DHA conjugate 5. temperature under argon with 4-dimethylaminopyridine, dicyclohexylcarbodiimide, and DHA. The reaction mixture 45 is stirred at ambient temperature, diluted with ether, passed EXAMPLE 8

tert-butyldimethylsilyl chloride 1 equivalent DHA TAXOTERE Ho imidazole X- NH O dicyclohexylcarbodiimide 4-dimethylaminopyridine

O US 7,199,151 B2

-continued O

O

X ul Heaqueous HF O NH Q

Ph tert-CH3(CH3)2Sió

H O

HO O O o o o o o o

w Ph Y Yo Y Y O i HO H AC es Ph conjugate 6

A solution of taxotere in dimethylformamide is mixed at Adrenergic: Adrenalone; Amidephrine Mesylate; Apracloni ambient temperature under argon with imidazole and tert dine Hydrochloride: Brimonidine Tartrate; Dapiprazole butylydimethylsilyl chloride. The reaction mixture is stirred 35 Hydrochloride; Deterenol Hydrochloride; Dipivefrin; at ambient temperature, diluted with methylene chloride, Dopamine Hydrochloride; Ephedrine Sulfate: Epineph washed with water, Saturated aqueous Sodium chloride, rine: Epinephrine Bitartrate: Epinephryl Borate; Espro dried, and concentrated. Radial chromatography of the resi quin Hydrochloride; Etafedrine Hydrochloride: due is performed to produce intermediate E. A solution of Hydroxyamphetamine Hydrobromide: Levonordefrin; 40 Mephentermine Sulfate; Metaraminol Bitartrate; Metizo intermediate E in methylene chloride is mixed at ambient line Hydrochloride; Naphazoline Hydrochloride: Norepi temperature under argon with 4-dimethylaminopyridine, nephrine Bitartrate; Oxidopamine: Oxymetazoline dicyclohexylcarbodiimide, and 1 equivalent of DHA. The Hydrochloride; Phenylephrine Hydrochloride; Phenyl reaction mixture is stirred at ambient temperature, diluted propanolamine Hydrochloride; Phenylpropanolamine with ether, passed through celite, and concentrated. Radial 45 Polistirex: Prenalterol Hydrochloride; Propylhexedrine; chromatography of the residue is performed to produce Pseudoephedrine Hydrochloride; Tetrahydrozoline intermediate H (and intermediate F which was used above Hydrochloride; Tramazoline Hydrochloride; Xylometa on Example 6. A solution of intermediate H in acetonitrite at Zoline Hydrochloride. 0°C. under argon is mixed with aqueous HF and the reaction Adrenocortical steroid: Ciprocinonide; Desoxycorticoster mixture is stirred at the same temperature. After dilution 50 one Acetate; Desoxycorticosterone Pivalate: Dexametha with ether, the reaction mixture is washed with water, some Acetate; Fludrocortisone Acetate; Flumoxonide; saturated aqueous sodium chloride, dried, and concentrated. Hydrocortisone Hemisuccinate; Methylprednisolone Radial chromatography of the residue is performed to pro Hemisuccinate; Naflocort; Procinonide; Timobesone duce Taxotere-DHA conjugate 6. Acetate; Tipredane. DHA may be conjugated to virtually any drug compound 55 Adrenocortical Suppressant: Aminoglutethimide; TriloStane. or diagnostic agent and used according to the methods of the Alcohol deterrent: Disulfiram. present invention so long as the pharmaceutical agent has a Aldosterone antagonist: Canrenoate Potassium, Canrenone; use outside of the central nervous system. Pharmaceutical Dicirenone; Mexrenoate Potassium; Prorenoate Potas agents include the following categories and specific 60 sium; Spironolactone. examples. It is not intended that the category be limited by the specific examples. Those of ordinary skill in the art will Amino acid: Alanine: Aspartic Acid; Cysteine Hydrochlo be able to identify readily those pharmaceutical agents that ride, Cystine; Histidine; Isoleucine; Leucine; Lysine; Lysine have utility outside of the central nervous system. Those of Acetate; Lysine Hydrochloride; Methionine; Phenylalanine: ordinary skill in the art will recognize also numerous other 65 Proline; Serine: Threonine; Tryptophan; Tyrosine; Valine. compounds that fall within the categories and that are useful Ammonia detoxicant: Arginine: Arginine Glutamate; Argi according to the invention. nine Hydrochloride. US 7,199,151 B2 23 24 Anabolic: Bolandiol Dipropionate; Bolasterone; Boldenone Androgen: Fluoxymesterone; Mesterolone; Methyltestoster Undecylenate; Bolenol; Bolmantalate: Ethylestrenol; one; Nandrolone Decanoate; Nandrolone Phenpropi Methenolone Acetate; Methenolone Enanthate; Mibole onate; Nisterime Acetate: Oxandrolone; Oxymetholone: rone; Nandrolone Cyclotate; Norbolethone; Pizotyline: Silandrone; Stanozolol; Testosterone; Testosterone Cypi Quinbolone; Stenbolone Acetate; Tibolone; Zeranol. onate; Testosterone Enanthate; Testosterone Ketolaurate; Testosterone Phenylacetate; Testosterone Propionate; Tre Analeptic: Modafinil. stolone Acetate. Analgesic: Acetaminophen; Alfentanil Hydrochloride; Ami Anesthesia, adjunct to: Sodium Oxybate. nobenzoate Potassium; Aminobenzoate Sodium; Ani Anesthetic: Aliflurane; Benoximate Hydrochloride; Ben doxime; Anileridine: Anileridine Hydrochloride; Anilo 10 Zocaine; Biphenamine Hydrochloride; Bupivacaine pam Hydrochloride; Anirolac, Antipyrine; Aspirin; Hydrochloride: Butamben; Butamben Picrate; Chlorop Benoxaprofen; Benzydamine Hydrochloride; Biciifadine rocaine Hydrochloride; Cocaine; Cocaine Hydrochloride; Hydrochloride: Brifentanil Hydrochloride; Bromadoline Cyclopropane; Desflurane; Dexivacaine; Diamocaine Maleate; Bromfenac Sodium; Buprenorphine Hydrochlo Cyclamate; Dibucaine; Dibucaine Hydrochloride; Dyclo ride; Butacetin; Butixirate; Butorphanol; Butorphanol 15 nine Hydrochloride; Enflurane; Ether; Ethyl Chloride; Tartrate; Carbamazepine; Carbaspirin Calcium; Carbi Etidocaine; Etoxadrol Hydrochloride; Euprocin Hydro phene Hydrochloride; Carfentanil Citrate: Ciprefadol chloride: Fluroxene; Halothane; Isobutamben; Isoflurane; Succinate; Ciramadol; Ciramadol Hydrochloride; Clonix Ketamine Hydrochloride; Levoxadrol Hydrochloride: eril; Clonixin; Codeine; Codeine Phosphate: Codeine Lidocaine; Lidocaine Hydrochloride; Mepivacaine Sulfate; Conorphone Hydrochloride; Cyclazocine; Dex Hydrochloride; Methohexital Sodium; Methoxyflurane: oxadrol Hydrochloride; Dexpemedolac, Dezocine; Midazolam Hydrochloride; Midazolam Maleate; Minax Diflunisal; Dihydrocodeine Bitartrate; Dimefadane; olone; Nitrous Oxide; Norflurane; Octodrine; Oxet Dipyrone; Doxpicomine Hydrochloride; Drinidene: Ena hazaine; Phencyclidine Hydrochloride; Pramoxine doline Hydrochloride: Epirizole; Ergotamine Tartrate; Hydrochloride: Prilocaine Hydrochloride: Procaine Ethoxazene Hydrochloride; Etofenamate; Eugenol; Feno 25 Hydrochloride: Propanidid; Proparacaine Hydrochloride: profen; Fenoprofen Calcium; Fentanyl Citrate; Floctafe Propofol; Propoxycaine Hydrochloride: Pyrrocaine; nine: Flufenisal; Flunixin: Flunixin Meglurine: Flupirtine Risocaine; Rodocaine; Roflurane; Salicyl Alcohol; Sevof Maleate: FluproduaZone: Fluradoline Hydrochloride; lurane; Teflurane; Tetracaine; Tetracaine Hydrochloride: Flurbiprofen; Hydromorphone Hydrochloride; Ibufenac: Thiamylal; Thiamylal Sodium; Thiopental Sodium; Tile Indoprofen; Ketazocine; Ketorfanol: Ketorolac 30 tamine Hydrochloride; Zolamine Hydrochloride. Tromethamine: Letimide Hydrochloride; Levomethadyl Anorectic compounds including dexfenfluramine. Acetate; Levomethadyl Acetate Hydrochloride; Levo Anorexic: Aminorex: Amphecloral; Chlorphentermine nantradol Hydrochloride; Levorphanol Tartrate; Lofemi Hydrochloride; Clominorex: Clortermine Hydrochloride: Zole Hydrochloride; Lofentanil Oxalate; Lorcinadol; Lor Diethylpropion Hydrochloride; Fenfluramine Hydrochlo noxicam, Magnesium Salicylate; Mefenamic Acid; 35 ride; Fenisorex: Fludorex: Fluminorex; Levamfetamine Menabitan Hydrochloride; Meperidine Hydrochloride; Succinate; Mazindol; Mefenorex Hydrochloride; Phen Meptazinol Hydrochloride; Methadone Hydrochloride; metrazine Hydrochloride; Phentermine: Sibutramine Methadyl Acetate; Methopholine; Methotrimeprazine; Hydrochloride. Metkephamid Acetate; Mimbane Hydrochloride; Mirfen Antagonist: Atipamezole; Atosiban; Bosentan; Cimetidine; tanil Hydrochloride; MolinaZone; Morphine Sulfate: 40 Cimetidine Hydrochloride; Clentiazem Maleate; Detirelix Moxazocine; Nabitan Hydrochloride; Nalbuphine Hydro Acetate; Devazepide; Donetidine: Etintidine Hydrochlo chloride; Nalmexone Hydrochloride; Namoxyrate; Nant ride; Famotidine: Fenmetozole Hydrochloride: Flumaze radol Hydrochloride; Naproxen; Naproxen Sodium; nil; Icatibant Acetate; Icotidine: Isradipine; Metiamide: Naproxol; Nefopam Hydrochloride; Nexeridine Hydro Nadide; Nalmefene; Nalmexone Hydrochloride; Nalox chloride; Noracymethadol Hydrochloride; Ocfentanil 45 one Hydrochloride; Naltrexone; Nilvadipine; Oxilorphan; Hydrochloride; Octazamide; Olvanil; Oxetorone Fuma Oximetidine Hydrochloride; Oxmetidine Mesylate: rate; Oxycodone: Oxycodone Hydrochloride: Oxycodone Quadazocine Mesylate; Ranitidine: Ranitidine Bismuth Terephthalate: Oxymorphone Hydrochloride; Pemedolac: Citrate; Ranitidine Hydrochloride; Sufotidine; Teludipine Pentamorphone; Pentazocine; Pentazocine Hydrochlo Hydrochloride; Tiapamil Hydrochloride; Tiotidine: ride; Pentazocine Lactate; Phenazopyridine Hydrochlo 50 Vapiprost Hydrochloride; Zaltidine Hydrochloride. ride; Phenyramidol Hydrochloride; Picenadol Hydrochlo Anterior pituitary activator: Epimestrol. ride; Pinadoline; Pirfenidone; Piroxicam Olamine; Anterior pituitary Suppressant: Danazol. Pravadoline Maleate; Prodilidine Hydrochloride: Profa Anthelmintic: Albendazole; Anthelmycin; Bromoxanide; dol Hydrochloride; Propiram Fumarate; Propoxyphene Bunamidine Hydrochloride; Butonate; Cambendazole; Hydrochloride: Propoxyphene Napsylate: Proxazole; 55 Carbantel Lauryl Sulfate; Clioxanide; Closantel: Proxazole Citrate; Proxorphan Tartrate; Pyrroliphene Cyclobendazole; Dichlorvos.; Diethylcarbamazine Cit Hydrochloride: Remifentanil Hydrochloride: Salcolex; rate; Dribendazole; Dymanthine Hydrochloride; Salethamide Maleate; Salicylamide: Salicylate Meglu Etibendazole; Fenbendazole; Furodazole: Hexylresorci mine; Salsalate: Sodium Salicylate: Spiradoline Mesylate: nol; Mebendazole; Morantel Tartrate; Niclosamide: Nit Sufentanil; Sufentanil Citrate; Talmetacin; Talniflumate; 60 ramisole Hydrochloride: Nitrodan: Oxantel Pamoate: Talosalate: Tazadolene Succinate; Tebufelone; Tetry Oxfendazole; Oxibendazole; Parbendazole; Piperamide damine; Tifurac Sodium; Tilidine Hydrochloride; Tiopi Maleate; Piperazine; Piperazine Citrate; Piperazine Ede nac; Tonazocine Mesylate: Tramadol Hydrochloride: tate Calcium; Proclonol; Pyrantel Pamoate: Pyrantel Tar Trefentanil Hydrochloride; Trolamine; Veradoline Hydro trate; Pyrvinium Pamoate; Rafoxanide; Stilbazium chloride; Verilopam Hydrochloride: Volazocine: Xorpha 65 Iodide; Tetramisole Hydrochloride; Thiabendazole; Ticar nol Mesylate: Xylazine Hydrochloride; Zenazocine bodine; Tioxidazole; Triclofenol Piperazine; Vincofos; Mesylate: Zomepirac Sodium, Zucapsaicin. Zilantel. US 7,199,151 B2 25 26 Anti-acne: Adapalene; Erythromycin Salnacedin; Inocoter Astromicin Sulfate; Avilamycin; AVoparcin, Azithromy one Acetate. cin; Azlocillin; AZlocillin Sodium; Bacampicillin Hydro Anti-adrenergic: Acebutolol; Alprenolol Hydrochloride; chloride; Bacitracin; Bacitracin Methylene Disalicylate: Atenolol; Bretylium Tosylate: Bunolol Hydrochloride: Bacitracin Zinc: Bambermycins; Benzoylpas Calcium; Carteolol Hydrochloride: Celiprolol Hydrochloride; Ceta Berythromycin; Betamicin Sulfate; Biapenem; Biniramy molol Hydrochloride: Cicloprolol Hydrochloride; Dex cin; Biphenamine Hydrochloride; Bispyrithione Mag propranolol Hydrochloride; Diacetolol Hydrochloride: sulfex; Butikacin; Butirosin Sulfate; Capreomycin Sul Dihydroergotamine Mesylate; Dilevalol Hydrochloride; fate; Carbadox; Carbenicillin Disodium; Carbenicillin Esmolol Hydrochloride; Exaprolol Hydrochloride: Fen Indanyl Sodium; Carbenicillin Phenyl Sodium; Carbeni spiride Hydrochloride; Flestolol Sulfate; Labetalol 10 cillin Potassium; Carumonam Sodium; Cefaclor; Hydrochloride: Levobetaxolol Hydrochloride: Cefadroxil, Cefamandole; Cefamandole Nafate; Cefa Levobunolol Hydrochloride; Metalol Hydrochloride; mandole Sodium; Cefaparole; Cefatrizine; Cefazaflur Metoprolol; Metoprolol Tartrate; Nadolol; Pamatolol Sul Sodium; Cefazolin; Cefazolin Sodium; CefbuperaZone: fate; Penbutolol Sulfate; Phentolamine Mesylate; Prac Cefdinir, Cefepime; Cefepime Hydrochloride; Cefetecol; tolol; Propranolol Hydrochloride; Proroxan Hydrochlo 15 Cefixime; Cefnmenoxime Hydrochloride; Cefnetazole; ride; Solypertine Tartrate; Sotalol Hydrochloride: Cefnetazole Sodium; Cefonicid Monosodium; Cefonicid Timolol; Timolol Maleate; Tiprenolol Hydrochloride; Sodium; CefoperaZone Sodium; Ceforanide; Cefotaxime Tolamolol; Zolertine Hydrochloride. Sodium; Cefotetan: Cefotetan Disodium; Cefotiam Anti-allergic: Amlexanox; Astemizole; AZelastine Hydro Hydrochloride: Cefoxitin: Cefoxitin Sodium; Ce?pimi chloride; EclaZolast; Minocrornil; Nedocromil; Nedocro Zole; Ce?pimizole Sodium; Ce?piramide: Ce?piramide mil Calcium; Nedocromil Sodium; Nivinedone Sodium; Sodium; Ce?pirome Sulfate; Cefpodoxime Proxetil: Cef Pemirolast Potassium; Pentigetide; Pirquinozol; Poi prozil; Cefroxadine: Cefsulodin Sodium; Ceftazidime; sonoak Extract; Probicromil Calcium; Proxicromil: Repi Ceflibuten; Ceftizoxime Sodium; Ceftriaxone Sodiumn; rinast: Tetrazolast Meglumine: Thiazinamium Chloride: Cefuroxime; Cefuroxime Axetil: Cefuroxime Pivoxetil: Tiacrilast; Tiacrilast Sodium; Tiprinast Meglumine; Tix 25 Cefuroxime Sodium; Cephacetrile Sodium; Cephalexin; aOX. Cephalexin Hydrochloride; Cephaloglycin; Cephalori Anti-amebic: Berythromycin; Bialamicol Hydrochloride; dine; Cephalothin Sodium; Cephapirin Sodium; Cephra Chloroquine; Chloroquine Hydrochloride; Chloroquine dine; Cetocycline Hydrochloride; Cetophenicol; Phosphate; Clamoxyquin Hydrochloride; Clioquinol: Chloramphenicol; Chloramphenicol Palmitate; Chloram Emetine Hydrochloride: Iodoquinol; Paromomycin Sul 30 phenicol Pantothenate Complex: Chloramphenicol fate; Quinfamide: Symetime Hydrochloride; Teclozan; Sodium Succinate; Chlorhexidine Phosphanilate: Tetracycline: Tetracycline Hydrochloride. Chloroxylenol; Chlortetracycline Bisulfate; Chlortetracy Anti-androgen: Benorterone; Cioteronel; Cyproterone cline Hydrochloride; Cinoxacin: Ciprofloxacin: Ciprof Acetate; Delmadinone Acetate: Oxendolone; Topterone: loxacin Hydrochloride: Cirolemycin; Clarithromycin; Zanoterone. 35 Clinafloxacin Hydrochloride; Clindamycin; Clindamycin Anti-anemic: Epoetin Alfa; Epoetin Beta; Ferrous Sulfate, Hydrochloride: Clindamycin Palmitate Hydrochloride: Dried; Leucovorin Calcium. Clindamycin Phosphate; Clofazimine; Cloxacillin Benza Anti-anginal: Amlodipine Besylate; Amlodipine Maleate; thine; Cloxacillin Sodium; Cloxyquin; Colistimethate Betaxolol Hydrochloride; Bevantolol Hydrochloride; Sodium; Colistin Sulfate; Coumermycin; Coumermycin Butoprozine Hydrochloride; Carvedilol; Cinepazet Male 40 Sodium; Cyclacillin: Cycloserine; Dalfopristin; Dapsone; ate; Metoprolol Succinate; Molsidomine; Monatepil Daptomycin; Demeclocycline; Demeclocycline Hydro Maleate; Primidolol; Ranolazine Hydrochloride; Tosifen; chloride; Demecycline; Denofungin: Diaveridine: Verapamil Hydrochloride. Dicloxacillin; Dicloxacillin Sodium; Dihydrostreptomy Anti-anxiety agent: Adatanserin Hydrochloride; Alpidem; cin Sulfate; Dipyrithione; Dirithromycin; Doxycycline: Binospirone Mesylate: Bretazenil; Glemanserin; Ipsa 45 Doxycycline Calcium; Doxycycline Fosfatex; Doxycy pirone Hydrochloride; Mirisetron Maleate; Ocinaplon; cline Hyclate; Droxacin Sodium: Enoxacin; Epicillin; Ondansetron Hydrochloride; Panadiplon; Pancopride; Epitetracycline Hydrochloride; Erythromycin; Erythro Pazinaclone; Serazapine Hydrochloride; Tandospirone mycin Acistrate; Erythromycin Estolate; Erythromycin Citrate; Zalospirone Hydrochloride. Ethylsuccinate; Erythromycin Gluceptate; Erythromycin Anti-arthritic: Lodelaben. 50 Lactobionate; Erythromycin Propionate; Erythromycin Anti-asthmatic: Ablukast, Ablukast Sodium; AZelastine Stearate; Ethambutol Hydrochloride; Ethionamide: Hydrochloride: Bunaprolast; Cinalukast: Cromitrile Fleroxacin; Floxacillin: Fludalanine: Flumequine; Fosfo Sodium; Cromolyn Sodium: Enofelast; Isamoxole; Keto mycin; Fosfomycin Tromethamine; Fumoxicillin; Fura tifen Fumarate; Levcromakalim; Lodoxamide Ethyl: Zolium Chloride; Furazolium Tartrate; Fusidate Sodium; Lodoxamide Tromethamine; Montelukast Sodium; Onta 55 Fusidic Acid, Gentamicin Sulfate; Gloximonam; Grami Zolast: Oxarbazole; Oxatomide: Piriprost; Piriprost Potas cidin; Haloprogin: Hetacillin: Hetacillin Potassium; sium; Pirolate: Pobilukast Edamine; Quazolast; Repiri Hexedine; Ibafloxacin; Imipenem; Isoconazole; Isepami nast; Ritolukast; Sulukast: Tetrazolast Meglumine: cin; Isoniazid; Josamycin; Kanamycin Sulfate; Kitasamy Tiaramide Hydrochloride; Tibenelast Sodium; Tome cin; Levofuraltadone; Levopropylcillin Potassium; lukast; Tranilast; Verlukast; Verofylline; Zarirlukast. 60 Lexithromycin; Lincomycin; Lincomycin Hydrochloride; Anti-atherosclerotic: Mifobate; Timefuronc. Lomefloxacin; Lomefloxacin Hydrochloride; Lomefloxa Antibacterial: Acedapsone; Acetosulfone Sodium; Alame cin Mesylate; Loracarbef: Mafenide; Meclocycline: cin; Alexidine; Amdinocillin; Amdinocillin Pivoxil; Ami Meclocycline Sulfosalicylate; Megalomicin Potassium cycline; Amifloxacin; Amifloxacin Mesylate; Amikacin: Phosphate; Mequidox; Meropenem; Methacycline; Meth Amikacin Sulfate; Aminosalicylic acid; Aminosalicylate 65 acycline Hydrochloride; Methenamine; Methenamine Sodium; Amoxicillin; Amphomycin; Ampicillin; Ampicil Hippurate; Methenamine Mandelate; Methicillin Sodium; lin Sodium; Apalcillin Sodium; Apramycin; Aspartocin, Metioprim; Metronidazole Hydrochloride; Metronidazole US 7,199,151 B2 27 28 Phosphate: Mezlocillin: Mezlocillin Sodium; Minocy Sulfate; Isopropamide Iodide; Mepenzolate Bromide: cline; Minocycline Hydrochloride; Mirincamycin Hydro Methylatropine Nitrate; Metoquizine: Oxybutynin Chlo chloride; Monensin; Monensin Sodium; Nafcillin ride; Parapenzolate Bromide; Pentapiperium Methylsul Sodium; Nalidixate Sodium; Nalidixic Acid; Natamycin; fate; Phencarbamide: Poldine Methylsulfate; Proglumide: Nebramycin; Neomycin Palmitate; Neomycin Sulfate: Propantheline Bromide; Propenzolate Hydrochloride: Neomycin Undecylenate; Netilmicin Sulfate; Neutramy Scopolamine Hydrobromide: Tematropium Methylsul cin; Nifuradene; Nifuraldezone; Nifuratel; Nifuratrone; fate; Tiquinamide Hydrochloride; Tofenacin Hydrochlo Nifurdazil; Nifurimide; Nifurpirinol; Nifurcquinazol; ride; Toquizine; Triampyzine Sulfate; Trihexyphenidyl Nifurthiazole; Nitrocycline; Nitrofurantoin: Nitromide: Hydrochloride; Tropicamide. Norfloxacin; Novobiocin Sodium; Ofloxacin; Orme 10 Anticoagulant: Ancrod; Anticoagulant Citrate Dextrose toprim: Oxacillin Sodium; Oximonam. Oximonam Solution; Anticoagulant Citrate Phosphate Dextrose Sodium; Oxolinic Acid: Oxytetracycline: Oxytetracycline Adenine Solution; Anticoagulant Citrate Phosphate Dex Calcium: Oxytetracycline Hydrochloride; Paldimycin; trose Solution; Anticoagulant Heparin Solution; Antico Parachlorophenol; Paulomycin; Pefloxacin; Pefloxacin agulant Sodium Citrate Solution: Ardeparin Sodium; Mesylate: Penamecillin; Penicillin G BenZathine; Peni 15 Bivalirudin; Bromindione; Dalteparin Sodium; Desiru cillin G Potassium; Penicillin G Procaine; Penicillin G din; Dicumarol; Heparin Calcium; Heparin Sodium; Sodium; Penicillin V: Penicillin V BenZathine; Penicillin Lyapolate Sodium; Nafanostat Mesylate; Phenprocou V Hydrabamine; Penicillin V Potassium; Pentizidone mon; Tinzaparin Sodium; Warfarin Sodium. Sodium; Phenyl Aminosalicylate: Piperacillin Sodium; Anticoccidal: Maduramicin. Pirbenicillin Sodium; Piridicillin Sodium; Pirlimycin Anticonvulsant: Albutoin: Ameltolide; Atolide; Buramate; Hydrochloride: Pivampicillin Hydrochloride: Pivampicil Carbamazepine; Cinromide: Citenamide; Clonazepam, lin Pamoate: Pivampicillin Probenate; Polymyxin B Sul Cyheptamide: Dezinamide: Dimethadione; Divalproex fate; Porfiromycin; Propikacin; Pyrazinamide: Pyrithione Sodium: Eterobarb; Ethosuximide: Ethotoin: Flurazepam Zinc, Quindecamine Acetate; Quinupristin; Racepheni Hydrochloride: Fluzinamide; Fosphenytoin Sodium; col; Ramoplanin; Ranimycin; Relomycin; Repromicin; 25 Gabapentin; Ilepcimide; Lamotrigine; Magnesium Sul Rifabutin; Rifametane; Rifamexil; Rifamide: Rifampin; fate; Mephenytoin: Mephobarbital; Methetoin: Methsux Rifapentine; Rifaximin; Rolitetracycline; Rolitetracycline imide: Milacemide Hydrochloride; Nabazenil; Nafimi Nitrate; Rosaramicin; Rosaramicin Butyrate; Rosarami done Hydrochloride: Nitrazepam; Phenacemide: cin Propionate; Rosaramicin Sodium Phosphate: Rosa Phenobarbital; Phenobarbital Sodium; Phensuximide; ramicin Stearate; Rosoxacin; Roxarsone; Roxithromycin; 30 Phenytoin: Phenytoin Sodium; Primidone: Progabide: Sancycline; Sanfetrinem Sodium; Sarmoxicillin; Sarpicil Ralitoline: Remacemide Hydrochloride; Ropizine: Sabe lin; Scopafungin; Sisomicin; Sisomicin Sulfate; Spar luzole: Stiripentol; Sulthiame: Thiopental Sodium; Tile floxacin; Spectinomycin Hydrochloride; Spiramycin; tamine Hydrochloride; Topiramate; Trimethadione; Val Stallimycin Hydrochloride; Steflimycin; Streptomycin proate Sodium; Valproic Acid; Vigabatrin: Zoniclezole Sulfate: Streptonicozid; Sulfabenz; Sulfabenzamide; Sul 35 Hydrochloride; Zonisamide. facetamide: Sulfacetamide Sodium; Sulfacytine; Sulfadi Antidepressant: Adatanserin Hydrochloride; Adinazolam; azine; Sulfadiazine Sodium; Sulfadoxine; Sulfalene; Sul Adinazolam Mesylate, Alaproclate; Aletamine Hydro famerazine; Sulfameter, Sulfamethazine; Sulfamethizole; chloride; Amedalin Hydrochloride; Amitriptyline Hydro Sulfamethoxazole; Sulfamonomethoxine; Sulfamoxole; chloride: Amoxapine; Aptazapine Maleate; AZaloxan Sulfanilate Zinc; Sulfanitran; Sulfasalazine; Sulfasomi 40 Fumarate; Azepindole: Azipramine Hydrochloride; Bipe Zole; Sulfathiazole; Sulfazamet; Sulfisoxazole; Sulfisox namol Hydrochloride: Bupropion Hydrochloride; Butace azole Acetyl; Sulfisoxazole Diolamine: Sulfomyxin; tin; Butriptyline Hydrochloride; Caroxazone; Cartazolate: Sulopenem; Sultamicillin; Suncillin Sodium; Talampicil Ciclazindol; Cidoxepin Hydrochloride: Cilobamine lin Hydrochloride; Teicoplanin; Temafloxacin Hydrochlo Mesylate; Clodazon Hydrochloride; Clomipramine ride; Temocillin; Tetracycline; Tetracycline Hydrochlo 45 Hydrochloride; Cotinine Fumarate; Cyclindole: Cype ride; Tetracycline Phosphate Complex; Tetroxoprim; namine Hydrochloride: Cyprolidol Hydrochloride; Thiamphenicol; Thiphencillin Potassium; Ticarcillin Cyproximide; Daledalin Tosylate; Dapoxetine Hydro Cresyl Sodium; Ticarcillin Disodium; Ticarcillin Mono chloride; Dazadrol Maleate; Dazepinil Hydrochloride: sodium; Ticlatone; Tiodonium Chloride; Tobramycin; Desipramine Hydrochloride; Dexamisole; Deximafen; Tobrarnycin Sulfate; Tosufloxacin; Trimethoprim; Trime 50 Dibenzepin Hydrochloride; Dioxadrol Hydrochloride: thoprim Sulfate; Trisulfapyrimidines; Troleandomycin; Dothiepin Hydrochloride; Doxepin Hydrochloride: Trospectomycin Sulfate: Tyrothricin; Vancomycin; Van Duloxetine Hydrochloride: Eclanamine Maleate; comycin Hydrochloride; Virginiamycin; Zorbarnycin. Encyprate; Etoperidone Hydrochloride; Fantridone Anticholelithic: Monoctanoin. Hydrochloride: Fehmetozole Hydrochloride; Fenmetra Anticholelithogenic: Chenodiol; Ursodiol. 55 mide; Fezolamine Fumarate: Fluotracen Hydrochloride; Anticholinergic: Alverinc Citrate; Anisotropine Methylbro Fluoxetine: Fluoxetine Hydrochloride: Fluparoxan mide; Atropine; Atropine Oxide Hydrochloride; Atropine Hydrochloride; Gamfexine; Guanoxyfen Sulfate: Imafen Sulfate; Belladonna; Benapryzine Hydrochloride; Ben Hydrochloride: Imiloxan Hydrochloride: Imipramine Zetimide Hydrochloride; Benzilonium Bromide: Hydrochloride; Indeloxazine Hydrochloride; Intriptyline Biperiden; Biperiden Hydrochloride; Biperiden Lactate; 60 Hydrochloride; Iprindole: Isocarboxazid; Ketipramine Clidinium Bromide: Cyclopentolate Hydrochloride; Dex Fumarate; Lofepramine Hydrochloride; Lortalamine: etimide: Dicyclomine Hydrochloride; Dilhexy verine Maprotiline: Maprotiline Hydrochloride; Melitracen Hydrochloride; Domazoline Fumarate; Elantrine; Hydrochloride; Milacemide Hydrochloride; Minaprine Elucaine; Ethybenztropine: Eucatropine Hydrochloride; Hydrochloride; Mirtazapine: Moclobemide: Modaline Glycopyrrolate: Heteronium Bromide: Homatropine 65 Sulfate; Napactadine Hydrochloride; Naparnezole Hydro Hydrobromide: Homatropine Methylbromide; Hyos chloride: Nefazodone Hydrochloride; Nisoxetine: cyamine, Hyoscyamine Hydrobromide; Hyoscyamine Nitrafudam Hydrochloride; Nomifensine Maleate; US 7,199,151 B2 29 30 Nortriptyline Hydrochloride; Octriptyline Phosphate: Nitrate: Fenticonazole Nitrate; Filipin; Fluconazole; Opipramol Hydrochloride: Oxaprotiline Hydrochloride; Flucytosine; Fungimycin; Griseofulvin; Hamycin; Iso Oxypertine; Paroxetine; Phenelzine Sulfate; Pirandamine conazole, Itraconazole; Kalafungin; Ketoconazole; Hydrochloride; Pizotyline: Pridefine Hydrochloride: Pro Lomofungin; Lydimycin; Mepartricin; Miconazole; lintane Hydrochloride: Protriptyline Hydrochloride: Qui Miconazole Nitrate; Monensin; Monensin Sodium; Naf pazine Maleate; Rolicyprine; Seproxetine Hydrochloride: tifine Hydrochloride; Neomycin Undecylenate; Nifuratel; Sertraline Hydrochloride: Sibutramine Hydrochloride; Nifurmerone; Nitralamine Hydrochloride; Nystatin: Sulpiride: Suritozole; Tametraline Hydrochloride; Tam Octanoic Acid, Orconazole Nitrate; Oxiconazole Nitrate; pramine Fumarate; Tandamine Hydrochloride; Thiazesim Oxifungin Hydrochloride; Parconazole Hydrochloride: Hydrochloride; Thozalinone; Tomoxetine Hydrochloride; 10 Partricin; Potassium Iodide: Proclonol; Pyritone Zinc; Trazodone Hydrochloride; Trebenzomine Hydrochloride; Pyrrolnitrin; Rutamycin; Sanguinarium Chloride: Saper Trimipramine; Trimipramine Maleate; Venlafaxine conazole; Scopafungin: Selenium Sulfide: Sinefungin; Hydrochloride; Viloxazine Hydrochloride; Zimeldine Sulconazole Nitrate; Terbinafine; Terconazole; Thiram; Hydrochloride; Zometapine. Ticlatone; Tioconazole; Tolciclate; Tolindate; Tolnaftate; Antidiabetic: Acetohexamide; Buformin; Butoxamine 15 Triacetin: Triafungin: Undecylenic Acid; Viridofulvin; Hydrochloride: Camiglibose; Chlorpropamide: Ciglita Zinc Undecylenate; Zinoconazole Hydrochloride. Zone; Englitazone Sodium; Etoformin Hydrochloride; Antiglaucooma agent: AlprenoXime Hydrochloride; Col Gliamilide; Glibornuride; Glicetanile Sodium; Gliflu forsin; Dapiprazole Hydrochloride; Dipivefrin Hydro mide; Glipizide. Glucagon; Glyburide; Glyhexamide: chloride; Naboctate Hydrochloride; Pilocarpine; Pirnab Glymidine Sodium; Glyoctamide: Glyparamide: Insulin; 1C. Insulin, Dalanated; Insulin Human; Insulin Human, Antihemophilic: Antihemophilic Factor. Isophane; Insulin Human Zinc, Insulin Human Zinc, Antihemorrhagic: Poliglusam. Extended; Insulin, Isophane; Insulin Lispro; Insulin, Neu Antihistaminic: Acrivastine; Antazoline Phosphate: Astemi tral; Insulin Zinc; Insulin Zinc, Extended; Insulin Zinc, Zole: AZatadine Maleate; Barmastine; Bromodiphenhy Prompt; Linogliride: Linogliride Fumarate; Metformin; 25 dramine Hydrochloride; Brompheniramine Maleate; Methyl Palmoxirate; Palmoxirate Sodium; Pioglitazone Carbinoxamine Maleate; Cetirizine Hydrochloride; Chlo Hydrochloride: Pirogliride Tartrate; Proinsulin Human; rpheniramine Maleate; Chlorpheniramine Polistirex: Cin Seglitide Acetate; Tolazamide: Tolbutamide: Tolpyrra narizine; Clemastine; Clemastine Fumarate; Closiramine mide; TroglitaZone; Zopolrestat. Aceturate; Cycliramine Maleate; Cyclizine; Cyprohepta Antidiarrheal: Rolgamidine, Diphenoxylate hydrochloride 30 dine Hydrochloride; Dexbrompheniramine Maleate; Dex (Lomotil), Metronidazole (Flagyl), Methylprednisolone chlorpheniramine Maleate; Dimethindene Maleate; (Medrol), Sulfasalazine (AZulfidine). Diphenhydramine Citrate; Diphenhydramine Hydrochlo Antidiuretic: Argipressin Tannate; Desmopressin Acetate; ride; Dorastine Hydrochloride; Doxylamine Succinate; Lypressin. Ebastine; Levocabastine Hydrochloride; Loratadine: Antidote: Dimercaprol; Edrophonium Chloride; Fomepi 35 Mianserin Hydrochloride: Noberastine; Orphenadrine Zole; Leucovorin Calcium; Levoleucovorin Calcium; Citrate; Pyrabrom: Pyrilamine Maleate; Pyroxamine Methylene Blue: Protamine Sulfate. Maleate; Rocastine Hydrochloride; Rotoxamine; Tazifyl Antidyskinetic: Selegiline Hydrochloride. line Hydrochloride; Temelastine; Terfenadine: Tripelen Anti-emetic: Alosetron Hydrochloride: Batanopride Hydro namine Citrate; Tripelennamine Hydrochloride, Triproli chloride; Bemesetron; BenZquinamide; Chlorpromazine; 40 dine Hydrochloride; Zolamine Hydrochloride. Chlorpromazine Hydrochloride; Clebopride: Cyclizine Antihyperlipidemic: Cholestyramine Resin; Clofibrate; Hydrochloride; Dimenhydrinate; Diphenidol; Diphenidol Colestipol Hydrochloride: Crilvastatin: Dalvastatin: Dex Hydrochloride; Diphenidol Pamoate: Dolasetron Mesy trothyroxine Sodium; Fluvastatin Sodium; Gemfibrozil; late; Domperidone; Dronabinol; Fludorex: Flumeridone; Lecimibide; Lovastatin; Niacin; Pravastatin Sodium; Galdansetron Hydrochloride; Granisetron; Granisetron 45 Probucol; Simvastatin; Tiqueside; Xenbucin. Hydrochloride: Lurosetron Mesylate: Meclizine Hydro Antihyperlipoproteinemic: Acifran; Beloxamide: Bezafi chloride; Metoclopramide Hydrochloride; Metopimazine; brate; Boxidine; Butoxamine Hydrochloride; Cetaben Ondansetron Hydrochloride; Pancopride; Prochlorpera Sodium: Ciprofibrate; Gemcadiol; Halofenate: Lifibrate; zine: Prochlorperazine Edisylate: Prochlorperazine Male Meglutol; Nafenopin: Pimetine Hydrochloride; Theofi ate; Promethazine Hydrochloride; Thiethylperazine; Thi 50 brate; Tilbric Acid; Treloxinate. ethylperazine Malate: Thiethylperazine Maleate; Antihypertensive: Alfuzosin Hydrochloride; Alipamide: Trimethobenzamide Hydrochloride; Zacopride Hydro Althiazide; Amiquinsin Hydrochloride; Amlodipine chloride. Besylate: Amlodipine Maleate; Anaritide Acetate; Anti-epileptic: Felbamate; Loreclezole; Tolgabide. Atiprosin Maleate; Belfosdil; Bemitradine; Bendacalol Anti-estrogen: Clometherone; Delmadinone Acetate; 55 Mesylate; Bendroflumethiazide; Benzthazide. Betaxolol Nafoxidine Hydrochloride: Nitromifene Citrate; Ralox Hydrochloride: Bethanidine Sulfate; Bevantolol Hydro ifene Hydrochloride; Tamoxifen Citrate; Toremifene Cit chloride; Biclodil Hydrochloride; Bisoprolol; Bisoprolol rate; Trioxifene Mesylate. Fumarate; Bucindolol Hydrochloride; Bupicomide: Antifibrinolytic: Nafamostat Mesylate. Buthiazide, Candoxatril; Candoxatrilat; Captopril; Antifungal: Acrisorcin; Ambruticin; Amphotericin B; AZa 60 Carvedilol; Ceronapril; Chlorothiazide Sodium: Cicleta conazole; AZaserine; Basifungin; Bifonazole; Biphe nine: Cilazapril; Clonidine; Clonidine Hydrochloride; namine Hydrochloride; Bispyrithione Magsulfex; Buto Clopamide: Cyclopenthiazide. Cyclothiazide; Dar conazole Nitrate; Calcium Undecylenate; Candicidin; odipine; Debrisoquin Sulfate; Delapril Hydrochloride: Carbol-Fuchsin; Chlordantoin: Ciclopirox: Ciclopirox Diapamide; Diazoxide; Dilevalol Hydrochloride; Dilt Olamine: Cilofungin: Cisconazole; Clotrimazole; 65 iazem Malate; Ditekiren: Doxazosin Mesylate; Ecadotril; Cuprimyxin; Denofungin; Dipyrithione; Doconazole; Enalapril Maleate; Enalaprilat; Emalkiren: Endralazine Econazole; Econazole Nitrate; Enilconazole; Ethonam Mesylate: Epithiazide: Eprosartan; Eprosartan Mesylate: US 7,199,151 B2 31 32 Fenoldoparn Mesylate: Flavodilol Maleate; Flordipine; damine Hydrochloride; Bromelains; Broperamole; Floseduinan; Fosinopril Sodium; Fosinoprilat, Guana Budesonide; Carprofen; Cicloprofen; Cintazone; Clipro benz, Guanabenz, Acetate; Guanacline Sulfate; Guanadrel fen; Clobetasol Propionate; Clobetasone Butyrate; Clopi Sulfate; Guancydine; Guanethidine Monosulfate; rac; CloticaSone Propionate; Cormethasone Acetate; Guanethidine Sulfate; Guanfacine Hydrochloride; Cortodoxone; Deflazacort: Desonide; Desoximetasone; Guanisoquin Sulfate; Guanoclor Sulfate; Guanoctine Dexamethasone Dipropionate; Diclofenac Potassium; Hydrochloride; Guanoxabenz: Guanoxan Sulfate; Guan Diclofenac Sodium; Diflorasone Diacetate; Diflumidone oxyfen Sulfate; Hydralazine Hydrochloride; Hydralazine Sodium; Diflunisal; Difluprednate; Diftalone; Dimethyl Polistirex: Hydroflumethiazide; Indacrinone; Indapam Sulfoxide: Drocinonide; Endrysone; Enlimomab: Enoli ide; Indolapril Hydrochloride; Indoramin; Indoramin 10 cam Sodium; Epirizole; Etodolac; Etofenamate; Felbinac: Hydrochloride; Indorenate Hydrochloride; Lacidipine; Fenamole: Fenbufen, Fenclofenac; Fenclorac, Fendosal; Leniquinsin; Levcromakalim; Lisinopril; Lofexidine Fenpipalone: Fentiazac, Flazalone: Fluazacort; Flufe Hydrochloride: Losartan Potassium; Losulazine Hydro namic Acid, Flumizole; Flunisolide Acetate; Flunixin; chloride; Mebutamate; Mecamylamine Hydrochloride; Flunixin Meglumine: Fluocortin Butyl; Fluorometholone Medroxalol; Medroxalol Hydrochloride; Methalthiazide; 15 Acetate: FluguaZone: Flurbiprofen; Fluretofen; Flutica Methyclothiazide; Methyldopa; Methyldopate Hydro some Propionate; Furaprofen; Furobufen; Halcinonide; chloride; Metipranolol; Metolazone; Metoprolol Fuma Halobetasol Propionate; Halopredone Acetate; Ibufenac: rate; Metoprolol Succinate; Metyrosine; Minoxidil; Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol: Monatepil Maleate; Muzolimine; Nebivolol; Nitren Ilonidap; Indomethacin; Indomethacin Sodium; Indopro dipine; Ofornine: Pargyline Hydrochloride; Pazoxide: fen, Indoxole; Intrazole; Isoflupredone Acetate; Isoxepac; Pelanserin Hydrochloride; Perindopril Erburmine; Phe Isoxicam; Ketoprofel; Lofemizole Hydrochloride; Lor noxybenzamine Hydrochloride; Pinacidil: Pivopril; Poly noxicam; Loteprednol Etabonate; Meclofenamate thiazide; Prazosin Hydrochloride: Primidolol; Prizidilol Sodium; Meclofenamic Acid; Meclorisone Dibutyrate; Hydrochloride: Quinapril Hydrochloride: Quinaprilat; Mefenamic Acid; Mesalamine; MeseclaZone; Methyl Quinazosin Hydrochloride; Quinelorane Hydrochloride; 25 prednisolone Suleptanate; Morniflumate; Nabumetone; Quinpirole Hydrochloride: Quinucliun Bromide: Rami Naproxen; Naproxen Sodium; Naproxol; Nimazone: pril; Rauwolfia Serpentina; Reserpine; Saprisartan Potas Olsalazine Sodium; Orgotein; Orpanoxin: Oxaprozin; sium; Saralasin Acetate: Sodium Nitroprusside; Sulfinalol Oxyphenbutazone: Paranyline Hydrochloride; Pentosan Hydrochloride; Tasosartan; Teludipine Hydrochloride; Polysulfate Sodium; Phenbutazone Sodium Glycerate; Temocapril Hydrochloride; Terazosin Hydrochloride; 30 Pirfenidone; Piroxicam, Piroxicam Cinnamate; Piroxicam Terlakiren; Tiamenidine; Tiamenidine Hydrochloride; Olamine: Pirprofen; Prednazate; Prifelone: Prodolic Acid; Ticrynafen; Tinabinol; Tiodazosin; Tipentosin Hydro ProquaZone: Proxazole; Proxazole Citrate; Rimexolone: chloride; Trichlormethiazide; Trimazosin Hydrochloride; Romazarit; Salcolex, Salnacedin; Salsalate; Sangui Trimethaphan Carnsylate; Trimoxamine Hydrochloride; narium Chloride; Seclazone; Sermetacin; Sudoxicam, Tripamide; Xipamide; Zankiren Hydrochloride; Zofeno 35 Sulindac: Suprofen; Talmetacin; Talniflumate: Talosalate: prilat Arginine. Tebufelone; Tenidap: Tenidap Sodium; Tenoxicam; Tesi Antihypotensive: Ciclafrine Hydrochloride; Midodrine cam; Tesimide; Tetrydamine; Tiopinac; Tixocortol Piv Hydrochloride. alate: Tolimetin; Tolimetin Sodium; Triclonide; Triflumi Anti-infective: Difloxacin Hydrochloride; Lauryl Isoquino date; Zidometacin, Zomepirac Sodium. linium Bromide; Moxalactam Disodium; Ornidazole; 40 Antikeratinizing agent: Doretinel; Linarotene; Pelretin. Pentisomicin; Sarafloxacin Hydrochloride; Protease Antimalarial: Acedapsone: Amodiaquine Hydrochloride; inhibitors of HIV and other retroviruses: Integrase Inhibi Amquinate; Arteflene; Chloroquine; Chloroquine Hydro tors of HIV and other retroviruses; Cefaclor (Ceclor); chloride; Chloroquine Phosphate: Cycloguanil Pamoate: Acyclovir (Zovirax), Norfloxacin (Noroxin); Cefoxitin Enpiroline Phosphate; Halofantrine Hydrochloride: (Mefoxin); Cefuroxime axetil (Ceftin): Ciprofloxacin 45 Hydroxychloroquine Sulfate; Mefloquine Hydrochloride: (Cipro). Menoctone; Mirincamycin Hydrochloride; Primaquine Anti-infective, topical: Alcohol; Aminacrine Hydrochloride; Phosphate: Pyrimethamine; Quinine Sulfate; Tebuquine. Benzethonium Chloride; Bithionolate Sodium; Bro Antimicrobial: Aztreonam; Chlorhexidine Gluconate; Imi mchlorenone; Carbamide Peroxide; Cetalkonium Chlo durea; Lycetamine; Nibroxane: Pirazmonam Sodium; ride; Cetylpyridinium Chloride; Chlorhexidine Hydro 50 Propionic Acid; Pyrithione Sodium; Sanguinarium Chlo chloride; Clioquinol; Domiphen Bromide: Fenticlor; ride; Tigemonam Dicholine. Fludazonium Chloride; Fuchsin, Basic; Furazolidone; Antimigraine: Dolasetron Mesylate: Naratriptan Hydrochlo Gentian Violet; Halquinols: Hexachlorophene: Hydrogen ride: Sergolexole Maleate; Sumatriptan Succinate; Peroxide: Ichthammol: Imidecyl Iodine: Iodine: Isopropyl Zatosetron Maleate. Alcohol; Mafenide Acetate; Meralein Sodium; Mer 55 Antimitotic: Podofilox. cufenol Chloride; Mercury, Ammoniated; Methylbenze Antimycotic: Amorolfine. thonium Chloride; Nitrofurazone; Nitromersol; Octeni Antinauseant: Buclizine Hydrochloride: Cyclizine Lactate; dine Hydrochloride: Oxychlorosene: Oxychlorosene Naboctate Hydrochloride. Sodium; Parachlorophenol, Camphorated; Potassium Per Antineoplastic: Acivicin; Aclarubicin; Acodazole Hydro manganate; Povidone-Iodine; Sepazonium Chloride; Sil 60 chloride; Acronine; Adozelesin; Aldesleukin; Altre ver Nitrate; Sulfadiazine, Silver: Symclosene; Thimer tamine; Ambomycin; Ametantrone Acetate; Aminoglute fonate Sodium; Thirerosal: Troclosene Potassium. thimide; Amsacrine; Anastrozole; Anthramycin; Anti-inflammatory: Alclofenac; Alclometasone Dipropi Asparaginase; Asperlin, AZacitidine, AZetepa, onate; Algestone Acetonide; Alpha Amylase; Amcinafal; AZotomycin; Batimastat; BenZodepa; Bicalutamide: Amcinafide: Amfenac Sodium; Amiprilose Hydrochlo 65 Bisantrene Hydrochloride; Bisnafide Dimesylate; Bize ride; Anakinra, Anirolac, AnitraZafen; Apazone; Bal lesin; Bleomycin Sulfate: Brequinar Sodium; Bropir Salazide Disodium; Bendazac, Benoxaprofen; Benzy imine; BuSulfan; Cactinomycin; Calusterone; Carace US 7,199,151 B2 33 34 mide; Carbetimer; Carboplatin: Carmustine; Carubicin atrimustine; axinastatin 1; axinastatin 2; axinastatin 3: Hydrochloride; Carzelesin; Cedefingol: Clorambucil; Cir aZasetron; azatoxin; azatyrosine; baccatin III derivatives; olemycin; Cisplatin: Cladribine: Crisinatol Mesylate: balanol; batimastat; BCR/ABL antagonists; benzochlor Cyclophosphamide; Cytarabine; Dacarbazine; Dactino ins; benzoylstaurosporine; beta lactam derivatives; beta mycin; Daunorubicin Hydrochloride; Decitabine; Dexor alethine; betaclamycin B; betulinic acid; bFGF inhibitor; maplatin: DeZaguanine; DeZaguanine Mesylate; Diazi bicalutamide; bisantrene; bisaziridinylspermine; bisna quone; Docetaxel; Doxorubicin; Doxorubicin fide; bistratene A: bizelesin; breflate; bropirimine; budoti Hydrochloride; Droloxifene; Droloxifene Citrate; Dro tane; buthionine Sulfoximine; calcipotriol; callphostin C: mostanolone Propionate; Duazomycin; Edatrexate. Eflo camptothecin derivatives; canarypox IL-2; capecitabine; rnithine Hydrochloride; Elsamitrucin; Enloplatin: Enpro 10 carboxamide-amino-triazole; carboxyamidotriazole; mate: Epipropidine: Epirubicin Hydrochloride: CaRest M3; CARN 700; cartilage derived inhibitor; car Erbulozole; Esorubicin Hydrochloride; Estramustine; Zelesin; casein kinase inhibitors (ICOS); castanosper Estramustine Phosphate Sodium; Etanidazole; Ethiodized mine; cecropin B; cetrorelix; chlorins; chloroquinoxaline Oil I 131; Etoposide; Etoposide Phosphate; Etoprine; Sulfonamide; cicaprost, cis-porphyrin, cladribine; clo Fadrozole Hydrochloride; Fazarabine: Fenretinide; 15 rnifene analogues; clotrimazole; collismycin A; collismy Floxuridine: Fludarabine Phosphate: Fluorouracil; cin B; combretastatin A4, combretastatin analogue; con Flurocitabine; Fosquidone; Fostriecin Sodium; Gemcit agenin, crambescidin 816; crisinatol; cryptophycin 8: abine; Gemcitabine Hydrochloride; Gold Au 198: cryptophycin A derivatives; curacin A; cyclopentan Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide: thraquinones; cycloplatam, cypemycin; cytarabine ocfos Ilmofosine; Interferon Alfa-2a: Interferon Alfa-2b: Inter fate; cytolytic factor; cytostatin; dacliximab, decitabine; feron Alfa-n1; Interferon Alfa-n3; Interferon Beta-la; dehydrodidemnin B; deslorelin; dexifosfamide; dexra Interferon Gamma-Ib, Iproplatin; Irinotecan Hydrochlo Zoxane; deXVerapamil: diaziquone; didemnin B; didox; ride; Lanreotide Acetate; Letrozole; Leuprolide Acetate; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol. Liarozole Hydrochloride; Lometrexol Sodium; Lomus 9-; dioxamycin; diphenyl spiromustine; docosanol; dola tine; Losoxantrone Hydrochloride: Masoprocol; May 25 setron: doxifluridine; droloxifene; dronabinol; duocarmy tansine; Mechlorethamine Hydrochloride: Megestrol cin SA; ebselen; ecomustine; edelfosine; edrecolomab; Acetate; Melengestrol Acetate; Melphalan: Menogaril; eflornithine; elemene; emitefur; epirubicin; epristeride: Mercaptopurine; Methotrexate; Methotrexate Sodium; estramustine analogue; estrogen agonists; estrogen Metoprine; Meturedepa; Mitindomide: Mitocarcin: antagonists; etanidazole; etoposide phosphate; exemes Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mito 30 tane; fadrozole; faZarabine; fenretinide; filgrastim; finas sper; Mitotane; Mitoxantrone Hydrochloride: Mycophe teride; flavopiridol; flezelastine; fluasterone; fludarabine; nolic Acid; Nocodazole; Nogalamycin; Ormaplatin: Oxi fluorodaunorunicin hydrochloride; forfenimex; formes Suran, Paclitaxel; Pegaspargase; Peliomycin; tane; fostriecin: fotemustine; gadolinium texaphyrin, gal Pentamustine: Peplomycin Sulfate; Perfosfamide; Pipo lium nitrate; galocitabine; ganirelix; gelatinase inhibitors; broman; Piposulfan; Piroxantrone Hydrochloride; Plica 35 gemcitabine; glutathione inhibitors; hepsulfam; heregu mycin; Plomestane: Porfimer Sodium; Porfiromycin; lin; hexamethylene bisacetamide; hypericin; ibandronic Prednimustine: Procarbazine Hydrochloride; Puromycin; acid; idarubicin; idoxifene; idramantone; ilmofosine; illo Puromycin Hydrochloride: Pyrazofurin; Riboprine; mastat; imidazoacridones; imiquimod; immunostimulant Rogletimide: Safingol: Safingol Hydrochloride: Semus peptides; insulin-like growth factor-1 receptor inhibitor; tine; SimtraZene; Sparfosate Sodium; Sparsomycin; 40 interferon agonists, interferons; interleukins; iobenguane; Spirogermanium Hydrochloride; Spiromustine; Spiropl iododoxoribicin; ipomeanol, 4-, irinotecan; iroplact; atin: Streptonigrin: Streptozocin; Strontium Chloride Sr irsogladine; isobengaZole; isohomohalicondrin B; 89; Sulofenur; Talisomycin; Taxane: Taxoid: Tecogalan itasetron: jasplakinolide; kahalalide F; lamellarin-N triac Sodium; Tegafur. Teloxantrone Hydrochloride; Temopor etate; lanreotide; leinamycin; lenograstim; lentinan Sul fin; Teniposide; Teroxirone; Testolactone; Thiamiprine; 45 fate; leptolstatin; letrozole; leukemia inhibiting factor; Thioguanine: Thiotepa; Tiazofurin; Tirapazamine; Topo leukocyte alpha interferon; leuprolide--estrogen-progest tecan Hydrochloride; Toremifene Citrate; Trestolone erone; leuprorelin; levamisole; liarozole; linear Acetate; Triciribine Phosphate: Trimetrexate; Trimetrex polyamine analogue; lipophilic disaccharide peptide; ate Glucuronate; Triptorelin; Tubulozole Hydrochloride; lipophilic platinum compounds; lissoclinamide 7: lobap Uracil Mustard; Uredepa; Vapreotide: Verteporfin; Vin 50 latin, lombricine; lometrexol; lonidamine; losoxantrone; blastine Sulfate; Vincristine Sulfate; Vindesine; Vindesine lovastatin; loxoribine; lurtotecan; lutetium texaphyrin, Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate; Vinleu lysofylline; lytic peptides; maitansine; mannostatin A; rosine Sulfate; Vinorelbine Tartrate; Vinrosidine Sulfate; marimastat; masoprocol; maspin; matrilysin inhibitors; Vinzolidine Sulfate; Vorozole; Zeniplatin: Zinostatin: matrix metalloproteinase inhibitors; menogaril; merbar Zorubicin Hydrochloride. 55 one; meterelin; methioninase; metoclopramide: MIF Other anti-neoplastic compounds include: 20-epi-1.25 dihy inhibitor, mifepristone; miltefosine; mirimoStim; mis droxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubi matched double stranded RNA; mitoguaZone; mitolactol; cin; acylfulvene; adecypenol; adoZelesin; aldesleukin; mitomycin analogues; mitonafide; mitotoxin fibroblast ALL-TKantagonists; altretamine; ambamustine; amidox; growth factor-Saporin; mitoxantrone; mofarotene; mol amifostine; aminolevulinic acid; amrubicin; amsacrine; 60 gramostim; monoclonal antibody, human chorionic gona anagrelide; anastrozole; andrographolide; angiogenesis dotrophin; monophosphoryl lipid A+myobacterium cell inhibitors; antagonist D; antagonist G.; antarelix; anti wall sk; mopidamol; multiple drug resistance gene inhibi dorsalizing morphogenetic protein-1, antiandrogen, pro tor, multiple tumor Suppressor 1-based therapy; mustard static carcinoma; antiestrogen; antineoplaston; antisense anticancer agent; mycaperoxide B; mycobacterial cell oligonucleotides; aphidicolin glycinate; apoptosis gene 65 wall extract; myriaporone; N-acetyldinaline; N-substi modulators; apoptosis regulators; apurinic acid; ara-CDP tuted benzamides; nafarelin; nagreStip; naloxone+penta DL-PTBA, arginine deaminase; asulacrine; atameStane; Zocine; napavin; naphterpin, nartograstim; nedaplatin: US 7,199,151 B2 35 36 memorubicin; neridronic acid; neutral endopeptidase; buthionine and sulfoximine) and Multiple Drug Resistance nilutamide; nisamycin; nitric oxide modulators; nitroxide reducing agents such as Cremaphor EL. The compounds of antioxidant; nitrullyn; O6-benzylguanine; octreotide; oki the invention also can be administered with cytokines Such cenone; oligonucleotides; onapristone; ondansetron; as granulocyte colony Stimulating factor. ondansetron; oracin; oral cytokine inducer, ormaplatin: Antineutropenic: Filgrastim; Lenograstim; MolgramoStim; osaterone; oxaliplatin, oxaunomycin; paclitaxel ana Regramostim; Sargramostim. logues; paclitaxel derivatives; palauamine; palmitoyl Antiobsessional agent: Fluvoxamine Maleate. rhizoxin; pamidronic acid; panaxytriol; panomifene; para Antiparasitic: Abamectin; ClorSulon; Ivermectin. bactin; paZelliptine; pegaspargase; peldesine; pentosan Antiparkinsonian: Benztropine Mesylate; Biperiden; polysulfate Sodium; pentostatin: pentroZole; perflubron; 10 Biperiden Hydrochloride; Biperiden Lactate; Carmanta perfosfamide; perillyl alcohol; phenazinomycin; pheny dine: Ciladopa Hydrochloride; Dopamantine; Ethopro lacetate; phosphatase inhibitors; picibanil; pilocarpine pazine Hydrochloride; LaZabemide; Levodopa; Lometra hydrochloride; pirarubicin; piritrexim; placetin A; place line Hydrochloride; Mofegiline Hydrochloride: tin B; plasminogen activator inhibitor, platinum complex; Naxagolide Hydrochloride; Pareptide Sulfate; Procyclid platinum compounds; platinum-triamine complex; por 15 ine Hydrochloride: Quinelorane Hydrochloride; Ropin fimer Sodium; porfiromycin; propyl bis-acridone; prostag irole Hydrochloride: Selegiline Hydrochloride; Tolca landin J2, proteasome inhibitors; protein A-based immune pone; Trihexyphenidyl Hydrochloride. modulator; protein kinase C inhibitor; protein kinase C Antiperistaltic: Difenoximide Hydrochloride; Difenoxin; inhibitors, microalgal; protein tyrosine phosphatase Diphenoxylate Hydrochloride: Fluperamide: Lidamidine inhibitors; purine nucleoside phosphorylase inhibitors; Hydrochloride: Loperamide Hydrochloride: Malethamer; purpurins; pyrazoloacridine; pyridoxylated hemoglobin Nufenoxole; Paregoric. polyoxyethylene conjugate; raf antagonists; raltitrexed: Antipneumocystic: Atovaquone. ramosetron; ras farnesyl protein transferase inhibitors; ras Antiproliferative agent: Piritrexim Isethionate. inhibitors: ras-GAP inhibitor; retelliptine demethylated: Antiprostatic hypertrophy: Sitogluside. rhenium Re 186 etidronate; rhizoxin: ribozymes: RII 25 Antiprotozoal: Amodiaquine; AZanidazole; Bamnidazole; retinamide; rogletimide; rohitukine; romurtide; roquin Carnidazole; Chlortetracycline Bisulfate; Chlortetracy imex: rubiginone B1; ruboxyl; Safingol; Saintopin: cline Hydrochloride: Flubendazole: Flunidazole; SarCNU; sarcophytol A, sargramostim; Sdi 1 mimetics; Halofuginone Hydrobromide: Imidocarb Hydrochloride: Semustine; senescence derived inhibitor 1; sense oligo Ipronidazole; Metronidazole; Misonidazole; Moxinida nucleotides; signal transduction inhibitors; signal trans 30 Zole: Nitarsone; Partricin; Puromycin; Puromycin Hydro duction modulators; single chain antigen binding protein; chloride; Ronidazole; Sulnidazole; Tinidazole. sizofiran; Sobuzoxane: sodium borocaptate; sodium phe Antipruritic: Cyproheptadine Hydrochloride: Methdilazine: nylacetate; Solverol: Somatomedin binding protein; Son Methdilazine Hydrochloride; Trimeprazine Tartrate. ermin; sparfosic acid; spicamycin D; spiromustine; sple Antipsoriatic: Acitretin: Anthralin; Azaribine; Calcipotriene: nopentin; spongistatin 1; squalamine; stem cell inhibitor; 35 Cycloheximide: Enazadrem Phosphate; Etretinate; Liaro stem-cell division inhibitors; stipiamide; stromelysin Zole Fumarate; Lonapalene; Tepoxalin. inhibitors; Sulfinosine; Superactive vasoactive intestinal Antipsychotic: Acetophenazine Maleate; Alentemol Hydro peptide antagonist, Suradista; Suramin; Swainsonine; syn bromide: Alpertine; Azaperone: Batelapine Maleate; Ben thetic glycosaminoglycans; tallimustine; tamoxifen peridol; BenZindopyrine Hydrochloride; Brofoxine; Bro methiodide; tauromustine; tazarotene; tecogalan Sodium; 40 mperidol; Bromperidol Decanoate. Butaclamol tegafur, tellurapyrylium; telomerase inhibitors; temopor Hydrochloride: Butaperazine; Butaperazine Maleate; Car fin; temozolomide; teniposide; tetrachlorodecaoxide; tet phenazine Maleate; Carvotroline Hydrochloride; Chlor razomine; thaliblastine; thalidomide; thiocoraline; throm promazine; Chlorpromazine Hydrochloride; Chlorpro bopoietin; thrombopoietin mimetic; thymalfasin; thixene; Cinperene; Cintriamide: Clomacran Phosphate: thymopoietin receptor agonist; thymotrinan; thyroid 45 Clopenthixol; Clopimozide; Clopipazan Mesylate; Clo stimulating hormone; tin ethyl etiopurpurin; tira roperone Hydrochloride; Clothiapine; Clothixamide paZamine; titanocene dichloride; topotecan; top sentin; Maleate; Clozapine: Cyclophenazine Hydrochloride: toremifene; totipotent stem cell factor; translation inhibi Droperidol; Etazolate Hydrochloride: Fenimide: Flucin tors; tretinoin; triacetyluridine; triciribine; trimetrexate: dole: Flunezapine: Fluphenazine Decanoate: Fluphena triptorelin; tropisetron; turosteride; tyrosine kinase inhibi 50 zine Enanthate: Fluphenazine Hydrochloride: Fluspiper tors; tyrphostins; UBC inhibitors: ubenimex; urogenital one: Fluspirilene: Flutroline; Gevotroline Hydrochloride: sinus-derived growth inhibitory factor; urokinase receptor Halopemide: Haloperidol; Haloperidol Decanoate; Ilo antagonists; vapreotide; variolin B; vector system, eryth peridone: Imidoline Hydrochloride; Lenperone; Mazap rocyte gene therapy; velaresol; Veramine; Verdins; verte ertine Succinate; Mesoridazine; Mesoridazine Besylate: porfin; Vinorelbine; Vinxaltine; vitaxin; Vorozole; Zanot 55 Metiapine; Milenperone; Milipertine; Molindone Hydro erone; Zeniplatin: Zilascorb; Zinostatin stimalamer. chloride; Naranol Hydrochloride: Neflumozide Hydro Anti-cancer Supplementary Potentiating Agents: Tricy chloride: Ocapridone; Olanzapine; Oxiperomide: Penflu clic anti-depressant drugs (e.g., imipramine, desipramine, ridol; Pentiapine Maleate; Perphenazine; Pimozide: amitryptyline, clomipramine, trimipramine, doxepin, Pinoxepin Hydrochloride; Pipamperone; Piperacetazine: nortriptyline, protriptyline, anoxapine and maprotiline); 60 Pipotiazine Palmitate; Piquindone Hydrochloride: non-tricyclic anti-depressant drugs (e.g., Sertraline, traZ Prochlorperazine Edisylate: Prochlorperazine Maleate; odone and citalopram); Ca' antagonists (e.g., Verapamil, Promazine Hydrochloride; Remoxipride: Remoxipride nifedipine, nitrendipine and caroverine); Calmodulin inhibi Hydrochloride; Rimcazole Hydrochloride; Seperidol tors (e.g., prenylamine, trifluoroperazine and clomi Hydrochloride: Sertindole: Setoperone; Spiperone: Thior pramine); Amphotericin B; Triparanol analogues (e.g., 65 idazine; Thioridazine Hydrochloride; Thiothixene; Thio tamoxifen); antiarrhyhmic drugs (e.g., quinidine); anitihy thixene Hydrochloride; Tioperidone Hydrochloride; pertensive drugs (e.g., reserpine); Thiol depleters (e.g., Tiospirone Hydrochloride; Trifluoperazine Hydrochlo US 7,199,151 B2 37 38 ride; Triflupridol; Triflupromazine; Triflupromazine Hydrochloride: Fenoterol: Fenprinast Hydrochloride: Hydrochloride; Ziprasidone Hydrochloride. Guaithylline: Hexoprenaline Sulfate; Hoquizil Hydro Antirheumatic: Auranofin, Aurothioglucose: Bindarit; chloride; Ipratropium Bromide: Isoetharine; Isoetharine Lobenzarit Sodium; Phenylbutazone: Pirazolac: Prino Hydrochloride: Isoetharine Mesylate: Isoproterenol mide Tromethamine; Seprilose. Hydrochloride: Isoproterenol Sulfate; Metaproterenol Antischistosomal: Becanthone Hydrochloride; Hycanthone: Polistirex: Metaproterenol Sulfate; Nisbuterol Mesylate: Lucanthone Hydrochloride; Niridazole; Oxamniquine; Oxtriphylline: Picumeterol Fumarate; Piquizil Hydro Pararosaniline Pamoate: Teroxalene Hydrochloride. chloride: Pirbuterol Acetate; Pirbuterol Hydrochloride: Antiseborrheic: Chloroxine; Piroctone; Piroctone Olamine; Procaterol Hydrochloride; Pseudoephedrine Sulfate; Qua Resorcinol Monoacetate. 10 Zodine; Quinterenol Sulfate; Racepinephrine: Racepi Antisecretory: Arbaprostil: Deprostil: Fenoctimine Sulfate; nephrine Hydrochloride; Reproterol Hydrochloride; Rim Octreotide, Octreotide Acetate; Omeprazole Sodium; iterol Hydrobromide: Salmeterol: Salmeterol Xinafoate: Rioprostil; Trimoprostil. Soterenol Hydrochloride; Sulfonterol Hydrochloride; Antispasmodic: Stilonium Iodide; Tizanidine Hydrochlo Suloxifen Oxalate; Terbutaline Sulfate: Theophylline; ride. 15 Xanoxate Sodium; Zindotrine; Zinterol Hydrochloride. Antithrombotic: Anagrelide Hydrochloride; Bivalirudin; Carbonic anhydrase inhibitor: Acetazolamide: Acetazola Dalteparin Sodium; Danaparoid Sodium; Dazoxiben mide Sodium, Dichlorphenamide; Dorzolamide Hydro Hydrochloride: Efegatran Sulfate; Enoxaparin Sodium; chloride; Methazolamide: Sezolamide Hydrochloride. Ifetroban; Ifetroban Sodium; Tinzaparin Sodium; Cardiac depressant: Acecainide Hydrochloride; Acetylcho Trifenagrel. line Chloride; Actisomide; Adenosine; Amiodarone; Antitussive: BenZonatate; Butamirate Citrate; Chlophedi Aprindine: Aprindine Hydrochloride; Artilide Fumarate; anol Hydrochloride: Codeine Polistirex: Codoxime; Dex Azimilide Dihydrochloride: Bidisomide; Bucainide tromethorphan: Dextromethorphan Hydrobromide: Dex Maleate; Bucromarone; Butoprozine Hydrochloride: tromethorphan Polistirex: Ethyl Dibunate; Guaiapate: Capobenate Sodium; Capobenic Acid; Cifenline; Cifen Hydrocodone Bitaritrate; Hydrocodone Polistirex; Levo 25 line Succinate; Clofilium Phosphate: Disobutamide: Dis propoxyphene Napsylate: Noscapine; Pemerid Nitrate; opyramide: Disopyramide Phosphate; Dofetilide; Drobu Pipazethate: Suxemerid Sulfate. line; Edifolone Acetate; Emilium Tosylate: Encainide Anti-ulcerative: Aceglutamide Aluminum; CadeXomer Hydrochloride; Flecainide Acetate; Ibutilide Fumarate; Iodine; Cetraxate Hydrochloride; Enisoprost: Isotiquim Indecainide Hydrochloride; Ipazilide Fumarate; ide; Lansoprazole, LaVoltidine Succinate; Misoprostol; 30 Lorajmine Hydrochloride: Lorcainide Hydrochloride: Nizatidine; Nolinium Bromide; Pantoprazole; Pifarnine: Meobentine Sulfate; Mexiletine Hydrochloride: Pirenzepine Hydrochloride; Rabeprazole Sodium: Remi Modecainide: Moricizine; Oxiramide: Pirmenol Hydro prostol; Roxatidine Acetate Hydrochloride; Sucralfate: chloride; Pirolazamide; Pranolium Chloride; Procaina Sucrosofate Potassium; Tolimidone. mide Hydrochloride: Propafenone Hydrochloride; Anti-urolithic: Cysteamine: Cysteamine Hydrochloride; 35 Pyrinoline; Quindonium Bromide: Quinidine Gluconate: Tricitrates. Quinidine Sulfate; Recainam Hydrochloride; Recainam Antiviral: Acemannan, Acyclovir, Acyclovir Sodium, Ade Tosylate: Risotilide Hydrochloride; Ropitoin Hydrochlo fovir; Alovudine; Alvircept Sudotox: Amantadine Hydro ride: Sematilide Hydrochloride; Suricainide Maleate; chloride; Aranotin; Arildone: Atevirdine Mesylate; Avri Tocainide; Tocainide Hydrochloride; Transcainide. dine; Cidofovir; Cipamfylline; Cytarabine 40 Cardioprotectant: Dexrazoxane: Draflazine. Hydrochloride; Delavirdine Mesylate: Desciclovir; Cardiotonic: Actodigin; Amrinone; Bemoradan; Butopam Didanosine; Disoxaril: Edoxudine; Enviradene; ine; Carbazeran; Carsatirin Succinate; Deslanoside; Digi Enviroxime; Famciclovir, Farnotine Hydrochloride; talis; Digitoxin; Digoxin; Dobutamine; Dobutamine Fiacitabine; Fialuridine; Fosarilate; Foscarnet Sodium; Hydrochloride; Dobutamine Lactobionate; Dobutamine Fosfonet Sodium; Ganciclovir, Ganciclovir Sodium; 45 Tartrate; Enoximone: Imazodan Hydrochloride; Indol Idoxuridine; Kethoxal; Lamivudine; Lobucavir; Memo idan; Isomazole Hydrochloride; Levdobutamine Lacto tine Hydrochloride; Methisazone; Nevirapine; Penciclo bionate; Lixazinone Sulfate; Medorinone; Millrinone; Pel vir; Pirodavir; Ribavirin; Rimantadine Hydrochloride: rinone Hydrochloride; Pimobendan: Piroximone: Saquinavir Mesylate: Somantadine Hydrochloride; Prinoxodan; Proscillaridin; Quazinone; Tazolol Hydro Sorivudine: Statolon; Stavudine: Tilorone Hydrochloride; 50 chloride; Vesnarinone. Trifluridine; Valacyclovir Hydrochloride: Vidarabine; Cardiovascular agent: Dopexamine; Dopexamine Hydro Vidarabine Phosphate: Vidarabine Sodium Phosphate: chloride. Viroxime; Zalcitabine; Zidovudine; Zinviroxime. Choleretic: Dehydrocholic Acid: Fencibutirol; Hymec Appetite suppressant: Dexfenfluramine Hydrochloride; romone; Piprozolin; Sincalide; Tocamphyl. Phendimetrazine Tartrate; Phentermine Hydrochloride. 55 Cholinergic: Aceclidine: Bethanechol Chloride; Carbachol: Benign prostatic hyperplasia therapy agent: Tamsulosin Demecarium Bromide: Dexpanthenol; Echothiophate Hydrochloride. Iodide: Isoflurophate; Methacholine Chloride; Neostig Blood glucose regulators: Human insulin; Glucagon; mine Bromide: Neostigmine Methylsulfate; Physostig Tolazamide; Tolbutamide: Chloropropamide: Acetohexa mine; Physostigmine Salicylate: Physostigmine Sulfate; mide and Glipizide. 60 Pilocarpine: Pilocarpine Hydrochloride; Pilocarpine Bone resorption inhibitor: Alendronate Sodium: Etidronate Nitrate; Pyridostignine Bromide. Disodium; Pamidronate Disodium. Cholinergic agonist. Xanomeline; Xanomeline Tartrate. Bronchodilator: Albuterol; Albuterol Sulfate; AZanator Cholinesterase Deactivator: Obidoxime Chloride; Prali Maleate; Bamifylline Hydrochloride; Bitolterol Mesylate: doxime Chloride; Pralidoxime Iodide; Pralidoxime Mesy Butaprost; Carbuterol Hydrochloride; Clorprenaline 65 late. Hydrochloride: Colterol Mesylate; Doxaprost; Doxofyl Coccidiostat: Arprinocid; Narasin; Semduramicin; Semdu line; Dyphylline; Enprofylline; Ephedrine: Ephedrine ramicin Sodium. US 7,199,151 B2 39 40 Cognition adjuvant: Ergoloid Mesylates; Piracetam; Free oxygen radical scavenger: Pegorgotein. Pramiracetam Hydrochloride; Pramiracetam Sulfate; Gastrointestinal Motility agents: Cisapride (Propulsid); Tacrine Hydrochloride. Metoclopramide (Reglan): Hyoscyamine (Levsin). Cognition enhancer: Besipirdine Hydrochloride: Linopird Glucocorticoid: Amcinonide; Beclomethasone Dipropi ine: Sibopirdine. 5 onate; Betamethasone; Betamethasone Acetate; Depressant: Omeprazole. Betamethasone Benzoate: Betamethasone Dipropionate: Diagnostic aid: Aminohippurate Sodium; Anazolene Betamethasone Sodium Phosphate: Betamethasone Val Sodium; Arclofenin; Arginine; Bentiromide; Benzylpeni erate; Carbenoxolone Sodium; Clocortolone Acetate; Clo cilloyl Polylysine; Butedronate Tetrasodiun; Butilfenin: cortolone Pivalate; Cloprednol; Corticotropin; Corticotro Coccidioidin; Corticorelin Ovine Triflutate; Corticotro 10 pin, Repository; Corticotropin Zinc Hydroxide: Cortisone pin, Repository; Corticotropin Zinc Hydroxide; Diatri Acetate; Cortivazol: Descinolone Acetonide; Dexametha Zoate Meglumine; Diatrizoate Sodium; Diatrizoic Acid; sone; Dexamethasone Sodium Phosphate; Diflucortolone; Diphtheria Toxin for Schick Test: Disofenin; Edropho Diflucortolone Pivalate: Flucloronide; Flumethasone; nium Chloride; Ethiodized Oil: Etifenin; Exametazime; Flumethasone Pivalate: Flunisolide; Fluocinolone Ferristenc; Ferumoxides; Ferumoxsil; Fluorescein; Fluo 15 Acetonide; Fluocinonide; Fluocortolone; Fluocortolone rescein Sodium; Gadobenate Dimeglumine; Gadoteridol; Caproate: Fluorometholone: Fluperolone Acetate: Flu Gadodiamide; Gadopentetate Dimeglumine; Gadover prednisolone: Fluprednisolone Valerate: Flurandrenolide; setamide: Histoplasmin: Impromidine Hydrochloride; Formocortal: Hydrocortisone; Hydrocortisone Acetate; Indigotindisulfonate Sodium; Indocyanine Green; loben Hydrocortisone Buteprate; Hydrocortisone Butyrate; guane Sulfate I 123: Iobenzamic Acid: Iocarmate Meglu Hydrocortisone Sodium Phosphate; Hydrocortisone mine; Iocarmic Acid, Iocetamic Acid, Iodamide: Ioda Sodium Succinate; Hydrocortisone Valerate; Medrysone; mide Megilumine: Iodipamide Meglumine; Iodixanol: Methylprednisolone; Methylprednisolone Acetate; Meth Iodoxamate Meglumine; Iodoxamic Acid, Ioglicic Acid; ylprednisolone Sodium Phosphate; Methylprednisolone Ioglucol, Ioglucomide: Ioglycamic Acid, Iogulamide: Sodium Succinate; Nivazol; Paramethasone Acetate; Iohexol; Iomeprol; Iopamidol; Iopanoic Acid, Iopentol; 25 Prednicarbate; Prednisolone; Prednisolone Acetate; Pred Iophendylate; I profenin, Iopronic Acid, Ioprocemic Acid; nisolone Hemisuccinate; Prednisolone Sodium Phos Iopydol; Iopy done; Iosefamic Acid, Ioseric Acid, IoSula phate; Prednisolone Sodium Succinate; Prednisolone mide Meglumine; IoSumetic Acid; Iotasul; Iotetric Acid; Tebutate; Prednisone; Prednival; Ticabesone Propionate: Iothalamate Meglumine; Iothalamate Sodium; Iothalamic Tralonide; Triamcinolone; Triamcinolone Acetonide; Tri Acid; Iotrolan; Iotroxic Acid: Ioversol; Ioxaglate Meglu 30 amcinolone Acetonide Sodium; Triamcinolone Diacetate; mine; Ioxagiate Sodium; Ioxaglic Acid, Ioxilan, Ioxotri Triamcinolone Hexacetonide. zoic Acid; Ipodate Calcium; Ipodate Sodium; Isosulfan Gonad-stimulating principle: Buserelin Acetate; Clomi Blue; Leukocyte Typing Serum; Lidofenin; Mebrofenin: phene Citrate; Ganirelix Acetate; Gonadorelin Acetate; Meglumine; Metrizamide; Metrizoate Sodium; Gonadorelin Hydrochloride; Gonadotropin, Chorionic; Metyrapone; Metyrapone Tartrate; Mumps Skin Test 35 Menotropins. Antigen; Pentetic Acid; Propyliodone; Quinaldine Blue: Schick Test Control; Sermorelin Acetate; Sodium Iodide Hair growth stimulant: Minoxidil. I 123: Sprodiamide: Stannous Pyrophosphate: Stannous Hemostatic: Aminocaproic Acid: Oxamarin Hydrochloride: Sulfur Colloid; Succimer; Teriparatide Acetate; Tetrofos Sulmarin; Thrombin; Tranexamic Acid. min; Tolbutamide Sodium; Tuberculin; Tyropanoate 40 Histamine H2 receptor antagonists: Ranitidine (Zantac); Sodium; Xylose. Famotidine (Pepcid); Cimetidine (Tagamet); Nizatidine Diuretic: Ambuphylline; Ambuside; Amiloride Hydrochlo (Axid). ride; Azolimine; AZosemide; Brocrinat: Bumetanide; Hormone: Diethylstilbestrol; Progesterone; 17 hydroxy Chlorothiazide; Chlorthalidone; Clazolimine; Clorex progesterone; Medroxyprogesterone; Norgestrel; Nor olone; Ethacrynate Sodium: Ethacrynic Acid; Etozolin; 45 ethynodrel; Estradiol; Megestrol (Megace); Norethin Fenguizone; Furosemide; Hydrochlorothiazide; Isosor drone; Levonorgestrel; Ethyndiol; Ethinyl estradiol; bide; Mannitol; Mefruside; Ozolinone; Piretanide; Mestranol; Estrone: Equilin; 17 alpha dihydroequilin; Spiroxasone; Torsemide; Triamterene; Triflocin, Urea. equilenin; 17 alpha dihydroequilenin; 17 alpha estradiol; Doparminergic agent: Ibopamine. 17 beta estradiol; Leuprolide (lupron); Glucagon; Testo Ectoparasiticide: Nifluridide; Permethrin. 50 lactone; Clomiphene; Han menopausal gonadotropins; Emetic: Apomorphine Hydrochloride. Human chorionic gonadotropin: Urofollitropin; Bro Enzyme inhibitor: Acetohydroxamic Acid; Alrestatin mocriptine; Gonadorelin; Luteinizing hormone releasing Sodium; Aprotinin; Benazepril Hydrochloride; Benazep hormone and analogs; Gonadotropins; Danazol; Test rilat; Benurestat; Bromocriptine; Bromocriptine Mesy osterone; Dehydroepiandrosterone; Androstenedione; late: Cilastatin Sodium; Flurofamide; Lergotrile; Lergot 55 Dihydroestosterone; Relaxin: Oxytocin; Vasopressin; Fol rile Mesylate; Levcycloserine; Libenzapril; Pentopril; liculostatin; Follicle regulatory protein; Gonadoctrinins; Pepstatin: Perindopril; Polignate Sodium; Sodium Amy Oocyte maturation inhibitor; Insulin growth factor; Fol losulfate; Sorbinil; Spirapril Hydrochloride: Spiraprilat; licle Stimulating Hormone; Luteinizing hormone; TamoX Taleranol; Teprotide; Tolfamide; Zofenopril Calcium. ifen; Corticorelin Ovine Triffutate; Cosyntropin: Estrogen: Chlorotrianisene; Dienestrol; Diethylstilbestrol; 60 Metogest; Pituitary, Posterior; Seractide Acetate. Somal Diethylstilbestrol Diphosphate: Equilin; Estradiol; Estra apor, Somatrem: Somatropin; Somenopor, Somidobove. diol Cypionate; Estradiol Enanthate; Estradiol Undecy Hypocholesterolemic: Lifibrol. late; Estradiol Valerate; EstraZinol Hydrobromide: Estriol, Estrofurate; Estrogens, Conjugated; Estrogens, Hypoglycemic: DarglitaZone Sodium; Glimepiride. Esterified; Estrone; Estropipate; Ethinyl Estradiol; Fenes 65 Hypolipidemic: Azalanstat Dihydrochloride; Colestolone: trel; Mestranol; Nylestriol: Quinestrol. Surfomer; Xenalipin. Fibrinolytic: Anistreplase; Bisobrin Lactate; Brinolase. Hypotensive: Viprostol. US 7,199,151 B2 41 42 HMGCoA reductase inhibitors: Lovastatin (Mevacor); Sim NMDA antagonist: Selfotel. vastatin (Zocor); Pravastatin (Pravachol); Fluvasatin (Le Non-hormonal sterol derivative: Pregnenolone Succinate. Scol). Oxytocic: Carboprost; Carboprost Methyl: Carboprost Immunizing agent: Antirabies Serum; Antivenin (Latrodec Tromethamine; Dinoprost; Dinoprost Tromethamine: tus mactans); Antivenin (Micrurus Fulvius); Antivenin 5 Dinoprostone; Ergonovine Maleate; Meteneprost; Meth (Crotalidae) Polyvalent; BCG Vaccine; Botulism Anti ylergonovine Maleate: Oxytocin; Sparteine Sulfate. toxin: Cholera Vaccine; Diphtheria Antitoxin; Diphtheria Plasminogen activator: Alteplase; Urokinase. Toxoid; Diphtheria Toxoid Adsorbed; Globulin, Immune; Platelet activating factor antagonist: Lexipafant. Hepatitis B Immune Globulin; Hepatitis B Virus Vaccine Platelet aggregation inhibitor: Acadesine; Beraprost; Bera Inactivated; Influenza Virus Vaccine; Measles Virus Vac 10 prost Sodium, Ciprostene Calcium; ItaZigrel, Lifarizine; cine Live: Meningococcal Polysaccharide Vaccine Group Oxagrelate. A; Meningococcal Polysaccharide Vaccine Group C; Post-stroke and post-head trauma treatment: Citicoline Mumps Virus Vaccine Live: Pertussis Immune Globulin; Sodium. Pertussis Vaccine; Pertussis Vaccine Adsorbed; Plague Potentiator: Pentostatin: Talopram Hydrochloride. Vaccine; Poliovirus Vaccine Inactivated; Poliovirus Vac 15 Progestin: Algestone Acetophenide; Amadinone Acetate; cine Live Oral; Rabies Immune Globulin; Rabies Vaccine; Anagestone Acetate; Chlormadinone Acetate; Cingestol; Rho(D) Immune Globulin; Rubella Virus Vaccine Live: Clogestone Acetate; Clomegestone Acetate; Desogestrel; Smallpox Vaccine; Tetanus Antitoxin; Tetanus Immune Dimethisterone; Dydrogesterone; Ethynerone; Ethyno Globulin; Tetanus Toxoid: Tetanus Toxoid Adsorbed; diol Diacetate; Etonogestrel; Flurogestone Acetate; Typhoid Vaccine; Yellow Fever vaccine; Vaccinia Gestaclone; Gestodene; Gestonorone Caproate; Immune Globulin; Varicella-Zoster Immune Globulin. Gestrinone; Haloprogesterone; Hydroxyprogesterone Immunomodulator: Dimepranol Acedoben; Imiquimod: Caproate; Levonorgestrel; Lynestrenol; Medrogestone; Interferon Beta-1b: Lisofylline: Mycophenolate Mofetil: Medroxyprogesterone Acetate; Methynodiol Diacetate; Prezatide Copper Acetate. Norethindrone; Norethindrone Acetate; Norethynodrel; Immunoregulator: Azarole; Fanetizole Mesylate; Frentizole; 25 Norgestimate; Norgestomet; Norgestrel; Oxogestone Oxamisole Hydrochloride; Ristianol Phosphate; Thymo Phenpropionate; Progesterone; Quingestanol Acetate; pentin; Tilomisole. Quingestrone; Tigestol. Immunostimulant: Loxoribine; Teceleukin. Prostaglandin: Cloprostenol Sodium; Fluprostenol Sodium; Immunosuppressant: Azathioprine; Azathioprine Sodium; Gemeprost; Prostalene; Sulprostone. Cyclosporine; Daltroban: Gusperimus Trihydrochloride; 30 Prostate growth inhibitor: Pentomone. Sirolimus; Tacrolimus. Prothyrotropin: Protirelin. Impotence therapy adjunct: Delequanine Hydrochloride. Psychotropic: Minaprine. Inhibitor: Acarbose; Atorvastatin Calcium; Benserazide; Pulmonary surface: Beractant; Colfosceril Palmitate. Brocresine; Carbidopa; Clavulanate Potassium; Radioactive agent: Fibrinogen I 125: Fludeoxyglucose F 18; DaZmegrel, Docebenone; Epoprostenol; Epoprostenol 35 Fluorodopa F 18; Insulin I 125; Insulin I 131; Iobenguane Sodium; Epristeride; Finasteride: Flurbiprofen Sodium; I 123: Iodipamide Sodium I 131; Iodoantipyrine I 131; Furegrelate Sodium; Lufironil; Miglitol; Orlistat; Pimage Iodocholesterol I 131; Iodohippurate Sodium I 123; dine Hydrochloride: Pirmagrel; Ponalrestat; Ridogrel; Iodohippurate Sodium I 125 Iodohippurate Sodium I 131; Sulbactam BenZathine; Sulbactam Pivoxil; Sulbactam Iodopyriacet I 125; Iodopyracet I 131; Iofetamine Hydro Sodium; Suronacrine Maleate; Tazobactam; Tazobactam 40 chloride I 123: Iomethin I125; Iomethin I 131; Iothala Sodium; Ticlopidine Hydrochloride; Tirilazad Mesylate: mate Sodium I 125; Iothalamate Sodium I 131 Iotyrosine Tolrestat; Velnacrine Maleate; Zifrosilone; Zileuton. I 131; Liothyronine I 125; Liothyronine I 131: Merisoprol Keratolytic: Alcloxa; Aldioxa; Benzoyl Peroxide; Diben Acetate Hg 197; Merisoprol Acetate Hg 203; Merisoprol Zothiophene; Etarotene; Isotretinoin; Motretinide; Picot Hg 197; Selenomethionine Se 75; Technetium Tc 99m rin Diolamine; Resorcinol; Resorcinol Monoacetate; Sali 45 Antimony Trisulfide Colloid; Technetium Tc 99m Bici cylic Acid, Sumarotene; Tazarotene; Tetroquinone; sate; Technetium Tc 99m Disofenin; Technetium Tc 99m Tretinoin. Etidronate; Technetium Tc 99m Exametazime; Techne LHRH agonist: Deslorelin; Goserelin; Histrelin; Lutrelin tium Tc 99m Furifosmin, Technetiumn Tc 99m Glu Acetate; Nafarelin Acetate. ceptate; Technetium Tc 99m Lidofenin; Technetium Tc Liver disorder treatment: Malotilate. 50 99m Mebrofenin; Technetium Tc 99m Medronate; Tech Luteolysin: Fenprostalene. netium Tc 99m Medronate Disodium; Technetium Tc 99m Memory adjuvant: Dimoxamine Hydrochloride: Ribaminol. Mertiatide; Technetium Tc 99m Oxidronate; Technetium Mental performance enhancer: Aniracetam. Tc 99m Pentetate; Technetium Tc 99m Pentetate Calcium Mood regulator: Fengabine. Trisodium; Technetium Tc 99m Sestamibi; Technetium Tc Mucolytic: Acetylcysteine; Carbocysteine; Domiodol. 55 99m Siboroxime; Technetium Tc 99m Succimer; Techne Mucosal Protective agents: Misoprostol (Cytotec). tium Tc 99m Sulfur Colloid; Technetium Tc 99m Mydriatic: Berefrine. Teboroxime; Technetium Tc 99m Tetrofosmin, Techne Nasal decongestant: Nemazoline Hydrochloride; Pseu tium Tc 99m Tiatide; Thyroxine I 125; Thyroxine I 131: doephedrine Polistirex. Tolpovidone I 131; Triolein I 125: Triolein I 131. Neuroleptic: Duoperone Furnarate; Risperidone. 60 Regulator: Calcifediol; Calcitonin; Calcitriol: Clodronic Neuromuscular blocking agent: Atracurium Besylate: Cisa Acid; Dihydrotachysterol: Etidronic Acid; Oxidronic tracurium Besylate; Doxacurium Chloride; Gallamine Acid, Piridronate Sodium; Risedronate Sodium; Secalcif Triethiodide; Metocurine Iodide; Mivacurium Chloride; erol. Pancuronium Bromide; Pipecuronium Bromide: Rocuro Relaxant: Adiphenine Hydrochloride; Alcuronium Chloride: nium Bromide: Succinylcholine Chloride; Tubocurarine 65 Aminophylline: AZumolene Sodium; Baclofen; Benzoc Chloride; Vecuronium Bromide. tamine Hydrochloride; Carisoprodol; Chlorphenesin Car Neuroprotective: Dizocilpine Maleate. bamate; ChlorZoxazone; Cinflumide: Cinnamedrine; US 7,199,151 B2 43 44 Clodanolene; Cycloberzaprine Hydrochloride; Dant tabanate; Pirenperone; Ripazepam, Rolipram; rolene; Dantrolene Sodium; Fenalamide: Fenyripol Sulazepam; Taciamine Hydrochloride; Temazepam; Tri Hydrochloride; Fetoxylate Hydrochloride: Flavoxate flubazam; Tybamate; Valnoctamide. Hydrochloride; Fletazepam; Flumetramide: Flurazepam Amyotrophic lateral Sclerosis agents: Riluzole. Hydrochloride: Hexafluorenium Bromide: Isomylamine Cerebral ischemia agents: Dextrorphan Hydrochloride. Hydrochloride; Lorbamate; Mebeverine Hydrochloride; Paget’s disease agents: Tiluldronate Disodium. Mesuprine Hydrochloride; Metaxalone; Methocarbamol; Unstable angina agents: Tirofiban Hydrochloride. Methixene Hydrochloride; Nafomine Malate; Nelleza Uricosuric: BenZbromarone; Irtemazole; Probenecid; prine Maleate; Papaverine Hydrochloride; Pipoxolan Sulfinpyrazone. Hydrochloride: Quinctolate; Ritodrine; Ritodrine Hydro 10 Vasoconstrictor: Angiotensin Amide; Fely pressin; Methy chloride; Rolodine: Theophylline Sodium Glycinate; sergide; Methysergide Maleate. Thiphenamil Hydrochloride; Xilobam. Vasodilator: Alprostadil; AZaclorzine Hydrochloride; Bam Repartitioning agent: Cimaterol. ethan Sulfate: Bepridil Hydrochloride: Buterizine: Scabicide: Amitraz: Crotaniton. Cetiedil Citrate; Chromonar Hydrochloride; Clonitrate; Sclerosing agent: Ethanolamine Oleate; Morrhuate Sodium; 15 Diltiazem Hydrochloride; Dipyridamole; Droprenil Tribenoside. amine; Erythrity1 Tetranitrate; Felodipine: Flunarizine Sedative: Propiomazine. Hydrochloride; Fostedil; Hexobendine; Inositol Niaci Sedative-hypnotic: Allobarbital; Alonimid; Alprazolam; nate; Iproxamine Hydrochloride: Isosorbide Dinitrate; Amobarbital Sodium; Bentazepam; Brotizolam: Butabar Isosorbide Mononitrate; Isoxsuprine Hydrochloride; Lid bital; Butabarbital Sodium: Butalbital; Capuride; Car oflazine; Mefenidil; Mefenidil Fumarate; Mibefradil bocloral; Chloral Betaine; Chloral Hydrate; Chlordiazep Dihydrochloride; Mioflazine Hydrochloride: Mixidine: oxide Hydrochloride; Cloperidone Hydrochloride; Nafronyl Oxalate; Nicardipine Hydrochloride; Nicer Clorethate; Cyprazepam; Dexclamol Hydrochloride; goline; Nicorandil; Nicotinyl Alcohol; Nifedipine; Nimo Diazepam; Dichloralphenazone; Estazolam: Ethchlor dipine; Nisoldipine; Oxfenicine; Oxprenolol Hydrochlo Vynol, Etomidate, Fenobam; Flumitrazepam, Fosazepam, 25 ride; Pentaerythritol Tetranitrate; Pentoxifylline; Glutethimide; Halazeparn; Lorimetazepam, Mecloqua Pentrinitrol; Perhexiline Maleate; Pindolol; Pirsidomine; lone; Meprobamate; Methaqualone; Midaflur: Paralde Prenylamine: Propatyl Nitrate; Suloctidil; Terodiline hyde; Pentobarbital; Pentobarbital Sodium; Perlapine; Hydrochloride; Tipropidil Hydrochloride; Tolazoline Prazepam, Quazepam, Reclazepam, Roletamide; Seco Hydrochloride; Xanthinol Niacinate. barbital; Secobarbital Sodium; Suproclone: Thalidomide: 30 Vulnerary: Allantoin. Tracazolate; Trepipam Maleate; Triazolam; Tricetamide: Wound healing agent: ErSofermin. Triclofos Sodium; Trimetozine: Uldazepam; Zaleplon; Xanthine oxidase inhibitor: Allopurinol; Oxypurinol Zolazepam Hydrochloride; Zolpidem Tartrate. Other pharmaceutical agents include: 1-decpyrrolidinone; Selective adenosine A1 antagonist: Apaxifylline. 1-dodecpyrrolidinone; 16-alpha fluoroestradiol; 16-epi Serotonin antagonist: Altanserin Tartrate; Amesergide; Ket 35 estriol: 16alpha-gitoxin; 17alpha estradiol; 17beta estra anserin; Ritanserin. diol; 1alpha-hydroxyvitamin D2: 2'-nor-cGMP; 20-epi-1, Serotonin inhibitor: Cinanserin Hydrochloride: Fenclonine: 25 dihydroxyvitamin D3; 22-oxacalcitriol: 2CVV: Fonazine Mesylate; Xylamidine Tosylate. 3-isobutyl GABA; 6-FUDCA: 7-methoxytacrine; abam Serotonin receptor antagonist: Tropanserin Hydrochloride. ectin; abanoquil; abecarnil; abiraterone; acadesine; acam Steroid: Dexamethasone Acefurate; Mometasone Furoate. 40 prosate; acarbose; aceclofenac; acemannan; acetomepre Stimulant: Amfonelic Acid; Amphetamine Sulfate; Ampy genol; acetyl-L-carnitine; acetylcysteine, N-: zine Sulfate; Arbutamine Hydrochloride; Azabon; Caf acetylmethadol; acifran; acipimox; acitemate; acitretin: feine; Ceruletide; Ceruletide Diethylamine: Cisapride; aclarubicin, aclatonium; napadisilate; aconiazide; acriv Dazopride Fumarate; Dextroamphetamine; Dextroam astinet; adafenoxate; adapalene; adatanserin; adecypenol; phetamine Sulfate; Difluanine Hydrochloride; Dimefline 45 adefovir dipivoxil; adelmidrol; ademetionine; adina Hydrochloride; Doxapram Hydrochloride; Etryptamine Zolam; adiposin; adoZelesin; adrafinil; alacepril; aladap Acetate; Ethamivan: Fenethylline Hydrochloride: Fluba cin; alaptide; albendazole; albolabrin; aldecalmycin; nilate Hydrochloride: Flurothyl; Histamine Phosphate: aldesleukin; alendronic acid; alentemol; alfacalcidol; Indriline Hydrochloride; Mefexamide: Methamphetamine alfuzosin; alglucerase; allinastine; alosetron; alpha Hydrochloride; Methylphenidate Hydrochloride; Pemo 50 idosone; alprostadil; altretamine; altromycin B; ambam line: Pyrovalerone Hydrochloride: Xamoterol: Xamoterol ustine; amelometaSone; ameSergide; amezinium metilsul Fumarate. fate; amfebutamone; amidox; amifloxacin; amifostine; Suppressant: Amflutizole; Colchicine; Tazofelone. amiodarone; amisulpride; amlexanox; amlodipine; amlo Symptomatic multiple Sclerosis: Fampridine. dipine; ampiroxicam, amrinone; amrubicin; amsacrine; Synergist: Proadifen Hydrochloride. 55 amylin; amythiamicin; anagrelide; anakinra; ananain; Thyroid hormone: Levothyroxine Sodium; Liothyronine anaritide; anastrozole; andrographolide; anordrin; apado Sodium; Liotrix. line; apafant; apaxifylline; aphidicolin glycinate: apra Thyroid inhibitor: Methimazole; Propylthiouracil. clonidine, aprosulate sodium; aptiganel; apurinic acid; Thyromimetic: Thyromedan Hydrochloride. aranidipine; arbekacin; arbidol; arbutamine; ardeparin Tranquilizer: Bromazepam; Buspirone Hydrochloride: 60 Sodium; arecatannin B1; argatroban; aripiprazol; aroti Chlordiazepoxide: Clazolam; Clobazam; Clorazepate nolol; asimadoline; aspalatone; asperfuran, aspoxicillin; Dipotassium; CloraZepate Monopotassium; Demoxepam, astemizole; asulacrine; atamestane; atenolol, S-: atevird Dexmedetomidine: Enciprazine Hydrochloride; Gepirone ine; atosiban; atovaquone; atpenin B; atrimustine; atri Hydrochloride; Hydroxyphenamate; Hydroxyzine Hydro nositol; aureobasidin A. azadirachtine; aZasetron; azaty chloride; Hydroxy Zine Pamoate; Ketazolam; Lorazepam, 65 rosine; azelaic acid; azelastine; azelnidipine; azimilide; Lorzafone, Loxapine; Loxapine Succinate; Medazepam azithromycin; azosemide; aztreonam, baccatin III; baco Hydrochloride; Nabilone; Nisobamate: Oxazepam; Pen side A: bacoside B; bactobolamine; balazipone: balhimy US 7,199,151 B2 45 46 cin; balofloxacin; balsalazide; bambuterol; baohuoside 1: cytidine; dimethyl prostaglandin A1: barnidipine; basifungin; batebulast; batimastat; beauveri dimethylhomospermine; dimiracetam; dioxamycin; cin; becaplermin; becliconazole; befloxatone; belfosdil; diphency prone; diphenyl spiromustine; diprafenone; bellenamine; benflumetol; benidipine; benzisoxazole; dipropylnorspermine; dirithromycin; discodermolide; dis benzochlorins; benzoidazoxan; benzoylstaurosporine; ulfiram; ditekiren; docarpamine; docosanol, 1-, dolfetilide; benztropine; bepridil; beractant; beraprost; berlafenone; dolasetron; domitroban; dopexamine; dorZolamide; dos bertosamil: besipirdine; beta-alethine; betaclamycin B; malfate; dotarizine: doxacurium chloride: doxazosin; betamipron; betaxolol; betulinic acid; bevantolol; doxifluridine: doxofylline; draculin; draflazine; drolox bicalutamide: bifemelane; bimakalim, bimithil; bino ifene; dronabinol; drosperidone; drotaverine acephylli spirone; bioxalomycin alpha2; biriperone; bis-benzimida 10 nate; droxicam; ebiratide; ebrotidine; ebselen; ecabapide: Zole A, bis-benzimidazole B; bisantrene; bisaramil; ecabet, ecadotril; ecdlisteron; echicetin; echistatin; eco bisaziridinylspermine; bisnafide; bisoprolol; bistramide mustine; ecteinascidin 722; ecteinascidin 729; ecteinas D; bistramide K: bistratene A: boldine; bopindolol; brefel cidin 743; edaravone; edelfosine; edobacomab: edrecolo din; breflate; brimonidine; bromfenac; bromperidol; mab; efegatran; eflornithine; efonidipine; egualen; bropirimine; bucindolol; budesonide; budipine; budoti 15 elcatonin; eletriptan; elgodipine; eliprodil, eltenac; tane; bunaprolast; bunaZosin; butenafine; buthionine Sul emakalim, emedastine; emiglitate; emitefur, emoctakin; foXimine; butiXocort propionate; cadexomer iodine, cal enadoline hydrochloride; enalapril; enazadrem, englita anolide A, calcipotriol, calphostin C; camonagrel; Zone; enlimomab, enoxacin; enoxaparin Sodium; enoxi candesartan; candesartan cilexetil, candoXatril; candoxat mone: entacapone: enterostatin: epoprostenol; rilat, capecitabine; capromab, capsaicin; captopril; carba epoxymexrenone; epristeride, eprosartan; eptastigmine; Zomycin C; carbetocin, carbovir, carboxamide-amino erdosteine; ersentilide; ersofermin; erythritol; esuprone: triazole; carboxyamidotriazole; carboxymethylated beta etanidazole; etanterol; ethacizin; ethinylestradiol; eti 1,3-glucan; carperitide; carteolol, carumonam, carvedilol; Zolam: etodolac, etoposide phosphate; etrabamine; ever carvotroline; carZelesin; castanospermine; cebaracetam, ninomicin; examorelin; exemestane; fadrozole; faeriefun cecropin B; cefcapene pivoxil, cefdaloxime pentexiltosi 25 gin, famciclovir, fampridine; fantofarone; faropenem; late; cefdinir, cefditoren pivoxil, cefepime; cefetamet; fasidotril; fasudil; fazarabine; fedotozine; felbamate; cefetamet pivoxil, cefixime; cefluprenam; cefimetazole; fenofibrate; fenoldopam; fenretinide; fenspiride; fenti cefiminox, cefodizime, cefoselis, cefotetan, cefotiam: conazole; fepradinol; ferpifosate sodium; ferristene; fer cefotiam hexetil, cefoZopran; ce?pimizole; ce?piramide: rixan: ferumoxsil; fexofenadine; flavopiridol; flecainide; ce?pirome, cefpodoxime proxetil, cefprozil; cefsulodin; 30 flerobuterol; fleroxacin; flesinoxan; flezelastine; flobufen; cefteram; ceftibuten, ceftriaxone; cefuroxime axetil: flomoxef florfenicol; florifenine; flosatidil; fluasterone; celastrol; celikalim celiprolol; cepacidine A; cericlamine: fluconazole; fludarabine; flumazenil; flumecinol; flume cerivastatin: ceronapril; certoparin Sodium; cetiedil; ceti quine; flunarizine; fluocalcitriol; fluorodaunorunicin rizine; chloroorienticin A; chloroorienticin B; chloroqui hydrochloride; fluoxetine, R-; fluoxetine, S-; fluparoxan; noxaline Sulfonamide; cibenzoline; cicaprost; 35 flupirtine; flurbiprofen axetil: flurithromycin; fluticasone ciclesonide; cicletanine; cicloprolol; cidofovir; propionate; flutrimazole; fluvastatin: fluvoxamine; cilansetron; cilaZapril; cilnidipine; cilobradine; ciloStaZol; forasartan; forfenimex; formestane; formoterol; formot cimetropium bromide; cinitapride; cinolazepam, cioter erol, R.R-; fosfomycin; trometamol; fosinopril; fospheny onel; ciprofibrate, ciprofloxacin; ciprostene; cis-porphy toin; fostriecin, fotemustine, gabapentin; gadobenic acid; rin, cisapride; cisatracurium besilate, cistinexine; citalo 40 gadobutrol; gadodiamide: gadodiamide-EOB-DTPA; pram; citicoline; citreamicin alpha; cladribine; gadolinium texaphyrin, gadoteric acid, gadoteridol; clarithromycin, clausenamide; clebopride; clinafloxacin: gadoversetamide; galantamine; galdansetron; gallopamil; clobazam, clobetaSone butyrate; clodronic acid; clom galocitabine; gamolenic acid; ganirelix; gepirone; ethiazole; clopidogrel; clotrimazole; colestimide; colfos gestrinone; girisopam; glaspimod; glaucocalyxin A; ceril palmitate; collismycin A; collismycin B; combret 45 glutapyrone; glycopine; glycopril; granisetron; grepa astatin A4, complestatin; conagenin; contignasterol; floxacin; halichondrin B; halofantrine; halomon; halopre contortrostatin: cosalane; costatolide; cotinine; coumer done; hatomamicin; hatomarubigin A; hatomarubigin B; mycin A1, cucumariosid; curacin A; curdlan Sulfate; hatomarubigin C.; hatomarubigin D; ibogaine; ibopamine; curiosin; cyclazosin; cyclic HPMPC; cyclobenzaprine; ibudilast, illimaquinone, ilmofosine; illomastat; illoperi cyclobut A: cyclobut G; cyclocapron; cycloplatam, 50 done; iloprost; imidapril; imidazenil; indinavir, indolidan; cyclosin; cyclothialidine; cyclothiazomycin; cypemycin; indometacin farnesil; indometacin; tropine ester; cyproterone; cytarabine ocfosfate; cytochalasin B; daclix indoramin; inocoterone; inogatran; inolimomab; inter imab, dactimicin; daidzein; daidzin; dalfopristin; dalte feron alfa: interferon alfa-2a: interferon alfa-2b; inter parin Sodium; danaparoid; daphnodorin A; dapiprazole; feron alfa-N1; interferon alfa-n3; interferon beta; inter dapitant; darifenacin; darlucin A; darsidomine; ddUTP: 55 feron beta-1a1; interferon beta-1b; interferon gamma-1a: decitabine; deferiprone; deflazacort; dehydrodidemnin B; interferon gamma-1b; interferon omega; interferon, con dehydroepiandrosterone; delapril; deleguamine; delfapra sensus; interleukin-1; interleukin-1 alpha; interleukin-1 Zine; delmopinol; delphinidin; deoxypyridinoline; depro beta; interleukin-10; interleukin-11; interleukin-12; inter done; depsidomycin; deramciclane; dermatan Sulfate; leukin-12; interleukin-15; interleukin-2; interleukin-3; desflurane, desirudin; deslorelin; desmopressin; 60 interleukin-4; interleukin-5; interleukin-7; interleukin-8; desogestrel; desoxoamiodarone; detajmium bitartrate; iobenguane; iobitridol; iodoamiloride; iododoxorubicin; dexifosfamide; dexketoprofen; dexloxiglumide; dexme iofratol; iomeprol; iopentol; iopromide; iopyrol; iotriside; detomidine; dexpemedolac; dexraZOxane; dexSotalol; ioversol, ioxilan; ipazilide; IpdR; ipenoxazone; ipida dextrin 2-Sulphate; dexVerapamil, dezinamide; dezocine; crine; ipomeanol, 4-, ipriflavone; ipsapirone; irbesartan; diaziquone; diclofenac digolil; diclofenac potassium; dic 65 irinotecan, irloxacin; irsogladine, irtemazole; isalsteine; ranin; didemnin B; didox; dienogest; diethylhomosper isbogrel, isepamicin; isobengaZole; isofloxythepin; iso mine; diethylnorspermine; dihydrexidine; dihydro-5-aza homohalicondrin B; isopropyl unoprostone; isradipine; US 7,199,151 B2 47 48 itameline; itasetron; itopride; itraconazole, ketoprofen, pirodavir, pirodomast; piroXicam cinnamate; propager R-; ketoprofen, S-; ketorolac.; lacidipine; lactitol; lactivi manium; propentofylline; propionylcanitine, L- propi cin; laennec; lafutidine, lamellarin-N triacetate; lami ram; propiram-paracetamol; propiverine; propyl bis-ac fiban; lamivudine; lamotrigine; lanoconazole; lan ridone; prostaglandin J2, prostratin; protegrin: perisone; lanreotide; lanSoprazole; latanoprost; lateritin; protoSufloxacin; prulifloxacin; pyrazoloacridine; laurocapram; lazabemide; lemefloxacin; lemildipine; quaZepam; quetiapine; quiflapon; quinagolide; quinapril; leminoprazole; lenercept; lenograstim; lentinan Sulfate; quinfamide; quinupristin; raloxifene; raltitrexed; rama leptin; leptolstatin; lercanidipine; lerisetron; lesopitron; troban; ramripril; ramosetron; ranelic acid; ranitidine bis letraZuril; letrozole; leucomyzin; leuprorelin; levcro muth citrate; ranolazine; recainam, regavirumab, relaxin, makalim; levetiracetam; levobetaxolol; levobunolol; 10 levobupivacaine; levocabastine; levocarnitine; levodro repirinast; resinferatoxin; reticulon; reviparin Sodium; propizine; levofloxacin; levomoprolol; levonorgestrel; revizinone; ricasetron; ridogrel; rifabutin: rifapentine; levormeloxifene; levosimendan; levosulpiride; rifaximin, rilopiroX, riluzole; rimantadine, rimexolone; linotroban; linsidomine; lintitript; lintopride; liothyronine rimoprogin, riodipine; ripisartan; risedronic acid; rispen sodium; lirexapride; lisinopril; lobaplatin; lobucavir, 15 Zepine; risperidone; ritanserin; ritipenem; ritipenem lodoxamide, lombricine; lomefloxacin, lomerizine; lom acoxil, ritolukast; ritonavir, rizatriptan benzoate, rohituk etrexol; lonazolac, lonidamine; loracarbefloratadine; lor ine; rokitamycin; ropinirole; ropivacaine; roquinimex: glumide, lomoxicam, losartan; losigamone; losoxantrone; roXatidine; roXindole; roXithromycin; rubiginone B1; loteprednol; loviride; loxoribine; lubeluzole; lurtotecan; ruboxyl, rufloxacin; rupatidine; ruzadolane; Safingol; luteinizing hormone; lutetium; luZindole; lydicamycin; safironil; Saintopin; salbutamol, R-; Salmeterol; salme lysofylline; lysostaphin, magainin 2 amide; magnolol; terol, R-Salnacedin; Sameridine; Sampatrilat, Sanfetrinem; mallotochromene; mallotojaponin; malotilate; mangafo Saprisartan; sapropterin; Saquinavir, SarCNU, sarcophy dipir, manidipine; maniwamycin A; mannostatin A; tol A sargramostim; Sarpogrelate; Saruplase; Saterinone; manumycin E; manumycin F; mapinastine; marimastat; satigrel, Satumomab pendetide; selegiline; selenium thi Martek 8708; Martek 92211; masoprocol; maspin; mas 25 osemicarbazone; sematilide; semduramicin; Semotiadil; Setolide; meterelin; methoxatone; methylhistamine, R-al Semustine; sermorelin; Sertaconazole; sertindole; Sertra pha; methylinosine monophosphate; methylprednisolone line; Setiptiline; Sevirumab; sevoflurane; seZolamide; sil aceponate; methylprednisolone Suleptanate; metipamide: ipide; silteplase; simendan; simvastatin; sinitrodil; sinna metoclopramide; metoprolol, S-; metrifonate; mibefradil; bidol; sipatrigine; sirolimus; sizofiran, Somatomedin B; michellamine B; microcolin A; midodrine; mifepristone; 30 Somatomedin C; Somatrem; somatropin; Sonermin; miglitol; millacemide; milameline; mildronate; milnacip Sotalol; staurosporine; stavudine; stepronin; stipiamide: ran; milrinone; miltefosine; minaprine; miokamycin; stiripentol; stobadine; succibun; sucralfate; sulfasalazine: mipragoside; mirfentanil; mirimostim; mirtazapine; miso Sulfinosine; Sulfoxamine; Sulopenem; Sultamicillin; Sulto prostol; mitoguaZone; mitolactol, mitonafide; mitox pride; Sulukast, Sumatriptan; Symakalim, tandospirone; antrone; mivacurium chloride; mivaZerol; mixanpril; 35 tapgen; taprostene; tasosartan; taZanolast, tazarotene; mizolastine; mizoribine; moclobemide; modafinil; moex teicoplanin; telenZepine; tellurapyrylium; telmesteine; ipril; mofarotene; mofeZolac, molgramostim; mometa telmisartan; temocapril; temoporfin, temozolomide: Sone; montirelin; mopidamol; moracizine; mosapramine; tenidap; teniposide; tenosal; tenoxicam, tepirindole; tep mosapride; motilide; moxiraprine; moxonidine; nadi oxalin; terazosin; terbinafine; terfenadine; terflavoxate; floxacin; nadroparin calcium; nafadotride; nafamo.stat; 40 terguride; terlakiren; terlipressin; terodiline; tertatolol; nafarelin; naftopidil, naglivan; nagrestip; nalmefene; testosterone buciclate; tetrachlorodecaoxide; tetraZomine; naphterpin, napsagatran; naratriptan; nartograstim; thaliblastine; thalidomide; thiocoraline; thiofedrine; thi nasaruplase; nateplase; niperotidine: niravoline; nisamy omarinol; thioperamide; thyroid stimulating hormone; cin; nisin; niSoldipine; nitaZoxanide; nitecapone; nitren tiagabine; tianeptine; tiapafant; tibolone; ticlopidine; dipine; nitrendipine, S-: nitrofurantoin monohydrate; 45 tienoxolol; tilisolol; tilnoprofen arbamel; tiludronic acid; nitrullyn; nizatidine; ofloxacin, okicenone; olanzapine; tinzaparin sodium, tiotropium bromide; tipredane; tique olopatadine; olprinone; olsalazine, omeprazole; onapris side; tirandalydigin; tirapazamine; tirilazad; tirofiban: tone; ondansetron; ondansetron, R-; ontaZolast; oracin; tiropramide; top sentin; torasemide; toremifene; tosu otenZepad, oxaliplatin, oxamisole, Oxandrolone; floxacin; trafermin; trandolapril; traXanox; tretinoin, tre Oxaprozin, oxaunomycin; oXcarbazepine; oxiconazole; 50 tinoin tocoferil; triacetyluridine; tricaprilin; trichohyalin; oxiracetam; oxodipine; oZagrel; palauamine; palinavir, trichosanthin, alpha; triciribine; trientine; triflavin; tri palmitoylrhizoxin; pamaqueside; pamicogrel; pamidronic megestone; triptorelin; troglitaZone; trombodipine; tro acid; panamesine; panaxytriol; panipenem; panipenum; pisetron; trospectomycin; trovafloxacin; troVirdine; pannorin; panomifene; pantethine; pantoprazole; parabac tucaresol; tulobuterol; tylogenin, urapidil; uridine triph tin, parnaparin Sodium; paroxetine; parthenolide; paZel 55 osphate; Valaciclovir, Valproate magnesium; Valproate liptine; paZufloxacin; pefloxacin: pegaspargase; semisodium; Valsartan; vamicamide; Vanadeine; Vani peldesine; pemedolac, pemirolast, penciclovir, pentafu nolol; vapreotide; variolin B; velaresol; venlafaxine; side; pentamidine; pentamorphone; pentigetide; pentosan; Veramine; Verapamil, (S); Verdins; Veroxan; verteporfin; pentostatin: pentroZole; perflubron; perfosfamide; per Vesnarinone; vexibinol; vigabatrin; vinburnine citrate; golide; perindoprilat, peroSpirone; phenaridine; phenazi 60 Vinburnine resinate; Vinconate; Vinorelbine; Vinpocetine; nomycin; phenserine; phensuccinal; phentolamine mesi Vinpocetine citrate; Vintoperol; vinxaltine; Voriconazole; late; phenylacetate; phenylalanyl ketoconazole; Vorozole; Voxergolide; Xemilofiban, Ximoprofen; yan picenadol; picibanil; picroliv; picumeterol; pidotimod; gambin: Zabicipril; Zacopride; Zacopride, R-; Zafirlukast; pilocarpine hydrochloride; pilsicainide; pimagedine; Zalcitabine; Zaleplon; Zalospirone; Zaltoprofen, Zan pimilprost; pimobendan; pinacidil; pinocebrin; pioglita 65 amivir, Zankiren, Zanoterone; Zatebradine; Zatosetron; Zone; pipecuronium bromide: pirarubicin; piretanide; pir Zenarestat; Zeniplatin: Zifrosilone; Zilascorb; Zileuton; fenidone; piritrexim; pirlindole; pirmagrel, pirmenol; Zinostatin stimalamer, Ziprasidone; Zoledronic acid; US 7,199,151 B2 49 50 Zolmitriptan; Zolpidem; Zonisamide; Zopiclone; Zopi As used herein, a taxane is a molecule that possesses the clone, S-; Zopolrestat; Zotepine. following tricyclic carbon-atom connectivity network, The invention also embraces novel compositions of mat which may incorporate carbon-carbon multiple bonds, and ter that are covalent conjugates of DHA and pharmaceutical which through the involvement of carbon-atom-noncarbon agents that are noncentral nervous system active agents. atom bonds may include Substituents, functional groups, and Noncentral nervous system active agents have no function or additional rings. use within the central nervous system. Their only use is

outside of the central nervous system. Such agents include all drugs within certain of the foregoing categories and only Some drugs within other of the foregoing catagories. For 10 example, the entire catagory of blood glucose regulators have no use or function within the central nervous system. In contrast, certain anti-cancer agents are useful in the central nervous system whereas others are not. For example, central nervous system cancers are not hormone dependent, 15 and, therefore, an anti-cancer agent Such as Tamoxifen which treats certain hormone dependent cancers is not useful A taxoid is a molecule structurally related to a taxane in in the central nervous system. Those skilled in the art will be which the above taxane carbon-atom connectivity network is able to identify readily those catagories and/or members of altered, for example, by cleavage of one or more of the a catagory which are noncentral nervous system active carbocyclic rings, by deletion or addition of carbon Substitu agents. Among the foregoing compounds, the following ents, by connection of carbon atoms normally not bonded to catagories and/or members of the following catagories are each other, by disconnection of carbon atoms normally noncentral nervous system active agents: adrenocortical bonded to each other, or by some other reorganization of or steroid; adrenocortical Suppressant; aldosterone antagonist; adjustment to the taxane carbon-atom connectivity network, amino acid; anabolic; androgen; antagonist; anthelmintic; 25 but in which one or more structural features characteristic of anti-acne agent; anti-adrenergic; anti-allergic; anti-amebic; the taxane carbon-atom connectivity network are conserved. anti-androgen; anti-anemic; anti-anginal; anti-arthritic; anti The compounds useful in the invention may be delivered asthmatic; anti-atherosclerotic; antibacterial; anticholelithic; in the form of anti-cancer cocktails. An anti-cancer cocktail anticholelithogenic; anticholinergic; anticoagulant; anticoc is a mixture of any one of the compounds useful with this cidal; antidiabetic; antidiarrheal; antidiuretic; antidote; anti 30 estrogen; antifibrinolytic; antifungal; antiglaucoma agent; invention with another anti-cancer agent Such as an anti antihemophilic; antihemorrhagic; antihistamine; antihyper cancer drug, a cytokine, and/or supplementary potentiating lipidemia; antihyperlipoproteinemic; antihypertensive; anti agent(s). The use of cocktails in the treatment of cancer is routine. In this embodiment, a common administration thypotensive; anti-infective; anti-infective, topical; anti-in vehicle (e.g., pill, tablet, implant, injectable solution, etc.) flanmmatory; antikeratinizing agent; antimalarial; 35 antimicrobial; antimitotic; antimycotic, antineoplastic, would contain both the conjugate useful in this invention antineutropenic, antiparasitic; antiperistaltic, antipneu and the anti-cancer drug and/or Supplementary potentiating mocystic; antiproliferative; antiprostatic hypertrophy; anti agent. protozoal; antipruritic; antipsoriatic; antirheumatic; antis The compounds of the invention, when used in cocktails, chistosomal; antiseborrheic; antisecretory; antispasmodic; 40 are administered in therapeutically effective amounts. A antithrombotic; antitussive; anti-ulcerative; anti-urolithic; therapeutically effective amount will be determined by the antiviral; appetite Suppressant; benign prostatic hyperplasia parameters discussed below; but, in any event, is that therapy agent, bone resorption inhibitor, bronchodilator; amount which establishes a level of the drug(s) in the area of the tumor which is effective in inhibiting the tumor carbonic anhydrase inhibitor, cardiac depressant; cardiopro growth. tectant; cardiotonic; cardiovascular agent; choleretic; cho 45 linergic; cholinergic agonist, cholinesterase deactivator, When administered, the formulations of the invention are coccidiostat; diagnostic aid; diuretic; ectoparasiticide; applied in pharmaceutically acceptable amounts and in enzyme inhibitor, estrogen; fibrinolytic; free oxygen radical pharmaceutically acceptable compositions. Such prepara Scavenger; glucocorticoid; gonad-stimulating principle; hair tions may routinely contain salts, buffering agents, preser growth stimulant; hemostatic; hormone; hypocholester 50 Vatives, compatible carriers, and optionally other therapeutic olemic; hypoglycemic; hypolipidemic; hypotensive; immu ingredients. When used in medicine the salts should be nizing agent; immunomodulator; immunoregulator; immu pharmaceutically acceptable, but non-pharmaceutically nostimulant; immunosuppressant; impotence therapy acceptable salts may conveniently be used to prepare phar adjunct; inhibitor, keratolytic: LHRH agonist; liver disorder maceutically acceptable salts thereof and are not excluded treatment; luteolysin; mucolytic; mydriatic; nasal deconges 55 from the scope of the invention. Such pharmacologically tant; neuromuscular blocking agent; non-hormonal sterol and pharmaceutically acceptable salts include, but are not derivative; oxytocic; plasminogen activator, platelet activat limited to, those prepared from the following acids: hydro ing factor antagonist, platelet aggregation inhibitor, poten chloric, hydrobromic, Sulphuric, nitric, phosphoric, maleic, tiator, progestin, prostaglandin; prostate growth inhibitor; acetic, Salicylic, p-toluene Sulfonic, tartaric, citric, methane prothyrotropin; pulmonary Surface; radioactive agent; regu 60 Sulfonic, formic, malonic, succinic, naphthalene-2-sulfonic, lator, relaxant, repartitioning agent; Scabicide: Sclerosing and benzene Sulfonic. Also, pharmaceutically acceptable agent; selective adenosine A1 antagonist; Steroid; Suppres salts can be prepared as alkaline metal or alkaline earth salts, Sant; symptomatic multiple Sclerosis; synergist; thyroid hor Such as Sodium, potassium or calcium salts. mone; thyroid inhibitor; thyromimetic; amyotrophic lateral Suitable buffering agents include: acetic acid and a salt Sclerosis agents; Paget’s disease agents; unstable angina 65 (1–2% W/V); citric acid and a salt (1–3% W/V); boric acid agents; uricoSuric; vasoconstrictor; vasodilator, Vulnerary; and a salt (0.5–2.5% W/V); and phosphoric acid and a salt wound healing agent; Xanthine oxidase inhibitor. (0.82% W/V). US 7,199,151 B2 51 52 Suitable preservatives include benzalkonium chloride insufficient at such doses, even higher doses (or effective (0.003–0.03% W/V); chlorobutanol (0.3–0.9% W/V); para higher doses by a different, more localized delivery route) bens (0.01-0.25% W/V) and thimerosal (0.004–0.02% may be employed to the extent that patient tolerance permits. W/V). Continuous IV dosing over, for example 24 hours or mul The active compounds of the present invention may be a tiple doses per day are contemplated to achieve appropriate pharmaceutical composition having a therapeutically effec systemic levels of compounds. tive amount of a conjugate of the invention optionally A variety of administration routes are available. The included in a pharmaceutically-acceptable carrier. The term particular mode selected will depend of course, upon the “pharmaceutically-acceptable carrier as used herein means particular drug selected, the severity of the disease state one or more compatible solid or liquid filler, dilutants or 10 being treated and the dosage required for therapeutic effi encapsulating Substances which are suitable for administra cacy. The methods of this invention, generally speaking, tion to a human or other animal. The term “carrier denotes may be practiced using any mode of administration that is an organic or inorganic ingredient, natural or synthetic, with medically acceptable, meaning any mode that produces which the active ingredient is combined to facilitate the effective levels of the active compounds without causing application. The components of the pharmaceutical compo 15 clinically unacceptable adverse effects. Such modes of sitions are capable of being commingled with the molecules administration include oral, rectal, Sublingual, topical, nasal, of the present invention, and with each other, in a manner transdermal or parenteral routes. The term “parenteral such that there is no interaction which would substantially includes Subcutaneous, intravenous, intramuscular, or infu impair the desired pharmaceutical efficacy. Sion. Intravenous routes are preferred. Compositions Suitable for parenteral administration con The compositions may conveniently be presented in unit veniently comprise a sterile preparation of the conjugates of dosage form and may be prepared by any of the methods the invention. This preparation may be formulated according well known in the art of pharmacy. All methods include the to known methods. Formulations for taxanes can be found in step of bringing the conjugates of the invention into asso Chapter 9 of Taxol. Science and Applications, CRC Press, ciation with a carrier which constitutes one or more acces Inc., 2000 Corporate Boulevard, N.W., Boca Raton, Fla. 25 sory ingredients. In general, the compositions are prepared 33431. In general, Taxol has been formulated as a 6 mg/ml by uniformly and intimately bringing the compounds into cremophor EL (polyoxyethylated castor oil)/ethanol mix association with a liquid carrier, a finely divided solid ture, which is diluted to final volume with normal saline or carrier, or both, and then, if necessary, shaping the product. 5% dextrose. A 15 mg/ml solution of taxotere has been Compositions suitable for oral administration may be formulated in polysorbate 80 (polyoxyethylene sorbitanmo 30 presented as discrete units such as capsules, cachets, tablets, nooleate)/ethanol mixture, diluted with 5% dextrose. or lozenges, each containing a predetermined amount of the The sterile preparation thus may be a sterile solution or active compound. Other compositions include Suspensions Suspension in a non-toxic parenterally-acceptable diluent or in aqueous liquors or non-aqueous liquids Such as a syrup, solvent. In addition, sterile, fixed oils are conventionally an elixir, or an emulsion. employed as a solvent or Suspending medium. For this 35 purpose any bland fixed oil may be employed including Other delivery systems can include time-release, delayed synthetic mono or di-glycerides. In addition, fatty acids Such release or Sustained release delivery systems. Such systems as oleic acid find use in the preparation of injectables. can avoid repeated administrations of the active compounds Carrier formulations suitable for oral. Subcutaneous, intra of the invention, increasing convenience to the Subject and venous, intramuscular, etc. can be found in Remington's 40 the physician. Many types of release delivery systems are Pharmaceutical Sciences, Mack Publishing Company, Eas available and known to those of ordinary skill in the art. ton, Pa. They include polymer based systems such as polylactic and A subject as used herein means humans, primates, horses, polyglycolic acid, polyanhydrides and polycaprolactone; cows, pigs, sheep, goats, dogs, cats and rodents. nonpolymer systems that are lipids including sterols such as The conjugates of the invention are administered in 45 cholesterol, cholesterol esters and fatty acids or neutral fats effective amounts. An effective amount means that amount Such as mono-, di and triglycerides; hydrogel release sys necessary to delay the onset of inhibit the progression of tems; Silastic systems; peptide based systems; wax coatings, halt altogether the onset or progression of or diagnose the compressed tablets using conventional binders and excipi particular condition being treated. In general, an effective ents, partially fused implants and the like. In addition, a amount for treating cancer will be that amount necessary to 50 pump-based hardware delivery system can be used. Some of inhibit mammalian cancer cell proliferation in-situ. When which are adapted for implantation. administered to a subject, effective amounts will depend, of A long-term Sustained release implant also may be used. course, on the particular condition being treated; the severity "Long-term' release, as used herein, means that the implant of the condition; individual patient parameters including is constructed and arranged to deliver therapeutic levels of age, physical condition, size and weight; concurrent treat 55 the active ingredient for at least 30 days, and preferably 60 ment; frequency of treatment; and the mode of administra days. Long-term Sustained release implants are well known tion. These factors are well known to those of ordinary skill to those of ordinary skill in the art and include some of the in the art and can be addressed with no more than routine release systems described above. Such implants can be experimentation. It is preferred, generally that a maximum particularly useful in treating Solid tumors by placing the dose be used, that is, the highest safe dose according to 60 implant near or directly within the tumor, thereby affecting Sound medical judgment. localized, high-doses of the compounds of the invention. Dosage may be adjusted appropriately to achieve desired The conjugates of the invention also are useful, in general, drug levels, locally or systemically. Generally, daily oral for treating mammalian cell proliferative disorders other doses of active compounds will be from about 0.01 mg/kg than cancer, including psoriasis, actinic keratosis, etc. They per day to 1000 mg/kg per day. It is expected that IV doses 65 further are useful in treating diabetes and its complications, in the range of about 1 to 1000 mg/m per day will be excess acid secretion, cardiovascular conditions involving effective. In the event that the response in a subject is cholesterol (e.g., hyperlipidemia and hypercholesterolemia), US 7,199,151 B2 53 54 diarrhea, ovarian diseases (e.g. endometriosis, ovarian cysts, 4. The pharmaceutical preparation of claim 1, wherein the etc.) and as contraceptive agents. agent is fluocalcitriol. Those skilled in the art will be able to recognize with no 5. The pharmaceutical preparation of claim 1, wherein the more than routine experimentation numerous equivalents to agent is calcipotriol. the specific products and processes described above. Such 5 6. The pharmaceutical preparation of claim 1, wherein the equivalents are intended to be included within the scope of agent is calcipotriene. the appended claims. 7. The pharmaceutical preparation of claim 1, wherein the The invention claimed is: agent is calcifediol. 1. A pharmaceutical preparation comprising: 8. The pharmaceutical preparation of claim 1, wherein the a covalent conjugate of cis-docosahexaenoic acid and an 10 agent is secalciferol. agent, and 9. The pharmaceutical preparation of claim 1, wherein the a pharmaceutically acceptable carrier, wherein the agent agent is dihydrotachysterol. is selected from the group consisting of calcitriol, 10. The pharmaceutical preparation of claim 1, wherein 22-oxacalcitriol, fluocalcitriol, calcipotriol, calcipot the agent is 20-epi-1.25 dihydroxyvitamin D3. riene, calcifediol, secalciferol, dihydrotachysterol, 15 20-epi-1.25 dihydroxyvitamin D3, 1 alpha-hydroxyvi 11. The pharmaceutical preparation of claim 1, wherein tamin D2, and alfacalcidol. the agent is 1 alpha-hydroxyvitamin D2. 2. The pharmaceutical preparation of claim 1, wherein the 12. The pharmaceutical preparation of claim 1, wherein agent is calcitriol. the agent is alfacalcidol. 3. The pharmaceutical preparation of claim 1, wherein the agent is 22-oxacalcitriol. k k k k k