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(12) Patent Application Publication (10) Pub. No.: US 2003/0087814 A1 Lederman (43) Pub US 20030087814A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0087814 A1 Lederman (43) Pub. Date: May 8, 2003 (54) COMPOSITIONS AND METHODS FOR Publication Classification INCREASING COMPLIANCE WITH THERAPES USING ALDEHYDE DEHYDROGENASE INHIBITORS AND (51) Int. Cl." ..................... A61K 38/13; A61K 31/7048; TREATING ALCOHOLISM A61K 31/137; A61K 31/545; A61K 31/445; A61K 31/353; (76) Inventor: Seth Lederman, New York, NY (US) A61K 31/13 Correspondence Address: (52) U.S. Cl. .............................. 514/11; 514/27; 514/649; Pillsbury Winthrop LLP 514/317; 514/456; 514/708; 1600 Tysons Boulevard 514/592; 514/659 McLean, VA 22102 (US) (21) Appl. No.: 10/287,153 (57) ABSTRACT (22)22) FileFilled: Nov.. 4, 2002 Compositions and methods for treating, preventing, or Related U.S. Application Data reducing alcoholism, in particular methods for increasing patient compliance with therapies that require the intake of (60) Provisional application No. 60/338,901, filed on Nov. an ALDH inhibitor comprising the Step of administering a 5, 2001. monoamine oxidase B inhibitor. US 2003/0O87814 A1 May 8, 2003 COMPOSITIONS AND METHODS FOR receive additional therapies, e.g., DEPO forms of disulfiram. INCREASING COMPLIANCE WITH THERAPES In fact, patient compliance is a significant problem with USING ALDEHYDE DEHYDROGENASE these types of therapies. INHIBITORS AND TREATING ALCOHOLISM 0008 Although multiple forms of ALDH exist. ALDH-I (also known as ALDH-2) and ALDH-II (also known as RELATED APPLICATIONS ALDH-1) are the major enzymes responsible for the oxida 0001. This patent application claims the benefit of the tion of acetaldehyde. ALDH-I has a higher affinity for filing date of U.S. Patent Application No. 60/338,901 filed acetaldehyde than ALDH-II, and is thought to be the primary on Nov. 5, 2001, the entire contents of which are hereby enzyme involved in alcohol detoxification Keung, W. M., et expressly incorporated by reference. al., Proc. Natl. Acad. Sci. USA 95:2198-2203 (1998)). The discovery that 50% of the Asian population carries a muta BACKGROUND OF THE INVENTION tion in ALDH-I that inactivates the enzyme, together with the low occurrence of alcohol abuse in this population 0002) 1. Field of the Invention supports the contention that it is this isozyme of ALDH that is primarily responsible for alcohol detoxification. Recent 0003. The present invention relates to compositions and studies also implicate ALDH-I in the metabolism of methods for increasing patient compliance with therapies monoamine neurotransmitters Such as Serotonin (5-HT) and comprising the administration of aldehyde dehydrogenase dopamine (DA)Keung, W. M., et al., Proc. Natl. Acad. Sci. inhibitors, and for preventing, ameliorating or treating alco holism. Such compositions and methods may be used to USA 95:21.98-2203 (1998)). facilitate alcohol cessation, and may comprise a combina 0009 Disulfiram, also known as tetraethylthioperoxydi tion of aldehyde dehydrogenase inhibitors and monoamine carbonic diamide, bis-diethylthiocarbamoyl disulfide, tetra oxidase inhibitors. ethylthiuram disulfide, CronetalTM, Abstenil TM, StopetylTM, ContrainTM, AntadixTM, AnietanolTM, ExhoranTM, ethyl thi 0004 2. Description of the Related Art urad, Antabuse TM, Etabuse TM, RO-sulfiram, AbstinylTM, Thi 0005 Alcohol is a commonly abused drug. According to uranide TM, EsperalTM, TetradineTM, NoxalTM, Tetraeti TM Swift, Supra), is a potent irreversible inhibitor of ALDH-II the Diagnostic and Statistical Manual of Mental Disorders and inhibits ALDH-I only slightly. Recent Studies Suggest (DSM-IV), problematic alcohol use is divided into alcohol that the inhibition of ALDH-I by disulfiram occurs indirectly abuse and alcohol dependence. via its metabolites, e.g., S-methyl-N,N-diethylthiocarbamate 0006 Alcohol abuse involves recurrent alcohol con sulfoxide (DETC-MeSO) Yourick et al., Alcohol 4:463 Sumption that negatively affects one's life, whereas alcohol (1987); Youricket al., Biochem. Pharmacol. 38:413 (1989); dependence includes alcohol abuse and additionally Symp Hart et al., Alcohol 7:165 (1990); Madan et al., Drug Metab. toms of tolerance and withdrawal McRae et al., “Alcohol Dispos. 23:1153-1162 (1995)). Ingestion of alcohol while and Substance Abuse,” In: Advances in the Pathophysiology taking disulfiram results in the accumulation of aldehydes, and Treatment of Psychiatric Disorders: Implications for which causes tachycardia, flushing, diaphoresis, dyspnea, Internal Medicine, 85(3):779-801 (2001); Swift, R. M., New nausea and vomiting (also known collectively as the disul England J. Med 340:1482–1490 (1999); Kick, S., Hospital firam or disulfiram-ethanol reaction). Practice 95-106 (1999). In 1997, the estimated lifetime 0010 Although disulfiram has been available in the prevalence for alcohol abuse was 9.4% and for alcohol United States for many decades, patients frequently have dependence was 14.1%, with men having Significantly difficulty complying with disulfiram treatment therapies. higher rates of dependence than women McRae et al., One reason for poor compliance is the lack of motivation for Supra). Alcohol abuse and dependence commonly lead to the patient to continue to take disulfiram, that is, other than other problems. Such as alcohol-related violence, motor Self-motivation (i.e., there is no positive reinforcement for vehicle accidents, and medical consequences of chronic taking disulfiram). Another reason is because of the discom alcohol ingestion including death McRae et al., Supra; fort that arises if the patientingests alcohol during disulfiram Swift, Supra). therapy McRae et al., Supra; Swift, R. M., Supra; Kick, S., 0007 One of the pharmacotherapies that have been Sug Supra). In fact, disulfiram has not proven to be useful in gested for treating alcoholism, including facilitating alcohol maintaining long-term Sobriety Kick, Supra). cessation, is the administration of agents that inhibiting the 0011 Coprine (N5-(hydroxycyclopropyl)-L-glutamine) enzyme aldehyde dehydrogenase (ALDH), an enzyme has been shown to inhibit ALDH via its active metabolite, involved in the removal of acetaldehyde, a toxic metabolite 1-aminocyclopropanol (ACP). U.S. Pat. No. 4,076,840 of alcohol. Examples of ALDH inhibitors include, e.g., describes the Synthesis and use of cyclopropylbenzamides, disulfiram, coprine, cyanamide, 1-aminocyclopropanol including coprine, for the treatment of alcoholism. In rat (ACP), daidzin, cephalosporins, antidiabetic Sulfonyl ureas, Studies, coprine effectively Suppressed ethanol consumption, metronidazole, and any of their metabolites or analogs exhibiting ALDH-inhibiting activity including, e.g., S-me and was shown to be a more potent inhibitor of ALDH as thyl N,N-diethyldithiocarbamate, S-methyl N,N-dieth compared to disulfiram Sinclair et al., Adv. Exp. Med. Biol. yldithiocarbamate sulfoxide, and S-methyl N,N-diethylthio 132:481-487 (1980); U.S. Pat. No. 4,076,840). carbamate Sulfoxide. Patients who consume Such inhibitors 0012 Cyanamide has been described as an alcohol-sen of ALDH experience mild to severe discomfort if they ingest Sitizing agent that is less toxic than disulfiram Ferguson, alcohol. The efficacy of therapies using ALDH inhibitors Canad. M.A.J. 74:793-795 (1956); Reilly, Lancet 911-912 depends on the patient's own motivation to Self-administer (1976)). Although cyanamide is unable to inhibit either the ALDH inhibitors, e.g., oral forms of the inhibitors, or to ALDH-I or ALDH-II in vitro, a reactive product of cyana US 2003/0O87814 A1 May 8, 2003 mide catabolism inhibits both isozymes in Vivo, indicating comprising administering a therapeutically effective amount that cyanamide inhibits ALDH via a reactive species De of an ALDH inhibitor in combination with an MAOB Master et al., Biochem. Biophys. Res. Com. 107:1333-1339 inhibitor. (1982). Cyanamide has been used for treating alcoholism 0018. There is provided in one embodiment of the present but has not been approved in the U.S. Citrated calcium invention compositions and methods for increasing the rate cyanamide is marketed in other countries as Temposil', of continuous abstinence, delaying resumption of abuse or Dipsane TM and AbstemTM, and plain cyanamide is marketed dependence and/or preventing relapses in patients being as Colme TM in Spain See, U.S. Pat. No. 6,255,497). treated for alcoholism. 0013 Daidzin is a selective potent reversible inhibitor of ALDH-I, originally purified from an ancient Chinese herbal 0019. There is further provided a method for increasing treatment for alcohol abuse. Its analogs include daidZein-7- patient compliance with therapies that require Self-adminis O-o-carboxynonyl ether (deczein), daidZein-7-O-(o-car tration of an ALDH inhibitor comprising the step of admin boxyhexyl ether (hepzein), daidzein-7-O-o-carboxypen istering a therapeutically effective amount of a MAOB tyl ether (heXZein), daidzein, puerarin, and inhibitor. dicarboxymethyl-daidzein Keung, Chemico-Bio. Int. 130 0020. According to one embodiment of the invention, the 132:919-930 (2001)). U.S. Pat. Nos. 5,204,369; 5,886,028; patient to be treated Suffers from a disease requiring treat 6,121,010; and 6,255,497 describe methods for treating ment with an ALDH inhibitor and consumes or can consume alcohol dependence or abuse using these compounds. alcohol during therapy. The therapy does not involve forcing 0.014. One of the major problems associated with thera the patient to intake alcohol as part of the treatment. Accord pies using ALDH inhibitors is ensuring
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