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 patient compliance ing to one preferred embodiment of this invention, the with the regimen. According to applicant's knowledge, there patient to be treated is Suffering from alcoholism. have been no teachings that Suggest pharmacotherapies that 0021. A composition according to the latter embodiment adequately address this problem. For example, WO of the invention comprises an MAOB inhibitor and an 99/21540 describes the administration of disulfiram in com ALDH inhibitor. The ALDH inhibitor may inhibit ALDH-I. bination with compounds that bind to the D1 and/or D5 The ALDH inhibitor may be, e.g., disulfiram, coprine, receptors and mimic dopamine to reduce craving for addic cyanamide, 1-aminocyclopropanol (ACP), daidzin, cepha tive Substances in mammals. However, WO 99/21540 does losporins, antidiabetic Sulfonyl ureas, metronidazole, or any not Suggest pharmacotherapy for ensuring patient compli of their metabolites or analogs exhibiting ALDH-inhibiting ance with the regimen, which is important for the Success of activity including, e.g., S-methyl N,N-diethyldithiocarbam the treatment. ate, S-methyl N,N-diethyldithiocarbamate Sulfoxide, or 0.015. Another pharmacotherapy that has been suggested S-methyl N,N-diethylthiocarbamate sulfoxide. In a more for treating alcoholism involves the inhibition of monoam preferred embodiment, the ALDH inhibitor is disulfiram or ine oxidases (MAOs). MAOs catalyze the oxidation of a an ALDH-inhibiting metabolite thereof. According to one variety of monoamines, including epinephrine, norepineph preferred embodiment, the amount of disulfiram or an rine, Serotonin and dopamine. MAOS are iron containing ALDH-inhibiting metabolite thereof administered is 500 mg enzymes that exist as two isozymes A (MAOA) and B per day. (MAOB). Various publications have described treatments 0022. In one embodiment, the MAOB inhibitor is, e.g., for alcoholism using MAOB inhibitors e.g., WO92/21333, Selegiline, pargyline, desmethylselegiline, rasagiline R(+) WO 96/37199). WO 96/35425 discusses a treatment for N-propargyl-laminoindan, 3-N-phenylacetylamino-2,5-pi alcoholism using a selective MAOB inhibitor in combina peridinedione or caroxyaZone. In a more preferred embodi tion with a partial agonist of the 5-TH1A receptor. WO ment, the MAOB inhibitor is selegiline. According to one 00/71109 discusses a treatment for alcohol withdrawal preferred embodiment, the amount of Selegiline adminis symptoms using the MAOB inhibitor desmethylselegiline in tered is 15 mg or leSS per day. combination with a Second drug that treats alcohol with drawal symptoms. U.S. Pat. No. 6,239,181 describes meth DETAILED DESCRIPTION OF THE ods for alleviating Symptoms associated with alcoholic INVENTION neuropathy by administering the MAOB inhibitor, sel egiline. However, none of the above references teach or 0023. An MAOB inhibitor according to this invention is Suggest the use of MAOB inhibitors in therapies using a compound that inhibits MAOB but causes much less or no ALDH inhibitors. Moreover, none of these references teach inhibition of MAOA activity, or a compound that selectively that MAOB inhibitors have a sustained effect on ensuring inhibits MAOB (e.g., within a particular dosage range). patient compliance with other therapies. Hereinafter, the activity of an MAOB inhibitor as used according to this invention will be referred to as “selective 0016. The present invention provides a solution for the MAOB inhibitor activity.” deficiencies in traditional therapies using ALDH inhibitors to Stop, prevent or reduce recidivism, thus, promoting com 0024. In one embodiment, the MAOB inhibitor is pliance. The present invention also provides unexpectedly Selected from the group consisting of Selegiline (JumeXCE), Jumexal(R) Carbex(R), Eldepryl(R), Movergan(R); Aptapryl(R), new and better compositions and methods for treating dis Anipryl(R); Eldeprine(R); Plurimen(R), desmethylselegiline, eases that require the self-administration of an ALDH inhibi pargyline (Eudatin(R), Supirdyl(R), Eutonyl(R) U.S. Pat. No. tor. 3,155,584), rasagiline R(+)N-propargyl-laminoindan, SUMMARY OF THE INVENTION 3-N-phenylacetylamino-2,5-piperidinedione, caroxyaZone, 0.017. The present invention provides compositions and AGN-1135WO 92/21333), MDL 72195 WO92/21333), J methods for preventing, treating or reducing alcoholism 508 WO92/21333), lazabemide WO 00/45846), millace US 2003/0O87814 A1 May 8, 2003 mide WO 00/45846), IFO WO 00/45846), mofegiline 0029 ALDH inhibitors according to the invention are WO 00/45846), and 5-(4-(4,4,4-trifluorobutoxy)phenyl)-3- compounds that are capable of inhibiting the activity of one (2-methoxyethyl)-1,3,4-oxadiazol-2(3H)-one WO or more of the several isozymes of ALDH, e.g., ALDH-I and 00/45846). In another embodiment, prodrugs or metabolites ALDH-II. According to one embodiment, the ALDH is of the MAOB inhibitors are contemplated. Said metabolite involved in alcohol metabolism. ALDH inhibitors according should have substantially the same or better selective to this invention include, e.g., disulfiram, coprine, cyana MAOB inhibitor activity as its unmetabolized form. mide, 1-aminocyclopropanol (ACP), daidzin, cephalospor ins, antidiabetic Sulfonyl ureas, metronidazole, and any of 0025) A prodrug of a MAOB inhibitor is a derivatized their metabolites or analogs exhibiting ALDH-inhibiting MAOB inhibitor that is metabolized in vivo into the active activity. In another embodiment, the ALDH inhibitor is inhibitory agent. Prodrugs according to this invention pref disulfiram or an ALDH-inhibiting metabolite thereof. Such erably have Substantially the same or better therapeutic metabolites include, e.g., S-methyl N,N-diethyldithiocar value than the underivatized MAOB inhibitor. For example, bamate, S-methyl N,N-diethyldithiocarbamate sulfoxide, a prodrug useful according to this invention can improve the and S-methyl N,N-diethylthiocarbamate sulfoxide. penetration of the drug acroSS biological membranes leading to improved drug absorption; prolong duration of the action 0030) The term “ALDH inhibitor” according to the of the drug, e.g., Slow release of the parent drug from the invention or metabolite thereof, as used herein, includes prodrug and/or decrease first-pass metabolism of the drug, pharmaceutically acceptable Salts of those compounds. target the drug action; improve acqueous Solubility and Stability of the drug (e.g., intravenous preparations, eye 0031. The term “alcoholism” according to the invention brows etc.); improve topical drug delivery (e.g., dermal and includes alcohol abuse and alcohol dependence as described ocular drug delivery); improve the chemical and/or enzy below. matic stability of drugs (e.g., peptides); or decrease side 0032. The term “alcohol abuse” is defined in the Diag effects due to the drug. Methods for making prodrugs are nostic and Statistical Manual of Mental Disorders (DSM readily known in the art. IV). Alcohol abuse as a maladaptive pattern of alcohol use that leads to clinically significant impairment or distress. 0026. The term “MAOB inhibitor” according to this Symptoms include one or more of the following occurring invention or metabolite thereof, as used herein includes within a 12-month period: (1) recurrent alcohol use that pharmaceutically acceptable Salts of those compounds. results in a failure to fulfill major role obligations at work, Pharmaceutically acceptable salts of MAOB inhibitors use School or home; (2) recurrent alcohol use in physically ful according to the methods of this invention are Salts hazardous situations; (3) recurrent alcohol-related legal prepared from pharmaceutically acceptable reagents. In one problems; and (4) continued alcohol use despite having embodiment, Said pharmaceutically acceptable Salt is a persistent or recurrent Social or interpersonal problems hydrochloride salt. caused or exacerbated by the effects of the Substance 0.027 Methods known in the art for evaluating the activ McRae et al., Supra, Swift, R. M., Supra; Kick, S., Supra). ity of MAOB and MAOA can be used for selecting MAOB 0033 Alcohol dependence occurs when symptoms of inhibitors according to this invention. For example, blood abuse are accompanied by three or more of the following: samples can be drawn to determine platelet MAO activity (1) tolerance defined by either: (a) a need for markedly using radiolabelled benzylamine or phenylethylamine. (i.e., increased amounts of alcohol to achieve intoxication or evaluating MAOB inhibitory activity). Murphy, D. L., et desired effect, or (b) markedly diminished effect with con al., Psychopharm. 62:129-132 (1979); Murphy, D. L., et al., tinued use of the same amount of alcohol; (2) withdrawal Biochem. Med 16:254-265 (1976); all incorporated by ref manifested by either: (a) characteristic withdrawal Syn erence herein. In one embodiment, MAOB activity is drome for alcohol or (b) alcohol taken to relieve or avoid decreased greater than 80% compared to MAOB enzyme withdrawal Symptoms; (3) alcohol taken in larger amounts activity before treatment. In a preferred embodiment, over a longer period than as intended; (4) a persistent desire MAOB activity is decreased greater than 90% or 95% or unsuccessful efforts to reduce or control drinking; (5) compared to MAOB activity before treatment. much time spent in activities necessary to obtain alcohol, use 0028 MAOA inhibitory activity can, for example, be alcohol, or recover from its effects; (6) important Social, evaluated by measuring levels of 3-methoxy-4-hydroxyphe occupational, or recreational activities being given up or nylglycol (MHPG) or 5-hydroxyindoleacetic acid (5-HIAA) reduced because of drinking, and (7) continued use despite in the plasma of blood or in cerebral spinal fluid (CSF) by knowledge of having a persistent or recurrent physical or using gas chromatography-mass Spectroscopy (gc-ms). psychological problem caused or exacerbated by alcohol Murphy, D. L., et al., Clinical Pharmacology in Psychiatry, McRae et al., Supra, Swift, R. M., Supra; Kick, S., Supra). 3rd Series., Eds. Dahl, Gram, Paul, and Potter, Springer 0034 Alcohol abuse or dependence can also result in Verlag: 1987; Major, L. F., et al., J. Neurochem. 39:229-231 other Symptoms including dyspepsia or epigastric pain, (1979); Jimerson, D. C., et al., Biomed. Mass. Spectrom. headache, diarrhea, difficulty in Sleeping, fatigue, unex 8:256-259 (1981); all incorporated by reference herein). In plained weight loSS, apparent malnutrition, easy bruising, one embodiment, after administration of the MAOB inhibi increased mean corpuscular Volume, elevated transaminase tor, plasma MHPG levels should not be reduced lower than levels (especially an aspartate transaminase level greater 45% of pretreatment levels of plasma MHPG. In a preferred than of alanine transaminase), elevated y-glutamyl trans embodiment, after administration of the MAOB inhibitor, ferase levels, iron-deficiency anemia, hepatomegaly, jaun plasma MHPG or CSF 5-HIAA levels should not be reduced dice, Spider angiomata, ascites, and peripheral edema. more than 80% of pretreatment levels of MHPG or 5-HIAA Behavioral Symptoms associated with alcohol abuse or levels, respectively. dependence include absenteeism from work or School, US 2003/0O87814 A1 May 8, 2003 increasing irritability, difficulties with relationships, Verbal afternoon. In another preferred embodiment, a composition or physical abuse, and depression McRae et al., Supra; comprising about 125 mg of disulfiram and about 5 mg of Swift, R. M., Supra; Kick, S., Supra). Selegiline is administered twice a day, in the morning and at 0.035 Alcoholism is often diagnosed using question noon or late afternoon. naires, known to those of ordinary skill in the art, which are 0041) Selegiline can be administered twice a day, in the Structured to obtain information related to the Symptoms of morning and at noon or late afternoon. An initial daily alcohol abuse and/or dependence as outlined by the Diag non-oral dose can be at least about 0.01 mg per kg of body nostic and Statistical Manual of Mental Disorders (DSM weight, calculated on the basis of the free Secondary amine, IV). The most commonly used Screening test used for with progressively higher doses being employed depending detecting alcohol abuse or dependence is the CAGE ques upon the response to therapy. The final daily dose can be tionnaire Kick, S., Supra). Alcoholics Anonymous describes between about 0.05 mg/kg of body weight to about 0.15 another questionnaire. mg/kg of body weight (all Such doses being calculated in the basis of the free Secondary amine). 0036) A patient to be treated for, or protected against, the onset of alcoholism according to this invention can be a 0042. The present invention when employing selegiline human, including children and adults, who are Susceptible to is not limited to a particular form of Selegiline and the drug or are Suffering from alcoholism or who are being treated for can be used either as a free base or as a pharmaceutically alcoholism and are Susceptible to experiencing relapses. A acceptable acid addition Salt. In the latter case, the hydro patient who is having difficulty complying with, or is being chloride salt is preferred. However, other salts useful in the induced to comply with, treatments using ALDH inhibitors invention include those derived from organic and inorganic or their active metabolites according to this invention can be acids Such as, without limitation, hydrobromic acid, phos a human, including children and adults. phoric acid, Sulfuric acid, methane Sulfonic acid, acetic acid, tartaric acid, lactic acid, Succinic acid, citric acid, malic acid, 0037 Compositions according the present invention maleic acid, aconitic acid, Salicylic acid, thalic acid, comprise a pharmaceutically acceptable carrier together embonic acid, enanthic acid, and the like. with an ALDH inhibitor and an MAOB inhibitor. According to one embodiment, the ALDH inhibitor is disulfiram, or a 0043. The treating physician will know how to increase, metabolite or prodrug thereof. According to another embodi decrease or interrupt treatment based upon the patient's ment, the composition comprises 500 mg, 250 mg, 125 mg, response. Improvement for alcoholics or potentially relaps or 60 mg of disulfiram, or metabolite or prodrug thereof. ing alcoholics can be assessed by observing increased absti According to yet another embodiment, the MAOB inhibitor nence from consuming alcohol by the patient, following the is Selegiline, or a metabolite or prodrug thereof. According methods of this invention, as compared to patients where to a further embodiment, the composition comprises 15 mg therapy did not comprise the co-administration of a MAOB or less of Selegiline, or metabolite or prodrug thereof. inhibitor. Improvement in compliance with Self-administer ing ALDH inhibitors can be assessed by observing the 0.038. In a preferred embodiment, the composition com increased duration over which patients, following the meth prises 500 mg, 250 mg, 125 mg or 60 mg of disulfiram, or ods of this invention, take the ALDH inhibitor as compared metabolite or prodrug thereof, and 15 mg or less of Sel to patients whose therapy did not comprise the co-adminis egiline, or metabolite or prodrug thereof. In a more preferred tration of an MAOB inhibitor. embodiment, the composition comprises about 60 mg of disulfiram, or a metabolite or prodrug thereof, and about 2 0044 Any suitable route of administration can be mg of Selegiline, or a metabolite or prodrug thereof. employed for providing the patient with an effective dosage of a composition of this invention. For example, oral, 0.039 The effective dosage of a composition of the inven peroral, buccal, nasal, pulmonary, vaginal, lingual, Sublin tion administered to a patient is at least an amount required gual, rectal, parenteral, transdermal, intraocular, intrave to minimize, reduce or eliminate one or more Symptoms nous, intraarterial, intracardial intramuscular, intraperito asSociated with preventing or treating alcoholism, typically neal, intracutaneous, Subcutaneous, Sublingual, intranasal, one of the Symptoms discussed above. The magnitude of a intramuscular, and intrathecal administration and the like prophylactic or therapeutic dose of the composition of the can be employed as appropriate. The term parenteral as used invention in the treatment of a patient will vary with the herein includes Subcutaneous, intracutaneous, intravenous, Symptoms being exhibited, the Severity of the patient's intramuscular, intra-articular, intrasynovial, intrasternal, affliction, the desired degree of therapeutic response, the intrathecal, intralesional and intracranial injection or infu route of administration, and the concomitant therapies being Sion techniques. According to one preferred aspect of this administered. The dose and dose frequency will also vary invention, the route of administration is the oral route. according to the age, weight and response of the individual patient. Generally, however, treatment for alcoholism will be 004.5 The composition can be conveniently presented in ongoing, although the intensity of treatment can vary unit dosage form and prepared by any of the methods depending on the patient's condition and exposure to bio well-known in the art of pharmacy. Dosage forms can chemical and environmental Stimuli that can warrant a include tablets, Scored tablets, coated tablets, pills, caplets, variation on the treatment. Dosages can be administered in capsules (e.g., hard gelatin capsules), troches, dragees, pow a single or multiple dosage regimen. ders, aeroSols, Suppositories, parenterals, dispersions, Sus pensions, Solutions, transdermal patches and the like, includ 0040 According to one preferred embodiment of the ing Sustained release formulations well known in the art. In invention, the composition comprising 500 mg, 250 mg, 125 one preferred embodiment, the dosage form is a Scored mg or 60 mg of disulfiram and 15 mg or less Selegiline is tablet or a transdermal patch. U.S. Pat. No. 5,192,550, administered twice a day, in the morning and at noon or late incorporated herein by reference, describes a dosage form US 2003/0O87814 A1 May 8, 2003 for Selegiline comprising an outer wall with one or more improvement in Symptoms and whether the dosage of the pores, in which the wall is impermeable to Selegiline but composition of the invention needs to be adjusted. permeable to external fluids. This dosage form can have 0052 According to the methods of this invention, the applicability for oral, Sublingual or buccal administration. MAOB inhibitor can be included in the composition com 0046) The compositions of this invention can be orally prising the ALDH inhibitor. Alternatively, the MAOB administered in any orally acceptable dosage form includ inhibitor can be administered Simultaneously with the com ing, but not limited to, capsules, tablets, and aqueous SuS position comprising the ALDH inhibitor, or at any time pensions and Solutions. In the case of tablets for oral use, during the treatment of the patient with the ALDH inhibitor. carriers which are commonly used include lactose and corn Starch. Lubricating agents, Such as magnesium Stearate, are 0053. The various terms described above such as “thera also typically added. For oral administration in a capsule peutically effective amount,” are encompassed by the above form, useful diluents include lactose and dried corn Starch. described dosage amounts and dose frequency Schedule. When aqueous Suspensions are administered orally, the Generally, a therapeutically effective amount of an MAOB active ingredient (i.e., ALDH inhibitor and/or MAOB inhibitor is that amount at which MAOB is inhibited but inhibitor) is combined with emulsifying and Suspending MAOA exhibits slight or no reduction in activity in the agents. If desired, certain Sweetening and/or flavoring and/or patient. Slight reduction in activity preferably comprises leSS coloring agents can be added. than about 30% reduction in activity, more preferably less 0047 The compositions according to this invention can than about 20% reduction in activity, and yet more prefer be in the form of a Sterile injectable preparation, for ably less than about 10% reduction in activity. In one example, as a Sterile injectable aqueous or oleaginous SuS embodiment, the dosage of Selegiline is an amount equal to pension. This Suspension can be formulated according to or less than 15 mg per day. In another embodiment, the techniques known in the art using Suitable dispersing or dosage of pargyline is equal to or less than 30 mg/day. wetting agents (such as, for example, Tween 80) and Sus 0054 Throughout this specification, the word “comprise” pending agents. The Sterile injectable preparation can also be or variations Such as “comprises' or “comprising” will be a Sterile injectable Solution or Suspension in a non-toxic understood to imply the inclusion of a Stated integer or group parenterally-acceptable diluent or Solvent, for example, as a of integers but not the exclusion of any other integer or Solution in 1,3-butanediol. Among the acceptable vehicles group of integers. and Solvents that can be employed are mannitol, water, Ringer's Solution and isotonic Sodium chloride Solution. In Statement Regarding Preferred Embodiments addition, Sterile, fixed oils are conventionally employed as a 0.055 While the invention has been described with Solvent or Suspending medium. For this purpose, any bland respect to preferred embodiments, those skilled in the art fixed oil can be employed including Synthetic mono- or will readily appreciate that various changes and/or modifi diglycerides. Fatty acids, Such as oleic acid and its glyceride cations can be made to the invention without departing from derivatives are useful in the preparation of injectables, as are the Spirit or Scope of the invention as defined by the natural pharmaceutically-acceptable oils, Such as olive oil or appended claims. All documents cited herein are incorpo castor oil, especially in their polyoxyethylated versions. rated in their entirety herein. These oil Solutions or Suspensions can also contain a long chain alcohol diluent or dispersant such as Ph. Helv or a Similar alcohol. What is claimed is: 1. A composition comprising a monoamine oxidase B 0.048 Methods for making transdermal patches including (MAOB) inhibitor and an aldehyde dehydrogenase (ALDH) Selegiline transdermal patches have been described in the inhibitor. art. See e.g., U.S. Pat. Nos. 4,861,800; 4.868,218; 5,128, 2. The composition according to claim 1, wherein the 145; 5,190,763; and 5,242,950; and EP-A 404807, EP-A aldehyde dehydrogenase inhibitor inhibits the activity of 509761, EP-A593807, and EP-A5509761, all of which are aldehyde dehydrogenase-I. incorporated by reference herein. 3. The composition according to claim 1, wherein the 0049 Compositions of this invention can also be admin aldehyde dehydrogenase inhibitor is Selected from the group istered in the form of Suppositories for rectal administration. consisting: of disulfiram, coprine, cyanamide, 1-aminocy These compositions can be prepared by mixing a compound clopropanol, daidzin, cephalosporin, antidiabetic Sulfonyl of this invention with a Suitable non-irritating excipient urea, metronidazole, and metabolites or analogs thereof that which is Solid at room temperature but liquid at the rectal exhibit aldehyde dehydrogenase-inhibiting activity. temperature and therefore will melt in the rectum to release 4. The composition according to claim 1, wherein the the active components. Such materials include, but are not aldehyde dehydrogenase is disulfiram or a metabolite or limited to, cocoa butter, beeswax and polyethylene glycols. analog thereof that exhibits aldehyde dehydrogenase-inhib 0050. The compositions of this invention can be admin iting activity. istered by nasal aerosol or inhalation. Such compositions are 5. The composition according to claim 1, wherein the prepared according to techniques well-known in the art of composition comprises an amount of disulfiram Selected pharmaceutical formulation and can be prepared as Solutions from the group consisting of about 500 mg, about 250 mg, in Saline, employing benzyl alcohol or other Suitable pre about 125 mg and about 60 mg of disulfiram. Servatives, absorption promoters to enhance bioavailability, 6. The composition according to claim 1, wherein the fluorocarbons, and/or other Solubilizing or dispersing agents monoamine oxidase B inhibitor is Selected from the group known in the art. consisting of: Selegiline, pargyline, desmethylselegiline, 0051 Patients can be regularly evaluated by physicians, rasagiline, 3-N-phenylacetylamino-2,5-piperidinedione and e.g., once a week, to determine whether there has been an carOXyaZOne. US 2003/0O87814 A1 May 8, 2003

7. The composition according to of claim 1, wherein the 21. The method according to claim 10, wherein the patient monoamine oxidase inhibitor B is Selegiline. is a human. 8. The composition according to claim 7, wherein the 22. A method of increasing patient compliance with a composition comprises an amount of Selegiline Selected therapeutic regimen comprising Self-administration of an from the group consisting of about 15 mg or less, about 10 aldehyde dehydrogenase inhibitor, comprising the Step of mg or less, about 5 mg or less, about 2.5 or leSS and about administering to the patient a therapeutically effective 1 or leSS mg of Selegiline. amount of a monoamine oxidase B inhibitor. 9. The composition according to claim 1, wherein the 23. The method according to claim 22, wherein the patient monoamine oxidase inhibitor B is Selegiline and the alde Suffers with alcoholism. hyde dehydrogenase inhibitor is disulfiram. 24. The method according to claim 22, wherein the 10. A method for preventing, treating or reducing alco aldehyde dehydrogenase inhibitor inhibits aldehyde dehy holism in a patient in need for treatment thereof comprising drogenase-I. the Step of administering a therapeutically effective amount 25. The method according to claim 22, wherein the of a composition comprising a monoamine oxidase B inhibi aldehyde dehydrogenase inhibitor is Selected from the group tor and an aldehyde dehydrogenase inhibitor. consisting of disulfiram, coprine, cyanamide, 1-aminocy 11. The method of claim 10 wherein the aldehyde dehy clopropanol, daidzin, cephalosporin, antidiabetic Sulfonyl drogenase inhibitor inhibits aldehyde dehydrogenase-I. urea, metronidazole, and metabolites or analogs thereof 12. The method according to claim 10, wherein the exhibiting aldehyde dehydrogenase-inhibiting activity. aldehyde dehydrogenase inhibitor is Selected from the group 26. The method according to claim 22, wherein the consisting of disulfiram, coprine, cyanamide, 1-aminocy aldehyde dehydrogenase inhibitor is disulfiram, or a metabo clopropanol, daidzin, cephalosporin, antidiabetic Sulfonyl lite or analog thereof that exhibits aldehyde-dehydrogenase urea, metronidazole, and metabolites or analogs thereof inhibiting activity. exhibiting aldehyde dehydrogenase-inhibiting activity. 27. The method according to claim 26, wherein the 13. The method according to claim 10, wherein the amount of disulfiram administered to Said patient per day is aldehyde dehydrogenase inhibitor is disulfiram, or a metabo Selected from the group consisting of about 500 mg, about lite or analog thereof that exhibits aldehyde-dehydrogenase 250 mg, about 125 mg and about 60 mg. inhibiting activity. 28. The method according to claim 22, wherein the 14. The method according to claim 13, wherein the monoamine oxidase B inhibitor is Selected from the group amount of disulfiram administered to Said patient per day is consisting of: Selegiline, pargyline, desmethylselegiline, Selected from the group consisting of about 500 mg, about rasagiline, 3-N-phenylacetylamino-2,5-piperidinedione and 250 mg, about 125 mg and about 60 mg. carOXyaZOne. 15. The method according to claim 10, wherein the 29. The method according to claim 22, wherein the monoamine oxidase B inhibitor is Selected from the group consisting of: Selegiline, pargyline, desmethylselegiline, monoamine oxidase B inhibitor is Selegiline. 30. The method according to claim 29, wherein the rasagiline, 3-N-phenylacetylamino-2,5-piperidinedione and amount of Selegiline administered to Said patient per day is carOXyaZOne. Selected from the group consisting of 15 mg or less, 10 mg 16. The method according to claim 10, wherein the or less, 5 mg or less, 2.5 mg or less, and 1 mg or less of monoamine oxidase B inhibitor is Selegiline. Selegiline. 17. The method according to claim 16, wherein the amount of Selegiline administered to Said patient per day is 31. The method according to claim 22, wherein the Selected from the group consisting of 15 mg or less, 10 mg monoamine oxidase inhibitor B is Selegiline and the alde or less, 5 mg or less, 2.5 mg or less, and 1 mg or less of hyde dehydrogenase inhibitor is disulfiram. Selegiline. 32. The method according to claim 31, wherein the 18. The method according to claim 10, wherein the composition is administered orally, parentally or transder monoamine oxidase inhibitor B is Selegiline and the alde mally. hyde dehydrogenase inhibitor is disulfiram. 33. The method according to claim 32, wherein the 19. The method according to claim 10, wherein the composition is administered as a capsule, a tablet or a composition is administered orally, parentally or transder transdermal patch. mally. 34. The method according to claim 22, wherein the patient 20. The method according to claim 19, wherein the is a human. composition is administered as a capsule, a tablet or a transdermal patch.