US 2011 0065628A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0065628A1 Johnson et al. (43) Pub. Date: Mar. 17, 2011

(54) MEDICATION COMBINATIONS FOR THE Related U.S. Application Data TREATMENT OF ALCOHOLISMAND DRUG (60) Provisional application No. 60/966,265, filed on Aug. ADDCTION 27, 2007. Publication Classification Inventors: (75) Bankole A. Johnson, (51) Int. Cl. Charlottesville, VA (US); Nassima A63L/485 (2006.01) Ait-Daoud Tiouririne, A6II 3/55 (2006.01) Charlottesville, VA (US); Wendy J. A6II 3/55 (2006.01) Lynch, Charlottesville, VA (US) A 6LX 3/59 (2006.01) A63/496 (2006.01) A6II 3/56 (2006.01) (73) Assignee: UNIVERSITY OF VIRGINA A638/02 (2006.01) PATENT FOUNDATION, A6IP 25/30 (2006.01) Charlottesville, VA (US) A6IP 25/32 (2006.01) A6IP 25/36 (2006.01) A6IP3/04 (2006.01) (21) Appl. No.: 12/675,486 (52) U.S. Cl...... 514/1.1: 514/282: 514/215: 514/221; 514/259.41: 514/253.04: 514/253.07: 514/171 (22) PCT Fled: May 20, 2008 (57) ABSTRACT The present invention provides for the use of combinations of (86) PCT NO.: PCT/USO8/64232 drugs to treat addictive disorders. More specifically, the present invention provides compositions and methods for S371 (c)(1), treating disorders using combinations of drugs such as topi (2), (4) Date: Feb. 26, 2010 ramate, ondansetron, and naltrexone. Patent Application Publication Mar. 17, 2011 Sheet 1 of 15 US 2011/0065628A1

3

Mean :::: EEEE EEE

D',ay E::::::: :::: B

EEEE

:::: 1 EEE E::: ::

O EEE Plac Ond 1 Ond 4 Ond 16 Plac Ond 1 Ond 4 Ond 16

Start of double blind End of study Placebo (Plac) geton 1 ug/kg b.i.d. n Ondansetron 4 g/kg I Ondansetron 16 ug/kg b.i.d. b.i.d. (Ond 4) (Ond 16)

FIG. 1A Patent Application Publication Mar. 17, 2011 Sheet 2 of 15 US 2011/0065628A1

3 i

Mean :::: :::: I Drinks 1 EEE ::::

Day 2 EEE ::::

:::: S ::::: EEE: 1 :::: EEE :::: E :::: EEE

O EEE Plac Ond 1 Ond 4 Ond 16 Plac Ond 1 Ond 4 Ond 16

Start of double blind End of study Placebo (Plac) --: 25,Ondansetron 1 ug/kg b.i.d. Ondansetron 4 ug/kg I Ondansetron 16 g/kg b.i.d. b.i.d. (Ond 4) (Ond 16)

F.G. 1B Patent Application Publication Mar. 17, 2011 Sheet 3 of 15 US 2011/0065628A1

0.3 Mean 0.2 Log CDT 0.1 Ratio -0.0 -0. -0.2 -0.3 -0.4 Plac Ond 1 Ond 4 Ond 16 Ondansetron doses in lug/kg b.i.d.

Placebo (Plac) ndeton 1 g/kg b.i.d. Ondansetron 4 ug/kg Ondansetron 16 g/kg b.i.d. b.i.d. (Ond 4) (Ond 16)

FIG. 2A Patent Application Publication Mar. 17, 2011 Sheet 4 of 15 US 2011/0065628A1

Mean

CDT Ratio

Plac Ond 1 Ond 4 Ond 16 Ondansetron doses in g/kg b.i.d.

Placebo (Plac) Ondansetron 1 ug/kg b.i.d. (Ond 4) Ondansetron 4 g/kg H Ondansetron 16 ug/kg b.i.d. b.i.d. (Ond 4) (Ond 16)

FIG. 2B Patent Application Publication Mar. 17, 2011 Sheet 5 of 15 US 2011/0065628A1

6 O Group Mean -0- 0. Naltrexone 4O -- 0.3 Naltrexone -0- 1.0 Naltrexone 2O -- 3.0 Naltrexone

O

-2O

AQ S S S S) (S 19 QS QS SS AS S S AS as es 1S AS Time (10 minute time blocks)

FIG. 3 Patent Application Publication Mar. 17, 2011 Sheet 6 of 15 US 2011/0065628A1

1O 9 Mean 8

drinks/ 6 drinking 5 day 4 \ 3 2 1 O O 1 2 3 4 5 6 7 8 ? A Study Weeks Baseline Start of double-blind Ondansetron 4 u g/kg b.i.d. + Naltrexone 25 mg b.i.d. group -O-Placebo group

FIG. 4A Patent Application Publication Mar. 17, 2011 Sheet 7 of 15 US 2011/0065628A1

12

11 1O Mean 9 drinks/ 8 drinking 7 day 6 5 4 3 2 1. O O l 2 3 4 5 6 7 8 A A Study Weeks Baseline Start of double-blind

Ondansetron 4 u g/kg b.i.d. + Naltrexone 25 mg b.i.d. group -O-Placebo group

FIG. 4B Patent Application Publication Mar. 17, 2011 Sheet 8 of 15 US 2011/0065628A1

|| || || 1 1 2 3 4 5 6 7 8 9 1 0 1 1 12 Week of Study - A - Placebo -O-2.5 mg Rit - a 5.0 mg Rit

FIGS Patent Application Publication Mar. 17, 2011 Sheet 9 of 15 US 2011/0065628A1

Alcohol Dependent patients N=360

Early Onset Alcoholics Late Onset Alcoholics (EOA) N=180 (LOA) N=180 •Alcoholism onsets 25 years •Alcoholism onset >25 years •High family history of alcoholism •Less family history of alcoholism in 1st degree relatives in list degree relatives "Antisocial behaviors and symptoms •Few antisocial behaviors and symptoms

Cognitive Behavioral Therapy Cognitive Behavioral Therapy

Placebo Ondansetron Ondansetron -- Ondansetron Ondansetron Placebo Placebo Naltrexone Placebo Naltrexone Naltrexone Naltrexone Placebo N=45 N=45 N=45

F.G. 6 Patent Application Publication Mar. 17, 2011 Sheet 10 of 15 US 2011/0065628A1

Study

years

Subject Enrolled Completed

Effect of Naltrexone/Topiramate on Alcohol Consumption

o

E p e

Vehicle 5 Top 10 Top Nalf Naf10 Top 1 Nal -24 5 Top FIG. 8 Patent Application Publication Mar. 17, 2011 Sheet 11 of 15 US 2011/0065628A1

Efferents to Frontal Cortex

8 HippocampuS

Efferents to Hippocampus

5HT3 receptors 3- endorphins Serotonin 5HT3 receptor facilitated GABA interneurons Dopamine Afferent from the Hippocampus to the N. Accumbens Patent Application Publication Mar. 17, 2011 Sheet 12 of 15 US 2011/0065628A1

7

6 Ethanol intake 5 (-12%) (g/kg) w

3

2 1 2 3 4. 5 6 7 Session

FIG 10A

Ethanol intake (glkg)

Session

FIG 10B Patent Application Publication Mar. 17, 2011 Sheet 13 of 15 US 2011/0065628A1

6 (1%) Ethanol 5 W intake (g/kg) 4

3

2 1 2 3 4. 5 6 7 Session

FIG 10C

7 6 (17%) Ethanol intake 5 w (g/kg)

3

2 1 2 3 4. 5 6 7

Session

FIG 10D Patent Application Publication Mar. 17, 2011 Sheet 14 of 15 US 2011/0065628A1

7

6

Ethanol 5 - intake (g/kg)Ik 4. - (28%)

3 - W

Session

FIG 10E Patent Application Publication Mar. 17, 2011 Sheet 15 of 15 US 2011/0065628A1

Prefrontal cortex Arnygdala GLU Serotonin Lateral septum Cholinergic Modulatory Input Hippocampus. Excitatory input From Raphe. Nuclei From PPTg and LDT.g | ExcitatoryGU Input CB1R Enkephalin Dopamine inhibitory input (D1, D2, D3) From Nucleus Ya GABA Arcuatus Inhibitory Input

Neuron h GABA Neuron 5-HT3-R Receptors Mu a 3 GABA inhibitory Feedback N GABA Neuron REINFORCEENT Wentral Tegmental Area H (WTA) — H Nucleus(nACC) Accumbens —

FIG 11 US 2011/0065628 A1 Mar. 17, 2011

MEDICATION COMBINATIONS FOR THE targeted towards correcting or ameliorating the underlying TREATMENT OF ALCOHOLISMAND DRUG abnormalities. Because these abnormalities involve several ADDICTION neurotransmitters, combinations of medications targeting specific systems may yield better clinical outcomes than CROSS REFERENCE TO RELATED treatment of only one affected pathway would alone. Hence, APPLICATIONS obtaining optimal treatment matching combinations for vari 0001. This application is entitled to priority pursuant to 35 ous types of alcoholic remains an important research goal. U.S.C. S 119(e) to U.S. provisional patent application No. 0006 Alcohol abuse and dependence are widespread and 60/966,265, filed on Aug. 27, 2007. The entire disclosure of it is estimated that 14 million American adults abused alcohol the afore-mentioned patent application is incorporated herein or were dependent on it in 1992 and that approximately 10% by reference. of Americans will be affected by alcohol dependence some time during their lives. Alcohol dependence, characterized by STATEMENT REGARDING FEDERALLY the preoccupation with alcohol use, tolerance, and with SPONSORED RESEARCH ORDEVELOPMENT drawal, is a chronic disorder with genetic, psychosocial, and environmental factors influencing its development and mani 0002 This invention was made in part with United States festations. Studies have demonstrated the significance of Government support under National Institutes of Health opioids (i.e., beta-endorphin), dopamine (DA), serotonin Grant Nos. AAO12964 and AA13074. The United States Gov (5-HT), Y-amino-butyric acid (GABA), and glutamate for the ernment has certain rights in the invention. development and maintenance of alcohol dependence. To date, most pharmacotherapy trials have focused on single FIELD OF THE INVENTION pharmacological agents. However, because of the failure to 0003. The present invention relates generally to the use of find consistent results with these drug therapies, investigating combination therapies to treat addiction-related diseases and the efficacy of combining drugs that target multiple neu disorders and impulse control disorders, particularly alcohol rotransmitter systems or genes is perhaps more important to related diseases and disorders. the development of future pharmacotherapies for treatment of alcohol dependence and treatment of other addictive disor BACKGROUND ders and impulse control disorders. 0004 Neuroscientific advances have greatly increased the 0007 Various medications and behavioral therapy have understanding of the pharmaco-behavioral effects of various been used to treat alcohol dependence. The neuronal targets neurotransmitter systems in the acquisition and maintenance of alcohol include many neurotransmitter systems and the of alcohol dependence. Medications that interact either molecules participating in or regulating the systems, includ directly or indirectly with neurotransmitters that modulate ing GABA, glutamate, DA, opioids, and serotonin (for a cortico-mesolimbic dopamine (CMDA) neurons have been review see Johnson, 2004, Expert Opin. Pharmacother. 5:9: central to most pharmacological strategies in the last decade 1943-1955). (for reviews, see Wise and Bozarth, 1987, Psychol. Rev., 0008. Despite the number of studies performed in this 94:469-492; Hyman and Malenka, 2001, Nat. Rev. Neurosci. area, few drugs for alcohol dependence are approved in the 2:695-703: Koob, 2003, Alcohol Clin. Exp. Res., 27:232 U.S. The approved drugs are disulfiram, naltrexone, Vivit 243); and Weiss and Porrino, 2002, J. Neurosci., 22:3332 rex R/Vivitrol(R) (a long-acting depot formulation of naltrex 3337). The addictive effects of most abused drugs and alcohol one), and acamprosate. Disulfiram is an irreversible inhibitor are mediated through increased dopaminergic activity in the of aldehyde dehydrogenase leading to increased levels of cortico-mesolimbic system that originates in the Ventral teg acetaldehyde, a toxic intermediate in alcohol metabolism. mental area, relays in the nucleus accumbens, and sends Patients who take disulfiram and drink alcohol experience an forward profuse connections to the cortex and other higher increased dilation of arterial and capillary tone producing brain centers. Direct DA antagonists have failed to demon hypotension, nausea, vomiting, flushing, headache and pos strate therapeutic efficacy consistently, possibly because the sibly in some, worse symptoms. Therefore, the concept high degree of neuroadaptation that occurs with direct post behind the use of disulfiram is that the alcohol-dependent synaptic blockade mitigates against any long-standing thera individual associates drinking with unpleasant adverse events peutic effect (Johnson and Ait-Daoud, 2002, Psychopharma and, as a result, avoids further alcohol consumption. Never cology, 149:327-344: Kreek et al., 2002, Nat. Rev. Drug theless, recent research shows that disulfiram has limited Discov. 1:710-726. utility because compliance is low unless it is administered by 0005 Three major issues have promulgated scientific a partner or spouse. interest in the development of medicational adjuncts to psy 0009 Naltrexone's principal site of action is at the Lopioid chosocial or behavioral therapy for the treatment of alcohol receptors in the mesolimbic pathway, putatively blocking the ism. First, up to one-half of alcoholics relapse shortly after reinforcing effects of alcohol by decreasing DA release in the detoxification, psychosocial, or behavioral treatment. Sec nucleus accumbens (NAc). Studies using naltrexone report ond, advances in the neurosciences have implicated several that the opioid antagonist is more effective than placebo in target neurotransmitter systems such as those within the reducing craving and heavy drinking, and increasing the per mesocorticolimbic pathway which mediate some of alcohol's centage of non-drinking days, but does not necessarily rewarding effects associated with its abuse liability. Selective enhance abstinence. Although these studies Support the effi medications designed to oppose these neuronal systems may cacy of naltrexone, others report limited utility for the drug enhance the effectiveness of alcoholism treatments. Third, only when individuals were highly compliant or even not at Some alcoholics may possess biological abnormalities which all. predispose them to disease. These biologically-Vulnerable 0010 Acamprosate, a structural analogue of GABA, was alcoholics might benefit from specific adjunctive medication approved to promote abstinence in recently detoxified indi US 2011/0065628 A1 Mar. 17, 2011

viduals. Although the exact mechanism of action is unknown, a placebo-controlled trial, 271 participants were stratified the drug is thought to restore glutamatergic-mediated inhibi into EOA and LOA subtypes by 1, 4, and 16 g/kg twice-daily tory and excitatory neurotransmission in the NAc. Despite the doses ofondansetron compared with placebo (Johnson, 2000, important contributions these drugs make to alcohol treat J. Am. Med. Assoc., 284:963-971). Patients with EOA who ment, abstinence or even reduced heavy drinking levels still received ondansetron showed significant reductions in drink remain elusive for many. This suggests the need for discov ing (particularly those receiving 4 g/kg twice daily) com ering medications providing more efficacious treatments. pared with LOA across all groups. In another study, it was 0011 Serotonin (5-HT) dysfunction probably contributes shown that ondansetron treatment is more likely to be asso to the development of alcoholism. Serotonin's receptors con ciated with improved drinking outcomes among EOA com tribute to alcohol use in animals, as alcohol increases basal pared with LOA (Kranzler et al., (2003, Alcohol. Clin. Exp. levels of 5-HT affecting receptors. Of the seven distinct fami Res., 27:1150-1155). Ondansetron continues to be examined lies of 5-HT receptors, three are known to contribute to alco for individuals with early-onset alcoholism. hol dependence: 5-HT, receptors might be associated with 0016. The reasons for these differential effects are alcohol consumption and the development of tolerance; unknown; however, one hypothesis suggests that alcoholics 5-HT, receptors with reward; and 5-HT receptors with the with a biological predisposition have a dysregulation of sero development of reinforcement. Based on such evidence, sev tonergic function primarily associated with serotonin trans eral serotonergic drugs have been examined, but with incon porter (SERT) function (Johnson, 2000, Alcohol. Clin. Exp. sistent results. Presently only Sertraline and ondansetron (a Res. 24:1597-1601). The polymorphic variation of the SERT serotonin-3 (5-HT) antagonist) appear to show any promise (the 5'-HTTLPR) is hypothesized to be involved with the with certain subtypes of alcoholic patients and fluoxetine effectiveness of ondansetron and sertraline in EOA and LOA with depressed alcoholics (see Kenna, 2005, Drug Discovery alcohol-dependent individuals, respectively. Given that epi Today: Therapeutic Strategies, 2:1:71-78 and Johnson, 2000, demiologic studies demonstrate that alcohol dependence has Alcohol. Clin. Exp. Res., 24:1597-1601). an approximately 50-60% heritability, the prospect for posi 0012. The 5-HT receptor is involved in the expression of tive outcomes to drug therapy at least partly dependent on alcohol's rewarding effects. Behavioral pharmacological genetic predisposition in some alcoholics is strong. Recent studies show that many of alcohol's rewarding effects are studies have, therefore, attempted to delineate the genetic mediated by interactions between DA and 5-HT receptors in components associated with alcohol dependence. These find the midbrain and cortex. 5-HT receptors are densely distrib ings highlight the important role that 5-HT plays in alcohol uted in the terminals of mesocorticolimbic DA containing consumption, although drug trials using serotonergics have neurons, where they regulate DA release in these brain had difficulty delineating responders from non-responders. regions. These DA pathways, particularly those in the NAc, 0017 Animal studies suggest that fluctuating DA levels are critically involved in mediating the rewarding effects of contribute to craving leading in turn to relapse in abstinent abused substances including alcohol. Demonstration that alcoholics. Reward associated with alcohol cues manipulat 5-HT receptor blockade reduces DA activity, and therefore ing DA release by the mesolimbic pathway and positive the rewarding effects of abused drugs (including alcohol), symptoms of Schizophrenia seem to share similar dopamin comes from at least three different animal paradigms. 5-HT ergic dysfunction. Neuroleptics that regulate DA occupancy receptor antagonists: 1) attenuate hyperlocomotion in the rat at DRD2, possibly causing an up-regulation of DRD2, might induced by DA or ethanol injection into the nucleus accum be associated with reduced positive symptoms of schizophre bens; 2) inhibit DiMe-C7 (a neurokinin)-induced hyperloco nia and reduced substance use. motion, which is also attenuated by the DA antagonist, 0018 Haloperidol, tiapride, olanzapine, and clozapine fluiphenazine; and 3) decrease alcohol consumption in several have all demonstrated various degrees of efficacy reducing animal models and across different species. craving and alcohol consumption or increasing abstinence. 0013 Despite reductions in drinking in lab studies with Although they are theoretically interesting drugs to study, the animals and in human drinking sessions in which Subjects risks associated with the side effects of typical or atypical have been administered selective serotonin re-uptake inhibi neuroleptics have outweighed the benefits for using DA tors (SSRIs), most double-blind placebo-controlled studies antagonists as serious treatments for alcoholism. using SSRIs have not reduced drinking or any other measures 0019 Aripiprazole, an atypical neuroleptic, has few of the of alcohol dependency. Recent research however, Suggests limiting side effects associated with these related medica that because of the heterogeneity of the disease, perhaps tions. Aripiprazole is a partial dopamine agonist (PDA) with subtypes of alcoholics respond differently to SSRIs. mixed HT activity. As with other PDAs, aripiprazole has 0014 Animal studies demonstrated that the 5-HT recep a high affinity to bind to DA receptors but with low intrinsic tor facilitates some of the biochemical and behavioral effects activity, Subsequently acting as an antagonistoragonist under of alcohol through midbrain DA release. 5-HT, antagonists conditions of hyper- or hypodopaminergic availability, are consistently shown to suppress alcohol preference in ani respectively. Additionally, as a mixed HT receptor drug mal studies, with recent evidence suggesting the 5-HT aripiprazole has been proposed as a medication that may receptor Subunit requisite for 5-HT antagonist-induced reduce alcohol consumption. reductions in alcohol consumption. 0020 Nevertheless, extensive research on such medica 0015 Ondansetron, a 5-HT, receptorantagonist, has func tions as direct dopamine blocking agents has not proven to be tionally opposite effects to SSRIs and blocks serotonin ago useful as clinical treatment for alcohol or drug use related nism at the 5-HT, receptor. Ondansetron can be effective for disorders. This is probably because direct dopamine blocking early-onset alcoholics (EOA) but not late-onset alcoholics agents produce rapid neuroadaptation in the brain, thereby (LOA), where age of onset of alcoholism (younger versus reducing any early therapeutic gains. Furthermore, because older than 25 years old) is the basis for subtyping alcoholics of their propensity for adverse events, direct dopamine block (Johnson, 2000, Alcohol. Clin. Exp. Res., 24:1597-1601). In ing agents are not taken reliably by patients; hence limiting US 2011/0065628 A1 Mar. 17, 2011

their capacity to be effective as a treatment for alcohol or Med. Assoc., 295:2003-2017) combined pharmacotherapies Substance use, abuse, or dependence. (naltrexone and acamprosate) with behavioral therapy. How 0021 Midbrain and cortical DA pathways mediate alco ever, current evidence for the usefulness of combination phar hol's rewarding effects. Alcohol consumption increases macotherapy is lacking (Williams, 2005, Am. Fam. Physi GABA receptor activity which inhibits midbrain DA neurons cian, 72:9:1775-1780). Combination therapies are also being and facilitates DA neurotransmission. Non-N-methyl-D-as tested in an attempt to treat other addiction-related diseases partate (NMDA) glutamate antagonists oppose GABA activ and disorders. ity, thereby decreasing DA release. Topiramate (a GABA/ 0027. There is a long-felt need in the art for compositions glutamate modulator) and gabapentin are FDA-approved and methods useful for treating addiction-related diseases antiepileptics. Topiramate is thought to have multiple mecha and disorders. The present application satisfies this need. nisms of action, including enhanced GABA inhibition that results in decreased DA facilitation in the midbrain, antago SUMMARY OF THE INVENTION nism of kainate to activate the kainite or AMPA type glutamate receptor Subtypes, and inhibition of carbonic anhy 0028. The present invention, in one aspect, differs from drase Type II and IV isoenzymes (Johnson, 2004, Alcohol. prior art in that it discloses combinations of multiple medi Clin. Exp. Res., 28:1137-1144). Gabapentin reduces cations, preferably at least three different medications, which glutamate and increases GABA neurotransmission in the can be used in single combined formulations, or used singly, brain. Theoretically therefore, the unique pharmacology of within specific dosing ranges to produce severe reduction or these medications is well suited to the treatment of alcohol cessation of alcohol or drug taking In one aspect, two or more dependence or withdrawal and could normalize the brain medications are administered. In another aspect, three or dysregulation seen during the early abstinence period. more medications are administered. Further, the invention 0022. In a double-blind placebo-controlled trial, 150 men encompasses a unique dosing strategy to enable the combi and women were titrated up to a maximum of 300 mg of nation to be provided safely and with a minimum of adverse topiramate per day during a 12-week period (Johnson et al., eVentS. 2003, Lancet,361: 1677-1685). Participants in the topiramate 0029. Nevertheless, it must be emphasized that this is a arm reported significantly fewer drinks per day, drinking complex neuroadaptive brain system and the effects of neural days, and drinks per drinking day, significantly more days of changes can often be reversed with chronic medication abstinence, and significantly less craving than placebo. administration. One important point about the present inven Because abstinence was not a goal at the start of the study, the tion is that because most of the neuromodulation that is pro medication might be more beneficial during the abstinence posed occurs via ion channels—mainly glutaminergic and initiation phase of treatment. Although gabapentin has seen serotonergic—the capacity for neuronal neuroadaptation is increased use as an alternative to benzodiazepines in alcohol reduced. Therefore, it would be reasonable to expect this withdrawal syndrome, its use as a potential adjunct to naltr combination to work uniquely well because the brain will not exone for promoting abstinence in alcoholism is also being show rapid neuroadaptation following chronic medication investigated. administration. 0023 The basis for combining naltrexone and acampro 0030. It is proposed herein that a more promising sate lies in positive and negative reinforcement of alcohol approach than the use of direct dopamine antagonists will be dependence. Naltrexone can influence positive reinforcement the development of medications that are indirect modulators of alcohol use affected by the B-endorphin opiate system, of cortico-mesolimbic DA function through effects at sero which modulates dopamine release. Negative reinforcement, tonergic, opiate, glutamate (GLU), or gamma-amino-butyric which occurs when one drinks to reduce anxiety, or relieve acid (GABA) receptors. To date, the most promising agent withdrawal, might be helped by the abstinence reinforcing from this approach has been topiramate, a Sulfamate-substi effects of acamprosate. Although each drug individually tuted fructopyranose derivative. Indeed, topiramate is a safe appears to provide modest yet significant effects on treatment and efficacious treatment for alcohol dependence. Yet, there and drinking outcomes, taking advantage of naltrexone's remains a pharmacological opportunity to enhance topira reduction in relapse rates and acamprosate's reduced drinking mate's therapeutic response. Given that cortico-mesolimbic frequency and abstinence promotion was the basis for the neurons have interactions with several neurotransmitter sys COMBINE trial which combined both in addition to behav tems including opioids in critical brain reinforcement regions ioral strategies for treating alcohol dependence. Such as the nucleus accumbens (NAcc), and alcohol has mul 0024 Naltrexone has been administered with ondansetron tiple and varied effects at these same neurotransmitters, it is in EOA. In an 8-week, double-blind, placebo-controlled trial, reasonable to propose that adding the opiate antagonist, nal the combination was found to significantly reduce drinks per trexone, to topiramate would act to modulate CMDA function day and drinks per drinking day and to have a positive effect contemporaneously and Suppress alcohol reinforcement on the percentage of days abstinent compared with placebo more reliably. Essentially, this combination of topiramate and (Ait-Daoud et al., 2001, Psychopharmacology, 154:23-27). maltrexone would lead to an added or synergistic therapeutic The authors suggested that adding ondansetron to naltrexone response intreating alcohol-dependent individuals. Further, it can provide a synergistic action in the EOA patient Subtype. is proposed that because delivery of the topiramate and nal 0025 Both ondansetron and topiramate have proven to be trexone combination would lead to CMDA neuromodulation efficacious in treating alcohol dependence in humans, pre in widespread areas of the brain rostrally from the ventral Sumably through their actions on cortico-mesolimbic dopam tegmental area and through the orbito-frontal cortex—the ine (CMDA). neuropharmacological effects of the medication combination 0026 Various types of combination therapies have been would be less Susceptible to neuroadaptation, and therapeutic used in an attempt to treat and prevent alcohol dependence effects would be maintained with long-term and chronic dos and binge drinking For example, Anton et al. (2006, J. Am. ing. Additionally, as described above, ondansetron's effects US 2011/0065628 A1 Mar. 17, 2011 make it useful as a third drug for drug combination therapies medications, potentially useful on their own, Such as gabap encompassed by the present invention. entin and naltrexone and naltrexone and Sertraline have all 0031. Further, because both topiramate and naltrexone failed to show an improvement of effect over the single medi have the ability to produce weight loss probably through cation or placebo. Hence, finding the right combination of different mechanisms (naltrexone by peripheral effects on gut medication that will be superior to either medication alone, or motility and Satiety and topiramate through central or meta even placebo, is not obvious, has hitherto not been achieved bolic effects on glucose metabolism)—these effects also reliably, and is not predictable from ordinary skill or knowl might add up or be synergistic to produce atherapeutic agent edge of the art. that could be used to treat obesity. Indeed, the attraction of 0036 Regarding direct dopamine blocking agents, a more this combination for the treatment of obesity would be that promising approach for their use than what has been tested weight loss would be induced alongside a decrease in crav previously, is hypothesized herein to encompass the use of ings or impulsivity (also mediated through CMDA neurons) neuromodulators of dopamine function (rather than direct to consume large amounts of food. dopamine blocking agents) as potential treatments for alcohol 0032. The present application discloses the combination use, abuse, or dependence. Such medications should have of topiramate, ondansetron, and naltrexone for the treatment reduced potential to induce rapid neuroadaptation and a of addictive disorders and for associated impulsivity includ favorable adverse-effect profile. Additionally, we propose ing obesity. The present invention encompasses formulating that the right combination of such neuromodulators, not pres the combination of topiramate and naltrexone, as well as ently obvious given the state-of-the-art, may be even more other drugs, in multiple formats to optimize the invention. beneficial by enhancing efficacy and reducing adverse events. 0033. When compounds of the invention are to be admin 0037. In one embodiment, the present invention provides istered at the same time, they can be administered in a formu compositions and methods for treating or preventing an alco lation containing more than one compound of the invention. hol-related disease or disorder comprising administering to a 0034. The present invention encompasses an approach subject a therapeutically effective amount of at least two that combines drugs for the treatment or prevention of addic anti-alcohol agents or compounds, and optionally other thera tive disorders such as alcohol dependence. Because the rein peutic agents. Preferably, at least three anti-alcohol agents or forcing effects of most abused drugs are also mediated by compounds are used in the combination therapy. The present CMDA neurons, the present invention provides combination invention further encompasses the adjunctive use of psycho therapy with drugs such as topiramate, ondansetron, and nal Social management techniques. In one aspect, the drug com trexone as efficacious treatments for addictive disorders bination therapy is more effective alone than when combined including (but not limited to) alcohol, eating, cocaine, meth with psychosocial management techniques. In another amphetamine, marihuana, tobacco abuse and addiction, and aspect, the drug combination therapy combined with psycho other addictive behaviors, including, but not limited to, gam Social management techniques is more effective than drug bling and sex. Based on the unexpected discoveries described combination therapy alone. In one aspect, the present inven herein, one of ordinary skill in the art will now appreciate that tion provides methods for treating or preventing an alcohol the compounds of the invention useful for combination drug related disease or disorder in a subject comprising adminis therapy can in some instances be used singly instead of as part tering an effective amount of at least two compounds, or of a combination. Additionally, based on the present applica preferably at least three compounds, or analogs, homologs, tion, one of ordinary skill in the art will also appreciate that derivatives, modifications, and pharmaceutically acceptable the compounds of the invention useful for combination drug salts thereof, selected from the group consisting of seroton therapy can in some instances be used in any combination. ergic agents, serotonin antagonists, selective serotonin re Until the present discovery ofuseful combination therapies as uptake inhibitors, serotonin receptor antagonists, opioid disclosed herein, one or ordinary skill in the art would not antagonists, dopaminergic agents, dopamine release inhibi have had such an appreciation. tors, dopamine antagonists, norepinephrine antagonists, 0035. Notably, the exact medication combination(s) that GABA agonists, GABA inhibitors, GABA receptor antago may be useful is neither obvious nor is it likely to be the nists, GABA channel antagonists, glutamate agonists, simple addition of any two or more compounds that might glutamate antagonists, glutamine agonists, glutamine antago singly have an effect. As evidence for this, a case in point is nists, anti-convulsant agents, NMDA-blocking agents, cal that the combinations that so far have been tried and pub cium channel antagonists, carbonic anhydrase inhibitors, lished in the scientific literature have not been demonstrated neurokinins, Small molecules, peptides, vitamins, co-factors, to be more effective than the single medication but also not anti-orexin agents, regulators of cannabanoid receptor-1, and even more effective than placebo. For instance, whilst a Euro Corticosteroid Releasing Factor antagonists. In one aspect, pean study proposed that the combination of naltrexone and the neurokinin is NPY. The present invention further encom acamprosate would have an additive effect, this was not the passes administering other Small molecules and peptides. finding of the study. While the results of that study suggested 0038. In one embodiment, the alcohol-related disease or that the combination may be better than acamprosate, it did disorder being treated includes, but is not limited to, early not show that the combination was significantly better than onset alcoholic, late-onset alcoholic, alcohol-induced psy maltrexone alone (Kiefer et al., Arch Gen Psychiatry, 2003, chotic disorder with delusions, alcohol abuse, excessive 60:92-99). Furthermore, in a much larger sample study con drinking, heavy drinking, problem drinking, alcohol intoxi ducted recently in the US, the combination of naltrexone and cation, alcohol withdrawal, alcohol intoxication delirium, acamprosate was no better than either medication alone or alcohol withdrawal delirium, alcohol-induced persisting placebo (Anton et al., JAMA 2006, 295:2003-2017). There dementia, alcohol-induced persisting amnestic disorder, fore, there is no reliable evidence that the combining naltrex alcohol dependence, alcohol-induced psychotic disorder with one and acamprosate has additive effects on alcohol treat hallucinations, alcohol-induced mood disorder, alcohol-in ment. Furthermore, proposed combinations of other duced or associated bipolar disorder, alcohol-induced or US 2011/0065628 A1 Mar. 17, 2011

associated posttraumatic stress disorder, alcohol-induced analyze the effectiveness of treatment. The parameters ana anxiety disorder, alcohol-induced sexual dysfunction, alco lyzed when measuring alcohol consumption or frequency of hol-induced sleep disorder, alcohol-induced or associated alcohol consumption include, but are not limited to, heavy gambling disorder, alcohol-induced or associated sexual dis drinking days, number of heavy drinking days, average drink order, alcohol-related disorder not otherwise specified, alco ing days, number of drinks per day, days of abstinence, num hol intoxication, and alcohol withdrawal. In one aspect, the ber of individuals not drinking heavily or abstinent over a alcohol-related disease or disorder is early onset alcoholic. In given time period, and craving. Both Subjective and objective another aspect, the alcohol-related disease or disorder is late measures can be used to analyze the effectiveness of treat onset alcoholic. ment. For example, a Subject can self-report according to 0039. In one embodiment, the present invention provides guidelines and procedures established for Such reporting. The compositions and methods for reducing the frequency of procedures can be performed at various times before, during, alcohol consumption compared with the frequency of alcohol and after treatment. Additionally, assays are available for consumption before the treatment. One of ordinary skill in the measuring alcohol consumption. These assays include breath art will appreciate that the frequency can be compared with alcohol meter readings, measuring serum CDT and GGT prior consumption by the Subject or with consumption by a levels, and measuring 5-HTOL urine levels. control Subject not receiving the treatment. In one aspect, the 0049. The present invention further provides adjunctive type of alcohol consumption is heavy drinking In another therapies to be used in conjunction with the combination drug aspect, it is excessive drinking. therapies. The present invention further provides adjunctive 0040. In one embodiment, the present invention provides therapy or treatment wherein the subject is also submitted to compositions and methods for reducing the quantity of alco a psychosocial management program. Psychosocial manage hol consumed in a subject compared with the amount of ment programs are known in the art and include, but are not alcohol consumed before the treatment or compared with the limited to, Brief Behavioral Compliance Enhancement Treat alcohol consumption by a control Subject not receiving the ment, Cognitive Behavioral Coping Skills Therapy, Motiva treatment. tional Enhancement Therapy, Twelve-Step Facilitation 0041. One of ordinary skill in the art will appreciate that in Therapy (Alcoholics Anonymous), Combined Behavioral Some instances a subject being treated for and addictive dis Intervention, Medical Management, psychoanalysis, psycho order is not necessarily dependent. Such subjects include, for dynamic treatment, and Biopsychosocial, Report, Empathy, example, Subjects who abuse alcohol, drink heavily, drink Needs, Advice, Direct Advice and Assessment. The present excessively, are problem drinkers, or are heavy drug users. invention further encompasses the use of additional adjunct The present invention provides compositions and methods for therapies and treatment, including hypnosis and acupuncture. treating or preventing these behaviors in non-dependent Sub 0050. The present invention further provides for advice to jects. be provided to Subjects in conjunction with drug combination 0042. In one embodiment of the invention, the present therapy. Advice constitutes a set of instructions pertaining to invention provides compositions and methods for improving the potential consequences of excessive drinking, a calendar the physical or psychological sequelae associated with alco or other method for monitoring drinking, and instructions or hol consumption compared with a control Subject not receiv Suggestions about how to reduce or stop drinking Any of these ing the treatment. strategies either alone or in any combination, and no matter 0043. In one embodiment, the present invention provides how brief or lengthy, can constitute advice. The advice can be compositions and methods for increasing the abstinence rate provided in a format such as written, electronic, or interper of a Subject compared with a control Subject not receiving the Sonal. In one embodiment, the drug combination therapy is treatment. more effective at treatment or prevention than merely admin 0044. In one embodiment, the present invention provides istering a placebo and providing advice, administering no compositions and methods for reducing the average level of drugs and providing advice, or not administering drugs or alcohol consumption in a Subject compared with the level of providing advice. In one aspect, the combination drug therapy alcohol consumption before the treatment or compared with is more effective at treatment or prevention than drug therapy the level of alcohol consumption by a control subject not used in combination with a psychosocial management pro receiving the treatment. gram. 0045. In one embodiment, the present invention provides 0051. In one embodiment, at least one of the compounds compositions and methods for reducing alcohol consumption being administered is administered at least once a day. In one and for increasing abstinence compared with the alcohol con aspect, it is administered at least twice a day. In another sumption by the subject before treatment or with a control embodiment, it is administered at least once a week. In yet Subject not receiving the treatment. another embodiment, it is administered at least once a month. 0046. In one embodiment, the present invention provides 0052. In one embodiment, at least one of the compounds is compositions and methods for treating a Subject with a pre a serotonin receptor antagonist. In one aspect, the serotonin disposition to early-onset alcoholism. receptor is the serotonin-3 receptor. In one aspect, the com 0047. In one embodiment, the present invention provides pound is ondansetron. compositions and methods for treating a Subject with a pre 0053. In one embodiment, at least three different com disposition to late-onset alcoholism. pounds are administered to the Subject. 0048 One of ordinary skill in the art will appreciate that 0054. It will be appreciated by one of ordinary skill in the there are multiple parameters or characteristics of alcohol art that the multiple compounds, preferably three or more consumption which may characterize a Subject afflicted with compounds, being administered do not necessarily have to be an alcohol-related disease or disorder. It will also be appre administered at the same time or in equal doses. In one aspect, ciated that combination therapies may be effective in treating the compounds being administered as part of the drug com more than one parameter, and that there are multiple ways to bination therapy are separately administered. In another US 2011/0065628 A1 Mar. 17, 2011 aspect, a first compound is administered before a second or mg/day. In another aspect, topiramate is administered at a third compound is administered. In yet another aspect, a first dosage of 400 mg/day. In a further aspect, topiramate is compound and a second compound are administered nearly administered at a dosage of about 300 mg/day. In yet a further simultaneously, while a third compound is administered at a aspect, topiramate is administered at a dosage of about 275 different time. In a further aspect, the first compound is mg/day. In one aspect, topiramate is administered at a dose of administered Subsequent to administration of a second com about 1 mg/day. In one aspect, up to about 300 mg/day is pound or third compound. administered. 0063. In one embodiment, topiramate is provided at a dose 0055. The invention further provides pharmaceutical of about 1 mg/kg. In one aspect, topiramate is provided at a compositions comprising compounds of the invention. The dose of about 10 mg/kg. In one aspect, topiramate is provided pharmaceutical composition may comprise one or more com at a dose of about 100 mg/kg. In one embodiment, topiramate pounds of the invention, and biologically active analogs, is administered at a dosage ranging from about 0.1 mg/kg/day homologs, derivatives, modifications, and pharmaceutically to about 100 mg/kg/day. acceptable salts thereof, and a pharmaceutically acceptable 0064 Topiramate (CHNOS: IUPAC name: 2,3:4.5- carrier. In one embodiment, the compounds are administered Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfa as a pharmaceutical composition. mate; CAS Registry No. 97240-79-4) has the following struc 0056. The route of administration can vary depending on ture: the type of compound being administered. In one aspect, the compounds are administered via routes such as oral, topical, rectal, intramuscular, intramucosal, intranasal, inhalation, O. NH2. ophthalmic, and intravenous. O N/N 0057 The present invention further provides for adminis / Y. tration of a compound of the invention as a controlled-release O O formulation. 0058. In one embodiment, the present invention provides the As O O l" administering at least three compounds, wherein at least three HC CH of the compounds are topiramate, ondansetron, and naltrex O 0065. An important aspect of psychotropic drugs is to 0059. In one embodiment, the present invention provides produce weight gain. These increases in weight gain can compositions and methods for treating alcohol-related dis induce a range of metabolic problems including abnormal eases and disorders using pharmaceutical compositions com Sugar, fat, and carbohydrate metabolism. Because topiramate prising effective amounts of topiramate, ondansetron, and can cause weight loss and improve endocrine function, it is proposed herein that topiramate may be used to ameliorate maltrexone. weight gain caused by other psychotropic drugs with which it 0060. The dosage of the active compound(s) being admin is combined as well as alcohol and any other abused drugs. istered will depend on the condition being treated, the par 0.066 An important adverse event of topiramate is cogni ticular compound, and other clinical factors such as age, sex, tive impairment. In the general population, this is reported by weight, and health of the subject being treated, the route of 2.4% of individuals who take topiramate (Johnson & Johnson administration of the compound(s), and the type of composi Pharmaceutical Research & Development. Investigator's tion being administered (tablet, gel cap, capsule, solution, Brochure: Topiramate (RWJ-17021-000), 10th ed.: Decem Suspension, inhaler, aerosol, elixir, lozenge, injection, patch, ber 2005). In the substance abuse field, the occurrence rate of ointment, cream, etc.). It is to be understood that the present cognitive impairment is about 18.7% (Johnson B A, Ait invention has application for both human and Veterinary use. Daoud N. Bowden C L et al. Oral topiramate for treatment of 0061 For example, in one embodiment relating to oral alcohol dependence: a randomised controlled trial. Lancet administration to humans, a dosage of between approxi 2003, 361: 1677-1685). Topiramate-associated cognitive mately 0.1 and 300 mg/kg/day, or between approximately 0.5 effects are due to its anti-glutaminergic properties. It is, there fore, not obvious that ondansetron, a serotonin-3 receptor and 50 mg/kg/day, or between approximately 1 and 10 mg/kg/ antagonist, will alleviate these complaints of cognitive day, is generally sufficient, but will vary depending on Such impairment. Ondansetron appears to have cholinergic effects, things as the disorder being treated, the length of treatment, perhaps though interactions with the GABA system, that the age, sex, weight, and/or health of the Subject, etc. The seem to ameliorate topiramate-associated cognitive impair combinations of drugs can be administered in formulations ment. Hence, it is to be expected that the rate of cognitive that contain all drugs being used, or the drugs can be admin impairment reported by this triple combination would be less istered separately. In some cases, it is anticipated that multiple than that for topiramate on its own. doses/times of administration will be required or useful. 0067 Ondansetron is disclosed herein as a drug useful in Additionally, for most treatment regimens, at least two com the combination drug therapy of the invention. The dosage pounds will be used. In one aspect, at least three compounds and treatment regimen for administering ondansetron when it will be administered. The present invention further provides is being used as one compound of a combination therapy can for varying the length of time of treatment. be varied based on the other drug or drugs with which it is 0062 Topiramate is disclosed herein as a drug useful in being administered, or based on other criteria Such as the age, combination drug therapy. In one embodiment, topiramate is sex, health, and weight of the Subject. The present invention provided at a dosage ranging from about 15 mg/day to about therefore provides for the use of ondansetron at varying doses 2500 mg/day. In one aspect, topiramate is administered at a Such as about 0.01 g/kg, about 0.1 ug/kg, about 1.0 ug/kg, dosage ranging from about 25 mg/day to about 1000 mg/day. about 5.0 g/kg, about 10.0 ug/kg, about 0.1 mg/kg, about 1.0 In yet another aspect, topiramate is administered at a dosage mg/kg, about 5.0 mg/kg, and about 10.0 mg/kg. In another ranging from about 50 mg/day to about 500 mg/day. In one embodiment, ondansetron is administered at a dosage rang aspect, topiramate is administered at a dosage of about 400 ing from about 0.01 ug/kg to about 100 ug/kg per application. US 2011/0065628 A1 Mar. 17, 2011

In one aspect, ondansetron is administered at a dosage rang about 15% of individuals in alcohol trials are unable to toler ing from about 0.1 ug/kg to about 10.0 ug/kg per application. ate a naltrexone dose of 50 mg/day. This has led to the devel In yet another aspect, ondansetron is administered at a dosage opment of depot formulations that release naltrexone slowly ranging from about 1.0 ug/kg to about 5.0 g/kg per applica to reduce the incidence of nausea and Vomiting. Nevertheless, tion. In a further aspect, ondansetron is administered at a these depot formulation(s) appear to have similar compliance dosage of about 4.0 ug/kg per application. In another aspect, rates to the oral form of the medication. Importantly, ondansetron is administered at a dosage of about 3.0 ug/kg ondansetron reduces nausea and decreases Vomiting by slow per application. In one aspect, ondansetron is administered at ing gut motility. Therefore, a combination that adds a dose of about 4 ug/kg twice daily (about 0.25 to 0.6 mg twice ondansetron to naltrexone will diminish the nausea and Vom daily for body weights between about 50 kg and 150 kg). iting caused by naltrexone. This is an important therapeutic 0068 Ondansetron (CHNO; CAS Registry No. advance because many more people will be able to tolerate 996.14-02-5; IUPAC name: 9-methyl-3-(2-methyl-1H-imi the treatment due to increased compliance, and higher doses dazol-1-yl)methyl-1,2,3,9-tetrahydrocarbazol-4-One) has than the typically administered naltrexone dose of 50 mg/day the following structure: can be given to improve the therapeutic response. 0072. In one embodiment where at least three compounds are administered, topiramate, ondansetron, and naltrexone CH are administered. In one aspect, topiramate is administered at a dosage of as much as about 400 mg/day, ondansetron is N administered at a dosage of about 1 to 10 ug/kg twice daily, HC and naltrexone is administered at a dosage of about 25 mg/ap plication to about 150 mg/application. In a further aspect, X's. topiramate is administered at a dosage of about 300 mg/day, ondansetron is administered at a dosage of about 4.0 ug/kg A Y-N- twice daily, and naltrexone is administered at a dosage of about 25-50 mg/application. 0069. The present invention further provides for the use of 0073. In one aspect, the treatment comprises combining other drugs such as naltrexone as part of the drug combination ondansetron and naltrexone at full doses at the beginning of therapy disclosed herein. In one embodiment, naltrexone is the treatment, followed by titrating topiramate administration administered at a dose of about 10 mg/day. In one aspect, up from 0 to about 300 mg/day over the first few weeks of the maltrexone is administered at a dosage at a dosage of about 50 treatment, preferably for about 6 weeks. This titration proce mg/day. In one aspect, naltrexone is administered at a dosage dure is used to avoid the development of important adverse of about 100 mg/day. In one aspect, naltrexone is adminis events that would preclude further medication administra tered at a dosage ranging from about 1 mg to about 300 mg per tion. For example, ondansetron can be administered at an application. In another aspect, naltrexone is administered at a approximate dose of 4 g/kg twice daily (about 0.25 to 0.60 dosage ranging from about 10 mg to about 50 mg per appli mg twice daily for body weights between 50 and 150 kg), and cation. In a further aspect of the invention, naltrexone is maltrexone at a dose of up to 100 mg/day. Then, topiramate administered at a dosage of about 25 mg per application. In administration would be titrated from 0 to about 300 mg/day one embodiment, naltrexone is administered at least once a over a period of about six weeks. month. In a further embodiment, naltrexone is administered 0074 This varied administration schedule is based on the once a month. In one embodiment, naltrexone is administered observations described herein where the combination of topi at least once a week. In another embodiment, naltrexone is ramate and ondansetron is additive but the addition of naltr administered at least once a day. In a further embodiment, exone completely blunts the response to alcohol reinforce maltrexone is administered at least twice a day. In one aspect, ment. This is an unexpected result, as the initial assumption maltrexone is administered twice a day. for the experiments described herein was that the addition of 0070 Naltrexone (CHNO; 17-(Cyclopropylmethyl)- maltrexone to topiramate and ondansetron would simply be 4.5 a-epoxy-3, 14-dihydroxymorphinan-6-one hydrochlo additive. Instead, the triple combination produces a complete ride; CAS Registry No. 16590-41-3) has the following struc blunting of alcohol reinstatement in animals. Translated to ture: humans, this triple combination encompasses producing a major Suppression of the drive to relapse following a period of

recovery from alcohol. Therefore, the invention further encompasses the ability to come close to abolishing the drive or propensity to drink excessively and should be of help to stop or severely reduce alcohol consumption by alcoholics who are still drinking when they start the medication. One of ordinary skill in the art will appreciate that the doses and scheduling of administration can be adjusted based on vari ables Such as the age, sex, weight, overall health, and severity of the particular alcohol-related problem in the subject to be treated. 0075. In one embodiment, the results of treating a subject with a combination of two or more compounds are additive compared with the effects of using any of the compounds 0071 Naltrexone also has important adverse events— alone. This does not mean that if three or more compounds are nausea and Vomiting—that reduce compliance to it. Indeed, administered that the results will be additive as to the combi US 2011/0065628 A1 Mar. 17, 2011

nation of all drugs, just two or more. In one aspect, the effects I0084. The present invention provides for multiple meth seen when using two or more compounds are greater than ods for delivering the compounds of the invention. The com when using any of the compounds alone. In one embodiment, pounds may be provided, for example, as pharmaceutical the results of treating a subject with a combination of two or compositions in multiple formats as well, including, but not more compounds are synergistic compared with the effects of limited to, tablets, capsules, pills, lozenges, syrups, oint using the compounds alone, at least with regard to two com ments, creams, elixirs, Suppositories, Suspensions, inhalants, pounds. injections (including depot preparations), and liquids. 0076. In one embodiment, other compounds may be used I0085. The present invention further encompasses biologi in combination with topiramate and naltrexone, for example, cally active analogs, homologs, derivatives, and modifica ondansetron. tions of the compounds of the invention. Methods for the 0077. Additional compounds can be used to treat subjects preparation of Such compounds are known in the art. In one of the invention. In addition to the combination treatment of at aspect, the compounds are topiramate, naltrexone, and least two drugs, or at least three drugs, described above, the ondansetron. present invention further provides for the administration of at I0086. The compositions and methods described hereinfor least one additional compound to treat or prevent diseases and treating or preventing alcohol-related diseases and disorders disorders of the invention, including, but not limited to, dis are also useful for treating or preventing other addiction ulfiram, acamprosate, Sertraline, galanthamine, nalmefene, related diseases and disorders and impulse control disorders. naloxone, desoxypeganine, benzodiazepines, neuroleptics, In one aspect, the compositions and methods elicitan indirect risperidone, rimonabant, traZodone, baclofen, regulators of effect on CMDA neurons. Such effects may be elicited, for cannabanoid receptor-1, regulators of orexin, and aripipra example, by regulating serotonergic, opiate, glutamate, or Zole. In one aspect, an additional compound is used with the y-amino-butyric acid receptors. In one aspect, the addictive combination therapy drugs topiramate and ondansetron. One diseases and disorders include eating disorders, impulse con of ordinary skill in the art will appreciate that in Some cases trol disorders, nicotine-related disorders, methamphetamine the combination therapy using these additional compounds related disorders amphetamine-related disorders, cannabis will have additive effects and in some cases Synergistic related disorders, cocaine-related disorders, hallucinogen use effects. Methods for testing these combinations and analyz disorders, inhalant-related disorders, benzodiazepine abuse ing the results are known in the art. or dependence related disorders, and opioid-related disor 0078. In addition to the combination drug therapy ders. described herein for treating or preventing addiction-related I0087. The compositions and methods described hereinare diseases and disorders such as alcohol-related diseases and also useful for treating or preventing heavy drug use, includ disorders, additional types of compounds can be adminis ing, but not limited to, cocaine, methamphetamine, other tered to treat further the addiction-related diseases and disor stimulants, phencyclidine, other hallucinogens, marijuana, ders or to treat other diseases and disorders. The additional sedatives, tranquilizers, hypnotics, and opiates. It will be types of compounds include, but are not limited to, adrener appreciated by one of ordinary skill in the art that heavy use or gics, adrenocortical steroids, adrenocortical Suppressants, abuse of a Substance does not necessarily mean the Subject is aldosterone antagonists, amino acids, analeptics, analgesics, dependent on the Substance. anorectic compounds, anorexics, anti-anxiety agents, antide I0088. The compositions and methods of the present inven pressants, antihypertensives, anti-inflammatories, antinause tion are also useful as a multi-faceted combination therapy ants, antineutropenics, antiobsessional agents, antiparkinso approach to treating and regulating weight loss, obesity, and nians, antipsychotics, appetite Suppressants, blood glucose weight gain. The invention provides not just single com regulators, carbonic anhydrase inhibitors, cardiotonics, car pounds, but instead acts on multiple points in the feeding and diovascular agents, choleretics, cholinergics, cholinergic Satiety pathway. Further, because some drugs such as topira agonists, cholinesterase deactivators, cognition adjuvants, mate, ondansetron, and naltrexone have the ability to produce cognition enhancers, hormones, memory adjuvants, mental weight loss, probably through different mechanisms (on performance enhancers, mood regulators, neuroleptics, neu dansetron by peripheral effects on gut motility and Satiety, roprotectives, psychotropics, relaxants, sedative-hypnotics, maltrexone by decreasing the impulse to binge, and topira stimulants, thyroid hormones, thyroid inhibitors, thyromi mate through central or metabolic effects on glucose metabo metics, cerebral ischemia agents, vasoconstrictors, and lism), these effects also might add up or be synergistic to vasodilators. produce atherapeutic agent that could be used to treat obesity 0079. In one embodiment, the present invention provides or to aid in inducing weight loss in overweight individuals or methods and compositions useful for decreasing mesocorti in any case where it would be beneficial to lose weight. colimbic dopamine activity. Indeed, the attraction of this combination for the treatment of 0080. In one embodiment, the present invention provides obesity would be that weight loss would be induced alongside methods and compositions useful for regulating mesocorti a decrease in cravings or impulsivity (also mediated through colimbic dopamine activity. CMDA neurons) to consume large amounts of food. 0081. In one embodiment, the present invention provides I0089. Therefore, the combination therapy of the present methods and compositions useful for inhibiting glutamate invention for the treatment of addictive disorders and associ function. ated impulsivity, including obesity, is a new and useful 0082 In one embodiment, the present invention provides therapy. Based on the data and descriptions provided herein, methods and compositions useful for facilitating Y-amino as well as what is known in the art, one of ordinary skill in the butyric acid activity. art will know how to combine and use drugs such as topira 0083. In one embodiment, the present invention provides mate, ondansetron, and naltrexone in multiple formats to methods and compositions useful for regulating Y-amino optimize the invention. These pharmacological formats butyric acid activity. include (but are not limited to) tablets, gel caps, capsules, US 2011/0065628 A1 Mar. 17, 2011

chewable and orally absorbable materials (for example, sub hol-related diseases and disorders and weight control dis lingual tablets), elixirs, Suspensions, inhalants, sprays, eases and disorders. The method comprises administering an patches, ointments and balms, long-acting intramuscular effective amount of at least three compounds of the invention, injections (with FDA-approved polylactide capsules or nano or analogs, derivatives, modifications, and pharmaceutically technology), and intravenous, Subcutaneous, intramucosal, or acceptable salts thereof. In one aspect, the compounds any other avenues for injection. include, but are not limited to, serotonergic agents, serotonin 0090. In one embodiment, the present invention provides antagonists, selective serotonin re-uptake inhibitors, seroto compositions and methods for treating obesity or being over nin receptor antagonists, opioid antagonists, dopaminergic weight comprising administering to a subject in need thereof agents, dopamine release inhibitors, dopamine antagonists, an effective amount of at least two compounds, or analogs, norepinephrine antagonists, y-amino-butyric acid agonists, derivatives, modifications, or pharmaceutically acceptable y-amino-butyric acid inhibitors, y-amino-butyric acid recep salts thereof, selected from the group consisting of seroton tor antagonists, y-amino-butyric acid channel antagonists, ergic agents, serotonin antagonists, selective serotonin re glutamate agonists, glutamate antagonists, glutamine ago uptake inhibitors, serotonin receptor antagonists, opioid nists, glutamine antagonists, anti-convulsant agents, N-me antagonists, dopaminergic agents, dopamine release inhibi thyl-D-aspartate-blocking agents, calcium channel antago tors, dopamine antagonists, y-amino-butyric acid agonists, nists, carbonic anhydrase inhibitors, neurokinins, and y-amino-butyric acid inhibitors, y-amino-butyric acid recep Corticosteroid Releasing Factor antagonists. In one aspect, tor antagonists, y-amino-butyric acid channel antagonists, the compounds are topiramate, ondansetron, and naltrexone. glutamate agonists, glutamate antagonists, anti-convulsant 0100. In one embodiment, the addiction-related disease or agents, and NMDA-blocking agents, thereby treating or pre disorder is drug use. In one embodiment, the present inven venting, optionally in combination with at least one addi tion provides a method for treating or preventing heavy drug tional therapeutically active compound. use. The method encompasses administering an effective 0091. In one embodiment of treating obesity, the addi amount of at least three compounds, or biologically active tional therapeutically active compound is selected from the analogs, derivatives, modifications, or pharmaceutically group consisting of antidiabetic agents, antihyperlipidemic acceptable salts thereof, selected from the group consisting of agents, antiobesity agents, antihypertensive agents, and serotonergic agents, serotonin antagonists, selective seroto agents for the treatment of complications resulting from or nin re-uptake inhibitors, serotonin receptor antagonists, associated with diabetes. opioid antagonists, dopaminergic agents, dopamine release 0092. In one embodiment of treating obesity, the subject inhibitors, dopamine antagonists, norepinephrine antago has a body mass index of about 30.0 or greater. nists, y-amino-butyric acid agonists, y-amino-butyric acid 0093. In one embodiment of treating being overweight, inhibitors, y-amino-butyric acid receptor antagonists, the subject has a body mass index of between 25.0 and 29.9. y-amino-butyric acid channel antagonists, glutamate ago 0094. In one aspect, a subject being treated for obesity is nists, glutamate antagonists, glutamine agonists, glutamine also Subjected to a psychosocial management program. antagonists, anti-convulsant agents, N-methyl-D-aspartate 0095. In one aspect, a subject being treated for being over blocking agents, calcium channel antagonists, carbonic anhy weight is also subjected to a psychosocial management pro drase inhibitors, neurokinins, Small molecules, peptides, Vita gram or provided with advice regarding the benefits of main mins, co-factors, and Corticosteroid Releasing Factor taining normal weight. antagonists. 0096. The compositions, combination therapies, and psy 0101. In one aspect, the heavy drug use is selected from the chosocial management programs useful for treating alcohol group consisting of cocaine, methamphetamine, other stimu related diseases and disorders and obesity are also useful for lants, phencyclidine, other hallucinogens, marijuana, seda regulating weight gain and weight loss. In one embodiment, tives, tranquilizers, hypnotics, and opiates. In one aspect, the the present invention provides compositions and methods frequency of said heavy drug use is at least once a month. In useful for preventing or inhibiting weight gain. In another another aspect, the heavy drug use is at least once a week. In aspect, the present invention provides compositions and one aspect, advice is provided to the Subject. In one aspect, the methods useful for stimulating weight loss. For example, the advice is provided in a format selected from the group con compositions and methods of the invention can be used to sisting of written, electronic, or interpersonal. In one aspect, treat an overweight Subject, such as one with a body mass the method is more effective at treating or preventing heavy index of about 25.0 to about 29.9. One of ordinary skill in the drug use than administering a placebo and providing advice, art will appreciate that similar dosages and drugs can be used administering no drugs and providing advice, or not admin compared with preventing or reducing weight gain, but will istering drugs or providing advice. In one aspect, the method also understand how to make useful modifications in the is more effective at treating or preventing heavy drug use than dosages of compounds administered and the regimens used. the method used in combination with a psychosocial manage In one embodiment, the present invention provides treatments ment program. for regulating weight control using Such drugs as topiramate, 0102 The invention provides all possible combination and ondansetron, and naltrexone. permutations for the use of Such drugs to treat addictive 0097. In one embodiment, the compositions and methods diseases and disorders, either singly or in any combination. In are also useful for Suppressing appetite. one embodiment, the addictive disorders include, but are not 0098. In one embodiment, the composition and methods limited to, eating disorders, impulse control disorders, gam are also useful for Suppressing thoughts, urges, compulsions, bling disorders, sexual disorders, nicotine-related disorders, or cravings for food. amphetamine-related disorders, cannabis-related disorders, 0099. In one embodiment, the compositions and methods cocaine-related disorders, hallucinogen use disorders, inhal of the present invention are also useful for treating or prevent ant-related disorders, benzodiazepine abuse- or dependence ing an addiction-related disease or disorder other than alco related disorders, and opioid-related disorders. Food and eat US 2011/0065628 A1 Mar. 17, 2011 10 ing disorders include, for example, binge eating. In one 0112 FIG. 8 graphically illustrates the combined effect of aspect, the combination pharmacotherapy is provided in con topiramate and naltrexone on alcohol consumption in alco junction with behavioral modification therapy or interven hol-preferring (P) rats. Rats received either vehicle, topira tion. mate at 5 mg/kg, topiramate at 10 mg/kg, naltrexone at 1/mg/ 0103) One of ordinary skill in the art will appreciate that kg and topiramate at 5 mg/kg, naltrexone at 1/mg/kg and the compounds, combinations, dosages, and administration topiramate at 10 mg/kg, or naltrexone at 1 mg/kg. Each data regimens described above for treating alcohol related disor point represents the mean (tSE) of 8 rats as a change from ders are also applicable to the treatment of the other addictive baseline. disorders described herein. 0113 FIG. 9 schematically illustrates some of the brain 0104. The invention further provides kits for administer pathways and their regulation related to addiction. ing the compounds of the invention. 0114 FIG. 10, comprising 5 panels FIGS. 10A to 10E, graphically illustrates the combined effect of topiramate (10 BRIEF DESCRIPTION OF THE DRAWINGS mg/kg, IP), ondansetron (0.001 mg/kg, IP), and naltrexone (1 mg/kg, IP) on alcohol consumption in alcohol-preferring (P) 0105 FIG. 1, comprising FIGS. 1A (Early Onset Alcohol rats. 10A Topiramate alone; 10B Ondansetron alone: ics) and 1B (Late Onset Alcoholics), graphically illustrate the 10C Vehicle: 10D Topiramate+Ondansetron: 10E effects of ondansetron treatment. The data represent the mean Topiramate+Ondansetron--Naltrexone. Data are plotted (tSE) of drinking outcomes (mean drinkS/day) during the across seven consecutive sessions, which include a 3-day double-blind response period for Early and Late Onset Alco baseline period, the test session in which the ondansetron, holics. The left panel of each figure represents the start of the topiramate, and naltrexone injection was administered, and double blind study and the right panel of each represents the the three sessions that followed the test session. Each data end of the study. Open bars represent placebo, Small squares point represents a mean (SE) of at least six rats. The ordinate represent ondansetron at 1 lug/kg. Large squares represent represents ethanol intake in g/kg and the abscissa represents ondansetron at 4 g/kg, Vertical lines in the bar represent session number. ondansetron at 16 ug/kg. 0115 FIG. 11 is a schematic model summarizing some of 0106 FIG.2, comprising FIGS. 2A (EOA) and 2B (LOA), the interactive pathways in the brain involved in related to graphically illustrates the effects of ondansetron on Carbo addiction and addictive behavior, as well as various receptors hydrate Deficient Transferrin (CDT) ratio in Early and Late and neurotransmitters known to be involved. Onset Alcoholics. The ordinate represents Mean Log CDT Ration. Mean log CDT ratio-mean log CDT at a given visit DETAILED DESCRIPTION (i.e., 4, 8, or 12)/mean log CDT at visit 0.**=p<0.01; *=p<0. 05. Open bars represent placebo: Small squares represent Abbreviations, Generic Names, and Acronyms ondansetron at 1 ug/kg. Large squares represent ondansetron 0116 5-HT serotonin at 4 g/kg:Vertical lines in the barrepresent ondansetron at 16 I0117 5-HT, a subtype of serotonin receptor, the seroto Lig/kg. nin-3 receptor 0107 FIG.3 graphically illustrates the effects of Naltrex 0118 5-HTOL-5-hydroxytryptophol one on alcohol consumption in non-human primates (rhesus 0119) ADE alcohol deprivation effect monkeys). Naltrexone was administered at 0.1 (o), 0.3 (O), I0120 ASPD—antisocial personality disorder 1.0 (D) or 3.0 () g/kg. The ordinate represents cumulative I0121 BBCET Brief Behavioral Compliance Enhance deliveries as percent change from baseline. The abscissa rep ment Treatment resents time in 10 minute blocks. 0.122 BED binge eating disorder 0108 FIG.4, comprising FIGS. 4A (Drinks/Day) and 4B I0123 b.i.d.—twice a day (Drinks/Drinking Day), graphically illustrates the effects of 0.124 BRENDA Biopsychosocial, Report, Empathy, the combination of Ondansetron and Naltrexone (O) or pla Needs, Direct advice, and Assessment cebo (o) on drinking outcomes in Early Onset Alcoholics in 0.125 CBI-combined behavioral intervention an eight week study. Baselines are indicated by arrow at time 0.126 CBT Cognitive Behavioral Coping Skills Zero and the Start of the Double-Blind is indicated by an Therapy, also referred to as cognitive behavioral therapy arrow at time point 1. The data are presented as mean (tSE). I0127 CDT carbohydrate-deficient transferrin 0109 FIG.5 graphically illustrates the effects of treatment I0128 CMDA cortico-mesolimbic dopamine with Ritanserin in conjunction with Cognitive Behavioral I0129 DA dopamine Therapy. The ordinate represents the mean number of drinks 0.130 DSM Diagnostic and Statistical Manual of Men since the last visit and the abscissa indicates the time period of tal Disorders assessment in the study (in weeks). Subjects were treated with I0131 EOA early-onset alcoholic(s) 2.5 mg Ritanserin (O), 5.0 mg Ritanserin(), or received I0132 GABA Y-amino-butyric acid (also referred to as placebo (A). y-aminobutyric acid and Y-aminobutyric acid) 0110 FIG. 6 is a schematic representation of an experi 0.133 GGT Y-glutamyl transferase mental recruitment and design protocol for using alcohol I0134) ICD impulse control disorder dependent patients in a study. I0135) IP intraperitoneal 0111 FIG. 7 graphically illustrates a representative I013.6 LOA late-onset alcoholic(s) example of a study time line comparing the number of I0137 MET Motivational Enhancement Therapy enrolled subjects (cross-hatched bars) and the number of I0138 MM Medical Management Subjects completing (open bars) the study. The ordinate rep 0.139 NAc nucleus accumbens (also referred to as resents Study Years and the abscissa represents the number of nACC) Subjects. 0140 Naltrexone—au opioid receptor antagonist US 2011/0065628 A1 Mar. 17, 2011 11

0141 NMDA N-methyl-D-aspartate 0156. As used herein, the term “affected cell refers to a 0142 NOS—not otherwise specified cell of a subject afflicted with a disease or disorder, which 0143 Ondansetron (ZofranR)—a serotonin receptor affected cell has an altered phenotype compared with a sub antagonist ject not afflicted with a disease, condition, or disorder. 0144 P alcohol-preferring rats (O157 Cells or tissue are “affected” by a disease or disorder 0145 SSRI selective serotonin re-uptake inhibitor if the cells or tissue have an altered phenotype relative to the 0146 Topiramate (Topamax(R)—an anticonvulsant same cells or tissue in a subject not afflicted with a disease, 0147 TSF Twelve-Step Facilitation Therapy (e.g., condition, or disorder. Alcoholics Anonymous) 0158. As used herein, an “agonist' is a composition of 0148 VTA ventral tegmental area matter that, when administered to a mammal Such as a human, enhances or extends a biological activity of interest. Such Definitions effect may be direct or indirect. 0149. In describing and claiming the invention, the follow 0159. The term “alcohol abuser, as used herein, refers to ing terminology will be used in accordance with the defini a subject who meets DSM IV criteria for alcohol abuse (i.e., tions set forth below. Unless defined otherwise, all technical “repeated use despite recurrent adverse consequences') but is and Scientific terms used herein have the same meaning as not dependent on alcohol. commonly understood by one of ordinary skill in the art to (0160 Alcohol-related disorders' as used herein refers to which this invention belongs. Although any methods and diseases and disorder related to alcohol consumption and materials similar or equivalent to those described herein can include, but are not limited to, alcohol-induced psychotic be used in the practice or testing of the present invention, the disorder, with delusions; alcohol abuse; excessive drinking; preferred methods and materials are described herein. As heavy drinking; problem drinking; alcohol intoxication; alco used herein, each of the following terms has the meaning hol withdrawal; alcohol intoxication delirium; alcohol with associated with it in this section. Specific and preferred values drawal delirium; alcohol-induced persisting dementia; alco listed below for radicals, Substituents, and ranges are for hol-induced persisting amnestic disorder, alcohol illustration only; they do not exclude other defined values or dependence; alcohol-induced psychotic disorder, with hallu other values within defined ranges for the radicals and sub cinations; alcohol-induced mood disorder; alcohol-induced stituents. or associated bipolar disorder; alcohol-induced or associated 0150. As used herein, the articles “a” and “an refer to one post traumatic stress disorder; alcohol-induced anxiety dis or to more than one, i.e., to at least one, of the grammatical order; alcohol-induced sexual dysfunction; alcohol-induced object of the article. By way of example, “an element’ means sleep disorder; and alcohol-related disorder not otherwise one element or more than one element. specified (NOS). 0151. The term “about, as used herein, means approxi 0.161. As used herein, “amino acids' are represented by mately, in the region of roughly, or around. When the term the full name thereof, by the three letter code corresponding "about is used in conjunction with a numerical range, it thereto, or by the one-letter code corresponding thereto, as modifies that range by extending the boundaries above and indicated in the following table: below the numerical values set forth. In general, the term “about is used herein to modify a numerical value above and below the stated value by a variance of 20%. 0152 “Addictive disorders' include, but are not limited to, FullName Three-Letter Code One-Letter Code eating disorders, obesity-related disorders, impulse control Aspartic Acid Asp D disorders, alcohol-related disorders, nicotine-related disor Glutamic Acid Glu E ders, amphetamine-related disorders, methamphetamine-re Lysine Lys K Arginine Arg R lated disorders, cannabis-related disorders, cocaine-related Histidine His H disorders, gambling, sexual disorders, hallucinogen use dis Tyrosine Tyr Y orders, inhalant-related disorders, benzodiazepine abuse or Cysteine Cys C dependence related disorders, and opioid-related disorders. Asparagine ASn N Glutamine Gln Q 0153. One of ordinary skill in the art will appreciate that Serine Ser S addictive disorders such as those related to alcohol or drugs, Threonine Thr T does mean that a subject is dependent unless specifically Glycine Gly G defined as such. Alanine Ala A. Valine Wall V 0154 The term “additional therapeutically active com Leucine Leu L pound, in the context of the present invention, refers to the Isoleucine Ile I use or administration of a compound for an additional thera Methionine Met M peutic use other than just the particular disorder being treated. Proline Pro P Such a compound, for example, could include one being used Phenylalanine Phe F to treat an unrelated disease or disorder, or a disease or dis Tryptophan Trp W order which may not be responsive to the primary treatment for the addictive disease or disorder being treated. Disease 0162 The expression "amino acid as used herein is and disorders being treated by the additional therapeutically meant to include both natural and synthetic amino acids, and active agent include, for example, hypertension and diabetes. both D and Lamino acids. "Standard amino acid means any 0155 As used herein, the term “aerosol refers to suspen of the twenty standard L-amino acids commonly found in sion in the air. In particular, aerosol refers to the particlization naturally occurring peptides. "Nonstandard amino acid resi or atomization of a formulation of the invention and its sus due” means any amino acid, other than the standard amino pension in the air. acids, regardless of whether it is prepared synthetically or US 2011/0065628 A1 Mar. 17, 2011

derived from a natural source. As used herein, “synthetic 0180. An “antagonist' is a composition of matter that amino acid also encompasses chemically modified amino when administered to a mammal Such as a human, inhibits or acids, including but not limited to salts, amino acid deriva impedes a biological activity attributable to the level or pres tives (such as amides), and Substitutions. Amino acids con ence of an endogenous compound in the mammal. Such effect tained within the peptides of the present invention, and par may be direct or indirect. ticularly at the carboxy- or amino-terminus, can be modified 0181. As used herein, the term “anti-alcohol agent” refers by methylation, amidation, acetylation or Substitution with to any active drug, formulation, or method that exhibits activ other chemical groups which can change the peptide's circu ity to treat or prevent one or more symptom(s) of alcohol lating half-life without adversely affecting their activity. addiction, alcohol abuse, alcohol intoxication, and/or alcohol Additionally, a disulfide linkage may be present or absent in withdrawal, including drugs, formulations and methods that the peptides of the invention. significantly reduce, limit, or prevent alcohol consumption in 0163 The term “amino acid is used interchangeably with mammalian Subjects. “amino acid residue.” and may refer to a free amino acid and 0182. The term “appetite suppression', as used herein, is a to an amino acid residue of a peptide. It will be apparent from reduction, a decrease or, in cases of excessive food consump the context in which the term is used whether it refers to a free tion, an amelioration inappetite. This Suppression reduces the amino acid or a residue of a peptide. desire or craving for food. Appetite Suppression can result in 0164 Amino acids have the following general structure: weight loss or weight control as desired. 0183 The term “average drinking, as used herein, refers to the mean number of drinks consumed during a one week period. The term “average drinking is used interchangeably | herein with the term “average level of drinking.” R--cool 0184. A “compound, as used herein, refers to any type of NH2 Substance or agent that is commonly considered a drug, or a candidate for use as a drug, as well as combinations and 0.165 Amino acids may be classified into seven groups on mixtures of the above. the basis of the side chain R: (1) aliphatic side chains; (2) side 0185. A “control' subject is a subject having the same chains containing a hydroxylic (OH) group; (3) side chains characteristics as a test Subject, Such as a similar type of containing Sulfur atoms; (4) side chains containing an acidic dependence, etc. The control Subject may, for example, be or amide group; (5) side chains containing a basic group, (6) examined at precisely or nearly the same time the test Subject side chains containing an aromatic ring; and (7) proline, an is being treated or examined. The control Subject may also, imino acid in which the side chain is fused to the amino group. for example, be examined at a time distant from the time at 0166 As used herein, the term “conservative amino acid which the test subject is examined, and the results of the substitution' is defined herein as exchanges within one of the examination of the control subject may be recorded so that the following five groups: recorded results may be compared with results obtained by 0167 I. Small aliphatic, nonpolar or slightly polar resi examination of a test Subject. dues: 0186. A “test” subject is a subject being treated. (0168 Ala, Ser, Thr, Pro, Gly: 0187. As used herein, a "derivative' of a compound refers (0169 II. Polar, negatively charged residues and their to a chemical compound that may be produced from another amides: compound of similar structure in one or more steps, as in 0170 Asp, ASn, Glu, Gln; replacement of H by an alkyl, acyl, or amino group. 0171 III. Polar, positively charged residues: 0188 A “disease' is a state of health of a subject wherein 0172 His, Arg, Lys; the Subject cannot maintain homeostasis, and wherein if the 0173 IV. Large, aliphatic, nonpolar residues: disease is not ameliorated then the Subject's health continues (0174 Met Leu, Ile, Val, Cys to deteriorate. In contrast, a “disorder in a subject is a state of 0175 V. Large, aromatic residues: health in which the Subject is able to maintain homeostasis, (0176 Phe, Tyr, Trp but in which the subject's state of health is less favorable than 0177. The nomenclature used to describe the peptide com it would be in the absence of the disorder. However, the pounds of the present invention follows the conventional definitions of “disease' and “disorder” as described above are practice wherein the amino group is presented to the left and not meant to Supersede the definitions or common usage the carboxy group to the right of each amino acid residue. In related to specific addictive diseases or disorders. the formulae representing selected specific embodiments of (0189 A disease, condition, or disorder is “alleviated” if the present invention, the amino- and carboxy-terminal the severity of a symptom of the disease or disorder, the groups, although not specifically shown, will be understood frequency with which Such a symptom is experienced by a to be in the form they would assume at physiologic pH values, patient, or both, are reduced. unless otherwise specified. 0190. As used herein, an “effective amount’ means an (0178. The term “basic” or “positively charged” amino amount Sufficient to produce a selected effect, Such as allevi acid, as used herein, refers to amino acids in which the R ating symptoms of a disease or disorder. In the context of groups have a net positive charge at pH 7.0, and include, but administering compounds in the form of a combination, Such are not limited to, the standard amino acids lysine, arginine, as multiple compounds, the amount of each compound, when and histidine. administered in combination with another compound(s), may 0179. As used herein, an “analog of a chemical com be different from when that compound is administered alone. pound is a compound that, by way of example, resembles Thus, an effective amount of a combination of compounds another in structure but is not necessarily an isomer (e.g., refers collectively to the combination as a whole, although the 5-fluorouracil is an analog of thymine). actual amounts of each compound may vary. The term “more US 2011/0065628 A1 Mar. 17, 2011

effective” means that the selected effect is alleviated to a the induction or stimulation of synthesis, levels, activity, or greater extent by one treatment relative to the second treat function of the protein of interest. The term also refers to any ment to which it is being compared. metabolic or regulatory pathway which can regulate the Syn 0191 The term "elixir, as used herein, refers in general to thesis, levels, activity, or function of the protein of interest. a clear, Sweetened, alcohol-containing, usually hydroalco The term includes binding with other molecules and complex holic liquid containing flavoring Substances and sometimes formation. Therefore, the term “protein inhibitor refers to active medicinal agents. any agent or compound, the application of which results in the 0192 The term “excessive drinker” as used herein, refers inhibition of protein function or protein pathway function. to men who drink more than 21 alcohol units per week and However, the term does not imply that each and every one of women who consume more than 14 alcohol units per week. these functions must be inhibited at the same time. One standard drink is 0.5 oz of absolute alcohol, equivalent to 0201 As used herein, an “instructional material” includes 10 oz of beer, 4 oz of wine, or 1 oz of 100-proof liquor. These a publication, a recording, a diagram, or any other medium of individuals are not dependent on alcohol but may or may not expression which can be used to communicate the usefulness meet DSM IV criteria for alcohol abuse. of a compound of the invention in the kit for effecting alle 0193 As used herein, a “functional molecule is a mol viation of the various diseases or disorders recited herein. ecule in a form in which it exhibits a property or activity by Optionally, or alternately, the instructional material may which it is characterized. A functional enzyme, for example, describe one or more methods of alleviating the diseases or is one that exhibits the characteristic catalytic activity by disorders in a subject. The instructional material of the kit of which the enzyme is characterized. the invention may, for example, be affixed to a container 0194 The term “heavy drinker,” as used herein, refers to which contains the identified compound invention or be men who drink more than 14 alcohol units per week and shipped together with a container which contains the identi women who consume more than 7 alcohol units per week. fied compound. Alternatively, the instructional material may One standard drink is 0.5 oz of absolute alcohol, equivalent to be shipped separately from the container with the intention 10 oz of beer, 4 oz of wine, or 1 oz of 100-proof liquor. These that the instructional material and the compound be used individuals are not dependent on alcohol but may or may not cooperatively by the recipient. meet DSM IV criteria for alcohol abuse. 0202 As used herein, a “ligand is a compound that spe 0.195 A“heavy drinking day,” as used herein, refers to the cifically binds to a target compound or molecule. A ligand consumption by a man or woman of more than about five or “specifically binds to or “is specifically reactive with a four standard drinks per drinking day, respectively. compound when the ligand functions in a binding reaction 0196. The term “heavy drug use.” as used herein, refers to which is determinative of the presence of the compound in a the use of any drug of abuse, including, but not limited to, sample of heterogeneous compounds. cocaine, methamphetamine, other stimulants, phencyclidine, 0203. A “receptor' is a compound or molecule that spe other hallucinogens, marijuana, sedatives, tranquilizers, hyp cifically binds to a ligand. notics, opiates at intervals or in quantities greater than the 0204 As used herein, the term “linkage” refers to a con norm. The intervals of use include intervals such as at least nection between two groups. The connection can be either once a month, at least once a week, and at least once a day. covalent or non-covalent, including but not limited to ionic “Heavy drug use’ is defined as testing “positive' for the use of bonds, hydrogen bonding, and hydrophobic/hydrophilic that drug on at least 2 occasions in any given week with at interactions. least 2 days between testing occasions. 0205 As used herein, the term “linker” refers to a mol 0.197 As used herein, the term “inhaler refers both to ecule that joins two other molecules either covalently or non devices for nasal and pulmonary administration of a drug, covalently, e.g., through ionic or hydrogen bonds or van der e.g., in solution, powder and the like. For example, the term Waals interactions. “inhaler' is intended to encompass a propellant driven 0206. The term “nasal administration' in all its grammati inhaler, such as is used to administer antihistamine for acute cal forms refers to administration of at least one compound of asthma attacks, and plastic spray bottles, such as are used to the invention through the nasal mucous membrane to the administer decongestants. bloodstream for systemic delivery of at least one compound 0198 The term “inhibit, as used herein, refers to the of the invention. The advantages of nasal administration for ability of a compound or any agent to reduce or impede a delivery are that it does not require injection using a syringe described function, level, activity, synthesis, release, binding, and needle, it avoids necrosis that can accompany intramus etc., based on the context in which the term “inhibit is used. cular administration of drugs, and trans-mucosal administra Preferably, inhibition is by at least 10%, more preferably by at tion of a drug is highly amenable to self administration. least 25%, even more preferably by at least 50%, and most 0207. As used herein, the term “nucleic acid’ encom preferably, the function is inhibited by at least 75%. The term passes RNA as well as single and double-stranded DNA and “inhibit is used interchangeably with “reduce” and “block.” cDNA. Furthermore, the terms, “nucleic acid, “DNA, (0199 The term “inhibit a complex,” as used herein, refers “RNA and similar terms also include nucleic acid analogs, to inhibiting the formation of a complex or interaction of two i.e. analogs having other than aphosphodiesterbackbone. For or more proteins, as well as inhibiting the function or activity example, the so-called "peptide nucleic acids,” which are of the complex. The term also encompasses disrupting a known in the art and have peptide bonds instead of phos formed complex. However, the term does not imply that each phodiester bonds in the backbone, are considered within the and every one of these functions must be inhibited at the same scope of the present invention. By “nucleic acid' is also time. meant any nucleic acid, whether composed of deoxyribo 0200. The term “inhibit a protein, as used herein, refers to nucleosides or ribonucleosides, and whether composed of any method or technique which inhibits protein synthesis, phosphodiester linkages or modified linkages Such as phos levels, activity, or function, as well as methods of inhibiting photriester, phosphoramidate, siloxane, carbonate, car US 2011/0065628 A1 Mar. 17, 2011 boxymethylester, acetamidate, carbamate, thioether, bridged 0214. A “recombinant polypeptide' is one which is pro phosphoramidate, bridged methylene phosphonate, bridged duced upon expression of a recombinant polynucleotide. phosphoramidate, bridged phosphoramidate, bridged meth 0215. A peptide encompasses a sequence of 2 or more ylene phosphonate, phosphorothioate, methylphosphonate, amino acids wherein the amino acids are naturally occurring phosphorodithioate, bridged phosphorothioate or Sulfone or synthetic (non-naturally occurring) amino acids. Peptide linkages, and combinations of Such linkages. The term mimetics include peptides having one or more of the follow nucleic acid also specifically includes nucleic acids com ing modifications: posed of bases other than the five biologically occurring bases 0216 1. peptides wherein one or more of the peptidyl (adenine, guanine, thymine, cytosine and uracil). Conven tional notation is used herein to describe polynucleotide —C(O)NR— linkages (bonds) have been replaced by a non sequences: the left-hand end of a single-stranded polynucle peptidyl linkage Such as a —CH2-carbamate linkage otide sequence is the 5'-end; the left-hand direction of a (—CH2OC(O)NR—), a phosphonate linkage, a —CH2-sul double-stranded polynucleotide sequence is referred to as the fonamide (—CH2-S(O)2NR—) linkage, a urea ( NHC(O) 5'-direction. The direction of 5' to 3' addition of nucleotides to NH-) linkage, a -CH2-secondary amine linkage, or with nascent RNA transcripts is referred to as the transcription an alkylated peptidyl linkage (—C(O)NR—) wherein R is direction. The DNA strand having the same sequence as an C1-C4 alkyl: mRNA is referred to as the “coding strand': sequences on the 0217 2. peptides wherein the N-terminus is derivatized to DNA strand which are located 5' to a reference point on the a —NRR1 group, to a —NRC(O)R group, to a NRC(O)OR DNA are referred to as "upstream sequences”: sequences on group, to a NRS(O)2R group, to a NHC(O)NHR group the DNA strand which are 3' to a reference point on the DNA where Rand R1 are hydrogen or C1-C4 alkyl with the proviso are referred to as "downstream sequences.” that R and R1 are not both hydrogen; 0208 Unless otherwise specified, a “nucleotide sequence 0218. 3. peptides wherein the C terminus is derivatized to encoding an amino acid sequence' includes all nucleotide —C(O)R2 where R2 is selected from the group consisting of sequences that are degenerate versions of each other and that C1-C4 alkoxy, and —NR3R4 where R3 and R4 are indepen encode the same amino acid sequence. Nucleotide sequences dently selected from the group consisting of hydrogen and that encode proteins and RNA may include introns. C1-C4 alkyl. 0209 “Obesity' is commonly referred to as a condition of 0219. The term “per application' as used herein refers to increased body weight due to excessive fat. Drugs to treat administration of a drug or compound to a subject. obesity are generally divided into three groups: (1) those that 0220. As used herein, the term “pharmaceutically accept decrease food intake. Such as drugs that interfere with able carrier includes any of the standard pharmaceutical monoamine receptors. Such as noradrenergic receptors, sero carriers, such as a phosphate buffered saline solution, water, tonin receptors, dopamine receptors, and histamine receptors; emulsions such as an oil/water or water/oil emulsion, and (2) those that increase metabolism; and (3) those that increase various types of wetting agents. The term also encompasses thermogenesis or decrease fat absorption by inhibiting pan any of the agents approved by a regulatory agency of the US creatic lipase (Bray, 2000, Nutrition, 16:953-960 and Leon Federal government or listed in the US Pharmacopeia for use hardt et al., 1999, Eur. J. Nutr., 38:1-13). Obesity has been in animals, including humans. defined interms of body mass index (BMI). BMI is calculated 0221. As used herein, the term “physiologically accept as weight (kg)/(height (m), according to the guidelines of able' ester or salt means an ester or salt form of the active the U.S. Centers for Disease Control and Prevention (CDC), ingredient which is compatible with any other ingredients of and the World Health Organization (WHO). Physical status: the pharmaceutical composition, and which is not deleterious The use and interpretation of anthropometry. Geneva, Swit to the subject to which the composition is to be administered. zerland: World Health Organization 1995. WHO Technical 0222. The term “prevent, as used herein, means to stop Report Series), for adults over 20 years old, BMI falls into one Something from happening, or taking advance measures of these categories: below 18.5 is considered underweight, against Something possible or probable from happening. In 18.5-24.9 is considered normal, 25.0-29.9 is considered over the context of medicine “prevention' generally refers to weight, and 30.0 and above is considered obese. action taken to decrease the chance of getting a disease or 0210. The term "oligonucleotide' typically refers to short condition. polynucleotides, generally no greater than about 50 nucle 0223) The term “problem drinker, as used herein, encom otides. It will be understood that when a nucleotide sequence passes individuals who drink excessively and who report that is represented by a DNA sequence (i.e., A, T, G, C), this also their alcohol consumption is causing them problems. Such includes an RNA sequence (i.e., A, U, G, C) in which “U” problems include, for example, driving while intoxicated, replaces “T” problems at work caused by excessive drinking, and relation 0211. The term "peptide' typically refers to short ship problems caused by excessive drinking by the Subject. polypeptides. 0224. As used herein, “protecting group” with respect to a 0212 “Polypeptide' refers to a polymer composed of terminal amino group refers to a terminal amino group of a amino acid residues, related naturally occurring structural peptide, which terminal amino group is coupled with any of variants, and synthetic non-naturally occurring analogs various amino-terminal protecting groups traditionally thereof linked via peptide bonds, related naturally occurring employed in peptide synthesis. Such protecting groups structural variants, and synthetic non-naturally occurring include, for example, acyl protecting groups such as formyl. analogs thereof. Synthetic polypeptides can be synthesized, acetyl, benzoyl, trifluoroacetyl. Succinyl, and methoxysucci for example, using an automated polypeptide synthesizer. nyl; aromatic urethane protecting groups such as benzyloxy 0213 The term “protein’ typically refers to large polypep carbonyl; and aliphatic urethane protecting groups, for tides. example, tert-butoxycarbonyl or adamantyloxycarbonyl. See US 2011/0065628 A1 Mar. 17, 2011

Gross and Mienhofer, eds. The Peptides, vol. 3, pp. 3-88 marker of interest which has been labeled, such as with a (Academic Press, New York, 1981) for suitable protecting radioactive isotope, allowing it to be distinguished from an groups. endogenous marker. 0225. As used herein, “protecting group” with respect to a 0233. A “subject of diagnosis or treatment is a mammal, terminal carboxy group refers to a terminal carboxyl group of including a human. a peptide, which terminal carboxyl group is coupled with any 0234. The term “subject comprises a predisposition to the of various carboxyl-terminal protecting groups. Such protect early onset of alcoholism, as used herein, refers to a subject ing groups include, for example, tert-butyl, benzyl, or other who has, or is characterized by, a predisposition to the early acceptable groups linked to the terminal carboxyl group onset of alcoholism. through an ester or ether bond. 0235. The term “symptom, as used herein, refers to any 0226. The term "psychosocial management program, as morbid phenomenon or departure from the normal in struc used herein, relates to the use of various types of counseling ture, function, or sensation, experienced by the patient and and management techniques used to Supplement the combi indicative of disease. In contrast, a sign is objective evidence nation pharmacotherapy treatment of addictive and alcohol of disease. For example, a bloody nose is a sign. It is evident related diseases and disorders. to the patient, doctor, nurse and other observers. 0227. As used herein, the term “purified’ and like terms 0236. As used herein, the term “treating may include relate to an enrichment of a molecule or compound relative to prophylaxis of the specific disease, disorder, or condition, or other components normally associated with the molecule or alleviation of the symptoms associated with a specific dis compound in a native environment. The term “purified' does ease, disorder or condition and/or preventing or eliminating not necessarily indicate that complete purity of the particular said symptoms. A "prophylactic' treatment is a treatment molecule has been achieved during the process. A "highly administered to a subject who does not exhibit signs of a disease or exhibits only early signs of the disease for the purified’ compound as used herein refers to a compound that purpose of decreasing the risk of developing pathology asso is greater than 90% pure. ciated with the disease. “Treating is used interchangeably 0228 “Reduce see “inhibit'. with “treatment herein. 0229. The term “regulate” refers to either stimulating or 0237. A “therapeutic' treatment is a treatment adminis inhibiting a function or activity of interest. tered to a subject who exhibits signs of pathology for the 0230. A “sample, as used herein, refers to a biological purpose of diminishing or eliminating those signs. sample from a subject, including, but not limited to, normal 0238 A “therapeutically effective amount” of a com tissue samples, diseased tissue samples, biopsies, blood, pound is that amount of compound which is sufficient to saliva, feces, semen, tears, and urine. A sample can also be provide a beneficial effect to the subject to which the com any other source of material obtained from a subject which pound is administered. contains cells, tissues, or fluid of interest. 0231. By “small interfering RNAs (siRNAs) is meant, Chemical Definitions inter alia, an isolated dsRNA molecule comprising both a sense and an anti-sense Strand. In one aspect, it is greater than 0239. As used herein, the term “halogen' or “halo' 10 nucleotides in length. siRNA also refers to a single tran includes bromo, chloro, fluoro, and iodo. Script which has both the sense and complementary antisense 0240. The term “haloalkyl as used herein refers to an sequences from the target gene, e.g., a hairpin. siRNA further alkyl radical bearing at least one halogen Substituent, for includes any form of dsRNA (proteolytically cleaved prod example, chloromethyl, fluoroethyl or trifluoromethyl and ucts of larger dsRNA, partially purified RNA, essentially pure the like. RNA, synthetic RNA, recombinantly produced RNA) as well 0241 The term "C-C alkyl” wherein n is an integer, as as altered RNA that differs from naturally occurring RNA by used herein, represents a branched or linear alkyl group hav the addition, deletion, substitution, and/or alteration of one or ing from one to the specified number of carbon atoms. Typi more nucleotides. cally, C-C alkyl groups include, but are not limited to, 0232 By the term “specifically binds, as used herein, is methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, Sec-bu meant a molecule which recognizes and binds a specific mol tyl, tert-butyl, pentyl, hexyl, and the like. ecule, but does not substantially recognize orbind other mol 0242. The term "C-C, alkenyl' whereinn is an integer, as ecules in a sample, or it means binding between two or more used herein, represents an olefinically unsaturated branched molecules as in part of a cellular regulatory process, where or linear group having from two to the specified number of said molecules do not substantially recognize or bind other carbonatoms and at least one double bond. Examples of Such molecules in a sample. The term "standard, as used herein, groups include, but are not limited to, 1-propenyl, 2-propenyl, refers to something used for comparison. For example, it can 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl, and the like. be a known standard agent or compound which is adminis 0243 The term "C-C, alkynyl' wherein n is an integer tered or added and used for comparing results when adding a refers to an unsaturated branched or linear group having from test compound, or it can be a standard parameter or function two to the specified number of carbon atoms and at least one which is measured to obtain a control value when measuring triple bond. Examples of Such groups include, but are not an effect of an agent or compound on a parameter or function. limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, Standard can also refer to an “internal standard’. Such as an 1-pentynyl, and the like. agent or compound which is added at known amounts to a 0244. The term "C-C cycloalkyl” wherein n=8, repre sample and is useful in determining such things as purifica sents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tion or recovery rates when a sample is processed or Subjected cycloheptyl, and cyclooctyl. to purification or extraction procedures before a marker of 0245. As used herein, the term “optionally substituted interest is measured. Internal standards are often a purified refers to from Zero to four substituents, wherein the substitu US 2011/0065628 A1 Mar. 17, 2011 ents are each independently selected. Each of the indepen encompasses the use of adjunctive treatments and therapy dently selected substituents may be the same or different than Such as psychosocial management regimes, hypnosis, and other substituents. acupuncture. 0246. As used herein the term “aryl' refers to an option 0253) In some embodiments, a first compound and a sec ally Substituted mono- or bicyclic carbocyclic ring system ond compound are administered nearly simultaneously. In having one or two aromatic rings including, but not limited to, other embodiments, a first compound is administered prior to phenyl, benzyl, naphthyl, tetrahydronaphthyl, indanyl, inde the second compound. In yet other embodiments, the first compound is administered Subsequent to the second com nyl, and the like. “Optionally substituted aryl includes aryl pound. If three or more compounds are administered, one of compounds having from Zero to four Substituents, and “sub ordinary skill in the art will appreciate that the three or more stituted aryl' includes aryl compounds having one or more compounds can be administered simultaneously or in varying substituents. The term (C-C alkyl)aryl refers to any aryl order. group which is attached to the parent moiety via the alkyl 0254. In certain embodiments disclosed herein, an indi group. vidual is given a pharmaceutical composition comprising a 0247 The term "heterocyclic group’ refers to an option combination of two or more compounds to treat or prevent an ally Substituted mono- or bicyclic carbocyclic ring system addiction-related disease or disorder or impulse control-re containing from one to three heteroatoms wherein the het lated disease or disorder. In some of these embodiments, each eroatoms are selected from the group consisting of oxygen, compound is a separate chemical entity. However, in other sulfur, and nitrogen. As used herein the term "heteroaryl' embodiments, the at least two compounds can be joined refers to an optionally Substituted mono- or bicyclic carbocy together by a chemical linkage, such as a covalent bond, so clic ring system having one or two aromatic rings containing that the at least two different compounds form separate parts from one to three heteroatoms and includes, but is not limited of the same molecule. In one aspect, the chemical linkage is to, furyl, thienyl, pyridyl and the like. selected such that after entry into the body, the linkage is broken, such as by enzymatic action, acid hydrolysis, base 0248. The term “bicyclic' represents eitheran unsaturated hydrolysis, or the like, and the two separate compounds are or saturated stable 7- to 12-membered bridged or fused bicy then formed. clic carbon ring. The bicyclic ring may be attached at any 0255 Data from previous structure-activity relationship carbon atom which affords a stable structure. The term (SAR) studies within the art may be used as a guide to deter includes, but is not limited to, naphthyl, dicyclohexyl, dicy mine which compounds to use and the optimal position or clohexenyl, and the like. positions on the molecules to attach the tether such that 0249. The compounds of the present invention contain one potency and selectivity of the compounds will remain high. or more asymmetric centers in the molecule. In accordance The tether or linker moiety is chosen from among those of with the present invention a structure that does not designate demonstrated utility for linking bioactive molecules together. the stereochemistry is to be understood as embracing all the Disclosed herein are representative compounds that can be various optical isomers, as well as racemic mixtures thereof. attached together in different combinations to form hetero 0250. The compounds of the present invention may exist bivalent therapeutic molecules. in tautomeric forms and the invention includes both mixtures 0256 Examples of linkers reported in the scientific litera and separate individual tautomers. For example the following ture include methylene (CH), linkers (Hussey et al., J. Am. Structure: Chem. Soc., 2003, 125:3692-3693; Tamiz et al., J. Med. Chem..., 2001, 44:1615-1622), oligo ethyleneoxy O( CHCHO ), units used to link naltrexamine to other N% NH opioids, glycine oligomers of the formula —NH (COCH-NH), COCHCHCO (NHCHCO)NH- used to link opioid antagonists and agonists together ((a) Portogh ese et al., Life Sci., 1982,31:1283-1286. (b) Portoghese et al., is understood to represent a mixture of the structures: J. Med. Chem., 1986, 29:1855-1861), hydrophilic diamines used to link opioid peptides together (Stepinski et al., Inter nat. J. of Peptide & Protein Res., 1991, 38:588-92), rigid N% NH and N1\N, double stranded DNA spacers (Paaret al., J. Immunol., 2002, 169:856-864) and the biodegradable linker poly(L-lactic acid) (Klok et al., Macromolecules, 2002, 35:746-759). The attachment of the tether to a compound can result in the 0251. The term “pharmaceutically-acceptable salt” refers compound achieving a favorable binding orientation. The to salts which retain the biological effectiveness and proper linker itselfmay or may not be biodegradable. The linker may ties of the compounds of the present invention and which are take the form of a prodrug and be tunable for optimal release not biologically or otherwise undesirable. In many cases, the kinetics of the linked drugs. The linker may be either confor compounds of the present invention are capable of forming mationally flexible throughout its entire length or else a seg acid and/or base salts by virtue of the presence of amino ment of the tether may be designed to be conformationally and/or carboxyl groups or groups similar thereto. restricted (Portoghese et al., J. Med. Chem., 1986, 29:1650 1653). Embodiments 0257 With respect to alcohol-related disorders, including but not limited to alcohol abuse and alcohol dependence, at 0252. The present invention encompasses the use of com least two compounds selected from the group consisting of binations of drugs or compounds to treat addictive and com topiramate, ondansetron, and naltrexone, and analogs, deriva pulsive diseases and disorders, particular alcohol-related dis tives, and modifications thereof, and pharmaceutically eases and disorders. The present invention further acceptable salts thereof, can be used to decrease ethanol US 2011/0065628 A1 Mar. 17, 2011

consumption associated with Such alcohol-related disorders. 0262 The effectiveness of treatment or prevention of alco In one aspect, topiramate and ondansetron are used. Accord hol-related diseases and disorders can be detected and mea ingly, the present invention provides a method for treating or Sured in several ways. For example, Subjects can self-report preventing alcohol-related disorders based on ethanol con according to guidelines and procedures set up for Such report Sumption, comprising administering to a Subject in need of ing. Objective measures of alcohol consumption include the Such treatment or prevention an effective amount of at least use of breath alcohol meter readings, measuring serum CDT two compounds selected from the group consisting of topira levels, and measuring serum Y-glutamyl transferase (GGT) mate, ondansetron, and naltrexone, and analogs, derivatives, levels. Urinary 5-HTOL may also be measured and is an and modifications thereof or a pharmaceutically acceptable indicator of recent alcohol consumption. 5-HTOL is a minor salt thereof. In a further aspect, the combination pharmaco metabolite of 5-HT. More than one of these types of assays therapy treatment is used in conjunction with behavioral may be performed to ensure accuracy. Other subjective and modification or therapy. objective measures are also known. These measurements can 0258. The present invention encompasses biologically be taken or performed at various times before, during, and active analogs, homologs, derivatives, and modifications of after treatment. the compounds of the invention. Methods for the preparation 0263. The routes of administration, dosage amounts, and of Such compounds are known in the art. In one aspect, the dosage forms described herein can be utilized for the admin compounds are topiramate, ondansetron, and naltrexone. istration of compounds of the invention or pharmaceutically 0259 Topiramate (CHNOS: IUPAC name: 2,3:4,5- acceptable salt thereof for the prevention or treatment of Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfa ethanol consumption. Suitable forms of the compounds for mate; CAS Registry No. 97240-79-4) has the following struc use in biologically active compositions and methods of the ture: present invention include its pharmaceutically acceptable salts, polymorphs, Solvates, hydrates, and prodrugs. 0264. Administration of an effective amount of at least O NH. two compounds of the invention, or pharmaceutically accept \\". able salts thereof, whether alone or in combination with a O o/ NN secondary therapeutic agent, to a subject will detectably treat O O or prevent ethanol consumption in the Subject. In exemplary embodiments, administration of at least two compounds of O O the invention, or pharmaceutically acceptable salts thereof, theHC As l"CH whether alone or in combination with additional therapeutic agents, will yield a reduction in ethanol consumption by at least about 10%, 20%, 30%, 50% or greater, up to about 0260 Ondansetron (CHNO; CAS Registry No. 75-90%, or about 95% or greater. 996.14-02-5; IUPAC name: 9-methyl-3-(2-methyl-1H-imi 0265. The present compositions can optionally comprise a dazol-1-yl)methyl-1,2,3,9-tetrahydrocarbazol-4-One) has Suitable amount of a pharmaceutically acceptable vehicle so the following structure: as to provide the form for proper administration to the patient. 0266 The present compositions can also be administered to a subject in combination with behavioral therapy or inter CH3 action. N 0267 Included within the scope of this invention are the various individual anomers, diastereomers and enantiomers as well as mixtures thereof. In addition, the compounds of this invention also include any pharmaceutically acceptable salts, for example: alkali metal salts, such as Sodium and potas sium; ammonium salts; monoalkylammonium salts; dialky lammonium salts; trialkylammonium salts; tetraalkylammo nium salts; and tromethamine salts. Hydrates and other 0261 Naltrexone (CHNO; 17-(Cyclopropylmethyl)- solvates of the compounds are included within the scope of 4.5a-epoxy-3, 14-dihydroxymorphinan-6-one hydrochloride; this invention. CAS Registry No. 16590-41-3) has the following structure: 0268 Additional therapeutic agents administered as com bination therapies to treat alcohol-related disorders can

include traditional anti-alcohol agents and/or other agents. Useful anti-alcohol agents in combinatorial formulations and coordinate treatment methods of the invention include, but are not limited to: disulfiram (Litten et al., Expert Opin Emerg. Drugs 10(2):323-43, 2005); maltrexone (Volpicelli et al., Arch. Gen. Psychiatry 49:876-880,1992: O'Malley et al., Arch. Gen. Psychiatry 49(11):881-887, 1992); acamprosate (CampralR) (Swift, N. Engl. J. Med. 340(19): 1482–1490, 1999); ondansetron (Pettinati et al., Alcohol Clin. Exp. Res. 24(7):1041-1049, 2000; Stoltenberg, Scott, Clinical & Experimental Research 27(12):1853-1859, 2003); sertraline (Zoloft(R) (Pettinati et al., Alcohol Clin. Exp. Res. 24(7): 1041-1049, 2000); tiapride (Shaw et al., Br. J. Psychiatry US 2011/0065628 A1 Mar. 17, 2011

150: 164–8, 1987); gamma hydroxybutyrate (Alcover(R) (Pol 0275. The other therapeutic agent can be an anti-phencyc drugo F. and Addolorato G., Alcohol Alcoholism 34(1), lidine (“anti-PCP) agent. Useful anti-PCP agents include, 15-24, 1999); galanthamine (Novel pharmacotherapies and but are not limited to, haloperidol. patents for alcohol abuse and alcoholism 1998-2001, Expert 0276. The other therapeutic agent can be an anti-Parkin Opinion on Therapeutic Patents, Vol. 11, No. 10, pages 1497 son’s-disease agent. Useful anti-Parkinson’s-disease agents 1521 (2001): U.S. Pat. No. 5,932.238); nalmefene (Revex) include, but are not limited to, dopamine precursors, such as (Drobes et al., Alcohol Clin Exp Res., 28(9): 1362-70 (2004); levodopa, L-phenylalanine, and L-tyrosine; neuroprotective naloxone (Julius, D., and Renault, P., eds., Narcotic Antago agents; dopamine agonists; dopamine reuptake inhibitors; nists: Naltrexone Progress Report, NIDA Research Mono anticholinergics such as amantadine and memantine; and 1.3, graph Series, Number 9. DHEW Publication No. (ADM) 5-trisubstituted adamantanes, such as 1-amino-3,5-dimethyl adamantane (U.S. Pat. No. 4,122,193 to Sherm et al.). 76-387, Bethesda, Md. National Institute on Drug Abuse, 0277. The other therapeutic agent can be an anti-depres 1976; Jenab and Inturrisi, Molecular Brain Research 27:95 sion agent. Useful anti-depression agents include, but are not 102, 1994); desoxypeganine (Doetkotte et al., Alcoholism: limited to, amitriptyline, clomipramine, doxepine, imi Clinical & Experimental Research, International Society for pramine, trimipramine, amoxapine, desipramine, mapro Biomedical Research on Alcoholism 12th World Congress on tiline, nortriptyline, protripylinc, fluoxetine, fluvoxamine, Biomedical Alcohol Research, Sep. 29-Oct. 2, 2004, Heidel paroxetine, Sertraline, Venlafaxine, bupropion, nefazodone, burg/Mannheim, Germany, 28(8) Supplement:25A, 2004); traZodone, phenelzine, tranylcypromine, Selegiline, cloni benzodiazepines (Ntais et al., Benzodiazepines for alcohol dine, gabapentin, and 2-pyridinyl 7-(pyridine-4-yl)pyrazolo withdrawal, Cochrane Database Syst. Rev. (3):CD005063, 1.5-alpyrimidin-3-yl)methanone compounds having at least 2005; Mueller TI et al., Alcohol Clin. Exp. Res. 29(8): 1411 one substituent on both the 2- and 4-pyridinyl rings. Useful 8, 2005); neuroleptics such as laevomepromazine (Neuro classes of antidepressant agents include without limitation cil(R) and thioridazine (Melleril.R.); piracetam; clonidine; car monoamine oxidase inhibitors, selective serotonin reuptake bamazepine; clomethiazole (DistraneurinR); levetiracetam; inhibitors, tricyclic antidepressants, tetracyclic antidepres quetiapine (Monnelly et al., J. Clin. Psychopharmacol. 24(5): sants, norepinephrine uptake inhibitors, selective norepi 532–5, 2004); risperidone; rimonabant; trazodone (Janiri et nephrine reuptake inhibitors, and serotonin and norepineph al., Alcohol 33(4):362-5, 1998); topiramate (Johnson B A et rine uptake inhibitors. al., Lancet 361: 1677-1685, 2003); aripiprazole (Beresford et 0278. The other therapeutic agent can be an anxiolytic al., J. Clin. Psychopharmacol. 25(4):363-6, 2005); and agent. Useful anxiolytic agents include, but are not limited to, modafinil (Saletu et al., Prog. Neuropsychopharmacol. Biol. benzodiazepines, such as alprazolam, chlordiazepoxide, Psychiatry 14(2):195-214, 1990); amperozide, and modafi clonazepam, cloraZepate, diazepam, halazepam, lorazepam, nil. oxazepam, and prazepam, non-benzodiazepine agents. Such 0269. The sulfamate derivatives of topiramate, or any of as buspirone; and tranquilizers, such as barbiturates. the other compounds of the invention and their derivatives, 0279. The other therapeutic agent can be an antipsychotic analogs or modifications thereof, may be used in conjunction drug. Useful antipsychotic drugs include, but are not limited with one or more other drug compounds and according to the to, phenothiazines, such as chlorpromazine, mesoridazine methods of the present invention so long as the pharmaceu besylate, thioridazine, acetophenazine maleate, fluphena tical agent has a use that is also effective in treating alcohol Zine, perphenazine, and trifluoperazine; thioxanthenes, such related disorders. Those of ordinary skill in the art will be able as chlorprothixene, and thiothixene; and other heterocyclic to identify readily those pharmaceutical agents that have util compounds, such as clozapine, haloperidol, loxapine, molin ity with the present invention. Those of ordinary skill in the art donc, pimozide, and risperidone. Exemplary anti-psychotic will recognize also numerous other compounds that fall drugs include chlorpromazine HCl, thioridazine HCl, within the categories and that are useful according to the fluphenazine HCl, thiothixene HCl, and molindone HC1. invention for treating alcohol-related disorders. In one aspect, 0280. The other therapeutic agent can be an anti-obesity the anti-alcohol compounds of the invention are used in com drug. Useful anti-obesity drugs include, but are not limited, to bination with drugs useful for other conditions. beta-adrenergic receptor agonists, for example beta-3 recep toragonists Such as, but not limited to, fenfluramine; dexfen 0270. The other therapeutic agent can be an anti-nicotine fluramine; sibutramine; bupropion; fluoxetine; phentermine; agent. Useful anti-nicotine agents include, but are not limited amphetamine; methamphetamine; dextroamphetamine; ben to, clonidine and bupropion. Zphetamine; phendimetrazine; diethylpropion; mazindol; 0271 The other therapeutic agent can be an anti-opiate phenylpropanolamine; norepinephrine; serotonin reuptake agent. Useful anti-opiate agents include, but are not limited inhibitors, such as Sibutramine; and pancreatic lipase inhibi to, methadone, clonidine, lofexidine, levomethadyl acetate tors. Such as orlistat. HCl, naltrexone, and buprenorphine. 0281. A list of types of drugs, and specific drugs within 0272. The other therapeutic agent can be an anti-cocaine categories which are encompassed within the invention is agent. Useful anti-cocaine agents include, but are not limited provided below. to, desipramine, amantadine, fluoxidine, and buprenorphine. 0282 Adrenergic: Adrenalone; Amidephrine Mesylate: 0273. The other therapeutic agent can be an appetite Sup Apraclonidine Hydrochloride; Brimonidine Tartrate; pressant. Useful appetite Suppressants include, but are not Dapiprazole Hydrochloride; Deterenol Hydrochloride: limited to, fenfluramine, phenylpropanolamine, and mazin Dipivefrin; Dopamine Hydrochloride; Ephedrine Sulfate: dol. Epinephrine: Epinephrine Bitartrate; Epinephryl Borate; 0274 The other therapeutic agent can be an anti-lysergic Esproquin Hydrochloride; Etafedrine Hydrochloride: acid diethylamide (“anti-LSD) agent. Useful anti-LSD Hydroxyamphetamine Hydrobromide: Levonordefrin; agents include, but are not limited to, diazepam. Mephentermine Sulfate; Metaraminol Bitartrate; Metizoline US 2011/0065628 A1 Mar. 17, 2011

Hydrochloride; Naphazoline Hydrochloride; Norepinephrine Hydrochloride; Pemedolac, Pentamorphone; Pentazocine; Bitartrate; Oxidopamine: Oxymetazoline Hydrochloride: Pentazocine Hydrochloride; Pentazocine Lactate; Phenylephrine Hydrochloride; Phenylpropanolamine Hydro Phenazopyridine Hydrochloride; Phenyramidol Hydrochlo chloride; Phenylpropanolamine Polistirex: Prenalterol ride; Picenadol Hydrochloride; Pinadoline; Pirfenidone; Hydrochloride; Propylhexedrine; Pseudoephedrine Hydro Piroxicam Olamine; Pravadoline Maleate; Prodilidine chloride; Tetrahydrozoline Hydrochloride; Tramazoline Hydrochloride; Profadol Hydrochloride; Propirarn Fuma Hydrochloride; Xylometazoline Hydrochloride. rate; Propoxyphene Hydrochloride; Propoxyphene Napsy 0283 Adrenocortical steroid: Ciprocinonide; Desoxycor late: Proxazole; Proxazole Citrate; Proxorphan Tartrate; Pyr ticosterone Acetate; Desoxycorticosterone Pivalate; Dexam roliphene Hydrochloride; Remifentanil Hydrochloride; ethasone Acetate; Fludrocortisone Acetate; Flumoxonide; Salcolex: Salethamide Maleate; Salicylamide: Salicylate Hydrocortisone Hemisuccinate; Methylprednisolone Meglumine; Salsalate: Sodium Salicylate: Spiradoline Mesy Hemisuccinate; Naflocort; Procinonide; Timobesone late; Sufentanil; Sufentanil Citrate; Talmetacin; Talniflumate; Acetate; Tipredane. Talosalate: Tazadolene Succinate; Tebufelone; Tetrydamine: 0284 Adrenocortical suppressant: Aminoglutethimide: Tifurac Sodium; Tilidine Hydrochloride; Tiopinac; Tonazo Trilostane. cine Mesylate: Tramadol Hydrochloride; Trefentanil Hydro 0285 Alcohol deterrent: Disulfiram. chloride; Trolamine; Veradoline Hydrochloride; Verilopam 0286 Aldosterone antagonist: Canrenoate Potassium; Hydrochloride; Volazocine: Xorphanol Mesylate: Xylazine Canrenone; Dicirenone; Mexrenoate Potassium; Prorenoate Hydrochloride; Zenazocine Mesylate: Zomepirac Sodium; Potassium; Spironolactone. Zucapsaicin. 0287 Amino acid: Alanine: Aspartic Acid; Cysteine 0290 Anorectic compounds including dexfenfluramine. Hydrochloride: Cystine: Histidine: Isoleucine; Leucine; 0291 Anorexic: Aminorex: Amphecloral; Chlorphenter Lysine; Lysine Acetate; Lysine Hydrochloride; Methionine: mine Hydrochloride; Clominorex; Clortennine Hydrochlo Phenylalanine: Proline: Serine: Threonine; Tryptophan; ride; Diethylpropion Hydrochloride; Fenfluramine Hydro Tyrosine; Valine. chloride; Fenisorex: Fludorex: Fluminorex; Levamfetamine 0288 Analeptic: Modafinil. Succinate; Mazindol; Mefenorex Hydrochloride; Phenmetra 0289 Analgesic: Acetaminophen; Alfentanil Hydrochlo zine Hydrochloride; Phentermine: Sibutramine Hydrochlo ride; Aminobenzoate Potassium; Aminobenzoate Sodium; ride. Anidoxime; Anileridine; Anileridine Hydrochloride; Anilo 0292 Anti-anxiety agent: Adatanserin Hydrochloride; pam Hydrochloride: Anirolac.; Antipyrine: Aspirin; Benox Alpidem; Binospirone Mesylate; Bretazenil; Glemanserin; aprofen; Benzydamine Hydrochloride; Biciifadine Hydro Ipsapirone Hydrochloride; Mirisetron Maleate; Ocinaplon; chloride; Brifentanil Hydrochloride; Bromadoline Maleate; Ondansetron Hydrochloride; Panadiplon; Pancopride; Pazi Bromfenac Sodium: Buprenorphine Hydrochloride: Butace naclone; Serazapine Hydrochloride; Tandospirone Citrate; tin; Butixirate; Butorphanol; Butorphanol Tartrate; Carbam Zalospirone Hydrochloride. azepine; Carbaspirin Calcium; Carbiphene Hydrochloride: 0293 Anti-cannabis agent: Rimonabant and other useful Carfentanil Citrate: Ciprefadol Succinate; Ciramadol; Cira drugs, including drugs regulating the cannabanoid receptors. madol Hydrochloride; Clonixeril; Clonixin: Codeine; 0294 Antidepressant: Adatanserin Hydrochloride; Adina Codeine Phosphate: Codeine Sulfate; Conorphone Hydro Zolam, Adinazolam Mesylate; Alaproclate; Aletamine chloride: Cyclazocine; Dexoxadrol Hydrochloride; Dex Hydrochloride; Amedalin Hydrochloride; Amitriptyline pemedolac, Dezocine; Diflunisal; Dihydrocodeine Bitaritrate; Hydrochloride. Amoxapine; Aptazapine Maleate; AZaloxan Dimefadane; Dipyrone; Doxpicomine Hydrochloride; Drin Fumarate; Azepindole: Azipramine Hydrochloride; Bipenar idene: Enadoline Hydrochloride: Epirizole; Ergotamine Tar nol Hydrochloride; Bupropion Hydrochloride; Butacetin: trate; Ethoxazene Hydrochloride; Etofenamate; Eugenol; Butriptyline Hydrochloride; Caroxazone; Cartazolate: Fenoprofen; Fenoprofen Calcium; Fentanyl Citrate; Floc Ciclazindol; Cidoxepin Hydrochloride: Cilobamine Mesy tafenine: Flufenisal; Flunixin: Flunixin Meglumine: Flupir late; Clodazon Hydrochloride; Clomipramine Hydrochlo tine Maleate: FluproduaZone: Fluradoline Hydrochloride; ride; Cotinine Fumarate; Cyclindole: Cypenamine Hydro Flurbiprofen; Hydromorphone Hydrochloride; Ibufenac: chloride; Cyprolidol Hydrochloride; Cyproximide: Indoprofen; Ketazocine; Ketorfanol: Ketorolac Daledalin Tosylate; Dapoxetine Hydrochloride; Dazadrol Tromethamine: Letimide Hydrochloride; Levomethadyl Maleate; Dazepinil Hydrochloride; Desipramine Hydrochlo Acetate; Levomethadyl Acetate Hydrochloride; Levonantra ride; Dexamisole; Deximafen; Dibenzepin Hydrochloride; dol Hydrochloride; Levorphanol Tartrate; Lofemizole Dioxadrol Hydrochloride; Dothiepin Hydrochloride; Dox Hydrochloride; Lofentanil Oxalate: Lorcinadol; Lomoxi epin Hydrochloride; Duloxetine Hydrochloride; Eclanamine cam: Magnesium Salicylate; Mefenamic Acid; Menabitan Maleate; Encyprate; Etoperidone Hydrochloride; Fantridone Hydrochloride; Meperidine Hydrochloride; Meptazinol Hydrochloride: Fehmetozole Hydrochloride; Fenmetramide: Hydrochloride; Methadone Hydrochloride; Methadyl Fezolamine Fumarate: Fluotracen Hydrochloride: Fluoxet Acetate; Methopholine; Methotrimeprazine; Metkephamid ine: Fluoxetine Hydrochloride: Fluparoxan Hydrochloride: Acetate; Mimbane Hydrochloride; Mirfentanil Hydrochlo Gamfexine; Guanoxyfen Sulfate: Imafen Hydrochloride: ride; MolinaZone: Morphine Sulfate; Moxazocine; Nabitan Imiloxan Hydrochloride: Imipramine Hydrochloride; Indel Hydrochloride; Nalbuphine Hydrochloride; Nalmexone oxazine Hydrochloride; Intriptyline Hydrochloride; prin Hydrochloride: Namoxyrate; Nantradol Hydrochloride: dole; Isocarboxazid; Ketipramine Fumarate; Lofepramine Naproxen; Naproxen Sodium; Naproxol; Nefopam Hydro Hydrochloride; Lortalamine: Maprotiline: Maprotiline chloride; Nexeridine Hydrochloride; Noracymethadol Hydrochloride; Melitracen Hydrochloride; Milacemide Hydrochloride; Ocfentanil Hydrochloride; Octazamide: Hydrochloride; Minaprine Hydrochloride; Mirtazapine; Olvanil; Oxetorone Fumarate: Oxycodone; Oxycodone Moclobemide: Modaline Sulfate; Napactadine Hydrochlo Hydrochloride: Oxycodone Terephthalate: Oxymorphone ride; Napamezole Hydrochloride: Nefazodone Hydrochlo US 2011/0065628 A1 Mar. 17, 2011 20 ride; Nisoxetine; Nitrafudam Hydrochloride: Nomifensine chloride; Trimethaphan Camsylate; Trimoxamine Hydro Maleate; Nortriptyline Hydrochloride; Octriptyline Phos chloride; Tripamide; Xipamide; Zankiren Hydrochloride: phate; Opipramol Hydrochloride: Oxaprotiline Hydrochlo Zofenoprilat Arginine. ride; Oxypertine: Paroxetine; Phenelzine Sulfate; Piran 0296 Anti-inflammatory: Alclofenac; Alclometasone damine Hydrochloride; Pizotyline; Pridefine Hydrochloride: Dipropionate; Algestone Acetonide; Alpha Amylase; Prolintane Hydrochloride; Protriptyline Hydrochloride: Qui Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose pazine Maleate; Rolicyprine; Seproxetine Hydrochloride; Hydrochloride; Anakinra, Anirolac, AnitraZafen; ApaZone; Sertraline Hydrochloride: Sibutramine Hydrochloride: Balsalazide Disodium; Bendazac. Benoxaprofen; Benzy Sulpiride; Suritozole; Tametraline Hydrochloride; Tam damine Hydrochloride; Bromelains; Broperamole; Budes pramine Fumarate: Tandamine Hydrochloride; Thiazesim onide; Carprofen; Cicloprofen; Cintazone; Cliprofen; Clobe Hydrochloride; Thozalinone; Tomoxetine Hydrochloride: tasol Propionate; Clobetasone Butyrate; Clopirac: Trazodone Hydrochloride; Trebenzomine Hydrochloride: Cloticasone Propionate; Cormethasone Acetate; Cortodox Trimipramine; Trimipramine Maleate; Venlafaxine Hydro one; Deflazacort: Desonide; Desoximetasone; Dexametha chloride; Viloxazine Hydrochloride; Zimeldine Hydrochlo sone Dipropionate; Diclofenac Potassium; Diclofenac ride; Zometapine. Sodium; Diflorasone Diacetate; Diflumidone Sodium; 0295) Antihypertensive: AflyZosin Hydrochloride; Alipa Diflunisal; Difluprednate; Diftalone; Dimethyl Sulfoxide: mide: Althiazide; Amiquinsin Hydrochloride; Amlodipine Drocinonide; Endrysone; Enlimomab: Enolicam Sodium; Besylate: Amlodipine Maleate; Anaritide Acetate; Atiprosin Epirizole; Etodolac.; Etofenamate; Felbinac; Fenamole: Fen Maleate; Belfosdil; Bemitradine; Bendacalol Mesylate; Ben bufen: Fenclofenac; Fenclorac: Fendosal: Fenpipalone: Fen droflumethiazide; Benzthiazide: Betaxolol Hydrochloride: tiazac, Flazalone; Fluazacort; Flufenamic Acid, Flumizole; Flunisolide Acetate: Flunixin: Flumixin Meglumine: Fluocor Bethanidine Sulfate; Bevantolol Hydrochloride; Biclodil tin Butyl; Fluorometholone Acetate: FluguaZone: Flurbipro Hydrochloride; Bisoprolol; Bisoprolol Fumarate; Bucindolol fen: Fluretofen; Fluticasone Propionate; Furaprofen; Hydrochloride; Bupicomide: Buthiazide: Candoxatril; Can Furobufen; Halcinonide; Halobetasol Propionate; Halopre doxatrilat; Captopril; Carvedilol; Ceronapril; Chlorothiazide done Acetate; Ibufenac; Ibuprofen; Ibuprofen Aluminum; Sodium: Cicletanine: Cilazapril; Clonidine; Clonidine Ibuprofen Piconol; Ilonidap: Indomethacin; Indomethacin Hydrochloride; Clopamide: Cyclopenthiazide: Cyclothiaz Sodium; Indoprofen; Indoxole: Intrazole; Isoflupredone ide: Darodipine; Debrisoquin Sulfate; Delapril Hydrochlo Acetate; ISOXepac; Isoxicam; Ketoprofen; Lofemizole ride; Diapamide: Diazoxide: Dilevalol Hydrochloride: Dilt Hydrochloride; Lornoxicam; Loteprednol Etabonate: iazem Malate; Ditekiren: Doxazosin Mesylate: Ecadotril; Meclofenamate Sodium; Meclofenamic Acid, Meclorisone Enalapril Maleate; Enalaprilat; Enalkiren: Endralazine Dibutyrate; Mefenamic Acid; Mesalamine; MeseclaZone: Mesylate: Epithiazide: Eprosartan; Eprosartan Mesylate: Methylprednisolone Suleptanate; Momiflumate; Nabume Fenoldopam Mesylate: Flavodilol Maleate; Flordipine; tone; Naproxen; Naproxen Sodium; Naproxol; Nimazone: Flosequinan; Fosinopril Sodium; Fosinoprilat; Guanabenz; Olsalazine Sodium; Orgotein; Orpanoxin: Oxaprozin; Guanabenz, Acetate; Guanacline Sulfate; Guanadrel Sulfate; Oxyphenbutazone; Paranyline Hydrochloride; Pentosan Guancydine; Guanethidine Monosulfate; Guanethidine Sul Polysulfate Sodium; Phenbutazone Sodium Glycerate; Pir fate; Guanfacine Hydrochloride; Guanisoquin Sulfate; Gua fenidone; Piroxicam, Piroxicam Cinnamate; Piroxicam Ola noclor Sulfate; Guanoctine Hydrochloride; Guanoxabenz; mine: Pirprofen; Prednazate; Prifelone: Prodolic Acid; Pro Guanoxan Sulfate; Guanoxyfen Sulfate; Hydralazine Hydro quaZone: Proxazole; Proxazole Citrate; Rimexolone: chloride; Hydralazine Polistirex; Hydroflumethiazide; Inda RomaZarit; Salcolex; Salnacedin; Salsalate; Sanguinarium crinone; Indapamide; Indolaprif Hydrochloride; Indoramin; Chloride; SeclaZone; Sermetacin; Sudoxicam, Sulindac; Indoramin Hydrochloride; Indorenate Hydrochloride: Laci Suprofen; Talmetacin; Talniflumate; Talosalate; Tebufelone: Tenidap: Tenidap Sodium; Tenoxicam, Tesicam, Tesimide; dipine; Leniquinsin; Levcromakalim; Lisinopril; Lofexidine Tetrydamine; Tiopinac; Tixocortol Pivalate: Tolimetin: Tol Hydrochloride; Losartan Potassium; Losulazine Hydrochlo metin Sodium; Triclonide; Triflumidate; Zidometacin; ride; Mebutamate; Mecamylamine Hydrochloride; Medrox Zomepirac Sodium. alol; Medroxalol Hydrochloride; Methalthiazide; Methy clothiazide; Methyldopa; Methyldopate Hydrochloride: 0297 Antinauseant: Buclizine Hydrochloride: Cyclizine Metipranolol; Metolazone: Metoprolol Fumarate; Meto Lactate; Naboctate Hydrochloride. prolol Succinate; Metyrosine; Minoxidil; Monatepil Male 0298 Antineutropenic: Filgrastim; Lenograstim; Molgra ate; Muzolimine; Nebivolol; Nitrendipine: Ofornine: Par mostim; Regramostim; Sargramostim. gyline Hydrochloride; Pazoxide; Pelanserin Hydrochloride: 0299 Antiobsessional agent: Fluvoxamine Maleate. Perindopril Erbumine; Phenoxybenzamine Hydrochloride: 0300 Antiparkinsonian: Benztropine Mesylate: Pinacidil: Pivopril; Polythiazide; Prazosin Hydrochloride: Biperiden; Biperiden Hydrochloride; Biperiden Lactate; Car Primidolol; Prizidilol Hydrochloride: Quinapril Hydrochlo mantadine: Ciladopa Hydrochloride; Dopamantine; Ethopro ride; Quinaprilat; Quinazosin Hydrochloride: Quinelorane pazine Hydrochloride; LaZabemide; Levodopa; Lometraline Hydrochloride: Quinpirole Hydrochloride: Quinuclium Bro Hydrochloride; Mofegiline Hydrochloride: Naxagolide mide: Ramipril; Rauwolfia Serpentina; Reserpine; Saprisar Hydrochloride; Pareptide Sulfate: Procyclidine Hydrochlo tan Potassium; Saralasin Acetate; Sodium Nitroprusside; Sul ride; Quinetorane Hydrochloride; Ropinirole Hydrochloride; finalol Hydrochloride: Tasosartan; Teludipine Selegiline Hydrochloride; Tolcapone; Trihexyphenidyl Hydrochloride; Temocapril Hydrochloride; Terazosin Hydrochloride. Antiperistaltic: Difenoximide Hydrochlo Hydrochloride; Terlakiren; Tiamenidine; Tiamenidine ride; Difenoxin; Diphenoxylate Hydrochloride; Fluperam Hydrochloride; Ticrynafen; Tinabinol; Tiodazosin; Tipen ide; Lidamidine Hydrochloride: Loperamide Hydrochloride: tosin Hydrochloride; Trichlormethiazide; Trimazosin Hydro Malethamer; Nufenoxole; Paregoric. US 2011/0065628 A1 Mar. 17, 2011

0301 Antipsychotic: Acetophenazine Maleate; Alente Hydrochloride; Dobutamine Lactobionate; Dobutamine Tar mol Hydrobromide: Alpertine; Azaperone; Batelapine Male trate; Enoximone: Imazodan Hydrochloride; Indolidan; Iso ate; Benperidol; BenZindopyrine Hydrochloride; Brofbxine: mazole Hydrochloride; Levdobutamine Lactobionate; Lix Bromperidol; Bromperidol Decanoate; Butaclamol Hydro azinone Sulfate; Medorinone; Millrinone; Pelrinone chloride; Butaperazine; Butaperazine Maleate; Carphenazine Hydrochloride: Pimobendan; Piroximone: Prinoxodan; Maleate; Carvotroline Hydrochloride; Chlorpromazine: Proscillaridin; Quazinone; Tazolol Hydrochloride: Chlorpromazine Hydrochloride; Chlorprothixene; Cin Vesnarinone. perene; Cintriamide: Clomacran Phosphate: Clopenthixol; 0307 Cardiovascular agent: Dopexamine; Dopexamine Clopimozide; Clopipazan Mesylate; Cloroperone Hydro Hydrochloride. chloride; Clothiapine; Clothixamide Maleate; Clozapine; (0308 Choleretic: Dehydrocholic Acid: Fencibutirol; Cyclophenazine Hydrochloride; Droperidol; Etazolate Hymecromone; Piprozolin; Sincalide; Tocamphyl. Hydrochloride: Fenimide: Flucindole: Flumezapine; (0309 Cholinergic: Aceclidine: Bethanechol Chloride: Fluphenazine Decanoate: Fluphenazine Enanthate: Carbachol; Demecarium Bromide: Dexpanthenol; Fluphenazine Hydrochloride: Fluspiperone: Fluspirilene: Echothiophate Iodide: Isoflurophate; Methacholine Chlo Flutroline; Gevotroline Hydrochloride; Halopemide: Halo ride; Neostigmine Bromide: Neostigmine Methylsulfate; peridol; Haloperidol Decanoate; Iloperidone: Imidoline Physostigmine; Physostigmine Salicylate; Physostigmine Hydrochloride; Lenperone; Mazapertine Succinate: Sulfate; Pilocarpine; Pilocarpine Hydrochloride; Pilocarpine Mesoridazine; Mesoridazine Besylate; Metiapine; Milenper Nitrate: Pyridostigmine Bromide. one; Milipertine: Molindone Hydrochloride; Naranol Hydro 0310 Cholinergic agonist: Xanomeline: Xanomeline Tar chloride: Neflumozide Hydrochloride; Ocaperidone; Olanza trate. pine; Oxiperomide; Penfluridol; Pentiapine Maleate; 0311 Cholinesterase Deactivator: Obidoxime Chloride: Perphenazine: Pimozide; Pinoxepin Hydrochloride; Pipam Pralidoxime Chloride; Pralidoxime Iodide; Pralidoxime perone; Piperacetazine; Pipotiazine Palniitate; Piquindone Mesylate. Hydrochloride; Prochlorperazine Edisylate: Prochlorpera 0312 Coccidiostat: Arprinocid; Narasin: Semduramicin; zine Maleate; Promazine Hydrochloride; Remoxipride: Semduramicin Sodium. Remoxipride Hydrochloride; Rimcazole Hydrochloride: 0313 Cognition adjuvant: Ergoloid Mesylates: Pirac Seperidol Hydrochloride: Sertindole: Setoperone; Spiper etam; Pramiracetam Hydrochloride; Pramiracetam Sulfate: one. Thioridazine: Thioridazine Hydrochloride; Thiothixene; Tacrine Hydrochloride. Thiothixene Hydrochloride; Tioperidone Hydrochloride: 0314 Cognition enhancer: Besipirdine Hydrochloride; Tiospirone Hydrochloride; Trifluoperazine Hydrochloride: Linopirdine: Sibopirdine. Trifluperidol; Triflupromazine; Triflupromazine Hydrochlo 0315 Hormone: Diethylstilbestrol; Progesterone; 17-hy ride; Ziprasidone Hydrochloride. droxy progesterone; Medroxyprogesterone; Norgestrel; Nor 0302) Appetite suppressant: Dexfenfluramine Hydrochlo ethynodrel; Estradiol; Megestrol (Megace); Norethindrone: ride; Phendimetrazine Tartrate; Phentermine Hydrochloride. Levonorgestrel; Ethyndiol: Ethinyl estradiol; Mestranol: 0303 Blood glucose regulators: Human insulin; Gluca Estrone; Equilin; 17-alpha-dihydroequilin; equilenin; 17-al gon; TolaZamide; Tolbutamide; Chloropropamide: Aceto pha-dihydroequilenin; 17-alpha-estradiol; 17-beta-estradiol; hexamide and Glipizide. Leuprolide (lupron); Glucagon; Testolactone; Clomiphene; 0304 Carbonic anhydrase inhibitor: Acetazolamide: Han memopausal gonadotropins; Human chorionic gonadot Acetazolamide Sodium, Dichlorphenamide; Dorzolamide ropin: Urofollitropin; Bromocriptine; Gonadorelin; Luteiniz Hydrochloride; Methazolamide: Sezolarmide Hydrochlo ing hormone releasing hormone and analogs; Gonadotropins; ride. Danazol; Testosterone; Dehydroepiandrosterone; Andros 0305 Cardiac depressant: Acecainide Hydrochloride; tenedione; Dihydroestosterone: Relaxin: Oxytocin; Vaso Acetylcholine Chloride; Actisomide: Adenosine; Amio pressin; Folliculostatin: Follicle regulatory protein; Gona darone; Aprindine; Aprindine Hydrochloride; Artilide Fuma doctrinins; Oocyte maturation inhibitor; Insulin growth rate; Azimilide Dihydrochloride; Bidisomide; Bucainide factor; Follicle Stimulating Hormone; Luteinizing hormone; Maleate; Bucromarone; Butoprozine Hydrochloride: Tamoxifen.: Corticorelin Ovine Triftutate; Cosyntropin: Capobenate Sodium; Capobenic Acid; Cifenline; Cifenline Metogest; Pituitary, Posterior; Seractide Acetate; Somalapor; Succinate; Clofilium Phosphate: Disobutamide: Disopyra Somatrem: Somatropin; Somenopor: Somidobove. mide: Disopyramide Phosphate; Dofetilide; Drobuline; Edi 0316 Memory adjuvant: Dimoxamine Hydrochloride; folone Acetate; Emilium Tosylate: Encainide Hydrochloride: Ribaminol. Flecainide Acetate; Ibutilide Fumarate; Indecainide Hydro 0317 Mental performance enhancer: Aniracetam. chloride: Ipazilide Fumarate; Lorajmine Hydrochloride: 0318 Mood regulator: Fengabine. Lorcainide Hydrochloride; Meobentine Sulfate; Mexiletine 0319 Neuroleptic: Duoperone Fumarate; Risperidone. Hydrochloride: Modecainide; Moricizine; Oxiramide: Pir 0320 Neuroprotective: Dizocilpine Maleate. menol Hydrochloride: Pirolazamide; Pranolium Chloride; 0321) Psychotropic: Minaprine. Procainamide Hydrochloride; Propafenone Hydrochloride: 0322 Relaxant: Adiphenine Hydrochloride; Alcuronium Pyrinoline; Quindonium Bromide: Quinidine Gluconate: Chloride; Aminophylline; AZumolene Sodium; Baclofen; Quinidine Sulfate; Recainam Hydrochloride; Recainam Benzoctamine Hydrochloride; Carisoprodol; Chlorphenesin Tosylate: Risotilide Hydrochloride; Ropitoin Hydrochloride: Carbamate; ChlorZoxazone; Cinflumide: Cinnamedrine; Sematilide Hydrochloride; Suricainide Maleate: Tocainide; Clodanolene; Cyclobenzaprine Hydrochloride; Dantrolene: Tocainide Hydrochloride; Transcainide. Dantrolene Sodium; Fenalanide; Fenyripol Hydrochloride: 0306 Cardiotonic: Actodigin; Amrinone; Bemoradan; Fetoxylate Hydrochloride: Flavoxate Hydrochloride; Fle Butopamine; CarbaZeran; Carsatirin Succinate; Deslanoside; tazepam; Flumetramide: -Flurazepam Hydrochloride; Digitalis; Digitoxin; Digoxin; Dobutamine; Dobutamine Hexafluorenium Bromide: Isomylamine Hydrochloride; Lor US 2011/0065628 A1 Mar. 17, 2011 22 bamate; Mebeverine Hydrochloride; Mesuprine Hydrochlo Terodiline Hydrochloride; Tipropidil Hydrochloride; Tolazo ride; Metaxalone; Methocarbamol; Methixene Hydrochlo line Hydrochloride; Xanthinol Niacinate. ride; Nafomine Malate; NeleZaprine Maleate; Papaverine 0334 Assays and methods for testing compounds of the Hydrochloride; Pipoxolan Hydrochloride; Quinctolate: Rito invention are described herein or are known in the art. For drine: Ritodrine Hydrochloride; Rolodine: Theophylline example, see Lippa et al., U.S. Pat. Pub. No. 2006/0173-64, Sodium Glycinate; Thiphenamil Hydrochloride; Xilobam. published Aug. 3, 2006. 0323 Sedative-hypnotic: Allobarbital; Alonimid; Alpra 0335 The invention further encompasses treating and pre Zolam; Amobarbital Sodium; Bentazepam; Brotizolam: But venting obesity, i.e., for affecting weight loss and preventing abarbital; Butabarbital Sodium: Butalbital; Capuride; Car weight gain. Obesity is a disorder characterized by the accu bocloral; Chloral Betaine; Chloral Hydrate; mulation of excess fat in the body. Obesity has been recog Chlordiazepoxide Hydrochloride; Cloperidone Hydrochlo nized as one of the leading causes of disease and is emerging ride; Clorethate: Cyprazepam; Dexclamol Hydrochloride; as a global problem. Increased instances of complications Diazepam; Dichloralphenazone; Estazolam; Ethchlorvynol: Such as hypertension, non-insulin-dependent diabetes melli Etomidate: Fenobam; Flunitrazepam; Fosazepam; Glute tus, arteriosclerosis, dyslipidemia, certain forms of cancer, thimide; Halazepam, Lorimetazepam, Mecloqualone; Mep sleep apnea, and osteoarthritis have been related to increased robamate; Methaqualone; Midaflur; Paraldehyde; Pentobar instances of obesity in the general population In one aspect, bital; Pentobarbital Sodium; Perlapine; Prazepam; the invention encompasses administering to a subject in need Quazepam. Reclazepam; Roletamide: Secobarbital; Seco thereof a combination therapy to induce weight loss. For barbital Sodium; Suproclone; Thalidomide: Tracazolate: example, subjects having a BMI of greater than about 25 Trepipam Maleate; Triazolam; Tricetamide; Triclofos (25.0-29.9 is considered overweight) are identified for treat Sodium; Trimetozine, Uldazepam, Zaleplon; Zolazepam ment. In one aspect, the individuals have a BMI of greater Hydrochloride; Zolpidem Tartrate. than 30 (30 and above is considered obese). In another aspect, 0324 Serotonin antagonist: Altanserin Tartrate; Ameser a Subject may be targeted for treatment to prevent weight gide; Ketanserin; Ritanserin. gain. In one embodiment, an individual is instructed to take at 0325 Serotonin inhibitor: Cinanserin Hydrochloride; least one compound of the invention at least once daily and at Fenclonine; Fonazine Mesylate; Xylamidine Tosylate. least a second compound of the invention at least once daily. 0326 Serotonin receptor antagonist: Tropanserin Hydro The compound may be in the form of, for example, a tablet, a chloride. lozenge, a liquid, etc. In one aspect, a third compound is also 0327 Stimulant: Amfonelic Acid; Amphetamine Sulfate; taken daily. In one embodiment, compounds may be taken AmpyZine Sulfate; Arbutamine Hydrochloride; Azabon; Caf more than once daily. In another embodiment, compounds are feine; Ceruletide: Ceruletide Diethylamine; Cisapride; Dazo taken less than once daily. The dosages can be determined pride Fumarate; Dextroamphetamine; Dextroamphetamine based on what is known in the art or what is determined to be Sulfate; Difluanine Hydrochloride; Dimefline Hydrochlo best for a Subject of that age, sex, health, weight, etc. Com ride; Doxapram Hydrochloride; Etryptamine Acetate; pounds useful for treating obesity according to the methods of Ethamivan: Fenethylline Hydrochloride: Flubanilate Hydro the invention, include, but are not limited to, topiramate, maltrexone, and ondansetron. See Weber (U.S. Pat. Pub. No. chloride: Flurothyl; Histamine Phosphate; Indriline Hydro 20070275970) and McElroy (U.S. Pat. No. 6,323,236) for chloride; Mefexamide; Methamphetamine Hydrochloride: additional information and techniques for administering Methylphenidate Hydrochloride; Pemoline: Pyrovalerone drugs useful for treating obesity, addictive disorders, and Hydrochloride: Xamoterol: Xamoterol Fumarate. Synergist: impulse control disorders, and for determining dosage Proadifen Hydrochloride. schemes. 0328 Thyroid hormone: Levothyroxine Sodium; Liothy 0336. The subjects being treated to induce weight loss ronine Sodium; Liotrix. may be monitored for a period of months. In one aspect, it is 0329. Thyroid inhibitor: Methimazole; Propyithiouracil. recommended that the dosage be adjusted so that each indi 0330. Thyromimetic: Thyromedan Hydrochloride. vidual loses weight at a rate of 10% of initial weight every 6 0331 Cerebral ischemia agents: Dextrorphan Hydrochlo months. However, the rate of weigh loss for each individual ride. may be adjusted by the treating physician based on the indi 0332 Vasoconstrictor: Angiotensin Amide: Felypressin; vidual’s particular needs. Methysergide; Methysergide Maleate. 0337 If the initial dosage is not effective, then the dosage 0333. Vasodilator: Alprostadil; AZaclorzine Hydrochlo of one or more compounds of the combination therapy can be ride; Bamethan Sulfate; Bepridil Hydrochloride: Buterizine; increased. If the initial dosage results in a more rapid weight Cetiedil Citrate; Chromonar Hydrochloride; Clonitrate; Dil loss than the above rate, the dosage of one or more of the at tiazem Hydrochloride; Dipyridamole; Droprenilamine; least two compounds can be reduced. Erythrity1 Tetranitrate; Felodipine: Flunarizine Hydrochlo 0338 Pharmaceutically-acceptable base addition salts can ride; Fostedil: Hexobendine; Inositol Niacinate; Iproxamine be prepared from inorganic and organic bases. Salts derived Hydrochloride; Isosorbide Dinitrate; Isosorbide Mononi from inorganic bases, include by way of example only, trate; IsoxSuprine Hydrochloride; Lidoflazine; Mefenidil; Sodium, potassium, lithium, ammonium, calcium and mag Mefenidil Fumarate; Mibefradil Dihydrochloride; Miofla nesium salts. Salts derived from organic bases include, but are zine Hydrochloride; Mixidine; Nafronyl Oxalate: Nicar not limited to, salts of primary, secondary and tertiary amines, dipine Hydrochloride; Nicergoline; Nicorandil; Nicotinyl Such as alkyl amines, dialkyl amines, trialkyl amines, Substi Alcohol; Nifedipine; Nimodipine; Nisoldipine; Oxfenicine; tuted alkyl amines, di(Substituted alkyl)amines, tri(Substi Oxprenolol Hydrochloride; Pentaerythritol Tetranitrate; Pen tuted alkyl)amines, alkenyl amines, dialkenyl amines, trialk toxifylline: Pentrinitrol; Perhexiline Maleate; Pindolol; Pir enyl amines, Substituted alkenyl amines, di(Substituted sidomine: Prenylamine: Propatyl Nitrate; Suloctidil; alkenyl)amines, tri(Substituted alkenyl)amines, cycloalkyl US 2011/0065628 A1 Mar. 17, 2011 amines, di(cycloalkyl)amines, tri(cycloalkyl)amines, Substi cialists. Uniformity and consistency of BBCET delivery are tuted cycloalkyl amines, disubstituted cycloalkyl amines, ensured by ongoing training and Supervision. BBCET is trisubstituted cycloalkylamines, cycloalkenyl amines, di(cy copyrighted material (Johnson et al., Brief Behavioral Com cloalkenyl) amines, tri(cycloalkenyl) amines, Substituted pliance Enhancement Treatment (BBCET) manual. In: cycloalkenyl amines, disubstituted cycloalkenyl amines, Johnson BA, Ruiz P. Galanter M, eds. Handbook of clinical trisubstituted cycloalkenyl amines, aryl amines, diary1 alcoholism treatment. Baltimore, Md.: Lippincott Williams amines, triaryl amines, heteroaryl amines, diheteroaryl & Wilkins: 2003, 282-301). amines, triheteroarylamines, heterocyclic amines, dihetero 0342. The present invention further encompasses the use cyclic amines, triheterocyclic amines, mixed di- and tri of psychosocial management regimens other than BBCET, amines where at least two of the substituents on the amine are including, but not limited to, Cognitive Behavioral Coping different and are selected from the group consisting of alkyl, Skills Therapy (CBT) (Project MATCH Research Group. Substituted alkyl, alkenyl, Substituted alkenyl, cycloalkyl, Matching Alcoholism Treatments to Client Heterogeneity: Substituted cycloalkyl, cycloalkenyl, Substituted cycloalk Project MATCH posttreatment drinking outcomes. J Stud enyl, aryl, heteroaryl, heterocyclic, and the like. Also Alcohol. 1997:58:7-29), Motivational Enhancement Therapy included are amines where the two or three substituents, (MET) (Project MATCH Research Group. Matching Alco together with the amino nitrogen, form a heterocyclic or holism Treatments to Client Heterogeneity: Project MATCH heteroaryl group. Examples of Suitable amines include, by posttreatment drinking outcomes. J. Stud. Alcohol. 1997, way of example only, isopropylamine, trimethyl amine, 58:7-29), Twelve-Step Facilitation Therapy (TSF) (Project diethyl amine, tri(iso-propyl)amine, tri(n-propyl)amine, MATCH Research Group. Matching Alcoholism Treatments ethanolamine, 2-dimethylaminoethanol, tromethamine, to Client Heterogeneity: Project MATCH posttreatment lysine, arginine, histidine, caffeine, procaine, hydrabamine, drinking outcomes. J. Stud. Alcohol. 1997, 58:7-29), Com choline, betaine, ethylenediamine, glucosamine, N-alkylglu bined Behavioral Intervention (CBI), (Anton et al., JAMA, camines, theobromine, purines, piperazine, piperidine, mor 2006, 295:2003-2017) Medical Management (MM) (Anton pholine, N-ethylpiperidine, and the like. It should also be et al., JAMA, 2006, 295:2003-2017), or the Biopsychosocial, understood that other carboxylic acid derivatives would be Report, Empathy, Needs, Direct advice, and Assessment useful in the practice of this invention, for example, carboxy (BRENDA) model (Garbutt et al., JAMA, 2005, 293:1617 lic acid amides, including carboxamides, lower alkyl car 1625). The present invention further encompasses the use of boxamides, dialkyl carboxamides, and the like. alternative interventions such as hypnosis or acupuncture to 0339) Pharmaceutically acceptable acid addition salts assist in treating an addictive disease or disorder. may be prepared from inorganic and organic acids. Salts 0343. The psychosocial management programs can be derived from inorganic acids include hydrochloric acid, used before, during, and after treating the subject with the hydrobromic acid, Sulfuric acid, nitric acid, phosphoric acid, combination drug therapy of the invention. and the like. Salts derived from organic acids include acetic 0344 One of ordinary skill in the art will recognize that acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, psychosocial management procedures, as well as alternative malic acid, malonic acid. Succinic acid, maleic acid, fumaric interventions such as hypnosis or acupuncture, can also be acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, used in conjunction with combination drug therapy to treat mandelic acid, methanesulfonic acid, ethanesulfonic acid, addictive and impulse-related disorders other than alcohol p-toluene-Sulfonic acid, Salicylic acid, and the like. related diseases and disorders. 0340 Psychosocial Intervention and Management 0345 The present invention further encompasses the use 0341 The drug combination treatments of the present of combination pharmacotherapy and behavioral (psychoSo invention can be further Supplemented by providing to Sub cial) intervention or training to treat other addictive and/or jects a form of psychosocial intervention and/or management, impulse control disorders. such as Brief Behavioral Compliance Enhancement Treat 0346 For example, binge eating disorder (BED) is char ment (BBCET). BBCET, a standardized, manual-guided, acterized by discrete periods of binge eating during which brief (i.e., delivered in about 15 minutes), psychosocial large amounts of food are consumed in a discrete period of adherence enhancement procedure, emphasizes that medica time and a sense of control over eating is absent. Persons with tion compliance is crucial to changing participants drinking bulimia nervosa have been reported to have electroencepha behavior (Johnson et al., Brief Behavioral Compliance lographic abnormalities and to display reduced binge eating Enhancement Treatment (BBCET) manual. In: Johnson BA, in response to the anti-epileptic drug phenytoin. In addition, Ruiz P. Galanter M, eds. Handbook of clinical alcoholism in controlled trials in patients with epilepsy, topiramate was treatment. Baltimore, Md.: Lippincott Williams & Wilkins: associated with Suppression of appetite and weight loss unre 2003, 282-301). Brief interventions (Edwards et al., J. Stud. lated to binge eating. Ondansetron has been shown to reduce Alcohol. 1977, 38:1004-1031) such as BBCET, have been binge eating. shown to benefit treatment of alcohol dependence. BBCET 0347 BED is a subset of a larger classification of mental was modeled on the clinical management condition in the disorders broadly defined as Impulse Control Disorders National Institute of Mental Health collaborative depression (ICDs) characterized by harmful behaviors performed in trial, which was used as an adjunct to the medication condi response to irresistible impulses. It has been suggested that tion for that study (Fawcett et al. Psychopharmacol Bull. ICDs may be related to obsessive-compulsive disorder or 1987,23:309-324). BBCET has been used successfully as the similarly, maybe forms of obsessive-compulsive disorders. It psychosocial treatment platform in the single-site and multi has also been hypothesized that ICDs may be related to mood site efficacy trials of topiramate for treating alcohol depen disorder or may be forms of affective spectrum disorder, a dence (Johnson et al., Lancet. 2003, 361: 1677-1685; Johnson hypothesized family of disorders sharing at least one com et al., JAMA, 2007,298:1641-1651). It is delivered by trained mon physiologic abnormality with major depression. In the clinicians, including nurse practitioners and other non-spe Diagnostic and Statistical Manual of Mental Disorders US 2011/0065628 A1 Mar. 17, 2011 24

(DSM-IV), the essential feature of an ICD is the failure to mania, Pathological Gambling, Trichotillomania, and resistan impulse, drive, or temptation to performan act that is Impulse Control Disorder not otherwise specified (NOS). harmful to the person or to others. For most ICDs, the indi 0355 Nicotine-related disorders include, but are not lim vidual feels an increasing sense of tension or arousal before ited to, Nicotine Dependence, Nicotine Withdrawal, and committing the act, and then experiences pleasure, gratifica Nicotine-Related Disorder not otherwise specified (NOS). tion, or release at the time of committing the act. After the act 0356 Amphetamine-related disorders include, but are not is performed, there may or may not be regret or guilt. ICDs are limited to, Amphetamine Dependence, Amphetamine Abuse, listed in a residual category, the ICDs Not Elsewhere Classi Amphetamine Intoxication, Amphetamine Withdrawal, fied, which includes intermittent explosive disorder (IED), Amphetamine Intoxication Delirium, Amphetamine-Induced kleptomania, pathological gambling, pyromania, trichotillo Psychotic Disorder with delusions, Amphetamine-Induced mania, and ICDs not otherwise specified (NOS). Examples of Psychotic Disorders with hallucinations, Amphetamine-In ICDs NOS are compulsive buying or shopping, repetitive duced Mood Disorder, Amphetamine-Induced Anxiety Dis self-mutilation, nonparaphilic sexual addictions, severe nail order, Amphetamine-Induced Sexual Dysfunction, Amphet biting, compulsive skin picking, personality disorders with amine-Induced Sleep Disorder, Amphetamine Related impulsive features, attention deficit/hyperactivity disorder, Disorder not otherwise specified (NOS), Amphetamine eating disorders characterized by binge eating, and Substance Intoxication, and Amphetamine Withdrawal. use disorders. 0357 Cannabis-related disorders include, but are not lim 0348 Many drugs can cause physical and/or psychologi ited to, Cannabis Dependence; Cannabis Abuse; Cannabis cal addiction. Those most well known drugs include opiates, Intoxication; Cannabis Intoxication Delirium, Cannabis-In Such as heroin, opium and morphine; sympathomimetics, duced Psychotic Disorder, with delusions; Cannabis-Induced including cocaine and amphetamines; sedative-hypnotics, Psychotic Disorder with hallucinations; Cannabis-Induced including alcohol, benzodiazepines, and barbiturates; and Anxiety Disorder; Cannabis-Related Disorder not otherwise nicotine, which has effects similar to opioids and sympatho specified (NOS); and Cannabis Intoxication. mimetics. Drug addiction is characterized by a craving or 0358 Cocaine-related disorders include, but are not lim compulsion for taking the drug and an inability to limit its ited to, Cocaine Dependence, Cocaine Abuse, Cocaine intake. Additionally, drug dependence is associated with drug Intoxication, Cocaine Withdrawal, Cocaine Intoxication tolerance, the loss of effect of the drug following repeated Delirium, Cocaine-Induced Psychotic Disorder with delu administration, and withdrawal, the appearance of physical sions, Cocaine-Induced Psychotic Disorders with hallucina and behavioral symptoms when the drug is not consumed. tions, Cocaine-Induced Mood Disorder, Cocaine-Induced Sensitization occurs if repeated administration of a drug leads Anxiety Disorder, Cocaine-Induced Sexual Dysfunction, to an increased response to each dose. Tolerance, sensitiza Cocaine-Induced Sleep Disorder, Cocaine-Related Disorder tion, and withdrawal are phenomena evidencing a change in not otherwise specified (NOS), Cocaine Intoxication, and the central nervous system resulting from continued use of the Cocaine Withdrawal. drug. This change motivates the addicted individual to con 0359 Hallucinogen-use disorders include, but are not lim tinue consuming the drug despite serious Social, legal, physi ited to, Hallucinogen Dependence, Hallucinogen Abuse, Hal cal, and/or professional consequences. lucinogen Intoxication, Hallucinogen Withdrawal, Halluci 0349 Attention-deficit disorders include, but are not lim nogen Intoxication Delirium, Hallucinogen-Induced ited to, Attention-Deficit/Hyperactivity Disorder, Predomi Psychotic Disorder with delusions, Hallucinogen-Induced nately Inattentive Type: Attention-Deficit/Hyperactivity Dis Psychotic Disorder with hallucinations, Hallucinogen-In order, Predominately Hyperactivity-Impulsive Type: duced Mood Disorder, Hallucinogen-Induced Anxiety Disor Attention-Deficit/Hyperactivity Disorder, Combined Type: der, Hallucinogen-Induced Sexual Dysfunction, Hallucino Attention-Deficit/Hyperactivity Disorder not otherwise gen-Induced Sleep Disorder, Hallucinogen Related Disorder specified (NOS); Conduct Disorder: Oppositional Defiant not otherwise specified (NOS), Hallucinogen Intoxication, Disorder; and Disruptive Behavior Disorder not otherwise and Hallucinogen Persisting Perception Disorder (Flash specified (NOS). backs). 0350 Depressive disorders include, but are not limited to, 0360 Inhalant-related disorders include, but are not lim Major Depressive Disorder, Recurrent; Dysthymic Disorder; ited to, Inhalant Dependence: Inhalant Abuse; Inhalant Depressive Disorder not otherwise specified (NOS); and Intoxication; Inhalant Intoxication Delirium; Inhalant-In Major Depressive Disorder. Single Episode. duced Psychotic Disorder, with delusions; Inhalant-Induced Psychotic Disorder with hallucinations; Inhalant-Induced 0351 Parkinson's disease includes, but is not limited to, Anxiety Disorder; Inhalant-Related Disorder not otherwise neuroleptic-induced parkinsonism. specified (NOS); and Inhalant Intoxication. 0352. Addictive disorders include, but are not limited to, 0361 Opioid-related disorders include, but are not limited eating disorders, impulse control disorders, alcohol-related to, Opioid Dependence, Opioid Abuse, Opioid Intoxication, disorders, nicotine-related disorders, amphetamine-related Opioid Intoxication Delirium, Opioid-Induced Psychotic disorders, cannabis-related disorders, cocaine-related disor Disorder, with delusions, Opioid-Induced Psychotic Disorder ders, gambling, sexual disorders, hallucinogen use disorders, with hallucinations, Opioid-Induced Anxiety Disorder, inhalant-related disorders, and opioid-related disorders, all of Opioid-Related Disorder not otherwise specified (NOS), which arc further subclassified as listed below. Opioid Intoxication, and Opioid Withdrawal. 0353 Eating disorders include, but are not limited to, 0362 Tic disorders include, but are not limited to, Bulimia Nervosa, Nonpurging Type; Bulimia Nervosa, Purg Tourette's Disorder, Chronic Motor or Vocal Tic Disorder, ing Type; and Eating Disorder not otherwise specified (NOS). Transient Tic Disorder, Tic Disorder not otherwise specified 0354) Impulse control disorders include, but are not lim (NOS), Stuttering, Autistic Disorder, and Somatization Dis ited to, Intermittent Explosive Disorder, Kleptomania, Pyro order. US 2011/0065628 A1 Mar. 17, 2011

0363 The present invention further encompasses the treat 0371. A “prodrug” refers to an agent that is converted into ment of at least two addictive diseases or disorders or impulse the parent drug in vivo. Prodrugs are often useful because, in control disorders simultaneously. For example, the present Some situations, they may be easier to administer than the invention provides for the simultaneous treatment of alcohol parent drug. They may, for instance, be bioavailable by oral related disorders and weight control (see Examples). administration whereas the parent is not. The prodrug may 0364 The present invention also encompasses the use of also have improved solubility in pharmaceutical composi the compounds and combination therapies of the invention in tions over the parent drug, or may demonstrate increased circumstances where mandatory treatment may be appli palatability or be easier to formulate. An example, without cable. For example, a court may require that a subject be limitation, of a prodrug would be a compound of the present treated or take part in a treatment program using compounds or combination therapies of the invention as part of a man invention which is administered as an ester (the “prodrug) to dated therapy related to alcohol abuse, excessive drinking, facilitate transmittal across a cell membrane where water drug use, etc. More particularly, the invention encompasses solubility is detrimental to mobility but which then is meta forensic uses where a court would require a Subject who has bolically hydrolyzed to the carboxylic acid, the active entity, been convicted of driving under the influence to be subjected once inside the cell where water-solubility is beneficial. A to the methods of the invention as part of a condition of bail, further example of a prodrug might be a short peptide probation, treatment, etc. (polyaminoacid) bonded to an acid group where the peptide is 0365. The invention also encompasses the use of pharma metabolized to provide the active moiety. ceutical compositions comprising compounds of the inven 0372. The invention encompasses the preparation and use tion to practice the methods of the invention, the composi of pharmaceutical compositions comprising a compound tions comprising at least one appropriate compound and a useful for treatment of the diseases disclosed herein as an pharmaceutically-acceptable carrier. active ingredient. Such a pharmaceutical composition may 0366 Other methods useful for the practice of the inven consist of the active ingredient alone, in a form Suitable for tion can be found, for example, in U.S. Pat. Pub. No. 2006/ administration to a Subject, or the pharmaceutical composi 0173064 (Lippa et al.), U.S. Pat. No. 6,323,236 (McElroy), tion may comprise the active ingredient and one or more U.S. Pat. Pub. No. 2007/0275970, PCT application PCT/US/ pharmaceutically acceptable carriers, one or more additional 2008/052628 (Johnson et al.) filed Jan. 31, 2008, and PCT ingredients, or some combination of these. The active ingre application PCT/US/2007/0881.00 (Johnson and Tiouririne), dient may be present in the pharmaceutical composition in the filed Dec. 19, 2007. form of a physiologically acceptable ester or salt, Such as in 0367. In one embodiment, a composition of the invention combination with a physiologically acceptable cation or may comprise one compound of the invention. In another anion, as is well known in the art. embodiment, a composition of the invention may comprise 0373 The formulations of the pharmaceutical composi more than one compound of the invention. In one embodi tions described herein may be prepared by any method known ment, additional drugs or compounds useful for treating other or hereafter developed in the art of pharmacology. In general, disorders may be part of the composition. In one embodi Such preparatory methods include the step of bringing the ment, a composition comprising only one compound of the active ingredient into association with a carrier or one or more invention may be administered at the same time as another other accessory ingredients, and then, if necessary or desir composition comprising at least one other compound of the able, shaping or packaging the product into a desired single invention. In one embodiment, the different compositions or multi-dose unit. may be administered at different times from one another. 0374. Although the descriptions of pharmaceutical com When a composition of the invention comprises only one positions provided herein are principally directed to pharma compound of the invention, an additional composition com ceutical compositions which are suitable for ethical adminis prising at least one additional compound must also be used. tration to humans, it will be understood by the skilled artisan 0368. The pharmaceutical compositions useful for prac that such compositions are generally suitable for administra ticing the invention may be, for example, administered to tion to animals of all sorts. Modification of pharmaceutical deliver a dose of between 1 ng/kg/day and 100 mg/kg/day. compositions suitable for administration to humans in order 0369 Pharmaceutical compositions that are useful in the to render the compositions Suitable for administration to vari methods of the invention may be administered, for example, ous animals is well understood, and the ordinarily skilled systemically in oral Solid formulations, or as ophthalmic, Veterinary pharmacologist can design and perform Such Suppository, aerosol, topical or other similar formulations. In modification with merely ordinary, if any, experimentation. addition to the appropriate compounds, such pharmaceutical Subjects to which administration of the pharmaceutical com compositions may contain pharmaceutically-acceptable car positions of the invention is contemplated include, but are not riers and other ingredients known to enhance and facilitate limited to, humans and other primates, mammals including drug administration. Other possible formulations, such as commercially relevant mammals such as cattle, pigs, horses, nanoparticles, liposomes, resealed erythrocytes, and immu sheep, cats, and dogs, and birds including commercially rel nologically based systems may also be used to administer an evantbirds Such as chickens, ducks, geese, and turkeys. appropriate compound, or an analog, modification, or deriva 0375 One type of administration encompassed by the tive thereof according to the methods of the invention. methods of the invention is parenteral administration, which 0370 Compounds which are identified using any of the includes, but is not limited to, administration of a pharmaceu methods described herein may be formulated and adminis tical composition by injection of the composition, by appli tered to a subject for treatment of the diseases disclosed cation of the composition through a Surgical incision, by herein. One of ordinary skill in the art will recognize that application of the composition through a tissue-penetrating these methods will be useful for other diseases, disorders, and non-Surgical wound, and the like. In particular, parenteral conditions as well. administration is contemplated to include, but is not limited US 2011/0065628 A1 Mar. 17, 2011 26 to. Subcutaneous, intraperitoneal, intramuscular, and sulphate. Known diluents include, but are not limited to, intrasternal injection, and kidney dialytic infusion techniques calcium carbonate, sodium carbonate, lactose, microcrystal 0376 Pharmaceutical compositions that are useful in the line cellulose, calcium phosphate, calcium hydrogen phos methods of the invention may be prepared, packaged, or sold phate, and Sodium phosphate. Known granulating and disin in formulations suitable for oral, rectal, vaginal, parenteral, tegrating agents include, but are not limited to, corn starch topical, pulmonary, intranasal, inhalation, buccal, oph and alginic acid. Known binding agents include, but are not thalmic, intrathecal or another route of administration. Other limited to, gelatin, acacia, pre-gelatinized maize starch, poly contemplated formulations include projected nanoparticles, vinylpyrrolidone, and hydroxypropyl methylcellulose. liposomal preparations, resealed erythrocytes containing the Known lubricating agents include, but are not limited to, active ingredient, and immunologically-based formulations. magnesium Stearate, Stearic acid, silica, and talc. 0377. A pharmaceutical composition of the invention may 0384 Tablets may be non-coated or may be coated using be prepared, packaged, or sold in bulk, as a single unit dose, known methods to achieve delayed disintegration in the gas or as a plurality of single unit doses. As used herein, a “unit trointestinal tract of a subject, thereby providing Sustained dose' is a discrete amount of the pharmaceutical composition release and absorption of the active ingredient. By way of comprising a predetermined amount of the active ingredient. example, a material Such as glyceryl monostearate or glyceryl The amount of the active ingredient is generally equal to the distearate may be used to coat tablets. Further by way of dosage of the active ingredient which would be administered example, tablets may be coated using methods described in to a subject, or a convenient fraction of such a dosage such as, U.S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874 to form for example, one-half or one-third of Such a dosage. osmotically-controlled release tablets. Tablets may further 0378. The relative amounts of the active ingredient, the comprise a Sweetening agent, a flavoring agent, a coloring pharmaceutically acceptable carrier, and any additional agent, a preservative, or some combination of these in order to ingredients in a pharmaceutical composition of the invention provide pharmaceutically elegant and palatable preparation. will vary, depending upon the identity, size, and condition of 0385 Hard capsules comprising the active ingredient may the subject treated and further depending upon the route by be made using a physiologically degradable composition, which the composition is to be administered. By way of Such as gelatin. Such hard capsules comprise the active ingre example, the composition may comprise between 0.1% and dient, and may further comprise additional ingredients 100% (w/w) active ingredient. including, for example, an inert Solid diluent such as calcium 0379. In addition to the active ingredient, a pharmaceuti carbonate, calcium phosphate, or kaolin. cal composition of the invention may further comprise one or 0386 Soft gelatin capsules comprising the active ingredi more additional pharmaceutically active agents. Particularly ent may be made using a physiologically degradable compo contemplated additional agents include anti-emetics and sition, Such as gelatin. Such soft capsules comprise the active Scavengers such as cyanide and cyanate Scavengers. ingredient, which may be mixed with water oran oil medium 0380 Controlled- or sustained-release formulations of a Such as peanut oil, liquid paraffin, or olive oil. pharmaceutical composition of the invention may be made 0387 Lactulose can also be used as a freely erodible filler using conventional technology. and is useful when the compounds of the invention are pre 0381. A formulation of a pharmaceutical composition of pared in capsule form. the invention suitable for oral administration may be pre 0388 Liquid formulations of a pharmaceutical composi pared, packaged, or sold in the form of a discrete solid dose tion of the invention which are suitable for oral administration unit including, but not limited to, a tablet, a hard or soft may be prepared, packaged, and sold either in liquid form or capsule, a cachet, a troche, or a lozenge, each containing a in the form of a dry product intended for reconstitution with predetermined amount of the active ingredient. Other formu water or another suitable vehicle prior to use. lations suitable for oral administration include, but are not 0389 Liquid Suspensions may be prepared using conven limited to, a powdered or granular formulation, an aqueous or tional methods to achieve Suspension of the active ingredient oily Suspension, an aqueous or oily solution, or an emulsion. in an aqueous or oily vehicle. Aqueous vehicles include, for 0382. As used herein, an “oily' liquid is one which com example, water and isotonic saline. Oily vehicles include, for prises a carbon-containing liquid molecule and which exhib example, almond oil, oily esters, ethyl alcohol, vegetable oils its a less polar character than water. Such as arachis, olive, Sesame, or coconut oil, fractionated 0383. A tablet comprising the active ingredient may, for Vegetable oils, and mineral oils such as liquid paraffin. Liquid example, be made by compressing or molding the active Suspensions may further comprise one or more additional ingredient, optionally with one or more additional ingredi ingredients including, but not limited to, Suspending agents, ents. Compressed tablets may be prepared by compressing, in dispersing or wetting agents, emulsifying agents, demul a Suitable device, the active ingredient in a free-flowing form cents, preservatives, buffers, salts, flavorings, coloring Such as a powder or granular preparation, optionally mixed agents, and Sweetening agents. Oily Suspensions may further with one or more of a binder, a lubricant, an excipient, a comprise a thickening agent. Known Suspending agents Surface active agent, and a dispersing agent. Molded tablets include, but are not limited to, Sorbitol syrup, hydrogenated may be made by molding, in a Suitable device, a mixture of the edible fats, Sodium alginate, polyvinylpyrrolidone, gum active ingredient, a pharmaceutically acceptable carrier, and tragacanth, gum acacia, and cellulose derivatives such as at least sufficient liquid to moisten the mixture. Pharmaceu Sodium carboxymethylcellulose, methylcellulose, and tically acceptable excipients used in the manufacture oftab hydroxypropylmethylcellulose. Known dispersing or wetting lets include, but are not limited to, inert diluents, granulating agents include, but are not limited to, naturally occurring and disintegrating agents, binding agents, and lubricating phosphatides such as lecithin, condensation products of an agents. Known dispersing agents include, but are not limited alkylene oxide with a fatty acid, with a long chain aliphatic to, potato starch and sodium starch glycollate. Known Surface alcohol, with a partial ester derived from a fatty acid and a active agents include, but are not limited to, sodium lauryl hexitol, or with a partial ester derived from a fatty acid and a US 2011/0065628 A1 Mar. 17, 2011 27 hexitol anhydride (e.g., polyoxyethylene Stearate, heptadeca cally acceptable excipient which is solid at ordinary room ethyleneoxycetanol, polyoxyethylene Sorbitol monooleate, temperature (i.e. about 20°C.) and which is liquid at the rectal and polyoxyethylene Sorbitan monooleate, respectively). temperature of the subject (i.e. about 37° C. in a healthy Known emulsifying agents include, but are not limited to, human). Suitable pharmaceutically acceptable excipients lecithin and acacia. Known preservatives include, but are not include, but are not limited to, cocoa butter, polyethylene limited to, methyl, ethyl, or n-propyl parahydroxybenzoates, glycols, and various glycerides. Suppository formulations ascorbic acid, and Sorbic acid. Known Sweetening agents may further comprise various additional ingredients includ include, for example, glycerol, propylene glycol, Sorbitol, ing, but not limited to, antioxidants and preservatives. Sucrose, and saccharin. Known thickening agents for oily 0396 Retention enema preparations or solutions for rectal Suspensions include, for example, beeswax, hard paraffin, or colonic irrigation may be made by combining the active and cetyl alcohol. ingredient with a pharmaceutically acceptable liquid carrier. 0390. In one aspect, a preparation in the form of a syrup or As is well known in the art, enema preparations may be elixir or for administration in the form of drops may comprise administered using, and may be packaged within, a delivery active ingredients together with a Sweetener, which is prefer device adapted to the rectal anatomy of the Subject. Enema ably calorie-free, and which may further include methylpa preparations may further comprise various additional ingre raben or propylparaben as antiseptics, a flavoring and a Suit dients including, but not limited to, antioxidants and preser able color. vatives. 0391 Liquid solutions of the active ingredient in aqueous 0397. A pharmaceutical composition of the invention may or oily solvents may be prepared in Substantially the same be prepared, packaged, or sold in a formulation Suitable for manner as liquid Suspensions, the primary difference being vaginal administration. Such a composition may be in the that the active ingredient is dissolved, rather than Suspended form of for example, a Suppository, an impregnated or coated in the solvent. Liquid solutions of the pharmaceutical com vaginally-insertable material Such as a tampon, a douche position of the invention may comprise each of the compo preparation, or gel or cream or a solution for vaginal irriga nents described with regard to liquid Suspensions, it being tion. understood that Suspending agents will not necessarily aid 0398 Methods for impregnating or coating a material with dissolution of the active ingredient in the solvent. Aqueous a chemical composition are known in the art, and include, but Solvents include, for example, water and isotonic saline. Oily are not limited to methods of depositing orbinding a chemical Solvents include, for example, almond oil, oily esters, ethyl composition onto a Surface, methods of incorporating a alcohol, vegetable oils such as arachis, olive, sesame, or coco chemical composition into the structure of a material during nut oil, fractionated vegetable oils, and mineral oils such as the synthesis of the material (i.e. Such as with a physiologi liquid paraffin. cally degradable material), and methods of absorbing an 0392 Powdered and granular formulations of a pharma aqueous or oily solution or Suspension into an absorbent ceutical preparation of the invention may be prepared using material, with or without Subsequent drying. known methods. Such formulations may be administered 0399 Douche preparations or solutions for vaginal irriga directly to a subject, used, for example, to form tablets, to fill tion may be made by combining the active ingredient with a capsules, or to prepare an aqueous or oily Suspension or pharmaceutically acceptable liquid carrier. As is well known Solution by addition of an aqueous or oily vehicle thereto. in the art, douche preparations may be administered using, Each of these formulations may further comprise one or more and may be packaged within, a delivery device adapted to the of a dispersing or wetting agent, a Suspending agent, and a vaginal anatomy of the Subject. Douche preparations may preservative. Additional excipients, such as fillers and Sweet further comprise various additional ingredients including, but ening, flavoring, or coloring agents, may also be included in not limited to, antioxidants, antibiotics, antifungal agents, these formulations. and preservatives. 0393 A pharmaceutical composition of the invention may 0400. As used herein, “parenteral administration of a also be prepared, packaged, or sold in the form of oil in water pharmaceutical composition includes any route of adminis emulsion or a water-in-oil emulsion. The oily phase may be a tration characterized by physical breaching of a tissue of a Vegetable oil such as olive or arachis oil, a mineral oil such as Subject and administration of the pharmaceutical composi liquid paraffin, or a combination of these. Such compositions tion through the breach in the tissue. Parenteral administra may further comprise one or more emulsifying agents includ tion thus includes, but is not limited to, administration of a ing naturally occurring gums such as gum acacia or gum pharmaceutical composition by injection of the composition, tragacanth, naturally occurring phosphatides such as Soybean by application of the composition through a Surgical incision, or lecithin phosphatide, esters or partial esters derived from by application of the composition through a tissue-penetrat combinations of fatty acids and hexitol anhydrides such as ing non-Surgical wound, and the like. In particular, parenteral Sorbitan monooleate, and condensation products of Such par administration is contemplated to include, but is not limited tial esters with ethylene oxide such as polyoxyethylene sor to. Subcutaneous, intraperitoneal, intramuscular, and bitan monooleate. These emulsions may also contain addi intrasternal injection, and kidney dialytic infusion tech tional ingredients including, for example, Sweetening or niques. flavoring agents. 04.01 Formulations of a pharmaceutical composition suit 0394. A pharmaceutical composition of the invention may able for parenteral administration comprise the active ingre be prepared, packaged, or sold in a formulation Suitable for dient combined with a pharmaceutically acceptable carrier, rectal administration. Such a composition may be in the form such as sterile water or sterile isotonic saline. Such formula of for example, a Suppository, a retention enema preparation, tions may be prepared, packaged, or sold in a form Suitable for and a solution for rectal or colonic irrigation. bolus administration or for continuous administration. Inject 0395 Suppository formulations may be made by combin able formulations may be prepared, packaged, or sold in unit ing the active ingredient with a non irritating pharmaceuti dosage form, Such as in ampules or in multi-dose containers US 2011/0065628 A1 Mar. 17, 2011 28 containing a preservative. Formulations for parenteral admin sitions preferably include a solid fine powder diluent such as istration include, but are not limited to, Suspensions, solu Sugar and are conveniently provided in a unit dose form. tions, emulsions in oily or aqueous vehicles, pastes, and 04.05 Low boiling propellants generally include liquid implantable Sustained-release or biodegradable formulations. propellants having a boiling point of below 65° F. at atmo Such formulations may further comprise one or more addi spheric pressure. Generally, the propellant may constitute tional ingredients including, but not limited to, Suspending, about 50% to about 99.9% (w/w) of the composition, and the stabilizing, or dispersing agents. In one embodiment of a active ingredient may constitute about 0.1% to about 20% formulation for parenteral administration, the active ingredi (w/w) of the composition. The propellant may further com ent is provided in dry (i.e., powder or granular) form for prise additional ingredients such as a liquid non-ionic or Solid reconstitution with a suitable vehicle (e.g., Sterile pyrogen anionic Surfactant or a solid diluent (preferably having a free water) prior to parenteral administration of the reconsti particle size of the same order as particles comprising the tuted composition. active ingredient). 0406 Pharmaceutical compositions of the invention for 0402. The pharmaceutical compositions may be prepared, mulated for pulmonary delivery may also provide the active packaged, or sold in the form of a sterile injectable aqueous or ingredient in the form of droplets of a solution or Suspension. oily Suspension or solution. This suspension or Solution may Such formulations may be prepared, packaged, or sold as beformulated according to the known art, and may comprise, aqueous or dilute alcoholic solutions or Suspensions, option in addition to the active ingredient, additional ingredients ally sterile, comprising the active ingredient, and may conve Such as the dispersing agents, Wetting agents, or Suspending niently be administered using any nebulization or atomiza agents described herein. Such sterile injectable formulations tion device. Such formulations may further comprise one or may be prepared using a non-toxic parenterally acceptable more additional ingredients including, but not limited to, a diluent or solvent, such as water or 1,3-butane diol, for flavoring agent such as Saccharin Sodium, a volatile oil, a example. Other acceptable diluents and solvents include, but buffering agent, a surface active agent, or a preservative Such are not limited to, Ringer's Solution, isotonic sodium chloride as methylhydroxybenzoate. The droplets provided by this Solution, and fixed oils such as synthetic mono- or di-glycer route of administration preferably have an average diameter ides. Other parentally-administrable formulations which are in the range from about 0.1 to about 200 nanometers. useful include those which comprise the active ingredient in 0407. The formulations described herein as being useful microcrystalline form, in a liposomal preparation, or as a for pulmonary delivery are also useful for intranasal delivery component of a biodegradable polymer systems. Composi of a pharmaceutical composition of the invention. tions for Sustained release or implantation may comprise 0408. Another formulation suitable for intranasal admin pharmaceutically acceptable polymeric or hydrophobic istration is a coarse powder comprising the active ingredient materials such as an emulsion, an ion exchange resin, a spar and having an average particle from about 0.2 to about 500 ingly soluble polymer, or a sparingly soluble salt. micrometers. Such a formulation is administered in the man 0403. Formulations suitable for topical administration ner in which Snuff is taken, i.e., by rapid inhalation through include, but are not limited to, liquid or semi-liquid prepara the nasal passage from a container of the powder held close to tions such as liniments, lotions, oil in water or water in oil the nares. emulsions such as creams, ointments or pastes, and solutions 04.09 Formulations suitable for nasal administration may, or Suspensions. Topically-administrable formulations may, for example, comprise from about as little as about 0.1% for example, comprise from about 1% to about 10% (w/w) (w/w) and as much as about 100% (w/w) of the active ingre active ingredient, although the concentration of the active dient, and may further comprise one or more of the additional ingredient may be as high as the solubility limit of the active ingredients described herein. ingredient in the solvent. Formulations for topical adminis 0410 A pharmaceutical composition of the invention may tration may further comprise one or more of the additional be prepared, packaged, or sold in a formulation Suitable for ingredients described herein. buccal administration. Such formulations may, for example, 0404 A pharmaceutical composition of the invention may be in the form of tablets or lozenges made using conventional be prepared, packaged, or sold in a formulation Suitable for methods, and may, for example, comprise about 0.1% to pulmonary administration via the buccal cavity. Such a for about 20% (w/w) active ingredient, the balance comprising mulation may comprise dry particles which comprise the an orally dissolvable or degradable composition and, option active ingredient and which have a diameter in the range from ally, one or more of the additional ingredients described about 0.5 to about 7 nanometers, and preferably from about 1 herein. Alternately, formulations suitable for buccal admin to about 6 nanometers. Such compositions are conveniently in istration may comprise a powder or an aerosolized or atom the form of dry powders for administration using a device ized solution or Suspension comprising the active ingredient. comprising a dry powder reservoir to which a stream of pro Such powdered, aerosolized, or atomized formulations, when pellant may be directed to disperse the powder or using a dispersed, preferably have an average particle or droplet size self-propelling solvent/powder-dispensing container Such as in the range from about 0.1 to about 200 nanometers, and may a device comprising the active ingredient dissolved or Sus further comprise one or more of the additional ingredients pended in a low-boiling propellant in a sealed container. described herein. Preferably, such powders comprise particles wherein at least 0411 A pharmaceutical composition of the invention may 98% of the particles by weight have a diameter greater than be prepared, packaged, or sold in a formulation Suitable for 0.5 nanometers and at least 95% of the particles by number ophthalmic administration. Such formulations may, for have a diameter less than 7 nanometers. More preferably, at example, be in the form of eye drops including, for example, least 95% of the particles by weight have a diameter greater a 0.1% to 1.0% (w/w) solution or suspension of the active than 1 nanometer and at least 90% of the particles by number ingredient in an aqueous or oily liquid carrier. Such drops have a diameter less than 6 nanometers. Dry powder compo may further comprise buffering agents, salts, or one or more US 2011/0065628 A1 Mar. 17, 2011 29 other of the additional ingredients described herein. Other active agent may also contain a hydrophilic low molecular opthalmically-administrable formulations which are useful weight compound as a base or excipient. Such hydrophilic include those which comprise the active ingredient in micro low molecular weight compounds provide a passage medium crystalline form or in a liposomal preparation. through which a water-soluble active agent, Such as a physi 0412. A pharmaceutical composition of the invention may ologically active peptide or protein, may diffuse through the be prepared, packaged, or sold in a formulation Suitable for base to the body surface where the active agent is absorbed. intramucosal administration. The present invention provides The hydrophilic low molecular weight compound optionally for intramucosal administration of compounds to allow pas absorbs moisture from the mucosa or the administration sage or absorption of the compounds across mucosa. Such atmosphere and dissolves the water-soluble active peptide. type of administration is useful for absorption orally (gingi The molecular weight of the hydrophilic low molecular val, Sublingual, buccal, etc.), rectally, vaginally, pulmonary, weight compound is generally not more than 10000 and pref nasally, etc. erably not more than 3000. Exemplary hydrophilic low 0413. In some aspects, Sublingual administration has an molecular weight compounds include polyol compounds, advantage for active ingredients which in Some cases, when given orally, are subject to a substantial first pass metabolism Such as oligo-, di- and monosaccharides such as Sucrose, and enzymatic degradation through the liver, resulting in mannitol, lactose, L-arabinose, D-erythrose, D-ribose, D-xy rapid metabolization and a loss of therapeutic activity related lose, D-mannose, D-galactose, lactulose, cellobiose, genti to the activity of the liver enzymes that convert the molecule biose, glycerin, and polyethylene glycol. Other examples of into inactive metabolites, or the activity of which is decreased hydrophilic low molecular weight compounds useful as car because of this bioconversion. riers within the invention include N-methylpyrrolidone, and 0414. In some cases, a Sublingual route of administration alcohols (e.g., oligovinyl alcohol, ethanol, ethylene glycol, is capable of producing a rapid onset of action due to the propylene glycol, etc.). These hydrophilic low molecular considerable permeability and vascularization of the buccal weight compounds can be used alone or in combination with mucosa. Moreover, Sublingual administration can also allow one another or with other active or inactive components of the the administration of active ingredients which are not nor intranasal formulation. mally absorbed at the level of the stomach mucosa or diges 0418 When a controlled-release pharmaceutical prepara tive mucosa after oral administration, or alternatively which tion of the present invention further contains a hydrophilic are partially or completely degraded in acidic medium after base, many options are available for inclusion. Hydrophilic ingestion of, for example, a tablet. polymers such as a polyethylene glycol and polyvinyl pyr 0415. Sublingual tablet preparation techniques known rolidone, Sugar alcohols such as D-Sorbitol and Xylitol, sac from the prior art are usually prepared by direct compression charides such as Sucrose, maltose, lactulose, D-fructose, dex of a mixture of powders comprising the active ingredient and tran, and glucose, Surfactants such as polyoxyethylene excipients for compression, Such as diluents, binders, disin hydrogenated castor oil, polyoxyethylene polyoxypropylene tegrating agents and adjuvants. In an alternative method of glycol, and polyoxyethylene Sorbitan higher fatty acid esters, preparation, the active ingredient and the compression excipi salts such as sodium chloride and magnesium chloride, ents can be dry- or wet-granulated beforehand. In one aspect, organic acids such as citric acid and tartaric acid, amino acids the active ingredient is distributed throughout the mass of the Such as glycine, beta-alanine, and lysine hydrochloride, and tablet. WO 00/16750 describes a tablet for sublingual use that aminosaccharides such as meglumine are given as examples disintegrates rapidly and comprises an ordered mixture in of the hydrophilic base. Polyethylene glycol, sucrose, and which the active ingredient is in the form of microparticles polyvinyl pyrrolidone are preferred and polyethylene glycol which adhere to the surface of water-soluble particles that are are further preferred. One or a combination of two or more Substantially greater in size, constituting a Support for the hydrophilic bases can be used in the present invention. active microparticles, the composition also comprising a 0419. The present invention contemplates pulmonary, mucoadhesive agent. WO 00/57858 describes a tablet for nasal, or oral administration through an inhaler. In one Sublingual use, comprising an active ingredient combined embodiment, delivery from an inhaler can be a metered dose. with an effervescent system intended to promote absorption, 0420. An inhaler is a device for patient self-administration and also a pH-modifier. of at least one compound of the invention comprising a spray 0416) The compounds of the invention can be prepared in inhaler (e.g., a nasal, oral, or pulmonary spray inhaler) con a formulation or pharmaceutical composition appropriate for taining anaerosol spray formulation of at least one compound administration that allows or enhances absorption across of the invention and a pharmaceutically acceptable dispers mucosa. Mucosal absorption enhancers include, but are not ant. In one aspect, the device is metered to disperse an amount limited to, a bile salt, fatty acid, Surfactant, or alcohol. In of the aerosol formulation by forming a spray that contains a specific embodiments, the permeation enhancer can be dose of at least one compound of the invention effective to Sodium cholate, sodium dodecyl Sulphate, sodium deoxycho treat a disease or disorder encompassed by the invention. The late, taurodeoxycholate, Sodium glycocholate, dimethylsul dispersant may be a surfactant, such as, but not limited to, foxide or ethanol. In a further embodiment, a compound of polyoxyethylene fatty acid esters, polyoxyethylene fatty acid the invention can be formulated with a mucosal penetration alcohols, and polyoxyethylene Sorbitan fatty acid esters. enhancer to facilitate delivery of the compound. The formu Phospholipid-based surfactants also may be used. lation can also be prepared with pH optimized for solubility, 0421. In other embodiments, the aerosol formulation is drug stability, and absorption through mucosa Such as nasal provided as a dry powder aerosol formulation in which a mucosa, oral mucosa, Vaginal mucosa, respiratory, and intes compound of the invention is present as a finely divided tinal mucosa. powder. The dry powder formulation can further comprise a 0417. To further enhance mucosal delivery of pharmaceu bulking agent, such as, but not limited to, lactose, Sorbitol, tical agents within the invention, formulations comprising the Sucrose, and mannitol. US 2011/0065628 A1 Mar. 17, 2011 30

0422. In another specific embodiment, the aerosol formu the art and described, for example in Genaro, ed., 1985, lation is a liquid aerosol formulation further comprising a Remington's Pharmaceutical Sciences, Mack Publishing Co., pharmaceutically acceptable diluent, such as, but not limited Easton, Pa., which is incorporated herein by reference. to, sterile water, saline, buffered saline and dextrose solution. 0429 Typically, dosages of the compounds of the inven 0423. In further embodiments, the aerosol formulation tion which may be administered to an animal, preferably a further comprises at least one additional compound of the human, range in amount from about 1.0 ug to about 100g per invention in a concentration Such that the metered amount of kilogram of body weight of the animal. The precise dosage the aerosol formulation dispersed by the device contains a administered will vary depending upon any number of fac dose of the additional compound in a metered amount that is tors, including but not limited to, the type of animal and type effective to ameliorate the symptoms of disease or disorder of disease state being treated, the age of the animal and the disclosed herein when used in combination with at least a first route of administration. Preferably, the dosage of the com or second compound of the invention. pound will vary from about 1 mg to about 10 g per kilogram 0424 Thus, the invention provides a self administration of body weight of the animal. More preferably, the dosage method for outpatient treatment of an addiction related dis will vary from about 10 mg to about 1 g per kilogram of body ease or disorder Such as an alcohol-related disease or disorder. weight of the animal. Such administration may be used in a hospital, in a medical 0430. The compounds may be administered to a subject as office, or outside a hospital or medical office by non-medical frequently as several times daily, or it may be administered personnel for self administration. less frequently, such as once a day, once a week, once every 0425 Compounds of the invention will be prepared in a two weeks, once a month, or even less frequently, such as formulation or pharmaceutical composition appropriate for once every several months or even once a year or less. The nasal administration. In a further embodiment, the com frequency of the dose will be readily apparent to the skilled pounds of the invention can be formulated with a mucosal artisan and will depend upon any number of factors, such as, penetration enhancer to facilitate delivery of the drug. The but not limited to, the type and severity of the disease being formulation can also be prepared with pH optimized for solu treated, the type and age of the animal, etc. bility, drug stability, absorption through nasal mucosa, and 0431. The invention also includes a kit comprising the other considerations. compounds of the invention and an instructional material that 0426 Capsules, blisters, and cartridges for use in an describes administration of the compounds. In another inhaler or insufflator may be formulated to contain a powder embodiment, this kit comprises a (preferably sterile) solvent mix of the pharmaceutical compositions provided herein; a Suitable for dissolving or Suspending the composition of the Suitable powder base. Such as lactose or starch; and a perfor invention prior to administering the compound to the mam mance modifier, Such as 1-leucine, mannitol, or magnesium mal. stearate. The lactose may be anhydrous or in the form of the 0432. As used herein, an “instructional material” includes monohydrate. Other Suitable excipients include dextran, glu a publication, a recording, a diagram, or any other medium of cose, maltose, Sorbitol. Xylitol, fructose, Sucrose, and treha expression that can be used to communicate the usefulness of lose. The pharmaceutical compositions provided herein for the compounds of the invention in the kit for effecting alle viation of the various diseases or disorders recited herein. inhaled/intranasal administration may further comprise a Optionally, or alternately, the instructional material may suitable flavor, such as menthol and levomenthol, or Sweet describe one or more methods of alleviating the diseases or eners, such as saccharin or saccharin Sodium. disorders. The instructional material of the kit of the invention 0427 For administration by inhalation, the compounds for may, for example, be affixed to a container that contains a use according to the methods of the invention are conve compound of the invention or be shipped together with a niently delivered in the form of an aerosol spray presentation container that contains the compounds. Alternatively, the from pressurized packs or a nebulizer, with the use of a instructional material may be shipped separately from the Suitable propellant, e.g., dichlorodifluoromethane, trichlorof container with the intention that the instructional material and luoromethane, dichlorotetrafluoroethane, carbon dioxide or the compound be used cooperatively by the recipient. other Suitable gas. In the case of a pressurized aerosol, the 0433 Without further description, it is believed that one of dosage unit may be determined by providing a valve to deliver ordinary skill in the art can, using the preceding description a metered amount. Capsules and cartridges of e.g., gelatin for and the following illustrative examples, make and utilize the use in an inhaler or insufflator may be formulated containing compounds of the present invention and practice the claimed a powder mix of the drugs and a suitable powder base such as methods. The following working examples, therefore, spe lactose or starch. cifically point out the preferred embodiments of the present 0428. As used herein, “additional ingredients' include, but are not limited to, one or more of the following: excipi invention, and are not to be construed as limiting in any way ents; Surface active agents; dispersing agents; inert diluents; the remainder of the disclosure. granulating and disintegrating agents; binding agents; lubri Examples cating agents; Sweetening agents, flavoring agents; coloring agents; preservatives; physiologically degradable composi 0434. A series of background drug combination studies tions such as gelatin; aqueous vehicles and solvents; oily are provided herein. Examples 1 and 2 are examples of using vehicles and solvents; Suspending agents; dispersing or wet various combinations of two different drugs at a time, and ting agents; emulsifying agents, demulcents; buffers; salts; serve as preludes to the topiramate, ondansetron, and naltr thickening agents; fillers; emulsifying agents; antioxidants; exone combination studies disclosed in Example 3. antibiotics; antifungal agents; stabilizing agents; and pharma ceutically acceptable polymeric or hydrophobic materials. Example 1 Other “additional ingredients’ which may be included in the 0435 The studies described herein demonstrate, interalia: pharmaceutical compositions of the invention are known in a) ondansetron’s effectiveness in the treatment of EOA and US 2011/0065628 A1 Mar. 17, 2011

LOA; b) that EOA differs from LOA in serotonergic function; LNAA ratio was positively correlated with legal problems c) that age of onset discriminates between Subtypes of alco (0.313; p <0.05) on the Addiction Severity Index and self holic; d) naltrexone's effects on alcohol drinking in non directedness (0.287: p<0.05) on the Temperament and Char human primates; e) maltrexone's effects on drinking in acter Inventory (TCI). However, plasma TRYP/LNAA ratio humans; f) that the combination of ondansetron and naltrex was negatively correlated with harm avoidance on (0.351; one is clinically safe and effective in the treatment of EOA: p<0.05) on the TCI and vigor (-0.260;p-0.05) on the Profile and g) evidence of our expertise with Cognitive Behavioral of Mood States. Further, alcoholics with an additional diag Therapy as a psychosocial platform for testing the effective nosis of antisocial personality disorder (ASPD) had compara ness of putative therapeutic medications. tively lower plasma TRYP/LNAA ratios than those without 0436 a) Ondansetron is Effective at Improving the Drink ASPD (mean 0.019+0.0067 vs. 0.018 0.007: p<0.05 respec ing Outcomes of EOA but not LOA tively). These results were consistent with those of others 0437. It was hypothesized herein that the drinking out which have found an association between low 5-HT function comes of EOA, compared with LOA, would be more and an early age of alcoholism onset and related antisocial improved by the selective serotonin antagonist, ondansetron. behaviors. EOA differ from LOA by having greater serotonergic abnor 0443 c) Age of Onset Discriminates Between Subtypes of mality, an earlier age of onset, and antisocial behaviors. Thus, Alcoholic EOA may be especially responsive to treatment with a selec 0444. In a cohort (N-253) of the alcoholics enrolled into tive serotonergic agent. our effectiveness study of ondansetron for the treatment of 0438. The design was as follows: 321 alcoholics alcoholism, we studied baseline differences between the three (EOA=161: LOA=160; mean age 40.6 years; 70.5% male, groups using a comprehensive set of psychopathological vari and 78.6% white) received one lead in week of single-blind ables. These analyses were conducted using two different placebo followed by 11 weeks of double-blind outpatient models. First, we examined the impact of specifying different treatment using a 2x4 factorial design which examined age of ages of onset for the Subtyping that is, by comparing EOA onset (EOA vs. LOA) and medication dose (placebo, or and LOA depending upon whether the cut-off age for the ondansetron 1, 4, or 16 ug/kg b.i.d) combined with weekly distinction was s20 or s25 years. Second, we examined age standardized group Cognitive Behavioral Therapy. Efficacy of onset as a continuous variable by inclusion of a Middle measures were: 1) Self reported drinking (Drinks/Day, Onset Group (MOA) i.e., EOAs20 years; MOA-20-25 Drinks/Drinking Day, Percent Days Abstinent, and Total years, and LOA->25 years. Days Abstinent/study week), and 2) plasma Carbohydrate 0445 First, there were no important differences in psycho Deficient Transferrin level (CDT). pathological profile based on different cut-off onset ages for 0439. The results were that at endpoint, EOA who EOA (i.e., s20 or s25 years) or LOA (i.e. >20 or >25 years). received ondansetron (1 or 4 g/kg b.i.d.), compared with Second, using the s25 years or >25 years cut-off criteria for those on placebo had fewer Drinks/Day (1.89 or 1.56 vs. 3.30; onset age, EOA compared with LOA did have significantly p<0.05) and Drinks/Drinking Day (4.75 or 4.28 vs. 6.90; (p<0.05) higher: a) Visual Analogue Scores for the craving p<0.05). Ondansetron 4 Jug/kg b.i.d was Superior to placeboat measures of “thinking about the next time I will use alcohol increasing Percent Days Abstinent (70.10 vs. 50.20; p-0.05) (21.8+2.7 vs. 17.6+2.4): “I want to buy alcohol (35.2+3.1 vs. and Total Days Abstinent/study week (6.74 vs. 5.92; p <0.05). 26.3+2.8), “I have the urge or desire to use alcohol (24.3+3.2 Among EOA, there was a reduction in the mean log CDT ratio vs. 16.4+2.3), and “if offered I can refuse alcohol (30.3+3.5 between endpoint and enrollment for those on Ondansetron (1 vs. 20.9+2.6); b) hostility scores on the “resentment” (3.2+0.2 and 4 ug/kg b.i.d) but not placebo (-0.17 and 0.19 vs. +0.11; vs. 2.4+0.2), “assault” (4.2-0.3 vs. 3.3+0.3), “suspicion” p-0.05). Drinking outcomes in LOA were not improved sub (3.5+0.3 vs. 2.6+0.2), and “addictive propensity” (27.7+0.5 stantially by ondansetron. As an illustration, the figures below vs. 25.3+0.5) subscales of the Buss-Durkee; c) reduction in shows the Mean+SE Drinks/Day and the Mean+SE log childhood problem behaviors” (34.9+1.1 vs. 38.6+0.9); d) plasma by treatment condition, respectively. male family history (8.5+0.8 vs. 5.3+0.5) on the Comprehen 0440. In Summary, we concluded that ondansetron (par sive Drinker Profile (123); e) “depression-dejection” ticularly the 4 ug/kg b.i.d dose) is an effective treatment for (21.5+1.6 vs. 14.8+1.2), “anger-hostility” (11.7+1.0 vs. EOA, presumably by ameliorating underlying serotonergic 6.6+0.6), “fatigue-inertia” (10.0+0.7 vs. 6.3+0.5) and “con abnormality. (see FIGS. 1-7). fusion-bewilderment” (9.3+0.5 vs. 6.6+0.4) on the Profile of 0441 b) EOA may have a Greater Predisposition to 5-HT Mood States, and e) there were more EOA than LOA with Abnormality than LOA antisocial personality disorder (ASPD) (18.9% vs. 6.4%). 0442. This study was conducted based upon the hypoth These results show that EOA differ from LOA on psycho esis that the younger an alcoholic's age of onset the more pathological characteristics associated with craving, hostility, likely he/she is to develop behavioral problems associated family history, impulse-control, and antisocial behaviors. with 5-HT dysfunction such as impulsivity and a broad range 0446. d) Naltrexone's Effects on Alcohol Drinking in of antisocial behaviors just the type of individual likely to Non-Human Primates have EOA. We studied the relationship between plasma 0447 Studies in non-human primates show that naltrex TRYP/LNAA ratio in 58 (Males=42) treatment-seeking alco one is associated with dose-dependent reductions in alcohol holics. Subjects had a mean: a) chronological age of 41.5 (SD drinking From the figure opposite, it can be seen that increas 8.3) years; b) age of onset 24.2 (SD 9.7) years, and c) an ing doses of naltrexone (g/kg) produced dose-dependent average duration of illness of 17.3 (SD 8.9) years. Briefly, age decreases in alcohol consumption (8% w/v) in three non food of onset was significantly and positively correlated with deprived rhesus monkeys under a fixed ratio schedule of plasma TRYP/LNAA ratio (0.292; p<0.05); this is consistent reinforcement. During these 3 hour sessions, both water and with an association between earlier onset of alcoholism and alcohol were concurrently available. These results support reduced tryptophan availability. Additionally, plasma TRYP/ clinical evidence of naltrexone as a treatment medication for US 2011/0065628 A1 Mar. 17, 2011 32 alcoholism. However, the time-course data also show that erence condition and 570 maltrexone) of Croop and Col maltrexone's non specific pharmacological effects play an leagues, it is notable that they reported a 15% rate of subject important role in its ability to reduce drinking behavior (see withdrawal due to naltrexone induced nausea. In our own FIG.3). study of ondansetron’s effectiveness (N=321; 88 of whom 0448 e) Naltrexone's Effects on Alcohol Consumption in received the 4 ug/kg dose) (see C.a. above), no side-effect was Humans reported more often than placebo, and nausea was not 0449 In an open-label study, we evaluated the efficacy of reported. Therefore, it is reasonable to expect that maltrexone, an opioid antagonist, in the treatment of alcohol ondansetron will reduce naltrexone's propensity to induce dependence. Since up to 92% of alcoholics are also co-de nausea, thereby enhancing compliance. pendent on nicotine, our cohort included dually dependent 0453 Preliminary analyses of the data showed that at end individuals. Naltrexone was chosen due to evidence which point, those who received ondansetron--maltrexone VS. pla Suggests utility in the treatment of alcoholism, and some cebo had fewer: 1) Drinks/Day (adjusted mean 0.99+0.60 vs. evidence that opioid-DA interaction may mediate the rein 3.68+0.63; F1, 16–9.35, p=0.008); 2) Drinks/Drinking Day forcing effects of nicotine. From a local newspaper advertise (3.14+0.87 vs. 6.76+0.71: F1, 13=10.45, p=0.007) (see FIG. ment, we enrolled 10 Subjects (6 males and 4 females; aged 3. below). There was a trend towards an improvement in 40+2.56 years) into the study. All patients met DSM III-R Percent Days Abstinent among those receiving the medica criteria for both alcohol and nicotine dependence. Patients tion combination vs. placebo from enrollment to endpoint were instructed that the goal of treatment was abstinence by (adjusted mean 72.06+8.64 vs. 48.24+9.12: F1, 16–3.53, the end of the study. Patients received naltrexone (50 mg/day) p=0.08). There were no significant differences in baseline in unmarked capsules with a riboflavin tracer for an 8 week drinking between the treatment groups. These data are strik period. Weekly attendance included combined coping skills ing given the small cohort, and the effect sizes for the Drinks/ therapy for alcohol and nicotine dependence, nursing visits, Day and DrinkS/Drinking Day results were large—1.4 and and completion of rating scales. The results showed that there 1.7, respectively based on covariate adjustment and log trans was a significant decrease in alcohol consumption (3.29+2.16 formation. Drop-out rate was about 25%. drinks/day vs. 2.16+1.88 drinks/day; p <0.05), and a notice 0454. In summary, these results provide strong evidence able reduction in smoking (21.10+5.57 cigarettes/day vs. that the combination of ondansetron and naltrexone is safe 15.93+3.09 cigarette/day). Objective biochemical measures and effective for the treatment of EOA. Further, this finding of alcohol consumption and nicotine (urine cotinine from Supports the hypothesis that the combination of ondansetron 33% to 54%), and craving showed a similar trend. No patient and naltrexone would provide added and possibly even syn reported clinically significant nicotine withdrawal Symp ergistic therapeutic benefit given that the typical effect sizes toms. Drop-out rate at 30% was similar to that observed in for these medications alone are in the 0.2-0.5 range. medication trials for alcoholism. This study Supports the 0455 g) Additional Recent Clinical Trial Experience clinical evidence that naltrexone is a useful adjunct to Cog Using Cognitive Behavioral Therapy nitive Behavioral Therapy for the treatment of alcoholism. 0456. The applicants have considerable experience with Naltrexone's effects on cigarette Smoking appears Small but the use of Cognitive Behavioral Therapy as the psychosocial may warrant further exploration. foundation for assessing the efficacy of putative therapeutic 0450 f) Safety and Effectiveness of Combining compounds. As an example, provided below are the results Ondansetron and Naltrexone in Treating EOA from our center participating in a large multi center clinical 0451. In an 8-week double-blind clinical trial, we tested trial. Dr. Johnson was the lead author in the publication that the safety and effectiveness of ondansetron (4 g/kg)+naltr resulted from this multi center study (see FIG. 5). exone (50 mg/day) vs. placebo for the treatment of alcohol 0457 Ritanserin, a 5-HT2 antagonist, has been shown to ism. We enrolled 20 DSM-IV diagnosed EOA (Males=15, reduce alcohol preference and consumption in rats, presum females=5; mean age=38.0+1.78 years; Ethnicity—Cauca ably via its interaction with midbrain dopamine fibers. In this sian=12, Hispanics=8). Ten of these subjects received the study, we examined the efficacy of ritanserin on alcohol con medication combination and the rest (N=10) got placebo in Sumption in a 12-week, outpatient, placebo-controlled clini addition to weekly sessions of manual-driven Cognitive cal trial. This study overlapped in time and recruitment effort Behavioral Therapy. All subjects were currently drinking at with the ondansetron study described above. Therefore, our enrollment. Only one subject with constipation and who research group has the expertise to conduct multiple treat received the medication combination reported any side-effect ment studies simultaneously. Fifty-four patients from our attributable to the study medication which was rated above center who met DSM III-R criteria for alcoholism partici minimal. Minimal nausea and fatigue vs. constipation were pated and were randomized to receive placebo, 2.5 mg, or 5 reported by two vs. three subjects, respectively who received mg of ritanserin. All patients received Standardized manual the medication combination. Comparatively, minimal head driven Cognitive Behavioral Therapy for alcoholism. Cogni aches and constipation were reported in four and two Subjects tive Behavioral Therapy was conducted by counselors with on placebo, respectively. No side-effect persisted between extensive experience with behavioral treatments, and over weekly study visits, or required medical intervention. No 500 therapy hours were logged. These groups did not differ in subject withdrew from the study due to side-effects. From age, sex distribution, or severity of alcoholism. FIG.3 shows these data, there was no clinical difference in the side-effect that there was no significant difference on alcohol consump profile between the treatment groups. This would suggest that tion between the three groups and no treatment effect using a the side-effect profile of ondansetron--maltrexone is benign repeated measures analysis of variance (F=2.81; df 2,17. and unlikely to be significantly different from placebo. p=0.088). There was no within time effect nor group interac 0452 While the small subject numbers in this study do not tion. Similarly, there was no difference in craving between the permit meaningful percentage comparisons with the much treatment groups. These results show that at these doses, larger sample size study (Total N=865; 295 received the ref ritanserin had no clinically significant effect on alcohol con US 2011/0065628 A1 Mar. 17, 2011

Sumption or craving. These results are consistent with those hol-preferring rats. While topiramate alone produced modest of other researchers in this multi-center trial. decreases in alcohol consumption (FIG. 10A; e.g., 12%-8% 0458. A typical experimental design chart is provided in decrease from baseline), when combined with naltrexone and FIG. 6. In some cases telephone screening procedures are a dose of ondansetron that did not affect alcohol consumption used. For example, in one trial the ratio of telephone screens on its own (FIG. 10B), robust and persistent decreases from to enrollment was approximately 4:1 (see FIG. 7). Our tele baseline were observed on alcohol consumption as measured phone screening procedures are highly effective at identify under a two-bottle 24-hour consumption procedure (FIG. ing eligible subjects for our studies. Most Subjects are 10D topiramate+ondansetron; FIG. 10E topiramate+on excluded from the study at the telephone screening stage. Of dansetron--maltrexone, e.g., 28%+5% decrease from base those who appear to meet eligibility criteria on the telephone line). Data are plotted across 7 consecutive sessions, which screen and who show up for the intake interview, less than include a 3-day baseline period, the test session in which the 30% of these are excluded from enrollment. The most com compound(s) were administered, and the 3 sessions that fol mon reasons for exclusion at intake are abnormal laboratory lowed the test session. Each data point represents a mean tests, and/or other significant health problems. (SE) of at least 6 rats. The data suggest an additive beneficial 0459 FIG. 7 is a representative example of enrollment and effect of the topiramate/ondansetron/naltrexone combination projected completion rates adjusting for start up and wind as compared with each of the drugs alone. down periods of about 8 weeks. The telephone screening 0466. The addictive effects of most abused drugs and alco procedures are highly effective at identifying eligible Subjects hol are mediated through increased dopaminergic activity in for our studies. Most subjects are excluded from the study at the cortico-mesolimbic system that originates in the Ventral the telephone screening stage. Of those who appear to meet tegmental area, relays in the nucleus accumbens, and sends eligibility criteria on the telephone screen and who show up forward profuse connections to the cortex and other higher for the intake interview, less than 30% of these are excluded brain centers. FIG. 11 schematically illustrates that the from enrollment. The most common reasons for exclusion at opioid, glutamate, and serotonergic systems are all modula intake are abnormal laboratory tests, and/or other significant tors of cortico-mesolimbic dopamine function. health problems. 0467. The disclosures of each and every patent, patent application, and publication cited herein are hereby incorpo Example 2 rated by reference herein in their entirety. 0468 Headings are included herein for reference and to 0460 Examination of the Combined Administration of aid in locating certain sections. These headings are not Topiramate and Naltrexone as a Potential Treatment for Alco intended to limit the scope of the concepts described therein hol Dependence Using Animal Models under, and these concepts may have applicability in other 0461 FIG. 8 demonstrates the combined effect of topira sections throughout the entire specification. mate (5 and 10 mg/kg, intraperitoneally) and naltrexone (1 0469. The previous description of the disclosed embodi mg/kg, intraperitoneally) on alcohol consumption in alcohol ments is provided to enable any person skilled in the art to preferring (P) rats. While topiramate alone only modestly make or use the present invention. Various modifications to decreased alcohol consumption (at the 10-mg/kg dose these embodiments will be readily apparent to those skilled in although this effect is not yet significant), when combined the art, and the generic principles defined herein may be with a dose of naltrexone that did not affect alcohol consump applied to other embodiments without departing from the tion on its own, significant decreases from baseline were spirit or scope of the invention. Accordingly, the present observed on alcohol consumption at both topiramate doses invention is not intended to be limited to the embodiments (see FIG. 8). No significant differences were observed fol shown herein but is to be accorded the widest scope consistent lowing vehicle injection. Data are plotted as change from with the principles and novel features disclosed herein. baseline consumption, and each data point represents a mean (+SE) of 8 rats. 1. A method for treating or preventing an addictive disease 0462 Model for Neural Control or disorder in a subject in need thereof, said method compris 0463. The neural control mechanisms described herein are ing administering to said Subject an effective amount of at presented schematically in FIG. 9. least three compounds, or biologically active analogs, deriva tives, modifications, or pharmaceutically acceptable salts Example 3 thereof, wherein said at least three compounds are selected from the group consisting of serotonergic agents, serotonin 0464 Examination of the Combined Administration of antagonists, selective serotonin re-uptake inhibitors, seroto Ondansetron, Topiramate, and Naltrexone as a Potential nin receptor antagonists, opioid antagonists, dopaminergic Treatment for Alcohol Dependence Using Animal Models agents, dopamine release inhibitors, dopamine antagonists, 0465. The effects of ondansetron, topiramate, and naltrex norepinephrine antagonists, y-amino-butyric acid agonists, one, medications shown to be efficacious in treating alcohol y-amino-butyric acid inhibitors, y-amino-butyric acid recep dependent humans, on measures of alcohol dependence were tor antagonists, y-amino-butyric acid channel antagonists, determined in animal models in order to determine whether glutamate agonists, glutamate antagonists, glutamine ago these medications may produce additive effects when com nists, glutamine antagonists, anti-convulsant agents, N-me bined. The experiments examined their ability to modulate thyl-D-aspartate-blocking agents, calcium channel antago total consumption under a 24-hour-access two-bottle choice nists, carbonic anhydrase inhibitors, neurokinins, Small procedure wherein rats had unlimited access to alcohol solu molecules, peptides, vitamins, co-factors, and Corticosteroid tions (10%) and water. FIG. 10 demonstrates the combined Releasing Factor antagonists, and optionally administering at effect of topiramate (10 mg/kg, intraperitoneally), least one additional therapeutically active compound, thereby ondansetron (0.001 mg/kg, intraperitoneally), and naltrexone treating or preventing an addictive disease or disorder in a (1 mg/kg, intraperitoneally) on alcohol consumption in alco Subject. US 2011/0065628 A1 Mar. 17, 2011 34

2. The method of claim 1, wherein said subject is a human. Brief Behavioral Compliance Enhancement Treatment, Cog 3. The method of claim 2, wherein said addictive disease or nitive Behavioral Coping Skills Therapy, Motivational disorder is selected from the group consisting of alcohol Enhancement Therapy, Twelve-Step Facilitation Therapy, related diseases and disorders, obesity-related diseases and Combined Behavioral Intervention, Medical Management, disorders, eating disorders, impulse control disorders, nico psychoanalysis, psychodynamic treatment, and Biopsycho tine-related disorders, amphetamine-related disorders, meth social, Report, Empathy, Needs, Direct Advice and Assess amphetamine-related disorders, cannabis-related disorders, ment. cocaine-related disorders, hallucinogen use disorders, inhal 17. The method of claim 1, wherein said subject is further ant-related disorders, benzodiazepine abuse or dependence Subjected to hypnosis or acupuncture. related disorders, and opioid-related disorders. 18. The method of claim 1, wherein at least one of said at 4. The method of claim3, wherein said addictive disease or least three compounds is administered at least once a week. disorder is an alcohol-related disease or disorder. 19. The method of claim 18, wherein at least one of said at 5. The method of claim 4, wherein said alcohol-related least three compounds is administered at least once a day. disease or disorder is selected from the group consisting of 20. The method of claim 1, wherein at least one of said at early onset alcoholic, late onset alcoholic, alcohol-induced least three compounds is a serotonin receptor antagonist. psychotic disorder with delusions, alcohol abuse, heavy 21. The method of claim 20, wherein said serotonin recep drinking, excessive drinking, alcohol intoxication, alcohol tor is the serotonin-3 receptor. withdrawal, alcohol intoxication delirium, alcohol with 22. The method of claim 1, wherein three compounds are drawal delirium, alcohol-induced persisting dementia, alco administered to said Subject. hol-induced persisting amnestic disorder, alcohol depen 23. The method of claim 1, wherein said at least three dence, alcohol-induced psychotic disorder with compounds are separately administered. hallucinations, alcohol-induced mood disorder, alcohol-in 24. The method of claim 23, wherein a first compound of duced or associated bipolar disorder, alcohol-induced or said at least three compounds is administered before a second associated post traumatic stress disorder, alcohol-induced compound of said at least three compounds is administered. anxiety disorder, alcohol-induced sexual dysfunction, alco 25. The method of claim 1, wherein a first compound, a hol-induced sleep disorder, alcohol-induced or associated second compound, and a third compound of said at least three gambling disorder, alcohol-induced or associated sexual dis compounds are administered nearly simultaneously. order, alcohol-related disorder not otherwise specified, alco 26. The method of claim 1, wherein a first compound of hol intoxication, and alcohol withdrawal. said at least three compounds is administered subsequent to 6. The method of claim 5, wherein said treatment reduces administration of a second or third compound of said at least the frequency of alcohol consumption compared with the three compounds. frequency before said treatment or compared with a control 27. The method of claim 1, wherein said at least three Subject not receiving said treatment. compounds are administered as a pharmaceutical composi 7. The method of claim 6, wherein said alcohol consump tion. tion comprises heavy drinking or excessive drinking. 28. The method of claim 1, wherein said at least three 8. The method of claim 5, wherein said treatment reduces compounds are administered via a route selected from the the quantity of alcohol consumed compared with the amount group consisting of oral, topical, rectal, intramuscular, intra of alcohol consumed before said treatment or compared with mucosal, and intravenous. a control Subject not receiving said treatment. 29. The method of claim 28, wherein said at least three 9. The method of claim 8, wherein said alcohol consump compounds are administered via an oral route. tion comprises heavy drinking or excessive drinking. 30. A pharmaceutical composition comprising at least 10. The method of claim 5, wherein said treatment three compounds of claim 1, or biologically active analogs, improves the physical or psychological sequelae associated homologs, derivatives, modifications, or pharmaceutically with alcohol consumption compared with a control Subject acceptable salts thereof, and a pharmaceutically acceptable not receiving said treatment. carrier. 11. The method of claim 5, wherein said treatment 31. The pharmaceutical composition of claim 30, said increases the abstinence rate of said subject compared with a composition comprising effective amounts of topiramate, control Subject not receiving said treatment. ondansetron, and naltrexone, and biologically active analogs, 12. The method of claim 5, wherein said treatment reduces homologs, derivatives, modifications, or pharmaceutically the average level of alcohol consumption compared with the acceptable salts thereof. level before said treatment or compared with a control subject 32. The method of claim 1, wherein at least one of said at not receiving said treatment. least three compounds is administered as a controlled-release 13. The method of claim3, wherein said treatment reduces formulation. alcohol consumption and increases abstinence compared 33. The method of claim 1, wherein three of said at least with the alcohol consumption and abstinence before said three compounds are topiramate, naltrexone, and treatment or compared with a control Subject not receiving ondansetron, or biologically active analogs, homologs, said treatment. derivatives, modifications, or pharmaceutically-acceptable 14. The method of claim 5, wherein said subject comprises salts thereof. a predisposition to early-onset alcoholism or late-onset alco 34. The method of claim 33, wherein three compounds, or holism. biologically active analogs, homologs, derivatives, modifica 15. The method of claim 5, further wherein said subject is tions, or pharmaceutically-acceptable salts thereof, are Submitted to a psychosocial management program. administered. 16. The method of claim 15, wherein said psychosocial 35. The method of claim 33, wherein at least one additional management program is selected from the group consisting of therapeutically active compound is administered. US 2011/0065628 A1 Mar. 17, 2011

36. The method of claim 33, wherein topiramate is admin 60. The method of claim 1, further wherein advice is pro istered at a dosage ranging from about 15 mg/day to about vided to said subject. 2500 mg/day. 61. The method of claim 60, further wherein said advice is 37. The method of claim 36, wherein topiramate is admin provided in a format selected from the group consisting of istered at a dosage ranging from about 25 mg/day to about written, electronic, or interpersonal. 1000 mg/day. 62. The method of claim 61, wherein said method is more 38. The method of claim 37, wherein topiramate is admin effective at treating or preventing an addictive disease or istered at a dosage ranging from about 50 mg/day to about 500 disorder than a method selected from the group consisting of mg/day. administering a placebo and providing advice, administering 39. The method of claim 38, wherein topiramate is admin no drugs and providing advice, and not administering drugs istered at a dosage of about 300 mg/day or about 275 mg/day. or providing advice. 40. The method of claim 33, wherein topiramate is admin 63. The method of claim 1, wherein said method is more istered at a dosage ranging from about 0.1 mg/kg/day to about effective in alleviating said addictive disease or disorder than 100 mg/kg/day. said method used in combination with a psychosocial man 41. The method of claim 36, wherein topiramate is admin agement program. istered at a dose of bout 300 mg/day. 64. The method of claim 5, wherein said alcohol-related 42. The method of claim 33, wherein topiramate is admin disease or disorder is alcohol abuse. istered at least once a week. 65. The method of claim 2, further wherein at least one 43. The method of claim 42, wherein topiramate is admin compound administered to said subject is selected from the istered at least once a day. group consisting of disulfiram, acamprosate, Sertraline, gal 44. The method of claim 33, wherein naltrexone is admin anthamine, nalmefene, naloxone, desoxypeganine, benzodi istered at a dosage ranging from about 1.0 mg per application azepines, neuroleptics, risperidone, rimonabant, traZodone, to about 100 mg per application. and aripiprazole. 45. The method of claim 44, wherein naltrexone is admin 66. The method of claim 33, further wherein at least one istered at a dosage ranging from about 10 mg per application compound administered to said subject is selected from the to about 50 mg per application. group consisting of disulfiram, acamprosate, Sertraline, gal 46. The method of claim 45, wherein naltrexone is admin anthamine, nalmefene, naloxone, desoxypeganine, benzodi istered at a dosage of about 25 mg per application. azepines, neuroleptics, risperidone, rimonabant, traZodone, 47. The method of claim 33, wherein naltrexone is admin and aripiprazole. istered at least once a week. 67. The method of claim 1, further wherein said subject is 48. The method of claim 47, wherein naltrexone is admin administered at least one compound selected from the group istered at least once a day. consisting of adrenergics, adrenocortical steroids, adrenocor 49. The method of claim 48, wherein naltrexone is admin tical Suppressants, aldosterone antagonists, amino acids, ana istered at least twice a day. leptics, analgesics, anorectic compounds, anorexics, anti 50. The method of claim 49, wherein naltrexone is admin anxiety agents, antidepressants, antihypertensives, anti istered twice a day. inflammatories, antinauseants, antineutropenics, 51. The method of claim 33, wherein ondansetron is antiobsessional agents, antiparkinsonians, antipsychotics, administered at a dosage ranging from about 0.01 ug/kg per appetite Suppressants, blood glucose regulators, carbonic application to about 100 ug/kg per application. anhydrase inhibitors, cardiotonics, cardiovascular agents, 52. The method of claim 51, wherein ondansetron is choleretics, cholinergics, cholinergicagonists, cholinesterase administered at a dosage ranging from about 0.1 ug/kg per deactivators, cognition adjuvants, cognition enhancers, hor application to about 10.0 g/kg per application. mones, memory adjuvants, mental performance enhancers, 53. The method of claim 52, wherein ondansetron is mood regulators, neuroleptics, neuroprotectives, psychotro administered at a dosage ranging from about 1.0 ug/kg per pics, relaxants, sedative-hypnotics, stimulants, thyroid hor application to about 5.0 ug/kg per application. mones, thyroid inhibitors, thyromimeties, cerebral ischemia 54. The method of claim 53, wherein ondansetron is agents, vasoconstrictors, and vasodilators. administered at a dosage of about 4.0 g/kg per application or 68. The method of claim 1, wherein the effect of said at about 3.0 g/kg per application. least three compounds is additive. 55. The method of claim 33, wherein ondansetron is 69. The method of claim 1, wherein the effect of said at administered at least once a week. least three compounds is synergistic. 56. The method of claim 33, wherein ondansetron is 70. The method of claim 1, wherein said treatment administered at least once a day. decreases mesocorticolimbic dopamine activity. 57. The method of claim 56, wherein ondansetron is 71. The method of claim 1, wherein said treatment inhibits administered once a day. glutamate function. 58. The method of claim 33, wherein topiramate is admin 72. The method of claim 1, wherein said treatment facili istered at a dosage of about 300 mg/day, ondansetron is tates Y-amino-butyric acid activity. administered at a dosage of about 4.0 ug/kg per application, 73.-125. (canceled) and naltrexone is administered at a dosage of about 25 mg per 126. A method for treating or preventing alcohol abuse in a application. Subject in need thereof, said method comprising administer 59. The method of claim 34, wherein topiramate is admin ing to said Subject an effective amount of at least three com istered at a dosage of about 300 mg/day, ondansetron is pounds, or biologically active analogs, derivatives, modifica administered at a dosage of about 4.0 ug/kg per application, tions, or pharmaceutically acceptable salts thereof, selected and naltrexone is administered at a dosage of about 25 mg per from the group consisting of serotonergic agents, serotonin application. antagonists, selective serotonin re-uptake inhibitors, seroto US 2011/0065628 A1 Mar. 17, 2011 36 nin receptor antagonists, opioid antagonists, dopaminergic selected from the group consisting of serotonergic agents, agents, dopamine release inhibitors, dopamine antagonists, serotonin antagonists, selective serotonin re-uptake inhibi norepinephrine antagonists, Y-amino-butyric acid agonists, tors, serotonin receptor antagonists, opioid antagonists, y-amino-butyric acid inhibitors, y-amino-butyric acid recep dopaminergic agents, dopamine release inhibitors, dopamine tor antagonists, y-amino-butyric acid channel antagonists, antagonists, norepinephrine antagonists, y-amino-butyric glutamate agonists, glutamate antagonists, glutamine ago acid agonists, y-amino-butyric acid inhibitors, y-amino-bu nists, glutamine antagonists, anti-convulsant agents, N-me tyric acid receptor antagonists, y-amino-butyric acid channel thyl-D-aspartate-blocking agents, calcium channel antago antagonists, glutamate agonists, glutamate antagonists, nists, carbonic anhydrase inhibitors, neurokinins, Small glutamine agonists, glutamine antagonists, anti-convulsant molecules, peptides, vitamins, co-factors, and Corticosteroid agents, N-methyl-D-aspartate-blocking agents, calcium Releasing Factor antagonists, thereby treating or preventing channel antagonists, carbonic anhydrase inhibitors, neuroki alcohol abuse in a Subject. nins, Small molecules, peptides, Vitamins, co-factors, and 127. The method of claim 126, wherein said at least three Corticosteroid Releasing Factor antagonists, thereby treating compounds, or biologically active analogs, derivatives, modi or preventing excessive drinking in a Subject. fications, or pharmaceutically acceptable salts thereof, are 131. The method of claim 130, wherein said at least three topiramate, ondansetron, and naltrexone. compounds, or biologically active analogs, derivatives, modi 128. A method for treating or preventing heavy drinking in fications, or pharmaceutically acceptable salts thereof, are a Subject in need thereof, said method comprising adminis topiramate, ondansetron, and naltrexone. tering to said Subject an effective amount of at least three 132. A method for treating or preventing problem drinking compounds, or biologically active analogs, derivatives, modi in a subject in need thereof, said method comprising admin fications, or pharmaceutically acceptable salts thereof, istering to said Subject an effective amount of at least three selected from the group consisting of serotonergic agents, compounds, or biologically active analogs, derivatives, modi serotonin antagonists, selective serotonin re-uptake inhibi fications, or pharmaceutically acceptable salts thereof, tors, serotonin receptor antagonists, opioid antagonists, selected from the group consisting of serotonergic agents, dopaminergic agents, dopamine release inhibitors, dopamine serotonin antagonists, selective serotonin re-uptake inhibi antagonists, norepinephrine antagonists, y-amino-butyric tors, serotonin receptor antagonists, opioid antagonists, acid agonists, y-amino-butyric acid inhibitors, y-amino-bu dopaminergic agents, dopamine release inhibitors, dopamine tyric acid receptor antagonists, y-amino-butyric acid channel antagonists, norepinephrine antagonists, y-amino-butyric antagonists, glutamate agonists, glutamate antagonists, acid agonists, y-amino-butyric acid inhibitors, y-amino-bu glutamine agonists, glutamine antagonists, anti-convulsant tyric acid receptor antagonists, y-amino-butyric acid channel agents, N-methyl-D-aspartate-blocking agents, calcium antagonists, glutamate agonists, glutamate antagonists, channel antagonists, carbonic anhydrase inhibitors, neuroki glutamine agonists, glutamine antagonists, anti-convulsant nins, Small molecules, peptides, Vitamins, co-factors, and agents, N-methyl-D-aspartate-blocking agents, calcium Corticosteroid Releasing Factor antagonists, thereby treating channel antagonists, carbonic anhydrase inhibitors, neuroki or preventing heavy drinking in a Subject. nins, Small molecules, peptides, Vitamins, co-factors, and 129. The method of claim 128, wherein said at least three Corticosteroid Releasing Factor antagonists, thereby treating compounds, or biologically active analogs, derivatives, modi or preventing problem drinking in a Subject. fications, or pharmaceutically acceptable salts thereof, are 133. The method of claim 132, wherein said at least three topiramate, ondansetron, and naltrexone. compounds, or biologically active analogs, derivatives, modi 130. A method for treating or preventing excessive drink fications, or pharmaceutically acceptable salts thereof, are ing in a subject in need thereof, said method comprising topiramate, ondansetron, and naltrexone. administering to said Subject an effective amount of at least 134.-144. (canceled) three compounds, or biologically active analogs, derivatives, modifications, or pharmaceutically acceptable salts thereof, c c c c c