US 20100152161A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0152161 A1 BARAK (43) Pub. Date: Jun. 17, 2010

(54) COMPOSITIONS FORWEIGHT (60) Provisional application No. 60/670,290, filed on Apr. MANAGEMENT 12, 2005. (75) Inventor: Nir BARAK, Tel-Aviv (IL) (30) Foreign Application Priority Data Correspondence Address: Apr. 22, 2004 (IL) ...... 161595 MARTIN D. MOYNIHAN d/b/a PRTSI, INC. P.O. BOX16446 Publication Classification ARLINGTON, VA 22215 (US) (51) Int. Cl. (73) Assignee: Mor Research Applications Ltd., A6II 3/4402 (2006.01) Tel-Aviv (IL) A6IP3/00 (2006.01) A6II 3/55 (2006.01) (21) Appl. No.: 12/714,503 A 6LX 3/59 (2006.01) A6II 3/554 (2006.01) (22) Filed: Feb. 28, 2010 A63/496 (2006.01) A6II 3/55 (2006.01) Related U.S. Application Data A6II 3/4439 (2006.01) (63) Continuation of application No. 1 1/363.332, filed on (52) U.S. Cl...... 514/211.07: 514/357: 514/356; Feb. 28, 2006, which is a continuation-in-part of appli- 514/220; 514/259.41; 514/211.13: 514/253.07; cation No. 1 1/283,865, filed on Nov. 22, 2005, now 514/253.04: 514/214.02: 514/254.05; 514/338 abandoned, which is a continuation-in-part of applica tion No. 1 1/283.928, filed on Nov. 22, 2005, said appli- (57) ABSTRACT cation No. 1 1/283,865 is a continuation-in-part of application No. PCT/IL05/00440, filed on Apr. 21, Methods and compositions for preventing or reducing weight 2005, said application No. 1 1/283,928 is a continua gain associated with treatment, which utilize an H tion-in-part of application No. PCT/IL05/00440, filed agonist Such as betahistine, betahistine metabolite or a beta on Apr. 21, 2005. histine salt are disclosed. Patent Application Publication Jun. 17, 2010 Sheet 1 of 4 US 2010/0152161 A1

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COMPOSITIONS FORWEIGHT second leading cause of unnecessary deaths. Healthcare costs MANAGEMENT of American adults with obesity amount to approximately 100 billion dollars. RELATED APPLICATIONS 0005 Weight gain has also been found to occur as a result of various factors, including, for example, use of certain 0001. This application is a continuation of U.S. patent , cessation of Smoking, and advent of a holiday season. application Ser. No. 1 1/363.332 filed on Feb. 28, 2006, which 0006 Drugs which are known to cause weight gain is a continuation-in-part (CIP) of U.S. patent applications include , particularly atypical antipsychotics; Nos. 11/283,865 and 11/283,928, co-filed on Nov. 22, 2005, , particularly the tricyclic antidepressants; each being a continuation-in-part (CIP) of PCT Patent Appli mood-stabilizers; calcium channel blockers; anti-convul cation No. PCT/IL2005/000440, filed on Apr. 21, 2005, sants; proton pump inhibitors; antidiabetic agents; antihyper which claims priority from U.S. Provisional Patent Applica tensives; and hormones. Certain selective serotonin-reuptake tion No. 60/670,290, filed on Apr. 12, 2005 and from Israel inhibitors (SSRIs) also have an effect on weight gain, Patent Application No. 161595, filed on Apr. 22, 2004. The although other SSRIs, such as, sertraline, sibutramine and teachings of the above applications are hereby incorporated fluoxetine, often have the opposite effect, and are, in fact, by reference as if fully set forth herein. used as appetite Suppressants. 0007 Weight gain associated with use of certain drugs FIELD OF THE INVENTION may significantly affect patient compliance with the drug administration regime. 0002 The present invention relates to novel compositions 0008 Certain drug categories, such as the SSRIs and tri and methods for regulating food intake in human Subjects and cyclic antidepressants, cause food cravings. Furthermore, more particularly to compositions and methods for prevent Such drugs may stimulate appetite by blocking of histamine ing or treating conditions in which weight management is receptors. For example, it has recently been shown that atypi beneficial. The present invention further relates to composi cal antipsychotics, such as and , as well tions and methods of preventing or reducing weight gain as tricyclic and tetracylic antidepressants, such as amitrip associated with drug treatment, Smoking cessation and the tyline and mirtazapine, respectively, which are potent H. like. antagonists, have a high propensity to induce weight gain (Wirshing, 1999). BACKGROUND OF THE INVENTION 0009 Atypical antipsychotics have been frequently cited as causing a higher increase in weight gain than conventional 0003) Obesity is a chronic, complex, multi-factorial dis antipsychotics (see, for example, Bustillo, 1996). Weight ease, involving Social, cultural, genetic, physiological and gain was found to be greatest with clozapine, olanzapine, psychological components, and is associated with Substan , and , and less with and tially increased morbidity and mortality. Over-nutrition is , and an additive effect on weight gain was found attributed as the cause of about 400,000 deaths a year in the to occur in patients treated with USA (Mokdad, 2004), and may considered to be an epidemic. and concomitantly with a drug from another class which may Based on the body-mass index, defined as the ratio of weight cause weight gain through a different mechanism, Such as and squared height, (ranging normally from 18.5 to 24.9), (Kane, 2003). Weight gain with clozapine and olan about one third of the adult population is overweight (an Zapine was found to persist for up to 30 weeks of treatment, index of from 25 to 29.9), and more than one quarter is obese and to be associated with a higher mean weight gain than for (index greater than 30) (National Center for Health Statistics, risperidone, haloperidol and sertindole (Wirshing, 2004). 2000). Environmental and behavioral changes brought about Risperidone-treated patients were found to gain weight for an by economic development and modernization have been initial 8-week period and then reach plateau level. Weight linked to the rise in global obesity. The environmental factors gain was also found to be more problematic for children and which foster the tendency toward obesity include lack of adolescents than for adults. physical activity combined with high-calorie foods. The 0010. The mechanisms by which antipsychotic drugs prevalence of overweight and obesity is increasing world cause weight gain are not clear. Antipsychotic drugs have wide at an alarming rate in both developing and developed multiple effects on neurotransmitter systems, which in turn countries, in children and adults, men and women. The num have a range of effects on energy homeostasis. Most of the ber of overweight and obese people has continued to increase antipsychotics work through some degree of dopamine since 1960, a trend that is not slowing down. Today, 64.5% of blockade (Wirshing, 2004), but modulation of the serotoge adult Americans—about 127 million—are categorized as nic, histaminergic, and adrenergic systems, all of which have being overweight or obese and nearly one-third (30.5%)— potential impact on weight regulation, may also be involved. about 60 million—are obese, as reported in the National Most of the atypical antipsychotics work through a combina Health and Nutrition Examination Survey (NHANES) by the tion of receptor systems. Olanzapine and clozapine have the Centers for Disease Control and Prevention (CDC). highest affinity for the H receptor of all the atypical antipsy 0004 Obesity significantly increases the risk of illness chotics, and are also associated with the highest weight gain. from about thirty serious medical conditions and is associated A logarithmic relationship between H1 receptor affinity and with increases in deaths from all-causes. Among these are weight gain has been demonstrated (Wirshing, 1999). In addi high pressure, diabetes, osteoarthritis, heart disease, tion, many atypical antipsychotics exhibit activity at several stroke, gallbladder disease and cancer of the breast, prostate serotonin receptor Subtypes, including the 5-HT2, Subtype, and colon (National Task Force on the Prevention and Treat which appears to mediate Some effects on appetite. Olanza ment of Obesity, 2000). Furthermore, each year, obesity pine and clozapine both have high affinities for 5-HT, causes at least 300,000 excess deaths in the U.S., being the 5-HT, Hi-histaminergic, and M-muscarinic receptors. US 2010/0152161 A1 Jun. 17, 2010

Clozapine also has high affinity for O-adrenergic receptors. 0017. In addition, a subject suffering from nicotine with Ziprasidone, which is associated with minimal weight gain, drawal may turn to food for emotional comfort. Also, since has more serotogenic and less adrenergic, histaminic and Smoking dulls the taste buds, food begins to taste better to new muscarinic receptor affinity. Quetiapine has relatively high non-Smokers, which can lead to increased food intake. affinity for histamine receptors; risperidone has modest H. Weight gain may also be caused by drugs prescribed to assist affinity, but notable affinity for 5-HT, and 5-HT, receptors. in Smoking cessation. Anti-Smoking medications include There are also endocrine effects of atypical antipsychotics, ZybanTM (bupropion hydrochloride). which presumably also play a role in weight gain. 0018 Weight gain frequently also occurs during a holiday 0011. A dual effect of the atypical antipsychotics in season, when the Subject may have more opportunity to over weight gain has been proposed: one, appetite stimulation by a indulge in food, due to increased leisure time, increased avail direct effect on the brain, that may be observable in the short ability of food, reduced exercise etc., or due to increased term; and second, a delayed endocrine/metabolic dysfunction participation in meals in a Social context. Such weight gain is that promotes fat deposition (Baptista, 2004). Involvement of greater during holidays, such as religious or national holi the cytokine peptides leptin and tumor necrosis factor days, which are associated with consumption of specific (TNF)-a in anti-psychotic-induced weight gain has also been foods or festive meals. Examples of such holidays include Suggested. Thanksgiving, Christmas, and Passover. 0019. There are several different treatment options for 0012. The use of atypical antipsychotics has also been management of weight, including: dietary therapy, physical found to place patients at risk for various metabolic disorders, activity, behavior therapy, drug therapy and Surgery. For the including metabolic syndrome, which results in weight gain, majority of overweight and obese people, who find they are as well as in hypertriglyceridemia, and in increased insulin, unable to change their lifestyle, drug therapy is the most glucose, and low-density lipoprotein cholesterol levels (Lie favorable and applicable option. Although hundreds of mil berman, 2004). According to a recent review (Newcomer, lions of people are seeking drug therapy for the treatment of 2005), clozapine and olanzapine treatment are associated obesity, current drug therapies do not meet this need due to with an increased risk of diabetes mellitus and dyslipidemia. their undesired side effects and limited efficacy. A smaller effect is observed with risperidone and quetiapine. 0020 Medications for the treatment of obesity are cur In general, it appears from the rank order of risk of diabetes rently approved for use in adults with a body-mass index of 30 and dyslipidemia observed for the atypical antipsychotics, or higher, or with a body-mass index of 27 or higher who have that the risk is related to the differing weight gain liabilities of obesity-related medical problems (Physicians’ Desk Refer the drugs. It is suggested that the increased incidence of ence, 2001). Approximately 10 percents of women and 3 diabetes in patients receiving antipsychotics is not due purely percents of men with a body-mass index of 30 or higher to weight gain, since patients can develop diabetes without reportedly use weight-loss medications (Serdula, 1999). significant weight gain, and diabetes usually improves rap 0021 Medications currently approved for weight loss in idly when the antipsychotic is withdrawn (Koller, 2001; Kol the United States fall into two categories: those that decrease ler, 2002). The mechanisms leading to diabetes can include food intake by reducing appetite or increasing Satiety (appe the drug induced weight gain, but there is also evidence of a tite Suppressants), and those that decrease nutrient absorp direct metabolic effect. This may be related to antagonism at tion. A potentially third category, medications increasing the 5-HT, or histamine H receptors or to an elevation of energy expenditure. Such as ephedrine, is not currently serum leptin beyond that induced by increased body weight approved for treating obesity in the United States. alone (Lean, 2003). 0022. The only FDA-approved for obesity that 0013 Dyslipidemia is most often associated with clozap reduces nutrient absorption is orlistat (XenicalTM), which acts ine and olanzapine, and is primarily seen as an increase in by binding to gastrointestinal lipases in the lumen of the gut, triglyceride levels, but may also manifest as increased total preventing hydrolysis of dietary fat into absorbable free fatty cholesterol, LDL-cholesterol and decreased HDL-choles acids and monoacylglycerols. terol (Barrett, 2004). 0023. Most appetite suppressants work primarily by 0014. The use of atypical antipsychotics have also been increasing the availability of anorexigenic neurotransmit associated with an increase in eating disorders, such as binge ters—notably norepinephrine, serotonin, dopamine, or some eating disorder, and bulimia nervosa (Theisen, 2003), which combination of these neurotransmitters—in the central ner may be a secondary effect of the weight gain associated with Vous system. Noradrenergic drugs available in the United these medicaments, resulting in reduced self esteem and States include phentermine, diethylpropion, phendimetra repeated unsuccessful dietary trials. Zine, and benzphetamine. Some of these drugs are considered 0015 Weight gain commonly occurs also as a result of by the Drug Enforcement Administration (DEA) to have a cessation of Smoking. This may be due to the fact that Smok potential for abuse. Amphetamines, which are considered to ing burns calories, artificially elevates heart rate and increases have a particularly high potential for abuse are no longer . Upon cessation of Smoking, the Subject has to recommended for weight loss for this reason. The Food and readjust to a lower metabolic rate. Drug Administration (FDA) approves the medications for use 0016 Furthermore, nicotine is an appetite suppressant. of “a few weeks' only (generally presumed to be 12 weeks or Nicotine stimulates release of adrenaline, which acts upon the less) for the treatment of obesity. liver to step-up the breakdown of glycogen so that more 0024. Side effects of noradrenergic medications include glucose will be liberated into the blood. Nicotine also affects insomnia, dry mouth, constipation, , palpitations, release of insulin, which controls glucose levels in the blood. and hypertension (Physicians' Desk Reference, 2001). Hence, nicotine causes slight hyperglycemia, and as a result, 0025 Serotonergic agents act by increasing the release of the body and brain may slow down the hormones and other serotonin, inhibiting its reuptake, or both. Fenfluramine (Pon signals that trigger feelings of hunger. diminTM) and dexfenfluramine (ReduxTM), medications that US 2010/0152161 A1 Jun. 17, 2010

both stimulate serotonin release and inhibit its reuptake, were tion of histamine, both seem to be crucial for the strength of withdrawn from the market in the United States in 1997 the signal. Some studies have indicated that hista because of associations with valvular heart disease and pull mine may suppress appetite by acting on hypothalamic his monary hypertension. Some selective serotonin-reuptake taminergic neurons that participate in the regulation of food inhibitors have induced weight loss in short-term studies, and intake (Sakata, 1997: Benning, 2000; Sakata, 1995). Thus, it fluoxetine (Prozac) has undergone considerable evaluation to was reported that histamine injected intracerebroVentricu determine its efficacy for weight loss (Goldstein, 1993). larly acts as an appetite Suppressant, and that depletion of However, after initial weight loss, steady regain was observed histamine stimulates feeding (Tuomisto, 1994). Changes in in later stages of the treatment (National Task Force on the histaminergic tone in the CNS have been associated with Prevention and Treatment of Obesity). Sertraline (ZoloftTM), genetic models of obesity (Machidori, 1992). In addition, evaluated as an adjunct for weight maintenance after a very intracerebroventricular injection of leptin has been correlated low-calorie diet, showed a similar lack of long-term efficacy with changes in the turnover rate of hypothalamic neuronal (Wadden, 1995). Sibutramine (MeridiaTM, ReductilTM), an histamine (Yoshimatsu, 1999). Since histamine is unable to inhibitor of both norepinephrine reuptake and serotonin cross the blood brain barrier, these effects would not be reuptake that also weakly inhibits dopamine reuptake, is expected to be seen with systemic administration of hista approved by the FDA for weight loss and weight maintenance 1C. in conjunction with a reduction diet. Side effects of sibutra 0031. In both humans and rodents, treatment with an H mine include increased blood pressure and pulse frequency antagonist resulted in hyperphagia (Fukagawa, 1989), and rate (McMahon, 2000). administration of H antagonists led to hypophagia (Attoub. 0026 Rimonabant (Sanofi), which is claimed to stop food 2001). The selective histamine H receptor antagonist NNC cravings, represents a new class of drugs that inhibit the 38-109 has been reported to increase hypothalamic histamine activity of the CB1 receptor. The CB1 receptor forms a part of levels, in parallel with decreases in food intake and body the endocannabinoid system. The CB1 receptor has been weight, according to studies in intact HEK293 cells express found in the brain, fat cells and other parts of the body, and has ing human or rathistamine H receptors (Malmof 2005). The been associated with regulating food intake and with tobacco intrasynaptic concentration of histamine is primarily con dependency (Pi-Sunyer et al., 2004). The endocannabinoid trolled by feedback signals from presynaptic histamine H. system helps to regulate pleasure, relaxation, and pain toler receptors that inhibit both the conversion of L-histadine to ance. Little is currently known about the long-term effects of histamine and the release of histamine into the synaptic clefts. inhibition of this system. Further, neurologists point out that Thus, by reducing the inhibition using a selective histamine the endocannabinoid system helps to protect the brain under H receptor antagonist, the synaptic concentration of hista Some circumstances (such as stroke and head injury) Such that mine increases together with the signaling from the histamine brain damage in these circumstances might be worse in H1 receptor, and food intake is consequently inhibited. How patients taking drugs that block the endocannabiniod system. ever, the long-term effects of H receptors on anorexigenic 0027. The Rimonabant drug is currently undergoing phase activities for body-weight homeostasis have not been docu III clinical trials. Presently reported side effects associated mented because of the off-target activity (Leurs, 1995) and therewith include anxiety, nausea and diarrhea. toxicity profile of H inhibitors (Onderwater, 1998). 0028 Hence, although some of the currently approved 0032 Betahistine (also known by its chemical names 2-2- medications show moderate effects and can help some (methylamino)ethylpyridine and N-methyl-2-pyridineetha patients in losing weight, there is a continuing need for effi neamine) is an orally active histamine-like drug extensively cacious treatment regimes and drugs for alleviating the seri used in the symptomatic treatment of vestibular disorders, ous and prevalent disorder—the weight excess. mainly Menier's disease and vertigo (including vertigo in 0029. Histamine, a potent bioactive substance that has patients with migraine (Amelin, 2003), dizziness with recur been studied for nearly a century, is an aminergic neurotrans rent vertigo (Acta Otolaryngol., 2003), vertigo in patients mitter. Four histamine receptors have been identified: H. H. with vascular and traumatic cerebral injuries (Gusev, 1998), H, and H. leading to the discovery and therapeutic use of and benign paroxysmal positional vertigo (Fujino, 1994)). potent receptor antagonists. Activation of the H receptor is Studies have shown that betahistine can be further utilized in associated with effects on Smooth muscle and central neu the treatment of a variety of disorders, including the after rons; activation of the H receptor stimulates acid secretion in effects of craniocerebral injury and vascular events (Odinak, the stomach, while activation of the H receptor results in a 2005), preventing or reducing myocardial infraction after pre-synaptic autoregulatory effect. occurrence of coronary occlusion (U.S. Pat. No. 4,159,332), 0030. Histamine has been implicated, among others, in the multiple sclerosis (Boika, 2002), cutaneous hypersensitivity regulation of arousal state (Lin et al., 1990), locomotor activ in patients with grass pollen allergy (Synman, 1995), arterio ity (Clapham, 1994), cardiovascular control (Imamura, sclerotic (Seipel, 1977), acute deafness (Grahne, 1996), water intake (Lecklin, 1998), food intake (Leurs, 1976), vertebral-basilar insufficiency (Botez, 1975), and sea 1998), and memory formation (Blandina, 1996). It has been sickness (J. Vestib. Res. 2003). Suggested that histaminergic neural circuits arising in the 0033 Betahistine is a structural analog of histamine, in tuberomammilary nucleus and projecting into the Satiety cen which the imidazole ring of the histamine is replaced by a ters of the hypothalamus participate in regulation of food pyridine ring. Betahistine is an H receptor agonist, and has intake. Histaminergic neurons project into hypothalamic cen been found to exhibit an H-agonism activity of about 0.07 ters known to participate in food intake i.e. the paraventricular times that of histamine, and to cause hypotensive response, nucleus and Ventromedial hypothalamus, where the anorectic bronchoconstriction, and increased vasopermeability after effect is thought to be mediated by postsynaptic histamine H parenteral administration. Receptor binding studies have also receptors. The density of this receptor, together with the shown that betahistine is a potent H-receptor antagonist. H-receptor-mediated control of the intrasynaptic concentra Betahistine is able to cross the blood brain barrier and act US 2010/0152161 A1 Jun. 17, 2010

centrally by enhancing histamine synthesis is tuberomammil therewith. The prior art further does not teach or suggest the lary nuclei of the posterior hypothalamus. Adverse side use of orally administered Hagonists for regulating food effected associated with betahistine are typically minor and intake in humans. include skin rashes of various types, urticaria, and itching. 0040. There is thus a widely recognized need for and it Gastric upset, nausea, and headache have also been reported would be highly advantageous to have histamine-related by Some patients. agents for regulation of food intake in humans and for reduc 0034. It has been found (Rossi et al., 1999) that high doses ing weight gain associated with e.g., drug treatment, devoid of betahistine, delivered intraperitoneally, increased water of the above limitations. intake and decreased food intake in pygmy goats. This was SUMMARY OF THE INVENTION Suggested as being due to stimulation of both H and H2 receptors, since in addition to its known action as an H 0041. The present invention successfully addresses the receptor agonist, betahistine has been shown to act as a weak shortcomings of the presently known methods for regulating partial agonist of peripheral histamine H2 receptors (Arrang food intake by providing such methods that utilize H recep toragonists, which are highly efficientinhumans, which have et al., 1985). This idea is further supported by recent findings a pharmacological half life of at least 3 hours and which are showing that the hypophagic effect of histamine was blocked devoid of the limitations of the currently known methods. The by the H-receptor antagonist, cimetidine, in pygmy goats. present invention further provides methods for preventing or These similarities in the hypophagic effects of histamine and reducing weight gain associated with external factors such as betahistine Suggest an involvement of H-receptors in the drug treatment, Smoking cessation and the like. hypophagic effect of betahistine in pygmy goats. H-recep 0042. According to one aspect of the present invention tors are not, however, associated with weight change in there is provided a method of treating a condition in which humans (Rasmussen, 1993). regulating a food intake in a human Subject is beneficial, the 0035) Szelag et al. (2001) found that betahistine, when method comprising administering to the Subject a therapeu given intraperitoneally, decreased food intake in rats, whereas tically effective amount of an Hagonist, which has a phar this effect was not seen when betahistine was given intragas macological half-life of at least 3 hours. trically (Szelag, 2002). It was suggested that the effect of 0043. According to further features in preferred embodi betahistine administration on food intake involves increasing ments of the invention described below, the condition is histamine synthesis and release as a result of H receptor selected from the group consisting of overeating, overweight, inhibition. However, since activation of H receptors is obesity, and a disorder caused or exacerbated thereby. The known to stimulate hydrochloric acid secretion (see, for condition caused or exacerbated by the conditions according example, Clayman, 1977), it was further suggested that the to this aspect of the present invention may be selected from lack of the influence of betahistine on food intake after intra the group consisting of a muscosceletal disorder, a cardiovas gastrical administration may be due to the fact that betahistine cular disorder, a dermatological disorder, a sleep disorder, a increased hydrochloric acid release by activation ofH recep metabolic condition, diabetes and a diabetes-related condi tors, thereby abolishing the central anorectic activity of beta tion. histine. 0044 According to still further features in the described preferred embodiments, the condition is associated with high 0036. It was also suggested that the effects on H receptors fat consumption. in humans may differ significantly from those in rats due to 0045. According to still further features in the described variations in circadian rhythm between the species. There preferred embodiments, the condition is associated with a fore, it appears that the anorectic response of betahistine is psychological factor. The condition according to this aspect dependent upon species and route of administration. Never of the present invention optionally comprises binge eating theless, Szelag et al. fail to teach the effect of betahistine disorder, night eating syndrome, obsessive eating, compul administered orally or by any other route of administration, sive eating or bulimia. on food intake in humans. 0046 According to still further features in the described 0037 Lecklin et al. (2002) found that inhibition of hista preferred embodiments the condition is associated with a mine catabolism by intraperitoneal injection of metoprine, a drug treatment. The drug may optionally consist of a steroid histamine-N-methyltransferase inhibitor, resulted in sup hormone or a , as is detailed hereinbelow. pressed daily energy intake and ingestion of fat in rats. 0047 According to another aspect of the present inven 0038 Pharmacokinetic studies showed that betahistine is tion, there is provided a method of improving a compliance of transformed, mainly in the liver, to 2-(2-aminoethyl)-pyri a human Subject to caloric restriction, the method comprising dine (AEP) and to 2-(2-hydroxyethyl)-pyridine (HEP), (Ster administering to the subject a therapeutically effective noson, 1974) whereas both betahistine and the metabolites amount of an Hagonist, which has a half-life of at least 3 bind to histamine receptors. hours. 0039. The cited references corroborate the complexity of 0048. According to still another aspect of the present appetite regulation, which includes, among other factors, spe invention, there is provided a method of reducing a desire of cies specificity and route of administration. It has further been a human Subject to consume fats, the method comprising found (Seifert et al., 2003) that multiple differences exist in administering to the subject a therapeutically effective agonist and antagonist of histamine receptors amount of an Hagonist, which has a half-life of at least 3 between different species, such as humans and guinea pigs. hours. The prior art does not teach or suggest the use of Hagonists 0049 According to yet another aspect of the present for regulating food intake in humans. The prior art further invention, there is provided a method of treating a condition does not teach or suggest the use of such Hagonists that have associated with a metabolic derangement in a human Subject, a pharmacological halflife that permits an efficient treatment the method comprising administering to the Subject a thera US 2010/0152161 A1 Jun. 17, 2010 peutically effective amount of an H agonist which has a 0059 Also alternatively, the drug may be a mood-stabi half-life of at least 3 hours. The metabolic derangement may lizer (such as ); a (Such as be, for example, dyslipidemia, Such as hypercholesterolemia diltiazem, nicardipine, Verapamil and nimopidipine); an anti or lipemia. convulsant (Such as , divalproex, , Sodium valproate, valproic acid, and ); a proton 0050. As used herein, the term “metabolic derangement' pump inhibitor (Such as omeprazole, esomeprazole, lanSopra refers to an imbalance in the level of one or more metabolites Zole and pantoprazole); an antidiabetic agent (Such as a Sul within a body. A common metabolic derangement is typically fonylurea, including chlorpropamide, glipizide, glyburide, associated with an imbalance in the level of metabolites such and glimepiride, a meglitinide, a biguanide, a thiazolidinedi as cholesterol, including LDL and HDL, triglycerides and the one, an alpha-glucosidase inhibitor, and insulin); an antihy like. According to still another aspect of the present invention, pertensive (such as an alpha-adrenergic blocker, including there is provided a method of reducing total cholesterol level doxazocin, prazocin and teraZosin; or a , includ in a human Subject, the method comprising administering to ing acebutolol, atenolol, metoprolol, nadolol, pindolol and the Subject atherapeutically effective amount of an Hagonist propanolol); or an anti-Smoking medication. which has a half-life of at least 3 hours. 0060. Further alternatively, the drug may be a hormone, Such as, for example, a steroid hormone. Non-limiting 0051. According to still another aspect of the present examples of Such steroid hormones include a invention, there is provided a method of reducing low-density (such as a , including prednisone and ; lipoprotein (LDL) cholesterol or increasing high-density and a , including aldosterone and fluidro lipoprotein (HDL) cholesterol levels in a human subject, the cortisone); and a sex steroid (such as an androgen, including method comprising administering to the Subject a therapeu testosterone and dehydroepiandrosterone; an estrogen, Such tically effective amount of an Hagonist which has a half-life as estradiol; and a progestagen, Such as progesterone or of at least 3 hours. progestin), or mixtures thereof. Thus, for example the sex 0052 According to still another aspect of the present steroid may comprise estrogen and progestagen, Such as pro invention, there is provided a method of reducing triglyceride vided as an oral contraceptive formulation; or estrogen and level in a human Subject, the method comprising administer progestin, Such as used for hormone replacement therapy. ing to the Subject a therapeutically effective amount of an H 0061 According to yet further features in preferred agonist which has a pharmacological half-life of at least 3 embodiments of the invention, weight gain prevented or hours. reduced by the method of the present invention may be due to 0053 According to yet another aspect of the present cessation of Smoking. invention there is provided a method of treating an eating 0062 According to still further features in preferred disorder, the method comprising administering to the Subject embodiments of the invention described below, weight gain prevented or reduced by the method of the present invention a therapeutically effective amount of an Hagonist, said H. may occur during a holiday season. agonist having a pharmacological half-life of at least 3 hours. 0063. According to further features in the described pre 0054 The eating disorder can be, for example, bulimia and ferred embodiments, the pharmacological half-life of the H binge eating disorder. agonist ranges from about 3 hours to about 12 hours, prefer 0055 According to a further aspect of the present inven ably from about 3 hours to about 8 hours, more preferably tion there is provided a method of preventing weight gain or from about 3 hours to about 5 hours. reducing weight in a Subject, the method comprising admin 0064. According to still further features in the described istering to the Subject atherapeutically effective amount of an preferred embodiments, the H agonist is further an H Hagonist, said Hagonist having a pharmacological half antagonist. life of at least 3 hours. 0065 According to still further features in the described 0056. According to further features in preferred embodi preferred embodiments, the Hagonist is characterized by ments of the invention described below, weight gain pre blood brain barrier permeability. vented or reduced by the method of the present invention may 0066. According to still further features in the described be associated with a drug treatment. preferred embodiments, the Hagonist is selected from the group consisting of betahistine, a betahistine metabolite, a 0057 The drug may be, for example, an antipsychotic. betahistine pharmaceutically acceptable salt, a betahistine Examples of Such antipsychotics include, without limitation, prodrug, a betahistine derivative and any combination selective serotonin-reuptake inhibitors (such as fluvoxamine, thereof. Preferably, the betahistine metabolite is 2-(2-amino escitalopram, citalopram, and paroxetine); monoamine oxi ethyl)-pyridine or 2-(2-hydroxyethyl)-pyridine. Also prefer dase inhibitors (such as isocarboxazid, phenelzine and tranyl ably, the betahistine salt is betahistine dihydrochloride, beta cypromine); conventional antipsychotics (such as haloperi histine mesilate, or betahistine trimebutine maleate. Also dol, molindone and thioridazine); and atypical antipsychotics preferably, the betahistine derivative is selected from the (such as clozapine, olanzapine, risperidone, quetiapine, group of compounds represented by the general formula I: sertindole, aripiprazole and Ziprasidone, oran antagonist of a 5-HT, 5-HT, Hi-histaminergic or M-muscarinic recep tor). Formula I 0058 Alternatively, the drug may be an . R3 Examples of Such antidepressants include, without limita tion, a tricyclic antidepressant (Such as amitryptyline, amox R2 N1.R4 R. R. apine, clomipramine, desipramine, doxepin, imipramine, R10 nortryptyline, protriptyline or trimipramine), a tetracyclic 2 antidepressant (Such as mirtazapine or maprotiline), a sero R N R11 tonin-norepinephrine reuptake inhibitor (such as Venlafaxine R5 R6 R or dulloxetine); and additional antidepressants such as bupro pion hydrochloride, mirtazapine, nefazadone and traZadone. US 2010/0152161 A1 Jun. 17, 2010

0067 wherein each of R-R is independently selected therapeutically effective amount of an agent for treating a from the group consisting of hydrogen, alkyl, cycloalkyl and metabolic derangement, as is detailed herein. aryl. 0079. Such pharmaceutical compositions can be used in 0068 According to still further features in the described the treatment of conditions associated with high fat consump preferred embodiments, in each of the methods described tion, such as dyslipidemia, and hypercholesterolemia, for herein, administering is effected by a route selected from the reducing total cholesterol level in a human Subject, for reduc group consisting of the oral, transdermal, intravenous, Sub ing low-density lipoprotein cholesterol and increasing high cutaneous, intramuscular, intranasal, intraauricular, Sublin density lipoprotein cholesterol levels in a human Subject and/ gual, rectal, transmucosal, intestinal, buccal, intramedullar, or for reducing triglyceride level in a human Subject. intrathecal, direct intraventricular, intraperitoneal, and 0080 According to still further features in the described intraocular routes. Preferably, administering is effected by preferred embodiments, each of the methods described herein the oral, transdermal, buccal, transmucosal, rectal or Sublin further comprises administering to the Subject a therapeuti gual routes. More preferably, administering is effected by the cally effective amount of an additional active agent such as, oral, buccal or transdermal routes. for example, a weight control agent. The weight control agent 0069. According to still further features in the described may be, for example, an appetite Suppressant. Representative preferred embodiments, the therapeutically effective amount examples of Suitable appetite Suppressants include, without ranges from about 2 mg per day to about 96 mg per say, limitation, noradrenergic agents, serotonergic agents, preferably from about 10 mg per day to about 50 mg per day. dopamingergic agents, endocannabinoid receptor blockers, 0070 According to still further features in the described or combinations thereof. preferred embodiments, administering is effected from about I0081. According to still further features in the described 1 to about 4 times per day, preferably, twice per day. preferred embodiments, the additional active agent may be a non-steroidal anti-inflammatory drug, a , an 0071. According to still further features in the described antigout agent, an immunosuppressant, a drug affecting preferred embodiments, administering is effected according mineralization, an angiotensin-converting enzyme inhibitor, to the development of hunger of the subject. an antiarrhythmic drug, an , an antiplatelet, a 0072 According to still further features in the described thrombolytic, a beta-adrenergic blocking drug, a centrally preferred embodiments, administering is performed such that acting drug, a digitalis drug, a nitrate, a peripheral adrenergic a decrease of the body weight of the subject that ranges from antagonist, a vasodilator, an acne medication, an antipruretic about 1 to about 5 percent is effected, without restricting the agent, an anti- agent, an anti-eczema agent, a hyp food intake of the subject. Preferably, such administering is notic, an anti-histamine, a PPAR-gamma antagonist, insulin, performed such that no down-regulation of H receptors is a , an HMG-CoA reductase inhibitor, a bile acid effected. sequestrant, a cholesterol absorption inhibitor, nicotinic acid, 0073. As used herein, the term “down-regulation' with a derivative, analog and metabolite thereof, and any mixture regard to receptors refers to a decrease in the responsiveness thereof. of the receptor, or to a decrease in the number or density of I0082. According to still further features in the described receptors. Decreasing the responsiveness of a receptor also preferred embodiments, the additional active agent may be a includes a complete shutdown of the receptor. nutritional Supplement. An example of Such a nutritional 0074 According to still further features in the described supplement is Histidine (Kasaoka S. Nutrition 20:991-996 preferred embodiments, the H agonist forms a part of a (2004). pharmaceutical composition, which further comprises a phar I0083. According to still further features in the described maceutically acceptable carrier. Such a composition may preferred embodiments, the methods described herein are optionally provide a slow release composition. used for inducing weight loss. Alternatively, these methods 0075. As used herein a “pharmaceutical composition' are used for maintaining weight loss or preventing a weight refers to a preparation of one or more of the active ingredients gain after or during a weight reducing diet. Further alterna described herein, either compounds or physiologically tively, these methods are used for preventing weight gain in a acceptable salts thereof, with other chemical components Subject having a condition associated with weight gain. Such as traditional drugs, physiologically suitable carriers I0084. In each of the methods described herein, the H and excipients. Thus, pharmaceutical compositions, accord agonist is preferably not used for treating patients also having ing to the present invention, can include, for example, the H a medical condition that has previously been described as agonist described herein and an additional active ingredient, treatable by Such an agonist. as is detailed herein. I0085 Thus, in each of the various aspects of the present 0076 For example, pharmaceutical compositions, accord invention, the subjects treated by any of the methods ing to the present invention, can include a therapeutically described herein are preferably subjects that do not also suffer effective amount of the Hagonist described herein and a from a condition that has already been described in the art as therapeutically effective amount of a drug associated with treatable by the Hagonist described herein. Such conditions weight gain, as is detailed herein. include, for example, Menier's disease, Vertigo, seasickness, 0077 Such compositions can be used to treat a medical the after-effects of craniocerebral injury and vascular events, condition is which treatment with the drug is beneficial, as myocardial infraction after occurrence of coronary occlusion, detailed herein, while reducing or preventing weight gain multiple Sclerosis, cutaneous hypersensitivity inpatients with associated with the drug treatment, as discussed in detail grass pollen allergy, arteriosclerotic dementia, acute deaf hereinbelow. ness, and vertebral-basilar insufficiency. 0078 Pharmaceutical compositions, according to the 0086. Unless otherwise defined, all technical and scien present invention, can include, for example, a therapeutically tific terms used herein have the same meaning as commonly effective amount of the Hagonist described herein and a understood by one of ordinary skill in the art to which this US 2010/0152161 A1 Jun. 17, 2010

invention belongs. Although methods and materials similar or 0098. As used herein, the term “carrier refers to a diluent, equivalent to those described herein can be used in the prac adjuvant, excipient, or vehicle with which the therapeutic is tice or testing of the present invention, Suitable methods and administered. materials are described below. In case of conflict, the patent (0099. Herein the term “excipient” refers to an inert sub specification, including definitions, will control. In addition, stance added to a pharmaceutical composition to further the materials, methods, and examples are illustrative only and facilitate processes and administration of the active ingredi not intended to be limiting. entS. 0087. As used herein the term “method’ refers to manners, 0100. As used herein, the singular form “a” “an and means, techniques and procedures for accomplishing a given “the include plural references unless the context clearly task including, but not limited to, those manners, means, dictates otherwise. For example, the term “a compound” or techniques and procedures either known to, or readily devel “at least one compound may include a plurality of com oped from known manners, means, techniques and proce pounds, including mixtures thereof. dures by practitioners of the chemical, pharmacological, bio 0101 Throughout this disclosure, various aspects of this logical, biochemical and medical arts. invention can be presented in a range format. It should be 0088 As used herein, the term “treating includes abro understood that the description in range format is merely for gating, Substantially inhibiting, slowing or reversing the pro convenience and brevity and should not be construed as an gression of a condition, Substantially ameliorating clinical or inflexible limitation on the scope of the invention. Accord aesthetical symptoms of a condition or Substantially prevent ingly, the description of a range should be considered to have ing the appearance of clinical or aesthetical symptoms of a specifically disclosed all the possible Subranges as well as condition. individual numerical values within that range. For example, 0089. As used herein, the term “preventing includes bar description of a range such as from 1 to 6 should be consid ring an organism from acquiring a condition in the first place. ered to have specifically disclosed Subranges Such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 0090. As used herein the term “regulating with regard to to 6 etc., as well as individual numbers within that range, for food intake refers to controlling or adjusting the food intake to example, 1, 2, 3, 4, 5, and 6. This applies regardless of the a desired level. breadth of the range. 0091. The term “comprising means that other steps and 0102. Whenevera numerical range is indicated herein, it is ingredients that do not affect the final result can be added. meant to include any cited numeral (fractional or integral) This term encompasses the terms "consisting of and “con within the indicated range. The phrases “ranging/ranges sisting essentially of. between a first indicate number and a second indicate num 0092. The phrase “consisting essentially of means that ber and “ranging/ranges from a first indicate number “to a the composition or method may include additional ingredi second indicate number are used herein interchangeably and ents and/or steps, but only if the additional ingredients and/or are meant to include the first and second indicated numbers steps do not materially alter the basic and novel characteris and all the fractional and integral numerals therebetween. tics of the claimed composition or method. 0093. The term “therapeutically effective amount” or BRIEF DESCRIPTION OF THE DRAWINGS “pharmaceutically effective amount denotes that dose of an 0103) The invention is herein described, by way of active ingredient or a composition comprising the active example only, with reference to the accompanying drawings. ingredient that will provide the therapeutic effect for which With specific reference now to the drawings in detail, it is the active ingredient is indicated. stressed that the particulars shown are by way of example and 0094. As used herein, the term “agonist’ describes a sub for purposes of illustrative discussion of the preferred stance that is capable of binding to a receptor on a cell and embodiments of the present invention only, and are presented thereby initiating a physiological activity or pathway. The in the cause of providing what is believed to be the most phrases “H-receptor agonist and "H agonist are used useful and readily understood description of the principles herein interchangeably. and conceptual aspects of the invention. In this regard, no 0095. As used herein, the term “antagonist’ describes a attempt is made to show structural details of the invention in Substance that acts within the body to reduce the physiologi more detail than is necessary for a fundamental understand cal activity of another Substance. ing of the invention, the description taken with the drawings 0096. As used herein, the phrase “pharmacological half making apparent to those skilled in the art how the several life” describes the time required for half the quantity of a drug forms of the invention may be embodied in practice. or other substance deposited in a living organism to be 0104. In the drawings: metabolized or eliminated from the plasma by normal bio 0105 FIGS. 1 (a-b) present results obtained in prior art logical processes. This phrase is also referred to herein inter studies, demonstrating the effect of Metoprine treatment on changeable as “half life'. the total caloric intake (FIG. 1a) and the fat intake (FIG.1b) 0097. As used herein, the term “pharmaceutically accept in rats; able' means approved by a regulatory agency of the Federal 0106 FIGS. 2(a-b) present results obtained in prior art or a state government or listed in the U.S. Pharmacopeia or studies, demonstrating the effect of Metoprine treatment on other generally recognized pharmacopeia for use in animals, the total caloric intake, compared with the carbohydrate and more particularly in humans. Herein, the phrases “physi intake (FIG. 2a) and the protein intake (FIG.1b) in rats; ologically suitable carrier and “pharmaceutically acceptable 0107 FIG. 3 presents plots demonstrating the effect of carrier are interchangeably used and refer to an approved overweight (expressed as the body mask index) on the relative carrier or a diluent that does not cause significant irritation to risk of death from cardiovascular disease (dotted line), cancer an organism and does not abrogate the biological activity and (dashed line) and other causes in men (upper plots) and properties of the administered conjugate. women (bottom plots); US 2010/0152161 A1 Jun. 17, 2010

0108 FIG. 4 is a bar graph presenting the effect of oral mine would be expected to have little affect on the desire of a administration of betahistine (blue bars) and a placebo (yel human Subject to consume fats. low bars) on the total caloric intake of humans following 14 0117. Furthermore, histamine has a pharmacological half days and 28 days of treatment; life of only a few minutes. Therefore, the duration of action of 0109 FIG. 5 is a bar graph presenting the effect of oral the drug is very short, and it would need to be administered administration of betahistine (blue bars) and a placebo (yel frequently in order to build up and maintain a high enough low bars) on the fat, carbohydrate and protein intake of concentration in the blood to be therapeutically effective. A humans following 14 days and 28 days of treatment; and drug having a longer half life would therefore require less 0110 FIG. 6 is a bar graph presenting the effect of oral frequent administration, which may lead to increased patient administration of betahistine (blue bars) and a placebo (yel compliance with the dosing regime. This may also result in low bars) on the weight change in humans following 14 days fewer side effects, as peaks and troughs of the level of the drug and 28 days of treatment. in the bloodstream of the patient may be decreased, leading to a more even drug level in the blood over a period of time. DETAILED DESCRIPTION OF THE INVENTION 0118 While several studies have suggested a role for 0111. The present invention is of novel methods for regu H-receptor agonists other than histamine in regulating food lating food intake in a human Subject; for improving a com intake, none of these studies has established a direct effect of pliance of a human Subject to caloric restriction; and for Such agonists on food intake in humans. reducing a desire of a human Subject to consume fats, all of 0119 The present inventors have now surprisingly found which utilize H-receptoragonists that have a pharmacologi that certain H-agonists, which are characterized by relatively cal half-life that allows an efficient treatment regime thereof. long half-life, particularly as compared with histamine, can The present invention further provides a method for prevent be efficiently utilized for regulating food intake in humans. ing or reducing weight gain in a human Subject, by adminis More specifically, it was found that betahistine, a presently tration of H-receptor agonists that have a pharmacological known and approved drug for treating Menier's disease and half-life that allows an efficient treatment regime thereof. associated conditions, and which has a half-life of about 3.5 0112 The principles and operation of the compositions hours, efficiently affects food intake and caloric intake and and methods according to the present invention may be better reduces weight, as well as fat consumption, in obese female understood with reference to the drawings and accompanying subjects. As is exemplified in the Examples section that fol descriptions. lows, in a randomized placebo controlled double-blinded 0113 Before explaining at least one embodiment of the study, it was found that betahistine hydrochloride decreased invention in detail, it is to be understood that the invention is appetite, increase Satiety lowered food intake and particularly not limited in its application to the details set forth in the affected fat consumption. following description or exemplified by the Examples. The 0.120. It is therefore demonstrated herein that the admin invention is capable of other embodiments or of being prac istration of an H receptoragonist that has a pharmacological ticed or carried out in various ways. Also, it is to be under halflife that permits reasonable and efficient treatment there stood that the phraseology and terminology employed herein with (e.g., of at least 3 hour) can be beneficially used for is for the purpose of description and should not be regarded as regulating food intake and caloric intake in a human Subject limiting. and hence for treating medical and psychological conditions 0114. As is described hereinabove, many of the presently associated with overweight. Without being bound to any par used appetite Suppressants are known to have a potential for ticular theory, it is assumed that betahistine, as well as other abuse. Furthermore, these appetite Suppressants are associ H receptor agonists, decrease food intake by a different ated with various side effects, ranging from insomnia, dry mode of action than the currently used anti-obesity medica mouth, constipation, euphoria, palpitations and hypertension, tions. to Valvular heart disease and pulmonary hypertension. In 0121 Thus, according to one aspect of the present inven addition, many of these agents have been found to show a lack tion there is provided a method of treating of a condition in of long-term efficacy, with steady weight-gain occurring after which regulating a food intake in a human Subject is benefi initial weight loss. cial, which is effected by administering to the subject a thera 0115. As is further described hereinabove, studies have peutically effective amount of an Hagonist that has a phar shown a relationship between histamine and regulation of macological half-life of at least 3 hours. food intake. Thus, for example, as shown in FIG. 1, inhibition 0.122. It should be noted that as used herein the term “treat of histamine catabolism by the histamine N-methyltrans ment' also includes amelioration or alleviation of a patho ferase inhibitor, metoprine, which is typically utilized as a logical condition and/or one or more symptoms thereof, cur cytotoxic, anti-cancer agent, has been shown to Suppress total ing such a condition, or preventing the genesis of Such a food intake and ingestion of fat by rats (Lecklin et al., 2002). condition. Treatment had no marked effect on intakes of carbohydrates I0123. The pharmacological half-life of the Hagonist uti or protein, as shown in FIG. 2, indicating that an increase in lized in this and other aspects of the present invention pref the brain histamine content may reduce specifically “fat erably ranges from about 3 hours to about 12 hours, more appetite', namely, the desire to specifically ingest fats, as preferably from about 3 hours to about 8 hours, and even more opposed to other food types. preferably from about 3 hours to about 5 hours. Such a phar 0116 Systemic administration of histamine, however, is macological half life is highly advantageous since, as is dis extremely inefficient in its centrally mediated anti-obesity cussed hereinabove, such a drug remains in the blood for action because exogenous histamine poorly penetrates the longer periods than, for example, histamine, achieving blood brain barrier. Histamine has therefore been adminis steadier blood levels, and therefore fewer side effects. The H tered as an appetite Suppressant hitherto by intracerebroven agonist of the present invention therefore needs to be admin ticular injection. Similarly, systemic administration of hista istered far less frequently than, for example, histamine, which US 2010/0152161 A1 Jun. 17, 2010

has a half life of only about 2 minutes. Since, as is known in in this way inhibit food intake. H receptors are located not the art, 97% of a drug is eliminated after 5 half lives, the only on histaminergic neurons, but also nonhistaminergic administration should be repeated at intervals of less than 5 neurons as heteroreceptors, and modulate the release of 5-HT half lives, and usually less, depending on various parameters, and noradrenaline. Thus, the effects of H ligands on food including the clearance rate and the initial concentration intake may express through other endogenous Substances administered. (Morimoto et al., 2001). 0.124. In clinical practice, the choice of the dosage interval I0130. Also preferably, the Hagonist is characterized by usually represents a compromise between the desirability of blood brain barrier permeability, and therefore is able to cross minimizing the variations of effectiveness between doses and the blood brain barrier and enter brain tissue, thereby acting patient inconvenience from too frequent dosing, which on central H and H receptors. This enables the agonist to be results in poor compliance. Dosage regimes of one or two administered by the systemic route, in contrast to, for administrations per day are considered optimal. example, histamine, which has very poor blood brain barrier 0.125. Using a drug having a halflife within the above cited permeability and has therefore previously been administered range allows for selecting the administration times so as to as an appetite Suppressant by intracerebroventicular injec ensure maximal effectiveness of the drugattimes of day when tion. the effect is most required. Such as at known meal times, I0131 The H agonist of the present invention can be periods of the day at which the Subject most commonly expe administered as any pharmaceutically acceptable salt, Such riences significant levels of hunger, etc., and to be least effec as, for example, dihydrochloride, mesilate, or trimebutine tive at times of day when no effect is necessary, such as, for maleate. Alternatively, the drug can be administered as any example, during periods when the Subject is expected to be metabolite, prodrug, or derivative, or combination thereof. asleep. 0.132. The phrase “pharmaceutically acceptable salt 0126 Drugs having a very long half life have the disad refers to a charged species of the parent compound and its Vantage that once or twice daily administration is clearly not counter ion, which is typically used to modify the solubility possible. Less than daily administration is associated with characteristics of the parent compound and/or to reduce any poor patient compliance, as the Subject tends to forget the significant irritation to an organism by the parent compound, necessity to take a medication which is not part of his daily while not abrogating the biological activity and properties of routine. For example, the histamine-N-methyltransferase the administered compound. inhibitor, metoprine, which, as discussed above, has been I0133. The term “prodrug” refers to an agent, which is shown to decrease food intake in rats, both by intraperitoneal converted into the active compound (the active parent drug) in injection and by central infusion, has a half life of 216 hours. vivo. Prodrugs are typically useful for facilitating the admin Furthermore, the issue of toxicity must be considered with istration of the parent drug. They may, for instance, be bio drugs having such long half lives. available by oral administration whereas the parent drug is 0127. In addition, it is known that a prolonged presence of not. The prodrug may also have improved solubility as com Hagonists may lead to downregulation of the H receptor. pared with the parent drug in pharmaceutical compositions. 0128. Downregulation of a particular receptor after con tinuous activation can result in decreased response to agonist 0.134. As used herein, the term “metabolite' describes the administration, due to adaptive changes in the receptors that actual active moiety of the compound which is formed as a limit their Subsequent responsiveness, or to decrease in the result of metabolitic processes that occur in Vivo upon admin number or density of receptors. These receptor-specific istration of the compound. changes include a rapid uncoupling of receptors from activa 0.135 The term “derivative' describes the result of chemi tion of their cognate G proteins, mediating functional desen cally altering, modifying or changing a compound or a por sitization; a rapid redistribution of receptors into relatively tion thereof. Such that it maintains its original functionality in inaccessible compartments in the plasma membrane or inside at least one respect. the cell, variously referred to as sequestration, endocytosis, or 0.136. According to a preferred embodiment of the present internalization; with prolonged agonist exposure, termed invention the Hagonist is betahistine. Betahistine is a struc down-regulation. Considerable progress has been made in tural analog of histamine, which has been shown to have a recent years in identifying the receptor modifications binding affinity profile which is qualitatively close to that of involved in these changes (Krupnicket al., 1998), although histamine for both H and H receptors (Fossati et al., 2001). many of the details of the molecular modifications and pro Furthermore, it is pharmacologically relevant, since pharma tein-protein interactions that are involved in bringing about cokinetic data have shown that therapeutic dosages of beta these changes remain to be determined. Down-regulation of a histine in humans give plasma concentrations which fall in receptor type may lead to desensitization or tolerance to the the same range as its affinities for H and H receptors. The agonist for the receptor. It is therefore believed that use of an pharmacological relevance of betahistine for H receptors is H receptor agonist having a half-life of less than 12 hours, further confirmed in vivo in animals and humans, attributable preferably less than 8 hours and more preferably less than 5 to the increased blood flow in microcirculation in the auditory hours prevents continuous exposure of the receptor to the and internal vestibular system (Meyer et al., 1974). Since agonist, and thereby down-regulation of the receptor is betahistine has already been widely used for treating vertigo avoided. and other disorders, it has been tested and is approved for use 0129. The Hagonist of the present invention is preferably in human medicine. also an H antagonist. H antagonists have been shown to 0.137 Betahistine is readily absorbed through the oral have an effect on regulation of food intake. It has been Sug route and is converted to at least two metabolites, 2-(2-ami gested that the inhibition of H receptor activity increases noethyl)-pyridine and 2-(2-hydroxyethyl)-pyridine. Betahis histamine release and synthesis. Histamine Subsequently tine has an elimination halflifetime of 3.5 hours, and most of increases histaminergic neuron activity via H receptors and the dose is excreted via the urine as metabolites. Hence, US 2010/0152161 A1 Jun. 17, 2010

betahistine may be administered according to a convenient chain groups. Preferably, the alkyl group has 1 to 20 carbon dosage regime, as discussed above. atoms. Whenever a numerical range; e.g., "1-20, is stated 0138. The side effects associated with betahistine are herein, it implies that the group, in this case the alkyl group, minor, consisting mainly of skin rashes of various types, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, urticaria, itching, gastric upset, nausea, headache, and exac etc., up to and including 20 carbon atoms. More preferably, erbation of symptoms in patients with a history of peptic the alkyl is a medium size alkyl having 1 to 10 carbon atoms. ulcer. Most preferably, unless otherwise indicated, the alkyl is a 0.139. Betahistine can be utilized in this and other aspects lower alkyl having 1 to 4 carbon atoms. The alkyl group may of the present invention either per se or as a metabolite, a be substituted or unsubstituted. pharmaceutically acceptable salt, a prodrug or a derivative 0147 A “cycloalkyl group refers to an all-carbon mono thereof. cyclic or fused ring (i.e., rings which share an adjacent pair of 0140 Betahistine metabolites that can be efficiently used carbon atoms) group wherein one of more of the rings does in the context of the present invention include, for example, not have a completely conjugated pi-electron system. 2-(2-aminoethyl)-pyridine and 2-(2-hydroxyethyl)-pyridine. Examples, without limitation, of cycloalkyl groups are cyclo As is further described in the art (see, for example, Fossati et propane, cyclobutane, cyclopentane, cyclopentene, cyclo al., 2001) these metabolites are also characterized by H-re hexane, cyclohexadiene, cycloheptane, cycloheptatriene, and ceptoragonist activity and therefore can also be utilized in the adamantane. A cycloalkyl group may be substituted or unsub various aspects of the present invention. stituted. 0141 Representative examples of betahistine pharmaceu 0.148. An “alkenyl group refers to an alkyl group which tically acceptable salts that can be efficiently used in the consists of at least two carbon atoms and at least one carbon context of the present invention include, without limitation, carbon double bond. betahistine hydrochloride, betahistine dihydrochloride, beta 0149. An “alkynyl group refers to an alkyl group which histine mesilate, and betahistine trimebutine maleate. consists of at least two carbon atoms and at least one carbon 0142 Betahistine derivatives that are suitable for use in the carbon triple bond. context of this and other aspects of the present invention 0150. An “aryl group refers to an all-carbon monocyclic include, for example, compounds having the general Formula or fused-ring polycyclic (i.e., rings which share adjacent pairs I: of carbon atoms) groups having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl

Formula I group may be substituted or unsubstituted. 0151. A "heteroaryl group refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and Sulfur and, in addition, having a completely conjugated pi-electron system. Examples, with out limitation, of heteroaryl groups include pyrrole, furane, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine. 0143. In Formula I, each of R-R is preferably indepen 0152. A "heteroalicyclic' group refers to a monocyclic or dently selected from the group consisting of hydrogen, alkyl, fused ring group having in the ring(s) one or more atoms Such cycloalkyl and aryland any combination thereof. as nitrogen, oxygen and Sulfur. The rings may also have one or 0144 Optionally, each of R-R can also be selected from more double bonds. However, the rings do not have a com other Substituents, as long as features Such as the blood brain pletely conjugated pi-electron system. The heteroalicyclic barrier permeability, the halflife and the binding to the H-re may be substituted or unsubstituted. Representative examples ceptor of the compound are not adversely affected. Thus, each are piperidine, piperazine, tetrahydrofurane, tetrahydropyr of R-R can be further independently selected, for example, ane, morpholino and the like. from alkenyl, alkynyl, alkoxy, aryloxy, hydroxy, thiohydroxy, 0153. A “hydroxy' group refers to an —OH group. thioalkoxy, thioaryloxy, halide, amino, nitro, cyano, carbo 0154 An “alkoxy' group refers to both an —O-alkyl and nyl, C-carboxy, O-carboxy, C-carmabyl, N-carbamyl, sulfo an —O-cycloalkyl group, as defined herein. nyl, Sulfinyl, Sulfonamide, urea, thiourea, guanidine, guanyl. 0.155. An “aryloxy' group refers to both an —O-aryland O-carbamyl. N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, an —O-heteroaryl group, as defined herein. C-amido, N-amido, N-sulfonamido, and S-sulfonamido or, 0156. A “thiohydroxy group refers to a —SH group. alternatively, at least two of R-R and/or at least two of 0157. A “thioalkoxy' group refers to both an —S-alkyl Rs-R form at least one four-, five- or six-membered aro group, and an —S-cycloalkyl group, as defined herein. matic, heteroaromatic, alicyclic or heteroalicyclic ring. 0158. A “thioaryloxy' group refers to both an —S-aryl 0145. It will be appreciated by one of skills in the art that and an —S-heteroaryl group, as defined herein. the feasibility of each of the substituents (R-R) to be 0159. A “carbonyl group refers to a C(=O) R' located at the indicated positions depends on the Valency and group, where R' is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, chemical compatibility of the substituent, the substituted heteroaryl (bonded through a ring carbon) or heteroalicyclic position and other substituents. Hence, the present invention (bonded through a ring carbon) as defined herein. is aimed at encompassing all the feasible Substituents for any 0160 A “thiocarbonyl group refers to a —C(=S) R' position. group, where R is as defined herein for R'. 0146. As used herein, the term “alkyl refers to a saturated 0.161 A“C-carboxy' group refers to a C(=O)—O R' aliphatic hydrocarbon including straight chain and branched group, where R is as defined herein. US 2010/0152161 A1 Jun. 17, 2010

0162 An "O-carboxy” group refers to an R'C(=O)—O 0186. As is demonstrated in the Examples section that group, where R is as defined herein. follows, clinical studies have indicated that administering a 0163 A “halide' group refers to fluorine, chlorine, bro 16 mg dose of betahistine twice a day for a month, without mine or iodine. restricting their food intake, resulted in a significant weight 0164. A “sulfinyl group refers to an —S(=O)—R' loss, particularly as compared with a control group. group, where R is as defined herein. 0187 Hence, according to an embodiment of the present 0.165. A “sulfonyl group refers to an —S(=O) R' invention, a treatment regime is performed Such that upon group, where R is as defined herein. repetitious administration, a decrease of the body weight of (0166 An "S-sulfonamido' group refers to a S(=O)— the subject that ranges from about 1 to about 5 percent is NR'R" group, with R" is as defined herein and R" is as defined effected, without restricting the food intake of the subject. for R'. 0188 Since, as is discussed in detail hereinabove, constant (0167. An “N-sulfonamido” group refers to an R'S(=O) presence of a Hagonist may result in Substantial downregu NR" group, where R' and R" are as defined herein. lation of the H receptor, a more preferred treatment regime 0168 An "O-carbamyl group refers to an —OC(=O)— according to the present invention is performed Such that Such NR'R" group, where R' and R" are as defined herein. a decrease in a body weight is achieved without effecting (0169. An “N-carbamyl group refers to an R"OC(=O)— downregulation of the H receptor. Such a treatment regime NR' group, where R' and R" are as defined herein. can be designed by adjusting the dosing and the administra 0170 An "O-thiocarbamyl group refers to an —OC tion intervals to the half life of the selected H1 agonist. (—S)—NR'R" group, where R' and R" are as defined herein. 0189 The dosage may vary depending upon the dosage (0171 An “N-thiocarbamyl group refers to an R"OC form employed and the route of administration utilized. The (—S)NR' group, where R' and R" are as defined herein exact formulation, route of administration and dosage can be 0172 An "amino' group refers to an —NR'R" group chosen by the individual physician in view of the patient's where R and R" are as defined herein. condition. (See e.g., Fingl, et al., 1975, in “The Pharmaco (0173 A “C-amido' group refers to a C(=O) NR'R" logical Basis of Therapeutics’. Ch. 1 p. 1). Dosage amount group, where R' and R" are as defined herein. and interval may be adjusted individually to provide plasma (0174. An "N-amido” group refers to an R'C(=O) NR" levels of the Hagonist which are sufficient to maintain the group, where R' and R" are as defined herein. regulating effects. (0175. A “urea” group refers to an NR'C(=O) NR"R" 0190. When the Hagonist is betahistine, which is com group, where RandR" areas defined hereinandR" is defined mercially available as tablets of 8 mg or 16 mg, the daily as either R' or R". dosage range is from 24 to 48 mg, administered orally in 0176 A “guanidino' group refers to an —R'NC(=N)— divided doses. For example, the 8 mg tablet is administered as NR"R" group, where R', R" and R" are as defined herein. 1 to 2 tablets 3 times daily, and the 16 mg tablet is adminis (0177. A “guanyl group refers to an R'R"NC(—N)— tered as 0.5 to 1 tablet 3 times daily. group, where R' and R" are as defined herein. (0191). The Hagonist of the present invention may option 0.178 A “nitro' group refers to an —NO group. ally be administered in the form of a slow-release preparation, 0179 A “cyano' group refers to a C=N group. having a reduced rate of release of the active Substance, in 0180. The term “phosphonyl describes a - O P(=O) order to further increase patient convenience and compliance (OR)(OR") group, with R' and R" as defined hereinabove. and optionally the efficiency of the active agent. The slower 0181. The term “phosphinyl' describes a PRR" group, the rate of release, the less the blood concentrations fluctuate with R' and R" as defined hereinabove. within a dosing interval. This enables higher doses to be given 0182. The term “thiourea” describes a NR' C(=S)– less frequently, while maintaining therapeutic concentrations NR"R" group, with R' and R" as defined hereinabove and R" over prolonged periods. Furthermore, slow-release prepara as defined herein for R' and R". tions are beneficial in reducing potential side-effects of the 0183 In any of the methods described herein, the Hago active ingredient due to transiently high peak blood concen nist can be administered by any route selected from the oral, trations being reached soon after administration. transdermal, intravenous, Subcutaneous, intramuscular, intra 0.192 Slow release preparations typically include slow nasal, intraauricular, Sublingual, rectal, transmucosal, intes release biodegradable carriers. Slow release biodegradable tinal, buccal, intramedullar, intrathecal, direct intraventricu carriers are well known in the art. These are materials that lar, intraperitoneal, or intraocular routes. Preferably, the route may form particles that may capture therein an active com of administration is selected from the oral, transdermal, buc pound(s) and slowly degrade/dissolve under a suitable envi cal, transmucosal, rectal or Sublingual routes. More prefer ronment (e.g., aqueous, acidic, basic, etc.) and thereby ably, the Hagonist is administered using the oral, buccal or degrade/dissolve in body fluids and release the active com transdermal route. pound(s) therein. The particles are preferably nanoparticles 0184 The Hagonist is optionally and preferably admin (i.e., in the nanometer range, e.g., in the range of about 1 to istered as a total dose of from about 2 mg to about 96 mg per about 500 nm in diameter, preferably about 50-200 nm in day. More preferably, the total dose is from about 5 mg to diameter, most preferably about 100 nm in diameter). about 50 mg per day, more preferably from about 10 mg to 0193 The rate at which a drug is released is generally about 50 mg, more preferably from about 16 mg to about 48 dependent on the rate at which the dosage form disintegrates mg and most preferably it is from about 24 mg to 48 mg. or dissolves. Disintegration greatly increases the drug's Sur 0185. The Hagonist is preferably administered once or face area in contact with GI fluids, thereby promoting drug several times a day, for example from about 1 to about 4 times dissolution and absorption. Disintegrants and other excipi per day, and, more preferably, twice per day. Alternatively, the ents (e.g., diluents, lubricants, Surfactants, binders, dispers Hagonist may be administered according to the develop ants) are often added during manufacture to facilitate these ment of hunger of the Subject. processes. Surfactants increase the dissolution rate by US 2010/0152161 A1 Jun. 17, 2010

increasing the wettability, solubility, and dispersibility of the the relative risk of death from various disorders caused or drug. Disintegration of solid forms may be retarded by exces exacerbated thereby, is demonstrated in FIG. 3. As shown in sive pressure applied during the tableting procedure or by FIG.3, cardiovascular disease increases significantly in over special coatings applied to protect the tablet from the diges weight Subjects, both male and female, as compared to those tive processes of the gut. Hydrophobic lubricants (e.g., mag within the normal body-mass index range (i.e. from 18.5 to nesium Stearate) may bind to the active drug and reduce its 24.9). A further sharp increase is observed in subjects classi bioavailability. fied as obese (i.e. having body mass of greater than 30). 0194 Dissolution rate determines the availability of the Similarly, an increase in the relative risk of death from cancer drug for absorption. When slower than absorption, dissolu is seen in overweight Subjects, particularly in obese subjects, tion becomes the rate-limiting step. Overall absorption can be with a greater increase amongst females. The relative risk of controlled by manipulating the formulation. For example, death from other causes is seen to increase sharply in obese reducing the particle size increases the drug's Surface area, individuals. thus increasing the rate and extent of GI absorption of a drug whose absorption is normally limited by slow dissolution. 0201 Additional conditions that are treatable by the Dissolution rate is affected by whether the drug is in salt, method according to this aspect of the present invention crystal, or hydrate form. include, for example, conditions that are associated with a 0.195 Oral slow-release forms are often designed to main psychological factor, such as binge eating disorder, night tain therapeutic drug concentrations for greater than 12 hours. eating syndrome, obsessive eating, compulsive eating and The absorption rate can be controlled by coating drug par bulimia. ticles with wax or other water-insoluble material, by embed 0202 Bulimia is a psychological condition in which the ding the drug in a matrix from which it is released slowly Subject engages in recurrent binge eating followed by inten during transit through the GI tract, or by complexing the drug tionally doing one or more of the following in order to com with ion-exchange resins. pensate for the intake of the food and prevent weight gain: 0196. Thus, for example, a slow-release formulation in Vomiting; inappropriate use of , enemas, or tablet form, may be based on the use of a hydrophilic polymer other medication; excessive exercising: fasting. Some which Swells in contact with gastrointestinal fluids, to form a may demonstrate bulimic behaviors in their ill gel, which creates a barrier that enrobes the tablet. The barrier ness: binge-eating and purging themselves of food on a regu limits physical exchanges between the inside of the tablet and lar or infrequent basis at certain times during the course of the Surrounding medium. As a consequence, intrusion of their disease. Bulimia may occur without the serious weight water towards the tablet matrix and diffusion of drug are loss which is symptomatic of anorexia. An increase in binge slowed down, allowing a controlled slow release of the drug. eating has been reported amongst patients receiving atypical 0.197 Various types of polymers may be used as a matrix antipsychotics (Theisen, 2003), apparently as a result of for the slow-release of drugs, such as polyvinyl chloride, attempts to compensate for weight gain induced by the antip polyethylene polyamides, ethylcellulose, silicone, poly (hy sychotic. The use of betahistine to avoid this weight gain may droxyethyl methacrylate), other acrylic co-polymers, and therefore be beneficial in preventing the resulting compensa tory behavior which leads to bulimia. Furthermore, the reduc polyvinylacetate-polyvinyl chloride copolymers. tion in appetite resulting from administration of betahistine 0198 Thus, a slow-release formulation for delivery of the Hagonist of the present invention provides for release over a further contributes to the prevention of the overeating/purg period that ranges from about 2 hour to about 24 hours, ing cycle which characterizes bulimia. preferably from about 4 hours to about 24 hours and hence, 0203 As is detailed hereinbelow, it has been suggested for release over a period of at least 4 hour, at least 5 hours, at that the Hagonist described herein interferes with appetite least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, stimulating histaminergic activity of Steroidal or anti-psy at least 10 hours, at least 11 hours, at least 12 hours, at least 13 chotic drugs. hours, at least 14 hours, at least 15 hours, at least 16 hours, at (0204 PeptideYY (PYY) is a peptide with 36 amino acids least 17 hours, at least 18 hours, at least 19 hours, at least 20 that originates from the intestine. Studies have shown that hours, at least 21 hours, at least 22 hours, at least 23 hours, or elevated PYY levels were detected in patients suffering from at least 24 hours. Alternatively, such a slow-release formula eating disorders (Hagan, 2002). In addition, thioperamide, an tion provides for release of the Hagonist over a period of H antagonist, has been shown to block the ability of more than 24 hours and up to 48 hours. increased levels of PYY to increase food consumption (Itoh, 0199 The method according to this aspect of the present 1999). Since Hantagonists increase neuronal histamine lev invention can thus be efficiently used for treating any condi els and since this increased histamine binds to H receptors, tion in which regulating food intake is beneficial. These the Hagonist described hereincan be further efficiently used include, for example, overeating, overweight, obesity, and in treating such eating disorders via its histaminergic activity. disorders caused or exacerbated thereby. 0205 Hence, according to another aspect of the present 0200 Diseases caused by or exacerbated by these condi invention there is provided a method of treating an eating tions include, for example, muscosceletal disorders (such as disorder, and particularly bulimia. The method according to osteoarthritis, spine-related pains, etc.), cardiovascular disor this aspect of the present invention is effected by administer ders (such as hypertension, atherosclerosis, etc.), dermato ing to a subject Suffering from an eating disorder Such as logical disorders (such as fungal and other ), sleep bulimia a therapeutically effective amount of the Hagonist disorder (Such as Snoring and obstructive sleep apnea), meta described herein. bolic conditions (dyslipidemia, lipemia or hypercholester 0206. The Hagonist described herein may be further uti olemia), diabetes and diabetes-related problems, as well as lized for preventing or at least reducing weight gain, and cancer (particularly breast, prostate and colon cancer). The preferably weight gain caused by factors other than excessive effect of overweight, expressed by the body mass index, on food consumption. US 2010/0152161 A1 Jun. 17, 2010

0207 Thus, according to a further aspect of the present 0215 Weight gain may also occur due to the use of hor invention, there is provided a method of preventing or reduc mones, particularly steroid hormones, such as ing weight gain, which is effected by administering to the or sex steroids. Corticosteroids include , (for Subject a therapeutically effective amount of an Hagonist example, prednisone and cortisol), and that has a pharmacological half-life of at least 3 hours, as (for example, aldosterone and fludrocortisone). Sex steroids described hereinabove. include androgens (for example, testosterone and dehydroe 0208 Such weight gain may be due to factors which piandrosterone), estrogens (such as estradiol), and proge include, for example, use of certain drugs, cessation of Smok stagens, (for example, progesterone and progestin). Estro ing, or due to a holiday season, as discussed hereinabove and gens and progestagens are administered as oral is further detailed hereinbelow. contraceptives. Estrogen and progestin are administered as 0209 Thus, in one embodiment, the method according to hormone replacement therapy for menopausal women. this aspect of the present invention, can be implemented to 0216. Other drugs which may cause weight gain include reduce or prevent weight gain associated with drug treatment. antidepressants, including, for example, tricyclic antidepres 0210 Presently, many drugs are known to cause weight sants (such as amitryptyline, amoxapine, clomiprimine, gain. Representative examples include, without limitation, desipramine, doxepin, imipramine, nortryptyline, protrip antipsychotics, antidepressants, mood-stabilizers, calcium tyline and trimipramine), tetracyclic antidepressants (such as channel blockers, anti-convulsants, proton pump inhibitors, mirtazapine and maprotiline), serotonin-norepinephrine antidiabetic agents, antihypertensives, hormones, and anti reuptake inhibitors (such as Venlafaxine and dulloxetine), and Smoking medications. other anti- (such as bupropion hydrochloride, 0211. As is described in the art, the histaminergic system mirtazapine, nefazadone and traZadone); mood-stabilizers, has been implicated in weight gain associated with steroid Such as lithium; calcium channel blockers (such as diltiazem, induced and antipsychotic-induced weight gain (Poyurovsky nicardipine, Verapamil and nimopidipine); anti-convulsants et al., 2005). Hence, the H-receptor agonists of the present (such as carbamazepine, divalproex, lamotrigine, Sodium val invention may be co-administered together with a drug treat proate, Valproic acid, and gabapentin); proton pump inhibi ment which is knownto cause appetite stimulation and weight tors (such as omeprazole, esomeprazole, lansoprazole and gain in humans due to its histaminergic activity. It is assumed pantoprazole); antidiabetic agents, such as Sulfonylureas (for that the Hagonist utilized herein interferes with appetite example, chlorpropamide, glipizide, glyburide, and glime stimulating histaminergic activity of the steroidal or anti piride); and antihypertensives, such as alpha-adrenergic psychotic drug mentioned above and thus prevents or reduces blockers, (for example, prazosin, doxazosin or terazosin), or the weight gain caused by Such drug treatment. beta blockers, (for example, acebutolol, atenolol, metoprolol. 0212 Representative examples of antipsychotic drugs nadolol, pindolol and propanolol). associated with weight gain include, without limitation, 0217. As discussed in the Background section herein selective serotonin-reuptake inhibitors (SSRIs) (such as flu above, weight gain associated with use of certain drugs may Voxamine, escitalopram, citalopram, or paroxetine), be due to, for example, food cravings, decreased exercise monoamine oxidase inhibitors (such as isocarboxazid, capacity, or stimulation of appetite, for example by blocking phenelZine and tranylcypromine), conventional antipsychot of histamine receptors. Involvement of 5-HT, 5-HT, ics (such as haloperidol, molindone and thioridazine), and H-histaminergic, and M-muscarinic receptors in weight atypical antipsychotics, (Such as clozapine, olanzapine, ris gain has also been described. peridone, quetiapine, sertindole, aripiprazole and Ziprasi 0218. In another embodiment, the method according to done. Particular examples of antipsychotic drugs associated this aspect of the present invention, can be implemented to with weight gain are those which are antagonists of serotonin reduce or prevent weight gain associated with Smoking ces receptors, including 5-HT, and 5-HT, Subtypes, or of sation. H-histaminergic, and M-muscarinic receptors. These 0219 Weight gain associated with cessation of smoking include, for example, clozapine, olanzapine, risperidione and may be attributed, for example, to the fact that nicotine pirenzepine. increases heart rate and increases metabolism, such that read 0213. As discussed hereinabove, the mechanisms by justment to a lower metabolic rate is required once nicotine is which antipsychotic drugs cause weight gain are not clear, but no longer present in the bloodstream; to the fact that nicotine appear to involve multiple effects on neurotransmitter sys is an appetite Suppressant; and to the need for emotional tems, such as the serotogenic, histaminergic, and adrenergic comfort in a subject Suffering from the unpleasant symptoms systems. associated with nicotine withdrawal. 0214. Atypical antipsychotics, particularly clozapine, 0220 Weight gain associated with cessation of smoking olanzapine, risperidone, and quietiapine, have been shown to may also occur due to the use of drugs in this respect. Pres cause a higher increase in weight gain than conventional ently, there are a few drugs that are given in this respect. These antipsychotics. The effect of these antipsychotics may include, for example, nicotine-replacement products, such as involve both appetite stimulation by a direct effect on the nicotine patches, nicotine gum (nicotine polacrilex), nicotine brain, and a delayed endocrine/metabolic dysfunction that inhaler, and nicotine nasal spray, as well as the newer non promotes fat deposition. One study (Poyurovsky 2005) has nicotine-based medications, such as ZybanTM (bupropion identified an attenuating effect of betahistine on weight gain hydrochloride), and future therapies such as Cannabioind due to olanzapine, from week 2 to the end of the study. Since receptor affecting AcompliaTM (rimonabant). Administration olanzapine is a potent H antagonist, and betahistine was of the Hagonist described herein can be effected in combi found not to interfere with the antipsychotic effect of olanza nation with any of these and other drugs for Smoking cessa pine, it has been suggested that the antagonistic effect of tion. betahistine on the presynaptic H receptor may account for 0221 Weight gain also frequently occurs during a holiday the weight gain attenuation. season. This may be due to the fact that with greater leisure US 2010/0152161 A1 Jun. 17, 2010 time at his disposal, a Subject has more opportunity to eat effected by administering to a subject in need thereofathera more frequently, or because partaking of elaborate meals is peutically effective amount of an H agonist, as described often an integral part of a holiday celebration. This is exac herein. erbated by holidays, particularly religious or national holi 0229 Reducing the fat consumption of a subject can be days, which are associated with festive meals, or consump further utilized for treating conditions associated with meta tion of particular kinds of food. These include, for example, bolic derangement. the festive Thanksgiving meal, Christmas dinner, the Jewish 0230. Thus, according to still another aspect of the present Passover meal, and the like. invention, there is provided a method of treating a condition 0222. The H-receptor agonists described herein can be associated with a metabolic derangement in a human Subject, further efficiently used for improving a compliance of a which is effected by administering to the subject a therapeu human Subject to caloric restriction. Thus, according to tically effective amount of the Hagonist described herein. another aspect of the present invention, there is provided a 0231. Such conditions are typically associated with meta method of improving a compliance of a human Subject to bolic derangement and more particularly with adverse imbal caloric restriction, which is effected by administering to the ance of metabolites such as total cholesterol, HDL-choles Subject a therapeutically effective amount of an Hagonist as terol, LDL-cholesterol, triglycerides and the like and include, described herein. The method, according to this aspect of the for example, dyslipidemia, Such as hypercholesterolemia or present invention can be beneficially practiced with human lipemia and diabetes. Subject undergoing a weight reducing diet or any other caloric 0232 Dyslipidemias are disorders of lipoprotein metabo restriction. lism, including lipoprotein overproduction or deficiency. 0223. By efficiently regulating food intake in human sub These disorders may be manifested by elevation of the serum jects and improving a compliance thereof to caloric restric total cholesterol, low-density lipoprotein (LDL) cholesterol tion the methods described hereinabove may further be used and triglyceride concentrations, and a decrease in the high for inducing weight loss, for maintaining weight loss or pre density lipoprotein (HDL) cholesterol concentration and venting a weight gain after or during a weight reducing diet, therefore include, for example, lipemia and hypercholester or for preventing weight gain in a Subject having a condition olemia. associated with weight gain. For inducing or maintaining 0233 Lipemia is a condition in which an excess of fats or weight loss, the H receptor agonist of the present invention lipids is found in the blood of subject. may optionally be administered in conjunction with other 0234) Hypercholesterolemia is a condition in which high methods of treatment, such as diet, exercise, behavioral therapy, drug therapy, or Surgical therapy. levels of cholesterol are found in the blood of a subject. 0235 A direct connection has been shown between coro 0224. The H-receptor agonists described herein can be nary artery disease and dyslipidemia. Dyslipidemias may be further efficiently used for reducing a desire of a human genetic in origin, or may be due to dietary factors (such as Subject to consume fats. Some neurotransmitters and neuro excess saturated fats, “trans' fatty acids, cholesterol, excess modulators have been shown to control both amount eaten calories, or alcohol) or drug use (including steroid hormones, and selection of food in a mancronutrient specific manner diuretics, beta-blockers, cyclosporine and amiodarone, or (Lecklin et al., 2002). For example, as is discussed herein olanzapine). Dyslipidemias may also be associated with above and is further demonstrated in FIGS. 1 and 2, meto , diabetes mellitus, hepatobiliary obstruction, prine has been shown to Suppress daily ingestion of fats in nephritic syndrome and chronic renal failure, or with sys rats, while having no effect on intakes of carbohydrates or temic diseases such as porphyries, systemic lupus erythema proteins, indicating that an increase in the brain histamine tosis, and lymphomas. The most commonly used options for content may specifically affect the desire to consume fats. pharmacologic treatment of dyslipidemia include , 0225. As is demonstrated in the Examples section that HMG-CoA reductase inhibitors (such as ), bile acid follows, it has been found that betahistine treatment resulted sequestrants, cholesterol absorption inhibitors, nicotinic acid in a significant decrease infat consumption in human Subjects and derivatives thereof. over a 28 day trial, while consumption of carbohydrates was 0236 High cholesterol level, as well as other manifesta not significantly altered. The increase in brain histamine tions of dyslipidemia, can cause the formation and accumu caused by administration of the H-receptor agonists of the lation of plaque deposits in the arteries, leading to plaque present invention may therefore be effective in reducing the ruptures and blockages in the arteries, which increase the risk desire of a human Subject to consume fats. for heart attack, stroke, circulation problems, and death. 0226. Thus, according to still another aspect of the present Patients suffering from metabolic derangement that is mani invention, there is provided a method of reducing the desire of fested by dyslipidemia are therefore typically instructed to a human Subject to consume fats, which is effected by admin follow a low fat diet as a first measure, before being pre istering to the subject a therapeutically effective amount of scribed drugs which affect cholesterol metabolism. However, the Hagonist described herein. patient compliance with these instructions is generally not 0227. The clinical finding that the Hagonist of the present high, and currently there are no available drugs for helping invention reduces fat intake in humans is of unique impor patients to adhere to such a diet. Therefore, the Hagonist of tance, not only with regard to obese Subjects, but also with the present invention, in reducing the desire of a patient to regard to patients Suffering from conditions that are associ consume fats, helps such patients to maintain a low fat diet. ated with fat consumption and/or in which reduced fat con 0237 Hence, according to still another aspect of the Sumption is beneficial. present invention, there is provided a methodofreducing total 0228 Thus, according to a further aspect of the present cholesterol level in a human subject, which is effected by invention, there is provided a method of treating a condition administering to the subject a therapeutically effective in which reduced fat consumption is beneficial, which is amount of the Hagonist described herein. US 2010/0152161 A1 Jun. 17, 2010

0238 Total cholesterol consists of HDL cholesterol and an amphetamine Suitable for co-administration with the H LDL cholesterol. High density lipoprotein (HDL), com agonist of the present invention is Fentermine. monly referred to as “good cholesterol, tends to carry cho 0245 Additional examples of such active ingredients lesterol away from the arteries and back to the liver, where it include canabinoid receptor antagonists. A non-limiting is passed from the body. It is also believed that HDL choles example of a canabinoid receptor antagonist Suitable for co terol removes excess cholesterol from plaque in arteries, thus slowing the buildup. An increase in HDL cholesterol is there administration with the Hagonist of the present invention is fore considered beneficial. In contrast, LDL cholesterol is Rimonabant, a recently developed drug that is currently considered to be “bad” cholesterol, being responsible for undergoing Phase III trials and which is claimed to stop food plaque formation and deposits. Reducing LDL-cholesterol is cravings. believed to be responsible for reducing or stopping the for 0246 Alternatively, the additional active agent may be an mation of new cholesterol plaques on the artery walls; reduc agent for the treatment of a musculoskeletal disorder, a car ing existing cholesterol plaques on the artery walls; widening diovascular disorder, a dermatological disorder, a sleep dis narrowed arteries; preventing the rupture of cholesterol order, a metabolic condition, dyslipidemia (including hyper plaques, which initiates blood clot formation; decreasing the cholesterolemia and lipemia), diabetes or a diabetes-related risk of heart attacks; and decreasing the risk of strokes. condition. Such agents are not necessarily associated with 0239 Thus, according to still another aspect of the present weight gain, but may be administered together with the H invention, there is provided a method of reducing low-density agonist of the present invention, for treatment of additional lipoprotein cholesterol and increasing high-density lipopro conditions from which the subject may suffer. tein cholesterol levels in a human subject, which is effected 0247 Representative examples of agents for the treatment by administering to the subject a therapeutically effective of musculoskeletal disorders include, without limitation, amount of the Hagonist described herein. anti-inflammatory agents, including non-steroidal anti-in 0240 Triglycerides are common types of fats (lipids) that flammatory drugs, muscle relaxants, anti-gout agents (such as are essential for good health when present in normal amounts. allopurinol, colchicine, and uricoSuric drugs), immunosup They account for about 95 percent of the body's fatty tissue. pressants (such as glucocorticoids, gold, and cytotoxic Triglycerides are both present in food and manufactured by agents) and drugs affecting bone mineralization (e.g., diphos the body. Abnormally high triglyceride levels are associated phonates, calcitonin, estrogen analogs). with a number of diseases and conditions, such as cirrhosis, 0248 Representative examples of non-steroidal anti-in underactive thyroid, poorly controlled diabetes, and pancre flammatory drugs include, without limitation, piroxicam, atitis. High triglyceride levels are also associated with known isoxicam, tenoxicam, Sudoxicam, and CP-14.304; Salicy risk factors for heart disease, such as low levels of HDL lates, such as aspirin, disalcid, benorylate, trilisate, Safapryn, cholesterol, high levels of LDL cholesterol and obesity. Trig Solprin, diflunisal, and fendosal; acetic acid derivatives, such lycerides may also contribute to atherosclerosis. as diclofenac, fenclofenac, indomethacin, Sulindac, tolmetin, 0241 Hence, according to still another aspect of the isoxepac, furofenac, tiopinac, Zidometacin, acematacin, fen present invention, there is provided a method of reducing tiazac, Zomepirac, clindanac, oxepinac, felbinac, and ketoro triglyceride level in a human subject, which is effected by lac, fenamates, such as mefenamic, meclofenamic, flufe administering to the subject a therapeutically effective namic, niflumic, and tolfenamic acids; propionic acid amount of the Hagonist described herein. derivatives, such as ibuprofen, naproxen, benoxaprofen, flur 0242. In any of the methods described herein, the Hago biprofen, ketoprofen, fenoprofen, fenbufen, indopropfen, pir nist may optionally be administered together with a therapeu profen, carprofen, oxaprozin, pranoprofen, miroprofen, tioX tically effective amount of an additional active agent that may aprofen, Suprofen, alminoprofen, and tiaprofenic; pyrazoles, affect the condition being treated. Such as phenylbutaZone, oxyphenbutaZone, feprazone, aza 0243 According to a preferred embodiment of the present propaZone, and trimethaZone. invention, the additional active ingredient can be, for 0249 Non-limiting examples of steroidal anti-inflamma example, a weight control agent. Any of the presently known tory drugs include, without limitation, corticosteroids such as and approved weight control agents or related Substances can hydrocortisone, hydroxyltriamcinolone, alpha-methyl dex be used according to this embodiment. Hence, representative amethasone, dexamethasone-phosphate, beclomethasone examples of Such active ingredients include, for example, dipropionates, clobetasol Valerate, desonide, desoxymetha lipase inhibitors. A non-limiting example of a lipase inhibitor Sone, desoxycorticosterone acetate, dexamethasone, dichlor suitable for co-administration with the H agonist of the isone, diflorasone diacetate, diflucortolone Valerate, fluadre present invention is Orlistat, which acts by binding to gas nolone, fluclorolone acetonide, fludrocortisone, trointestinal lipases in the lumen of the gut, preventing flumethasone pivalate, fluosinolone acetonide, fluocinonide, hydrolysis of dietary fat into absorbable free fatty acids and flucortine butylesters, fluocortolone, fluprednidene (flupred monoacylglycerols. Orlistat is currently the only FDA-ap nylidene) acetate, flurandrenolone, halcinonide, hydrocorti proved medication for obesity that reduces nutrient absorp Sone acetate, hydrocortisone butyrate, methylprednisolone, tion. triamcinolone acetonide, cortisone, cortodoxone, fluc 0244. Additional examples of such active ingredients etonide, fludrocortisone, difluorosone diacetate, fluradre include Sibrutamine, an inhibitor of both norepinephrine nolone, fludrocortisone, difluorosone diacetate, fluradre reuptake and serotonin reuptake that also weakly inhibits nolone acetonide, medrysone, amcinafel, amcinafide, dopamine reuptake, which is approved by the FDA for weight betamethasone and the balance of its esters, chloropred loss and weight maintenance in conjunction with a reduction nisone, chlorprednisone acetate, clocortelone, clescinolone, diet. Additional examples of Such active ingredients include dichlorisone, diflurprednate, flucloronide, flunisolide, fluo amphetamines, although the administration thereof might be romethalone, fluperolone, fluprednisolone, hydrocortisone restricted to a limited time period. A non-limiting example of Valerate, hydrocortisone cyclopentylpropionate, hydrocor US 2010/0152161 A1 Jun. 17, 2010 tamate, meprednisone, paramethasone, prednisolone, pred the liver, secondarily inducing increased expression of LDL nisone, beclomethasone dipropionate, triamcinolone, and receptors, resulting in an increased removal of LDL-C from mixtures thereof. the plasma. 0250 Representative examples of agents for the treatment 0257 Cholesterol absorption may also be affected by of cardiovascular disorder include, without limitation; angio Cholesteryl Ester Transfer Protein (CETP) inhibitors, which tensin-converting enzyme inhibitors (such as captopril, play a major role in atherogenesis, by reducing cholesteryl enalapril, or lisinopril); antiarrhythmic drugs (such as amio ester accumulation within macrophages and the arterial wall, darone); , antiplatelets or thrombolytics (Such and thus reducing foam cell formation and affecting the cho as aspirin); centrally acting drugs (such as clonidine, guanfa lesterol absorption. The most promising presently known cine or methyldopa); digitalis drugs (such as digoxin); diuret CETP inhibitor is avisimibe. ics (such as chlorthalidone); nitrates (such as nitroglycerin); 0258 Bile acid sequestrants area class of cholesterol low peripheral adrenergic antagonists (such as reserpine); and ering drugs that help rid the body of cholesterol by depleting vasodilators (such as hydralazine). cholesterol levels in the body. Bile is released from the liver 0251 Representative examples of agents for the treatment and aids in the emulsification of fats. Cholesterol is a major of sleep disorders include, without limitation, medi component of bile, and most of the cholesterol from bile is cations, such as benzodiazepines (including flurazepam, esta reabsorbed into the bloodstream in the small intestine. Bile Zolam, temazepam and triazolam); Zaleplon and Zolpidem; acid sequestrants act at the level of the Small intestine and eSZopiclone; antidepressants, such as traZodone, antihista function in binding to bile, thus preventing cholesterol from mines (such as diphenhydramine products). being reabsorbed into circulation. Instead, the medication and 0252 Representative examples of agents for the treatment bile will form an insoluble complex and be excreted in the of diabetes include, without limitation, a meglitinide (such as feces. Examples of commonly prescribed bile acid sequester repaglinide or nateglinide), a biguanide (such as metformin), ants include Cholestyramine (Questran?R) and colestipol a thiazolidinedione (such as rosiglitaZone, troglitaZone or (ColestidR). pioglitaZone), and an alpha-glucosidase inhibitor (such as 0259 Representative examples of cholesterol biosynthe acarbose or meglitol) and insulin. sis inhibitors include squalene inhibitors (such as monooxy 0253 Non-limiting examples of agents for the treatment genase and synthase). Squalene is an isoprenoid compound of dyslipidemia include agents that lower serum total choles structurally similar to beta-carotene, is an intermediate terol, low-density lipoprotein (LDL) cholesterol and triglyc metabolite in the synthesis of cholesterol. In humans, about eride concentrations such as, for example, fibrates, HMG 60 percent of dietary squalene is absorbed. It is transported in CoA reductase inhibitors, bile acid sequestrants, cholesterol serum generally in association with very low density lipopro absorption inhibitors including triglyceride absorption teins and is distributed ubiquitously in human tissues, with inhibitors, cholesterol biosynthesis inhibitors, including trig the greatest concentration in the skin, where it is one of the lycerides absorption inhibitors, nicotinic acid and any ana major components of skin Surface lipids. Squalene inhibitors logs, metabolites and derivatives thereof. (e.g., monooxygenase and synthase) serve as cholesterol bio 0254 HMG-CoA reductase inhibitors (statins) are well synthesis inhibitors. known drugs that effectively reduce LDL-cholesterol levels 0260 Nicotinic acid is a known agent that lowers total by inhibiting the enzyme that regulates the rate of cholesterol cholesterol, LDL-cholesterol, and triglyceride levels, while production and increasing the clearance of LDL-cholesterol raising HDL-cholesterol levels. There are three types of nico present in the blood by the liver. Representative examples of tinic acid drugs: immediate release, timed release, and commonly prescribed statins include Atorvastatin, Fluvasta extended release. Nicotinic acid or niacin, the water-soluble tin, Lovastatin, Pravastatin and Simvastatin. B , improves all lipoproteins when given in doses well 0255 Proliferative Activated Receptor (PPAR) agonists, above the vitamin requirement. also known as fibrates, are fatty acid-activated members of 0261 Additional active agents that can be utilized accord the nuclear receptor Superfamily that play important roles in ing to this embodiment of the present invention include, for lipid and glucose metabolism, and have been implicated in example, , growth factors and toxins. obesity-related metabolic diseases such as hyperlipidemia, 0262 Non-limiting examples of analgesics (pain reliev insulin resistance, and coronary artery disease. Fibrates are ers) include aspirin and other salicylates (such as choline or generally effective in lowering elevated plasma triglycerides magnesium salicylate), ibuprofen, ketoprofen, naproxen and cholesterol and act as PPAR agonists. The most pro Sodium, and acetaminophen. nounced effect of fibrates includes a decrease in plasma trig 0263 Growth factors are hormones which have numerous lyceride-rich lipoproteins (TRLs). Levels of LDL cholesterol functions, including regulation of adhesion molecule produc (LDL-C) generally decrease in individuals with elevated tion, altering cellular proliferation, increasing vasculariza baseline plasma concentrations, and HDL cholesterol (HDL tion, enhancing collagen synthesis, regulating bone metabo C) levels are usually increased when baseline plasma concen lism and altering migration of cells into given area. Non trations are low. Non-limiting examples of commonly pre limiting examples of growth factors include insulin-like scribed fibrates include bezafibrate, gemfibrozil and growth factor-1 (IGF-1), transforming growth factor-fi (TGF fenofibrate. (B), a bone morphogenic protein (BMP) and the like. 0256 Representative examples of cholesterol absorption 0264. Non-limiting examples of toxins include the cholera inhibitors include eZetimibe. Ezetimibe is the first of a new toxin, which also serves as an adjuvant. class of cholesterol absorption inhibitors that potently and 0265. When utilized in each of the methods and aspects selectively inhibits dietary and biliary cholesterol absorption described above, the H agonist of the present invention at the brush border of the intestinal epithelium, without optionally and preferably forms a part of a pharmaceutical affecting the absorption of triglyceride or fat-soluble vita composition. The pharmaceutical composition comprises, in mins. Ezetimibe thus reduces overall cholesterol delivery to addition to the H agonist, a pharmaceutically acceptable US 2010/0152161 A1 Jun. 17, 2010 carrier, and may optionally further comprise one or more glycol, water, ethanol and the like. The composition, if components selected from binding agents, stabilizers, dilu desired, can also contain minor amounts of wetting or emul ents, excipients, Surfactants, flavors, and odorants. Sifying agents, or pH buffering agents. These compositions 0266. As used herein a “pharmaceutical composition' can take the form of solutions, Suspensions, emulsion, tablets, refers to a preparation of one or more of the active ingredients pills, capsules, powders, Sustained-release formulations and described herein, either compounds or physiologically the like. acceptable salts thereof, with other chemical components 0271 Further techniques for formulation and administra Such as traditional drugs, physiologically suitable carriers tion of active ingredients may be found in "Remington's and excipients. Thus, a pharmaceutical composition, accord Pharmaceutical Sciences.” Mack Publishing Co., Easton, Pa., ing to the present embodiments, can include the Hagonist latest edition, which is incorporated herein by reference as if described herein, either as the Sole active ingredient, or com fully set forth herein. bined with any of the active ingredients described herein, 0272. The pharmaceutical compositions herein described including, for example, weight control agents, drugs that a may also comprise Suitable solid or gel phase carriers or treatment therewith is associated with weight gain (e.g., excipients. Examples of Such carriers or excipients include, antipsychotics, antidepressants and the like), agents for the but are not limited to, calcium carbonate, calcium phosphate, treatment of a musculoskeletal disorder, a cardiovascular dis various Sugars, starches, cellulose derivatives, gelatin and order, a dermatological disorder, a sleep disorder, a metabolic polymers such as polyethylene glycols. condition, diabetes or a diabetes-related condition, and agents 0273 Pharmaceutical compositions for use in accordance for treating dyslipidemia (including lipemia and hypercho with the present invention thus may beformulated in conven lesterolemia, e.g., cholesterol and/or triglycerides absorption tional manner using one or more pharmaceutically acceptable inhibitors and cholesterol and/or triglycerides biosynthesis carriers comprising excipients and auxiliaries, which facili inhibitors), all as is detailed hereinabove. tate processing of the active ingredients into preparations 0267 Pharmaceutical compositions comprising one or which, can be used pharmaceutically. Proper formulation is more of the active ingredients described herein can therefore dependent upon the route of administration chosen. include, for example, the Hagonist described herein and an 0274 Pharmaceutical compositions that comprise two or agent for treating dyslipidemia (e.g., cholesterol and/or trig more active ingredient, as described hereinabove, can be for lyceride absorption inhibitor, cholesterol and/or triglyceride mulated either as a single packaged pharmaceutical dose unit biosynthesis inhibitor, ezetimibe, orlistat, a cholesteryl ester (further referred to herein as a “unitary dosage form”) that transfer protein (CETP) inhibitor, a bile acid sequesterant, a includes the two or more active ingredients or as two or more fibrate, an HMG-CoA reductase inhibitor, a squalene inhibi separate units (e.g. two or more dosage forms) each including tor, nicotinic acid, a derivative, analog and metabolite thereof, a single active ingredient and all preferably further packaged and any mixture thereof, as is detailed hereinabove); the H into a single delivery device (e.g., a capsule). agonist described herein and a drug associated with weight (0275 Since the Hagonist described herein is character gain (e.g., an antipsychotic, an antidepressant, a mood-stabi ized by a desirable pharmacokinetic, reflected by a timed lizer, a calcium channel blocker, an anti-convulsant, a proton plasma peak concentration, the composition of the present pump inhibitor, an antidiabetic agent, an antihypertensive, a invention is formulated such that the maximal efficacy of the hormone, an anti-Smoking medication and any combination active ingredients would provide an optimal effect with thereof, as is detailed hereinabove); the Hagonists described regard to the intended use of the combined composition. herein and a weight control agent (e.g., Sibrutamine, Orlistat, 0276 Preferably, the composition of the present invention Rimonabant, and more, as is detailed hereinabove); the H is formulated Such that a plasma peak concentration of each of agonist described herein and agent for treating diabetes, and the active ingredients occurs Substantially simultaneously. the like. Thus, for example, compositions comprising one or more 0268. The purpose of a pharmaceutical composition is to drugs associated with weight gain and the H agonist facilitate administration of an active ingredient (herein the H described herein are formulated such that the plasma peak agonist described above, optionally combined with other concentration of the Hagonist would occur within the time active ingredients) to an organism (herein, a human being). frame in which the plasma concentration of the drug causes Pharmaceutical compositions of the present invention may be appetite stimulation. manufactured by processes well known in the art, e.g., by 0277 One approach for achieving the above, is to attenu means of conventional mixing, dissolving, granulating, dra ate the release of the Hagonist with respect to the release of gee-making, levigating, emulsifying, encapsulating, entrap the other active ingredient(s) or, Vice versa, attenuate the ping or lyophilizing processes. release of the other active ingredient(s) with respect to the 0269. Such pharmaceutical carriers can be sterile liquids, release of the Hagonist. In order to achieve Such staggered Such as water and oils, including those of petroleum, animal, release, bothagents may be indelayed release form of varying Vegetable or synthetic origin, such as peanut oil, soybean oil, release profile, or one agent may be in immediate release form oil, sesame oil and the like. Water is a preferred and the other agent(s) in delayed release form. In another carrier when the pharmaceutical composition is administered approach, the agents are delivered as individual pulses, at intravenously. Saline solutions and aqueous dextrose and spaced-apart time intervals. glycerol Solutions can also be employed as liquid carriers, 0278. An exemplary formulation includes capsules hous particularly for injectable solutions. ing tablets or drug-containing beads or particles, a first por 0270. Suitable pharmaceutical excipients include without tion of which comprises the Hagonist, and a second portion limitation, calcium carbonate, calcium phosphate, various of which comprises another active ingredient, wherein each Sugars and types of starch, cellulose derivatives, gelatin, Veg portion provides a different drug release profile. The capsule etable oils, polyethylene glycols, Sodium Stearate, glycerol material may be either hard or soft, and as will be appreciated monostearate, talc, Sodium chloride, glycerol, propylene, by those skilled in the art of pharmaceutical Science, typically US 2010/0152161 A1 Jun. 17, 2010

comprises a tasteless, easily administered and water soluble formulation in which one agent is provided in an outer, imme compound Such as gelatin, starch or cellulose. diate release layer, which is released as a first pulse, while the 0279 A unitary dosage form may comprise a single tablet other agentis contained within a core which is separated from with the first and second dosage units each representing an the outer layer by a film layer of an enteric coating. The integral and discrete layer thereof. For example, drug-con enteric coating slowly dissolves after the delivery of the first taining particles or drug-containing beads can be compressed pulse of drug allowing the release of the second pulse. together into a single tablet using conventional tableting 0284. Formulations for oral delivery can include standard CaS. carriers such as pharmaceutical grades of mannitol, lactose, 0280 Delayed release may be achieved by any method starch, magnesium Stearate, sodium saccharine, cellulose, known in the art. As will be appreciated by those skilled in the magnesium carbonate, etc. Examples of Suitable pharmaceu art, a number of methods are available for preparing drug tical carriers are described in “Remington's Pharmaceutical containing tablets or other dosage units which provide a vari Sciences” by E. W. Martin. Such compositions will contain a ety of drug release profiles. Such methods include coating a therapeutically effective amount of the compound, preferably drug or drug-containing composition, increasing the drug's in purified form, together with a suitable amount of carrier so particle size, placing the drug within a matrix, and forming as to provide the form for proper administration to the patient. complexes of the drug with a suitable complexing agent. The formulation should be suitable for the mode of adminis Delayed release may be provided, for example, by coating a tration. drug or a drug-containing composition with a selected mem 0285 For oral administration, the active ingredients can brane coating material, typically although not necessarily a be formulated readily by combining the active ingredients polymeric material. Exemplary delayed release forms of H with pharmaceutically acceptable carriers well known in the agonist preparations are described hereinabove. art. Such carriers enable the active ingredients of the inven 0281. When a coating is used to provide delayed release tion to be formulated as tablets, pills, dragees, capsules, liq dosage units, particularly preferred coating materials com uids, gels, syrups, slurries, Suspensions, and the like, for oral prise bioerodible, gradually hydrolyzable and/or gradually ingestion by a patient. Pharmacological preparations for oral water-soluble polymers. The “coating weight,” or relative use can be made using a solid excipient, optionally grinding amount of coating material per dosage unit, generally dictates the resulting mixture, and processing the mixture of granules, the time interval between ingestion and drug release. Suitable after adding suitable auxiliaries if desired, to obtain tablets or membrane coating materials for effecting delayed release dragee cores. Suitable excipients are, in particular, fillers such include, but are not limited to: cellulosic polymers such as as Sugars, including lactose, sucrose, mannitol, or sorbitol; hydroxypropyl cellulose, hydroxyethyl cellulose, hydrox cellulose preparations such as, for example, maize starch, ypropyl methyl cellulose, methyl cellulose, ethyl cellulose, wheat starch, rice starch, potato starch, gelatin, gum traga cellulose acetate, cellulose acetate phthalate, cellulose canth, methyl cellulose, hydroxypropylmethyl-cellulose, acetate trimelitate, hydroxypropylmethyl cellulose phtha Sodium carbomethylcellulose; and/or physiologically accept late, cellulose ester-ether phthalate, hydroxypropylcellulose able polymers such as polyvinylpyrrolidone (PVP). If phthalate, alkali salts of cellulose acetate phthalate, alkaline desired, disintegrating agents may be added, such as cross earth salts of cellulose acetate phthalate, hydroxypropylm linked polyvinyl pyrrolidone, agar, or alginic acid or a salt ethyl cellulose hexahydrophthalate, cellulose acetate hexahy thereof Such as Sodium alginate. drophthalate, and carboxymethylcellulose Sodium; acrylic 0286 Dragee cores are provided with suitable coatings. acid polymers and copolymers preferably formed from For this purpose, concentrated Sugar Solutions may be used acrylic acid, methacrylic acid, acrylic acid alkyl esters, meth which may optionally contain gum arabic, talc, polyvinyl acrylic acid alkyl esters, and the like, e.g. copolymers of pyrrolidone, carbopol gel, polyethylene glycol, titanium acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, dioxide, lacquer Solutions and Suitable organic solvents or methyl methacrylate and/or ethyl methacrylate, vinyl poly solvent mixtures. Dyestuffs or pigments may be added to the mers and copolymers such as polyvinyl pyrrolidone, polyvi tablets or dragee coatings for identification or to characterize nyl acetate, polyvinylacetate phthalate, vinylacetate crotonic different combinations of active ingredient doses. acid copolymer, and ethylene-Vinyl acetate copolymers; and 0287 Pharmaceutical compositions, which can be used shellac, ammoniated shellac, shellac-acetyl alcohol, and shel orally, include push-fit capsules made of gelatin as well as lac n-butyl Stearate. soft, sealed capsules made of gelatin and a plasticizer, Such as 0282 Alternatively, the delayed release dosage units, e.g., glycerol or Sorbitol. The push-fit capsules may contain the tablets or particles, may be formulated by dispersing the active ingredients in admixture with filler Such as lactose, active ingredient within a matrix of a Suitable material such as binders such as starches, lubricants such as talc or magnesium an insoluble plastic, a hydrophilic polymer, or a fatty com Stearate and, optionally, stabilizers. In soft capsules, the pound. The insoluble plastic matrices may be comprised of active ingredients may be dissolved or Suspended in Suitable for example, polyvinyl chloride or polyethylene. Hydrophilic liquids, such as fatty oils, liquid paraffin, or liquid polyethyl polymers useful for providing a matrix for a delayed release ene glycols. In addition, stabilizers may be added. All formu dosage unit include, but are not limited to, those described lations for oral administration should be in dosages Suitable above as Suitable coating materials. Fatty compounds for use for the chosen route of administration. as a matrix material include, but are not limited to, waxes 0288 For transdermal administration, the composition generally (e.g., carnauba wax) and glyceryl tristearate. Once can be formulated in a form of a gel, a cream, an ointment, a the active ingredient is mixed with the matrix material, the paste, a lotion, a milk, a Suspension, an aerosol, a spray, a mixture can be compressed into tablets or processed into foam, a serum, a Swab, a pledget, a pad or a patch. Formula individual drug-containing particles. tions for transdermal delivery can typically include carriers 0283. Further examples of compositions in which one Such as water, liquid alcohols, liquid glycols, liquid polyalky agent is delayed with respect to the other agent include a lene glycols, liquid esters, liquid amides, liquid protein US 2010/0152161 A1 Jun. 17, 2010

hydrolysates, liquid alkylated protein hydrolysates, liquid accompanied by a notice associated with the container in a lanolin, lanolin derivatives, glycerin, mineral oil, silicone, form prescribed by a governmental agency regulating the petroleum jelly, lanolin, fatty acids, vegetable oils, parabens, manufacture, use or sale of pharmaceuticals, which notice is waxes, and like materials commonly employed in topical reflective of approval by the agency of the form of the com compositions. Various additives, known to those skilled in the positions or human or veterinary administration. Such notice, art, may be included in the transdermal formulations of the for example, may be of labeling approved by the U.S. Food invention. For example, solvents may be used to solubilize and Drug Administration for prescription drugs or of an certain active ingredients substances. Other optional addi approved product insert. Compositions comprising the H tives include skin permeation enhancers, opacifiers, anti-oxi dants, gelling agents, thickening agents, stabilizers, and the agonist of the invention, and optionally other active ingredi like. ents, formulated in a compatible pharmaceutical carrier may 0289 For buccal administration, the compositions may also be prepared, placed in an appropriate container, and take the form of tablets or lozenges formulated in conven labeled for treatment of an indicated condition, as is detailed tional manner. herein. 0290 For administration by inhalation, the active ingredi 0296. Thus, for example, pharmaceutical compositions ents for use according to the present invention are conve comprising the Hagonist of the invention and a drug that a niently delivered in the form of an aerosol spray presentation treatment therewith is associated with weight gain (e.g., an from a pressurized pack or a nebulizer with the use of a antipsychotic), can be packaged in a packaging material and Suitable propellant, e.g., dichlorodifluoromethane, trichlorof identified in print, in or on the packaging material, for use in luoromethane, dichloro-tetrafluoroethane or carbon dioxide. the treatment of a condition for which the drug indicated, In the case of a pressurized aerosol, the dosage unit may be while reducing or preventing weight gain associated with this determined by providing a valve to deliver a metered amount. drug treatment, as is detailed hereinabove. Capsules and cartridges of, e.g., gelatin for use in an inhaleror 0297 Pharmaceutical compositions comprising the H insufflator may be formulated containing a powder mix of the agonist of the invention, a cholesterol and/or triglycerides active ingredientanda Suitable powder base Such as lactose or absorption inhibitor and/or a cholesterol and/or triglycerides starch. biosynthesis inhibitor can be packaged in a packaging mate 0291. The active ingredients described herein may be for mulated for parenteral administration, e.g., by bolus injection rial and identified in print, in or on the packaging material, for or continuous infusion. Formulations for injection may be use in the treatment of a condition associated with metabolic presented in unit dosage form, e.g., in ampoules or in multi derangement (e.g., dyslipidemia), as is detailed hereinabove. dose containers with optionally, an added preservative. The 0298. Additional objects, advantages, and novel features compositions may be suspensions, Solutions or emulsions in of the present invention will become apparent to one ordi oily or aqueous vehicles, and may contain formulatory agents narily skilled in the art upon examination of the following Such as Suspending, stabilizing and/or dispersing agents. examples, which are not intended to be limiting. Additionally, 0292 Pharmaceutical compositions for parenteral admin each of the various embodiments and aspects of the present istration include aqueous Solutions of the active preparation invention as delineated hereinabove and as claimed in the in water-soluble form. Additionally, suspensions of the active claims section below finds experimental Support in the fol ingredients may be prepared as appropriate oily injection lowing examples. suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters Such as ethyl oleate, triglycerides or liposomes. Aqueous EXAMPLES injection Suspensions may contain Substances, which increase the Viscosity of the Suspension, Such as Sodium car 0299 Reference is now made to the following example, boxymethyl cellulose, sorbitol or dextran. Optionally, the which together with the above descriptions, illustrate the Suspension may also contain Suitable stabilizers or agents invention in a non limiting fashion. which increase the solubility of the active ingredients to allow for the preparation of highly concentrated Solutions. Example 1 0293. The composition can be formulated as rectal com positions such as Suppositories or retention enemas, using, 0300. The following study was conducted to evaluate the e.g., conventional Suppository bases such as cocoa butter or effect of oral administration of betahistine on food intake: other glycerides. 0301 Twenty obese but otherwise healthy persons were 0294 The pharmaceutical compositions herein described recruited. Their characteristics upon recruitment are shown in may also comprise Suitable solid of gel phase carriers or excipients. Examples of Such carriers or excipients include, Table 1. Exclusion criteria for the study were age younger but are not limited to, calcium carbonate, calcium phosphate, than 18, active diseases, medication use, known hypersensi various Sugars, starches, cellulose derivatives, gelatin and tivity or contra-indication for the use of betahistine. polymers such as polyethylene glycols. 0302 Each subject was randomly allocated to receive 0295 Compositions of the present invention may, if betahistine 16 mg at 10:00 and 16:00 or placebo. Weight, desired, be presented in a pack or dispenser device, such as an caloric intake (24 hour recall) and appetite during the day FDA approved kit, which may contain one or more unit dos (VAS, Visual Analogue Score) were obtained on day 0, 14 and age forms containing the active ingredient. The pack may, for 28 of the study. Subjects were instructed to eat according to example, comprise metal or plastic foil. Such as ablisterpack. their appetite without limitations. The pack or dispenser device may be accompanied by instruc 0303 Statistical significance was assessed with t-test. tions for administration. The pack or dispenser may also be BMI stands for body mass index. US 2010/0152161 A1 Jun. 17, 2010 20

woman, as observed in blood tests, was measured before and TABLE 1. after the betahistine treatment and are presented in Table 2 below. Patients characteristics

Treatment betahistine Placebo TABLE 2 Age 489 38 - 15 NS Day 0 Day 30 Change Weight (kg) 93 - 17 90 - 4 NS BMI 35.17.3 32.71.7 NS Total cholesterol 167 155 -7% Mean caloric intake (kcal) 975 - 472 1397 - 693 NS HDL-cholesterol S4 58 +7% Mean appetite score (VAS) 45 - 15 SO 12 NS LDL-cholesterol 99 84 -15% Triglycerides 69 62 -10% NS denotes no statistical significance (p value s-0.05) Fructoseamine 195 2O2 +4% 0304) Of the 20 subjects recruited, 8 did not complete the study and were excluded from the final analysis: 0320. As seen in Table 2, the results show that during the 0305 Subject No. 3 (placebo) dropped out on day 3 due to 30-day time period studied, the total cholesterol level of the side effects weakness. Subject decreased, with a corresponding decrease in the level (0306 Subject No. 5 (betahistine) reported on day 5 food of LDL-cholesterol and an increase in the level of HDL aversion that did not allow her to consume any food. She was cholesterol. The level of triglycerides decreased, while the instructed to reduce the dose by half and was excluded from level of fructoseamine increased very slightly. It is therefore the results analysis. concluded that the subject restricted her fat intake, (as shown 0307 Subject No. 9 (placebo) was excluded for protocol by the decrease in LDL-cholesterol), without reducing her violation. carbohydrate intake, (as shown by the slight increase in fruc 0308 Subject No. 11 (placebo) dropped out on week 4 due tosamine level), indicating that betahistine has a specific to flu. effect on reducing fat intake in a human Subject. 0309 Subject No. 13 (placebo) was lost to follow up. 0321. It is appreciated that certain features of the inven 0310. Subject No. 15 (betahistine) dropped out on week 4 tion, which are, for clarity, described in the context of separate due to flu. embodiments, may also be provided in combination in a 0311 Subject No. 16 (placebo) dropped out on week 3 due single embodiment. Conversely, various features of the to dyspnea. invention, which are, for brevity, described in the context of a 0312 Subject No. 17 (betahistine) was lost to follow up. single embodiment, may also be provided separately or in any 0313. The effect of betahistine treatment on the total suitable subcombination. caloric intake, and on the specific consumption offat, carbo 0322. Although the invention has been described in con hydrates and protein of the participants in this study was also junction with specific embodiments thereof, it is evident that studied. The obtained data are presented in FIGS. 4 and 5. many alternatives, modifications and variations will be appar 0314. As can be seen in FIG. 4, treatment with betahistine ent to those skilled in the art. Accordingly, it is intended to was found to reduce total caloric intake as compared to the embrace all Such alternatives, modifications and variations placebo. The caloric intake decreased to 80 percents of the that fall within the spirit and broad scope of the appended pre-treatment level at day 14 of treatment, and to 68 percents claims. at day 28. No decrease was seen with the subjects receiving 0323 All publications, patents and patent applications placebo. mentioned in this specification are herein incorporated in 0315. As can be seen in FIG. 5, while only a small reduc their entirety by reference into the specification, to the same tion in carbohydrate consumption occurred with betahistine extent as if each individual publication, patent or patent appli treatment (6%), fat and protein consumption were reduced by cation was specifically and individually indicated to be incor 49% and 35%, respectively. At the same time patients treated porated herein by reference. In addition, citation or identifi with placebo increased their carbohydrates, fats and protein cation of any reference in this application shall not be consumption by 24%. 3% and 37% respectively. construed as an admission that Such reference is available as 0316. It is therefore clearly shown that betahistine signifi prior art to the present invention. cantly reduces the caloric intake and fat consumption of a human subject. Therefore, administration of betahistine may BIBLIOGRAPHY be efficiently utilized for both improving compliance of a 0324 Albera, R. etal. Acta. Otolaryngol. 123(5):588-593 human Subject to caloric restriction, and for reducing the (2003). desire of a human Subject to consume fat. 0325 Amelin, A. V. et al. Zh. Nevrol. Psikhaitr. Im S.S. 0317. The effect of betahistine administration on weight Korsakova 103(5): 43-48 (2003). change was also studied. The results are presented in FIG. 6. 0326 Arrang, J.-M., et al. Eur: J. Pharmacol. 111: 73-84 Four out of seven Subjects in the treatment group lost more (1985). than 1 kg during the study period, in comparison to only one 0327. Attoub. S. Life Sci. 69: 469-78 (2001). out of five in the placebo group. 0328 Babarich, N. C., et al. J. Clin. Psychiatry 65: 1480 0318. These clinical data clearly show that betahistine is 1482 (2004). an efficient medication for weight management. 0329 Barrett, E., et al. Diabetes Care 27: 596-601 (2004). 0330 Bienning, C. Int. Sendai Histamine Symp. P39-40 Example 2 (2000). 0319. In a further study, a healthy, overweight woman was 0331 Blandina, P. Br. J. Pharmacol. 119: 1656-64 (1996). treated twice daily with betahistine 16 mg for a month without 0332 Boiko, A. N., et al. Zh. Nevrol. Psikhaitr. Im S.S. any dietary changes. The level of certain metabolites of the Korsakova 102(1): 42-45 (2002). US 2010/0152161 A1 Jun. 17, 2010

0333 Botez, M. Encephale 1(3): 279-86 (1975). 0372 Poyurovsky, M. et al. Int. Clin. Psychopharmacol. 0334 Bustillo, J. R. et al. Am. J. Psychiatryi 153: 817-819 20:101-103 (2005). (1996). 0373 Rasmussen, M. H. Brit. Med. J.306: 1093-6 (1993). 0335 Clapham, J. Eur: J. Pharmacol. 259: 107-14 (1994). 0374 Rossi, R., et al. Physiol. and Behav. 66: 517-521 0336 Clayman, C. B. J. Amer: Med. Assoc. 238:1289 (1999). Sakata, T. Obes. Res. (Suppl. 4) S541-S548 (1995). 1290 (1977). 0375 Sakata, T. Nutrition 13:403-11 (1997). 0337 Fossati, A. et al. Pharmacol. Res. 43389-392 0376 Saloughian et al., U.S. Pharmacist, 29: 2 (2004). (2001). 0377 Seifert et al., J. Pharmacol. Exp. Therap. 305(3): 0338 Fujino, A. et al. Arch. Otolaryngol. 120(5): 497-504 1104, 2003. (1994). 0378 Seipel, J. H. et al. J. Clin. Pharamacol. 17: 140-161 0339 Fukagawa, K. Am. J. Physiol. 256: R605 R611 (1977). (1989). 0379 Serdula, M. K. J. Amer: Med. Assoc. 282: 1353-8 (0340 Goldstein, D. J. Obes. Res. 2: 92-98 (1993). (1999). 0341 Gordon, C. R. et al. J. Vestib. Res. 13: 103-111 0380 Snyman, J. R., et al. Immunopharmacology 30(1): (2003). 71-8 (1995). (0342 Grahne, B., et al. Med. Monatasschr:30(6):273-275 0381 Steprinoson, L. A. Drug Metab. Dispos. 2; 123-8 (1976). (1974). 0343 Gusev, E. et al. Zh. Nevrol. Psikhaitr. Im S.S. Kor 0382 Szelag, A., Malgorzata, T., and Merwid-Lad, A. Pol sakova 98:19-21 (1998). ish J. Pharmacol. 53: 701-707 (2001). (0344) Hagan, M. M. Peptides 23:377-382 (2002). (0383 Szelag, A. Adv. Clin. Exp. Med 11(3): 293-300 (0345 Imamura, M. Circ. Res. 78: 863-9 (1996). (2002). (0346) Itoh, E., et al. Biol. Psychiatry 45: 475-481 (1999). 0384. Theisen, F. M., et al. J. Neural Transm. 110: 11-121 (0347 Kane, J. M. Am. J. Psychiatry 160: 290–296 (2003). (2003). (0348 Koller, E., et al. Am. J. Med 111: 716-23 (2001). (0385 Tuomisto, L. Meth. Find. Exp. Clin. Pharmacol. 16: (0349 Koller, E. (2002) Pharmacotherapy 22: 841-52 355-9 (1994). 0350 Krupnick J. G. et al., Ann. Rev. Pharmacol. Toxicol. 0386 Wadden, T. A. Obes. Res. 3: 549-57 (1995). 38: 289-319 (1998). (0387 Wirshing, D. A. et al. J. Clin. Psychiatry 60: 358 0351 Lean, M. Diabetes Care 26: 1597-1605 (2003). 363 (1999). 0352 Lecklin, A. Brain Res. 793: 279-88 (1998). (0388 Wirshing, D. A. J. Clin. Psychiatry 65: 13-26 0353 Lecklin et al. Inflamm. Res. 51: suppl. 1, S53-S54 (2004). (2002) (0389 Yoshimatsu, H. Diabetes 48: 2286-91 (1999). 0354) Leurs, R. Br. J. Pharmacol. 116: 2315-21 (1995). 0355 Leurs, R. Trends Pharmacol. Sci. 19: 177-84 What is claimed is: (1998). 1. A method of reducing weight gain associated with a drug 0356. Lieberman, J. A. Prim. Care Companion J. Clin. treatment in a human Subject, the method comprising admin Psychiatry 6: 8-13 (2004). istering to a human Subject treated with the drug a therapeu 0357 Lin, J.S. et al. Brain Res. 523: 325-30 (1990). tically effective amount of betahistine, a betahistine pharma 0358 Machidori, H. Brain Res. 590: 180-6 (1992). ceutically acceptable salt or a betahistine metabolite being 0359 McMahon, F. G. Arch. Intern. Med. 160: 2185-91 2-(2-aminoethyl)-pyridine. (2000). 2. The method of claim 1, wherein said drug is selected 0360 Malmo, K., et al. Int. J. Obesity 1-11 (2005). from the group consisting of an antipsychotic, an antidepres 0361 Meyer, J. S., et al. J. Clin. Pharmacol. 14: 280-9 sant, a mood-stabilizer, a calcium channel blocker, an anti (1974). convulsant, a proton pump inhibitor, an antidiabetic agent, an 0362 Mitchell, J. E., et al. Current Drug Targets 2: 17-29 antihypertensive, a hormone, an anti-Smoking medication (2003). and any combination thereof. 0363 Mokdad, A. H., J. Amer: Med. Assoc. 291: 1238-45 3. The method of claim 2, wherein said drug is selected (2004). from the group consisting of a selective serotonin-reuptake 0364 Morimoto, T. Behav. Brain Res. 124: 145-150 inhibitor, a monoamine oxidase inhibitor, a conventional (2001). antipsychotic, and an . 0365 National Center for Health Statistics, Health 4. The method of claim 3, wherein said atypical antipsy E-Stats, Hyattsville, Md., (2000). chotic is an antagonist of a receptor selected from the group 0366 National Task Force on the Prevention and Treat consisting of a 5-HT, receptor, a 5-HT, receptor, a H-his ment of Obesity, J. Amer: Med. Assoc. 276: 1907-15 taminergic receptor, and a M-muscarinic receptor. (1996). 5. The method of claim 2, wherein said drug is selected 0367 National Task Force on the Prevention and Treat from the group consisting of clozapine, olanzapine, risperi ment of Obesity, Arch. Intern. Med. 160: 898-904 (2000). done, quetiapine, sertindole, aripiprazole, Ziprasidone, 0368. Odinak, M. M. et al. Zh. Nevrol. Psikhaitr. Im S.S. bupropion hydrochloride, mirtazapine, nefazadone, traza Korsakova 105(7): 55-57 (2005). done, lithium, diltiazem, nicardipine, Verapamil, nimopid 0369 Onderwater, R. C. Toxicology 125: 117-29 (1998). ipine, carbamazepine, divalproex, lamotrigine, Sodium Val 0370 Physicians' Desk Reference, 55' edition, Montvale, proate, valproic acid, gabapentin, omeprazole, esomeprazole, N.J. (2001). lansoprazole, pantoprazole, a Sulfonylurea, a meglitinide, a 0371 Pi-Sunyer et al. American Heart Association (AHA) biguanide, a thiazolidinedione, an alpha-glucosidase inhibi Scientific Sessions, New Orleans, La. (2004). tor, insulin, chlorpropamide, glipizide, glyburide, glime US 2010/0152161 A1 Jun. 17, 2010 22 piride, chlorpropamide, glipizide, glyburide, glimepiride, an nel blocker, an anti-convulsant, a proton pump inhibitor, an alpha-adrenergic blocker, a beta blocker and a steroid hor antidiabetic agent, an antihypertensive, a hormone, an anti O. Smoking medication and any combination thereof. 6. The method of claim 1, wherein said weight gain causes 22. The pharmaceutical composition of claim 21, wherein a metabolic disorder. said drug is selected from the group consisting of a selective 7. The method of claim 6, wherein said metabolic disorder serotonin-reuptake inhibitor, a monoamine oxidase inhibitor, is selected from the group consisting of metabolic syndrome, a conventional antipsychotic, and an atypical antipsychotic. diabetes and dyslipidemia. 8. The method of claim 1, wherein said betahistine salt is 23. The pharmaceutical composition of claim 22, wherein selected from the group consisting of betahistine dihydro said atypical antipsychotic is an antagonist of a receptor chloride, betahistine mesilate, and betahistine trimebutine selected from the group consisting of a 5-HT2 receptor, a maleate. 5-HT, receptor, a Hi-histaminergic receptor, and a M-mus 9. The method of claim 1, wherein said administering is carinic receptor. effected by a route selected from the group consisting of the 24. The pharmaceutical composition of claim 21, wherein oral, transdermal, intravenous, Subcutaneous, intramuscular, said drug is selected from the group consisting of clozapine, intranasal, intraauricular, Sublingual, rectal, transmucosal, olanzapine, risperidone, quetiapine, sertindole, aripiprazole, intestinal, buccal, intramedullar, intrathecal, direct intraven Ziprasidone, bupropion hydrochloride, mirtazapine, nefaza tricular, intraperitoneal, and intraocular routes. done, traZadone, lithium, diltiazem, nicardipine, Verapamil, 10. The method of claim 1, wherein said administering is nimopidipine, carbamazepine, divalproex, lamotrigine, effected orally. Sodium valproate, Valproic acid, gabapentin, omeprazole, 11. The method of claim 1, wherein said therapeutically esomeprazole, lansoprazole, pantoprazole, a Sulfonylurea, a effective amount ranges from about 2 mg per unit dosage to meglitinide, a biguanide, a thiazolidinedione, an alpha-glu about 96 mg per unit dosage. cosidase inhibitor, insulin, chlorpropamide, glipizide, gly 12. The method of claim 11, wherein said therapeutically buride, glimepiride, chlorpropamide, glipizide, glyburide, effective amount ranges from about 10 mg per day to about 50 glimepiride, an alpha-adrenergic blocker, a beta blocker and a mg per day. steroid hormone. 13. The method of claim 1, wherein said administering is 25. The pharmaceutical composition of claim 20, being effected from about 1 to about 4 times per day. packaged in a packaging material and identified in print, in or 14. The method of claim 13, wherein said administering is on said packaging material, for use in the treatment of a effected twice per day. medical condition in which treatment with said drug is ben 15. The method of claim 1, wherein said betahistine, beta eficial while reducing or preventing weight gain associated histine salt or betahistine metabolite forms a part of a phar with said drug treatment. maceutical composition, said pharmaceutical composition 26. The pharmaceutical composition of claim 20, wherein further comprising a pharmaceutically acceptable carrier. said therapeutically effective amount of said drug is associ 16. The method of claim 15, wherein said pharmaceutical ated with a weight gain, and said therapeutically effective composition is a slow-release composition. amount of betahistine or betahistine salt is effective in reduc 17. The method of claim 15, wherein said pharmaceutical ing said weight gain. composition is in a form selected from the group consisting of 27. The pharmaceutical composition of claim 20, wherein a tablet, a pill, a dragee and a capsule. said betahistine salt is selected from the group consisting of 18. The method of claim 1, further comprising administer betahistine dihydrochloride, betahistine mesilate, and beta ing to the Subject a therapeutically effective amount of an histine trimebutine maleate. additional active agent. 28. The pharmaceutical composition of claim 20, wherein 19. The method of claim 18, wherein said additional active said therapeutically effective amount of said betahistine or agent is selected from the group consisting of a non-steroidal said betahistine salt ranges from about 2 mg per unit dosage to anti-inflammatory drug, a muscle relaxant, an antigout agent, about 96 mg per unit dosage. an immunosuppressant, a drug affecting bone mineralization, 29. The pharmaceutical composition of claim 20, being an angiotensin-converting enzyme inhibitor, an antiarrhyth formulated such that said betahistine or said betahistine salt is mic drug, an anticoagulant, an antiplatelet, a thrombolytic, a in a slow-release form. centrally acting drug, a digitalis drug, a nitrate, a peripheral adrenergic antagonist, a vasodilator, an acne medication, an 30. The pharmaceutical composition of claim 20, being antipruretic agent, an anti-psoriasis agent, an anti-eczema formulated for oral administration. agent, a hypnotic, an anti-histamine, a fibrate, an HMG-CoA 31. The pharmaceutical composition of claim 30, being in reductase inhibitor, a nutritional Supplement, a bile acid a form selected from the group consisting of a tablet, a pill, a sequestrant, a cholesterol absorption inhibitor, nicotinic acid, dragee and a capsule. a derivative, analog and metabolite thereof, and any mixture 32. A method treating a medical condition in which treat thereof. ment with a drug that causes weight gain is beneficial, while 20. A pharmaceutical composition comprising a therapeu reducing weight gain associated with the drug treatment, the tically effective amount of betahistine, a betahistine salt or a method comprising administering to a subject in need thereof betahistine metabolite being 2-(2-aminoethyl)-pyridine, and a therapeutically effective amount of the drug and further a therapeutically effective amount of a drug, said drug being administering to said Subject a therapeutically effective associated with weight gain. amount of betahistine, a betahistine salt or a betahistine 21. The pharmaceutical composition of claim 20, wherein metabolite being 2-(2-aminoethyl)-pyridine. said drug is selected from the group consisting of an antipsy 33. The method of claim 1, wherein said therapeutically chotic, an antidepressant, a mood-stabilizer, a calcium chan effective amount of the drug is associated with weight gain, US 2010/0152161 A1 Jun. 17, 2010

and said therapeutically effective amount of betahistine, beta 38. The method of claim32, wherein said betahistine salt is histine salt or betahistine metabolite is effective in reducing selected from the group consisting of betahistine dihydro said weight gain. chloride, betahistine mesilate, and betahistine trimebutine 34. The method of claim 32, wherein said drug is selected maleate. from the group consisting of an antipsychotic, an antidepres 39. The method of claim 32, wherein administering said sant, a mood-stabilizer, a calcium channel blocker, an anti betahistine, betahistine salt or betahistine metabolite is convulsant, a proton pump inhibitor, an antidiabetic agent, an effected by a route selected from the group consisting of the antihypertensive, a hormone, an anti-Smoking medication oral, transdermal, intravenous, Subcutaneous, intramuscular, and any combination thereof. intranasal, intraauricular, Sublingual, rectal, transmucosal, 35. The method of claim 34, wherein said drug is selected intestinal, buccal, intramedullar, intrathecal, direct intraven from the group consisting of a selective serotonin-reuptake tricular, intraperitoneal, and intraocular routes. inhibitor, a monoamine oxidase inhibitor, a conventional 40. The method of claim 32, wherein administering said antipsychotic, and an atypical antipsychotic. betahistine, betahistine salt or betahistine metabolite is 36. The method of claim 35, wherein said atypical antip effected orally. sychotic is an antagonist of a receptor selected from the group 41. The method of claim 32, wherein said therapeutically consisting of a 5-HT, receptor, a 5-HT, receptor, a H-his effective amount of said betahistine, betahistine salt or beta taminergic receptor, and a M-muscarinic receptor. histine metabolite ranges from about 2 mg per unit dosage to 37. The method of claim 34, wherein said drug is selected about 96 mg per unit dosage. from the group consisting of clozapine, olanzapine, risperi 42. The method of claim 32, wherein said betahistine, done, quetiapine, sertindole, aripiprazole, Ziprasidone, betahistine salt or betahistine metabolite forms a part of a bupropion hydrochloride, mirtazapine, nefazadone, traza pharmaceutical composition, said pharmaceutical composi done, lithium, diltiazem, nicardipine, Verapamil, nimopid tion further comprising a pharmaceutically acceptable car ipine, carbamazepine, divalproex, lamotrigine, sodium Val rier. proate, valproic acid, gabapentin, omeprazole, esomeprazole, 43. The method of claim 42, wherein said pharmaceutical lansoprazole, pantoprazole, a Sulfonylurea, a meglitinide, a composition is a slow-release composition. biguanide, a thiazolidinedione, an alpha-glucosidase inhibi 44. The method of claim 42, wherein said pharmaceutical tor, insulin, chlorpropamide, glipizide, glyburide, glime composition is in a form selected from the group consisting of piride, chlorpropamide, glipizide, glyburide, glimepiride, an a tablet, a pill, a dragee and a capsule. alpha-adrenergic blocker, a beta blocker and a steroid hor O. c c c c c