US20060084686A1 - Methods of food intake management - Google Patents

Methods of food intake management Download PDF

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US20060084686A1
US20060084686A1 US11/283,865 US28386505A US2006084686A1 US 20060084686 A1 US20060084686 A1 US 20060084686A1 US 28386505 A US28386505 A US 28386505A US 2006084686 A1 US2006084686 A1 US 2006084686A1
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agonist
betahistine
administering
subject
hours
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Nir Barak
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Mor Research Applications Ltd
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Mor Research Applications Ltd
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Priority claimed from IL16159504A external-priority patent/IL161595A0/xx
Priority to US11/283,865 priority Critical patent/US20060084686A1/en
Assigned to MOR RESEARCH APPLICATIONS LTD. reassignment MOR RESEARCH APPLICATIONS LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BARAK, NIR
Application filed by Mor Research Applications Ltd filed Critical Mor Research Applications Ltd
Priority to US11/363,332 priority patent/US7728015B2/en
Publication of US20060084686A1 publication Critical patent/US20060084686A1/en
Priority to AU2006202950A priority patent/AU2006202950A1/en
Priority to US11/882,677 priority patent/US20080004324A1/en
Priority to US11/882,688 priority patent/US20080051440A1/en
Priority to US11/882,678 priority patent/US20080051439A1/en
Priority to US11/882,741 priority patent/US20080003306A1/en
Priority to US11/882,740 priority patent/US20080004322A1/en
Priority to US11/882,687 priority patent/US20080004254A1/en
Priority to US12/714,503 priority patent/US20100152161A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to novel methods for regulating food intake in human subjects and more particularly to methods of preventing or treating conditions in which weight management is beneficial.
  • the present invention further relates to methods of preventing or reducing weight gain associated with drug treatment, smoking cessation and the like.
  • Obesity is a chronic, complex, multi-factorial disease, involving social, cultural, genetic, physiological and psychological components, and is associated with substantially increased morbidity and mortality. Over-nutrition is attributed as the cause of about 400,000 deaths a year in the USA (Mokdad, 2004), and may considered to be an epidemic. Based on the body-mass index, defined as the ratio of weight and squared height, (ranging normally from 18.5 to 24.9), about one third of the adult population is overweight (an index of from 25 to 29.9), and more than one quarter is obese (index greater than 30)( National Center for Health Statistics, 2000). Environmental and behavioral changes brought about by economic development and modernization have been linked to the rise in global obesity.
  • the environmental factors which foster the tendency toward obesity include lack of physical activity combined with high-calorie foods.
  • the prevalence of overweight and obesity is increasing worldwide at an alarming rate in both developing and developed countries, in children and adults, men and women.
  • the number of overweight and obese people has continued to increase since 1960, a trend that is not slowing down.
  • NHANES National Health and Nutrition Examination Survey
  • Weight gain has also been found to occur as a result of various factors, including, for example, use of certain drugs, cessation of smoking, and advent of a holiday season.
  • Drugs which are known to cause weight gain include antipsychotics, particularly atypical antipsychotics; antidepressants, particularly the tricyclic antidepressants; mood-stabilizers; calcium channel blockers; anti-convulsants; proton pump inhibitors; antidiabetic agents; antihypertensives; and hormones.
  • Certain selective serotonin-reuptake inhibitors (SSRIs) also have an effect on weight gain, although other SSRIs, such as, sertraline, sibutramine and fluoxetine, often have the opposite effect, and are, in fact, used as appetite suppressants.
  • Weight gain associated with use of certain drugs may significantly affect patient compliance with the drug administration regime.
  • Certain drug categories such as the SSRIs and tricyclic antidepressants, cause—food cravings,—. Furthermore, such drugs may stimulate appetite by blocking of histamine receptors. For example, it has recently been shown that atypical antipsychotics, such as olanzapine and clozapine, as well as tricyclic and tetracylic antidepressants, such as amitriptyline and mirtazapine, respectively, which are potent H 1 antagonists, have a high propensity to induce weight gain ( Wirshing 1999).
  • Atypical antipsychotics have been frequently cited as causing a higher increase in weight gain than conventional antipsychotics (see, for example, Bustilllo, 1996). Weight gain was found to be greatest with clozapine, olanzapine, risperidone, and quetiapine, and less with aripiprazole and ziprasidone, and an additive effect on weight gain was found to occur in patients treated with antipsychotic medications and concomitantly with a drug from another class which may cause weight gain through a different mechanism, such as valproate ( Kane, 2003).
  • Weight gain with clozapine and olanzapine was found to persist for up to 30 weeks of treatment, and to be associated with a higher mean weight gain than for risperidone, haloperidol and sertindole ( Wirshing, 2004). Risperidone-treated patients were found to gain weight for an initial 8-week period and then reach plateau level. Weight gain was also found to be more problematic for children and adolescents than for adults.
  • Antipsychotic drugs have multiple effects on neurotransmitter systems, which in turn have a range of effects on energy homeostasis. Most of the antipsychotics work through some degree of dopamine blockade ( Wirshing, 2004), but modulation of the serotogenic, histaminergic, and adrenergic systems, all of which have potential impact on weight regulation, may also be involved. Most of the atypical antipsychotics work through a combination of receptor systems. Olanzapine and clozapine have the highest affinity for the H 1 receptor of all the atypical antipsychotics, and are also associated with the highest weight gain. A logarithmic relationship between H1 receptor affinity and weight gain has been demonstrated ( Wirshing, 1999).
  • atypical antipsychotics exhibit activity at several serotonin receptor subtypes, including the 5-HT 2C subtype, which appears to mediate some effects on appetite.
  • Olanzapine and clozapine both have high affinities for 5-HT 2A , 5-HT 2C , H 1 -histaminergic, and M 1 -muscarinic receptors.
  • Clozapine also has high affinity for ⁇ 1 -adrenergic receptors.
  • Ziprasidone which is associated with minimal weight gain, has more serotogenic and less adrenergic, histaminic and muscarinic receptor affinity.
  • Quetiapine has relatively high affinity for histamine receptors; risperidone has modest H 1 affinity, but notable affinity for 5-HT 2A and 5-HT 2C receptors. There are also endocrine effects of atypical antipsychotics, which presumably also play a role in weight gain.
  • a dual effect of the atypical antipsychotics in weight gain has been proposed: one, appetite stimulation by a direct effect on the brain, that may be observable in the short term; and second, a delayed endocrine/metabolic dysfunction that promotes fat deposition ( Baptista, 2004). Involvement of the cytokine peptides leptin and tumor necrosis factor (TNF)- ⁇ in anti-psychotic-induced weight gain has also been suggested.
  • TNF tumor necrosis factor
  • atypical antipsychotics has also been found to place patients at risk for various metabolic disorders, including metabolic syndrome, which results in weight gain, as well as in hypertriglyceridemia, and in increased insulin, glucose, and low-density lipoprotein cholesterol levels ( Lieberman, 2004).
  • metabolic syndrome which results in weight gain, as well as in hypertriglyceridemia, and in increased insulin, glucose, and low-density lipoprotein cholesterol levels
  • clozapine and olanzapine treatment are associated with an increased risk of diabetes mellitus and dyslipidemia.
  • risperidone and quetiapine A smaller effect is observed with risperidone and quetiapine.
  • Dyslipidemia is most often associated with clozapine and olanzapine, and is primarily seen as an increase in triglyceride levels, but may also manifest as increased total cholesterol, LDL-cholesterol and decreased HDL-cholesterol ( Barrett, 2004).
  • nicotine is an appetite suppressant. Nicotine stimulates release of adrenaline, which acts upon the liver to step-up the breakdown of glycogen so that more glucose will be liberated into the blood. Nicotine also affects release of insulin, which controls glucose levels in the blood. Hence, nicotine causes slight hyperglycemia, and as a result, the body and brain may slow down the hormones and other signals that trigger feelings of hunger.
  • a subject suffering from nicotine withdrawal may turn to food for emotional comfort. Also, since smoking dulls the taste buds, food begins to taste better to new non-smokers, which can lead to increased food intake. Weight gain may also be caused by drugs prescribed to assist in smoking cessation. Anti-smoking medications include ZybanTM (bupropion hydrochloride).
  • Such weight gain is greater during holidays, such as religious or national holidays, which are associated with consumption of specific foods or festive meals. Examples of such holidays include Thanksgiving, Christmas, and Passover.
  • Medications currently approved for weight loss in the United States fall into two categories: those that decrease food intake by reducing appetite or increasing satiety (appetite suppressants), and those that decrease nutrient absorption.
  • a potentially third category medications increasing energy expenditure, such as ephedrine, is not currently approved for treating obesity in the United States.
  • appetite suppressants work primarily by increasing the availability of anorexigenic neurotransmitters—notably norepinephrine, serotonin, dopamine, or some combination of these neurotransmitters—in the central nervous system.
  • Noradrenergic drugs available in the United States include phentermine, diethylpropion, phendimetrazine, and benzphetamine. Some of these drugs are considered by the Drug Enforcement Administration (DEA) to have a potential for abuse. Amphetamines, which are considered to have a particularly high potential for abuse are no longer recommended for weight loss for this reason.
  • DEA Drug Enforcement Administration
  • Amphetamines which are considered to have a particularly high potential for abuse are no longer recommended for weight loss for this reason.
  • the Food and Drug Administration (FDA) approves the medications for use of “a few weeks” only (generally presumed to be 12 weeks or less) for the treatment of obesity.
  • noradrenergic medications include insomnia, dry mouth, constipation, euphoria, palpitations, and hypertension ( Physicians' Desk Reference, 2001).
  • Serotonergic agents act by increasing the release of serotonin, inhibiting its reuptake, or both.
  • Fenfluramine (PondiminTM) and dexfenfluramine (ReduxTM), medications that both stimulate serotonin release and inhibit its reuptake, were withdrawn from the market in the United States in 1997 because of associations with valvular heart disease and pulmonary hypertension.
  • Some selective serotonin-reuptake inhibitors have induced weight loss in short-term studies, and fluoxetine (Prozac) has undergone considerable evaluation to determine its efficacy for weight loss ( Goldstein, 1993). However, after initial weight loss, steady regain was observed in later stages of the treatment ( National Task Force on the Prevention and Treatment of Obesity ).
  • Sertraline (ZoloftTM), evaluated as an adjunct for weight maintenance after a very-low-calorie diet, showed a similar lack of long-term efficacy ( Wadden, 1995).
  • Sibutramine (MeridiaTM, ReductilTM), an inhibitor of both norepinephrine reuptake and serotonin reuptake that also weakly inhibits dopamine reuptake, is approved by the FDA for weight loss and weight maintenance in conjunction with a reduction diet. Side effects of sibutramine include increased blood pressure and pulse frequency rate ( McMahon, 2000).
  • Rimonabant which is claimed to stop food cravings, represents a new class of drugs that inhibit the activity of the CB1 receptor.
  • the CB1 receptor forms a part of the endocannabinoid system.
  • the CB1 receptor has been found in the brain, fat cells and other parts of the body, and has been associated with regulating food intake and with tobacco dependency ( Pi - Sunyer et al., 2004).
  • the endocannabiniod system helps to regulate pleasure, relaxation, and pain tolerance. Little is currently known about the long-term effects of inhibition of this system.
  • neurologists point out that the endocannabinoid system helps to protect the brain under some circumstances (such as stroke and head injury,) such that brain damage in these circumstances might be worse in patients taking drugs that block the endocannabiniod system.
  • the Rimonabant drug is currently undergoing phase III clinical trials. Presently reported side effects associated therewith include anxiety, nausea and diarrhea.
  • Histamine a potent bioactive substance that has been studied for nearly a century, is an aminergic neurotransmitter.
  • Histamine receptors Four histamine receptors have been identified: H 1 , H 2 , H 3 , and H 4 , leading to the discovery and therapeutic use of potent receptor antagonists.
  • H 1 , H 2 , H 3 , and H 4 leading to the discovery and therapeutic use of potent receptor antagonists.
  • Activation of the H 1 receptor is associated with effects on smooth muscle and central neurons; activation of the H 2 receptor stimulates acid secretion in the stomach, while activation of the H 3 receptor results in a pre-synaptic autoregulatory effect.
  • Histamine has been implicated, among others, in the regulation of arousal state ( Lin et al., 1990), locomotor activity ( Clapham, 1994), cardiovascular control ( Imamura, 1996), water intake ( Lecklin, 1998), food intake ( Leurs, 1998), and memory formation ( Blandina, 1996). It has been suggested that histaminergic neural circuits arising in the tuberomammilary nucleus and projecting into the satiety centers of the hypothalamus participate in regulation of food intake. Histaminergic neurons project into hypothalamic centers known to participate in food intake i.e.
  • H 1 antagonist resultsed in hyperphagia ( Fukagawa, 1989), and administration of H 3 antagonists led to hypophagia ( Attoub, 2001).
  • the selective histamine H 3 receptor antagonist NNC 38-109 has been reported to increase hypothalamic histamine levels, in parallel with decreases in food intake and body weight, according to studies in intact HEK293 cells expressing human or rat histamine H 3 receptors ( Malmof, 2005).
  • the intrasynaptic concentration of histamine is primarily controlled by feedback signals from presynaptic histamine H 3 receptors that inhibit both the conversion of L-histadine to histamine and the release of histamine into the synaptic clefts.
  • Betahistine is an orally active histamine-like drug extensively used in the symptomatic treatment of vestibular disorders, mainly Menier's disease and vertigo (including vertigo in patients with migraine ( Amelin, 2003), dizziness with recurrent vertigo ( Acta Otolaryngol., 2003), vertigo in patients with vascular and traumatic cerebral injuries ( Gusev, 1998), and benign paroxysmal positional vertigo ( Fujino, 1994)).
  • Studies have shown that betahistine can be further utilized in the treatment of a variety of disorders, including the after-effects of craniocerebral injury and vascular events ( Odinak, 2005), preventing or reducing myocardial infraction after occurrence of coronary occlusion (U.S.
  • Betahistine is a structural analog of histamine, in which the imidazole ring of the histamine is replaced by a pyridine ring. Betahistine is an H 1 receptor agonist, and has been found to exhibit an H 1 -agonism activity of about 0.07 times that of histamine, and to cause hypotensive response, bronchoconstriction, and increased vasopermeability after parenteral administration. Receptor binding studies have also shown that betahistine is a potent H 3 -receptor antagonist. Betahistine is able to cross the blood brain barrier and act centrally by enhancing histamine synthesis is tuberomammillary nuclei of the posterior hypothalamus. Adverse side effected associated with betahistine are typically minor and include skin rashes of various types, urticaria, and itching. Gastric upset, nausea, and headache have also been reported by some patients.
  • H 2 -receptors are not, however, associated with weight change in humans ( Rasmussen, 1993).
  • betahistine when given intraperitoneally, decreased food intake in rats, whereas this effect was not seen when betahistine was given intragastrically ( Szelag, 2002). It was suggested that the effect of betahistine administration on food intake involves increasing histamine synthesis and release as a result of H 3 receptor inhibition. However, since activation of H 2 receptors is known to stimulate hydrochloric acid secretion (see, for example, Clayman, 1977), it was further suggested that the lack of the influence of betahistine on food intake after intragastrical administration may be due to the fact that betahistine increased hydrochloric acid release by activation of H 2 receptors, thereby abolishing the central anorectic activity of betahistine.
  • Lecklin et al. (2002) found that inhibition of histamine catabolism by intraperitoneal injection of metoprine, a histamine-N-methyltransferase inhibitor, resulted in suppressed daily energy intake and ingestion of fat in rats.
  • betahistine is transformed, mainly in the liver, to 2-(2-aminoethyl)-pyridine (AEP) and to 2-(2-hydroxyethyl)-pyridine (HEP), ( Sternoson, 1974) whereas both betahistine and the metabolites bind to histamine receptors.
  • AEP 2-(2-aminoethyl)-pyridine
  • HEP 2-(2-hydroxyethyl)-pyridine
  • the cited references corroborate the complexity of appetite regulation, which includes, among other factors, species specificity and route of administration. It has further been found ( Seifert et al., 2003) that multiple differences exist in agonist and antagonist pharmacology of histamine receptors between different species, such as humans and guinea pigs.
  • the prior art does not teach or suggest the use of H 1 agonists for regulating food intake in humans.
  • the prior art further does not teach or suggest the use of such H 1 agonists that have a pharmacological half life that permits an efficient treatment therewith.
  • the prior art further does not teach or suggest the use of orally administered H 1 agonists for regulating food intake in humans.
  • the present invention successfully addresses the shortcomings of the presently known methods for regulating food intake by providing such methods that utilize H 1 receptor agonists, which are highly efficient in humans, which have a pharmacological half life of at least 3 hours and which are devoid of the limitations of the currently known methods.
  • the present invention further provides methods for preventing or reducing weight gain associated with external factors such as drug treatment, smoking cessation and the like.
  • a method of treating a condition in which regulating a food intake in a human subject is beneficial comprising administering to the subject a therapeutically effective amount of an H 1 agonist, which has a pharmacological half-life of at least 3 hours.
  • the condition is selected from the group consisting of overeating, overweight, obesity, and a disorder caused or exacerbated thereby.
  • the condition caused or exacerbated by the conditions according to this aspect of the present invention may be selected from the group consisting of a muscosceletal disorder, a cardiovascular disorder, a dermatological disorder, a sleep disorder, a metabolic condition, diabetes and a diabetes-related condition.
  • condition is associated with high fat consumption.
  • condition is associated with a psychological factor.
  • the condition according to this aspect of the present invention optionally comprises binge eating disorder, night eating syndrome, obsessive eating, compulsive eating or bulimia.
  • the condition is associated with a drug treatment.
  • the drug may optionally consist of a steroid hormone or a psychoactive drug, as is detailed hereinbelow.
  • a method of improving a compliance of a human subject to caloric restriction comprising administering to the subject a therapeutically effective amount of an H 1 agonist, which has a half-life of at least 3 hours.
  • a method of reducing a desire of a human subject to consume fats comprising administering to the subject a therapeutically effective amount of an H 1 agonist, which has a half-life of at least 3 hours.
  • a method of treating a condition associated with a metabolic derangement in a human subject comprising administering to the subject a therapeutically effective amount of an H 1 agonist which has a half-life of at least 3 hours.
  • the metabolic derangement may be, for example, dyslipidemia, such as hypercholesterolemia or lipemia.
  • metabolic derangement refers to an imbalance in the level of one or more metabolites within a body.
  • a common metabolic derangement is typically associated with an imbalance in the level of metabolites such as cholesterol, including LDL and HDL, triglycerides and the like.
  • a method of reducing total cholesterol level in a human subject comprising administering to the subject a therapeutically effective amount of an H 1 agonist which has a half-life of at least 3 hours.
  • a method of reducing low-density lipoprotein (LDL) cholesterol or increasing high-density lipoprotein (HDL) cholesterol levels in a human subject comprising administering to the subject a therapeutically effective amount of an H 1 agonist which has a half-life of at least 3 hours.
  • LDL low-density lipoprotein
  • HDL high-density lipoprotein
  • a method of reducing triglyceride level in a human subject comprising administering to the subject a therapeutically effective amount of an H 1 agonist which has a pharmacological half-life of at least 3 hours.
  • a method of treating an eating disorder comprising administering to the subject a therapeutically effective amount of an H 1 agonist, said H 1 agonist having a pharmacological half-life of at least 3 hours.
  • the eating disorder can be, for example, bulimia and binge eating disorder.
  • a method of preventing weight gain or reducing weight in a subject comprising administering to the subject a therapeutically effective amount of an H 1 agonist, said H 1 agonist having a pharmacological half-life of at least 3 hours.
  • weight gain prevented or reduced by the method of the present invention may be associated with a drug treatment.
  • the drug may be, for example, an antipsychotic.
  • antipsychotics include, without limitation, selective serotonin-reuptake inhibitors (such as fluvoxamine, escitalopram, citalopram, and paroxetine); monoamine oxidase inhibitors (such as isocarboxazid, phenelzine and tranylcypromine); conventional antipsychotics (such as haloperidol, molindone and thioridazine); and atypical antipsychotics (such as clozapine, olanzapine, risperidone, quetiapine, sertindole, aripiprazole and ziprasidone, or an antagonist of a 5-HT 2A , 5-HT 2C , H 1 -histaminergic or M 1 -muscarinic receptor).
  • selective serotonin-reuptake inhibitors such as fluvoxamine, escitalopram, citalopram, and paro
  • the drug may be an antidepressant.
  • antidepressants include, without limitation, a tricyclic antidepressant (such as amitryptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortryptyline, protriptyline or trimipramine), a tetracyclic antidepressant (such as mirtazapine or maprotiline), a serotonin-norepinephrine reuptake inhibitor (such as venlafaxine or duloxetine); and additional antidepressants such as biproprion hydrochloride, mitrazapine, nefazadone and trazadone.
  • a tricyclic antidepressant such as amitryptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortryptyline, protriptyline or trimipramine
  • the drug may be a mood-stabilizer (such as lithium); a calcium channel blocker (such as diltiazem, nicardipine, verapamil and nimopidipine); an anti-convulsant (such as carbamazepine, divalproex, lamotrigine, sodium valproate, valproic acid, and gabapentin); a proton pump inhibitor (such as omeprazole, esomeprazole, lansoprazole and pantoprazole); an antidiabetic agent (such as a sulfonylurea, including chlorpropamide, glipizide, glyburide, and glimepiride, a meglitinide, a biguanide, a thiazolidinedione, an alpha-glucosidase inhibitor, and insulin); an antihypertensive (such as an alpha-adrenergic blocker, including doxazocin, pr
  • the drug may be a hormone, such as, for example, a steroid hormone.
  • steroid hormones include a corticosteroid (such as a glucocorticoid, including prednisone and cortisol; and a mineralocorticoid, including aldosterone and fludrocortisone); and a sex steroid (such as an androgen, including testosterone and dehydroepiandrosterone; an estrogen, such as estradiol; and a progestagen, such as progesterone or progestin), or mixtures thereof.
  • the sex steroid may comprise estrogen and progestagen, such as provided as an oral contraceptive formulation; or estrogen and progestin, such as used for hormone replacement therapy.
  • weight gain prevented or reduced by the method of the present invention may be due to cessation of smoking.
  • weight gain prevented or reduced by the method of the present invention may occur during a holiday season.
  • the pharmacological half-life of the H 1 agonist ranges from about 3 hours to about 12 hours, preferably from about 3 hours to about 8 hours, more preferably from about 3 hours to about 5 hours.
  • the H 1 agonist is further an H 3 antagonist.
  • the H 1 agonist is characterized by blood brain barrier permeability.
  • the H 1 agonist is selected from the group consisting of betahistine, a betahistine metabolite, a betahistine pharmaceutically acceptable salt, a betahistine prodrug, a betahistine derivative and any combination thereof.
  • the betahistine metabolite is 2-(2-aminoethyl)-pyridine or 2-(2-hydroxyethyl)-pyridine.
  • the betahistine salt is betahistine dihydrochloride, betahistine mesilate, or betahistine trimebutine maleate.
  • the betahistine derivative is selected from the group of compounds represented by the general formula I:
  • administering is effected by a route selected from the group consisting of the oral, transdermal, intravenous, subcutaneous, intramuscular, intranasal, intraauricular, sublingual, rectal, transmucosal, intestinal, buccal, intramedullar, intrathecal, direct intraventricular, intraperitoneal, and intraocular routes.
  • administering is effected by the oral, transdermal, buccal, transmucosal, rectal or sublingual routes. More preferably, administering is effected by the oral, buccal or transdermal routes.
  • the therapeutically effective amount ranges from about 2 mg per day to about 96 mg per say, preferably from about 10 mg per day to about 50 mg per day.
  • administering is effected from about 1 to about 4 times per day, preferably, twice per day.
  • administering is effected according to the development of hunger of the subject.
  • administering is performed such that a decrease of the body weight of the subject that ranges from about 1 to about 5 percent is effected, without restricting the food intake of the subject.
  • such administering is performed such that no down-regulation of H 1 receptors is effected.
  • downstream-regulation refers to a decrease in the responsiveness of the receptor, or to a decrease in the number or density of receptors. Decreasing the responsiveness of a receptor also includes a complete shutdown of the receptor.
  • the H 1 agonist forms a part of a pharmaceutical composition, which further comprises a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier may optionally provide a slow release composition.
  • each of the methods described herein further comprises administering to the subject a therapeutically effective amount of an additional active agent such as, for example, a weight control agent.
  • the weight control agent may be, for example, an appetite suppressant.
  • suitable appetite suppressants include, without limitation, noradrenergic agents, serotonergic agents, dopamingergic agents, endocannabinoid receptor blockers, or combinations thereof.
  • the additional active agent may be a non-steroidal anti-inflammatory drug, a muscle relaxant, an antigout agent, an immunosuppressant, a drug affecting bone mineralization, an angiotensin-converting enzyme inhibitor, an antiarrhythmic drug, an anticoagulant, an antiplatelet, a thrombolytic, a beta-adrenergic blocking drug, a centrally acting drug, a digitalis drug, a nitrate, a peripheral adrenergic antagonist, a vasodilator, an acne medication, an antipruretic agent, an anti-psoriasis agent, an anti-eczema agent, a hypnotic, an anti-histamine, a PPAR-gamma antagonist, insulin, a fibrate, an HMG-CoA reductase inhibitor, a bile acid sequestrant, a cholesterol absorption inhibitor, nicotinic acid, a derivative, analog and metabolit
  • the additional active agent may be a nutritional supplement.
  • a nutritional supplement is Histidine (Kasaoka S. Nutrition 20:991-996(2004).
  • the methods described herein are used for inducing weight loss.
  • these methods are used for maintaining weight loss or preventing a weight gain after or during a weight reducing diet.
  • these methods are used for preventing weight gain in a subject having a condition associated with weight gain.
  • the H 1 agonist is preferably not used for treating patients also having a medical condition that has previously been described as treatable by such an agonist.
  • the subjects treated by any of the methods described herein are preferably subjects that do not also suffer from a condition that has already been described in the art as treatable by the H 1 agonist described herein.
  • Such conditions include, for example, Menier's disease, vertigo, seasickness, the after-effects of craniocerebral injury and vascular events, myocardial infraction after occurrence of coronary occlusion, multiple sclerosis, cutaneous hypersensitivity in patients with grass pollen allergy, arteriosclerotic dementia, acute deafness, and vertebral-basilar insufficiency.
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
  • treating includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.
  • the term “preventing” includes barring an organism from acquiring a condition in the first place.
  • regulating with regard to food intake refers to controlling or adjusting the food intake to a desired level.
  • composition or method may include additional ingredients and/or steps, but only if the additional ingredients and/or steps do not materially alter the basic and novel characteristics of the claimed composition or method.
  • terapéuticaally effective amount denotes that dose of an active ingredient or a composition comprising the active ingredient that will provide the therapeutic effect for which the active ingredient is indicated.
  • agonist describes a substance that is capable of binding to a receptor on a cell and thereby initiating a physiological activity or pathway.
  • H 1 -receptor agonist and “H 1 agonist” are used herein interchangeably.
  • the term “antagonist” describes a substance that acts within the body to reduce the physiological activity of another substance.
  • the phrase “pharmacological half-life” describes the time required for half the quantity of a drug or other substance deposited in a living organism to be metabolized or eliminated from the plasma by normal biological processes. This phrase is also referred to herein interchangeable as “half life”.
  • a “pharmaceutical composition” refers to a preparation of one or more of the active ingredients described herein, either compounds or physiologically acceptable salts thereof, with other chemical components such as traditional drugs, physiologically suitable carriers and excipients.
  • the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • physiologically suitable carrier and “pharmaceutically acceptable carrier” are interchangeably used and refer to an approved carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered conjugate.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered.
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate processes and administration of the active ingredients.
  • a compound or “at least one compound” may include a plurality of compounds, including mixtures thereof.
  • FIGS. 1 a - b present results obtained in prior art studies, demonstrating the effect of Metoprine treatment on the total caloric intake ( FIG. 1 a ) and the fat intake ( FIG. 1 b ) in rats;
  • FIGS. 2 a - b present results obtained in prior art studies, demonstrating the effect of Metoprine treatment on the total caloric intake, compared with the carbohydrate intake ( FIG. 2 a ) and the protein intake ( FIG. 1 b ) in rats;
  • FIG. 3 presents plots demonstrating the effect of overweight (expressed as the body mask index) on the relative risk of death from cardiovascular disease (dotted line), cancer (dashed line) and other causes in men (upper plots) and women (bottom plots);
  • FIG. 4 is a bar graph presenting the effect of oral administration of betahistine (blue bars) and a placebo (yellow bars) on the total caloric intake of humans following 14 days and 28 days of treatment;
  • FIG. 5 is a bar graph presenting the effect of oral administration of betahistine (blue bars) and a placebo (yellow bars) on the fat, carbohydrate and protein intake of humans following 14 days and 28 days of treatment; and
  • FIG. 6 is a bar graph presenting the effect of oral administration of betahistine (blue bars) and a placebo (yellow bars) on the weight change in humans following 14 days and 28 days of treatment.
  • the present invention is of novel methods for regulating food intake in a human subject; for improving a compliance of a human subject to caloric restriction; and for reducing a desire of a human subject to consume fats, all of which utilize H 1 -receptor agonists that have a pharmacological half-life that allows an efficient treatment regime thereof.
  • the present invention further provides a method for preventing or reducing weight gain in a human subject, by administration of H 1 -receptor agonists that have a pharmacological half-life that allows an efficient treatment regime thereof.
  • appetite suppressants are known to have a potential for abuse. Furthermore, these appetite suppressants are associated with various side effects, ranging from insomnia, dry mouth, constipation, euphoria, palpitations and hypertension, to valvular heart disease and pulmonary hypertension. In addition, many of these agents have been found to show a lack of long-term efficacy, with steady weight-gain occurring after initial weight loss.
  • histamine is extremely inefficient in its centrally mediated anti-obesity action because exogenous histamine poorly penetrates the blood brain barrier. Histamine has therefore been administered as an appetite suppressant hitherto by intracerebroventicular injection. Similarly, systemic administration of histamine would be expected to have little affect on the desire of a human subject to consume fats.
  • histamine has a pharmacological half-life of only a few minutes. Therefore, the duration of action of the drug is very short, and it would need to be administered frequently in order to build up and maintain a high enough concentration in the blood to be therapeutically effective. A drug having a longer half life would therefore require less frequent administration, which may lead to increased patient compliance with the dosing regime. This may also result in fewer side effects, as peaks and troughs of the level of the drug in the bloodstream of the patient may be decreased, leading to a more even drug level in the blood over a period of time.
  • H 1 -receptor agonists While several studies have suggested a role for H 1 -receptor agonists other than histamine in regulating food intake, none of these studies has established a direct effect of such agonists on food intake in humans.
  • H 1 -agonists which are characterized by relatively long half-life, particularly as compared with histamine, can be efficiently utilized for regulating food intake in humans. More specifically, it was found that betahistine, a presently known and approved drug for treating Menier's disease and associated conditions, and which has a half-life of about 3.5 hours, efficiently affects food intake and caloric intake and reduces weight, as well as fat consumption, in obese female subjects. As is exemplified in the Examples section that follows, in a randomized placebo controlled double-blinded study, it was found that betahistine hydrochloride decreased appetite, increase satiety lowered food intake and particularly affected fat consumption.
  • an H 1 receptor agonist that has a pharmacological half life that permits reasonable and efficient treatment therewith (e.g., of at least 3 hour) can be beneficially used for regulating food intake and caloric intake in a human subject and hence for treating medical and psychological conditions associated with overweight.
  • betahistine, as well as other H 1 receptor agonists decrease food intake by a different mode of action than the currently used anti-obesity medications.
  • a method of treating of a condition in which regulating a food intake in a human subject is beneficial which is effected by administering to the subject a therapeutically effective amount of an H 1 agonist that has a pharmacological half-life of at least 3 hours.
  • treatment also includes amelioration or alleviation of a pathological condition and/or one or more symptoms thereof, curing such a condition, or preventing the genesis of such a condition.
  • the pharmacological half-life of the H 1 agonist utilized in this and other aspects of the present invention preferably ranges from about 3 hours to about 12 hours, more preferably from about 3 hours to about 8 hours, and even more preferably from about 3 hours to about 5 hours.
  • Such a pharmacological half life is highly advantageous since, as is discussed hereinabove, such a drug remains in the blood for longer periods than, for example, histamine, achieving steadier blood levels, and therefore fewer side effects.
  • the H 1 agonist of the present invention therefore needs to be administered far less frequently than, for example, histamine, which has a half life of only about 2 minutes. Since, as is known in the art, 97% of a drug is eliminated after 5 half lives, the administration should be repeated at intervals of less than 5 half lives, and usually less, depending on various parameters, including the clearance rate and the initial concentration administered.
  • the choice of the dosage interval usually represents a compromise between the desirability of minimizing the variations of effectiveness between doses and patient inconvenience from too frequent dosing, which results in poor compliance. Dosage regimes of one or two administrations per day are considered optimal.
  • Using a drug having a half life within the above cited range allows for selecting the administration times so as to ensure maximal effectiveness of the drug at times of day when the effect is most required, such as at known meal times, periods of the day at which the subject most commonly experiences significant levels of hunger, etc., and to be least effective at times of day when no effect is necessary, such as, for example, during periods when the subject is expected to be asleep.
  • Drugs having a very long half life have the disadvantage that once or twice daily administration is clearly not possible. Less than daily administration is associated with poor patient compliance, as the subject tends to forget the necessity to take a medication which is not part of his daily routine.
  • the histamine-N-methyltransferase inhibitor, metoprine which, as discussed above, has been shown to decrease food intake in rats, both by intraperitoneal injection and by central infusion, has a half life of 216 hours. Furthermore, the issue of toxicity must be considered with drugs having such long half lives.
  • H1 agonists may lead to downregulation of the H1 receptor.
  • Downregulation of a particular receptor after continuous activation can result in decreased response to agonist administration, due to adaptive changes in the receptors that limit their subsequent responsiveness, or to decrease in the number or density of receptors.
  • These receptor-specific changes include a rapid uncoupling of receptors from activation of their cognate G proteins, mediating functional desensitization; a rapid redistribution of receptors into relatively inaccessible compartments in the plasma membrane or inside the cell, variously referred to as sequestration, endocytosis, or internalization; with prolonged agonist exposure, termed down-regulation.
  • the H 1 agonist of the present invention is preferably also an H 3 antagonist.
  • H 3 antagonists have been shown to have an effect on regulation of food intake. It has been suggested that the inhibition of H 3 receptor activity increases histamine release and synthesis. Histamine subsequently increases histaminergic neuron activity via H 1 receptors and in this way inhibit food intake.
  • H 3 receptors are located not only on histaminergic neurons, but also nonhistaminergic neurons as heteroreceptors, and modulate the release of 5-HT and noradrenaline. Thus, the effects of H 3 ligands on food intake may express through other endogenous substances ( Morimoto et al., 2001).
  • the H 1 agonist is characterized by blood brain barrier permeability, and therefore is able to cross the blood brain barrier and enter brain tissue, thereby acting on central H 1 and H 3 receptors.
  • This enables the agonist to be administered by the systemic route, in contrast to, for example, histamine, which has very poor blood brain barrier permeability and has therefore previously been administered as an appetite suppressant by intracerebroventicular injection.
  • the H 1 agonist of the present invention can be administered as any pharmaceutically acceptable salt, such as, for example, dihydrochloride, mesilate, or trimebutine maleate.
  • the drug can be administered as any metabolite, prodrug, or derivative, or combination thereof.
  • phrases “pharmaceutically acceptable salt” refers to a charged species of the parent compound and its counter ion, which is typically used to modify the solubility characteristics of the parent compound and/or to reduce any significant irritation to an organism by the parent compound, while not abrogating the biological activity and properties of the administered compound.
  • prodrug refers to an agent, which is converted into the active compound (the active parent drug) in vivo.
  • Prodrugs are typically useful for facilitating the administration of the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • the prodrug may also have improved solubility as compared with the parent drug in pharmaceutical compositions.
  • metabolite describes the actual active moiety of the compound which is formed as a result of metabolitic processes that occur in vivo upon administration of the compound.
  • derivative describes the result of chemically altering, modifying or changing a compound or a portion thereof, such that it maintains its original functionality in at least one respect.
  • the H 1 agonist is betahistine.
  • Betahistine is a structural analog of histamine, which has been shown to have a binding affinity profile which is qualitatively close to that of histamine for both H 1 and H 3 receptors ( Fossati et al., 2001). Furthermore, it is pharmacologically relevant, since pharmacokinetic data have shown that therapeutic dosages of betahistine in humans give plasma concentrations which fall in the same range as its affinities for H 1 and H 3 receptors. The pharmacological relevance of betahistine for H 1 receptors is further confirmed in vivo in animals and humans, attributable to the increased blood flow in microcirculation in the auditory and internal vestibular system ( Meyer et al., 1974). Since betahistine has already been widely used for treating vertigo and other disorders, it has been tested and is approved for use in human medicine.
  • Betahistine is readily absorbed through the oral route and is converted to at least two metabolites, 2-(2-aminoethyl)-pyridine and 2-(2-hydroxyethyl)-pyridine. Betahistine has an elimination half life time of 3.5 hours, and most of the dose is excreted via the urine as metabolites. Hence, betahistine may be administered according to a convenient dosage regime, as discussed above.
  • betahistine The side effects associated with betahistine are minor, consisting mainly of skin rashes of various types, urticaria, itching, gastric upset, nausea, headache, and exacerbation of symptoms in patients with a history of peptic ulcer.
  • Betahistine can be utilized in this and other aspects of the present invention either per se or as a metabolite, a pharmaceutically acceptable salt, a prodrug or a derivative thereof.
  • Betahistine metabolites that can be efficiently used in the context of the present invention include, for example, 2-(2-aminoethyl)-pyridine and 2-(2-hydroxyethyl)-pyridine. As is further described in the art (see, for example, Fossati et al., 2001) these metabolites are also characterized by H 1 -receptor agonist activity and therefore can also be utilized in the various aspects of the present invention.
  • betahistine pharmaceutically acceptable salts that can be efficiently used in the context of the present invention include, without limitation, betahistine hydrochloride, betahistine dihydrochloride, betahistine mesilate, and betahistine trimebutine maleate.
  • Betahistine derivatives that are suitable for use in the context of this and other aspects of the present invention include, for example, compounds having the general Formula I:
  • each of R 1 -R 12 is preferably independently selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl and any combination thereof.
  • each of R 1 -R 12 can also be selected from other substituents, as long as features such as the blood brain barrier permeability, the half life and the binding to the H 1 -receptor of the compound are not adversely affected.
  • each of R 1 -R 12 can be further independently selected, for example, from alkenyl, alkynyl, alkoxy, aryloxy, hydroxy, thiohydroxy, thioalkoxy, thioaryloxy, halide, amino, nitro, cyano, carbonyl, C-carboxy, O-carboxy, C-carmabyl, N-carbamyl, sulfonyl, sulfinyl, sulfonamide, urea, thiourea, guanidine, guanyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, N-sulf
  • alkyl refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups.
  • the alkyl group has 1 to 20 carbon atoms. Whenever a numerical range; e.g., “1-20”, is stated herein, it implies that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. More preferably, the alkyl is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, unless otherwise indicated, the alkyl is a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be substituted or unsubstituted.
  • a “cycloalkyl” group refers to an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group wherein one of more of the rings does not have a completely conjugated pi-electron system.
  • examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, cycloheptane, cycloheptatriene, and adamantane.
  • a cycloalkyl group may be substituted or unsubstituted.
  • alkenyl refers to an alkyl group which consists of at least two carbon atoms and at least one carbon-carbon double bond.
  • alkynyl group refers to an alkyl group which consists of at least two carbon atoms and at least one carbon-carbon triple bond.
  • aryl group refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted.
  • 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.
  • heteroaryl groups include pyrrole, furane, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine.
  • a “heteroalicyclic” group refers to a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, oxygen and sulfur.
  • the rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system.
  • the heteroalicyclic may be substituted or unsubstituted. Representative examples are piperidine, piperazine, tetrahydrofurane, tetrahydropyrane, morpholino and the like.
  • a “hydroxy” group refers to an —OH group.
  • alkoxy refers to both an —O-alkyl and an —O-cycloalkyl group, as defined herein.
  • aryloxy refers to both an —O-aryl and an —O-heteroaryl group, as defined herein.
  • a “thiohydroxy” group refers to a —SH group.
  • a “thioalkoxy” group refers to both an —S-alkyl group, and an —S-cycloalkyl group, as defined herein.
  • a “carbonyl” group refers to a —C( ⁇ O)—R′ group, where R′ is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) or heteroalicyclic (bonded through a ring carbon) as defined herein.
  • a “thiocarbonyl” group refers to a —C( ⁇ S)—R′ group, where R′ is as defined herein for R′.
  • C-carboxy refers to a —C( ⁇ O)—O—R′ group, where R′ is as defined herein.
  • An “O-carboxy” group refers to an R′C( ⁇ O)—O— group, where R′ is as defined herein.
  • a “halide” group refers to fluorine, chlorine, bromine or iodine.
  • a “sulfinyl” group refers to an —S( ⁇ O)—R′ group, where R′ is as defined herein.
  • a “sulfonyl” group refers to an —S( ⁇ O) 2 —R′′ group, where R′ is as defined herein.
  • S-sulfonamido refers to a —S( ⁇ O) 2 —NR′R′′ group, with R′ is as defined herein and R′′ is as defined for R′.
  • N-sulfonamido refers to an R′S( ⁇ O) 2 —NR′′ group, where R′ and R′′ are as defined herein.
  • An “O-carbamyl” group refers to an —OC( ⁇ O)—NR′R′′ group, where R′ and R′′ are as defined herein.
  • N-carbamyl refers to an R′OC( ⁇ O)—NR′— group, where R′ and R′′ are as defined herein.
  • O-thiocarbamyl refers to an —OC( ⁇ S)—NR′R′′ group, where R′ and R′′ are as defined herein.
  • N-thiocarbamyl refers to an R′′OC( ⁇ S)NR′— group, where R′ and R′′ are as defined herein
  • amino refers to an —NR′R′′ group where R′ and R′′ are as defined herein.
  • C-amido refers to a —C( ⁇ O)—NR′R′′ group, where R′ and R′′ are as defined herein.
  • N-amido refers to an R′C( ⁇ O)—NR′′ group, where R′ and R′′ are as defined herein.
  • a “urea” group refers to an —NR′C( ⁇ O)—NR′′R′′′ group, where R′ and R′′ are as defined herein and R′′′ is defined as either R′ or R′′.
  • a “guanidino” group refers to an —R′NC( ⁇ N)—NR′′R′′′ group, where R′, R′′ and R′′′ are as defined herein.
  • a “guanyl” group refers to an R′R′′NC( ⁇ N)— group, where R′ and R′′ are as defined herein.
  • a “nitro” group refers to an —NO 2 group.
  • a “cyano” group refers to a —C ⁇ N group.
  • phosphonyl describes a —O—P( ⁇ O)(OR′)(OR′′) group, with R′ and R′′ as defined hereinabove.
  • phosphinyl describes a —PR′R′′ group, with R′ and R′′ as defined hereinabove.
  • thiourea describes a —NR′—C( ⁇ S)—NR′′R′′′ group, with R′ and R′′ as defined hereinabove and R′′′ as defined herein for R′ and R′′.
  • the H 1 agonist can be administered by any route selected from the oral, transdermal, intravenous, subcutaneous, intramuscular, intranasal, intraauricular, sublingual, rectal, transmucosal, intestinal, buccal, intramedullar, intrathecal, direct intraventricular, intraperitoneal, or intraocular routes.
  • the route of administration is selected from the oral, transdermal, buccal, transmucosal, rectal or sublingual routes. More preferably, the H 1 agonist is administered using the oral, buccal or transdermal route.
  • the H 1 agonist is optionally and preferably administered as a total dose of from about 2 mg to about 96 mg per day. More preferably, the total dose is from about 5 mg to about 50 mg per day, more preferably from about 10 mg to about 50 mg, more preferably from about 16 mg to about 48 mg and most preferably it is from about 24 mg to 48 mg.
  • the H 1 agonist is preferably administered once or several times a day, for example from about 1 to about 4 times per day, and, more preferably, twice per day.
  • the H 1 agonist may be administered according to the development of hunger of the subject.
  • a treatment regime is performed such that upon repetitious administration, a decrease of the body weight of the subject that ranges from about 1 to about 5 percent is effected, without restricting the food intake of the subject.
  • a more preferred treatment regime according to the present invention is performed such that such a decrease in a body weight is achieved without effecting downregulation of the H 1 receptor.
  • Such a treatment regime can be designed by adjusting the dosing and the administration intervals to the half life of the selected H1 agonist.
  • the dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl, et al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch. 1 p. 1). Dosage amount and interval may be adjusted individually to provide plasma levels of the H 1 agonist which are sufficient to maintain the regulating effects.
  • the daily dosage range is from 24 to 48 mg, administered orally in divided doses.
  • the 8 mg tablet is administered as 1 to 2 tablets 3 times daily
  • the 16 mg tablet is administered as 0.5 to 1 tablet 3 times daily.
  • the H 1 agonist of the present invention may optionally be administered in the form of a slow-release preparation, having a reduced rate of release of the active substance, in order to further increase patient convenience and compliance and optionally the efficiency of the active agent.
  • the slower the rate of release the less the blood concentrations fluctuate within a dosing interval. This enables higher doses to be given less frequently, while maintaining therapeutic concentrations over prolonged periods.
  • slow-release preparations are beneficial in reducing potential side-effects of the active ingredient due to transiently high peak blood concentrations being reached soon after administration.
  • Slow release preparations typically include slow release biodegradable carriers.
  • Slow release biodegradable carriers are well known in the art. These are materials that may form particles that may capture therein an active compound(s) and slowly degrade/dissolve under a suitable environment (e.g., aqueous, acidic, basic, etc.) and thereby degrade/dissolve in body fluids and release the active compound(s) therein.
  • the particles are preferably nanoparticles (i.e., in the nanometer range, e.g., in the range of about 1 to about 500 nm in diameter, preferably about 50-200 nm in diameter, most preferably about 100 nm in diameter).
  • the rate at which a drug is released is generally dependent on the rate at which the dosage form disintegrates or dissolves.
  • Disintegration greatly increases the drug's surface area in contact with GI fluids, thereby promoting drug dissolution and absorption.
  • Disintegrants and other excipients e.g., diluents, lubricants, surfactants, binders, dispersants
  • Surfactants increase the dissolution rate by increasing the wettability, solubility, and dispersibility of the drug.
  • Disintegration of solid forms may be retarded by excessive pressure applied during the tableting procedure or by special coatings applied to protect the tablet from the digestive processes of the gut.
  • Hydrophobic lubricants e.g., magnesium stearate
  • Dissolution rate determines the availability of the drug for absorption. When slower than absorption, dissolution becomes the rate-limiting step. Overall absorption can be controlled by manipulating the formulation. For example, reducing the particle size increases the drug's surface area, thus increasing the rate and extent of GI absorption of a drug whose absorption is normally limited by slow dissolution. Dissolution rate is affected by whether the drug is in salt, crystal, or hydrate form.
  • Oral slow-release forms are often designed to maintain therapeutic drug concentrations for greater than 12 hours.
  • the absorption rate can be controlled by coating drug particles with wax or other water-insoluble material, by embedding the drug in a matrix from which it is released slowly during transit through the GI tract, or by complexing the drug with ion-exchange resins.
  • a slow-release formulation in tablet form may be based on the use of a hydrophilic polymer which swells in contact with gastrointestinal fluids, to form a gel, which creates a barrier that enrobes the tablet.
  • the barrier limits physical exchanges between the inside of the tablet and the surrounding medium. As a consequence, intrusion of water towards the tablet matrix and diffusion of drug are slowed down, allowing a controlled slow release of the drug.
  • polymers may be used as a matrix for the slow-release of drugs, such as polyvinyl chloride, polyethylene polyamides, ethylcellulose, silicone, poly (hydroxyethyl methacrylate), other acrylic co-polymers, and polyvinylacetate-polyvinyl chloride copolymers.
  • a slow-release formulation for delivery of the H 1 agonist of the present invention provides for release over a period that ranges from about 2 hour to about 24 hours, preferably from about 4 hours to about 24 hours and hence, for release over a period of at least 4 hour, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 13 hours, at least 14 hours, at least 15 hours, at least 16 hours, at least 17 hours, at least 18 hours, at least 19 hours, at least 20 hours, at least 21 hours, at least 22 hours, at least 23 hours, or at least 24 hours.
  • such a slow-release formulation provides for release of the H 1 agonist over a period of more than 24 hours and up to 48 hours.
  • the method according to this aspect of the present invention can thus be efficiently used for treating any condition in which regulating food intake is beneficial. These include, for example, overeating, overweight, obesity, and disorders caused or exacerbated thereby.
  • Diseases caused by or exacerbated by these conditions include, for example, muscosceletal disorders (such as osteoarthritis, spine-related pains, etc.), cardiovascular disorders (such as hypertension, arteriosclerosis, etc.), dermatological disorders (such as fungal and other infections), sleep disorder (such as snoring and obstructive sleep apnea), metabolic conditions (dyslipidemia, lipemia or hypercholesterolemia), diabetes and diabetes-related problems, as well as cancer (particularly breast, prostate and colon cancer).
  • muscosceletal disorders such as osteoarthritis, spine-related pains, etc.
  • cardiovascular disorders such as hypertension, arteriosclerosis, etc.
  • dermatological disorders such as fungal and other infections
  • sleep disorder such as snoring and obstructive sleep apnea
  • metabolic conditions dyslipidemia, lipemia or hypercholesterolemia
  • diabetes and diabetes-related problems as well as cancer (particularly breast, prostate and colon cancer).
  • FIG. 3 The
  • cardiovascular disease increases significantly in overweight subjects, both male and female, as compared to those within the normal body-mass index range (i.e. from 18.5 to 24.9).
  • a further sharp increase is observed in subjects classified as obese (i.e. having body mass of greater than 30).
  • an increase in the relative risk of death from cancer is seen in overweight subjects, particularly in obese subjects, with a greater increase amongst females. The relative risk of death from other causes is seen to increase sharply in obese individuals.
  • Additional conditions that are treatable by the method according to this aspect of the present invention include, for example, conditions that are associated with a psychological factor, such as binge eating disorder, night eating syndrome, obsessive eating, compulsive eating and bulimia.
  • Bulimia is a psychological condition in which the subject engages in recurrent binge eating followed by intentionally doing one or more of the following in order to compensate for the intake of the food and prevent weight gain: vomiting; inappropriate use of laxatives, enemas, diuretics or other medication; excessive exercising; fasting.
  • Some anorectics may demonstrate bulimic behaviors in their illness: binge-eating and purging themselves of food on a regular or infrequent basis at certain times during the course of their disease. Bulimia may occur without the serious weight loss which is symptomatic of anorexia.
  • An increase in binge eating has been reported amongst patients receiving atypical antipsychotics ( Theisen, 2003), apparently as a result of attempts to compensate for weight gain induced by the antipsychotic.
  • betahistine to avoid this weight gain may therefore be beneficial in preventing the resulting compensatory behavior which leads to bulimia. Furthermore, the reduction in appetite resulting from administration of betahistine further contributes to the prevention of the overeating/purging cycle which characterizes bulimia.
  • H 1 agonist described herein interferes with appetite-stimulating histaminergic activity of steroidal or anti-psychotic drugs.
  • Peptide YY is a peptide with 36 amino acids that originates from the intestine. Studies have shown that elevated PYY levels were detected in patients suffering from eating disorders ( Hagan, 2002). In addition, thioperamide, an H 3 antagonist, has been shown to block the ability of increased levels of PYY to increase food consumption ( Itoh, 1999). Since H 3 antagonists increase neuronal histamine levels and since this increased histamine binds to H 1 receptors, the H 1 agonist described herein can be further efficiently used in treating such eating disorders via its histaminergic activity.
  • a method of treating an eating disorder and particularly bulimia.
  • the method according to this aspect of the present invention is effected by administering to a subject suffering from an eating disorder such as bulimia a therapeutically effective amount of the H 1 agonist described herein.
  • the H 1 agonist described herein may be further utilized for preventing or at least reducing weight gain, and preferably weight gain caused by factors other than excessive food consumption.
  • a method of preventing or reducing weight gain which is effected by administering to the subject a therapeutically effective amount of an H 1 agonist that has a pharmacological half-life of at least 3 hours, as described hereinabove.
  • Such weight gain may be due to factors which include, for example, use of certain drugs, cessation of smoking, or due to a holiday season, as discussed hereinabove and is further detailed hereinbelow.
  • the method according to this aspect of the present invention can be implemented to reduce or prevent weight gain associated with drug treatment.
  • drugs are known to cause weight gain.
  • Representative examples include, without limitation, antipsychotics, antidepressants, mood-stabilizers, calcium channel blockers, anti-convulsants, proton pump inhibitors, antidiabetic agents, antihypertensives, hormones, and anti-smoking medications.
  • the histaminergic system has been implicated in weight gain associated with steroid-induced and antipsychotic-induced weight gain ( Poyurovsky et al. 2005).
  • the H 1 -receptor agonists of the present invention may be co-administered together with a drug treatment which is known to cause appetite stimulation and weight gain in humans due to its histaminergic activity. It is assumed that the H 1 agonist utilized herein interferes with appetite stimulating histaminergic activity of the steroidal or anti-psychotic drug mentioned above and thus prevents or reduces the weight gain caused by such drug treatment.
  • antipsychotic drugs associated with weight gain include, without limitation, selective serotonin-reuptake inhibitors (SSRIs) (such as fluvoxamine, escitalopram, citalopram, or paroxetine), monoamine oxidase inhibitors (such as isocarboxazid, phenelzine and tranylcypromine), conventional antipsychotics (such as haloperidol, molindone and thioridazine), and atypical antipsychotics, (such as clozapine, olanzapine, risperidone, quetiapine, sertindole, aripiprazole and ziprasidone.
  • SSRIs selective serotonin-reuptake inhibitors
  • monoamine oxidase inhibitors such as isocarboxazid, phenelzine and tranylcypromine
  • conventional antipsychotics such as haloperidol, molindone and thiorida
  • antipsychotic drugs associated with weight gain are those which are antagonists of serotonin receptors, including 5-HT 2A , and 5-HT 2C subtypes, or of H 1 -histaminergic, and M 1 -muscarinic receptors. These include, for example, clozapine, olanzapine, risperidione and pirenzepine.
  • Atypical antipsychotics particularly clozapine, olanzapine, risperidone, and quietiapine, have been shown to cause a higher increase in weight gain than conventional antipsychotics.
  • the effect of these antipsychotics may involve both appetite stimulation by a direct effect on the brain, and a delayed endocrine/metabolic dysfunction that promotes fat deposition.
  • One study Poyurovsky 2005 has identified an attenuating effect of betahistine on weight gain due to olanzapine, from week 2 to the end of the study.
  • olanzapine is a potent H 1 antagonist, and betahistine was found not to interfere with the antipsychotic effect of olanzapine, it has been suggested that the antagonistic effect of betahistine on the presynaptic H 3 receptor may account for the weight gain attenuation.
  • Weight gain may also occur due to the use of hormones, particularly steroid hormones, such as corticosteroids or sex steroids.
  • Corticosteroids include glucocorticoids, (for example, prednisone and cortisol), and mineralocorticoids (for example, aldosterone and fludrocortisone).
  • Sex steroids include androgens (for example, testosterone and dehydroepiandrosterone), estrogens (such as estradiol), and progestagens, (for example, progesterone and progestin). Estrogens and progestagens are administered as oral contraceptives. Estrogen and progestin are administered as hormone replacement therapy for menopausal women.
  • antidepressants including, for example, tricyclic antidepressants (such as amitryptyline, amoxapine, clomiprmine, desipramine, doxepin, imipramine, nortryptyline, protriptyline and trimipramine), tetracyclic antidepressants (such as mirtazapine and maprotiline), serotonin-norepinephrine reuptake inhibitors (such as venlafaxine and duloxetine), and other anti-depressants (such as biproprion hydrochloride, mitrazapine, nefazadone and trazadone); mood-stabilizers, such as lithium; calcium channel blockers (such as diltiazem, nicardipine, verapamil and nimopidipine); anti-convulsants (such as carbamazepine, divalproex, lamotrigine, sodium valproate,
  • tricyclic antidepressants
  • weight gain associated with use of certain drugs may be due to, for example,—food cravings, decreased exercise capacity, or stimulation of appetite, for example by blocking of histamine receptors.
  • Involvement of 5-HT 2A , 5-HT 2C , H 1 -histaminergic, and M 1 -muscarinic receptors in weight gain has also been described.
  • the method according to this aspect of the present invention can be implemented to reduce or prevent weight gain associated with smoking cessation.
  • Weight gain associated with cessation of smoking may be attributed, for example, to the fact that nicotine increases heart rate and increases metabolism, such that readjustment to a lower metabolic rate is required once nicotine is no longer present in the bloodstream; to the fact that nicotine is an appetite suppressant; and to the need for emotional comfort in a subject suffering from the unpleasant symptoms associated with nicotine withdrawal.
  • Weight gain associated with cessation of smoking may also occur due to the use of drugs in this respect.
  • drugs that are given in this respect. These include, for example, nicotine-replacement products, such as nicotine patches, nicotine gum (nicotine polacrilex), nicotine inhaler, and nicotine nasal spray, as well as the newer non-nicotine-based medications, such as ZybanTM (bupropion hydrochloride), and future therapies such as Cannabioind receptor affecting AcompliaTM (rimonabant).
  • Administration of the H 1 agonist described herein can be effected in combination with any of these and other drugs for smoking cessation.
  • Weight gain also frequently occurs during a holiday season. This may be due to the fact that with greater leisure time at his disposal, a subject has more opportunity to eat more frequently, or because partaking of elaborate meals is often an integral part of a holiday celebration. This is exacerbated by holidays, particularly religious or national holidays, which are associated with festive meals, or consumption of particular kinds of food. These include, for example, the festive Thanksgiving meal, Christmas dinner, the Jewish Passover meal, and the like.
  • the H 1 -receptor agonists described herein can be further efficiently used for improving a compliance of a human subject to caloric restriction.
  • a method of improving a compliance of a human subject to caloric restriction which is effected by administering to the subject a therapeutically effective amount of an H 1 agonist as described herein.
  • the method, according to this aspect of the present invention can be beneficially practiced with human subject undergoing a weight reducing diet or any other caloric restriction.
  • the methods described hereinabove may further be used for inducing weight loss, for maintaining weight loss or preventing a weight gain after or during a weight reducing diet, or for preventing weight gain in a subject having a condition associated with weight gain.
  • the H 1 receptor agonist of the present invention may optionally be administered in conjunction with other methods of treatment, such as diet, exercise, behavioral therapy, drug therapy, or surgical therapy.
  • the H 1 -receptor agonists described herein can be further efficiently used for reducing a desire of a human subject to consume fats.
  • Some neurotransmitters and neuromodulators have been shown to control both amount eaten and selection of food in a mancronutrient specific manner ( Lecklin et al., 2002).
  • metoprine has been shown to suppress daily ingestion of fats in rats, while having no effect on intakes of carbohydrates or proteins, indicating that an increase in the brain histamine content may specifically affect the desire to consume fats.
  • betahistine treatment resulted in a significant decrease in fat consumption in human subjects over a 28 day trial, while consumption of carbohydrates was not significantly altered.
  • the increase in brain histamine caused by administration of the H 1 -receptor agonists of the present invention may therefore be effective in reducing the desire of a human subject to consume fats.
  • a method of reducing the desire of a human subject to consume fats which is effected by administering to the subject a therapeutically effective amount of the H 1 agonist described herein.
  • the clinical finding that the H 1 agonist of the present invention reduces fat intake in humans is of unique importance, not only with regard to obese subjects, but also with regard to patients suffering from conditions that are associated with fat consumption and/or in which reduced fat consumption is beneficial.
  • a method of treating a condition in which reduced fat consumption is beneficial which is effected by administering to a subject in need thereof a therapeutically effective amount of an H 1 agonist, as described herein.
  • Reducing the fat consumption of a subject can be further utilized for treating conditions associated with metabolic derangement.
  • a method of treating a condition associated with a metabolic derangement in a human subject which is effected by administering to the subject a therapeutically effective amount of the H 1 agonist described herein.
  • Such conditions are typically associated with metabolic derangement and more particularly with adverse imbalance of metabolites such as total cholesterol, HDL-cholesterol, LDL-cholesterol, triglyderides and the like and include, for example, dyslipidemia, such as hypercholesterolemia or lipemia and diabetes.
  • Dyslipidemias are disorders of lipoprotein metabolism, including lipoprotein overproduction or deficiency. These disorders may be manifested by elevation of the serum total cholesterol, low-density lipoprotein (LDL) cholesterol and triglyceride concentrations, and a decrease in the high-density lipoprotein (HDL) cholesterol concentration and therefore include, for example, lipemia and hypercholesterolemia.
  • LDL low-density lipoprotein
  • HDL high-density lipoprotein
  • Lipemia is a condition in which an excess of fats or lipids is found in the blood of subject.
  • Hypercholesterolemia is a condition in which high levels of cholesterol are found in the blood of a subject.
  • Dyslipidemias may be genetic in origin, or may be due to dietary factors (such as excess saturated fats, “trans” fatty acids, cholesterol, excess calories, or alcohol) or drug use (including steroid hormones, diuretics, beta-blockers, cyclosporine and amiodarone, or olanzapine). Dyslipidemias may also be associated with hypothyroidism, diabetes mellitus, hepatobiliary obstruction, nephritic syndrome and chronic renal failure, or with systemic diseases such as porphyries, systemic lupus erythematosis, and lymphomas.
  • dietary factors such as excess saturated fats, “trans” fatty acids, cholesterol, excess calories, or alcohol
  • drug use including steroid hormones, diuretics, beta-blockers, cyclosporine and amiodarone, or olanzapine.
  • Dyslipidemias may also be associated with hypothyroidism, diabetes mellitus, hepatobiliary obstruction
  • the most commonly used options for pharmacologic treatment of dyslipidemia include fibrates, HMG-CoA reductase inhibitors (such as statins), bile acid sequestrants, cholesterol absorption inhibitors, nicotinic acid and derivatives thereof.
  • High cholesterol level can cause the formation and accumulation of plaque deposits in the arteries, leading to plaque ruptures and blockages in the arteries, which increase the risk for heart attack, stroke, circulation problems, and death.
  • Patients suffering from metabolic derangement that is manifested by dyslipidemia are therefore typically instructed to follow a low fat diet as a first measure, before being prescribed drugs which affect cholesterol metabolism.
  • patient compliance with these instructions is generally not high, and currently there are no available drugs for helping patients to adhere to such a diet. Therefore, the H 1 agonist of the present invention, in reducing the desire of a patient to consume fats, helps such patients to maintain a low fat diet.
  • a method of reducing total cholesterol level in a human subject which is effected by administering to the subject a therapeutically effective amount of the H 1 agonist described herein.
  • Total cholesterol consists of HDL cholesterol and LDL cholesterol.
  • High density lipoprotein (HDL) commonly referred to as “good” cholesterol, tends to carry cholesterol away from the arteries and back to the liver, where it is passed from the body. It is also believed that HDL cholesterol removes excess cholesterol from plaque in arteries, thus slowing the buildup. An increase in HDL cholesterol is therefore considered beneficial. In contrast, LDL cholesterol is considered to be “bad” cholesterol, being responsible for plaque formation and deposits.
  • Reducing LDL-cholesterol is believed to be responsible for reducing or stopping the formation of new cholesterol plaques on the artery walls; reducing existing cholesterol plaques on the artery walls; widening narrowed arteries; preventing the rupture of cholesterol plaques, which initiates blood clot formation; decreasing the risk of heart attacks; and decreasing the risk of strokes.
  • a method of reducing low-density lipoprotein cholesterol and increasing high-density lipoprotein cholesterol levels in a human subject which is effected by administering to the subject a therapeutically effective amount of the H 1 agonist described herein.
  • Triglycerides are common types of fats (lipids) that are essential for good health when present in normal amounts. They account for about 95 percent of the body's fatty tissue. Triglycerides are both present in food and manufactured by the body. Abnormally high triglyceride levels are associated with a number of diseases and conditions, such as cirrhosis, underactive thyroid, poorly controlled diabetes, and pancreatitis. High triglyceride levels are also associated with known risk factors for heart disease, such as low levels of HDL cholesterol, high levels of LDL cholesterol and obesity. Triglycerides may also contribute to athereosclerosis.
  • a method of reducing triglyceride level in a human subject which is effected by administering to the subject a therapeutically effective amount of the H 1 agonist described herein.
  • the H 1 agonist may optionally be administered together with a therapeutically effective amount of an additional active agent that may affect the condition being treated.
  • the additional active ingredient can be, for example, a weight control agent.
  • a weight control agent Any of the presently known and approved weight control agents or related substances can be used according to this embodiment.
  • representative examples of such active ingredients include, for example, lipase inhibitors.
  • a non-limiting example of a lipase inhibitor suitable for co-administration with the H 1 agonist of the present invention is orbital, which acts by binding to gastrointestinal lipases in the lumen of the gut, preventing hydrolysis of dietary fat into absorbable free fatty acids and monoacylglycerols.
  • Orlistat is currently the only FDA-approved medication for obesity that reduces nutrient absorption.
  • active ingredients include Sibrutamine, an inhibitor of both norepinephrine reuptake and serotonin reuptake that also weakly inhibits dopamine reuptake, which is approved by the FDA for weight loss and weight maintenance in conjunction with a reduction diet.
  • active ingredients include amphetamines, although the administration thereof might be restricted to a limited time period.
  • a non-limiting example of an amphetamine suitable for co-administration with the H 1 agonist of the present invention is Fentermine.
  • canabinoid receptor antagonists include canabinoid receptor antagonists.
  • a non-limiting example of a canabinoid receptor antagonist suitable for co-administration with the H 1 agonist of the present invention is Rimonabant, a recently developed drug that is currently undergoing Phase III trials and which is claimed to stop food cravings.
  • the additional active agent may be an agent for the treatment of a musculoskeletal disorder, a cardiovascular disorder, a dermatological disorder, a sleep disorder, a metabolic condition, dyslipidemia (including hypercholesterolemia and lipemia), diabetes or a diabetes-related condition.
  • agents are not necessarily associated with weight gain, but may be administered together with the H 1 agonist of the present invention, for treatment of additional conditions from which the subject may suffer.
  • agents for the treatment of musculoskeletal disorders include, without limitation, anti-inflammatory agents, including non-steroidal anti-inflammatory drugs, muscle relaxants, anti-gout agents (such as allopurinol, colchicine, and uricosuric drugs), immunosuppressants (such as glucocorticoids, gold, and cytotoxic agents) and drugs affecting bone mineralization (e.g., diphosphonates, calcitonin, estrogen analogs).
  • anti-inflammatory agents including non-steroidal anti-inflammatory drugs, muscle relaxants, anti-gout agents (such as allopurinol, colchicine, and uricosuric drugs), immunosuppressants (such as glucocorticoids, gold, and cytotoxic agents) and drugs affecting bone mineralization (e.g., diphosphonates, calcitonin, estrogen analogs).
  • non-steroidal anti-inflammatory drugs include, without limitation, piroxicam, isoxicam, tenoxicam, sudoxicam, and CP-14,304; salicylates, such as aspirin, disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal; acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, and ketorolac; fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids; propionic acid derivatives, such as i
  • Non-limiting examples of steroidal anti-inflammatory drugs include, without limitation, corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylesters, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone buty
  • agents for the treatment of cardiovascular disorder include, without limitation, angiotensin-converting enzyme inhibitors (such as captopril, enalapril, or lisinopril); antiarrhythmic drugs (such as amiodarone); anticoagulants, antiplatelets or thrombolytics (such as aspirin); centrally acting drugs (such as clonidine, guanfacine or methyldopa); digitalis drugs (such as digoxin); diuretics (such as chlorthalidone); nitrates (such as nitroglycerin); peripheral adrenergic antagonists (such as reserpine); and vasodilators (such as hydralazine).
  • angiotensin-converting enzyme inhibitors such as captopril, enalapril, or lisinopril
  • antiarrhythmic drugs such as amiodarone
  • anticoagulants such as antiplatelets or thrombolytics
  • centrally acting drugs such as clon
  • agents for the treatment of sleep disorders include, without limitation, hypnotic medications, such as benzodiazepines (including flurazepam, estazolam, temazepam and triazolam); zaleplon and zolpidem; eszopiclone; antidepressants, such as trazodone, antihistamines (such as diphenhydramine products).
  • hypnotic medications such as benzodiazepines (including flurazepam, estazolam, temazepam and triazolam); zaleplon and zolpidem; eszopiclone; antidepressants, such as trazodone, antihistamines (such as diphenhydramine products).
  • agents for the treatment of diabetes include, without limitation, a meglitinide (such as repaglinide or nateglinide), a biguanide (such as metformin), a thiazolidinedione (such as rosiglitazone, troglitazone or pioglitazone), and an alpha-glucosidase inhibitor (such as acarbose or meglitol) and insulin.
  • a meglitinide such as repaglinide or nateglinide
  • a biguanide such as metformin
  • a thiazolidinedione such as rosiglitazone, troglitazone or pioglitazone
  • an alpha-glucosidase inhibitor such as acarbose or meglitol
  • agents for the treatment of dyslipidemia include fibrates, HMG-CoA reductase inhibitors, bile acid sequestrants, cholesterol absorption inhibitors, cholesterol biosynthesis inhibitors, nicotinic acid and derivatives thereof.
  • statins HMG-CoA reductase inhibitors
  • statins are well known drugs that effectively reduce LDL-cholesterol levels by inhibiting the enzyme that regulates the rate of cholesterol production and increasing the clearance of LDL-cholesterol present in the blood by the liver.
  • statins include Atorvastatin, Fluvastatin, Lovastatin, Pravastatin and Simvastatin.
  • Proliferative Activated Receptor (PPAR) agonists also known as fibrates, are fatty acid-activated members of the nuclear receptor superfamily that play important roles in lipid and glucose metabolism, and have been implicated in obesity-related metabolic diseases such as hyperlipidemia, insulin resistance, and coronary artery disease. Fibrates are generally effective in lowering elevated plasma triglycerides and cholesterol and act as PPAR agonists. The most pronounced effect of fibrates includes a decrease in plasma triglyceride-rich lipoproteins (TRLs). Levels of LDL cholesterol (LDL-C) generally decrease in individuals with elevated baseline plasma concentrations, and HDL cholesterol (HDL-C) levels are usually increased when baseline plasma concentrations are low.
  • Non-limiting examples of commonly prescribed fibrates include bezafibrate, gemfibrozil and fenofibrate.
  • Ezetimibe is the first of a new class of cholesterol absorption inhibitors that potently and selectively inhibits dietary and biliary cholesterol absorption at the brush border of the intestinal epithelium, without affecting the absorption of triglyceride or fat-soluble vitamins. Ezetimibe thus reduces overall cholesterol delivery to the liver, secondarily inducing increased expression of LDL receptors, resulting in an increased removal of LDL-C from the plasma.
  • Cholesterol absorption may also be affected by Cholesteryl Ester Transfer Protein (CETP) inhibitors, which play a major role in atherogenesis, by reducing cholesteryl ester accumulation within macrophages and the arterial wall, and thus reducing foam cell formation and affecting the cholesterol absorption.
  • CETP Cholesteryl Ester Transfer Protein
  • cholesterol biosynthesis inhibitors include squalene inhibitors (such as monooxygenase and synthase).
  • Squalene is an isoprenoid compound structurally similar to beta-carotene, is an intermediate metabolite in the synthesis of cholesterol. In humans, about 60 percent of dietary squalene is absorbed. It is transported in serum generally in association with very low density lipoproteins and is distributed ubiquitously in human tissues, with the greatest concentration in the skin, where it is one of the major components of skin surface lipids.
  • Squalene inhibitors e.g., monooxygenase and synthase serve as cholesterol biosynthesis inhibitors.
  • Nicotinic acid is a known agent that lowers total cholesterol, LDL-cholesterol, and triglyceride levels, while raising HDL-cholesterol levels.
  • nicotinic acid drugs There are three types of nicotinic acid drugs: immediate release, timed release, and extended release. Nicotinic acid or niacin, the water-soluble B vitamin, improves all lipoproteins when given in doses well above the vitamin requirement.
  • Additional active agents that can be utilized according to this embodiment of the present invention include, for example, analgesics, growth factors and toxins.
  • Non-limiting examples of analgesics include aspirin and other salicylates (such as choline or magnesium salicylate), ibuprofen, ketoprofen, naproxen sodium, and acetaminophen.
  • Growth factors are hormones which have numerous functions, including regulation of adhesion molecule production, altering cellular proliferation, increasing vascularization, enhancing collagen synthesis, regulating bone metabolism and altering migration of cells into given area.
  • growth factors include insulin-like growth factor-1 (IGF-1), transforming growth factor- ⁇ (TGF- ⁇ ), a bone morphogenic protein (BMP) and the like.
  • Non-limiting examples of toxins include the cholera toxin, which also serves as an adjuvant.
  • the H 1 agonist of the present invention optionally and preferably forms a part of a pharmaceutical composition.
  • the pharmaceutical composition comprises, in addition to the H 1 agonist, a pharmaceutically acceptable carrier, and may optionally further comprise one or more components selected from binding agents, stabilizers, diluents, excipients, surfactants, flavors, and odorants.
  • compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical excipients include without limitation, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, sodium stearate, glycerol monostearate, talc, sodium chloride, glycerol, propylene, glycol, water, ethanol and the like.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • compositions herein described may also comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols.
  • compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • Formulations for oral delivery can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin. Such compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should be suitable for the mode of administration.
  • the active ingredients can be formulated readily by combining the active ingredients with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the active ingredients of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient.
  • Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active ingredient doses.
  • compositions which can be used orally, include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration.
  • the composition can be formulated in a form of a gel, a cream, an ointment, a paste, a lotion, a milk, a suspension, an aerosol, a spray, a foam, a serum, a swab, a pledget, a pad or a patch.
  • Formulations for transdermal delivery can typically include carriers such as water, liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid amides, liquid protein hydrolysates, liquid alkylated protein hydrolysates, liquid lanolin, lanolin derivatives, glycerin, mineral oil, silicone, petroleum jelly, lanolin, fatty acids, vegetable oils, parabens, waxes, and like materials commonly employed in topical compositions.
  • Various additives may be included in the transdermal formulations of the invention. For example, solvents may be used to solubilize certain active ingredients substances.
  • Other optional additives include skin permeation enhancers, opacifiers, anti-oxidants, gelling agents, thickening agents, stabilizers, and the like.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the active ingredients for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the active ingredient and a suitable powder base such as lactose or starch.
  • compositions described herein may be formulated for parenteral administration, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers with optionally, an added preservative.
  • the compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active preparation in water-soluble form. Additionally, suspensions of the active ingredients may be prepared as appropriate oily injection 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 injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the active ingredients to allow for the preparation of highly concentrated solutions.
  • composition can be formulated as rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
  • compositions herein described may also comprise suitable solid of gel phase carriers or excipients.
  • suitable solid of gel phase carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols.
  • compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may, for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.
  • Compositions comprising the H 1 agonist of the invention, and optionally other active ingredients, formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition, as is detailed herein.
  • Each subject was randomly allocated to receive betahistine 16 mg at 10:00 and 16:00 or placebo. Weight, caloric intake (24 hour recall) and appetite during the day (VAS, Visual Analogue Score) were obtained on day 0, 14 and 28 of the study. Subjects were instructed to eat according to their appetite without limitations.
  • BMI body mass index
  • Subject No. 5 (betahistine) reported on day 5 food aversion that did not allow her to consume any food. She was instructed to reduce the dose by half and was excluded from the results analysis.
  • Subject No. 16 dropped out on week 3 due to dyspnea.
  • treatment with betahistine was found to reduce total caloric intake as compared to the placebo.
  • the caloric intake decreased to 80 percents of the pre-treatment level at day 14 of treatment, and to 68 percents at day 28. No decrease was seen with the subjects receiving placebo.
  • betahistine significantly reduces the caloric intake and fat consumption of a human subject. Therefore, administration of betahistine may be efficiently utilized for both improving compliance of a human subject to caloric restriction, and for reducing the desire of a human subject to consume fat.
  • betahistine is an efficient medication for weight management.

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US11/283,865 US20060084686A1 (en) 2004-04-22 2005-11-22 Methods of food intake management
US11/363,332 US7728015B2 (en) 2004-04-22 2006-02-28 Compositions for weight management
AU2006202950A AU2006202950A1 (en) 2004-04-22 2006-07-11 Methods and Compositions for Weight Management
US11/882,687 US20080004254A1 (en) 2004-04-22 2007-08-03 Compositions for weight management
US11/882,740 US20080004322A1 (en) 2004-04-22 2007-08-03 Methods of food intake management
US11/882,677 US20080004324A1 (en) 2004-04-22 2007-08-03 Methods of preventing weight gain
US11/882,741 US20080003306A1 (en) 2004-04-22 2007-08-03 Compositions for weight management
US11/882,688 US20080051440A1 (en) 2004-04-22 2007-08-03 Compositions for weight management
US11/882,678 US20080051439A1 (en) 2004-04-22 2007-08-03 Methods of food intake management
US12/714,503 US20100152161A1 (en) 2004-04-22 2010-02-28 Compositions for weight management

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IL16159504A IL161595A0 (en) 2004-04-22 2004-04-22 Betahistine as a weight management agent
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US20080051439A1 (en) * 2004-04-22 2008-02-28 Mor Research Applications Ltd. Methods of food intake management
US20080051440A1 (en) * 2004-04-22 2008-02-28 Mor Research Applications Ltd. Compositions for weight management
US20080033019A1 (en) * 2006-08-07 2008-02-07 Duke University Cholesterol lowering drug combination
US20100234413A1 (en) * 2007-04-11 2010-09-16 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions
US20090048232A1 (en) * 2007-04-11 2009-02-19 Roberto Ciccocioppo Compositions and methods for prophylaxis and treatment of addictions
US8426439B2 (en) 2007-04-11 2013-04-23 Omeros Corporation Compositions and methods for prophylaxis and treatment of addictions
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US20140072935A1 (en) * 2012-09-07 2014-03-13 Tina M. Herron Method of Regulating Caloric Intake
WO2024182465A3 (en) * 2023-02-28 2024-10-24 Alco Therapeutics, Llc Methods for treating obsessive compulsive related disorders, tic disorders and glutamate excitotoxicity related disorders

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