CN1933835A - Methods of preventing weight gain - Google Patents

Abstract

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, utilizing H1-receptor agonists that have a pharmacological half-life that allows an efficient treatment regime thereof are disclosed. The methods can be efficiently used for treating conditions such as overeating, overweight, obesity, binge eating disorder, night eating syndrome, obsessive eating, compulsive eating and bulimia, as well as conditions associated with metabolic derangement such as dyslipidemia.

Description

The method of control food intake

Invention field

The present invention relates to the new method of the individual food intake of mediator, and more particularly, the present invention relates to prevent or treat the method that controlling body weight is useful disease.

Background of invention

Obesity is a kind of chronic, complicated multi-factor disease, comprises society, culture, genetics and physiology and psychological component, and relevant with the M ﹠ M that rolls up.400,000 people's the cause of death have an appointment every year at USA can be owing to supernutrition (Mokdad, 2004), and can be counted as a kind of epidemic.Based on be defined as body weight and height square the Body Mass Index (scope is usually at 18.5-24.9) of ratio, have 1/3rd to be overweight (index is 25-29.9) among the crowd of growing up approximately, and surpassing 1/4th is fat (index is greater than 30) (National Center forHealth Statistics, 2000).The change of environment and behavior has brought expanding economy and modernization to rise relevant with the fat number in the whole world.The environmental factors that cultivation trends towards fat trend comprises the shortage physical exertion and is associated with high heat and low-cost food.Overweight and fat prevalence worldwide increases with alarming speed, no matter is in developing country, still in developed country, no matter is child or adult, no matter is male or women.Since the sixties in last century, the overweight and quantity obese people continues to increase, and does not also have slow downward trend.Today, 64.5% U.S. adult-Yue 100,000,000 2 thousand 7 hundred ten thousand-be classified as overweight or fat, and near 1/3rd (30.5%)-and Yue 6,000 ten thousand-be fat, " national health is studied with nutritional survey " (the National Health and NutritionExamination Survey) that (CDC) is done as CDC (Centers for Disease Control and Prevention) reported in (NHANES).

Obesity has significantly increased the initiation potential of about 30 kinds of serious medical conditions and has increased relevant with the death of all reasons.Hypertension, diabetes, osteoarthritis, heart disease, apoplexy, gallbladder disease and breast carcinoma, carcinoma of prostate and colon cancer (National Task Force on thePrevention and Treatment of Obesity, 2000) are wherein arranged.In addition, annual obesity causes surpassing at least 300,000 people's death in the U.S., is deputy nonessential main causes of death.Suffer from the adult health care cost total of the fat U.S. and be about 1,000 hundred million dollars.

Exist the treatment of several different controlling body weight to select, comprise dietotherapy, physical exertion, the behavior therapy, pharmacotherapy and operation.Just find that they can not change with regard to the most of overweight and fat people of its life style, pharmacotherapy is favourable and the most practical selection.The fat pharmacotherapy although millions of people seeks treatment, present pharmacotherapy can't satisfy this demand because of its unwanted side effect and limited effect.

Ratified at present to be used to have Body Mass Index to be more than 30 or 30 or to have the medicine (Physicians ' Desk Reference, 2001) that Body Mass Index is existence and the adult treatment obesity of fat relevant medical problem more than 27 or 27.Use weight reduction medicine (Serdula, 1999) having women that Body Mass Index is about 10% more than 30 or 30 and 3% male according to reports.

The medicine that is used for weight reduction in U.S.'s approval at present is classified as two classes: those are by reducing appetite or increasing the medicine (appetite suppressant) that satiety reduces food intake; Reduce the medicine of alimentation with those.In the U.S., do not ratify the medicine that the 3rd possible class increases energy expenditure at present, be used for the treatment of obesity such as ephedrine.

Unique FDA-approves and reduces alimentation to be used for fat medicine be orlistat (Xenical), and it is by working in conjunction with the gastrointestinal lipase in the enteric cavity, thereby prevents that dietary fat is hydrolyzed into absorbable free fatty and monoacylglycerol class.

Mainly anoretic neurotransmitter-particularly the availability that is combined among the central nervous system of norepinephrine, 5-hydroxy tryptamine, dopamine or some these neurotransmitter works most of appetite suppressant by increasing.Available norepinephrine energy medicine comprises phentermine, amfepramone, phendimetrazine and benzfetamine in the U.S..Drug EnforcementAdministration (DEA) has considered the probability of some the existence abuse in these medicines.Because of should be former thereby will think that no longer the amphetamine class recommendation that has the height abuse potential especially is used for weight reduction.FDA (The Food and DrugAdministration) (FDA) has only ratified this medicine and has used " a few week " (generally be estimated as for 12 weeks or below 12 weeks) in the treatment obesity.

The norepinephrine energy side effects of pharmaceutical drugs comprise insomnia, dry mouth, constipation, euphoria, cardiopalmus and hypertension (Physicians ' Desk Reference, 2001).

5-hydroxy tryptamine can activating agent both work by increasing 5-hydroxy tryptamine and discharge, suppress its reuptake or they.The medicine fenfluramine (Pondimin) that stimulates 5-hydroxy tryptamine to discharge and suppress its reuptake withdraws from from American market because of relevant with valvular heart disease and pulmonary hypertension in 1997 with dexfenfluramine (Redux).Some selectivity five hydroxytryptamine reuptake inhibitor is induced in short-term research and is lost weight, and fluoxetine (Prozac) has experienced a large amount of evaluations (Goldstein, 1993) of determining its effect that loses weight.Yet, after initial losing weight, in the later stage of treatment, observe the stable National of recovery again Task Force on thePrevention and Treatment of Obesity).Be evaluated as the characteristic (Wadden, 1995) that the Sertraline (Zoloft) of keeping the adjuvant of body weight behind the very low calorie diet shows similar shortage long-term efficacy.(Meridia Reductil) also has weak inhibitory action to dopamine reuptake, and the FDA approval combines it and is used to lose weight and weight maintenance with the minimizing meals for norepinephrine reuptake and serotonin reuptake inhibitor sibutramine.The side effect of sibutramine comprises blood pressure and pulse rate rising (McMahon, 2000).

Requirement stops food addiction Rimonabant (Sanofi) and has represented a kind new medicine thing that suppresses CB 1 receptor active.CB 1 receptor has constituted the ingredient of interior cannabinoid system.In brain, adipose cell and other body part, found CB 1 receptor, and with regulate food intake relevant with tobacco dependence (Pi-Sunyer etc., 2004).Interior cannabinoid system helps to regulate joyful, lax and pain toleration.Be scarcely acquainted with at present relevant suppress this system long term.In addition, the cannabinoid system helped to protect in some cases brain (such as the apoplexy craniocerebral injury) in neuropathist pointed out, make cerebral lesion in these situations may be in taking blocking-up deterioration more among the patient of medicine of cannabinoid system.

The Rimonabant medicine is carrying out the III clinical trial phase at present.The associated side effect of report at present comprises anxiety, feels sick and diarrhoea.

Therefore, help some patient's weight reduction, there is the demand that continues in effective therapeutic scheme and the medicine of alleviating serious and general disease-excess weight although some in the medicine of present approval shows the effect of appropriateness and have.

Effective bioactive substance histamine of having studied since the nearly century is that amine can neurotransmitter.4 kinds of histamine receptor: H have been identified ₁, H ₂, H ₃And H ₄, caused the discovery of effective receptor antagonist and treatment to be used.H ₁Receptor activation is with relevant to the effect of smooth muscle and axoneuron; H ₂The activation of receptor stimulates the secretion of acid in the stomach, and H ₃The activation of receptor causes the presynaptic self-regulation effect.

Histamine relates to wake-up states (Lin etc. 1990), spontaneous activity (Clapham, 1994), cardiovascular control (Imamura, 1996), water intake (Lecklin, 1998), food intake (Leurs, 1998) and memory form the adjusting of (Blandina, 1996) etc.Some research studies show that histamine can be by working and appetite-suppressing (Sakata, 1997 to the hypothalamus histaminergic nerve unit that participates in the food intake adjusting; Bjenning, 2000; Sakata, 1995).Therefore, the histamine of intracerebral ventricle injection works as appetite suppressant according to reports, and histamine exhausts stimulate appetite (Tuomisto, 1994).The change of histaminergic character and fat genetic model relevant (Machidori, 1992) among the CNS.In addition, the intracerebral ventricle injection Leptin changes relevant (Yoshimatsu, 1999) with the turnover rate of hypothalamus neurons histamine.Because histamine can not pass through blood brain barrier, can observe these effects so can't estimate to use whole body to give histamine.

In people and rodent, use H ₁Antagonist for treating causes hyperalimentation (Fukagawa, 1989), and gives H ₃Antagonist causes appetite decline (hypophagia) (Attoub, 2001).Yet, H ₃Receptor to the equilibrated active long term of appetite that subtracts of body weight because of H ₃Activity of missing the target of inhibitor (Leurs, 1995) and toxicity characteristic (Onderwater, 1998) and file record is not arranged.

Betahistine is oral to have active histamine class medicine, and it is widely used in vestibular disorder, mainly is dizzy and symptomatiatria Meniere.Betahistine is the analog of histamine, and wherein the imidazole ring of histamine is replaced by pyridine ring.Betahistine is H ₁Receptor stimulating agent, and find the H that it shows ₁-agonist activity is about the H of histamine ₁0.07 times of-agonist activity, and behind parenterai administration, cause hypotension, bronchoconstriction and vascular permeability to increase.Receptors bind research confirms that also betahistine is effective H ₃-receptor antagonist.Betahistine can be by blood brain barrier and by the synthetic central action that passed through of the histamine of (is) in the tuberomammillary nucleus that promotes PH.The adverse side effect relevant with betahistine is general less and comprise various types of erythra, urticaria and scratch where it itches.Noisy, nauseating and headache that some patient has also reported.

Have been found that the betahistine that send by intraperitoneal (Rossi etc. 1999) has increased water intake and reduced food intake in short and small goat.This results suggest is former because stimulate H ₁And H ₂Due to the receptor, because remove known as H ₁Outside the effect of receptor stimulating agent, confirm that also betahistine is as the periphery histamine H ₂The weak partial agonist of receptor work (Arrang etc. 1985).This design has further obtained the support of recent discovery, and what promptly confirm histamine in short and small goat subtracts the appetite effect by H ₂The blocking-up of-receptor antagonist cimetidine.Active these similaritys of appetite that subtract of histamine and betahistine are pointed out H in short and small goat ₂-receptor and betahistine to subtract the appetite effect relevant.Yet, H ₂-receptor does not change relevant (Rasmussen, 1993) with the body weight of human body.

Szelag etc. (2001) find that when giving betahistine by intraperitoneal, it has reduced the food intake of rat, and this acting on do not observed (Szelag, 2002) when giving betahistine by administration by gavage.Prompting betahistine administration comprises that to the effect of food intake to increase histamine synthetic and discharge as H ₃The result that receptor suppresses.Yet, because known H ₂Receptor activation can stimulate hydrochloric acid secretion (for example, referring to Clayman, 1977), thus further prompting after the administration by gavage administration, lack betahistine to the influence of food intake may be because of betahistine by activation H ₂Receptor increases hydrochloric acid and discharges due to this fact, has eliminated the maincenter anorexia activity of betahistine thus.Also point out H in the human body ₁The effect of receptor may obviously be different from those effects in rat, and this may be due to physiological rhythm changes between kind.Therefore, kind and route of administration are depended in the anorexia reaction that seems betahistine.However, but Szelag etc. do not have instruction by the effect of betahistine oral or that give by any other route of administration to the human body food intake.

Lecklin etc. (2002) find by peritoneal injection histamine N-methyltransferase inhibitor metoprine suppress histamine catabolism cause in the rat every day caloric intake and fat take in and be suppressed.

Pharmacokinetic confirms that betahistine mainly changes into 2-(2-amino-ethyl)-pyridine and 2-(2-ethoxy)-pyridine (HEP) (Sternoson, 1974) in liver, and betahistine and metabolite are all in conjunction with histamine receptor.

The list of references of citation has definitely confirmed the complexity of appetite stimulator, comprises factors such as kind specificity and route of administration.Further find (Seifert etc., 2003) aspect the agonist of histamine receptor and antagonist pharmacology between variety classes, such as there being multiple difference in people and the Cavia porcellus.Do not instruct in the prior art or prompting H ₁The application of agonist in mediator's food intake.Prior art does not have instruction or prompting to have the H of the pharmacology half-life that can effectively treat yet ₁The application of agonist.The H that does not also have instruction or prompting orally give in the prior art ₁The application of agonist in mediator's food intake.

Therefore, think that there is widespread demand in the activating agent that do not have above-mentioned limitation relevant with histamine to mediator's food intake and has that they are highly beneficial.

Summary of the invention

The present invention uses H by providing ₁These class methods of receptor stimulating agent have successfully solved the defective of the method that becomes known for regulating food intake at present, described H ₁Receptor stimulating agent to the people highly effectively and have at least 3 hours pharmacology half-life and do not have the limitation of present known method.

It is the method for useful disease that one aspect of the present invention provides the food intake of treatment mediator individuality, and this method comprises the H that described individuality is treated effective dose ₁Agonist, described H ₁Agonist has at least 3 hours pharmacology half-life.

According to the further feature in the following preferred embodiment of the invention, described disease is selected from gluttony, overweight, fat and because of its disease that causes or aggravate.Because of the disease of this aspect of the present invention causes or the disease of aggravating can be selected from muscle skeleton disease, cardiovascular disorder, dermatosis, sleep disorder, metabolic disease, diabetes and the disease relevant with diabetes.

According to the further feature in the preferred embodiment, described disease is relevant with higher fatty acid consumption.

According to the further feature in the preferred embodiment, described disease is relevant with psychological factor.The disease of this aspect of the present invention comprises binge eating disorder, night eating syndrome, mandatory diet, mandatory feed or bulimia nerovsa alternatively.

According to the further feature in the preferred embodiment, described disease is relevant with Drug therapy.Described medicine can be made up of steroid hormone or psychoactive drug alternatively.

Another aspect of the present invention provides improves the method for individual human to the compliance of heat restriction, and this method comprises the H that described individuality is treated effective dose ₁Agonist, it has at least 3 hours half-life.

Another aspect of the present invention provides and has reduced the method that individual human consumes the demand of fat, and this method comprises the H that described individuality is treated effective dose ₁Agonist, it has at least 3 hours half-life.

Another aspect of the present invention provides the method for the treatment individual human disease relevant with metabolism disorder, and this method comprises the H that described individuality is treated effective dose ₁Agonist, it has at least 3 hours half-life.For example, described metabolism disorder can be unusual lipidemia, such as hypercholesterolemia or lipidemia.

Term used herein " metabolism disorder " refers to one or more metabolite level imbalances in the body.General and the metabolite of common metabolism disorder such as cholesterol, comprises that LDL is relevant with the off-leveling of HDL, triglyceride etc.

Another aspect of the present invention provides the method that reduces the individual human total cholesterol level, and this method comprises the H that described individuality is treated effective dose ₁Agonist, it has at least 3 hours half-life.

Another aspect of the present invention provides the method for reduction individual human low density lipoprotein, LDL (LDL) cholesterol levels and middle-high density lipoprotein (HDL) cholesterol levels, and this method comprises the H that described individuality is treated effective dose ₁Agonist, it has at least 3 hours half-life.

Another aspect of the present invention provides the method that reduces the individual human triglyceride levels, and this method comprises the H that described individuality is treated effective dose ₁Agonist, it has at least 3 hours pharmacology half-life.

According to the further feature in the described preferred embodiment, the described pharmacology half-life is at about 3 hours-Yue 12 hours, and preferred about 3 hours-Yue 8 hours, more preferably from about 3 hours-Yue 5 hours scope.

According to the further feature in the described preferred embodiment, described H ₁Agonist also is H ₃Antagonist.

According to the further feature in the described preferred embodiment, described H ₁Agonist is characterised in that the blood brain barrier permeability.

According to the further feature in the described preferred embodiment, described H ₁Agonist is selected from betahistine, betahistine metabolite, the pharmaceutically acceptable salt of betahistine, betahistine prodrug, betahistine derivant and combination arbitrarily thereof.Preferred betahistine metabolite is 2-(2-amino-ethyl)-pyridine or 2-(2-ethoxy)-pyridine.Preferred betahistine salt is betahistine dihydrochloride, betahistine mesylate or betahistine trimebutine maleate.Also preferred betahistine derivant is selected from the chemical compound group that general formula I is represented:

General formula I

R wherein ₁-R ₁₂Be selected from hydrogen, alkyl, cycloalkyl and aryl independently of one another.

According to the further feature in the described preferred embodiment, described administration is undertaken by being selected from following approach: in oral, transdermal, intravenous, subcutaneous, intramuscular, intranasal, the atrium, Sublingual, rectum, stride mucosa, intestinal, suck, in the marrow, in the sheath, directly in the ventricle, intraperitoneal and ophthalmic approach.Preferred administration by oral, transdermal, suck, stride mucosa, rectum or Sublingual approach and carry out.More preferably administration by oral, suck or stride mucosal route and carry out.

According to the further feature in the described preferred embodiment, described treatment effective dose is at about 2mg/ days-Yue 96mg/ days, the scope of preferably about 10mg/ days-Yue 50mg/ days.

According to the further feature in the described preferred embodiment, with about 4 times/day of the about 1-of administration, preferred 2 times/day.

According to the further feature in the described preferred embodiment, carry out administration according to individual hungry situation.

According to the further feature in the described preferred embodiment, carry out administration, make that under the situation that does not limit individual food intake whose body weight reduces the scope at about 1-about 5%.Preferably carry out this class administration, make not to H ₁Receptor is reduced.

The term of the relevant receptor of this paper " downward modulation " refers to quantity or the density that reduces the reactive of receptor or reduce receptor.The reactivity that reduces receptor also comprises makes the complete inhibitor of receptor.

According to the further feature in the described preferred embodiment, H ₁Agonist constitutes the ingredient of pharmaceutical composition, and this pharmaceutical composition further comprises pharmaceutically acceptable carrier.

According to the further feature in the described preferred embodiment, every kind of method described herein includes the extra activating agent of described individuality being treated effective dose, such as: weight control agent for example.For example, weight control agent can be appetite suppressant.The representational example of suitable appetite suppressant includes, but are not limited to norepinephrine energy activating agent, 5-hydroxy tryptamine energy activating agent, dopaminergic activity agent, interior Cannabined receptor blocker or its combination.

According to the further feature in the described preferred embodiment, described extra activating agent can be the activating agent of treatment muscle skeleton disease, cardiovascular disorder, dermatosis, sleep disorder, metabolic disease, diabetes or the disease relevant with diabetes.The representational example of this class activating agent includes, but are not limited to the on-steroidal AID, muscle relaxant, antigout drug, immunosuppressant, influence the medicine of bone mineralising, the alpha-adrenergic blockade medicine, angiotensin converting enzyme inhibitor, anti-arrhythmic, the anticoagulant medicine, antiplatelet drug, the thrombolytic medicine, BABD, calcium channel blocker, the central action medicine, the Folium Digitalis Purpureae medicine, nitrate, the periphery 1 adrenergic antagonists, vasodilation, the acne medicine, antipruritic, corticosteroid, antipsoriatic, antieczematic, sleeping pill, antidepressants, antihistaminic, sulfonylureas, meglitinide, biguanide, thiazolidinedione, alpha-glucosidase inhibitor, PPAR (peroxisome proliferation activated receptor)-γ antagonist, insulin, fibrate (fibrate), the HMG-CoA reductase inhibitor, bile acid multivalent chelator, cholesterol absorption inhibitor, nicotinic acid, its derivant, its analog and metabolite thereof and they are mixture arbitrarily.

According to the further feature in the described preferred embodiment, methods described herein are used to induce and lose weight.Perhaps, these methods be used for keeping lose weight behind reducing diet or process prevent weight increase.Perhaps these methods also are used to prevent exist the weight increase of the individuality of the disease relevant with weight increase.

Except as otherwise noted, all technology used herein and scientific terminology have the identical implication with one of ordinary skill in the art's common sense of the present invention.Can be used for implementing or testing the present invention to method and material similar or that be equal to described herein, suitable method and material are as described below.With regard to opposite situation, patent specification comprises that definition can be controlled.In addition, described material, method and embodiment only are indicative and have not been used for the qualification effect.

Term used herein " method " refers to mode, means, technology and the operating procedure that is used to finish appointed task, it is known or be easy to from those modes, means, technology and the operating procedure of known mode, means, technology and operating procedure research and development to include, but are not limited to the technical staff of chemistry, pharmacology, biology, biochemistry and medical domain.

Term used herein " treatment " comprises elimination, suppresses basically, slows down or reverses disease progression, and clinical or aesthstic symptom or the prophylactic basically clinical or aesthstic symptom of improving disease basically occur.

This paper refers at term used aspect the relevant food intake " adjusting " desired level is controlled or is adjusted in food intake.

Term " comprises " referring to and can add additional step and the component that does not influence final result.This term comprise term " by ... form " and " mainly by ... composition ".

Term " mainly by ... form " refer to compositions or method can comprise extra component and/or step, but condition does not only contain the fundamental sum new feature that changes compositions required for protection or method in fact for described extra component and/or step.

Term " treatment effective dose " or " medicine effective quantity " are represented active component or are comprised the dosage of the compositions of active component, the therapeutical effect that this dosage can provide described active component to show.

Term used herein " agonist " has been described and can and have been started the material of physiologically active or approach thus in conjunction with the receptor on the cell.Term " H ₁-receptor stimulating agent " and " H ₁Agonist " can exchange use in this article.

The material that works to reduce another kind of material physiologically active in vivo described in term used herein " antagonist ".

Term used herein " pharmacology half-life " has been described and has been deposited on the intravital medicine of living organism or other material by normal biological processes metabolism or eliminate the required time of half amount from blood plasma.This term can also be called " half-life " in this article interchangeably.

" pharmaceutical composition " used herein refers to one or more preparation of active component described herein, described active component both can be chemical compound, also can be its physiologically acceptable salt, also contain other active component in this pharmaceutical composition, such as suitable carriers and excipient on traditional medicine, the physiology.

Term used herein " pharmaceutically acceptable " refers to be listed by the pharmacopeia of administrative organization's approval of federation or state government or American Pharmacopeia or other general approval and is used for animal and more specifically says so being used for people's mode.The term of this paper " suitable carriers on the physiology " and " pharmaceutically acceptable carrier " can exchange carrier or the diluent that uses and refer to through approval, and they can not produce the biological activity and the characteristic of the conjugate that significant stimulation and elimination give to organism.

Term used herein " carrier " refers to diluent, adjuvant, excipient or the vehicle that gives with therapeutic agent.

Term herein " excipient " refers to and joins in the pharmaceutical composition further to help the inert substance of active component processing and administration.

Unless explanation is arranged in the context clearly in addition, otherwise singulative used herein " a kind of (a) ", " a kind of (an) " and " this (the) " comprise the plural form of related situation.For example, term " a kind of chemical compound " or " at least a chemical compound " can comprise multiple chemical compound, comprise its mixture.

In the context of the present specification, can list each side of the present invention in the mode of certain limit.Should understand description in the scope mode only for convenience and for the purpose of brief, and should not be considered as the inflexible qualification of having of the scope of the invention.Therefore, range describe should be considered as having all possible subrange of concrete disclosure and each numerical value in this scope.For example, the description such as the 1-6 claim should be considered as having the subrange of concrete disclosure, such as 1-3,1-4,1-5,2-4,2-6,3-6 etc., and each numerical value in this scope, for example 1,2,3,4,5 and 6.The width of using this term and scope is irrelevant.

No matter how numerical range is represented in this article, all refers to the numerical value (sectional or whole) of any citation in the scope shown in comprising.The numerical value of the term between the numerical value of the numerical value of first expression and second expression " scope between the two (ranging)/scope (ranges) " and first expression " to " " scope (ranging)/scope (ranges) " of the numerical value of second expression can exchange in this article use and refer to comprise first and the numerical value shown in second and should the interval in all segmentation and whole numerical value.

The accompanying drawing summary

In this article only by embodiment and with reference to the accompanying drawings to describe the present invention.With regard to the accompanying drawing of the detailed description that is specifically related at present, emphasize specific expression as an example and purpose only be to discuss the preferred embodiments of the invention explanatoryly, and list to think the description of the most useful and easy to understand why to the principle of the invention and notion aspect as the reason that provides.In this respect, do not attempt making the apparent several forms description taken together with the accompanying drawings how of the present invention of those skilled in the art to show the detailed content of structure of the present invention than the necessary more detailed mode of the present invention basic comprehension, in fact to have comprised.

In the accompanying drawings:

Accompanying drawing 1 (a-b) has shown the result who obtains in the prior art research, has shown the effect of metoprine treatment to rat total amount of heat picked-up (accompanying drawing 1a) and fat picked-up (accompanying drawing 1b);

Accompanying drawing 2 (a-b) has shown the result who obtains in the prior art research, shows in the rat to compare (accompanying drawing 2a) and protein uptake (accompanying drawing 1b) are absorbed in the metoprine treatment to total amount of heat effect with the carbohydrate picked-up;

Accompanying drawing 3 has shown the effect of the relative mortality risk degree that expression overweight (being expressed as body weight (body mask) index) causes other reason because of (last figure) and women's (figure below) among cardiovascular disease (continuous line), cancer (hacures) and the male.

Accompanying drawing 4 is for showing that orally give betahistine (blue rod) and placebo (yellow rod) are to treating 14 days and the bar of the effect that 28 days descendants' total amount of heat is absorbed;

Accompanying drawing 5 is for showing that orally give betahistine (blue rod) and placebo (yellow excellent) are to treating 14 days and the bar of the effect of 28 days descendants' evaporation, carbohydrate and protein uptake; And

Accompanying drawing 6 is for showing that orally give betahistine (blue rod) and placebo (yellow rod) are to treating 14 days and the bar of the effect of 28 days descendants' body weight change.

Detailed Description Of The Invention

The invention is characterized in and use the H with the pharmacology half-life that can implement effective therapeutic scheme₁The individual food intake of-receptor stimulating agent mediator, improve individual human to the method for heat restriction compliance and reduce the method that individual human consumes the demand of fat.

Principle and operating procedure with reference to accompanying drawing and the accompanying drawing composition of describing that the present invention may be better understood and method.

Before in detail explaining at least one embodiment of the present invention, should understand the present invention be not limited to apply in listed detailed content or take embodiment as the typical case in the following description. The present invention can implement or carry out other embodiment in every way. In addition, the purpose that should understand word used herein and term is to describe, and should not be considered as the restriction effect.

As indicated above, there is the possibility of abuse in the appetite inhibitor of known many present uses. In addition, these appetite inhibitors relate to various side effects, comprise insomnia, dry mouth, constipation, euphoria, palpitaition and hypertension; Relate to valvular heart disease and pulmonary hypertension. In addition, have been found that the many shortage long-term efficacy that show in these activating agents, increase and body weight stably occurs after initial losing weight.

As what above further describe, studies confirm that the correlation between histamine and the food intake adjusting. Therefore, for example, just as shown in Figure 1, confirmed that suppressing histamine catabolism with general histamine N-methyl transferase inhibitor metoprine as the cytotoxicity anticarcinogen has suppressed the total foodstuff picked-up of rat and taken in fat (Lecklin etc., 2002). Just as shown in Figure 2, treatment does not produce remarkable effect to the picked-up of carbohydrate or protein, shows that the increase of brain histamine content can reduce " fat-appetite " specifically, and is namely especially to absorbing the demand of fat, opposite with other food type.

Yet it is extremely invalid in the antiobesity action of maincenter mediation that whole body gives histamine, because exogenous histamine is difficult to penetrate blood-brain barrier. Thus up to now with histamine as appetite inhibitor by the intraventricular injection administration. Similarly, estimate that whole body gives histamine consumes fat to individual human almost not effect of demand.

In addition, histamine only has the pharmacology half-life of a few minutes. Therefore, thresold action period of this medicine is short, and needs frequent drug administration in order to set up and keep the effective blood concentration of sufficiently high treatment. Have than the long half-lift medicine need thus lower administration frequency, this can be so that the patient increases the compliance of dosage regimen. This can also so that side effect is less, because peak value and the valley of patient's blood flow Chinese traditional medicine level can be reduced, thereby cause the levels of drugs in the blood more even within time limit a period of time.

Although the H of the non-histamine of several research research promptings₁The effect of-receptor stimulating agent in regulating food intake, but a kind of direct effect of this excitomotor to people's food intake of having established do not had in these researchs.

The present invention at present unexpectedly discovery feature be some H of half-life (particularly comparing with histamine) of relatively growing₁-activator can be used for mediator's food intake effectively. More particularly, find that the treatment meniere's disease of at present known and approval and relevant disease and the medicine Betahistine with about 3.5 hour half-life affect food intake and calorie intake and weight reduction and the fat consumption of Obese Women individuality effectively. As in the part of embodiment hereinafter take the double-blind study of randomization placebo for typical, discovery Betahistine hydrochloride has reduced appetite, reduced food intake and has affected especially fat consumption.

Therefore, this paper confirms to have and can carry out rationally and the H of the pharmacology half-life of effectively treating₁The food intake that receptor stimulating agent (for example at least 3 hours) can be valuably be used for mediator's individuality is with calorie intake and be used for the treatment of thus and overweight relevant medical science and mental disease. Be not subjected to the how constraint of particular theory, infer Betahistine and other H₁Receptor stimulating agent reduces food intake by the different modes of action of the slimming drugs of non-present use.

Therefore, it is the method for useful disease that one aspect of the present invention provides the food intake for the treatment of mediator individuality, by described individuality being treated the H with pharmacology half-life of at least 3 hours of effective dose₁Activator carries out.

Should notice that term used herein " treatment " also comprises improvement or alleviates pathologic condition and/or its one or more symptoms, cures this class disease or prevents the generation of this class disease.

The H that uses in this aspect of the present invention and the other side₁The pharmacology half-life of activator is preferably at about 3 hours-Yue 12 hours, and more preferably from about 3 hours-Yue 8 hours, and even more preferably about 3 hours-Yue 5 hours scope. This class pharmacology half-life is highly beneficial, because as mentioned above, this class medicine has kept ratio such as the longer time limit in blood of histamine, has obtained more stable blood levels and thus still less side effect. H of the present invention₁Activator thus need to be far below the administration frequency of the histamine that for example only has about 2 minute half-life. As known in the art because 97% medicine eliminates after 5 half-life, so should 5 half-life with interior and common less half-life interval repeat administration, this depends on various parameters, comprises clearance rate and initial administration concentration.

In clinical practice, the selection of spacing of doses has usually represented patient's inconvenience of the variation of validity between the dosage being down to minimum requirement and causing because of frequent drug administration too and has caused the compromise of compliance between relatively poor. The dosage in administration/sky is the preferred plan of consideration once or twice.

Use has the medicine of the half-life in the above-mentioned scope and has considered the selection administration time, in order to do the time spent needing most, such as when the known meal time, namely the time limit on the same day of the obvious hungry level of individual most of usually experience this moment is guaranteed the maximum validity of medicine on the same day, and when effect is unnecessary, such as, for example the effect in the time limit process when estimating that individuality is in sleep state is minimum.

Medicine existent defect long half-lift of having the utmost point, i.e. administration every day 1 time or 2 times are obvious impossible. It is poor relevant with patient's compliance to be lower than administration every day, because individual tend to forget not to be the necessity of taking medicine of part of its of routine every day. For example, verifiedly can reduce the food intake of rat by intraperitoneal injection with by maincenter infusion histamine N-methyltransferase inhibitor chlorobenzene ammonia as mentioned above, it has 216 hours half-life. In addition, must consider to have the toxicity problem of the medicine the long half-lift like this.

In addition, there is H in known prolongation₁Activator can cause H₁Receptor down-regulated.

The downward modulation of special receptor can cause the reaction of activator administration is descended after continuous activation, this be because of limit its subsequently reactive acceptor adaptive change or due to acceptor quantity or density descends. These acceptors-specificity change comprises that acceptor causes quick uncoupling because of its connection G protein activation, thereby mediates functional desensitization; Acceptor fast redistribution enters relatively to be difficult to the compartment or the cell interior that enter in the plasma membrane, is called separately in sequester, endocytosis or the cell and takes the photograph; Contact with the activator that prolongs, be called downward modulation. Relate in evaluation in recent years and obtained suitable progress (Krupnick etc. 1998) aspect the acceptor modification of these changes, but, relating to many in the details of the molecular modification that brings these changes and protein-protein interaction is still determined. The downward modulation of acceptor type can cause the desensitization of the activator of this receptor or tolerance. Therefore, think to have to be lower than 12 hours, preferably be lower than 8 hours and more preferably less than the H of half-life of 5 hours₁Receptor stimulating agent has prevented acceptor and activator continuous contact, and has avoided thus the downward modulation to acceptor.

H of the present invention₁Activator also is preferably H₃Antagonist. Confirmed H₃Antagonist has the effect of regulating food intake. Pointed out and suppressed H₃Receptor active can increase histamine release and synthetic. Histamine passes through H subsequently₁Acceptor increases the histaminergic neuron activity and suppress food intake in this mode. H₃Acceptor not only is positioned on the histaminergic neuron, and is positioned on the non-histaminergic neuron as heteroreceptor, and regulates 5-HT and norepinephrine release. Therefore, H₃Part can be expressed (Morimoto etc. 2001) by other endogenous material to the effect of food intake.

In addition, preferred H₁Activator is characterised in that the blood-brain barrier permeability, and can and enter brain tissue by blood-brain barrier thus, thus to maincenter H₁And H₃Acceptor works. This can give activator by the whole body approach, for example, and has extreme difference blood-brain barrier permeability and opposite as the histamine of appetite inhibitor administration by intraventricular injection in advance thus.

Can be with H of the present invention₁Activator is as any pharmaceutically acceptable salt, such as, for example dihydrochloride, mesylate or the administration of Trimebutine maleate. Perhaps, can be with medicine as its arbitrarily metabolin, prodrug or derivative or its combination medicine-feeding.

Term " pharmaceutically acceptable salt " refers to the charged kind of parent compound and counter ion counterionsl gegenions thereof, it generally is used for changing the dissolubility property of compound every day and/or reduces parent compound to any significant stimulation of organism, can not eliminate biologically active and the characteristic of the compound that gives simultaneously.

Term " prodrug " refers to the reagent that changes in vivo reactive compound (active parent drug). Prodrug generally is used for being conducive to the administration of parent drug. For example, they can have biocompatible by oral administration, and parent drug does not have. Prodrug is compared the solubility that also has improvement with the parent drug in the pharmaceutical composition.

The substantial activity part of the compound that esoteric metabolic process result formed when term used herein " metabolin " was described as compound administration.

Term " derivative " describe to change, modifies or change the result of compound or its part, so that it has kept its original degree of functionality at least in one aspect.

According to a preferred embodiment of the present invention, described H₁Activator is Betahistine. Betahistine is the analogue of histamine, verified it have to H₁And H₃Acceptor in conjunction with affinity qualitatively with histamine near (Fossati etc. 2001). In addition, this is correlated with at pharmacology because pharmacokinetic data confirmed Betahistine in human body therapeutic dose so that PC belong to it H₁And H₃The scope that the affinity of acceptor is identical. Confirmed further that in unit and human body Betahistine is to H₁The pharmacology correlation of acceptor increases (Meyer etc., 1974) owing to blood flow in the microcirculation in the vestibular system in the sense of hearing and the body. Because Betahistine has been widely used in dizzy and other illness for the treatment of, so it has been carried out test and has ratified to be used for human body medicine.

Betahistine is easy to be absorbed and change at least two kinds of metabolin 2-(2-amino-ethyl)-pyridine and 2-(2-ethoxy)-pyridine by oral route. Betahistine has 3.5 hours elimination half-life, and most of dosage is drained as metabolin by urine. Therefore, can give Betahistine according to convenient dosage as mentioned above.

The side effect relevant with Betahistine is less, main by various types of fash, nettle rash, scratch where it itches, noisy, nauseating, headache and aggravated to form by the symptom among the patient of peptic ulcer history.

Betahistine itself or as its metabolin, pharmaceutically acceptable salt, prodrug or derivative can be used for of the present invention this on the one hand and other side.

The Betahistine metabolin that can be effective in the context of the invention comprises: for example 2-(2-amino-ethyl)-pyridine and 2-(2-ethoxy)-pyridine. As (for example, referring to Fossati etc., 2001) that further describe in this area, the feature of these metabolins also is H₁-receptor agonist activity and can also be used for different aspect of the present invention thus.

The representational example that can effectively be used for the pharmaceutically acceptable salt of Betahistine of the context of the invention includes, but are not limited to Betahistine hydrochloride, Betahistine dihydrochloride, Betahistine mesylate and Betahistine Trimebutine maleate.

The Betahistine derivative that is applicable to this aspect of the present invention and other side comprises: the compound that for example has general formula I:

General formula I

In general formula I, R₁-R ₁₂Preferably be selected from independently of one another hydrogen, alkyl, cycloalkyl and aryl and arbitrarily combination thereof.

Alternatively, R₁-R ₁₂Also be selected from separately other substituting group, as long as such as blood-brain barrier permeability, half-life with in conjunction with H₁This category feature of-acceptor is not subjected to harmful effect. Therefore, for example, R₁- R ₁₂Further be selected from independently of one another alkenyl, alkynyl, alkoxyl, aryloxy group, sulfydryl, thio alkoxy, thio-aryloxy, halogen, amino, nitro, cyano group, carbonyl, C-carboxyl, O-carboxyl, C-carbamoyl, N-carbamoyl, sulfonyl, sulfinyl, sulfonamide, urea, thiocarbamide, guanidine, amidino groups, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino-, N-acylamino-, N-sulfonamido and S-sulfonamido, perhaps R₁-R ₄In at least two/or R₅-R ₁₂In at least two form at least one 4-, 5-or 6-unit aromatics, heteroaromatic, alicyclic or assorted alicyclic ring.

It will be appreciated by those skilled in the art that be positioned at shown in locational substituting group (R₁-R ₁₂) separately feasibility depends on substituent valence and chemical compatibility, the position of substitution and other substituting group. Therefore, the object of the invention is to comprise practicable substituting group on all optional positions.

Term used herein " alkyl " refers to saturated aliphatic hydrocarbon, comprises straight chain and branched group. Preferred alkyl is with 1-20 carbon atom. Regardless of digital scope described herein, for example " 1-20 ", its implication is: with regard to alkyl, group can contain 1 carbon atom, 2 carbon atoms etc., at the most and comprise 20 carbon atoms. More preferably alkyl is the medium sized alkyl with 1-10 carbon atom. Except as otherwise noted, most preferably alkyl is low alkyl group with 1-4 carbon atom. Alkyl can be substituted or not be substituted.

" cycloalkyl " refers to entirely-carbon monocycle or fused rings (i.e. the total right ring of adjacent carbon atom) base, and wherein one of a plurality of rings are without the pi-electronic system of total conjugated. The example of cycloalkyl is not limited to cyclopropane, cyclobutane, pentamethylene, cyclopentene, cyclohexane, cyclohexadiene, cycloheptane, cycloheptatriene and adamantane. Cycloalkyl can be substituted or not be substituted.

" alkenyl " refers to the alkyl that is comprised of at least two carbon atoms and at least one carbon-to-carbon double bond.

" alkynyl " refers to the alkyl that is comprised of at least two carbon atoms and at least one carbon-to-carbon triple bond.

" aryl " refers to entirely-carbon monocycle or fused polycycle (i.e. the total right ring of adjacent carbon atom) base, and it is with the pi-electronic system of total conjugated. The example of aryl is not limited to phenyl, naphthyl and anthryl. Aryl can be substituted or not be substituted.

" heteroaryl " refers to monocycle or fused rings (i.e. the ring of total adjacent atom pair) base, it on ring with one or more atoms, such as, for example nitrogen, oxygen return sulphur, and with the pi-electronic system of total conjugated. The example of heteroaryl includes, but are not limited to pyrroles, furans, thiophene, imidazoles, azoles, thiazole, gives a tongue-lashing azoles, gives a tongue-lashing pyridine, pyrimidine, quinoline, isoquinolin purine.

" assorted alicyclic " group refers on ring with one or more atoms, such as monocycle or the fused rings group of nitrogen, oxygen and sulphur. These rings are also with one or more pairs of keys. Yet these are also without the pi-electronic system of total conjugated. Heterolipid ring compounds of group can be substituted or not be substituted. Representational example is piperidines, piperazine, oxolane, oxinane, morpholino etc.

" hydroxyl " refers to-the OH group.

" alkoxyl " refer to as defined herein-the O-alkyl and-the O-cycloalkyl.

" aryloxy group " refer to as defined herein-the O-aryl and-the O-heteroaryl.

" sulfydryl " refers to-the SH group.

" thio alkoxy " refer to as defined herein-the S-alkyl and-the S-cycloalkyl.

" thio-aryloxy " refer to as defined herein-the S-aryl and-the S-heteroaryl.

" carbonyl " refer to-C (=O)-R ' group, wherein R ' is as defined herein hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl (by annular atoms in conjunction with) or heterolipid ring compounds of group (by ring carbon atom in conjunction with).

" thiocarbonyl " refer to-C (=S)-R ' group, wherein R ' such as this paper to R ' definition.

" C-carboxyl " refer to-C (=O)-O-R ' group, wherein R ' as defined herein.

" O-carboxyl " refer to R ' C (=O)-the O-group, wherein R ' as defined herein.

" halogen " group refers to fluorine, chlorine, bromine or iodine.

" sulfinyl " refer to-S (=O)-and R ' group, wherein R ' is as defined herein.

" sulfonyl " refer to-S (=O) ₂-R ' group, wherein R ' as defined herein.

" S-sulfonamido " refer to-S (=O) ₂-NR ' R " group, wherein R ' as defined herein and R " such as to R ' definition.

" N-sulfonamido " refer to R ' S (=O) ₂-NR ", wherein R ' and R are " as defined herein.

" O-carbamoyl " refer to-OC (=O)-" group, wherein R ' and R are " as defined herein for NR ' R.

" N-carbamoyl " refers to R " OC (=O)-and NR '-group, wherein R ' and R are " as defined herein.

" O-thiocarbamoyl " refer to-OC (=S)-" group, wherein R ' and R are " as defined herein for NR ' R.

" N-thiocarbamoyl " refers to R, and " (=S) NR '-group, wherein R ' and R are " as defined herein for OC.

" amino " refers to-NR ' R, and " group, wherein R ' and R are " as defined herein.

" C-acylamino-" refer to-C (=O)-" group, wherein R ' and R are " as defined herein for NR ' R.

" N-acylamino-" refer to R ' C (=O)-" group, wherein R ' and R are " as defined herein for NR.

" urea " base refers to-NR ' C (=O)-NR " R  group, wherein R ' and R " as defined herein and R  such as to R ' or R " definition.

" guanidine radicals " refer to-R ' NC (=N)-NR " R  group, wherein R ', R " and R " ' as defined herein.

" amidino groups " refers to R ' R " NC (=N)-wherein R ' and R " as defined herein.

" nitro " refers to-NO ₂Group.

" cyano group " refers to-the C=N group.

Term " phosphono " described-and ((OR ") group, wherein R ' and R are " as hereinbefore defined for=O) (OR ') for O-P.

Term " phosphinyl " has been described-PR ' R, and " group, wherein R ' and R are " as hereinbefore defined.

Term " thiourea " described-NR '-C (=S)-NR " R  group, wherein R ' and R " as hereinbefore defined and R  such as to R ' and R " definition.

In any means described herein, can give described H by any approach that is selected from following approach ₁Agonist: in oral, transdermal, intravenous, subcutaneous, intramuscular, intranasal, the atrium, Sublingual, rectum, stride mucosa, intestinal, suck, in the marrow, in the sheath, directly in the ventricle, intraperitoneal and ophthalmic approach.That preferred route of administering is selected from is oral, transdermal, suck, stride mucosa, rectum or Sublingual approach.More preferably use oral, suck or transdermal route gives described H ₁Agonist.

Alternatively and preferably give described H as the about 96mg/ of about 2mg-days accumulated dose ₁Agonist.More preferably accumulated dose is about the about 50mg/ of 5mg-days, the about 50mg of 10mg-more preferably from about, the about 48mg of 16mg-more preferably from about, and 24mg-48mg most preferably from about.

Preferably with described H ₁Agonist is administered once or several times every day, about 4 times/day of for example about 1-, and more preferably 2 times/day.Perhaps, can give H according to individual hungry situation about taking place ₁Agonist.

Described in the following examples part, clinical research is verified under the situation of not erstricted diet picked-up, and 2 betahistine administrations with 16mg dosage made and lost weight significantly in 1 month every day, particularly compared with matched group.

Therefore, implement therapeutic scheme, make when repetitively administered, under the situation that does not limit individual food intake, make individual losing weight reach about 1-about 5% according to one embodiment of the invention.

As described in detail above, because H ₁The constant existence of agonist can make H ₁Receptor is reduced significantly, so implement the preferred therapeutic scheme of the present invention, makes not to H ₁The purpose that realization loses weight under the situation that receptor is reduced.Can be by adjusting administration and designing this class therapeutic scheme with the dosing interval of half-life of selected H1 agonist.

Dosage can change according to used dosage form and the different of used route of administration.Definite preparation, route of administration and dosage can be selected according to patient's situation by each clinicist.(for example, referring to Fingl etc., 1975, " The Pharmacological Basis of Therapeutics ", Ch.1p.1).Can adjust dosage and interval respectively so that the H that is enough to keep regulating action is provided ₁The blood plasma level of agonist.

Work as H ₁Agonist is during for the betahistine that is purchased as 8mg or 16mg tablet, and every day, dosage range 24-48mg passed through oral administration according to fractionated dose.For example, with 8mg tablet administration every day 3 times, each 1-2 sheet, and with 16mg tablet administration every day 3 times, each 0.5-1 sheet.

Can alternatively can H of the present invention ₁Agonist slows down the form administration of the slow releasing preparation of rate of release to have active substance, so that further increase patient's convenience and compliance and increase the effect of activating agent alternatively.Rate of release is slow more, and the blood concentration fluctuation in the dosing interval is more little so.This can make and give higher dosage with lower frequency, and keep treatment concentration in the extended period.In addition, slow releasing preparation is of value to the possible side effect of active component that of short duration peak value blood drug level that minimizing reaches rapidly after because of administration produces.

Slow releasing preparation generally comprises the biodegradable carrier of slow release.The degradable carrier of slow-release bio is that this area is well-known.They are to form particulate material, and described granule can be captured wherein reactive compound so that its slowly degraded and/or dissolving and degrades/dissolves and release of active compounds in body fluid thus in suitable environment (for example moisture, acid, alkalescence etc.).Described granule is preferably nanoparticle (promptly in nanometer range, for example diameter is in the about 500nm scope of about 1-, and preferred diameter is in about 50-200nm scope, and most preferred diameters is at about 100nm).

Rate of drug release generally depends on dosage form disintegrate or dissolved speed.The fluidic medical surfaces of the general remarkable increase contact GI of disintegrate is long-pending, promotes medicine dissolution and absorption thus.Usually in preparation process, add disintegrating agent and other excipient (for example diluent, lubricant, show activating agent, binding agent, dispersant) to help these processes.Surfactant increases dissolution rate by wettability, dissolubility and the dispersibility that increases medicine.Can be by the excessive pressure that applies in the tabletting operating procedure process or by for preventing that tablet from stoping the solid dosage forms disintegrate in the special-purpose coatings that the digestion process of intestinal is coated with.Hydrophobic lubricant (for example magnesium stearate) can and reduce bioavailability in conjunction with active medicine.

Dissolution rate has determined medicine for the availability that absorbs.When slower than absorption, stripping becomes rate-limiting step.Can be by operation said preparation control overall absorption.For example, reduce the surface area that granular size can increase medicine, increase common GI absorbance and the degree that absorb thus because of the limited medicine of slow stripping.It is the influence of salt, crystallization or hydrate forms that dissolution rate is subjected to medicine.

Usually can oral slow release formulation be designed to and medicine concentration can be kept more than 12 hours.Can be by giving the drug particles coating with wax or other water-insoluble material, can be in by pharmaceutical pack being embedded in it by the substrate that slowly discharges in the GI road course of conveying, or by making the compound absorbance of controlling of medicine and ion exchange resin.

Therefore, for example, the slow releasing preparation of tablet form can be based on the application of hydrophilic polymer, and described hydrophilic polymer is in contact swelling and form gel during gastro-intestinal Fluid, thereby generates the barrier of giving tablet coating.This barrier has limited the physical exchange between tablet inside and the surrounding medium.As a result of, water enters tablet matrix and drug diffusion is slowed down, thereby makes the controlled drug slow release.

Can be with various types of polymer as the substrate of medicament slow release,, ethyl cellulose polyamide-based, siloxanes, poly-(hydroxyethyl methylacrylate), other acrylic copolymer and polyvinylacetate-polyvinyl chloride copolymer as polrvinyl chloride, polyethylene.

Therefore, be used to send H of the present invention ₁The slow releasing preparation of agonist provides at about 2 hours-Yue 24 hours, the release in preferred about 4 hours-Yue 24 hour time limit scope, and release in following time bar is provided thus: at least 4 hours, 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.Perhaps, this class slow releasing preparation is at conventional 24 hours and reach in 48 hour time limit H is provided ₁The release of agonist.

It is useful any disease that the method for this aspect of the present invention can be used for the treatment of the adjusting food intake thus effectively.They comprise: for example gluttony, disease overweight, fat and that therefore cause or aggravate.

Because of these diseases cause or the disease of aggravating comprises: for example the muscle skeleton disease is (such as osteoarthritis, the pain relevant etc.) with spinal column, cardiovascular disorder is (such as hypertension, arteriosclerosis etc.), dermatosis (such as fungus and other infection), sleep disorder (such as snoring and obstructive sleep apnea), metabolic disease (unusual lipidemia, lipidemia or hypercholesterolemia), diabetes and the problem relevant and cancer (breast carcinoma particularly with diabetes, carcinoma of prostate and colon cancer).Represented the effect of the relative risk degree of the overweight death that the various diseases that cause thus or aggravate are caused represented by Body Mass Index in the accompanying drawing 3.Shown in accompanying drawing 3, to compare with the normal type index range (being 18.5-24.9), cardiovascular disease significantly increases in overweight individuality, no matter is male or women.Observe rapid increase at the individuality that is categorized as obesity (Body Mass Index that promptly has is greater than 30).Similarly, at overweight individuality, the relative risk degree of particularly observing in obese individuals because of cancer mortality increases, and wherein increases bigger in the women.The relative risk degree of observing because of other former cause death sharply increases in obese individuals.

Other disease of the method treatment of this aspect of available the present invention comprises: for example relevant disease with psychological factor, and such as binge eating disorder, night eating syndrome, mandatory diet, mandatory feed and bulimia nerovsa.

Perhaps, described disease may be relevant with Drug therapy, and is such as using steroid hormone or psychoactive drug treatment (such as traditional antidepressants, benzodiazepines, lithium and antipsychotic drug), relevant with weight increase usually.

Described in this area, the histaminergic system relates to steroid and induces the weight increase (Poyurovsky etc. 2005) relevant with the inductive weight increase of antipsychotic drug.Therefore, can be with H of the present invention ₁-receptor stimulating agent and knownly produce people's appetite stimulation because of histaminergic is active and the Drug therapy of weight increase gives jointly.Infer H used herein ₁Agonist can disturb the active and prevention or reduce the weight increase that causes because of this class Drug therapy thus of the histaminergic that stimulates appetite of above-mentioned steroid or antipsychotic drug.

H described herein ₁-receptor stimulating agent can also be used to improve the compliance of individual human to the heat restriction effectively.Therefore, another aspect of the present invention provides improves the method for individual human to the compliance of heat restriction, by described individuality being treated the H as described herein of effective dose ₁Agonist carries out.The method of this aspect of the present invention can be implemented the individual human of experience reducing diet or other heat restriction arbitrarily valuably.

Food intake by mediator's individuality effectively and improve its compliance to the heat restriction, method mentioned above can be further used for inducing losing weight, keep losing weight or prevent weight increase behind the reducing diet or in the process, or there is the weight increase of the individuality of the disease relevant with weight increase in prevention.Lose weight in order to induce or to keep, can be with H of the present invention ₁Receptor stimulating agent combines with other Therapeutic Method alternatively and gives, such as meals, exercise, the behavior therapy, pharmacotherapy or operative therapy.

H described herein ₁-receptor stimulating agent can also be used to reduce the demand that individual human consumes fat effectively.Verified some neurotransmitter and neuroregulator can be with macrometabolic element (mancronutrient) the specificity mode amounts of keeping on a diet with to the selection (Lecklin etc., 2002) of food.For example, as what represent among Fig. 1 and 2 mentioned above and attached, confirmed that metoprine suppresses the rat fat picked-up of every day, and to carbohydrate or not influence of proteinic picked-up, this shows that the increase of brain histamine content can influence the demand that consumes fat especially.

As indicated in the embodiment part hereinafter, have been found that the betahistine treatment can make the fat consumption of individual human significantly reduce in test in 28 days, and the consumption of carbohydrate is not significantly changed.Because of giving H of the present invention ₁The brain histamine increase that-receptor stimulating agent causes can effectively reduce the demand that individual human consumes fat thus.

Therefore, another aspect of the present invention provides and has reduced the method that individual human consumes the demand of fat, by described individuality being given the H of treatment effective dose described herein ₁Agonist carries out.

Clinical discovery H of the present invention ₁Agonist can reduce people's fat picked-up, not only in obese individuals, and all has this unique importance in suffering from the patient that and/or minimizing fat consumption relevant with fat consumption is useful disease.

Therefore, another aspect of the present invention provides treatment to reduce the method that fat consumption is useful disease, by to there being this individuality that needs to give the H of treatment effective dose as described herein ₁Agonist carries out.

Reduce individual fat consumption and can be further used for treating the disease relevant with metabolism disorder.

Therefore, another aspect of the present invention provides the method for the treatment disease relevant with metabolism disorder in the individual human, by described individuality being given the H of treatment effective dose described herein ₁Agonist carries out.

This class disease is general relevant with metabolism disorder, and it is more particularly,, relevant as the bad imbalance of T-CHOL, HDL-cholesterol, LDL-cholesterol, triglyceride etc. with metabolite, and comprise: for example unusual lipidemia, such as hypercholesterolemia or lipidemia.

Unusual lipidemia is the lipoprotein metabolism obstacle, comprises that lipoprotein produces excessively or shortage.These diseases show as serum total cholesterol, low density lipoprotein, LDL (LDL) cholesterol and triglyceride concentration raises and high density lipoprotein (HDL) cholesterol concentration descends, and comprise thus: for example lipidemia and hypercholesterolemia.

Lipidemia is to find fat or the excessive disease of lipid in individual blood.

Hypercholesterolemia is a disease of finding high-level cholesterol in individual blood.

The verified directly related property between coronary artery disease and unusual lipidemia.Unusual lipidemia can derive from heredity or may be because of (such as supersaturation fat, " transfers " fatty acid, cholesterol, heat is excessive or ethanol) due to the dietary factors or drug use (comprising steroid hormone, diuretic, beta blocker, cyclosporin and amiodarone or olanzapine).Unusual lipidemia also may be relevant with chronic renal failure with hypothyroidism, diabetes, hepatic duct obstruction, the nephritic syndrome, or relevant with systemic disease, such as porphyria, systemic lupus erythematosus (sle) and lymphoma.The most frequently used selection of the Drug therapy of unusual lipidemia comprises fibrate, HMG-CoA reductase inhibitor (such as statins), bile acid multivalent chelator, cholesterol absorption inhibitor, nicotinic acid and derivant thereof.

The performance of elevated cholesterol and other unusual lipidemia can cause in the tremulous pulse plaque deposition thing to form and accumulate, thereby causes plaque rupture and obstruction in the tremulous pulse, increases heart attack, apoplexy, circulatory problems and dead risk.Generally thus requiring the patient who suffers from the metabolism disorder that shows as unusual lipidemia to follow low-fat diet as primary measure, after this is influence the opening according to the medicine of writing out a prescription of cholesterol metabolism.Yet the patient is generally not high to the compliance of these requirements, and does not still have the available patient of helping to keep the medicine of these class meals at present.Therefore, H of the present invention ₁Agonist consumes in the fatty demand the minimizing patient and can help this class patient to keep low-fat diet.

Therefore, another aspect of the present invention provides the method that reduces total cholesterol level in the individual human, by described individuality being given the H of treatment effective dose described herein ₁Agonist carries out.

T-CHOL is made up of HDL cholesterol and LDL cholesterol.So-called " well " high density lipoprotein of cholesterol (HDL) trends towards carrying cholesterol and leaves tremulous pulse and turn back to liver, discharges from health there.Think that also the HDL cholesterol can remove excessive cholesterol in the speckle from tremulous pulse, delay it thus and accumulate.Think that thus the increase of HDL cholesterol is useful.On the contrary, think that the LDL cholesterol is " bad " cholesterol, it can cause speckle to form and deposition.Think that reducing the LDL-cholesterol can reduce or stop to form on the arterial wall new cholesterol speckle; Reduce the cholesterol speckle that exists on the arterial wall; Widen narrow tremulous pulse; Prevent to cause clot * the cholesterol plaque rupture; Reduce the danger of heart attack; With the danger that reduces apoplexy.

Therefore, another aspect of the present invention provides the method that reduces low-density lipoprotein cholesterol level in the individual human and increase the HDL-C level, by described individuality being given the H of treatment effective dose described herein ₁Agonist carries out.

Triglyceride is is the fat (lipid) of the necessary common type of good health when existing with normal amount.They account for about 95% of body fat tissue.Triglyceride is present in the food and by the health manufacturing.Unusual high triglyceride levels is relevant with numerous disease and illness, such as liver cirrhosis, thyroid activation deficiency, unmanageable diabetes and pancreatitis.The high triglyceride level is also relevant with known heart disease risk factor, such as low-level HDL cholesterol, high-caliber LDL cholesterol and obesity.Triglyceride can also cause atherosclerosis (athereosclerosis).

Therefore, another aspect of the present invention provides the method that reduces triglyceride levels in the individual human, by described individuality being given the H of treatment effective dose described herein ₁Agonist carries out.

In any means described herein, can be with described H ₁Agonist gives jointly with the activating agent that the another kind for the treatment of effective dose can influence the disease of being treated.

According to a preferred embodiment of the present invention, described another kind of active component for example can be weight control agent.This embodiment can be used the weight control agent or the related substances of known at present arbitrarily and approval.Therefore, the representational example of this class active component for example comprises lipase inhibitor.Be suitable for and H of the present invention ₁The limiting examples of the lipase inhibitor of agonist co-administered is orlistat (orbital), and it can be by in conjunction with the gastrointestinal lipase in the enteric cavity, prevents that dietary fat is hydrolyzed into absorbable fatty acid and an acylglycerol class and works.Orlistat is the obesity medicine that present unique FDA-approval is used to reduce alimentation.

The extra example of this class active component comprises selective serotonin reuptake inhibitor (SSRIs).Be suitable for and H of the present invention ₁The limiting examples of the SSRI of agonist co-administered is sibutramine (Sibrutamine), it is the inhibitor of norepinephrine reuptake and serotonin reuptake transporter, also can produce weak inhibitory action, combine with reducing diet by the FDA approval and be used to lose weight and weight maintenance dopamine reuptake.

The extra example of this class active component comprises the amphetamine class.But, its administration may be subjected to the restriction in finite time time limit.Be suitable for and H of the present invention ₁The limiting examples of the amphetamine of agonist co-administered is Fentermine.

The extra example of this class active component comprises cannabinoid (canabinoid) receptor antagonist.Be suitable for and H of the present invention ₁The limiting examples of the cannabinoid of agonist co-administered (canabinoid) receptor antagonist is a Rimonabant, and it is a medicine of the present III phase of carrying out of researching and developing testing and require to stop the food addiction.

Perhaps, described extra activating agent can be for being used for the treatment of the activating agent of muscle skeleton disease, cardiovascular disorder, dermatosis, sleep disorder, metabolic disease, unusual lipidemia (comprising hypercholesterolemia and lipidemia), diabetes or the disease relevant with diabetes.

The representational example that is used for the treatment of the activating agent of muscle skeleton disease includes, but are not limited to: anti-inflammatory agent comprises nonsteroid anti-inflammatory drugs; Muscle relaxant; Antigout drug (such as allopurinol, colchicine and uricosuric eliminant); Immunosuppressant (such as corticosteroid, gold and cytotoxic agent) and influence the medicine (for example diphosphate, calcitonin, oestrogen-mimicking) of bone mineralising.

The representational example of nonsteroid anti-inflammatory drugs includes, but are not limited to: piroxicam, isoxicam, tenoxicam, sudoxicam and CP-14,304; Salicylate is such as aspirin, salsalate, benorylate, Choline magnesium trisalicylate, safapryn, chloroquine (solprin), diflunisal and fendosal; Acetogenin s is such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, Isoxepac, furofenac, tiopinac, zidometacin, acemetacin (acematacin), fentiazac, zomepirac, clindanac, Oxepinac, felbinac and ketorolac; Fenamates is such as mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid and tolfenamic acid; Propanoic derivatives is such as ibuprofen, naproxen, benzene Lip river sweet smell, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen (indopropfen), pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, sulfur Lip river sweet smell, suprofen, alminoprofen and tiaprofenic acid; Pyrazoles is such as Phenylbutazone, oxyphenbutazone, feprazone, azapropazone and trimetazone.

The limiting examples of steroidal antiinflammatory drug comprises, but be not limited to: corticosteroid, such as hydrocortisone, the hydroxyl triamcinolone, the Alpha-Methyl dexamethasone, dexamethasone phosphate, beclomethasone dipropionate, the valeric acid clobetasol, desonide, desoximetasone, percorten, dexamethasone, dichlorisone, dichlorisone, nerisona, fluadrenolone, flucloronide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylesters, fluocortolone, fluprednidene acetate (fluprednidene) (fluprednidene (fluprednylidene)), Cordran, halcinonide, hydrocortisone acetate, the hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, flurandrenolide (fluradrenolone), fludrocortisone, diflurosone diacetate, fluradrenoloneacetonide, medrysone, amcinafal (amcinafel), amcinafide, the counterbalance of betamethasone and esters thereof, chloroprednisone, chloroprednisone acetate (chlorprednisone acetate), clocortolone (clocortelone), clescinolone, dichlorisone, difluprednate (diflurprednate), the flucloronide, flunisolide, fluorometholone (fluoromethalone), fluperolone, fluprednisolone, the valeric acid hydrocortisone, the hydrocortisone cipionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone and composition thereof.

The representational example that is used for the treatment of the activating agent of cardiovascular disorder includes, but are not limited to: alpha-adrenergic blockade medicine (such as doxazosin (doxazocin), prazosin (prazocin) or terazosin); Angiotensin-convertion enzyme inhibitor (such as captopril, enalapril or lisinopril); Anti-arrhythmic (such as amiodarone); The anticoagulant medicine; Antiplatelet drug or thrombolytics (such as aspirin); BABD (such as acebutolol, atenolol, metoprolol, nadolol, pindolol or propranolol); Calcium channel blocker (such as diltiazem, nicardipine, verapamil or nimopidipine); Central action medicine (such as clonidine, guanfacine or methyldopa); Folium Digitalis Purpureae medicine (such as digoxin); Diuretic (such as chlortalidone); Nitrate esters (such as nitroglycerin); Periphery 1 adrenergic antagonists (such as reserpine); And vasodilation (such as hydralazine).

The representational example that is used for the treatment of sleep disorder includes, but are not limited to: sleeping pill, such as benzodiazepines (comprising flurazepam, estazolam, temazepam and triazolam); Zaleplon and zolpidem; Eszopiclone; Antidepressants are such as trazodone; Antihistaminic (such as the diphenhydramine product).

The representational example that is used for the treatment of the activating agent of diabetes includes, but are not limited to: sulfonylureas (such as chlorpropamide, glipizide, glibenclamide and glimepiride); Meglitinide (such as repaglinide or Nateglinide); Biguanide (such as metformin); Thiazolidinedione (such as rosiglitazone, troglitazone or pioglitazone) and alpha-glucosidase inhibitor (such as acarbose or meglitol) and insulin.

The limiting examples that is used for the treatment of the activating agent of unusual lipidemia comprises fibrate, HMG-CoA reductase inhibitor, bile acid multivalent chelator, cholesterol absorption inhibitor, cholesteral biosynthesis inhibitor, nicotinic acid and derivant thereof.

HMG-CoA reductase inhibitor (statins) is the medicine of well-known effective reduction LDL-cholesterol levels, and they reach this purpose by the LDL-cholesterol that inhibition cholesterol regulating generation rate and increase hepatic clearance are present in the blood.Usually the representational example of opening according to the statins of writing out a prescription comprises atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin.

Proliferator activated receptor (PPAR) agonist, be also referred to as fibrate and be the fatty acid-activatory member in the nuclear receptor superfamily that in lipid and glucose metabolism, plays an important role, and they relate to and obesity-relevant metabolic disease, such as hyperlipemia, insulin resistant and coronary artery disease.Fibrate generally can effectively reduce the plasma triglyceride class of rising and cholesterol and and play the PPAR agonist.The most significant effect of fibrate comprises and reduces the plasma lipoprotein (TRLs) be rich in triglyceride.LDL cholesterol (LDL-C) level generally reduces in the individuality with the rising of baseline plasma concentration, and HDL cholesterol (HDL-C) level raises when the baseline plasma concentration is low usually.Usually the limiting examples of opening according to the fibrate of writing out a prescription comprises bezafibrate, gemfibrozil and fenofibrate.

The representational example of cholesterol absorption inhibitor comprises ezetimibe.Ezetimibe is the cholesterol absorption inhibitor of first kind of newtype, and they can be effectively and optionally suppress meals and biliary cholesterol and absorb at enteric epithelium stricture of vagina edge place, absorb and can not influence triglyceride or fatsoluble vitamin.Ezetimibe has reduced T-CHOL thus to the sending of liver, and next induces ldl receptor expression to increase, and causes removing fast from blood plasma LDL-C.

Can also be used in cholesterol ester transfer protein (CETP) inhibitor that atheroma plays a major role in forming influences cholesterol absorption, by reducing cholesteryl ester accumulating and induce foam cell to form and influence cholesterol absorption thus and carry out in macrophage and arterial wall.The known CETP inhibitor that is hopeful most is avisimibe at present.

The representational example of cholesteral biosynthesis inhibitor comprises Squalene inhibitor (such as monooxygenase and synthase).Squalene be on the structure with the similar isoprenoid compounds of beta-carotene, be the intermediate metabolite of cholesterol in synthetic.In human body, about 60% meals Squalene is absorbed.Generally to be transferred in serum with the bonded mode of very low density lipoprotein (VLDL) and omnipresence is distributed in the tissue, Cmax is in skin for it, and wherein it is one of main component in the skin surface lipid.Squalene inhibitor (for example monooxygenase and synthase) is as cholesteral biosynthesis inhibitor.

Nicotinic acid is known hypercholesterolemia reducing, LDL-cholesterol and triglyceride levels, and the activating agent of rising HDL-cholesterol levels.There is three types nicotinic acid medicine: discharge at once, regularly discharge and prolongation release.Water-soluble (vitamin) B nicotinic acid or nicotinic acid improve all lipoproteins when giving with the dosage that suitably is higher than vitamin requirement.

Can for example comprise analgesic, somatomedin and toxin according to the extra activating agent that this embodiment of the present invention is used.

The limiting examples of analgesic (pain relief agents) comprises aspirin and other Salicylate (such as choline or magnesium salicylate), ibuprofen, ketoprofen, naproxen sodium and acetaminophen.

Somatomedin is the hormone with many functions, and described function comprises that regulating adhesion molecule produces, changes cell proliferation, increase vascularization, promotion collagen protein synthesis, regulates bone metabolism and change cell migration and go into the appointed area.The limiting examples of somatomedin comprises insulin-class growth factor-1 (IGF-1), transforming growth factor-beta (TGF-β), bone morphogenetic protein (BMP) etc.

The limiting examples of toxin comprises cholera toxin, and it also plays adjuvant.

When be used for said method and aspect each in the time, H of the present invention ₁Agonist constitutes the ingredient of pharmaceutical composition alternatively and preferably.This pharmaceutical composition removes and comprises H ₁Outside the agonist, can also comprise pharmaceutically acceptable carrier, and can comprise further alternatively that one or more are selected from the composition of binding agent, stabilizing agent, diluent, excipient, surfactant, correctives and aromatic.

The purpose of pharmaceutical composition is to help to give the active component (H that this paper is above-mentioned to organism (being the people in this article) ₁Agonist).Can be by method well-known in the art, for example mixing, dissolving, granulation, system ingot, pulverizing, emulsifying, encapsulation, embedding or the freeze drying process by routine prepares pharmaceutical composition of the present invention.

This class pharmaceutical carrier can be sterile liquid, such as water and oil, comprises oil; Animal, plant or synthetic source are such as Oleum Arachidis hypogaeae semen, soybean oil, Dormant oils, Semen Sesami wet goods.When giving described pharmaceutical composition by intravenous, water is preferred carrier.Saline solution and D/W and glycerite also can be used as liquid-carrier, especially for injectable solution.

Suitable drug excipient includes, but are not limited to calcium carbonate, calcium phosphate, various types of saccharide and various types of starch, cellulose derivative, gelatin, vegetable oil, polyethylene glycols, sodium stearate, glyceryl monostearate, Pulvis Talci, sodium chloride, glycerol, propylene glycol, water, ethanol etc.If desired, described compositions can also contain a spot of wetting agent or emulsifying agent or pH buffer agent.These compositionss can also adopt forms such as solution, suspension, Emulsion, tablet, pill, capsule, powder, slow releasing preparation.

Be used for the added technique of active component preparation and administration can be in latest edition " Remington ' sPharmaceutical Sciences; " Mack Publishing Co., Easton finds among the PA, and the listed in this article document intactly is incorporated herein by reference.

Pharmaceutical composition described herein can also comprise suitable solid or gel phase carrier or excipient.The example of this class carrier or excipient includes, but are not limited to calcium carbonate, calcium phosphate, various saccharide, starch, cellulose derivative, gelatin and polymer, such as polyethylene glycols.

Thus can be in a usual manner, use one or more pharmaceutically acceptable carrier preparations that comprise excipient and auxiliary agent to be used for pharmaceutical composition of the present invention, described pharmaceutically acceptable carrier helps active component is processed into the preparation that can use on medicine.Appropriate formulation depends on the route of administration of selection.

The preparation that is used for oral delivery can comprise standard vector, such as under pharmaceutical grade mannitol, lactose, starch, magnesium stearate, the saccharin sodium, cellulose, magnesium carbonate etc.The case description of suitable pharmaceutical carrier is in " Remington ' s PharmaceuticalSciences " of E.W.Martin..This based composition contains the chemical compound for the treatment of effective dose, and preferred purified form and an amount of carrier are so that make the dosage form that is suitable for patient's administration.Preparation should be suitable for administering mode.

For oral administration is easy to by active component and pharmaceutically acceptable carrier well-known in the art are merged the preparation active component.This class carrier can be mixed with tablet, pill, lozenge, capsule, liquid, gel, syrup, unguentum, suspension etc. with active component of the present invention, so that the oral absorption of patient.Use solid excipient, grind the gained mixture alternatively, and if desired, obtain the pharmaceutical preparation that label or ingot core prepare oral application adding proper auxiliary agent post-treatment granulate mixture.Suitable excipient is in particular: filler such as saccharide, comprises lactose, sucrose, mannitol or sorbitol; Cellulosics, for example corn starch, wheaten starch, rice starch, potato starch, gelatin, tragakanta, methylcellulose, hydroxypropyl methyl-cellulose, sodium carboxymethyl cellulose; And/or physiologically acceptable polymer, such as polyvinylpyrrolidone (PVP).If desired, can add disintegrating agent, such as crospolyvinylpyrrolidone, agar or alginic acid or its salt, such as sodium alginate.

Suitable coatings is provided for the ingot core.For this purpose, can use priming, it can contain arabic gum, Pulvis Talci, polyvinylpyrrolidone, carbomer gel, Polyethylene Glycol, titanium dioxide, lacquer solution and appropriate organic solvent or solvent mixture alternatively.Dyestuff or pigment can be joined in tablet or the lozenge coatings so that differentiate or characterize the various combination of active component dosage.

The pharmaceutical composition that can orally use comprises by pushing of making of gelatin-formula capsule and by gelatin and plasticizer, the soft seal capsule of making such as glycerol or sorbitol.Push-the formula capsule can contain active component with such as this class filler of lactose, such as this class binding agent of starch, such as Pulvis Talci or this series lubricant agent of magnesium stearate and the optional mixture of stabilizing agent.In soft capsule, active component can be dissolved in or be suspended in suitable liquid, such as fatty oil, liquid paraffin or liquid macrogol class.In addition, can add stabilizing agent.All oral medicinal preparations all should exist with the dosage of the route of administration that is suitable for selecting.

In order to carry out transdermal administration, described compositions can be mixed with the form of gel, cream, ointment, paste, lotion, Emulsion, suspension, aerosol, spray, foam, serosity, swab, pledget, pad or patch.The preparation that is used for transdermal delivery generally can comprise carrier, such as water, liquid alcohols, liquid polyhydric alcohols, liquid macrogol class, liquid esters, liquid amide class, liquid protein hydrolyzate, liquefied alkyl protein hydrolysate, liquid lanolin, lanolin derivative, glycerol, mineral oil, siloxanes, vaseline, lanoline, fatty acid, vegetable oil, parabens, wax be usually used in the similar substance of topical composition.Can comprise in the preparation capable of permeating skin of the present invention and well known to a person skilled in the art various additives.For example, solvent can be used for some active component material of solubilising.Other extra regulator comprises dermal osmosis accelerator, opacifier, antioxidant, gellant, thickening agent, stabilizing agent etc.

In order to suck administration, described compositions can adopt the tablet or the lozenge form of preparation in a usual manner.

In order to carry out inhalation, self-pressurization medicated bag or use spray form in the aerosol apparatus of suitable propellant to send to be used for active component of the present invention advantageously, described propellant for example is dichlorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane or carbon dioxide.With regard to pressurized aerosol, can measure dosage unit with the amount of sending metering by mounted valve.For example, can prepare capsule and cartridge case that the gelatin that is used for inhaler or insufflator is made, they contain active component and suitable powder substrate, such as the mixture of powders of lactose or starch.

Can be parenterai administration, for example bolus injection or continuous infusion are prepared active component described herein.For example injection preparation can be mixed with at ampoule or contain unit dosage forms in the multi-dose container of antiseptic of interpolation alternatively.Described compositions can be the suspension in oil or water carrier, solution or Emulsion, and can contain reagent preparation, such as suspending agent, stabilizing agent and/or dispersant.

The parenterai administration pharmaceutical composition comprises the active component water capacity liquid formulation of water-soluble form.In addition, the suspension of active component can be prepared into suitable oily injection suspension.Suitable lipophilic solvent or carrier comprise: fatty oil, such as Oleum sesami; Or the synthetic fatty acid esters, such as ethyl oleate, triglyceride or liposome.Aqueous injection suspension can contain the material that increases this suspension viscosity, such as sodium carboxymethyl cellulose, sorbitol or glucosan.This suspension can also contain suitable stabilizers alternatively or increase the solubilization of active ingredient degree so that can prepare the reagent of high concentrated solution.

For example, use suppository base commonly used, described compositions can be mixed with rectal compositions such as cocoa butter or other glyceride type, such as suppository or enema,retention.

Pharmaceutical composition described herein can also comprise suitable gel phase carrier or excipient solid.The example of this class carrier or excipient includes, but are not limited to calcium carbonate, calcium phosphate, various saccharide, cellulose derivative, gelatin and polymer, such as polyethylene glycols.

If desired, compositions of the present invention can be made medicated bag or dispenser device, such as the test kit of FDA approval, it can contain one or more unit dosage forms that contains active component.For example, medicated bag can comprise metal or plastic foil, such as blister pack.Can attach the administrable description in medicated bag or the dispenser device.The government authorities that can also attach management drug manufacture, use or sale in medicated bag or the dispenser goes out the announcement form on the container of being attached to of certificate, and this announcement reflects that the dosage form of compositions or people or beastly administration have obtained the approval of administrative organization.For example, this class announcement can be labeled as the product inset that approval is used for prescription drugs or approval by FDA Food and Drug Administration.Can also prepare and comprise H of the present invention ₁Agonist and optional other active component with compatibility pharmaceutical carrier composition prepared, put it into suitable containers, and the disease of labelling shown in being used for the treatment of, as what describe in detail herein.

Extra purpose of the present invention, advantage and new feature are apparent to those skilled in the art when checking the following example, but these embodiment have not been used for the qualification effect.In addition, as indicated above and hereinafter in the claim part claimed various embodiments of the present invention and various aspects in the following example, provided support separately with experiment method.

Embodiment

Explain the present invention referring now to hereinafter embodiment and in conjunction with foregoing description in non-limiting mode.

Embodiment 1

Carry out following research so that estimate of the effect of betahistine oral administration to food intake:

Recruit 10 obesities, but healthy people.Their feature is as shown in table 1 during recruitment.Culling level in this research is to be lower than 18 years old age, active disease, use medicine, known allergy or the contraindication of using betahistine is arranged.

Every individual randomization is distributed so that accept betahistine 16mg or placebo at 10:00 and 16:00.The body weight, the heat that obtain when the 0th, 14 and 28 day of this research in the same day are taken in (recalling in 24 hours) and appetite (VAS, visual analogue scale).Specified individual is unrestricted according to its appetite diet.

Use t-test evaluation significance,statistical.BMI represents Body Mass Index.

Table 1. patient characteristic
				The average heat of treatment age body weight (kg) BMI is taken in (kcal) average appetite scoring (VAS)	Betahistine 48 ± 9 93 ± 17 35.1 ± 7.3 975 ± 472 45 ± 15	Placebo 38 ± 15 90 ± 4 32.71.7 1397 ± ± 693 50 ± 12	NS NS NS NS NS
NS represents not have significance,statistical (p value＞0.05)

In the individuality of 20 recruitments, do not finish this research and from final analysis, get rid of for 8:

No. 3 individualities (placebo) withdraw from the 3rd day because of side effect-weakness.

No. 5 individualities (betahistine) can't make her consume any food the 5th day report anorexia.Specify her dosage to reduce by half and from interpretation of result, get rid of.

No. 9 individualities (placebo) are excluded because of the violation scheme.

No. 11 individualities (placebo) withdraw from the 4th week because of influenza.

No. 13 individualities (placebo) lose the chance of following up a case by regular visits to.

No. 15 individualities (betahistine) withdraw from the 4th week because of influenza.

No. 16 individualities (placebo) withdraw from the 3rd week because of dyspnea.

No. 17 individualities (betahistine) lose the chance of following up a case by regular visits to.

Also studied the betahistine treatment to the effect of the total amount of heat absorption of the participant in this research with to the concrete effect that consumes of fat, carbohydrate and protein.With the data rows that obtains in attached Figure 4 and 5.

As can be observed in accompanying drawing 4, find to use the betahistine treatment to compare and to reduce the total amount of heat absorption with placebo.Before heat is taken in treatment the 14th day and reduced to treatment 80% of level, and in the time of the 28th day, reduce to 68% of the preceding level of treatment.In accepting the individuality of placebo, do not observe reduction.

As can be observed in accompanying drawing 5, a small amount of reduction (6%) that carbohydrate consumes only appears although use betahistine to treat, and fat and proteinic consumption have reduced 49% and 35% respectively.Use the patient of placebo treatment increasing by 24%, 3% and 37% aspect carbohydrate, fat and the protein depletion respectively simultaneously.

Clearly illustrate that thus betahistine has significantly reduced the heat absorption and the fat consumption of individual human.Therefore, give betahistine and can be used to improve individual human effectively to the compliance of heat restriction and reduced the demand that individual human consumes fat.

Also studied the effect that the betahistine administration changes body weight.To the results are shown in the accompanying drawing 6.In the treatment group, there are 4 in this research process, to lose weight in 7 individualities, and by comparison, only have 1 in 5 in the placebo group The above results is arranged above 1kg.

These clinical datas clearly illustrate that betahistine is the active drug that is used for weight maintenance.

Embodiment 2

In another day, use 16mg betahistine 2 treatments women's every day that health is overweight 1 month, but change without any meals.As viewed in blood testing, betahistine treatment front and back have been measured some metabolite level of this women and it have been listed in the following table 2.

Table 2

	The 0th day	The 30th day	Change
				T-CHOL	167	155	-7％
The HDL-cholesterol	54	58	+7％
				The LDL-cholesterol	99	84	-15％
Triglyceride	69	62	-10％
				Fructosamine	195	202	+4％

As viewed in the table 2, the result shows that in the 30-that is studied days time bar processes, individual total cholesterol level reduces, and correspondingly the LDL-cholesterol levels reduces and the HDL-cholesterol levels increases.The level of triglyceride reduces, and the level of fructosamine extremely increases slightly.Therefore reach a conclusion, its fat picked-up of individual limit (as the LDL-cholesterol reduce confirm) and do not reduce its carbohydrate picked-up (as the fructosamine level increase slightly confirm), show that betahistine has specific effect to the fat picked-up that reduces individual human.

Be appreciated that some feature of the present invention of for clarity sake describing can also provide with compound mode in single embodiment in each embodiment of context.On the contrary, the different characteristic of describing in the single embodiment of context for simplicity's sake also can be respectively or is provided with the sub-portfolio form of any appropriate.

Although be described in conjunction with a specific embodiment thereof the present invention, obviously can there be the scheme of many alternatives, modifications and variations, this is apparent to those skilled in the art.Therefore, comprise that all treatments are alternative, the scheme of modifications and variations, they all belong to the essence and the scope of the claim that awaits the reply.

The full content of all open source literatures, patent and the patent application mentioned in this description is introduced this description as a reference, just as will shown in every piece of open source literature, patent or patent application identical with the degree that is incorporated herein by reference respectively especially.In addition, citation in this picked-up or any list of references of determining should be considered as admitting that this class list of references is as utilizing at prior art of the present invention.

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Claims (46)

1. the food intake of treatment mediator individuality is the method for useful disease, and this method comprises the H that described individuality is treated effective dose ₁Agonist, described H ₁Agonist has at least 3 hours pharmacology half-life.

2. improve the method for individual human to the compliance of heat restriction, this method comprises the H1 agonist of described individuality being treated effective dose, described H ₁Agonist has at least 3 hours half-life.

3. reduce the method that individual human consumes the demand of fat, this method comprises the H that described individuality is treated effective dose ₁Agonist, described H ₁Agonist has at least 3 hours half-life.

4. treat the method for the disease relevant with metabolism disorder in the individual human, this method comprises treats the H of effective dose to the described individuality that these needs are arranged ₁Agonist, described H ₁Agonist has at least 3 hours pharmacology half-life.

5. the method for total cholesterol level in the reduction individual human, this method comprises treats the H of effective dose to the described individuality that these needs are arranged ₁Agonist, described H ₁Agonist has at least 3 hours pharmacology half-life.

6. low-density lipoprotein cholesterol level and increase the method for HDL-C level in the reduction individual human, this method comprises treats the H of effective dose to the described individuality that these needs are arranged ₁Agonist, described H ₁Agonist has at least 3 hours pharmacology half-life.

7. the method for triglyceride levels in the reduction individual human, this method comprises the H1 agonist of the described individuality that these needs are arranged being treated effective dose, described H ₁Agonist has at least 3 hours pharmacology half-life.

8. each described method among the claim 1-3, the wherein said pharmacology half-life was at about 3 hours-5 hours.

9. each described method among the claim 1-8, wherein said H ₁Agonist also is H ₃Antagonist.

10. each described method among the claim 1-9, wherein said H ₁Agonist is characterised in that the blood brain barrier permeability.

11. each described method among the claim 1-10, wherein said H ₁Agonist is selected from betahistine, betahistine metabolite, the pharmaceutically acceptable salt of betahistine, betahistine prodrug, betahistine derivant and combination arbitrarily thereof.

12. the described method of claim 11, wherein said betahistine metabolite are selected from 2-(2-amino-ethyl)-pyridine and 2-(2-ethoxy)-pyridine.

13. the described method of claim 11, wherein said betahistine salt are selected from betahistine dihydrochloride, betahistine mesylate and betahistine trimebutine maleate.

14. the described method of claim 11, wherein said betahistine derivant is selected from the chemical compound that general formula I is represented:

General formula I

R wherein ₁-R ₁₂Be selected from hydrogen, alkyl, cycloalkyl and aryl independently of one another.

15. each described method among the claim 1-14, wherein said administration is undertaken by being selected from following approach: in oral, transdermal, intravenous, subcutaneous, intramuscular, intranasal, the atrium, Sublingual, rectum, stride mucosa, intestinal, suck, in the marrow, in the sheath, directly in the ventricle, intraperitoneal and ophthalmic approach.

16. the described method of claim 15, wherein said administration is undertaken by oral.

17. the described method of claim 15, wherein said administration is undertaken by transdermal.

18. each described method among the claim 1-14, wherein said administration is oral by being selected from, transdermal, the approach of sucking, stride mucosa, rectum and Sublingual approach carry out.

19. each described method among the claim 1-18, wherein said treatment effective dose is in about 2mg/ unit dose-Yue 96mg/ unit dose scope.

20. the described method of claim 19, wherein said treatment effective dose is in the scope of about 10mg/ days-Yue 50mg/ days.

21. each described method among the claim 1-20 is wherein with about 4 times/day of the about 1-of described administration.

22. the described method of claim 21 is wherein carried out described administration 2 times/day.

23. the described method of each claim among the claim 1-18 is wherein carried out described administration according to individual hungry situation about taking place.

24. each described method among the claim 1-18 is wherein carried out described administration, makes under the situation that does not limit individual food intake, whose body weight reduces the scope at about 1-about 5%.

25. the described method of claim 24 is wherein carried out described administration, makes not carry out the downward modulation of H1 receptor.

26. the described method of claim 1, wherein said disease are selected from gluttony, disease overweight, fat and that therefore cause or aggravate.

27. the described method of claim 1, wherein said disease is relevant with psychological factor.

28. the described method of claim 27, wherein said disease comprise binge eating disorder, night eating syndrome, mandatory diet, mandatory feed and bulimia nerovsa.

29. the described method of claim 26, wherein said disease is relevant with Drug therapy.

30. the described method of claim 29, wherein said medicine is selected from steroid hormone and psychoactive drug.

31. the described method of claim 26 wherein causes because of described disease or the described disease of aggravating is selected from muscle skeleton disease, cardiovascular disorder, dermatosis, sleep disorder, metabolic disease, diabetes and the disease relevant with diabetes.

32. the described method of claim 4, wherein said disease is relevant with higher fatty acid consumption.

33. the described method of claim 4, wherein said disease are unusual lipidemia.

34. the described method of claim 33, wherein said disease are hypercholesterolemia.

35. each described method among the claim 1-31, wherein said H ₁Agonist constitutes the ingredient of pharmaceutical composition, and described pharmaceutical composition further comprises pharmaceutically acceptable carrier.

36. the described method of claim 35, wherein said pharmaceutical composition are slow releasing composition.

37. each described method among the claim 1-35 further comprises the extra activating agent of described individuality being treated effective dose.

38. the described method of claim 37, wherein said extra activating agent is selected from the on-steroidal AID, muscle relaxant, antigout drug, immunosuppressant, influence the medicine of bone mineralising, the alpha-adrenergic blockade medicine, angiotensin converting enzyme inhibitor, anti-arrhythmic, the anticoagulant medicine, antiplatelet drug, the thrombolytic medicine, BABD, calcium channel blocker, the central action medicine, the Folium Digitalis Purpureae medicine, nitrate, the periphery 1 adrenergic antagonists, vasodilation, the acne medicine, antipruritic, corticosteroid, antipsoriatic, antieczematic, sleeping pill, antidepressants, antihistaminic, sulfonylureas, meglitinide, biguanide, thiazolidinedione, alpha-glucosidase inhibitor, PPAR-γ antagonist, insulin, fibrate, the HMG-CoA reductase inhibitor, bile acid multivalent chelator, cholesterol absorption inhibitor, nicotinic acid, its derivant, its analog and metabolite thereof and their mixture arbitrarily.

39. the described method of claim 37, wherein said extra activating agent is a weight control agent.

40. the described method of claim 39, wherein said weight control agent are appetite suppressant.

41. the described method of claim 40, wherein said appetite suppressant are selected from norepinephrine energy activating agent, 5-hydroxy tryptamine energy activating agent, dopaminergic activity agent, interior Cannabined receptor blocker or its combination.

42. each described method among the claim 1-39 is wherein carried out described administration according to individual hungry situation about taking place.

43. each described method among the claim 1-42 is used to induce lose weight.

44. each described method among the claim 1-42 is used for keeping losing weight or prevent behind the reducing diet or the weight increase of process.

45. each described method among the claim 1-42 is used for preventing existing the weight increase of the individuality of the disease relevant with weight increase.

46. the described method of claim 34, further comprise the extra activating agent of described individuality being treated effective dose, described extra activating agent is selected from fibrate, HMG-CoA reductase inhibitor, bile acid multivalent chelator, cholesterol absorption inhibitor, nicotinic acid, its derivant, its analog and metabolite thereof and they mixture arbitrarily.

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