CN1909903A

CN1909903A - Compositions of an anticonvulsant and mirtazapine to prevent weight gain

Info

Publication number: CN1909903A
Application number: CN 200580002274
Authority: CN
Inventors: K·M·加德; K·R·R·克里希南
Original assignee: Duke University
Current assignee: Orexigen Therapeutics Inc; Duke University
Priority date: 2004-01-13
Filing date: 2005-01-11
Publication date: 2007-02-07

Abstract

Disclosed are compositions for affecting weight loss comprising a first compound and a second compound, where the first compound is a psychotherapeutic agent and the second compound is a anticonvulsant. Also disclosed are methods of affecting weight loss, increasing energy expenditure, increasing satiety in an individual, or suppressing the appetite of an individual, comprising identifying an individual in need thereof and treating that individual with a psychotherapeutic agent and an anticonvulsant.

Description

Be used to influence the anticonvulsant that loses weight and the compositions of psychosis

Related application

The application requires to be filed on October 5th, 2004 by Gadde etc., the U.S. Provisional Patent Application serial number 60/616 of " COMPOSITIONS OF AN ANTICONVULSANT AND ANANTIPSYCHOTIC DRUG AND METHODS OF USING THE SAME FORAFFECTING WEIGHT LOSS " by name, 393, by the U.S. Provisional Patent Application serial number 60/567 of Ranga Krishnan in " the COMPOSITIONS FORAFFECTING WEIGHT LOSS " by name of submission on May 3rd, 2004,896, equal to submit on January 13rd, 2004 by Gadde, the U.S. Provisional Patent Application serial number 60/535 of " METHOD FOR REDUCINGWEIGHT GAIN RISK ASSOCIATED WITH ANTIDEPRESSANTTHERAPY " by name, 800, with equal by Gadde to submit on January 13rd, 2004, and the U.S. Provisional Patent Application serial number 60/535 of " METHOD FOR REDUCING WEIGHT GAINRISK ASSOCIATED WITH ANTIDEPRESSANT THERAPY " by name, 799 priority is incorporated their full contents into this paper as a reference.

Background of invention

Invention field

The present invention is used in the individuality treatment of obesity and is used to influence the pharmaceutical composition that loses weight and the field of method.

Association area is described

Obesity is to accumulate the disease that excess fat is a feature in vivo.Obesity has been considered as the one of the main reasons of disease, and has occurred as global problem.In the general population, the case of the increase of the cancer of complication such as hypertension, non-insulin-dependent diabetes mellitus, arteriosclerosis, dyslipidemia, some form, sleep apnea and osteoarthritis relates to the case of the obesity of increase.

Obesity defines according to Body Mass Index (BMI).Obesity is calculated as weight (kg)/[highly (m)] ²According to U.S. CDC (CDC) and (the WorldHealth Organization Physical status:The use and interpretation ofanthropometry.Geneva of The World Health Organization (WHO), Switzerland:World Health Organization 1995.WHOTeclanical Report Series) guidance, for the adult who surpasses 20 years old, BMI falls into one of these classifications: will be considered as shortage in weight in 18.5,18.5-24.9 be normal, 25.0-29.9 be overweight, and with 30.0 and more than be considered as obesity.

Before 1994, usually obesity is considered as psychological problems.1994, the discovery of adipostatic hormone leptin (Zhang et al., " Positional cloning of the mouse obese geneand its human homologue, " Nature 1994; 372:425-432) propose such understanding, promptly in some cases, obesity may have biochemical basis.The inference of this understanding is the viewpoint that treatment of obesity can realize by chemical method.From that time, there are many such chemical therapeutic methods to come into the market.Foremost during these are attempted is to introduce Fen-Phen, the combination of fenfluramine and phentermine.Unfortunately, find that fenfluramine causes heart-valve complication, this causes the death of user in some cases.From then on, fenfluramine has withdrawed from market.About other combination therapy, some limited success particularly in the field of spirituality eating disorder, have been obtained.Such example is Devlin, et al., and Int.J.Eating Disord.28:325-332,2000, wherein the combination of phentermine and fluoxetine is presented in the treatment carousing-eating disorders some effects.Certainly, this disease is a problem for fraction colony only.

Except satisfying medically those individualities of the strict difinition of obesity, a considerable amount of adults are overweight.The individuality that these are overweight will also benefit from the availability of effective slimming compositions.Therefore, unsatisfied needs are arranged in the art, promptly providing to influence the pharmaceutical composition that loses weight, and can not have other disadvantageous side effect.

Summary of the invention

The invention discloses and be used for the compositions that loses weight of influence (affecting), it comprises first chemical compound and second chemical compound, and wherein said first chemical compound is that psychotropic drug and described second chemical compound are anticonvulsants.

The invention also discloses the method for the risk that reduces the weight increase relevant with using antidepressants or other psychosis.

Detailed description of the preferred embodiments

As if upgrade relevant with cardiovascular side effects and the toxicity probability of monobasic antidepressants still less, described cardiovascular side effects and toxicity and former generation antidepressants are associated such as tricyclics or oxidase inhibitor (MAOIs).At present, upgrade monobasic antidepressants and comprise selectivity 5-hydroxy tryptamine reuptake inhibitor (for example, fluoxetine, fluvoxamine, Sertraline, paroxetine, citalopram, and escitalopram), venlafaxine, duloxetine, nefazodone, mianserin setiptiline, viqualine trazodone, cianopramine, and mirtazapine.The weight increase is about upgrading monobasic antidepressants, particularly about paroxetine (PAXIL ^PAXIL CR ^)) and subject matter (Fava, J.Clin.Psych.61 (suppl.11): the 37-41 (2000) of mirtazapine; Carpenter et al, J.Clin.Psych.60:45-49 (1999); Aronne et al, J.Clin.Psych.64 (suppl.8): 22-29 (2003), both full contents are incorporated this paper into as a reference with them).Major part is used paroxetine, mirtazapine, and other antidepressants are such as venlafaxine (EFFEXOR ^, EFFEXOR XR ^) treatment weight in patients significantly increase.These patients of great majority find owing to treatment, even after interrupting using specific antidepressants, weight reduction is difficult.Weight is increased among the patient to be unacceptable and to be main cause (Cash et al, the Percep.Motor Skills 90:453-456 (2000) that does not comply with for anti-depressant therapy; Deshmukh et al, Cleveland Clinic J.Med.70:614-618 (2003), both full contents are incorporated this paper into as a reference with them).Do not fettered, think that the possible mechanism that increases for observed weight comprises the antagonism and the anticholinergic effect in the paroxetine situation of the histamine H1-receptor of mirtazapine by any specific theory.

Zonisamide is commercially available anticonvulsant, and it is used as the auxiliary treatment for the adult with part epilepsy.Do not fettered by any specific theory, think antiepileptic activity mechanism seemingly: the 1) sealing of sodium-passage; With, 2) the inwardly minimizing of T type calcium current.In addition, zonisamide combines with GABA/ benzene diaza  receptor complex, and can not be created in the variation in the chloride outflow.In addition, zonisamide promotes 5-hydroxy tryptamine and dopaminergic nerve transmission and has weak inhibitory action to carbonic anhydrase.

Zonisamide has been presented among the patient of performance initial stage obesity and has caused tangible weight saving (suitable with commercially available appetrol) (Gadde etc., JAMA 289:1820-1825 (2003) incorporates its full content into this paper as a reference).Supposition be zonisamide to 5-hydroxy tryptamine, the influence of the CNS concentration of dopamine and carbonic anhydrase is that this effect is responsible for.Exist zonisamide to increase evidence (Hashiguti et al, the J Neural Transm Gen Sect.1993 of 5-hydroxy tryptamine and dopamine synthesis rate; 93:213-223; Okada et al, Epilepsy Res.1992; 13:113-119 incorporates their both full contents into this paper as a reference).There is other evidence, shows that zonisamide stimulates dopamine D ₂Receptor (Okada et al, Epilepsy Res.1995; 22:193-205 incorporates its full content into this paper as a reference).Zonisamide is tolerated well, compares with placebo treatment, and fatigue is the only side effect that takes place more frequently.

Therefore, the inventor has determined to use usually anticonvulsant reducing or preventing and use medicine such as antidepressants, particularly upgrades monobasic antidepressants, and antihistaminic and 5-hydroxytryptamine receptor antagonist are such as 5HT ₂During the weight that the C receptor antagonist is relevant increases is effective.

Aspect of the present invention provides, and to small part, reduces the method for the risk of the weight increase relevant with anti-depressant therapy.These methods comprise uses the anticonvulsant that promotes that weight reduces.Method of the present invention is effective in the individuality that increases at the weight irrelevant with using antidepressants also.

Therefore, aspect first, the present invention relates to the compositions that is used for the treatment of obesity or is used to influence weight saving, described compositions comprises first chemical compound and second chemical compound, and wherein said first chemical compound is that the psychotropic drug and second chemical compound are anticonvulsants.

In certain embodiments, described anticonvulsant is being effective aspect the minimizing convulsions in mammal.Described mammal can be selected from by mice, rat, and rabbit, Cavia porcellus, Canis familiaris L., cat, sheep, goat, cattle, primate is such as the group of monkey, chimpanzee and ape and people's composition.

In some embodiments, psychotropic drug is antidepressants, antimigrane, antibipolar, anti-mania medicine, mood stabilizer, or antuepileptic.The example of antidepressants comprises paroxetine and mirtazapine.The example of Antimigrane medicine comprises sumatriptan, Zolmitriptan, elatriptan and other triptans.The example of Antibipolar medicine comprises, lithium, valproate, carbamazepine (carbamezepine), oxidation horse Xiping (oxycarbamezepine), lamotrogine, tiagabine, olanzapine, clozapine, risperidone, Quetiapine, Aripiprazole, Ziprasidone and benzene diaza  class.In some embodiments, psychotropic drug comprises lithium salts.In other embodiment, psychotropic drug is a valproate, and it comprises the salt of valproate (valproate) and the free acid form of valproic acid.The pharmaceutical salts of these medicines or prodrug, the slow releasing preparation of said medicine, and in the combination of said medicine is also included within.In some embodiments, lithium salts can be lithium carbonate or Lithium Citrate de.In some embodiments, the lithium medicine exists with the form of slow releasing preparation.

In some embodiments, the present invention relates to comprise the compositions of zonisamide and lithium salts, it is as described herein and exist with the form of preparation as herein described.In other embodiment, the present invention relates to compositions, described compositions comprises zonisamide and valproic acid, or the different salt of its pharmaceutical salts such as valproate, its ester, amide or prodrug.

In certain embodiments, antidepressants are chemical compounds of formula I

Wherein W is a nitrogen, CH, oxygen, or sulfur;

R ₁Be selected from by hydrogen, randomly the C of Qu Daiing _1-6Alkyl, the randomly C of Qu Daiing _3-8Cycloalkyl, the randomly C of Qu Daiing _2-6Alkenyl, the randomly C of Qu Daiing _2-6Alkynyl, the randomly C of Qu Daiing _1-6The group that alkoxyalkyl and the aryl that randomly replaces and aralkyl are formed;

R ₂, R ₃, R ₄, and R ₅Each is independently selected from by hydrogen, halogen, the randomly C of Qu Daiing _1-6Alkyl, the randomly C of Qu Daiing _1-6Alkoxyl, the randomly C of Qu Daiing _2-6Alkenyl, the randomly C of Qu Daiing _2-6Alkynyl, the randomly C of Qu Daiing _1-6Alkoxyalkyl, the randomly C of Qu Daiing _1-6Alkylthio group, whole haloalkyl, CN, COR ₁₀, CONHR ₁₀, assorted alkyl and NO ₂The group of forming;

R ₆, R ₇, R ₈, and R ₉Each is independently selected from by hydrogen, halogen, the randomly C of Qu Daiing _1-6Alkyl, the randomly C of Qu Daiing _1-6Alkoxyl, the randomly C of Qu Daiing _2-6Alkenyl, the randomly C of Qu Daiing _2-6Alkynyl, the randomly C of Qu Daiing _1-6Alkoxyalkyl, the randomly C of Qu Daiing _1-6Alkylthio group, whole haloalkyl, CN, COR ₁₀, CONHR ₁₀, assorted alkyl and NO ₂The group of forming;

Term " pharmaceutical salts " refers to the preparation of chemical compound, and the preparation of described chemical compound does not cause the obvious stimulation to the biology of using it, and does not eliminate the biological activity and the character of chemical compound.Pharmaceutical salts can be by making all example hydrochloric acids of chemical compound of the present invention and mineral acid, hydrobromic acid, and sulphuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, reactions such as salicylic acid obtain.Pharmaceutical salts can also form salt such as ammonium salt by making chemical compound of the present invention and alkali reaction, alkali metal salt such as sodium or potassium salt, alkali salt such as calcium or magnesium salt, organic base is such as hexanamine, N-methyl D-glycosamine, the salt of trihydroxymethylaminomethane, and with aminoacid such as arginine, the salt that lysine etc. form.

" prodrug " refers to be converted in vivo the medicament of parent drug.Prodrug often is useful, because in some cases, they can be easier to use than parent drug.They can, for example, by the Orally administered biological utilisation that can be, and parent drug is quite different.Prodrug can also have the dissolubility above the raising of parent compound in pharmaceutical composition, maybe can show the palatability of increase or be easier to preparation.Be not limited under this situation, an example of prodrug is a chemical compound of the present invention, described chemical compound of the present invention as ester (" prodrug ") thus use and promote it to pass the transmission that water solubility wherein is unfavorable for the cell membrane that moves, but in case in cell, described chemical compound of the present invention is hydrolyzed to carboxylic acid by metabolism, active individual, water solubility is favourable in described cell.Another example of prodrug can be the small peptide (amino acids) in conjunction with acidic-group, thereby wherein said peptide is provided active part by metabolism.

In another embodiment, described antidepressants are tricyclics.The example of tricyclics includes, but not limited to imipramine, desipramine, trimeprimine, nortriptyline, clomipramine, doxepin, amitriptyline, maprotiline, protriptyline, dosulepin (dothiapen), setiptiline, cianopramine, and maprotiline.Maprotiline, a kind of very effective antidepressants are not extensive use of, because it causes the risk of epilepsy.The combination of maprotiline and zonisamide or other anticonvulsant has the other benefit of the risk that reduces epilepsy, except reducing the risk that increases owing to the weight of using antidepressants to cause.For zonisamide combination with clomipramine, the three cyclisation things that the risk of another kind of and relative higher epilepsy is correlated with, they also are correct.

In another embodiment, described antidepressants are oxidase inhibitor (MAO inhibitor).The example of MAO inhibitor includes, but not limited to phenelzine (Nardil ^), tranylcypromine (Parnate ^), isocarboxazid (Marplan ^), moclobemide (Aurorix ^), brofaromine, cimoxatone, clorgiline, and lazabemide.

In certain embodiments, antihistaminic is setiptiline (setiptilinie), teciptiline, ORG8282 (Organon, Netherlands), or MO 8282 (Mochida, Japan) one of them.

In some embodiments, described 5HT _2CReceptor antagonist is selected from colozapine, N-desmethylclozapine, and clozapine-N-oxide.

In some embodiments, second chemical compound is an anticonvulsant.The example of anticonvulsant comprises barbiturate (ester), benzene diaza  class, GABA analog, hydantoins, miscellaneous multiple anticonvulsant, phenyl triazine, and butanimide.The example of barbiturate (ester) comprises pentobarbital.The example of benzene diaza  class comprises clonazepam, chlorine nitrogen , benzene diaza  and diazepam.The example of GABA analog comprises tiagabine, pregabalin, and gabapentin.The example of hydantoins comprises fosphenytoin, phenytoin and 5,5-phenytoin.The example of miscellaneous anticonvulsant comprises carbamazepine, valproate, valproic acid, two valproic acids (divalproex), felbamate, levetiracetam, carbamazepine, topiramate, oxcarbazepine and zonisamide.The example of phenyl triazine is a lamotrigine.The example of butanimide comprises mesuximide and ethosuximide.The slow releasing preparation of said medicine, its pharmaceutical salts or prodrug, and in the combination of said medicine is also included within.

In one embodiment, the present invention relates to the compositions that is used for the treatment of obesity or is used to influence weight saving, described compositions comprises zonisamide and mirtazapine.In another embodiment, the compositions that the present invention relates to be used for the treatment of obesity He be used to influence weight saving, described compositions comprises zonisamide and paroxetine.In another embodiment, the compositions that the present invention relates to be used for the treatment of obesity He be used to influence weight saving, described compositions comprises zonisamide and venlafaxine.

In certain embodiments, the present invention relates to be used to influence the compositions that weight reduces or is used to prevent weight to increase, described compositions comprises zonisamide and mirtazapine.In other embodiments, the compositions that the present invention relates to be used for weight saving or be used to prevent weight to increase, described compositions comprises amfebutamone and mirtazapine.In other embodiments, the present invention relates to be used to influence the compositions that weight reduces or is used to prevent weight to increase, described compositions comprises zonisamide and setiptiline.In other embodiments, the present invention relates to be used to influence the compositions that weight reduces or is used to prevent weight to increase, described compositions comprises amfebutamone and setiptiline.In other embodiments, the present invention relates to influences the compositions that weight reduces or prevention weight increases, and described compositions comprises zonisamide, amfebutamone, and mirtazapine.In other embodiments, the present invention relates to influences the compositions that weight reduces or prevention weight increases, and described compositions comprises zonisamide, amfebutamone and setiptiline.

In whole present disclosure, be appointed as when mentioning, for example zonisamide, amfebutamone, setiptiline, mirtazapine, or during the particular compound of valproate, should be understood that the scope of present disclosure contains the pharmaceutical salts of indication chemical compound, ester, amide or prodrug.In addition, if specified chemical compound comprises chiral centre, the scope of present disclosure also comprises the compositions of the racemic mixture that comprises two kinds of enantiomers, and the compositions that comprises the every kind of enantiomer that is substantially free of other enantiomer separately.Therefore, for example, this paper is intended to comprise the compositions of the S enantiomer that is substantially free of the R enantiomer, or comprises the compositions of the R enantiomer that is substantially free of the S enantiomer.So-called " being substantially free of " means, and described compositions comprises and is less than 10%, or is less than 8%, or is less than 5%, or is less than 3%, or is less than 1% less important enantiomer.Surpass one chiral centre if specified chemical compound comprises, the scope of present disclosure also comprises the compositions of the mixture that comprises various diastereomers, and the every kind of diastereomer that comprises the diastereomer that is substantially free of other.Therefore, for example, the mirtazapine that is purchased is the racemic mixture that comprises two kinds of independent enantiomers." mirtazapine " of indication comprises the compositions of the racemic mixture that comprises mirtazapine in whole present disclosure, comprise the compositions of (+) enantiomer that is substantially free of (-) enantiomer and comprise the compositions of (-) enantiomer that is substantially free of (+) enantiomer.

In yet another aspect, the present invention relates to influence the method for weight saving, described method comprises that evaluation needs the individual of its and treats this individuality with psychotropic drug and anticonvulsant.Described psychotropic drug and anticonvulsant are as mentioned above.

In certain embodiments, individuality has the Body Mass Index (BMI) above 25.In other embodiment, individuality has the BMI above 30.In other embodiments, individuality has the BMI above 40.Yet in some embodiments, individuality can have and is less than 25 BMI.In some of these embodiments, it can be useful for health that influences weight saving or cosmetic purpose, reduces BMI thus even further.In some embodiments, because the result of anti-depressant therapy, individuality has reached above-mentioned BMI.In other embodiments, under the situation of not using antidepressants, individuality reaches above-mentioned BMI.

In some embodiments, the treatment step of said method comprises to individuality uses first chemical compound and second chemical compound, and wherein first chemical compound is a psychotropic drug, and second chemical compound is an anticonvulsant.

In some embodiments, first chemical compound and second chemical compound are almost used simultaneously.In other embodiments, first chemical compound was used before second chemical compound.In other embodiments, first chemical compound is used after second chemical compound.

In certain embodiments, first chemical compound and second chemical compound are used separately.In other embodiments, thus first chemical compound and second chemical compound are covalently bound each other to make them form single chemical individual.Then, single chemical individual is digested and is metabolised to the chemical individual of two independent physiologically actives; One of them is first chemical compound and another is second chemical compound.

In certain embodiments, first chemical compound is that the zonisamide and second chemical compound are mirtazapines.In other embodiments, first chemical compound is an amfebutamone, and second chemical compound is a mirtazapine.In other embodiments, first chemical compound is a zonisamide, and second chemical compound is a setiptiline.In other embodiments, first chemical compound is an amfebutamone, and second chemical compound is a setiptiline.In other embodiments, first chemical compound is the combination of zonisamide and amfebutamone, and second chemical compound is a mirtazapine.In other embodiments, first chemical compound is the combination of zonisamide and amfebutamone, and second chemical compound is a setiptiline.

In some embodiments, first chemical compound is a zonisamide, and second chemical compound is lithium salts, and it is as described herein, and exists with preparation as herein described.In other embodiment, first chemical compound is a zonisamide, and second chemical compound is valproic acid, or its pharmaceutical salts, such as the different salt of valproate, its ester, amide or prodrug.

In some embodiments, first chemical compound is a topiramate, and second chemical compound is a lithium salts, and it is as described herein and exist with preparation as herein described.In other embodiment, first chemical compound is a topiramate, and second chemical compound is a valproic acid, or its pharmaceutical salts, such as the different salt of valproate, its ester, amide or prodrug.

In yet another aspect, the present invention relates in individuality to increase the method for satiety, described method comprises that evaluation needs its individuality, and should individuality with first chemical compound and second compounds for treating, wherein said first chemical compound is a psychotropic drug, and second chemical compound is an anticonvulsant.

Aspect another, the present invention relates to suppress the method for individual appetite, described method comprises that evaluation needs its individuality, and should individuality by use first chemical compound and second compounds for treating to individuality, wherein said first chemical compound is a psychotropic drug, and second chemical compound is an anticonvulsant.

In yet another aspect, the present invention relates to increase the method for energy expenditure in the individuality, described method comprises that evaluation needs its individuality, and should individuality by use first chemical compound and second compounds for treating to individuality, wherein first chemical compound is that the psychotropic drug and second chemical compound are anticonvulsants.

In some embodiment disclosed herein, thereby comprise that to individual administration the Pharmaceutical composition of two or more combination of compounds influences weight saving.In in these embodiments some, every kind of chemical compound is independent chemical entities.Yet, in other embodiment, two kinds of chemical compounds by chemical bond such as, covalent bond makes the different piece of two kinds of different compound formation same moleculars thereby link together.Thereby after selecting chemical bond in entering body, interrupt described key such as waiting, and then form two independent chemical compounds by enzymatic catalysis, acid hydrolysis, basic hydrolysis.

Aspect of the present invention also relates to the method for the risk that reduces the weight increase, and the risk that described weight increases is associated with antidepressants, antihistaminic or using of 5-hydroxytryptamine receptor antagonist.Others of the present invention also relate to the method that makes minimumization of metabolism risks and assumptions, and described metabolism risks and assumptions is associated with the weight increase, such as hypertension, diabetes and dyslipidemia.In one embodiment, described method comprises to a certain amount of zonisamide of the administration of having accepted antidepressants, or the anticonvulsant of other promotion weight saving, and described amount is enough to reduce the risk of the weight increase that is associated with antidepressants.In an alternate embodiment, described method comprises the amount with the risk that is enough to reduce the weight increase that is associated with antidepressants, to administration zonisamide or the topiramate of having accepted antidepressants, or other promotes the anticonvulsant of weight saving (to comprise blocking-up kainate/AMPA (D, L-alpha-amido-3-hydroxy-5-methyl base-different  azoles propanoic acid) reagent of hypotype glutamate receptor) and amfebutamone or other combination of compounds, described other chemical compound suppresses by picked-up or other mechanism increases activity of norepinephrine and/or dopamine.

In certain embodiments, method of the present invention relates to the risk that reduces the weight increase in individuality, and described individuality has been in the treatment of antidepressants, maybe will begin the treatment of antidepressants.In these embodiments, as described herein except antidepressants, use the compositions that comprises anticonvulsant and psychotropic drug to individuality, wherein said psychotropic drug is not antidepressants.Therefore, in some embodiments, comprise the compositions of zonisamide or comprise zonisamide and the compositions of amfebutamone to the individual administration of taking mirtazapine or setiptiline.In other embodiment, use the compositions that comprises zonisamide or comprise zonisamide and the compositions of valproate to the individuality of taking mirtazapine or setiptiline.In other embodiments, use the compositions that comprises zonisamide or comprise zonisamide and the compositions of venlafaxine to the individuality of having taken mirtazapine or setiptiline.

In certain embodiments, use the medicament of reduction weight increase risk in the method for the invention to comprise zonisamide or topiramate (and pharmaceutical salts).In other embodiment, use other first sulfonamide, such as at United States Patent (USP) 4, described in 172,896 those, or other sulfamate (ester) (comprising the monosaccharide that sulfamate (ester) replaces), such as at United States Patent (USP) 4, those that describe in 513,006 are incorporated their full contents into this paper as a reference.

In other embodiments, the medicament that reduces weight increase risk is an amfebutamone; And in other embodiment, use at United States Patent (USP) 3,819, disclosed chemical compound in 706 and 3,885,046, both full contents are incorporated this paper into as a reference with them.In other embodiments, the medicament that reduces the risk of weight increase is such as suppressing or other mechanism by reuptake, increasing norepinephrine and/or the active chemical compound of dopamine.All above-mentioned United States Patent (USP)s are.

Increase norepinephrine and/or the active chemical compound of dopamine and comprise the norepinephrine agonist, such as phendimetrazine and benzfetamine; NRI such as atomoxetine, amfebutamone, radafaxine, thionisoxetine and reboxetine; Dopamine agonist, such as cabergoline, amantadine, lisuride, pergolide, ropinirole, pramipexole and bromocriptine; Norepinephrine releasing agent, for example amfepramone; Blended dopamine/NRI, for example, amfebutamone; Dopamine reuptake inhibitor and NRI, for example amfebutamone and Mazindol; Or selective serotonin reuptake inhibitor (SSRI) and NRI, such as sibutramine, venlafaxine and duloxetine.

Be suitable for to accept any antidepressants that are associated with the weight increase according to the mammal of the present invention's treatment.Yet typically, antidepressants are (for example to upgrade monobasic antidepressants, selective serotonin reuptake inhibitor (for example, fluoxetine, fluvoxamine, Sertraline, paroxetine, citalopram, and escitalopram), venlafaxine, nefazodone, and mirtazapine)), paroxetine or mirtazapine in particular.

The reduction weight used in pharmaceutical composition as herein described increases antidepressants, the route of administration that the amount of the medicament of risk can accept with patient, patient and the result who seeks changes.Best dosage regimen for concrete patient can easily be determined by those skilled in the art.

According to the present invention, for example the combination of zonisamide or topiramate and amfebutamone (comprising slow releasing preparation) provides the effective means that makes the metabolism risk minimization, and described metabolism risk increases with weight and/or antidepressants are used be associated (for example, type ii diabetes).Described combination can ratio as, independent zonisamide or topiramate treatment are more effective, and have side effect still less.On neuro pharmacology, come the neurotransmitter of three kinds of all main modulation of appetite of targeting and weight with the combination of for example amfebutamone and zonisamide or topiramate, that is, and 5-hydroxy tryptamine, norepinephrine and dopamine.For example, the side effect of zonisamide or topiramate (such as somnolence, psychomotor is slow, and cognitive impairment is tired and depressed) can be passed through, and for example the insomnia of amfebutamone, activation, psychomotor excite with antidepressant effect and offsets.On the other hand, zonisamide or topiramate for example can reduce the risk of the epilepsy that is associated with for example amfebutamone.Two types medicine of low dosage more can be used in the combined therapy, further reduce side effect burden generally thus.

About the pharmacokinetics of zonisamide, its renal excretion and inhibition or the minimum potential that reduces hepatomicrosome enzyme be with antidepressants, particularly upgrade the favourable character in the monobasic antidepressants applied in any combination notion.

In yet another aspect, the present invention relates to pharmaceutical composition, it is as described herein, comprises the combination of psychotropic drug and anticonvulsant, or as described hereinly comprises link molecule and physiology acceptable carrier, diluent or excipient or its combination.

The route of administration that is fit to can see with the details of some embodiments of the compositions that is suitable for them, and for example U.S. Patent number 6,110, and 973,5,763,493,5,731,000,5,541,231,5,427,798,5,358,970 and 4,172, in 896, and in the patent of quoting,, comprise that any accompanying drawing all incorporates this paper into as a reference with their full content.

Term " pharmaceutical composition " refers to chemical compound of the present invention and other chemical constituent, such as the mixture of diluent or carrier.Described pharmaceutical composition promotes described chemical compound using to biology.The multinomial technology of administered compound is present in the prior art, includes, but not limited to oral, injection, aerosol, parenteral and local application.Pharmaceutical composition can also obtain by making reactions such as chemical compound and inorganic or all example hydrochloric acids of organic acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethyl sulfonic acid, right-toluenesulfonic acid, salicylic acid.

Term " carrier " definition promotes the chemical compound that chemical compound is integrated in cell or tissue.For example, dimethyl sulfoxine (DMSO) is the carrier of using always, because it promotes that many organic compound are being shot and gets in the biological cell or tissue.

Term " diluent " is defined in chemical compound diluted in the water, and it is with the solubilized target chemical compound and stablize the biologically active form of described chemical compound.To be dissolved in salt in the buffer solution as the diluent in this area.A kind of buffer solution commonly used is phosphate buffered saline(PBS), because the salt condition in its anthropomorphic dummy's blood.Because buffer salt can be controlled the pH of solution at low concentration, the buffering diluent seldom changes the biological activity of chemical compound.

The biological activity of chemical compound and the carrier or the diluent of character are not eliminated in term " physiology is acceptable " definition.

Pharmaceutical composition as herein described be caned itself, or uses to people patient with such pharmaceutical compositions, in described pharmaceutical composition, when in combined therapy, mix with other active component, or the carrier or the excipient that are fit to.The preparation of the application's chemical compound and the technology of using can see " Remington ' s Pharmaceutical Sciences, " Mack Publishing Co., Easton, and PA, the 18th edition, in 1990.

The route of administration that is fit to can, for example comprise oral, rectum, stride mucosa or intestinal is used; Parenteral is sent, and comprises intramuscular, subcutaneous, intravenous, intramedullary injection, and in the sheath, directly in the ventricle, intraperitoneal, intranasal or intraocular injection.

Alternatively, described chemical compound can for example by directly compound injection being arrived kidney or heart area, often be used with the form of durative action preparation or slow releasing preparation with part rather than systemic fashion.In addition, can for example in wrapping, come drug administration in the targeted delivery of drugs system by liposome with tissue specificity antibody.Described liposome optionally absorbs with target organs and by described organ.

Pharmaceutical composition of the present invention can be in itself known mode, for example by routine mixing, dissolving, granulating, dragee-manufacturing, grinding, emulsifying, seal, embedding or tableted method prepare.

Therefore, can use one or more physiology acceptable carriers, prepare the pharmaceutical composition of using according to the present invention in a usual manner, described physiology acceptable carrier comprises and promotes the excipient and the adjuvant of reactive compound in the preparation that can be medicinal.The preparation that is fit to depends on the route of administration of selection.Any of well-known technology, carrier and excipient can suitably and as this area, for example, that is understood in above-mentioned Remington ' s Pharmaceutical Sciences uses.

For injection, can preferably prepare medicament of the present invention such as Hanks ' s solution, Ringer's mixture or physiology salt buffer with aqueous solution with the physiological compatibility buffer.Use for striding mucosa, the penetrating agent that will be suitable for barrier to be seen through is used in the described preparation.These penetrating agent are that this area is known usually.

For Orally administered, can be by described reactive compound combination be easily prepared with pharmaceutical carrier well-known in the art.These carriers can make chemical compound of the present invention be configured to tablet, pill, dragee, capsule, liquid, gel, syrup, slurry, suspension etc. to be used for patient's to be treated orally ingestible.Can be by one or more solid excipients and drug regimen of the present invention be mixed, randomly grind the mixture that obtains, and if desired, behind the auxiliary agent that add to be fit to, handle particulate mixture and obtain tablet or dragee core and obtain the pharmaceutical preparation that is used to orally use.Particularly, the excipient that is fit to be filler such as sugar, comprise lactose, sucrose, mannitol or Sorbitol; Cellulose preparation such as, for example, corn starch, wheaten starch, rice fecula, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropyl methyl-cellulose, sodium carboxymethyl cellulose, and/or polyvinylpyrrolidone (PVP).If desired, can add disintegrating agent, such as crosslinked polyvinylpyrrolidone, agar or alginic acid or its salt such as sodium alginate.

Suitable coating is provided for the dragee core.For this purpose, can use spissated sugar juice, it can randomly comprise Radix Acaciae senegalis, Talcum, polyvinylpyrrolidone, carbopol gel, Polyethylene Glycol, and/or titanium dioxide, lacquer solution and the organic solvent or the solvent mixture that are fit to.Dyestuff or pigment can be added tablet or dragee coating to be used to identify or characterize the various combination of active compound doses.

Can orally use, comprise the pharmaceutical preparation that use in the Sublingual, it comprises by what gelatin was made and pushes-agree with capsule, and by gelatin and plasticizer, the capsule of the soft sealing of making such as glycerol or Sorbitol.Described pushing-agree with capsule can comprise with filler such as lactose, binding agent is such as starch, and/or lubricant such as Talcum or magnesium stearate and the blended active component of stabilizing agent randomly.In soft capsule, reactive compound can be dissolved or suspended in suitable liquid, in fatty oil, liquid paraffin or liquid macrogol.In addition, can add stabilizing agent.Being used for all Orally administered preparations should exist to be suitable for these dosage of using.

Use for sucking, described compositions can be taked the tablet prepared in a usual manner or the form of lozenge.

For using by suction, using the propellant that is fit to, dichlorodifluoromethane for example, Arcton 11, dichlorotetra-fluoroethane, carbon dioxide, or under the situation of other gas that is fit to, chemical compound is sent with the form of aerosol spray from the packing of pressurized or aerosol apparatus easily used according to the present invention.In the aerocolloidal situation of pressurized, thereby dosage unit can be determined by providing valve to send quantitative amount.Can prepare and be used in inhaler or insufflator, for example the capsule of gelatin and cartridge case, the mixture of powders of its inclusion compound and powder substrate such as the lactose or the starch that are fit to.

Can prepare chemical compound and be used for parenteral administration, described parenteral administration is by injection, for example, and by injecting or lasting infusion carries out.The preparation that is used to inject can be with unit dosage form, and for example ampoule or the multi-dose container with antiseptic with interpolation exists.Described compositions can take such form as suspension, solution or Emulsion in oiliness or aqueous excipient, and can comprise ingredients (formulatory agents) such as suspending agent, stabilizing agent and/or dispersant.

The pharmaceutical preparation that is used for parenteral administration comprises the aqueous solution of the reactive compound that exists with water-soluble form.In addition, the suspension of reactive compound can be prepared as suitable oily injection suspension.Lipophilic solvent that is fit to or carrier or excipient comprise fatty oil such as Oleum sesami, or synthetic fatty acid ester, such as ethyl oleate or triglyceride, or liposome.The aqueous injection suspension can comprise the material of the viscosity that increases suspension, such as sodium carboxymethyl cellulose, Sorbitol or glucosan.Randomly, thus the reagent that described suspension can also comprise suitable stabilizing agent or increase the dissolubility of chemical compound is allowed the solution of preparation high concentration.

Alternatively, active component can exist to be used for the excipient to be fit to powder type before use, and the water of for example aseptic no pyrogen makes up.

Described chemical compound can also be formulated in rectal compositions such as suppository or the retention enema, for example comprises conventional suppository bases such as cocoa butter or other glyceride.

Except foregoing preparation, described chemical compound can also be formulated as durative action preparation.These durative action preparations can be by implanting (for example, hypodermically or intramuscularly) or using by intramuscular injection.Therefore, for example, described chemical compound can be prepared (for example, being configured to the Emulsion in acceptable oil) or ion exchange resin with the polymer or the lyophobic dust that are fit to, or is configured to sl. sol. derivant, for example, is configured to sl. sol. salt.

The pharmaceutical carrier of hydrophobic compound of the present invention is the cosolvent system, and described cosolvent system comprises benzyl alcohol, non-polar surfactant, water miscibility organic polymer, and water.Cosolvent system commonly used is a VPD cosolvent system, and described VPD cosolvent system is the 3%w/v benzyl alcohol solution of supplying volume in dehydrated alcohol, non-polar surfactant's polyoxyethylene sorbitan monoleate of 8%w/v ^TM, the Liquid Macrogol of 65%w/v.Natively, the ratio of cosolvent system can change considerably and not destroy its dissolubility and toxic characteristic.In addition, the characteristic of cosolvent component can change: for example, can use other hypotoxic non-polar surfactant to replace POLYSORBATE 80 ^TMThe fraction size of Polyethylene Glycol can change; The polymer of other biocompatibility can replace Polyethylene Glycol, for example, and polyvinylpyrrolidone; And other sugar or polysaccharide can replace glucose.

Alternatively, can use other delivery system of dewatering medicament chemical compound.Liposome and Emulsion are the delivery medium of dewatering medicament or the well-known example of carrier.Also can use some organic solvent such as dimethyl sulfoxine, although be cost with bigger toxicity usually.In addition, can use slow-released system, send chemical compound such as the semi permeability substrate of the solid hydrophobic polymer that comprises therapeutic agent.Various sustained-release materials are determined, and are that those skilled in the art are well-known.Slow releasing capsule can, depend on their chemical property, discharge chemical compound reach several weeks to as many as above 100 days.According to the chemical property and the biological stability of described therapeutic agent, can use the other strategy of protein stabilization.

The chemical compound lot that is used in the drug regimen of the present invention can be provided as the salt with drug compatibility counter ion counterionsl gegenions.Can form drug compatibility salt with many acid, described acid includes, but are not limited to hydrochloric acid, sulphuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid etc.Compare with corresponding free acid or alkali form, salt tends to easier dissolving in aqueous or other proton solvent.

The pharmaceutical composition that is suitable for use among the present invention comprises such compositions, comprises active component with its amount that is intended to purpose of effective acquisition in described compositions.More specifically, the treatment effective dose means effective prevention, slows down or improves the symptom of disease or prolongs the amount of chemical compound of the experimenter's treated survival.To determining fully in those skilled in the art's limit of power, of treatment effective dose especially according to detailed disclosure provided herein.

Can select the accurate preparation of pharmaceutical composition of the present invention according to patient's situation by each doctor, path of using and dosage (see, for example .1975 such as Fingl, at " ThePharmacological Basis of Therapeutics ", Ch.1 p.1 in).Typically, being applied to the dosage range of patient's compositions can be from about 0.5 to 1000mg/kg weight in patients.According to patient's needs, dosage can be single or be administered twice in the process at one day or many days or series more frequently.Attention has determined to treat the people's of at least some diseases dosage for nearly all particular compound of mentioning in this disclosure.Therefore, in most of situation, the present invention will use those identical dosage, or the dosage between about 0.1% and 500%, more preferably fixed people's dosage about 25% and 250% between.When not determining people's dosage, as in the situation of newfound medical compounds, can be from ED ₅₀Or ID ₅₀Value, or infer suitable people's dosage from other value that is fit to of studying in external or the body is as by the toxicity research in the animal and efficacy study are examined and determine.

Although will on the basis of drug-drug, determine accurate dose, in most of situations, can make some summaries about dosage.Adult patient's dosage every day can be: for example, oral dose is between every kind of composition 0.1mg and the 6000mg, preferably between 1mg and 5000mg, for example between 25 to 5000mg, or intravenous, subcutaneous or intramuscular dosage are between every kind of composition 0.01mg and the 100mg, preferably between 0.1mg and 60mg, for example 1 of every kind of composition arrive 40mg, described every kind of composition is to be calculated as the pharmaceutical composition of the present invention of free alkali or every kind of composition of its pharmaceutical salts, and described compositions is used 1-4 time every day.Alternatively, compositions of the present invention can be by the intravenous infusion that continues, preferably with every kind of composition many to every day 400mg dosage use.Therefore, Orally administered total daily dose of every kind of composition will typically arrive in the scope of 2500mg 1, and will typically arrive in the scope of 400mg 0.1 by total daily dose of parenteral administration.Compatibly, described chemical compound will be used the period of one section continued treatment, for example reach a week or more all, or several months or several years.

In some embodiments, the dosage range of lithium carbonate, for oral dose, will cause about 0.5 and about 1.5meq/l between the blood levels of lithium.In preferred embodiments, the dosage range of lithium carbonate for oral dose, will be about 900mg/ days.

In certain embodiments, the dosage range of valproate for oral dose, arrives in about 5000mg/ days the scope about 250.In preferred embodiments, the dosage range of described valproate for oral dose, will be about 1500mg/ days.

In other embodiments, the dosage range of zonisamide for oral dose, arrives in about 600mg/ days the scope about 25.In some embodiments, dosage is 25mg/ days.In other embodiment, dosage is 50mg/ days.In other embodiment, dosage is 100mg/ days.

In other embodiments, the dosage range of mirtazapine (mitrazepine) for oral dose, arrives in about 500mg/ days the scope about 5.In some embodiments, described dosage is 8mg/ days.In other embodiment, described dosage is 16mg/ days.In other embodiment, described dosage is 32mg/ days.In some embodiments, described dosage is 15mg/ days.In other embodiment, described dosage is 30mg/ days.In other embodiment, described dosage is 45mg/ days.

In other embodiment, for venlafaxinor venlafaxin XR, for oral dose, dosage range is in about 20mg arrives about 600mg/ days scope.In some embodiments, dosage is 25mg/ days.In other embodiment, dosage is 37.5mg/ days.In other embodiment, dosage is 50mg/ days.In some embodiments, dosage is 75mg/ days.In other embodiment, dosage is 100mg/ days.In other embodiment, dosage is 150mg/ days.

Thereby amount that can independent control dosage and provide at interval and be enough to keep regulating effect, or the blood plasma level of the active part of minimal effective concentration (MEC).Described MEC will change for every kind of chemical compound, but can estimate from vitro data.Obtain the necessary dosage of MEC and will depend on individual feature and route of administration.Yet, HPLC mensuration or bioassay can be used for determining plasma concentration.

Can also use the MEC value to determine dosing interval.Should use certain scheme to use compositions, described scheme maintains the time that the above blood plasma level of MEC reaches 10-90%, preferably in the time of 30-90% and most preferably in time of 50-90%.

In the situation of local application or selectivity picked-up, effective local concentration of medicine may be not relevant with plasma concentration.

Certainly, the amount of the compositions of being used will depend on the experimenter who is treated, experimenter's body weight, the painful order of severity, the mode of using and prescriber's judgement.

If desired, described compositions can exist with packing or riffle sampler device, and it can comprise one or more unit dosage forms that comprise active component.Described packing can for example comprise metal or plastic foil, such as blister.Described packing or riffle sampler device can attached description to use.Described packing or riffle sampler can also have the relevant notice of container that exists with the form of stipulating with government organs, production, use or the sale of described government organs regulating medicine, described notice have reflected that the approval of described mechanism carries out the medicament forms that people or veterinary use.Such notice for example, can be the label that is used for prescription drug of U.S. food and drug surveilance office approval, or the plug-in unit of the product of approval.Can also prepare and comprise the compound compositions of the present invention that is formulated in the compatibility pharmaceutical carrier, be placed in the proper container, and labelling is carried out in the treatment of its indication.

It will be understood by those skilled in the art that, can under the prerequisite that does not deviate from essence of the present invention, make many and various improvement.Therefore, should be understood that clearly that form of the present invention only is illustrational, limits the scope of the invention and be not inclined to.

Hereby the above-mentioned all documents quoted and the full content of other information source are incorporated herein by reference, as Gadde etc., Obesity Res.9:544-551 (2001) and Gadde etc., JAMA 289:1820-1825 (2003) is such.

Embodiments more of the present invention

Embodiments more of the present invention are as follows:

In first embodiment, the present invention relates to influence the compositions of weight saving, described compositions comprises first chemical compound and second chemical compound, and wherein said first chemical compound is a psychotropic drug, and described second chemical compound is an anticonvulsant.

In second embodiment, the present invention relates to the compositions of first embodiment, wherein said psychotropic drug is selected from the group of being made up of lithium carbonate, Lithium Citrate de, valproate, its mixture and pharmaceutical salts thereof or prodrug.

In the 3rd embodiment, the present invention relates to the compositions of first embodiment, wherein said second chemical compound is selected from by barbiturate (ester), benzene diaza , GABA analog, hydantoins, anticonvulsant, phenyl triazine, butanimide, its pharmaceutical salts or prodrug, and the group of combination composition.

In the 4th embodiment, the present invention relates to the compositions of the 3rd embodiment, wherein said barbiturate (ester) is pentobarbital or its pharmaceutical salts or prodrug.

In the 5th embodiment, the present invention relates to the compositions of the 3rd embodiment, wherein said benzene diaza  is selected from by clonazepam, alprazolam, chlordiazepoxide, chlorine nitrogen , diazepam, halazepam, lorazepam, oxazepam, prazepam, flurazepam, temazepam, triazolam, the group that its pharmaceutical salts or prodrug and their combination are formed.

In the 6th embodiment, the present invention relates to the compositions of the 3rd embodiment, wherein said GABA analog is selected from the group of being made up of tiagabine, gabapentin, pregabalin, its pharmaceutical salts or prodrug and their combination.

In the 7th embodiment, the present invention relates to the compositions of the 3rd embodiment, wherein said hydantoin is selected from by fosphenytoin, phenytoin, 5,5-phenytoin, the group that its pharmaceutical salts or prodrug and their combination are formed.

In the 8th embodiment, the present invention relates to the compositions of the 3rd embodiment, wherein said miscellaneous anticonvulsant is selected from by carbamazepine, valproate, valproic acid, two valproic acids, felbamate, levetiracetam, carbamazepine, topiramate, Aura Xiping, zonisamide, the group that its pharmaceutical salts or prodrug and their combination are formed.

In the 9th embodiment, the present invention relates to the compositions of the 3rd embodiment, wherein said phenyl triazine is a lamotrigine.

In the tenth embodiment, the present invention relates to the compositions of the 3rd embodiment, wherein said butanimide is selected from the group of being made up of mesuximide, ethosuximide and combination thereof.

In the 11 embodiment, the present invention relates to the compositions of first embodiment, wherein said first chemical compound is a psychotropic drug, and described second chemical compound is a zonisamide.

In the 12 embodiment, the present invention relates to the compositions of first embodiment, wherein said first chemical compound is lithium carbonate or Lithium Citrate de, and described second chemical compound is a zonisamide.

In the 13 embodiment, the present invention relates to the compositions of first embodiment, wherein said first chemical compound is a valproate.And described second chemical compound is a zonisamide.

In the 14 embodiment, the present invention relates to the compositions of the 12 or the 13 embodiment, wherein said zonisamide exists with long-acting (time-release) preparation.

In the 15 embodiment, the present invention relates to influence the method for weight saving, it comprises that evaluation needs the individual of its and treats this individuality with psychotropic drug and anticonvulsant.

In the 16 embodiment, the present invention relates to the method for the 15 embodiment, wherein said individuality has the Body Mass Index above 25.

In the 17 embodiment, the present invention relates to the method for the 15 embodiment, wherein said psychotropic drug is selected from by lithium carbonate, Lithium Citrate de and valproate, the group that the slow releasing preparation of said medicine and the combination of said medicine are formed.

In 18 embodiments, the present invention relates to the method for the 15 embodiment, wherein said anticonvulsant is selected from by barbiturate (ester), benzene diaza  class, GABA analog, hydantoins phenyl triazine, and butanimide, and the group of pharmaceutical salts or prodrug composition.

In the nineteen embodiment, the present invention relates to the method for the 15 embodiment, wherein said anticonvulsant is selected from by pentobarbital, clonazepam, chlorine nitrogen , benzene diaza , diazepam, tiagabine, gabapentin, pregabalin, fosphenytoin, phenytoin, phenytoin, 5, the 5-phenytoin, carbarnazepine, valproate, valproic acid, two valproic acids, felbamate, levetiracetam, carbamazepine, topiramate, Aura Xiping, zonisamide, lamotrigine, mesuximide, ethosuximide, the group that the slow releasing preparation of said medicine and the combination of said medicine are formed.

In the 20 embodiment, the present invention relates to the method for the 15 embodiment, wherein said first chemical compound and described second chemical compound are almost used simultaneously.

In the 21 embodiment, the present invention relates to the method for the 15 embodiment, wherein said first chemical compound was used before described second chemical compound.

In the 22 embodiment, the present invention relates to the method for the 15 embodiment, wherein said first chemical compound is used after described second chemical compound.

In the 23 embodiment, the present invention relates to increase the method for satiety in the individuality, described method comprises that evaluation needs its individuality, and should individuality with first chemical compound and second compounds for treating, wherein said first chemical compound is a psychotropic drug, and described second chemical compound is an anticonvulsant.

In the 24 embodiment, the present invention relates to the method for the 23 embodiment, wherein said first chemical compound and described second chemical compound are almost used simultaneously.

In the 25 embodiment, the present invention relates to the method for the 23 embodiment, wherein said first chemical compound was used before described second chemical compound.

In the 26 embodiment, the present invention relates to the method for the 23 embodiment, wherein said first chemical compound is used after described second chemical compound.

In the 27 embodiment, the present invention relates to increase the method for energy expenditure in the individuality, described method comprises that evaluation needs its individuality, and should individuality with first chemical compound and second compounds for treating, wherein said first chemical compound is a psychotropic drug, and described second chemical compound is an anticonvulsant.

In the 28 embodiment, the present invention relates to the method for the 27 embodiment, wherein said first chemical compound and described second chemical compound are almost used simultaneously.

In the second nineteen embodiment, the present invention relates to the method for the 27 embodiment, wherein said first chemical compound was used before described second chemical compound.

In the 30 embodiment, the present invention relates to the method for the 27 embodiment, wherein said first chemical compound is used after described second chemical compound.

In a hentriaconta-embodiment, the present invention relates to suppress the method for individual appetite, described method comprises that evaluation needs its individuality, and should individuality with first chemical compound and second compounds for treating, wherein said first chemical compound is a psychotropic drug, and described second chemical compound is an anticonvulsant.

In the 32 embodiment, the present invention relates to the method for a hentriaconta-embodiment, wherein said first chemical compound and described second chemical compound are almost used simultaneously.

In the 33 embodiment, the present invention relates to the method for a hentriaconta-embodiment, wherein said first chemical compound was used before described second chemical compound.

In the 34 embodiment, the present invention relates to the method for a hentriaconta-embodiment, wherein said first chemical compound is used after described second chemical compound.

In the 35 embodiment, the present invention relates to influence the method for weight saving in the individuality, described method comprises that evaluation needs its individuality, and treats this individuality with the combination of lithium carbonate and zonisamide.

In the 36 embodiment, the present invention relates to influence the method for weight saving in the individuality, described method comprises that evaluation needs the individual of its and treats this individuality with the combination of valproate and zonisamide.

In the 37 embodiment, the present invention relates to the 35 or the method for the 36 embodiment, wherein said individuality has and surpasses 30 BMI.

In the 38 embodiment, the present invention relates to the 35 or the method for the 36 embodiment, wherein said individuality has and surpasses 25 BMI.

In the 3rd nineteen embodiment, the present invention relates to the 35 or the method for the 36 embodiment, wherein said lithium carbonate or valproate exist with the form of durative action preparation.

In the 40 embodiment, the present invention relates to the 35 or the method for the 36 embodiment, the plasma concentration level of wherein said lithium carbonate or valproate and zonisamide is followed similar concentration curve.

In the 41 embodiment, the present invention relates to the method for the 3rd nineteen embodiment, wherein said lithium carbonate or valproate and zonisamide are used basically simultaneously.

42 embodiments in, the present invention relates to the method for the 3rd nineteen embodiment, wherein said lithium carbonate or valproate were used before zonisamide.

In the 43 embodiment, the present invention relates to the method for the 3rd nineteen embodiment, wherein said lithium carbonate or valproate are used after zonisamide.

Embodiment

The following examples are not restrictive, and only are the representatives of various aspects of the present invention.

Embodiment 1: the application of independent zonisamide:

The individuality of antidepressants has been taken in evaluation, maybe will take the individuality of antidepressants, owing to use antidepressants to increase the individuality of weight, or be easy to owing to the individuality that uses antidepressants to gain in weight.Except anti-depressant therapy, instruct each individuality on basis once a day, to take the tablet of the zonisamide of 25mg.

Described individual monitoring is reached the period of several months.Thereby recommendation makes each individuality come weight reduction with the speed of per 6 months 10% starting weight to dosage adjustment.Yet, can adjust the speed of each individual weight saving by the treatment doctor by on the basis that specifically needs at individuality.

The dosage of zonisamide can be from about 25mg to about 800mg/ days, usually administration every day 1 time or be divided into (for example, equally) multidose.Preferably, described dosage is from about 100mg to about 600mg/ days, and more preferably, dosage is from about 200mg to about 400mg/ days.Yet it may be essential using the dosage outside these scopes.Usually with 25mg, the dosage of 50mg and 100mg prepares and sale zonisamide tablet.The combination of independent tablet or tablet can be used to realize required administration.

Embodiment 2: the application of independent topiramate:

The individuality of antidepressants has been taken in evaluation, maybe will take the individuality of antidepressants, owing to use antidepressants to increase the individuality of weight, or be easy to owing to the individuality that uses antidepressants to gain in weight.Except anti-depressant therapy, instruct each individuality on basis once a day, to take the tablet of the topiramate of 25mg.

The dosage of topiramate can be from about 25mg to about 1600mg, preferably from about 50mg to about 600mg, more preferably from about 100mg to about 400mg.Yet it may be essential using the dosage outside these scopes.

Embodiment 3: the combination of zonisamide and mirtazapine (mitrazepine):

Evaluation has the individuality that surpasses 25 BMI.Instruct individuality except taking on the basis once a day a slice mirtazapine tablet, on basis once a day, take a slice zonisamide tablet.Beginning, medicine is following to be used: 8mg mirtazapine and 64mg zonisamide; Or 16mg mirtazapine and 128mg zonisamide; Or 32mg mirtazapine and 252mg zonisamide; Usually wherein the ratio of mirtazapine/zonisamide is 1: 8.

If initial dose does not have effect, can increase them.

Embodiment 4: the combination of zonisamide and paroxetine:

Evaluation has the individuality that surpasses 25 BMI.Instruct each individuality,, on basis once a day, take a slice zonisamide tablet except taking on the basis once a day a slice paroxetine tablet.Beginning is used medicine is following: 10mg paroxetine and 60mg zonisamide; Or 20mg paroxetine and 120mg zonisamide; Or 30mg paroxetine and 180mg zonisamide; Or 40mg paroxetine and 240mg zonisamide; Usually wherein the ratio of paroxetine/zonisamide is 1: 6.

If initial dose does not have effect, can increase them.

Embodiment 5: the combination of zonisamide and lithium carbonate:

Evaluation has the individuality that surpasses 25 BMI.Instruct each individuality,, on basis once a day, take the zonisamide tablet of 1 25mg except on basis once a day, taking the Lithotabs of a slice 300mg.

If initial dose does not have effect, the dosage of zonisamide can increase about 25mg every day so.If initial dose causes weight saving faster than above-mentioned speed, can reduce every kind dosage of zonisamide or lithium carbonate.

In some cases, the zonisamide combination of using dose every day with in a whole day, use twice or three times or more frequently lithium carbonate be favourable.Lithium carbonate can also exist with the durative action preparation form, and wherein said dosage is used once every day, but lithium carbonate or progressed into blood flow in 12 hour period in one day.

Can use Lithium Citrate de, or the pharmaceutical salts of any other lithium replacement lithium carbonate, carry out said method.

Embodiment 6: the combination of zonisamide and lithium carbonate:

Evaluation has the individuality that surpasses 25 BMI.Instruct each individuality on basis once a day, to take the zonisamide tablet of a slice 25mg.In addition, instruct each individuality on basis once a day, to take the tablet of the lithium carbonate of a slice 300mg.

Described individual monitoring is reached the period of several months.Thereby recommendation makes each individuality come weight reduction with the speed of per 6 months 10% starting weight to dosage adjustment.Yet, can adjust the speed of each individual weight saving by the treatment doctor by on the basis that specifically needs at individuality.Recommend periodically to check serum creatinine.

If initial dose does not have effect, thereby the dosage of lithium carbonate can increase and obtains 0.5 to the blood levels of 1.5meq/l so.If initial dose causes can reducing every kind dosage of zonisamide or lithium carbonate than the weight saving faster of above-mentioned speed.

Embodiment 7: the combination of zonisamide and valproate:

Evaluation has the individuality that surpasses 25 BMI.Instruct each individuality except the tablet of the valproate of taking a slice 500mg on the basis once a day, on basis once a day, take the tablet of the zonisamide of a slice 50mg.

If initial dose does not have effect, the dosage of zonisamide can increase about 30mg every day so, but the accumulated dose of every day is no more than 600mg.If initial dose causes can reducing every kind dosage of zonisamide or valproate than the weight saving faster of above-mentioned speed.

In some cases, use the zonisamide of dose every day and in a whole day, use twice or three times or the valproate combination of dosage more frequently is favourable.Valproate can also exist with durative action preparation, wherein said dosage once-a-day administration, but valproate or progressed into blood flow in 12 hour period in a whole day.

Embodiment 8: the combination of zonisamide and valproate:

Evaluation has the individuality that surpasses 25 BMI.Instruct each individuality on basis once a day, to take the zonisamide tablet of a slice 50mg.In addition, instruct each individuality on basis once a day, to take the tablet of the valproate of a slice 250mg.

If initial dose does not have effect, dosage every day of valproate can be increased to many to 3000mg with the interval of 20mg so.If initial dose causes can reducing every kind dosage of zonisamide or valproate than the weight saving faster of above-mentioned speed.

Embodiment 9: the combination of zonisamide and olanzapine:

Evaluation has the individuality that surpasses 25 BMI.Instruct each individuality,, on basis once a day, take the tablet of a slice zonisamide except taking on the basis once a day the tablet of a slice olanzapine.Beginning, following drug administration: 5mg olanzapine and 60mg zonisamide, or 10mg olanzapine and 120mg zonisamide; Usually wherein the ratio of olanzapine/zonisamide is 1: 12.

If initial dose does not have effect, can increase them.

Embodiment 10: the combination of zonisamide and risperidone:

Evaluation has the individuality that surpasses 25 BMI.Instruct each individuality except taking the tablet of risperidone on the basis once a day, on basis once a day, take the tablet of a slice zonisamide.Beginning, following drug administration: 0.5mg risperidone and 30mg zonisamide, 1mg risperidone and 60mg zonisamide, or 2mg risperidone and 120mg zonisamide; Usually wherein the ratio of olanzapine/zonisamide is 1: 60.

If initial dose does not have effect, can increase them.

Embodiment 11: zonisamide and/or amfebutamone prevent that the weight relevant with mirtazapine or setiptiline treatment from increasing

Background

Mirtazapine shows the sizable prospect as the Therapeutic Method of sleep apnea, but it causes weight to increase in some patients.This weight increases the restriction mirtazapine as the Therapeutic Method of sleep apnea or as the application of antidepressants.Induce in the rodent models that weight increases at mirtazapine, add zonisamide, or amfebutamone, or zonisamide adds amfebutamone and follows the treatment of mirtazapine to reduce the weight increase relevant with mirtazapine.

Melanocortin system control energy balance.Mirtazapine and setiptiline change the melanocortin loop.Zonisamide, or amfebutamone, or zonisamide adds amfebutamone and has reversed this variation in neuronal activity.

Described melanocortin system is by the proopiomelanocortin in hypothalamic arcuate nucleus (POMC) neuron, relevant melanocortin receptor (MC4 R) and wild grey protein related peptide neuron composition.In humans and animals, determined melanocortin system control energy balance fully and in the people the modal genetic cause of obesity be the congenital deficiency of MC4 R.

Shown that recently many chemical compounds that influence the energy balance change the activity in melanocortin loop.Particularly, shown that amfebutamone and zonisamide increase the neuronic electrophysiology activity of POMC.As the part of the research, identified that some can regulate the receptor of POMC neuronal activity; Particularly, shown that 5-HT 2C and 5-HT 1B receptor increase the neuronic activity of POMC as dopamine D 2 R.The clearly effect of 5-HT 2CR in regulating the POMC neuronal activity shows chemical compound, induces anabolic state thereby change the energy balance as mirtazapine, and helping weight increases, and described mirtazapine is the antagonist for described receptor.

Pharmacology in the body

We have developed model and have come the influence of clinical preceding check mirtazapine to weight increase.Carry out dosage range research and determined in " rat-weight increases mensuration ", showed the dosage of the weight increase that causes by mirtazapine or setiptiline best.The test zonisamide, or amfebutamone, or zonisamide adds amfebutamone and reduces mirtazapine that response follows or setiptiline and treat observed weight and increase.Beginning, the dosage (bid) of the zonisamide of use 30mg/kg is except the dosage (bid) in 20mg/kg arrives the scope of experiment of 90mg/kg.Beginning is used amfebutamone with 190mg/kg/ days dosage, and described dosage is in 50-190mg/kg/ days scope of experiment.With mirtazapine or setiptiline as the solution in minipump.The concentration range of solution at 0.1 μ M between the 10mM.In some experiments, provide about 1mg/kg/ days dosage thereby calculate described concentration.In some experiments, described concentration is 10 μ M.

In the 4X3 experimental design, rat is accepted the secretion mirtazapine, or setiptiline, or the implant of excipient.Some rats are also accepted the auxiliary treatment of carrying out with saline, and some rats are accepted zonisamide, and some rats are accepted amfebutamone, and other acceptance adds the auxiliary treatment that amfebutamone carries out with zonisamide.By this way, the winding of 10 rats might be made up by the institute of weight saving medicine and mirtazapine or setiptiline.

Rat quantity and group
Rat quantity and group				The weight saving medicament	Excipient	Setiptiline (tbd)	Mirtazapine (tbd)
Excipient	10	10	10	The weight saving medicament	Excipient	Setiptiline (tbd)	Mirtazapine (tbd)
Excipient	10	10	10	Zonisamide (tbd)	10	10	10
Amfebutamone (tbd)	10	10	10	Zonisamide (tbd)	10	10	10
Amfebutamone (tbd)	10	10	10	Zonisamide (tbd)+amfebutamone (tbd)	10	10	10

Electrophysiology

Measure the POMC neuron to mirtazapine with to the electric physiological responses of setiptiline.Then, determine whether, or amfebutamone, or zonisamide adds the auxiliary treatment that amfebutamone carries out and has prevented because the active expection of the POMC that mirtazapine or setiptiline cause reduces with zonisamide.

The subthreshold dosage of initial stage data show zonisamide and amfebutamone is collaborative to have suppressed the acute food intake in the mice, and this is in the mice of fasting after 16 hours, and zonisamide and amfebutamone suppress the effective synergistic further evidence of food intake.

Before other clinical, in the experiment, shown that zonisamide and amfebutamone all suppress food intake for every kind.These effects disappeared through 4 hours, but when every kind of independent chemical compound be when not having effect, combination is effective.The effect of the minimizing weight of zonisamide and amfebutamone is also fully confirmed (Gadde etc., 2003 in the people; Gadde etc., 2001).

Show that the combination of zonisamide and amfebutamone has effectively increased the neuronic electrophysiologic activity from the POMC of the brain section of POMC-EGFP mice.Show that the increase greatly of the usefulness ratio of the spontaneous effect in the expection POMC neuron will stimulate the remarkable secretion from the neuronic α-MSH of POMC, thereby and activate MC4R-subsequently and suppress food intake and reduce weight increase.

Method

Pharmacology in the body

Use is weighed when the experiment beginning and is about the Sprague-Dawley female rats of 300 grams.Under isoflurane anesthesia, the subcutaneous miniature osmotic pumps of implantation Alzet (2ml2) between scapula.After recovery, rat is put back in their nest cages.Described minipump is per hour sent 5 μ L, continues 14 days.Use the dosage range (be dissolved in the DMSO/ saline from 0.1 to 20mg/kg/ day) of mirtazapine.Animal laid and provides laboratory feedstuff (chow) separately with standard.The consumption of per 3 days record food and the weight of animal, thus will reduce to minimum to the interference of animal.

We have shown amfebutamone in mice, zonisamide and zonisamide add amfebutamone behind peritoneal injection, have the appreciable impact to food intake.Use following group: every group of 6 rats, 7 groups of (mirtazapines of 6 dosage (0.1,0.5,1,5,10,20mg/kg) ,+saline), we have developed long-term infusion methods and have tested amfebutamone, or zonisamide and zonisamide add the influence that amfebutamone increased weight in 14 days

Determine in the research in the early stage, zonisamide, and amfebutamone and zonisamide add amfebutamone causes weight saving in this rat model dosage; Then carry out aid in treatment experiment (mirtazapine adds zonisamide and adds amfebutamone).

Electrophysiology

Record is from the neuronic electrophysiology activity of proopiomelanocortin (POMC) of the brain section of POMC-EGFP mice.By these and only in these cells expressing green fluorescent protein (EGFP) identify POMC neuron in these mices.Use standard electric physiology technology to be recorded in the frequency of the action potential in these neurons.Particularly, the free cell (loose cell) that is connected in the paster structure is used for determining the action potential frequency, and the interference of pair cell is reduced to minimum.

Shown zonisamide, or amfebutamone, or zonisamide adds amfebutamone and has increased the neuronic activity of POMC.It is active to write down the basis, and then mirtazapine or setiptiline is added in the solution of organizing to measure the influence of antidepressants to the POMC neuronal activity.If mirtazapine or setiptiline suppress the neuronic activity of POMC, test is by use amfebutamone, or zonisamide or zonisamide add the increase of the neuronal activity of amfebutamone processing brain section.

Embodiment 11:

Zonisamide adds amfebutamone and prevents that handling relevant weight with olanzapine increases

Background

In this experiment, test is combined into pair influence that the weight relevant with the olanzapine application increases of capable aid in treatment with medicine.Particularly, in effective rodent models that olanzapine-inductive weight increases, zonisamide or zonisamide are added amfebutamone add and follow the olanzapine processes and displays to reduce the weight increase relevant with olanzapine.

Described melanocortin system is by the proopiomelanocortin in hypothalamic arcuate nucleus (POMC) neuron, relevant melanocortin receptor (MC4 R) and wild grey protein related peptide neuron composition.In humans and animals, determined melanocortin system control energy balance fully, and the modal genetic cause of obesity is the congenital deficiency of MC4 R in the people.Shown that recently many chemical compounds that influence the energy balance change the activity in melanocortin loop.Particularly, shown that amfebutamone and zonisamide increase the neuronic electrophysiology activity of POMC.Show that also the cannabinoid antagonist activates this identical loop.We have identified some that can regulate in the neuronic receptor of POMC; Particularly, we have shown that 5-HT 2C and 5-HT 1B receptor increase the neuronic activity of POMC, as dopamine D 2 R.D2R and the 5-HT 2CR clearly effect in regulating the POMC neuronal activity shows chemical compound, as olanzapine, induces anastate thereby changed the energy balance, and helping weight increases, and described olanzapine is the antagonist for two kinds of such receptors.

Research design

Pharmacology in the body

Rat is accepted the implant of secretion olanzapine (or the excipient in matched group).Some also accept the aid in treatment of carrying out with zonisamide; Other acceptance adds the aid in treatment that amfebutamone carries out with zonisamide.Beginning, the dosage (bid) of the zonisamide of use 30mg/kg is except the dosage in the scope of experiment from 20mg/kg to 90mg/kg (bid).Used amfebutamone begins the dosage at 190mg/kg/ days, and described dosage is in 50-190mg/kg/ days scope of experiment.With olanzapine as solution in minipump.The concentration range of described solution at 0.1 μ M between the 10mM.In some experiments, described concentration is calculated so that the dosage of about 1.75mg/kg/ day to be provided.In some experiments, described concentration is 10 μ M.

Rat quantity and group
Rat quantity and group			The medicament of weight saving	Excipient	Olanzapine (1.75mg/ days)
Excipient	10	10	The medicament of weight saving	Excipient	Olanzapine (1.75mg/ days)
Excipient	10	10	Zonisamide (tbd)	10	10
Zonisamide (tbd)+amfebutamone (tbd)	10	10	Zonisamide (tbd)	10	10

The increase of the speed of the autokinesis current potential of initial stage data show in the POMC neuron, described initial stage data about zonisamide combination with amfebutamone to the active influence of the neuronic electrophysiology of POMC from the brain section of POMC-EGFP mice.This big increase stimulates the remarkable secretion from the neuronic α-MSH of POMC, thereby and activates MC4R subsequently and suppress food intake and reduce weight increase.

Method

Pharmacology in the body

Use is weighed when the experiment beginning and is about the female Sprague-Dawley rat of 300 grams.Under isoflurane anesthesia, the subcutaneous miniature osmotic pumps of implantation Alzet (2ml2) between scapula.After recovery, described rat is put back in their nest cages.Described minipump is per hour sent 5 μ L, continues 14 days.Olanzapine is dissolved in dH ₂The lactic acid of O+10% dilution.About 3.5 pH makes olanzapine can dissolve and produce golden solution fully.In medicine group or vehicle group, this pH level does not all have influence to animal.Described animal is laid separately, and provided with the standard laboratory feedstuff.Write down food consumption and animal weight in per 3 days, so that drop to minimum to the interference of animal.

Be presented in mice behind the peritoneal injection in 24 hours the process, zonisamide and zonisamide add amfebutamone food absorption are had appreciable impact.Exploitation similarly based on the method for minipump, is used following group:

Every group of 6 rats, 7 groups (zonisamide of 6 dosage ,+saline)

Every group of 6 rats, 7 groups (amfebutamone of 6 dosage ,+saline),

Test zonisamide and zonisamide and add the influence that amfebutamone increased weight in 14 days.

With more small-scale initial research, in this rat model, determine to cause the zonisamide of weight saving and the dosage of amfebutamone.Then carry out aid in treatment experiment (olanzapine adds zonisamide and adds amfebutamone).The animal of test comes to: 60+42+42=144 rat.Described experiment is carried out 3 times to confirm this result.

Electrophysiology

Record is from the neuronic electrophysiology activity of proopiomelanocortin (POMC) of the brain section of POMC-EGFP mice.By these and only in these cells expressing green fluorescent protein (EGFP) identify POMC neuron in these mices.Use standard electric physiology technology to be recorded in the frequency of the action potential in these neurons.Particularly, the free cell that is connected in the paster structure is used for determining the action potential frequency, simultaneously the interference of pair cell is reduced to minimum.

Shown that zonisamide and zonisamide add amfebutamone and increased the neuronic activity of POMC.The record basis is active, and then olanzapine is added in the tissue groove to measure the influence of olanzapine to the POMC neuronal activity.Pharmacology data shows that olanzapine increases the neuronic activity of POMC.Then, handle the increase that brain section is tested neuronal activity once more by add amfebutamone with zonisamide or zonisamide.

Embodiment 12: zonisamide, the case research of lamotrigine (lamotrogine) and clonazepam combination

The 49 years old women who suffers from I type biopolar disease uses clonazepam 1mg qHS by her psychopathist, and fluoxetine 20mg qd and lamotrigine 300mg qD have treated just above 1 year.A special discomfort is that she has " to the expectation that continues of diet ".Her psychopathist begins to take zonisamide 100mg qD to her.She reports that zonisamide has significantly reduced her to the serious hope of food and prevented the increase of weight.Taking medicine continues to carry out, although and multiple stimulus is arranged at home, she continues to make progress well on this therapeutic scheme.

Embodiment 13: zonisamide, the case research of paroxetine and risperidone combination

Treat 45 years old female patient suffering from social phobia and Schizoaffective disease in order to the paroxetine that risperidone is promoted.She has the appetite of remarkable increase and has increased by 40 pounds.Independent amfebutamone test does not cause significant weight to alleviate.Therefore, she begins to take zonisamide 100mg, after be increased to 200mg.In 3 weeks, she has alleviated 12 pounds.Then, dosage is increased to 300mg, is increased to 600mg then.In 5 months, her weight has been got back to baseline.Psychotic symptoms also is improved.

Embodiment 14: zonisamide, olanzapine, the case research of the combination of valproate and amfebutamone

When accepting olanzapine and valproate above 5 years, one is diagnosed as 30 years old female patient with bipolar disease and has increased 56lbs.Although obviously increased weight,, continue to her these medicines of administration because her mental sickness has obtained effective control.She has BMI is 33.8kg/m ²Obesity clinically.In the trial that helps weight to reduce, added amfebutamone with 150mg/ days and continue administration amfebutamone and valproate simultaneously.When the dosage of amfebutamone was raised to 300mg/ days, described patient reported that sensory function is hyperfunction; Therefore, dosage is subtracted back 150mg/ days.After 6 months, the patient has alleviated 23.6lbs.Yet when continuing to accept amfebutamone, described patient increases 10.6lbs once more in ensuing 10 middle of the month.At that point, zonisamide adding her pharmaceutical admixtures in 100mg/ days, and after 2 weeks, is increased to 200mg/ days with described dosage.In ensuing 4 months, described patient has alleviated 15lbs, and report is free from side effects.She is keeping not having the state of bipolar disease symptoms.

Described case is for example understood two advantages of amfebutamone and zonisamide combined therapy.1) although amfebutamone helps to have reduced the weight that is caused by olanzapine and valproate to be increased, described patient can not take the more amfebutamone of high dose (300-400mg/ days), because the generation of hypomania symptom.Use antidepressant drug in responsive patient, to induce risk manic or the hypomania symptom that sufficient document record is arranged.2) begin to have alleviated weight described patient, and after having increased some weight that alleviate once more, zonisamide further helps to offset the weight relevant with olanzapine and valproate to be increased by the use amfebutamone.

Claims

1. pharmaceutical composition that is used to prevent that the weight relevant with using psychotropic drug from increasing, it comprises first chemical compound and second chemical compound, wherein said first chemical compound is a psychotropic drug, and described second chemical compound is an anticonvulsant.

2. the pharmaceutical composition of claim 1, wherein said psychotropic drug is selected from the group of being made up of lithium carbonate, Lithium Citrate de, valproate, their mixture and their pharmaceutical salts or prodrug.

3. the pharmaceutical composition of claim 1, wherein said anticonvulsant is selected from by topiramate, zonisamide, and pharmaceutical salts or prodrug, and the group formed of combination.

4. the pharmaceutical composition of claim 1, wherein said first chemical compound is a psychotropic drug, and described second chemical compound is a zonisamide.

5. the pharmaceutical composition of claim 4, wherein said first chemical compound is lithium carbonate or Lithium Citrate de.

6. the pharmaceutical composition of claim 4, wherein said first chemical compound is a valproate.

7. the pharmaceutical composition of claim 1, wherein said first chemical compound is a lithium salts, and described second chemical compound is a zonisamide.

8. the pharmaceutical composition of claim 1, wherein said first chemical compound is a valproic acid, or its pharmaceutical salts, ester, amide or prodrug, and described second chemical compound is a zonisamide.

9. the pharmaceutical composition of claim 1, wherein said first chemical compound is a mirtazapine, and described second chemical compound is a zonisamide.

10. the pharmaceutical composition of claim 1, wherein said first chemical compound is a mirtazapine, and described second chemical compound is an amfebutamone.

11. the pharmaceutical composition of claim 1, wherein said first chemical compound is a setiptiline, and described second chemical compound is a zonisamide.

12. the pharmaceutical composition of claim 1, wherein said first chemical compound is a setiptiline, and described second chemical compound is an amfebutamone.

13. the pharmaceutical composition of claim 1, wherein said first chemical compound is a mirtazapine, and the combination that is zonisamide and amfebutamone of described second chemical compound.

14. the pharmaceutical composition of claim 1, wherein said first chemical compound is a setiptiline, and the combination that is zonisamide and amfebutamone of described second chemical compound.

15. one kind prevents the method that lose weight relevant with using psychotropic drug, described method comprises that evaluation needs its individuality, and treats this individuality with psychotropic drug and anticonvulsant.

16. the method for claim 15, wherein said psychotropic drug is selected from by lithium carbonate, Lithium Citrate de, and valproate, and the group of pharmaceutical salts, ester, amide or prodrug composition, and described anticonvulsant is a zonisamide.

17. the method for claim 15, wherein said psychotropic drug is selected from by mirtazapine, and setiptiline, and the group of pharmaceutical salts, ester, amide or prodrug composition, and described anticonvulsant is a zonisamide.

18. a method that suppresses individual appetite, described method comprise that evaluation needs the individual of its and should individuality with first chemical compound and second compounds for treating, wherein said first chemical compound is a psychotropic drug, and described second chemical compound is an anticonvulsant.

19. the method for claim 18, wherein said psychotropic drug is selected from by lithium carbonate, Lithium Citrate de, and valproate, and the group of pharmaceutical salts, ester, amide or prodrug composition, and described anticonvulsant is a zonisamide.

20. the method for claim 18, wherein said psychotropic drug is selected from by mirtazapine, and setiptiline, and the group of pharmaceutical salts, ester, amide or prodrug composition, and described anticonvulsant is a zonisamide.