MXPA06005623A - Combination drug therapy to treat obesity - Google Patents

Abstract

Provided are methods of achieving desirable weight loss in an overweight or obese individual by administering at least one anticholinesterase agent and at least one antidepressant. The invention also provides for pharmaceutical compositions and kits for simultaneous delivery of at least one anticholinesterase agent and at least one antidepressant.

Description

DRUG COMBINATION THERAPY TO TREAT OBESITY CROSS REFERENCES TO RELATED REQUESTS This application claims the benefit of the U.S. Provisional Patent Application. No. 60 / 523,610, filed on November 19, 2003, the disclosure of which is hereby incorporated herein by reference in its entirety. DECLARATION REGARDING THE RIGHTS TO THE INVENTIONS CARRIED OUT UNDER INVESTIGATION AND FEDERALLY SPONSORED DEVELOPMENT NOT APPLICABLE BACKGROUND OF THE INVENTION Obesity is the most common nutritional disorder in the United States and perhaps in the developed world. • Numerous studies indicate that the reduction of excessive body weight dramatically decreases the risk of chronic diseases, such as diabetes, hypertension, hyperlipidemia, coronary heart disease and musculoskeletal diseases. Currently available pharmacological treatments for obesity and weight loss have included the administration of a selective serotonin reuptake inhibitor (SSRI) together with the anorectic, phentermine (see, U.S. Patent No. 6,548,551); the administration of optically pure sibutramine metabolites, (see, U.S. Patent No. 6,538,034); and administration of reserpine with an antidepressant such as trazodone, bupropion or fluoxetine (see, U.S. Patent No. 4,895,845). Other pharmacological treatments have included the administration of an acetylcholinesterase reactivator (see, U.S. Patent No. 5,900,418), an aza-indolyl derivative (see, of U.S. Patent No. 6,583,134) or compounds that increase thermogenesis and increase lipolysis ( see, from U.S. Patent No. 6,534,496). Problems with current drug treatments for weight loss and obesity include that medications fail to help many patients achieve weight loss in the first place. Pharmacological regimens that work initially often fail to help many patients continue to achieve weight loss or maintain a stable weight. Clearly, there is still a need for effective pharmacological treatments to achieve the desired weight loss and for the treatment of obesity. The present invention meets these and other needs. BRIEF SUMMARY OF THE INVENTION The present invention provides methods to treat obesity, achieving desirable weight loss, preventing undesirable weight gain, facilitating weight loss, aiding weight loss, methods for maintaining a stable weight and methods. to reduce body weight in an obese or overweight individual, the methods generally comprise administering to the individual an effective amount of a combination of one or more cholinesterase inhibitors and one or more antidepressants. In a preferred embodiment, the methods comprise administering to an obese or overweight individual an effective amount of venlafaxine and rivastigin. Commonly, the methods are carried out over a prolonged period. The invention also provides pharmaceutical compositions comprising a mixture of one or more cholinesterase inhibitors and one or more antidepressants. In a preferred embodiment, the pharmaceutical compositions comprise controlled release formulations. BRIEF DESCRIPTION OF THE DRAWINGS NOT APPLICABLE DESCRIPTION DETAIL OF THE INVENTION Definitions The term "obese" or "obesity" refers to an individual having a body mass index (BMI) of 30 kg / m2 or more, due to excess adipose tissue. Obesity can also be defined on the basis of the body fat content: greater than 25% of the body fat content for a male or more than 30% of the body fat content for a female. An individual with "pathological obesity" has a body mass index greater than 35 kg / m2. The term "overweight" refers to an individual who has a body mass index of 25 kg / m2 or more, but less than 30 kg / m2. The term "body mass index" or "BMI" refers to a measurement of the weight-to-height ratio that estimates whether the weight of an individual is appropriate for its height. As used herein, the body mass index of an individual is calculated as follows: BMI = (pounds x 700) / (height in inches) 2 or BMI = (kilograms) / (height in meters) 2 The term " Basal body weight "refers to the body weight presented by the individual at the start of treatment. As used herein, "administer" means oral administration, administration as a suppository, topical, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration or implantation of a slow release device, eg, a pump mini-osmotic, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., oral, nasal, vaginal, rectal or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. The terms "cholinesterase inhibitor" and "anticholinesterase" refer interchangeably to a pharmaceutical compound that inhibits the activity of the enzyme acetylcholinesterase (AChE). Cholinesterase inhibitors are generally classified as "reversible", "pseudo-irreversible" or "slow reversal /" and "irreversible." "Reversible" cholinesterase inhibitors are typically non-covalent inhibitors. Cholinesterase inhibitors "pseudo-irreversible," "pseudo-reversible" or "slow-reverse" react covalently or non-covalently with AChE with high affinity. The pseudo-irreversible cholinesterase inhibitors typically, but not exclusively, have a carbamoyl ester bond and are hydrolyzed by AChE, but much more slowly than acetylcholine. The attack by the active center serine of AChE gives rise to a carbamoylated AChE. The duration of inhibition by carbamoylation anticholinesterase agents may be from about 3 to 4 hours. The half-life of such carbamoylating agents, for example, physostigmine, neostigmine and pyridostigine, can be from about 1 to 2 hours. The difference between the "pseudo-irreversible" and "reversible" cholinesterase inhibitors generally reflects the quantitative differences in the deacylation rates of the acyl enzyme. In the case of "pseudo-irreversible" cholinesterase inhibitors, the half-life (t? / 2) for the hydrolysis of the dimethylcarbamoyl enzyme is approximately 15 to 30 minutes. "Irreversible" cholinesterase inhibitors are commonly organophosphorus compounds. With the "irreversible" cholinesterase inhibitors, the active enzyme can regenerate spontaneously after several hours or so slowly that the return of AChE activity depends on the synthesis of the new enzyme. Anticholinesterase agents are well known and discussed in detail in, for example, Goodman and Gilman's The Pharmacological Basis of Therapeutics, Chapter 8, 10th Ed., Hardman, Li bird and Goodman-Gilman, Eds., McGraw-Hill ( 2001), incorporated herein by reference. The terms "controlled release", "sustained release", "prolonged release" and "deferred release" are proposed to refer interchangeably to any formulation containing a drug in which the release of the drug is not immediate, ie, with a "controlled release" formulation, oral administration does not result in the immediate release of the drug within an absorption tank. The terms are used interchangeably with "non-immediate release" as defined by Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams &; Wiikins (2003). As discussed herein, immediate and non-immediate release can be defined kinetically by reference to the following equation: k k k Shape of r Deposit from to Area? ? ? Dosage Absorption Target drug release absorption elimination The "absorption deposit" represents a solution of the drug administered at a particular absorption site and kr, ka and ke are the constants of the first-order rate for (1) the release of the drug from the formulation, ( 2) absorption and (3) elimination, respectively. For the immediate-release dosage forms, the rate constant for the kr release of the drug is much greater than the constant ka.de of the absorption rate. For controlled release formulations, the opposite occurs, ie, kr «ka, such that the release rate of the drug from the dosage form is the limiting step in the rate of supply of the drug to the area objective. The terms "sustained release" and "prolonged release" are used in their conventional sense to refer to a drug formulation that provides for the gradual release of a drug over a prolonged period, for example, 12 hours or more and that, preferably, although not necessarily, resulting in substantially constant blood levels of a drug over a prolonged period. As used herein, the term "delayed release" refers to a pharmaceutical preparation that passes intact through the stomach and dissolves in the small intestine. General The present invention provides an effective pharmacological treatment to achieve the desired weight loss in an overweight or obese individual and which effects the continued weight loss and weight management over a prolonged period. The co-administration of one or more anticholinesterase agents and one or more antidepressant agents inexplicably provides the sustained weight loss of a greater amount of body weight that is achieved by administering any category of drug alone, especially in view of the side effects of increasing weight that are frequently associated with the long-term administration of antidepressants (see, for example, Masand and Gupta, Ann.Clin., Psych.14: 175 (2002); and Deshmukh and Franco, Cleve.Clin.J.Med. : 614 (2003)).

Detailed Modes Methods of Treatment In one aspect, the present invention provides methods for the treatment of obesity. In another aspect, the invention provides methods to facilitate, assist and achieve desirable weight loss in an obese or overweight individual. In another aspect the present invention provides methods for reducing body weight in an obese or overweight individual. In another aspect the present invention provides methods for reducing body weight in an obese or overweight individual. In another aspect, the invention provides methods for maintaining a stable weight and for preventing undesirable weight gain in an obese or overweight individual. In general, the methods comprise administering to an obese or overweight individual an effective amount of a combination of one or more cholinesterase inhibitors and one or more antidepressants for an effective time to produce and / or maintain weight loss. Commonly, the combination of one or more cholinesterase inhibitors and one or more antidepressants is administered to the individual over a prolonged period. Typically, the methods are carried out for at least 20 days, more typically for at least 40, 60, 80 or 100 days and commonly for at least 150, 200, 250, 300, 350 days, 1 year or more. Certain individuals receive the present treatment methods for more than one year, typically at least 400, 450, 500, 550, 600, 650, 700, 800, 900, 1000 days and successfully maintain a lower weight. However, individuals can be treated with the present methods and successfully maintain a lower weight for 2 years, 3 years, 4 years or more. Importantly, the present methods maintain the desired weight loss and weight stabilization during the prolonged treatment period. The methods are for use in the treatment of individuals who have not been diagnosed or who do not suffer from depression, but they are also used for the treatment of individuals diagnosed and suffering from depression. Typically, the anticholinesterase includes one or more of a reversible or a pseudo-irreversible anticholinesterase. Exemplary reversible inhibitors include tacrine, donepezil and galantamine. Exemplary pseudo-irreversible inhibitors include physostigmine, eptastigmine, pyridostigmine, neostigmine, ganstigmine and rivastigmine. The pseudo-irreversible cholinesterase inhibitors also comprise carbamate insecticides, including carbaryl (Sevin), propoxur (Baygon) and aldicarb (Temik). Typically, pseudo-irreversible anticholinesterases comprise a carbamate residue, for example, rivastigmine, eptastigmine, physostigmine, neostigmine, pyridostigmine and ganstigin. Other clinically employed reversible anticholinesterase agents suitable for use in the present invention include demecarium, ambenonium and edrophonium. Additional cholinesterase inhibitors that may find use in the present invention include huperzine A, T-82, phenserin, quilostigmine and TAK-147. In a preferred embodiment, rivastigmine is administered. In a preferred embodiment, galantamine is administered. In a preferred embodiment, donepezil is administered. Those skilled in the art will readily recognize that other non-listed anticholinesterase agents are also applicable. In certain embodiments, the anticholinesterase includes one or more of the irreversible anticholinesterase agents. For example, inhibition of cholinesterase activity can be achieved by the use of an organophosphate, including an organofluorophosphate, an organocyanophosphate, an organothiophosphate or an organothiocyanophosphate. Exemplary irreversible inhibitors include sarin, etrifonate, soman, tabun, diisopropyl fluorophosphate (DFP), and the insecticides parathion, paraoxon, and malathion. These therapeutic agents covalently modify cholinesterase by acylation of active site serine. It has been reported that the average life of action of the metriofonate is approximately 15 days in humans. Irreversible inhibition may be attractive to improve the patient's attachment. If necessary, the effects of the irreversible cholinesterase inhibitors can be counter-acting by giving the patient atropine and / or pralidoxime. The former is a non-specific antagonist of the muscarinic acetylcholine receptor and the latter reactivates cholinesterase by reversing the acylation of active site serine. In certain embodiments, the anticholinesterase includes one or more cholinesterase inhibitory agents that bind with the acyl cavity of the active center of the AChE, the choline sub-site of the active center of AChE, or the peripheral anionic site of the AChE. For example, the binding of edrophonium and tacrine to the choline sub-site in the vicinity of tryptophan 86 and glutamate 202 of the AChE. Donepezil binds with greater affinity to the active center of the AChE. Propidium and fasciculin of peptide toxin are linked to the peripheral anionic site in AChE. This is reviewed in Goodman and Gilman's The Pharmacological Basis of Therapeutics, supra, at pages 175-89, incorporated herein, by reference. In certain modalities, the anticholinesterase also acts on the nicotinic acetylcholine receptors as an allosteric enhancer of its action. An exemplary anticholinesterase that is also a nicotinic receptor enhancer is galantamine.

The doses administered of anticholinesterase agents and antidepressants are in accordance with the dose and programming regimens practiced by those skilled in the art. The general guide to determining the appropriate dose of all pharmacological agents used in the present methods is provided in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th Ed., Hardman, Limbird and Goodman-Gilman, Eds., McGraw -Hill (2001) and in the Physicians' Desk Reference (PDR), for example, in Eds. 57a or 58a, Thompson PDR (2003 or 2004, each of which is incorporated herein, by the The published doses of anticholinesterase agents and antidepressants have different indications from those of treatments to promote weight loss or to inhibit weight gain, typically effective doses of anticholinesterase and antidepressant agents to practice the present invention. they may be equal to or less than (eg, approximately 25, 50, 75 or 100%) the published doses for other indications, such as Alzheimer's disease and depression, respectively. The appropriate dose of one or more cholinesterase inhibitors will vary according to the route of administration and formulation of the composition chosen, among other factors, such as the response of the patient.

The dose can be increased or reduced over time, as required by a particular patient. Commonly, a patient is administered a low dose, which is then increased to an effective dose tolerable for the patient. For example, effective parenteral doses of neostigmine are from about 0.5 mg to about 2.0 mg per dose and the equivalent oral doses are from about 15 to 30 mg per dose or more. Appropriate oral doses of edrophonium chloride are from about 2 mg to about 10 mg per day and oral doses of ambenonium are from about 2.5 mg to about 5 mg per day. The pyridostigmine can be administered in "immediate release" preparations in doses from 30 mg to 60 mg and in sustained release formulations of approximately 180 mg. For use in carrying out the present methods, rivastigmine can be administered in an amount of about 0.4 mg to about 6.0 mg, per dose and commonly at about 1.0, 1.5, 2.0, 2.5, 3.0, 4.5 mg per dose and up to 12.0 mg / day. In the present methods, galantamine can be administered in doses of approximately 2-12 mg per day and commonly in approximately 4, 6, 8 or 10 mg per day. Donepezil may be administered in doses between about 1 and 10 mg per day, preferably about 5 mg or 10 mg per day.

To provide non-limiting exemplifications, an initial dose of rivastigmine may be 1.25 mg twice a day, eg, one before breakfast and one before the meal (see, PDR, 57th Ed., 2003 (supra)). If the patient loses weight with this dose, the dose is not increased. If weight is not lost, the dose taken before the meal can be increased to 2.5 mg. With some patients, a major problem is the ingestion of food during the afternoon, i.e., after the meal. In this case, the next stage would be the administration of 1.25 mg, two to three hours after the dose taken before the meal, instead of increasing the pre-meal dose to 2.5 mg, to achieve a total daily dose of 4.5 mg. The maximum daily dose is commonly 12 mg per day. The total daily dose can be distributed to the patient in three intervals (morning, lunch and afternoon), according to the needs of the patient. If the patient suspends the medication for a week or more, the treatment can be restarted starting again with a small dose and the dose can be increased relatively quickly. Rivastigmine has very few interactions with other drugs because it is not metabolized by cytochrome P450. Side effects that, commonly, they are gastrointestinal can be managed by means of the adjustment of the dose. If necessary, a proton pump inhibitor (e.g., lansoprazole, omeprazole) can be used. As another example, an initial dose of galantamine can be 4 mg twice a day, taken with breakfast and with food. If this is not effective, the dose can be increased to 8 mg twice a day. The maximum dose is commonly 12 mg twice a day. To provide an additional example, donepezil is typically administered only once a day, due to its long duration. An initial dose may be 5 mg and the highest dose is commonly 10 mg. If a patient can not tolerate a full dose of a cholinesterase inhibitor, in particular, a second cholinesterase inhibitor may be administered along with one that is not well tolerated, for example, a small dose of donepezil plus rivastigmine. For certain patients, the methods are carried out by first administering an anticholinesterase agent alone and, subsequently, co-administering an anticholinesterase and an antidepressant. For certain patients, the methods are carried out by first administering an antidepressant alone and, subsequently, co-administering an anticholinesterase and an antidepressant. The patient can initially be administered either an antidepressant or an anticholinesterase alone for 3 days, 5 days, 7 days, 10 days, 14 days, 20 days or 30 days before starting the administration of both, ie an anticholinesterase and an antidepressant To provide a non-limiting example, a patient is administered venlafaxine alone for a week (7 days) or 10 days and then both venlafaxine and rivastigmine are administered. The antidepressant agents that are used in the present invention are not limited by their mechanism of action and any kind of antidepressant is applicable. For example, tricyclic antidepressants (TCAs) and analogues of these, serotonin reuptake inhibitors, monoamine oxidase inhibitors (MAOIs), serotonin agonists and pro-drugs thereof, norepinephrine reuptake inhibitors, inhibitors of Dopamine reuptake and serotonin reuptake accelerators can all be administered in combination with one or more anticholinesterase agents to achieve weight loss or weight stabilization or to prevent weight gain. The serotonin reuptake inhibitors comprise both selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Norepinephrine reuptake inhibitors comprise both the specific inhibitors of norepinephrine reuptake and the mixed norepinephrine-dopamine reuptake inhibitors (NDRIs). Serotonin-norepinephrine-dopamine reuptake inhibitors or "triple reuptake inhibitors" also find use in the present invention. The tricyclic antidepressants which are used in the present invention comprise amineptine, amitriptyline, clomipramine, desipramine, doxepin, dosulepine, imipramine, nortriptyline, protriptyline, trimipramine, amoxapine, tetracyclic maprotiline and muscle relaxant cyclobenzaprine. Other tricyclic antidepressants not listed and analogous thereof can also be used. In a preferred embodiment, an effective amount of one or more anticholinesterase agents is co-administered together with an effective amount of a selective inhibitor of serotonin reuptake. The selective serotonin reuptake inhibitors that are exemplified include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline, although unlisted SSRIs are also applicable. In a preferred embodiment, citalopram is co-administered with one or more anticholinesterase agents. In a further preferred embodiment, an effective amount of galantamine is co-administered with an effective amount of citalopram. In an additional preferred embodiment, an effective amount of donepezil is coadministered together with an effective amount of sertraline. In a preferred embodiment, an effective amount of one or more serotonin-norepinephrine reuptake inhibitors is co-administered with one or more cholinesterase inhibitors. Exemplary serotonin-norepinephrine reuptake inhibitors include milnacipran, mirtazapine, venlafaxine, duloxetine, (-) l- (1-dimethylaminomethyl-5-methoxybenzo-cyclobutane-1-yl) cyclohexanol (S33005), DVS-233 (desvenlafaxine ), DVS-233 SR and sibutramine, although non-listed SNRIs are also used. In a preferred embodiment, venlafaxine is co-administered with one or more anticholinesterase agents. In a further preferred embodiment, an effective amount of venlafaxine is coadministered together with an effective amount of rivastigmine. In a preferred embodiment, an effective amount of duloxetine is co-administered together with an effective amount of one or more anticholinesterase agents. In other embodiments, an effective amount of one or more selective norepinephrine reuptake inhibitors is co-administered together with one or more cholinesterase inhibitors. Exemplary selective norepinephrine reuptake inhibitors include reboxetine and atomoxetine. In a preferred embodiment, an effective amount of one or more norepinephrine-dopamine reuptake inhibitors is co-administered together with one or more cholinesterase inhibitors. The norepinephrine-dopamine reuptake inhibitors that are exemplified include amineptine, GW353162 and bupropion. In the case of bupropion, it is thought that metabolites are responsible for blocking noradrenergic resorption. In a preferred embodiment, an effective amount of one or more triple reuptake inhibitors (serotonin-norepinephrine-dopa ina) is co-administered together with one or more cholinesterase inhibitors. The exemplified triple resorption inhibitors include SEP-225289, DOV 216.303 and (+) -1- (3,4-dichlorophenyl) -3-azabicyclo- [3.1.0] hexane hydrochloride (DOV 21.947). The monoamine oxidase inhibitors which are used in the present invention comprise befloxatone, brofaromine, deprenyl, isocarboxazide, moclobemide, pargyline, phenelzine, selegiline and tranylcypromine, together with their sustained delivery and transdermal delivery forms. Other antidepressants that can be co-administered with an anticholinesterase agent to achieve weight loss or stabilization or prevention of weight gain include maprotiline, thianeptine, nefazodone and trazodone. The appropriate doses for the antidepressants will depend on the route of administration and the formulation of selected composition, among other factors. For example, tricyclic antidepressants are administered in a dose of about 25 to about 600 mg / day and commonly in a dose of about 75 to about 300 mg / day. The serotonin reuptake inhibitors are administered in a dose of about 5 to about 400 mg / day and are commonly administered from about 20 to about 250 mg / day. In particular, by practicing the present methods, venlafaxine can be administered at about 9 mg to about 225 mg per dose and approximately 37.5 mg, 75 mg, 150 mg or 225 mg per dose are commonly administered. Venlafaxine is typically administered at approximately 25-550 mg / day and commonly at approximately 37.5-375 mg / day, more typically at approximately 75-225 mg / day and more typically at approximately 37.5, 75, 150, 225 or 300 mg / day. As appropriate for a particular patient, the daily doses of venlafaxine can be divided and administered once, twice, three times, four or more times a day. To carry out the present methods, citalopram is administered at about 5-60 mg / day, and preferably at about 10 mg / day., 20 or 30 mg / day. Commonly, citalopram is administered once a day, for example in the morning or in the afternoon. However, some patients are given doses of citalopram two or more times a day. Atypical antidepressants, including bupripion, nefazodone and trazodone, are administered at a dose of approximately 50-600 mg / day and commonly at approximately 150-400 mg / day. The monoamine oxidase inhibitors are typically administered in a dose of about 5-90 mg / day and commonly at about 10-60 mg / day. To provide specific, non-limiting examples, a usual dose of SSRI citalopram is 20 mg per day. It can be administered once a day, commonly in the morning. Relaxes the patient and makes the decrease in food intake more tolerable. There are no known harmful interactions between citalopram and cholinesterase inhibitors. Citalopram can be administered together with venlafaxine. The dose can vary from 5 to 60 mg per day. As another example, venlafaxine potentiates the effects of cholinesterase inhibitors. Venlafaxine can be administered initially from 30 to 40 mg per day, with gradual increments in the dose up to 100 to 150 mg per day in a week or two before the co-administration of one or more cholinesterase inhibitors. If side effects inhibit the use of a higher dose of one or more cholinesterase inhibitors, an increase in the dose of venlafaxine may increase weight loss. For the obese pathologist, a dose of 375 mg per day can be used. Venlafaxine is preferably administered at the same time as cholinesterase inhibitors. The absorption of venlafaxine is not influenced by the presence of food. With doses higher than 300 mg per day, a slight increase in blood pressure may occur in 15% of patients. This is easily compensated by the administration of a diuretic, loop diuretic, ACE inhibitor or angiotensin-II receptor type 1 inhibitor or other antihypertensive agent. Larger doses of venlafaxine can also cause an increase in heart rate. If this is a problem, the dose of venlafaxine should be reduced. The use of a beta-blocker agent is apt to interfere with the therapeutic effects of venlafaxine. Venlafaxine has a very small effect on the metabolism of other drugs and other drugs have only a minor effect on the metabolism of venlafaxine. The combined treatment of the present invention can be administered prophylactically to prevent undesirable weight gain or to maintain a stable weight or, therapeutically, to achieve a desirable weight loss and maintain such weight loss over a sustained period of time. Generally, when practicing the present methods, the effective amounts of one or more anticholinesterase agents are co-administered with one or more antidepressants.; they can be administered together or separately, simultaneously or at different times. Anticholinesterase agents and antidepressants can be administered independently one, two, three, four times a day or more or less frequently, as needed. Preferably, one or more of the anticholinesterase agents and one or more antidepressants are administered both once a day and at the same time, for example, as a mixture. Preferably, a combination of one or more anticholinesterase agents and one or more antidepressants are administered in a sustained release formulation. Commonly, subjects treated according to the present invention can lose at least about 10, 15 to 20 pounds after approximately 50, 60 to 70 days of treatment; at least about 20, 25, 30 to 35 pounds after about 80, 90, 100 to 110 days of treatment and, at least, about 35, 40, 45, 50 to 55 pounds after about 200, 300, 350 to 400 days of treatment. Typically, individuals treated according to the present methods can lose at least about 5% and more commonly at least about 10%, 15% or 20% of their baseline body weight and stably maintain this loss of desirable weight by means of a treatment regime for 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 700, 800, 900, 1000 days or more. It is important to note that the administration of an effective amount of one or more cholinesterase inhibitors and an effective amount of one or more antidepressants over a prolonged period facilitates stable weight and prevention of undesirable weight gain during the period prolonged treatment The combined treatment of the present invention is particularly appropriate for obese and overweight individuals, but it can also be administered to any individual wishing to lose weight, maintain a stable weight or prevent undesirable weight gain. In some modalities, an additional anorectic is administered. Anorexigens that are exemplified include, without limitation, amphetamine, methamphetamine, dextroamphetamine, fenter ina, benzfetamine, phendimetrazine, phenmetrazine, diethylpropion, mazindol, fenfluramine, and phenylpropanolamine. Mild stimulants can also be given additionally. The stimulants that are exemplified include pseudoephedrine, methylphenidate and odafinil. Pharmaceutical Formulations / Routes of Administration The present invention further provides a pharmaceutical composition that includes a mixture of an effective amount of one or more cholinesterase inhibitors and one or more antidepressants. Generally, the pharmaceutical compositions comprise an anticholinesterase agent selected from a group consisting of a reversible inhibitor, a pseudo-irreversible inhibitor and an irreversible inhibitor of AChE. In certain embodiments, the pharmaceutical compositions comprise one or more cholinesterase inhibitors comprising a carbamate residue. In one embodiment, the pharmaceutical composition includes one or more anticholinesterase agents selected from a group including rivastigmine, galantamine and donepezil. In certain embodiments, the pharmaceutical compositions comprise one or more antidepressants that are a selective inhibitor of serotonin reuptake (SSRI), an inhibitor of serotonin-norepinephrine reuptake (SNRI), a norepinephrine reuptake inhibitor, a dopamine reuptake inhibitor, a norepinephrine-dopamine reuptake inhibitor (NDRI), an inhibitor of serotonin-epinephrine-dopamine reuptake, a resorption accelerator of serotonin, a serotonin agonist and pro-drugs thereof. In one embodiment, the pharmaceutical composition includes one or more antidepressants selected from the group which includes venlafaxine, duloxetine, fluoxetine, citalopram, escitalopram, fluvoxamine, paroxetine, S33005, DVS-233 (desvenlafaxine), DVS-233 SR, bupropion, GW353162 and sertraline. . In a preferred embodiment, the pharmaceutical composition includes effective amounts of rivastigmine and venlafaxine. In a preferred embodiment, the pharmaceutical composition includes effective amounts of galantamine and citalopram. In a preferred embodiment, the pharmaceutical composition includes effective amounts of donepezil and sertraline. In a preferred embodiment the pharmaceutical composition includes effective amounts of galantamine and paroxetine. In a preferred embodiment, the pharmaceutical composition includes effective amounts of galantamine and duloxetine. A combination of one or more anticholinesterase agents and one or more antidepressants can be administered to a subject, eg, a human patient, a pet, such as a cat or a dog, independently or together in the form of their pharmaceutically salts acceptable or in the form of a pharmaceutical composition wherein the compounds are mixed with approte vehicles or excipient (s) in a therapeutically effective amount, eg, in effective doses to achieve desirable weight loss, or maintenance or prevention of weight gain undesirable An anticholinesterase-antidepressant combination of this invention can be incorporated into a variety of formulations for therapeutic administration. More particularly, a combination of the present invention can be formulated in pharmaceutical compositions, together or separately, by formulating with suitable carriers or diluents that are pharmaceutically acceptable, and can be formulated into solid, semi-solid, liquid or solid form preparations. gaseous, such as tablets, capsules, pills, powders, granules, dragees, gels, mixtures, ointments, solutions, suppositories, injections, inhalants and aerosols. As such, the administration of an anticholinesterase-antidepressant combination can be achieved in various forms, including oral, buccal, parenteral, intravenous, intradermal (e.g., subcutaneous, intramuscular), transdermal, etc. administration. In addition, the compound can be administered locally rather than systemically, for example, in a sustained release or depot formulation. In a preferred embodiment, the invention provides a pharmaceutical composition that includes at least one anticholinesterase agent and at least one antidepressant. Formulations suitable for use in the present invention are found in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wiikins (2003), which is incorporated herein by reference. The pharmaceutical compositions described herein may be made in a manner known to those skilled in the art, i.e., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

The following methods and excipients are merely exemplifications and are not limiting in any way. In a preferred embodiment, an anticholinesterase-antidepressant combination is prepared for delivery in a sustained release, controlled release, prolonged release, delayed release or delayed release formulation, for example, in semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Several types of sustained release materials have been established and are well known to those skilled in the art. Current extended release formulations come coated film tablets, multiparticulate or pellet systems, matrix technologies utilizing hydrophilic or lipophilic materials and wax-based tablets with pore forming excipients (see, eg, Huang, et al. , Drug Dev. Ind. Pharm. 29:79 (2003); Pearnchob, et al. ,. Drug Dev. Ind. Pharm. 29: 925 (2003); Maggi et al. Eur J. Pharm Biopharm. 55:99 (2003); Khanvilkar, et al., Drug Dev. Ind. Pharm. 228: 601 (2002); and Schmidt, et al., Int. J. Pharm. 216: 9 (2001)). Sustained-release delivery systems can, depending on their design, release the compounds over the course of hours or days, for example, during 4,6,8,10,12,16,20,24 hours or more. Commonly, sustained release formulations can be prepared using polymers of natural or synthetic origin, for example, polymeric vinyl pyrrolidones, such as polyvinyl pyrrolidone (PVP); carboxyvinyl hydrophilic polymers; hydrophobic and / or hydrophilic hydrocolloids, such as methylcellulose, ethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose; and carboxypolymethylene. Sustained or prolonged release formulations can also be prepared using natural ingredients, such as minerals, including titanium dioxide, silicon dioxide, zinc oxide and clay (see, U.S. Patent 6,638,521, incorporated herein by reference). The prolonged release formulations that are employed, which can be used to deliver a combination anticholinesterase-antidepressant of the present invention, comprise those described in US Pat. Nos.6, 635, 680; 6,624,200; 6,613,361; 6,613,358, 6,596,308; 6,589,563; 6,562,375; 6,548,084; 6,541,020; 6,537,579; 6,528,080 and 6,524,621, each of which is incorporated herein by reference. Controlled release formulations of particular interest comprise those described in the US patents. Nos. 6,607,751; 6,599,529; 6,569,463; 6,565,883; 6,482,440; 6,403,597, 6,319,919; 6,150,354; 6,080,736; 5,672,356; 5,472,704; 5,445,829; 5,312,817 and 5,296,483, each of which is incorporated herein by reference. Those skilled in the art will readily recognize other applicable sustained release formulations. For oral administration, a combination of anticholinesterase-antidepressant can be easily formulated by combining it with readily acceptable carriers that are well known in the medium. Such carriers allow the compounds to be formulated as tablets, lozenges, lozenges, capsules, emulsions, lipophilic and hydrophilic suspensions, liguids, gels, syrups, mixtures, suspensions, and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by mixing the compounds with a solid excipient, by optional grinding a resulting mixture and by processing the granule mixture, after adding the appropriate auxiliaries, if desired, to get tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, comprising lactose, sucrose, mannitol or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, hydroxypropylmethyl cellulose, sodium / sodium carboxymethylcellulose and / or polyvinyl pyrrolidone (PVP) . If desired, disintegrating agents, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt derived therefrom such as sodium alginate, may be added. Pharmaceutical preparations that can be used orally include easy-swallow capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Easy to swallow capsules may contain active ingredients blended with fillers such as lactose, linkers such as starches and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration should be in appropriate doses for such administration. The dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which may optionally contain arabic gum, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, solutions for varnishing and appropriate organic solvents or solvent mixtures. Dyes or pigments can be added to the tablets or to the dragee coatings for identification or for characterization of the different combinations of the doses of the active compound.

The compounds can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. For injection, an anticholinesterase-antidepressant can be formulated into preparations by dissolving, suspending or emulsifying them in an aqueous or non-aqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, higher aliphatic acid esters or propylene glycol and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives. Preferably, a combination of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution or physiological saline buffer. Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with the addition of a preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical formulations for parenteral administration comprise aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds can be prepared as appropriate oily suspensions for injection. Suitable lipophilic solvents or carriers comprise fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides or liposomes. Suspensions for aqueous injection may contain substances that increase the viscosity of the suspension, such as sodium carmellose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds that favor the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution, before use, with a suitable vehicle, e.g., sterile, pyrogen-free water. Systemic administration can also be by transdermal or transmucosal means. For transmucosal or transdermal administration, appropriate penetrants are used in the formulation to permeate the barrier. For topical administration, the agents are formulated in ointments, creams, balsams, powders and gels. In one embodiment, the agent for transdermal / percutaneous delivery can be DMSO. Transdermal / percutaneous delivery systems may include, e.g., patches. For transmucosal administration, appropriate penetrants are used in the formulation to permeate the barrier. Such penetrants are generally known in the industry. Transdermal / percutaneous formulations that are exemplified, which may find use in the present invention, comprise those described in US Pat. Nos. 6,589,549; 6,544,548; 6,517,864; 6,512,010; 6,465,006; 6,379,696; 6,312,717 and 6,310,177, each of which is hereby incorporated by reference. For buccal administration, the compositions may take the form of tablets or tablets / lozenges / lozenges formulated in the conventional manner. In addition to the formulations described previously, a combination of the present invention anticholinesterase-antidepressant can also be formulated as a depot preparation. Such prolonged activity formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. In such a way that, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins or as slightly / sparingly soluble derivatives, for example, as a slightly / sparingly soluble salt. The pharmaceutical compositions may also include suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Pharmaceutical compositions suitable for use in the present invention comprise compositions wherein the active ingredients are contained in a therapeutically effective amount. The amount of the composition administered, of course, will depend on the subject to whom the treatment is being administered, the weight of the subjects, the severity of the condition, the manner of administration and the judgment / judgment of the prescribing physician. The determination of an effective amount is well within the ability of those skilled in the art, especially in view of the detailed statement that is provided herein. Generally, an effective or effective amount of a combination of one or more anticholinesterase agents and one or more antidepressants is determined by the initial administration of a low dose or a small amount of an anticholinesterase agent alone, an antidepressant alone or a combination of an anticholinesterase agent and an antidepressant and then the administered dose or dosages are progressively increased, adding the second medication as necessary, until the desired effect of weight loss or stability or prevention of weight gain is observed in the subject is being treated, with minimal or non-toxic side effects. Applicable methods for determining an appropriate dose and dosage scheme for the administration of a combination present day invention are described, for example, in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th Ed., Hardman, Limbird and Goodman- Gilman, Eds., McGraw-Hill (2001), and in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams and Wiikins (2003), both incorporated herein, herein, for reference. The amount and range of the dose / dosage can be adjusted individually to provide plasma levels of the active compounds that are sufficient to maintain the therapeutic effect. Preferably, therapeutically effective levels will be achieved by the administration of single daily doses, but efficient multiple dose daily schedules are comprised in this invention. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration. A person skilled in the art will be able to optimize the therapeutically effective local dosages / dosages without undue experimentation. The pharmaceutical compositions of the present invention can be provided in a kit. In certain embodiments, a kit of the present invention includes one or more anticholinesterase agents and one or more antidepressants in separate formulations. In certain embodiments, the kits comprise one or more anticholinesterase agents and one or more antidepressants within the same formulation. In certain embodiments, the kits provide one or more anticholinesterase agents and one or more antidepressants in formulations with uniform dosage throughout the course of treatment. In certain embodiments, the kits provide one or more anticholinesterase agents and one or more antidepressants in graduated dosages throughout the course of treatment, either increasing or decreasing, but commonly increasing to an effective dosage level, in accordance with requirements of an individual. In one embodiment, the kits comprise one or more pharmaceutical compositions comprising one or more anticholinesterase agents selected from the group consisting of a reversible inhibitor., a pseudo-irreversible inhibitor and an irreversible inhibitor. In one embodiment, the kits comprise one or more pharmaceutical compositions comprising one or more anticholinesterase agents selected from a group consisting of rivastigmine, galantamine and donepezil. In certain embodiments, the kits comprise one or more antidepressants selected from the group consisting of a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), an inhibitor of epinephrine reuptake, a dopamine reuptake inhibitor, a norepinephrine-dopamine reuptake inhibitor (NDRI), an inhibitor of serotonin-norepinephrine-dopamine reuptake, and mixtures thereof. In one embodiment, the kits comprise one or more pharmaceutical compositions comprising one or more antidepressants selected from the group consisting of venlafaxine, duloxetine, paroxetine, citalopram, escitalopram, fluvoxamine, S33005, DVS-233 (desvenlafaxine), DVS-233 SR, bupropion, GW353162 and sertraline. In a preferred embodiment, the kits comprise one or more pharmaceutical compositions comprising effective amounts of rivastigmine and venlafaxine. In a preferred embodiment, the kits comprise one or more pharmaceutical compositions comprising effective amounts of galantamine and citalopram. In a preferred embodiment, the kits comprise one or more pharmaceutical compositions comprising effective amounts of donepezil and sertraline. In a preferred embodiment, the kits comprise one or more pharmaceutical compositions comprising effective amounts of galantamine and paroxetine. In a preferred embodiment, the kits comprise one or more pharmaceutical compositions comprising effective amounts of galantamine and duloxetine. All publications and patent applications cited in this specification are incorporated herein by reference as if each individual publication or patent application were specifically and individually indicated for its modality for reference. Although the above invention has been described in some detail by way of illustration and example, for purposes of clarity of understanding, this will be readily apparent to those who have ordinary knowledge or skills in the art, in light of the teachings of This invention, that certain changes and modifications can be carried out without distancing themselves from the spirit or scope of the statements that are annexed. The invention will be described in more detail by means of specific examples. The following examples are offered for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize a variety of non-critical parameters that can be changed or modified to provide essentially the same results. EXAMPLES The following examples illustrate the treatment regimens that were exemplified and the resulting synergistic effects for achieving long-term stable weight loss, by coadministering, to an individual, an anticholinesterase agent and an antidepressant. Each patient is assigned an alphanumeric denominator. -in 3 fifteen twenty 4 > - fifteen twenty Medications HCTZ Atenolol Hydralazine Lisinopril Rosiglitazone Metformin causes diarrhea Atorvastatin Levothyroxine doxazosin metformin 10 alprazolam candesartan fifteen 25 Patient B2 Weight Camb. Days Venlafaxine Rivastigmine Trazadone Diethylpropion Comments Weight in to en in in Treatment by Height 68.5 205.0 0.0 0 breakfast lunch bedtime breakfast lunch dinner am pm phone BMI 30.8 200.0 5.0 14 75mg 75mg 1.5 1.5 Sex F 193.0 12.0 42 75 75 1.5 1.5 Date of birth . 02-02-56 185.0 20.0 56 75 75 1.5 1.5 Age at the beginning 47 184.0 21.0 70 75 75 1.5 1.5 Initial Information 78 75 75 1.5 1.5 B.P. 175.0 30.0 98 75 75 3.0 3.0 Pulse 171.0 34.0 112 10 75 75 3.0 3.0 HPN Rx 169.0 36.0 126 75 8/75/10 3.0 8 / 3.0 / 10 166.0 39.0 140 75 75 3.0 3.0 Col. T. 173.0 32.0 154 75 75 3.0 3.0 Loss of I interest HDL 15 TRG. Col. Rx.

Atero.

Diabetes 2 20 Diab. Rx Depression Depression Rx.

I • ^ 1 I fifteen twenty I fifteen twenty I Lp O fifteen twenty 1 U-i i- • I fifteen twenty vjl fifteen twenty fifteen twenty I sv fifteen 25 Patient Kl Weight Camb. Days Venlafaxine Rivastigmine Trazadon Dietilpropio Comments Weight in en al en en in Rosaglitazona, 4- Height 72.0 0 breakfast lunch lie down breakfast lunch dinner 1 1-99 BMI 33.6 247.5 0.0 22 150mg 150mg 3.0mg 3.0mg Sex M 245.0 2.5 27 150 150 3.0 3.0 Date of birth. 10-16-46 236.3 11.3 56 150 150 3.0 3.0 Age at the beginning 56 232.0 15.5 71 150 150 3.0 3.0 Initial Info 227.8 19.8 93 150 150 3.0 3.0 B.P. - 134/80 223.8 23.8 240 150 150 3.0 3.0 Pulse 84 247 100 100 4.5 4.5 10 HPN Rx SI 221.8 25.8 269 100 100 4.5 4.5 A1C below 6.0 Ui Col. T. 144 HDL 39 TRG. 264 15 Col. Rx. YES Atero.

Diabetes 2 SI Diab. Rx 20 Depression Depres. Rx.

Medication is Metformin Rosiglitazone Glyburide Sildeinañl Niaspan Atorvastatin Lisinopril Hydralazine Psilium 10 Niacin oo Viagra Bacitracin fifteen 25 Ui fifteen twenty Medications levothyroxine rivastigmine venlafaxine fish oil chromium picolinate linseed oil metronidazole gel a fifteen 25 I sv fifteen twenty 284. 75 41.3 315 75 6.0 6.0 6.0 Diabetes 2 NO 287.75 38.3 336 75 6.0 6.0 6.0 Diab. Rx 287.50 38.5 363 150 6.0 6.0 6.0 / 3.0 New Orleans 281.75 44.3 376 150 6.0 6.0 6.0 / 3.0 272.0 54.0 405 Vomiting Depression 280.5 45.5 419 150 6.0 6.0 6.0 / 3.0 Depres. Rx. 278.5 47.5 433 150 6.0 6.0 6.0 / 3.0 279.5 46.5 154 150 7.5 7.5 7.5 Medications 279.0 47.0 468 150 7.5 7.5 7.5 HCTZ 280.0 46.0 482 150 6.0 6.0 6.0 Oat Metoprolol 276.0 50.0 498 150 6.0 6.0 6.0 / 3.0 10 Nisoldipine 273.8 52.2 510 Lisinopril 272.8 53.2 530 150 6.0 6.0 6.0 / 3.0 PIO @ Allopurinol 273.5 52.5 558 150 6.0 6.0 6.0 / 3.0 Beer 24 CA US 4D Celecoxib 272.8 53.2 579 150 150 150/75 6.0 6.0 6.0 / 3.0 Colchicine 150 150 225/0 6.0 6.0 9.0 / 0 15 twenty Patient 01 Weight Camb. Days Venlafaxine Rivastigmine Trazadone Diethylpropion Comments Weight in in at at 64.25 209.5 0.0 0 breakfast lunch bedtime breakfast lunch dinner pm BMI 3631 193.3 16.3 73 75mg 75mg 1.5mg 1.5mg Sex F 188.8 20.8 94 75 75 1.5 1.5 Birth date. 7-21-58 176.5 33.0 121 75 75 75 1.5 1.5 1.5 Age at start 44 179.5 30.0 135 75 75 75 1.5 1.5 1.5 Initial information 149 75 75 75 1.5 1.5 1.5 B.P. 120/82 182.0 27.5 167 75 75 75 1.5 1.5 1.5 Pulse 75 171 75 75 75 1.5 1.5 1.5 10 HPN Rx SI 180.0 29.5 222 75 75 75 3.0 3.0 3.0 177.5 32.0 235 75 75 75 1.5 1.5 1.5 Col. T. 194 HDL 39 TRG 104 Col. Rx. NO 15 Atero.

Diabetes 2 NO Diab. Rx 20 Depression Depres. Rx.

Ui fifteen twenty fifteen twenty 1 sv fifteen twenty Diab. Rx Depression Depression Rx. DO NOT HCTZ Medications Lisinopril Nisoldipine 10 Metoprolol Pravastatinal Sildenafil 00 fifteen 25 sv vo fifteen twenty - 1 or Patient T2 Weight Camb. Days Venlafaxine Rivastigmine Trazadone Diethylpropion Comments Weight in en al en in Height 66.25 210.0 0.0 0 breakfast lunch bedtime breakfast lunch dinner pm BMI 30.8 190.5 19.5 63 75mg 75mg 1.5mg l, 5mg Was in Trazodone and Paroxetine Sex F 187.8 22.3 92 75 75 1.5 1.5 Date of birth 6-10-47 180.0 30.0 240 75 75 1.5 1.5 Age at start 55 Lost interest Initial Info I B.P. 122/72 Pulse 82 HPN Rx SI Col. T. 186 HDL 45 15 TRG. 208 Col. Rx. YES Atero.

Diabetes 2 NO 20 Diab. Rx NJ Patient 2 / E-R Weight? Weight Days Venlafaxine Rivastigmine Trazadone Diethylpropion Comments in on at in at Height 65 310.75 0.0 0 breakfast lunch bedtime breakfast lunch dinner pm BMI 51.8 309.0 1.75 13 75mg 75mg 1.5mg 1.5mg Sex M 307.25 3.50 27 75mg 75 3.0 3.0 Birthdate. 298.78 12.00 41 150 150 3.0 3.0 Age at the beginning 293.5 17.25 55 150 150 3.0 3.0 Initial Information 291.0 19.75 69 150 150 3.0 3.0 B.P. 140/88 290.0 20.75 83 150 150 3.0 3.0 Pulse 288.0 22.75 97 150/150 150 3.0 / 3.0 3.0 HPN Rx 280.8 30.00 111 150/150 150 3.0 / 3.0 3.0 10 278.8 32.00 125 150/150 150 3.0 / 3.0 3.0 Col. T 280.5 30.25 139 150/150 150 3.0 / 3.0 3.0 LO HDL 275.8 35.00 153 150/150 150 3.0 / 3.0 3.0 TRG. 275.5 38.25 167 75 75 75 3.0 3.0 Col. Rx. 271.5 39.25 182 75 75 75 3.0 3.0 271.5 39.25 195 75 75 75 3.0 3.0 15 Atero. 271.2 39.25 209 75 75 75 3.0 6.30 3.0 268.2 42.55 216 75 75 75 3.0 6.0 3.0 Diabetes 2 Diab. Rx Depression Depression. Rx.

Patient 6 / B-G Weight? Weight Days Venlafaxine Rivastigmma Trazadona Diethylpropion Comments in on at in at Height 259.2 0.0 0 breakfast lunch bedtime breakfast lunch dinner pm BMI 242.5 16.7 13 150mg 1.5 Sex 241.5 17.7 20 150 1.5 Date of birth. 237.5 21.7 28 150 1.5 Age at the start 57 237.5 21.7 42 150 1.5 Initial information 235.0 24.2 56 150 1.5 B.P. 150 3.0 Pulse 225 4.5 HPN Rx 10 - ~? Ui Col. T. HDL TRG. Col. Rx. 15 Atero.

Diabetes 2 Diab. Rx Depression Depression. Rx.

CTN Patient 8 / P-B Weight? Weight Days Venlafaxine Rivastigmine Trazadone Diethylpropion Comments in on in in Height 251.5 0.0 0 breakfast lunch bedtime breakfast lunch dinner pm BMI 246.5 5.0 14 75mg 1.5mg Sex M 241.8 9.7 28 Date of birth. 241.8 9.7 42 Age at the beginning 46 241.8 9.7 56 75 1.5 Initial information 243.8 7.7 70 75 1.5 B.P. 240.8 10.7 84 75 150 1.5 Pulse 10 HPN Rx Col. T. ~ ^? HDL TRG. Col. Rx. 15 Atero.

Diabetes 2 Diab. Rx Depression Depression. Rx. 00 Patient 11 / A- Weight? Weight Days Venlafaxine Rivastigmine Trazadone Diethylpropion Comments S in en al en en in Height 67.5 165.0 0.0 0 breakfast lunch bedtime breakfast lunch dinner am pm BMI 24.5 159.0 6.0 14 9mg 9mg 0.4mg 0.4mg Only by phone Sex 155.0 10.0 28 18 18 0.8 0.8 Date of birth. F 155.0 10.0 41 9 9 0.8 0.8 Age at start 32 154.0 11.0 56 11 11 1.5 1.5 Initial information 156.0 9.0 87 19 19 1.5 1.5 VD B.P. 154.0 11.0 97 75 75 1.5 1.5 10 Pulse 151.0 14.0 116 75 75 1.5 1.5 HP Rx 150.0 15.0 126 75 75 1.5 1.5 75 75 3.0 3.0 Tonsil Surgery Col. T. HDL 15 TRG. Col. Rx.

Atero.

Diabetes 2 20 Diab. Rx Depression Depression Rx.

Medications HCTZ Lisinopril Nisoldipine Metoprolol Pravastatin Sildenafil or Bacitracin 10 aderal fifteen twenty Patient 13 / L- Weight? Weight Days Venlafaxine Rivastigmine Trazadone Diethylprgpion I Comments V en en al • en in Height 71.2 274.8 0.0 0 breakfast lunch bedtime breakfast lunch dinner pm BMI 38.1 268.2 6.6 14 75XR l, 5mg Sex M 264.0 10.8 21 75IR 1.5 Date of birth. 262.0 12.8 32 75 1.5 Age at the start 63 265.5 9.3 39 75 1.5 Initial Info 263.2 11.6 53 75 1.5 B.P. 120/78 260.8 14.0 68 75 1.5 Pulse 64 263.5 11.3 81 75 1.5 10 i HP x SI 254.0 20.8 95 150 3.0 258.0 16.8 109 150 3.0 Bleeding G.I. Col. T. 252.0 22.8 123 150 3.0 7-13 PIÓ Suspended 15 HDL TRG. Col. Rx. YES Atero.

Diabetes 2 Diab. Rx 00 20 25

Claims (57)

1. CLAIMS 1. A method for treating obesity, said method comprising administering to a subject in need thereof an effective amount of a combination of one or more cholinesterase inhibitors and one or more antidepressants, whereby said obesity is treated. The method according to claim 1, wherein said one or more cholinesterase inhibitors are selected from the group consisting of a reversible cholinesterase inhibitor, a pseudo-irreversible cholinesterase inhibitor, an irreversible cholinesterase inhibitor and mixtures of the same. 3. The method according to claim 2, wherein one or more of said reversible cholinesterase inhibitors are selected from the group consisting of tacrine, donepezil, edrophonium, galantamine and mixtures thereof. 4. The method according to claim 2, wherein one or more of said pseudo-irreversible cholinesterase inhibitors are selected from the group consisting of physostigmine, eptastigmine, piridostig ina, neostigmine, ganstigmina, rivastigmine, demecarium, ambenonium and mixtures the same. The method according to claim 2, wherein one or more of said irreversible cholinesterase inhibitors comprises an organophosphate. 6. The method according to claim 2, wherein one or more of the irreversible cholinesterase inhibitors are selected from the group consisting of sarin, metrifonate, so an, tabun, diisopropyl fluorophosphate and mixtures thereof. The method according to claim 1, wherein said one or more antidepressants is selected from the group consisting of tricyclic antidepressants and analogs thereof, serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, inhibitors of norepinephrine reuptake inhibitors, dopamine reuptake inhibitors, norepinephrine reuptake-dopamine reuptake inhibitors of serotonin-norepinephrine-dopamine, resorption accelerators serotonin, serotonin agonists and prodrugs thereof, inhibitors monoamine oxidase and mixtures thereof. 8. The method according to claim 7, wherein said tricyclic antidepressant and analogs thereof are selected from the group consisting of amineptine, amitriptyline, ipramina clo, desipramine, doxepin, dothiepin, imipramine, nortriptyline, protriptyline, trimipramine, amoxapine, aprotilin, cyclobenzaprine and mixtures thereof. 9. The method according to claim 7 wherein said inhibitors of serotonin reuptake are selective reuptake inhibitors selected serotonin from the group consisting of citalopram, escitalopram, fluoxetine, fluvoxa ina, paroxetine, sertraline and mixtures thereof. 10. The method according to claim 7, wherein said reuptake inhibitors of serotonin-norepinephrine are selected from the group consisting of ilnacipran, rairtazapina, venlafaxine, duloxetine, S33005, DVS-233 (desvenlafaxine), DVS-233 SR , sibutramine and mixtures thereof. The method according to claim 7, wherein said norepinephrine reuptake inhibitors are selective inhibitors of norepinephrine reuptake selected from the group consisting of reboxetine, atomoxetine and mixtures thereof. The method according to claim 7, wherein said norepinephrine-dopamine reuptake inhibitors are selected from the group consisting of amineptine, bupropion, GW353162 and mixtures thereof. 13. The method according to claim 7, wherein said monoamine oxidase inhibitor is selected from the group consisting of befloxatone, brofaromine, deprenyl, isocarboxazid, moclobemide, pargyline, phenelzine, selegiline, tranylcypromine and mixtures thereof. The method according to claim 1, which comprises administering a combination of effective amounts of a cholinesterase inhibitor and a selective inhibitor of serotonin reuptake. 15. The method according to claim 14, wherein said combination comprises effective amounts of galantamine and citalopram. 16. The method according to claim 15, wherein said galantamine is administered in an amount of 4 mg / dose and said citalopram is administered in an amount of 20 mg / dose. 17. The method according to claim 15, wherein said galantamine and said citalopram are administered once per day. 18. The method according to claim 14, wherein said combination comprises effective amounts of donepezil and sertraline. 19. The method according to claim 1, which comprises administering a combination of effective amounts of a cholinesterase inhibitor and a serotonin-norepinephrine reuptake inhibitor. The method according to claim 19, wherein said combination comprises effective amounts of rivastigmine and venlafaxine. The method according to claim 20, wherein said rivastigmine is administered in an amount of 0.4-6.0 mg / dose and said venlafaxine is administered in an amount of 37.5-225 mg / dose. 22. The method according to claim 20, wherein said rivastigmine and said venlafaxine are administered twice per day. The method according to claim 1, wherein said cholinesterase inhibitor is selected from the group consisting of rivastigmine, galantamine and donepezil and said antidepressant is selected from the group consisting of venlafaxine, citalopram, escitalopram, fluvoxamine, paroxetine, duloxetine , sertraline, bupropion, G 353162, S33005, DVS-233 (desvenlafaxine), DVS-233 SR and mixtures thereof. The method according to claim 1, wherein said cholinesterase inhibitor and said antidepressant are administered at the same time. 25. The method according to claim 1, wherein said combination is administered in a controlled release formulation. 26. The method according to claim 1, wherein said cholinesterase inhibitor and said antidepressant are administered at different times. 27. The method according to claim 1, wherein said subject loses at least 15 pounds after approximately 70 days of treatment. The method according to claim 1, wherein said subject loses at least about 20 pounds after approximately 100 days of treatment. 29. The method according to claim 1, further comprising administering an effective amount of an anorectic. 30. The method according to claim 29, wherein said anorectic is selected from the group consisting of amphetamine, methamphetamine, dextroamphetamine, phentermine, benzfetamine, phendimetrazine, phenmetrazine, diethylpropion, azindole, fenfluramine, phenylpropanole and mixtures thereof. . 31. A method for achieving desirable weight loss, said method comprising administering to a subject in need thereof an effective amount of a combination of one plus cholinesterase inhibitors and one or more antidepressants, whereby said subject loses an amount desirable weight. 32. A method for preventing undesirable weight gain, said method comprising administering to a subject in need thereof an effective amount of a combination of one or more cholinesterase inhibitors and one or more antidepressants, whereby said subject is It prevents you from increasing an undesirable amount of weight. 33. The method according to claim 31 or claim 32, wherein said subject is overweight. 34. The method according to claim 31 or claim 32, wherein said subject is obese. 35. A method for facilitating weight loss in an individual not suffering from depression, said method comprising administering to said individual an amount of a combination of one or more cholinesterase inhibitors and one or more antidepressants sufficient to effect weight loss. 36. A method for aiding weight loss in an individual in need thereof, the method comprising administering to said individual, over a sustained period of time, an amount of a combination of one or more cholinesterase inhibitors and one or more enough antidepressants to help in weight loss. 37. A method for maintaining a stable weight in an individual, said method comprising administering to said individual an effective amount of a combination of one or more cholinesterase inhibitors and one or more antidepressants, whereby said individual maintains a stable weight. 38. The method according to claim 37, wherein said individual is obese. 39. A method for reducing body weight in an individual in need thereof, the method comprising administering to said individual, over a sustained period of time, an amount of a combination of one or more cholinesterase inhibitors and one or more sufficient antidepressants. to cause the reduction in body weight in said individual. 40. A pharmaceutical composition comprising a mixture of effective amounts of one or more cholinesterase inhibitors and one or more antidepressants. 41. The pharmaceutical composition of claim 40, wherein said one or more cholinesterase inhibitors are selected from the group consisting of a reversible cholinesterase inhibitor, a pseudo-irreversible cholinesterase inhibitor, an irreversible cholinesterase inhibitor, and mixtures thereof. . 42. The pharmaceutical composition of claim 40, wherein one or more reversible cholinesterase inhibitors are selected from the group consisting of tacrine, donepezil, edrophonium, galantamine and mixtures thereof. 43. The pharmaceutical composition of claim 40, wherein said one or more pseudo-irreversible cholinesterase inhibitors are selected from the group consisting of physostigmine, eptastigmine, pyridostigmine, neostigmine, ganstigmine, rivastigmine, demecarium, ambenonium and mixtures thereof. 44. The pharmaceutical composition of claim 40, wherein said one or more irreversible cholinesterase inhibitors comprise an organophosphate. 45. The pharmaceutical composition of claim 40, wherein said one or more irreversible cholinesterase inhibitors are selected from the group consisting of sarin, metrifonate, soman, tabun, diisopropyl fluorophosphate and mixtures thereof. 46. The pharmaceutical composition of claim 40, wherein said one or more antidepressants are selected from the group consisting of tricyclic antidepressants and analogues thereof, serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dopamine reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, serotonin-norepinephrine-dopamine reuptake inhibitors, serotonin reuptake accelerators, serotonin agonists and serotonin agonists and prodrugs thereof and mixtures of same. 47. The pharmaceutical composition of claim 40, wherein said one or more cholinesterase inhibitors are selected from the group consisting of rivastigmine, galantamine and donepezil, and said one or more antidepressants are selected from the group consisting of venlafaxine, citalopram, escitalopram , fluvoxamine, paroxetine, duloxetine, sertraline, bupropion, S33005, DVS-233 (desvenlafaxine), DVS-233 SR and mixtures thereof. 48. The pharmaceutical composition of claim 40, wherein said one or more cholinesterase inhibitors comprise rivastigmine and said one or more antidepressants comprise velafaxine. 49. The pharmaceutical composition of claim 40, wherein said one or more cholinesterase inhibitors comprise galantamine and said one or more antidepressants comprise citalopram. 50. The pharmaceutical composition of claim 40, wherein said one or more cholinesterase inhibitors comprise donepezil, and said one or more antidepressants comprise sertraline. 51. The pharmaceutical composition of claim 40, wherein said one or more cholinesterase inhibitors comprise galantamine, and said one or more antidepressants comprise duloxetine. 52. The pharmaceutical composition of claim 40, wherein said one or more cholinesterase inhibitors comprise galantamine, and said one or more antidepressants comprise paroxetine. 53. The pharmaceutical composition of claim 40, wherein said composition is a controlled release composition. 54. A kit comprising a mixture of effective amounts of one or more cholinesterase inhibitors and one or more antidepressants. 55. The kit of claim 54, wherein said one or more cholinesterase inhibitors are selected from the group consisting of a reversible cholinesterase inhibitor, a pseudo-irreversible cholinesterase inhibitor, an irreversible cholinesterase inhibitor, and mixtures thereof. 56. The kit of claim 54, wherein said one or more antidepressants are selected from the group consisting of tricyclic antidepressants and analogs thereof, serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, resorption inhibitors. of norepinephrine, dopamine reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, serotonin-norepinephrine-dopamine reuptake inhibitors, serotonin reuptake accelerators, serotonin agonists and serotonin agonists and prodrugs thereof and mixtures thereof . 57. The kit of claim 56, wherein said one or more cholinesterase inhibitors is selected from the group consisting of ribastigmine, galantamine and donepezil and said one or more antidepressants are selected from the group consisting of venlafaxine, citalopram, escitalopram, fluvoxamine , paroxetine, duloxetine, sertraline, bupropion, GW353162, S33005, DVS-233 (desvenlafaxine), DVS-233SR and mixtures thereof.