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WO2000006140A2 - Procedes et compositions permettant de traiter et de prevenir certains troubles psychiatriques et medicaux par le moclobemide - Google Patents

Procedes et compositions permettant de traiter et de prevenir certains troubles psychiatriques et medicaux par le moclobemide Download PDF

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Publication number
WO2000006140A2
WO2000006140A2 PCT/US1999/017417 US9917417W WO0006140A2 WO 2000006140 A2 WO2000006140 A2 WO 2000006140A2 US 9917417 W US9917417 W US 9917417W WO 0006140 A2 WO0006140 A2 WO 0006140A2
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Prior art keywords
moclobemide
human
derivative
metabolite
depression
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Ceased
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WO2000006140A3 (fr
Inventor
Donald F. Klein
Seth Lederman
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Vela Pharmaceuticals Inc
Tinea Pharmaceuticals Inc
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Janus Pharmaceuticals Inc
Vela Pharmaceuticals Inc
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Priority to MXPA01001178A priority Critical patent/MXPA01001178A/es
Priority to CA002338330A priority patent/CA2338330A1/fr
Priority to JP2000561995A priority patent/JP2002521433A/ja
Priority to AU53305/99A priority patent/AU5330599A/en
Publication of WO2000006140A2 publication Critical patent/WO2000006140A2/fr
Publication of WO2000006140A3 publication Critical patent/WO2000006140A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to methods and compositions for treating or preventing low affect disorders, which are characterized by malaise and lethargy. Such low affect disorders may be associated with a general psychological or medical condition.
  • This invention also relates to treating partial therapy-refractory depression, partial therapy- refractory atypical depression, and adolescent depression.
  • the invention further relates to a method for treating malaise, lethargy, hypersomnia, weight gain, carbohydrate craving, obesity, overeating, leaden paralysis, rejection sensitivity, sexual inhibition, somatoform disorder, somatised symptoms, learning disability, conduct disorder, oppositional defiant disorder or conduct disturbance either individually or in combination, with moclobemide, a moclobemide metabolite, a moclobemide derivative, or a moclobemide composition.
  • Moclobemide is a selective and reversible monoamine oxidase (MAO) subtype A inhibitor. Kettler, R. et al . , 1990, Acta Ps chiatr. Scand. , Sup . 360 (82) : 101-103. Unlike other monoamine oxidase inhibitors, which irreversibly and non- selectively bind MAO and can have severe food and drug interactions that limit their therapeutic utility, moclobemide is part of a distinct class of selective MAO inhibitors that inhibit predominantly or selectively either monoamine oxidase A (MAO-A) or monoamine oxidase B (MAO-B) .
  • MAO-A monoamine oxidase A
  • MAO-B monoamine oxidase B
  • Compounds that selectively inhibit MAO-B, and thereby inhibit the degradation of dopamine are useful for the treatment of neurological and neurodegenerative diseases of the dopaminergic pathway, such as Parkinson's disease. Livingston, M.G. and Livingston, H.M. , 1996, Drug Safety, 14 (4) :218-227.
  • Compounds that selectively inhibit MAO-A predominantly affect the degradation of serotonin and norepinephrine, leading to increased concentrations of these neurotransmitters in synapses, and are useful for depression. Livingston and Livingston, 1996.
  • moclobemide has no appreciable affinity for muscarinic, dopaminergic, serotonergic, adrenergic, H- L -histaminergic, benzodiazepine or opioid receptors.
  • Moclobemide is extensively distributed in the body and rapidly eliminated from plasma by metabolic conversion in the liver. After single-dose oral administration, moclobemide is almost completely absorbed; however, bioavailability ranges from 44% to 69% because of substantial first-pass metabolism. Guentert, T.W. et al . , 1990, Acta Psvchiatr. Scand., Suppl. 360 (82) : 91-93. After multiple administrations, moclobemide displays increased bioavailability (approx. 85%) , possibly due to saturation of first-pass metabolism. Id. Moclobemide is metabolized to at least 19 different metabolites, one of which has moderate MAO-A inhibitory activity. Jauch, R.
  • moclobemide is far less likely than traditional MAO inhibitors to induce hypertensive reactions with the concomitant administration of svmpathomimetic drugs, or consumption of tyramine-rich foods.
  • Moclobemide 's excellent safety and positive tolerance profile have made it a popular anti-depressive in Canada, Europe, Australia, New Zealand, South Africa, and Latin America. Angst J. et al., 1996, Int. Clin. Psvchopharmacol . , ll(Suppl. 3):3-7; Glick, I.D. et al . , 1995 Schatzberg, A.F. and Nemeroff, C.B. (Ed.), The American Psychiatric Press Textbook of Psvchopharmacology, Washington, DC, pp. 839-846)) .
  • Prescribing medications such as irreversible MAOI ' s with potentially harmful or deadly side effects to treat depression has traditionally caused some measure of concern among physicians, who worry that depressed patients may attempt suicide with the very medicines they are prescribing.
  • moclobemide is an MAO inhibitor, as an anti-depressive, it appears to be less prone to deadly drug and food interactions and less toxic in overdose. Patients taking other MAO inhibitors must adhere to restrictive diets which require the avoidance of, inter alia, red wines, beer, aged cheese and meats, liver, yeast extracts and fava or broad beans .
  • moclobemide 's side-effect profile is so benign, it enjoys good compliance rates.
  • Compliance is an integral component of successful treatment because the morbidity and mortality rates associated with untreated psychiatric illness are high. If a patient persistently rejects medical treatment for psychiatric illness because the initial experience in pharmacological intervention was bad, then the prognosis can be just as poor as if the patient had not been treated at all. When used in the treatment of major depression, moclobemide has proved itself an effective, gentle, patient- friendly drug.
  • Moclobemide sold under the tradename AURORIXTM or MANERIXTM (F. Hoffman-La Roche, Basel, Switzerland), has been shown to be effective in the treatment of various psychiatric disorders.
  • moclobemide is marketed in Canada, Europe, Australia, New Zealand, South Africa, and Latin America as an antidepressive agent, for which it has demonstrated significant therapeutic effect in certain patient populations. Angst J. et al., 1996; Glick, I.D. et al . , 1995.
  • a review of the pharmacological properties and therapeutic use of moclobemide in depressive illness was published by Fulton and Benfield in Drugs , 52(3) :450-478, 1996, updating a previous review of Fitton et al . , 1992, Drugs , 43 (4) : 561-596.
  • moclobemide as an anti- depressant is described in United States Patent No. 4,210,754 to Burkard et al .
  • moclobemide has been shown to have similar efficacy to tricyclic antidepressants (TCAs) , selective serotonin reuptake inhibitors (SSRIs) , and nonselective, irreversible MAO inhibitors. Fulton and Benfield, 1996; Fitton et al . , 1992.
  • moclobemide has been shown to be effective in treating elderly patients suffering from depression or age-related dementia.
  • Moclobemide has also been reported to be effective in the management of tobacco addiction (PCT publication WO 95/28934; PCT publication WO 90/04387), attention deficit disorder (Trott, G.E. et al . , 1992, Psychopharmacol . , 106 Suppl .: 134-136) , and anxiety disorders such as social phobia, obsessive-compulsive disorder and panic (United States Patent No. 5,371,082 to Versiani et al . ; Liebowitz, M.R. et al . , 1990, Acta Psvchiatr. Scand., Suppl. 360 (82) : 29-34 ; Angst, J. et al . , 1996, Int. Clin.
  • MAOIs irreversible monoamine oxidase inhibitors
  • MAOI-drug and MAOI-food interactions that are possible, particularly with sympathomimetic medications or tyramine- containing foods, resulting in hypertensive reactions.
  • MAOI efficacy is documented for a given condition, many practitioners are reluctant to prescribe drugs from this class because of the risk of serious adverse reactions. This appears to be so even when MAOIs are more effective than other available treatments.
  • moclobemide has not been extensively studied in the United States.
  • depression is a clinically discernable condition generally known in the art as a depressed mood or a marked loss of interest or pleasure in nearly all activities lasting for a period of time (i.e., weeks, months, or years).
  • Depression also known as "major depression” is defined in DSM-IV as five or more symptoms present over at least a two week period, wherein at least one of the symptoms must be depressed mood or loss of interest or pleasure and the other symptoms are selected from the group consisting of: (1) depressed mood most of the day, nearly every day; (2) markedly diminished interest or pleasure in all, or almost all, actvities most of the day, nearly everyday; (3) significant weight loss when not dieting or weight gain or decrease or increase in appetite nearly every day; (4) insomnia or hypersomnia nearly every day; (5) psychomotor agitation or retardation nearly every day; (6) fatigue or loss of energy nearly every day; (7) feelings of worthlessness or excessive or inappropriate guilt nearly every day; (8) diminished ability to think or concentrate or indecisiveness nearly every day; and (9) recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide .
  • a condition that presents similar symptoms but arises from, for example, a general medical condition or a direct physiological effect of taking a substance should not necessarily be considered depression.
  • a Mood Disorder Due to a General Medical Condition is a diagnosis made based on history, laboratory findings, or physical examination, wherein the mood disturbance is judged to be a direct physiological consequence of a specific general medical condition (e.g., multiple sclerosis, stroke, hyperthyroidism) (pp. 325, and 366-367 of DSM-IV) .
  • a Substance-Induced Mood Disorder is distinguishable from depression by the fact that a substance (i.e., a drug of abuse, a medication, or a toxin) is judged to be etiologically related to the mood disturbance (pp. 325- 326, and 370-371 of DSM-IV) .
  • DSM-IV also distinguishes an Adjustment Disorder With Depressed Mood due to, for example, Bereavement, or periods of sadness from depression.
  • the criteria for diagnosing depression does not include the appearance of the symptoms: malaise or lethargy.
  • malaise or lethargy There is a need for methods and compositions for treating illnesses, characterized by the symptoms malaise and lethargy, especially in patients who are not clinically depressed or are subclinically depressed. Applicants have solved this problem by providing methods and compositions for treating and preventing illnesses characterized by malaise and lethargy. Illnesses characterized by malaise and lethargy are described herein as low affect disorders or LAD, described in more detail below.
  • atypical depression has undergone dramatic changes since its initial exposition.
  • atypical was synonymous with nonmelancholic, i.e., absent the usual features of depression such as weight loss and insomnia, and displaying other symptoms normally absent in depression, such as anxiety.
  • AD typically depression
  • a similar patient group was described by Klein, in Liebowitz, M.R.
  • DSM-III did not include any specific concept of AD.
  • AD has been recognized as a distinct, clinically-identifiable syndrome
  • conflicting definitions continue to be used in the literature.
  • Some groups use the term AD to describe depression with phobic anxiety, while others use AD to describe depression with reverse vegetative features.
  • Davidson et al formalized these two definitions into A-type and V-type AD, respectively.
  • A-type atypical depressives were described as anxious phobic, tense, and more prone to atypical pain
  • V-type depressives had increased appetite and weight, increased libido, increased sleep, mood lability, and irritability. Id.
  • DSM-IV defines AD as a mood reactive depression with associated reverse vegetative symptoms or marked interpersonal rejection sensitivity.
  • DSM-IV includes AD as an episode specifier for major depressive episodes or dysthymia.
  • the AD mood specifier can be used for depressive episodes occurring either in unipolar and bipolar mood disorders.
  • DSM-IV AD is used interchangeably with "Columbia Criteria AD” to refer to AD meeting the criteria identified in either or both of the foregoing paradigms .
  • the criteria for diagnosing atypical depression does not include the appearance of the symptoms of malaise and lethargy.
  • MAOI ' s have traditionally presented a significant risk of negative drug interactions with common antidepressants. Thus, they are generally considered to have limited utility for the treatment of antidepressant therapy resistant patients. As discussed above, MAOI ' s are prone to negative interactions with sympathomimetic medications, resulting in hypertensive shock. The most serious of such interactions may be fatal. Livingston and Livingston, 1996.
  • MAOI 's tend to interact negatively with drugs that enhance serotonin production or release, such as TCA's. Although the exact mechanism of interaction is unknown, the co- administration of the two serotonergic compounds is thought to cause serotonin syndrome. Sternbach, H. , 1991, Am. J. Psychiatry, 148:705-13. This syndrome is characterized by restlessness, shivering, diaphoresis, tremor, hyperreflexia and myoclonus.
  • Drugs that are likely to cause this syndrome with co-administered conventional MAOIs are the selective serotonin reuptake inhibitors (SSRI) , citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.
  • SSRI selective serotonin reuptake inhibitors
  • Some opioids such as pethidine (meperidine) , may also cause symptoms of the serotonin syndrome when co- administered with conventional MAOIs, and, sometimes such combinations cause a central depression syndrome that involves excessive sedation and ultimately coma and death. Livingston and Livingston, 1996.
  • moclobemide can be safely and effectively used in alone or in combination with tricyclic and tetracyclic antidepressants to treat therapy-resistant or refractory depression (RD) .
  • Stabl M. et al . , 1995; Konig and Wolfersdorf, 1997.
  • Initial results involving the coadministration of moclobemide and SSRIs have been varied.
  • One pilot study described the effective coadminstration of moclobemide and fluvoxamine (SSRI) to therapy-resistant patients. [Ebert et al . (1995)]
  • five cases of fatal intoxications from "serotonin syndrome" after coadministration of moclobemide and an SSRI have been reported. [Neuvonen et al . , (1993)]
  • therapy- resistant atypical depression or refractory atypical depression also presents a significant pharmacological challenge due to the dangerous potential for adverse drug interactions as described above (e.g., with SSRI ' s and TCA's) .
  • a patient with RD or RAD can not readily be switched from the drug to which he has failed to respond or to another antidepressant. Rather, switching between antidepressants typically entails a "wash-out period" of several weeks, due to the relatively long half-lives of many common antidepressants, to ensure elimination of the prior drug from the patient's system. Throughout this delay, the therapy- resistant patient remains untreated, potentially leading to increased severity of depression and serious psychological and physiological complications.
  • partial RD depressive and atypical depressive patients who partially respond to antidepressive treatment
  • PRD partial RAD patients
  • PRAD patients i.e., patients who after antidepressive therapy experienced a decrease or elimination of some but not all of their depressive or atypical depressive symptoms such that they cannot be described as depressive or atypically depressive under the criteria in DSM-IV.
  • PRD or PRAD patients include those patients who: (1) experience transient complete recovery from depression or atypical depression; (2) subsequently develop depression or atypical depression that is only partially responsive to treatment after 6 months or who develop one or more of the symptoms of depression or atypical depression; and (3) cannot be described as depressive or atypically depressive under the criteria in DSM-IV.
  • the efficacy of moclobemide alone or in combination with other antidepressants such as TCAs , tetracyclic antidepressants or SSRIs in treating PRD or PRAD patients has not yet been demonstrated.
  • the DSM-IV recognizes that adolescents are susceptible to certain distinct disorders, such as adolescent antisocial behavior (DSM-IV, p. 684), attention deficit/hyperactivity disorder (pp. 78-85) , adolescent-onset type Conduct Disorder (pp. 85-91) , and Oppositional Defiant Disorder (pp. 91-94) .
  • DSM-IV adolescent antisocial behavior
  • pp. 78-85 attention deficit/hyperactivity disorder
  • adolescent-onset type Conduct Disorder pp. 85-91
  • Oppositional Defiant Disorder pp. 91-94
  • adolescent depression is a not well- characterized disorder that afflicts adolescents and includes specialized symptoms of mood reactivity, social anxiety, and mood-associated rejection sensitivity or hypersensitivity to interpersonal rejection.
  • depressive episodes in adolescents typically differ in character from those experienced by adult depressives (DSM-IV, pp. 320-327) .
  • DSM-IV adult depressives
  • the human sexual response can generally be divided into three phases: libido, excitement, and orgasm. It has been shown that certain antidepressants can have deleterious effects on any of these three phases. Problems with excitement may include impotence, painful erection, spontaneous erection, penile or clitoral priapism, and difficulty with vaginal lubrication. Problems with orgasm encompasses delayed orgasm, painful orgasm, anorgasmia, spontaneous ejaculation, retrograde ejaculation, and anhedonic ejaculation (ejaculation without orgasm) . [Margolese, H.C. and P. Assalian, J.Sex Marital Ther.
  • moclobemide has been suggested to be involved in the sexual hyperarousal of some patients with major depression, to the best of applicant's knowledge, the use of moclobemide to treat sexual inhibition in patients who are subclinically depressed or who are not clinically depressed has never been reported.
  • the present invention relates to the use of moclobemide, a metabolite of moclobemide, or a derivative of moclobemide for treating or preventing certain psychiatric and medical disorders.
  • Moclobemide, or moclobemide metabolite, or moclobemide derivative according to this invention may be in the form of a pharmaceutically acceptable salt, hydrate, or solvate.
  • moclobemide, moclobemide metabolite or moclobemide derivative includes moclobemide, a metabolite of moclobemide, or a derivative of moclobemide; or a prodrug of moclobemide, a metabolite of moclobemide, or a derivative of moclobemide; or pharmaceutically acceptable salt, hydrate, solvate of moclobemide, a metabolite of moclobemide, a derivative of moclobemide; or prodrug thereof.
  • the present invention also encompasses the use of a composition in the methods of this invention, wherein the composition comprises moclobemide, a metabolite of moclobemide, or a derivative of moclobemide together with a pharmaceutically acceptable carrier.
  • Moclobemide metabolites according to this invention are those with MAO-A inhibitor activity, such as moclobemide- N-oxide .
  • the invention encompasses the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition in treating or preventing certain disorders associated with low affect as defined herein.
  • one embodiment of the present invention relates to the treatment of low affect disorders by administration of a therapeutically effective amount of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition.
  • Another embodiment of the present invention is the treatment of disorders associated with LAD, by administration of a therapeutically effective amount of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition.
  • the invention also encompasses the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to treat or prevent adolescent depression.
  • the invention also encompasses the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to treat the symptoms of malaise and lethargy.
  • the invention also encompasses the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition in treating PRD or PRAD by administration to a patient exhibiting, at a sub- syndromal level, symptoms commonly associated with the development of depression or atypical depression, either alone or in conjunction with psychotherapy.
  • the present invention also encompasses methods for treating PRD or PRAD in a human by administering a therapeutically effective amount of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to said human .
  • the invention also encompasses the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to treat individual symptoms commonly associated with atypical depression, such as hypersomnia, weight gain, leaden paralysis, and rejection sensitivity, in patients who are not clinically depressed or who are subclinically depressed.
  • one embodiment of the present invention is a method for treating a human with hypersomnia, weight gain, leaden paralysis, and/or rejection sensitivity by administering a therapeutically effective amount of moclobemide, a moclobemide' metabolite, a moclobemide derivative or a moclobemide composition, to said human.
  • the invention relates to the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to treat a LAD patient, suffering from sexual inhibition, somatization, somatoform disorder, carbohydrate cravings, obesity or overeating, who is not clinically depressed or who is subclinically depressed.
  • Another object of this invention is to provide a method for treating or preventing an illness selected from the group consisting of a learning disability, conduct disorder, oppositional defiant disorder, or a conduct disturbance, in a human who is in need of treatment for said illness and who does not suffer from attention deficit hyperactivity disorder, comprising the step of administering moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition thereof.
  • the present invention further encompasses the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to treat patients who are immunocompromised or immunosupressed, as a result of, for example, viral infection including HIV, cancer, medication, or post-operative trauma.
  • one embodiment of the present invention is a method for treating LAD in an immunocompromised or immunosupressed patient by administering a therapeutically effective amount of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to said human.
  • the use of other moclobemide derivatives is also encompassed by the present invention.
  • moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition may be administered before, along with, or after other psychoactive compounds, particularly those with antidepressant activity.
  • the present invention encompasses the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to treat or prevent LAD, adolescent depression, or the above-identified individual symptoms commonly associated with AD, in conjunction with other known antidepressants, such as tricyclic antidepressants, serotonin-reuptake inhibitors, atypical antidepressants and other monoamine oxidase inhibitors.
  • Such known antidepressant compounds include, without limitation, tricyclic antidepressants such as amitriptyline, clomipramine, doxepin, imipramine, (+) -trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, and protryptiline; serotonin-reuptake inhibitors such as (+) - fluoxetine, (+) -fluoxetine, fluvoxamine, paroxetine, sertraline, and (+) -venlafaxine or an active optical isomer thereof; atypical antidepressants such as bupropion, nefazodone, and trazodone; and other monoamine oxidase inhibitors, such as phenelzine, tranylcypromine, and (-)- selgiline, either singly or in combination.
  • tricyclic antidepressants such as amitriptyline, clomipramine, doxepin, imipramine, (+)
  • the present invention encompasses the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition in conjunction with other known antidepressants without the resulting negative drug interactions commonly associated with MAOI ' s .
  • the present invention further encompasses the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition in conjunction with traditional psychotherapy to treat or prevent LAD, adolescent depression, PRD or PRAD in a human by administering moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to said human, before, during, or after psychotherapeutic intervention.
  • the invention provides for methods for using moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition either alone or in conjunction with psychotherapy, antidepressants, or additional psychoactive medication such as lithium, in all potential human patient populations, including men, women, children and the elderly.
  • the humans to be treated do not have depression, atypical depression and/or attention deficit hyperactivity disorder.
  • One preferred class of patients to be treated with moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition thereof is immunocompromised or immunosupressed patients.
  • malaise and "lethargy” are as known in the art.
  • malaise can be characterized by a feeling of discomfort
  • lethargy can be characterized as drowsiness.
  • the term "affect" is defined as emotional feeling, tone, or mood, including its external manifestations .
  • low affect is defined as emotional tone tending towards sadness, lethargy, malaise, melancholy, dejection, listlessness, or withdrawal in the absence of external stimuli, such as reactive depression that is inappropriate or is abnormally protracted or prolonged (e.g., wherein the initial cause of the depression is bereavement) commonly associated with such emotions.
  • LAD low affect disorder
  • DSM-IV depression, as defined in DSM-IV, by the presence of these characteristic symptoms, which do not appear in the DSM-IV definition of "depression” .
  • LAD may be present in conjunction with a general medical or psychological condition, or may be independent of any additional symptoms. For example, LAD may be accompanied by symptoms meeting the criteria for RD or RAD.
  • not clinically depressed or “subclinical depression” refers to a condition which does not meet the criteria of major depression or atypical depression according to DSM-IV.
  • subclinical depression additionally refers to a condition as readily known in the art and can be characterized by low affect .
  • RD refractory depression
  • refractory AD or "RAD” is defined as a syndrome that: (1) meets the Research Diagnostic Criteria (RDC) for major, minor, or intermittent depression, (2) includes mood reactivity, (3) includes two or more of hypersomnia, weight gain, increased appetite, leaden paralysis, acute, mood-associated rejection sensitivity, or a long-standing pattern of hypersensitivity to interpersonal rejection, and (4) is resistant to treatment with selective serotonin reuptake inhibitors (SSRI's), tricyclic antidepressants (TCA's), or other standard antidepressant medications after a period of 6 months.
  • SSRI's selective serotonin reuptake inhibitors
  • TCA's tricyclic antidepressants
  • a patient with RAD as defined herein, may be depressed, display mood reactivity, have an increased appetite and hypersomnia, and be SSRI -refractory or nonresponsive after 6 months of treatment with at least one
  • partial RD refers to a patient who after antidepressive therapy experience decrease or elimination of some but not all of his/her depressive symptoms such that he/she cannot be described as depressive under the criteria of DSM-IV.
  • PRD patients include those patients who: (1) experience transient complete recovery from depression; (2) subsequently develop depression that is only partially responsive to treatment after 6 months or who develop one or more of the symptoms of depression; and (3) cannot be described as depressive under the criteria in DSM-IV.
  • partial RAD refers to a patient who after antidepressive therapy experience decrease or elimination of some but' not all of his/her atypical depressive symptoms such that he/she cannot be described as atypically depressive under the criteria of DSM-IV.
  • PRAD patients include those patients who: (1) experience transient complete recovery from atypical depression; (2) subsequently develop atypical depression that is only partially responsive to treatment after 6 months or who develop one or more of the symptoms of atypical depression; and (3) cannot be described as atypically depressive under the criteria in DSM-IV.
  • adolescent depression describes a novel subset of depressed individuals with unique manifestations of depression thought to be related to the complicated social, psychological, and biochemical environment of adolescence.
  • adolescent depression is defined as a syndrome that (1) begins between the ages of 9 and 19, and that includes (2) mood reactivity, (3) social anxiety, and (4) mood-associated rejection sensitivity or hypersensitivity to interpersonal rejection.
  • Adolescent depression according to this invention is distinct from known adolescent syndromes as descrbed in DSM-IV.
  • sexual inhibition describes an inhibition of or deficiency in a sexual response, i.e., libido, excitement, or orgasm.
  • sexual inhibition does not include inhibition of or deficiency in a sexual response directly caused by a physical defect which makes a sexual response physically impossible.
  • somatoform disorder is used to describe a group of disorders having clinically significant physical symptoms that suggest a general medical condition and are not fully explained by a general medical condition, by the effects of a substance, or by another metal disorder (i.e., results in medical treatment or causes significant impairment in functioning) , as defined in DSM-IV ( supra) .
  • a somatised symptom refers to any symptom resulting from somatization or a somatoform disorder which is a physical expression of psychological distress or anxiety.
  • a somatised symptom can be a lack of energy or the presence of fatigue, muscular aches and pains or a symptom that occurs in a somatoform disorder such as nausea, impaired coordination/balance, paralysis, blindness, deafness, seizures, dissociative symptoms, loss of consciousness and pain during sexual intercourse, menstruation or urination.
  • carbohydrate craving refers to a clinically significant tendancy to frequently crave carbohydrate-containing foods (particularly, carbohydrate-rich containing snack foods such as potato chips, pastries, cookies) , which is well known in the art (e.g., Wurtman, R.J. et al . , Obes . Res. Suppl 4:477S-480S (1995) . Patients suffering from this tendancy do not necessarily suffer from obesity.
  • conduct disorder refers to a repetitive and persistent pattern of behavior in which the basic rights of others or major age- appropriate societal norms or rules are violated, as defined in DSM-IV (supra) .
  • a patient experiencing a conduct disorder does not have Attention- Deficit/Hyperactivity Disorder as defined in DSM-IV.
  • oppositional defiant disorder refers to a recurrent pattern of negativistic, defiant, disobedient, and hostile behavior toward authority figures that persists for at least six months, as defined in DSM-IV.
  • a patient experiencing an oppositional defiant disorder does not have Attention-Deficit/Hyperactivity Disorder as defined in DSM- IV.
  • conduct disturbance refers to a clinically significant behavior in patient which is repetitive and persistent, in which the basic rights of others or major age-appropriate societal norms or rules are violated, wherein said patient's behavior does not meet the criteria of a conduct disorder or oppositional defiant disorder as defined in DSM-IV.
  • a patient experiencing a conduct disturbance does not have Attention-Deficit/Hyperactivity Disorder as defined in DSM-IV.
  • conduct disturbance refers to a clinically significant behavior in a patient experiencing conduct disorder, oppositional defiant disorder or conduct disturbance, which is repetitive and persistent and violates the basic rights of others or major age-appropriate societal norms or rules.
  • Said conduct disturbances according to this invention include aggressive conduct; causes or threatens physical harm to humans or animals; non-agressive conduct that causes property loss or damage; deceitfulness or theft; serious violations of rules; and negativistic, defiant, disobedient, and hostile behavior toward authority figures.
  • said human having a conduct disturbance or a conduct disorder or oppositional defiant disorder does not have Attention- Deficit/Hyperactivity Disorder.
  • learning disability is as known in the art.
  • a human with a learning disability according to this invention does not suffer from attention deficit hyperactivity disorder.
  • LAD Low Affect Disorder
  • DSM-IV depression, as defined in DSM-IV, by the presence of these characteristic symptoms, which do not appear in the DSM-IV definition of "depression”.
  • the LAD patient being treated in the methods of this invention is not clinically depressed or is subclinically depressed.
  • LAD a diagnosis of LAD can include patients who suffer from these symptoms as part of clinically defined syndromes such as depression or atypical depression.
  • LAD as used herein, is meant to encompass patients with malaise and lethargy who are suffering from a concomitant medical condition, such as an autoimmune disorder in which "malaise” is a diagnostic feature, e . g. , systemic lupus. Accordingly, it should be understood that LAD patients may also suffer from concomitant psychiatric problems.
  • LAD is not the same disorder as "depression” known in the art or defined in DSM-IV. To the best of applicant's knowledge, the use of moclobemide to treat LAD has never been reported.
  • the invention encompasses the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to treat the symptoms of malaise and lethargy.
  • the patient suffering from malaise and lethargy is not clinically depressed or is subclinically depressed.
  • the present invention also provides a method of treating LAD in a human, which comprises administering to said human suffering from LAD a therapeutically effective amount of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition.
  • the present invention encompasses a method of treating PRAD or PRD in a human, which comprises administering to said human suffering from PRAD or RAD, respectively, a therapeutically effective amount of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition either alone or in conjunction with psychotherapy or additional psychoactive medication, in a manner designed to minimize or eliminate any symptoms associated with depression or atypical depression, respectively, of a subsyndromal intensity.
  • the PRD or PRAD patient is administered a therapeutically affective amount of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition with another therapeutic agent such as a TCA, a SSRI, a antipsychotic drug.
  • a therapeutically affective amount of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition with another therapeutic agent such as a TCA, a SSRI, a antipsychotic drug.
  • the present invention encompasses a method of treating adolescent depression in a human, which comprises administering to said human suffering from adolescent depression a therapeutically effective amount of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition.
  • the present invention also encompasses the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to treat individual symptoms commonly associated with atypical depression, such as hypersomnia, weight gain, leaden paralysis, and rejection sensitivity, in patients who are not clinically depressed or who are subclinically depressed.
  • AD refractory AD
  • RAD refractory AD
  • SSRI's SSRI's
  • TCA's refractory AD
  • a' patient with RAD would continue to meet the DSM-IV or Columbia criteria for AD after 6 months of treatment with at least one antidepressant.
  • the invention provides a method for using moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to a patient, who is not clinically depressed or who is subclinically depressed, and who is suffering from sexual inhibition, somatization, somatoform disorder, carbohydrate cravings, obesity or overeating.
  • the invention also provides a method for treating a somatised symptom comprising the step of administering moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to a human who in need of treatment for a somatised symptom.
  • the human is not clinically depressed or is subclinically depressed.
  • Such method may be useful for preventing the onset of depression or AD.
  • the somatised symptoms can be selected from the group consisting of lack of energy, fatigue, muscular aches and pains or a symptom that occurs in a somatoform disorder such as nausea, impaired coordination/balance, paralysis, blindness, deafness, seizures, dissociative symptoms, loss of consciousness and pain during sexual intercourse, menstruation or urination.
  • Another object of this invention is to provide a method for treating or preventing an illness selected from the group consisting of a learning disability, conduct disorder, oppositional defiant disorder, or a conduct disturbance, in a human who is in need of treatment for said illness and who does not suffer from attention deficit hyperactivity disorder, comprising the step of administering moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition.
  • the invention also provides a method for treating a conduct disturbance comprising the step of administering moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to a human in need of treatment for a conduct disturbance.
  • Said conduct disturbance can be selected from the group consisting of aggressive conduct; causes or threatens physical harm to humans or animals; non- agressive conduct that causes property loss or damage; deceitfulness or theft; serious violations of rules; and negativistic, defiant, disobedient, and hostile behavior toward authority figures.
  • the present invention encompasses the use of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition to treat patients who are immunocompromised or immunosupressed.
  • moclobemide as well as certain other moclobemide derivatives, can be synthesized according to the method described in United States Patent No. 4,210,754 to Burkard et al . , and in United States Patent No. 4,906,626 to Amrein et al . , which are incorporated by reference herein in their entirety.
  • Prodrugs i.e. drugs that are metabolized in vivo into the active agent, and methods for making prodrugs are readily know in the art (e.g., Balant, L.P., "Prodrugs for the Improvement of Drug Absorption Via Different Routes of Administration, " Eur. J. Drug Metab. Pharmacokinet . 15:143-153 (1990); and Bundgaard, H. , “Novel Chemical Approaches in Prodrug Design," Drugs of the Future 16:443-458 (1991) ; incorporated by reference herein) .
  • derivatives according to this invention have MAOI activity.
  • the magnitude of a prophylactic or therapeutic dose of the active ingredient e . g.
  • moclobemide, a moclobemide metabolite, a moclobemide derivative) in accordance with the present invention will vary with the severity of the patient's affliction and the route of administration.
  • the dose and dose frequency will also vary according to the age, weight and response of the individual patient.
  • the recommended daily dose range for the conditions described herein lies within the range of from about 50 mg to about 1200 mg per day, generally divided equally into doses given one to four times a day.
  • a daily dose range should be between 150 mg and 900 mg per day, usually divided equally into a two to four times a day dosing.
  • a daily dose range should be between 150 mg and 600 mg per day, usually divided equally into a two to four times a day dosing. It may be necessary to use dosages outside these ranges in some cases, and the treating physician will know how to increase, decrease or interrupt treatment based upon patient response.
  • the various terms described above such as "therapeutically effective amount,” are encompassed by the above-described dosage amounts and dose frequency schedule.
  • the treating physician will generally prescribe the period of treatment and frequency of dose of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition on a patient-by-patient basis.
  • treatment with moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition may be carried out for as long a period as necessary, either in a single, uninterrupted session, as is preferred for LAD, adolescent depression, RD, and RAD, or in discrete sessions timed to coincide with exposure to biochemical or hormonal stimuli likely to trigger symptoms, as is preferred for treating the symptoms commonly associated with AD, in the absence of depression.
  • moclobemide, a moclobemide metabolite, or a moclobemide derivative therapy may be carried out for a period of at least 4 weeks.
  • moclobemide When used for treating or preventing LAD, adolescent depression, or the symptoms commonly associated with depression or AD in patients who do not have depression or AD by DSM-IV criteria, moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition may be administered before, along with, or after psychoactive compounds without antidepressant activity, such as lithium.
  • Moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition may also be administered before, along with, or after traditional psychotherapy.
  • moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition may be utilized in accordance with the present invention as an adjunct to conventional behavioral therapy that aims to eliminate, minimize, or prevent depressive symptoms commonly associated with the above-described disorders.
  • any suitable route of administration may be employed for providing the patient with an effective dosage of moclobemide, a moclobemide metabolite, a moclobemide derivative or a moclobemide composition.
  • oral, rectal, parenteral, transdermal, subcutaneous, sublingual, intranasal, intramuscular, intrathecal and the like may be employed as appropriate.
  • Dosage forms include tablets, coated tablets, caplets, capsules ( e . g. hard gelatin capsules), troches, dragees, dispersions, suspensions, solutions, patches and the like, including sustained release formulations well known in the art. See, e . g.
  • compositions of the present invention may also comprise other therapeutic ingredients.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids. Since the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Such acids include maleic, acetic, benzene-sulfonic (besylate) , benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
  • Particularly preferred are hydrobromic, hydrochloric, maleic, phosphoric, and sulfuric acids.
  • compositions include compositions suitable for oral, rectal, transdermal, sublingual, and parenteral administration (including subcutaneous, intramuscular, intrathecal and intravenous) , although the most suitable route in any given case will depend on the nature and severity of the condition being treated.
  • the most preferred route of administration of the present invention is the oral route.
  • the composition may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
  • a suitable dosage range for use is, e . g. , from about 50 mg to about 1200 mg per day, generally divided equally into a one to four times a day dosing, preferably from about 150 mg to about 900 mg per day, generally divided equally into a two to four times a day dosing and most preferably from about 150 mg to about 600 mg per day, generally divided equally into a two to four times a day dosing. Patients may be upward titrated from below to within this dose range to achieve satisfactory control or prevention of symptoms as appropriate.
  • moclobemide, a moclobemide metabolite, or a moclobemide derivative can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e . g. , oral or parenteral (including intravenous injections or infusions) .
  • any of the usual pharmaceutical media may be employed, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, for example, suspensions, elixirs and solutions; or aerosols; or carriers such as starches, sugars, microcrystalline cellulose, stabilizers, diluents, granulating agents, lubricants, binders, fillers, disintegrating agents and the like in the case of oral solid preparations such as, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • the preferred solid oral preparation is tablets.
  • the most preferred solid oral preparation is coated tablets.
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques .
  • the preparation of coated tablets, sachets, and hard gelatin capsules containing moclobemide as the active ingredient is described in United States Patent No. 4,906,626, which is incorporated herein by reference.
  • the compounds of the present invention may also be administered by controlled release or sustained release means and/or delivery devices such as those described in U.S. Patent Nos.
  • compositions containing moclobemide or salts thereof may also be used to stabilize compositions containing moclobemide or salts thereof; acceptable stabilizers include but are not limited to L-cysteine hydrochloride, glycine hydrochloride, malic acid, sodium metabisulfite, citric acid, tartaric acid and L- cysteine dihydrochloride . See, e . g. U.S. Patent No. 5,358,970, which is incorporated herein by reference.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets or aerosol sprays, each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
  • Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with one or more of a binder, filler, stabilizer, lubricant, inert diluent, and/or surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • each tablet contains from about 50 mg to about 300 mg of the active ingredient
  • each cachet or capsule contains from about 50 mg to about 300 mg of the active ingredient.
  • the tablet, cachet or capsule contains one of four dosages: about 50 mg, about 75 mg, about 100 mg, and about 150 mg of active ingredient.
  • the active ingredient is blended with the lactose until a uniform blend is formed.
  • the smaller quantity of corn starch is blended with a suitable quantity of water to form a corn starch paste. This is then mixed with said uniform blend until a uniform wet mass is formed.
  • the remaining corn starch is added to the resulting wet mass and mixed until uniform granules are obtained.
  • the granules are then screened through a suitable milling machine, using a 1/4 inch stainless steel screen.
  • the milled granules are then dried in a suitable drying oven until the desired moisture content is obtained.
  • the dried granules are then milled through a suitable milling machine using 1/4 mesh stainless steel screen.
  • the magnesium stearate is then blended and the resulting mixture is compressed into tablets of desired shape, thickness, hardness and disintegration.
  • Tablets are coated by standard aqueous or nonaqueous techniques. For example, 2.5 mg of hydroxypropymethylcellulose can be dissolved in 25 mg of deionized water. An aqueous (10 mg) suspension of 1.88 mg talc, 0.5 mg of titanium dioxide, 0.1 mg of yellow iron oxide, and 0.02 mg of red iron oxide is stirred into this solution. The coating suspension is sprayed on the tablets and the coated tablets are dried overnight at 45 * C.
  • the active ingredient (moclobemide) , lactose, and corn starch are blended until uniform; then the magnesium stearate is blended into the resulting powder.
  • the resulting mixture is encapsulated into suitably sized two-piece hard gelatin capsules.
  • moclobemide 20 40 100 lactose BP 134.5 114.5 309.0 starch BP 30.0 30.0 60.0 Pre-gelatinized Maize Starch BP 15.0 15.0 30.0 magnesium stearate 0.5 0.5 1.0 Compression Weight 200.0 200.0 500.0
  • the active ingredient (moclobemide) is sieved through a suitable sieve and blended with lactose, starch, and pre-gelatinized maize starch. Suitable volumes of purified water are added and the powders are granulated. After drying, the granules are screened and blended with the magnesium stearate. The granules are then compressed into tablets using punches.
  • Tablets of other strengths may be prepared by altering the ratio of active ingredient to lactose or the compression weight and using punches to suit.
  • single unit dosage forms of moclobemide in 50, 100, 150, and 200 mg are preferred and can be easily manufactured by those of skill in the art.

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Abstract

La présente invention concerne des procédés et des compositions dans lesquels on utilise le moclobémide, un métabolite du moclobémide, un dérivé du moclobémide ou une composition de moclobémide pour faciliter le traitement ou la prévention des troubles affectifs avec apathie, de la dépression des adolescents, de la dépression partielle rebelle à la thérapie, de la dépression atypique partielle rebelle à la thérapie, des problèmes d'alimentation et des symptômes de ces troubles. L'invention permet également de traiter les symptômes de somatisation, les troubles de l'apprentissage et du comportement par le moclobémide, un métabolite du moclobémide, un dérivé du moclobémide ou une composition de moclobémide.
PCT/US1999/017417 1998-07-31 1999-07-30 Procedes et compositions permettant de traiter et de prevenir certains troubles psychiatriques et medicaux par le moclobemide Ceased WO2000006140A2 (fr)

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MXPA01001178A MXPA01001178A (es) 1998-07-31 1999-07-30 Metodos y composiciones para tratamiento y la prevencion de ciertos trastornos psiquiatricos y medicos mediante el empleo de la moclobemida.
CA002338330A CA2338330A1 (fr) 1998-07-31 1999-07-30 Procedes et compositions permettant de traiter et de prevenir certains troubles psychiatriques et medicaux par le moclobemide
JP2000561995A JP2002521433A (ja) 1998-07-31 1999-07-30 モクロベマイドを用いる、ある種の精神医学的および医学的異常の処置と予防の方法および組成物
AU53305/99A AU5330599A (en) 1998-07-31 1999-07-30 Methods and compositions for treating and preventing certain psychiatric and medical disorders using moclobemide

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MXPA01001178A (es) 2002-04-24

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