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WO1996035425A1 - Composition pharmaceutique permettant de traiter la dependance alcoolique ou l'abus d'alcool et comprenant au moins un agoniste partiel des recepteurs 5th1a et au moins un inhibiteur selectif de monoamine-oxydase - Google Patents

Composition pharmaceutique permettant de traiter la dependance alcoolique ou l'abus d'alcool et comprenant au moins un agoniste partiel des recepteurs 5th1a et au moins un inhibiteur selectif de monoamine-oxydase Download PDF

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Publication number
WO1996035425A1
WO1996035425A1 PCT/BR1996/000018 BR9600018W WO9635425A1 WO 1996035425 A1 WO1996035425 A1 WO 1996035425A1 BR 9600018 W BR9600018 W BR 9600018W WO 9635425 A1 WO9635425 A1 WO 9635425A1
Authority
WO
WIPO (PCT)
Prior art keywords
th1a
receptors
monoamino
accordance
partial agonist
Prior art date
Application number
PCT/BR1996/000018
Other languages
English (en)
Inventor
Luiz Roberto Mallat Tostes
Original Assignee
Luiz Roberto Mallat Tostes
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Luiz Roberto Mallat Tostes filed Critical Luiz Roberto Mallat Tostes
Priority to EP96913395A priority Critical patent/EP0824351A1/fr
Priority to AU56410/96A priority patent/AU5641096A/en
Publication of WO1996035425A1 publication Critical patent/WO1996035425A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim

Definitions

  • the present invention refers to a pharmaceutical composition that can be used in treating alcohol dependence or abuse and other psychiatric disorders related thereto, more specifically for treating the subgroup of alcoholic patients and of depressive and anxious syndromes related to alcoholism.
  • Alcoholism is a serious public health problem throughout the world, especially in the western world, affect ⁇ ing, for instance, about 15% of the male population. It often results both in psychiatric and clinic complications. Background of the Invention
  • the techniques available at the present for treating alcoholism can be divided into two great groups: psychosocial techniques and psychotherapic techniques.
  • the psychosocial techniques often comprise psychotherapic and sociotherapic interventions for the purpose of achieving absolute abstinence and, in principle, they are based on the aspect of avoiding the "first drink”.
  • the use of medicines in the treatment of alcoholism can be classified as belonging to three principal groups, namely: (a) use of medicines in the treatment of the alcohol abstinence syndrome; (b) use of medicines in the so-called “aversive treatment", generating a deep indisposition if the patient takes alcoholic beverages and (c) use of medicines to reduce the "compulsion" for alcohol.
  • the carbamazepine-buspirone association has a synergic effect, that is to say, a therapeutic effect which is superior to the individual therapeutic effect of each of the substances used separately
  • a synergic effect that is to say, a therapeutic effect which is superior to the individual therapeutic effect of each of the substances used separately
  • other types of associations have been developed, such as moclobemide/buspirone and neuroleptics (in low doses)/partial agonists of receptors 5-TH1A, which are intended for different subgroups of alco ⁇ holic patients.
  • These two types of composition are the object of Brazilian Patent Applications PI 9402744, filed on 12/8/94 and PI 9402362-0, filed on 9/6/94, respectively.
  • compositions are suitable for a specific subgroup of alcoholic patients, so that its clinic use has generated a new classification for alcoholism on the basis of the clinical characteristics and on the family history, which can be summarized as follows:
  • CMZ carbamazepine
  • MCB moclobemide
  • NLP low doses of neuroleptics
  • SF/AP social phobia or avoidance personality (*) - may or may not be present; when present they are of moderate intensity.
  • compositions have the drawback of being therapeutically effective only in those cases in which there is a family history of alcoholism. Therefore, it is an object of the present invention to provide a pharmaceutical composition which effectively re ⁇ cutes the desire of drinking of any patients who suffer from alcohol dependence or abuse, with or without a family alcoholism history, part from having a faster action without, however, causing unwanted side effects such as late dyscinesia, which is a side effect liable to occur and which sometimes is irreversible, caused by neuroleptic medicines.
  • Another object of the invention is to provide a method for treating any alcoholic patients, which will reduce his desire of drinking.
  • a further object of the invention is to provide a method for treating patients who suffer from psychiatric dis ⁇ orders genetically connected with alcoholism.
  • the present invention refers to a pharmaceutical composition which comprises at least one compound selected from the group of partial agonists of the 5-TH1A receptors and at least one selective inhibitor compound of B-type monoamino- oxydase (MAO) .
  • the invention also refers to a method for treating alcohol dependence or abuse, which comprises the adminis ⁇ tration, to a patient suffering from such alcohol dependence or abuse, of a pharmaceutical composition comprising at least one partial agonist compound of 5-TH1A receptors and at least one selective inhibitor of B-type monoamino-oxidase (MAO) .
  • the present invention further refers to a method for treating psychiatric disorders genetically connected with alcoholism, which comprises the administration, to a patient suffering from such disorders, of a pharmaceutical composition as defined above.
  • the present invention still refers to the use of an associ- ation of at least one partial agonist compound of 5-TH1A receptors and at least one selective inhibitor of B-type monoamino-oxidase (MAO) for treating alcohol dependence or abuse or psychiatric disorders genetically connected with alcoholism.
  • MAO B-type monoamino-oxidase
  • buspirone as well as its pharmaceutically acceptable acid-addition salts are particularly preferred.
  • the other component of the composition in accordance with the invention is at least one selective inhibitor com- pound of monoamino-oxidase of type B (MAO-B) .
  • MAO-B monoamino-oxidase of type B
  • This group in ⁇ cludes such compounds as selegiline, Ro 41-1049 and Ro 19-6327 (lazabemide) .
  • the preferred one is selegiline.
  • Selegiline for instance, was initially used as adjuvant in the treatment of Parkinson's disease and, more recently, as monotherapy in the initial cases of these disease (CHRISP P, MAMMEN GJ & SORKIN EM - Selegiline.
  • CHRISP P MAMMEN GJ & SORKIN EM - Selegiline.
  • a very im ⁇ portant evidence of the "synergistic effect" of the present invention is the fact that many patients who present intoler ⁇ ance to the partial antagonists of 5-TH1A receptors, when ad ⁇ ministrated in isolated form or even in the compositions already known from the prior art, are capable of tolerating high dosage of said antagonists, provided that they are asso- ciated with the selective MAO-B inhibitor.
  • This intolerance to the antagonists of 5-TH1A receptors is an important clinical indicator that the patient will respond to the association of said antagonists with the selective MAO-B inhibitors, and not to the other previously developed compositions.
  • the present invention also relates to a method for treating patients who suffer from alcohol dependence or abuse, this method comprising the administration to the patient of a composition as defined above.
  • the invention is also effective in a method of treating patients having psychiatric conditions as anxiety disorders or depressive disorders such as alimentary disorders and those described in several systems of diagnosis such as DSM-III, DSM-III-R, DSM-IV, CID-IX and CID-X who have genetic heredity connected with alcoholism of some close relative, al ⁇ though themselves not being considered as alcohol-dependent patients.
  • the patient is an engineer, 45 years old, whose psy- chiatric problems began 8 years ago, presenting depression, intense anxiety, generalized phobic symptoms and also symptoms of derealization and depersonilization.
  • Various electroencephalograms were requested and no abnormality was disclosed.
  • the patient's father had been an alcoholic during most of his life, and his only sister had suffered from a depressive episode.
  • the psychiatric problems began, the patient did not present any condition of alcohol abuse, al ⁇ though he was described as a person who used to drink and did not like to take medicines with which one is not allowed to take alcoholic drinks.
  • the atypical depressive-anxious condi ⁇ tion of the patient proved to be difficult to control with medicines.
  • Example 2 The female patient is a 36-year-old psychologist with no children, whose psychiatric problems had began two years before starting the treatment, after she had a divorce. After returning to her parents' home, she began to make daily use of alcoholic drinks with friends and come back home late at night. At first, she usually drank little, doses, about two doses of vodka a day, but the alcohol dependence progressed rapidly and, after eight months, she was already taking six dosage of vodka a day during the week, increasing the quantity on weekends. She presented classic symptoms of alcohol depend- ence, such as tremors and nausea in the morning. She then be ⁇ gan to make use of benzodiazepinis after waking up, in order to soften these symptoms.
  • Trifluorperazine was suspended and a composition according to the invention was used. Initially a formulation containing buspirone and selegiline was employed so as to provide a dosage of 90 mg/day of buspirone and 2.5 mg/day of selegiline and afterwards, the amount of selegiline was increased to provide a dosage of 5 mg/day, whereby, for the first time since the beginning of the treatment, a recovery from alcoholism was observed, and the patient reported that she had decreased the daily amount of vodka since she felt that her "organism did not allow more".
  • a further increase in the selegiline dosage was then carried out up to 10 mg/day, and a substantial recovery was observed, and the patient then started to drink only one or two cans of beer a day.
  • the depressive condition improved parallelly. With a formulation providing a dosage of 15 mg/day of selegiline associated with 60 mg/day of buspirone, there was a complete remission of the depressive condition and the ingestion of alcohol, which returned to a socially ac ⁇ cepted level.
  • Example 3 The female patient is a 33-year-old architect, sin ⁇ gle, who presented problems of excessive use of alcoholic drinks ever since she was 18 years old. Alcoholism progressed rapidly, and at 23 she attempted suicide by taking medicines during a period of high alcoholic intoxication. After this episode, she was subjected to psychiatric treatment, having received various medicines and having been subjected to se ⁇ veral therapeutic approaches, without results. The ingestion of alcohol was not daily, but once it occurred, the frequence was of about 3 or 4 times a day, whereby there was a loss of control over the amount taken with frequent alcoholic "black ⁇ outs" (amnesia).
  • Example 4 The patient is a 45-year-old manager, who came to
  • the amount of selegiline was increased in the composition so as to provide 15 mg/day together with a dosage of 60 mg/day of buspirone. with the complete disap ⁇ pearance of the desire to drink, except on important festivity occasions, and even so at very small dosage. Trifluorperazine was gradually suspended from the composition without any ad- verse impact on the condition. There were clear improvements also in patient's social relationship, who became more polite and sought the company of other people without having to re ⁇ sort to drinking.
  • the patient is a 39-years-old house-wife who pre ⁇ sented a depressive condition with intense anxiety associated therewith, which started when she was 27, without any apparent reason. She had already used several tricyclic antidepressants, inhibitors of monoamino-oxidase and inhibitors of recaptation of serotonine, without any satisfac ⁇ tory result. Clinically, the anxious condition predominated over the depressive one, multiple somatic anxiety symptoms be ⁇ coming apparent, in addition to the condition of high blood pressure not affected by the treatments, which high blood pressure had been attributed to her emotional state.
  • a composition comprising trifluorperazine and buspirone (1:5) was administrated to her and with a dosage of 4/20 mg/day there was a considerable reduction of the anxious condition, the residual depressive condition persisting.
  • the composition was administered providing dosages up to 6/20 mg/day but it was not tolerated. With all these approaches, the patient characteristically presented reactions of intolerance to buspirone, especially to the dosage applied in the morning, in the form of very unpleasant subjective symptoms, although short-lived. Since the dosage of 4/20 mg/day of trifluoperazine/ buspirone was the one that yield better re ⁇ sults, including the normalization of the figures of arterial pressure, it was maintained, and a tricyclic antidepressant, namely maprotiline, was added to the composition providing a total dosage of 50 mg/day.
  • the female patient is a 32-years-old house-wife, who suffered from panic disorder ever since she was 18 years old.
  • the clinical condition was typical and quite serious, the pa ⁇ tient having been forced to interrupt her studies since she did not manage to remain at school, a situation which invari ⁇ ably caused panic crisis.
  • the crisis had decreased in intensity and frequency, they were still incapacitating problems such as, for instance, difficulty in travelling by bus at rush hours, or in walking far from home without com- pany.
  • Her father had been an alcoholic who died due to hepatic cirrhosis.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne une composition pharmaceutique utile dans le traitement de la dépendance alcoolique ou de l'abus d'alcool, comprenant au moins un composé choisi dans le groupe d'agonistes partiels des récepteurs 5-TH1A et au moins un composé inhibiteur sélectif de la monoamine-oxydase (M.A.O.) de type B. Elle concerne également un procédé permettant de traiter la dépendance alcoolique, l'abus d'alcool ou les complications génétiques provoquées par l'alcoolisme qui consiste à administrer, à un patient souffrant de ces troubles, une composition pharmaceutique comprenant au moins un composé agoniste partiel des récepteurs 5-TH1A et au moins un composé inhibiteur sélectif de la monaamine-oxydase (M.A.O.) de type B.
PCT/BR1996/000018 1995-05-09 1996-05-09 Composition pharmaceutique permettant de traiter la dependance alcoolique ou l'abus d'alcool et comprenant au moins un agoniste partiel des recepteurs 5th1a et au moins un inhibiteur selectif de monoamine-oxydase WO1996035425A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP96913395A EP0824351A1 (fr) 1995-05-09 1996-05-09 Composition pharmaceutique permettant de traiter la dependance alcoolique ou l'abus d'alcool et comprenant au moins un agoniste partiel des recepteurs 5th1a et au moins un inhibiteur selectif de monoamine-oxydase
AU56410/96A AU5641096A (en) 1995-05-09 1996-05-09 A pharmaceutical composition useful in treating alcohol depe ndence or abuse comprising at least one partial agonist of 5 -th1a receptors and at least one selective inhibitor of mono amino-oxidase

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BR9501972A BR9501972A (pt) 1995-05-09 1995-05-09 Composição farmacêutica metodo para tratamento de dependência ou abuso de álcool e método para tratamento de distúrbios psiquiátricos geneticamente relacionados ao alcoolismo
BRPI9501972-3 1995-05-09

Publications (1)

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WO1996035425A1 true WO1996035425A1 (fr) 1996-11-14

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PCT/BR1996/000018 WO1996035425A1 (fr) 1995-05-09 1996-05-09 Composition pharmaceutique permettant de traiter la dependance alcoolique ou l'abus d'alcool et comprenant au moins un agoniste partiel des recepteurs 5th1a et au moins un inhibiteur selectif de monoamine-oxydase

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EP (1) EP0824351A1 (fr)
AU (1) AU5641096A (fr)
BR (1) BR9501972A (fr)
WO (1) WO1996035425A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2768338A1 (fr) * 1997-09-17 1999-03-19 Synthelabo Compositions pharmaceutiques contenant un inhibiteur de la monoamine oxydase et leur application en therapeutique
WO2003039525A1 (fr) * 2001-11-05 2003-05-15 Krele Pharmaceuticals Llc Compositions et methodes permettant d'augmenter l'observance therapeutique au moyen d'inhibiteurs de l'aldehyde deshydrogenase et traitement de l'alcoolisme
WO2008143552A1 (fr) 2007-05-23 2008-11-27 Viktor Ivanovich Roschin Agent, composition pharmaceutique, ingrédient actif de cette composition pharmaceutique et méthode de traitement de la dépendance à l'alcool éthylique et/ou aux drogues servant à traiter les complications psychosomatiques et neurologiques de patients alcooliques et/ou toxicomanes
WO2008143553A1 (fr) 2007-05-23 2008-11-27 Viktor Ivanovich Roschin Médicament servant au traitement de patients souffrant de maladies provoquées par l'activité excessive de la monoaminooxydase et méthode de traitement de patients souffrant de maladies provoquées par l'activité excessive de la monoaminooxydase
EP3170499A1 (fr) 2010-09-01 2017-05-24 Tonix Pharmaceuticals, Inc. Traitement contre la cocaïnomanie

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990004387A2 (fr) * 1988-10-26 1990-05-03 Massachusetts Institute Of Technology Composition de traitement de symptomes relatifs au manque de tabac

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990004387A2 (fr) * 1988-10-26 1990-05-03 Massachusetts Institute Of Technology Composition de traitement de symptomes relatifs au manque de tabac

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TENNANT F.: "Clinical trial of multiple treatment agents for cocaine dependence: A placebo-control;elimination study", NIDA RES. MONOGR. SER., 1990, -/105 (512-513), USA, XP000603021 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2768338A1 (fr) * 1997-09-17 1999-03-19 Synthelabo Compositions pharmaceutiques contenant un inhibiteur de la monoamine oxydase et leur application en therapeutique
WO1999013879A1 (fr) * 1997-09-17 1999-03-25 Sanofi-Synthelabo Compositions pharmaceutiques contenant un inhibiteur de la monoamine oxydase et leur application en therapeutique
WO2003039525A1 (fr) * 2001-11-05 2003-05-15 Krele Pharmaceuticals Llc Compositions et methodes permettant d'augmenter l'observance therapeutique au moyen d'inhibiteurs de l'aldehyde deshydrogenase et traitement de l'alcoolisme
US8093300B2 (en) 2001-11-05 2012-01-10 Krele Pharmaceuticals, Inc. Compositions and methods for increasing compliance with therapies using aldehyde dehydrogenase inhibitors and treating alcoholism
US8481599B2 (en) 2001-11-05 2013-07-09 Tonix Pharmaceuticals Inc. Compositions and methods for increasing compliance with therapies using aldehyde dehydrogenase inhibitors and treating alcoholism
WO2008143552A1 (fr) 2007-05-23 2008-11-27 Viktor Ivanovich Roschin Agent, composition pharmaceutique, ingrédient actif de cette composition pharmaceutique et méthode de traitement de la dépendance à l'alcool éthylique et/ou aux drogues servant à traiter les complications psychosomatiques et neurologiques de patients alcooliques et/ou toxicomanes
WO2008143553A1 (fr) 2007-05-23 2008-11-27 Viktor Ivanovich Roschin Médicament servant au traitement de patients souffrant de maladies provoquées par l'activité excessive de la monoaminooxydase et méthode de traitement de patients souffrant de maladies provoquées par l'activité excessive de la monoaminooxydase
EP3170499A1 (fr) 2010-09-01 2017-05-24 Tonix Pharmaceuticals, Inc. Traitement contre la cocaïnomanie

Also Published As

Publication number Publication date
AU5641096A (en) 1996-11-29
EP0824351A1 (fr) 1998-02-25
BR9501972A (pt) 1997-08-26

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