WO1996035425A1

WO1996035425A1 - A pharmaceutical composition useful in treating alcohol dependence or abuse comprising at least one partial agonist of 5-th1a receptors and at least one selective inhibitor of monoamino-oxidase

Info

Publication number: WO1996035425A1
Application number: PCT/BR1996/000018
Authority: WO
Inventors: Luiz Roberto Mallat Tostes
Original assignee: Individual
Current assignee: Individual
Priority date: 1995-05-09
Filing date: 1996-05-09
Publication date: 1996-11-14
Anticipated expiration: 1997-11-09
Also published as: AU5641096A; EP0824351A1; BR9501972A

Abstract

The invention refers to a pharmaceutical composition useful in treating alcohol dependence or abuse, which comprises at least one compound selected from the group of partial agonists of 5-TH1A receptors and at least one selective inhibitor compound of B-type monoamino-oxidase (MAO). The invention also relates to a method for treating alcohol dependence or abuse or genetic complications caused by alcoholism, which comprises the administration, to a patient suffering from these disorders, of a pharmaceutical composition comprising at least one partial agonist compound of 5-TH1A receptors and at least one selective inhibitor compound of B-type monoamino-oxidase (MAO).

Description

A PHARMACEUTICAL COMPOSITION USEFUL IN TREATING ALCOHOL DEPENDENCE OR ABUSE COMPRISING ATLEAST ONE PARTIAL AGONISTOF5-TH1A RECEPTORS ANDAT LEASTONESELECTIVEINHIBITOROFMONOAMINO-OXIDASE

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".

On the other hand, the possibility of using medi¬ cines in the treatment of alcoholism has been considered in the last decades, and two good revisions can be found in HALIKAS JA - Psychotropic Medication used in the Treatment of Alcoholism", Hospital and Community Psychiatry, vol. 34, No. 11, 55 pages 1035-1039, in MEYER RE - Pharmacotherapy of Alcoholism", Journal of Clinical Psychiatry, vol. 50, No. 11, pages 403-412 and in LITTN RZ & ALLEN JP - "Reducing the De¬ sire to Drink - Pharmacology and Neurobiology, Recent Develop¬ ments in Alcoholism", vol. 11: Ten Years of Progress, ed Marc Gallanter, Plenum Press, New York, 1993.

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 latter group is the one that has concentrated the attention of researchers for the last few years. A study of the available literature on the subject shows eleven medi¬ cines or groups of medicines studied with a view to reducing "compulsion" for alcohol: lithium, inhibitors of the recaptation of serotonin (zimelidin, fluoxetin, viqualin, paroxetin, sertralin), buspirone, ondonsetron, ritanserin, naltrexon, bromocryptin, neuroleptics, acaprosate (calcium acetyl homotaurinate) , gama-hydroxy-butylic acid and desipramin.

A new therapeutic approach was disclosed in 1990 with the use of a medicamentous association of carbamazepine and buspirone for treating alcohol dependence (MALLAT-TOSTES LR - Alcoolismo - Rapida Inducao do "Beber Controlado" = Alcoholism - a Rapid Induction of "Controlled Drinking" by Carbamazepin-Buspiron Association, Jornal Brasileiro de Psiquiatria, vol. 39, pages 285-292, 1990; OLIVEIRA IR, ROCHA FP, PEREIRA ET el al - Combined Carbamazepine-Buspirone Treat¬ ment of Alcohol Dependence, Journal of Clinical Psychiatry, vol. 54, No. 12, page 488, 1993, MALLAT-TOSTES LR - Uso da Associaςao Carbamazepina-Buspirona no Tratamento do Alcoolismo - Atualizacao, Jornal Brasileiro de Psiquiatria, vol. 44, pages 93-97, 1995). By using this medicines association, it has been possible not only significantly to reduce the "compulsion" for alcohol, but also to allow the patients to make controlled and social use of alcoholic drinks. In other words, unlike other approaches in which the patients are com- pelled to choose between "being a drinking alcoholic" or "be¬ ing a non-drinking alcoholic", the use of above medicine asso¬ ciation has made it possible to cause the patients to recover control over drinking alcohol and to have the same behaviour in relation to alcohol like any other people. 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 In the last few years, the use of pharmaceutical compositions for the purpose of inducing the controlled use of alcohol has been improved, and 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. In addition, scientific articles have been published which describe the use of these two other associations (MALLAT-TOSTES LR - ϋso da associagao moclobemida-buspirona no tratamento do alcoolismo, Jornal Brasileiro de Psiquiatria, vol. 44, n° 3, pp 137-142, 1995 and MALLAT-TOESTES LR - Uso da associacao de doses baixas de neurolepticos com buspirona no tratamento do alcolismo, Jornal Brasileiro de Psiquiatria, vol. 44, n°, 1995).

Each of the above-described compositions is 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:

GROUP A B C

MEDICAMENTS CMZ/BUS MCB/BUS NLP/BUS

Presence of

SF/AP - + +

Disease denial mechanism +/-(*) ++ ++

Progression rapid slow rapid of alcoholism (years) (decades) (years) (incl. drinking in the morning)

Impairment of the laboring activity early late early

Isolates symptoms of the psychotic series +/-(*)

Family history alcoholism alcohol. alcohol, or psychosis

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.

An important characteristic of the use of these com- positions is that they proved to be effective not only in the treatment of alcohol dependence, but also in depressive and anxious syndromes in former alcoholics who had given up drink¬ ing, as well as in depressive an anxious syndromes in first- degree alcohol-dependent patients. These anxiety conditions which respond to the above formulations are of the most dif¬ ferent possible types and, according to the modern classifica¬ tions, such as the present American classification (DSM-IV) and the 10th edition of the International Classification of Diseases, they would be classified as major depression, cysthymia, bipolar affective disorder, panic disorder, social phobia, avoidance personality generalized anxiety disorder, obsessive-compulsive disorder and even some conditions of alimentary disorder such as compulsively-eating disorder.

However, the above-referred-to 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¬ duces 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.

Summary of the Invention

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.

Detailed Description of the Invention

It has been surprisingly found that the association of compounds selected from the group comprising partial agonists of the 5-TH1A receptors and selective inhibitors com- pounds of B-type monoamino-oxidase (MAO) provides excellent results, not only for reducing the desire of alcoholic pa¬ tients to drink, but also allowing these patients to make con¬ trolled use of alcoholic drinks.

Among the partial agonist compounds of the 5-TH1A receptors useful in the present invention, 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) . This group in¬ cludes such compounds as selegiline, Ro 41-1049 and Ro 19-6327 (lazabemide) . Among them the preferred one is selegiline.

These compounds are fully known from the prior art, but so far only effects on disorders other than those con- nected with alcoholism were known. 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. A review of its pharmacology, symtomatica benefits and protective potential in Parkinson's disease, Drugs Aging, vol. 1 No. 3, pp 228-48, 1991. It seems not only to alleviate the parkinsonian symptoms, but also to retard the course of the disease, prolonging the life time of the patients, in which case this has been called neuroprotecting effect. This medicine is very well tolerated in low dosages (up to 20 mg/day), and does not present any side effects and inter¬ actions with tiranine (present in some foodstuffs) which are a common characteristic of non-selective MAO inhibitors and seem not to cause dependence (Abuse Liability of 1-deprenyl: Exam¬ ination of the clinical and preclinical Pharmacological data. Clinical Pharmacology and Therapeutic, vol. 56, No. 6 (suppl.), 1994). The few side effects of selegiline and the possible neuroprotecting effects thereof have encouraged its use in other neurological conditions such as narcolepsy, Alzheimer's disease, late dyscinesia, deficient attention dis¬ order and others. In high dosage (30 up to 60 mg/day), it has been used in depressed patients (AGOSTI B, STEWART JW & QUITKIN FM - Life satisfaction and psychosocial functioning in chronic depression: effect of acute treatment with antidepressants, Journal of Affective Disorders, vol. 23 N. 1, pp. 35-41, 1991; SUNDERLAND T, COHEN RM, MOLCHAN S et al - High-dosage selegiline in treatment-resistant older depressive patients, Archives of general Psychiatry, vol. 51, No. 8, pp. 607-15, 1994), having proved to be effective. However, in these higher dosage, its selectivity by MAO-B disappears, and begins to have the same disadvantages of the traditional MAO inhibitors.

The applicant has found that the association of se¬ lective inhibitor compounds of MAO-B with partial antagonists of 5-TH1A receptors presents a "supra-additive" effect in the treatment of alcoholism and of psychiatric and depressive syn- dromes related to alcoholism, in any patient, even without a family alcoholism history, when the inhibitor compound is used in amounts which preserve its selectivity towards MAO-B. These dosage are usually in the range of 2.5 - 15 mg/day. 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. In general, excellent results of reduction of the desire of drinking are achieved by using compositions having a weight ratio from the partial agonist compound of 5-TH1A receptors to the selective MAO-B inhibitor in the range of 24:1 - 1:1, preferably 12:1 - 2:1.

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 invention will be better illustrated by the ex¬ amples given below, noting, however, that such examples aim solely at a better visualization of the surprising and unex¬ pected effects obtained by the present invention, but they should not be taken as being limitative of the scope thereof.

Example 1

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. When 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. Several attempts were made with various tricyclic antidepressants, with carefully adjusted dosage, and there was no therapeutic response, apart from the fact that the side effects were very intense. Toranylcipromin was then tried, which is a typical inhibitor rather than a selective MAO one, with initially favourable results, which, however, did not re- main so as time went by. The use of the selective inhibitors of serotonin recaptation with fluoxetin and paroxetin also did show any effect. Several therapies were then established with associations of antidepressants which equally did not give good results. The patient presented some recovery with the use of carbamazepine, which, however, had to be discontinued be¬ cause of the intolerable side effects. The chronic and immune depressive-anxious condition of the patient impaired his mar¬ riage relationship, causing serious disagreement with his wife. He then began to take alcoholic drinks daily, in in- creasing quantities. His divorce aggravated the use of alco¬ hol, and after three months he was in a condition of deep alcoholic intoxication. Associations of moclobemide and buspirone and of low dosage of neuroleptics and buspirone were then tried, without any results. Since the clinical condition of the patient became worse and worse, the doctors asked for his sister's help, with whom the patient remained for the pe¬ riod of one month, and with the help of his relatives, he man¬ aged to discontinue the use of alcohol. However, intense depressive and anxious symptomatology persisted. An associ- ation of tranilcoprimin and mianserine was then tried, which brought some but insufficient relief, and the patient could not, for instance, work again. The patient followed the med¬ ical orders to withhold himself of taking alcoholic drinks due to the use of tranylcyprominee. A composition comprising an association of selegiline/buspirone was then used. The used dosage was such that it initially provided 2.5/15 and later increased to 5/30 mg/day of selegiline/buspirone. After 5 days using this later dosage the patient presented a signif¬ icant recovery from the depressive condition and also from the anxious, phobic symptoms, as well as from the symptoms of de- realization and depersonilization. This dosage was maintained for the period of 10 more days, whereby the recovery was sta¬ bilized. Since there still were residual symptoms, a further increase to the dosage of 10/45 mg/day was effected and this dosage brought about a complete remission of the depressive condition, which had not been achieved in the 8 years of pre¬ ceding treatments. Upon trying to make a careful adjustment of the dosage, attempts were made to reduce both the selegiline and the buspirone, with return of the symptoms in each of these attempts. After three months of consolidation of the re¬ covery of the patient, the latter was allowed to make use of alcoholic drinks, which was made successfully, and the patient again began to make social use of alcohol, only on special oc- casions. In fact, his "desire to drink" decreased and there were even occasions on in which, upon going out with friends, the patient preferred to making use of soft drinks and fruit juices, even if his friends were drinking alcoholic drinks.

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. She was systematically absent from work on Mondays, as a result of the condition of alcoholic intoxication in which she was on weekends. Urged by her par- ents, she accepted to seek medical assistance. The psychiatric appraisal showed her to be a patient with a slight-to-moderate depressive condition, having always been shy and restrained in social contact. Initially she was treated with clomipramine, in a dosage of 100 mg/day, recovering from the depression without any effect, however, in the ingestion of alcoholic drinks. The clomipramine presented adverse interaction with alcohol, sertraline was tried in a dosage of 50 mg/day. There was a complete remission of the depressive condition, but also a significantly important aggravation of alcoholism. The asso¬ ciation of moclobemide with buspirone was then initiated, but the patient showed intolerance to moclobemide in the form of dysphoric excitatory reaction with very low dosage (50 mg/day). Moclobemide was then suspended, and buspirone re¬ main, the dosage of which were gradually increased up to 60 mg/day. A some recovery from alcoholism and depression oc¬ curred. Higher dosage of buspirone (90 mg/day), although well tolerated, did not bring any therapeutic gain, and lower dosage (45 mg/day) caused aggravation of both the depressive condition and alcoholism. The addition of low dosage of neuroleptics to buspirone was then tried. The patient did not stand the sedative effect of chloropromazine, and then trifluorperazine was tried at increasing dosage upo to 6 mg/day, without any clinical progress. 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). She also presented a slight depressive con¬ dition, with hypersomnia, fatigability, crisis of crying and serious insomnia. Over these years several pharmacotherapeutic approaches were tried, especially tricyclic antidepressants, without satisfactory results. Several eletroencephalograms were carried out which did not show any alteration in the brain biolectric activity. Even so, carbamazepine had already been tried, with aggravation of the condition, which gave way to an attempt at suicide. The psychiatric appraisal showed the patient to be with important traces of social phobia and avoidance personality, alcoholism being often used to facili¬ tate social interaction. In fact, she never drank at home, al- though she often went out with the purpose of drinking. The association of moclobemide and buspirone was then tried at in¬ creasing dosage, without obtaining any therapeutic result. A composition comprising buspirone and chloropromazine was used so as to give 10 mg/day of buspirone and 50 mg/day of choropromazine, with some reduction in the frequency of ingestion of alcoholic drinks. With this kind of composition, even varying the dosage of each component, a controlled use of alcohol was achieved, while the slight depressive condition and a obstinate insomnia persisted. However, a new formu- lation was tried replacing the cholorpromazine by selegiline at a daily dosage of 15 mg of buspirone and 2,5 mg of selegiline with the disappearance of the residual depressive condition.

Example 4 The patient is a 45-year-old manager, who came to

Rio de Janeiro on the initiative of his family in search for treatment for alcohol dependence. He lived alone in the coun¬ try in southern Brazil, and the use of alcohol had started 3 years before, after he had lost his father. The patient stated that he had began to drink in order to "fight the cold weather", but the alcohol dependence had progressed rapidly and, two and a half years later, he became unable of working, having been sent to a public institution for treatment of alcoholism. He used to drink only beer, but in large quan¬ tity, having the classic symptoms of dependence such as trem¬ ors in the morning, and alleged that he usually started to drink in the morning in order to avoid these tremors. An psy- chiatric examination did not show any associated depressive condition. However, he was a very restrained person in social contact, having no friends or any relationship with people of the opposite sex. He was initially treated with an association of carbamazepine and buspirone, without any therapeutic re- suit. The association of moclobemide and buspirone did not bring any benefits either, and so the association of low dosage of neuroleptic with buspirone was tried. He did not stand the effect of chloropromazine, but with the use of a composition comprising trifluorperazine and buspirone provid- ing the dosage of 8 and 40 mg/day, respectively, a significant reduction in the ingestion of alcohol was observed. He then started to drink one or two cans of beer a day, without get¬ ting drunk. In spite of the great recovery from the general "drunk" condition, the daily and uninterrupted use of alcohol, even if in a small quantity, was still not quite acceptable. An increase in the dosage of the said composition up to 12/60 mg/day of trifluoorperazine and buspirone was tried, without obtaining any therapeutic gains, for which reason one returned to the dosage of 8/40 mg/day. Selegiline was then added to the composition firstly at the dosage of 2.5 mg/day of selegiline, which was gradually increased to 5 and 10 mg/day. In the first week with the dosage of 10 mg/day, a clear improvement was already noted, and the patient managed to remain a few days without drinking. 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.

Example 5

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. Her fa¬ ther had been an alcoholic, having died from alcoholic cirrhosis at 45 years old, but the patient had never gone be¬ yond the limit in the use of alcohol, even stating that she did not like to drink. She was initially medicated with the association of carbamazepine and buspirone, in the highest tolerable dosage (500/25 mg/day) without recovery. The doctors used then an association of meclobemide with buspirone, but she could not tolerate dosages higher than 100/30 mg/day. 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. With these three medicines there was a complete control of the psychiatric condition, in spite of the appearance of side effects such as the increase of 10 kg in weight and a serious impairment for the sexual function. In spite of the side effects, the patient opted for maintain¬ ing the medicines due to the significant improvement which they had brought. In the four subsequent months, several at¬ tempts were made to reduce the dosage of these medicines all of them resulting in the return either of anxiety or de- pression. Selegiline was then added to the composition al¬ ready in use at dosage of 5 mg/day and, whereby the dosage of trifluoperazine could be successfully reduced. Increases in selegiline also allowed the patient to tolerate higher amounts of buspirone and successive adjusts in the daily dosage of selegiline and buspirone allowed trifluorperazine and maprotiline to be suspended, the improvement in the psychiat¬ ric condition and in the control of the arterial pressure be¬ ing maintained, with the return to the earlier weight and normalization of the sexual function. She remains entirely health with the adminstration of teh above composition render¬ ing a dosage of 10/45 mg/day of selegiline and buspirone.

Example 6

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. She only started treatment at 26 years of age, having been medicated with adequate dosage of various tricyclic antidepressants, associated with clonazepam, with only partial response. Although 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. Low dosage of serotonine receptation inhibitors (5 mg/day of fluoxetine and 10 mg/day of paroxetine) were then tried, with intolerable side effects. She did not responded to the association of carbamazepine and buspirone; however, an important improvement was noted with the use of composition of moclobemide and buspirone at the dosage of 50/30 mg/day, but she did not stand higher dosage. With this treatment, she managed to return to work, to study and to assume all her household functions. She remained, how¬ ever, still without symptoms, with discrete crises of panic occurring at the frequence of 4 to 5 times a week and signif¬ icantly interfering with the patient's life quality. A compo- sition containing an association of trifluoperazine with buspirone was then tried in a total dosage of 4/20 mg/day and a complete control of the symptoms was achieved. However, an important gain in weight and the disappearance of sexual de¬ sire resulted from this treatment, for which reason the pa- tient opted for returning to the association of meclobemide and buspirone. To this formulation of meclobemide and buspirone, selegiline was then added and a dosage of 5 mg/day of selegiline and 30 mg/day of buspiorne showed an important improvement in the patient's condition. Moreover, even after elimination of moclobemide from the composition, which com¬ pound was no more necessary for achieving the desired effects, the patient was considered perfectly healthy for the first time in 6 years of treatment.

Claims

1- A pharmaceutical composition characterized by comprising at least one partial agonist compound of the 5-TH1A receptors and at least one selective inhibitor compound of monoamino-axidase (MAO) of type B.

2- A composition in accordance with claim 1, charac¬ terized in that the partial agonist compound of the 5-TH1A receptors is buspirone or its pharmaceutically acceptable acid-addition salts. 3- A composition in accordance with claim 1, charac¬ terized in that the selective inhibitor compound of monoamino- oxidase type B is selegiline or its pharmaceutically acceptable acid-addition salts.

4- A composition in accordance with claim 1, charac- terized in that the partial agonist compound of 5-TH1A receptors and said at least one selective inhibitor compound of B-type monoamino-oxidase are present at a ratio of about 24:1 - 1:1 by weight.

5- A composition in accordance with claim 1, charac- terized in that the partial agonist compound of 5-TH1A receptors and said at least one selective inhibitor compound of B-type monoamino-oxidase are present at a ratio of 12:1 - 21 by weight.

6- A method for treating alcohol dependence or abuse, characterized by comprising the administration, to a patient suffering from alcohol dependence or abuse, of a com¬ position in accordance with any one of claims 1 - 5.

7- A method for treating psychiatric disorders ge¬ netically connected to alcoholism, characterized by comprising the administration, to a patient suffering from one or more of these disorders, of a composition in accordance with any one of claims 1 - 5.

8- A method in accordance with claim 7, character¬ ized in that said psychiatric disorders include several anx- iety disorders or depressive disorders.

9- A method in accordance with claim 7, character- ized in that said psychiatric disorders include alimentary disorders.

10- A method in accordance with claim 7, character¬ ized in that said psychiatric disorders include those foreseen in the diagnosis systems DSM-III, DSM-III-R, DSM-IV, CID-IX and CID-X, including the appendices.

11- Use of at least one partial agonist compound of the 5-TH1A receptors in association with at least one selec¬ tive inhibitor compound of monoamino-axidase (MAO) of type B for treating alcohol dependence or abuse.

12- Use of at least one partial agonist compound of the 5-TH1A receptors in association with at least one selec¬ tive inhibitor compound of monoamino-axidase (MAO) of type B for treating psychiatric disorders genetically connected to alcoholism.