WO1995028934A2

WO1995028934A2 - Use of mao-a inhibitors for the manufacture of a medicament in the treatment of tobacco withdrawal symptoms in smokers

Info

Publication number: WO1995028934A2
Application number: PCT/EP1995/001492
Authority: WO
Inventors: Roman Amrein; Ivan Berlin; Alain Puech
Original assignee: F. Hoffmann-La Roche Ag; Assistance Publique-Hopitaux De Paris
Priority date: 1994-04-22
Filing date: 1995-04-20
Publication date: 1995-11-02
Also published as: WO1995028934A3; AU2446895A

Abstract

The invention is concerned with the use of monoamine oxidase-A inhibitors for the manufacture of medicaments for the control of the consumption of tobacco products and, respectively, of withdrawal symptoms in smokers.

Description

USE OF MAO-A INHIBITORS FOR THE MANUFACTURE OF A MEDICAMENT IN THE TREAT^¬ MENT OF TOBACCO WITHDRAWAL SYMPTOMS IN SMOKERS

The present invention is concerned with a method for the control of the consumption of tobacco products and, respectively, of withdrawal symptoms which occur among smokers, especially when they make efforts to reduce smoking or to give it up completely.

The widest variety of proposals have been made to assist smokers in giving up or reducing the consumption of tobacco products. One of these proposals, which has found use in practice, comprises supplying nicotine to the body in an alternative manner, e.g. transdermally. This method has obvious shortcomings which follow from the very fact that a toxic active substance is used. It has also been proposed to use monoamine oxidase-B (MAO-B) inhibitors for the treatment of addictions after the consumption of intoxicants, especially alcohol, and of tobacco products.

Monoamine oxidase (MAO) inhibitors are used for the treat¬ ment of Parkinson's disease and of depressions. Certain MAO inhibitors inhibit predominantly or selectively monoamine oxidase A or monoamine oxidase B. Compounds which predomin¬ antly or selectively inhibit monoamine oxidase B (and thus the degradation of dopamine) are used for the treatment of symptoms of parkinsonism. MAO-A inhibitors inhibit predominantly the degradation of serotonin and noradrenalin and, in the case of human beings, also of of dopamine, but to a small extent. They are used in depressive states, but not in the case of Parkinson's disease. A clear difference between the two types of MAO inhibitors therefore exists with respect to activity (and thus with respect to use).

It was therefore surprising that addiction and withdrawal symptoms caused by the consumption of tobacco products can be reduced or eliminated by the administration of MAO-A inhibitors. Typically, this takes place, as has been found, not by diminishing the patients desire ("craving") in the initial withdrawal phase (this would be a dopaminergic effect, as can be brought about by MAO-B inhibitors), but by enabling the patients to resist this desire better and to take on a certain composure with respect to their addictive state.

The invention is accordingly concerned with the use of MAO-A inhibitors for the treatment and prevention of withdrawal symptoms caused by the consumption of tobacco products and the use of MAO-A inhibitors as active substances for the manufacture of medicaments for the said purpose.

Examples of MAO-A inhibitors which can be used in accord- ance with the invention are the benzamides described in US Patent 4 210 754, especially p-chloro-N-(2-morpholinoethyl)- benzamide (moclobemide), as well as compounds such as toloxatone and befloxatone.

For the purpose in accordance with the invention the MAO-A inhibitors can be used in conventional commercial formulations, preferably in oral administration forms, e.g. as tablets, dragέes or capsules.

The active substances can be processed with pharmaceut¬ ically inert, inorganic or organic excipients for the manufacture of tablets, coated tablets, dragέes and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used e.g. as such excipients for tablets, dragέes and hard gelatine capsules. Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols etc. Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc. Moreover, the pharmaceutical preparations can also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents or anti- oxidants. They can also contain still other therapeutically valuable substances.

In general, the active substances are administered in doses which come into consideration or which are recommended for their known pharmaceutical use. In the use of moclobemide in accordance with the invention the convenient dose is about 100- 600 mg, preferably 300-450 mg, per day for an adult. Conveniently, the treatment with the MAO-A inhibitor commences before breaking the habit (withdrawal of the tobacco product), e.g. 1 -2 weeks previously, and is continued for at least about 6 weeks.

In one study moclobemide was administered to 80 trialists in a dose of 2 x 200 mg per day for 9 weeks and subsequently 1 x 200 mg for 4 weeks. The treatment was commenced 1 week before the withdrawal. The effect (complete nicotine abstention) was observed during this period and subsequently during 9 months under spontaneous conditions. The subjective assertions of the patients and the - stronger than assertive - serum level of cotinin, a main metabolite of nicotine wi$h a substantially longer half-life than nicotine, were taken as parameters for the effect of the treatment. The thus-obtained results of the study are presented hereinafter:

% Abstinent trialists

After According to subjective According to objective assertions criteria*

Moclobemide Placebo Moclobemide Placebo

3 months 45% 25% 39% 23%

6 months 39% 18% 32% 16%

9 months 27% 16% 25% 14%

* Determination of the blood cotinin level These results show a clear difference between the treat¬ ment group and the placebo group, with no essential difference occurring between the data for the trialists and the objective analytical findings.

Claims

1. The use of monoamine oxidase-A inhibitors for the manufacture of medicaments for the control of the consumption of tobacco products and, respectively, of withdrawal symptoms in smokers.

2. The use of moclobemide according to claim 1.

3. The use of moclobemide according to claim 1 with instructions for a dose of 100-600 mg per day.

4. The use of moclobemide according to claim 1 with instructions to commence treatment about 2 weeks before the withdrawal.

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