FR2750605A1 - Anti-alcoholic and nootropic medicaments - Google Patents

Abstract

Anti-alcoholic and nootropic medicaments for sublingual admin. contain L-threonine (I), opt. in salt form, and vitamin B6 (II). The compsns. are pref. formulated as tablets comprising 100-200 mg (I), 5-10 mg (II), 1-2 mg methylcellulose and 1-2 mg magnesium stearate.

Description

PHARMACEUTICAL COMPOSITION WITH ANTI-ALCOHOLIC EFFECTS AND
nootropics
The present invention relates to the medical field, namely a new pharmaceutical composition with anti-alcoholic and nootropic effects.

 The problem of research and the creation of drugs to treat alcoholism remains current, despite the efforts of many researchers around the world.

 Currently, the reduction in alcohol consumption is relatively easy with drugs that produce alcohol-like effects (eg, tranquilizers, barbiturates, 7-GABA). antihistamines with tranquilizing effect). It is recognized that this mode of therapy can lead to drug addiction that significantly worsens the course of alcoholism and further weakens intellectual activity. The use of various psychotropic and sensitizing drugs to treat alcoholism also does not achieve the desired effect, quite the contrary, they hinder the availability of the subject to the therapeutic measures to be taken.

 In view of this, it is very important to continue the research and development of new anti-alcoholic drugs that have the above-mentioned disadvantages and minimize the pathological passion for alcohol (addiction), and at the same time have a nootropic effect (that is, they improve attention, memory, and intellectual activity).

We know the drugs, such as SAAVETM and the
TropamineTM of MATRIX TECHNOLOGIES, INC. (J. of Psychoactive Drugs, 20 (3), Jul-Sep 1988, p.333).

SAAVETM represents an amino acid composition, such as DL-phenylalalin, L-tryptophan, Lglutamine and 5-pyridoxal phosphate, recommended as a dietary supplement for treating alcohol and drug addiction sufferers (eg , heroin, opiates and others). Since TropamineTM is richer in additives than SAAVETM, including amino acids, such as DL-phenylalamin, Ltyrosine, L-tryptophan, L-glutamine, and 5-pyridoxal phosphate, it also represents , a dietary supplement to treat addicts.

In fact, both drugs are only food additives, that is, they work in addition to other therapeutic drugs, and they include L-tryptophan whose use as a component of drug or food additive, was still banned in 1989 by the FDA (Food and Drug
US Administration). In addition, these drugs do not exert nootropic effect.

 For treating alcohol abusers or alcoholics, mixtures containing amino acids as food additives (International Application WO 89/04165) or in the form of compositions (FR-A-2607391) are employed. ) containing all the substituted or unsubstituted amino acids and, in addition, various chemical compounds (sugars, polymeric carbohydrates, organic acids, phenolic fatty substances, phenolic aldehydes, aspirin, for example). The amino acids contained in these mixtures do not exhibit specific anti-alcoholic activity because they are enteral foods, which are generally used as restorative products or as amino acid sources to maintain the tissue nitrogen balance, when they are administered. to a patient. Of interest are amino acid-containing compositions, such as L-methionine, which is used in combination with vitamin B6 (US-A-4,528,295) and L-alanine (international application WO 95/04529) to to lower the blood acetaldehyde concentration and to treat the alcohol withdrawal syndrome. Nevertheless, the doses of amino acids and vitamin B6 used for these mixtures are 5 to 10 times higher than the daily requirements, which could cause, in a well-known manner, disorders of the protein metabolism and amino acids, as well as acute disorder of vitamin balance and allergic aggravations. For treating certain pathological conditions (US-A-4,405,629; 4,397,866; international application WO 80/02372) amino acids are used as precursors for increasing brain and medial levels of serotonin (Ltryptophan), in adrenaline (L-phenilalanine and Ltyrosine), and glycine (L-threonine). Even in this case, very high doses are used, which results in acute metabolic disorders of biogenic amines and glycine in other metabolic pathways.

 The analysis of the information concerning the use of amino acids for medical purposes shows that they are interesting by their ability to correct the nitrogen balance or their anabolic effect as food products.

 The compositions of certain amino acids have not found a medical application (except SAAVETM, excluding L-tryptophan) because of their nonphysiological doses. The complete absence of such compositions in the nomenclatures of drugs, even in the countries working especially on this subject, proves it.

 The present invention relates to the preparation of a new medical composition having simultaneously an alcoholic and nootropic effect, and which is nontoxic and without side effects.

To achieve this object, the invention provides a composition comprising, as active ingredients, an amino acid, such as L-threonine or a pharmaceutically acceptable salt thereof, and vitamin B6 at therapeutically effective doses. Vitamin B6 represented by a whole group of compounds, such as 2-methyl-3-hydroxypyridine derivatives.

R: CH2OH, CHO, CH2NH2
R ': H, PO (OH) 2
Threonine Vitamins and coenzymatic forms of vitamin B6
The composition according to the invention has a high anti-alcoholic and nootropic efficacy and can be used to prevent or treat alcoholism (to suppress the pathological taste or addiction for alcohol), to reveal the hidden addiction to alcohol and to improve intellectual activity (especially attention).

 This medicine can be administered in the form of a tablet or powder. It is preferably used in the form of a sublingual tablet, a tablet containing 0.1-0.2 g of L-threonine and 0.005-0.10 g of vitamin B6. As additives, this tablet comprises 0.0010, 002 g of methylcellulose and 0.001-0.002 g of magnesium stearate.

 The active ingredients of the drug are obtained by microbiological or chemical synthesis (for Lthreonine) and by chemical synthesis for vitamin B6.

 The active ingredients of the composition according to the invention are constituted by an amino acid, such as L-threonine, and vitamin B6. L-threonine (L-Thr) represents a monoamino-monocarboxylic acid (L-α-amino-p-oxybutyric acid) unsubstituted and constitutive of all albumin, except protamines. It is a substance of crystalline structure soluble in water.

(1) CH3CH (OH) CH (NH2) COOH-L-amino-ss-oxybutyric acid,
L-threonine.

Vitamin B6 is represented by a whole group of compounds, such as the 2-methyl-3-hydroxypyridine derivatives of the general formula: (2)

 Vitamin B6 comes in three natural forms (vitamères) (formula 2): - pyridoxine (pyridoxol), where R = CH20H, R = H; pyridoxal, where R = CHO, R '= H; pyridoxamine, where R = CH 2 NH 2, R '= H.

 They are all soluble in water and in ethanol and poorly soluble in other organic solvents.

 In addition, the group of compounds having the properties of vitamin B6 comprises the phosphoric ethers of vitamers (in formula (2) R '= RO (OH) 2) pyridoxine phosphate, pyridoxal phosphate and pyridoxamine. In the human body, these three compounds are easily transformed into each other. The main coenzymatic form is pyridoxal phosphate, which is the active center of nitrogen metabolism enzymes.

Other objects, advantages and features will appear on reading the description of various examples and embodiments of the invention, given in a non-limiting manner and with reference to the appended drawing in which: FIG. 1 graphically represents the duration in
days that is necessary for the disappearance of
symptoms specific to alcohol withdrawal syndrome,
in a test group and the control group or "of
"- Figure 2: represents on a graphical scale of
1 to 8 on the ordinate the average values of
absolute powers per frequency range
electroencephalogram (EEG) in the group
test and in the control or "control" group,
in stages of testing, the frequency ranges
spreading in abscissae.

The pharmacological effects of the composition according to the invention are studied on groups of patients of different ages, for example:
- out of 12 people aged between 30 and 40, practically in good health;
- 64 adolescents, aged between 16 and 17, in good health, but at various neuropathic and emotional stages and with varying degrees of social adjustment;
- 544 stage II and III patients aged between 18 and 55 (the control group included 113 people treated with neurotropic drugs, antidepressants and tranquilizers).

 The patients take the composition according to the invention in the form of a sublingual tablet, comprising from 0.1 to 0.2 g of L-threonine, from 0.005 to 0.001 g of vitamin B 6, a binder and a lubricant, or in the form of a sublingual powder. containing L-threonine and vitamin B6 in the same proportions.

 In addition to the clinical examination, some patients were subjected to electroencephalographic and psychophysiological examinations.

The results obtained made it possible to conclude that the composition according to the invention produces no side effect but allows:
1) to stimulate, in practically healthy people and in ethyl patients, the cognitive processes, and to improve the attention and the capacity of work and to reduce the phenomenon of fatigue;
2) to provoke reactions in people with a hidden addiction to alcohol;
3) reduce or completely eliminate addiction for alcohol.

 It is found that the use of the composition according to the invention can be recommended without limitation for the personnel of industrial enterprises whose production requires a high speed of psycho-physiological reaction and "switching" of attention. In fact, the treatment with the aid of the composition of the present invention makes it possible to increase from 13-35W the work performance in the ethylic patients at stages II-III.

 The results of the studies on the effect of the composition of the present invention are illustrated by Examples I to IV.

Example I
The volunteers of the group (average age of 37.5 years, 9 men and 3 women, including 8 doctors, 2 pedagogues, a psychologist, a journalist) are subjected to studies in 2 stages 7 days apart. The results obtained are recorded in a special protocol taking into account the evolution of the general state of the patients evaluated every 15 minutes. To ensure objective evaluation, the composition is administered at a rate of 0.20.3g to 0.6-0.7g per dose sublingually. The subjects under examination are observed for 4 to 5 hours.

 The analysis of the results obtained showed that most people treated had a feeling of general relaxation and relaxation, within 10 to 15 minutes after taking this pharmacological composition. Between the 15th and the 25th minute there is the appearance of a state of sedation, of comfort, as well as the desire of contact and exchange of opinions on the dynamics of their state of health. All treated people note a loss of discomfort and shyness. Between the 45th and 75th minute, a feeling of freshness and a willingness to work appear.

 In most cases, the composition of the invention is administered in the afternoon, when the subjects experience drowsiness, an unpleasant heaviness of the head, general fatigue. The examination revealed that within 1.5 to 2 hours after taking the composition according to the invention, these sensations disappeared completely and that the feeling of psychological and physical comfort still persists for 4.5 to 5 hours. In almost all patients, we note the depth of sleep, the feeling of rest and satisfaction on waking.

 In four subjects there is an improvement in appetite within 1.5 hours after taking the composition according to the invention. A similar effect is observed at the end of the second treatment step a week later.

 In three female volunteers, who for several years were subjected to an alcohol withdrawal syndrome of untouched etiology characterized by extreme fatigue, lack of appetite, headaches and sleep disturbances, the composition of the invention was was given to these patients at a rate of 0.2g three times a day for three weeks. In all patients, there was a noticeable improvement in general condition and an increase in work capacity due to the increased concentration of attention.

Example II
The subjects of the second group (64 teenagers aged 16 to 17, including 46 boys and 18 girls) were subjected to an examination concerning the effect produced by the composition according to the invention on their general and emotional state, on their neuro-physiological reactions and their intellectual abilities.

In order to evaluate their psychic, nervous and emotional state, their levels of social adaptation and vital stability, the particular tests of the international complex INTERADOL adolescent examination program were used (J.Komarek et al, 1989). In addition, the surveys and visual surveillance, the dynamic assessment of emotional state using the Loucher test, and the assessment of intellectual ability in dynamics were carried out using the test of doing the same. addition of 184 pairs of numbers (Krepilina table), the immediate memory and attention test (Soulte test), as well as a pulse and blood pressure measurement.

 All adolescents took the composition according to the invention at a rate of 0.2 g by sublingual administration and were examined before and 30 minutes after taking this composition.

 In 25W patients (group I: adolescents abusing alcohol or having alcohol addiction) having taken the composition according to the invention, there are pronounced vascular reactions, such as hyperaemia of the facial epidermis, hands and body; moderate sweating. Most teenagers in this group felt slightly dizzy, mood-enhancing, as if they had "had a drink". The adolescent group was characterized by some astheno-neurotic disorders, chronic depression, and low or medium levels of social adjustment.

 In 34 k adolescents (group II) with high levels of neurosis and emotional instability, there was a significant improvement in mood, the appearance of balance after taking the composition according to the invention.

 32% of adolescents (group III) did not show reactions after taking the composition of the invention and in 9% of cases (group IV), the composition according to the invention caused the depression of the emotional state followed by a feeling of dissatisfaction with oneself.

 Group IV and Group III, in particular, included adolescents with stable emotional status, lack of asthenovascular disorders, and high levels of social adjustment.

The study of the effects produced by the composition of the invention on neurophysiological functions and on intellectual capacity has revealed the fact (Table 1) that this composition has no effect on the immediate storage capacity. However, a significantly positive effect on the Table 1 function has been established.
Immediate memory capacity and its dynamics in adolescents (with different reactions to the composition)

<SEP> groups examined <SEP><SEP> data initial <SEP> 30 <SEP> minutes <SEP> after <SEP><SEP><SEP> taken from <SEP> P
<tb> the <SEP> composition <SEP> claimed
<tb> M * <SEP>#<SEP> m <SEP> M * <SEP>#<SEP> m
<tb> Group <SEP> I
<tb> (16 <SEP> adolescents) <SEP> 49.3 <SEP> 12.799 <SEP> 3.305 <SEP> 37.0 <SEP> 13.375 <SEP> 4.230 <SE> 0.05
<tb> specific <SEP> reactions
<tb> Group <SEP> II
<tb> (22 <SEP> adolescents) <SEP> 44.6 <SEP> 18.465 <SEQ> 4.768 <SEP> 49.3 <SE> 13.87 <SEP> 3.581
<tb> improved mood <SEP>
<tb> Group <SEP> III
<tb> (20 <SEP> adolescents) <SEP> 37.1 <SEP> 12.044 <SEP> 3,219 <SEP> 41.1 <SEP> 18,333 <SEP> 6,111
<tb> without <SEP> changes
<tb> Group <SEP> IV
<tb> (6 <SEP> adolescents) <SEP> 33.3 <SEP> 15.055 <SEP> 6.146 <SEP> 45.0 <SEP> 13.78 <SEP> 5.627
<tb> overwhelming <SEP> mood
<tb> * Immediate memory measured in%;
M - arithmeric average; # - dispersion Table 2
Characteristic of the attention and its dynamics among adolescents (with different reactions to the taking of the composition) (examination of the attention using the Schulte test)

<SEP> Groups Reviewed <SEP> Parameters <SEP> Data <SEP> Initials <SEP> 30 <SEP> Minutes <SEP> After <SEP> The <SEP><SEP> Take of <SEP> P
<tb> studied <SEP> the <SEP> composition
<tb> M * <SEP>#<SEP> m <SEP> M * <SEP>#<SEP> m
<tb> Group <SEP> I <SEP> Time <SEP> total
<tb> Execution <SEP> 421.3 <SEP> 88.64 <SEP> 22.88 <SEP> 302.9 <SEP> 82.97 <SEP> 23.01 <SE> 0.01
<tb> (16 <SEP> teenagers <SEP> Time <SEP> of
<tb> switching <SEP> of <SEP> 142.6 <SEP> 52.94 <SEP> 13.67 <SEP> 83.8 <SEP> 38.17 <SEP> 10.50 <SEP> 0.05
<tb> reactions <SEP> specific <SEP> attention
<tb> Nbr <SEP> of <SEP> errors <SEP> 6.2 <SEP> 5.87 <SEP> 1.51 <SEP> 2.0 <SEP> 3.18 <SE> 0.88 <SEP> 0.05
<tb> Group <SEP> II <SEP> Time <SEP> total
<tb> Execution <SEP> 378.2 <SEP> 79.99 <SEP> 20.65 <SEP> 297.3 <SEP> 53.28 <SEP> 13.75 <SEP> 0.01
<tb> (22 <SEP> adolescents) <SEP> Time <SEP> of
<tb> switching <SEP> of <SEP> 137.1 <SEP> 50.29 <SEP> 12.98 <SEP> 85.9 <SEP> 46.88 <SEP> 12.10 <SEP> 0.01
<tb> attention
<tb> improved <SEP> mood <SEP> Nbr <SEP> of <SEP> errors <SEP> 5.3 <SEP> 3.95 <SEP> 1.02 <SEP> 2.5 <SEP> 3, 06 <SEP> 0.79 <SEP> 0.05
<tb> Group <SEP> III <SEP> Time <SEP> total
<tb> runtime <SEP> 474.0 <SEP> 125.5 <SEP> 32.40 <SEP> 285.4 <SEP> 114.1 <SEP> 30.49 <SE> 0.01
<tb> (20 <SEP> adolescents) <SEP> Time <SEP> of
<tb> Switching SEP> 136.3 SEP 80.0 SEP 22.18 SEP 97.5 SEP 54.2 SEP 15.62 SEP 0.05
<tb> attention
<tb> without <SEP> changes <SEP> Nbr <SEP> of <SEP> errors <SEP> 4.7 <SEP> 3.28 <SEP> 0.84 <SEP> 2.0 <SEP> 1, 91 <SEP> 0.53 <SEP> 0.05
<tb> Group <SEP> IV <SEP> Time <SEP> total
<tb> of execution <SEP> 419.0 <SEP> 70.51 <SEP> 28.78 <SEP> 400.1 <SE> 62.18 <SEP> 25.38
<tb> (6 <SEP> adolescents) <SEP> Time <SEP> of
<tb> switching <SEP> of <SEP> 145.5 <SEP> 43.81 <SEP> 17.88 <SEP> 137.00 <SEP> 42.76 <SEP> 17.46
<tb> attention
<tb> Mood <SEP> overwhelmed <SEP> Nbr <SEP> of <SEP> errors <SEP> 6.6 <SEQ> 2.80 <SEP> 1.14 <SEP> 2.8 <SEP> 1, 32 <SEP> 0.54 <SEP> 0.05
<tb> * Time is measured in seconds; errors made in absolute values
M - arithmetic mean; # - attention dispersion (Table 2). This effect is obviously not dependent on the nature of the reactions of the subjects / adolescents on the taking of the composition according to the invention, for the groups mentioned above (I to IV)
In most adolescents (groups I, II and
III, in particular), the "switching" time of attention was reduced by 1.5 times and more and was followed by a decrease in the number of errors made during the Schulte test. Row correlation between speed and accuracy of execution is best (r = 0.52, where r is the correlation coefficient) for adolescents abusing alcohol (group I) and lowest for adolescents having a degradation of the mood after receiving the composition of the invention (group IV). This composition also causes the calculation speed to be increased during the test consisting in adding 184 pairs of digits (437.1 + 36.4 seconds before setting the composition and 352.8 + 10.4 seconds). after taking, P <0.05 according to the criterion of
Fischer).

 In 40% of the adolescents undergoing examination, there was a slowing of the pulse (in the presence of an initial tachycardia) and a lowering of nominal systolic blood pressure (its initial high values reaching 130 to 150 mm of mercury column ).

Example III
The effect that the composition of the invention produces on the evolution of alcohol withdrawal syndrome (ASA) was studied on 481 subjects. Clinical evaluations of certain symptoms were performed in dynamic mode (in points), electroencephalogram (EEG) results and computation time.

The patients of the (main) studied group took the composition of the invention according to the following protocol:
- the first day: 1 to 3 tablets taken 3 times a day (the unit dose was 0.1 to 0.3 g, and the daily intake of 0.3 to 0.9 g);
- from the second day: 1 to 2 tablets per dose, 3 times a day (the unit dose was 0.1 to 2 g, the daily intake of 0.3 to 0.6 g) for 3 to 4 weeks. The composition studied was administered in the form of tablets or powder, 30 minutes before the meal, sublingually (without water).

We evaluated:
- the evolution of certain symptoms, in points;
- the general state (overall evaluation by a sum of points)
the effectiveness of the composition of the invention on the symptomatology of SSA. The severity of the disease and the general condition of the patients were evaluated using special psychotropic drug efficacy control cards and according to the glossary of "Standardized Psycho-Pathological Symptoms and Syndromes for Uniform Clinical Evaluation of Patients". alcoholism or alcoholic psychoses "(M, 1976). Investigations were conducted prior to medical treatment and at 1, 3, 7, 10, 14, 21 and 28 days from the start of treatment.

For the vast majority of patients there has been a
SSA complex (severe or moderate) with somatic, neurotic and psychopathological disorders.

 The results of the tests revealed the positive effect of the composition of the invention on the vast majority of subjects (Tables 3 and 4).

During the course of treatment, immediately after taking the composition, a slight relaxation was noted, followed by a pleasant intratissive heat, while the subjects felt fresh, full of strength throughout the day. From the 2nd to the 5th day after taking the composition according to the invention, the subjects showed a decrease in feelings of anxiety, emotional tension, irritability, depressive state, feeling of guilt . Sleep and appetite seemed normalized, patients seemed to be able to experience positive emotions and
Integral evaluation of the dy na @ ics of abstinence phenomena in the test and control groups ("Concern, Tremor, Tachycardia, etc." block) (M - arithmetic average in points, # - scatter in points)

Days <SEP> 1 <SEP> 3 <SEP> 7 <SEP> 10 <SEP> 14 <SEP> 21 <SEP> 28
<tb> of <SEP> treatment
<tb> Group <SEP> M <SEP>#<SEP> M <SEP>#<SEP> M <SEP>#<SEP> M <SEP>#<SEP> M <SEP>#<SEP> M <SEP >#<SEP> M <SEP>#
<tb> Primary <SEP> 0.52 <SEP> 0.51 <SEP> 0.47 <SEP> 0.51 <SEP> 0.00 <SEP> 0.00 <SEP> 0.04 <SEP> 0 , <SEP> 0.05 <SEP> 0.23 <SEP> 0.04 <SEP> 0.20 <SEP> 0.04 <SEP> 0.20
<tb><SEP> control <SEP> 0.48 <SEP> 0.51 <SEP> 0.42 <SEP> 0.51 <SEP> 0.47 <SEP> 0.51 <SEP> 0.23 <SEP> 0.43 <SEP> 0.26 <SEP> 0.45 <SEP> 0.19 <SEP> 0.40 <SEP> 0.12 <SEP> 0.33
<tb> Authenticity <SEP> 0.26 <SEP> 0.29 <SEP> 3.92 <SEP> 2.04 <SEP> 1.86 <SEP> 1.71 <SEP> 1.06
<tb><SEP> Differences <SEP> P <0.001 <SEP> P <0.01 <SEP> P <0.01 <SEP> P <0.01 <SEP> P <0.05
<tb> Table 4
Integral evaluation of the condition of patients (Block "Therapeutic orientations, Attitude towards professional activity.

Sociability etc. ") (M - arithmetic mean in points, # - scatter in points)

Days <SEP> 1 <SEP> 3 <SEP> 7 <SEP> 10 <SEP> 14 <SEP> 21 <SEP> 28
<tb> of <SEP> treatment
<tb> Group <SEP> M <SEP>#<SEP> M <SEP>#<SEP> M <SEP>#<SEP> M <SEP>#<SEP> M <SEP>#<SEP> M <SEP >#<SEP> M <SEP>#
<tb> Primary <SEP> 0.04 <SEP> 0.20 <SEP> 0.10 <SEP> 0.30 <SEP> 0.53 <SEP> 0.51 <SEP> 0.54 <SEP> 0 , 51 <SEP> 0.69 <SEQ> 0.48 <SEP> 0.74 <SEP> 0.45 <SEP> 0.79 <SEP> 0.42
<tb> of <SEP> control <SEP> 0.04 <SEP> 0.20 <SEP> 0.05 <SEP> 0.22 <SEP> 0.16 <SEP> 0.37 <SEP> 0.15 <SEP> 0.37 <SEP> 0.16 <SEP> 0.37 <SEP> 0.23 <SEP> 0.43 <SEP> 0.58 <SEP> 0.51
<tb> Authenticity <SEP> 0.00 <SEP> 0.54 <SEP> 2.52 <SEP> 3.16 <SEP> 3.81 <SEP> 4.16 <SEP> 1.37
<tb><SEP> Differences <SEP> P <0.01 <SEP> P <0.01 <SEP> P <0.001 <SEP> P <0.001 <SEP> P <0.05
<tb> understand humor. Stabilization and then mood improvement were followed by an increase in general activity (Figure 1).

 The efficacy of the composition claimed on the symptomatology of SSA is analyzed in Table 5. The results obtained reveal that an effect already appears during the first day of treatment and persists until the 7th to 10th day, the effectiveness being function of the nature of pathological disorders.

 The effect of the drug on the evolution of neurotic and astheno-vegetative disorders is less pronounced.

 Around the 7th day of treatment, there are clear differences between the groups of trials and control (or control) groups in terms of patients' attitudes towards their physical appearance, their professional activity, their family (Table 4). .

During this same period, high activity was observed without motor and volitional impulsivity.

 Scales such as "fitness for criticism" and "therapeutic orientations" are characterized by lower evolutions, however, the variations in values were more visible in the treated group than in the control group. The cure being longer (2-3 months), there was a clear orientation of the patients towards the medical treatment.

The effect of the composition according to the invention on the electrical activity of the brain during the
SSA, the examination being carried out in two stages. The first step consisted of an EEG examination two hours after the single dose of 0.3 g of the composition according to the invention. The second step consisted of dynamic recordings of EEG parameters during medical treatment. After registration of the basic bio-electrical activity, the patient receives the pharmacological composition or a placebo, then the EEG parameters are continuously recorded and analyzed for 20 minutes. Then, further examinations are performed 60, 90, 120 and 240 minutes after administration of the composition.

 During medical treatment, the E.E.G recordings and analysis were performed. basic once a week.

 For the analysis, the parts of the E.E.G are selected. which are free of artifacts and correspond to a duration of one minute 45 seconds.

 Statistical analysis consists of a calculation of the arithmetic means and dispersion rates (o) of the relative powers of the rhythms for five frequency ranges (see Tables 6-8), as well as the total spectral powers of E.E.G. The resulting data are logarithmically transformed by calculating the natural logarithms of the initial data. The purpose of this mathematical operation is to reconcile the initial data with the normal dispersion criteria. The results obtained are shown in Tables 6 to 8 and in Figure 2.

Table 6 shows the average logarithmic values of the relative powers of EE.sub.EG, in frequency ranges, as well as the total spectral powers recorded during the first 20 minutes following the administration of the composition of the present invention and the placebo (the level placebo being zero Table 5
Structure of the SSA according to the composition according to the invention administered

nn <SEP> SSA <SEP> link <SEP> day <SEP> 2nd <SEP> day <SEP> 3rd <SEP> day <SEP> 4th <SEP> day <SEP> 5th <SEP> day <SEP> 6th <SEP> day <SEP> 7th <SEP> day
<tb> 1 <SEP> Passion <SEP> for <SEP> alcohol <SEP> ++ <SEP> ++ <SEP> ++ <SEP> ++ <SEP> ++ <SEP> ++ <SEP > +++
<tb> 2 <SEP> Motor <SEP> Agitation <SEP> ++ <SEP> ++ <SEP> ++ <SEP> ++ <SEP> ++ <SEP> ++ <SEP> ++
<tb> 3 <SEP> Agitation, <SEP> Tension <SEP> ++ <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++ <SEP > +++
<tb> 4 <SEP> Concern, <SEP> Fear <SEP> ++ <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++ <SEP > +++
<tb> 5 <SEP> Depression <SEP> ++ <SEP> ++ <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++
<tb> Obsession <SEP> of <SEP> Suicide
<tb> 6 <SEP> Lability <SEP> affective <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++ <SEP > +++
<tb> Tears
<tb> 7 <SEP> Ideas <SEP> of <SEP> Guilt, <SEP> ++ <SEP> ++ <SEP> ++ <SEP> +++ <SEP> +++ <SEP> +++
<tb> Relations
<tb> 8 <SEP> Exhaustion, <SEP> Asthenia <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++
<tb> 9 <SEP> Indolence, <SEP> Fainting <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++
<tb> 10 <SEP><SEP> Disorders <SEP> Sleep <SEP> ++ <SEP> ++ <SEP> +++ <SEP> ++ <SEP> +++ <SEP> +++
<tb> 11 <SEP> Sleep <SEP> broken <SEP> ++ <SEP> ++ <SEP> ++ <SEP> +++ <SEP> +++ <SEP> +++
<tb> 12 <SEP> Early <SEP> Waves <SEP> ++ <SEP> ++ <SEP> ++ <SEP> +++ <SEP> +++ <SEP> +++
<tb> 13 <SEP> Irritability, <SEP> Dysphoria <SEP> ++ <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++
<tb> 14 <SEP> Weakness, <SEP> Courbature <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++
<tb> 15 <SEP> Sudation, <SEP> Palpitations <SEP> + <SEP> + <SEP> + <SEP> ++ <SEP> ++ <SEP> ++
<tb> 16 <SEP> Arrhythmia <SEP> + <SEP> + <SEP> + <SEP> ++ <SEP> ++ <SEP> ++
<tb> 17 <SEP> Thirst, <SEP> Throat <SEP> dry <SEP> ++ <SEP> ++ <SEP> ++ <SEP> ++ <SEP> ++ <SEP> ++
<tb> 18 <SEP> Damage <SEP> of <SEP> head, <SEP> Vertigo <SEP> ++ <SEP> ++ <SEP> ++ <SEP> ++ <SEP> ++ <SEP> + +
<tb> 19 <SEP> Severe <SEP> tremors <SEP> + <SEP> + <SEP> + <SEP> ++ <SEP> ++
<tb> 20 <SEP> Shortness of breath <SEP> ++ <SEP> ++ <SEP> ++ <SEP> ++
<tb> 21 <SEP> Gastrointestinal <SEP> Disorders <SEP> ++ <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++ <SEP> +++
<tb> Evalutation: 0 - no effect; + - weak effect; ++ - average effect; +++ - strong effect Table 6
Variations in EEG specular parameters due to composition at 20 minutes after administration (placebo level being nil)

Intervals <SEP><SEP> Ranges of <SEP> Frequencies <SEP> Power
<tb> exam <SEP>#<SEP>#<SEP>&alpha;<SEP> ss1 <SEP> ss2 <SEP> total
<tb> 0.5-4.0 <SEP> 4.0-8.0 <SEP> 8.0-13.0 <SEP> 13.0-20.0 <SEP> 20.0-32.0 <SEP> DE <SEP> the GET
<Tb>

(min) <SEP> HD <SEP> HG <SEP> HD <SEP> HG <SEP> HD <SEP> HG <SEP> HD <SEP> HG <SEP> HD <SEP> HG
<tb> 0.0-3.5 <SEP> 0.08 <SEP> -0.31 <SEP> 0.07 <SEP> -0.06 <SEP> 0.04 <SEP> 0.08 <SEP > -0.05 <SEP> 0.02 <SEP> -0.02 <SEP> 0.05 <SEP> 0.10
<tb> 3.5-7.0 <SEP> -0.47 <SEP> ** - 0.62 <SEP> 0.03 <SEP> -0.09 <SEP> 0.11 <SEP> 0, 04 <SEP> 0.02 <SEP> 0.04 <SEP> 0.05 <SEP> 0.07 <SEP> 0
<tb> 7.0-10.5 <SEP> * -0.69 <SEP> *** - 0.70 <SEP> 0 <SEP> -0.11 <SEP> 0.14 <SEP> 0, 03 <SEP> 0 <SEP> 0.03 <SEP> 0.03 <SEP> 0.09 <SEP> 0.11
<tb> 10.5-14.0 <SEP> * -0.59 <SEP> ** - 0.52 <SEP> 0.01 <SEP> -0.10 <SEP> * 0.14 <SEP> 0.12 <SEP> -0.03 <SEP> 0 <SEP> 0.01 <SEP> 0.05 <SEP> ** 0.26
<tb> 14.0-17.0 <SEP> ** - 0.09 <SEP> * -0.52 <SEP> 0.04 <SEP> -0.07 <SEP> * 0.13 <SEP> 0.06 <SEP> -0.07 <SEP> -0.02 <SEP> -0.02 <SEP> 0.06 <SEP> ** 0.29
<tb> 17.0-20.5 <SEP> ** - 0.87 <SEP> -0.43 <SEP> 0.05 <SEP> -0.01 <SEP> * 0.18 <SEP> 0 , 06 <SEP> 0.03 <SEP> 0.01 <SEP> 0.01 <SEP> 0.03 <SEP> ** 0.36
<tb> HD - right hemisphere; HG - left hemisphere;
Authenticity of differences: * P <0.05 ** P <0.01 *** P <0.001 Table 7
Dynamics the spectral parameters of the EEG within two hours after taking the composition according to the invention (the level of placebo being @ul)

<SEP> Ranges of <SEP> Frequencies <SEP> (Hz) <SEP> Power
<tb> Steps <SEP>#<SEP>#<SEP>&alpha;<SEP> ss1 <SEP> ss2 <SEP> total
<tb> examination <SEP> 0.5-4.0 <SEP> 4.0-8.0 <SEP> 8.0-13.0 <SEP> 13.0-20.0 <SEP> 20 , 0-32.0 <SEP> of <SEP> the EEG
<Tb>

(Min)
<tb> HD <SEP> HG <SEP> HD <SEP> HG <SEP> HD <SEP> HG <SEP> HD <SEP> HG <SEP> HD <SEP> HG
<tb> 45 <SEP> *** - 1.23 <SEP> *** - 14.6 <SEP> -0.21 <SEP> -0.19 <SEP> 0.20 <SEP> * 0, <SEP> ** - 0.10 <SEP> *** - 0.15 <SEP> -0.03 <SEP> * -0.10 <SEP> 0.27
<tb> 60 <SEP> ** - 0.77 <SEP> *** - 1.29 <SEP> -0.10 <SEP> * -0.13 <SEP> * 0.13 <SEP> ** 0.18 <SEP> 0 <SEP> -0.01 <SEP> 0.03 <SEP> 0.10 <SEP> 0.10
<tb> 90 <SEP> *** - 0.98 <SEP> *** - 1.32 <SEP> ** - 0.14 <SEP> ** - 0.12 <SEP> 0.01 <SEP > ** 0.14 <SEP> 0 <SEP> 0.02 <SEP> 0.04 <SEP> 0.04 <SEP> 0.02
<tb> 120 <SEP> *** - 1.16 <SEP> *** - 1.43 <SEP> -0.13 <SEP> ** - 0.18 <SEP> 0.07 <SEP> 0 , 11 <SEP> -0.03 <SEP> -0.01 <SEP> 0.04 <SEP> 0.01 <SEP> * 0.11
<tb> Table 8
HD - right hemisphere; HD - left hemisphere;
Authenticity of differences: * P <0.05 ** P <0.01 *** <0.001
Comparative analysis of changes in frequency ranges of EEG in the test group and the control group during treatment (total values of the right hemisphere and the left hemisphere)

<SEP> ranges of <SEP> frequencies <SEP> (Hz) <SEP> Power
<tb> Weeks <SEP>#<SEP>#<SEP>&alpha;<SEP> ss1 <SEP> ss2 <SEP> total
<tb> of <SEP> 0.5-4.0 <SEP> 4.0-8.0 <SEP> 8.0-13.0 <SEP> 13.0-20.0 <SEP> 20.0 -32.0 <SEP> of <SEP> the EEG
<tb> treatment
<tb> E <SEP> C <SEP> E <SEP> C <SEP> E <SEP> C <SEP> E <SEP> C <SEP> E <SEP> C <SEP> E <SEP> C
<tb> 0 <SEP> 2.9 <SEP> 2.7 <SEP> 3.6 <SEP> 3.5 <SEP> 7.4 <SEP> 7.2 <SEP> 6.4 <SEP> 6 , 4 <SEP> 7.5 <SEP> 7.7 <SEP> 2.6 <SEP> 2,3
<tb> 1 <SEP> ** 1.3 <SEP> 2.2 <SEP> * 2.8 <SEP> 3.1 <SEP> ** 9.1 <SEP> 7.9 <SEP> 7, 1 <SEP> 6.5 <SEP> 8.0 <SEP> 7.9 <SEP> ** 3.4 <SEP> 2.1
<tb> 2 <SEP> * 1.1 <SEP> 1.4 <SEP> 1.9 <SEP> 1.7 <SEP> * 9.4 <SEP> 8.6 <SEP> 7.8 <SEP > 7.5 <SEP> 8.2 <SEP> 8.1 <SEP> * 2.9 <SEP> 2.1
<tb> 3 <SEP> 1.4 <SEP> 1.2 <SEP> 1.8 <SEP> 1.8 <SEP> 8.9 <SEP> 9.1 <SEP> 8.1 <SEP> 7 , 8 <SEP> 8.8 <SEP> 8.6 <SEP> 2.9 <SEP> 3.2
<tb> 4 <SEP> 1.3 <SEP> 1.1 <SEP> 1.8 <SEP> 1.8 <SEP> 8.7 <SEP> 9.0 <SEP> 7.9 <SEP> 7 , 8 <SEP> 8.6 <SEP> 8.6 <SEP> 2.9 <SEP> 3.1
<tb> E - test group; C - control group;
Authenticity of differences: * P <0.05 ** P <0.01 noted, however, some decline in the power of the right hemisphere a rhythm.

 Table 8 shows the variation of the log mean values of the relative powers by spectral frequency ranges in the test group and in the control or control group during the 4 weeks of medical treatment. It can be seen that the indisputable differences between these groups, reflected in a permanent decrease in the power of slow rates (6 or 0) and in the increase in activity, followed by the increase of the total power of the EEG, persist during the first two weeks and then fade due to the elevation of these values in the control group.

 The comparative analysis of the variations of the spectral characteristics of the E.E.G. under the effect of the composition according to the invention and placebo, is illustrated in Figure 2 where are indicated the initial values of the absolute power frequency ranges, and their variations within 60 minutes after the single take of 0 3 g of the composition and around the 7th day after the start of the treatment.

 In Figure 2, we see a fast normalization of the spectral parameters of E.E.G. by the action of the composition according to the invention, which seems to be a function of the stimulating effect of said composition on the bioenergetic processes in the cells of the brain. In the group of patients taking the placebo, the variation in the spectral characteristics of E.E.G. is much less visible.

 During the examination, a comparison was made of the pharmaco-electroencephalographic profile of the composition of the invention and the profiles of the psychotropic substances of the main classes. The results obtained make it possible to classify this composition as a psycho-pharmacological substance with effect stimulating the cognitive processes.

 The effect of the composition according to the invention on the calculation time was studied for 7 to 10 days of the treatment on patients suffering from alcoholism.

For this test, 184 pairs of numbers were added, taking into account the speed of execution and the number of errors made.

 The examination showed that, during the frequent administration of the composition of the invention, there is a tendency to increase the speed of execution between the 3rd and the 5th day after the start of the treatment. From the 7th to the 10th day, there was a statistically indisputable increase in computation speed, which is maintained even during long-term administration.

Example IV
The effect of the composition according to the invention on the passion for alcohol has been studied. 180 patients with stage II chronic alcoholism were examined.

The age of patients was between 18 and 65 years, the duration of illness was 3 to 20 years, the duration of dipsomania 2 to 20 days, the intensity of ethylism is evaluated between 4 and 7 points.

 Most patients noted that they could not overcome their dependence on alcohol themselves.

 The clinical examination revealed several variants of alcohol dependence update. Most often (variant I) alcohol dependence was followed by affective disorders, such as mood instability, high irritability, pessimism, unmotivated anxiety, tension, lack of self-confidence, despair, sleep disorders.

In most cases, these phenomena were followed by vegetative disorders, such as sweating, hypertension, thirst, tremors, vasomotor disorders.

 In some patients, there was a second variant (sensory and psychic) of the actualization of addiction for alcohol. Patients in this group were constantly experiencing stomach tightness similar to feeling hungry, excessive salivation, thirst, depression, feeling sore, and overwhelmed mood. . This series of symptoms was followed by a feeling of lack of alcohol.

Pathological addiction was followed by predominant physical discomfort, for the third group (variant
III), and a behavioral disorder, for the fourth group (variant IV).

 In the aforementioned groups, the composition according to the invention was administered sublingually at a rate of 0.1 to 0.3 g per dose for 4 to 5 days without simultaneous administration of psychotropic drugs.

 The analysis of the results obtained revealed that the effectiveness of the composition according to the invention was highest in patients whose pathological addiction structure had predominant affective disorders (variant I) or the combination of sensory factors, such as feeling hungry, and psychic factors, such as the sensation of lack of alcohol (variant II).

 In the first group of patients, the composition according to the invention caused the attenuation of phenomena such as excessive sensitivity, the feeling of anxiety, irritation, tension. The patients noted the normalization of sleep, the appearance of the feeling of self-confidence, the noticeable improvement of the physical state, the normalization, the improvement then the stabilization of the mood; the disappearance of the lack of prospects for medical treatment. After the first medical treatment, the patients were subjected to 3 to 6 repeated treatments lasting 4 to 5 days. During the repetitive treatments, the patients observed the positive effect of the composition according to the invention on the symptoms that appeared. Only in 8% of cases did a "misfire" (a single intake of alcohol) cause the relapse of the disease.

 In the patients of the second group (where the sensory and psychological factors predominate), an improvement of the general state is observed in the 30 to 50 minutes following the taking of the composition of the invention, namely: the diminution of the weakness and of curvature, the disappearance of addiction for alcohol, the appearance of relaxation and general serenity; very often, there is a noticeable improvement, the patients wanting to "eat their fill". The appeased hunger, then appeared a sense of physical and psychological comfort and sometimes deep sleep. Even in this group, it was only for 8% of patients that a failure caused the relapse of the disease.

 A less pronounced effect of the composition according to the invention was noted in patients whose addiction for alcohol was followed by a feeling of physical discomfort (group III). Nevertheless, after taking the composition according to the invention, the improvement of the general state has been observed by evaluating it as the serenity of the soul.

 In cases where the structure of the actual pathological addiction for alcohol involves a predominance of behavioral disorders (group IV), the composition of the invention is inefficient and requires the simultaneous administration of psychotropic drugs.

Example V
The effect of the composition according to the invention on alcohol addiction has been studied by means of a double-blind test. Two researchers independently examined the general condition of the patients. A third-party operator randomly administered the composition of the invention or the placebo. As a placebo, phytin (inositol-hexaphosphoric acid) was chosen, and 3 days later one drug was substituted for the other. At the end of the treatment, the results obtained by the two independent reviewers were compared and the prescribed treatment protocols were revealed.

 The average age of patients in this group is 34 + 1.8 years (from 26 to 43 years), the average duration of the disease is 7.7 + 1.7 years (from 3 to 20 years), the duration of dipsomania is 5.6 + 2.2 days (from 2 to 14 days), the intensity of addiction for alcohol was evaluated at 5.8 + 0.28 points (from 4 to 7 points ).

 Most of the patients observed that after the appearance of the sensation of lack of alcohol, the fight to abstain from the alcohol lasted several hours, and even at two patients several days. All the patients indicated that they could not overcome the lack of alcohol themselves. At the time of the examination, in 70% of the cases the addiction for alcohol is followed by affective disorders. We complain about irritability, dark and melancholic mood, emotional tension, a feeling of worthlessness. All the patients believed that their poor general condition was due to the impossibility of consuming alcohol. In 20% of cases, patients noted that the feeling of lack of alcohol appeared when they were hungry.

 Patients who received the placebo as initial drug did not observe any effects during the first 2 to 3 days. Around the 3rd day, addiction for alcohol disappeared in all patients. The patients did not notice the replacement of the composition of the invention by the placebo.

 When the composition according to the invention is administered as an initial medicine, some patients (30W) noted the disappearance of addiction for alcohol immediately after the first intake, in others (70%) this addiction disappeared towards the 2nd -3rd day.

 The divergence of assessments of the general condition of patients (including the reality of addiction for alcohol) performed by two independent reviewers was insignificant. Only in 10% of cases were physicians unable to distinguish the nature of the drug administered: the composition of the invention or the placebo.

 Clinicians have come to the conclusion that the double-blind test has confirmed the high efficacy of the composition of the invention as an addictive drug for alcohol.

Example VI
The results of clinical examinations, psychophysiological and electro-physiological tests have revealed that the composition of the invention has, in addition to the anti-alcoholic effects, a nootropic effect, that is to say, it improves the attention and the speed of calculation. It is these properties that have led to recommending the composition of the invention for treating ethyl patients whose professional activities require high attention and the speed of psychotropic reactions. To prove this thesis, the effect of the composition according to the invention on patients aged 25 to 60 who are alcoholic in stages II and III (the duration of the disease being from 10 to 30 years) was studied. practicing an activity in an industrial enterprise. Fifty patients were treated in a day hospital organized in a mechanics company. Patients' clinical condition, work performance, level of fatigue and trauma were considered. As a control, patients (28 patients) treated in hospitals were tested. Patients in both groups worked in a small-part stamping shop, which required high attention and some ability to change jobs.

 The examination revealed a decrease in accidents (such as finger injuries) after taking the composition of the invention, as well as a subjective feeling of attenuation of fatigue at the end of the working day. After administration of the composition of the invention, an increase in yield of 15 to 35% was observed.

 The examination has shown that the administration, for a short time, of the composition according to the invention makes it possible to improve the attention, the intellectual activity, as well as the speed of the neurophysiological reactions; the administration is recommended to the ethyl patients, but also to the healthy persons whose professional activities require fast psychomotor reactions.

 The results of the tests have shown that the long-term administration of the composition of the invention does not cause in patients any dependence, allergic reactions or other pathological aggravations.

The composition of the invention having anti-alcoholic and nootropic effects may apply: 1) for the therapy of adults or children, in order to
deal:
- the decline in intellectual activity followed by
attention disorders;
- encephalopathies of various etiologies; and 2) addiction:
- to prevent relapses of alcoholism;
- to reduce and eliminate addiction for alcohol;
- to treat alcohol deficiency syndrome.

 Of course, the present invention is not limited to the examples and embodiments described and shown, but it is capable of many variants accessible to those skilled in the art without one deviates from the spirit of the invention.

Claims (11)

 1. A pharmaceutical composition having an alcoholic and nootropic action, for sublingual administration, characterized in that it comprises, as active ingredients, an amino acid, such as L-threonine or one of its pharmaceutically acceptable salts, and vitamin B6, at therapeutically effective doses.  2. Pharmaceutical composition according to claim 1, characterized in that it comprises an amino acid, such as L-threonine, or one of its pharmaceutically acceptable salts, and vitamin B6, according to a respective mass ratio ( 10-20) :( 0.5-1).  3.- pharmaceutical composition according to claim 1, characterized in that it comprises an amino acid, such as L-threonine or a pharmaceutically acceptable salt thereof, and vitamin B6, in a mass ratio of 20: 1.  4. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that it is in the form of a powder.  5.- pharmaceutical composition according to any one of claims 1 to 3, characterized in that it is in the form of a tablet.  6. Pharmaceutical composition according to any one of claims 1 to 3 or 5 in the form of a tablet, characterized in that it further comprises methylcellulose and magnesium stearate, as specific additives.  7.- pharmaceutical composition according to claim 6, characterized in that the dosage of its active ingredients is as follows, per tablet:  L-threonine or its salt pharmaceu--0,1-0,2g  acceptable  vitamin B6 -0.005-0.010g  methylcellulose -0.001-0.002g  magnesium stearate -0.001-0.002g  8.- A pharmaceutical composition for reducing and / or for suppressing the pathological passion or addiction for alcohol and for treating alcohol deficiency syndrome, according to any one of claims 1 to 7, characterized in that it is under a form suitable for sublingual administration.  9. The composition of claim 8, characterized in that said composition is intended to be administered in a dosage of 1.5 to 4 mg / kg body weight of the patient.  10. A composition for improving attention, according to any one of claims 1 to 7, characterized in that it is in a form suitable for sublingual administration.  11. The composition of claim 10, characterized in that it is intended to be administered in a dosage of 1.5 to 4 mg / kg body weight of the patient.