RU2152787C2 - Drug against stress, activity level decrease and ageing and method of its preparing - Google Patents

Abstract

FIELD: medicine, pharmacy. SUBSTANCE: invention proposes the drug that is the composition showing synergistic, biological, neurometabolic and providing cellular trophism and also etiopathogenic and homeostatic effects. Composition is developed on the basis of combination the following active components: (a) with respect to oxidative and catabolic stress: methionine with aminoethanolphenoxy acetates and/or aminoethylphenoxy acetamides; (b) with respect to anabolic stress: hydrooxopyrimidine carboxylates and/or oxopyrrolidine acetamides with potassium, zinc or lithium; (c) vasodilating and lipidemia normalizing preparations: nicotinic alcohol and/or acid or their derivatives with magnesium and iodine; (d) energy activating and (e) antitoxic compounds: aspartate, fructose, vitamin B₁, vitamin B₆, hydroorthophosphate and sulfate. Method of preparing the drug involves the following stages: (a) pharmaceutical preparing two complementary types of capsules or tablets with cover that are soluble in stomach and intestine being the latter have enterosoluble envelope; (b) prolonged release of vasodilating preparation from intestine-soluble standard dose. Invention provides emotional-affective stabilization and maintenance of human mental functions under stress conditions. EFFECT: improved method of preparing, enhanced effectiveness of drug. 7 tbl, 3 ex

Description

 The invention relates to an orally administered drug having etiopathogenic activities against stress, decreased activity and aging and enhanced therapeutic efficacy resulting from its synergistic biological, neurometabolic and cell trophic composition. The invention also relates to a method for producing this medication. This medicine supports and enhances adaptive ability and neuropsychic and biological resistance, at the same time protects the brain, liver and heart from stress, and corrects the main ultrastructural and metabolic imbalances resulting from acute and chronic stress, prolonged biological “life woes” (wear), oxidative stress, ischemia-hypoxia, chronic alcoholism and premature aging and, thus, is intended for the treatment of stress-related patholo gii. The non-standard pharmaceutical method of its manufacture, in addition, provides control over its release and adsorption of active substances and prolongs the cerebral vasodilating effect, which together provides maximum biological value and therapeutic efficacy.

 Acute and chronic stress, which is a negative and constant feature of modern life, includes the development of three processes: firstly, aggression against the body of stress factors in ever-increasing sizes, diversity and constancy; secondly, the reaction of the body, which may be adaptive, insufficiently adaptive or pathologically dependent on stress; and, thirdly, intense, accelerating and constant accumulation of wear and tear in the brain and in the body as a result of "life troubles", premature aging.

 The adaptive response of the body (general adaptation syndrome) includes three successive stages: direct adaptation, long-term adaptation and the stage of depletion - a neuropsychic and biological decrease in the level of activity (Selye N., The evolution of the stress concept, American Scientist, 61, 692-699, 1973 ) Chronic wear means a progressive violation of neuropsychic and biological functions (incapacity), which leads to a decrease in the ability to adapt and to a decrease in the viability and stability of the body, and this is a consequence of the accumulation of stressful situations and stress-induced damage over time. When due to an increase in the intensity, frequency and constancy of stress and a decrease in the level of activity, the body's adaptability is exhausted, diseases associated with insufficient adaptation appear, which means the emergence of stress-related pathologies: neuropsychiatric and psychosomatic diseases (Wilder JF, Plutchik R., Stress and psychiatry (part 25.11), pp. 1198-1203, Kaplan HI, Sadock BJ (ed.), Comprehensive Textbook of Psychiatry / IV, Volume I, Williams and Wilkins, Baltimore, 1985).

 The human brain, due to its triple function — neurobiological, mental, and social — and due to the loss after birth of the ability to regenerate neurons through cell division, is a global “receiver” of stresses (ischemic, due to hypoxia, oxidative, etc.) and a “storage” of chronic progressive, neuropsychic and biological decrease in activity level. Thus, in the central nervous system specific ultrastructural and biochemical imbalances and injuries are accumulated that affect all levels of metabolism (energy, anabolism, catabolism), they accumulate with age and cause a violation of the normal functions of the brain and body. Decreased blood flow through the brain as a result of stress and aging (progressive chronic hypoxia) and neural hypoanabolism (impaired and reduced synthesis of nucleic acids and proteins, decreased and impaired Nissl bodies, accumulations of granular endoplasmic reticulum and free ribosomes, and the Golgi apparatus) lead to a decrease in plasticity and anabolic regeneration of both functional (enzymes and neurotransmitters) and ultrastructural (neurosomes and outgrowths of neurons) (Terry RD, Gershon S. (ed.), Aging, Volume 3, (Neurobiology of Aging), Raven Press, New York, 1976). Oxidative stress, neural hypercatabolism, peroxidation of lipids, in particular membranes, and premature chronic decrease in the activity level of subcellular organelles, mainly mitochondria, in all cases ultimately lead to progressive accumulation of lipofuscin pigments (pigments, wear, aging pigments, tertiary liposomes, subcellular waste resulting from peroxidation, polymerization and cross-linking of free radicals) in neurons and glial cells (Riga D. , Riga S., Popescu A., Constantinescu E., Perieteanu M., Subcellular genesis of nerve lipofuscian pigments, 4th European Anatomical Congress, Basle, Switzerland, 1977, Acta Anatomica, 99, 307-308, 1977, ZS. - NAGY, I. (ed.), Lipofuscin-1987: State of the Art, Academiai Kiado, Budapest, 1988).

The need to develop a specific drug with etiopathogenic activity against stress, a decrease in the level of activity and premature aging is due to the pronounced negative effects of stress:
a) on an individual level - by professional unsuitability, illness, premature aging and death, and
b) at the social level - important economic and social direct and indirect losses (Cooper C., Arbose J., Executive stress goes global, International Management, 39, 42-48, 1984).

 As follows from the prior art, efforts aimed at obtaining drugs effective to control and treat stress and reduce the level of activity have not yet been successful in obtaining a specific drug with an etiopathogenic effect; so far only symptomatic tasks have been solved or stimulating effects achieved.

So, for example, to improve the symptomatology caused by stress, impaired visual adaptation, reduce the ability to respond to stress and stress-related disorders (anxiety, depression, asthenia, insomnia, nervous, neurovegetative and psychosomatic disorders), it is known to use psychotrophic drugs (Podinger W., Schmidlin P.E., Wider F., Index Psychopharmacorum, H., Huber, Bern, 1983). Depending on the prevailing symptomatology, the use of the following drugs is known:
a) anxiolytics (small tranquilizers): diazepam, meprobromate, methylpentinol, etifoxin;
b) antipsychotics (main tranquilizers): chlorpromazine, promethazine, azaperone;
c) beta-adrenergic receptor blockers: bunitrolol;
d) antidepressants: tricyclic, tetracyclic compounds, individually or together with antipsychotics;
e) psychostimulating agents: caffeine, amphetamine or their derivatives;
e) sedatives and hypnotics: combined in the formula of phenobarbital and codeine (Romanian patents NN 60376 and 64161).

 The disadvantage of these psychotrophic drugs is that they serve only for the main symptomatic treatment, but do not have an etiopathogenic effect against stress; they do not reduce the chronic decrease in the level of activity caused by stress, do not affect stress through anabolic regeneration, they alter the normal (anti-stress) adaptation reactions of the body and have numerous harmful effects. In addition, anxiolytics and psychostimulating drugs (such as amphetamine and caffeine) often lead to the need to increase dosages due to the phenomenon of acquired tolerance and cause a significant harmful reaction, namely dependence on psychoactive compounds (Lader M., Benzodiazepines - the opium of the masses ?, p. 605-615, in Smith AD, Llinas R., Kostyuk PO (eds.); Commentaries in Neurosciences, Pergamon Press, Oxford, 1980; WHO Europe, Prevention of Mental, Psychosocial and Neurological Disorders in the European Region, 38th Session, Copenhagen, September 12-17, 1988).

 Many anti-stress medicinal compositions are also known for use in stimulating, activating, stimulating, trophic, tonic, strengthening - neuropsychic and / or biological - purposes. They are used to treat disorders caused by acute and chronic stress caused by pathological stress and, in particular, to treat their most common consequences: nervous, mental and biological depletion, accelerated chronic decrease in activity level, premature aging.

 a) Some of these compositions contain multivitamins: water-soluble (American Medical Assocition, AMA Drug Evaluations, Publishing Sciences Group, Action, Mass., 1973), water-soluble together with fat-soluble (US patent N 3493659) or provitamins along with bioelements (French patent N 7404 M).

 b) Other mixtures include amino acids with or without vitamins (acetyl aspartic acid, arginine glutamate, citrulline with folic acid), either aspartate-based (Romanian patents NN 55069 and 77472; French patent N 2521429), or glutamates (Romanian patent N 76141), or on cysteine (Romanian patent N 74505), arginine (French patent N 2494113), or on complex formulations, which usually include glycine, lysine, tyrosine, ornithine, histidine (French patent N 5937 M; Romanian patent N 76044).

 c) Other compositions contain stimulants and their combinations: amphetamine, amphetamine with caffeine or caffeine with vitamins (Romanian patents NN 62137 and 66014).

 The disadvantage of these products, even when they are complex medicinal compositions, is the inability to carry out etiopathogenic anti-stress therapy by simultaneously combining a number of different actions (vasodilator, normolipidemic, energy-activating, antitoxic, regulating catabolism of action, including lipofuscinolysis and anabolic regeneration); they have not undergone preclinical studies in relation to counteracting experimental stress induced in animals, they cannot prevent or slow down the wear of the nervous system by counteracting oxidative stress, and they do not support natural adaptation mechanisms - anti-stress mechanisms.

 In addition, first of all, drugs, including methylxanthines and / or amphetamines, are unfavorable because they provide incomplete, limited drug treatment with a short duration of action, which, in the case of chronic or high-dose use, causes new imbalances, which reinforce the existing ones. to reduce neuropsychological and biological resistance to stress, the intensification of cell catabolism and to reduce adaptive responses to stress; Moreover, their use causes numerous harmful reactions (Syed IE, The effects of caffeine, Journal of the American Pharmaceutical Association, NS 16, 568-572, 1976; Iversen LL, Iversen SD, Snyder SH (ed.), Handbook of Psychopharmacology Volume 11 (Stimulats), Plenum Press, New York, 1978).

 The use of methionine in hepatic pathology as a liver protecting compound is well known (Wade A., Reynolds J.E. F. (eds.), The Extra Pharmacopoeia, The Pharmaceutical Press, London, 1978). Successful studies of the authors of the present invention revealed that methionine additionally has specific neurotrophic activity and has an etiopathogenic effect against stress. In this regard, the authors using quantitative histochemical methods showed an antagonistic effect against chronic oxidative stress, determined by the reduction of lipofuscin pigments in the brain (in the final brain and in the intermediate brain) of old rats (Riga S., Pambuccian G., Oeriu S., Changes in lipofuscin pigments of rat central nervous system under-SH groups 'releasing substances' influence, 9th International Congress of Gerontology, Volume 3 (Section Session, Abstracts), thesis N 1103, p. 383, Kiev, USSR, 1972) . Further, the authors revealed its complex effect on stress, decreased activity and aging (catabolic regulation - antilipofuscinogenesis, lipofuscinolysis and anabolic regeneration - increased RNA synthesis) at the level of the nervous system of old rats using a complex methodology: selective isolation of living nerve cells from the brain, morphometric and biochemical methods (Riga S., Studies on Nucleic Acids in Central Nervous System in Senescence Processes, Ph. D. Thesis, Institute of Medicine and Pharmacy, Bucharest, 1976, in Roman language).

 It is also known that meclofenoxate due to its actions on the energy and metabolic regulation of nerve cells has a wide field of clinical application in psychiatry, neurology, as well as in the treatment of pathology determined by hypoxia during stressful intervention in the brain, in geriatrics, neurosurgery, anesthesiology, intensive care ( Coirault R., Deligne P., Rouif J., Une orientation therapeutique nouvelle. L'ANP 235 (ester dimethyl-amino-ethylique de l'acide para-chloro-phenoxy-acetique), Agressologie, 1, 113-138, 1960 (in French)). Further, using light microscopy and histochemistry (only as a qualitative method), the ability of meclofenoxate to reduce the content of lipofuscin pigments in the nervous system of old guinea pigs (Nandy K., Bourne GH, Effect of centrophenoxine on lipofuscin pigments in the neurons of senile guinea pigs) was revealed. Nature (Lond.), 210, 313-314, 1966); this was also confirmed using electron microscopy (Hasan M., Glees P., EI-Ghazzawi, E., Age-associated chages in the hypothalamus of guinea pig: effect of dimethylaminoethyl p-chlorophenoxyacetate. An electron microscopic and histochemical study. Experimental Gerontology, 9, 153-159, 1974). According to authors who have priority research in the field of preclinical methodology (quantitative - morphometry and qualitative - type of distribution, autofluorescence, histochemistry), and using their experimental scheme based on a three-variant study (statistical comparison of three groups - control young, control old and processed old) the ability of meclofenoxate to specifically and significantly reduce the content of lipofuscin pigments in the brain of old rats was established; based on this, the authors of the present invention introduced into the scientific literature of this technical field the concept of lipofuscinolysis (Riga S., Riga D., Effect of centrophenoxine on the lipofuscin pigments in the nervous system of old rats, Brain Research, 72, 265-275), also confirmed by electron microscopy (Riga D., Riga S., Selective lipofuszinolytische Effekte von Centrophenoxin am Nervensystem alter Ratten, pp. 22-27, Kugler J. (ed.), Hirnstoffwechsel und Hirndurchblutung, Schnetztor Verlag, Konstanz, Schweiz, 1977). Later, this concept was also used by other researchers. As a result of its lipofuscinolytic action, a proven antagonistic effect on oxidative stress, meclofenoxate has an etiopathogenic activity against brain stress, decreased activity and aging (Riga S., Riga D., Dynamics of lipofuscin pigments, directing factor of brain aging, 6th Congress Medical International de la Federation Internationale des Resistants (FIR), Prague, Czechoslovakia, November 30-December 2, 1976, Resumes, p. 70, 1976) and regarding the retardation of rat aging (ZS.-Nagy, I., An attempt to answer the questions of theoretical gerontology on the basis of the membrane hypothesis of aging, Advances in the Biosciences, 64, 393-413, 1987).

 The use of the two above compounds with separate administration or without enhancing the anti-stress effect using a neurometabolic composition with an etiopathogenic effect has no advantages, since they only provide incomplete protection of the brain from stress, decreased activity and aging, because their effects on functional and metabolic regulation, as well as on subcellular regeneration, are only partial.

A medicine having an etiopathogenic anti-stress effect, an anti-activity and aging reduction effect in accordance with the invention is made in the form of a synergistic biological, neurometabolic and trophic cell composition developed in accordance with a specific anti-stress therapeutic concept by interconnecting and synergizing the following active ingredients:
a) compounds active against oxidative and catabolic stresses (antilipofuscinogenic, lipofuscinolytic and designed to remove lipofuscin): methionine plus aminoethanolphenoxyacetates and / or aminoethylphenoxyacetamides;
b) anti-anabolic stress components (for functional and ultrastructural anabolic regeneration): hydroxypyrimidine carboxylates and / or oxopyrrolidine acetamides with potassium, zinc and lithium;
c) vasodilators (directed against stress caused by hypoxia and ischemia) and lipid-normalizing compounds: nicotinic alcohol and / or nicotinic acid or their derivatives with magnesium and iodine;
d) energy-activating and
e) antitoxic components: aspartate, fructose, vitamin B ₁ , vitamin B ₆ , hydroorthophosphate and sulfate.

A method for producing a medicament in accordance with the present invention for oral administration of maximum biological value and therapeutic efficacy includes:
a) for controlled delivery to the place of release and absorption of the active compounds from the drug, the preparation of the pharmaceutical composition in the form of two complementary types of capsules or film-coated tablets (soluble in the stomach and intestinal-soluble unit doses), the latter are enteric-coated tablets, and
b) to achieve a prolonged anti-ischemic and anti-hypoxic effect of nicotine alcohol or acid or their derivatives, the preparation of the composition in the form of an enteric-soluble capsule or film-coated tablet, which slows down the action in comparison with the form in the form of a granule or tablet.

The medicine in accordance with the invention has the following advantages:
- it represents a new medicine and a new pharmacotherapeutic strategy in the field of health promotion and prevention, regulation and treatment of stress, biological wear and tear, premature aging caused by stress diseases;
- it was developed and tested in accordance with the concept of a biological drug, it is a synergistic biological, neurometabolic and trophic cells (cerebral, hepatic, myocardial and nonspecific) composition, it has wide therapeutic efficacy, is free from toxicity and harmful effects, to he does not develop tolerance and dependence;
- it was created and tested within the framework of a specific therapeutic concept, namely, etiopathogenic and homeostatic, directed against stress, decreased activity and aging, thereby guaranteeing increased therapeutic effectiveness based on its active components (compounds with activity against oxidative and catabolic stress , anabolic stress, vasodilators, active against stress caused by hypoxia and ischemia, and normalizing lipidemia, antiviral and antitoxic compounds), is intended for the treatment of pathology caused by free radicals, hypercatabolic and hypoanabolic conditions, hypoxic-ischemic pathology, dyslipidemia, energy depletion and pathology due to toxic deficiency;
- the biological composition based on it and its specific anti-stress effect determines a wide range of preventive, therapeutic and restorative applications for all age categories (children, young people, adults and the elderly) for both healthy and sick people;
- it is recommended for healthy people, especially during activities with high voltage and efficiency, as it counteracts the anti-homeostatic effect of stress and lowering the level of activity (at the neuropsychic and biological levels) and increases working capacity in stressful situations by increasing resistance to mental (intellectual ) and physical (biological) action;
- it is recommended for patients with pathology caused by stress, psychosomatic, psychiatric and neurological pathology, for geriatric medicine and therapy.

 The administration of the medicament of the present invention can make an effective contribution to maintaining and improving mental and biological health, significantly reducing the economic and social losses caused by stress throughout the society, reducing the level of biological activity, premature aging and stress related pathology.

The pharmaceutical preparation technique of the medicament of the present invention provides the following advantages:
- in the case of oral administration, it provides maximum biological value and therapeutic efficacy;
- it guarantees the controlled regulation of the release and absorption of active compounds from the drug by preparing the pharmaceutical composition in the form of two complementary types of pharmaceutical unit doses (capsules or film-coated tablets): soluble in the stomach and soluble in the intestine;
- for a form with an enteric coating, the technological process of its manufacture is completely non-toxic and does not have a harmful effect on the environment, namely, spraying with an aqueous dispersion of a stomach resistant to the action of the polymer and intestinal soluble polymer;
- it guarantees a prolonged or long-term anti-ischemic and antihypoxic effect due to the release of a vasodilating component from the intestinally soluble standard dose with a time-controlled release;
- various coloring of two complementary forms, soluble in the stomach and intestines, and packaging the medicine in the form of a calendar in a transparent film under normal conditions with silica gel protection or using vacuum packaging technology guarantees the correctness, simplicity, differentiation and visualization (daily, weekly, monthly) of treatment and suitable drug stability;
- due to the flexibility of dosing, it makes it possible to differentiate treatment against stress and against a decrease in the level of activity depending on individual characteristics and neuropsychic reactivity, as well as obtaining actions mainly at the level of the brain in relation to oxidative and catabolic stress or anabolic stress;
- it makes it possible to administer the medicine in accordance with chronotherapy at predetermined intervals (chronological dosing).

Preferred Embodiment
The following are six examples of pharmaceutical preparation of a medicament according to the invention. To achieve controlled delivery to the site of release and absorption of the active substances, the authors developed a selective drug composition consisting of two complementary standard doses soluble in the stomach and intestines. Two complementary unit doses are made either in the form of capsules or in the form of film-coated tablets and are colored differently for identification by oral administration. In each of the examples below, the necessary amounts of active ingredients and adjuvants are used to obtain 100 capsules or tablets with a film coating.

 These examples serve only to illustrate the invention and do not limit its scope.

 Example 1

A) The composition for 100 gastric-soluble unit doses includes the following ingredients, g:
DL-methionine - 13.50
Meclofenoxate hydrochloride (hydrochloride (2- (dimethylamino) ethyl (para-chlorophenoxy) acetate) - 24.00
Zinc Sulfate, Anhydrous - 0.90
Nicotinic acid with a quick exit - 0.90
DL-aspartic acid magnesium salt, anhydrous - 8.00
D (-) - fructose - 0.90
Vitamin B ₁ hydrochloride - 0.70
Vitamin B ₆ hydrochloride - 1.00
B) The composition for 100 intestinally soluble unit doses includes the following ingredients, g:
Orotic acid, anhydrous (1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinecarboxylic acid) - 29.00
Potassium hydroorthophosphate, anhydrous - 8.80
Lithium carbonate - 0.20
Slow release nicotinic acid - 7.00
Magnesium Oxide - 1.80
Potassium iodide - 0.01
D (-) - fructose - 0.90
The minimum active anti-stress daily dose involves the administration of two stomach-soluble unit doses and one intestinal-soluble unit dose.

A) A method for preparing a stomach-soluble unit dose
The above composition for producing 100 stomach-soluble unit doses can be prepared in two preferred ways, namely by mixing granules and powders or film-coated tablets and powders.

a) The preparation of a mixture consisting of granules of meclofenoxate and powders of other active ingredients is carried out in accordance with the physicochemical properties of the active substances and using the method of successive dilutions, thereby obtaining the following six mixtures (I-VI):
I 24.00 g of meclofenoxate hydrochloride [20], onto which 15.00 g of isopropyl alcohol is poured in the form of a thin film, is granulated with a sieve 10 with a filament base and dried at 35 ^o C. The granule thus obtained after drying is homogenized through a sieve 20 , then ground into powder with 0.277 g of Aerosil [90] and briquetted using a punch with a diameter of 9 mm. The resulting briquette is ground on a sieve 20;
II 0.90 g of anhydrous zinc sulfate [20], 0.90 g of D (-) - fructose [20] are individually homogenized by stirring, then they are included in the following mixture:
III consisting of 0.90 g of nicotinic acid [20], 0.70 g of vitamin B ₁ hydrochloride [20] and 1.00 g of vitamin B ₆ hydrochloride [20];
IV to obtain a mixture (IV = II + III);
V 24.277 g of mixture I [20], 13.50 g of DL-methionine [20] and 8.00 g of anhydrous magnesium salt of DL-aspartic acid [20] are homogenized to give a mixture;
VI, mixture IV is gradually incorporated into the previously obtained mixture V, and the resulting product is converted into powder using 0.549 g of talc [90] to obtain the final mixture VI (composition for 100 stomach-soluble unit doses).

 Integer numbers or numbers in parentheses are codes of German standard sieve specifications for each type of raw material used in the technology for preparing pharmaceutical compositions.

 b) Obtaining a mixture including film-coated tablets of meclofenoxate and powders of other active substances is carried out in two stages. In a first step, a film-coated meclofenoxate tablet is made. After granulation of meclofenoxate in accordance with the method described above, with the exception of the briquetting step, the mixture is pressed using a lenticular punch with a diameter of 7 mm and then the tablets are coated with a stomach-soluble polymer. The second stage is to obtain other mixtures in accordance with the method described in section a).

 To obtain pharmaceutical preparations of active substances, you can also use other known adjuvants, with which you can achieve technological and therapeutic prescription of the drug.

The composition of the stomach-soluble unit doses obtained in accordance with the methods described in section a) or b) is packaged in hard-gelatin capsules (enclosed in a shell) as follows:
a) filling the capsules with granules and powders is carried out in one stage using the same dosing device (used for granule powders) with their subsequent closing;
b) filling the capsules with granules and powders is carried out in two stages using successively two different metering devices (one for tablets and the other for powders), followed by their closure. In both methods, capsule filling and closing operations are carried out automatically using filling and closing devices, guided by GMP (high technology practice).

 The gastric soluble composition may also be packaged in soft-gelatin capsules.

 In addition, other methods of preparation can be used to produce pharmaceutical preparations of stomach-soluble standard doses, for example, compressing the active ingredients and adjuvants, followed by coating the tablets with a film obtained from a stomach-soluble polymer in the form of an aqueous dispersion, for example, a dispersion of hydroxypropyl methylcellulose with a viscosity of 3 cP and 5 -6 cP, a copolymer of methacrylate or a stomach-soluble polymer dissolved in an organic solvent, namely hydroxypropylmethyl cellulose with a viscosity of 15 cP and 50 cP, 3 cP and 5-6 cP, methacrylate copolymer.

 In all of the above cases, a stomach-soluble unit dose of the drug (stomach-soluble capsule or film-coated tablet) is prepared in accordance with the requirements of the Pharmacopoeia (Romanian Pharmacopoeia (RO. Ph.X), Xth ed., Medical Publishing House, Bucharest, 1993, Roman; European Pharmacopoeia (Eur. Ph.), 2nd ed., Maisonneuve, Sainte-Ruffine, Volume I, 1980 and Volume II NN 1-13, 1980-1990; The United States Pharmacopoeia (USP XXII), XXII rev ., The United States Pharmacopoeial Convention, Rockvill, Md., 1990; British Pharmacopoeia (BP 1988), Volume 1 and Volume 2, Her Majesty's Stationery Office, London, 1988).

B) a method of preparing a soluble intestinal dosage unit
The novelty of this method in accordance with the invention is in the preparation of intestinally soluble unit doses capable of guaranteeing a controlled release and absorption of active ingredients, as well as a prolonged anti-ischemic and anti-hypoxic effect. Two pressing medical problems are solved in accordance with the method according to the invention, but the pharmaceutical process is carried out in the reverse order. Thus, the new pharmaceutical method provides time-controlled release of nicotinic acid, which is a vasodilating active ingredient, and coating the capsules with an enteric coating after filling and closing, which makes them resistant to the action of the stomach environment and soluble in the intestine.

 To slow the yield, nicotinic acid is prepared either in the form of a sustained-release granule uniformly incorporated into another powder mass or in the form of a sustained-release tablet in a capsule together with the rest of the powdered ingredients.

a) The following describes the manufacturing process of the composition for 100 intestinally soluble unit doses, granules with a controlled release time of nicotinic acid. To slow the yield, ethyl cellulose is used as an insoluble polymer in the first stage, and diethyl phthalate as a plasticizer in a ratio (weight / weight) of 1 / 0.18-1 / 0.24, and in the second stage, carnauba wax in a ratio of with the above delayed release (weight / weight) 1 / 0.47-1 / 0.53. To prepare the contents of the capsules obtained by the method of successive dilutions, as follows, four mixtures (I-IV) are obtained:
I to 7,000 g of nicotinic acid [20], 0.430 g of aerosil [90], 0.262 g of polyvinylpyrrolidone [90], formed as a homogeneous mixture, a solution containing 4.080 g of isopropyl alcohol, 3,000 g of methylene chloride and 0.178 g of diethyl phthalate is added as a thin film in which 0.870 g of ethyl cellulose was dissolved in a water bath; the mass thus obtained is granulated through a sieve 10 with a thread-like base, dried at 35 ^° C. and then the granules are sorted by size using a sieve 10 with a thread-like base; then, with stirring, add a solution containing 2,000 g of isopropyl alcohol, 1,300 g of methylene chloride, in which 0.434 g of carnauba wax was dissolved in a water bath; the mixture is granulated through a sieve 10 with a thread-like base, dried at 35 ^o C and then sorted by size using a sieve 10 with a thread-like base;
II in 0.90 g of D (-) - fructose [45] include, in a homogeneous mixture, 0.01 g of potassium iodide [45], 0.001 g of sodium thiosulfate [45], 0.20 g of lithium carbonate [45];
III, 1.80 g of magnesium oxide is added to mixture II [45], then the resulting product is homogenized by re-sieving through a sieve 10;
IV mixture III is included in a homogeneous mixture containing 29.00 g of anhydrous orotinic acid [20] and 8.80 g of anhydrous potassium hydrogen phosphate [20], finally converted to powder using 0.2628 g of aerosil [90]; in this way receive the final mixture IV (composition for 100 intestinally soluble unit doses).

 Integer numbers or numbers in parentheses are codes of German standard sieve specifications for each type of raw material used in the technology for preparing pharmaceutical compositions.

 b) The preparation of the composition for 100 intestinally soluble unit doses containing a tablet with a controlled release time of nicotinic acid is carried out in two stages. The first step is to produce a sustained release tablet by compressing granules with a slower release of nicotinic acid in accordance with the method described above using a lenticular punch with a diameter of 6 mm. The second stage consists in obtaining other mixtures according to the invention in accordance with the method described in section a).

 Two options make it possible to differentiate the release time of nicotinic acid: during a period of about 2-3 hours in the case of using the method described in section a), and in the range of about 7-8 hours in the case of using the method described in section b).

 The gut-soluble unit dose composition prepared in accordance with the methods described in section a) or b) is enclosed in hard-gelatin capsules (enclosed in a shell) under conditions similar to those described for filling and closing stomach-soluble capsules.

 An intestinal-soluble composition may also be enclosed in soft gelatine capsules.

 As indicated above, another novelty of the process of the invention is the enteric coating of hard-shell gelatin capsules. Preferred is a technology that includes an enteric coating in the form of an aqueous dispersion, since it is economical and at the same time meets the standards for protecting the environment from pollution. The process of applying the enteric coating is carried out using a fluidized bed, which will allow uniformly coating the capsules over their entire surface.

One of the preferred dispersible enteric coating compositions for 100 capsules is as follows, g:
Cellulose acetate phthalate - 5.160
Diethyl phthalate - 1,840
25% ammonium hydroxide - 1,500
Dye - 0.006
The ratio (weight / weight) of the intestinal soluble polymer / plasticizer is 1 / 0.33-1 / 0.39, and the ratio (weight / weight) of the intestinal soluble polymer / dye is 1 / 0.0010-1 / 0.0012 . Other enteric coating aqueous dispersion compositions used in the method of the invention may contain other gastric and intestinal soluble polymers instead of acetyl cellulose phthalate, for example polyvinylacetyl phthalate, hydroxypropyl methylcellulose phthalate, trimethylacetyl cellulose, methacrylate copolymer. Although it has been found that for the enteric coating, aqueous dispersions of the above polymers are preferred, they can also be used dissolved in organic solvents. Instead of diethyl phthalate, dibutyl phthalate, propylene glycol, triacetin can also be used as a plasticizer. Used plasticizers improve the flexibility and strength of the coating, increase the resistance to delamination or cracking and reduce the passage of water vapor through the film. An economical, environmentally friendly method and application for producing an enteric coating with a water dispersion according to the invention of industrial equipment with high productivity, accuracy and productivity satisfies GMP quality requirements.

The enteric coating of the capsules is preferably carried out using batch film coating equipment, which ensures that the resulting film is adequately dried and avoids any film inhomogeneities, sticking of the capsules or deformation of the capsules. Similarly, an enteric coating can also be applied using continuous film coating equipment, taking into account that the drying time increases in direct proportion to the film thickness to achieve its optimum drying and uniformity. Due to the sensitivity of the wall of the gelatin capsule to aqueous solutions, the coating is carried out in two stages. The first stage consists in pre-coating a thin layer of an enteric polymer film to achieve a weight of approximately 15-20 mg / capsule. In this phase, in the aqueous dispersion, the ratio between the maximum amount of air and the minimum amount of polymer must be maintained in order to achieve rapid drying of the film. The average temperature at which the coating is applied is 70 ^° C. In the second stage, the film thickness and its weight are gradually increased using sputtering, changing the above ratio, namely increasing the flow of the aqueous polymer dispersion due to the air part of the flow, which is accompanied by a gradual increase in the drying time depending on the thickness of the resulting film. The second stage continues until the film weighs approximately 60-70 mg / capsule. The optimal weight is determined based on the result of the disintegration test in accordance with Eur.Ph., 1980: resistance to the action of the stomach environment ≤2 h, solubility in the intestine ≤1 h.

 In addition, to obtain a pharmaceutical preparation in the form of a stomach-soluble unit dose, other manufacturing methods can be used, for example, pressing the active ingredients after obtaining a form with a delayed release of nicotinic acid using well-known adjuvants, followed by coating the film of the tablet thus obtained with a polymer film resistant to the action of the environment of the stomach and soluble in the intestine, in the form of an aqueous dispersion or dissolved in an organic solvent.

 In all of the above cases, an intestinal-soluble unit dose of the drug (intestinal-soluble capsule or film-coated tablet) is prepared in accordance with the requirements of RO.Ph.X, 1993, Eur.Ph., 1980, USP XXII, 1990, and BP, 1988.

Example 2
A) The composition for 100 gastric-soluble unit doses includes the following ingredients, g:
DL-methionine - 16.50
Meclofenoxate hydrochloride (hydrochloride of (2- (dimethylamino) ethyl (para-chlorophenoxy) acetate) - 28.00
Zinc Sulfate, Anhydrous - 1.20
Nicotinic acid with a quick exit - 1.10
Magnesium salt DL aspartic acid, anhydrous - 10.00
D (-) - fructose - 1.10
Vitamin B ₁ hydrochloride - 0.90
Vitamin B ₆ hydrochloride - 1.20
In this composition, meclofenoxate hydrochloride can be replaced with meclofenoxate gibenzate within the same limits.

B) The composition for 100 intestinally soluble unit doses includes the following ingredients, g:
Orotic acid, anhydrous (1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinecarboxylic acid) - 34.00
Potassium hydroorthophosphate, anhydrous - 10.80
Lithium carbonate - 0.30
Sustained-release Niacin - 9.00
Magnesium Oxide - 2.20
Potassium iodide - 0.014
D (-) - fructose - 1.10
In this composition, orotic acid can be used both in anhydrous form and in the form of monohydrate within the same limits.

 The minimum active anti-stress daily dose involves the administration of two stomach-soluble unit doses and one intestinal-soluble unit dose.

 The pharmaceutical technology for the manufacture of two complementary unit doses is carried out in accordance with the steps described in example 1.

 Example 3

 A) The preparation of stomach-soluble unit doses is not limited to Examples 1 and 2, namely, using preparations from the class of aminoethanol phenoxyacetates, 24.00 g of meclofenoxate hydrochlorin can be replaced with 16.00 g of meclosulfonate hydrochloride, as can be seen from this example, which also allows you to achieve the desired therapeutic effect of the drug.

In this case, the composition for 100 gastric-soluble unit doses includes the following ingredients, g:
L (-) - methionine - 13.50
Meclosulfonate hydrochloride ((2- (dimethylamino) ethyl (ortho-chloro-para-dimethylamidosulfonylphenoxy) acetate hydrochloride) - 16.00
Zinc Sulfate, Anhydrous - 0.90
Nicotinamide (Vitamin PP) with fast release - 0.90
Magnesium salt of L (+) - aspartic acid, anhydrous - 8.00
D (-) - fructose - 0.90
Vitamin B ₁ mononitrate - 0.70
Vitamin B ₆ hydrochloride - 1.00
B) The preparation of a gut-soluble unit dose is not limited to Examples 1 and 2, hydroxopyrimidine carboxylates can be replaced by oxopyrrolidine acetamides in the following ratio (weight / weight) 1 / 1.48-1 / 1.60, based on 1 unit of orotic acid. Thus, 29.00 g of anhydrous orotic acid is replaced by 45.50 g of piracetam, as can be seen from the present example, which also allows to achieve a therapeutic effect of the drug.

In this case, the composition for 100 intestinally soluble unit doses includes the following ingredients, g:
Piracetam (2-oxo-1-pyrrolidinacetamide) - 45.50
Potassium hydroorthophosphate, anhydrous - 8.80
Lithium carbonate - 0.20
Slow Release Nicotine Alcohol - 6.50
Magnesium Oxide - 1.80
Potassium iodide - 0.01
D (-) - fructose - 0.90
Similarly, 45.50 g of piracetam can be replaced by other compounds from the class of oxopyrrolinidacetamides, for example: by 18.00 g of oxyiracetam (4-hydroxy-2-oxo-1-pyrrolidinacetamide);
13.00 g of etiracetam ((±) alpha-ethyl-2-oxo-1-pyrrolidinacetamide);
7.00 g of dimethylphenylpiracetam (N- [2- (2,6-dimethylphenyl] -2-oxo-1-pyrrolidinacetamide);
20.50 g of pramiracetam (N- [2- (diisopropioamino) ethyl] -2-oxo-1-pyrrolidinacetamide);
23.00 g of aniracetam (1-para-anisoyl-2-pyrrolidinone).

 The minimum active anti-stress daily dose involves the administration of two stomach-soluble unit doses and one intestinal-soluble unit dose.

 The pharmaceutical technology for the manufacture of two complementary unit doses is carried out in accordance with the steps described in example 1.

 Example 4

 A) In accordance with the procedure of Example 3, 20.00 g of meclosulfonate hydrochloride can be used instead of 28.00 g of meclofenoxate hydrochloride, as described below.

Therefore, in this case, the composition for 100 stomach-soluble unit doses includes the following ingredients, g:
L (-) - methionine - 16.50
Meclosulfonate hydrochloride ((2- (dimethylamino) ethyl (ortho-chloro-para-dimethylamidosulfonylphenoxy) acetate hydrochloride) - 20.00
Zinc Sulfate, Anhydrous - 1.20
Nicotinamide (Vitamin PP) with a quick release - 1.05
Magnesium salt of L (+) - aspartic acid, anhydrous - 10.00
D (-) - fructose - 1.10
Vitamin B ₁ Mononitrate - 0.90
Vitamin B ₆ hydrochloride - 1.20
B) In accordance with the data of Example 3, 51.20 g of piracetam can be used instead of 34.00 g of anhydrous orotic acid, as described below.

Piracetam (2-oxo-1-pyrrolidinacetamide) - 51.20
Potassium hydroorthophosphate, anhydrous - 10.80
Lithium carbonate - 0.30
Slow Release Nicotine Alcohol - 7.90
Magnesium Oxide - 2.20
Potassium iodide - 0.014
D (-) - fructose - 1.10
In turn, 51.20 g of piracetam can be replaced by other compounds of the class of oxopyrrolidine acetamides, for example:
22.00 g of oxyiracetam;
17.00 g of etiracetam;
8.00 g of dimethylphenylpiracetam;
24.50 g of pramiracetam;
27.00 g of aniracetam.

 The minimum active anti-stress daily dose involves the administration of two stomach-soluble unit doses and one intestinal-soluble unit dose.

 The pharmaceutical technology for the manufacture of two complementary unit doses is carried out in accordance with the steps described in example 1.

 Example 5

A) The preparation of gastric-soluble standard doses based on aminoethanol phenoxyacetates is not limited to Examples 1-4, while 24.00-28.00 g of meclofenoxate hydrochloride can be replaced by:
19.00-23.00 g of exophenoxate hydrochloride ((2-diethylamino) ethyl (para-chlorophenoxy) acetate hydrochloride);
5.00-7.00 g adaphenoxate (2- (1-adamantylamino) ethyl (para-chlorophenoxy) acetate),
which also allows to achieve the therapeutic effect of the drug.

 By way of illustration, an alternative is proposed below with the replacement of 24.00 g of meclofenoxate hydrochloride with 19.00 g of eclofenoxate hydrochloride.

In this case, the composition for 100 gastric-soluble unit doses includes the following ingredients, g:
L (-) - methionine - 13.50
Eclofenoxate hydrochloride (hydrochloride of (2- (diethylamino) ethyl (para-chloro-phenoxy) acetate) - 19.00
Zinc Sulfate, Anhydrous - 0.90
Nicotine alcohol with a quick exit - 0.80
DL-aspartic acid magnesium salt, anhydrous - 8.00
D (-) - fructose - 0.90
Vitamin B ₁ hydrochloride - 0.70
Vitamin B ₆ hydrochloride - 1.00
Within the class of aminoethanol phenoxyacetates, partial or complete replacement of meclofenoxate with its therapeutic homologs can be done in the following range of ratios (weight / weight):
- meclofenoxate / meclosulfonate = 1 / 0.65-1 / 0.72;
- meclofenoxate / eclofenoxate = 1 / 0.79-1 / 0.83;
- meclofenoxate / adaphenoxate = 1 / 0.20-1 / 0.26;
B) Preparation of gut-soluble unit doses is not limited to Examples 1 to 4, and oxopyrrolidine acetamides can be replaced with hydroxopyrimidine carboxylates. Their ratios are calculated in terms of 1 unit of anhydrous orotic acid, respectively, the ratio (weight / weight) of orotic acid and piracetate is in a weight ratio of 1 / 1.50-1 / 1.60, as can be seen from the present example, which also allows to achieve the therapeutic effect of the drug. In this case, the composition for 100 intestinally soluble unit doses includes the following ingredients, g:
Orotic acid, anhydrous (1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinecarboxylic acid) - 15.20
Piracetam (2-oxo-1-pyrrolidinacetamide) - 24.00
Potassium hydroorthophosphate, anhydrous - 8.80
Lithium carbonate - 0.20
Slow release nicotinic acid - 7.00
Magnesium Oxide - 1.80
Potassium iodide - 0.01
D (-) - fructose - 0.90
The minimum active anti-stress daily dose involves the administration of two stomach-soluble unit doses and one intestinal-soluble unit dose.

 The pharmaceutical technology for the manufacture of two complementary unit doses is carried out in accordance with the steps described in example 1.

Example 6
A) Examples 1-5 do not limit the scope of the invention, so that when receiving a gastric-soluble unit dose of aminoethanol phenoxyacetates can be replaced as follows:
a) completely on aminoethylphenoxyacetamides, for example, on:
6.00-8.00 g of mefexamide hydrochloride ((M- [2-diethylamino) ethyl] -2- (para-methoxyphenoxy) acetamide hydrochloride);
1.80-2.20 g of phenoxedyl hydrochloride (2- (para-butoxyphenoxy) -N- (2,5-diethoxyphenyl) - (N- [2-diethylamino) ethyl] acetamide hydrochloride);
2.50-3.50 g of fexicain hydrochloride (2- (para-butoxyphenoxy) -N- (orthomethoxyphenyl) - (N- [2- (1-pyrrolidinyl) ethyl] acetamide hydrochloride);
6.00-8.00 g ofipexide hydrochloride ((1 - [(para-chlorophenoxy) acetyl] -4-piperonylpiperazine hydrochloride);
b) or partially on aminoethylphenoxyacetamides, which leads to a relationship between the active substances from two different classes, which also allows to achieve therapeutic effects of the drug. An illustrative example of the partial replacement of meclofenoxate hydrochloride with mefexamide hydrochloride is provided below.

In this case, the composition for 100 gastric-soluble unit doses includes the following ingredients, g:
DL-methionine - 16.50
Meclofenoxate hydrochloride (2- (dimethylamino) ethyl (para-chloro-phenoxy) acetate hydrochloride) - 22.83
Mefexamide hydrochloride (N- [2- (diethylamino) ethyl] (para-methoxyphenoxy) acetamide hydrochloride) - 6.52
Zinc Sulfate, Anhydrous - 0.90
Nicotinic acid magnesium salt, anhydrous, with a quick exit - 1,00
L (+) - aspartic acid - 9.20
D (-) - fructose - 1.10
Vitamin B ₁ Mononitrate - 0.90
Vitamin B ₆ hydrochloride - 1.20
Partial or complete replacement of meclofenoxate with aminoethylphenoxyacetamides is carried out in the following range of ratios of meclofenoxate and its substituents (weight / weight):
meclofenoxate / mefexamide = 1 / 0.24-1 / 0.29;
meclofenoxate / phenoxidil = 1 / 0.07-1 / 0.08;
meclofenoxate / fexicaine = 1 / 0.10-1 / 0.13;
meclofenoxate / phipexide = 1 / 0.24-1 / 0.29;
B) Orotic acid-based examples also do not limit the scope of the invention, so that in the composition the amount of orotic acid can partially be replaced to the same extent with salts of orotic acid with biologically acceptable components with or without crystallization water, as described in this example, which also allows in this case to achieve the therapeutic effect of the drug.

In this case, the composition for 100 intestinally soluble unit doses includes the following ingredients, g:
Orotic acid, anhydrous (1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinecarboxylic acid) - 19.00
Orotic acid zinc salt - 1,50
Potassium hydroorthophosphate, anhydrous - 8.80
Potassium salt of orotic acid - 4.50
Orotic acid lithium salt - 1.30
Anhydrous magnesium salt of nicotinic acid, with a prolonged release - 9.00
Magnesium Oxide - 2.20
Magnesium salt of orotic acid - 9.70
Sodium iodide - 0.014
D (-) - fructose - 1.10
The minimum active anti-stress daily dose involves the administration of two stomach-soluble unit doses and one intestinal-soluble unit dose.

 The pharmaceutical technology for the manufacture of two complementary unit doses is carried out in accordance with the steps described in example 1.

Brief Description of the Drawings
The anti-stress medicine, reducing activity level and aging according to the invention was tested in laboratory animals. Below are described three tests of preclinical trials carried out in accordance with the etiopathogenic-therapeutic three-dimensional experimental design, which are presented in Table 1, which allow one to analyze a normal (control, healthy) brain in comparison with that subjected to stress, and with that restored due to therapeutic action of drugs against stress, decrease in activity level and aging. Violations of normal brain function were achieved using three types of stress characteristic of humans (mental, biological, and general), and recovery from stress was achieved by administering the drug for preventive, therapeutic, and restorative purposes.

 The objectives of the complex experimental scheme developed by the authors of the drug according to the invention were to identify the normal, ultrastructural and biochemical state of the brain in order to identify the characteristic damage caused in the brain as a result of stress, wear and aging, to identify the main mechanisms of this phenomenon and Based on these facts, to develop, apply and conduct preclinical trials of the effectiveness of etiopathogenic therapy against stress, decrease in activity level and aging (Riga S., Rig a D., Results of preclinical researches on experimental cheking-up of the Antagonic-Stress drug, Institute of Neurology and Psychiatry, Bucharest, 1985-1989, in Romanian).

 For each type of stress, the nervous system was examined using three types of methodology. The first was the selective isolation of living cells (neurons and neuroglial) from the brain and their analysis using phase contrast microscopy (Norton WT, Poduslo SE, Neuronal soma and whole neuroglia of rat brain: a new isolation technique, Science, 167, 1144 -1146, 1970; Riga D., Riga S., Varzaru A., Perieteanu M., Marculescu Z., Morphological stuies on neuronal and glial live cell populations, selectively isolated from the brain. Light microscopy investigation (part 1), Military Sanitary Review, 87, 141-147, 1984, in Romanian). The second methodology was neuromorphology, a structural analysis of the brain using light, fluorescence microscopy (Thompson SW, Hunt RD Selected Histochemical and Histopathological Methods, CCThomas, Sprigfield, III, 1966) and electron microscopy (Hayat MA, Principles and Techniques of Electron Microscopy, Volume I (Biological Applications) Van Nostrand Reinhold, New York, 1970; Riga D., Riga S., Popescu A., Perieteanu M., Constantinescu E., The methodology of lipofuscin pigment research in neuroanatomy, 3th International Symposium on Teaching of Morphological Sciences, Tel Aviv, Israel, 1977; Israel Journal of Medical Sciences, 14, 903, 1978). The third methodology, neurobiochemical, was carried out by isolating from the brain and studying informative macromolecules - nucleic acids (Santen RJ, Agranoff BW, Studies on the estimation of deoxyribonucleic acid and robonucleic acid in rat brain, Biochimica et Biophysica Acta, 72, 251-262, 1963 ; Munro HN, Fleck A., Recent Developments in the measurement of nucleic acids in biological materials, Analyst, 91, 78-88, 1966) and proteins (Lowry O.N., Rosenbrough NJ, Farr AL, Randall RJ, Protein measurement with the Folin phenol reagent, Journal of Biological Chemistry, 193, 265-275, 1965; Lajtha A. (ed.), Handbook of Neurochemisty, Volume I (Chemical Architecture of Nervous System), Plenum Press, New York, 1969) .

 The purpose of using these methodologies, which mutually verify and confirm the results obtained with their help, was to conduct a comprehensive study by quantitative and qualitative methods of the brain in normal condition, the brain subjected to stress, and the brain restored due to stress treatment, wear and tear, at all levels of morphobiochemical organization (regional, tissue, cellular, subcellular and macromolecular levels).

 Preclinical test I. The effectiveness of the drug according to the invention as a prophylactic agent for protecting the brain from the effects of mental stress.

 Violation of normal brain activity due to mental stress was received, causing chronic pain in adult rats daily for 2 weeks. A direct current of 4 mA was applied to the floor of the cell, causing a conditioned reflex of climbing onto a platform placed inside the cell; after 30 minutes, a current of 6 mA began to flow through this platform for 2 seconds, repeating this at random intervals for 3 hours, which caused chronic pain (modified test by Desiderato O., Tesa M., Shock-stress, gaster lesion and habituation in the chronic gastric fistula rat, Physiological Behavior, 16, 67-73, 1976). Thus, an animal model of neurosis was experimentally created (stress, neurosis, pain, fear, anxiety). Prophylactic protection of the brain was carried out by daily administration of the drug according to the invention before exposure to mental stress for the same period of time - 2 weeks.

 The research methodology, in particular, consists in the selective isolation of living cells (neurons or neuroglial) from the cerebral cortex and their analysis using phase contrast microscopy; thus, normal morphological features were revealed and compared, cell damage due to mental stress and anti-stress protection of nerve structures as a result of the treatment applied.

The data of a preclinical trial of the effectiveness of the drug of the invention for prophylactic protection are shown in FIG. 1-6, which, when compared, show specific protection against mental stress achieved at the cellular level (catfish and outgrowths of neurons), and at the subcellular level (by stabilizing lysosome membranes, protecting lipoprotein membranes of other neuro- and glioplasmic organelles and
due to anti-catabolic action, ultrastructural homeostatic action - protection of subcellular integrity).

Preclinical Test II. The therapeutic efficacy of a medicament according to the invention for restoring informational macromolecules in the brain destroyed by exposure to biological stress
Violation of normal brain function due to biological stress was obtained by constant ethanol intoxication in adult rats for 2 months (at a concentration of 15% daily, orally, in drinking water). Thus, an experimental model of chronic alcoholism was created in animals using the intestinal route of exposure. Brain recovery was carried out by daily administration of the stress medication according to the invention at the same time as the biological stress factor and for the same time period of 2 months.

 The research methodology, in particular, consists in the isolation and study of informational macromolecules of the brain - nucleic acids (DNA and RNA) and proteins (general, water-soluble and water-insoluble); thus, the normal neurobiochemical typology was identified and compared, damage to the macromolecules of the nervous tissue as a result of biological stress, and normalization of stress as a result of the treatment applied.

 The results of a preclinical study of the therapeutic efficacy of the medicament according to the invention are shown in Tables 2 and 3. When comparing the results, a characteristic effect is seen with respect to stress and a decrease in the level of activity, since the disturbances caused by biological stress at the level of informational macromolecules of the nervous system are reduced. Treatment led to a noticeable stimulation of anabolism, to the regeneration of ribosomes and proteins, expressed in an increase in the amount of total RNA, the amount of total protein (OH), the amount of water-soluble proteins (GRP) and in the increase in the ratios of RNA / DNA, RNA / OD, which is accompanied by anticatabolic protection of nerves cells, protection against oxidative stress and protection against cross-linking of macromolecules, which was manifested in a decrease in the number of water-insoluble proteins (VNRP) and the ratio (VNRP / OD) • 100. The effectiveness of the treatment of stress for resuscitation of the studied structures is statistically significant and is between 64.7% (for total DNA) and 85.2% (for total RNA), which can be seen from table 2, and between 76.4% (for the ratio (VNRP / OD) • 100) and 94.0% (for the ratio of RNA / OD), as shown in table 3.

Preclinical Test III. Therapeutic restorative efficacy of a medicament according to the invention with respect to resuscitation of nerve structures and restoration of informational brain macromolecules impaired by exposure to general stress
Violation of normal brain activity as a result of general stress was obtained by the accumulation in adult rats (8-9 months of age) of chronic wear and tear as a result of "life troubles" for 16-17 months of life until physiological old age (24-26 months), accompanied by socio -sensory deprivation, thus creating an experimental model on animals of accelerated reduction in activity and aging. Brain resuscitation was achieved by restoring treatment to the old rats daily for 2 months with the medicament of the invention having anti-stress activity, decreased activity level and anti-aging.

 The selected comprehensive brain research methodology, in particular, consists in the use of neuromorphological methods (light, fluorescence and electron microscopy) and neurobiochemical methods (isolation and study of informational macromolecules). The results obtained with their help, mutually verify and confirm each other. Thus, the normal macromolecular typology of the brain, the brain with impaired function as a result of general stress, and the brain resuscitated by therapeutic rehabilitation treatment were revealed and compared.

 The data of the preclinical evaluation of the therapeutic restorative efficacy of the drug of the invention are shown in FIG. 7-27 and in tables 4 and 5. The presented comparative results show that the drug significantly reduces the disorders and injuries found in the brain when exposed to stress, chronic wear and accelerated aging, which is based on its intense and complex specific etiopathogenic actions with respect to neuropsychic and biological resuscitation.

 The effectiveness of treatment at the level of catabolic regulation of nerve cells was demonstrated on the basis of data on a significant decrease in lipofuscin pigments, which is accompanied by resuscitation of neurons at the subcellular level. These therapeutic actions were detected at the cellular-subcellular level using light microscopy-cytochemistry, as can be seen from FIG. 7-9, using fluorescence microscopy, as shown in FIG. 10-12, and by electron microscopy, as can be seen from FIG. 13-15. The oxidative stress counteraction, shown on the basis of a noticeable decrease in lipofuscin pigments, was carried out in accordance with the complex mechanism: antilipofuscingenesis, neural and glial lipofuscinolysis, and lipofuscin elimination by transporting previously produced lipofuscin (fragmentation and partial dissolution) from neurons to glia and further. The successive stages of this mechanism in their dynamics are shown by electron microscopy of the brain, the initial and intermediate stages in FIG. 16-18 and the intermediate and final stages in FIG. 19-21.

 The effectiveness of treatment in relation to the anabolic regulation of nerve cells was shown by restoring the population of Nissl bodies (accumulations of granular endoplasmic reticulum and free ribosomes), accompanied by the regeneration and resuscitation of other neural subcellular compartments. Therapeutic effects are proven at the cellular-subcellular level using light microscopy-cytochemistry (Fig. 22-24) and using electron microscopy (Fig. 25-27). Counteraction to chronic stress and an accelerated decrease in the level of activity of the nervous system (hypoanabolism + hypercatabolism), assessed by the restoration of Nissl bodies and neural subcellular regeneration, was carried out in accordance with a complex mechanism: anabolic regeneration, restoration of ribosomes and proteins, which was manifested by an increase in the amount of total RNA, total proteins, water-soluble proteins and the ratios of RNA / DNA, RNA / OD associated with protection against catabolism and cross macromolecular bonds, which was it was found to reduce the amount of water-insoluble protein in the ratio (GNP / OD) • 100, as can be seen from tables 4 and 5. The restorative effectiveness of drugs with respect to resuscitation from stress, decreased activity and aging is statistically significant and is between 45.0 % (for GNRP) and 82.0% (for total RNA), which can be seen from table 4, and at a level between 55.9% (for the ratio (GNP / OD) • 100) and 111.3% (for the ratio RNA / OD), as shown in table 5.

In all three of the preclinical tests described above, only part of the methodologies were used to obtain the results:
- selective isolation of living nerve cells from the brain in a preclinical test 1,
- neurobiochemistry in preclinical test II,
- neuromorphology and neurobiochemistry in preclinical test III.

 Using other brain studies shown in Table 1, similar and equivalent results were obtained for each type of stress, which are also statistically significant (they differ only in intensity); impaired normal brain function due to mental, biological and general stress and therapeutic results once again confirmed the effectiveness of the treatment against stress, reduced activity and aging when using the medicine according to the invention for both preventive and therapeutic and restorative purposes.

 Using an experimental neuro-psycho-biological model and a set of methodologies, the inventors showed at the etiopathogenic level that three types of stress (mental, biological, and general) cause, accelerate, and increase the deterioration and aging of the brain as a result of exceeding the adaptive capabilities of the nervous system (including including those with respect to oxidation and free radicals) due to the intensity, frequency and constancy of stress. Thus, the etiology of stress and a chronic decrease in the level of activity (stress caused by ischemia and hypoxia, oxidative stress, stress caused by free radicals, peroxidation) leads to the appearance of a characteristic pathology in the brain, namely, structural and biochemical disorders and damage at the cellular, subcellular and macromolecular levels (peroxidation, polymerization, crosslinking). Structural and biochemical diagnosis of this pathology was carried out on the basis of data on a decrease in anabolism (regeneration), an increase in catabolism (degradation), and in the accumulation of lipofuscin pigments in nerve cells.

 The effectiveness of the etiopathogenic actions of the medicament according to the invention in relation to stress, decrease in activity level and aging is precisely proved in preclinical tests based on data on the correction of disorders and resistance to damage manifested in the brain under the influence of stress, which is also seen from tables 6 and 7. In these tables the stages and therapeutic mechanism in the etiopathogenic sequence are summarized, experimentally tested on animal models, on the neural (cellular), subcellular and macromolecular levels. They show therapeutic intervention, at metabolic and ultrastructural levels, in relation to two main areas of metabolism, namely anabolic regeneration and regulation of catabolism with the removal of peroxidized subcellular waste. These therapeutic mechanisms enhance ultrastructural and metabolic homeostatic interventions and form the basis of nerve cell plasticity, aimed at increasing the stability of the nervous system and the body's ability to adapt, which is a natural anti-stress process.

The described experimental scheme, based on three examples of preclinical testing, also shows the prophylactic, therapeutic and restorative effectiveness of the drug according to the invention in relation to stress, decrease in activity level and aging precisely in those areas of the brain that are directly involved and are constantly under stress due to chronic exposure stress factors, constant stress with a general adaptive reaction and neuropsychological and biological decline in level of activity. As can be seen from the drawings and tables, this structural-macromolecular specificity of the therapeutic effect is characterized in the brain at the following levels:
- at the regional level: the final brain, cerebral cortex, hippocampus; diencephalon, reticular formation;
- at the tissue and cellular level: neurons and neuroglia (astrocytes, microglia and oligodendrocytes);
- at the subcellular level: the anabolic system (Nissl bodies; free ribosomes, granular endoplasmic reticulum, Golgi apparatus) and the catabolism system (lipofuscin pigments; primary - secondary - tertiary lysosomes);
- at the macromolecular level: nucleic acids (DNA and RNA) and proteins (general, soluble and insoluble).

 As part of the preclinical examination, additional studies were conducted on guinea pigs and mice, which showed in comparative terms that the influence of stress factors - a decrease in the level of activity-aging in long-term experiments leads to the same typology of brain damage (metabolic and ultrastructural) in rats, marine mumps and mice, regardless of the type of animal. The results of the authors are also confirmed by similar data published in the prototype regarding rodents (Samorajski T., Keefe JR, Ordy JM, Intracellular localization of lipofuscin age pigments in the nervous system, Journal of Gerontology, 19, 262-276, 1964; Johnson Jr. JE, Miquel J., Fine structural changes in the lateral vestibular nucleus of aging rats, Mechanisms of Ageing and Development, 3, 203-224, 1974), primates (Brody H., Harman D., Ordy JM (eds.) , Aging, Volume I (Clinical, Morphologic and Neurochemical Aspects in Aging Central Nervous System), Raven Press, New York, 1975) and people (Brody H., The deposition of aging pigment in the human cerebral cortex, Journal of Gerontology, 15, 258-261, 1960; Riga D., Light and electron microscopic topography of changes induced by aging in the central nervous system, Annual scientific session of "Vi ctor Babes Institute, Bucharest, March 29, 1974, in Romanian; Davison A.N., Thompson R.H.S. (eds.), The Molecular Basis of Neuropathology, Edward Arnold, London, 1981; Condorelli DF, Avola R., Ragusa N., Giuffrida Stella AM, Macromolecular synthesis in developing and aging brain, pp. 243-257, Castellani A., Balduini C., Volpe P. (eds.), Macromolecules in the Functioning Cell, Consiglo Nazionale delle Ricerche, Roma, 1988).

 Consequently, the same typology of damage in animals and humans and the fact that the authors received damage to the normal activity of the brain of animals using types of stress characteristic of humans (mental stress - pain, fear; biological stress - ethanol dependence; and general stress - accelerated wear and aging), allowed to conclude that the actions and mechanisms of anti-stress resuscitation (tested in preclinical studies on the animal’s brain) are similar to those for the brain about the human brain.

 This therapeutic finding is further demonstrated in three series of clinical trials of the drug of the invention in accordance with the clinical scheme approved by the Pharmacovigilance and Drug Commitee of the Ministry of Health, Bucharest, Romania. Since pathology is directly related to stress, an accelerated decrease in activity levels and premature aging, to establish the equivalence of preclinical (in animals) and clinical (in humans) pathologies and therapeutic effects, clinical studies covered three types of diseases: neurasthenia, chronic alcoholism, and chronic cerebral circulatory failure .

Clinical trial I. Therapeutic efficacy of the drug of the invention in the treatment of neurasthenia
Neurasthenia (fatigue syndrome), classified by the WHO as stress-dependent and somatoform disorders, was studied at the stage of the disease (20 patients) and at the stage of the syndrome (10 patients) to test the drug for a wide range of forms of neurasthenia, psychosomatic and somatopsychic disorders.

 The characteristics of the test group were as follows: 30 patients (15 hospitalized and 15 working patients under chronic stress), both sexes (15 men and 15 women), from 20 to 58 years (average age 37 years). The selected group was homogeneous due to the application of the inclusion criterion (positive diagnosis) associated with the exclusion criterion (different diagnoses), (World Health Organization (WHO), Tenth Revision of the International Classification of Diseases (ICD-10), chapter V (F ): Mental, Behavioral and Developmental Disorders, WHO, Geneva, 1987), and by recording similar symptom intensities and deficiencies in labor productivity. Treatment with a medication against stress, decreased activity and aging was carried out exclusively by oral dosing for one month.

 The assessment methodology that was used before, during and at the end of the treatment period included: a scale for assessing the degree of neurasthenia (including 10 target symptoms, the degree of manifestation of each of which was evaluated using a 4-point system), 8 psychological tests (7 psychometric attention, memory , general intellectual efficiency, the general average characteristic of mental ability and one personal test), paraclinical studies - bioelectric (electroencephalogram and electrocardiogram) and biologo-humoral (ordinary laboratories torus tests).

The therapeutic efficacy of the medicament according to the invention turned out to be “very good” and “good” in relation to neurasthenic disease and syndrome for both inpatients with neurasthenia and for working patients; while neuropsychic and somatic actions persisted for a long period of time. No adverse reactions have been reported. Therapeutic benefits obtained after 1-2 weeks of treatment (Gorgos S., Botezat-Antonescu I., Results of clinical trial with Antagonisc-Stress drug in neurastenia, "Titan" University Policlinic, "Titan" Mental Health Center, Bucharest, 1988 , in Romanian) was proved clinically and paraclinically by the presence of such facts as:
a) quantitative and qualitative regression and the disappearance of symptomatology specific to neurasthenia, the normalization of biorhythm wakefulness-sleep, the disappearance of neurovegetative disorders of psychosomatic disorders; as well as
b) the normalization of the characteristics of a particular activity with the restoration of motivation and ability to work, accompanied by an increase in professional efficiency;
c) emotional stabilization (general emotional) and increased neuropsychic resistance to the effects of psychosocial stress factors in case of continued work in a stress-causing environment;
d) regulation of cerebral electrogenesis, as a result of metabolic regulation, and functional normalization of nerve cells;
e) the manifestation of myocardial anti-ischemic, moderately hypotensive, hepatoprotective and lipid-normalizing effects in those patients who suffered from these disorders before treatment.

Clinical trial II. Therapeutic efficacy of the drug of the invention in the treatment of chronic alcoholism
The studied cases of chronic alcoholism (ethanol dependence) were moderate and severe, with a duration of alcoholism of 10 to 35 years with a neuropsychiatric and somatic decrease in the level of activity and negative psychosocial consequences.

 The characteristics of the test group were as follows: 30 inpatients, only men (since the frequency of severe alcoholism in men is 2-5 times higher than in women), the age is from 31 to 59 years (average age 47 years). The homogeneity of the selected group was achieved through the use of a criterion for including and within each of them a criterion of severity (based on anamnestic, psychiatric-psychological, psychosocial, somatic, screening tests, lack of therapeutic results when using the previous set of drugs and treatments), as well as a criterion for exceptions (American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders (DSM-III), third edition, revised and revised, American Psychiatric Association, Washington, DC, 1987). Treatment with a medication against stress, decreased activity and aging was carried out exclusively by oral dosing for one month.

 The assessment methodology that was used before, during and at the end of the treatment period included: a psychiatric assessment - an interview exam, a scale for assessing the degree of chronic alcoholism (10 points), a Hamilton depression degree scale (21 points), a psychological rating - according to Bourdon-Anfimov , Herwig III, Wechsler intellectual test COD test for adults, Klazow, auditive Ray, Wechsler memory scale (MQ), Raven (1938b IQ matrix I sheet), Lusher; clinical evaluation - neurological, ophthalmic, therapeutic; paraclinical assessment - bioelectric (electroencephalogram and electrocardiogram), hematological, metabolic, immunological and screening tests.

The pronounced therapeutic efficacy consisted in obtaining a rapid therapeutic improvement that was continuous, intense, multi-faceted and stable. No toxic effects or adverse reactions were noted. Therapeutic Usefulness (Predescu V., Neicu N., Stefanescu P., Prelipceanu D., Andrucovici I., David E., Vrabie E., Roman I., Simoca I., Budileanu M., Sima I., Negru T. , Dumitrescu G., Reu G., Results of clinical trial with Antagonic-Stress drug in psychic impairments induced by constant alcohol consumption (chronic alcoholism, ethanol dependence), "Gh. Marinescu" Clinical Hospital, Department of Psychiatry, Bucharest, 1988, in Romanian), recorded using an integrated clinical and paraclinical methodology, is a consequence of the multilateral effects of the drug and its effectiveness:
a) psychotropic consequences - psychotonicity of metabolic regulation, antidepressant, nootrophic, sleep normalizing effect, neuropsychic resuscitation; remission in the treatment of symptoms of withdrawal symptoms, acquired dependence and tolerance; synergistic effect as a result of an increase (normalization) and preservation and maintenance of mental abilities, accompanied by stabilization of behavior from affective / emotional and related / social points of view, which increases resistance to stress factors;
b) neurotropic effects - cerebro-vasodilator, correction of cerebral electrogenesis, regression up to the disappearance of signs and symptoms of alcohol toxic deficiency, encephalomyeloleneuropathy;
c) somatotrophic effects - ocular - trophic and vasodilating effects; hepatoprotective and antitoxic effects - rapid remission of hepatic cytolytic syndrome and liver failure syndrome; cardiovascular - improvement of myocardial blood supply, reduction of bioelectric signs of alcoholic myocardiopathy, a disease that is also caused by chronic smoking, moderate hypotensive effect; general recovery of the body and anabolic stimulation;
g) hematological effects - antianemic effect, normalization of macrocytosis and moderate leukocytosis;
e) metabolic consequences - anabolic recovery, lipid-lowering and hypoglycemic effects;
f) immunological effects - immunostimulation by restoring the humoral and cell-mediated immune deficiency.

Clinical trial III. Therapeutic efficacy of a drug of the invention in the treatment of chronic cerebral circulatory failure
Of the several types of chronic cerebral circulatory insufficiency, the authors selected decompensations arising in the vertebrobasilar region, patients had both a weak and insufficient vascular system, a somatic basis for a biological decrease in the level of activity and aging, the body of which was characterized by the presence of signs of exposure to stress factors, risk factors, and diseases caused by stressful.

 The characteristics of the test group were as follows: 30 inpatients, both sexes (11 men and 19 women), from 47 to 72 years (average age 59 years). The selected group was homogeneous due to the application of the inclusion criterion (positive diagnosis) and the exclusion criterion (different diagnoses) (Organization Mondiale de la Sante (OMS), Applacation a la Neurologie de la Classification Internationale des Maladies (CIM-AN), OMS, Geneva , 1989, in French). Treatment with a medication against stress, decreased activity and aging was carried out exclusively by oral dosing for one month.

 The assessment methodology used before, during and at the end of the treatment period included: a neurological examination card, a scale for assessing chronic cerebral circulatory failure (including 10 target symptoms, the degree of manifestation of each of which was evaluated using a 4-point system), bioelectric studies (electroencephalogram and electrocardiogram) and bio-humoral studies (laboratory tests).

The therapeutic efficacy of the drug according to the invention was very good (fast, general and reliable). No adverse reactions have been reported. Therapeutic Benefits (Stamatoiu I., Dimitriu R., Nicolae I., Results of clinical trial with Antagonisc-Stress drug in cronic cerebral circulatory insufficiency, from vertebrobasicular territory, Clinical Hospital of Bucharest Municipality, Department of Neurology, Bucharest, 1988, Romanian tongue; Rora S., Macoveli M., Results of clinical trial with Antagonic-Stress drug in chronic vertebrobasilar insufficiency, "Gh. Marinescu" Clinical Hospital Department of Neurology, Bucharest, 1988, in Romanian), recorded using clinical and paraclinical methods, confirms the effectiveness of the drug to protect the brain and treat the brain from ischemia, hypoxia, chronic stress and accelerated wear and tear It is in:
a) rapid regression of neurological and asthenic symptomatology, accompanied by the disappearance of symptoms;
b) a marked improvement in cortical electrogenesis and a decrease in the complete disappearance of the bioelectric signal of myocardial ischemia;
c) obtaining a general biological reaction of neuropsychic resuscitation (as a result of cerebral vasodilating, nootrophic and psychotonic metabolic actions) and somatic resuscitation (as a result of hepatoprotective, moderate antihypertensive and normolipidemic effects, as well as synergies with the treatment of hypoglycemia).

 The versatile and enhanced therapeutic efficacy of the drug according to the invention, confirmed by three preclinical tests and three clinical trials, was obtained due to the fact that the drug was developed from the standpoint of a biological drug, which can be seen from the pharmaceutical examples, as well as due to its specific and synergistic actions in relation to stress, decreased activity and aging.

 Thus, the medicine is a synergistic, biological, neurometabolic and trophic cell composition with active anti-stress active ingredients (psychotrophic, neurotrophic, hepatotrophic and myocardophropic components), the main (normal) components of biological systems and the central nervous system that overcome the blood-brain barrier, active and have a physiological affinity with the biochemical structures of neurons and neuroglia, specific Ki control cerebral circulation and metabolism. Being a biological medicine, it is well absorbed by the body and is non-toxic, does not cause harmful reactions, does not lead to the development of tolerance to it and dependence, and it is not dangerous with regard to overdose or intoxication; the medicine itself has antitoxic, detoxifying and homeostatic effects. In addition, it becomes possible to use it with prolonged administration as a medicine for neuropsychological and biological support, to achieve and combine actions in relation to vascular, energy, polymetabolic and ultrastructural regulation of the brain, which is necessary in conditions of strengthening and prolonging the duration of stress factors and intensification neuropsychic and biological wear.

Specific homeostatic and etiopathogenic actions of the drug in relation to stress, wear and aging are achieved with its direct use (primary and secondary) or in the form of prodrugs due to its active anti-stress components, which have synergistic and polyvalent effects:
a) in relation to oxidative and catabolic stress;
b) in relation to anabolic stress;
c) vasodilating and normalizing lipidemia effect;
d) energy activating effect; and
e) antitoxic effect.

 a) The active components against oxidative and catabolic stress of the anti-stress medication, reduction of activity level and aging according to the invention are methionine, aminoethanol phenoxyacetates (meclofenoxate, meclosulfonate, eclofenoxate, adaphenoxate) and / or aminoethylphenoxyacetamide, phenexiphexidexidexidexexpexidexexpex.

 Methionine is a natural antioxidant that counteracts oxidative stress through the biosynthesis of thiol compounds, as well as catabolic stress, as a donor of methyl groups, metabolically supporting these biochemical reactions of the general adaptation syndrome against the effects of stress.

 Meclofenoxate is a biological compound, an organic ester, which, as a result of hydrolysis, turns into two naturally occurring metabolically active substances in the brain: parachlorophenoxyacetic acid, phytohormone (auxin) and brain modulator of neurotransmitters, and dimethylaminoethanol, a natural amino alcohol, and a precursor in the brain cerebral lipids (phospholipids and sphingolipids).

 The etiopathogenic effect of active compounds against oxidative and catabolic stress is achieved by providing metabolic support: maintaining biological systems of antioxidant protection, the ability to remove free radicals, counteracting lipid peroxidation, polymerization and cross-linking in macromolecules (counteracting the formation and accumulation of lipofuscin pigment), lipofuscinolysis, and restoration negative balances (thiol, sulfur, methyl, choline, phosphate atidnogo) caused by stress, aging, hypoxia-ischemia and alcoholism in the organism and brain, counteract excessive calcium accumulation in the brain (induced by the damage of cell membranes and the influence of free radicals). Thus, the active ingredients against oxidative and catabolic stress also have antitoxic effects on the nervous system.

 The specific effect of the constituents on oxidative and catabolic stress is enhanced by the use of other active ingredients in the drug of the invention.

 So, for example, to act against anabolic stress, they use orotic acid (lipofuscinolysis), piracetam (a decrease in the number of cerebral unesterified fatty acids in relation to their increased content under stress), zinc (antioxidant), lithium (anticatabolic), and the whole class of compounds acts by anabolic regeneration that counteracts catabolism and degradation.

 Vasodilating and normalizing lipidemia components, an example of which is nicotinamide (which reduces the amount of cerebral unesterified fatty acids in relation to their increased content under stress), counteract the stress caused by hypoxia-ischemia and chronic alcoholism, which leads to the accumulation of lipofuscin pigment in the brain.

 In turn, the antitoxic components support the homeostatic effect of the active ingredients against oxidative and catabolic stress by detoxifying and removing the products of catabolism in the nervous tissue at a structural, metabolic and molecular level.

 Thus, the active ingredients in relation to oxidative and catabolic stress are anti-aging agents, since they slow down the wear at the subcellular level and aging processes in the brain, whose tissue is highly sensitive to oxidative stress and the action of free radicals.

 The therapeutic efficacy of the drug according to the invention with respect to counteracting oxidative and catabolic stress was shown at the neural level: by protecting, stabilizing, increasing the stability of neural and glial membranes (when modeling mental stress in animals); neurobiochemically by protecting cerebral macromolecules and reducing the number of cross-links in protein macromolecules; and also neuromorphologically (using light, fluorescence electron microscopy) based on the action in relation to the formation of lipofuscin, lipofuscinolysis in neurons and glia, as well as data on the elimination of lipofuscin (when modeling animal chronic alcoholism and aging). The homeostatic effect against oxidative and catabolic stress has been proven in clinical trials in the treatment of chronic alcoholism based on remission of hepatitis and pancreatic cytolytic (hypercatabolic) syndrome and on the basis of rapid functional and metabolic normalization of the liver.

 b) The components active against anabolic stress of the medicament according to the invention having anti-stress activity, reducing activity and aging are hydroxopyrimidine carboxylates (orotic acid and orotates as bioelements) and / or oxopyrrolidine acetamides (piracetam, oxiracetam, etiracetam, dimethylphenyl, pramiracetam, aniracetam) associated with potassium, zinc and lithium.

Orotic acid (vitamin B ₁₃ ) has a pronounced effect on anabolic regeneration, since it is a natural metabolic precursor common to pyrimidine nitrogen-containing bases (uracil, cytosine, thymine, 5-methylcytosine) nucleic acids (DNA, RNA) and macroergic pyrimidine nucleotides (UTP, CTF and TTF) or coenzyme compositions (UDF-glucose, UDF-galactose, CDP-choline) that are involved in carbohydrate and lipid metabolism: which, along with protein and nucleic acid metabolism from are especially important to the brain. Thus, orotic acid has a lipotrophic effect, stimulating the synthesis of phospholipids, as well as increasing the synthesis of glycogen in the cells of the liver, myocardium and nerve cells, and as a result of increased RNA synthesis in the brain, it provides subcellular and metabolic support for long-term memory. Thus, orotic acid is a strong natural anabolic and biological support for the brain, liver and myocardium.

 Piracetam activates the biosynthesis of cerebral macromolecules (RNA, proteins) and lipids, primarily during recovery from hypoxia and in old animals, in which it enhances the synthesis of polyribosomes and their distribution, providing energy transfer between systems that produce and consume energy (cell anabolism, subcellular regeneration).

 Potassium, zinc, lithium and other neuroactive bioelements of the drug of the invention (magnesium, iodine, primary acid phosphate, sulfate) are intracellular mono- and divalent cations and anions important for living matter. They play structural (plastic) and metabolic (dynamic) roles and are involved in the main biocatalytic systems of the functional adaptation of the cell - enzymes, hormones, vitamins and macroergic compounds. They have specific functions in relation to the metabolism and physiology of the nerve cell: neurotransmitter activity, processes of excitation and inhibition, nerve cell conduction and axoplasmic transport, memory and neurosecretion. With a decrease in the level of activity as a result of stress, chronic alcoholism, hypoxia-ischemia, their negative balance is observed, in particular magnesium, zinc, sulfate and iodine. Magnesium is a subcellular stabilizer, lithium is a humoral stabilizer, and the limbic system exhibits an increased sensitivity to this bioelement, and the concentration of zinc is increased in the hippocampus.

 The therapeutic efficacy of the active compounds against anabolic stress is also supported by other active ingredients of the medicament of the invention, as previously noted for other bioelements, taking into account the dependence of cerebral anabolism on cerebral blood flow and on energy metabolism of nerve tissue.

 Thus, the activity of the drug against oxidative and catabolic stress is carried out using methionine and aminoethanol phenoxyacetates. In the brain, methyl groups supplied by methionine are actively absorbed in the process of anabolism of neurotransmitters, in cerebral lipid biosynthesis, and in post-transcriptional methylation of nerve cell macromolecules - nucleic acids and proteins. Meclofenoxate enhances the synthesis of cerebral RNA and macroergic nucleotides, and through the product of its hydrolysis (dimethylaminoethanol), it participates in the same manner as meclosulfonate in the synthesis of cerebral phospholipids.

 Active vasodilator components (in relation to stress caused by hypoxia-ischemia) provide the supply of nutrients that are necessary for anabolic regeneration and to counteract the processes caused by anabolic stress (hypoxia-ischemic stress).

Energy-activating compounds: aspartate (a precursor in the biosynthesis of purines and pyrimidines), fructose, vitamin B ₁ vitamin B ₆ and primary acid phosphate provide the energy support needed to enhance anabolism.

 The therapeutic efficacy of the medicament according to the invention in counteracting anabolic stress, chronic alcoholism and nerve tissue wear and intensive functional ultrastructural anabolic activation and regeneration of nerve cells have been demonstrated on the brain of animals using neurobiochemical methods based on data on the increase in the amount of RNA, total proteins and water-soluble proteins as well as the neuromorphological method (using light and electron microscopy) based on e data on the restoration of the population of Nisslet bodies, granular endoplasmic reticulum and free ribosomes in neurons. Anabolic regeneration has been clinically proven in the treatment of chronic alcoholism based on data on remission of liver failure and immunodeficiency, antianemic effect and weight gain.

 c) The active vasodilating components (in relation to stress caused by hypoxia-ischemia) and lipidemia-normalizing components of the medicament according to the invention, which have anti-stress activity, decrease in activity level and aging, are nicotinic alcohol and / or acid or their derivatives (nicotinamide, magnesium nicotinate ) based on magnesium and iodine.

 They act in an etiopathogenic manner by increasing cerebral blood flow, increasing the permeability of the blood-brain barrier and glucose transport, by improving the supply of nerve and myocardial cells with anabolites and their purification from catabolites. These compounds have an antispastic, antispasmodic effect, physiological cerebral vasodilator effect (primarily vasotrophic) and provide natural antihypoxic and anti-ischemic protection of the brain. In addition, they act as agents that normalize lipidemia and lipid homeostasis by lowering high levels of triglycerides, total cholesterol, VLDL cholesterol (cholesterol with a very low density of lipoprotein), LDL cholesterol (cholesterol with a low density of lipoprotein) and increase low HDL -cholesterol (high density lipoprotein cholesterol). In turn, the normalizing lipidemia effect has positive effects on the expansion of cerebral vessels.

Moreover, the therapeutic efficacy of vasodilating and lipid-normalizing components is also based on the action of other active drug compounds of the invention. Active ingredients for oxidative and catabolic stress, substances active for anabolic stress, and energy activating substances act as psychotrophic-psychotonic compounds for regulating metabolism, and thus, in addition to functional and metabolic stimulation of the brain, they are secondary cerebral vasodilating components - neurometabolics. Active components in relation to oxidative and catabolic stress, orotates and potassium, are components that are active in relation to anabolic stress, and aspartates, fructose, vitamin B _1, vitamin B ₆ are energy-activating ingredients that counteract stress caused by hypoxia and ischemia. Orotic acid, meclofenoxate, meclosulfonate and methionine act as agents that normalize lipidemia in the blood, as well as through increased intracellular lipid synthesis at the level of the liver, brain and myocardium or due to choleretic action (magnesium and orotic acid).

 Components with the vascular effect of the drug according to the invention in the form of a soluble standard dose in the stomach without a delayed release and in the form of a soluble standard dose in the intestine with a prolonged release provide both a quick vasodilating effect and a prolonged one over a long period (approximately 2-3 hours) in the case of a sustained release granule and for about 8 hours in the case of a sustained release tablet), which is necessary for the regulation of stress caused by ish hemia-hypoxia, decreased levels of activity and normal and pathological aging. The combined introduction of two complementary standard doses allows you to achieve long-term vasodilation (immediate + prolonged), which is necessary for cerebral and myocardial ischemic pathology.

 The vasodilating effect of the drug according to the invention can be enhanced by replacing in the composition of the stomach-soluble standard dose of aminoethanolphenoxyacetates (basic esters) with aminoethylphenoxyacetamides (stabilizing amides), including cerebral and peripheral vasodilator phenoxedil, (the action of which is based on the musculotrophic ), and the psychotonicity of metabolic regulation (vasodilation by neurometabolic activation) is preferable.

 The therapeutic efficacy of the drug according to the invention with respect to counteracting hypoxic-ischemic stress and dyslipidemia has been proven in the clinical setting in the treatment of chronic cerebral circulatory failure in the remission of ischemic symptoms, in ophthalmic positive effects and in cerebral and myradial electrogenic correction and in the treatment of chronic alcoholism in normalizing lipid and positive effects on vision.

d) The energy-activating components of the medicament according to the invention, which has activity against stress, decreased activity and aging, are: aspartate, D (-) - fructose, vitamin B ₁ , vitamin B ₆ and hydroorthophosphate, which provide energetic metabolism of the nerve cell, overstrained and energetically depleted as a result of stress and decreased activity.

 Aspartic acid, which is a glucose-forming amino acid whose concentration is 96 μmol / 100 g of nerve tissue and stored in the brain in its form for storage, namely in the form of N-acetyl aspartic acid at a concentration of 490 μmol / 100 g of nerve tissue, provides energy released as a result of its metabolism in the tricarboxylic acid cycle and GABA-shunt (especially intense in the brain); it is also a neurotransmitter of excitation and provides a mobile connection between the metabolism of carbohydrates, energy, nucleic acids and proteins in the nerve cell.

 D (-) - fructose, a natural monosaccharide that is metabolized independently of the insulin pathway, increases liver glycogen reserves or quickly integrates in the form of monophosphoric acid ester (D (-) - fructose-6-phosphate) in pentose-phosphate shunt (oxidative decomposition inherent in nerve cells) or in anaerobic glycolysis.

Vitamin B ₁ , vitamin B ₆ and vitamin PP (nicotinamide), the latter refers to vasodilating components, are exogenous biocatalysts that are absolutely necessary for life and normal nervous functions. In their forms of phosphoric acid esters (thiamine pyrophosphate and pyridoxal-5-phosphate) or nucleotides (nicotinamide mono- or dinucleotides) they are coenzymes (prosthetic group) for the numerous main enzymes involved in energy, carbohydrate, protein and lipid metabolisms. As a result of the increased intensity of cerebral metabolisms, the nervous system concentrates these vitamins in various zones and is sensitive to their imbalance; negative balance determined by stress, wear and tear, aging and toxic deficiency caused by chronic alcoholism. Vitamin B ₁ plays a major role in the metabolism of lactic acid, pyruvic acid and in the tricarboxylic acid cycle, and vitamin B ₆ in the activation of the GABA shunt, thus being a metabolic way of counteracting stress in the nerves.

Hydroorthophosphate is a support factor, a metabolic reserve in energy metabolism, and it is involved in the phosphorylation of glucides, being an integral part of carbohydrate metabolism; participates in the phosphorylation of vitamins B ₁ , B ₆ and PP to activate them in coenzymes; and participates in the synthesis of energy-storage macroergic compounds, such as ATP, UTP, etc.

 The therapeutic efficacy of energy-activating components is confirmed by the action of other active ingredients of the medicament according to the invention, which are involved in a homeostatic manner in many stages of cerebral carbohydrate and energy metabolism.

 Thus, the components that are active against oxidative and catabolic stress act as follows: aminoethanol phenoxyacetates increase the transport of glucose and phosphate from the blood to the brain, carry out oxidative decomposition of glucose through the pentose phosphate shunt, the main exergonic cycle of tricarboxylic acids, and the use of oxygen in nerve cells ; components such as aminoethylphenoxyacetamides have a strong energy-activating, psycho-excitatory effect; methionine acts indirectly by participating in biological methylation (synthesis of adrenaline, acetylcholine and creatine).

 The components active against anabolic stress act as follows: orotic acid saves energy during the direct synthesis of pyrimidine nitrogen-containing bases, coenzymes and macroergic compounds with uracil during the repeated synthesis of glycogen stores, piracetam stimulates energy-generating systems, increases glucose consumption, aerobic glycolysis, synthesis ATP at the brain level and in vitro respiratory coefficient of mitochondria (a subcellular organelle responsible for ATP biosynthesis); and potassium and zinc are involved in many enzymatic reactions accompanied by the release of energy.

 Vasodilating components (active against hypoxic-ischemic stress) carry out the action by increasing the number of anabolites and oxygen in the brain; nicotinamide, a precursor in the synthesis of coenzymes NAD (NAD) and NADP (NADP), plays an important role in cellular oxidation-reduction processes, magnesium is directly involved in many exergonic reactions, in the biosynthesis of macroergic compounds, in oxidative phosphorylation; and iodine produces a general activation of metabolism mainly in the brain, especially high in the hypothalamus, and also accumulates in the spinal cord and in the medulla oblongata.

 The combination of energy-activating neurometabolic components with those involved in the neotrophic-psychotonic regulation of metabolism (aminoethanol phenoxyacetates, aminoethylphenoxyacetamides, hydroxypyrimidinecarboxylates and / or oxopyrolidineacetamides), and with methyl group donors (methionine, and pramiraceramacramide ) in relation to the mental state creates a psychoexciting (antiasthenic) effect, strengthening mstvennyh abilities (attention, memory, intellectual activity), an antidepressant effect, higher resistance to stress, wear and tear, hypoxia, and the normalization of cerebral electrogenesis. These effects have been confirmed in clinical settings in the treatment of neurasthenia, chronic alcoholism and chronic cerebral circulatory failure using the medicament of the invention.

 d) The antitoxic components of the drug according to the invention, which has activity against stress, decreased activity and aging, exhibit etiopathogenic activity against hypercatabolism and conditions associated with deficiency of toxicants caused by oxidative stress and the accumulation of endogenous toxic compounds, which manifest themselves at the ultrastructural and metabolic levels when exposure to stress and a decrease in the level of activity, with hypoxia-ischemia, chronic alcoholism and aging.

In this case, metabolic detoxification processes are activated, which in turn leads to:
- reducing the number of free radicals formed during oxidative stress with the help of aminoethanolphenoxyacetates, methionine, orotic acid and zinc;
- eliminate acidosis and cellular gipoksidoza caused by the accumulation of lactic and pyruvic acids the oxidative stress, hypercatabolism glucide, thiamine-carbohydrate imbalance, hypoxia-ischemia, alcoholism through aminoetanolfenoksiatsetatov, orotic acid, potassium, zinc, magnesium, vitamin B ₁ and vitamin In ₆ ;
- elimination of the accumulated excess of ammonia as a result of protein catabolism using aspartic acid - through the urea cycle by transamination - together with vitamin B ₆ , asparagine and magnesium;
- intervention in sulfoconjugation with methionine and sulfate, in glucuronoconjugation with fructose, in methylation with methionine and pramiracetam;
- counteracting the excessive accumulation of calcium in the brain with the help of aminoethanol phenoxyacetates.

Subcellular detoxification processes are also activated, which lead to:
- reducing the number of cross-links that make protein enzymes insoluble and inactive;
- reduction of lipid peroxidation caused by oxidative and catabolic stress by acting on lipofuscinogenesis using lipofuscinolysis and elimination of lipofuscin.

 Methionine, an essential amino acid, a natural detoxifier and lipotrophic substance, a sulfur source, a metabolic donor of methyl groups and a precursor of -SH and sulfate groups play a complex role, representing an important metabolic support for antitoxic and detoxifying activity.

 Oral administration of the drug according to the invention has the advantage of direct antitoxic and hepatoprotective effects and actively supports metabolic detoxifying processes in the liver, given the main role of the liver in these processes. This fact has been clinically confirmed in the treatment of chronic alcoholism using this medication.

 The combination of antitoxic (at the metabolic-ultrastructural level), vasodilator (antihypoxic, antiischemic, antispasmodic) and anabolic regenerative (at the subcellular-functional level) actions with activity against oxidative hypercatabolic stress (removal of neural lipid peroxides) and energy-activating actions at the plastic and plastic levels leads to trophic action (in relation to nervous tissue, liver, myocardium) and to neuropsychic and biological rean mation using drugs of the present invention.

Industrial applicability
The therapeutic indications for the use of the drugs of the invention are due to:
- its inclusion in the fundamental processes occurring in neurons and neuroglia, and their maintenance due to the biological, neurometabolic and cell trophic composition;
- maintaining and increasing adaptive ability and neuropsychic and biological resistance due to polymetabolic regulation and subcellular regeneration, primarily of nerve cells, liver and myocardial cells;
- the simultaneous achievement of the protection of the brain, liver and heart from impaired normal function caused by acute and chronic stress, from a decrease in the level of brain activity and from accelerating aging by homeostatic intervention at the level of the brain and body;
- correction of the main metabolic and ultrastructural imbalances caused by stress, prolonged biological wear and stress related illnesses due to its vascular, energy-activating, antitoxic effects and effects on the regulation of catabolism and anabolic regeneration;
- a complex etiopathogenic, anti-stress effect against a decrease in the level of activity, anti-ischemic, anti-hypoxic and anti-toxic effects based on its synergistic biological and metabolic composition (components that have a neotrophic-psychotonic effect, vasodilators, energy activators, stimulators of the synthesis of proteins and nucleic acids, amino acids, vitamins and bioelements).

The administration of the drug of the present invention to healthy people (in accordance with the concept of improving health - preventive medicine) has the following effects:
- it increases the overall viability of the body, strengthens the neuropsychic tone;
- it increases the ability to mental and physical stress, increasing intellectual and athletic performance and abilities;
- it increases neuropsychic and biological adaptive ability;
- it increases resistance to overvoltage, stress and a decrease in the level of activity;
- it determines the quick recovery in case of fatigue, exhaustion, excessive work, after prolonged stress or insomnia;
- it greatly slows down the wear of the brain and the body and provides an increase in the functional life expectancy and overall life expectancy, thus preventing a decrease in the level of activity, including presclerotic and atherosclerotic;
- it is suitable for widespread use for patients of all ages (children, young people, adults and the elderly), being especially indicated for 35-40-year-olds (when adaptive ability and resistance begin to decrease steadily and progressively) and most preferably for people of those professions that require enhanced mental activity, or those that require a lot of stress and a coefficient of aggression (management personnel, students, athletes, pilots, teams for space flights and special tasks, etc.).

 Since brain stimulation is achieved through ultrastructural, energy and metabolic regulation, the administration of the drug of the invention is not accompanied by depression, nervous exhaustion, tolerance, psychological and physical dependence; in contrast, it has an intense, strengthening neuropsychic and general effect, obtained over an extended period.

The medicine according to the invention is administered to sick people for therapeutic and rehabilitation purposes, increasing the daily active dose depending on the nature and severity of the disease and the characteristics of each patient. Due to the flexibility of its dosage, the drug is used for pathology associated with stress, psychiatric and neurological pathology in geriatrics and therapy in cases of:
- states of neuropsychic overstrain, disadaptive reaction to stress, acute and chronic psychosocial stress;
- states of exhaustion and biological stress caused by debilitating and hypercatabolic diseases during recovery;
- nervous disorders: such as impaired attention and memory, concentration, decreased intellectual ability, low ability to exercise, mental and physical asthenia, overwork during work, exhaustion, sleep disturbances; neurovegetative disorders, emotional lability, depression;
- disorders related to stress and diseases related to stress: coronary heart disease, moderate arterial hypertension, liver failure, chronic pancreatopathy; dyslipidemia; as an additional therapy for diabetes and its complications;
- psychogenic sexual dysfunctions: impotence, frigidity, etc .;
- disorders of endocrine conditions as a result of disorders of the hypothalamic-pituitary complex, with menopause and andropause;
- cerebral toxic pathology: acute and chronic alcoholism (alcohol abuse and dependence on it, withdrawal syndrome, mental and neurological decrease in activity level due to alcoholism, detoxification process); abuse and dependence on other psychoactive substances; intoxication with carbon monoxide or organic solvents;
- chronic cerebral circulatory failure and other forms of cerebral vascular pathology: hypoxia, ischemia, thromboembolism, atherosclerosis;
- neuropsychiatric disorders caused by head trauma, and disorders caused by post-traumatic stress;
- involutive syndromes before and during physiological aging: poor resistance to stress, physical and mental fatigue, decreased attention and memory, decreased mental ability, emotional lability, depression, decreased adaptive ability, etc.

 The administration of the medicament according to the invention enhances social adaptive capacity, reduced as a result of stress, stress-related disorders and diseases, psychiatric and neurological diseases or old age, due to its therapeutic effects on behavior and emotional-affective stabilization and maintenance of mental functions.

Claims (8)

1. Medicinal composition against stress, lowering the level of activity and aging for use in prophylactic, therapeutic and restorative purposes, characterized in that it is a synergistic biological, neurometabolic and trophic cell composition consisting of: a) 20.1 - 52.3 % of ingredients active against oxidative and catabolic stress, namely for antilipofuscinogenesis, lipofuscinolysis and lipofuscin removal selected from the group consisting of methionine with aminoethanolpheno siatsetami and / or aminoetilfenoksiatsetamidami; b) 7.0 - 35.1% of the ingredients active against anabolic stress, namely for functional and ultrastructural anabolic regeneration, selected from the group consisting of hydroxypyrimidine carboxylates and / or oxopyrolidinacetamides with potassium, zinc and lithium; c) 6.7 - 8.6% of active ingredients with a vasodilating effect, effective against stress caused by hypoxia-ischemia, and normalizing lipidemia, and including nicotinic alcohol and / or acid or their derivatives, which include magnesium and iodine; g) and e) 16.6 - 19.9% of energy-activating and antitoxic active ingredients selected from the group consisting of aspartate, fructose,
vitamin B ₁ , vitamin B ₆ , hydroorthophosphate and sulfate. 2. The drug composition according to claim 1, characterized in that it contains the following active ingredients: 18.0 - 19.1% methionine; 31.0 - 33.1% of meclofenoxate or other aminoethanol phenoxyacetates, for example, meclosulfonate, eclofenoxate, adaphenoxate in a weight ratio of 1 / 0.65 - 1 / 0.72, 1 / 0.79 - 1 / 0.83 and 1/0, 20 - 1 / 0.26, respectively, in relation to the amount of meclofenoxate and / or aminoethylphenoxyacetamides, for example mefexamide, phenoxedil, fexicaine, fipexide in a weight ratio of 1 / 0.24 - 1 / 0.29, 1 / 0.07 - 1 / 0.08, 1 / 0.10 - 1 / 0.13 and 1 / 0.24 - 1 / 0.29, respectively, with respect to the amount of meclofenoxate; 18.8 - 20.0% hydroxypyrimidine carboxylates, for example orotic acid, or within the same range of orotates of the bioelements included in the medicine, and / or 28.3 - 31.4% of piracetam or other oxopyrolidinacetamides, for example, oxiracetam, ethiracetam, dimethylphenylpiracetam, pramiracetam or Aniracetam in a weight ratio of 1 / 0.39 - 1 / 0.44, 1 / 0.28 - 1 / 0.34, 1 / 0.15 - 1 / 0.16, 1 / 0.44 - 1/0 , 48 and 1 / 0.50 - 1 / 0.53, respectively, with respect to the amount of piracetam; 2.5 - 2.9% potassium; 0.3 - 0.7% zinc; 0.025 - 0.033% lithium; 5.2 to 6.6% of nicotinic alcohol and / or acid or derivatives thereof, for example nicotinamide or magnesium nicotinate; 1.5 - 1.9% magnesium; 0.005 - 0.007% iodine; 9.7 - 10.6% aspartate; 1.7 - 2.0% fructose; 0.9 - 1.3% vitamin B ₁ ; 1.2 - 1.5% vitamin B ₆ ; 2.6 - 3.5% hydroorthophosphate; 0.5 - 1.0% sulfate, with all percentages indicated in relation to 100 g of the minimum daily active dose. 3. The drug composition according to claim 1, characterized in that its active ingredients are preferably included in two pharmaceutical unit doses that are complementary to the biological value and therapeutic activity of the drug, namely: a) in a stomach-soluble capsule or coated tablet containing 240 - 280 mg of meclofenoxate hydrochloride, 135 - 165 mg of DL-methionine, 80 - 100 mg of anhydrous magnesium DL-aspartate, 9 - 11 mg of D (-) - fructose, 7 - 9 mg of vitamin B ₁ hydrochloride; 10 to 12 mg of Vitamin B ₆ hydrochloride, 9 to 11 mg of nicotinic acid with immediate release for immediate release, and 9 to 11 mg of anhydrous zinc sulfate, and b) to an intestinally soluble capsule or coated tablet containing 290 to 340 mg of anhydrous orotinic acids, 9 - 11 mg of D (-) - fructose, 70 - 90 mg of nicotinic acid in slow release for prolonged release, 88 - 108 mg of anhydrous potassium hydrogen phosphate, 18 - 22 mg of magnesium oxide, 2 - 3 mg of lithium carbonate and 0, 1 - 0.14 mg potassium iodide.  4. The medicinal composition according to claims 1 to 3, used in preventive medicine to maintain and increase the adaptive ability of neuropsychic and biological resistance, to simultaneously protect the nervous and endocrine systems, liver, heart and blood from stress and to correct the main ultrastructural and metabolic imbalances stress - a decrease in the level of activity - aging: a) by increasing the overall vitality of the body, ability to mental and physical stress and resistance to overvoltage, Tress and accelerated wear and b) by the rapid recovery from the fatigue states, after prolonged stress or insomnia.  5. The drug composition according to claims 1 to 3, used in therapy and restorative medicine for stress-dependent pathologies and accelerated aging, in particular, for a) conditions of neuropsychic overstrain, disadaptive reactions to stress, acute and chronic stress associated with stress disorders and diseases; b) impaired attention and memory, impaired ability to concentrate, decreased intellectual activity, decreased ability to exercise, neurovegetative disorders, depression; c) coronary heart diseases, moderate arterial hypertension, liver failure, chronic pancreatopathy, dyslipidemia; d) impotence, frigidity, andropause, menopause; e) acute and chronic alcoholism, abuse, withdrawal syndrome and dependence on psychoactive substances; f) chronic cerebral circulatory failure and other forms of cerebral vascular pathology: hypoxia, ischemia, thromboembolism, atherosclerosis; g) involutive syndromes in the normal and pathological period preceding aging, and in aging.  6. A method for producing medicinal compositions according to claims 1 to 3, characterized in that for ensuring pharmaceutical stability, maximum biological value and therapeutic efficacy, it involves granulating or compressing meclofenoxate or its related compounds in the form of a unit dose soluble in the stomach and slowed down nicotinic acid the output or its derivatives with a slower release in the form of a soluble intestinal dose, mixing them with other components in the form of a powder, their subsequent encapsulation hard gelatin capsules with hard or soft shells, enteric coating of standard doses containing a vasodilator with a delayed release, or pressing them followed by coating with a film obtained from a polymer soluble in the stomach or intestines, respectively, in the form of an aqueous dispersion or solution in an organic solvent .  7. The method according to claim 6, characterized in that the retardation of the release of a vasodilator, for example, nicotinic alcohol and / or acid and / or their derivatives, included in the intestinally soluble standard dose, is achieved depending on the time required for the release of the active substance or using granules with a delayed yield, using ethyl cellulose as a retardant and diethyl phthalate as a plasticizer in a weight ratio of 1 / 0.18 - 1 / 0.24, followed by coating the granules with carnauba wax as a second retardan this in a weight ratio with ethyl cellulose of 1 / 0.47 - 1 / 0.53, or using a tablet with a slower yield, obtained by pressing granules with a slower output. 8. The method according to claim 6, characterized in that the enteric coating is applied to gelatin capsules with a hard or soft shell filled with a soluble intestinal dosage unit using an aqueous dispersion of a polymer resistant to the environment of the stomach — soluble in the intestine, for example cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate or methacrylate copolymer mixed with a plasticizer selected from the group consisting of diethyl phthalate, dibutyl phthalate, propylene glycol or triacetin, when than the weight ratio of intestinal soluble polymer and plasticizer is 1 / 0.33 - 1 / 0.39, and the weight ratio of intestinal soluble polymer and dye is 1 / 0.0010 - 1 / 0.0012, using a fluidized bed for coating at an average temperature of 70 ^° C., using, in another embodiment, the spraying and drying step, and thereby producing a final coating film of approximately 60 to 70 mg per capsule.

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