Medicine against stress, against the reduction of the level of activity and anti-aging and method thereof

 

(57) Abstract:

The invention relates to medicine, namely to cure stress, reduce activity and aging and how to obtain it. Medicine has etiopathogeny and homeostatic effect, has been studied in preclinical and clinically tested in geriatrics, neurological, psychiatric and stress-related pathology. Medicine is energiticheskuyu biological, neurometabolic and providing trophic cells of the composition, based on combining the following active ingredients: a) against oxidative and catabolic stress: methionine with aminoethylethanolamine and/or aminoethylethanolamine; b) in respect of anabolic stress: hydrooximethylcarbamile and/or oxopropionate with potassium, zinc and lithium; a vasodilator and normalizing lipidemia drugs: nicotine, alcohol and/or acid or derivatives thereof with magnesium and iodine; d) energoactivity and (e) toxic compounds: aspartate; fructose; vitamin B1vitamin B6; gidrogenfosfat and sulfate. Distinctive features of the method of manufacturing leiam, soluble in the stomach, and soluble in the intestine, the latter have intersolubility shell; b) prolonged release of vasodilator compound soluble in the intestine standard dose. The invention provides emotional-affective stabilization and maintenance of the mental functions of a person in stress conditions. 2c. and 6 C.p. f-crystals, 27 ill., 7 table.

The invention relates to oral input by the medicine with etiopathogeny activities in relation to stress, decreasing the level of activity and aging and enhanced therapeutic efficacy, which is the consequence of his sinergeticheskoj biological, neurometabolic and providing trophic cells of the composition. The invention also relates to a method for obtaining this medication. This medicine supports and enhances the ability to adapt and neuropsychiatric and biological stability, protects against stress brain, liver and heart and corrects the main ultrastructural and metabolic imbalances resulting from acute and chronic stress, prolonged biological "life problems" (wear), oxidative stress, ischemia-hypoxia is run by the stress pathology. Custom pharmaceutical method of its manufacture, in addition, provides control over its release and adsorption of active substances and prolong cerebral vasodilator action, which in combination provides maximum bioavailability and therapeutic efficacy.

Acute and chronic stress, which is negative and constant feature of modern life, includes the development of three processes: first, the aggression against the body of stress factors in the ever-increasing size, diversity and stability; second, the reaction of the organism, which may be adaptive, adaptive enough or pathologically dependent on stress; and, thirdly, intensive, accelerated and permanent accumulating in the brain and in the body of the wear in the "life of trouble", and premature aging.

Adaptive reaction of the body (General adaptation syndrome) consists of three consecutive stages: immediate adaptation, long-term adaptation and the stage of exhaustion - neuropsychiatric and biological reduction of activity level (Selye H., The evolution of the stress concept, American Scientist, 61, 692-699, 1973). Chronic wear oznaeeny capacity to adapt and reduce the viability and sustainability of the organism, and this is the result of accumulation over time of stress and induced stress damage. When, due to the increased intensity, frequency and constancy of stress and reduce the activity level of adaptability of the organism is exhausted, there are diseases associated with a lack of adaptation, which means the appearance of stress-related pathology: neuropsychiatric and psychosomatic diseases (Wilder J. F. , R. Plutchik, Stress and psychiatry (part 25.11), pp. 1198-1203, Kaplan, H. I. , Sadock B. J. (ed), Comprehensive Textbook of Psychiatry/IV, volume I, Williams and Wilkins, Baltimore, 1985).

The human brain because of its threefold function of neurobiological, psychological and social - and because of the loss after the birth of the capacity to regenerate neurons through cell division is a global "listener" stress (ischemic, caused by hypoxia, oxidative, and so on) and "drive" chronic, progressive, neuropsychiatric and biological reduction of activity level. Thus, in the Central nervous system accumulate specific ultrastructural and biochemical imbalances and corruption on all levels of metabolism (energy, anabolism, Kneginje blood flow through the brain as a result of stress and aging (progressive chronic hypoxia) and the neural geoanalyst (violation and reduced synthesis of nucleic acids and proteins reduction and violation Taurus Nissle, accumulations of granular endoplasmic reticulum and free ribosomes, and Golgi apparatus) lead to lower ductility and anabolic regeneration as functional (enzymes and neurotransmitters), and ultrastucture (narooma and outgrowths of neurons) (Terry, R. D., who S. (ed), Aging, volume 3, (Neurobiology of Aging), Raven Press, new York, 1976). Oxidative stress, neural hypercatabolism, peroxidizable lipids, in particular membranes, and premature chronic decrease in the activity level of subcellular organelles, mainly mitochondria, in all cases, eventually lead to progressive accumulation of pigments lipofuscin (pigments, wear, pigments aging, tertiary liposomes insoluble subcellular waste generated as a result of peroxidizable, 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 specific drugs with etiopathogeny activity against stress, snjeza:

a) at the individual level - professional unsuitability, disease, premature aging and death and

b) at the social level is an important economic and social direct and indirect losses (Cooper S., Arbose J., Executive stress goes global, International Management, 39, 42-48, 1984).

As follows from the prior art, efforts to obtain drugs that are effective for the control and treatment of stress and reduce the level of activity, still had no success in obtaining a specific drug with etiopathogeny action; so far been addressed only symptomatologically objectives achieved or stimulating effects.

So, for example, to improve the symptomatology, stress, disorders of visual adaptation, reducing the ability to respond to stress and stress-related disorders (anxiety, depression, fatigue, insomnia, neurological, autonomic and psychosomatic disorders), known application psychotronic drugs (Podinger W., Schmidlin, R. E., Wider F., Index Psychopharmacorum, H. , Huber, Bern, 1983). Depending on the prevailing of symptomatology known application of the following drugs:

a) anxiolytics (minor tranquilizers): diazepam, meprobamate, methylin is;

in) blockers beta-adrenergic receptor: bunitrolol;

g) antidepressants: tricyclic, tetracyclic compounds, individually or in conjunction with neuroleptics;

d) stimulating agents: caffeine, amphetamine, or derivatives thereof;

e) sedative and hypnotic funds: United in the formula of phenobarbital and codeine (patents Romania NN 60376 and 64161).

The disadvantage of these psychotronic drugs is that they are only for primary symptomatic treatment, but do not have etiopathogeny action against stress; they do not reduce the chronic decrease in activity level, stress, does not affect the stress through anabolic regeneration, they alter the normal (anti-stress) adaptation reactions of the body and have numerous harmful effects. In addition, the anxiety and psychoactive drugs (such as amphetamine and caffeine) often lead to the need for increased dosages due to the phenomenon of acquired tolerance and cause significant adverse reaction, namely the dependence on psychoactive compounds (Lader M, Benzodiazepines - the opium of the masses?, pages 605-615, Smith A. D., Llinas R., Kostyuk P. O. (editor ); Commentaries in Neuroscienc"ptx2">

Also there are many anti-stress drug compositions used for stimulating, energizing, stimulating, trophic, tonic, strengthening - neuropsychiatric and/or biological purposes. They are used to treat disorders caused by acute and chronic stress, stress-related pathology and, in particular, to ensure their most common effects: nervous, mental and biological depletion, accelerated chronic reduction of the level of activity of premature aging.

a) Some of these songs contain vitamins: water-soluble (American Medical Assocition, AMA Drug Evaluations, Publishing Sciences Group, Action, Mass., 1973), together with water-soluble fat-soluble (U.S. patent N 3493659) or provitamins together with Bioelements (French patent N 7404 M).

b) Other compounds include amino acids with or without vitamins (acetylaspartate acid, argininepatch, citrulline with folic acid), either based on aspartato (patents Romania NN 55069 and 77472; French patent N 2521429) or glutamate (patent Romania N 76141), or cysteine (patent Romania N 74505), arginine (French patent N 2494113) or complex structures, which are usually along with the above the LASS="ptx2">

in Other compositions contain stimulating ingredients and their combinations: amphetamine, amphetamine with caffeine or caffeine with vitamins (patents Romania NN 62137 and 66014).

The disadvantage of these products, even when they are comprehensive medicinal composition, is the inability to carry out etiopathogeny anti-stress therapy by simultaneous combination of several different actions (vasodilator, normolipidemic, energoactivity, antitoxic, regulating the catabolism of actions, including lipofuscinosis and anabolic regeneration); they were not in preclinical studies in combating experimental stress induced in animals, they can't prevent or slow down the deterioration of the nervous system by combating oxidative stress and do not support natural adaptation mechanisms - anti-stress mechanisms.

In addition, first of all medications, including the methylxanthines and/or amphetamines, are unfavorable because they provide an incomplete, limited medical treatment with a short duration of action, which in the case of chronic use or principically and biological resistance to stress, intensification of cellular catabolism and decrease in adaptive responses to stress; moreover, their use causes many harmful reactions (Syed I. E., The effects of caffeine, Journal of the American Pharmaceutical Association, NS 16, 568-572, 1976; Iversen L. L. , Iversen, S. D., Snyder S. H. (editor), Handbook of Psychopharmacology, volume 11 (Stimulats), Plenum Press, new York, 1978).

It is well known the use of methionine in pechenochki pathology as protecting the liver connection (Wade, A., Reynolds, J. E. F. (ed), The Extra Pharmacopoeia, The Pharmaceutical Press, London, 1978). Successful research of the authors of the present invention have revealed that the methionine additionally has specific neurotrophic activity and provides etiopathogeny effect against stress. In this regard, the authors use quantitative histochemical methods showed antagonistic activity against chronic oxidative stress, determined by the reduction of pigments lipofuscin in the brain (in the end the brain and in the interim the 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, page 383, Kiev, USSR, 1972). Next, the authors revealed its complex effect on stress, reduce the Skye regeneration the increase in RNA synthesis at the level of the nervous system of aged rats using an integrated methodology: selective discharge of living nerve cells of the brain, morphometric and biochemical methods (Riga, S., Studies on Nucleic Acids in the Central Nervous System in Senescence Processes, Ph. D. Thesis, Institute of Medicine and Pharmacy, Bucharest, 1976, on ROM. language).

It is also known that meklofenoxat due to its action on energy and metabolic regulation of nerve cells has a wide range of clinical applications in psychiatry, neurology, and in the treatment of pathologies defined by hypoxia in stress intervention in the brain, geriatrics, neurosurgery, anesthesiology, intensive care (Coirault R. , P. Deligne, Rouif J., Une orientation therapeutique nouvelle. L A. N. P. 235 (ester dimethyl-amino-ethylique de l acide para-chloro-phenoxy-acetique), Agressologie, 1, 113-138, 1960 (in French)). Next, with the use of light mikroskopie-histochemistry (only as a qualitative method) was found ability meklofenoxat to reduce the content of pigments lipofuscin in the nervous system of old Guinea pigs (Nandy K., Bourne, G. H., Effect of centrophenoxine on lipofuscin pigments in the neurons of senile guinea-pigs. Nature (Lond. ), 210, 313-314, 1966); it was also confirmed using electron microscopy (Hasan M, Glees ology, 9, 153 to 159, 1974). According to the authors, with research priorities in the field of preclinical methodology (quantitative morphometry and qualitative - type distribution, autofluorescence, histochemistry), and using their experimental scheme based on a triple path study (a statistical comparison of three groups - control young control old and treated old) installed capacity meklofenoxat specific and significantly reduce the amount of pigments lipofuscin in the brain of old rats; based on this, the authors of the present invention introduced into the scientific literature in this field of technology the concept of lipofuscinosis (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, pages 22-27, J. Kugler (ed), Hirnstoffwechsel und Hirndurchblutung, Schnetztor Verlag, Konstanz, Schweiz, 1977). Later this concept was also used by other researchers. As a result of their lipofuscinosis actions proved antagonistic action against oxidative stress, meklofenoxat has etiopathogeny activity against stress dical International de la Federation Internationale des Resistants (F. I. R.), Prague, Czechoslovakia, November 30-December 2, 1976, Resumes, page 70, 1976) and in relation to aging rats (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).

Application of the above two compounds with separate introduction or without strengthening anti-stress action with neurometabolic composition with etiopathogeny action has no advantages, because they provide only incomplete protection of the brain from stress, reduce activity and aging, because their effect on the functional and metabolic regulation, and cellular regeneration are only partial.

Medicine with etiopathogeny anti-stress action, action against reduction of the level of activity and ageing in accordance with the invention made in the form of sinergeticheskoj biological, neurometabolic and providing trophic cells of the composition, developed in accordance with the specific anti-stress therapeutic concept by linkages and synergies following active ingredients:

a) compounds active against oxidative and catabolic stress (antilipopolysaccharide, lipofuze of aminoethylethanolamine;

b) components against anabolic stress (for functional and ultrastructural anabolic regeneration): hydrooximethylcarbamile and/or oxopyrrolidin with potassium, zinc and lithium;

C) vasodilators (directed against stress caused by hypoxia and ischemia) and compounds that normalize lipidemia: nicotine, alcohol and/or nicotinic acid or derivatives thereof with magnesium and iodine;

g) energoactivity and

d) anti-toxic components: aspartate, fructose, vitamin b1, vitamin b6, gidrogenfosfat and sulfate.

The method of obtaining drugs in accordance with the present invention to achieve in oral introduction maximum biological value and therapeutic efficacy includes:

a) for controlled delivery to the place of release and absorption of the active compounds of the medication - preparation of a pharmaceutical composition in the form of two complementary types of capsules or film-coated tablets (soluble in the stomach, and soluble in the intestine standard dose), the latter are tablets with intersolubility shell, and

b) to achieve prolonged antisemites in the form of enteric capsules or film-coated tablets that slows down the action, compared with the form in the form of granules or tablets.

Medication in accordance with the invention has the following advantages:

it is a new drug and new drug strategy in the field of health promotion and the prevention, control and treatment of stress, biological deterioration, premature aging, stress-related diseases;

it was designed and tested in accordance with the concept of biological medicine is energiticheskuyu biological, neurometabolic and providing trophic cells (cerebral, hepatic, myocardial, and nonspecific) the composition has as a result of this broad therapeutic efficacy, devoid of toxicity and harmful effects, it does not develop tolerance and dependence;

- it was created and tested within a particular therapeutic concept, namely etiopathogeny and homeostatic, directed against stress, reduce activity and aging, thereby ensuring enhanced therapeutic efficacy, based on its active constituents (compounds with actisetup, active against stress caused by hypoxia and ischemia, and normalizing lipidemia, energoactivity and toxic compounds) is approved for treatment of diseases caused by free radicals, hypercatabolism and gipotalamicescom States, gipoksena-coronary artery disease, dyslipidemia, energy depletion and pathology caused by Toxicological;

biological composition based on it and its specific anti-stress effect defines a broad area of preventive, therapeutic and restorative applications for all age groups (children, young people, adults and the elderly) for both healthy and sick people;

it is recommended for healthy people, especially during operation with high voltage and efficiency, since it counteracts antihemostatic the effects of stress and lower levels of activity (on neuropsychiatric and biological levels) and increases ability to work in stressful situations by increasing resistance to mental (intellectual) and physical (biological) action;

it is recommended for patients geriatric medicine and therapy.

Medication according to the present invention can effectively contribute to maintaining and improving mental and biological health in a significant reduction of economic and social losses caused in society by stress, a reduction in biological activity, premature aging and stress related disorders.

Pharmaceutical machinery preparing medicines according to the present invention gives the following advantages:

in the case of oral administration, it provides maximum bioavailability and therapeutic effectiveness;

- it guarantees a controlled regulation of the release and absorption of active compounds from drugs through preparation of pharmaceutical compositions in the form of two complementary types of pharmaceutical standard doses (capsules or film-coated tablets): soluble in the stomach, and soluble in the intestine;

for forms with intersolubility shell technology of its manufacturing process is completely non-toxic and has no harmful impact on the environment, namely spraying water dispersion resistant environment of the stomach, and soluble in kisdata due to release controlled time vasodilator component of the enteric standard dose;

- different coloring two complementary forms, soluble in the stomach and intestines, and packing of drugs in the calendar view in a transparent film under normal conditions with the protection of silica gel or by using vacuum packaging technology ensures correctness, simplicity, differentiation and visibility (daily, weekly, monthly) treatment and suitable stability of the medication;

- due to the flexibility of dosing it enables you to differentiate treatment against stress and against the reduction of the level of activity depending on the individual characteristics and neuropsychical reactivity, as well as gaining mainly at the level of brain action against oxidative and catabolic stress or anabolic stress;

- it allows you to enter a medicine in accordance with chronotherapy intervals of time (chronological dosing).

The preferred embodiment of the invention

Below are six examples of the pharmaceutical preparation of medicines according to the invention. To achieve controlled delivery of vysvobozena and absorption of active substances, the authors have developed a drug to the and intestines. Two complementary standard dose is made either in the form of capsules or in the form of film-coated tablets and their different paint for identification in oral introduction. In each of the following examples use the required quantity of active substances and adjuvants to get 100 capsules or tablets coated.

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

Example 1.

A) the Composition for 100 soluble in the stomach of standard doses includes the following ingredients:

DL-methionine - 13,50

Hydrochloride meklofenoxat (hydrochloride (2- (dimethylamino)ethyl(pair-chlorophenoxy)acetate) - 24,00

Zinc sulfate, anhydrous - 0,90

Nicotinic acid with a quick exit - 0,90

Magnesium salt of DL-aspartic acid, anhydrous - 8,00

D(-)-fructose - 0,90

Hydrochloride, vitamin B1- 0,70

Hydrochloride, vitamin b6- 1,00

B) Composition to 100 soluble in the intestine standard doses includes the following ingredients:

Orotic acid, anhydrous (1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinecarbonitrile acid) - 29,00

Hydroalcoholic potassium, anhydrous - 8,80

Lithium carbonate - 0,20 D(-)-fructose - 0,90

Minimum active against stress daily dose involves the introduction of two soluble in the stomach of standard doses and one soluble in the intestine standard dose.

A) Method of preparing soluble in the stomach of a standard dose

The above composition to obtain 100 soluble in the stomach of standard doses can be made in two preferred ways, namely by mixing the granules and powders, or film-coated tablets and powders.

a) preparation of a mixture consisting of granules of meklofenoxat powders and other active ingredients is carried out in accordance with the physico-chemical properties of active substances and using the method of serial dilution, thereby obtaining six of the following compounds (I-VI):

I 24,00 g of the hydrochloride of meklofenoxat [20], which is drained of 15.00 g of isopropyl alcohol in the form of a thin film, granularit using sieves 10 with filamentous basis and dried at 35oC. the thus Obtained pellets after drying homogenized through a sieve of 20, then grind into powder with 0,277 g of Aerosil [90] and bitteroot using a punch with a diameter of 9 mm, the resulting briquette pound on the sieve 20;

II 0,90 g bessagnet part of the following mix:

III consisting of from 0.90 g of nicotinic acid [20], 0,70 g of the hydrochloride of vitamin b1[20] and 1.00 g of the hydrochloride of vitamin b6[20];

IV) in the mixture (IV = II+III);

V 24,277 g of a mixture of I [20], 13,50 g DL-methionine [20] and 8.00 g of anhydrous magnesium salt of DL-aspartic acid [20] homogenize, receiving the mixture;

VI in the previously obtained mixture V gradually include a mixture of IV and the resulting product is converted into a powder by using 0,549 g talc [90], getting the final mix VI (composition to 100 soluble in the stomach of standard doses).

Integers or numbers in parentheses represent the codes of the German standard specifications for sieves for each type of raw materials used in technology of preparation of pharmaceutical compositions.

b) obtaining a mixture comprising film-coated tablets meklofenoxat and powders other active substances, is carried out in two stages. In the first stage made film-coated tablet meklofenoxat. After granulation meklofenoxat in accordance with the above-described method, except under preforming, the mixture is pressed using lenticular punch with a diameter of 7 mm and after this tablet cover is soluble in the stomach S="ptx2">

To obtain pharmaceutical preparations of active substances can also be applied to other known adjuvants, to help you to achieve technological and therapeutic drug administration.

The composition is soluble in the stomach of standard doses received in accordance with the methods described in a) or b), Packed in gelatin capsules, hard shell (enclosed in the shell) as follows:

a) filling capsules, granules and powders is carried out in one stage, using the same dosing device (used for granules-powders) with their subsequent closure;

b) filling capsules, granules and powders is carried out in two stages, using successively two different dosing devices (one for tablets and one for powders) with their subsequent closure. In both methods of operation for filling and closing the capsules carried out automatically by means of the filling and closing devices, guided GMP practices of high technologies).

Soluble in the stomach, the composition may also be Packed in gelatin capsules, soft shell.

In addition, to obtain pharmaceutical preparations , active substances and adjuvants with subsequent coating of tablets film, derived from dissolving in the stomach of the polymer in aqueous dispersion, for example dispersion hydroxypropylmethylcellulose with a viscosity of 3 JV and 5-6 SP, a copolymer of methacrylate or soluble in the stomach polymer dissolved in an organic solvent, namely hydroxypropylmethylcellulose with a viscosity of 15 SP 50 SP, 3 SP and 5-6 SP, methacrylate copolymer.

In all the above cases, soluble in the stomach of a standard dose of the drug (dissolved in the stomach capsule or film-coated tablet) receive, in accordance with the requirements of the Pharmacopoeia (Romanian Pharmacopoeia (RO. Ph.X), X ed., Medical Publishing House, Bucharest, 1993, on ROM. language; the European Pharmacopoeia (Eur. Ph.), 2 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) Method of preparation soluble in the intestine standard dose

The novelty of this method is in accordance with the invention consists in obtaining soluble in the intestine standard doses, is able to ensure a controlled process of release and absorption of active substances, as well as prolonged antiischemic and antihypoxic action. Two vital medicalstudents in reverse order. So, a new pharmaceutical method provides a controlled release time nicotinic acid, representing a vasodilator active ingredient, and a coating of capsules intersolubility shell after filling and closing, which makes them resistant to the action environment of the stomach, and soluble in the intestine.

For slow release nicotinic acid is prepared either in the form of granules with a slow release, uniformly included in other powdery mass, either in the form of a slow release tablets enclosed along with the rest of the powdered ingredients in the capsule.

(a) the Following describes the manufacturing process of the composition to 100 soluble in the intestine standard doses of granules with a controlled time-release nicotinic acid. To slow down the output of the first stage is used as the insoluble polymer ethylcellulose, and as a plasticizer diethylphthalate in the ratio (weight/weight) 1/0,18-1/0,24, and in the second stage as a moderator of exit enter Carnauba wax in a ratio with the above moderators output (weight/weight) 1/0,47-1/0,53. For making the contents of the capsules produced by the method of the last g of Aerosil [90], 0,262 g polyvinylpyrrolidone [90], is formed as homogenous mixture, add in the form of a thin film of a solution containing 4,080 g of isopropyl alcohol, 3,000 g of methylene chloride and 0,178 g diethylphthalate, which in a water bath was dissolved 0,870 g ethyl cellulose; thus received a lot granularit through a sieve with 10 threadlike basis, dried at 35oC and then the granules are sorted by size using sieves with 10 threadlike basis; then added with stirring a solution containing 2,000 g of isopropyl alcohol, 1,300 g of methylene chloride, which on a water bath was dissolved 0,434 g Carnauba wax; mix granularit through a sieve with 10 threadlike basis, dried at 35oC and then sorted by size using sieves with 10 threadlike basis;

II a 0.90 g of D(-)-fructose [45] include in the form of a homogeneous mixture of 0.01 g of potassium iodide [45], 0.001 g of sodium thiosulfate [45], 0.20 g of lithium carbonate [45];

III to a mixture of II type of 1.80 g of magnesium oxide [45], then the resulting product is homogenized by repeated sieving through a sieve 10;

IV a mixture of III include in a homogeneous mixture containing 29,00 g anhydrous orotovoy acid [20] and 8,80 g anhydrous gidrogenfosfat potassium [20], at the end turn what's in the gut of standard doses).

Integers or numbers in parentheses represent the codes of the German standard specifications for sieves for each type of raw materials used in technology of preparation of pharmaceutical compositions.

b) the Manufacture of the composition to 100 soluble in the intestine standard doses containing tablet with controlled time-release nicotinic acid, is carried out in two stages. The first stage is to obtain a slow release tablets by compressing granules, sustained-release nicotinic acid in accordance with the above-described method 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 give the ability to differentiate the time of the release nicotinic acid: during the period of about 2-3 hours in the case of using the method described in section a), and in the range of approximately 7-8 hours in the case of using the method described in section b).

The composition is soluble in the intestine standard dose received in accordance with the methods described in a) or b), conclude in zapolneniya and closing soluble in the stomach capsules.

Enteric composition may also be enclosed in gelatin capsules, soft shell.

As indicated above, another novelty of the method according to the invention consists in intersolubility coating gelatin capsules with a hard shell. It is preferable technology, including intersolubility floor in the form of an aqueous dispersion, since it is economical and at the same time meets the standards of environmental protection from pollution. The process of applying Intercollege coating is carried out using a fluidized bed, which will uniformly cover the capsule across their surface.

One of the preferred compositions dispersed Intercollege coverage for 100 capsules is as follows, g:

Cellulose acetate phthalate - 5,160

Diethylphthalate - 1,840

25% ammonium hydroxide - 1,500

Dye - 0,006

The ratio (weight/weight) soluble in the intestine of the polymer/plasticizer is 1/0,33-1/0.39 and the ratio (weight/weight) soluble in the intestine of the polymer/dye is 1/0,0010-1/0,0012. Other compositions are aqueous dispersions for Intercollege coating used in the method according to the invention may contain, instead of OFWs: polyvinylacetate, phthalate of hydroxypropylmethylcellulose, trimethylacetylchloride, methacrylate copolymer. Although it was found that for Intercollege coverage preferred aqueous dispersions of the above polymers, they can also be used dissolved in organic solvents. As a plasticizer instead of diethylphthalate can also be used dibutyl phthalate, propylene glycol, triacetin. Used plasticizers to 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. Cost-effective, will have no adverse impact on the environment method and application to obtain Intercollege coating aqueous dispersion according to the invention of industrial equipment with high productivity, precision and performance meet the quality requirements of GMP.

Intersolubility coating of the capsules is preferably performed using the equipment for the manufacture of film coating periodic actions, which provide for the proper drying of the formed film and avoids any inhomogeneities in the film, adhesion of capsules or deformatory continuous film coating, taking into account the fact that the drying time increases in direct proportion to the thickness of the film to achieve its optimum drying and uniformity. Because of the sensitivity of the walls of the capsules to aqueous solutions the coating is performed in two stages. The first stage consists of pre-coating a thin layer intersolubility polymer film to reach a weight of approximately 15-20 mg/capsule. In this phase, a water dispersion of a need to maintain the ratio between the maximum amount of air and a minimal amount of polymer to achieve a rapid drying of the film. The average temperature at which the applied coating is 70oC. In the second stage, gradually increase the film thickness and its weight, using sputtering, by changing the above-mentioned ratio, namely increasing the flow of aqueous polymer dispersion due to the air stream, which is accompanied by the increase of the drying time depending on the thickness of the resulting film. The second stage continues until they reach a weight of a film about 60-70 mg/capsule. Optimal weight set on the basis of the disintegration test according to Eur.Ph., 1980: the sustainability of ski preparation in the form of soluble in the stomach of a standard dose can be applied at other ways of making, for example, the pressing of active substances upon receipt of form with samadhanam output of nicotinic acid using well-known adjuvants with subsequent coating thus obtained tablets with a film of polymer that is resistant to the action environment of the stomach, and soluble in the intestine, in the form of an aqueous dispersion or dissolved in an organic solvent.

In all the above cases, soluble in the intestine standard dose of the drug (enteric capsule or film-coated tablet) receive, in accordance with the requirements of the RO.Ph.X, 1993, Eur.Ph., 1980, USP XXII, 1990, and BP, 1988.

Example 2

A) the Composition for 100 soluble in the stomach of standard doses includes the following ingredients:

DL-methionine - 16,50

Hydrochloride meklofenoxat (hydrochloride (2-(dimethylamino)ethyl (pair-chlorophenoxy)acetate) - 28,00

Zinc sulfate, anhydrous - 1,20

Nicotinic acid with a quick exit - 1,10

Magnesium salt of DL-aspartic acid, anhydrous - 10,00

D(-)-fructose - 1,10

Hydrochloride, vitamin b1- 0,90

Hydrochloride, vitamin B6- 1,20

In this composition hydrochloride meklofenoxat can be replaced by giventhat of meklofenoxat in the same PR is you, g:

Orotic acid, anhydrous (1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinecarbonitrile acid) - 34,00

Hydroalcoholic potassium, anhydrous - 10,80

Lithium carbonate - 0,30

Niacin slow release - 9,00

Magnesium oxide - 2,20

Potassium iodide - 0,014

D(-)-fructose - 1,10

In this part of orotic acid may be used in the anhydrous form and in the form of monohydrate in the same range.

Minimum active against stress daily dose involves the introduction of two soluble in the stomach of standard doses and one soluble in the intestine standard dose.

Pharmaceutical manufacturing technology two complementary standard doses is carried out in accordance with the stages described in example 1.

Example 3.

A) Obtaining soluble in the stomach of standard doses are not limited to examples 1 and 2, namely the use of drugs from the class of aminoethylethanolamine, 24,00 g hydrochlorine of meklofenoxat can be replaced by 16,00 g of the hydrochloride microsurface, as you can see from this example that also allows you to achieve the desired therapeutic effect of the medication.

In this case, the composition for are microsurface (hydrochloride (2- (dimethylamino)ethyl(ortho-chloro-para-dimethylaminomethylphenol) acetate) - 16,00

Zinc sulfate, anhydrous - 0,90

Nicotinamide (vitamin PP) with a quick exit - 0,90

Magnesium salt of L(+)-aspartic acid, anhydrous - 8,00

D(-)-fructose - 0,90

Mononitrate vitamin b1- 0,70

Hydrochloride, vitamin b6- 1,00

B) Obtaining soluble in the intestine standard dose is not limited to the examples 1 and 2, hydroxyaminomonocarboxylic can be replaced by oxopropionate in the following ratio (weight/weight) 1/1,48-1/1,60 in terms of 1 unit orotovoy acid. Thus, 29,00 g anhydrous orotovoy acid substituted 45,50 g / kg, as can be seen from this example that also allows you to reach therapeutic effect of the medication.

In this case, the composition for 100 soluble in the intestine standard doses includes the following ingredients:

Piracetam (2-oxo-1-pyrrolidinyl) - 45,50

Hydroalcoholic potassium, anhydrous - 8,80

Lithium carbonate - 0,20

Nicotine alcohol extended exit - 6,50

Magnesium oxide - 1,80

Potassium iodide - 0,01

D(-)-fructose - 0,90

Similarly, 45,50 g / kg can be replaced by other compounds from the class of oxopropylidene, for example: 18,00 g oxirane the>/BR>7,00 g dimethylphenylpiperazinium (N-[2-(2,6 - dimetilfenil]-2-oxo-1-pyrrolidineethanol);

20,50 g pramiracetam (N-[2-(diisopropylamino)ethyl]-2-oxo-1-pyrrolidineethanol);

23,00 g aniracetam (1-pair-anisoyl-2-pyrrolidinone).

Minimum active against stress daily dose involves the introduction of two soluble in the stomach of standard doses and one soluble in the intestine standard dose.

Pharmaceutical manufacturing technology two complementary standard doses is carried out in accordance with the stages described in example 1.

Example 4.

(A) In accordance with the method of example 3 of 20.00 g of the hydrochloride microsurface can be used instead of 28.00 g of the hydrochloride of meclofenoxate provided as described below.

Therefore, in this case, the composition for 100 soluble in the stomach of standard doses includes the following ingredients:

L(-)-methionine - 16,50

Hydrochloride microsurface (hydrochloride (2- (dimethylamino)ethyl(ortho-chloro-para-dimethylaminomethylphenol)acetate) - 20,00

Zinc sulfate, anhydrous - 1,20

Nicotinamide (vitamin PP) with a quick exit - 1,05

Magnesium salt of L(+)-aspartic acid, anhydrous - 10,00

D(-)-fruchi with the data of example 3, 51,20 g / kg may be used instead 34,00 g anhydrous orotovoy acid, as is described below.

Piracetam (2-oxo-1-pyrrolidinyl) - 51,20

Hydroalcoholic potassium, anhydrous - 10,80

Lithium carbonate - 0,30

Nicotine alcohol with prolonged out - of 7.90

Magnesium oxide - 2,20

Potassium iodide - 0,014

D(-)-fructose - 1,10

In turn, 51,20 g / kg can be replaced by other compounds of the class of oxopropionate, for example on:

22,00 g oksiratsetam;

17,00 g etiracetam;

8.00 g of dimethylphenylacetate;

24,50 g pramiracetam;

27,00 g aniracetam.

Minimum active against stress daily dose involves the introduction of two soluble in the stomach of standard doses and one soluble in the intestine standard dose.

Pharmaceutical manufacturing technology two complementary standard doses is carried out in accordance with the stages described in example 1.

Example 5.

A) Obtaining soluble in the stomach of standard doses based aminoethylethanolamine not limited to the examples 1-4, with 24,00-28,00 g of the hydrochloride of meklofenoxat can be replaced with:

19,00-23,00 g of the hydrochloride of exogeneity (hydrochloride (2-diethylamino)ethyl(pair-chlorophenoxy)acetate);

5,00-whitesage effect of the medication.

As the following illustration offered the option of replacing 24,00 g of the hydrochloride of meklofenoxat on 19,00 g of the hydrochloride of alienista.

In this case, the composition for 100 soluble in the stomach of standard doses includes the following ingredients:

L(-)-methionine - 13,50

Hydrochloride of clofenotane (hydrochloride (2- (diethylamino)ethyl(para-chloro-phenoxy)acetate) - 19,00

Zinc sulfate, anhydrous - 0,90

Nicotine alcohol with a quick exit - 0,80

Magnesium salt of DL-aspartic acid, anhydrous - 8,00

D(-)-fructose - 0,90

Hydrochloride, vitamin b1- 0,70

Hydrochloride, vitamin B6- 1,00

Within the class of aminoethylethanolamine partial or complete substitution of meklofenoxat on its therapeutic homologues can be done in the following range of proportions (weight/weight):

- meklofenoxat/macrocultural = 1/0,65-1/0,72;

- meklofenoxat/alienist = 1/0,79-1/0,83;

- meklofenoxat/Difenoxin = 1/0,20-1/0,26;

B) Obtaining soluble in the intestine standard doses are not limited to the examples 1 to 4, and oxopropionate can be replaced by hydroxodimethylglyoximate. Their ratio is calculated in terms of 1 unit of anhydrous orotovoy acid, soutwest be seen from this example, that also allows you to reach therapeutic effect of the drug. In this case, the composition for 100 soluble in the intestine standard doses includes the following ingredients:

Orotic acid, anhydrous (1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinecarbonitrile acid) - 15,20

Piracetam (2-oxo-1-pyrrolidinyl) - 24,00

Hydroalcoholic potassium, anhydrous - 8,80

Lithium carbonate - 0,20

Niacin slow release - 7,00

Magnesium oxide - 1,80

Potassium iodide - 0,01

D(-)-fructose - 0,90

Minimum active against stress daily dose involves the introduction of two soluble in the stomach of standard doses and one soluble in the intestine standard dose.

Pharmaceutical manufacturing technology two complementary standard doses is carried out in accordance with the stages described in example 1.

Example 6

(A) Examples 1-5 do not limit the scope of the invention so that upon receipt soluble in the stomach of standard doses aminoethylethanolamine can be replaced as follows:

a) fully on aminoethylethanolamine, for example:

6,00-8,00 g of the hydrochloride methoxamine (hydrochloride (M-[2-diethylamino)ethyl]-2-(para - methoxime the l) - (N-[2-diethylamino)ethyl] ndimethylacetamide);

2,50-3,50 g of the hydrochloride of Mexicana (hydrochloride of 2-(para-butoxyethoxy)-N-(ortho - methoxyphenyl)- N-[2-(1-pyrrolidinyl)ethyl] ndimethylacetamide);

6,00-8,00 g of the hydrochloride of fipexide (hydrochloride (1-[(para-chlorophenoxy) acetyl]-4-piperonylpiperazine);

b) or partially on aminoethylethanolamine, which leads to the relationship between existing substances from two different classes, which also allows to achieve therapeutic effects of the medication. Shown to illustrate an example of partial replacement of the hydrochloride meklofenoxat on hydrochloride methoxamine presented below.

In this case, the composition for 100 soluble in the stomach of standard doses includes the following ingredients:

DL-methionine - 16,50

Hydrochloride meklofenoxat (hydrochloride of 2-(dimethylamino)ethyl (para-chloro-phenoxy)acetate) - to 22.83

Hydrochloride methoxamine (hydrochloride of N-[2-(diethylamino) ethyl](a pair of methoxyphenoxy)ndimethylacetamide) - 6,52

Zinc sulfate, anhydrous - 0,90

Magnesium salt of nicotinic acid, anhydrous, with quick access to 1.00

L(+)-aspartic acid - 9,20

D(-)-fructose - 1,10

Mononitrate vitamin b1- 0,90

Hydrochloride, vitamin b6- 1,20

Part is otnoshenii of meklofenoxat and his deputies (weight/weight):

meklofenoxat/mefenamic = 1/0,24-1/0,29;

meklofenoxat/phenoxides = 1/0,07-1/0,08;

meklofenoxat/Mexican = 1/0,10-1/0,13;

meklofenoxat/fipexide = 1/0,24-1/0,29;

B) Examples based on orotovoy acid also do not limit the scope of the invention, so that the composition of the number orotovoy acid may be partially replaced in the same position on salt orotovoy acid with a biologically acceptable components with or without water of crystallization, as described in the present example, which also allows in this case to achieve therapeutic effect of the medication.

In this case, the composition for 100 soluble in the intestine standard doses includes the following ingredients:

Orotic acid, anhydrous (1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinecarbonitrile acid) - 19,00

Zinc salt orotovoy acid - 1,50

Hydroalcoholic potassium, anhydrous - 8,80

Potassium salt orotovoy acid - 4,50

Lithium salt orotovoy acid - 1,30

Magnesium salt of nicotinic acid, anhydrous slow exit - 9,00

Magnesium oxide - 2,20

Magnesium salt orotovoy acid - 9,70

Sodium iodide - 0,014

D(-)-fructose - 1,10

Minimum active against stress daily dose preezy.

Pharmaceutical manufacturing technology two complementary standard doses is carried out in accordance with the stages described in example 1.

Brief description of drawings

Medicine against stress, reduce activity and aging according to the invention was tested on laboratory animals. The following describes the three test pre-clinical trials conducted in accordance with etiopathogeny-therapeutic trehvariantnoy scheme of the experiment, which are presented in table 1, and allows for the analysis of normal (control, healthy) brain compared to those subjected to stress, and with that, restored thanks to therapeutic action of drugs against stress, reduce activity and aging. Disruption of normal brain function was achieved when using three types of stress, characteristic of people (mental, biological and General), and recovery from stress was achieved by the introduction of drugs in the preventive, therapeutic and restorative purposes.

The goal of a comprehensive experimental scheme, developed by the authors medication according to the invention consisted in identifying structural, ultrastructural and biochemisty him of stress, when the wear and aging, to reveal the basic mechanisms of this phenomenon and, on the basis of these facts, to formulate, implement and conduct pre-clinical efficacy trials etiopathogeny therapy against stress, decreasing the level of activity and ageing (Riga , S., Riga, D., Results of preclinical researches on experimental cheking-up of the Antagonic-Stress drug, Institute of Neurology and Psychiatry, Bucharest, 1985-1989, in Romanian language).

For each type of stress the nervous system was investigated using three types of methodology. The first consisted in the electoral selection of living brain cells (neurons and neuroglial) and their analysis using phase-contrast microscopy (W. T. Norton, Poduslo, S. E., Neuronal soma and whole neuroglia of the 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 language). The second methodology was neuromorphology, structural analysis of the brain using light, fluorescence microscopy (Thompson S. W., Hunt, R. D. Selected Histochemical and Histopathological Methods, C. C. Thomas, Sprigfield, III, 1966) and electron microscopy (M. A. Hayat, Principles and Techniques of Electron Microscopy, volume I (Biological Applications) Van Nostrand Reinhold, new York, 1970; Riga, D., Riga, S., Popescu, A., Perieteanu M., Constantinedical Sciences, 14, 903, 1978). The third methodology, neurobiochemistry, was carried out by extraction from brain research informative macromolecules - nucleic acids (Santen R. J., Agranoff, B. W., Studies on the estimation of deoxyribonucleic acid and robonucleic acid in rat brain, Biochimica et Biophysica Acta, 72, 251-262, 1963; Munro, H. N., Fleck, A., Recent Developments in the measurement of nucleic acids in biological materials, Analyst, 91, 78-88, 1966) and protein (Lowry O. H., N. J. Rosenbrough, Farr A. L., Randall R. J., 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 the Nervous System), Plenum Press, new York, 1969).

The purpose of using these methodologies, which mutually check and confirm the results consisted in the comprehensive study of quantitative and qualitative methods of brain normal brain subjected to stress, and brain rehabilitated through treatment for stress, wear, at all levels morfomekhanicheskii organization (regional, tissue, cellular, subcellular and macromolecular levels).

Preclinical test I. Efficacy of a drug according to the invention as a prophylactic to protect the brain from exposure to mental stress.

Disruption of normal activities Gy chronic pain. To the floor of the cell was summed direct current strength 4 mA, causing reflex of getting on the platform, placed into the cell; after 30 minutes through this platform began to pass within 2 seconds, the current 6 mA, repeating it with chaotic intervals for 3 hours, which caused chronic pain (modified test Desiderat O., Tesa M., Shock-stress, gaster lesion and habituation in the chronic gastric fistula rat, Physiological Behaviour, 16, 67-73, 1976). Thus, for animals was established experimental model of anxiety (stress, neurosis, pain, fear, anxiety). Preventive protection of the brain was carried out by daily administration of medication according to the invention before exposure to mental stress during the same period of time - 2 weeks.

The research methodology, in particular, consists in the selective allocation of living cells (neurons and neuroglial) from the cerebral cortex and their analysis using phase-contrast microscopy; thus identified and compared morphological features of normal cellular damage caused by mental stress and anti-stress protection of nerve structures in the applied treatment.

Data preclinical ispri their comparison shows specific protection from mental stress, achieved at the cellular level (soma and processes of neurons), and at the subcellular level (by stabilizing the membranes of lysosomes, protection of lipoprotein membranes of other neuro - and glioblastoma organelles and

due to the anti-catabolic effect, ultrastructural homeostatic action - protect cellular integrity).

Pre-clinical test II. therapeutic efficacy of a drug according to the invention for recovery in the brain of informational macromolecules, destroyed by exposure to biological stress

Disruption of normal brain function due to biological stress was obtained by continuous ethanol intoxication adult rats for 2 months (at a concentration of 15% daily, oral, water for drinking). Thus in animals using intestinal routes of exposure was established experimental model of chronic alcoholism. The recovery of the brain was carried out by daily administration of medication from stress according to the invention at the same time with the factor of biological stress and during the same time period - 2 months.

The research methodology, in particular, consists in the selection and islh and water-insoluble); thus was revealed and compared neurobiochemistry typology normal, damage to the nervous tissue macromolecules in the biological stress and normalization in relation to stress in the applied treatment.

Data preclinical studies of therapeutic effectiveness of drugs according to the invention are shown in tables 2 and 3. When comparing results show the typical effect against stress and reduced level of activity as violations caused by biological stress on the level of informational macromolecules of the nervous system, is reduced. The treatment led to a marked stimulation of anabolism, for regeneration of ribosomes and proteins, expressed in the increase in the number of total RNA, total protein (HE), number of water-soluble proteins (GRP) and increasing ratios of RNA/DNA, RNA/OP, which is accompanied anti-catabolic protection of nerve cells, protection against oxidative stress and protection from cross-linking of macromolecules, which was manifested in the reduction of water-insoluble proteins (VNRP) and ratio (VNRP/OP)100. The effectiveness of treatment for stress to reinvigorate the studied structures is statistically significant and is located on the equations (VNRP/OP)100) and 94,0% (ratio RNA/OP), as shown in table 3.

Preclinical test III. Therapeutic recovery efficiency of the medicament according to the invention in relation to reinvigorate the nervous structures and recovery of information macromolecules brain disturbed by the effects of stress

Disruption of normal brain activity in the General stress was obtained by accumulation in adult rats (8-9 months of age) chronic wear in the "life problems" for 16-17 months of life to achieve physiological age (24-26 months), followed by socio-sensory deprivation, thus creating an animal experimental model of accelerated reduction of the level of activity and ageing. Reinvigorate the brain was achieved by daily within 2 months of the destination old rats restorative treatment medication according to the invention have activity against stress, decreasing the level of activity and anti-aging.

Selected comprehensive methodology for the study of the brain, in particular, is to use neuromorphological methods (light, fluorescence and electron microscopy) and neurobiochemistry met oraut and confirm each other. Thus, were identified and compared makromolekulare-structural typology of the brain in normal marrow with impaired function of the total stress and the brain, reanimated by therapeutic rehabilitation.

Data preclinical evaluation of therapeutic restorative drugs according to the invention shown in Fig. 7-27 and in tables 4 and 5. Comparative results show that the drug significantly reduces disturbance and damage identified in the brain when exposed to stress, chronic wear and accelerated aging that is based on intensive and complex specific etiopathogeny actions in relation to neuropsychiatric and biological reinvigorate.

The effectiveness of treatment at the level of catabolic regulation of nerve cells demonstrated on the basis of data about a considerable reduction of pigments lipofuscin, accompanied by the rehabilitation of the neurons at the subcellular level. These therapeutic actions identified 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 using electoro reduce pigments lipofuscin, carried out in accordance with the comprehensive mechanism: anterioposterior, neural and glial-lipofuscinosis and elimination of lipofuscin by transport previously produced lipofuscin (fragmentation and partial rastvorennye) of neurons in the stroma and later in the capillaries. Successive stages of this mechanism in their dynamics shown by electron microscopy of the brain, the initial and intermediate stages of Fig. 16-18 and intermediate and final stage in Fig. 19-21.

The effectiveness of the treatment in regard to anabolic regulation of nerve cells was shown by the recovery of the population Taurus Nissle (accumulations of granular endoplasmic reticulum and free ribosomes), followed by regeneration and rehabilitation of other neural subcellular compartment. Therapeutic effects proven in cellular-subcellular level using light microscopy, cytochemistry (Fig. 22-24) and using electron microscopy (Fig. 25-27). Combating chronic stress and accelerated decline in the activity of the nervous system (geoanalyst + hypercatabolism), activaloe recovery Taurus Nissle and neural cellular regeneration, Khujand is taynov, that was evident by the amount of total RNA, total protein, soluble protein and ratios of RNA/DNA, RNA/OP associated with protection from catabolism and macromolecular cross ties, which have been shown to reduce vodorastvorimogo protein ratio (VNRP/OP)100, as can be seen from tables 4 and 5. The recovery efficiency of the medicines in relation to reinvigorate a stress-reducing activity levels and aging statistically significant and is between the 45,0% (VNRP) and 82,0% (total RNA) that can be seen from table 4, and between 55,9% (ratio (VNRP/OP)100) and 111,3% (ratio RNA/OP), as shown in table 5.

In all three tests described above preclinical studies of a drug to produce results used only part of the methodology:

selective allocation of the brain of living nerve cells in preclinical test 1,

- nairobikenya in pre-clinical test II,

- neuromorphology and nairobikenya in preclinical test III.

The application of other studies of the brain, shown in table 1, for each type of stress were obtained similar and equivalent to achiev the e normal brain function due to mental, biological and General stress and therapeutic results again confirmed the effectiveness of the treatment against stress, reduce activity and aging with the use of the drug according to the invention in the prophylactic and therapeutic and remedial purposes.

Using experimental neuro-psycho-biological model and complex methodologies, the inventors have shown on etiopathogeny level that three types of stress (mental, biological and General) cause, accelerate and increase the wear and aging of the brain as a result of exceeding the adaptive capacity of the nervous system (including those in respect of oxidation and free radicals) because of the intensity, frequency and constancy of stress. Thus, etiology, is the impact of stress and chronic lower level of activity (stress caused by ischemia and hypoxia, oxidative stress, stress caused by free radicals, peroxidebased), leads to the appearance in the brain characteristic pathology, namely structural and biochemical disorders and injuries at the cellular, subcellular and macromolecular levels (peroxidizable, polymerizati the new data on the reduction of anabolism (regeneration), the increased catabolism (degradation) and in the accumulation of pigments lipofuscin in nerve cells.

Efficiency etiopathogenic action of drugs according to the invention in relation to stress, decreasing the level of activity and ageing exactly proven in pre-clinical tests based on the correction of violations and countering the damage that is manifested in the brain when exposed to stress, which also can be seen from tables 6 and 7. In these tables summarize the stage and therapeutic mechanism in etiopathogeny sequences, experimentally tested on animal models, neural (cell), subcellular and macromolecular level. They show therapeutic intervention on metabolic and ultrastructural levels, in relation to two main areas of metabolism, namely anabolic regeneration and regulation of catabolism with removing peroxidizing subcellular waste. These therapeutic mechanisms reinforce ultrastructural and metabolic homeostatic intervention and form the basis of the plasticity of nerve cells, aimed at increasing the stability of the nervous system and adaptive capacity of the organism, which is a natural ant is anyone testing in addition, shows the preventive, therapeutic and restorative efficacy of a drug according to the invention in relation to stress, decreasing the level of activity and aging in those areas of the brain that are directly involved and are constantly exposed to stress due to chronic exposure to stress factors, the constant voltage when the General adaptation reactions and neuropsychiatric and biological reduction of activity level. As can be seen from the drawings and tables, this structural macromolecular specificity of therapeutic effects characterized in the brain at the following levels:

at regional level: destination brain, the cerebral cortex, hippocampus; intermediate brain, the reticular formation;

- at the tissue and cellular level: neurons and neuroglia (astrocytes, microglia and oligodendrocytes);

on the subcellular level: anabolic system (bullock of Nissle; free ribosomes, granular endoplasmic reticulum, Golgi apparatus) and catabolism (the pigments lipofuscin; primary - secondary - tertiary complementary mechanism);

- at the macromolecular level: nucleic acids (DNA and RNA) and proteins (total, soluble and not what I'm on Guinea pigs and mice, as shown in comparative terms, the impact of stress factors - decrease in activity level, aging in long-term experiments leads to the same typology brain damage (metabolic and ultrastructural) in rats, Guinea pigs and mice, regardless of the type of animal. The results of the authors also confirmed by similar data published in the prototype against rodents (Samorajski T. , Keefe J. R., J. M. Ordy, Intracellular localization of lipofuscin age pigments in the nervous system, Journal of Gerontology, 19, 262-276, 1964; Johnson Jr. J. E., Miquel J., Fine structural changes in the lateral vestibular nucleus of aging rats, Mechanisms of Ageing and Development, 3, 203-224, 1974), primates (H. Brody, D. Harman, J. M. Ordy (ed-s), Aging, volume I (Clinical, Morphologic and Neurochemical Aspects in Aging Central Nervous System), Raven Press, new York, 1975) and humans (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 "Victor Babes" Institute, Bucharest, March 29, 1974, in Romanian; Davison, A. N., Thompson, R. H. S. (ed-s), The Molecular Basis of Neuropathology, Edward Arnold, London, 1981; Condorelli D. F., 'avola R., Ragusa N., Giuffrida Stella, A. M., Macromolecular synthesis in developing and aging brain, pages 243-257, A. Castellani, C. Balduini, Volpe P. (ed-s), Macromolecules in the Functioning Cell, Consiglo Nazionale delle Ricerche, Roma, 1988).

Therefore, the same typology damage in animals and humans and that is characteristic for a person (mental stress pain, fear; biological stress - ethanol dependence; and General stress accelerated wear and aging), allowed us to conclude that the actions and mechanisms of stress reinvigorate (tested in pre-clinical studies on the brain of the animal) are similar to those for the human brain.

This therapeutic conclusion, in addition, demonstrated in three series of experiments on the clinical use of drugs according to the invention in accordance with the clinical scheme approved Pharmacovigilance and Drug Commitee of the Ministry of Health, Bucharest, Romania. Because pathology is directly related with stress, accelerated the decline in activity and premature aging to establish the equivalence of pre-clinical (animal) and clinical (human) pathologies and therapeutic effects in clinical studies covered three types of diseases: neurasthenia, chronic alcoholism and chronic cerebral circulatory insufficiency.

Clinical trial I. therapeutic efficacy of a drug according to the invention in the treatment of neurasthenia

Neurasthenia (fatigue syndrome) attributable who categorized nervous hung the(10 patients) for testing drugs against a wide range of forms of neurasthenia, psychosomatic and somatic and mental disorders.

Characteristics of the test groups were as follows: 30 patients (15 hospitalized and 15 working patients in conditions of chronic stress), both sexes (15 men and 15 women) from 20 to 58 years (mean age 37 years). Selected group was homogeneous through the application of the criteria for inclusion (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 registering a similar intensities of symptoms and disadvantages of productivity. Treatment with medicine against stress, reduce activity and aging was carried out exclusively with the use of oral dosing in the course of one month.

The evaluation methodology used before, during and at the end of the treatment period included: a scale to assess the degree of neurasthenia (including 10 target symptoms, the degree of manifestation of each of which was rated on a 4 - point system), 8 psychological tests (7 psychometric on attention, memory, General intellectual efficiency, the overall average characteristics of tranceforma and electrocardiogram) and bio-humoral (conventional laboratory tests).

therapeutic efficacy of a drug according to the invention was "very good" and "good" in relation neurasthenic disease and syndrome as an in-hospital patients with neurasthenia, and for working patients; neuropsychic and somatic action was maintained for a long period of time. It has not been registered harmful reactions. therapeutic benefit obtained after 1-2 weeks of treatment (S. Gorgos, Botezat - Antonescu I., Results of clinical trial with Antagonisc-Stress drug in neurastenia, "Titan" University Policlinic, "Titan" Mental Health Centre, Bucharest, 1988, in Romanian language) has been proven clinically and paraclinical the existence of such facts as:

(a) quantitative and qualitative regression and disappearance of symptomology specific to neurasthenia, normalization of biorhythm wakefulness-sleep, disappearance of neurovegetative disorders psychosomatic disorders; along with

b) normalization of the characteristics of a specific activity with the restoration of motivation and ability to work, followed by increasing professional effectiveness;

C) emotional stabilization (obshenationalnaya) and increased neuropsychiatric resistance to the effects of psychosocial stress factors in cllective metabolic regulacije, and functional normalization of nerve cells;

e) a manifestation of anti-ischemic myocardial moderately hypotensive, hepatoprotective and normalizing lipidemia effects in those patients suffering from these disorders to treat.

Clinical trial II. therapeutic efficacy of a drug according to the invention in the treatment of chronic alcoholism

- Studied cases of chronic alcoholism (ethanol dependence) were moderate and heavy, with a duration of alcoholism from 10 to 35 years with neuropsychiatric and somatic reduction in activity level and negative psychosocial consequences.

Characteristics of the test groups were as follows: 30 inpatients, only men (because the frequency of severe alcoholism among men is 2-5 times higher than in women), aged from 31 to 59 years (mean age 47 years). The homogeneity of the selected groups was achieved through the application of the criterion for inclusion in the framework of each criterion severity (based on medical history, psychiatric, psychological, psychosocial, somatic, screening tests, lack of therapeutic results when using cal Manual of Mental Disorders (DSM-III), third edition, revised, American Psychiatric Association, Washington, DC, 1987). Treatment with medicine against stress, reduce activity and aging was carried out exclusively with the use of oral dosing in the course of one month.

The evaluation methodology used before, during and at the end of the treatment period included: psychiatric assessment interview-examination, the scale to assess the degree of chronic alcoholism (10 points), the scale Hamilton depression (21 points), psychological assessment - Bourdon-Anfimov, Herwig III subtest COD scale intellectual test Veksler for adults, Klazow, auditive Ray, scale memory Veksler (M. Q.), Raven (I. Q.-matrix b I sheet), Lusher; clinical assessment - neurological, ophthalmological, therapeutic; paraclinical evaluation - bioelectric (electroencephalogram and electrocardiogram), hematological, metabolic, and immunological screening tests.

Expressed therapeutic efficacy was fast in getting therapeutic improvement, which was constant, intense, multilateral and stable. There has been no toxic effects and adverse reactions. Therapeutic useful the ial 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 a comprehensive clinical and laboratory methodology, is a consequence of the multilateral effects of the medication and its effectiveness:

a) psychotropic effects - psychologiest metabolic regulation, antidepressant, Neotropical, normalizing the sleep action, neuropsychiatric doctrines; remission in the treatment of symptomology of the syndrome, acquired dependency and tolerance; Energeticheskie action as a result of increase (normalization) and preserving and maintaining mental abilities, followed by stabilization behavior affective/emotional, and family/social point of view, which increases the resistance to stress factors;

b) neurotropic effects - cerebral vasodilator, correction of cerebral electrogenesis, regression until the disappearance of the signs and symptoms of alcohol toxic deficit, encephalomyelopathy;

in) somatotropine effects - eye - trophic and vasodilator action; hepatoprotective and anti-toxic effect - rapid remission pectorales blood supply, reduction of bioelectric characteristics of alcohol myocardiopathy, disease, also called chronic Smoking, moderate hypotensive effect; the total recovery of the body and anabolic stimulation;

d) hematological effects - Antianemic effect, normalization of macrocytosis and moderate leukocytosis;

d) metabolic consequences of anabolic recovery, hypolipidemic and hypoglycemic action;

e) immunological effects - immunostimulation by restoring humoral and mediamoo cells, immunolo deficit.

Clinical trial III. therapeutic efficacy of a drug according to the invention in the treatment of chronic cerebral circulatory insufficiency

Of several types of chronic cerebral circulatory insufficiency, the authors chose decompensation occur in the vertebrobasilar region, patients had both weak and insufficient vascular system, the somatic basis of the biological reduction of the level of activity and ageing, the body which was characterized by the presence of signs of stress-factors, risk factors and diseases caused F, both sexes (11 men and 19 women), 47 to 72 years (mean age 59 years). Selected group was homogeneous through the application of the criteria for inclusion (positive diagnosis) and exclusion criterion (different diagnoses) (Organization Mondiale de la Sante (OMS), Applacation makes sense or not, a la de la Classification Internationale des Maladies (CIM-AN), OMS, Geneva, 1989, in French). Treatment with medicine against stress, reduce activity and aging was carried out exclusively with the use of oral dosing in the course of one month.

The evaluation methodology used before, during and at the end of the treatment period included: neurological examination map, scale for the assessment of chronic cerebral circulatory insufficiency (including 10 target symptoms, the degree of manifestation of each of which was rated on a 4-point system), bioelectric research (electroencephalogram and electrocardiogram) and bio - humoral research (laboratory tests).

therapeutic efficacy of a drug according to the invention proved to be very good (fast, General and reliable). It has not been registered harmful reactions. therapeutic benefit (Stamatoiu I., R. Dimitriu, Nicolae I., Results of clinical trial with Antagonisc-Stress drug in cronic cerebral circulacoveli M, Results of clinical trial with Antagonic-Stress drug in chronic vertebrobasilar insufficiency, "Gh. Marinescu" Clinical Hospital, Department of Neurology, Bucharest, 1988, in Romanian), fixed by means of clinical and paraclinical methods, confirms the efficacy of a drug to protect the brain and treat brain from ischemia, hypoxia, chronic stress and accelerated wear and consists of:

a) rapid regression of neurological and asthenic symptomologies, followed by disappearance of symptoms;

b) improved cortical electrogenesis and reduce until the complete disappearance of bioelectric signal myocardial ischemia;

C) obtaining a shared biological reactions neuropsychiatric reinvigorate (cerebral vasodilator, nutrinova and psihologicheskogo metabolic actions) and somatic reinvigorate (hepatoprotective, moderate antihypertensive and normolipidemic actions, and also as a result of synergies with the treatment of hypoglycemia).

Versatile and increased therapeutic efficacy of a drug according to the invention, confirmed three pre-clinical tests and three clinical trials, was obtained due to the fact, kterou, and also due to its specific and sinergeticheskogo action against stress, reduce activity and aging.

Thus, the drug is energiticheskuyu, biological, neurometabolic and providing trophic cell composition with active antistress active ingredients (psychotropin, neurotrophic, hepatotropic and myocardiopathy components), the main (normal) components of biological systems and the Central nervous system, which overcome the blood-brain barrier, are active and have the physiological affinity with biochemical structures of neurons and glial cell has, specifically in control of cerebral blood flow and metabolism. Representing biological medicine, it is easily absorbed and is non-toxic, does not cause harmful reactions that do not lead to the development of tolerance to it and dependency, and it is not dangerous and can cause overdose or intoxication; drug itself has anti-toxic, detoxifying and homeostatic actions. In addition, you can apply it with a long introduction as medicine for neurona, polimetallicheskoe and ultrastructural regulation of the brain that is necessary in terms of strengthening and increasing the duration of action of stress factors and intensification of neuropsychiatric and biological deterioration.

Specific homeostatic and etiopathogenic action of drugs in relation to stress, wear and ageing reach with his direct use (primary and secondary) or in the form of prodrugs, thanks to its active antistress components with more synergistic and more polyvalent action:

a) against oxidative and catabolic stress;

b) in respect of anabolic stress;

b) vasodilator and normalizing lipidemia action;

g) energoaktivami effect; and

d) anti-toxic effect.

a) Components that are active against oxidative and catabolic stress medicine against stress, reduce activity and aging according to the invention are: methionine, aminoethylethanolamine (meclofenoxate provided macrocultural, alienist, Difenoxin) and/or aminoethylethanolamine (mefenamic, phenoxides, Mexican, fipexide).

Methionine is particularly the joining, as well as catabolic stress, as a donor of methyl groups, metabolic supporting these biohimicheskie response the General adaptation syndrome against the effects of stress.

Meklofenoxat is a biological compound, an organic ester, which as a result of hydrolysis is converted in the brain into two natural metabolically active substances: parachlorometaxylenol acid, a phytohormone (auxin) and brain modulator of neurotransmitters, and dimethylaminoethanol, natural amerosport, the precursor of brain acetylcholine and cerebral lipids (phospholipids and sphingolipids).

Etiopathogenic action of the active compounds against oxidative and catabolic stress reach by providing metabolic support: maintaining biological antioxidant defense systems, the ability to remove free radicals, anti peroxidizability lipids, polymerization and cross-linking of the macromolecules (counter-mechanisms of formation and accumulation of the age pigment lipofuscin), lipofuscinosis, recovery, negative balances (Colnago, sulfur, methyl, halinowego,the action of excess accumulation of calcium in the brain (induced damage of cell membranes and the influence of free radicals). Thus, the active ingredients against oxidative and catabolic stress also have a toxic effect on the nervous system.

Specific action components against oxidative and catabolic stress increase due to the use of other active ingredients in the medicine according to the invention.

For example, for action against anabolic stress use Orotava acid (lipofuscinosis), piracetam (decrease the number of cerebral neeterificirovannah fatty acids in relation to their increased content under stress), zinc (antioxidant), lithium (anticatabolic), and the entire class of compounds acting through anabolic regeneration that prevents catabolism and degradation.

Vasodilator and normalizing lipidemia components, an example of which is nicotinamide (which reduces cerebral nonesterified fatty acids in relation to their increased content under stress), have anti-stress caused by hypoxia-ischemia and chronic alcoholism, leading to the accumulation in the brain of the pigment lipofuscin.

In its ocher is oxidative and catabolic stress through detoxification and removal of products of catabolism in nerve tissue on the structural, metabolic and molecular level.

Thus, the active ingredients against oxidative and catabolic stress are agents that protect against old age, because they slow down the wear on the subcellular level and the aging process in the brain tissue which has a high sensitivity to oxidative stress and free radicals.

therapeutic efficacy of a drug according to the invention in combating oxidative and catabolic stress was shown at the neural level: using protection, stabilization, stability of neural and glial membranes (in the simulation of mental stress on animals); neurobiochemical using protection cerebral macromolecules and reducing the amount of cross-linking in protein macromolecules; and neuromorphological (using light, fluorescence electron microscopy) on the basis of the action against the formation of lipofuscin, lipofuscinosis in neurons and glia, as well as data about the elimination of lipofuscin (when the animal models of chronic alcoholism and aging). Homeostatic effect against oxidative and kataboliticheskom and pancreatic cytolytic (hypercatabolism) syndrome and on the basis of rapid functional and metabolic normalization of the liver.

b) Components, active against anabolic stress medication according to the invention have activity against stress, reduce activity and aging, are hydroxyaminomonocarboxylic (as Bioelements drugs - orotic acid and orotate) and/or oxopropionate (piracetam, oksiratsetam, etirazetam, dimethylphenylpiperazinium, pramiracetam, aniracetam), associated with potassium, zinc and lithium.

Orotic acid (vitamin b13) has a pronounced action on the anabolic regeneration, because it is a natural metabolic precursor common to pyrimidine nitrogenous bases (uracil, cytosine, thymine, 5-methylcytosine) nucleic acids (DNA, RNA) and high energy pyrimidine nucleotides (UTP, TTF and TTF) or compositions of coenzymes (UDF - glucose, D.O.-galactose, CDP-choline), which are involved in carbohydrate and lipid metabolisms: which along with the metabolism of proteins and nucleic acids are especially important for the brain. Thus, orotic acid has lipotropin effect, stimulating the synthesis of phospholipids, as well as increasing the synthesis of glycogen in liver cells, myocardium and in nolichuckey support long-term memory. Thus, orotic acid is a powerful natural anabolic and biological support for the brain, liver and myocardium.

Piracetam activates the biosynthesis of cerebral macromolecules (RNA, proteins) and lipids, primarily when recovering from hypoxia and in older animals, in which it enhances the synthesis of polyribosome and their distribution, providing the energy transfer between systems that produce energy and consume (cellular anabolism, cellular regeneration).

Potassium, zinc, lithium and other neuroactive Bioelements drugs according to the invention (magnesium, iodine, monopotassium phosphate, sulfate) are intracellular one - and divalent cations and anions that are important to living matter. They play a structural (plastic) and metabolic (dynamic) role and involved in major biocatalytic system functional adaptation of cells, enzymes, hormones, vitamins and high energy compounds. They have specific functions in relation to the metabolism and physiology of nerve cells: neurotransmitter activity, the processes of excitation and inhibition, the conduction of the nerve cells and explanationsthe transport is poxie-ischemia observed a negative balance, in particular magnesium, zinc, sulfate, and iodine. Magnesium is a subcellular stabilizer, lithium - humoral regulator, and the limbic system shows increased sensitivity to this bioelement, and the concentration of zinc is increased in the hippocampus.

therapeutic efficacy of the active compounds against anabolic stress is also supported by other active ingredients of the medicaments according to the invention, as previously observed for other bio-elements, taking into account the dependence of cerebral anabolism from cerebral blood flow and energy metabolism of nervous tissue.

Thus, the activity of drugs against oxidative and catabolic stress by using methionine and aminoethylethanolamine. In the brain of a methyl group, supplied by methionine, actively absorbed in the process of anabolism neurotransmitters in cerebral lipid biosynthesis and post - transcriptional methylation of macromolecules nerve cells of nucleic acids and proteins. Meklofenoxat increases the synthesis of cerebral RNA and levels of high-energy nucleotides, and through the product of its hydrolysis (dimethylaminoethyl the effective vasodilator components (in relation to stress, caused by hypoxia-ischemia) provide nutrients that are necessary for anabolic regeneration and to counteract the processes caused by anabolic stress (gipoksena-ischemic stress).

Energoaktivami connection: aspartate (a precursor in the biosynthesis of purines and pyrimidines), fructose, vitamin b1vitamin b6and monopotassium phosphate provide energy support necessary to enhance anabolism.

therapeutic efficacy of a drug according to the invention in combating anabolic stress, chronic alcoholism and tear of the nervous tissue and intensive functional ultrastructural anabolic activation and regeneration of nerve cells have been demonstrated in the brain of animals with neurobiochemistry methods based on the data about the increase in the number of RNA, total protein and soluble protein, and neuromorphological method (using light and electron microscopy) based on the restoration of the population of the Taurus Nissle, granular endoplasmic reticulum and free ribosomes in neurons. Anabolic regeneration was what knosti and immunodeficiency, on Antianemic action and increased weight gain.

in Active vasodilator components (in relation to the stress caused by hypoxia-ischemia) and normalizing lipidemia components of the medication according to the invention have activity against stress, reduce activity and aging, are nicotinic alcohol and/or acid or their derivatives (nicotinamide, nicotinate magnesium) magnesium and iodine.

They act etiopathogeny way by increasing cerebral blood flow, increased permeability of the blood-brain barrier transport of glucose by improving the supply of nerve and myocardial cells anabolically and their purification from catabolites. These compounds possess anti-spastic, antispasmodic effect, physiological cerebral vasodilator (primary southcroft) and carry out natural antihypoxia and anti-ischemic brain protection. In addition, they act as agents, normalizing lipidemia and lipid homeostasis by reducing high levels of triglycerides, total cholesterol, VLDL-cholesterol (cholesterol very low density lipoprotein), LDL-cholesterol (cholesterol Yu lipoprotein). In turn normalizing lipidemia action has a positive impact on the expansion of the cerebral vessels.

Moreover, therapeutic efficacy of vasodilator and normalizing lipidemia components is also based on the action of other active compounds drugs according to the invention. Active ingredients against oxidative and catabolic stress, substances active against anabolic stress, and energoaktivami substances act as psychotronic-psihologicheskih compounds in relation to the regulation of metabolism, and thus, they in addition to functional and metabolic brain stimulation are secondary cerebral vasodilator components neurometabolite. The active components against oxidative and catabolic stress, orotate and potassium, are the ingredients that are active against anabolic stress and aspartate, fructose, vitamin b1vitamin b6refer to energoaktivami ingredients to combat stress caused by hypoxia and ischemia. Orotic acid, meclofenoxate provided macrocultural and methionine are acting as agents, normalizing Lily due choleretic action (magnesium and orotic acid).

Components of the vascular action of drugs according to the invention in the form of soluble in the stomach of a standard dose without slow-release and soluble in the intestine standard dose of slow release provide as rapid vasodilator action and prolonged over an extended period (approximately 2-3 hours in the case of granules with slow release and for about 8 hours in case of slow release tablets), which is necessary for the regulation of stress-induced ischemia-hypoxia, reduction of the level of activity in normal and pathological aging. The joint introduction of two complementary standard doses allows you to achieve long-term sosudorasshiratmi (immediate + extended) required for cerebral and myocardial ischemic pathology.

The vasodilator action of drugs according to the invention can be enhanced by replacing the composition soluble in the stomach of a standard dose of aminoethylethanolamine (basic esters) aminoethylethanolamine (stabilizing amides) and including cerebral and peripheral vasodilator to phenoxetol, (bastionhost metabolic regulation (vasodilation by neurometabolic activation).

therapeutic efficacy of a drug according to the invention in combating gipoksena-ischemic stress and dyslipidemia was proven in a clinical setting for the treatment of chronic cerebral circulatory insufficiency and remission of ischemic symptomology, ophthalmic positive effects on cerebral and miocardialny electrogenic correction in the treatment of chronic alcoholism on the normalization of the lipid profile and positive effects on vision.

g) Energoaktivami components of the medication according to the invention have activity against stress, reduce activity and aging, are: aspartate, D(-)-fructose, vitamin b1vitamin B6and hydroalcoholic, which provide the energy metabolism of the nerve cells, overstressed and energetically depleted as a result of stress and reduced activity level.

Aspartic acid, which glucosamineose amino acid, the concentration of which is 96 Ámol/100 g of nervous tissue and stored in the brain in its form, designed for storing, namely in the form of N-acetylcarnosine acid in koncentracyjnych acids and GABA-shunt (especially intensive in the brain); she is also a neurotransmitter excitation and performs mobile communication between the metabolisms of carbohydrates, energy, nucleic acids and proteins in the nerve cell.

D(-)-fructose, natural monosaccharide, which is metabolized independently of insulin path, increases the reserves of glycogen in the liver or quickly integrated in the form of ether monophosphoric acid (D(-)-fructose-6-phosphate in the pentose-phosphate shunt (oxidative decomposition, intrinsic nerve cells) or anaerobic glycolysis.

Vitamin b1vitamin B6and vitamin PP (nicotinamide), the latter refers to the vasodilator components are exogenous biocatalysts that are absolutely necessary for life and enjoyment of normal nerve functions. In its forms esters of phosphoric acid (tiaminpirofosfat and pyridoxal-5-phosphate) or nucleotides (nicotinamide mono - or dinucleotides) they are coenzymes enzymes for many of the major enzymes involved in energy, carbohydrate, protein and lipid metabolisms. As a result of increased intensity of cerebral metabolisms nervous system concentrates these vitamins in different zones and Chu what codevisitor, caused by chronic alcoholism. Vitamin b1plays a major role in the metabolism of lactic acid, pyruvic acid and the tricarboxylic acid cycle, and vitamin b6- activation of GABA-shunt, being thus metabolic by countering stress in nerves.

Hydroalcoholic is a supporting factor, metabolic reserve in energy metabolism, and it is involved in the phosphorylation of glycidol, as part of carbohydrate metabolism; involved in phosphorylation of vitamin B1IN6and PP to activate them in the coenzymes; and participates in the synthesis of energy-accumulating high energy compounds such as ATP, UTP, etc.

Therapeutic efficacy energoactivity components is confirmed by the effect of other active ingredients of the medicaments according to the invention, which homeostatic involved in many stages of cerebral glucose and energy metabolism.

Thus, the components that are active against oxidative and catabolic stress, are as follows: aminoethylethanolamine increases the transport of glucose and phosphate from the blood into the brain, osushestvlya acids, the use of oxygen in nerve cells; components such as aminoethylethanolamine, have a strong energoactivity, psychobabulous action; methionine acts indirectly, by participating in biological methylation (synthesis of adrenaline, acetylcholine and creatine).

The components that are active against anabolic stress, are as follows: orotic acid saves energy during direct synthesis of pyrimidine nitrogenous bases, coenzymes and high energy compounds with uracil during re-synthesis of glycogen, piracetam stimulates energy generation system, increases the utilization of glucose by aerobic glycolysis, ATP synthesis in the brain and in vitro respiratory quotient mitochondria (the cellular organelles responsible for the biosynthesis of ATP); and potassium, and zinc is involved in many enzymatic reactions, accompanied by release of energy.

Vasodilator components (active against gipoksena-ischemic stress) carry out the action by increasing the number of anabolicos and oxygen in the brain; nicotinamide, a precursor in the synthesis of coenzymes NAD (NAD) and NADP (NADP), plays an important role in cleocin is, the biosynthesis of high energy compounds in oxidative phosphorylation; and iodine produces a General activation of the metabolism mainly in the brain, especially in the hypothalamus, and also accumulates in the spinal cord and the medulla.

Association energoactivity neurometabolic components with those involved in neutrino-psihotehnicheskoi regulation of metabolism (aminoethylethanolamine, AMINOETHYLPIPERAZINE, hydrooximethylcarbamile and/or oxopropionate), and methyl group donors (methionine, pramiracetam), as well as with physiological cerebral vasodilator substances (with rapid and prolonged action) in relation to the mental state creates psihologii (antiasteniceski) effect, increased mental abilities (attention, memory, intellectual activity), antidepressant effect, higher resilience to stress, wear, hypoxia and normalization of cerebral electrogenesis. These effects were confirmed in a clinical setting for the treatment of neurasthenia, chronic alcoholism and chronic cerebral circulatory insufficiency when IP is latausha activity against stress reduction of the level of activity and aging, are etiopathogeny activity against hypercatabolism and conditions associated with a deficiency of toxicants due to oxidative stress and accumulation of endogenous toxic compounds exhibited on ultrastructural and metabolic level when exposed to stress and reduced level of activity during hypoxia-ischemia, chronic alcoholism and aging.

This activates the metabolic processes of detoxification, which in turn leads to the:

- reduce the number of free radicals formed during oxidative stress by aminoethylethanolamine, methionine, orotovoy acid and zinc;

- elimination of acidosis and cellular lipoxidase caused by accumulation of lactic and pyruvic acids in the result of oxidative stress, hypercatabolism of glucide, thiamine-carbohydrate imbalance, hypoxia-ischemia, alcoholism, using aminoethylethanolamine, orotovoy acid, potassium, zinc, magnesium, vitamin b1and vitamin b6;

- elimination of the accumulated excess of ammonia in the result of protein catabolism with aspartic acid via the urea cycle using transamine the power of methionine and sulfate, in glucuronoconjugation using fructose, methylation - using methionine and pramiracetam;

- to counter the excessive accumulation of calcium in the brain using aminoethylethanolamine.

Also activated processes of cellular detoxification, which result in:

- reduce the number of cross-links that make proteins-enzymes insoluble and inactive.

- reduction of peroxidizable lipids caused by oxidative and catabolic stress by affecting lipofuscinoses using lipofuscinosis and elimination of lipofuscin.

Methionine, an essential amino acid, is a natural detoxifier and lipotropes substance, the source of sulfur, metabolic donor of methyl groups and predecessor-SH and sulfate groups plays a complex role in presenting an important metabolic support antioxidant and detoxifying activity.

Oral medication according to the invention has the advantage of direct antioxidant and hepatoprotective actions and actively supports detoxifying metabolic processes in the liver, given the primary role of the liver in these processes. This fact was obyedinenie antitoxic (metabolic-ultrastructural level) vasodilator (anticipating, anti-ischemic, inflammatory and anabolic regenerative (sub-functional level) with activity against oxidative hypercatabolism stress (destruction of neural lipid peroxides) and energoactivity action on plastic and functional level leads to trophic action (in relation to the nervous tissue, liver, heart) and neuropsychiatric and biological rehabilitation of using the medicine according to the present invention.

Industrial applicability

Therapeutic indications for use drugs according to the invention is due to:

- included in the fundamental processes in neurons and glial cell has, and their maintenance due to biological, neurometabolic and providing trophic cells of the composition;

- maintaining and enhancing adaptive capacity and neuropsychiatric and biological stability thanks polimetallicheskoe regulation and cellular regeneration, especially nerve cells, liver cells and myocardium;

- simultaneous achievement of the protection of the brain, liver and heart from dysfunction caused osastoissa intervention at the level of the brain and of the body;

- correction of the basic metabolic and ultrastructural imbalances caused by stress, prolonged biological wear and associated with stress disease due to vascular, energoactivity, antitoxic action and effects on the regulation of catabolism and anabolic regeneration;

- comprehensive etiopathogeny, anti-stress action against a reduced level of activity, antiischemic, antihypoxia and antitoxic action based on his sinergeticheskoj biological and metabolic composition (components with neuroticism-psihologicheskim action vasodilator, activators of energy, stimulants to the synthesis of proteins and nucleic acids, amino acids, vitamins and bio-elements).

Introduction drugs of the present invention healthy people (in accordance with the concept of improving health and preventive medicine) provides the following effects:

- it increases the General vitality, strengthens neuropsychiatric tone;

- it increases the capacity for mental and physical stress, increasing intellectual and athletic efficiency and sposobnosti strain, stress and lower levels of activity;

it defines rapid recovery in case of fatigue, exhaustion, excessive work, after a long, stress or insomnia;

- it slows down the aging brain and the body and provides increased functional life expectancy and total life expectancy, thus preventing the reduction of the level of activity, including prescritions and atherosclerotic;

- it is suitable for use for patients of all ages (children, young people, adults and the elderly), as especially shown for 35-40-year-olds (when adaptive capacity and resilience of the start and progressively decrease), and most preferably for occupations that require enhanced mental activity, or those that require a lot of tension and coefficient of aggression (senior staff, students, athletes, pilots, command for space flights and special assignments, and so on).

Because stimulation of the brain reach due to ultrastructural, energy and metabolic regulation, the introduction of drugs according to the invention is not accompanied by depression, nervnye intensive, strengthening neuropsychiatric and the overall effect obtained over an extended period.

The medicine according to the invention is administered to sick people with therapeutic and rehabilitation goals, increasing daily active dose, depending on the nature and severity of the disease and the characteristics of each patient. Thanks to the flexibility of the dosage of the medicine can be used in the pathology associated with stress, psychiatric and neurological pathology in geriatrics and therapy in the following cases:

States neuropsychiatric overvoltage, disadaptive stress reactions, acute and chronic psychosocial stress;

- state depletion and biological stress caused debilitating and hypercatabolism diseases during convalescence;

nerve disorders such as impaired attention and memory, concentration, reduced intellectual ability, low ability to load, mental and physical fatigue, stress at work, exhaustion, sleep disorders; neuro disorder, emotional lability, depression;

- disorders, stress-related and disease-related stress: coronary heart disease, moderate arterial is through therapy in diabetes mellitus and its complications;

- psychogenic sexual dysfunction: impotence, frigidity, and so on;

- disorders of the endocrine States as a result of violations hypothalamohypophysial complex, the menopause and andropause;

- cerebral toxic pathology: acute and chronic alcoholism (alcohol abuse and dependence, withdrawal syndrome, mental and neurological decline in activity due to alcoholism, detox process); the abuse of and dependence on other psychoactive substances; poisoning by carbon monoxide or organic solvents;

chronic cerebral circulatory insufficiency and other forms of cerebral vascular pathology: hypoxia, ischemia, embolism, atherosclerosis;

- neuropsychiatric disorders caused by head injury, and disorders due to traumatic stress disorder;

- involutive syndromes before and during physiological aging: poor resistance to stress, physical and mental fatigue, decreased attention and memory, deterioration of mental abilities, emotional lability, depression, decreased adaptive capacity, etc.

The introduction of drugs on the image the disorders and diseases psychiatric and neurological diseases or old age, due to its therapeutic effects on behavior and emotional-affective stabilization and maintenance of cognitive function.

1. Medicinal composition against stress, decreasing the level of activity and ageing for use in prophylactic, therapeutic and remedial purposes, characterized in that it is a synergy of biological, neurometabolic and providing trophic cell composition consisting of: (a) 20,1 - 52.3% of ingredients that are active against oxidative and catabolic stress, namely for antilipopolysaccharide, lipofuscinosis and removal of lipofuscin selected from the group consisting of methionine with aminoethylethanolamine and/or aminoethylethanolamine; b) 7,0 - 35.1% of ingredients that are active against anabolic stress, namely functional and ultrastructural anabolic regeneration, selected from the group consisting of hydrooximethylcarbamile and/or oxopropionate with potassium, zinc and lithium;) of 6.7% and 8.6% active ingredients, with vasodilating action, effective against stress caused by hypoxia is e, which include magnesium and iodine; d) and e) of 16.6 19.9 per cent energoactivity and toxic active ingredients selected from the group consisting of aspartate, fructose,

vitamin B1vitamin B6, gidrogenfosfat and sulfate.

2. Medicinal composition for p. 1, characterized in that it contains the following active ingredients: 18,0 - 19,1% methionine; 31,0 - 33,1% meklofenoxat or other aminoethylethanolamine, for example macrocultural, alienist, Difenoxin 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, relative to the number of meclofenoxate provided and/or aminoethylethanolamine, for example mefenamic, phenoxetol, Mexican, 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, relative to the number of meklofenoxat; 18,8 - 20,0% of hydrooximethylcarbamile, for example Orotava acid, or such as within orotate bio-elements included in the medication, and/or to 28.3 - 31.4% of piracetam or other oxopropionate, for example oksiratsetam, etirazetam, dimethylphenylpiperazinium, 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, against the number n is, for example nicotinamide or magnesium nicotinate; 1,5 - 1,9% magnesium; 0,005 - 0,007% iodine; a 9.7 - 10.6% of the aspartate; 1,7 - 2,0% fructose; 0.9 to 1.3% of vitamin B1; 1.2 to 1.5% of vitamin B6; 2,6 - 3.5% gidrogenfosfat; 0,5 - 1,0% sulfate, all percentages refer to in relation to 100 g minimum daily active dose.

3. Medicinal composition for p. 1, characterized in that its active ingredients preferably include two pharmaceutical standard dose, complementary with respect to biological values and therapeutic activity of drugs, namely: (a) soluble in the stomach capsule or tablet with a coating containing 240 - 280 mg of the hydrochloride, meclofenoxate provided 135 - 165 mg DL-methionine, 80 - 100 mg of anhydrous DL-aspartate magnesium, 9 - 11 mg of D(-)-fructose, 7 - 9 mg of the hydrochloride of vitamin B1; 10 - 12 mg hydrochloride vitamin B6, 9 - 11 mg of nicotinic acid with nezametchennym the release for immediate release 9 - 11 mg of anhydrous zinc sulfate, and (b) soluble in the intestine capsule or tablet with a coating containing 290 - 340 mg of anhydrous orotovoy acid, 9 - 11 mg of D(-)-fructose, 70 - 90 mg of nicotinic acid sustained-release to extended release, 88 - 108 mg of anhydrous gidrogenfosfat potassium, 18 - 22 mg axiology in preventive medicine to maintain and enhance adaptive capacity neuropsychiatric and biological stability, simultaneous protection from the stress of the nervous and endocrine systems, liver, heart and blood, and for the correction of the main ultrastructural and metabolic imbalances in the stress - reducing activity - aging: a) by increasing the overall viability of the organism's abilities to mental and physical stress and resistance against overexertion, stress and accelerated wear and b) by the fast recovery state of fatigue after prolonged stress or insomnia.

5. Medicinal composition for PP.1 to 3, are used in therapy and regenerative medicine when dependent on stress pathology and accelerated aging, in particular, when (a) States neuropsychiatric overvoltage, disadaptive reactions to stress, acute and chronic stress, stress-related disorders and diseases; b) impaired attention and memory, disorders of ability to concentrate, decreased intellectual activity, reduced ability to exercise, neurovegetative disorders, depression; ischemic heart disease, moderate arterial hypertension, liver failure, chronic pancreati, dyslipidemia; g) impotency and dependence on psychoactive substances; e) chronic cerebral circulatory insufficiency and other forms of cerebral vascular pathology: hypoxia, ischemia, embolism, atherosclerosis; W) involutive syndromes under normal and pathological period prior to ageing, and ageing.

6. The method of obtaining pharmaceutical compositions for PP.1 to 3, characterized in that to provide pharmaceutical stability, maximum biological value and therapeutic efficacy it includes granulation or extrusion of meklofenoxat or related compounds in soluble form in the stomach of a standard dose of nicotinic acid sustained-release or its derivatives with a slow release of water-soluble in the intestine standard dose, mixing with other components in powder form, followed by their encapsulation in gelatin capsules with hard or soft shell, coating intersolubility shell standard doses, and containing salts substance with delayed output, or pressing with subsequent coating film, obtained from dissolving in the stomach or in the intestine of the polymer, respectively, in the form of an aqueous dispersion or solution in organic solvents, actinophage alcohol and/or acid and/or derivatives thereof, included in enteric standard dose, reach, depending on the time required for release of the active substance, or by using granules with delayed output using ethylcellulose as a retardant and diethylphthalate as a plasticizer in a weight ratio of 1/0,18 - 1/0,24, followed by coating granules of Carnauba wax as a second retardant in a weight ratio with ethylcellulose 1/0,47 - 1/0,53, or by using tablets, sustained-release, obtained by pressing of the granules with delayed output.

8. The method according to p. 6, characterized in that intersolubility coating applied to gelatin capsules with hard or soft shell, filled soluble in the intestine standard dose, using the aqueous dispersion of the polymer, resistant to the environment of the stomach - soluble in the intestine, for example cellulose acetate phthalate, polivinilatsetatftalat, phthalate of hydroxypropylmethylcellulose or methacrylate copolymer in a mixture with plasticizer selected from the group consisting of diethylphthalate, dibutyl phthalate, propylene glycol or triacetin, and the weight ratio of the solution is the IR of the polymer and the dye is 1/0,0010 - 1/0,0012, using to cover the fluidized bed at an average temperature of 70oC, in another embodiment, the stage of spraying and drying and obtaining in this way a final covering film constituting approximately 60 - 70 mg per capsule.

 

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