UA112719C2 - PHARMACEUTICAL COMPOSITION FOR THE CORRECTION OF SYMPTOMS OR THE TREATMENT OF ASTENIA AND / OR CHRONIC Fatigue Syndrome - Google Patents

Abstract

The invention relates to medicine, in particular to pharmacology, and relates to a pharmaceutical composition for the correction of symptoms of treatment of asthenia and / or chronic fatigue syndrome containing as active ingredients 2-ethylthiobenzimidazole hydrobromide and / or its pharmaceutically acceptable salt and levocarnitine in a therapeutically effective manner.

Description

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The influence of the studied substances on the dynamics of body mass is related to physical exertion. Notation: MD - combination of Bemitl and penocarnitine in a small dose), SD - combination of Bemitl and levocarnitine in a medium dose, BD - combination of Bemitl and lenocarnitine in a small dose P "0.05 compared with the stressed control and the Bonferroni test.

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The invention belongs to the field of medicine, in particular to pharmacology, namely to pharmaceutical compositions for the treatment of various conditions associated with insufficient energy potential, which is a consequence of a pathological process.

Bemityl was synthesized and studied at the Department of Pharmacology of the Military Medical Academy in the 1970s under the leadership of Professor V.M. Vynogradova It was established experimentally (Y.G. Bobkov et al., 1981, etc.), and then confirmed in clinical studies (A.S. Losev et al., 1990; A.V. Smirnov et al., 1990; Stroganov V.P. et al., 1990; Shakhnazarov A.S. et al., 1990; Sytnyk S.I., Pastushenkov V.A., 1993), which even with a single application of bemitil significantly increases the physical performance of animals and accelerates it recovery after extreme loads, especially in difficult conditions (altitude hypoxia, overheating, drafts, etc.).

With course use, the effect of bemitil increases in the first 3-5 days, and then it is steadily maintained at the achieved level (Smirnov A.V., 1993; Bobkov Y.G. et al., 1993), surpassing the speed and severity of the effect of piracetam and pyriditol (Aleksandrova A.I. et al., 1988).

In the experiment, the hepatoprotective effect of bemitil was revealed (Aleksandrova A.Y. et al., 1988), positive results were obtained in the treatment of acute cerebrovascular disorders in the model of cerebral hemorrhage (Plotnikova T.M. et al., 1993), the reparative effect was relatively of the mucous membrane of the small intestine in experimental peritonitis (Starokon P.M.,

Laryn Y.N., 1999).

The following possibilities of bemitil were also described: to increase the activity of antioxidant enzymes, especially superoxide dismutase (Katkov V.F. et al., 1989; Shakhnazarov A.S. et al., 1990); it was able to inactivate the hydroperoxide of IP more effectively than glutathione (Dizhe A.A. et al., 2002); prevent a decrease in the content of reduced glutathione, ZN groups, the activity of glutathione reductase, glutathione peroxidase of the liver during acute hypoxia in the experiment and enhance the synthesis of antioxidant enzymes of the glutathione system (I.V. Zarubina,

Mironova O.P., 2002); induce the activity of cytochrome P-450 of the mixed type, increasing the total content

From cytochrome P-450 in microsomes and monooxygenase activity (E.A. Sorokina et al., 2002); to reduce the blood lactate level in patients (Leosko V.A et al., 1996) and the intensity of POL, which is determined by the indirect antiradical pathway (Plotnikov M.B. et al., 1988, 1990); promote liver regeneration after partial hepatectomy in an experiment (Gaivoronska V.V. et al., 2002); have an antimutagenic effect (Durnev A.D. et al., 1988).

A hypothesis was put forward, according to which the mechanism of action of bemethyl (2-ethylthiobenzimidazole hydrobromide) and its analogues - derivatives of 2-thiobenzimidazole - is based on the activation of RNA synthesis in various cells, which leads to increased protein synthesis. Such action may be due to their interaction with the genome, probably due to the structural similarity of benzimidazole with purine bases - adenine and guanine (A.V. Smirnov, 1993; A.V. Smirnov et al., 1994). This effect is not organ- or tissue-specific, but it is always more pronounced in those organs and tissues in which RNA and, therefore, protein synthesis processes are actively taking place.

It is interesting that among drugs derived from benzimidazole, there are many means of the most diverse use, with various therapeutic directions: with antipsychotic (pimozide), actoprotective (bemitil, etomerzole), antiarrhythmic (mibefradil, ritmidazole), antiulcer (omeprazole, gastrozole, pantoprazole), antiallergic (astemizole), uricosuric (irtemazole), anthelmintic (mebendazole, thiabendazole). A group of benzimidazole derivatives (fenbendazole, oxafendazole, parbendazole, triclabendazole) used in veterinary medicine as anthelmintics is also presented. Does this mean that they all stimulate protein synthesis?

It is interesting that imidazole itself, as shown in an experiment on a model of myocardial ischemia (btyy ER ei aiYi., 1980), has a cardioprotective effect due to the specific inhibition of thromboxane-A2-synthetase. The latter, being a coronary constrictor and increasing in activity during ischemia, can cause further deterioration of coronary blood flow according to the "vicious circle" principle.

Smirnov A.V. and Hancho V.Yu. (1990) showed that the increase in protein synthesis occurs mainly in the brain, which they explained by the improvement of memory when using bemitil.

One way or another, it has been established that in order to maintain a high level of metabolism, as well as physical performance, an active course of gluconeogenesis in the liver and kidneys is necessary, which ensures the utilization of lactic acid and the resynthesis of glucose in various states with its high production, for example, with increased m "Yazic" activity. Enzymes of gluconeogenesis belong to proteins that have a rather short life, and their renewal is ongoing.

Strengthening the synthesis of these enzymes is the component in the mechanism of action of bemitil, which is the most important for increasing physical performance. In addition, bemythyl and its analogues activate protein synthesis, which provide the economizing effect characteristic of these drugs, reducing oxygen consumption and heat production, reducing the consumption of energy resources, including per unit of work performed.

Another hypothesis of the mechanism of action of bemitil was put forward by Yu.G. Bobkova. and co-authors (1993) and emphasizes the ability of the drug in the experiment to "accelerate the transition of superoxide radical and other free radicals into molecular oxygen, followed by its direct use in the metabolic cycle due to the activation of antioxidant enzymes - SOdD, catalase, glutathione peroxidase." We will leave this mechanism to the conscience of the authors.

Although bemythyl is an effective means of restorative and rehabilitative action and in various pathological conditions, it eliminates asthenia, increases work capacity, it can also be used in acute hypoxia.

It is interesting that in the modern training method of interval hypoxytherapy, in which artificial hypoxic hypoxia is created in patients with preventive (preconditioning) and therapeutic purposes, the use of, let's say, "correctors of the technique" is provided. In model experiments with this kind of "therapeutic" hypoxia, bemitil proved to be a reliable protector, "stimulating the development of adaptive metabolic changes in the brain, heart, liver, kidneys, and skeletal muscles" (Hagybipa I.M., 2001).

Encouraging data were obtained in the clinic, indicating the antihypoxic effect of bemitil for the prevention of myocardial damage in acute infarction, in connection with operations on the heart with artificial blood circulation, in chronic hypoxia of the fetus in pregnant women with preeclampsia, in chronic respiratory failure and viral hepatitis ( Yu.V. Lobzin, A.V. Smirnov, 1993; Yu.L. Shevchenko et al., 1995; N.Yu. Semigolovskyi et al., 1995, 1996, 1998; VA Leosko et al., 1996 ;

Ryabinin H.B. et al., 1999).

In the clinic, bemitil was also used for neuromuscular diseases (progressive

From myodystrophy, atrophic myotonia and secondary amyotrophy). An increase in muscle strength, creatine index, a decrease in POL products, and enzyme activity was noted (Lobzyn V.S.,

Pustozerov V.G., 1993). There are some reasons to count on the cerebroprotective properties of bemitil, since other benzimidazole derivatives in the experiment (models with ligation of carotid arteries, gravity) turned out to be, according to Gaeva L.M. and Shcherbakova T.N. (1994) in this aspect is even more active than cavinton, piracetam, phenibut and HOMK.

Bemitil is used to increase and restore performance, including in extreme conditions (heavy loads, hypoxia, overheating, etc.); to accelerate and strengthen the development of adaptation to the influence of various extreme factors; for the treatment of asthenic disorders of various nature (for neurasthenia, somatic diseases, after severe infections and intoxications, in the pre- and postoperative period during surgical interventions, etc.); in the complex therapy of the consequences of craniocerebral trauma, meningitis, encephalitis, disorders of cerebral blood circulation, as well as in the case of memory impairment.

Observations of the use of bemitil in patients with acute myocardial infarction date back to 1994-1995 (Semygolovsky N.Yu., 1995, 1996, 1998). The drug was prescribed to patients twice a day - in the morning and in the afternoon, for fear of its excessive psychostimulant effect at night.

Patients who received bemitil were somewhat more active, "more cheerful". A "hypothermic" effect of the drug was observed - the body temperature of patients on the 5-6th day of the disease was sometimes below 36.0 "C, which corresponds to the description of the properties of bemitil (A.V. Smirnov, 1993;

Bobkov Yu.G. et al., 1993, etc.) and is generally characteristic of thiourea derivatives (Pastushenkov L.V., 1968; Uryupov O.Yu., 1969).

The drug did not show any noticeable antianginal and antiarrhythmic effects. The dynamics of enzyme activity during its use did not differ reliably from the control, excluding a statistically significant decrease in ABP on the 3-4th day of the heart attack (p<0.05), compared to the control indicator. The latter corresponds to the observations of Yu.V. Lobzyna and A.V. Smirnova (1993) on the hepatoprotective properties of bemitil.

The study of the protective activity of the drug also revealed its hypocoagulation properties in patients with AMI, as indicated by a significant decrease in the main group of the average prothrombin index during the entire observation period (p<0.01-0.05) and the average content of fibrinogen - on the 5-6 day of AMI (p«0.05). A rapid reduction of stress hyperglycemia under the influence of bemitil was also noted, which coincides with the description of its action in other conditions (M. D. Mashkovsky, 1993) and possibly implies the need for substrate support for treatment with antihypoxants.

The accelerated decrease of the initially reliable elevated average systolic ECG indicator (p«e0.05) coincides with the data of L.A. Novikova (1994) on the inotropic activity of bemitil.

We did not observe any side effects when using the drug.

The experiment demonstrated the ability of bemitil, etomerzole, and jacton to accelerate liver regeneration after partial hepatectomy (acceleration of liver weight gain, increase in the content of nucleic acids and glycogen in it, improvement of functional status, which is manifested by a decrease in the level of bilirubin in the blood and a decrease in the duration of hexenal sleep).

The reparative activity of these agents exceeded the effect of a combination of regeneration stimulators, derivatives of purine and pyrimidine bases, riboxin and potassium orotate (Gaivoronskaya V.V. et al., 2002).

Carnitine

The international non-proprietary name of the drug is levocarnitine (I emosagpiipe). Carnitine chloride is produced in a 10 95% solution for injections (1 ml contains 100 mg of the substance).

The substance was first isolated from minced meat by V. S. Gulevich. (1905), but only in 1959 Eghii5 established the leading role of carnitine in the process of P-oxidation of fatty acids. In 1969, the physiological form of carnitine was identified, presented by I! -carnitine

The human body contains 20-25g of this substance, of which about 98-95 is in skeletal muscles and myocardium. The need for I-carnitine for an adult is 200-500 mg per day. Its largest amount is found in lamb (190 mg/100 g) and avocado. The biosynthesis of carnitine I takes place mainly in the liver (from lysine and methionine with the participation of reduced iron and cofactors for the synthesis of vitamins C, Bb, BZ), and its main consumers are the heart and skeletal muscles. It is interesting that scurvy causes a deficiency of carnitine in muscle tissue with its unchanged concentration in the liver, kidneys and plasma.

Antihypoxic properties of carnitine have been proven by Kagep. with collaborators (1987) and

A. L. Karaev and co-authors (1991). Carnitine belongs to drugs that actively affect metabolic processes. In addition to antihypoxic, it provides anabolic, antithyroid regenerating

With an action that stimulates fat metabolism.

The drug restores the alkaline reserve of the blood, does not affect the blood coagulation system, reduces the formation of ketoacids, increases the resistance of tissues to the effects of toxic decay products, activates aerobic processes and suppresses glycolysis, stimulates and accelerates reparative processes.

It has a fat-mobilizing effect - it includes a fatty acid metabolic shunt, the activity of which is not limited by oxygen, so carnitine is effective in acute hypoxia of the brain, myocardium and in other critical conditions.

Suslina 3.A. and co-authors (2003) studied the antioxidant effect of I-carnitine in the treatment of dyscirculatory encephalopathy on the background of diabetes. I-carnitine drug (2 g daily) in addition to the basic therapy increased the resistance of lipoproteins in the blood serum of patients to peroxidation, which indicates its antioxidant properties.

The authors noted the hypoglycemic effect of I-carnitine: its use made it possible to reduce the dose of hypoglycemic drugs by 42 95. Against the background of treatment with I-carnitine, improvements in abstract and practical thinking and memory were noted in the examined patients. The obtained results allowed the authors to recommend the inclusion of I-carnitine in the complex of treatment of patients with vascular diseases of the brain.

Many authors found a decrease in the level of carnitine in the myocardium in various heart diseases - from coronary disease, including myocardial infarction, to cardiomyopathies, hypertensive disease, valvular defects and congestive heart failure (Zradpoii I 5. ei ai., 1982; Vopiez N. ei a !., 1986; Keoiy" U. ei a!i., 1990).

Mazytiga U. and co-authors (1990) showed that the deficiency of carnitine in the myocardium mainly concerns free carnitine, while the indicators of total carnitine often remain normal due to an increase in bound carnitine in the form of an ester, mainly long-chain. Keodii? U. with co-authors (1990) noted a direct (although not linear) relationship between carnitine deficiency and a decrease in the ejection fraction of the left ventricle - its level was especially low in patients with an ejection fraction below 30 95. And Raiva! A. with co-authors (1990) revealed the prognostic significance of a decrease in the content of carnitine in the myocardium, observing for 5 years 40 patients, of which 18 "carnitine-deficient" had a mortality rate of 33.3 95, in contrast to 22 patients with a normal carnitine level with a mortality rate of 4.6 95.

One of the causes of carnitine deficiency in the myocardium is considered to be its release into the plasma during ischemia with subsequent washout. Thus, Kig2op R. and co-authors (1989) found an initial increase in the plasma concentration of carnitine in the first 48 hours after an acute myocardial infarction, and

SI Wagiei5 and UM) Kette (1990) recorded a decrease in free carnitine in the plasma after electrocardiostimulation of the atria in a group of patients who experienced myocardial ischemia in contrast to patients without ischemia or with non-lactate ischemia. Deficiency of carnitine in the myocardium as a result of ischemic damage to cells complicates the transfer of fatty acids into the mitochondria and leads to their accumulation in the cytoplasm (GV Poryadin, 1997; I orazspik a, 2000).

In 1979, IN Orie proposed the use of carnitine in myocardial ischemia. According to

Toleikis A.I. and co-author (1986), carnitine in an experiment with myocardial ischemia had a protective effect, filling the resulting deficiency (AG 5pPcid, 1978), which was also confirmed in the clinic in patients with angina pectoris and congestive circulatory failure (Savchuk V.Y. et al., 1991 ;

Yu.M. Belozerov, 1992; Katikamzhma eyi ai., 1984; SPegopi ei ai., 1985; Retapae? S. ei ai., 1985;

Opapao S., Vyssopi S., 1986; Sassiayoge I. eyi a!., 1991; Vogesnaga M. ei ai., 1994 and others) the usual dosage was 2 g per day for 1-6 months. The authors noted a decrease in the patients' need for nitrates, an increase in the anti-anginal effect of beta-blockers and calcium antagonists, and an increase in load transfer.

The positive effect of carnitine was also noted in patients with acute myocardial infarction, including its complicated course: cardiogenic shock and heart rhythm disturbances (Kebiz7i AS ei ai., 1984; Spiagiei!o 0. ei a!., 1986; Kiglop R. ei a! ., 1989; Ramipi R. ei a!., 1992; Sogrissi SS, I etcieti V, 1992; Sotissi s, I ospe E., 1993). The drug was administered intravenously - up to 21 g in the first hours of the disease and orally (up to 6 g per day for 30 days). A decrease in the area of necrosis and 12-month mortality, stabilization of hemodynamics, antiarrhythmic effect of the drug, increase in the contractility of the myocardium and urinary excretion of fatty acids were found. In cardiogenic shock, the use of the drug helped eliminate acidosis and reduce mortality from 80 to 50 95 (Sogrissi SS, I ospe R., 1993).

In the treatment of chronic heart failure, the effectiveness of daily oral intake of 2 g of I-carnitine for 1.5-12 months was studied (SpPidipi O. ei ai., 1988;

Eetapavie? S, 1991; Vogspaga |. her and I., 1994). The authors noted a subjective improvement in the patients, an increase in myocardial contractility, a decrease in the consumed doses of cardiac glycosides, diuretics, vasodilators, antiarrhythmics, and nitrates.

Zo The use of the drug as a cardioprotector during treatment with cytostatics, especially the anthracycline series, is also shown. According to Lazareva G.A. and co-author (2002), carnitine reduces the severity of changes in immunological functions in poisoning with hemolytic poisons (phenylhydrazine).

The drug is also used for coronary heart disease, various cardiomyopathies, obesity, diabetes, and in sports medicine. There are modern recommendations for the use of zinc-carnitine (150 mg twice a day) for the purpose of prevention and treatment of peptic ulcer disease, increasing the effectiveness of N. ruiogi eradication (Agakaja T. ei ai., 1990;

Mivpimaki N. ei a!., 1999).

A carnitine deficiency syndrome has been described (Green L.P., 1988; Kagraii 0. ei ai., 1975; UMage AG. ei ai., 1978, etc.;), which is manifested by muscle pains, kidney and heart failure.

It is known that cardiomyopathies in children belong to serious diseases of the myocardium with a continuously progressive course and a severe prognosis with high mortality (I. V. Leontyeva, 2001).

The systemic form of primary carnitine deficiency is clinically manifested by severe hypoglycemia, renal failure, and encephalopathy of the type of Reye's syndrome (Belozerov Yu.M., 1992). Carnitine replacement therapy has a certain effect.

In pediatrics, indications for the use of the drug are: consequences of birth trauma and asphyxia; hypotrophy and hypotonia of newborns; respiratory distress syndrome of newborns; care of premature newborns on full parenteral nutrition and children undergoing hemodialysis; a syndromic complex similar to Reye's syndrome (hypoglycemia, hypoketonemia, coma), which develops in children against the background of taking valproic acid; body weight deficiency in children and adolescents under 16 years of age; Propionova and others. "organic" acidemias, primary (genetic) carnitine deficiency.

The drug is also used for anorexia, hypotrophy, growth retardation in children. Carnitine increases the secretion and enzymatic activity of digestive juices (gastric and intestinal), improves food absorption. It reduces excess body weight and reduces fat content in muscles.

On the other hand, secondary acquired insufficiency of carnitine develops with its active removal (hemodialysis, valproic acid intake), with excessive use (ischemic lesions, trauma, recovery, pregnancy), with disorders of intake with food (parenteral nutrition, malabsorption, intestinal diseases), with impaired reabsorption in the kidneys (chronic renal failure).

The drug increases the threshold of resistance to physical exertion, leads to the elimination of post-exercise acidosis and, as a result, to the recovery of work capacity after prolonged exhausting loads. It increases glycogen reserves in the liver and muscles, promotes its more economical use.

The drug is prescribed independently or in complex therapy.

After 3 hours of intravenous administration, carnitine is no longer detected in the blood. It easily penetrates the liver, myocardium, and more slowly - into the muscles. It is excreted by the kidneys mainly in the form of acyl esters.

Carnitine is injected intravenously slowly (no more than 60 drops per minute!).

Before administration, each 100 mg of the carnitine chloride preparation (1 ml of a 10 95% solution) is dissolved in 50 ml of isotonic Mass solution or 5 95% glucose solution.

In the acute period of the disease, in the first three days, carnitine is administered at 10-14 mg/kg of the patient's body weight, in the following days - at 7 mg/kg of body weight. The total course of treatment is 7-10 days. If necessary, after 10-12 days, a repeated course of 7 mg/kg of body weight is carried out for 3-5 days.

In acute myocardial infarction, the drug is used in a daily dose of 100-200 mg/kg in 4 doses or as a continuous intravenous infusion for 48 hours, followed by a 2-fold reduction in the dose. Patients on chronic hemodialysis are administered 2 g once immediately after the end of the next session.

When prescribing the drug in the subacute and recovery periods of dyscirculatory encephalopathy and various brain lesions, patients are administered 0.5-1.0 g of carnitine chloride once a day for 3-5 days. If necessary, a repeat course is prescribed after 12-14 days.

The use of carnitine during hemodialysis allows you to level deviations in the lipid spectrum of the blood (reduces the level of triglycerides and cholesterol, increases the content of high-density lipoproteins), reduces the frequency of hypotension and heart rhythm disorders, helps to increase the number of erythrocytes and hemoglobin, and allows you to reduce the dose of erythropoietin.

As for side effects, allergic reactions are possible when carnitine is prescribed. In the case of rapid intravenous administration, pain may appear along the course of the veins that pass when the speed of administration is reduced. With diabetes in people who receive insulin and oral

With hypoglycemic agents, the development of hypoglycemia is possible. They also describe pain in the epigastric region, dyspeptic phenomena, muscle weakness.

Glucocorticoids contribute to the accumulation of carnitine in tissues (except the liver), other anabolics enhance its effect.

Contraindications, with the exception of increased individual sensitivity to the drug, are not described.

As mentioned, substances related to ethylthiobenzimidazole are widely described, including in patents.

You 1251374 - the use of 2-ethyl-mercaptobenzimidazole bromide as a psychotropic agent that has an actoprotective psychoenergizing and antihypoxic effect.

Vy 2061686 - use in pharmaceutical compositions of derivatives of 2-ethylthiobenzimidazole hydrobromide and hydrochloride, which show weak tranquilizing activity.

VI 2157684 is a drug belonging to the group of actoprotectors that have a moderate psychostimulant effect, in which the active ingredient is 2-ethyl-mercaptobenzimidazole hydrobromide, which is used for the treatment of systemic lupus erythematosus. As a compound with antihypoxic activity, it is used in related psychiatric disorders when stimulation of mental and physical functions is indicated.

Vy 2188012 - the use of 2-ethyl-mercaptobenzimidazole bromide in the treatment of patients with primary biliary cirrhosis as an immunomodulating agent that acts on the cellular link of immunity and contributes to increasing the effectiveness of other targeted drugs used in the complex therapy of cirrhosis.

You 2173144 - the use of actoprotectors containing as an active ingredient a derivative of 2-ethylthiobenzimidazole hydrobromide monohydrate for the treatment of Duchenne-Becker myodystrophy.

Due to its structural similarity to the purine bases adenine and guanine, this derivative enhances the synthesis of mitochondrial enzymes, increases the energy potential of muscle tissue, stimulating redox processes. An increase in the energy potential of muscle tissue promotes the activation of protein and enzyme synthesis, which leads to a decrease in the penetration of myocyte membranes, promotes muscle regeneration, and slows down the myodystrophic process.

VI 2017483 - the use of a medicinal product containing 2-ethylthiobenzimidazole hydrobromide monohydrate as a means that increases the body's resistance to hypoxia and recovery capacity during heavy physical exertion and under the influence of adverse factors, as well as for the elimination of polypharmacy, for the prevention of occupational deafness.

You 2019161 - for the prevention of acute attacks of glaucoma during geomagnetic storms.

You 2138263 - the use of 2-ethylthiobenzimidazole hydrobromide for the treatment of hypothalamic-pituitary insufficiency in women using the effect of increasing the resistance of the brain to asphyxia and circulatory hypoxia, which is manifested by a pronounced increase in cerebral blood circulation, improvement of oxygen supply to the brain, as well as the effect of inhibiting the degradation of the energy functions of the mitochondria of neuroglial cells.

Bemactor (Terra Medica Nova, MO 498) can be indicated as the closest analogue

Новости Фармации "Bemaktor") - a new drug for general medical practice. The drug causes a pronounced antiasthenic effect and accelerates the recovery process in various diseases. Bemactor was produced in the form of tablets (production "ISM-

OCTOBER"). However, its production has been discontinued since 1999. It is unavailable to doctors and patients. As written in the recommendations for use, it is used orally at 250-500 mg for 2-3 or 5-7 days (but no more than 10- 12 days due to the possibility of an excessive psychoactive effect).

When creating the invention, the task was to find a medicinal product capable of providing a combined biological effect in conditions of energy deficiency in the body.

The task is solved by a new combination of two agents that activate energy supply systems for the functioning of metabolic processes, and, at the same time, do not overlap with each other in terms of influencing the activation mechanisms. On the basis of this combination, a pharmaceutical composition was developed for the correction of the symptoms of asthenia and/or chronic fatigue syndrome both in isolation and in various diseases and/or in and/or post-morbid conditions in mammals, characterized by the fact that it contains 2 ethylthiobenzimidazole as active components and/or a pharmaceutically acceptable salt and levocarnitine in therapeutically effective amounts.

Acceptable therapeutically effective amounts are for 2-ethylthiobenzimidazole and/or its pharmaceutically acceptable salts 50-250 mg, levocarnitine 150-750 mg.

As pharmaceutically acceptable salts, it is possible to use, for example, such salts as

From ethylthiobenzimidazole hydrobromide (bemethyl), 2-ethylthiobenzimidazole hydrochloride.

The pharmaceutical composition may contain targeted additives to make the dosage form easier to take. In particular, it may contain fillers selected from the group of sugars, sugar substitutes, flavor substitutes, disintegrating agents, disintegrants, flavoring agents, in the following ratios, wt. for: ethylthiobenzimidazole 546-155 hydrobromide levocarnitine 21.86-44.55 filler selected from the group 9.09-42.62 sugars filler selected from the group 9.09-16.39 sugar substitutes filler selected from 2 42-6 .56 taste-masking group filler selected from the group 121-437 disintegrating components ' ' filler selected from the group of substitute agents 1.21-2.19 leavening filler selected from the group 0.30-0.55. flavorings

Sugar groups can be used as a filler, for example: lactose, glucose, sucrose, fructose, cyclodextrin.

As a filler group of sugar substitutes can be used, for example: mannitol, xylitol, sorbitol, isomalt, fructooligosaccharides.

Lemon juice, honey, steviosides, maltol, etc. can be used as a filler for the taste-masking group.

As a filler group of disintegrating components can be used, for example: croscarmellose sodium, starch, microcrystalline cellulose, agar, gelatin.

As a filler group of substitutes for disintegrating agents can be used, for example: sodium starch glycolate, silicate microcrystalline cellulose.

Food flavorings can be used as a filler for the flavoring group.

The composition can be presented in a solid dosage form. An example of this form is lozenges.

The compositions of the invention are used for the correction of the symptoms of the treatment of asthenia and/or chronic fatigue syndrome both in isolation and in various diseases and/or in and/or post-morbid conditions by administering a medicinal drug by administering within

B-ty and up to 20 days, if necessary with repeated use of a break lasting 2 or more days.

Technical result: the agents can significantly enhance each other's effects, including those related to the energy supply of the functioning of metabolic processes, and accordingly improve the condition of patients with various diseases or non-morbid conditions. When combined, there is an increase in the antiasthenic, antistress effect, physical and mental performance increases, and the antihypoxic effect increases significantly.

The use of a combination in the form of a fast-acting disintegrating tablet allows you to avoid such side effects of ethylthiobenzimidazole as a cumulative effect and an increased psychoactivating effect, which can be considered as an additional result.

The possibility of implementing the invention can be demonstrated by the following examples.

Example 1.

Tablets, weight for: ethylthiobenzimidazole hydrobromide 10 levocarnitine 30 lactose 34 xylitol 16 maltitol 4.7 microcrystalline cellulose 2.9 sodium starch glycolate 21 menthol flavoring 0.3.

Example 2.

Capsules, weight for: ethylthiobenzimidazole 15.15 levocarnitine 21.86 mannitol the rest.

Example 3.

Tablets for absorption, mass. 9o: ethylthiobenzimidazole B 46 hydrobromide of levocarnitine 44.55 maltitol 43 sodium saccharinate 0.09.

Example 4. Pharmacological activity.

The aim of this study was to examine the effects of repeated administration of the combination of bemityl and levocarnitine on two models of chronic fatigue syndrome in mice. The physical fatigue syndrome caused by repeated physical exertion was used as the first model.

The fatigue syndrome caused by repeated stress in mice was used as the second model.

Riboxin was used as a substance for comparison.

Research methods 4.1. Experimental animals.

All experiments were carried out in accordance with the principles of work with laboratory animals (Rhypsiriee5 oi Apitai! Sage, directive 86/609/EEC) in accordance with the Declaration of Helsinki. The purchase of animals and the conduct of experiments were carried out on the basis of the appropriate license from the Ethics Committee (Ministry of Agriculture of the Republic of Estonia). All persons who take care of animals and conduct experiments have personal licenses that allow them to conduct experiments on animals. During the experiments, every effort was made to minimize the number of animals and their suffering.

All experiments were performed on 120 male mice of the C57VI/6 line. The animals were purchased from Nagyap (England). The average age of the animals at the time of arrival at the vivarium of the University of Tartu Biomedical Center would be weeks (120 mice). After arrival, the animals were quarantined for 2 weeks in the vivarium of the Biomedical Center of the University of Tartu. After that, the animals were transferred to the vivarium of the Institute of Pharmacology (room number 3028). The animals were kept in plastic cages (5 mice per cage) measuring 25x45x12 cm (WxDxH) without restriction in food and water, with a 12-hour light cycle (the light turns on automatically at 8:00). Cages with animals were in special climatic containers (Zsapbig, Denmark).

The containers are equipped with HEPA filters for air purification and have 24-hour monitoring of air humidity and temperature. The relative humidity in the containers is maintained between 50:22 95, temperature 22:11 "C. Access to the animals is allowed only to personnel who have the appropriate license. Cleaning of the cages and provision of food and water was carried out once a day. Animal feed: granulated K70 ( and Asiatype, BiosKkpoYt, Sweden). The animals were kept in climatic containers for 1 week before the start of the experiments. 2 series of experiments were conducted and each series used 60 mice. The first series of experiments studied the effect of substances on the fatigue syndrome caused by repeated physical exertion (swimming In the second series of experiments, the effect of substances on the development of a behavioral syndrome caused by stress (chronic variable stress) was studied. For experiments with repeated physical loads, mice were taken at the age of 8-8.5 weeks, for experiments where variable stress was used , the age of the mice was 10-10.5 weeks.

In the first series of experiments, the body weight of mice before the start of the experiment was 22,750.3 g (n-60), in the second series of experiments, the weight of mice was 23.1:50.2 g (n-60).

All the studied substances were administered in the form of a suspension in 1 96 starch paste using a stomach probe once a day in the afternoon (12.00-13.00) for 7 days. Substance solutions were prepared daily immediately before the start of administration. The doses of the studied substances are shown in Table 1.

The doses of the investigated substances were used in the studies and their designation is in the text of the report.

Table 1

Doses (mg/kg) of substances provided Doses (mg/kg) of substances where levocarnitine Designation of the combination by the customer listed on levocarnitine 1 - substances in the report levocarnitine tartrate 185.8 mg/kg mg | tartrate 272.7 mg/kg bemitil 148.4 mg/kg and bemitil 148.4 mg/kg levocarnitine I - average dose (SD) levocarnitine 371.6 mg/kg tartrate 545.4 mg/kg average d levocarnitine 557.4 mg/kg tartrate 818.0 mg/kg

Physical fatigue syndrome caused by repeated physical exertion.

Before the experiments, the animals were coded and divided into b groups of 10 animals each using a randomization program.

The groups of animals, the studied substances and the scheme of the experiment are given.

The time after the last administration of the investigated substances is indicated.

Coo)

Table 2

MSU Pe pit nti ren

Mo c. load - once a day for 7 rotatingAndopen|anddepressed|recognition of animals and 2 times a day ' days - | field rod state of the new object within 7 days 1 Fcontrol//////7 1777771 - 0 | h4h | 48 hours 48 hours 448-50-72 hours control: physical session ek| University of Elnekh

Methods of physical exertion

Physical exercise in mice was carried out 2 times a day. For this, a 25x12x25 cm pool filled with water (25"C) was used. The animals were placed in the pool and were in the water for 6 minutes. The load was carried out in the morning from 8:00 a.m. to 11:00 a.m. and in the evening from 5:00 p.m. to 8:00 p.m. on all animals, except for the first control group. mice. During the last swimming session in the pool, the time during which the animals remained stationary while swimming was measured. 4 identical pools were used simultaneously in the experiment, and the swimming sessions were videotaped. Behavioral analysis was performed on the basis of the videotapes by a staff member who was not familiar with the administration protocol substances

The studied substances were administered daily in the intervals between swimming sessions (12.00-13.00).

24 hours after the last administration of the test substances, behavioral experiments were conducted according to the scheme shown in Table 2.

Fatigue syndrome induced by repeated variable stressor exposure in mice.

Before starting the experiments, the animals were coded and divided into 6 groups of 10 animals each using a randomization program. Stress exposure was carried out according to the scheme presented in Table 3, twice a day for seven days. The studied substances were administered once a day (12.00-13.00) for 7 days.

Table C

Characteristics of stress exposure (0.1 A, 30 sec, 10 blows) (0.1 A, 30 sec, 10 blows) 6

24-72 hours after the last administration of the substances, the behavior of the animals was evaluated: physical performance, the presence of symptoms of depressive behavior, fear, anxiety and mnestic functions.

Evaluation of behavioral reactions.

Assessment of physical performance was carried out by the duration of immobility of the animals during the last swimming session, as well as by means of the rotating rod test. Animals were tested using the rotating rod method 24 hours after the last administration of substances. In the experiments, a rotating rod with a diameter of 30 mm of the company was used

TE Buvietve, Toure Mo. 337500-М/А; Begiai Mo. 120402-06 (Germany) with automatic registration of the time mice are kept on the rod. In previous experiments, it was established that

With a given diameter of the rod, the optimal speed of rotation should be 20 rpm.

The ability to keep animals on the rod depended on the degree of their training. Therefore, during the experiment, on the 1st, 3rd and 5th days of administration, training sessions were conducted for all mice, including control animals without physical exertion. At the same time, the speed of rotation during each session, with the help of software, was gradually increased from 0 to 20 rpm. The device allowed simultaneous testing of up to 5 animals. The device was connected to a computer, which made it possible to automatically record data on the time the animals were kept on the rod.

Assessment of anxiety and fear was carried out using the "open field" test 48 hours after the last administration of substances. The open field is a box measuring 40x40x40 cm, divided into 16 squares. The number of crossed squares (motor activity) and the time the mice stayed in the central squares were evaluated. Animals with low levels of anxiety spend more time in the central squares.

Assessment of the ability of animals to actively avoid stress exposure (test for a depressive-like state) was carried out in the tail-hanging test. In this state, animals actively seek to climb onto the stand and get out of this state. Animals with depressive symptoms do not resist and remain motionless. The time during which the animals were stationary in 180 seconds was determined. observation. Testing was performed 48 hours after the last administration of substances.

Evaluation of episodic memory on the model of recognition of a new object in mice was carried out using the test of recognition of a new object. This test is widely used to assess episodic memory in animals. The test is based on the fact that a healthy animal spends much more time exploring a new object than an old one.

The experiment consisted of three phases: habituation phase, training phase and retention phase (table 2). 1) The habituation phase.

During this phase, mice were individually placed in a wooden box measuring 50x50x50 cm (length, width, and height), located in an experimental room dimly lit by incandescent lamps, with a constant illumination of 60 lux. The floor of the box was divided into 16 identical squares with a side length of 12.5 cm. The animal was in the box for 5 min, and the experimenter recorded the number of squares crossed. This indicator was then used to evaluate the motor activity of the mice. After 5 minutes, the animal was removed from the box and the floor of the box was wiped with 5 95 ethanol solution to eliminate the smell. 2) Training phase.

2 hours after the end of the habituation phase, the training phase was conducted. For this, the animal was again placed in the center of the box, on the floor of which two identical objects were placed. The objects were two wooden cubes located in opposite corners of the box (Fig. 1).

Scheme of experience for the study of episodic memory in the test of recognition of a new object in mice.

The animal was given the opportunity to explore the objects for 5 minutes, and at the same time, the time during which the animal explored each of the objects was recorded. These data are necessary to assess the degree of motivation and research activity of animals. After each animal, the floor of the box was wiped with 5% ethanol solution. At the end of the experiment, the animal was placed in its home cage.

The animal was given the opportunity to explore the objects for 5 min, and at the same time, the time during which the animal explored each of the objects was recorded. These data are necessary to assess the degree of motivation and research activity of animals. After each animal, the floor of the box was wiped with 5% ethanol solution. After the end of the experiment, the animal was placed in its home cage.

From 3) Retention phase.

72 hours after the last exercise, the animals were again placed in the box for research, in which one object was replaced by a new object of a different shape and color (Fig. 1).

The animal was again given the opportunity to explore the old and new objects for five minutes, and the time spent exploring each object was recorded by the experimenter.

The coefficient of preference for the study of a new object was represented as the ratio of the time of the study of a new object in relation to the total time of the study of the old and new objects according to the formula (Tnovx100)//Tst-Tnov), where Tst and Tnov are the time of the study of the old and new objects.

Statistical analysis

Mean values (M) and their standard error of the mean (t) were calculated for each group of mice. Further, the data were analyzed using univariate analysis of variance with subsequent application of the retrospective Bonferroni test (effect of the studied substances, effect of dose). Differences between groups were considered significant at p<0.05. Statistical data processing was carried out using the SgarpRay statistical software

RVIZM-5 (USA).

Research results and discussion of results.

Advancing the choice of dosage of bemitil and levocarnitine for experiments.

The doses of the studied substances were provided by the client of the study. After agreement, doses of levocarnitine base were converted to levocarnitine tartrate (see study methods, Table 1).

The influence of the studied substances on the behavior of mice against the background of repeated physical exertion for 7 days.

The influence of the studied substances on the body weight of animals during repeated physical exertion.

During the experiments, one animal in the control group with physical load died on the 3rd day of administration of substances. An autopsy revealed a perforation of the esophagus. Therefore, the number of animals in this group was 9 mice.

The influence of physical activity and the studied substances on the body weight of animals is shown in table 4 and fig. 2. (510)

Table 4

The effect of the studied substances on the dynamics of the body weight of animals during repeated physical exertion (day of administration, day of administration of the animals' bodies, load)

Mean values and standard errors of the mean (Mem) for a group of 9-10 mice are given. хр«0.05; and re0.01 compared to the control (Bonferroni test).

Dispersion analysis revealed a reliable influence of physical activity and the effects of substances on the dynamics of body weight: E5.53-4.763, p-0.001. Further analysis of intergroup differences using the Bonferroni test showed that repeated exercise significantly (p<0.01) reduced the body weight of mice. The studied combination of substances bemethylleukocarnitine reduced the loss of body weight when re-administered. The most obvious effect of substances is shown in fig. 2. As can be seen from fig. 2, the most noticeable effect on weight reduction as a result of physical exertion was provided by the combination of substances bemityl.-levocarnitine in small doses. The effect of medium and large doses of the bemityl-levocarnitine combination was manifested to a somewhat lesser extent. Riboxin did not significantly affect the dynamics of body weight during physical fatigue of animals (table 4, fig. 2).

The effect of the studied substances on the physical performance of mice after repeated physical exertion.

The physical fatigue of the mice was assessed by two tests: first, by the time of the stationary state during swimming in the pool in the last swimming session and, second, by the time of keeping the animals on the rotating rod. The results of the first experience are presented in Table 5.

Table 5

The influence of the studied substances on the duration (sec) of the immobile state of mice when swimming in the pool during the last swimming session

Substances under investigation: in the pool group and other PNYA TYNY PON SYN loads

Mean values and standard errors of the mean (Mem) for a group of 9-10 mice are given. as p«e0.01 compared to the control without exercise (Bonferroni test).

As the experiments showed, after repeated physical exertion (swimming in the pool), the animals developed a fatigue syndrome, which was manifested in an increase in immobility time during the last session of swimming in the pool. Analysis of variance showed statistically significant differences:

E5.53-3.746; p-0.0056. Statistical analysis of intergroup differences using a test

Bonferroni also revealed a statistically significant (p«e0.01) effect of physical activity on the animals' immobility time (table 5). The combination of substances bemethylcarnitine in small doses (MD) reduced the immobility time of mice in comparison with the control group that received physical loads, however, the data did not reach a statistically significant level. On the other hand, a reliable statistical difference with the control without physical exertion also disappeared, which indicates a partial effect of the combination of bemethyl and levocarnitine on physical performance. The same effect was exerted by medium (SD) and large doses (BD) of the combination of bemethyl-levocarnitine. Riboxin has no effect on physical performance in the swimming test (Table 5).

In the next experiment, the effect of substances on the physical performance of animals in the rotating rod test was evaluated. The results of the experiments are shown in Table 6.

Table 6

The influence of the studied substances on the retention time of mice on a rotating rod after repeated physical exertion

Mo groups and researched Number of mice in the group Time (sec) retention of mice on substances on a rotating rod 160.3x12.3 load 110.2510.0 4. Bemethylyllevocarnitine (MD 00010 160.6:212.94Ж 5. Bemethylyllevocarnitine (SD) 119, 4214.35 6. Bemethylallevocarnitine (BD) 107.7g3.8

Mean values and standard errors of the mean (Mem) for a group of 9-10 mice are shown. "р" 0.05 compared to the control without physical exertion; Ж p«e0.05 compared to the control after physical exertion (Bonferroni test).

As the experiments showed, after repeated physical exertion (swimming in the pool), the animals developed a fatigue syndrome, which manifested itself in a reduction in the time spent on the rotating rod. The variance analysis showed statistically significant differences: E5.53-5.212; p-0.0006.

Further intergroup statistical analysis using the Bonferroni test revealed a statistically significant (p<0.05) effect of physical activity on the time the animals were kept on the rotating rod (table 6). The combination of substances bemethylcarnitine in small doses (MD) statistically reliably (p<0.05) prevented the syndrome of physical fatigue, which was manifested in an increase in the time the mice stayed on the rotating rod. Medium (SD) and higher doses (BD) of the combination of bemethylallevocarnitine did not affect the physical performance of mice after exercise. The effect of riboxin was also not detected.

Effect of the studied substances on motor activity and anxiety level in mice in the open field test after repeated physical exertion.

Data on the influence of the substances under study on the behavior of animals in the open field test are presented in Table 7.

Table 7

The effect of the investigated substances on the motor activity (number of crossed sectors) and the level of anxiety (time in seconds spent in the central sectors) of mice after repeated physical exertion in the open field test

Time (sec)

Mo groups and subjects Number of mice in the Number of average stay in substances group sectors central sectors 12.85211.9 11.051.7 2. Control: physical and 140.8415.3 vn load 132.658.2 11.3zh1.8 135.7210.8 12.9:53.9 128.6:9.7 9.416 107.7x3.8 10.252.1

Mean values and standard errors of the mean (M.em) for a group of 9-10 mice are given.

Statistical analysis showed that repeated physical exertion does not affect motor activity (number of crossed sectors) and anxiety level (time spent in central sectors) in the open field test. Also, no statistically significant effects of substances were found in the open field test (Table 6).

The influence of the studied substances on the depressive-like state of mice after repeated physical exertion in the tail suspension test.

The results of this test are shown in Table 8.

Table 8

The effect of the studied substances on a depressive-like state in mice after repeated physical exertion

Tested substances Number of mice 7. : hanging by the tail 2. Control: physical load | -:/ (96 | 1420550 SHD.-/''// G:ZU(I

The assessment of a depressive-like state was determined by the time (sec) of immobility when hanging by the tail. Mean values and standard errors of the mean for a group of 9-10 mice are shown.

Repeated physical exertion, as well as the studied substances, did not affect the immobility time of mice in the tail suspension test (table 8).

The effect of repeated physical exertion and the studied substances on episodic memory in mice after repeated physical exertion.

The results of studying the effect of repeated physical exertion (swimming in the pool) and the studied substances on episodic memory in mice are presented in Table 9.

In animals of the control group without physical exertion, a pronounced predominance in the study of a new object was observed: the preference index in the control group was 76.0x22.3 95. Repeated physical exertion in the control group did not significantly affect the episodic memory of the animals. The effect of the studied substances on episodic memory was also not detected (table 9).

Table 9

The influence of the studied substances on the episodic memory of mice in the test of recognition of a new object after repeated physical exertion (swimming in the pool) 2. Control: physical exertion.d/ | (36277271

Mean values of the new object preference index are presented, standard errors of the mean (Met) for a group of 9-10 animals.

Conclusion.

Repeated physical exertion (swimming in the pool twice a day for 7 days) caused a syndrome of physical fatigue in mice, which was manifested in an increase in the duration of the stationary state when swimming in the pool during the last session and in a decrease in the time spent on the rotating rod. The combination of the studied substances bemethylallevocarnitine when repeatedly administered in small doses (74.2 mg/kgn185.8 mg/kg) eliminated physical fatigue in both tests. However, with repeated administration of medium (148.4 mg/kg-371.6 mg/kg) and high doses (222.6 mg/kg and 557.4 mg/kg) of the combination of bemethylleukocarnitine, this effect was manifested to a much lesser degree or disappeared. Riboxin in a dose of 148.6 mg/kg, administered once a day in parallel with physical activity for 7 days, did not affect the performance of animals.

Repeated physical exertion did not affect the level of spontaneous motor activity, the level of anxiety, episodic memory, and did not cause symptoms of depression in mice.

The investigated combinations of the substances bemethylleukocarnitine and riboxin also did not affect these parameters of the mice's behavior.

The effect of the studied substances on the dynamics of body weight of mice with repeated stress.

The influence of the studied substances on the dynamics of body weight during repeated variable stress is shown in Table 10.

Table 10

The influence of the studied substances on the dynamics of the body weight of animals with repeated stress, the day of administration, the day of administration of the animals' bodies

Average values and standard errors of the mean (M.m) for a group of 9-10 mice are shown. and re0.05 in comparison with the stressed group of mice.

Repeated stress caused a tendency to decrease body weight gain in mice. Under the influence of riboxin and a combination of substances bemethylleukocarnitine in a small dose, body weight gain slightly accelerated (Fig. 3). It should be noted that, although the variance analysis data showed the presence of a statistically significant group effect (E5.54-3.421, p<0.01), further analysis using the Bonferroni test revealed a statistically significant difference in the body weight dynamics of mice between stressed animals and animals that received riboxin (table 10, fig. 3).

The effect of the studied substances on the physical performance of mice after repeated stressful loads.

The physical fatigue of the mice was assessed by the time of immobility while swimming in the pool and the time spent on the rotating rod. The results of the experiments are presented in tables 11 and 12.

Table 11

The influence of the studied substances on the duration (sec) of the immobile state of mice when swimming in the pool after repeated stress

And swimming in the pool

Mean values and standard errors of the mean (Mem) for a group of 10 mice are shown. Ях p«0.001 compared to the control without stress; Ж p«0.05, КА p«e0.01 in comparison with the stressed control (Bonferroni test).

As studies have shown, repeated stress caused the animals to experience a fatigue syndrome, which was manifested in an increase in immobility time while swimming in the pool. The variance analysis showed statistically significant differences: E5.54-16.15; p-0.0001. Further statistical analysis using the Bonferroni test revealed a statistically significant (p<0.01) effect of stress on the immobility time of animals (table 11).

Table 12

The effect of the studied substances on the time the mice stayed on the rotating rod after repeated stress

Mo groups and studied g. - and Time (sec) keeping mice on

Mean values and standard errors of the mean (Mem) for a group of 10 mice are shown. хр«0.05 compared to the control without stress (Bonferroni test).

As the experiments showed, after repeated stressful loads, the animals developed a fatigue syndrome, which manifested itself in a reduction in the time spent on the rotating rod.

The variance analysis showed statistically significant differences: E5.54-3.665; p-0.0063.

Further statistical analysis of differences between individual groups using a test

Bonferroni revealed a statistically significant (p«e0.05) effect of stress on the time the animals were kept on the rotating rod (table 12). The combination of substances bemethylallevocarnitine in small doses (MD) partially reduced physical fatigue, which was manifested in an increase in the time the mice stayed on the rotating rod. At the same time, the statistically significant difference between the control group without stress and the group with a stressful load disappeared. However, the combination of bemythylleukocarnitine in medium and high doses (SD and BD) did not affect the time of stress animals kept on the rotating rod. Riboxin did not affect the retention time on the rotating rod in stressed animals.

Effect of the studied substances on motor activity and anxiety level in mice in the open field test after repeated stress.

Data on the influence of the studied substances on the behavior of animals in the open field test are presented in Table 13. Repeated variable stress probably (p<0.05) increased the motor activity of animals in the open field (Table 13). The studied substances partially inhibited motor activity, but the data did not reach the level of reliability. Repeated stress exposure did not affect the time spent by mice in the central sectors of the open field (an indicator of anxiety), and there was also no significant effect of the studied substances on this indicator. The variance analysis data were as follows: E5.54-2.19; p-0.067.

Table 13.

The effect of the studied substances on motor activity (number of crossed sectors) and anxiety level (time in seconds spent in the central sectors) after repeated stress exposure in mice in the open field test

Time (sec)

Mo groups and researched Number of mice Number of intersected stays in substance sectors central load sectors

Mean values and standard errors of the mean (Mem) for a group of 10 mice are shown. хр«0.05 compared to the control without stress (Bonferroni test).

The influence of the studied substances on the depressive-like state of mice after repeated stress exposure in the tail suspension test. The results of the experiments are shown in Table 14.

Table 14

The influence of the studied substances on a depressive-like state in mice after repeated stress.

The assessment of a depressive-like state was determined by the time (sec.) of immobility when hanging by the tail

Me groups and investigated substances. Art. of mice suspended by the tail 91.5:2.6 2. Control: repeated stress 169.97, 155 128.58, 3 4. Bemethyllevocarnitine (MD) 126.9410, 39 5. Bemethylallevocarnitine (SD) 121.6v212 ,29th 6. Bemethylallevocarnitine (BD) 107.74, Z

Mean values and standard errors of the mean (Mem) for a group of 10 mice are shown. Ях p«0.001 compared to the control without stress; Ж p«e0.05, ЖЖ p«e0.01, AK p«e0.001 in comparison with stressed controls (Bonferroni test).

The data of dispersion analysis showed a reliable influence of the group: E5.54-10.48; p "0.0001. The analysis of intergroup differences revealed a significant (p<0.001) influence of stress on the development of a depressive-like state, which was manifested in an increase in immobility time in the tail-hanging test. The studied combination of substances at all doses significantly reduced immobility time in the tail suspension test (Table 14). Riboxin also reduced immobility time in this test. Thus, it can be concluded that the studied substances weaken the depressive-like state in mice, which develops as a result of repeated stressor exposure.

The influence of repeated stress and the studied substances on episodic memory in mice.

The results of the study of the effect of repeated stress and the studied substances on episodic memory in mice are presented in Table 15.

The animals of the control group showed a preference for exploring a new object: the index of preference in the control group was 67.74.4 95. Repeated stressor exposure in the control group did not significantly affect the episodic memory of the animals. The effect of the studied substances on episodic memory was also not detected (table 15).

Table 15

The influence of the studied substances on the episodic memory of mice in the test of recognition of a new object after repeated stressor exposure

Me groups and investigated substances Index of preference of the new object 67,754,4 2. Control: stress 71,542,7 60,822,6 4. Bemethyllevocarnitine (MD) 70,8:3,3 5. Bemethylallevocarnitine (SD) 72,154,6 6 Bemethylallevocarnitine (BD) 62.44, 1

Mean values of the novel object preference index x standard errors of the mean (Met) for groups of 10 animals are presented.

Conclusion.

In mice, repeated stressful exposure led to increased physical fatigue, which was manifested in a slight decrease in body weight gain, an increase in the time of immobility when swimming in the pool, and a reduction in the time spent on the rotating rod. Repeated exposure to stress also led to the development of a depressive-like state, manifested in an increase in immobility time in the tail suspension test. The combination of the test substances bemethyl-levocarnitine when repeatedly administered in small doses (74.2 mg/kg-185.8 mg/kg) slightly increased body weight gain during stress and statistically significantly eliminated physical fatigue in both swimming and rotating rod tests. Repeated administration of medium (148.4 mg/kg–371.6 mg/kg) and high doses (222.6 mg/kg and 557.4 mg/kg) of the combination of bemethylallevocarnitine also reduced pool swimming immobility time, but in the rotating rod test this effect appeared to a much lesser degree or disappeared. Riboxin in a dose of 148.6 mg/kg, administered once a day for 7 days, increased the physical performance of animals when swimming in a pool, but did not affect the ability of mice to stay on a rotating rod.

The combination of bemethyl-levocarnitine in the entire range of doses reduced the depression-like state of animals caused by repeated stress. However, it should be noted that this effect may be associated with an effect that improves physical performance. Rather, the spectrum of action of these substances is dominated by their influence on physical performance, and not by their antidepressant effect.

Claims (4)

FORMULA OF THE INVENTION 1. A pharmaceutical composition for correction of symptoms, treatment of asthenia and/or chronic fatigue syndrome, which differs in that it contains 2-ethylthiobenzimidazole hydrobromide and/or a pharmaceutically acceptable salt and levocarnitine in therapeutically effective amounts as active components. 2. The pharmaceutical composition according to claim 1, which is characterized by the fact that as target additives it contains substances selected from the group of sugars, sugar substitutes, taste substitutes, disintegrating agents, disintegrating agents, flavoring agents, in the following ratios, by weight. 9o: g-ethylthiobenzimidazole 546-155 hydrobromide levocarnitine 21.86-44.55 filler selected from the group of sugars 9.09-42.62 filler selected from the group of sugar substitutes 9.09-16.39 filler selected from the group 2 42-6.56 taste-masking filler selected from the group of disintegrating components 121-437 filler selected from the group of leavening agent substitutes 121-219 filler selected from the group of flavors 0.30-0.55. 3. The composition according to claim 1, which differs in that it is presented in a solid dosage form. 4. The composition according to claim 3, which is characterized by the fact that the solid dosage form is a tablet for absorption. Dkig. MoOple and I same EE ontTool OO NOrynnya I A : E ! M kzachne van g av - 2 th Er mozkom sh ! I am in G E o NN renia! BM x and also Mk sheSh-SD and BV 25 ekyi a OM ; more Ж т Ро шо ек ве , -ч как я Лай The effect of the substances added to the body weight of mice during repeated physical exertion. Designation: MD - combination of Bemitil and penocarnitine in a map dose, SD - combination of Bemitil and levocarnitine in a medium dose and BD - combination of Bezhitil - pevocarnitine in a large dose. "r "BO, ro M in comparison with the countermeasure and Bonferroni test. Fig. 2 t- ZD Bo y t Y pz Kontvel Z ok pt z ih I reshe - et, zho Va nan SHY rush vi MI ak y. y y shchi KU nn: za Vaza: ZY EMMA Zh z E: Mn II ka y OO sha SHYN She. ves g SCHE nena KOYU she TO SHO i 5 3 IOV point MNN NIK Uzh i: MECKA MAH The influence of the study of rae-nutrients on the dynamics of the weight of mice during physical loading. Designation: MA - a combination of Bemityl with pevocarnitine in a small dose), SD - a combination of Bemitl and penocarnitine in an average dose, BD - a combination of Bemitl with lenocarnitine in a high dose of P "0.05 in the diet with the stressed contrapemitest Bbonferrani. Fig. WITH