RU2426535C2 - Application of beta-hydroxybutyrate or its pharmaceutically acceptable salts for preparation of medication which possesses cytoprotective activity, including neuroprotective, cardioprotective, anti-ischemic, anti-hypoxic, anti-stress, actoprotective and adaptogenic activity, medication and method of prevention, relief and treatment by means of said medication - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is application of beta-hydroxybutyrate or its salts in combination with other active substance or combination of active substances, selected from group, given in the invention formula, for preparation of medication, which possesses cytoprotective activity, including neuroprotective, cardioprotective, anti-ischemic, antihypoxic, antistress and adaptogenic activities, medication and method of prevention, relief and treatment by means of said medication. Demonstrated is synergic of medication components as cytoprotector in urgent states as it possesses complex impact on key links of pathogenesis of said diseases.

EFFECT: elaboration of medication which possesses cytoprotective activity.

24 cl, 3 tbl, 5 ex

Description

The invention relates to medicine, specifically to neurology, cardiology, obstetrics and gynecology, as well as surgery and traumatology, and in particular to drugs with cytoprotective activity.

Stroke is a clinical syndrome characterized by sudden onset of clinical symptoms, indicating focal and / or cerebral neurological deficiency, developing as a result of cerebral ischemia or hemorrhage. Every year in highly developed countries among every 10,000 people, 25-30 cases of stroke occur. Of the 100 stroke patients, 35-40 die in the first 3-4 weeks. The economic loss from a stroke in the United States is about $ 30 billion a year. Over 400 thousand strokes occur in Russia, which is equal in number to the population of the average regional city. Among the survivors, the majority have various functional disorders: by the end of the acute period, almost 80% of patients have motor disorders (most often these are paresis of varying severity), more than a third of patients have speech disorders.

According to the development mechanism, three types of stroke are distinguished: ischemic (synonyms: cerebral infarction, softening of the brain), when an acute blood supply deficiency (ischemia) of a certain part of the brain develops as a result of blockage of the cerebral vessel or for another reason; hemorrhagic (synonyms: cerebral hemorrhage, intracerebral hematoma), when blood is poured into the brain due to rupture of the cerebral vessel, disrupting normal blood circulation of the brain tissue; subarachnoid hemorrhage - hemorrhage in the subarachnoid space of the brain. On average, ischemic strokes account for 80% of all strokes, intracerebral hemorrhages - 17%, subarachnoid hemorrhages - 3%.

The whole complex of therapeutic measures for ischemic stroke can be divided into two blocks: the so-called basic therapy aimed at maintaining all vital functions of the body, and pathogenetic therapy aimed at restoring impaired blood flow, interrupting the fast mechanisms of glutamate excitotoxicity and suppressing the effects of delayed local inflammation. In the pathogenetic therapy unit, primary and secondary neuroprotection are distinguished. In the early 90s, it was shown that the development of stroke in the first minutes and hours of the disease occurs according to the fast mechanisms of necrotic cell death. The starting link is an energy deficit that initiates the so-called glutamate-calcium cascade, characterized by excessive release of excitatory aminacidergic neurotransmitters - aspartate and glutamate and excessive intracellular accumulation of Ca2 + ions - the main trigger of the terminal mechanisms of the cascade leading to cell death. The formation of the nuclear zone (the "core" of a heart attack) is completed in 5-8 minutes from the moment of acute cerebrovascular accident. This area of the brain is surrounded by a potentially viable zone of “ischemic penumbra” (penumbra), in which the level of blood flow is reduced, however, energy metabolism is generally preserved and there are functional, but not structural changes. The formation of 50% of the final volume of a heart attack occurs within the first 90 minutes from the moment of the development of a stroke, 70-80% - within 360 minutes, in connection with which the first 3-6 hours of the disease are called the “therapeutic window”, inside which therapeutic measures can to be most effective by saving the penumbra zone. At the same time, the processes that began in the first hours of the disease and underlie the activity of the glutamate-calcium cascade (changes in the metabolism of glutamate and calcium, free radical reactions, lipid peroxidation, excessive formation of nitric oxide, etc.) retain their significance in later terms, especially with the vast size of the area of ischemic lesion. They induce and support other “long-term consequences of ischemia”: a genome reaction with the inclusion of genetically programmed molecular programs, dysfunction of astrocytic and microglial cell pools with the development of immune changes and local inflammation in the focus of ischemia, impaired microcirculation and blood-brain barrier.

Delayed damage to cerebral tissue is realized through the mechanisms of programmed cell death - apoptosis and aponecrosis. “Long-term consequences of ischemia” cause “deformation” of cerebral infarction due to the spread of damage from the peri-infarction zone to the periphery of the penumbra. The time of "deformation" of heart attacks in each case is individual, ranging from 3 to 7 days after cerebrovascular accident. Evidence of the delayed irreversible damage to the brain from the moment of acute cerebrovascular accident and the onset of the first symptoms of the disease rooted the attitude to stroke as an emergency requiring quick and pathogenetically based medical care, preferably within 3 hours from the moment of its development. Experimental studies have shown that the return of blood to the ischemic zone through the revascularized section of the artery does not always lead to the complete normalization of local cerebral blood flow. Even just 5 minutes after the debut of ischemia in the “ischemic penumbra” zone, phased violations of cerebral tissue perfusion occur: in the first minutes there is hyperemia (or “luxurious perfusion”), then post-ischemic hypoperfusion, which is the result of severe microcirculation disturbances caused by release from ischemic tissue vasoactive and pro-inflammatory metabolites. The longer the pre-reperfusion period, the less the chance to quickly normalize microcirculation in the ischemic zone and the higher the risk of additional reperfusion damage to the cerebral tissue: oxidative, due to the inclusion of oxygen in the processes of free radical oxidation, and osmotic, caused by an increase in cytotoxic edema due to excess water and osmotically active substances.

The basis of specific therapy for ischemic stroke are two strategic directions: reperfusion and neuronal protection, aimed at protecting weak or almost non-functioning, but still viable neurons located around the hearth site (ischemic penumbra). The main cerebral thrombolytics are recognized as urokinase, streptokinase and their derivatives, as well as tissue plasminogen activator (TAP). All of them act directly or indirectly as plasminogen activators. Currently, the effectiveness of thrombolytics, in particular TAP, has been reliably proven. Hemodilution is often performed to increase cerebral perfusion pressure and improve the rheological properties of blood. It is based on two principles of the effect on the microcirculation of the ischemic brain: a decrease in blood viscosity and optimization of circulatory volume. It is advisable to carry out hypervolemic hemodilution with low molecular weight dextrans (reopoliglyukin, reomacrodex, etc.). For example, reopoliglyukin is administered intravenously in the first few days. Of the direct-acting anticoagulants in the acute period of ischemic stroke (with the exception of lacunar infarction), low molecular weight heparin (7.5 thousand units of fraxiparin 2 times a day for the first few days under the control of blood coagulation) is recommended. Subsequently, patients who have had a cardioembolic and atherothrombotic stroke are prescribed anticoagulants of indirect action: phenylin or syncumar, or warfarin under the control of blood prothrombin. One of the serious complications of both cerebral hemorrhage and extensive cerebral infarction is cerebral edema and increasing intracranial hypertension. Of the drugs used to combat cerebral edema, osmodiuretics are used: mannitol, which is administered intravenously for 20 minutes at a dose of 0.5-1.0 g / kg body weight, then in a halved dose every 4-5 days, depending on the level of osmolarity and condition kidney function. Aspirin is also an effective proven treatment for acute cerebral infarction. It can be used in two modes - 150-300 mg each or in small doses of 1 mg / kg body weight daily. Perhaps, although it is still in doubt, the use of antiplatelet agents with other effects, including ticlopidine, dipyridamole (chimes) and pentoxifylline (trentals). Neuroprotective therapy is aimed at protecting nerve cells from damage, which leads to various metabolic disorders that occur in the first minutes and hours of a stroke. Neuroprotective properties have: postsynaptic glutamate receptor antagonists (not yet available in clinical practice); presynaptic glutamate inhibitors (lubeluzole); antioxidants (emoxipin, alpha-tocopherol, carnosine, mexidol, mildronate, vitamin E, ascorbic acid); calcium channel blockers (nimodipine); drugs of predominantly neurotrophic action (piracetam, cerebrolysin, glycine, picamilon) and others. The main direction in the treatment of hemorrhagic stroke is to reduce the permeability of the vascular wall and prevent the destruction of the formed blood clot. For this, angioprotectors (parmidin, prodectin, ascorutin, troxevasin, etamsylate), vasoselective calcium channel blockers (nimodipine), vasoactive drugs (vinpocetine, cavinton, nicergoline, instenon, aminophylline, cinnarizine) are used.

It is generally recognized that such common diseases accompanied by hypoxia as coronary heart disease (CHD), heart failure and cerebral stroke occupy a leading position among the causes of disability and mortality. Russia took first place in mortality from these ailments, ahead of the former leader - Romania. 57 percent of our fellow citizens die from heart and blood vessel diseases. There is no such indicator in any developed country in the world. The statistics for Russia looks simply amazing: out of every 100 thousand people, we lose 330 men and 154 women every year from myocardial infarction, and 204 men and 151 women lose from strokes. In total, 1 million 300 thousand people a year die from cardiovascular diseases every year - the population of a large regional center. A large share here belongs to coronary heart disease and arterial hypertension with its complications (according to the University of Lausanne for the World Health Organization, a report on statistics of cardiovascular diseases in 34 countries of the world since 1972, material from IA Mednovosti.ru). Therefore, the development of new drugs for the treatment of the cardiovascular system is a very urgent problem.

Recently, in the clinical practice in the treatment of such diseases as biologically active substances with a wide pharmacological spectrum of action, succinic acid compounds - succinates (Ivnitsky Yu.Yu., Golovko A.I., Sofronov G.A. Amber acid in the system means of metabolic correction of the functional state and resistance of the body. - St. Petersburg, 1998. - 82 pp. - Bulletin of the exp. biol. and honey., 2000, T.129, No. 2, 149-151).

The advantage of exogenous succinate in the oxidation rate over other substrates of tissue respiration is especially pronounced under conditions of hypoxia. In addition, the anti-ischemic effect of exogenous succinic acid is associated not only with the activation of succinate dehydrogenase oxidation, but also with the restoration of the activity of the key enzyme of the redox activity of mitochondria - cytochrome oxidase. When using succinate, stabilization of hemodynamics and an increase in exercise tolerance were noted (Kovalenko A.L., Petrov A.Yu., Romantsov M.G. Pharmacological activity of succinic acid and the prospects for its use in the clinic // Reamberin - infusion solution for intensive care in pediatric clinic / Collection of articles under the editorship of MG Romantsov. - NTFF Polisan, St. Petersburg -2000, 64 pp.).

Succinate acts as an antistressor, adaptogen and actoprotector, and in the presence of pathological disorders it exhibits an atypically high therapeutic effect (Kondrashova M.N. Clarified and emerging issues on the way of studying the regulation of the physiological state of succinic acid // The therapeutic effect of succinic acid / Ed. B. N. Kondrashova, Pushchino, 1976, pp. 8-30; Lukyanova LD Hypoxia in pathologies. Molecular mechanisms and principles of correction // Collected scientific papers “Organofluorine compounds in biology and medicine.” - SP b, 2001 .-- P.56-69).

In the treatment of hypoxic complications arising from a wide variety of pathologies, various antioxidants (vitamins E, C, group B and their derivatives, thiol compounds, polyphenols, enzyme preparations, etc.) are widely used at present. The use of various combinations of antihypoxants and antioxidants (vitamin C + utiniol or riboxin; actovegin + instenon; cerebrolysin + reomacrodex) and their combinations with immunomodulators, vasoactive drugs, etc.

For the prevention of secondary complications caused by traumatic brain injury, namely, to restore neuropsychic status, neuroprotective agents are used that eliminate microcirculation or metabolism disorders leading to the death of brain neurons (Meddrum, 1995, E.I. Gusev et al., 2001 ) For this, vasoactive substances (nimodipine, sermion, aminophylline, etc.), nootropics (piracetam, mexidol, phenotropil, actovegin, etc.), barbiturates (phenobarbital), benzodiazepines (diazepam, etc.), lactic acidosis correctors (tromethamine) are also used. ) and etc.

Currently used and recommended drugs have, as a rule, a nootropic effect in relation to disorders caused by one of the factors of secondary brain damage. For example, vasoactive drugs either prevent the development and / or eliminate spasms of blood vessels leading to ischemia of the nervous tissue. So, barbiturates can reduce the intensity of hypoxia with hypercapnia, preventing the depletion of metabolic reserves, and prevent an increase in intracranial pressure. Benzodiazepines prevent the occurrence of secondary convulsive episodes, which, against the background of organic damage to the nervous tissue, can lead to high intracranial pressure, a change in blood pressure, a decrease in oxygen transport, and metabolic deficiency (R.D. Kasymov, A.N. Kondratiev, 2001, T.A. Skoromets, 2002, AIFaden, 1996, R. Martusa, M. Proctor, 1997). The combined use of these drugs is a variant of aggressive therapy for traumatic brain injury (I.A. Kachkov et al., 1999).

It should also be noted that with traumatic brain injury, brain tissue experiences an acute shortage of energy substrates. Their delivery from the outside is difficult due to a drop in blood flow. Switching to anaerobic glucose synthesis leads to excessive energy costs, which only increases intracellular entropy.

Unlike all antihypoxants, in particular succinic acid, which is one of the many natural elements of the Krebs oxidation cycle, which is characteristic of aerobic glycolysis, β-hydroxybutyrate belongs to the group of ketone bodies and is formed in the process of fat metabolism by restoring acetoacetate in the liver. It serves as a universal energy supplier for various tissues (heart, kidneys, skeletal muscles). Beta-hydroxybutyrate easily passes through the mitochondrial and cell membranes and enters the bloodstream. It is transported by blood to all other tissues. Thus, β-hydroxybutyrate, one of the two ketone bodies (the second is acetoacetate), can be oxidized in the tissues, providing ATP synthesis, bypassing glycolysis, i.e. and in anaerobic conditions, which is extremely important in conditions of catastrophic hypoxia.

Beta-hydroxybutyrate has a positive effect on humans and animals. Among other things, this includes increasing the activity of the heart muscle, for example, in chronic heart failure, providing an alternative glucose source of energy, for example, in diabetes and insulin resistance conditions, and treating disorders caused by damage to nerve cells, such as CNS cells, in particular by slowing down or preventing brain damage, such as that observed with Alzheimer's disease and Parkinsonism, as well as similar diseases and conditions (RF patent 2242227).

However, all previously proposed methods of treatment using beta-hydroxybutyrate were aimed at the treatment of long-term and chronic diseases - Alzheimer's disease, epilepsy, diabetes and other diseases requiring long-term treatment.

Known cytoprotectors, for example, described in the patent of the Russian Federation 2302236, can not be used for complex effects on pathological conditions of various etiologies.

The objective of the invention is to reduce the damaging effect on the activity of cardiac and nervous tissue ischemia, hypoxia, seizures and at the same time a positive effect on adaptive reactions, providing fast and stable compensation of neuropsychic functions in various pathologies, as well as increasing the effectiveness of treatment of urgent conditions.

Depending on the nature and severity of the pathological condition, its onset, dynamics and medical prognosis, the problem is solved using beta-hydroxybutyrate or its pharmaceutically acceptable salts in combination with another active substance or combination of active substances selected from the choline group of alfoscerate, such as gliatilin, ethyl methylhydroxypyridine succinate, meglumine sodium succinate (reamberin), magnesium and / or lithium preparations, piracetam, succinic acid, derivatives of barbituric acid, benzo diazepines, akatinola memantine, glycine, actovegin, valproic acid derivatives, loop and osmotic diuretics such as mannitol and furosemide, vitamins A, E, PP, group B, ascorbic acid, lipoic acid, riboxin, urokinase, streptokinase, tissue activator (plasmin TAP), low molecular weight dextrans, such as reopoliglukin and rheomacrodex, phenylin, syncumar, pentoxifylline, emoxipin, mildronate, nimodipine, cerebrolysin, ethamzilate, vinpocetine, cavinton, nicergoline, instenon, eufillin preparation of a drug having cytoprotective activity, including neuroprotective, cardioprotective, anti-ischemic, antihypoxic, anti-stress and adaptogenic activity.

The combination of these recommended drugs with beta-hydroxybutyrate can lead to a more pronounced therapeutic effect as a result of the "addition" of the actions of the drugs and the synergy of pharmacological effects associated with their action.

The use of this drug is proposed for the treatment of ischemic and hemorrhagic stroke, myocardial infarction, kidney, liver, cerebrovascular accidents, cicatricial changes in heart tissue, maternal and fetal pathologies associated with pregnancy and childbirth, traumatic brain injury and to prevent the effects of circulatory disorders, caused by surgery.

The use of this drug is proposed, which is made in the form of a solution for intravenous administration, a perfusion, blood substitute or plasma substitute solution.

It is proposed the use of this drug in case of urgent conditions or pathologies requiring emergency medical care.

A medicament having cytoprotective activity including neuroprotective, anti-ischemic, cardioprotective, antihypoxic, antistress, actoprotective and adaptogenic activity containing beta-hydroxybutyrate or its pharmaceutically acceptable salts in combination with another active substance or combination of active substances selected from the group of such as gliatilin, ethylmethylhydroxypyridine succinate, meglumine sodium succinate (reamberin), drugs Agnium and / or lithium, piracetam, succinic acid, derivatives of barbituric acid, benzodiazepines, akatinol memantine, glycine, actovegin, derivatives of valproic acid, loop and osmotic diuretics such as mannitol and furosemide, vitamins A, E, PP, group B, ascorbic acid acids, lipoic acid, riboxin, urokinase, streptokinase, tissue plasminogen activator (TAP), low molecular weight dextrans such as reopoliglukin and rheomacrodex, phenylin, syncumar, pentoxifylline, emoxipin, mildronate, nimodipine, cerebro ins, etamzilata, vinpocetine, cavinton, nicergoline, instenon, aminophylline, Sirmione.

This drug is made in the form of a solution for intravenous administration, perfusion, blood substitute or plasma substitute solution.

This drug is used in case of urgent conditions or pathologies associated with the development of life-threatening hypoxic or anoxic foci in the tissues and requiring emergency medical attention.

This medicine is used to treat ischemic and hemorrhagic stroke, myocardial infarction, kidney, liver, cerebrovascular accident, cicatricial changes in heart tissue, maternal and fetal pathologies associated with pregnancy and childbirth, and to prevent the effects of circulatory disorders caused by surgical intervention.

This medicine is used to treat neurological disorders caused by craniocerebral, spinal or head injuries.

A method is also proposed for the prevention, relief and treatment of conditions requiring the administration of a cytoprotective drug, characterized in that the drug according to any one of paragraphs 5-9 in an amount of from 0.001 to 10.0 g per day is used as a cytoprotective drug.

In this method, the indicated condition requiring the administration of a cytoprotective drug is acute stress and symptoms of depleting stress overload associated with the possible development of hypoxic or anoxic damage to organs or tissues in case of borderline neuropsychiatric pathology.

In this method, the indicated condition requiring the administration of a cytoprotective drug is acute stress and symptoms of depleting stress overload associated with the possible development of hypoxic or anoxic damage to organs or tissues under extreme conditions of warfare.

In this method, the indicated condition requiring the administration of a cytoprotective drug is a prolonged stress disorder with neurasthenia with anxiety-phobic disorders, alcoholism, and opium addiction.

In this method, the indicated condition requiring the introduction of a cytoprotective drug is a pathology of the cardiovascular system with a severe progressive course of coronary heart disease against the background of hypertension II-III art.

In this method, the indicated condition requiring the administration of a cytoprotective drug is a complication of coronarographic studies.

In this method, the drug is administered to elderly patients with coronary heart disease older than 70 years, long-term use of cardiotropic drugs in order to reduce the doses of these drugs.

In this method, the indicated condition requiring the administration of a cytoprotective drug is type 2 diabetes mellitus of moderate severity, while treatment is carried out for at least the first six days until satisfactory compensation of diabetes mellitus is achieved, and with repeated use of the drug, until resistance to carbohydrate load at an acceptable level for a considerable time.

In this method, the indicated condition requiring the administration of a cytoprotective drug is neurocirculatory dystonia, atherosclerotic discirculatory encephalopathy, with a decrease in memory and mental performance.

In this method, the indicated condition requiring the introduction of a cytoprotective drug is cerebral palsy, including in its spastic forms such as spastic diplegia, hemiparetic form, atonic-astatic form, as well as the consequences of birth, craniocerebral or other injuries.

In this method, the indicated condition requiring the administration of a cytoprotective drug is minimal cerebral dysfunction in children with functional and / or organic disorders of the central nervous system.

In this method, the indicated condition requiring the administration of a cytoprotective drug is intrauterine hypoxia of the fetus.

In this method, the indicated condition requiring the introduction of a cytoprotective drug is the condition after a severe traumatic brain injury with the removal of the brain crush area, while the drug is administered for at least 5 days during the first month until the pathological manifestations in patients disappear.

In this method, the indicated condition requiring the introduction of a cytoprotective drug is the pathology of the central and peripheral nervous system (meningitis, encephalitis of various origins, paresis, strokes), as well as emergency conditions, such as shock of any genesis.

In this method, said condition requiring administration of a cytoprotective drug is a condition after a heavy load and stress.

It has been established that beta-hydroxybutyrate has a complex effect on key pathogenesis links of various diseases, including disorders in the central nervous system and heart and other organs caused by ischemic and hemorrhagic stroke, myocardial infarction, kidneys, liver, cerebrovascular accident, scar tissue changes heart, maternal and fetal pathologies associated with pregnancy and childbirth, traumatic brain injury and to prevent the consequences of circulatory disorders caused by surgery treatment for acute and chronic coronary heart disease, with liver lesions of various etiologies, to increase the resistance of the human body to the non-electrolytic effect of alcohol, to ionizing radiation and poisons.

Beta-hydroxybutyrate or its pharmaceutically acceptable salts are used for the prevention and relief of manifestations of acute stress and symptoms of debilitating stress overload associated with the possible development of hypoxic or anoxic damage to organs or tissues in borderline neuropsychiatric pathology, for the prevention and relief of manifestations of acute stress and symptoms of debilitating stressful stress associated with the possible development of hypoxic or anoxic damage organ, tissue, under extreme conditions of warfare, for the relief of withdrawal syndrome in the treatment of opium addiction, for the comprehensive treatment of opiate withdrawal symptoms, for the comprehensive treatment of long-term stress disorders to correct neurotic disorders and stop neurotic manifestations in case of neurasthenia with anxiety-phobic disorders, alcoholism, opium addiction, to stop the craving for ethanol and withdrawal syndrome in the associated forms of alcoholism and opioids addiction, for the prevention and treatment of combined pathology of the cardiovascular system with a severe progressive course of coronary heart disease in the presence of hypertension II-III art., for the prevention of complications of coronary angiography, to reduce doses of long-term cardiotropic drugs for elderly patients with coronary heart disease older than 70 years, for the prevention and treatment of middle-aged patients suffering from diabetes mellitus of the second type of moderate severity with the help of course treatment with a pharmaceutical agent, while the treatment is carried out for at least the first six days until satisfactory compensation for diabetes is achieved, and with repeated use of the drug, until the resistance to carbohydrate load is maintained at an acceptable level, considerable time is needed for the treatment of elderly patients with type 2 diabetes, for stopping neurocirculatory dystonia, discirculatory encephalopathy of atherosclerotic genesis, with a decrease in memory and mental performance, for the prevention of oslo sting and treatment of acute pancreatitis, in the treatment of multiple sclerosis, to reduce the syndrome of autonomic dystonia and neurocirculatory dystonia in the hypotonic type, for the treatment of patients with cerebral palsy, including spastic forms such as spastic diplegia, hemiparetic form, atonic-astatic form, as well as the consequences of birth, craniocerebral or other trauma, for the treatment and rehabilitation of children with minimal cerebral dysfunction with functional and / or organic disorders f functions of the central nervous system, for the treatment of intrauterine hypoxia of the fetus, for the treatment of perinatal pathology of newborns (profuse regurgitation an hour or more after feeding, tilting the head in a dream, increased pulsation of the large fontanelle, muscle hypotension or hypertonicity, superficial sleep, confusion day and night), for the treatment of patients suffering from symptomatic and idiopathic epilepsy, for the symptomatic and pathogenetic treatment of cancer patients receiving radiation therapy, chemotherapy, therapy for the correction of neutropenia, pancytopenia due to radiation therapy, polychemotherapy, for the treatment of complex treatment of a burn disease with a lesion area of more than 40% of the body area, in case of severe septicotoxemia, for treatment of small area burns (from 1% of the body area) clinical practice, for the treatment of complex traumatic brain injury incompatible with life, in the case of long-term follow-up of patients after severe traumatic brain injury with the removal of the head crush area Osga conducts the course of the drug for at least 5 days during the first month before the disappearance of pathological manifestations in patients, in the complex treatment of patients with a clinic of diffuse axonal damage in a deep coma, in the complex treatment of pathology of the central and peripheral nervous system (meningitis, encephalitis of various origins , paresis, strokes), as well as in emergency conditions, such as shock of any genesis, to prevent and reduce the risk of postoperative complications and increase the speed of healing the wound surface, while administering the agent for at least 1 day before and / or after surgery, to prevent and reduce the risk of postoperative complications during elective surgery, while administering at least 1 day before surgery , to prevent and reduce the risk of postoperative complications when planning an operation using cardiopulmonary bypass, and / or and / or i / m is administered at least 1 day before op surgical intervention, with intravenous administration during the entire pre- and postoperative period, for treatment in the treatment of patients with purulent-inflammatory diseases, to normalize carbohydrate metabolism, especially with type 2 diabetes in middle-aged and elderly patients, with liver diseases, peptic ulcer of the stomach and duodenum, for the treatment of flaccid ulcers and wounds, including trophic origin, with varicose veins of the lower extremities, for the treatment of neuritis, radik LTL, neuralgia, peripheral paralysis, to improve metabolism of amino acids, including tryptophan, methionine, cysteine, glutamic acid, for the prevention and treatment of atherosclerosis, liver disease (infective hepatitis mild or moderate flow - in the absence of intense jaundice or incremental; chronic hepatitis, cirrhosis), diabetic polyneuritis and intoxications, for the prevention and treatment of scurvy, hemorrhagic diathesis, nose, uterine, pulmonary and other bleeding, in cases of overdose of anticoagulants, for infectious diseases, for poorly healing wounds and bone fractures, to improve tolerance heavy load and tension, to reduce the volume of therapeutic interventions for lesions and skin diseases (frostbite, wounds, infectious and degenerative lesions), to reduce the volume and therapeutic interventions for coronary heart disease (chronic coronary insufficiency, myocardial infarction), for myocardial dystrophy, myocardiopathy.

In addition, beta-hydroxybutyrate or its pharmaceutically acceptable salts are used to reduce or prevent fatty liver infection in Botkin's disease, hepatitis, liver cirrhosis, mainly in the early stages, in hypothyroidism, cystinuria, in chronic alcoholism, in combination with lecithin phospholipid and its an integral part of choline for at least 3 days with repeated courses at least twice a year. Beta-hydroxybutyrate is also used to improve the metabolism of tissues susceptible to oxidative stress when co-administered in combination with plant and / or artificial bioflavonoids for at least 1-3 days with intervals between courses of up to 1 week with repeated courses of at least 3 once a year, has a stimulating effect and accelerates the healing process of tissues.

Beta-hydroxybutyrate or its pharmaceutically acceptable salts are used to correct liver metabolism in acute and / or chronic intoxication, including alcohol, in case of liver dysfunction due to hepatitis, preservation and maintenance of mnemonic functions, if necessary, a long concentration of attention, in combination with succinic acid, its derivatives, as well as macro- and microelements (ions of magnesium, potassium, calcium, chromium, selenium, etc.), at least for 1 day with the repetition of courses at least once every three months eggs.

The invention is also directed to the prevention of secondary complications caused by traumatic brain injury (TBI), which should lead to the restoration of neuropsychic status. The essence of the application is that a mammal with an existing TBI is injected with a therapeutically effective amount of beta-hydroxybutyrate to restore and protect the nervous tissue in case of CNS injuries of ischemic, hypoxic, convulsive and mnemonic nature caused by traumatic brain injury. The outcome of a traumatic brain injury is determined mainly as primary, but also to a large extent, secondary brain damage due to ischemia, hypoxia, hypoxia with hypercapnia, increased seizure readiness, increased intracranial pressure, post-traumatic encephalopathy.

It was found that beta-hydroxybutyrate, offered both in monotherapy and in combination with other therapeutically active agents for the treatment of the post-traumatic period, has no analogues.

Its use leads to the minimization of such damaging factors as ischemia of nerve tissue, hypoxia, a decrease in convulsive activity with a positive effect on responses that provide compensatory restoration of neuropsychiatric functions in brain injury.

It was revealed that beta-hydroxybutyrate in the early period after traumatic brain injury has an anti-ischemic, antihypoxic, anticonvulsant effect, and also increases the adaptive capabilities of nervous tissue under extreme stress. Such a multicomponent nootropic effect of beta-hydroxybutyrate, which allows for the rapid restoration of nervous and mental functions during traumatic brain injury, is not described in the literature. It was found that the introduction of beta-hydroxybutyrate in case of traumatic brain injury prolongs the vital activity of brain cells during its total ischemia, lengthens the reserve time during hypoxia, hypoxia with hypercapnia, prevents the development and / or reduces the duration of seizures, and promotes the appearance and acquisition of new adaptive reactions.

The invention is illustrated by the following examples.

Combinations of drugs are prepared by simply mixing the components according to the rules adopted in drug technology and pharmaceutical chemistry.

Example 1

Preparation of a drug solution.

An exact sample of sodium beta-hydroxybutyrate - 0.2 g is dissolved in water for injection to a final volume of 10 ml. Saline is added to 9 ml of the resulting solution until a volume of 30 ml is obtained. The 0.6% sodium beta-hydroxybutyrate solution thus obtained was sterilized by filtration. The solution is ready to use.

Example 2

An exact sample of sodium beta-hydroxybutyrate - 0.2 g is dissolved in water for injection to a final volume of 10 ml. In 9 ml of the resulting solution, the exact weight of choline alfoscerate is dissolved - 7.5 g. After this, physiological saline is added to obtain a volume of 30 ml. The resulting solution contains 0.6% beta sodium hydroxybutyrate and 25% choline alfoscerate (gliatilin). The solution is packaged in single doses of 4 ml.

The drug is used in patients with acute conditions caused by traumatic brain injury, 4 ml per day for 5 days.

Example 3

An accurate sample of sodium beta-hydroxybutyrate - 0.3 g is dissolved in water for injection to a final volume of 10 ml. In 9 ml of the resulting solution, the exact weight of ethyl methylhydroxypyridine succinate (mexidol), 0.15 g, was dissolved. After that, physiological saline was added until a volume of 30 ml was obtained. The resulting solution contains 1.0% beta sodium hydroxybutyrate and 0.5% ethyl methyl hydroxypyridine succinate (Mexidol). The resulting solution is sterilized by filtration and used, depending on the condition, 1-3 bottles per day.

Possible solutions with other drugs are prepared in a similar way. Exemplary formulations are shown in table 1

Example 4

The studies were carried out at the Research Institute of Toxicology on the following models.

1.1 Model of acute histotoxic hypoxia.

Acute histotoxic hypoxia was modeled by intraperitoneal injection of white nonlinear male mice with an aqueous solution of sodium nitroprusside at a dose of 20 mg / kg 30 minutes after the last administration of the test compounds. The life span of the animals was recorded against the background of the administration of a tissue respiration inhibitor.

1.2 Model of acute circulatory hypoxia (gravitational overload).

Circulatory hypoxia was modeled using gravitational overloads in the craniocaudal direction. The magnitude of gravitational overloads was selected so that the lethality of animals (male mice) in the control group approached 50%, which was 18 g for 10 minutes. The gradient of the rise and fall of the load was 0.30-0.33g per second (Gaevy M.D., 1986, Pogorely V.E., 2001).

The results of the study.

The effect of the test drug beta-hydroxybutyrate on the tolerance of acute histotoxic hypoxia.

One of the most easily reproducible and often used to evaluate antihypoxic properties of the drug is a model of acute histototoxic hypoxia (OGTG).

Table 2 shows the effect of the study drug on the life expectancy of male mice under conditions of acute histotoxic hypoxia (sodium nitroprusside, 20 mg / kg), n = 10 in each group.

table 2 Study drugs Dose mg / kg Life span, min Survival rate (% of the total) Control (saline) 2 ml / kg 10 fifty Mexidol / Beta-Hydroxybutyrate one hundred 10 75 * Succinic acid / beta-hydroxybutyrate one hundred 10 70 Melatonin / Beta-Hydroxybutyrate one hundred 10 75 * Beta hydroxybutyrate one hundred 10 65 * Glycine / Beta-Hydroxybutyrate one hundred 10 75 * Memantine / Beta-Hydroxybutyrate one hundred 10 70 * Piracetam / Beta-Hydroxybutyrate one hundred 10 70 * Lipoic Acid / Beta-Hydroxybutyrate one hundred 10 75 * Actovegin / Beta-Hydroxybutyrate one hundred 10 70 Note: * - P≤0.05 in relation to control

As follows from the data presented in table 2, the introduction of beta-hydroxybutyrate in combinations increased the life expectancy of experimental animals against the background of the introduction of a tissue respiration inhibitor by 23-55%.

Thus, beta-hydroxybutyrate in combination has cytoprotective activity under conditions of tissue hypoxia in the above doses.

Example 5

The influence of the studied combinations with beta-hydroxybutyrate on the tolerance of circulatory hypoxia (gravitational overload).

Longitudinal gravitational overloads created by a centrifuge cause circulatory disorders of the brain, the severity and nature of which depends on the size, duration and vector of radial accelerations. With the craniocaudal acceleration vector (positive radial acceleration), blood moves in the caudal direction and cerebral ischemia occurs as a result of a drop in blood pressure in all vessels of the head.

The influence of the studied combinations on the resistance of male mice to circulatory hypoxia (gravitational overload), n = 10 in each group are shown in table 3.

Table 3 Group / drug Dose mg / kg Life span, min Survival rate (% of the total) Control (saline) 2 ml / kg 10 fifty Mexidol / Beta-Hydroxybutyrate one hundred 10 one hundred* Succinic acid / beta-hydroxybutyrate one hundred 10 75 Melatonin / Beta-Hydroxybutyrate one hundred 10 75 * Beta hydroxybutyrate one hundred 10 60 Glycine / Beta-Hydroxybutyrate one hundred 10 75 * Mexidol / Beta-Hydroxybutyrate one hundred 10 75 * Choline Alfoscerate / Beta-Hydroxybutyrate one hundred 10 75 * Lipoic Acid / Beta-Hydroxybutyrate one hundred 10 75 * Actovegin / beta-hydroxybutyrate one hundred 10 75 * Memantine / Beta-Hydroxybutyrate one hundred 10 75 Note: * - P≤0.05 in relation to control

As follows from the data presented in table 3, the introduction of the studied combinations with beta-hydroxybutyrate led to a significant increase in survival of animals.

These compositions do not exhaust all possible combinations and ratios, the maximum amounts of components are given below.

Reamberin in the form of a solution of d / inf., 1.5%, intravenously (iv) dropwise in a volume of 400-800 ml / day together with beta-hydroxybutyrate in an amount of 5 mg to 10 g (except for conditions after cranial brain injury accompanied by cerebral edema);

iv piracetam in acute conditions (for example, with acute cerebrovascular accident, coma) in a dose of up to 10-12 g / day in conjunction with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

derivatives of barbituric acid, for example phenobarbital, in a daily dose of 2-3 mg per kg (in one or two doses) together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

preparations from the class of benzodiazepines, for example, with phenazepam in a daily dose of 1 to 8 mg together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

Akatinol memantine in a daily dose (depending on the condition) from 10 to 60 mg orally in conjunction with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

iv Actovegin (including in the form of infusions) in doses of 80 mg - 2 g / day in several doses, alternating during the day with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

diuretics (for example, such as mannitol) depending on the condition in a dosage of 500 mg / kg body weight (with prophylactic therapy) to 1-1.5 g / kg together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day ;

furosemide - depending on the condition, from 20 to 160 mg / day in combination with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

nicotinamide depending on the state in an amount of 20-150 mg / day in conjunction with beta-hydroxybutyrate in an amount of from 5 mg / day to 10 g / day i / m, i / v;

iv lipoic acid (jet, drip) in a dose of 600-1200 mg / day in conjunction with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

ascorbic acid is administered parenterally in the form of sodium ascorbate in 1-3 ml of a 5% solution (single dose not higher than 0.2 g, daily 0.5 g) together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

Riboxin, depending on the iv status, in a jet or drip (40-60 drops per minute) - 200-800 mg / day together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

succinic acid, succinate, derivatives of succinate (for example, sodium succinate) in an amount of from 20 mg to 10 g / day in conjunction with beta-hydroxybutyrate in an amount of from 5 mg / day to 10 g / day;

urokinase, streptokinase and their derivatives:

urokinase - depending on the condition and the applied scheme, jet up to 5,000,000 IU / day in conjunction with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

streptokinase 250,000 IU for 30 minutes in conjunction with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

tissue plasminogen activator (TAP) up to 100 mg together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

reopoliglyukin infusion solution "Reopoliglukin-40" intravenously, depending on the condition and indications, up to 400-1000 ml per day (for 30-60 minutes) together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day. Similarly, Reomacrodex (reopoliglukin with glucose) solution for infusion 10% can be used;

mannitol - intravenously for 20-30 minutes at a dose of 0.5-1.0 g / kg body weight together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

fraxiparin - depending on the condition and recommendations subcutaneously from 2000 ME to 20,000 ME together with beta-hydroxybutyrate in an amount of from 5 mg / day to 10 g / day;

phenylin - in a dosage of 30 mg to 90 mg in conjunction with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

syncumar - in a dosage of 2 to 8 mg together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

warfarin - in a dosage of 2.5 to 20 mg in conjunction with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

ticlopidine in a dosage of 250 mg together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

dipyridamole (chimes) in a dosage of 25 to 150 mg together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

pentoxifylline for acute disorders of peripheral or cerebral circulation, ischemic stroke intravenously from 0.1 g to 0.3 g in 250-500 ml of isotonic sodium chloride solution or in 5% glucose solution for 90-180 minutes together with beta-hydroxybutyrate in amount from 5 mg / day to 10 g / day;

antioxidants:

emoxipin, depending on the indications, in / in a drip of 20-30 ml of a 3% solution in 200 ml of isotonic sodium chloride solution 1-3 times / day together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

Mildonium (Mildronate) - depending on the indications and condition, up to 500 mg / day in conjunction with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

calcium channel blockers:

nimodipine iv in drops, depending on the condition, starting from a dose of 2 mg for two hours together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g, provided the drug is well tolerated, especially in the absence of severe hypotension, the dose can be increased to 2 mg / h (about 30 μg / kg / h) together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

drugs of predominantly neurotrophic action:

cerebrolysin, depending on the state, parenterally in the form of intravenous infusions in a dose of 10-60 ml together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

glycine in a dosage of 2 mg together with beta-hydroxybutyrate in an amount of from 5 mg / day to 10 g / day;

picamilon - depending on the state, from 20 to 100 mg / day in conjunction with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

angioprotectors:

parmidin, depending on the state, from 250 to 1000 mg / day in conjunction with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

ascorutin from 500 mg to 2 g together with beta-hydroxybutyrate in an amount of from 5 mg / day to 10 g / day;

troxevasin from 300 mg to 1200 mg together with beta-hydroxybutyrate in an amount of from 5 mg / day to 10 g / day;

ethamylate, depending on the state, intravenously in a dosage of 0.25-0.75 g (2-6 ml of 12.5% solution) together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

iv vinpocetine in a drop of 10-20 mg in 500-1000 ml of isotonic sodium chloride solution (maximum daily dose - 1 mg / kg) together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day .;

iv Cavinton drip 20 mg in 500-1000 ml of infusion solution (maximum daily dose - 1 mg / kg) together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

nicergoline iv in a drop of 4-8 mg per 100 ml of 0.9% Nacl solution or 5 or 10% dextrose solution (up to 2-3 times / day) together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day ;

instenon depending on the severity of the condition 1-2 times a day, 1 ampoule intravenously or 1-2 times a day, one ampoule in the form of a drop infusion together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

eufillin iv slowly (within 4-6 minutes) at 0.12-0.48 g (5-10 ml of 2.4% solution), in 10-100 ml of isotonic sodium chloride solution together with beta-hydroxybutyrate in the amount of from 5 mg / day to 10 g / day;

cinnarizine, depending on the state, from 25 to 100 mg in conjunction with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

sermion - depending on the state, from 4 to 60 mg together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day;

derivatives of valproic acid:

intravenously (in the form of sodium valproate), 400-800 mg or intravenously, at the rate of 25 mg / kg, for 24, 36, 48 hours together with beta-hydroxybutyrate in an amount of 5 mg / day to 10 g / day .

Claims (24)

1. The use of beta-hydroxybutyrate or its pharmaceutically acceptable salts in combination with another active substance or combination of active substances selected from the group of choline alfoscerate, such as gliatilin, ethylmethylhydroxypyridine succinate, meglumine sodium succinate (reamberin), magnesium and / or lithium preparations, piracetam , succinic acid, derivatives of barbituric acid, benzodiazepines, akatinol memantine, glycine, actovegin, derivatives of valproic acid, loop and osmotic diuretics such as mannitol and furo emid, vitamins A, E, PP, group B, ascorbic acid, lipoic acid, riboxin, urokinase, streptokinase, tissue plasminogen activator (TAL), low molecular weight dextrans, such as reopoliglukin and rheomacrodex, phenylin, syncumar, pentoxifylline, emonipin, emoxipine, emoxipine nimodipine, cerebrolysin, etamzilate, vinpocetine, cavinton, nicergoline, instenon, aminophylline, sermion for the preparation of a medicinal product with cytoprotective activity, including neuroprotective, cardioprotective, anti-insemination mental, antihypoxic, antistress and adaptogenic activities. 2. The use according to claim 1, in which the drug is used to treat ischemic and hemorrhagic stroke, myocardial infarction, kidney, liver, cerebrovascular accident, cicatricial changes in heart tissue, maternal and fetal pathology associated with pregnancy and childbirth, cranial trauma and to prevent the consequences of circulatory disorders caused by surgical intervention. 3. The use according to claim 1 or 2, in which the drug is in the form of a perfusion, blood substitute or plasma substitute solution. 4. The use according to claim 1 or 2, in which the drug is used in case of urgent conditions or pathologies requiring emergency medical care. 5. A drug with cytoprotective activity, including neuroprotective, anti-ischemic, cardioprotective, antihypoxic, antistress, actoprotective and adaptogenic activity containing beta-hydroxybutyrate or its pharmaceutically acceptable salts in combination with another active substance or combination of active substances selected from the group of choline such as gliatilin, ethylmethylhydroxypyridine succinate, meglumine sodium succinate (reamberin), magnesium and / or lithium preparations, piracetam, succinic acid, derivatives of barbituric acid, benzodiazepines, akatinol memantine, glycine, actovegin, derivatives of valproic acid, loop and osmotic diuretics such as mannitol and furosemide, vitamins A, E, PP, group B, ascorbic acid, lipoic acid, ribox urokinase, streptokinase, tissue plasminogen activator (TAL), low molecular weight dextrans such as reopoliglukin and rheomacrodex, phenylin, syncumar, pentoxifylline, emoxipin, mildronate, nimodipine, cerebrolysin, etamsylate, vi potsetina, cavinton, nicergoline, instenon, aminophylline, Sirmione. 6. The drug according to claim 5, characterized in that it is made in the form of a perfusion, blood substitute or plasma substitute solution. 7. The drug according to claim 5, characterized in that it is used in case of emergence of urgent conditions or pathologies associated with the development of life-threatening hypoxic or anoxic foci in the tissues and requiring urgent medical attention. 8. The drug according to claim 5, characterized in that it is used to treat ischemic and hemorrhagic stroke, myocardial infarction, kidney, liver, cerebrovascular accident, cicatricial changes in heart tissue, maternal and fetal pathology associated with pregnancy and childbirth and to prevent the consequences of circulatory disorders caused by surgery. 9. The drug according to claim 5, characterized in that it is used for the treatment of neurological disorders caused by craniocerebral, spinal or head injuries. 10. A method for the prevention, relief and treatment of diseases requiring the introduction of a cytoprotective drug, characterized in that as a cytoprotective drug, the drug is used according to any one of claims 5 to 9. 11. The method according to claim 10, characterized in that said condition requiring administration of a cytoprotective drug is an acute stress state and symptoms of debilitating stress strain associated with the possible development of hypoxic or anoxic damage to organs or tissues in case of borderline neuropsychiatric pathology. 12. The method according to claim 10, characterized in that said condition requiring the administration of a cytoprotective drug is an acute stress state and symptoms of depleting stress overload associated with the possible development of hypoxic or anoxic damage to organs or tissues under extreme conditions of warfare. 13. The method according to claim 10, characterized in that said condition requiring the administration of a cytoprotective drug is a prolonged stress disorder with neurasthenia with anxiety-phobic disorders, alcoholism, and opium addiction. 14. The method according to claim 10, characterized in that said condition requiring the administration of a cytoprotective drug is a pathology of the cardiovascular system with a severe progressive course of coronary heart disease against hypertension II-III art. 15. The method according to claim 10, characterized in that said condition requiring administration of a cytoprotective drug is a complication of coronary angiography. 16. The method according to claim 10, characterized in that the drug is administered to elderly patients with coronary heart disease older than 70 years, long-term use of cardiotropic drugs in order to reduce the doses of these drugs. 17. The method according to claim 10, characterized in that said condition requiring the administration of a cytoprotective drug is type 2 diabetes mellitus of moderate severity, the treatment being carried out for at least the first six days, until satisfactory compensation of diabetes mellitus is achieved, and with repeated use of the drug, it will take considerable time to maintain resistance to carbohydrate load to an acceptable level. 18. The method according to claim 10, characterized in that said condition requiring the introduction of a cytoprotective drug is neurocirculatory dystonia, discirculatory encephalopathy of atherosclerotic origin, with a decrease in memory and mental performance. 19. The method according to claim 10, characterized in that said condition requiring the introduction of a cytoprotective drug is cerebral palsy, including spastic forms such as spastic diplegia, hemiparetic form, atonic-astatic form, as well as the consequences of the birth, cranial - brain or other injury. 20. The method of claim 10, wherein said condition requiring administration of a cytoprotective drug is minimal cerebral dysfunction in children with functional and / or organic dysfunctions of the central nervous system. 21. The method according to claim 10, characterized in that said condition requiring administration of a cytoprotective drug is intrauterine hypoxia of the fetus. 22. The method according to claim 10, characterized in that said condition requiring administration of a cytoprotective drug is a condition after severe traumatic brain injury with the removal of a brain crush area, while the drug is prescribed for at least 5 days during the first months before the disappearance of pathological manifestations in patients. 23. The method according to claim 10, characterized in that said condition requiring the administration of a cytoprotective drug is a pathology of the central and peripheral nervous system (meningitis, encephalitis of various origins, paresis, strokes), as well as emergency conditions, such as shock of any origin . 24. The method of claim 10, wherein said condition requiring administration of a cytoprotective drug is a condition after a heavy load and stress.