RU2503462C2 - Method of treating vertigo of various origins, kinetosis and vegetative-vascular dystonia (versions) and drug preparation - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: present group of inventions refers to medicine, namely therapy and neurology, and concerns treating kinetosis. That is ensured by administering a pharmaceutical composition containing an activated potentiated form of the antibodies to brain-specific protein S-100 and an activated potentiated form of the antibodies to endothelial NO-synthase.

EFFECT: method provides the effective treatment of kinetosis ensured by the synergetic action of the ingredients of the composition.

11 cl, 16 tbl, 4 ex

Description

The invention relates to medicine and can be used to treat dizziness of various origins, kinetoses, as well as vegetative-vascular dystonia, accompanied by both an increase and a decrease in blood pressure.

Vegetative-vascular dystonia (synonyms: neurocirculatory dystonia, neurocirculatory asthenia, psychovegetative syndrome, vegetoneurosis, autonomic dysfunction syndrome) is a polyetiological syndrome characterized by dysfunction of the autonomic (autonomous) nervous system (ANS), and functional (i.e., not organic) disorders from the side all body systems (mainly cardiovascular). The main clinical feature of patients with VVD is the presence of numerous complaints in patients, the variety of various symptoms and syndromes, which is due to the peculiarities of pathogenesis, involvement of hypothalamic structures in the process. The most common symptoms of VVD: cardialgia, asthenia, neurotic disorders, headache, sleep disturbance, dizziness, respiratory distress, palpitations, cold hands and feet, autonomic vascular paroxysms, hand tremors, internal tremors, cardiophobia, myalgia, joint pain, swelling tissues, heart failure, sensation of heat in the face, subfebrile condition, fainting.

Vegetative disorders, manifested in a violation of the regulation of the cardiovascular, respiratory and other body systems, can be an integral part of a number of painful conditions: hypertension, endocrine disorders, chronic coronary heart disease, etc. Vegetative-vascular dystonia and neurocircular dystonia can also be put to patients on the basis of a symptom complex characteristic of somatoform dysfunction of the autonomic nervous system.

As part of a complex symptom complex of vegetative-vascular dystonia, a syndrome of cerebrovascular disorders, characterized by headaches, dizziness, noise in the head and ears, weakness of the vestibular apparatus, a tendency to fainting, and kinetosis, is separately distinguished. Its development is based on cerebral angioedema, the pathogenetic basis of which is the dysregulation of the tone of the vessels of the brain hypertonic, hypotonic or mixed.

Kinetosis (synonyms: motion sickness, motion sickness, air sickness, motor sickness, etc.) - movement disease (from the Greek. Kynesis - movement) occurs when more or less prolonged and changing accelerations act on the body. Kinetosis is characterized by impaired coordination of movements, dizziness, nausea, vomiting, pallor, cold sweat, decreased blood pressure, and decreased heart rate. In severe cases, depression, asthenia, and clear consciousness are possible. However, after the termination of the acceleration, the symptoms of kinetoses disappear. Due to the fact that alternately different receptors of the vestibular apparatus are irritated during motion sickness, the cerebellum receives impulses that cause changes in the tone of various muscle groups of the neck, back, and limbs - hence the asymmetry of muscle tone, impaired coordination of movements. Manifestations of kinetoses are more pronounced in individuals with increased excitability of the sympathetic or parasympathetic parts of the nervous system or vestibular analyzer.

Dizziness attacks are largely due to changes in the functional relationships between the sympathetic and parasympathetic nervous systems towards the predominance of the function of the parasympathetic system. These changes are accompanied by vasomotor disorders in the inner ear with an increase in the permeability of the vessel walls and a subsequent increase in the amount of endolymph in the vestibular apparatus. Dizziness (vertigo) is a typical sign of damage to the vestibular analyzer of various genesis, including impaired function of the vestibular nerve and vestibular cochlear system, circulatory disorders in the vertebral-basilar system, pathology of the central nervous system (CNS), etc. Dizziness as a manifestation of kinetosis is accompanied by other vestibulo- autonomic disorders, including three types of reactions: vestibulomotor (nystagmus and deviation reactions), vestibulo-sensory (in addition to dizziness, this is nystagmus (or eaktsiya postvrascheniya), defensive movements) and vegetative (nausea, vomiting, sweating, palpitations, hot flashes, fluctuating heart rate and blood pressure).

The homeopathic medicine “AVIAMORE” (RU 2113230 C1, A61K 35/78, 1998) based on plant materials, which is intended for the treatment and prevention of kinetoses in the form of motion sickness in transport, sea and air sickness, is known in the art. The effectiveness of this drug in some cases may not be high enough.

Also known is a neurotropic drug based on antisera to the brain-specific protein S-100 (RU 2156621 C1, A61K 39/395, 09/27/2000). However, the use of this drug for the treatment of dizziness of various origins, kinetoses, as well as vegetative-vascular dystonia is not obvious and does not follow explicitly from the prior art.

The invention is aimed at expanding the therapeutic range of the drug based on the activated - potentiated form of antibodies to endothelial NO synthase and increasing the effectiveness of the treatment of vegetative-vascular dystonia of various origins, dizziness of various origins and kinetoses.

The solution to this problem is provided by the fact that for the treatment of dizziness of various origins, kinetoses and vegetative-vascular dystonia, according to the invention, an activated - potentiated form of antibodies to the brain-specific protein S-100 is introduced into the body.

Moreover, the activated-potentiated form of antibodies to the brain-specific protein S-100 is used in the form of an activated-potentiated aqueous or hydroalcoholic solution, the activity of which is due to the process of repeated dilution in an aqueous or hydroalcoholic solvent in combination with an external mechanical action - vertical shaking of each breeding.

In addition, an aqueous or aqueous-alcoholic solution of activated-potentiated forms of antibodies to the brain-specific protein S-100 was obtained by multiple sequential dilutions in combination with an external action - vertical shaking of each dilution from a matrix solution of affinity-purified antibodies to the brain-specific protein S-100 with a concentration of 0 5 ÷ 5.0 mg / ml.

It is possible to use a drug based on an activated-potentiated form of antibodies to the brain-specific protein S-100 in solid dosage form for the treatment of dizziness of various origins, kinetoses and vegetative-vascular dystonia, which contains an effective amount of granules of a neutral carrier saturated with a mixture of aqueous or aqueous-alcoholic solutions activated-potentiated forms of antibodies to the brain-specific protein S-100, and pharmaceutically acceptable additives, including lactose, microcristol cellulose llicheskuyu and magnesium stearate.

In addition, as an option, the solution of the problem is provided by the fact that for the treatment of dizziness of various origins, kinetoses and vegetative-vascular dystonia, according to the invention, an activated-potentiated form of antibodies to the brain-specific protein S-100 is introduced into the body simultaneously and combined with activated-potentiated form of antibodies to endothelial NO synthase.

In this case, the activated-potentiated form of antibodies to the brain-specific protein S-100 and the activated-potentiated form of antibodies to endothelial NO synthase are used in the form of an activated-potentiated aqueous or aqueous-alcoholic solution of each component, the activity of which is due to the process of multiple serial dilutions in aqueous or water-alcohol solvent in combination with external mechanical stress - vertical shaking of each dilution.

In addition, a mixture of various dilutions of antibodies to the brain-specific protein S-100 in combination with a mixture of various dilutions of antibodies to endothelial NO synthase prepared by homeopathic technology is prepared in the form of a single drug - a single dosage form.

The solution to this problem is also provided by the fact that the drug for the treatment of pathological syndrome, including dizziness of various origins, kinetoses and vegetative-vascular dystonia, according to the invention, is made in the form of a pharmaceutical composition and contains an activated-potentiated form of antibodies to the brain-specific protein S-100 and activated -potentiated form of antibodies to endothelial NO synthase.

At the same time, the activated-potentiated form of antibodies to the brain-specific protein S-100 and the activated-potentiated form of antibodies to endothelial NO synthase are used in the form of an activated-potentiated aqueous or aqueous-alcoholic solution, the activity of which is due to the process of multiple sequential dilutions in aqueous or aqueous alcohol solvent in combination with external mechanical action - vertical shaking of each dilution.

In addition, the drug can be made in solid dosage form and contain an effective amount of granules of a neutral carrier saturated with a mixture of aqueous or aqueous-alcoholic solutions of the activated-potentiated form of antibodies to the brain-specific protein S-100 and the activated-potentiated form of antibodies to endothelial NO synthase and pharmaceutically acceptable additives including lactose, microcrystalline cellulose and magnesium stearate.

In this case, aqueous or aqueous-alcoholic solutions of activated-potentiated forms of antibodies to the brain-specific protein S-100 and to endothelial NO synthase are obtained by repeated serial dilutions in combination with external exposure - vertical shaking of each dilution from matrix solutions of affinity-purified antibodies to brain-specific protein S -100 and to endothelial NO synthase with a concentration of 0.5 ÷ 5.0 mg / ml.

Moreover, each of the components of the claimed medicinal product is used in the form of a mixture of various, mainly hundred, dilutions prepared according to homeopathic technology.

In addition, the drug may contain active ingredients in a volume ratio of 1: 1, each component being used as a mixture of three matrix solutions, diluted, respectively, 100 ¹² , 100 ³⁰ , and 100 ²⁰⁰ times, which is equivalent to hundreds of dilutions of C12, C30, C200 prepared according to homeopathic technology.

The claimed pharmaceutical composition is recommended to be taken, preferably, 1-2 tablets 2-6 times (preferably 2-4 times) per day.

In the treatment of dizziness of various origins, kinetoses, as well as vegetative-vascular dystonia, separate, but combined and simultaneous use (administration to the body) of the claimed pharmaceutical composition in the form of two separately prepared preparations, both in the form of solutions, and in solid dosage forms (tablets) is possible , each of which contains an activated-potentiated form of ultra-low doses of affinity-purified antibodies to the brain-specific protein S-100 and, accordingly, an activated-potentiated form of ultra-small Lake affinity purified antibodies to endothelial NO-synthase.

The proposed combination of activated-potentiated forms of antibodies to the brain-specific protein S-100 and to endothelial NO synthase in a pharmaceutical composition (i.e., forms of antibodies to the brain-specific protein S-100 and to endothelial NO synthase prepared according to the homeopathic technology of potentiation by multiple sequential dilution and external exposure - repeated vertical shaking of each dilution (see, for example, V. Schwabe "Homeopathic medicines", M., 1967, p.14-29), which have an asset due to potentiation technology in pharmacological models and / or clinical methods for treating dizziness of various origins, kinetoses and vegetative-vascular dystonia) provides an unexpected synergistic therapeutic effect, confirmed by adequate (valid) experimental models and clinical studies, which consists in increasing the efficiency treatment of dizziness of various origins, kinetoses, and vegetative-vascular dystonia. The indicated technical result is provided by an increase in the neuroprotective activity of antibodies to the S-100 protein, due to the influence on the efficiency of the interaction of ligands with the sigma-1 receptor, the vegetative-stabilizing effect, the normalization of the vegetative status, as a manifestation of previously undetected properties of the activated-potentiated form of antibodies to the brain-specific protein S- 100, and the synergistic effect of both components on neuronal plasticity, and, as a result, increased brain resistance to toxic effects actions that improves integrative activity and restores interhemispheric connections of the brain, helps to eliminate cognitive impairment, stimulates reparative processes and accelerates the restoration of central nervous system functions, normalizes somatovegetative manifestations, increases cerebral blood flow, and, accordingly, ensures the expansion of the therapeutic range of the drug and increases the effectiveness of dizziness treatment kinetheses, as well as vegetative-vascular dystonia of various origins, including the vegetative vessel true dystonia, accompanied by both an increase and a decrease in blood pressure. In this case, the claimed drug, as well as its constituent components, do not have a sedative and muscle relaxant effect, do not cause addiction and addiction. Including, the claimed drug can be used as part of complex therapy.

In addition, the claimed drug expands the arsenal of drugs intended for the treatment of dizziness of various origins, kinetoses, as well as vegetative-vascular dystonia.

The drug is prepared mainly as follows.

For the preparation of the activated-potentiated form of the active components, monoclonal or, mainly, polyclonal antibodies are used, which can be obtained by known technologies - the techniques described, for example, in the book: Immunological methods, ed. G. Frimel, M., "Medicine", 1987, S. 9-33; or, for example, in an article by Laffly E., Sodoyer R. Hum. Antibodies. Monoclonal and recombinant antibodies, 30 years after. - 2005 - Vol.14. - N1-2. P.33-55.

Monoclonal antibodies are obtained, for example, using hybridoma technology. Moreover, the initial stage of the process includes immunization, based on the principles already developed in the preparation of polyclonal antisera. Further stages of the work include obtaining hybrid cells producing clones of antibodies of the same specificity. Their isolation in an individual form is carried out by the same methods as in the case of polyclonal antisera.

Polyclonal antibodies can be obtained by active immunization of animals. For this purpose, according to a specially developed scheme, animals are given a series of injections with the antigens required by the invention: brain-specific protein S-100 and endothelial NO synthase. As a result of this procedure, monospecific antisera with a high content of antibodies are obtained, which are used to obtain activated-potentiated forms of components. If necessary, the antibodies present in the antiserum are purified, for example, by affinity chromatography, using fractionation by salt precipitation or ion exchange chromatography.

Preferred for the preparation of the claimed pharmaceutical composition is the use of polyclonal antibodies to the brain-specific protein S-100 and to endothelial NO synthase, which are used as a matrix (primary) solution with a concentration of 0.5 ÷ 5.0 mg / ml for the subsequent preparation of activated potentiated form.

Preferred for the preparation of each component is the use of a mixture of three water-alcohol dilutions of the initial matrix solution of antibodies, diluted, respectively, 100 ¹² , 100 ³⁰ , and 100 ²⁰⁰ times, which corresponds to hundreds of dilutions C12, C30 and C200 prepared according to homeopathic technology. When performing the claimed drug in solid dosage form, a mixture of these components in a volume ratio of 1: 1 can be applied to a neutral carrier - lactose.

Preferred for the preparation of the claimed drug is the use of polyclonal antibodies to endothelial NO synthase and to the brain-specific protein S-100, which can be obtained by immunization of rabbits as follows.

For experimental studies, antibodies prepared by order of a specialized biotechnological company can be used.

To obtain polyclonal antibodies to the brain-specific protein S-100, the brain-specific protein S-100 is used, the physicochemical properties of which are described in the article by M.V. Starostina, S.M. Sviridov, Neurospecific protein S-100, Advances in modern biology, 1977, v.5, p.170-178; the book of MB Stark, Brain-specific proteins / antigens / and neuron functions, M., "Medicine", 1985; p.12-14, isolated from tissue of the brain of a bull by the following method:

- fabric frozen in liquid nitrogen is ground into powder in a special mill;

- the extraction of proteins is carried out in a ratio of 1: 3 (weight / volume) in the extraction buffer during homogenization;

- the homogenate is heated for 10 min at 60 ° C and cooled to 4 ° C in an ice bath;

- thermolabile proteins are removed by centrifugation;

- carry out stepwise fractionation with ammonium sulfate, followed by removal of precipitated impurity proteins;

- the S-100 protein-containing fraction is precipitated with 100% saturated ammonium sulfate when the pH is reduced to 4.0 and collected by centrifugation;

- the precipitate is dissolved in a minimum volume of a buffer containing EDTA and mercaptoethanol, dialyzed against deionized water and freeze-dried;

- fractionation of acidic proteins is continued by chromatography on ion-exchange media — DEAE cellulose DE-52 and then DEAE-Sephadex A-50;

- collected and dialyzed fractions containing S-100 protein are separated by molecular weight by gel filtration on Sephadex G-100;

- purified S-100 protein is dialyzed and freeze-dried.

The molecular weight of the purified brain-specific protein S-100 is 21,000 d.

Due to the high content of aspartic and glutamic acids, the brain-specific protein S-100 is strongly acidic and occupies the extreme anode position during electrophoresis in a discontinuous buffer system in a polyacrylamide gel, which facilitates its identification.

To obtain a brain-specific antiserum, a purified S-100 protein (antigen) is prepared in combination with methylated bovine serum albumin as a carrier with Freund's complete adjuvant, which is administered subcutaneously to a laboratory rabbit animal in the amount of 1- to a selected brain-specific protein S-100. 2 ml On the 8th, 15th day, re-immunization is carried out. Blood is taken (for example, from an ear vein) on the 26th and 28th day.

The resulting antiserum has a titer of 1: 500 - 1: 1000, forms a single precipitation band with extract from the nervous tissue, but does not react with extracts of heterologous organs, and forms a single precipitation peak with both pure S-100 protein and the extract of nervous tissue, which indicates the monospecificity of the obtained antiserum.

Polyclonal antibodies to endothelial NO synthase are prepared using the adjuvant and the whole endothelial NO synthase molecule of the following sequence as immunogen (antigen) for rabbit immunization:

It is possible to obtain polyclonal antibodies to endothelial NO synthase using the following sequence as an immunogen (antigen) of a whole molecule of endothelial NO synthase:

It is possible to obtain polyclonal antibodies to endothelial NO synthase using, as an immunogen (antigen), a synthetic peptide of endothelial NO synthase, selected, for example, from the following amino acid sequences:

Before blood sampling for 1-3 days, 1-3 intravenous injections are performed to increase the level of antibodies. During immunization, small blood samples are taken from rabbits to evaluate the amount of antibody. The maximum level of the immune response to the administration of most soluble antigens is achieved 40-60 days after the first injection. After the end of the first cycle of immunization of rabbits for 30 days, they restore health and re-immunization, including 1-3 intravenous injections. To obtain antisera from immunized rabbits, blood is collected in a 50 ml centrifuge tube. Using a wooden spatula, the formed clots are removed from the walls of the tube and the wand is placed in the clot formed in the center of the tube. Blood is placed in a refrigerator (temperature 4 ° C) at night. The next day, the clot attached to the spatula is removed and the remaining liquid is centrifuged at 13000g for 10 minutes. The supernatant (supernatant) is an antiserum. The resulting antiserum should be yellow. Add to the antiserum 20% (weight concentration) NaN ₃ to a final concentration of 0.02% and store until use in a frozen state at a temperature of -20 ° C (or without adding NaN ₃ at a temperature of -70 ° C). To isolate antibodies to endothelial NO synthase from antiserum, solid phase absorption is performed in the following sequence:

1. 10 ml of rabbit antiserum is diluted 2 times with 0.15 M NaCl, 6.26 g of Na ₂ SO ₄ are added, stirred and incubated for 12-16 hours at 4 ° C;

2. The precipitate formed is removed by centrifugation, dissolved in 10 ml of phosphate buffer and then dialyzed against the same buffer overnight at room temperature;

3. after removal of the precipitate by centrifugation, the solution is applied to a column with DEAE-cellulose, balanced with phosphate buffer;

4. The antibody fraction is determined by measuring the optical density of the eluate at 280 nm.

The antibodies are then purified by affinity chromatography by attaching the obtained antibodies to endothelial NO synthase, which is located on an insoluble matrix, followed by elution with concentrated salt solutions.

Thus obtained buffer solution of polyclonal rabbit antibodies to endothelial NO synthase, purified on antigen, with a concentration of 0.5 ÷ 5.0 mg / ml, preferably 2.0 ÷ 3.0 mg / ml, is used as a matrix ( primary) solution for the subsequent preparation of the activated-potentiated form according to homeopathic technology.

The activated-potentiated form of each component is prepared by uniformly decreasing the concentration by sequentially diluting 1 part of the matrix solution in 9 parts (for decimal dilution D) or 99 parts (for hundredth dilution C) or 999 parts (for thousandth dilution M) neutral solvent in combination with repeated (at least 10 times) vertical shaking ("dynamization") of each dilution obtained and the use of separate containers for each subsequent dilution to p radiation required potency - the multiplicity of dilution of homeopathic technology (see, eg, W. Schwabe "Homeopathic medicines", M., 1967, s.14-29.).

For example, for the preparation of the 12th hundredth C12 dilution, one part of the above matrix solution of antibodies to the brain-specific protein S-100 (or to NO synthase) with a concentration of 2.5 mg / ml is diluted in 99 parts of a neutral aqueous or aqueous-alcoholic solvent ( mostly 15% ethyl alcohol) and repeatedly (10 or more times) vertically shake - potentiate the obtained 1st hundredth C1 dilution. From the 1st hundredth C1 dilution prepare the 2nd hundredth dilution C2. This operation is repeated 11 times, obtaining the 12th hundredth dilution of C12. Thus, the 12th hundredth dilution of C12 is a solution obtained by diluting successively in different containers 12 times of the first part of the initial matrix solution of antibodies to NO synthase with a concentration of 2.5 mg / ml in 99 parts of a neutral solvent, t .e. a solution prepared by diluting the matrix solution in 100 ¹² times. Similar operations with the appropriate dilution ratio are carried out to obtain a dilution of C30 and C200.

When using, as a component (for example, an activated-potentiated form of antibodies to the brain-specific protein S-100), mixtures of different, mainly hundred, dilutions, each dilution of the component (for example, C12, C30, C200) is prepared separately according to the technology described above to the penultimate dilution (respectively, to obtain C11, C29, C199) and then bring one part of each penultimate dilution obtained into one container and mix with the required amount of a water-alcohol solvent (mainly 50-70% Tilova alcohol) (respectively, with 97 parts for centesimal dilution). In this case, an activated-potentiated form of antibodies to the brain-specific protein S-100 is obtained in an ultra-low dose, prepared by super-dilution of the matrix solution, respectively, 100 ¹² , 100 ³⁰ and 100 ²⁰⁰ times, equivalent to a mixture of hundred-percent dilutions of C12, C30 and C200, using homeopathic technology.

It is possible to use each component in the form of a mixture of various different dilutions according to homeopathic technology, for example, decimal and or hundredths (C12, C30, C100; D20, C30, C100 or D20, C30, M100, etc.), the effectiveness of which is determined experimentally .

When potentiating instead of shaking in the process of decreasing the concentration, it is also possible to exert external influence by ultrasound, electromagnetic or other physical effect.

To obtain the claimed pharmaceutical composition, aqueous or aqueous-alcoholic solutions of the active ingredients are mixed, mainly in a volume ratio of 1: 1 and used in liquid dosage form.

The claimed pharmaceutical composition can also be used in solid dosage form, which contains an effective amount of particles of a neutral carrier - lactose, saturated by soaking in a mixture of aqueous or aqueous-alcoholic solutions with an activated-potentiated form of antibodies to the brain-specific protein S-100 and an activated-potentized form antibodies to endothelial NO synthase, and pharmaceutically acceptable additives, including mainly lactose, microcrystalline cellulose and magnesium stearate.

To obtain a solid oral form of the claimed medicinal product, a fluidized bed is installed (for example, Huttlin Pilotlab type manufactured by Huttlin GmbH) irrigation until saturation of particles of a neutral substance - lactose (milk sugar) with a particle size of 100 ÷ 300 is introduced into the fluidized - boiling layer μm, a pre-prepared aqueous or aqueous-alcoholic solution of activated-potentiated forms of antibodies to the brain-specific protein S-100 and to endothelial synthase of nitric oxide (NO synthase), mainly in the ratio 1 kg of antibody solution per 5 or 10 kg of lactose (1: 5 - 1:10) with simultaneous drying in a stream of heated air supplied under the grate at a temperature not exceeding 40 ° C. The estimated amount of 10 ÷ 34 mass parts of dried granules saturated with the activated-potentiated form of antibodies is loaded into the mixer and mixed with 25 ÷ 85 mass. parts of the total load mass of “unsaturated” pure lactose (to reduce the cost and some simplification and acceleration of the process without reducing the effectiveness of the therapeutic effect). Then, magnesium stearate is added to this mixture in an amount of 0.1 ÷ 1 mass. parts of the total mass of the load and microcrystalline cellulose in an amount of 3 ÷ 10 mass. parts of the total mass of the load. The resulting tablet mass is uniformly mixed and tabletted by direct dry pressing (for example, in a Korsch tablet press - XL 400) with the formation of round tablets weighing 150 ÷ 500 mg, mainly weighing 300 mg, soaked in an aqueous-alcoholic solution (3.0-6.0 mg / table.) in an activated-potentiated form of antibodies to the brain-specific protein S-100 and to NO synthase in an ultra-low dose, each component prepared from a matrix solution diluted, respectively, in 100 ¹² , in 100 ³⁰ in 100 ²⁰⁰ , which is equivalent a mixture of hundred dilutions of C12, C30 and C200, pri copulating on homeopathic technology.

Glucose, sucrose, maltose, starch, isomaltose, isomalt and other monosaccharides, oligosaccharides and polysaccharides used in the manufacture of pharmaceutical preparations, as well as technological mixtures based on the latter with the addition of pharmaceutically acceptable additives (for example, isomalt, crospovidone, can also be used as a neutral carrier. , sodium cyclamate, sodium saccharin, anhydrous citric acid, etc.), including lubricants, disintegrants, binders and dyes.

Preferably, the claimed pharmaceutical composition is recommended to take 1-2 tablets 2-4 times a day.

Example 1

Investigation of the effect of a complex preparation, which includes activated-potentiated forms of polyclonal affinity purified rabbit antibodies to brain-specific protein S-100 (anti-S100) and to endothelial NO synthase (anti-eNOS) in ultra-low doses (SMD) obtained by super-dilution of the original matrix solution (concentration of 2.5 mg / ml) in 100 ¹² , 100 ³⁰ , 100 ²⁰⁰ times, equivalent to a mixture of hundreds of homeopathic dilutions of C12, C30, C200, in a 1: 1 ratio (SMD anti-S100 + anti-eNOS), and also the components included in its composition - activated-potential bath forms polyclonal rabbit antibodies to brain-specific proteins S100, purified on an antigen, in ultralow dose (SMD anti-S100), the obtained sverhrazvedeniem initial matrix solution 100 ^12, 100 ^30, 100 ^{to 200} times equivalent mixture of centesimal homeopathic dilutions C12, C30 , C200 and an activated-potentiated form of polyclonal rabbit antibodies to endothelial NO synthase purified on an antigen in an ultra-low dose (SMD anti-eNOS) obtained by super-dilution of the initial matrix solution 100 ¹² , 100 ³⁰ , 100 ²⁰⁰ times, equivalent to a mixture of cell All homeopathic dilutions of C12, C30, and C200 were carried out in vitro to bind the standard ligand of [ ³ H] pentazocine to the recombinant human sigma-1 receptor using the radioligand method.

Sigma-1 receptor is an intracellular receptor localized in the cells of the central nervous system, the cells of most peripheral tissues and immunocompetent cells. Receptors demonstrate a unique ability to translocate, which is caused by many psychotropic drugs. The dynamics of sigma-1 receptors is directly related to the various effects carried out by the drugs when they act on sigma-1 receptors. These effects include regulation of activity channels, ecocytosis, signaling, plasma membrane remodeling (raft formation), and lipid transport / metabolism. All this can contribute to the development of plasticity of neurons in the brain. There is evidence that sigma-1 receptors have a modulating effect on all major neurotransmitter systems: noradrenergic, serotonergic, dopaminergic, cholinergic systems and NMDA-regulated glutamate effects. Sigma-1 receptor plays an important role in the pathophysiology of neurodegenerative diseases, mental and affective disorders, and is involved in learning and memory. In this regard, the ability of drugs to influence the effectiveness of the interaction of ligands with the sigma-1 receptor indicates the presence of neuroprotective, anti-ischemic, anxiolytic, antidepressant, anti-asthenic components in the spectrum of their pharmacological activity, which allows us to consider these drugs as effective drugs, including including, for the treatment of cerebrovascular disease.

Potentiated distilled water (a mixture of homeopathic dilutions of C12 + C30 + C200) was tested as a control of the tested drugs.

In the experiment (for measuring total binding), 20 μl of the complex preparation of SMD anti-S100 + anti-eNOS or 10 μl of SMD AT to S100 or 10 μl of SMD AT to NOS was added to the incubation medium. Thus, the amount of SMD anti-S100 + anti-eNOS introduced into the experimental well when testing the complex preparation was identical to the number of SMD AT to S100 and SMD AT to NOS tested as single drugs, which allows a comparison of the effectiveness of the complex preparation with its individual components included in its composition. Potentiated distilled water was introduced into the incubation medium in a volume of 20 μl and 10 μl.

Then 160 μl (~ 200 μg protein) of the homogenate of the cell membranes of the Jurkat line (human leukemic T-lymphocyte line), and lastly 20 μl of the tritium-labeled [ ³ H] pentazocine radioligand (15 nM), were added.

To measure nonspecific binding, instead of preparations or potentized water, 20 μl of unlabeled ligand, haloperidol (10 μM), was added to the incubation medium.

Radioactivity was measured on a scintillation counter (Topcount, Packard) using a scintillation mixture (Microscint 0, Packard) after incubation for 120 minutes at 22 ° C in 50 mM Tris-HCl buffer (pH = 7.4) and filtering on glass fiber filters (GF / B, Packard). Specific binding (in experiment or control) was calculated as the difference between total (in experiment or control) and non-specific binding.

The results are presented as percent inhibition of specific binding in the control (distilled water was used as a control) (Table 1).

Table 1 The effect of drugs and potentiated water on the binding of a standard radioligand [ ³ H] pentazocine to a recombinant human sigma 1 receptor Experimental group The amount introduced into the experimental well % of specific radioligand binding in the control % inhibition of radioligand binding in the control 1st dimension 2nd dimension Average value SMD anti-S100 + anti-eNOS 20 μl 48,4 35.5 42.0 58.0 SMD anti-S100 10 μl 67.3 63.1 65,2 34.8 SMD anti-eNOS 10 μl 147.5 161.1 154.3 -54.3 Potentized water 20 μl 98.1 75.8 86.9 13.1 Potentized water 10 μl 140.1 106,2 123,2 -23.2

Note: % specific binding in the control = (specific binding in the experiment / specific binding in the control) * 100%; % inhibition of specific binding in the control = 100% - (specific binding in the experiment / specific binding in the control) * 100%).

Results reflecting inhibitions above 50% represent significant effects of the test compounds; inhibition from 25% to 50%, indicate effects from mild to moderate; inhibitions of less than 25% are considered minor effects of the test compound and are within the background level.

Thus, under the conditions of this experimental model, it was shown that: the complex preparation of SMD anti-S100 + anti-eNOS is more effective than its individual components (SMD anti-S100 and SMD anti-eNOS) inhibits the binding of the standard radioligand [ ³ H] pentazocine to recombinant human sigma 1 receptor; SMD anti-S100, introduced into the experimental well in a volume of 10 μl, inhibits the binding of the standard radioligand [ ³ H] pentazocine to the recombinant human sigma 1 receptor, but the severity of the effect is less than that of the complex drug SMD anti-S100 + anti-eNOS; SMD anti-eNOS introduced into the experimental well in a volume of 10 μl did not affect the binding of the standard radioligand [ ³ H] pentazocine to the recombinant human sigma 1 receptor; potentiated water introduced into the experimental well in a volume of 10 μl or 20 μl did not affect the binding of the standard radioligand [ ³ H] pentazocine to the recombinant human sigma 1 receptor.

Example 2

The drug was studied in the form of 300 mg tablets soaked in an aqueous-alcoholic solution (3 mg / tablet) of an activated-potentiated form of polyclonal rabbit antibodies to brain-specific protein S-100, purified on antigen, in an ultra-low dose (SMD anti-S100) obtained by super-dilution of the initial matrix solution (concentration of 2.5 mg / ml) 100 ¹² , 100 ³⁰ , 100 ²⁰⁰ times, equivalent to a mixture of hundred-percent homeopathic dilutions of C12, C30, C200; drug in the form of tablets weighing 300 mg, impregnated with a pharmaceutical composition containing water-alcohol solutions (6 mg / tablet) of activated-potentiated forms of polyclonal affinity purified rabbit antibodies to brain-specific protein S-100 (anti-S100) and to endothelial NO- synthase (anti-eNOS) in ultra-low doses (SMD) obtained by super-dilution of the initial matrix solution (with a concentration of 2.5 mg / ml) 100 ¹² , 100 ³⁰ , 100 ²⁰⁰ times equivalent to a mixture of hundred-percent homeopathic dilutions of C12, C30, C200 ( SMD anti-S100 + anti-eNOS); drug in the form of tablets weighing 300 mg, impregnated with an aqueous-alcoholic solution (3 mg / tablet) of an activated-potentiated form of polyclonal rabbit antibodies to endothelial NO synthase, purified on antigen, in an ultra-low dose (SMD anti-eNOS) obtained by super-dilution the initial matrix solution (with a concentration of 2.5 mg / ml) 100 ¹² , 100 ³⁰ , 100 ²⁰⁰ times, equivalent to a mixture of hundred-percent homeopathic dilutions of C12, C30, C200. As a placebo, 300 mg tablets were used containing auxiliary substances: lactose (lactose monohydrate) - 267 mg, microcrystalline cellulose - 30 mg, magnesium stearate - 3 mg.

The effectiveness of the studied drugs in the treatment of vertigo and other symptoms of motion sickness was evaluated on the model of kinetosis, or motion / motion sickness disease, which manifests itself in various vestibulo-autonomic disorders. Dizziness is a typical sign of damage to the vestibular analyzer of various origins, including impaired function of the vestibular nerve and vestibular cochlear system, circulatory disorders in the vertebral-basilar system, pathology of the central nervous system (CNS), etc. Dizziness as a manifestation of kinetosis is accompanied by other vestibular-vegetative disorders including three types of reactions: vestibulo-motor (nystagmus and deviation reactions), vestibulo-sensory (in addition to dizziness, this is nystagmus (or reaction I postvrascheniya), defensive movements) and vegetative (nausea, vomiting, sweating, palpitations, hot flashes, fluctuating heart rate and blood pressure).

A double-blind, placebo-controlled comparative clinical study in parallel groups of the effectiveness of the anti-pumping properties of the SMD composition anti-S100 + anti-eNOS, the SMD anti-S100, and the anti-eNOS preparation was carried out with the participation of 15 somatically healthy volunteers - men and women aged 15 to 60 years (average age 33.3 ± 0.75 years) with a low (n = 5; 33%) or medium (n = 10; 67%) degree of resistance to motion sickness.

To simulate the state of motion sickness and evaluate the effectiveness of the studied drugs, we used the most adequate and universally recognized model of kinetoses - a test with continuous cumulative effect of Coriolis accelerations (NCCI). The initial tolerance of the NKUK sample for all study participants was no more than 5 minutes. Vestibulo-autonomic disorders caused by kinetic effects (NCCI) were recorded using a set of diagnostic methods, including examination of a patient, a quantitative assessment of vestibulo-autonomic sensitivity disorders (Halle Scale), analysis of heart rate variability (HRV), and self-assessment of a functional state (SAN - well-being) , activity, mood). As criteria for the effectiveness of the therapy, the dynamics of tolerability and the duration of the recovery period under kinetic effects, changes in the severity of sensory-motor reactions (nystagmus), and HRV indicators (using the Biocom Wellness Scan system developed by AWS, LLC in accordance with the International Standard of the European Association of Cardiology and North American Association of Electrophysiology) and SAN data. Safety criteria were the nature, severity and timing of the occurrence of possible adverse events (AE) during the period of therapy associated with taking the drug; the influence of the studied drugs on the indicators characterizing the central nervous system function (reaction to a moving object [RDO], time of a simple motor reaction [VDPR]); dynamics of physical and functional indicators (heart rate [HR], systolic [SBP] and diastolic [DBP] blood pressure, Stange test, Gencha test); exercise tolerance (Harvard step test index). Safety was assessed both when taking a test dose of drugs, and when taking a course for 7 days.

All participants did not take any medication for 1 month prior to inclusion in the study. After the screening visit, participants were randomized into 4 groups depending on the drug taken (1 - SMD anti-S100 + anti-eNOS, 2 - SMD anti-S100; 3 - SMD anti-eNOS; 4 - placebo).

On the first day of the study (Visit 1), the initial functional and psychophysiological state of the volunteers was recorded, then a 5-fold test administration of the drug was carried out, after which the NKUK test was performed, the duration of the test was recorded, with the help of a comprehensive diagnostic examination, vegetative-vestibular disorders associated with motion sickness were detected and NYA. In the next 2-6 days, the volunteer received the prescribed drug 1 tablet 3 times a day. On the 7th day (Visit 2), the patient took the drug according to the scheme of the first day, repeated diagnostic tests were performed before and after the NKUK test. The study was organized in such a way that the research team worked with only one subject. The study was parallel and was conducted in the morning, with the participation, as a rule, of 4 people per day, one person per drug or placebo. The next 3 weeks there was a wash-out period, by the end of which a new drug / placebo was prescribed to patients of each subgroup, the study cycle was repeated (Visit 1, course drug administration; Visit 2). Thus, during the study, each volunteer participated in four study cycles. At the same time, it was monitored that all subjects took part in the assessment of each of the three drugs and placebo, which made it possible to level out the influence of individual characteristics of the subject on the effect of therapy. Analysis of the effectiveness of the drug was carried out according to all subjects who completed the full course of taking the studied drugs in accordance with the study protocol (n = 15).

Indicators of the severity of symptoms of motion sickness (dizziness, nausea, lethargy, pallor of the skin, sweating, etc.) after kinetic exposure (NKUK) against the background of a one-day intake of the studied drugs showed that all participants in the study reached approximately the same state of motion sickness, since the severity evaluated by the doctor According to the Galle scale, the symptoms of autonomic dysfunction did not significantly differ in all groups (Table 2, Visit 1). However, the time of the kinetic effect, which caused similar symptoms of motion sickness, differed in four groups and depended on the drug taken by the study participants (Table 3, Visit 1). One-day administration of the drug SMD anti-S100 + anti-eNOS led to the most distinct anti-pumping effect, which was manifested not only in a significantly longer tolerance time for the NCCA test (104.10 ± 13.14 sec versus 68.50 ± 6.57 sec in the group SMD anti-S100; 75.00 ± 6.79 sec in the SMD anti-eNOS group and 61.30 ± 3.15 sec in the placebo group), but also in the shortest nystagmus time (9.90 ± 1.20 sec versus 13.50 ± 1.51; 16.10 ± 1.68 and 13.30 ± 1.12 sec, respectively) and the most rapid recovery (96.90 ± 13.54 sec versus 194.20 ± 18.45; 202 , 50 ± 21.72 and 241.70 ± 38.41 sec, respectively).

Approximately similar indicators were recorded at Visit 2 after a course of taking medications. To achieve similar symptoms of motion sickness (Table 2, Visit 2), the kinetic effect was applied for the longest time to volunteers who received an anti-S100 + anti-eNOS SMD composition for 7 days (Table 3, Visit 2). The most pronounced anti-pumping effect of the SMD anti-S100 + anti-eNOS composition was also expressed in significantly shorter nystagmus time (9.50 ± 1.38 sec; p <0.01) and a longer recovery period (117.90 ± 15.65 sec; p <0.01). The monocomponent drug SMD anti-S100 had an anti-pumping effect, as evidenced by better than in the placebo group indicators of tolerance of the NKUK test, nystagmus time and recovery (Table 3, Visits 1 and 2), however, the SMD anti-S100 preparation was inferior to the SMD composition anti-S100 + anti-eNOS. The monocomponent drug SMD anti-eNOS did not show an anti-pumping effect, since the results of the NCCA test and the subsequent recovery period did not have significant differences from the placebo group (Table 3, Visits 1 and 2).

A comparative analysis of the NCCI test indices in the SMD anti-S100 + anti-eNOS and SMD anti-S100 groups during one-day administration of drugs showed that the addition of anti-eNOS SMD increased the tolerance of kinetic effects by 52%, reduced nystagmus time by 27% and helped to reduce the recovery period after the end of the kinetic effect by 50%, including the duration of dizziness - by 49%. However, the largest contribution of the anti-eNOS SMD component to the efficacy of the combined preparation (anti-S100 + anti-eNOS SMD compositions) was given during course administration, which was expressed as a 30% excess of the result achieved in the anti-S100 SMD group in terms of tolerance to kinetic effects and duration of nystagmus (for each of the parameters). In addition, the increase in the effect on Visit 2 in terms of tolerance of the NCCI sample and the duration of nystagmus relative to the data of Visit 1 when taking the SMD anti-S100 + anti-eNOS composition compared to the monocomponent drug SMD anti-S100 was more pronounced, which was confirmed by the data change indicators by 30% and 4% (against 21% and 0% in the anti-S100 SMD group).

In assessing the effectiveness of the anti-pumping properties of drugs, special attention was paid to the possible effect of drugs on the stability of the autonomic nervous system (ANS), in particular, a change in the balance between its sympathetic and parasympathetic departments. For this purpose, at each visit, HRV indicators were analyzed at rest and during the performance of functional tests (respiratory and orthostatic tests).

An analysis of HRV at rest (in a sitting position) before and after an IACC test (Table 4) found that while taking the studied drugs, there was a tendency to an increase in SDNN, which indicated an increase in heart rate variability due to the parasympathetic effect on heart rhythm. In response to the kinetic effect, the RMS-SD value, which characterizes the activity of the parasympathetic component of autonomic regulation, increased in all the studied groups. In the groups receiving the composition of SMD anti-S100 + anti-eNOS and SMD anti-S100, an increase in HF was noted, which also testified to a shift in the autonomic balance towards the parasympathetic link. Thus, after conducting an NKUK test, an increase in parasympathetic influences on the heart rhythm occurred in all the studied groups.

Analysis of HRV in transition states showed that a one-day intake of the SMD anti-S100 + anti-eNOS composition increased the reaction time (13.9 ± 1.14; p≤0.05) and stabilization time (24.2 ± 1.28; p ≤0.05) compared with SMD anti-S100 and placebo (Table 5). These same indicators exceeded the placebo group after kinetic exposure, which demonstrated the positive effect of the combined drug on the reactivity of the ANS (increased tolerance to changes in body position). The smallest difference between the maximum and minimum heart rate in the breathing test (Table 6) confirmed the best balance of the two divisions of the ANS after a one-day intake of the SMD anti-S100 + anti-eNOS composition (25.1 ± 2.66 bpm; p≤0.05) . By the end of the weekly course of therapy, the stabilizing effect on the balance of the ANS after the NCCA test (for orthostatic and respiratory tests) was also noted in the group receiving the composition of SMD anti-S100 + anti-eNOS (Tables 5, 6).

The results of the self-assessment of the functional state (well-being-activity-mood) of the volunteers, which the study participants performed after modeling motion sickness (NKUK tests) at the beginning and end of the course of therapy, showed that the subjects of all the studied groups gave “average” scores for each parameter (Table 7). Thus, against the background of taking the drugs, the tolerance of the IACC test was satisfactory. The largest increase in performance compared with the placebo group at the end of the 7-day intake (more than 10%) was observed in the anti-S100 + anti-eNOS SMD composition group.

The safety analysis included data from all volunteers participating in the study. During the entire period of observation, good tolerability of the studied drugs was noted. Adverse events associated with the use of drugs were not identified. All volunteers of the study groups completed the treatment within the time frame established by the study protocol; there were no early dropouts from the study.

According to the results of the physical examination, including heart rate, SBP and DBP, as well as according to the Harvard step test, the subjects did not register any pathological deviations during the study (Table 8). All detected changes did not go beyond the normal values. Moreover, subjectively, all subjects noted satisfactory health.

Along with hemodynamic indicators for assessing the safety of the studied drugs, their possible negative impact on higher nervous functions, the psychophysiological indicators (RDD, VDPR, UV, OV, KUV) were studied in volunteers. In addition, Stange and Gencha tests were performed to assess hypoxia tolerance.

According to the results obtained (Table 9), neither one-day nor course administration of drugs had a significant effect on the estimated parameters. Indicators of sensorimotor coordination (VAD, RDO) did not differ from the results of the placebo group before and after the NKUK test at both visits. The data on the study of such a complex function as the volume and stability of attention showed that the studied drugs, both before and after the NKUK test, did not change the degree of concentration and switching attention, not differing from the placebo group.

An analysis of the indices of standard exercise tests with breath holding showed a tendency to increase the tolerance of hypoxia by the subjects (Table 9). When holding the breath on inspiration, the duration of the Stange test increased after taking all the studied drugs, but only taking the composition of SMD anti-S100 + anti-eNOS allowed not to resume breathing much longer after kinetic exposure (68.1 ± 18.8 seconds initially and 91.7 ± 27.4 seconds after the NCCA test; p <0.05). An increase in the tolerance of hypoxia was also observed during the performance of the Gencha test (breath holding on exhalation; p> 0.05).

Thus, a study using experimental motion sickness demonstrated the anticonvulsant efficacy of the anti-S100 + anti-eNOS SMD composition and the anti-S100 single component SMD preparation. The studied drugs increase the resistance of the subjects to kinetic effects after reproducing the clinical and physiological effects of motion sickness, contributing to an easier clinical course of motion sickness and earlier recovery of subjects after cessation of exposure. In addition, it was shown that the anti-pumping effect of the combined drug (composition SMD anti-S100 + anti-eNOS) exceeds the effectiveness of the individual components. The effectiveness of the composition of SMD anti-S100 + anti-eNOS in the control of the vestibulo-vegetative and sensory reactions of the body during an experimental motion sickness increases with a course dose. It should be noted that SMD anti-eNOS in the form of a single drug does not have a protective effect against motion sickness, but when combined with SMD anti-S100, it significantly enhances the anti-pumping effect of the latter, which is manifested both in one-day and short-term administration of the drug. The best ability to correct transients, that is, affect the reactivity of the parasympathetic and sympathetic divisions of the ANS, as well as the adaptive capabilities of the ANS in a state of motion sickness (increase tolerance to sudden changes in body position), was noted in the composition of SMD anti-S100 + anti-eNOS, which is important constituent of the anticonvulsant properties of the drug. The composition of SMD anti-S100 + anti-eNOS and the monocomponent drug SMD anti-S100, when used as an anti-pumping agent, including when performing operator functions, are safe and do not adversely affect physical and psychophysiological parameters.

The composition of SMD anti-S100 + anti-eNOS and SMD anti-S100 can be recommended for the prevention and relief of motion sickness during motion sickness (including sea, air, traffic sickness) for people with low and moderate degrees of resistance. The drugs are highly safe and do not adversely affect the quality of professional activity.

table 2 Galle score indicators depending on the drug taken after the NKUK test A drug Halle Scale (points) Visit 1 (one-day appointment) (n = 15; M ± SE) Visit 2 (course admission) (n = 15; M ± SE) SMD anti-S100 + anti-eNOS 12.00 ± 0.63 12.30 ± 0.59 SMD anti-S100 13.30 ± 0.65 12.30 ± 0.46 SMD anti-eNOS 13.10 ± 0.78 12.00 ± 0.55 Placebo 13.40 ± 0.77 13.30 ± 0.45

Table 3 The dynamics of the indicators NKUK depending on the drug A drug Visit 1 (one-day reception) The tolerance of the sample NKUK, sec (n = 15; M ± SD) Nystagmus time, sec (n = 15; M ± SD) Recovery time, sec (n = 15; M ± SD) SMD anti-S100 + anti-eNOS 104.10 ± 13.14 ** 9.90 ± 1.20 * 96.90 ± 13.54 *** SMD anti-S100 68.50 ± 6.57 × 13.50 ± 1.51 194.20 ± 18.45 × SMD anti-eNOS 75.00 ± 6.79 16.10 ± 1.68 202.50 ± 21.72 × Placebo 61.30 ± 3.15 13.30 ± 1.12 241.70 ± 38.41 The value of P by the criterion of Kruskal-Wallis ¹ 0.0182 0,0658 0.0001 Visit 2 (course reception) SMD anti-S100 + anti-eNOS 134.70 ± 20.24 ** 9.50 ± 1.38 ** 117.90 ± 15.65 ** SMD anti-S100 82.70 ± 10.33 13.50 ± 1.69 167.50 ± 14.72 × SMD anti-eNOS 74.30 ± 9.49 × 17.30 ± 2.40 ×^^ 209.20 ± 21.62 ×Ч Placebo 63.70 ± 3.91 15.00 ± 1.47 199.60 ± 31.19 The value of P by the criterion of Kruskal-Wallis ¹ 0,0341 0,0244 0.0061 Note: ¹ , the Kruskal-Wallis test was used to determine the significance of differences between groups. If the criterion showed reliability, p <0.05; Mann-Whitney test was used to compare groups among themselves. * significance of differences compared with placebo, p <0.05; ** significance of differences compared with placebo, p <0.01; *** significance of differences compared with placebo, p <0.001. × significance of differences compared with SMD anti-S100 + anti-eNOS, p <0.05; ×Ч significance of differences compared with SMD anti-S100 + anti-eNOS, p <0.01; ×ЧЧ significance of differences compared with SMD anti-S100 + anti-eNOS, p <0.001.

Table 4 HRV parameters of study participants at rest before and after kinetic exposure Indicator Visit 1 (one-day reception) Visit 2 (course reception) After taking the drug After the test NKUK After taking the drug After the test NKUK SMD group anti-S100 + anti-eNOS (M ± SD) SDNN, ms 57.7 ± 5.51 68.2 ± 7.42 59.4 ± 5.03 65.6 ± 4.66 RMSSD, ms 43.1 ± 6.77 51.4 ± 9.22 47.0 ± 6.21 47.6 ± 5.33 TR, ms ² 979.0 ± 186.06 1678.3 ± 397.11 # 1067.2 ± 167.24 1381.0 ± 166.30 LF, ms ² 437.5 ± 709.6 709.6 ± 178.72 391.9 ± 75.61 588.5 ± 87.48 HF, ms ² 171.5 ± 51.08 228.4 ± 76.79 206.5 ± 58.32 218.5 ± 43.96 LF / HF, cu 4.2 ± 0.82 4.9 ± 0.83 3.3 ± 0.83 4.2 ± 0.91 SMD group anti-S100 (M ± SD) SDNN, ms 60.9 ± 4.62 70.9 ± 5.90 59.1 ± 4.80 68.8 ± 4.87 RMSSD, ms 44.3 ± 5.39 50.6 ± 6.56 42.4 ± 4.63 47.8 ± 5.57 TR, ms ² 832.2 ± 124.93 * 1342.8 ± 217.09 841.4 ± 149.93 1288.0 ± 163.52 # LF, ms ² 315.2 ± 52.38 * 550.9 ± 72.44 # 313.6 ± 66.71 540.7 ± 87.57 # HF, ms ² 151.4 ± 41.19 247.0 ± 69.53 # 138.3 ± 38.42 187.1 ± 39.80 LF / HF, cu 3.0 ± 0.54 4.0 ± 0.72 2.8 ± 0.53 4.0 ± 0.52 SMD group anti-eNOS (M ± SD) SDNN, ms 67.4 ± 7.73 78.6 ± 6.14 65.8 ± 8.68 69.0 ± 5.23 RMSSD, ms 53.0 ± 8.86 58.4 ± 7.68 59.6 ± 12.45 52.2 ± 5.30 TR, ms ² 1307.8 ± 324.24 1841.1 ± 359.79 # 1232.3 ± 292.51 1275.4 ± 172.47 LF, ms ² 576.5 ± 167.07 849.9 ± 194.2 # 527.2 ± 167.07 562.1 ± 89.38 HF, ms ² 313.3 ± 139.90 285.3 ± 65.92 218.9 ± 74.78 216.3 ± 63.72 LF / HF, cu 3.6 ± 0.87 3.9 ± 0.82 3.7 ± 1.14 3.8 ± 0.58 Placebo Group (M ± SD) SDNN, ms 64.6 ± 6.10 75.7 ± 6.42 61.1 ± 6.72 70.8 ± 6.79 RMSSD, ms 50.9 ± 7.74 53.1 ± 6.62 44.6 ± 6.63 44.3 ± 5.31 TR, ms ² 1062.2 ± 150.02 1917.8 ± 318.96 # 898.8 ± 169.62 1418.5 ± 227.59 # LF, ms ² 440.6 ± 77.30 832.4 ± 181.15 334.8 ± 75.94 611.4 ± 113.64 # HF, ms ² 253.9 ± 59.95 266.7 ± 61.94 166.0 ± 48.14 174.1 ± 44.96 LF / HF, cu 3.4 ± 0.72 5.0 ± 1.33 3.4 ± 0.93 4.8 ± 0.83 Note: * significance of differences compared with placebo, p≤0.05); # significance of differences compared to baseline, p≤0.05.

Table 5 HRV parameters of study participants during orthostatic test before and after kinetic exposure Indicator Visit 1 (one-day reception) Visit 2 (course reception) After taking the drug After the test NKUK After taking the drug After the test NKUK SMD group anti-S100 + anti-eNOS (M ± SD) Reaction to load, cu 1.30 ± 0.06 1.40 ± 0.04 1.30 ± 0.06 1.40 ± 0.06 Reaction time, sec 13.9 ± 1.14 * × 12.7 ± 1.24 * 11.8 ± 0.57 11.7 ± 1.09 Stabilization time, sec 24.2 ± 1.28 * × 21.9 ± 1.44 * 20.6 ± 0.74 22.4 ± 1.44 * × SMD group anti-S100 (M ± SD) Reaction to load, cu 1.40 ± 0.04 1.30 ± 0.04 1.30 ± 0.04 1.30 ± 0.05 Reaction time, sec 7.60 ± 1.05 10.6 ± 1.55 9.7 ± 1.21 10.0 ± 1.73 Stabilization time, sec 15.1 ± 1.16 * 18.3 ± 1.43 18.0 ± 1.18 18.0 ± 1.80 SMD group anti-eNOS (M ± SD) Reaction to load, cu 1.30 ± 0.04 1.30 ± 0.04 1.50 ± 0.12 1.30 ± 0.04 Reaction time, sec 8.20 ± 0.94 9.10 ± 1.12 9.2 ± 0.77 8.3 ± 0.70 Stabilization time, sec 16.5 ± 1.02 17.1 ± 1.33 19.0 ± 2.04 16.7 ± 0.98 Placebo Group (M ± SD) Reaction to load, cu 1.30 ± 0.04 1.30 ± 0.04 1.40 ± 0.06 1.30 ± 0.06 Reaction time, sec 9.5 ± 1.28 8.1 ± 0.90 10.4 ± 1.58 8.8 ± 1.09 Stabilization time, sec 18.3 ± 0.94 16.8 ± 1.09 18.0 ± 1.37 16.5 ± 1.11 Note: * significance of differences compared with placebo, p≤0.05); × significance of differences compared with SMD anti-S100, p≤0.05.

Table 6 HRV parameters of study participants during a breath test before and after kinetic exposure Indicator Visit 1 (one-day reception) Visit 2 (course reception) After taking the drug After the test NKUK After taking the drug After the test NKUK SMD group anti-S100 + anti-eNOS (M ± SD) The ratio of max heart rate / min heart rate, cu 1.5 ± 0.05 * 1.5 ± 0.06 1.5 ± 0.05 1.5 ± 0.05 The difference max heart rate - min heart rate, beats / min. 25.1 ± 2.66 * 26.5 ± 2.77 26.5 ± 2.37 24.9 ± 2.24 * SMD group anti-S100 (M ± SD) The ratio of max heart rate / min heart rate, cu 1.5 ± 0.06 1.6 ± 0.05 1.5 ± 0.04 1.6 ± 0.06 The difference max heart rate - min heart rate, beats / min. 27.7 ± 2.68 27.2 ± 2, 40 25.7 ± 2.24 26.9 ± 2.67 SMD group anti-eNOS (M ± SD) The ratio of max heart rate / min heart rate, cu 1.5 ± 0.05 1.5 ± 0.04 1.5 ± 0.06 1.6 ± 0.05 The difference max heart rate - min heart rate, beats / min. 26.7 ± 2.44 26.2 ± 2.04 27.7 ± 2.47 27.3 ± 2.12 Placebo Group (M ± SD) The ratio of max heart rate / min heart rate, cu 1.6 ± 0.07 1.6 ± 0.06 1.5 ± 0.05 1.6 ± 0.05 The difference max heart rate - min heart rate, beats / min. 31.2 ± 3.06 28.2 ± 2.50 27.7 ± 2.37 29.2 ± 2.44 Note: * significance of differences compared with placebo, p≤0.05

Table 7 The dynamics of the indicators of self-assessment of the functional state (well-being-activity-mood) of the study participants Indicator Visit 1 (one-day reception) Visit 2 (course reception) SMD group anti-S100 + anti-eNOS (M ± SE) Feeling well 4.3 ± 0.26 4.6 ± 0.27 Activity 4.2 ± 0.20 4.2 ± 0.22 Mood 5.0 ± 0.16 5.2 ± 0.13 SMD group anti-S100 (M ± SE) Feeling well 3.7 ± 0.21 4.3 ± 0.22 Activity 3.6 ± 0.17 4.0 ± 0.19 Mood 4,5 ± 0,16 4.9 ± 0.19 SMD group anti-eNOS (M ± SE) Feeling well 3.9 ± 0.25 4.1 ± 0.26 Activity 3.8 ± 0.25 3.9 ± 0.23 Mood 4.4 ± 0.19 4.6 ± 0.19 Placebo Group (M ± SE) Feeling well 4.0 ± 0.24 4.0 ± 0.24 Activity 3.8 ± 0.20 3.7 ± 0.26 Mood 4.3 ± 0.20 4.7 ± 0.24

Table 8 Dynamics of physical indicators and tolerance of physical activity of study participants before and after kinetic effects Indicator 1 visit (one-day reception) 2 visit (course reception) After taking the drug After the test NKUK After taking the drug After the test NKUK SMD group anti-S100 + anti-eNOS (M ± SE) Heart rate (bpm) 74.6 ± 3.36 68.4 ± 3.67 74.1 ± 3.10 67.7 ± 2.62 GARDEN (mmHg) 123.4 ± 2.83 125.9 ± 4.08 121.8 ± 2.65 128.3 ± 4.25 DBP (mmHg) 74.0 ± 3.09 79.3 ± 2.62 76.2 ± 2.43 80.3 ± 3.30 Step test index - 53.6 ± 2.60 - 52.3 ± 2.09 SMD group anti-S100 (M ± SE) Heart rate (bpm) 73.5 ± 2.57 69.7 ± 2.78 72.1 ± 2.84 67.7 ± 2.39 GARDEN (mmHg) 127.5 ± 2.55 133.5 ± 4.77 127.1 ± 2.55 129.9 ± 5.06 DBP (mmHg) 75.5 ± 2.65 82.6 ± 3.31 74.9 ± 2.41 82.3 ± 3.19 Step test index - 50.6 ± 1.71 - 53.0 ± 1.63 SMD group anti-eNOS (M ± SE) Heart rate (bpm) 76.5 ± 2.59 67.3 ± 1.98 77.3 ± 2.02 70.1 ± 3.23 GARDEN (mmHg) 127.3 ± 3.14 131.5 ± 5.16 123.5 ± 3.06 129.3 ± 4.13 DBP (mmHg) 75.2 ± 2.24 80.3 ± 2.66 73.9 ± 2.83 81.0 ± 3.22 Step test index - 51.8 ± 2.12 - 51.2 ± 2.21 Placebo Group (M ± SE) Heart rate (bpm) 74.5 ± 2.78 68.9 ± 3.46 73.9 ± 3.23 72.3 ± 3.58 GARDEN (mmHg) 125.3 ± 3.30 133.3 ± 4.73 124.3 ± 2.83 126.9 ± 3.95 DBP (mmHg) 76.2 ± 2.15 81.7 ± 2.83 75.4 ± 1.86 79.7 ± 3.03 Step test index - 50.0 ± 2.03 - 50.1 ± 1.99

Table 9 Dynamics of indicators of the psychophysiological state of study participants before and after kinetic effects Indicator 1 visit (one-day reception) 2 visit (course reception) After taking the drug After the test NKUK After taking the drug After the test NKUK SMD group anti-S100 + anti-eNOS (M ± Sb) The VDPR 257.5 ± 8.67 268.9 ± 10.18 269.6 ± 9.75 279.9 ± 12.24 RDO, cu 50.1 ± 3.92 49.5 ± 4.50 47.3 ± 4.86 47.0 ± 3.54 RDO,% hit on target 3.0 ± 0.95 4,5 ± 1,15 5.3 ± 1.58 4.0 ± 1.11 HC, sec 5.2 ± 0.34 5.2 ± 0.35 5.2 ± 0.41 5.1 ± 0.40 Volume of attention, sec. 41.7 ± 2.36 39.9 ± 2.38 38.1 ± 2.17 37.5 ± 2.04 KUV 17.4 ± 1.66 17.2 ± 1.51 18.0 ± 1.71 18.8 ± 1.72 Sample Stange 68.1 ± 4.85 91.7 ± 7.07 * 71.8 ± 6.02 85.5 ± 9.36 Gencha test 47.1 ± 4.03 50.1 ± 3.94 46.7 ± 3.28 48.1 ± 4.52 SMD group anti-S100 (M ± SE) The VDPR 258.9 ± 9.95 282.4 ± 13.56 268.4 ± 11.37 279.1 ± 9.20 RDO, cu 58.1 ± 6.40 57.5 ± 6.34 55.1 ± 5.06 53.8 ± 5.02 RDO,% hit on target 3.7 ± 1.50 2.0 ± 0.82 2.3 ± 0.83 5.0 ± 1.69 HC, sec 6.0 ± 0.40 6.4 ± 0.52 6.2 ± 0.42 6.0 ± 0.41 Volume of attention, sec. 42.6 ± 2.68 42.1 ± 2.27 42.7 ± 2.30 41.9 ± 2.52 KUV 14.5 ± 1.16 14.9 ± 1.26 15.3 ± 1.13 15.4 ± 1.18 Sample Stange 59.0 ± 4.09 72.6 ± 6.19 64.5 ± 4.93 75.9 ± 5.67 Gencha test 47.1 ± 4.48 49.4 ± 4.69 48.3 ± 4.30 48.8 ± 4.14 SMD group anti-eNOS (M ± SE) The VDPR 257.7 ± 8.49 279.4 ± 14.23 266.7 ± 13.19 275.5 ± 11.44 RDO, cu 48.3 ± 3.67 51.9 ± 4.39 52.5 ± 4.79 49.6 ± 4.22 RDO,% hit on target 2.3 ± 0.83 2.0 ± 0.82 3.3 ± 1.26 5.7 ± 1.68 HC, sec 5.9 ± 0.25 6.0 ± 0.34 5.5 ± 0.24 5.9 ± 0.33 Volume of attention, sec. 41.9 ± 2.10 43.8 ± 2.39 41.3 ± 2.00 42.5 ± 2.22 KUV 13.7 ± 1.34 14.8 ± 1.31 15.6 ± 1.24 14.1 ± 1.40 Sample Stange 62.5 ± 5.49 69.5 ± 5.09 56.7 ± 3.34 73.1 ± 7.98 Gencha test 43.1 ± 3.51 45.7 ± 3.15 43.4 ± 3.77 45.8 ± 4.03 Placebo Group (M ± SE) The VDPR 267.6 ± 7.64 290.1 ± 11.33 281.1 ± 9.78 263.3 ± 6.85 RDO, cu 60.7 ± 8.31 54.1 ± 5.57 51.1 ± 3.69 52.6 ± 5.38 RDO,% hit on target 3.7 ± 1.03 3.7 ± 1.24 3.3 ± 0.93 4.3 ± 1.61 HC, sec 6.1 ± 0.71 5.7 ± 0.36 5.5 ± 0.32 5.9 ± 0.71 Volume of attention, sec. 41.9 ± 2.09 42.4 ± 2.81 41.3 ± 2.18 39.6 ± 2.26 KUV 14.5 ± 1.64 14.5 ± 1.79 15.3 ± 1.55 15.9 ± 1.58 Sample Stange 63.7 ± 4.71 67.9 ± 6.90 64.8 ± 5.94 83.0 ± 12.24 Gencha test 44.7 ± 2.52 47.1 ± 3.30 43.7 ± 2.71 47.8 ± 3.78

During the study, the following methods were used and the following state parameters were determined:

- A sample with continuous cumulative effect of Coriolis accelerations (NCCI) (Markaryan S.S., Yuganov E.M., Sidelnikov I.A. Vestibular selection by the method of continuous cumulation of Coriolis accelerations // Military Medical Journal 1966. No. 9. С .59-62; Methods of research for the purpose of medical flight examination. - M.: Military Publishing, 1972).

The test allows you to identify a person's resistance to the effects of Coriolis accelerations and thus may indicate the degree of susceptibility of the subject to motion sickness.

The order of the sample. The test subject, sitting in a Baran’s chair or on an electrically rotating chair, assumes the position of the body and head so that the axis of rotation passes along the body. Eyes are closed. Against the background of constant uniform rotation of the chair at a speed of 180 degrees / second, (one revolution in two seconds), the subject at the end of the fifth revolution begins to perform head bends from the right shoulder to the left or from left to right and back at an angle of at least 30 degrees. to each side of the vertical. The inclinations are carried out continuously, without excessive tension of the neck muscles and head turns during the entire period of rotation. Each head movement from shoulder to shoulder is performed smoothly in 2 seconds without stopping in the extreme and middle positions. The slope speed is controlled using a metronome or the pronunciation time of the numbers 21 and 22, which should correspond to 2 seconds. Sample execution time counting must be started from the moment of the first head swinging.

Before the test, the subject is instructed, in particular, indicate that he must inform the doctor about the appearance of the illusion of swing, a feeling of warmth, heat, salivation, and nausea that may occur during the test. Prior to the test, several test head movements are performed so that the subject acquires the skill of controlling the speed of the swinging movements and learns the correct position of the head at the time of movement.

The appearance of pronounced vestibulo-autonomic disorders (pallor, hyperhidrosis, nausea, urge to vomit) during the continuous performance of the NCCA test are the criteria for the maximum tolerability of Coriolis accelerations. The time of the appearance of vestibulo-vegetative reactions from the beginning of the NKUK test and the time of their termination after the completion of the NKUK test are recorded. Coriolis acceleration tolerance tests were carried out in the morning, not earlier than 2 hours after eating and only once a day. On the day of the test, the subject was no longer exposed to other influences (in a pressure chamber, in a centrifuge, etc.).

- Methodology for the quantitative assessment of disorders of vestibulo-vegetative sensitivity (Halle Scale) (Quantitative assessment of disorders of vestibulo-vegetative sensitivity // Space Biology and Aerospace Medicine, 1981. - No. 3. - P.72-75). Based on the assessment of the severity (in points) of vestibulo-autonomic symptoms (dizziness, nausea, sweating, pallor of the skin, drowsiness, etc.) arising from an IACC test, the method allows to determine the degree of tolerance of Coriolis accelerations by a person (poor, satisfactory, good, excellent) .

- Study of heart rate variability (HRV) (Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart Rate Variability standards of measurement, physiological interpretation, and clinical use. Cir. 1996; 93: 1043 1065) .

The Biocom Wellness Scan system developed by AWS, LLC was used to collect HRV data. It was created in accordance with the International Standard of the European Association of Cardiology and the North American Association of Electrophysiology (International Task Force consisting of the European Society of Cardiology and the North American Society for Pacing and Electrophysiology, 1996).

The system contains the following components:

1. A personal computer (PC) with the Windows operating system.

2. Photoplethysmograph HRM-02 (PPG).

3. Ear sensor (PPG ear-clip).

4. Biocom Wellness Scan Software on CD.

5. Manual for use in electronic format (PDF).

A study to create a patient database included three tests to evaluate autonomic balance: a 5-minute record of HRV at rest; breath test orthostatic test.

HRV study stages

1. The researcher gives the subject a brief description of each test before starting.

2. The subject sits comfortably while in a relaxed state.

3. The ear probe is rubbed with alcohol and placed on the earlobe. Earrings, if any, must be removed before the test.

4. The researcher selects a 5-minute record of HRV at rest (Short-term Resting HRV Test) for execution.

5. The researcher follows the test instructions.

6. Immediately after the test is completed and the data are recorded in the database, the researcher selects the respiratory (Metronome Breathing Test) or the orthostatic test (Orthostatic Test).

7. The researcher follows the instructions for performing a respiratory or orthostatic test.

8. Immediately after the test is completed and the data are recorded in the database, the researcher looks at the results of all tests performed to determine whether they are acceptable. If any of the data does not meet the requirements of the study, the researcher repeats the test.

9. At the end of viewing the data, testing ends, and the ear sensor is removed from the subject's ear.

Description of the 5-minute HRV recording alone:

A short-term HRV test is used to assess the balance between the sympathetic and parasympathetic branches of the autonomic nervous system. It is a 5-minute record of FPG in a sitting position without provocative maneuvers. During the test, the study participant breathes randomly with a breathing rate of at least 9 breaths per minute to obtain valid HRV parameters. The following HRV parameters are calculated:

1. Parameters in the time domain:

1. HR

2. Mean NN

3. SDNN

4. RMS-SD

2. Parameters in the frequency domain:

5. Total Power

6. VLF

7. LF

8. HF

9. LF / HF Ratio

10. LF Norm

11. HF Norm

All HRV parameters in the time domain are calculated at normal inter-bit intervals (NN) caused by normal sinus heart beat recorded during the test.

The HRV frequency parameters are calculated from the power spectrum density (PSD) calculated by the Fast Fourier Transform (FFT) method.

Parameters in the time domain:

HR is the average heart rate calculated over the entire heart rate record. HR is measured in beats per minute (BPM).

Mean NN is the average bit rate over the entire record. Mean NN is measured in milliseconds.

SDNN is the standard declination of NN intervals, which is the square root of the NN spread. Since the magnitude under the root is mathematically equivalent to the total power in the spectral analysis, the SDNN reflects all the cyclic components responsible for variability. The actual SDNN value depends on the length of the record — the longer the record, the higher the SDNN value. Thus, in practice it is impossible to compare SDNN values calculated at different time intervals. SDNN is measured in milliseconds.

RMS-SD is the square root of the differences between consecutive NN intervals. This indicator estimates the high-frequency component of heart rate variability, which is associated with parasympathetic regulation of the heart. RMS-SD is measured in milliseconds.

Parameters in the frequency domain:

Total Power (TP) is an estimate of the density of the power spectrum in the range from 0 to 0.4 Hz. This indicator reflects the overall activity of the autonomic nervous system, with sympathetic activity making the greatest contribution. Total Power is calculated in milliseconds squared (ms ² ).

Very Low Frequency (VLF) is the power spectrum density in the range between 0.0033 and 0.04 Hz. The physiological essence of this indicator is that it is an indicator of the overall activity of various slow regulation mechanisms. VLF is calculated in milliseconds squared (ms ² ).

Low Frequency (LF) - power spectrum density in the range between 0.04 and 0.15 Hz. This indicator reflects both sympathetic and parasympathetic activity. It is a good indicator of sympathetic activity in long-term HRV records. A parasympathetic effect is presented in LF when the respiratory rate is less than 9 breaths per minute. LF is calculated in milliseconds squared (ms ² ).

High Frequency (HF) - power spectrum density in the range between 0.15 and 0.4 Hz. This indicator reflects parasympathetic activity. HF is also known as the “respiratory” component, as it corresponds to variations in the NN intervals caused by respiration (this phenomenon is known as respiratory sinus arrhythmia (RSA)). The heart rate increases during inspiration and decreases during exhalation. HF is calculated in milliseconds squared (ms ² ).

LF / HF Ratio is the ratio between the density of the power spectrum in the range of LF and HF. This indicator reflects the overall balance between sympathetic and parasympathetic activity. High values of this indicator are an indicator of the dominance of sympathetic activity, while low values are indicative of parasympathetic activity. LF / HF Ratio is calculated in normalized units.

Normalized Low Frequency (LF norm) is the relationship between the absolute value of LF and TP excluding VLF. This indicator minimizes the effect of VLF in the total power spectrum and highlights the changes in sympathetic regulation. LF Norm is calculated as a percentage.

Normalized High Frequency (HF norm) is the ratio between the absolute value of HF and TP excluding VLF. This indicator minimizes the effect of VLF in the total power spectrum and highlights the changes in parasympathetic regulation. HF norm is calculated as a percentage.

- breath test

This test is intended to evaluate the parasympathetic branch of the autonomic nervous system. The test gives a positive stimulation of parasympathetic regulation of the heart rhythm.

During this test, the subject breathes deeply and evenly with a respiratory rate of 6 breaths per minute. During the test, it is very important to exclude any events that may affect voluntary breathing, such as talking, coughing, sighing, etc. These interferences can cause unwanted heart rate fluctuations and can distort the results. Subject was instructed to breathe for 1 minute following the movement of the pacer shown on the computer screen. The following test parameters are calculated:

1. Minimal HR (bpm)

2. Maximal HR (bpm)

3. Standard Deviation of HR (bpm)

4. Mean ratio of HR max / HR min (E / I Ratio)

5. Maximal Variance of HR during test (bpm)

- Orthostatic test

This test is used to evaluate the effects of parasympathetic regulation on heart rate. The test is based on a change in the position of the body of the subject. The subject needs to be in a relaxed sitting position. After a minute recording of the heart rate, the subject is instructed to stand up, avoiding any sudden movements. Subject remains standing for one more minute. Heart rate monitoring continues throughout the test. The purpose of recording the baseline and standing maneuver is to evaluate the unsteady transient in the rhythm of the heart caused by a change in body position. Heart rate is monitored until a new stationary state of the heart rhythm is detected. The following test parameters are calculated:

1. 30:15 Ratio (the ratio between the maximum heart rate during the first 15 seconds after rising to the minimum heart rate during the first 30 seconds after rising, or reaction to the load, cu).

2. Time to reach maximum heart rate after rising (or reaction time, sec).

3. The time to reach a heart rate of 75% of the baseline level (or stabilization time, sec).

4. The minimum heart rate (bpm).

5. The maximum heart rate (bpm).

- Self-assessment of a functional state (SAN) (Doskin V.A., Lavrentieva N.A., Miroshnikov N.P., Sharay V.B. Test for differentiated self-assessment of a functional state // Psychology Issues, 1973. - No. 6. - P. 141-145).

The technique allows you to quantify the indicators of subjective state, characterizing three categories of symptoms: well-being, activity and mood (SAN), which are determined using a special form. On the form there are 30 pairs of words of the opposite meaning and between them a rating scale. Depending on the subjective assessment of his condition, the subject notes the severity of a particular sign on a seven-point scale. Signs by numbers characterize: 1-2, 7-8, 13-14, 19-20, 25-26 - well-being; 3-4, 9-10, 15-16, 21-22, 27-28 - activity; 5-6, 11-12, 17-18, 23-24, 29-30 - mood. When processing the results of well-being and mood, scores are transcoded from 7 to 1 from left to right, and activities from right to left.

For each sign (well-being, activity, mood), the arithmetic mean value, its error and standard deviation are calculated. This makes it possible to integrally evaluate the subjective state. The arithmetic mean value is a direct subjective characteristic of the functional state and working capacity, and the reliability of the results can be judged by the magnitude of the scatter of estimates within one group of signs (standard deviation).

- Psychometric tests

They were performed on computers using the “OKO” program (operator’s operational control), developed for this type of research by specialists from the Navy habitat and medical support department of the Central Research Institute of Shipbuilding of the Russian Ministry of Defense, under the guidance of Professor V.Yu. Rybnikov

The following psychophysiological indicators were determined:

- reaction to a moving object (RDO);

- time of a simple motor reaction (VAD);

- attention volume (OB);

- sustainability of attention (HC).

Due to the high variability of psychophysiological indicators, their measurement was carried out several times and then the arithmetic average of the entire series of values was calculated. In particular, the assessment of VLR was repeated 50 times, RDO - 20 times, 0 V and HC 5 times. In the RDO test, the number of hits on the target was also calculated from 20 values, and then the percentage of accurate hits was calculated. In the HC test, the average test execution time was examined, the number of correct answers as a percentage of their total number performed by the volunteer.

To integrate these indicators, the attention sustainability coefficient (SIL) was determined, which was calculated by dividing the percentage of correct answers by the average test execution time.

- Reaction to a moving object (RDO) (Maintaining the health of the floating composition of the Navy. A manual for doctors // Edited by General Zheglova VV, Sapova IA, Schegoleva BC - M .: Military Publishing. - 1990. - 192 p.).

The reaction to a moving object allows you to determine the accuracy of the test subject's response to the stimulus and to judge the balance of the processes of excitation and inhibition in the cerebral cortex. The essence of the reaction is the need to stop the fast movement of the object at a predetermined point. For this, an electric stopwatch, switched on remotely by the experimenter, can be used, the arrow of which the subject must stop exactly at the “O” mark by pressing a button on his remote control. This test can also be performed using a special computer program on a PC. The test subject’s response may be premature - the arrow of the electric stopwatch has not reached the “O” mark, delayed - the arrow has slipped the “O” mark, accurate - the arrow is stopped at the “O” mark. Each premature or delayed reaction has a quantitative characteristic in absolute units. To evaluate the results of the performed test, the relative accuracy of the answers is calculated (in% of the total number of reactions), as well as the arithmetic mean and algebraic mean of the deviations from all the presented reactions.

- A simple sensorimotor reaction to a light signal or a simple motor reaction time (VDPR) (Maintaining the health of the floating composition of the Navy. A guide for doctors // Edited by V. Zheglov, I. A. Sapova, BC Shchegoleva - M. : Military Publishing House, 1990 .-- 192 p.).

The time of a simple motor reaction is one of the informative techniques for characterizing the strength of nervous processes. In a simple sensorimotor reaction, two mental acts can be distinguished: the act of perception (sensory moment of reaction) and the response movement (motor component). Evaluation of VAR can be done in the traditional way (using chronoreflexometers), as well as using special computer programs. The subject is first explained the contents and rules of the test. Then he sits down on a chair, puts his hands on the table in front of the chronoreflexometer, the finger of the leading hand is placed on his corresponding button. After the test subject is ready, the doctor-researcher gives a command within 3-10 seconds. after it turns on the device. The test subject's task is to respond as soon as possible after the occurrence of the signal by pressing the button and turn off the light bulb. The time of a simple motor reaction is measured (in milliseconds) from the moment a special object appears on the monitor screen until the subjects press a button on the manipulator (keyboard or mouse). VLDP is measured, as a rule, 50 times, after which the arithmetic mean value of the indicator is determined.

- Harvard step test (Research methods in the physiology of military labor. Manual / Edited by B.C. Novikov. - M.: Military Publishing House, 1993. - 240 p.)

As a functional test, allowing to detect the reaction of the cardiovascular system to an adverse effect, and in particular the effect of Coriolis accelerations, a 2-minute Harvard step test was used (Karpman V.L. et al., 1988).

The technique is based on the assessment of vegetative shifts when performing physical activity of submaximal power and the body's regenerative capabilities to normalize heart rate.

The value of the step test characterizes the speed of recovery processes after quite intense muscular work. The faster the pulse is restored, the lower the value (P2 + P3 + P4), and therefore, the higher the step test index.

In athletes, this indicator is usually higher than in untrained people. With the toxic effects of drugs, it should be expected to decrease. At the same time, its increase indicates that the drug increases the functional reserves of the body and the ability to tolerate adverse environmental effects, including kinetic effects.

The test procedure consists in the fact that the subject crouches for 2 minutes with a frequency of 30 times per minute. Immediately after the load, the pulse for the first 30 seconds of each minute is counted at 2, 3 and 4 minutes. The step test index was calculated by the formula:

Harvard step test index = T * 100 / (P2 + P3 + P4) * 2,

where T is the load time in sec; P2, P3, P4 - pulse rate on the 2nd, 3rd, 4th minutes of the recovery period, * - multiplication sign.

Due to the fact that the preparations are intended for persons susceptible to motion sickness, including drivers, their safety was evaluated when a person performs responsible operator functions. For this purpose, the main predictors of the quality of the operator-type activity were investigated, for which they studied in detail the functional state of the central nervous system (in particular, the state of coordination and response systems, systems providing high efficiency of thin motor components of activity, as well as attention systems).

- Stange test (Maintaining the health of the floating composition of the Navy. A guide for doctors // Under the general editorship of Zheglova V.V., Sapova I.A., Schegoleva B.C. - M .: Military Publishing. - 1990. - 192 p.).

The essence of the test is to hold your breath after three breaths at 3/4 of the depth of a full breath. Prior to the test, the subject wears a clip or the subject holds his nose with his fingers. The delay time is recorded by the stopwatch. The sample can be performed twice at intervals of 3-5 minutes between determinations. According to the duration of breath holding, the sample is evaluated as follows:

- less than 39 seconds - unsatisfactory;

- 40-9 sec - satisfactory;

- over 50 sec - good.

- Gencha test (Maintaining the health of the floating composition of the Navy. A guide for doctors // Under the general editorship of Zheglov V.V., Sapova I.A., Schegoleva B.C. - M .: Military Publishing. - 1990. - 192 p.).

The essence of the test is to hold the breath on the exhale after three breaths. When conducting the Gencha test in the supine position, the duration of the breath holding in healthy people is 25-30 seconds. When it is repeated after a dosed walk (44 m for 30 seconds), the duration of the breath-holding is reduced to 17-22 seconds, and with functional failure of the body - up to 5-15 seconds. Sample evaluation was carried out as follows:

- less than 34 seconds - unsatisfactory;

- 35-39 sec - satisfactory;

- over 40 seconds - good.

Example 3

To study the effectiveness of the treatment of patients with the Autonomic Dysfunction Syndrome (VDS) of psychophysiological and dishormonal genesis with the claimed drug, 300 mg tablets were used, impregnated with a pharmaceutical composition containing aqueous-alcoholic solutions (6 mg / table.) Of activated - potentiated forms of polyclonal affinity-purified rabbit rabbits antibodies to the brain-specific protein S-100 (anti-S100) and to endothelial NO synthase (anti-eNOS) in ultra-low doses (SMD) obtained by super-dilution of the initial ma ternary solution (with a concentration of 2.5 mg / ml) 100 ¹² , 100 ³⁰ , 100 ²⁰⁰ times, equivalent to a mixture of hundred-percent homeopathic dilutions of C12, C30, C200 (SMD anti-S100 + anti-eNOS).

As a control group, we used a group of patients receiving the drug in the form of tablets weighing 300 mg, impregnated with an aqueous-alcoholic solution (3 mg / tablet) of an activated-potentiated form of polyclonal rabbit antibodies to brain-specific protein S-100, purified on antigen, in an ultra-low dose (SMD anti-S100) obtained by super-dilution of the initial matrix solution (concentration of 2.5 mg / ml) 100 ¹² , 100 ³⁰ , 100 ²⁰⁰ times, equivalent to a mixture of hundred-percent homeopathic dilutions C12, C30, C200

By design, the study was a single-center, open, randomized comparative clinical study of the efficacy and safety of the use of anti-S100 + anti-eNOS SMD and anti-S100 SMD drugs used as monotherapy in the treatment of patients with Autonomic Dysfunction Syndrome (SVD) of psychophysiological and dishormonal origin .

The study included 12 patients with a diagnosis of "SVD of psychophysiological genesis" and "SVD of dishormonal genesis", aged 23 to 61 years. The average age of the patients was 49.25 ± 12.63 years.

After determining whether the patient met the criteria for inclusion and exclusion of the protocol, the patients were randomized into one of the two studied groups: the SMD anti-S100 + anti-eNOS group - 6 patients (3 patients with an SVD of psychophysiological and 3 patients with an SVD of dishormonal origin). The average age of patients with SMD anti-S100 + anti-eNOS was 41.33 ± 12.5 years (17.7% of men and 82.3% of women); anti-S100 SMD group - 6 patients (3 patients with an SVD of psychophysiological and 3 patients with an SVD of dishormonal origin). The average age of anti-S100 SMD patients was 57.16 ± 4.35 years (17.7% of men and 82.3% of women).

During this study, 4 visits to the research center were conducted. The treatment phase lasted from Visit 1 to Visit 3. Visit 3 (Day 56 ± 5) was the first endpoint of the study, after which the follow-up phase began. Follow-up phase continued until Visit 4 (Day 84 ± 5).

The safety analysis included data from all patients participating in the study (n = 12). During the entire period of observation of patients, good tolerability of the drug was noted. Adverse events were absent. One patient failed to appear on her second visit; contact with her was lost. The patient was not included in the analysis. All patients of the study groups completed the treatment within the time period established by the study protocol; there were no prematurely retired patients.

When evaluating the effect of the drug SMD anti-S100 + anti-eNOS on the main manifestations of SVD, as well as anxiety and depressive disorders (Beck depression questionnaire), an improvement in the quality of life of patients was revealed, expressed in a statistically significant increase in the total score of the SF-36 questionnaire ( subscale “physical health” from 38.04 ± 2.44 to 47.84 ± 1.27, p = 0.005, subscale “mental health” from 57.88 ± 3.94 to 72.75 ± 1.64, p <0.01), as well as a statistically significant decrease in the total score for the Beck Depression Questionnaire (from 11.0 ± 1.4 to 5.5 ± 1.37, p <0.02)

When assessing the effect of the drug SMD anti-S100 on the main manifestations of SVD, as well as anxiety-depressive disorders of the patient (Beck depression questionnaire), an improvement in the quality of life of patients was revealed, expressed in a statistically significant increase in the total score of the SF-36 questionnaire, (signed “ mental health ”- from 56.107 ± 1.36 to 70.7 ± 1.39, p <0.001). There were no trends in increasing the total score for the “physical health” subscale in this group.

When analyzing the dynamics of anxiety-depressive disorders in the anti-S100 SMD group, a statistically significant decrease in the total score was revealed in the Beck Depression Questionnaire (from 10.5 ± 1.04 to 5.33 ± 1.5, p <0.02) (Table 10).

Table 10 SF-36 (physical health) SF-36 (Mental Health) Beck Depression Questionnaire SMD anti-S100 + anti-eNOS before treatment 38.04 ± 2.44 57.88 ± 3.94 11.0 ± 1.4 SMD anti-S100 + anti-eNOS after treatment 47.84 ± 1.27 * 72.75 ± 1.64 ** 5.5 ± 1.37 *** SMD anti-S100 before treatment 46.99 ± 8.09 56.107 ± 1.36 10.5 ± 1.04 SMD anti-S100 after treatment 49.17 ± 2.68 70.7 ± 1.39 **** 5.33 ± 1.5 ***

* - p from ref. = 0.005 ** - p from ref. <0.01 *** - p from ref. 0.02 **** - p from ref. 0.001

There were no significant intergroup differences after treatment for these indicators. When planning the study and recruiting patients, the groups were divided into the following subgroups:

1. Patients with a diagnosis of Autonomic Dysfunction Syndrome of psychophysiological origin (chronic stress) who will receive the drug SMD anti-S100 + anti-eNOS as monotherapy;

2. Patients with a diagnosis of Autonomic Dysfunction Syndrome of psychophysiological origin (chronic stress), who will receive the drug SMD anti-S100 as monotherapy;

3. Patients with a diagnosis of Vegetative Dysfunction Syndrome of dishormonal (menopausal) genesis who will receive the drug SMD anti-S100 + anti-eNOS as monotherapy;

4. Patients with a diagnosis of Vegetative Dysfunction Syndrome of dishormonal (climacteric) genesis, who will receive the drug SMD anti-S100 as monotherapy.

When analyzing the data obtained, subgroup trends corresponded to those in the general group analysis, although they had a lower degree of reliability, which is probably due to a small number of observations (Table 11, 12).

Table 11 SVD of dishormonal (menopausal) genesis SF-36 (physical health) SF-36 (Mental Health) Beck Depression Questionnaire SMD anti-S100 + anti-eNOS before treatment 38.5 ± 2.99 57.9 ± 4.42 11.0 ± 2.0 SMD anti-S100 + anti-eNOS after treatment 47.99 ± 1.48 * 72.75 ± 1.85 * 5.33 ± 0.57 *** SMD anti-S100 before treatment 47.39 ± 8.35 56.79 ± 1.23 10.0 ± 1.0 SMD anti-S100 after treatment 48.96 ± 3.16 70.71 ± 1.68 ** 4.66 ± 0.057 **** * - p from ref. <0.05 ** - p from ref. <0.005 *** - p from ref. = 0,053 **** - p from ref. = 0.01

Table 12 SVD psychophysiological (chronic stress) genesis SF-36 (physical health) SF-36 (Mental Health) Beck Depression Questionnaire SMD anti-S100 + anti-eNOS before treatment 37.57 ± 2.31 57.85 ± 4.39 11.0 ± 1.0 SMD anti-S100 + anti-eNOS after treatment 47.69 ± 1.32 * 72.73 ± 1.82 ** 5.66 ± 2.08 **** SMD anti-S100 before treatment 47.39 ± 8.35 55.42 ± 1.31 11.0 ± 1.0 SMD anti-S100 after treatment 48.96 ± 3.16 70.69 ± 1.65 *** 6.0 ± 2.0 **** * - p from ref. <0.02 ** - p from ref. <0.05 *** - p from ref. = 0.002 **** - p from ref. = 0.082

During the intergroup and intragroup analysis of the dynamics of blood pressure, integrative autonomic indicators, indicators of variational pulsometry, statistically significant trends were not detected, with the exception of the trend towards a decrease in the Autonomic Equilibrium Index (IVR). Most likely, this is due to an insufficient number of observations.

IIR is an integrative indicator calculated as the ratio of the Mo amplitude (the number of cardio intervals corresponding to the mode range) to the Variation Range (the difference between the maximum and minimum values of R-R). A decrease in this indicator indicates a shift in the vegetative equilibrium from sympathicotonia to normo- and vagotonia, i.e. an increase in the effect of the parasympathetic departments of the autonomic nervous system (ANS).

In the dyshormonal SVD group, there was a statistically significant tendency to a decrease in IVR in the anti-S100 + anti-eNOS SMD subgroup. At the same time, a statistically significant (p <0.05) difference was found between the anti-S100 + anti-eNOS SMD subgroup and the anti-S100 SMD subgroup (Table 13).

Table 13 Dyshormonal SVD IVR before treatment Post-treatment IVR SMD anti-S100 + anti-eNOS 721.1 ± 38.52 416.86 ± 73.72 * # SMD anti-S100 after treatment 48.96 ± 3.16 696.26 ± 61.85 * - p from ref. <0.05 # - p by comp. with SMD anti-S100. <0.05

Thus, in a clinical study of the claimed medicinal product SMD anti-S100 + anti-eNOS showed a positive impact on the quality of life of patients with Autonomic Dysfunction Syndrome (SVD) of psychophysiological and dishormonal origin, a positive effect on anxiety-depressive disorders of patients. The positive effect of the drug on the autonomic nervous system has been demonstrated. In addition, the high tolerance of the claimed drug is confirmed. Adverse events were absent.

Example 4

The efficacy of drugs for scopolamine amnesia in rats (model of Alzheimer's disease).

Alzheimer's disease (AD) is a neurodegenerative disease and is characterized by a decrease in cognitive functions, memory impairment, confusion, and changes in the emotional background. Although the main reason for the development of this pathology is currently considered to be the accumulation of amyloid beta, leading to the formation of amyloid beta plaques and neurofibrillary tangles in the brain tissue, AD is also accompanied by a deficiency of the cholinergic system. This is the basis for one of the most common methods of modeling AD in animals using an antagonist of the cholinergic scopolamine system. Administration of scopolamine to experimental animals (usually rats or mice) impairs learning ability and leads to memory impairment.

Various methods are used to evaluate the cognitive functions of rats and mice, in particular the Morris water maze. The essence of this test is that in a vessel with opaque water, animals released into the water from different points are forced to look for a hidden fixed platform. The advantage of this method is that it allows you to observe the learning process of the animal (forming an idea of the spatial location of the platform, regardless of where it was lowered into the water), and to evaluate the strength of memorization (for this a test test is carried out, when the platform is taken out).

Example 4 below examined the efficacy in rat scopolamine amnesia of the claimed drug in the form of a composition containing activated - potentiated forms of polyclonal affinity-purified rabbit antibodies to brain-specific protein S-100 (anti-S100) and to endothelial NO synthase (anti- eNOS) in ultra-low doses (SMD) obtained by super-dilution of the initial matrix solution (with a concentration of 2.5 mg / ml) 100 ¹² , 100 ³⁰ , 100 ²⁰⁰ times equivalent to a mixture of hundred-percent homeopathic dilutions C12, C30, C200 (SMD anti-S100 + anti-eNOS).

In a study of efficacy, the SMD anti-S100 + anti-eNOS drug for scopolamine amnesia in rats (Alzheimer's disease model) was used in 48 male Rj: Wistar (Han) rats (weight 180-280 g). For 4 days, rats were injected subcutaneously with saline (n = 12, intact) or scopolamine at a dose of 0.5 mg / kg (n = 36) (scopolamine-induced amnesia). Rats with scopolamine-induced amnesia were divided into 3 groups and, respectively, distilled water (7.5 ml / kg, n = 12, control, group No. 1), SMD anti-S100 (7.5 ml / kg, n = 12, group No. 2) and SMD anti-S100 + anti-eNOS (7.5 ml / kg, n = 12, group No. 3) intragastrically for 9 days (4 days before the start of scopolamine injection, 4 days against the background of administration scopolamine and 1 day after the end of scopolamine administration).

Within 4 days of scopolamine administration, 60 minutes after the administration of the test drugs and 30 minutes after the administration of scopolamine, a training session was conducted in the Morris maze (4 consecutive tests with an interval of 60 seconds). The Morris labyrinth is a round vessel (150 cm in diameter, 45 cm high), 30 cm filled with water (26-28 ° C). 18 cm from the edge of the vessel is a hidden platform (15 cm in diameter), recessed 1.5 cm below the water level. The water is made turbid by adding a non-toxic dye (for example, milk powder), which makes the platform invisible. For each test, the animal was placed in a maze at one of the starting points located at the same distance from the hidden platform, and allowed them to find it. If the animal could not find the platform in 120 seconds, it was placed on the platform for 60 seconds and then a new test was started. During 4 trials in random order, the animals began passing through the maze twice from each starting point. The tests were recorded on videotape, and then the distance covered in search of the platform in each test and the latent period of the search for the platform were analyzed.

On day 5, a test was performed: the platform was removed from the maze, and the rat was allowed to swim freely for 60 seconds. The time spent in the place where the platform used to be was recorded.

The introduction of scopolamine significantly impaired the learning ability of animals: in the control group No. 1, the time spent by the animals on the search for the platform and the distance that the animals sailed in search of the platform increased significantly (Tables 14, 15). The test showed that the memory of the animals of the control group No. 1 deteriorated significantly: in the place where the platform used to be, they spent less time than intact rats (Table 16). The introduction of SMD anti-S100 in group No. 2 did not lead to an improvement in the studied parameters (Tables 14, 15, 16). The introduction of SMD anti-S100 + anti-eNOS in group No. 3 led to some improvement in training, which was expressed in shortening the latent search time of the platform (Table 14) and the distance covered (Table 15) for 4 days of training, and memory improvement, which was expressed in increasing the time spent in the place where the platform was (Table 16).

Table 14 Latent period of platform search, sec Group Training 1 day 2 day 3 day 4 day Intact, n = 12 54.7 ± 6.2 30.8 ± 2.8 26.9 ± 5.1 20.5 ± 3.6 Control, n = 12 100.1 ± 6.8 *** 92.4 ± 9.3 *** 81.4 ± 10.7 *** 77.7 ± 9.4 *** SMD anti-S100, n = 12 106.8 ± 7.0 99.3 ± 7.8 95.6 ± 9.0 80.4 ± 1 1.1 SMD anti-S100 + anti-eNOS, n = 12 94.4 ± 7.2 90.7 ± 8.2 78.3 ± 8.6 60.1 ± 1 0.2 *** - significant difference from intact, p <0.05

Table 15 Distance covered in search of a platform, cm Group Training 1 day 2 day 3 day 4 day Intact, n = 12 1055.7 ± 94.6 659.5 ± 62.2 564.8 ± 119.3 406.1 ± 61.2 Control, n = 12 2587.1 ± 217.2 *** 2559.6 ± 250.5 *** 2397.9 ± 312.6 2366.1 ± 293.8 *** SMD anti-S100, n = 12 2797.2 ± 208.9 2865.2 ± 255.1 2857.0 ± 300.8 2457.4 ± 344.4 SMD anti-S100 + anti-eNOS, n = 12 2434.3 ± 222.8 2529.9 ± 282.7 2344.2 ± 283.0 1905.1 ± 343.7 *** - significant difference from intact, p <0.05

Table 16 Time spent in the place where the platform used to be, sec Group Try 0-30 sec 30-60 sec 0-60 sec Intact, n = 12 40.8 ± 4.1 36.8 ± 3.6 38.5 ± 2.6 Control, n = 12 18.4 ± 2.8 *** 18.8 ± 1.9 *** 18.8 ± 1.7 *** SMD anti-S100, n = 12 13.3 ± 2.1 21.5 ± 2.6 17.6 ± 1.3 SMD anti-S100 + anti eNOS, n = 12 19.1 ± 4.8 23.8 ± 2.2 21.2 ± 2.5 *** - significant difference from intact, p <0.05

Thus, in the model of Alzheimer's disease used, the use of the anti-S100 + anti-eNOS SMD complex was more effective than the isolated administration of anti-S100 SMD.

Claims (11)

1. A method of treating kinetoses, characterized in that an activated-potentiated form of antibodies to the brain-specific protein S-100 is introduced into the body. 2. The treatment method according to claim 1, characterized in that the activated-potentiated form of antibodies to the brain-specific protein S-100 is used in the form of an activated-potentiated aqueous or aqueous-alcoholic solution, the activity of which is due to the process of multiple sequential dilutions in aqueous or aqueous-alcoholic solvent in combination with external mechanical action - shaking of each dilution. 3. The treatment method according to claim 1 or 2, characterized in that the aqueous or aqueous-alcoholic solution of the activated-potentiated forms of antibodies to the brain-specific protein S-100 is obtained by repeated serial dilution in combination with an external action - vertical shaking of each dilution from the matrix solution affinity-purified antibodies to brain-specific protein S-100 with a concentration of 0.5 ÷ 5.0 mg / ml 4. The treatment method according to claim 1 or 2, characterized in that using an activated-potentiated form of antibodies to the brain-specific protein S-100 in solid dosage form, which contains an effective amount of granules of a neutral carrier, saturated with a mixture of activated or aqueous-alcoholic solutions of a potentiated form of antibodies to the brain-specific protein S-100, and pharmaceutically acceptable additives including lactose, microcrystalline cellulose and magnesium stearate. 5. The treatment method according to claim 1 or 2, characterized in that use is made of a mixture of different dilutions of antibodies to the brain-specific protein S-100, prepared according to homeopathic technology, prepared as a single drug. 6. A drug for the treatment of kinetosis, characterized in that it is made in the form of a pharmaceutical composition and contains an activated-potentiated form of antibodies to the brain-specific protein S-100. 7. The drug according to claim 6, characterized in that the activated-potentiated form of antibodies to the brain-specific protein S-100 is used in the form of an activated-potentiated aqueous or aqueous-alcoholic solution, the activity of which is due to the process of successive multiple dilutions in aqueous or aqueous-alcoholic solvent in combination with external mechanical action - shaking of each dilution. 8. The drug according to claim 6, characterized in that the pharmaceutical composition is in solid dosage form and contains an effective amount of granules of a neutral carrier saturated with a mixture of aqueous or aqueous-alcoholic solutions of an activated-potentiated form of antibodies to the brain-specific protein S-100 and pharmaceutically acceptable additives. 9. The drug according to claim 6 or 7, characterized in that aqueous or aqueous-alcoholic solutions of activated-potentiated forms of antibodies to the brain-specific protein S-100 are obtained by repeated serial dilutions in combination with an external action - vertical shaking of each dilution from matrix solutions affinity-purified antibodies to brain-specific protein S-100 with a concentration of 0.5 ÷ 5.0 mg / ml 10. The drug according to claim 6 or 7, characterized in that the activated-potentiated form of antibodies to the brain-specific protein S-100 is used as a mixture of various, mainly hundred, dilutions prepared by homeopathic technology. 11. The drug of claim 8, characterized in that the pharmaceutically acceptable additives include lactose, microcrystalline cellulose and magnesium stearate.