UA112750C2 - Combination pharmaceutical compositions and method of treatment of vertigo, kinetosis and vegetative-vascular dystonia - Google Patents

Abstract

The present invention relates to combination pharmaceutical compositions comprising an activated-potentiated form of an antibody to endothelial NO synthase and activated potentiated form of an antibody to brain-specific protein S-100 and its use for the treatment of vegetative-vascular dystonia (WD) and symptoms thereof.

Description

FIELD OF THE INVENTION

The present invention relates to combined medicinal products containing an activated potentiated form of an antibody to MO-synthase and an activated potentiated form of an antibody to protein 5-100, and their use for the treatment of vertigo of various etiologies, kinetosis and vegetative-vascular dystonia.

TECHNICAL LEVEL

Vegeto-vascular dystonia (VSD) (synonyms: neurocirculatory dystonia, neurocirculatory asthenia, psychovegetative syndrome, autonomic neurosis, autonomic dysfunction syndrome (SVD) and a polyetiological syndrome characterized by dysfunction of the autonomic (autonomic) nervous system (ANS) and functional (i.e., inorganic) disorders affecting most body systems (mainly the cardiovascular system).

The main clinical feature of patients with VSD is numerous complaints and various symptoms and syndromes caused by the specificity of the pathogenesis involved in the work of the hypothalamus structures. Among the most frequent symptoms of VSD: cardialgia, asthenia, neurotic disorders, headache, sleep disorders, dizziness, respiratory disorders, tachycardia, cold extremities, vegetative-vascular spasms, hand tremors, internal tremor, cardiophobia, muscle pain, joint pain, swelling of tissues, temporary cessation of pulse, feeling of heat in the face, low fever and loss of consciousness.

Vegetative symptoms, indicating disorders of the regulation of the vegetative-vascular, respiratory and other systems of the body, can also be part of a number of painful conditions, for example: hypertension, disorders of the endocrine system, chronic coronary heart disease, etc.

Thus, in patients, it is possible to confirm vegetative-vascular dystonia and neurocirculatory dystonia based on a complex of symptoms that are typical for somatoform dysfunction of the autonomic nervous system.

As part of the complex of symptoms of vegetative-vascular dystonia, it is possible to distinguish isolated cerebrovascular disorders characterized by headache, dizziness, noise in the ears and head, weakness of the vestibular apparatus, a tendency to loss of consciousness and motion sickness. The basis of their development is cerebral angiodystonia,

The pathogenetic basis of which is the deregulation of the vascular tone of the brain of a hypertonic, hypotonic or mixed nature.

Kinetosis (synonyms: swaying in transport, seasickness, altitude sickness, car sickness, etc.) is a movement-related disorder (from the Greek: Kupeviv5 - movement) that occurs when the body is exposed to more or less prolonged and variable acceleration. Disorders of movement coordination, dizziness, nausea, vomiting, paleness, cold sweat, decreased blood pressure, irregular heartbeat are typical for kinetosis. In severe cases, depression, asthenia, disorders of clarity of consciousness are possible. However, after stopping the accelerations, the symptoms of motion sickness disappear.

Given that during movement, various receptors of the vestibular apparatus are irritated, in turn, the cerebellum receives impulses that cause changes in the tone of various muscle groups of the neck, back, and limbs, thus causing asymmetry of muscle tone and coordination of muscle movement.

Manifestations of motion sickness are most pronounced in persons with increased excitability of the sympathetic or parasympathetic parts of the nervous system or the vestibular analyzer. Attacks of dizziness (vertigo) are largely caused by changes in the functional interaction between the sympathetic or parasympathetic nervous system in the direction of dominance of the function of the parasympathetic system. These changes are accompanied by vasomotor disorders of the inner ear with an increase in the permeability of the vascular walls and the subsequent amount of endolymph in the vestibular apparatus. Dizziness is a typical symptom of the loss of the vestibular apparatus of various etiologies, including dysfunction of the vestibular nerve and the vestibular cochlear system, blood circulation disorders of the vertebral-basilar system, pathology of the central nervous system (CNS), etc. Dizziness as a manifestation of motion sickness is accompanied by other vestibular-vegetative disorders, including three types of reactions: vestibular-motor (nystagmus and deviation reactions), vestibular-sensory (in addition to dizziness, it can be nystagmus (or post-rotation reaction), protective movements) and autonomic (nausea, vomiting, increased sweating, tachycardia, feeling hot, fluctuations in pulse and blood pressure).

In medicine, the well-known homeopathic preparation "AVIAMORE" (KO 2113230 C1, AbIK 35/78, 1998) is based on plant components and is intended for the treatment and prevention of locomotion sickness (kinetosis) in the form of motion sickness in transport, seasickness and altitude sickness. The effectiveness of this drug in most cases is not very high.

Neurotropic drugs based on antiserum to brain-specific 60 protein 5-100 are also known (VO 2156621 C1, Ab1KZ39/395, 27.09.2000).

Therefore, there is a constant need for new drugs that would have the desired therapeutic efficacy in the treatment of vertigo of various etiologies, motion sickness, and vegetative-vascular dystonia.

The therapeutic effect of the maximally diluted (or ultralow) form of antibodies potentiated with the help of homeopathic technology (activated potentiated form) was discovered by the author of this invention, Dr. O.I. Epstein. US Patent No. 7,582,294 describes an agent for the treatment of benign prostatic hyperplasia or prostatitis by administering a homeopathically activated form of antibodies to prostate-specific antigen (PSA). US Patent No. 7,700,096 describes a homeopathically potentiated form of antibodies to endothelial MO synthase.

Protein 5-100 is a cytoplasmic acidic calcium-binding protein produced mainly in the gray matter of the brain, primarily in glial and Schwann cells. The protein exists in several homo- or heterodimeric isoforms, consisting of two immunologically separated subunits - alpha and beta. Protein 5-100 is proposed for use as an aid in the diagnosis and evaluation of brain lesions and neurological damage resulting from traumatic brain injury such as stroke. See Uagdap ei a!I., OvzeishIpev5 oi 5-1008 Rgoivip ip Meshigoiodisa! Rizogaegv, ) Cancer Mei Azzos Moi. 61, Mo. 3, Magsp 2011, which is incorporated into this document by reference.

It was established that ultra-low doses of antibodies to protein 5-100 have anxiolytic, anti-asthenic, anti-aggressive, stress-protective, anti-hypoxic, anti-ischemic, neuroprotective and nootropic activity. See Saziadpe M. ei aiYi., Apiirodiez To 5-100 rgoieip5 Name aphioiuis-iike asimpu ai ipka-Iom/ dosev ip She adyy gaku Rpapt RIiaptasoi. 2008, 60(3):309-16; Epstein 0. 1.,

Antibodies to calcium-binding protein 5-1008 block the formation of long-term sensitization in the land snail, Rpagtasoi Viospet Vepam., 2009, 94(1):37-42; Voronina T.A. et al., Chapter 8. Antibodies to protein 5-100 in anxiety-depressive disorders in experimental and clinical conditions. In the book "Animal models in biological psychiatry", ed.

Kaluyeva A. V. M-U, "Moma zZsiepse Rybiizpegv, Ips.", 2006, p. 137-152, which are incorporated herein by reference.

Nitric oxide (NO) is a gaseous molecule that acts in the signaling of various biological processes. MO obtained from the endothelium is the main molecule in the regulation of vascular tone and

Its connection with vascular disease was confirmed. MO inhibits many processes known to be involved in the formation of atherosclerotic plaques, including monocyte adhesion, platelet aggregation, and vascular smooth muscle cell growth. Another important role of endothelial MO is to protect vascular walls from oxidative stress caused by its own metabolic products and products of lipid and lipoprotein oxidation. Endothelial dysfunction occurs in the very early stages of atherosclerosis. Accordingly, a local deficit

MO may be the final common factor that accelerates atherogenesis in humans.

In addition to its function in the vascular endothelium, MO has been found to modulate lipoprotein metabolism. A negative correlation has been reported between plasma concentrations of MO metabolites and total plasma and low-density lipoprotein (LDL) cholesterol levels, while HDL-LDL improves vascular function in hypercholesterolemic patients. The loss of MO exerts a significant influence on the development of the disease.

Diabetes mellitus is associated with an increase in the level of morbidity and mortality, which is mainly caused by the accelerated development of atherosclerosis. Moreover, reports show worsening lung function in diabetics. There is an opinion that insulin resistance leads to inflammation of the respiratory tract. A set of eyi ai!., Migis Ohide Meazitetepi Egot Viosa To

Gipdv, I5 Tpege And GipkK? Cancer U) Rpuzio! 2007; 3(1). Nitric oxide is synthesized by the endothelium from I-arginine by nitric oxide synthase (MO-synthase). MO synthase exists in different isoforms, including a constitutive form (CMO5) and an inducible form (IMO5). The constitutive form is present in normal endothelial cells, neurons, and some other tissues.

BRIEF DESCRIPTION OF THE INVENTION

In one aspect, the present invention is a combination drug containing an activated potentiated form of an antibody to brain-specific protein 5-100 and an activated potentiated form of an antibody to endothelial MO-synthase.

In one embodiment, the present invention is a combined drug containing an activated potentiated form of an antibody to brain-specific protein 5-100 and an activated potentiated form of an antibody to endothelial MO-synthase, where an antibody to the whole protein 5-100 or its parts is present.

In one variant, the present invention is a combined medicinal product containing an activated potentiated form of an antibody to brain-specific protein 5-100 and an activated potentiated form of an antibody to endothelial MO-synthase, where an antibody to the whole

MO-synthase or its parts.

In one embodiment, the combined medicinal product of this aspect of the invention includes an activated potentiated form of antibody to protein 5-100 in the form of a mixture of homeopathic dilutions (C12, C30, and C50) or (C12, C30, and C200) impregnated into a solid carrier. The activated potentiated form of the MO-synthase antibody, presented in the form of a mixture of (C12, C30, and C50) or (C12, C30, and C200) homeopathic dilutions, can subsequently be impregnated into a solid carrier.

In one embodiment, the combined medicinal product of this aspect of the invention includes an activated potentiated form of an antibody to MO-synthase in the form of a mixture of (C12, C30, and C50) or (C12, C30, and C200) homeopathic dilutions, impregnated into a solid carrier. The activated potentiated form of antibody to protein 5-100 is presented in the form of a mixture of homeopathic dilutions (C12, C30, and C50) or (C12, C30, and C200), and can subsequently be impregnated into a solid carrier.

If possible, the activated potentiated form of antibody to protein 955-100 is a monoclonal, polyclonal or natural antibody, preferably a polyclonal antibody. In one embodiment of this aspect of the invention, the activated potentiated form of the antibody to protein 5-100 is prepared by successive hundredfold dilutions in combination with shaking of each dilution. Vertical shaking is specially provided.

If possible, the activated potentiated form of the antibody to MO-synthase is a monoclonal, polyclonal or natural antibody, preferably a polyclonal antibody. In one embodiment of this aspect of the invention, the activated potentiated form of the MO-synthase antibody is prepared by serial hundredfold dilutions in combination with shaking of each dilution. Vertical shaking is specially provided.

In another aspect, the invention presents a method of treating vertigo of various etiologies, kinetosis and vegetative-vascular dystonia, including the administration of a combined medicinal product containing an activated potentiated form of an antibody to brain-specific protein 555-100 and an activated potentiated form of an antibody to endothelial MO-synthase to the corresponding patient.

In one embodiment, a method of treatment is presented by administering to the respective patient a combined medicinal product containing an activated potentiated form of an antibody to brain-specific protein 5-100 and an activated potentiated form of an antibody to endothelial MO synthase, and the administration of said combination leads to a significant improvement in locomotion sickness, which was measured using the SSEAS test.

In one variant, a method of treatment is presented by administering to a corresponding patient a combined drug containing an activated potentiated form of an antibody to brain-specific protein 5-100 and an activated potentiated form of an antibody to endothelial MO-synthase, and the introduction of the specified combination leads to a significant improvement in the stabilizing effect on the balance of the autonomic of the nervous system, which was measured using the CSEAS test.

In one variant of the invention, it is envisaged to introduce from 1 to 2 standard dosage forms of the activated potentiated form of antibody to protein 5-100 and from 1 to 2 standard dosage forms of the activated potentiated form of antibody to MO-synthase, and each dosage form is administered from 1 to 4 times per a day If possible, 1-2 standard dosage forms of each activated potentiated form of antibody should be administered twice daily.

DETAILED DESCRIPTION

The invention is defined with reference to the appended claims. For statements, the following glossary provides relevant definitions.

The term "antibody" as used herein refers to an immunoglobulin that specifically binds (and accordingly is defined as complementary) to a specific spatial and polar organization of another molecule.

As indicated in the claims, the antibodies may include all or part of an immunoglobulin, may be natural, polyclonal or monoclonal, and may include different classes and isotypes, such as DA, dO, CHE, Ids1, Idsga, ds2Bb and Ids3, M, etc. Its parts may include Rab, Em and E(ab)2, Rar', etc. The term "antibody" in the singular includes "antibodies" in the plural.

The term "activated potentiated form" or "potentiated form", respectively, in relation to the antibodies specified herein, is used to refer to the product of homeopathic potentiation of any original antibody solution.

"Homeopathic potentiation" means the application of homeopathic methods to add homeopathic activity to a stock solution of a corresponding substance. Although the term is not so limited, "homeopathic potentiation" may include, for example, repeated serial dilutions in combination with external processing, in particular, vertical (mechanical) shaking. In other words, the initial antibody solution is subjected to successive repeated dilutions and repeated vertical shaking of each obtained solution according to homeopathic technology. The preferred concentration of the original solution of the antibody in the solvent, preferably water or a mixture of water and ethyl alcohol, varies from about 0.5 to 5.0 mg/ml.

A preferred procedure for the preparation of each component (i.e., the antibody solution) is to use a mixture of C aqueous or aqueous-alcoholic dilutions of the original matrix solution (mother tincture), antibodies diluted 10072, 10030, and 100200 times, respectively, which is equivalent to hundreds of homeopathic dilutions (C12, C30, and C200), or using a mixture of three water or water-alcohol dilutions of the primary matrix solution of antibodies, diluted 10072, 10039, and 10059 times, respectively, which is equivalent to hundred homeopathic dilutions (C12, C30, and C50). Examples of homeopathic potentiation are described in

U.S. Patent Nos. 7,572,441 and 7,582,294, which are hereby incorporated by reference in their entirety for the stated purpose. While the term "activated potentiated form" is used in the claims, the examples use the term "ultra-low doses".

The expression "ultra-low doses" became a special term created during the research and use of homeopathically diluted and potentized form of the substance. The term "ultra-low dose" or "ultra-low doses" fully supports and is primarily synonymous with the term "activated potentiated" form used in the claims.

In other words, the antibody is in an "activated potentiated" or "potentiated" form in the presence of three factors. First of all, the "activated potentiated" form of the antibody is the product of a preparation process well known in the homeopathic field. Secondly, the "activated potentiated" form of the antibody must have biological activity determined by methods accepted in modern pharmacology. Thirdly, the biological activity manifested by the "activated-potentiated" form of the antibody cannot be explained

With the presence of the molecular form of the antibody in the final product of the homeopathic process.

For example, an activated potentiated form of antibodies can be prepared by subjecting the original, isolated antibody in molecular form to successive multiple dilutions in combination with an external action, for example, mechanical shaking.

External processing in the course of reducing concentration can also be accompanied, for example, by the influence of ultrasonic, electromagnetic or other physical factors. W. Schwabe "Homeopathic Medicines", M., 1967, US Patents MoMo 7,229,648 and 4,311,897, which are fully incorporated herein by reference and for the stated purpose, describe such processes which are common methods of homeopathic potentiation in homeopathic practice.

This procedure causes a uniform decrease in the molecular concentration of the initial molecular form of the antibody. This procedure is repeated until the required homeopathic activity is obtained. For an individual antibody, the required homeopathic activity can be determined by subjecting intermediate dilutions to biological tests in the desired pharmacological model. Although the term is not so limited, "homeopathic potentiation" may include, for example, repeated serial dilutions in combination with external processing, in particular, vertical (mechanical) shaking. In other words, the initial antibody solution is subjected to successive repeated dilutions and repeated vertical shaking of each obtained solution according to homeopathic technology.

The preferred concentration of the original solution of the antibody in the solvent, preferably water or a mixture of water and ethyl alcohol, varies from about 0.5 to 5.0 mg/ml. A preferred procedure for the preparation of each component (i.e., the antibody solution) is to use a mixture of 3 aqueous or aqueous-alcoholic dilutions of the primary matrix solution (mother tincture) of the antibodies diluted 10072, 10099, and 100200 times, respectively, which is equivalent to one-hundredth homeopathic dilution C12, C30 and C200, or the use of a mixture of 3 aqueous or water-alcohol dilutions of the primary matrix solution (mother tincture) of antibodies diluted 10072, 10030 and 10059 times, respectively, which is equivalent to hundreds of homeopathic dilutions of C12, C30 and C50.

Examples of obtaining the desired activity are also given, for example, in US Pat

Nos. 7,229,648 and 4,311,897, which are incorporated herein by reference for the stated purpose. The procedure applicable to the "activated potentiated" form of the antibody described herein is described in more detail below.

There is a lot of controversy in scientific circles about homeopathic treatment of people. While this invention is based on generally accepted homeopathic processes for obtaining an "activated potentiated" form of antibodies, it is not only based on the use of homeopathy in humans to prove its effectiveness. The inventor was surprised to discover in this application and sufficiently demonstrated in conventional pharmacological models that the solvent ultimately obtained after successive multiple dilutions of the original molecular form of antibodies had significant activity unrelated to the presence of residues of the molecular form of the antibody in the target dilution. An "activated potentiated" form of an antibody as defined herein is tested for biological activity in conventional pharmacological activity models, or in appropriate ip miigo or ip mimo experiments in suitable animal models. The experiments described below confirm the biological activity in such models. Human clinical studies also confirm that the activity observed in animal models correlates well with treatment in humans. Human studies have also confirmed the existence of the "activated potentiated" forms described herein for the treatment of certain diseases or disorders in humans generally accepted in medicine as pathological conditions.

In addition, the declared "activated potentiated" form of the antibody covers only solutions or solid preparations whose biological activity cannot be explained by the presence of the molecular form of the antibody remaining from the initial, initial solution. In other words, although it is assumed that the "activated potentiated" form of the antibody may contain remnants of the original molecular form of the antibody, one skilled in the art cannot attribute the biological activity observed in known pharmacological models to the remaining molecular form of the antibody with at least some degree of probability given the very low the concentration of the molecular form of the antibody remaining after successive dilutions. While the invention is not limited to any particular theory, the biological activity of the "activated potentiated" form of antibodies in this invention is not related to the original molecular form of the antibody. Preference is given to the "activated potentiated" form of the antibody in liquid

Zo or solid state, in which the concentration of the original molecular form of the antibody is below the detection threshold according to conventional methods of analysis, such as capillary electrophoresis and high-performance liquid chromatography. In particular, preference is given to the "activated potentiated" form in a liquid or solid state, in which the concentration of the original molecular form of the antibody is lower than Avogadro's number. In the pharmacology of molecular forms of therapeutic substances, it is common practice to draw up a "dose-effect" curve, in which the level of pharmacological response is plotted against the concentration of the active drug administered to the patient or tested intravenously. The minimum level of the drug that provides at least some detectable reaction is called the threshold dose. It is hereby specifically contemplated and preferred that the "activated potentiated" antibody form contains the molecular antibody, if present, at a concentration below the threshold dose for the molecular form of the antibody in a given biological model.

The tests used in this application are described below. (1) Constant Cumulative Coriolis Acceleration Test (CSACE) means a test capable of detecting a patient's resistance to the Coriolis effect of acceleration and thus indicating the degree of susceptibility of the patient to motion sickness. (Markaryan et al., Vestibular selection by the method of constant cumulative effect of Coriolis accelerations, Journal of military medicine, 1966, Mo 9. Pages 59-62; Voenizdat, Research methods for medical and aviation inspection, 1972).

The procedure for conducting the test is as follows: the patient is seated in a Barani chair or a chair with electric rotation in such a position that the axis of rotation is located along the body. The patient closes his eyes. With constant rotation of the chair at a speed of 180 degrees/sec. (one turn for 2 seconds), after the fifth turn, patients are asked to tilt their head from the right shoulder to the left or from left to right and back at an angle of at least 30 degrees. in each direction from the vertical. Tilts are performed continuously, without excessive tension of the neck muscles and head turns during the entire time of rotation. Thus, each movement of the head from shoulder to shoulder is carried out smoothly for 2 seconds without stopping at the central or peak position. The speed is controlled using a metronome or the time to say the numbers 21 and 22, which should correspond to 2 seconds. The time for conducting the test is counted from the first iasiayo sariyi5.

Before the test, the patient is asked to report any symptoms of shaking, hotness, salivation, nausea that may occur during the test. Before the test, the patient is asked to make several head movements so that the patient feels comfortable controlling the speed of the oscillations and can assume the correct position of the head during the movement. The appearance of pronounced vestibular-vegetative disorders (pallor, increased sweating, nausea, vomiting) during the CSEAS test is a criterion for limiting the tolerability of Coriolis acceleration effects. The time of manifestation of vestibular-autonomic reactions is recorded from the beginning of the CSEAS test to its completion.

Coriolis acceleration tolerability tests were performed in the morning no earlier than 2 hours after a meal and only once a day. On the day of the test, the patient was not exposed to other types of exposure (in an altitude chamber, centrifuge, etc.). (2) The method of quantitative assessment of disorders of vestibular-vegetative sensitivity (Halle Scale) is based on the evaluation of confirmations (in points) of vestibular-vegetative symptoms (dizziness, nausea, increased sweating, pallor of the skin, drowsiness, etc.) that occur during the CSEAS test. This technique makes it possible to determine the degree of tolerability of Coriolis accelerations by people (bad, satisfactory, good, excellent). (Quantitative evaluation of disorders of vestibular-vegetative sensitivity, Space biology and aeroastromedicine, 1981, Mo Z, pp. 72-75). (3) Determination of heart rate variability (HRV) is used to collect HRV data using the Viosot MUUePype55 bsap system. It was developed by AMU5, || sS., and produced in accordance with the International Standard of the European Association of Cardiologists and

North American Association of Electrophysiology (International working group consisting of

of the European Association of Cardiology and the North American Society of Electrocardiography and Electrophysiology 1996). (TazK Rogse oi Eigoreap Zosieiu oi Sagaioiodu apa (te Mogipi Ategisap

Zosieiu oi Rasipa apa EIesptornuzioiodu. Neapy Vaie Magiariyu 5iapdamyui5 oi teazigetepi, rpuzioiodisai! ipiegrgeiayop, apa siipisa! willow Sig. 1996; 93:1043 1065).

The following equipment is used: 1. Personal computer (PC) with the M/ipaohmuv operating system. 2. Photoplethysmograph NAM-02 (PRO).

From 3. Ear sensor (PPO clip). 4. Software Wiosot Umeipe55 5sap 5oimage on SO. 5. Instructions for use in electronic form (ROC).

The patient undergoes three tests of autonomous assessment of balance: a 5-minute recording of HRV at rest; breath rate analysis; orthostatic test.

HRV analysis procedure 1. Before starting the analysis, the researcher briefly informs the patient about the procedure of each test. 2. The patient sits in a comfortable and relaxed position. 3. The ear sensor is wiped with an alcohol solution and placed on the earlobe. 4. If the patient wears earrings, they must be removed before the test. 5. The researcher records a 5-minute resting HRV (short-term resting HRV analysis) for Her determination. 6. The researcher conducts the analysis according to the instructions. 7. Immediately after completing the analysis and entering the results into the database, the researcher chooses the next analysis, that is, the analysis of the respiratory rate (measurement of the respiratory rate with a metronome) or the orthostatic test. 8. The researcher carries out the instructions for conducting an analysis of the respiratory rate or an orthostatic test. 9. Immediately after completing the analysis and entering the results into the database, the researcher reviews the results of the conducted analyzes to determine their proper conduct. 10. After that, the analysis is completed and the ear sensor is removed.

Procedure for 5-minute HRV recording at rest

Analysis of short-term HRV is performed to assess the balance between the sympathetic and parasympathetic branches of the autonomic nervous system. It is a 5-minute recording of a photoplethysmograph performed in a sitting position without stimulating maneuvers. During the test, the participant is asked to breathe in a random order with a frequency of at least 9 breaths per minute to obtain valid HRV parameters. The following HRV parameters are calculated: 1. The parameters in the time zone are as follows: (a) HE, which is the average value of heart rate, measured in beats per minute (bpm).

(B) Average MM representing the average value of interbeat intervals measured in milliseconds. (c) ZOMM, which is the standard deviation of the MM intervals. Since the number under the square root is mathematically equivalent to the total power in the spectral analysis, the OMM displays all the cyclic components responsible for the variability. Actual value

ZOMM depends on the length of the record: the longer the record, the higher the 5ΩM indicator. Thus, in practice, it is impossible to compare the values of 5ΩMM calculated at different time intervals. BOMM is measured in milliseconds. (4) AM5-50, which is the square root of the differences between successive MM intervals. This indicator assesses the high-frequency component of heart rate variability associated with parasympathetic regulation of cardiac function. KM5-50 is measured in milliseconds.

All HRV parameters in the time zone are calculated at normal intervals between beats (MM) due to a normal sinus heartbeat during the test. 2. The parameters in the frequency range are as follows: (a) Total power (TP) is an estimate of the power spectral density in the range from 0 to 0.4 Hz. This indicator reflects the general activity of the autonomic nervous system, in which sympathetic activity is the greatest. Total power is calculated in milliseconds squared (mog). (B) Very low frequency (MI E) is the spectral power density in the range between 0.0033 and 0.04 Hz. The physiological nature of this indicator is that it is an indicator of the aggregate activity of various slow regulation mechanisms. MIR is calculated in milliseconds squared (mog). (c) Low frequency (I EP) is a spectral power density in the range between 0.04 and 0.15

Hz. This value reflects both sympathetic and parasympathetic activity. This is a good indicator of sympathetic activity in long-term HRV recordings. Parasympathetic breathing is present in GE when the respiratory rate is less than 9 breaths per minute. And E is calculated in square milliseconds (mog). (4) High frequency (HE) is the spectral power density in the range between 0.15 and 0.4 Hz.

This value reflects parasympathetic activity. NE is also known as the "respiratory" component because it corresponds to changes in the MM intervals caused by breathing (a phenomenon known as respiratory sinus arrhythmia (RsA)). Heart rate increases during inhalation and decreases during exhalation. NOT calculated in milliseconds squared (mog). (j) The ratio GR/NE is the ratio between the spectral power density in the range of GE and NE. This indicator reflects the overall balance between sympathetic and parasympathetic activity. High values of this indicator indicate the dominance of sympathetic activity, while the lowest - parasympathetic. The GE / NE ratio is calculated in normalized units. (Y) Normalized low frequency (I E pogt) is the ratio between the absolute value

YIR and TR without MIR. This measure minimizes the effect of total spectral power and emphasizes changes in sympathetic regulation. NO. E pogpt is calculated as a percentage. (94) The normalized high frequency (NOT pogt) is the ratio between the absolute value

NE and TR without MIR. This indicator minimizes the influence of MI E in the total spectral power and emphasizes changes in parasympathetic regulation. The interest rate is calculated as a percentage.

HRV frequency parameters are calculated from??? power spectral density (PO), which is calculated using the fast Fourier transform (FFT). (5) Respiration rate analysis procedure. The purpose of this test is to evaluate the parasympathetic branch of the autonomic nervous system. The test provides positive stimulation of the parasympathetic regulation of heart rate.

During the test, the patient is asked to breathe deeply and evenly at a rate of 6 breaths per minute. During the test, it is very important to exclude any circumstances that may affect voluntary breathing, such as talking, coughing, yawning, etc. Such interference can cause unwanted fluctuations in the heart rate and distort the results. The patient was asked to breathe for 1 minute according to the movement of the object shown on the screen.

The following test parameters are calculated: 1. Minimum NC (bpm); 2. Maximum NC (bpm); 3. Standard deviation of NC (beats/min); 4. The average ratio of NC tach / NE tip (EL ratio); and 5. Maximum NO deviation during the test (bpm).

(b) Orthostatic test procedure. The purpose of this trial is to assess the effects of parasympathetic regulation of heart rate. The test is based on changes in the patient's body position. The patient should sit relaxed. After recording the heart rate for one minute, the patient is asked to stand up without any sudden movements. The patient remains standing for another minute.

Heart rate is monitored throughout the test. The purpose of recording the baseline and stand-up is to assess the process of the unstable transition of the heart rate caused by a change in body position. Heart rate is monitored until stabilization.

The following test parameters are calculated: 1. The 30:15 ratio (which is the ratio of the maximum heart rate during the first 15 seconds after standing up to the minimum value of the heart rate during the first 30 seconds after standing up or in response to physical exertion, units). 2. The time to obtain the maximum NO value after recovery (or reaction time, sec.). 3. The time of obtaining NC 75 95 from the initial level (or stabilization time, sec.). 4. Minimum value of NC (beats/sec.). 5. Maximum value of NC (beats/sec.). (7) Self-assessment of functional status (M/VAM). This test enables numerical characterization of three types of subjective state: well-being, activity and mood (M/VAM), which are determined using a special form. The form contains 30 pairs of words with opposite meanings, and between them - a rating scale.

Depending on the subjective self-assessment of the condition, the patient notes the degree of a certain element on a 7-point scale. Number signs are deciphered: 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, the scores are recoded from 7 to 9 from left to right, and activity - from right to left. (Doskin et al., Test of differentiated self-assessment of functional state, Psychological issues, 1973, Mo.6b, pp. 141-145).

For each element (well-being, activity, mood) the arithmetic mean, its error and standard deviation are calculated. This provides an opportunity for a full assessment

From a subjective state. Arithmetic average is a direct subjective characteristic of the functional state and performance, and the validity of the obtained results can be determined by the amount of dispersion of estimates within one group of elements (standard deviation). (8) Psychometric tests. This test is performed using the OKO (Operator Operational Control) computer program developed under the Naval Personnel Health and Fitness Program for

of the Central Research Institute of Shipbuilding under the Ministry of Defense of the Russian Federation under the leadership of Prof. V.Yu. Rybnikova.

The following psychophysiological parameters are determined: - Reaction to a moving object (KMO); - Simple motor reaction time (SMR); - Volume of attention (KA); and - Stability of attention (AB).

Given the high variability of psychophysiological indicators, measurements are carried out several times, after which the arithmetic average for the entire series is determined.

In particular, the assessment "MKT was repeated 50 times, KMO - 20 times, KA and A5 - 5 times.

In the course of the CMO analysis, the number of hits on the target was also calculated for 20 values, and then the percentage of hits.

During the analysis of A5, the average time of the test was studied, the number of correct answers as a percentage of the total number performed by the subjects.

In order to combine indicators, the factor of stability of attention (AZE) was measured, which was calculated by dividing the percentage of correct answers by the average time of the test. (9) Reaction to a moving object (EMO). The reaction to a moving object makes it possible to determine the accuracy of the patient's response to stimulation and to assess the balance between the processes of excitation and inhibition in the cerebral cortex. The presence of a reaction is necessary to stop the rapid movement of the object at a preset point. To do this, you can use an electronic stopwatch, which the researcher will turn on remotely, the second hand of which the patient must stop exactly at the "0" mark by pressing the button on the control panel. This test can also be performed using a special computer program on a PC. The patient's reaction can be premature - the needle of the electronic stopwatch has not reached the "0" mark, late - the needle has crossed the "0" mark, accurate - the needle has stopped at the "0" mark. Each early or late reaction has quantitative characteristics in absolute units. To evaluate the results of the completed tests, the relative accuracy of the answers is calculated (in 9% of the total number), as well as the average arithmetic and average algebraic value of the deviations of all demonstrated reactions. (Zheglov et al., Delay in working capacity of personnel of the naval forces. Manual for doctors, 1990, p. 192). (10) Time of a simple sensorimotor reaction to a light signal or a simple motor reaction (ZMEAT). The time of a simple motor reaction is a method of characterizing the strength of nervous processes.

With a simple sensorimotor reaction, two mental acts are distinguished: the ability to perceive (sensory moment of reaction) and reactive movement (motor component).

Assessment of BMKT can be carried out in a traditional way (with the help of chronoreflexometers), as well as with the use of special computer programs. Before the test, the researcher explains the rules of the test to the patient. Then the patient is asked to sit on a chair, place his hands on the table in front of the chronoreflexometer and place his finger on the corresponding button. When the patient is ready, the research doctor gives the command, and after 3-10 seconds turns on the device. The patient's task is to press the button and turn off the light bulb as soon as possible after the start of the signal.

The time of a simple motor reaction is measured (in milliseconds) from the moment a special object appears on the monitor screen, before the patient presses a button on the manipulator (keyboard or mouse). 5MKT is measured, as a rule, 50 times, after which the arithmetic average of the indicator is determined. (Zheglov et al., Delay in working capacity of personnel of the naval forces. Manual for doctors, 1990, p. 192). (11) Harvard step test. This is a functional test that makes it possible to detect the reaction of the cardiovascular system to undesirable phenomena, in particular, to the effect of accelerations on

Coriolis. The 2-minute Harvard step test was used (V. L. Karpman et al., 1988; Novikov et al., Research methods in the physiology of military personnel.

Handbook, 1993, p. 240).

The method is based on the assessment of autonomic changes during squats and the body's ability to normalize heart rate.

The value of the step test characterizes the speed of recovery processes after intensive muscle work. The faster the pulse recovers, the lower the value (P2-P3--P4) and, accordingly, the higher the step test score.

As a rule, this indicator is higher in athletes than in others. The indicator may change in patients with drug addiction. At the same time, an increase in the indicator indicates that the drug increases the body's functional reserves and the ability to tolerate the negative impact of the environment, including kinetic action.

The test is carried out as follows: the patient squats for 2 minutes at a speed of 30 times per minute. On the 2nd, 3rd and 4th minutes after squats, the pulse is measured during the first 30 seconds of each minute. The value of the step test is calculated using the formula: indicator according to the Harvard step test - T x 100 / (P2-RZRAUI)2, where T is the squat time in seconds; Rg, RZ, P4 - pulse rate on the 2nd, 3rd and 4th minutes of the recovery period, "- multiplication sign.

Given the fact that the drugs are prescribed to persons prone to locomotion sickness, including drivers, their safety was evaluated when persons performed the functions of a responsible operator. In order to determine the key prognostic factors regarding the quality of the activity of operational species, a detailed study of the functional state of the central nervous system was conducted (for example, the state of coordination and reaction systems, systems that ensure high efficiency of fine motor components of activity, as well as attention systems). (12) Stange test. Stange's test is that the patient holds his breath after three exhalations for 3/4 of the full depth of inspiration.

Before the start of the test, a clip was put on the patient's nose, or the patient covered the nose with his fingers. The period of time during which the patient could hold his breath was measured using a stopwatch. (Zheglov et al., Delay in working capacity of personnel of the naval forces.

Guide for doctors, 1990, p. 192.

The test can be performed twice with intervals of 3-5 minutes between measurements.

The evaluation is carried out on the basis of the duration of the breath hold as follows: - less than 39 seconds. - unsatisfactory; - 40-9 sec. - satisfactory; - more than 50 seconds. - fine.

(13) Hench's test. Gench's test consists in the fact that the patient holds his breath on exhalation after three exhalations. (Zheglov et al., Delay in working capacity of personnel of the naval forces.

Guide for doctors, 1990, p. 192). When performing the Hench test in the supine position, the duration of breath retention in healthy subjects is 25-30 seconds. When the test is repeated after walking (44 m in 30 seconds), the duration of breath retention decreases to 17-22 seconds, and with functional defects of the body - to 5-15 seconds. The evaluation is carried out as follows: - less than 34 seconds. - unsatisfactory; - 35-39 sec. - satisfactory; - more than 40 seconds. - fine.

In one aspect, the present invention is a combined medicinal product containing a) an activated potentiated form of an antibody to MO-synthase and B) an activated potentiated form of an antibody to brain-specific protein 5-100. As stated above in this document, each of the individual components of the combination is well known and widely used in medical practice. However, the inventors of this application 3 surprisingly discovered that the introduction of the combination is useful, in particular, in the treatment of dizziness of various etiology, motion sickness and vegetative-vascular dystonia.

In another aspect, the invention presents a method of treating vegetative-vascular dystonia and its symptoms by introducing an activated potentiated form of antibodies to brain-specific protein 5-100 simultaneously with an activated potentiated form of antibodies to endothelial

MO-synthase in ultra-low doses of affinity-purified antibodies.

If possible, for the purpose of treatment, the combined drug should be administered from 1 to 4 times a day, with each administration using one or two combinations of standard dosage forms.

The medicinal product according to this application, intended for the treatment of vertigo of various etiologies, motion sickness and vegetative-vascular dystonia, contains active components in large quantities, mainly in a 1:1 ratio.

In order to treat dizziness of various etiologies, motion sickness and vegetative-vascular dystonia, the components of the drug can be administered separately. However, preference is given

From the simultaneous introduction of the combined components in one form - a solution and/or a solid dosage form (tablets) containing an activated potentiated form of antibodies to brain-specific protein 5-100 and, accordingly, an activated potentiated form of antibodies to endothelial MO-synthase.

In addition, during the treatment of vertigo of various etiologies, kinetosis and vegetative-vascular dystonia, it is possible to separately and simultaneously use (introduce) the declared medicinal product in the form of two separately prepared products, both in the form of a solution and in a solid medicinal form (tablets), each of which contains an activated potentiated form of antibodies to endothelial MO-synthase or protein 5-100.

The drug is mainly prepared as follows.

The combined medicinal product according to the present invention can be in solid or liquid form. Each of the activated potentiated forms of antibodies contained in the drug is prepared from the original molecular form of antibodies using a process adopted in homeopathic practice. The starting antibodies can be monoclonal or polyclonal antibodies prepared according to known processes, for example as described in the literature:

Immunological methods, H. Frimel, M., "Medicine", 1987, p. 9-33; "Nit. Apiirodievs. Moposiopai apa gesotbipapi apiibodiev, 30 uyeagz apyeg, Ganu E., Zodoueg V. - 2005-Moi. 14. - M 1-2. R.33-55, which are included in this document by reference.

Monoclonal antibodies can be obtained, for example, using hybridoma technology.

The initial stage of the process involves immunization based on principles previously developed during the preparation of polyclonal antiserum. The next stages of work include the production of hybrid cells that generate clones of antibodies with identical specificity. Their separate isolation is carried out using the same methods as in the preparation of polyclonal antisera.

Polyclonal antibodies can be obtained by active immunization of animals. For this, suitable animals (for example, rabbits) are given a series of injections of the appropriate antigen: brain-specific protein 5-100 and endothelial MO-synthase. The immune system of animals produces appropriate antibodies that are collected in animals in a known manner. This procedure makes it possible to prepare a monospecific serum saturated with antibodies.

If desired, serum containing antibodies can be purified, for example, by affinity chromatography, fractionation by salt precipitation, or ion exchange chromatography. The resulting purified, antibody-saturated serum can be used as a starting material for the preparation of an activated potentiated form of antibodies.

The preferred concentration of the obtained initial solution of the antibody in the solvent, preferably water or a mixture of water and ethyl alcohol, varies from approximately 0.5 to 5.0 mg/ml.

A preferred procedure for the preparation of each component is to use a mixture of three aqueous-alcoholic dilutions of the primary antibody matrix diluted 10072, 10039, and 100200, respectively, which is equivalent to a hundred homeopathic dilutions

C12, C30 and C200. To prepare a solid dosage form, the solid carrier is treated with the necessary dilution obtained by the homeopathic process. To obtain a standard dosage form of the combination of the invention, the carrier mass is enriched with each of the dilutions.

Both saturation orders are suitable for the preparation of the desired combined medicinal orma. ? in a preferred embodiment, the starting material for the preparation of the activated potentiated form containing the combination of the invention is polyclonal antibodies to brain-specific protein 5-100 and endothelial MO-synthase as a starting (matrix) solution having a concentration of 0.5 to 5.0 mg/ ml and used for further preparation of activated potentiated forms.

If possible, polyclonal antibodies to brain-specific protein 5-100 and endothelial MO-synthase are used to prepare the drug.

Polyclonal antibodies to endothelial MO-synthase are obtained with the help of an adjuvant as an immunogen (antigen) for immunization of rabbits and a whole molecule of bovine endothelial MO-synthase from the following sequence:

SEQUENCE 5EO IO Mo. 1

Mei Siu Avzp Yeey Yub beg Ma! Su Sbip Si Rgo Siu Rgo Ro sSuv 1 5 10 15

Spu Yeey Su Yeey su Yeey sSiu Yep sSiu is Sub Siu Yub ip spiu 16 20 25 zo

Rgo Aa oBZeg Ro Ai Ro bii Ro ego Ag Aa o Rgo Aa Rg Aya

From 35 40 45

TA Rgo Nie Aia Rgo Avr Niv bBeg Rio Aa Rgto Abp o beg Rio Tig 46 50 55 bo

Hey Tig Ag o Rgo Rgo Si Su Ro Guz Re Rgo Ag Ma! Guz District 61 65 70 75

Ter Sish be o sbuveg Ne Ti o Tug Abzr o Tb o Yeey Sub Ada o sSipo beg 76 80 85 90

Sip Sip Avr Su Ro Suz Tpg Ro Ag Suz Suz Is Siuveg ey 91 95 100 105

Mai Yei Rto Ag (uz (Ge bip To Ag o Rgo bBeg Rio Siu Rgo Ryu 106 110 115 120

Ro Aga Si bip o be) Se beg obip Aa Ag Azr Re Ne Avp aip 121 125 130 135

Tug Tug Beg Zeg Ne Yuuz Agd bBeg S.uveg Sip Aa Nie Si Si 136 140 145 150

Ah9 Yey SSip and Ma! bi Aha o Si Ma! Aa oobeg o Tygo sSiu TAgo Tu 151 155 160 165

Ni5 Yey Ag Si bBeg (ish Yey Ma! Rpe siu Aa Guz ip Aa Ter 166 170 175 180

Aha Avp Aa Rgo Aha Subz Ma! Su Ag Ne Sbip Tr su Ace Ace 181 185 190 195

Sip Ma! Rpe Avzr Aa Ag Avr Sub bBeg bBeg Aa Sip Si Mei RNe 196 200 205 210

TA Tug No Suz Avp No No Guz Tug Aa Tpg o Abp o Agu spu Avp 211 215 220 225

Hey Agd Beg Aa Ne To Ma! Rpe Rgo Sbip Ag Aa Ro su AF 226 230 235 240 suuu Avr RPpe Aga Ne Tr Abp bBeg SSip Ge Ma! Ag Tug Aa spu 241 245 250 255

Tug Agu oSbip o bii Abro Sbiuveg o Ma! Agu Siu Abr oRgo Aa o Avbpo Mai 256 260 265 270

Sim Ne Typ sei Sat Ne Sbip o Niv Siu TtroTyb o Rgo spu Avp 271 275 280 285 suu Ag RPpe Avr Ma Ieyy Ro Ieyy Ieyy Ieyy bip Aa Rgo Avr aiiy 286 290 295 00

Aa Ro bii Ge Rpe Mai Yey Ro Rgo Sish Yey Ma Yey Si Mai 301 305 Z10 315

Rio Yeey Si Niv Rgo Tyg o Yeey siy Tr RNne Aa Aa Yeey su Iey 316 320 325 30

Ag9 Tr o Tug Aa ey Rto Aa Ma bBeg Ab5p Mei Ge Ge Si Ne 331 335 340 345

Spu Siu Yiei bi Re bBeg Aa Aa Ro RNnNe be Siu Tr Tu Mei 346 350 355 360 zeg Tig bi Ne su Tig Ag AbpoYei Suz Avr Rio Nibv Ag Tug 361 365 370 375

Avp Ne Gay ish Abzr Ma! Aa Ma Sub May Av5r Ge Avr Tip Ag 376 380 385 390

TA Tig o Beg BZeg Hey Tr uz Avr Yub AiIa Aa Ma! Si No Avp 391 395 400 405

Yi ey Aa Ma! Hey oh Nibye Beg RYPe bSip Ge Aa uz Ma! Tib Ne Ma! 406 10 415 420

Avr Nie Niz Aa Aa Ti Ma! beg Re May Yuz Niv is Avr Aup 421 425 430 435

Sim Sip Gubv Aa o Ag o sSiu Su Suz Rgo Aa Ab5r Tr Aa Tr Ne 436 440 445 450

Mai Ro Ro Ne beg Sbiuveg Ge Tib Rio Ma Ripe Nibz ip am 451 455 460 465

Mei Ma! Avzp o Tug o Ne Yey beg Ro Ag RNiNe Aga Tug ip Ro Agr 466 470 475 480

Ro Tr Guz stu Bek Aa Ti o Yuz siu Aa Su Ne Ti Ag Guz 481 485 490 495

Guz Tig o Rie Guz Si Ma! Aa Abp Aa Ma Tuz Ne obeg Aa 5eg 496 500 505 510

Ye ey Mei (u TiIg Se Mei Aa (uz Ag Ma! Guz Aa Tipb Ne Iey 511 515 510 525

Tug Aga obBeg shi Tig o sSiu Agdu Aa bbip o bego Tu o Aa o Sip ip iey 526 530 535 540 syuu Ag Gay RPe Aga uz Aa RPpe Avr Rio Ag Ma Gay Suz Mei

BA 545 550 555

Azr Siy oTug Avzr Ma! Ma! run o Hey fight Ni bi Aa Yeu Ma) Hey 556 560 565 570

Mai Ma! Tigb obeg Ty o Rpe sSiu Abp o Su AbzroRgo Rgo ssh Avzpo stpu 571 575 580 585

Sim Zeg Re Aa Aa Aa eat Mei Si Mei beg (in Rgto Tug Avp 586 590 595 600 zeg Zeg Rgo Ag Rgo Si obip o Ni Sub bego Tu o TGTubv Ne Agu Re 601 605 610 615

Avp Zeg Ma! BZeg Sub bBeg Avr Rio Yeey Ma Beg be Tr Ag Ag 616 620 625 630

Guz Ag Guz bij beg beg Avzp o TIg o Abrobeg Aa o Siu Aa Yeey sSpu

631 635 640 645

TA Yey Ag RiPe Sub Ma Re sSiu Ge stu bBeg Ag Aa Tu Ryu 646 650 655 660

Ni5 Rpe Suz Aa Rpe Aa Agu Aia Ma! A5r Type Ag He spy Sp 661 665 670 675

Ye ey Siu (u bi Ag Se o Yeey bij Te Siiu bip o stu Ab5r am ey 676 680 685 690

Suvz SI oSbip o bii bii Aa Rbe Agd Su Tr o Aa Guz Aa Aa Ree 691 695 700 705

Sip Aa bZeg Suz Si Ti Rie Subz Ma! Siu Si ish Aa uz Aa 706 710 715 720

Aa Aha oSbip Abvr o Ne Rpe beg Rio Yub5 A bBeg Tr Ace Ag9 daip 721 725 730 735

Ag9 Tug Ag Gay bBeg TYg o beep Aa bij sSiiu Te) o beep Yee Hey Ro 736 740 745 750 siuu Yeey Ne Nibye Ma! Ние Агд Аг иЮу5 Мей РНпе sSip Aa TNgo Май 751 755 760 765

Hey Zeg Ma! (by AbpoYei beep o beg bZeg Tuv bZeg TT Ag Aa Teg 766 770 775 780

Not Yei Ma! Ag (esh Avr TP Aa Siu oSSip Si sSchu Yey ip Tug 781 785 790 795

Sip Rgo SCHYau Avr No No Sbiu No Sub Rio Rio Av5p Aga Rgto aitsu 796 800 805 810

Hey Ma! Si Aa yYeyy yeyy o beg A Ma! Si Azr o Ro Rgo Ro Ryu 811 815 820 825

TA Si beg Ma! Aa Ma ish biy Yee bi Tuz Siuveg Ro au 826 830 835 840 syuu Rgo Rgo Rgo bZeg Tr Ma! Ag Abr Rio Ag Gay Rgo Rgto Suzv 841 845 850 855

TA Yey Ag Sip Aa (es PTb Re Ripe Ge Avr Ne Tigb o 5Beg Ro 856 860 865 870

Rgo871 Zeg Rio Ag em Yeey Ag Yeey Yeey beg TYg o Yeey Aa Csi 875 880 885

Rgo Zeg (Yam oSbip o bip o Sb be bij TyboiTei beg Sip o Avr Rgo Ag 886 890 895 900

Ag9 Tug abi bi Tbfroiuz Tr o Re Ag Sub Rgo Tipg Yeey Hey si 901 905 910 915

Mai Yey Si bip Re Ro bZeg Ma! Aa Ge Rgo Aa Ro Gey Ieyy 916 920 925 930

Yi ei TNg Sip Hey Rgo Ge Ge bip RgoAgd Tug Tug ze Mai beg 931 935 940 945 zZeg Aia Ro Avp Aa Ni Rgo Su Si Ma! No. Tag o Mai Aa 946 950 955 960

Ma ey Aa TugAga TVgo bip o Azro Siuiei sSiu Rgo Gesh Nizv Tug 961 965 970 975

Siuu Mai Suv Zeg TI o Tr Gay bBeg Sipiesh Gubv Tygo sSpchu /Avr Ro 976 980 985 990

Ma! Rgo Sub Rypeye Aga su Aa Rgtobeg Rpe Ag ey Rio Rgo 991 995 1000 1005

Ar Rio Tug MaiRgo Sub Ne iYiei Ma Sbiu Ro ssiu Ti spiuNe 1006 1010 1015 1020

Aa Rgo Rpe Ag sSIu Ripe Tr Sip SishAgu Ge Nie Av5r Ne am 1021 1025 1030 1035 zeg Guz Su Hepbip o Rto Ai Rgo MeiTIg Yiei Ma! Re au sSuzv 1036 1140 1145 1050

Aha Suz Zeg Sipiey Abr Niye Yeiey TugAtg4 Azr ssh Ma) ip A5r 1051 1155 1160 1065

Aa Sip Sish AF iu Ma! Re sSiu Ag Ma Ge Tb Aa 0/0 Re 5eg 1066 1170 1175 1080

Agu Si Ro Azrbeg Rgo Shiub Ti o TugMa! Sip Abr Ne Ge Aga 1081 1185 1190 1095

Tig am Yeey Aalia Sish Ma Ni Ag Ma Yeey Sub Yeey ay 1096 1100 1105 1110

Sipu Nib Mei Rpe Ma! Suz Siu Avzr Ma Tii o Mei Aa Tygo 5beg Mai 1111 1115 1120 1125

Yey Siip Ti Ma!Sbiy Ag Ne Yey Aa Tig o Si sSiu Azr o Mei Si 1126 1130 1135 1140

Yi ei A5r Siy Aasiu Abr Ma! Not siuMa! Ge Ag Avr aipdaiip 1141 1145 1150 1155

Ag9 Tut Ni SbishAbr Ne Rpe Siu Hey Ti Ge Ag Tygo apa 1156 1160 1165 1170

Ma! Tit Zeg AgaYie Ag Tig o bip o begRye o bBeg Yeey Sip Sm Aga 1171 1175 1180 1185

No Gay Ag sSchuAia Ma! Rgo Tr o AaRpe A5r Rgto Rgo aizuR'go 1186 Rgo 1190 1195 1200

A5r TNg Siu Rgo 1201 1205

Polyclonal antibodies to MO-synthase can be obtained using a whole molecule of human endothelial MO-synthase from the following sequence:

SEQUENCE 5EO IO Mo. 2

Me ry Keats muye beg ma Av sv o U Bgto Rg Sug i 51 du ivy Su vy bu svo SU vo Su Suv Ou u SU Ou ha aa tv Re Av obo b Bgto sheeg At Or bgto Av o beg em

Z 35 shcha 46 yiv to Red div b se Vi beg Rg to Zeg lakes BO Se b 45 5 what BO

Siv Be te Si Su Bo fu Rebe to Ag MI uv Aa TS zvi Suvaeg Me Ti Tug o Avo Ti o beo Zeg AV Op Av b s

That's Vo va va

Ave OS Robuyn: Because AshshchAyu is biuveg in Uvi Re shchi 95 and Te

Rge YAZ fu iiu biv ОЙ Ag bgto bab bo SZu Rgo Bgto Av bo 15 te 115 150

C Si bez yeets Zeg biy Az o Atroavr be Me ABa Ot Tug Tu 121 Tikha 155 155

Veg beg Ne (uz Ag Zeg biuveg p Av Mi oS st A ev 325 45 145 ne siy siv Mag bib Av obi Mai Av Av o b biu yiv Sat Sv ivu

Ta5 150 185

Ag Z be Zi fey Uvi be ZU AV fu« (Z di TT Ah dep tv 17 175 188

Viv Bo «b sSuv Ua! In AvoNe b bro bu Buv fe Z Uvi 183 185 15 195 ne AvBr o Av o Aa Av oSuv Ag Zeg Av o sbchYa be Me be Tk oi 196 OO Ov 21

Ne Suz dep Nv Ne iue Tu Av bit Av At si Av be At 1 15 tai EV shcheg AV Me run Uvi Rne bo siy Ak was Ro Su du ZU Az ku 230 "5 seh

Re Av MNe Tpo Avp o Zeg Zi fe Ua! Ach Tu Av OB Te Av i 2-45 aka Vb biz iy dvo biu god Uvi Ag: Ob Ar bo A shi Uvi b Ne

BV go 205 0

TNE Siv yeu was Ne Zi Ni Su Tr bib Ro bu Ap Ou Ag 273 at 2VO 255

Rne Avr o svi b fs) be fe) Op AB o bho Azo ZSH be Rub

VA 2 255 c) div ivy be iv in biz Res si iv Uvi Sem Si mV bo iv kt zo5 Zo ziv azy Met t tvien Z bt5 ve div AV fe) bu iv AT Tv

ZV Z2o Zeo Kk

TU Av o cey Ro Av UVI be Avp Mer fe) be) Si Ne Ou su aa 335 Za B

Ge S be bo Action Av o bto be bag Su To Tu Meb bek Te

In zo 8 ZO

OIV No (in TR Ag vp ivy was yer to No Ag tugo Aesv No

I SHY VE g. we 475

Key S-Zy Av Mi Av Uvi Suv Mer Avr oiei Avo oi Ak TVO

ZV Zo ЗB ZO beg bag oiey ytroiuv era Av A UVE SM Me Aza ma AV

From ZoE 00 OB

Ua Kay Ni bBeg Tu bij iv Av ofuz Ua ila Ne Mag Yazo Me

В чо 415 а2й

NE Av Aa blih Av obeg Rbe Me uz Ni be) bib Aza b bi

By 455 430 "35 iv dia Ag Ou Zi Suv Mt Av Ar Te A bt Ne Uvi bo 435 "40 av zo go Ne bab biuvag be To Re ma be Nv obi Ob Me ma "5 455 BT "5

Av Tut Re be be R Av Re A: Bug iy BT Avr bro Tr sce ato 475 that iuue SU Beg Av iv fu Su Tezh o biu Me tb At was bu te "schi cha cho "scha

Na yuv Syp Uvi Ai Aza Av o Uvi fuv Me Zeg Az bee Bey Ma av 5sh BOB mo

MU TVg Ue Me Av iuv Ag Uvi fuv Av yii Ne yiv tya Z

Vii viv viv 55 ag Siv Ti Si Ag Av o siy be TU Av Yev b oiveo Su Az pra 5 535 I iv Bne Ag fuv A o Bpv Or bo AYU OM ivy was Me Akro Z

BA sorrel Ba EV

Here Avo UVI Mag obegb iv Siyu" MB about TV: fe Ma o beo Uvi Ua!

Be 560 555 Bl

Tag beg her be bib Akp ZU Ar obto Bo M Avo bizh bi beg

575 that 585 ke Av Aa AV oiayu MeEb Ve Me obegb SNU Re tTub Ave beg be

BOB BO keV OO

Ego ag bo byu bij Me oiuv Zb, TU fu Ne 4 Re Azp beg

VO 0 VoB a viv

Not Zag was Zeg Or R iv Ma bag beg Tr Ag Ap (uv Av vv ve0 schoV 5 and uv S be bes Aa TTG oder o begb Av o biU Ai o ivo bu Tv ovo 53 55 5lO Vk I Be was uma! Re slu is Siuveg Ash AV TU be vv Be still Bo 055 what

Suv Av RNe Av yo Av May o Azho Teg Ame ee oi b ber ЕЮ more Vb Yato Buk

Ou Xiu Azh i) ieu bij ivgu Si» byu Mu dov Z Sv bu S;

BIV B wai B viv sv obi a be Ag Si To Av osa AB Av Be b dia schi what she ee

Av Suk Siyu TNb Re Suye mai YeiU So Avr A o iiuv Av o Av o Av

Co., Ltd. 710 15 TO

A der Ne ne beg R iuv AeroZaeg To iuv At dyi JSC cha t | 30 w

Av iv) beg liv s AV O EMO SU iv biv ish g SU 18 738 TE 4 t

On Mi Uvi niv A Ag; was Me bne em yAbFa her be Aga be

TE 756 that 85 mV Ob Av yiv biy be be gub Z Te Av Av o tTVkK Ne ev va 7 TV to cha y ivou Az TE su SO sa sho S fvb Zm yuub ba RR

And 755 and 5

Oh two Mi Me su Mag Suv t bo Ap Agrobto bu Svu Ma 6 shOy 5 vo

SO Aa ivo ivz bob Abromai Si Avo Ro be Abo Bu Tg b 81 815 that OB

Be uv Av Ua b bi ben SV was in Beg bto bu bu o shchi Wo 535 Va

Ro be St Ttrome o Ayushkr Avr tu Agriets Bo be was TE fen shchav o. Ba y SZiy Av fe her Be Bebv ben Avo Me her o Zshsh B Br es that 85o | that 878

Eto Si fe ben Abo fe be) beg TVg obebv Av oyu b Ro Ag

NO What for

OO sZyt ost ssh o feo b Av oishcho be St Av oyu Az ma bug b ee what OO

Si Sp: o Tpo would be Re Ag was bo That same o jeeb iv So Udi vbeu schi vo ev ov

BE Siv be be byug o Mi Av obo b Av be yiv yeu vy be ma zh ev 930 et Ken biz vo imm Zi bo Ag Sub Te beg Uvi bBeg tsee Av shcha shk o pah

Re beg TE Ne Be S Ob Me Bo obeb TE Ma Av Oa Kwu av oko wa Oko

In TU Ag tlie beep Ave Si web bi b fen o Nia Tub snu MY va 25 97 i

Su Zeg TNe her Sam beg byu iz buye bo Ob Or bez ma bo ov ZO sova VO

Suk Rne Che Amos Av obto beg Re Apu vo che 3 Ar Re

Chem dob 1 to go Azov Avp o Rtoikhuv Tig TU Uzi di OR Me vi Avo Te oyu shchi 5 NN To ee Av Ma Zi ua! M Ag Ua iveibSuv iv b Ah SU Ne 1996 tyu tyu o

Ma Re uwai Suv bi Aza Ma Tebe Meb Av TVi Aza Uvi feno Ziv i TV 5 1195

Tne Uvi bi Abe ate Az be bo sYau Avr o Me Zi be Abe 1198 o m 14o (y did S AvoUya Me su Uzi iz Ap; Av b schYaa Ag TUug

You are 145 EE 155

No S Av onNebne Si fsho Tab o BemAtschr o tnR b sia mabtne shcha 1100 1155 ie

BE AYU Ne At bib beg be Begivn biv b Azh o Ovivits 1173 t Uv To t1v5

Aha Wu AV ovi to tr AV obne Or Re bo Ou begb odev TE 105 B 3150 1155 tva dvy bag 50

TM Z

Beg es bo was Me fe) Uvi su b Ou Te OB Me Av be tov 1 18 more

Vne Aga SHuU bra itr o Sp Ye Ag iv Miv Avo Me bib beg uv sche Ta 103 TZ syau iv sib B Tv. bo Me b vi i Be SOU Saiv AYU Sa 55 114 114 105 -g si ben Avo Niv iv o TUug Ag o Ao EM MV b Avp Av osi

To TV TV 106 actions in Si; Ua be bi" AtroMar o fvy TT Or Re Zeg AYU S 8 117 117 108

To obtain polyclonal antibodies to MO-synthase, it is also possible to use a fragment of endothelial MO-synthase, selected, for example, from the following sequences:

SEQUENCE 5EO IO Mo. WITH

Rgo Ter AiIa Rpe 1192 1195

SEQUENCE 5EO IO Mo. 4

Su Aia Mai Rgo 1189 1192

SEQUENCE 5EO IO Mo. 5

Ag9 1185

Niv I ey Ago Su Aa Mai Rgo Tgr Aa Rne Azr Rgo Rgo Siu Rgo 1186 1190 119 1200

Azr Tig Rgo apu Rgo 1201 1205

SEQUENCE 5EO IO Mo. 6

Aa RNe Ar Rgo Rgo au Rgo 1194 1195 1200

Azr Tig Rgo apu Rgo 1201 1205

SEQUENCE 5EO IO Mo. 7

No I ei Ago Su Aa Mai Rgo Tgr Aia Rpe Azr 1186 1190 1195 1196

SEQUENCE 5EO IO Mo. 8

Niv I ey Ago Su Aa Mai Rgo Tgr Aa Rne Avr Rgo Rgo Su Rgo 1186 1190 119 1200

Koo) Azr Tig Rgo apu Rgo

1201 1205

A typical procedure for preparing initial polyclonal antibodies to MO-synthase can be described as follows: 7-9 days before blood sampling, rabbits are given 1-3 intravenous injections to increase the level of polyclonal antibodies in the bloodstream. After immunization, blood samples are taken to detect the level of antibodies. As a rule, the maximum level of immune response to soluble antigen is reached 40-60 days after the first injection. After the completion of the first cycle of immunization, rabbits undergo a 330-day rehabilitation period, after which re-immunization is carried out with the help of 1-3 intravenous injections.

To obtain antiserum containing the necessary antibodies, the blood of immunized rabbits is taken and placed in a 50-ml centrifuge tube. Clots of the product formed on the walls of the test tube are removed with a wooden spatula, and a stick is placed to the clot in the center of the test tube. After that, the blood is placed in the refrigerator for 1 night at a temperature of approximately 4 °C.

The next day, the clot on the spatula is removed and the residual liquid is centrifuged for 10 minutes at 13,000 rpm. The supernatant is the necessary antiserum. The resulting antiserum is usually yellow in color. 20 95 MaMz (weight concentration) is added to the antiserum to obtain a final concentration of 0.02 95 and before use it is stored in a frozen state at a temperature of -20 "C (or without the addition of MaMz - at a temperature of -70 76). To separate the necessary antibodies to endothelial MO- synthase from the antiserum, the following sequence of absorption on the solid phase is suitable: (a) 10 ml of rabbit antiserum is subjected to a two-fold dilution of 0.15 M Mass, after which 6.26 g of Mag2505 is added, mixed and cultivated for approximately 12-16 hours at a temperature of 4 "С; (B) the precipitate is removed by centrifugation, dissolved in 10 ml of phosphate buffer and dialyzed against the same buffer for 1 night at room temperature; (c) after removing the sediment by centrifugation, the solution is placed on a column with DEAE-cellulose, equilibrated with a phosphate buffer; (4) the antibody fraction is determined by measuring the optical density of the eluate at 280 nm.

Isolated crude antibodies are purified using the method of affinity chromatography by attaching the obtained antibodies to endothelial MO-synthase, placed on the insoluble matrix of the medium for chromatography 3, followed by elution with concentrated water-salt solutions.

The resulting buffer solution is used as the starting solution for the homeopathic dilution process used to prepare the activated potentiated form of antibodies. The preferred concentration of the original matrix solution of antigen-purified rabbit polyclonal antibodies to endothelial MO-synthase is 0.5-5.0 mg/ml, preferably 2.0-3.0 mg/ml.

Brain-specific protein 5-100, expressed by neurons and glial cells (astrocytes and oligodendrogliocytes), directly or through interaction with other proteins, performs a number of functions in the central nervous system aimed at supporting normal brain functioning, including influencing learning and memory processes, growth and viability of neurons, regulation of metabolic processes in neuronal tissues, etc. To obtain polyclonal antibodies to brain-specific protein 5-100, brain-specific protein 5-100 is used, the physical and chemical properties of which are described in the article by M.V.

Starostina, S.M. Sviridova, Neurospecific protein 5-100, Progress of modern biology, 1977, volume 5, p. 170-178; in the book M.B. Shtarka, Brain-specific protein antigens and neuron functions, "Medicine", 1985; page 12-14. Brain-specific protein 5-100 is isolated from bull brain tissue using the following method: - bull brain tissue, frozen in liquid nitrogen, is turned into powder using a special grinder; - proteins are extracted in a ratio of 1:3 (mass/volume) using an extracting buffer with homogenization; - the homogenate is heated for 10 minutes. at a temperature of 60 "C, then cooled to 4 "C in an ice bath; heat-labile proteins are removed by centrifugation; - fractionation with ammonium sulfate is carried out in stages, with subsequent removal of precipitated proteins; - the fraction containing protein 5-100 is precipitated with 10095 saturated ammonium sulfate, which is carried out by lowering the pH level to 4.0; the necessary fraction 60 is collected by centrifugation;

- the precipitate is dissolved in a minimum volume of buffer containing EDTA and mercaptoethanol, the precipitate is dialyzed with deionized water and lyophilized; - after fractionation of acidic proteins, chromatography is carried out on an ion-exchange medium - DEAE-cellulose OE-52, and then DEAE-sephadex A-50; - collected and dialyzed fractions containing 5-100 proteins are separated according to molecular weight by gel filtration on Sephadex 5-100; - purified protein 5-100 is subjected to dialysis and lyophilized.

The molecular weight of the purified brain-specific protein is 5-100-21000 0. Due to the high concentration of aspartic and glutamic acid, the brain-specific protein 995-100 is highly acidic and occupies the extreme anodic position during electroendosmosis in the discontinuous buffer system of polyacrylamide gel, which facilitates its identification.

Polyclonal antibodies to protein 5-100 can also be obtained using a technique similar to that described for antibodies to endothelial MO-synthase, using an adjuvant. A whole molecule of protein 5-100 can be used as an immunogen (antigen) for immunization of rabbits:

Bychacha 5-1008 (SEQUENCE 5EO IO Mo.9)

Mei Zeg (bi Te ish SFub Aa o oMa! Mao Aa ysy Ne Avzr o Mai Riye 1 5 10 15

Ni5 Sip o Tub o Zeg Su Ag bi Su Avr o Tuz Ni Tuz Te Tub5 Guv 16 20 25 30 zeg Si Yiyei Tuz bi Yei) Ne Abp Abzp o Si Yei beg Niz Re Iiei

C1 35 40 45

Si Sish Ne o Gubv biy obip obi Ma! Ma! Abvr oiuz Ma! Mei siy Teg 46 50 55 bo

Y ey Azr beg Avr Su Abr sSchiu bij Sub Avzr RiPe Sipy Si RNe Mei 61 65 70 75

Ah Rpe Ma! Aa Mei Ne Tig Tit o Aa oSuz Nie Si Rne Rne a 76 80 85 90

No Sp 91 92

Lyudska 5-1008 (SEQUENCE 5EO IO Mo. 10)

My Zeg (y Yeeyy ish Sub Aa o My Ma Aa is Ne A5zr Mai/ RNe 1 5 10 15

No5 Sip Tug o bZeg sSiu Aga Sy Su Abvr o Tuz No Yub Yeey Tub5 Guv 16 20 25 30 zeg Si Yeeyey Guz biy Te Ne Abp Abzp o Si Yee beg Niz RNe Gay

C1 35 40 45

Si Sish Ne Guz Si obip o bii Ma! Ma! Abvr oiuz Ma! Mei si Tag 46 50 55 bo

Ye ey Azr Abvp o Abvr oSbiu Abr osSiu bij Sub Avzr Re Sipy Si RBe Mei 61 65 70 75

Ah Rpe Ma! Aia Mei Ma Ti o Tig o Aa oSuz Nie Si Rne Rne a 76 Sp 80 85 90

Niv 92 91

Lyudska 5-100A1 (SEQUENCE ZEO IO Mo. 11)

Mei 1 Siu be (ii Yiei bi Tho Aa o Mei Si TpgoiIie Ne /AvpoMai 5 10 15

Rpe Niv Aa Niye beg Spu iYuz bi sSiu Avr Tuz Tub Tubv vi beg 16 20 25 30

H uv uv bi Yeeey (uz biy Yey Hey bipo Tho biy Hey beg siu 0 Ree

From 35 40 45

Yi ey A5r Aa oSip o yuuz Azr o Ma! Azr Aa Ma! Ab5r oiub Ma! Mei Guz 46 50 55 bo

Sp Yey Avr ish Abp Siu Abr Siu bij Ma! Abr Re Sip Siy Tug 61 65 70 75

Ma! Ma yYeey Ma! Aa aa hey Tig o Ma! Aa buz Abzp Azp Rpe RNe 76 Si Abzpobeg 80 85 90

Ter 94 91

Bychacha 5-100A1 (SEQUENCE 5EO IO Mo. 12)

Mei Siu be (ii Yiei bi Tgo Aa o Mei Si TpgoiIie Ne /AvpoMai 1 5 10 15

Rpe Niv Aa Niye beg Spu iYuz bi sSiu Avr Tuz Tub Tubv vi beg 16 20 25 zo

Guz uv y Yeeey Sub bij Yey Yey bipo Tygb o si Yeey o beg sSiu 0 Ree

From 35 40 45

Ye ey Azr Aa o Sip o Yubz Azr Aa Ab5r Aa Ma! Abr Tuz Ma! Mei Guz 46 50 55 bo

Sim Yeya Avzr (shi Abp o Siu Abzr o sSiu bij Ma! Abzr Re Sip si Tu; 61 65 70 75

Mai Ma yYeesh Ma Aa Ag yYey Tit oh Ma! Aa Suz Abzp Abzp RnNe RNe 76 80 85 90

Tr Si Abpo Beg 91 94

To obtain antiserum, brain-specific 5-100 protein or a mixture of protein 5-100 (antigens) is prepared in combination with ethylated bovine serum albumin as a carrier substance with Freund's complete adjuvant and added to the isolated brain-specific protein 5-100, which is injected subcutaneously into the subject animal (rabbit) in the back area in a volume of 1-2 ml. On the 8th and 15th day, repeated immunization is carried out. Blood sampling (for example, from the ear vein) is carried out on the 26th and 28th day.

The obtained antiserum titer - 1:500-1:1000 - forms a single band of precipitation with an extract of nerve tissue, but does not react with extracts from heterologous bodies, and forms a single peak of precipitation both with pure protein 5-100 and with an extract of nerve tissue tissue, indicating that the antiserum obtained is monospecific.

The activated potentiated form of each component of the combination can be prepared from the original solution by homeopathic potentiation, if possible - by the method of proportional reduction of concentration by a series of dilutions of 1 part of each previous solution (starting from the original solution) in 9 parts (for decimal dilutions) or in 99 parts ( for hundredth dilutions), or in 999 parts (for thousandth dilutions - attenuation M) of a neutral solvent, starting from the concentration of the original antibody solution in the solvent, if possible, water or a mixture of water and ethyl alcohol, in the range from approximately 0.5 to 5.0 mg/ml , in combination with external influence. If possible, the external influence should include repeated vertical shaking (dynamization) of each dilution. If possible, separate containers should be used for each subsequent dilution to the required activity level or dilution factor. This method is generally accepted in homeopathic practice.

See, for example, V. Shvabe "Homeopathic Medicines", M., 1967, p. 14-29, which is incorporated herein by reference for its stated purpose.

For example, to prepare 12 percent dilutions (denoted as C12), one part of the original matrix solution of antibodies to brain-specific protein 5-100 (or endothelial MO-synthase) with a concentration of 2.5 mg/ml is diluted in 99 parts of a neutral aqueous or aqueous-alcohol solvent (if possible, 15 95 ethyl alcohol), and then vertically shaken many times (10 or more) to prepare the 1 hundredth

From dilution (denoted as C1). The 2nd hundredth dilution (C2) is prepared from the 1st hundredth dilution C1. This procedure is repeated 11 times to prepare the 12th hundredth dilution of C12. Thus, the 12th hundredth dilution of C12 is a solution obtained by 12 successive dilutions of one part of the original matrix solution of antibodies to brain-specific protein 5-100 with a concentration of 2.5 mg/ml in 99 parts of a neutral solvent in different containers, which is equivalent to a hundredth homeopathic dilution C12. Analogous procedures with the appropriate dilution factor are carried out to obtain C30, C50 and C200 dilutions. Intermediate dilutions to test activity can be tested in the required biological model. The preferred activated-potentiated forms for both antibodies that are a combination of the invention are a mixture of dilutions of C12, C30, and C200 or dilutions of C12, C30, and C50. When using a mixture of different homeopathic dilutions (first of all, hundreds) of the active substance as a biologically active component, each component of the drug (for example, C12, C30, C50, C200) is prepared separately according to the above procedure, until the penultimate dilution is obtained (for example , to

C11, C29, C49 and C199, respectively), and then one part of each component is added to one container based on the mixture of the drug and mixed with the required amount of solvent (for example, with 97 parts for hundreds of dilutions).

Thus, the activated potentiated form of antibodies to brain-specific protein 5-100 in an ultra-low dose is obtained by additional attenuation of the matrix solution, i.e. by 10072, 10039 and 100209 times, which is equal to the hundredfold solutions of C12, C30 and C200, or by 10072, 10039 and 10059 times , which is equal to hundreds of solutions of C12, C30 and C50, prepared according to homeopathic technology.

It is possible to use the active substance in the form of a mixture of other different solutions according to homeopathic technology, for example, decimal and/or hundredths (C12, C30, C100; C12, C30,

C50; 020, C30, C100 or 010, C30, M100, etc.). Efficiency is determined by the experimental method.

External treatment in the course of potentiation and reduction of concentration can also be carried out by means of ultrasonic, electromagnetic or any other physical influence accepted in homeopathic practice.

If possible, the combined medicinal product of the present invention may be in liquid form or in a solid standard dosage form. A preferred liquid form of the drug is a mixture, preferably in a 1:1 ratio, of an activated potentiated form of antibodies to endothelial MO synthase and an activated potentiated form of antibodies to protein 5-100. A preferred liquid carrier is water or a mixture of water and ethyl alcohol.

The solid standard dosage form of the drug according to the present invention can be prepared by impregnating a solid carrier acceptable in pharmaceutical practice with a mixture of activated potentiated form of aqueous or aqueous-alcohol solutions of the active components, which were first mixed in a ratio of 1:11 and used as a liquid dosage form. Alternatively, the medium can be enriched sequentially with each appropriate dilution.

Both saturation orders are acceptable.

If possible, the drug in a solid standard dosage form is prepared from granules of a carrier acceptable in pharmaceutical practice, which was previously saturated with water or water-alcohol dilutions of the activated potentiated form of antibodies. The solid dosage form can be in any form known in the pharmaceutical practice, including tablets, capsules, lozenges, and the like. Glucose, sucrose, maltose, starch, isomaltose, isomalt and other mono-, oligo- and polysaccharides used in the production of medicines can be used as inactive pharmaceutical ingredients, as well as technological mixtures of the above-mentioned inactive pharmaceutical ingredients with other auxiliary substances acceptable in pharmaceutical practice, for example, isomalt, crospovidone, sodium cyclamate, sodium saccharin, anhydrous citric acid, etc.), including glidants, disintegrants, binders and dyes.

Preferred carriers are lactose and isomalt. The pharmaceutical dosage form may additionally include standard pharmaceutical excipients, for example, microcrystalline cellulose, magnesium stearate and citric acid.

An example of the preparation of a solid standard dosage form is given below. To prepare a solid form for oral administration, 100-300-μm lactose granules are enriched with aqueous or water-alcohol solutions of activated potentiated form of antibodies to histamine, activated potentiated form of antibodies to endothelial MO-synthase and activated potentiated form of antibodies to protein 5-100 in a ratio of 1 kg of antibody solution for 5 or 10 kg of lactose (1:5-1:10). In order to saturate the lactose granules, they are subjected to saturation irrigation on a fluidized bed at a suitable installation (for example, "NISHIip

Riyuvnar" manufactured by Naship ztrN) with subsequent drying with a flow of heated air at a temperature below 40"C. The prescribed amount of dried granules (10-34 parts by mass) saturated with the activated-potentiated form of antibodies is placed in a mixer and mixed with 25-45 parts by mass of "unsaturated" pure lactose (which is used in order to reduce costs, simplify and accelerate the technological process without reducing the therapeutic efficiency), together with 0.1-1 mass parts of magnesium stearate and 3-10 mass parts of microcrystalline cellulose. The resulting tablet mass is homogeneously mixed and tableted by the method of direct dry pressing (for example, on a Kogesp-XI. 400 tablet press) to form 150-500-mg round tablets, if possible, 300-mg. After tableting, tablets of 300 mg are obtained, which are saturated with a water-alcohol solution (3.0-6.0 mg/table) of combinations of the activated potentiated form of antibodies. Each component of the combination used for infusion is in the form of a mixture of hundreds of homeopathic dilutions, preferably C12, C30 and C200.

If possible, 1-2 tablets of the declared drug are administered 2-4 times a day.

The combination of the activated potentiated form of antibodies to brain-specific protein 5-100 and the activated potentiated form of antibodies to endothelial MO-synthase in the medicinal product is prepared according to the homeopathic technology of potentiation by repeated further dilutions in combination with external mechanical action - vertical shaking of each dilution (see, for example , V. Shvabe "Homeopathic preparations", M., 1967, p. 14-29), which have activity due to potentiation technology within the framework of pharmacological models and/or clinical methods of treatment of dizziness of various etiologies, kinetosis and vegetative-vascular dystonia), which provides an unexpected synergistic therapeutic effect, confirmed on appropriate (valid) experimental models and in the course of clinical studies, which consists in increasing the effectiveness of the treatment of dizziness of various etiologies, kinetosis and vegetative-vascular dystonia. The above-mentioned technical result is provided by the strengthening of the neuroprotective activity of antibodies to protein 5-100, which is caused by the effect on the effectiveness of the interaction of ligands with the sigma-1 receptor, the vegetative stabilizing effect, the normalization of the state of the vegetative system as a manifestation of earlier unmanifested properties of the activated potentiated form of antibodies to brain-specific protein 5- 100 and synegic

Due to the effect of both components on neutral plasticity and as a result of this - due to the increase in the resistance of the brain to toxic effects, which improves the integration activity and restores the interhemispheric connections of the brain, facilitates the treatment of cognitive disorders, stimulates reparative processes and accelerates the recovery of the function of stabilized somato-vegetative manifestations, increases cerebral blood flow and, accordingly, provides an expansion of the therapeutic range of the drug and an increase in the effectiveness of the treatment of dizziness, motion sickness and vegetative-vascular dystonia of various etiologies, including vegetative-vascular dystonia, which is accompanied by an increase and decrease in blood pressure.

Moreover, the claimed drug and its components do not exert a sedative and muscle-relaxing effect, do not cause addiction and adaptation. The claimed drug can also be used as part of complex therapy.

Moreover, the claimed drug expands the range of drugs intended for the treatment of dizziness of various etiologies, motion sickness and vegetative-vascular dystonia.

In addition, the combined drug according to the present invention can be used for the treatment of attention deficit hyperactivity disorder, psychoorganic syndrome, encephalopathies of various etiologies, organic diseases of the nervous system, including stroke, Alzheimer's disease, Parkinson's disease. In order to treat the above-mentioned disorders, the combined medicinal product may contain active components in a volume ratio of 11. Thus, each component is used as a mixture of three matrix solutions (mother tincture) of antibodies diluted 10077, 10030 and 100200 times, respectively, which is equivalent to hundreds homeopathic dilutions (C12, C30, and C200), or a mixture of three antibody matrix solutions diluted 10072, 10030, and 10050 times, respectively, which is equivalent to one-hundredth homeopathic dilutions (C12, C30, and C50). The stated medicinal product is recommended to be taken, if possible, 1-2 tablets 2-6 times (if possible - 2-4 times) a day.

The declared drug, as well as its components, do not have a sedative and muscle-relaxing effect, do not cause addiction and adaptation.

EXAMPLES

Example 1.

Study of the effect of a complex drug containing ultra-low doses of activated and potentiated forms of polyclonal affinity-purified antibodies to a brain-specific protein

5-100 (anti-5-100) and endothelial MO-synthase (anti-eMmo5) rabbit, obtained by super-dilution of the original matrix solution (concentration: 2.5 mg/ml) (in 10072, 100350, 100200 times), which is equivalent to a mixture of hundreds homeopathic dilutions C12, C30, C200 (ratio: 1:1) ("NND anti-5-100zhanti-eMmo5"), as well as its components: activated potentiated form of rabbit polyclonal affinity-purified antibodies to ultra-low doses of brain-specific protein 5-100, purified on the antigen, obtained by ultra-dilution of the original matrix solution (in 10072, 10030, 100200 times, which is equivalent to a mixture of hundreds of homeopathic dilutions of C12, C30, C200 ("NND anti-5-100"), and activated potentiated form of polyclonal affinity-purified antibodies rabbit to ultralow doses of endothelial

MO-synthase, obtained by over-dilution of the original matrix solution (in 10072, 100990, 100200 times), which is equivalent to a mixture of hundreds of homeopathic dilutions of C12, C30, C200 ("NND anti-eMmO5"). Ip myo binding of the standard ligand ("H|ipentazocine" with recombinant human 01 receptor was evaluated using the radioligand method. Potentiated distilled water (a mixture of homeopathic dilutions C124C30-0200) was used as a control in relation to the tested drugs.

The sigma-1 receptor (01) is an intracellular receptor localized in cells of the central nervous system, cells of most peripheral tissues, and cells of the immune component. These receptors have a unique ability to move, which is associated with many psychotropic drugs. The dynamics of sigma-y receptors is directly related to various types of effects exerted by drugs that act on sigma-1 receptors.

Among such types of influence are the regulation of activity channels, exocytosis, signal transmission, plasma membrane restructuring (raft formation) and lipid transport/metabolism.

All of them are able to contribute to the plasticity of neurons in the brain. There is confirmation that sigma receptors have a modulating effect on all major neurotransmitter systems: noradrenergic, serotonergic, dopaminergic, cholinergic system and MMOA-regulated influence of glutamates. Sigma-1 receptors play an important role in the pathophysiology of neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease), psychiatric and affective disorders, and stroke; they also take part in the processes

From learning and memory In this regard, the ability of drugs to influence the effectiveness of the interaction of ligands with the sigma-y receptor indicates the presence of neuroprotective, anti-ischemic, anxiolytic, antidepressant and anti-asthenic components in the spectrum of their pharmacological activity, making it possible to consider these drugs effective , in particular, in the treatment of cerebrovascular diseases.

During the test (to measure total binding), 20 μl of the complex preparation NND anti-5-100--anti-eMo5 or 10 μl NND anti-5-100 or 10 μl NND anti-MO5 was added to the incubation medium. Thus, the amount of NLD anti-5-100-anti-eMo5 transferred to the test well during the test of the complex drug was identical to the amount of NLD anti-5-100 and NLD anti-MO5 tested as monopreparations, which made it possible to compare the efficacy the drug and its individual components. 20 μl and 10 μl of potentiated water were transferred to the incubation medium.

Next, 160 μl (approximately 200 μg of protein) of the homogenate of the cell line Uigkai (line of human leukemic T-lymphocytes) was added, and finally, 20 μl of the tritium-labeled radioligand IZN|Ipentazocine (15 nm) was added.

In order to measure nonspecific binding, 20 μl of unlabeled ligand - haloperidol (10 μm) was transferred to the incubation medium instead of drugs or potentiated water.

Radioactivity was measured using a scintillometer (Torsoshpi, RasKaga) and a scintillation mixture (Misgozsipi 0, RasKaga) after cultivation for 120 minutes at a temperature of 22°C in 50 mM Tris-HCl buffer (pH-7.4) and filtration using glass fiber filters (SG/ V, RasKaga). Specific binding (in test or control) was calculated as the difference between total (in test or control) and non-specific binding.

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

Table 1

Under investigation Amount of inhibition group of well of radioligands in the control of binding indicator of the control of anti-eMmo5 water water

Effect of drugs and potentiated water on standard ligand binding

INIpentazocin with recombinant human receptor 0-1

Note: 96 specific binding in the control - (specific binding during the test / specific binding in the control)" 100 9o;

Fo inhibition of specific binding in the control - 100 95 - (specific binding during the test/specific binding in the control) " 100 95).

Results showing inhibition greater than 50 95 represent a significant effect of the test compounds; suppression from 25 95 to 50 95 confirms a minor to moderate impact; an inhibition of less than 25 95 is considered a minor effect of the test compound and is within the background level.

Accordingly, this experimental model showed that the complex drug NND anti-5-100--anti-eMO5 is more effective than its individual components (NND anti-5-100 and NND anti-emo) in inhibiting the binding of the standard ligand (NIpentazocine with recombinant human receptor 0-1; NND anti-5-100, transferred to a test well in a volume of 10 μl, inhibit the binding of the standard ligand (ZNI|Ipentazocine with recombinant human receptor o- 1, but the intensity of this the effect is smaller than when using the anti-5-100-anti-eMmo5 NND complex drug; anti-eMo5 NND transferred to the test well in a volume of 10 μl did not affect the binding of the standard ligand I ("NIpentazocine" with recombinant human 0-1 receptor; potentiated water, transferred to the test well in a volume of 10 μl or 20 μl, did not affect the binding of the standard ligand (NIpentazocine with recombinant human 0-1 receptor.

Example 2.

The following preparation was used: 300-mg tablets impregnated with a water-alcohol solution (3 mg/tablet) of an activated potentiated form of rabbit polyclonal antibodies to brain-specific protein 5-100 (anti-5-100), purified on the antigen, in an ultra-low dose (NND anti-5-100), obtained by over-dilution of the original solution (with a concentration of 2.5 mg / ml) in 10012, 10030, 100200 times, equivalent to a mixture of hundreds of homeopathic dilutions of C12, C30,

From C200; 300-mg tablets impregnated with a water-alcohol solution (6 mg/tablet) of activated potentiated forms of rabbit polyclonal affinity-purified antibodies to brain-specific protein 5-100 (anti-5-100) and to eMoz (anti-eMo5) in an ultra-low dose ( NND anti-5-100 and NND anti-emo5), obtained by over-dilution of the original solution (with a concentration of 2.5 mg/ml) in 10012, 10030, 100200 times, equivalent to a mixture of hundreds of 35 homeopathic dilutions of C12, C30, C200; 300-mg tablets impregnated with a water-alcohol solution (3 mg/tablet) of activated potentiated form of rabbit polyclonal anti-eMmo5, purified on antigen, in an ultra-low dose (NND anti-eMmo5), obtained by ultra-dilution of the original solution (with a concentration of 2.5 mg /ml) in 10072, 100590, 100200 times, the equivalent mixture of hundreds of homeopathic dilutions C12, C30, C200; and (as a placebo) 300-mg tablets containing 40 excipients: lactose (lactose monohydrate) - 267 mg, microcrystalline cellulose - mg, magnesium stearate - 3 mg.

The effectiveness of the studied drugs in the treatment of dizziness (vertigo) and other symptoms of locomotion sickness was evaluated on the model of kinetosis or staggering/locomotion sickness, which occurs due to various vestibular-vegetative disorders.

Dizziness is a typical symptom of damage to the vestibular analyzer of various etiologies, including dysfunction of the vestibular nerve and cochlear system, blood circulation 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, which include three types of reactions: vestibular-motor (nystagmus and deviation reaction), vestibular-sensory (in addition to dizziness, nystagmus (or reaction after rotation), protective movements) and autonomic ( nausea, vomiting, increased sweating, frequent heartbeat, feeling hot, changes in pulse and blood pressure).

A double-blind placebo-controlled comparative study was conducted in parallel groups, including 15 somatically healthy subjects - men and women aged 15 to 60 years (mean age 33.32-0.75 years) with low (n-5; 33 95) or average (p-10; 67 95) by the degree of resistance to locomotion sickness, in order to analyze the properties of various preparations against locomotion sickness. Group I received NND anti-5-100zhanti-eMmo5, Group 2 - NND anti-5-100 and Group C - anti-eMo5.

To simulate locomotion sickness and evaluate the effectiveness of the studied drugs, the most appropriate and recognized models of motion sickness were used - tests with a constant cumulative effect of Coriolis accelerations (CSEAS). Initial tolerability of the test

All study participants had no more than 5 minutes of SSEAS. Vestibular-vegetative disorders due to kinetic influence (SSEAS) were recorded using a complex of diagnostic methods, including patient examination, quantitative assessment of disorders of vestibular-vegetative sensitivity (Halley scale), analysis of heart rate variability (HRV), and self-assessment of functional status (M/ YOU - well-being, activity and mood). As criteria for the effectiveness of the therapy, the dynamics of tolerability and the duration of the recovery period under kinetic influence were evaluated, as well as the change in indicators indicating sensory-motor reactions (nystagmus), HRV indicators (using the Viosot UmMeiYiIpe system55

Zsap, developed by AMU5, IIS C in accordance with the International Standard of the European Association of Cardiology and the North American Association of Electrophysiology) and the data of UUVAM.

The safety criteria were the nature, confirmation and conditions of the occurrence of possible adverse events (AEs) during the treatment period, related to taking drugs; the effect of the studied drugs on indicators characterizing the function of the central nervous system (CNS) (reaction to a moving object (MOO)), simple motor reaction time (T5MK);

From the dynamics of physical and functional factors (heart rate (HR), systolic and diastolic blood pressure (SVR, OVR), Stange criterion; physical load tolerance (Harvard step test). Safety was evaluated after a single dose and after a 7-day course of administration combinations of NND anti-5-100 and

NND anti-eMO5.

All patients did not take any drugs 1 month before the start of participation in the study. After screening, patients were randomly divided into 4 groups (Group! - NND anti-5-100--anti-eMo5, Group 2 - NND anti-5-100, Group C - NND anti-eMoZ5, and Group 4 - placebo ).

On the first day of the study (Visit 1), the initial functional and psychophysiological state of the patients was registered, then the patients were given 5 tablets of the corresponding NND antibodies, after which the SSEAS test was performed. The duration of the test was recorded; autonomic-vestibular disorders and AEs associated with locomotion sickness were detected with the help of a complex diagnostic examination.

In the next 2-6 days, patients received 1 tablet of the prescribed drug 3 times a day. On day 7 (Visit 2), patients received the same doses as on day 1 (Visit 1).

A comprehensive diagnostic examination was carried out before and after the CSEAS test. The study was designed in such a way that the research team could only work with one patient.

The study was parallel and was conducted in the first half of the day with the participation of, as a rule, 4 people per day, one for the drug or placebo. The next three weeks were a washout period, after which patients in each group were given the new drug or a placebo; the study cycle was repeated (Visit 1, course of taking the drug; Visit 2). Thus, during the study, each patient participated in 4 cycles of the study, ie, each patient participated in the group with a 3-week washout period between each cycle. This allowed the researcher to balance the effect of individual characteristics with the effect of treatment. The analysis of the effectiveness of the drug was carried out on the basis of data on all participants who completed the full course of taking the drug under study in accordance with the research protocol (item 15).

The factors that confirmed the symptoms of motion sickness (dizziness, nausea, inertness, pale skin, sweating, etc.) after kinetic exposure (SSEAS) against the background of one-day administration of the studied drugs showed that all study participants had approximately the same state of motion sickness, since the confirmation of the evaluated symptoms of 60 autonomic dysfunction according to the Halley scale, which was carried out by the research doctor, did not differ significantly in all groups (Table 2, Visit 1). However, the kinetic effect that caused similar motion sickness symptoms was different in the 4 groups and depended on the drug taken by the study patients (Table 3, Visit 1).

One-day administration of NND anti-5-100 and anti-eMmoO5 resulted in a clear effect against locomotion sickness, which manifests itself not only in a much longer time of tolerability of the test

SSEAS (104.10-13.14 sec. vs. 68.5026.57 sec. - in the NND anti-5-100 group; 75.00-6.79 sec. - in the NND anti-eMmo5 group and 61.30-3.15 5 sec. - in the placebo group), but also also for reduced nystagmus time (9.9021.20 sec. vs. 13.5051.51; 16.10-1.68 and 13.30-41.12 sec., respectively) and maximally fast recovery (96.905413.54 sec. vs. 194.20218.45; 202.50521.72 and 241.70-38.41 sec. . respectively).

Approximately similar indicators were registered during Visit 2 after receiving a course of drugs. To achieve similar symptoms of locomotion sickness (Table 2, Visit 2), patients who received the NND drug anti-5-100 zhi-anti-emo5 (Table 3, Visit 2) for 7 days were subjected to the longest kinetic exposure. The most pronounced effect against locomotion sickness when using the drug NND anti-5-100 and anti-eMmo5 was manifested in a significant reduction in the time of nystagmus (9.50:21.38 sec., p "0.01) and the duration of the recovery period (117.90315.65 sec. , p «0.01). Single-component NND anti-5-100 had no action against motion sickness, as evidenced by better tolerability of the CSEAS test, nystagmus recovery time, and recovery compared with the placebo group (Table 3, Visits 1 and 2), but the efficacy of NND anti-5-100 was lower than that of the drug NND anti-5-100zhanti-eMmo5.

The single-component NND anti-eMmo5 drug did not demonstrate an effect against locomotion sickness, as the SCEAS test results and the subsequent recovery period were not significantly different from the placebo group (Table 3, Visits 1 and 2). A comparative analysis of the CSEAS test indicators in the groups of NND anti-5-100 and anti-eMmo5 and NND anti-5-100 during one-day administration of drugs showed that the addition of NND anti-eMmo5 increased the tolerability of kinetic impact by 52 95, reduced the time of nystagmus by 2795 and contributed to the reduction of the recovery period after the cessation of the kinetic effect by 50 95, including the duration of dizziness - by 49 95. However, the greatest effect of the NND anti-eMo5 component on the effectiveness of the combined drug (NND anti-5-100 and anti-eMmo5 drugs) during

From the reception, it was expressed in an excess (by 30 95) of the result achieved in the NND anti-5-100 group on the factors of tolerability of kinetic impact and duration of nystagmus (for each parameter).

In addition, the increase in the effect during Visit 2 on the indicators of tolerability of the SSEAS test and the duration of nystagmus in relation to the data on Visit 1 when taking the drug NND anti-5-100 and anti-eMmo5 in comparison with the single-component drug NND anti-5-100 was expressed in increase in degree, which was confirmed by the change of these indicators to 30 95 and 4 95 (against 21 95 and

About 95 in the group receiving NND anti-5-100). When evaluating the effectiveness of drugs against motion sickness, special attention was paid to the possible influence of drugs on the stability of the autonomic nervous system (ANS), in particular, the change in the balance between its sympathetic and parasympathetic divisions. For this purpose, during each visit, HRV parameters were analyzed at rest and during functional tests (breathing and orthostatic tests).

Table 2

Indicators on the Halley scale depending on the drug used after passing the SSEAS test

Drug (p-15; MaZE") (p-15; MaeZE) emo x Me5E - Mean value x standard error

Table C

Dynamics of CSEAS test indicators depending on the used drug

Test tolerance Nystagmus time, sec. Recovery time, sec.

CSEAS, sec. (p-15; Mzh50) (p-15; M50) p-15; Mzh5OU) emo

Kruskal-Wallis1 emo

Kruskal-Wallis1

Notes:! to determine a significant difference between groups, the Kruskal test was used

Wallis. If the test showed a significant difference of p "0.05, the Mann-Whitney test was used to compare groups. x significant difference when compared with placebo, p«e0.05; "x significant difference when compared with placebo, p«e0.01; wkh | percent difference when compared with placebo, p«e0.001. x significant difference when compared with NND anti-5-100 and anti-eMmo5, p«e0 " Мх50 - Average value хз standard deviation

Analysis of HRV at rest (in a sitting position) before and after the CSEAS test (Table 4) showed that patients treated with study drugs had a tendency to increase the standard deviation of the MM intervals (5OMM), indicating an increase in heart rate variability due to parasympathetic influence on heart rhythm. In response to the kinetic effect, the value of EM5-50, which characterizes the activity of the parasympathetic component of autonomic regulation, increased in all experimental groups. In the groups receiving the drug NND anti-5-100 and anti-emo5 and NND anti-5-100, an increase in the high frequency (NE) was observed, which also indicates a change in the autonomic balance towards the parasympathetic connection. Thus, after the CSEAS tests, an increase in parasympathetic influence on heart rate was observed in all groups.

Table 4

HRV parameters of the study participants at rest before and after the kinetic effect of the CSEAS drug msec!

Note: "significant difference when compared with placebo, рх0.05); and significant difference when comparing with baseline parameters, р«:0.05. "Мх50 - Average value хз standard deviation

Analysis of HRV in the transition stage showed that one-day administration of the NND anti-5-100 - anti-eMo5 drug increased the reaction time (13.91.14; p x 0.05) and stabilization time (24.21.28; p x 0.05) in comparison with NND anti -5-100 and placebo (Table 5). According to the same factors, the values of the placebo group and after the kinetic effect were exceeded, which demonstrated the positive effect of the combined drug on ANS reactivity (increased tolerance to changes in body position). The smallest difference between the maximum and minimum heart rate during exhalation analysis (Table b) confirmed the better balance of the two departments of the ANS after a one-day intake of the drug NND anti-5-100 g anti-eMmo5 (25.12.66 beats/min, p x 0.05) .

By the end of the one-week course of treatment, a stabilizing effect on the ANS balance was also observed after the SSEAS test (when performing an orthostatic test and breath analysis) in the group receiving the drug NND anti-5-100 and anti-eMO5 (Tables 5 and 6).

Table 5

HRV parameters of the study participants during the orthostatic test before and after the kinetic effect of the CSEAS drug

Reaction to physical 1.30520.06 1.40530.04 1.30520.06 1.4020.06 pc yr unit. Sec. load, um. unit Sec. load, um. unit Sec.

Reaction to physical 1.3020.04 1.30520.04 1.40530.06 1.3020.06 yr yr unit. Sec.

Note: "significant difference when compared with placebo, px0.05); x significant difference when compared with NND anti-5-100, p«0.05. "Mx50 - Mean value xz standard deviation

Table 6

HRV parameters of study participants during exhalation analysis before and after kinetic exposure

Parameter of the SSEAS drug SSEAS drug max. NO/min. NO, um. unit

Continuation of the table 6 min. NO, beats/min. max. NO/min. NO, um. unit min. NO, beats/min. max. NO/min. NO, um. unit min. NO, beats/min.

Ratio 1.6--0.07 1.620.06 1.5:0.05 1.62-0.05 max. NO/min. NO, um. unit 31,253.06 28,252.50 27,152.37 29.22 44

The difference of max. NO -

Note: 7 significant difference when compared with placebo, re0.05 "Mx50 - Mean value xz standard deviation

The results of the self-assessment of the functional state (well-being, activity, mood) of the patients, which was carried out by the participants of the study after the simulation of locomotion sickness (SCEAS tests) at the beginning and at the end of the therapy, showed that the patients in all groups gave "average" points for each parameter (Table 7) . Thus, against the background of medication, the tolerability of the CSEAS test was satisfactory. The highest growth rates compared to the data of the placebo group at the end of the 7th day of administration (more than 10 95) were observed in the group receiving the drug NND anti-5-100 and anti-eMmo5.

Table 7

Dynamics of parameters of self-assessment of functional state (well-being-activity-mood) by research participants

MON kin KN KI about KV of SSEAS drug SSEAS load, um. unit Sec.

Zo

Continuation of table 7 load, um. unit Sec. load, um. unit "Mx50 - Average value xz standard deviation

The safety analysis included data on all patients who participated in the study. During the observation period, good tolerability of the studied drugs was noted. No adverse events associated with the use of the drug were detected. All patients in the studied groups completed the treatment within the terms established by the study protocol; no individual dropped out of the study early.

According to the results of the physical examination, including heart rate, systolic and diastolic blood pressure, and according to the data of the Harvard step test, no abnormal parameters were observed in the patients during the study (Table 8). All detected changes did not go beyond the standard range. In this case, subjectively, all patients reported satisfactory well-being.

Table 8

Dynamics of physical parameters and tolerability of physical load by study participants before and after kinetic exposure to 00 ru o M of SSEAS drug SSEAS blood pressure (mm Hg) blood pressure (mm Hg) write Her pony step test blood pressure ( mm Hg) blood pressure (mm Hg)

Ben ZO PNEZHYNN Nini AL PILIANYA by step test blood pressure (mm Hg.

Diastolic 75,212,24 80,322,66 73,9:12,83 81,0-3,22

En NANNYA No Nina BUT blood pressure (mm Hg) write Her vl step-test blood pressure (mm Hg) blood pressure (mm Hg) zsha | 0700 tr step-test "Mx50 - Average value xz standard deviation

In addition to hemodynamic parameters, in order to assess the safety of the studied drugs and their possible negative impact on the functions of the central nervous system, the following physiological parameters were also evaluated in patients: (EMO (reaction to a moving object),

ZMET (time of simple motor reaction), KA (attention span), stability of attention (AB) and factor of stability of attention (AZE)). In addition, a test was conducted to assess hypoxia tolerance

Barbell.

According to the obtained results (Table 9), neither one-day administration nor the course of administration of the drug had a significant effect on the evaluated parameters. Indicators of sensorimotor coordination (5ZMKT, EMO) did not differ from the results of the placebo group before and after the CSEAS test at both visits. Data from the study of such complex functions as the volume and stability of attention showed that the studied drugs before and after passing the CSEAS test did not change the degree of concentration and change of attention, which did not differ from the group receiving a placebo.

Analysis of standard breath-hold exercise tests showed a trend toward increased patient tolerance to hypoxia (Table 9). In the case of respiratory arrest, the duration according to the Stange criterion increased after taking all the studied drugs. However, only taking the combined NND anti-5-100 mg anti-eMmoO5 drug provided a significantly longer breath hold time after kinetic exposure (68.1x2418.8 sec. at the initial level and 91.7527.4 sec. after the SSEAS test; p "0.05). An increase in the tolerance of hypoxia was also noted when applying the Gench test (Stange criterion) (restraint on exhalation, P» 0.05).

Table 9

Dynamics of the parameters of the psychophysiological state of the study participants before and after the kinetic effect of 000 Pi M ut of the SSEAS drug SSEAS neck | shi | bad | appear Z zno target hit on target hit on target

EMO, 95 from 3.7-1.03 3.7-1.24 3.3-0.93 4.3: 21.61 hits on target

Thus, a study using an experimental model of motion sickness demonstrated the effectiveness of the combined NND anti-5-100 anti-emo drug and the single-component NND-5-100 drug. The studied drugs increased the resistance of patients to kinetic action after simulating the clinical and physiological effects of locomotion sickness, contributing to a more moderate course of the clinical process of locomotion sickness and a faster recovery of patients after the end of treatment. In addition, it was demonstrated that the effect of the combined drug (NND drugs anti-5-100 and anti-emMmob5) against motion sickness increases the effectiveness of individual components.

The effectiveness of the combined drug NND anti-5-100 i- anti-eMmoO5 in the control of vestibular-autonomic and sensory reactions of the body when using an experimental model of locomotion disease increases when taking a course of the drug. It should be noted that

NND anti-emo5 in the form of a monopreparation does not exert a protective effect against locomotion sickness, but when combined with NND anti-5-100 significantly increases the effect of the latter against locomotion sickness, which is manifested even after a one-day intake of the drug.

The best ability to correct transient processes, that is, to influence the reactivity of the parasympathetic and sympathetic departments of the CNS, as well as the adaptive properties of the ANS in the state of locomotion sickness (increased tolerance of sudden changes in body position) was observed when using the drug NND anti-5-100 and anti-eMmoO5, is an important component of its anti-motion sickness properties. The drug NND anti-5-100 i-anti-emo5 and the single-component drug NND anti-5-100 when used as means against locomotion sickness, including when performing the functions of the operator, are safe and do not have a negative impact on physical and psychophysiological parameters.

The combined drug NND anti-5-100 zh-anti-emOo5 and NND anti-5-100 can be recommended for the prevention and elimination of kinesia in locomotion sickness (including seasickness, altitude sickness, and motion sickness) in individuals with mild to moderate resistance . The combined drug has high safety indicators and does not have a negative impact on the quality of professional activity.

Example 3.

Zo To evaluate the effectiveness of treatment of patients with autonomic dysfunction syndrome (SVD) of psychophysiological and hormonal etiology, 300-mg tablets of the combined drug NND anti-5-100 and anti-eMmo5 and NND anti-5-100 were used. Tablets were saturated with a medicinal preparation containing water-alcohol solutions (6 mg/tablet) of activated potentiated form of rabbit polyclonal affinity-purified antibodies to brain-specific protein 5-100 (anti-5-100) and endothelial MO synthase (anti-eMmo5 ) in ultra-low doses (NNOD), obtained by ultra-dilution of the original concentrated solution (concentration - 2.5 mg/ml) in 100712, 10039, 100200 times, which is equivalent to a mixture of hundreds of homeopathic dilutions

C12, C30, C200 (NND anti-5-100--anti-eMo5).

The control group included patients who received 300-mg tablets saturated with a water-alcohol solution (3 mg/tablet) of an activated potentiated form of rabbit polyclonal antibodies to brain-specific protein 5-100, purified on the antigen, in ultra-low doses (NND anti-5 -100), obtained by over-dilution of the original concentrated solution (concentration - 2.5 mg/ml) in 100712, 10030, 100200 times, which is equivalent to a mixture of hundreds of homeopathic dilutions C12, C30, C200.

The test was conducted in the form of a single-center open randomized comparative clinical study of the effectiveness and safety of drugs containing NND anti-5-100zhanti-eMmoO5 and NND anti-5-100, as monotherapy, in the treatment of autonomic dysfunction syndrome (VDS) of psychophysiological and hormonal etiology.

The study involved 12 patients with psychophysiological STD and hormonal STD, aged from 23 to 61 years. The average age of the patients was 49.25:-12.63 years.

After confirmation of compliance of the patients with the inclusion and exclusion criteria, they were randomly divided into experimental groups: Group I received NND anti-5-100--anti-eMmo5 and included 6 patients (Z patients with SVD of psychophysiological etiology and Z - with

SVD of hormonal etiology). The average age in group I was 41.33:2-12.5 years (17.7 95 men and 82.3 95 women); Group 2 received NND anti-5-100 and included 6 patients (Z patients with SVD of psychophysiological etiology and Z - with SVD of hormonal etiology). The average age in group 2 was 57.16:24.35 years (17.7 95 men and 82.3 90 women).

During the research, four visits were made to each of the facilities. The treatment stage lasted from the 1st to the 3rd visit. Visit 3 (Day 56.-5) was the first endpoint of the study, after which the control phase began. The control stage lasted until the 4th Visit (Day 845).

The safety analysis included data on all patients enrolled in the study (p-12).

During the entire observation period, patients showed good tolerance of the drug.

No adverse events were reported. One patient did not show up for the 2nd Visit and was not included in the analysis. All other participants of the study completed the course of treatment within the terms determined in accordance with the study protocol. There were no cases of premature withdrawal from the study.

The evaluation of the effect of NND anti-5-100zhanti-eMmo5 on the main symptoms of SVD, as well as indicators of anxiety and depressive disorders (Beck's Self-Assessment of the Degree of Depression) revealed an improvement in the quality of life of patients, which was manifested as a statistically significant increase in the total score on the 5E-36 scale ( additional scale "physical health" - from 38.04x2.44 to 47.84:21.27, p-0.005, additional scale "mental health" - from 57.88:253.94 to 72.75:1.64, p-0.01), and also statistically significant a decrease in the overall index of the Self-Assessment Form of the degree of depression according to Beck (from 11.0:-1.4 to 5.5:21.37, p«e0.02).

The assessment of the effect of NND anti-5-100 on the main symptoms of SVD, as well as indicators of anxiety and depressive disorders (Beck's Self-Assessment of the Degree of Depression) revealed an improvement in the quality of life, which was manifested as a statistically significant increase in the total score on the ZE-36 scale (additional scale " physical health" - from 56.10751.36 to 70.71.39, r«e0.001). No trend towards an increase in the total score on the additional scale "physical health" was reported in this group.

Zo Analysis of changes in indicators of anxiety and depressive disorders in groups taking NND anti-

Z-100, revealed a statistically significant decrease in the overall index of the Beck self-assessment form of the degree of depression (from 10.5:-1.04 to 5.33.-1.5, p«0.02) (Table 10).

Table 10

ZE-36 (physical ZE-36 (mental Form of self-assessment of health) health) degree of depression by

Beka

NNDanti- 38.04x2.44 57.88:3.94 11.05-1.4 5-100 anti-emo5 before the start of treatment

NNDants - 47.84-41.277 72.1551.647 5.5-1.3777 5100 anti-eMmo5 after completion of treatment

NNDants-5-100 46.9928.09 56.107-1.36 10.5:-1.04 before treatment

NNDants-5-100 49.17x2.68 70.7341.397 5.33x1.577 after the end of treatment "- p compared to the initial value - 0.005 "x- p against the initial value "0.01 ja- p against the initial value " 0.02 ja.p against the original value of "0.001

There was no significant difference between the groups in relation to these parameters after the end of the treatment. During research planning and patient registration, the groups were divided into the following subgroups: 1. patients with autonomic dysfunction syndrome of psychophysiological etiology (chronic stress), who were to receive NND anti-5-100--anti-eMOZ5 as monotherapy;

2. patients with autonomic dysfunction syndrome of psychophysiological etiology (chronic stress), who were to receive NND anti-5-100 as monotherapy; 3. patients with vegetative dysfunction syndrome of hormonal (menopausal) etiology, who were to receive NND anti-5-100--anti-eMOZz as monotherapy; 4. patients with vegetative dysfunction syndrome of hormonal (menopausal) etiology, who were to receive NND anti-5-100 5-100 as monotherapy.

The trends in the subgroup analyzes were consistent with the trends in the overall group analysis, although they were less significant, possibly due to the small number of observations (Tables 11, 12).

Table 11

SVD of hormonal (menopausal) etiology

ZE-36 (physical ZE-36 (mental Form of self-assessment of health) health) degree of depression by

Beka

NND anti-5-100zhants - 38.5х22.99 57.94 42 11.0:2.0 emMo5 before the start of treatment

NND anti-5-100zhants- 47.99521.487 72.15:51.857 5.3350.5777 emMoz5 after completion of treatment

NND anti-5-100 before 47.3958.35 56.79-1.23 10.051.0 the start of treatment

NND anti-5-100 after 48.9653.16 70.71-1.687 4.6620.05777 completion of treatment "- p compared to the initial value "0.05 "х- p compared to the initial value "0.005 хх- p compared to the initial value is -0.053 yr compared to the initial value of -0.01

Table 12

SVD of hormonal etiology (chronic stress)

ZE-36 (physical ZE-36 (mental Form of self-assessment of health) health) degree of depression according to Beck

NND anti-5100anti-eMo5 37.5752.31 57.85:4.39 11.021.0 before treatment

NNDants - 5100 zhants-emMo5 47.6951.327 72.135-1.827 5.6612.08777 after completion of treatment

NND anti-5-100 before the beginning of treatment 47.3958.35 55.425-1.31 11.0-1.0

NND anti-5-100 after 48.9653.16 70.69521.6577 6.020 completion of treatment "- p compared to the initial value "0.02 "х- p compared to the initial value "0.05 хх- p compared to the initial value -0.002 yah compared to the original value of -0.082

Inter- and intragroup analysis of changes in blood pressure, integrative autonomic parameters, and variable pulsometric data did not show any statistically significant trends, except for a decrease in the Autonomic Balance Index (VBI). Presumably, this is due to the insufficient amount of observations.

MVI is an integrative parameter calculated as the ratio of the Mo amplitude (the number of cardio intervals corresponding to the range of modes) to the range of changes (the difference between the maximum and minimum value of K-K). A decrease in this parameter indicates a shift in the autonomic balance from sympathicotonia to normo- and vagotonia, i.e. an increase in the influence of the parasympathetic segments of the autonomic nervous system (ANS).

In the group with SVD caused by hormonal imbalance, a statistically significant tendency to decrease UVI was noted in the subgroup receiving NND anti-5-100--anti-eMoO5.

A statistically significant (p<0.05) difference was found between the subgroups receiving NND anti-5-100--anti-eMoO5 and NND anti-5-100 (Table 13).

Table 13

SVD caused by hormonal imbalance

PI Picnic Shawn treatment "- p compared to the initial value "0.05

Ya - r against NND anti-5-100. "0.05

Accordingly, the clinical study of the combined drug - NND anti-5-100--anti-emo5 demonstrated a positive effect on the quality of life of patients with autonomic dysfunction syndrome (SVD) and psychophysiological and hormonal etiology, a positive effect on the treatment of anxiety and depressive disorders in patients. A positive effect of the combined drug according to this invention on the autonomic nervous system was established. In addition, a good tolerability of the combined drug according to the present invention was noted. No adverse events were reported.

Example 4.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive decline, memory impairment, confusion, and emotional changes. Despite the fact that the main cause of this pathology is now considered to be the accumulation of beta amyloid, which leads to the formation of its deposits and neurofibrillary tangles in brain tissues, AYU is also accompanied by a deficiency of the cholinergic system. This serves as the basis for the most common method of modeling AI in animals using the cholinergic system antagonist scopolamine. Administration of scopolamine to experimental animals (usually rats or mice) inhibits learning ability and leads to memory impairment.

Various methods are used to assess cognitive function in rats and mice, including the Morris water maze test.

The essence of this test is that animals are released into a container with cloudy water from different positions, forcing them to look for a hidden platform. The advantage of this method is that it allows the researcher to control the learning process of the animals (forming an idea of the spatial location of the platform regardless of the place where the animal is released into the water) and to evaluate their memory (for this, the test is carried out with the platform removed).

The aim is to study the effectiveness of the combined medicinal product according to the present invention, which contains activated potentiated forms of polyclonal affinity-purified antigen brain-specific proteins 5-100 (anti-5-100) and endothelial MO-synthase (anti-emMo5) of rabbit in ultra-low doses (NND ), obtained by hyperdilution of a concentrated solution (with a concentration of 2.5 mg/ml) in 10072, 10030, 100200 times, which is equivalent to hundreds of homeopathic dilutions of C12, C30, C200 (NND anti-5-100 and anti-eMmo5), in case of amnesia caused by using scopolamine in rats.

During the study of the effectiveness of the drug NND anti-5-100 G anti-eMmosis in rats with amnesia caused by the use of scopolamine (a model of Alzheimer's disease), 48 male rats of the K line were used: Umiziag (Nap) (body weight - 180-280 g). For 4 days, rats were injected subcutaneously with saline solution (p-12, intact) or scopolamine at a dosage of 0.5 mg/kg (p-36) (amnesia caused by the use of scopolamine). Rats with scopolamine-induced amnesia were divided into 3 groups. They were injected intragastrically with distilled water (7.5 ml/kg, n-12, control group 1), or NND anti-5-100 (7.5 ml/kg, n-12, group 2) or NND anti-5-100zhanti-eMo5 ( 7.5 ml/kg, p-12, group 3) for 9 days (4 days before scopolamine injection, 4 days on scopolamine background and 1 day after the last scopolamine injection).

Morris water maze training was conducted for 4 days after scopolamine administration, 60 minutes after administration of test drugs and 30 minutes after administration of scopolamine (4 consecutive tests with an interval of 60 seconds). The Morris water maze is a round tank (diameter - 150 cm, height - 45 cm), 30 cm filled with water (26-28 "C).

At a distance of 18 cm from the edge of the container there is a hidden platform (diameter -15 cm), located 1.5 cm below the water level. Turbidity of the water is achieved by adding a non-toxic dye (for example, dry milk), which makes the platform invisible. During each test, the animal was lowered into the water from one of the starting points equidistant from the hidden platform and given the opportunity to find the platform.

If the animal could not find the platform within 120 seconds, it was placed on the platform and left there for 60 seconds, after which the test was started again. In the course of 4 tests in random order, the animals were forced to pass the maze twice from each starting point. The trials were videotaped, after which the distance traveled while searching for the platform was analyzed during each test, as well as the latent period of searching for the platform. On the 5th day, the test was repeated: the platform was removed from the maze, and the rats were allowed to swim freely for 60 seconds. The time spent in the place where the platform used to be was recorded.

Administration of scopolamine significantly impaired the ability of animals to learn.

In the control group, the time the animals spent searching for the platform and the distance they swam at the same time significantly increased (Tables 14, 15). The test shows that the memory of the animals in the control group deteriorated: the animals from this group spent less time in the place where the platform was previously located than the intact animals (Table 16). The introduction of NND anti-5-100 did not lead to improvement of the studied parameters (Tables 14, 15, 16). Administration of anti-5-100-anti-emo5 NND led to some improvement in learning ability, resulting in a reduction in the latency to seek the platform (Table 14) and distance traveled (Table 15) during the 4 days of training, and an improvement in memory that confirmed by the increase in time spent in the place where the platform used to be (Table 16).

Coo)

Table 14

Platform Search Latency, sec. anti-eMmo5, n-12 kich - the difference with the intact group is significant, p«0.05

Table 15

The distance traveled to find the platform, cm n-12 anti-eMmo5, n-12 kih - the difference with the intact group is significant, p«0.05

Table 16

The time spent in the place where the platform used to be, sec.

Group 30-60 sec. 40.84 36.8x3.6 38.5:2.6

Control room, p-12 18.4x2.877 18.82-1.977 18.v21.777

NND anti-5-100, p-12 13.3zh21 21.5:52.6 17.6521.3

NND anti-5-100 and anti-eMmov5, p-12 19,14,8 23,852,2 21,252,5 kich - the difference with the intact group is significant, p«0.05 10

Thus, in the model of Alzheimer's disease, the administration of the NND anti-5-100 and anti-emMmo5 complex was more effective compared to the administration of the NND anti-5-100 and an inert substance.

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Z-y: sStya Aza Niv 510 siv Aga Bey biy yo Ua biv div Her uva led 345 150 155 1650 sec DPE OSITU TP Tu Niv Bey Aka bid Beh biz ey Uvi Re obiu Aza 1655 170 1785 yiUue BZiv Aia TKo vahu Avpovia Rgo Akta was Cha1i Siu ha her stv Ts i8o 185 190

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290 255 309 uche Uvi Ben RrRre Rgo bij ii Usi Pen biz Mai vho Pe 5104 No Rgo 395 zo 315 BI;

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From Z5 380

Mes Avroreip Ar TE AKka Tvh Tk obeh bek peo ihr LUB AvroBuz Via 385 zva 295 1800

Visa Uai b1y i1ie Av Gaza deya Uzi Petz Niv bek Bbe 5313 Petz visa Buv

T05 410 315 chai tk Y1e Uzi Dvr Niv Niv AtTa div TVh Chai bek Re Meb Buv Niv 420 i25 430

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Tr tiv uv already RO Yire bas 5iu bek Bei tah Vho Ud1 re Niv biv 450 455 450 sim Me: Uai Av TUuh Iie Bei bek Ro Aza Bbe Ahch Tukh bid Bo Ave z55 476 alu "VO gka o tTkr Buv stu Beh Aiyaa TVh was stu Aza ziu her Taho Aku Buv Buu i85 459 495

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BI 530 555 580

Chai Bek iivsh bis No 5its Aivz Bey Uvi Bey wai Mai TV bek otTvya Bve 2855 ato 575 sSiu Azp o biu Avrovgko vho bid dvy b51u 0: bek Re Ata Aza Aia em

ZZYAO 58 Ya

Me Sila Me Beh s1u ho Tuye Avo» Bek Bach rko Ak Rko bi biv NIV 595 500 5O5

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BI 30 835 040

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Bach bzO o

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WITH; in the 70s

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AND

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And in it:

Azrovzhho Ahch Petz RKO rREO Suv Tykh ev Ah biv Ata bez Tykh Re BBe 850 55 vei

Gay der 112 Tih Bek Reb R bek Ko Aga Bey o bey AtYA Bey; Ber Zh 870 75 vo tych this Aza biv biv Bo Beh biv ZIB biv biz beb bib TV beb eh vah 85 vaz

Zip Ar o Rgo Ah dho Tuk biv bim Ter was Ter Rpe Da Suv Ro TvE 500 z05 zo

Pec rei bis Uaii Be biv biv Bce Rho bek Uvi Aia without Rgo Aia RKO z15 BEJ 95 pez obev yetso tre bis this Bo Ben yini Sip Rgo Aku Tuk Tuk Beh Uvi 93 945 545

Bek beh ALia Rko Azp oAia Niv Rgo 01Uu sti Mai niv beip Tk Udi Aza

ZA zZ35O zach B

Chai Bey Aza tui Ah TB obev vro biu ema bi rhb oiyeer Niv Tu pi eh ato 78 ak sSuv bek TB Ter obvev beh bij Beb was Tk biu dvr o Rho Uai rEo zvo 85 9390

Suv Re Tiz Aha s1u Aia Bko bek Re dka Pe); ro Ro Ave" ovo TUuk za5 T00o 1005

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T075 1ovO 18

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Taz 16095 1105

Ma Ted SU riz Ak Biu Nizh Me Re o wai Sub biu dvrouah TAE 105 1355 M 1120

Meib iya Tpzh Zek Uai her pip TvKoUdi Bi Aga 116 iem Atya TV bid 1185 3150 135 diU Azr Me bi) rev Avr opiuu ATa Sbiu AvroUai I1e biu chai tem Aka 1149 1145 1150 dvr osiv bip o Ahu Tukh Niv biz AvrotTie Rbe biu Gay TVEzh Without Ako tah 155 1160 1165

Z piz chai Mk bek Lk Lives Aha Ta biv bek vva bek this her 310 tItO 1175 150

Aga Ni ev Aga 01Uu viv Uai Rko TER o Acha Be dr Rez Rgo TU RKO 1185 I 1190 1195. 1200

Vzvotiv Vkhost utgy ho "10" and "ate 1203 kEi" VNT "213" Noto vartetpv

"Ey" "ro15 pZEREDO ORIGIN kiy" 1.23 хР23" /shchoi suree"protein" /vrganizme"Nefo zardlepe" "Oh 2

Mas siu dyarp about her was bek in dia bip piz Bgto yiu Bor rko Sug biu 1 5 19 15 iecch biu Bech B1u bep biu without sSiu Bei Suz Siu pu shiy Si Ro Ada 20 83 for izZkoRgo Aza Rho bii Reo Beh Ahu Aza Bgo Aza bek Gen Bay Rko Rgo 35 ay 45

Aza Rko 5ZIO Niv bek Rub RBkKo bek bak VBro ey) ate biv ro Rko pi 5o 55 vo

Oo1u rEo Buz RKe Rko Akch Uvi Buz Av tk bZim Uai biu bek Her TE to 5 that

Tuk Ar TNE Sem Zak AvVa bij dia bib bij Avrobiu Bto Suv Tk Rgo 85 20 ZE

Aka vka Sen bets biu Bek Sei Uvi Epe Rg Aha Bush ber OB bi» Ara i15a i05 To

Eko Bak o Rko bi rRZHO rRho Aza Rgo iya Siv bez Beh Beh peep liz Aho

Ti5 | 15:25

Avgv Re tiv Avpobip Tuk Tu bek bek o i1e uv Atu Beh biu bek siv 130 135 120

Via Nv sii 5ip Ak ip biv bij Ma1i -ib Aza yio Maii Atia Ata Tk 145 150 i55 159

Siu Tv Tu bip wo Do bij Yaeh bfz yeeb Maii Be biu ABa was bip. 155 170 175

Aiia TEr Ak Av Aza Rko Aka Suv Uvi b1u Akch i1a biz Tgr bi Buz 150 155 o

Tem bla in Re Ar o Ata At dvr oSuz Aga bej Ata bip svo Meb Re 7795 200 205

Tvh Tuk ii Su dep Ni Tib Bue TUuH Aia Tk Ap o dkch stu dp Her 210 eI5 220

Akch bek Aia g1ie TVZ Maiiii Rpe Rho biv Ak Suv RE b1U AkZ3 51Uu OR aa 230 235 shcha

Rpye Ak Ii Tr ody bek biv pez Uvi Aho Tukh Viv biu tuye Aga Siv 245 o 235 bip Avr obiu bek uUai Aha biu Avr o Bgo ATa Aa uaii pi) tiv Tyh 51 280 65 vii yii Suv ii6e bia niv bit Tur Tk Rgo biu Adyap biu AKCH Bve Avr chВ1 275 280 285 iem Eko bez eezch bez biv Ada ho der oba Bko Bo Biy Tiem Ba Gay eV av ZO pez o oBuo ho bi be be) Uvi pev Oda Ua R Pea siy Niya RKO Tvzhh Ty zp5 zb ZV zo

Siv TKko vBe ATa Aza ev biu without Ak Tr o Tugk Via em Ro Aza chai 325 330 | 335

Bek Avp Mei Pei Ten biv tiv biu b1u iecp bii Re Rko dia dita Rgo 340 z45 350

Vne Beh Pi Tr tuyu Mezh bet TB biz Bi pi Tak AkF Av be) was 355 zvo 355 two eye Pi Ako Tuk Avt iv Hey bis AvrouUaii Aia Uvi Su Mei Avo 370 yat5 zo i-y dvo Tak o Aku Tvzh Tvgobek begoyny Thr o There was a gift. There was a dia in 385 90 395 400.

IIe Uai der oniv Niz Liz ATia TV dia bek Rre Meit Puv Niv Gay IR 42O 425 430

Avp both s was a girl b1U 1u Suz Ego Aza AvroTsr Aza TEr i1e 435 420 445

Uzi Rko Rto iye Beh biu beh ped TE Reto Uzi BNe Kiz biv blo meh a50 455 450 chuai vva tuyu Be em Zect kb Aza Vpe dts TU ota ko dar BKko Tr 355 470 475 vo was schu zveh dia Aia Buz ZIiU Ts o sbiu her Tv oAkoa was Buv Tpy RBe 4135 429 495

Was svi Uvi Asia Avp viv Uvi Zub yyeee o beb div Beh bez Meb bu TV

For 505 Id

Uvi Mes Acha Guz Aku UMai Buv Achia TE her peo TUuk osi Beh Ba Tv

ZiA5 is 5eV

Si» da Aza siv bezh tuye Ata bil obip bec bi Ako Pec Re Da Guz 530 535 540 ia Rie AvroBgo Aka Uzi Tsets Suv Meb Ar Siv Tukh Ar Uzi Uzi b5eg 55 ZzaO 255 5ay yeip siy niv bij TB eat Uai bep in Uvi TNK o Vbeh TT Re stu Dep 555 57 515 sZvu dyaEr Rko Rko biz Auto o biU bra bek Re Aza Ata Aiz Pezp Place

ZVO 585 a

Me paye biUu Rky tu Avpobek Bay RE Aka Echo bro viv No Buv Zes 85 600 BO

TU Buv iie Ah RN AzooZek Ti dec bu Beh Dar Bko sea Uzi ve 610 15 ega zek lEr o Aka Ak Muz Ag Puv si bej meh dvo TNK Dar o zek ta U

BV ZY won 54o0

Aia yech biu Tak iz Ago Re Suz Mai Re bi Gu Siu Zeh Ak Ata 685 650 vaz

Tuk Rks Piv Raz Suz Aza RBe Aa aka AtTa Uvi Avrvo Te Acad beyu 01 660 665 Yeto

Si be Bgu bi siy Aga iz rez b1V o yivy Ziu bip biu Avrobivz ekh 615 680 585

Suv bi bEp obi 01 liz Be Aku Tu iTjr o Aza slp Aia At Re biv

BO Ya tov liz Aia Suv BM; tp Re Suv Uvi pi 010 Avr AtTa was Aza ATa AIta then 71 75 then

Ah Avrosze Ba bek ro Buz Ako Bek Tk Buz Aso bip Azh TU Ar 730 733

Iv: back Aza ip At bit pEU without Zip oiezy em osrko b5iu you GTe BIB

ECHO 7145 780 in Ni Aga tu Buv Mee Be bij Aia Te her dru bek uzi bi; dev 755 76 Ta evzy bil bek Beh Buv bek ih Ahea Wiz TV ate rez) Uvi ysa Beyu dar puta 715 780

Tnk Stiu B1u biv s stu pe bij Tuye bij Bho biu Dvr Pi ijev 61U

750 795

Mai psh vVyar ogo Rho Ata Bho TB p: Bgo Ua1i Diya Uvi 1 sta Be that v25 830 div tsuz biu Zet Rgo bi bi. Rto Ra bo biu Tur Uvi Wood ADvo Ro 815 vlo v45

Ara Bey Bko Rgo Su Tbzh This Yaka bip Aia em oTyh Re Be yvy dar 85 85 850

Ii1ie Trrh bek Ro rRko bek Rgo bip ben Petz Ahch Pe Petz bek TVk Tu 865 V7o oo875 shcha

Aia biz siy Bo Dku bEip biv biv bib HCez bio Div Bez beb Sip dvr 885 8950 85

And about Aka Aka their bi: siy TkbBoBuz Tv vne Agu Su Rko TV bem Tseh zay 05 910 siy Uvi yeez bis biy Re Rko Beh Chai Div dey; Bro aia Rgo Gay per 915 ZO zZ25

T-x TVeobip Bey obko Bey im beep vho pk Tukh Tuk Beh Uvi bek bug

ZO from Z40

Aia Rho bej TVh Vivsrho biUu 5103 tTie Nw Bbeo TB Mai Aha Zah Gay 345 z50 Z5 960 liv Tuk Ako TK obip lev bi ep ossiu BEO imni NBE Tukh u Tai Suv

From 65 to V ek TS Terobey beye shii vo was vrostu Av oRgo Uvi Ro Suv Re 50 985 for her Aga Bir Ata rjo Zek REJ Aa without RK Eto Avr Ru» bej Pe RI za5 To. 1005

Su iiie Ppvyuouai slu Rho siUu Tyh o sSyu 116 Aha Rko Be Ago bB1u RNe 15sh1o I1-5. 1022

Ter biz bin dka Pec Ni Avr o 1ie bi: beb puz bi bez biv Rro tah 1025 1630 1935 io9cha ko Meb Pt be Ua1! Re biu Suz Aro Sue bek o beep her bar o Niv rei 1045 ch5O 1055

Tukh Aa Avo bi U biy Av At biv biy so bi Mai Re bi AK i1beb 065 1070

Uai ev tv Via Be beh Ah 10 REOo AvroAni kb pu Tyh Tuk Mai kat 5 10850 ho855 ziy Avr osiv bev Ak Ta bib Bey Aia Ain siy Uvi Kiz Atu Uvi Pe 10859 1095 1100

Suz yin Siv Aha slu Kiv Mei Ra oUai Suv iu AvroUvi TE mezh Av. 1105 1116 12-35 11950

Tph Ap Uvi Peugeot siy To uv biz Aa Ge Bei Atia TU sb biU dvr 128 TEZU 1135

Me Siv ey Avro biv) Aiv stu Avo" in her su Uvo without Azh Avt siy 1145 1145 1150 bip.Ako Tuk Niz bib yzrozht3ie Roe biu im TvVk o ybesh Aga Tph biy biv 155 1160 1165

Uai TIE Bed dka ITe Ah TBh Siv Zee Re bek oi: bip ST) Aga vii 1179 1175 1180 iets da su Aia Uai Reo Tur ABa BnNe ADvoroBto vo biu bej Avo TVg 1185 TEO 1185 1509

Avp Veth ro "10" Z ke1ii5 4 "i12 RE "13 Bov. apr se? cori" SOURCE OF ABSORPTION "ry" 1,4 "vaZ" /vshchi sureee "protein" ?lorganisme"Vov saakid "400 3 ho tEV o ATa rve 1 "Fo" 4 "11 4 "122 RAK "ta" Voz Sapkyv

"teh "y PZHERELO ORIGIN "lu" 1.4 ha" Ddvoi buree" protein" /organisme "Vov bytes" herd 4 siu Alla Udi rko 1 "azh "vaj "12 REH "gi13h Vo Kaikyv "ee z"ve1" SOURCE OF ORIGIN " 3225 1..21 kr» voi bure-sprotain" "srganizme" Vovz saptcha" 00 U

Aha Niv peo dka biu Aza Uvi Vub Tsr Aza Re AvroBko re s1u Buo 1 5 10 15 vro Te Eko pu BEo "10" in "ation" 19 "gi" vv "gi3" Vov svahy "Y "251" SOURCE ORIGIN "Ed и: 1Й "83" /shchoi bure-"protein" loyupanizn-" Vov saikiv" "OO" b

Via Bpe Azr RE go 1u Rg Azr Te RK bi" RKO i B 10 "kdd "ii "ii" RT chIZ" Vo: gHatspkiv "ei "21 SOURCE OF PROGRESS kur v, 11 "a3" ivy burv-"preotein" /organisme "Vov Setszhchv" "volume 7

Niz pe Akea biu Ava Uai reko Tthr Aa le der 1 Z 10 kezyzh in "vii zh y

"21-122 RT "Ki3z Voz got used to "ag "zhav SOURCE of origin "ex 1,.20 "23" /lshchoi sureee "prohvin" ?orkatsivme "Vov taiga" "p" 8

None Without Any Biu Aid Mdi Rgo Ter A1ia Re Avrobto Vko biUu Rro Ar 1 5 10 15

TV go biUu RK 29 "10 Z "11 95 "vi VE "VIZ" Vov 'yeZzOakhih "20" "221" SOURCE OF ORIGIN "y 1.32 "vyZ" utoi rure-"protein" i/organisme"Vov Bavsitsv" " POZ 5

Mes Beh her Bez Bin Bush Aid Uvi Uzi Aia Pes Tiie Avor oUai Rpe NIV i 5 10 15 siy Tuk Beh biu Akshf piz bi Avr o Buv Niv was Hey Buv Buv Beh su that V ZO her Bush Sub pcesh BEiye AB Azy obizy Bay bek No Re tsets bis 510 tiv

ZV 40 45 was s biv s sb Udi Uvi Azr o was in Meb sli TV pev Avi beh Avr 5O 55 vo biUu Avr pi ZI Suv Avr o Vpe bip ybits re Mes Aza Rpe Uai Ata Mek 5.5 10 75 that

Ti TVe TVbh Aza Su Niv pis be Be bib biv Li ih 90 sei o "IM a "ii RVE "24135 NoOosho zarienv "220" "gri" SOURCE OF ORIGIN "ey 1-55 "ke" /toy suree"protein" borganismie" Noteo zarienv" "00" 10 mee be biy Pec biy Guz Aza Me Uvi Aiv Be; her Avrouv)' ve ni 1 Z 15 15 bij Tuye bek schu Akch bij studar obu No Buv ben pu was bek sii o 25 Zo pcep Buv biz Bei ITe dp dei si: bez es Kish Re this sat bra TE

From 40 to 45

Muz action beep Bii Uai Uvi Avb Buv Uvi Meb sim TBh Pe Ver oAvo Avr

ZO 5a you siu Avr o bBiu biy Su var o Rbe biy bi) RBe oMes Diya Rbe in Aza Mes va 70 75 Wb

Mai Te tv Aza Suv niv Sh: Re RBe bi: NEBO BI 85 5 kii0z 11 ka1i" ai kaia" RVE "213" Note brewed "shi" "251" SOURCE OF ORIGIN "reReich 1,584 "23" other suree"proteev" lorganisme" Nato Verieva" "adp" 11

Mek 5Biu Beh sich ev tv Tv Aba Mei bid tyk ez TI dev UZ Ne ii 5 To 75

Niv A1iz Ki bek piUu Guz iz B1u Ave Buv Tukh yiuv yei beh tsu uv 25 25 for bii rei was bi ey eat biya Tv obie ev bej bi RBe Pe) Ano Aza 45 o 45

Si was Ave Uaii Avr o ABa in Dvr zuz Ua) Mehye Was syn Without Avro ba 59 BO

AB Siu AvroSiu bib bayii Der RVe biy 516 Tukhk Uai Chai ieyu in Aza 5 Me 75 ZO

Aia this Tak Uzi ATa Su Avo Avt ne pe Tkrobich Ava Zeh 85 50 "2105 2:12 "24 ZA. "Lih RAT "KIZ Vo baki

FOR

"gi" SOURCE OF UPGRADING cups 1.4 "VE3" lori suraea-"protein" /organisme "Vov baprutsv" "ey"

Mayi zu Beh siy rez 10 yiv AtTa Me biz Ts bez yiye dey Uai Rve i 8 Her 15 niv ATiz Niz Bet SiUu Puv piz beiUu AvroBuyu Tuk Bush petsp vek puv Bud zo bij rez Buz sich Hey eshe bib yin biv Biy bes bi vve this Avr o Aa 45 bip Buv Ar o Aiaz Avr o Aza uaii Avr obu Za1i Meb pu biz Theo Avrobha

Bi) BU Ba

AvpoziU EurobiUu sich Uai OR pe biv bin tukh Uzi Uvi without UZ Ata 85 75 t5 VO

Aia ev Tvkouai yiyaa Sez dav o ABY WBe Re Tr biv Av bee 85 Zo

Claims (19)

FORMULA OF THE INVENTION 1. Combined medicinal product for the treatment of dizziness associated with disorders of the vestibular system, kinetosis and vegetative-vascular dystonia, containing a) antibodies in an activated potentiated form to brain-specific protein 5-100 in the form of a mixture of homeopathic dilutions of C12, C30 and C200, and b) antibodies in an activated potentiated form to endothelial MO-synthase in the form of a mixture of homeopathic dilutions C12, C30 and C200. 2. The combined medicinal product according to claim 1, which is characterized by the fact that the antibodies in the activated potentiated form to brain-specific protein 5-100 are antibodies to the whole molecule of bovine brain-specific protein 5-100. 3. Combined medicinal product according to claim 1, which is characterized by the fact that the antibodies in the activated potentiated form to brain-specific protein 5-100 are antibodies to brain-specific protein 5-100 with the sequence ZEO IU MO:9, 5EO IU MO:10, 5EO I MO :11 or 5EO IU MO:12. 4. The combined medicinal product according to claim 1, which is characterized by the fact that the antibodies in the activated potentiated form to endothelial MO-synthase are antibodies to the whole molecule of bovine MO-synthase. 5. The combined medicinal product according to claim 1, which is characterized by the fact that the antibodies in the activated potentiated form to endothelial MO-synthase are antibodies to the whole human MO-synthase molecule. 6. Combined medicinal product according to claim 1, which differs in that antibodies in an activated potentiated form to brain-specific protein 5-100 are presented in the form of a mixture of homeopathic dilutions C12, C30 and C200, impregnated in a solid carrier, and antibodies in an activated potentiated form to endothelial MO-synthases are presented in the form of a mixture of homeopathic dilutions C12, C30 and C200, impregnated in a solid carrier. 7. Combined medicinal product according to claim 1, which differs in that antibodies in an activated potentiated form to endothelial MO-synthase are presented in the form of a mixture of homeopathic dilutions C12, C30 and C200, impregnated in a solid carrier, and antibodies in an activated potentiated form to a brain-specific protein 5-100 are presented in the form of a mixture of homeopathic dilutions C12, C30 and C200, impregnated in a solid carrier. 8. Combined medicinal product according to claim 1, which is characterized by the fact that the antibody to brain-specific protein 5-100 in an activated potentiated form is a monoclonal, polyclonal or natural antibody. 9. The combined medicinal product according to claim 8, which is characterized by the fact that the antibody to brain-specific protein 5-100 in the activated potentiated form is a polyclonal Zo antibody. 10. The combined medicinal product according to claim 1, which is characterized by the fact that antibodies in an activated potentiated form to brain-specific protein 5-100 are prepared by successive hundredfold dilutions in combination with shaking of each dilution. 11. Combined medicinal product according to claim 1, which is characterized by the fact that the antibody to endothelial MO-synthase in an activated potentiated form is a monoclonal, polyclonal or natural antibody. 12. Combined medicinal product according to claim 11, which is characterized by the fact that the antibody to endothelial MO-synthase in the activated potentiated form is a polyclonal antibody. 13. The combined medicinal product according to claim 1, which is characterized by the fact that antibodies in an activated potentiated form to endothelial MO-synthase are prepared by successive hundredfold dilutions in combination with shaking of each dilution. 14. A method of treating vertigo/dizziness associated with disorders of the vestibular system, motion sickness and vegetative-vascular dystonia, which is characterized by the fact that the combined medicinal product according to claim 1 is administered. 15. A method of alleviating motion sickness, measured using the BKPK test (continuous accumulation of Coriolis accelerations), which is characterized by the fact that the combined medicinal product according to claim 1 is administered. 16. A method of improving the work of the autonomic nervous system, which was measured using the BKPK test, which is characterized by the fact that the combined medicinal product according to claim 1 is administered. 17. The method according to any of claims 14-16, which differs in that the combined pharmaceutical preparation is administered in 1-2 standard dosage forms, and each dosage form is administered from 1 to 4 times a day. 18. The method according to claim 17, which differs in that the combined pharmaceutical preparation is administered in 1-2 standard dosage forms, and each dosage form is administered 2 times a day. 19. Medicinal preparation for the treatment of patients suffering from dizziness associated with disorders of the vestibular system, motion sickness and vegetative-vascular dystonia, and the specified preparation is obtained using a) antibodies in an activated potentiated form to brain-specific protein 5-100 in the form of a mixture homeopathic dilutions C12, C30 and C200, b) antibodies in an activated potentiated form to endothelial MO-synthase in the form of a mixture of homeopathic dilutions C12, C30 and C200, each of which is prepared by successive repeated dilutions and repeated shaking of each obtained solution according to the homeopathic technology, and then either combine potentiated solutions by mixing them, or, alternatively, impregnate the carrier mass with the specified combined solution or solutions separately.