RU2631887C2 - Active drug ingredient, drug, pharmaceutical composition and method for treatment of demyelinating diseases of living organism, including disease prevention - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: invention is a drug for treatment of diseases of a living organism associated with inflammatory demyelination, represented by polyprenols derived from coniferous tree species of the general formula

This invention also includes a method for treatment of diseases of a living organism associated with inflammatory demyelination, characterised by introduction of an effective amount of polyprenols of the general formula (1) into the living organism to enhance myelination and formation of young neurons in white and gray brain material.

EFFECT: invention has a double positive effect in demyelinating conditions, namely it has a remyelinating effect, accelerates the process of neurogenesis, and also has an immunomodulating metabolic action, as well as allows to obtain a minimal side effect when using a medicinal product of plant origin.

4 cl, 10 dwg, 2 tbl, 5 ex

Description

Technical field

The invention is a group of inventions and relates to the field of medicine, namely to means and methods for the treatment and prevention of demyelinating diseases of a living organism, including multiple sclerosis and conditions associated with demyelination, polyneuropathy and / or symptoms or signs of such conditions.

State of the art

Demyelinating diseases (hereinafter referred to as DZ) are among the autoimmune diseases, the main pathomorphological manifestation of which is the destruction of myelin in the white or gray matter of the central and / or peripheral nervous system (hereinafter CNS, PNS). In recent years, a steady tendency towards an increase in the frequency of DZ has been observed all over the world, the number of cases with a clinical onset in children and adults over the age of 45 is growing, and the nature of the course of DZ has changed.

Currently, it is proved that the etiology of DZ is based on the interaction of environmental factors and the hereditary predisposition of the body. Among external factors, viruses (Epstein-Barr, herpes, measles, rubella, retroviruses), chronic bacterial and campylobacter infections, intoxications (solvents, gasoline, metals), nutritional features (the predominance of animal fats and proteins), psychoemotional stress are of greatest importance. , environmental degradation [Zavalishin IA, Zhuchenko TD, Peresedova AV, Bulletin of the Russian Academy of Medical Sciences. Sciences., 2001, No. 7, p. 18-22]. The pathogenetic mechanisms of DZ are similar and consist in the development of autoimmune reactions to neuroantigens, which are a number of proteins and lipids of the myelin sheath. The initial mechanism for the development of these diseases is the activation of peripheral T-lymphocytes specific for the myelin basic protein (MBP). Several activation paths are possible: 1) due to molecular mimicry, when the antigenic structure of bacteria or viruses is similar to MBP, therefore T-cell receptors cease to distinguish between “their” and “foreign” antigens; 2) T cells can be activated in a non-specific way due to the high local concentration of cytokines that accompanies any inflammatory reaction. The next stage of the pathological process is the penetration of autoreactive lymphocytes through the blood-brain barrier (BBB) by increasing the expression of adhesion molecules. Penetrated into the nervous system, T cells secrete pro-inflammatory cytokines (gamma interferon, lymphotoxin, TNF-a). Against this background, due to a sharp increase in the number of inflammatory mediators, the microenvironment of the brain is rapidly changing, and anti-myelin antibodies are formed in response. The final stage is the death of oligodendrocytes, the development of the demyelination process due to activation of the complement system, macrophages, microglia and phagocytosis of damaged structures.

One of the serious demyelinating diseases is multiple sclerosis (hereinafter referred to as PC), which is one of the most common. A feature of the disease is the simultaneous defeat of several parts of the central nervous system, which is manifested by a variety of neurological symptoms. For 85-90% of patients in the early stages, a remitting (undulating) course is characteristic, which subsequently, as a rule, is replaced by a progressive one. In addition, the specific causes of the disease are unclear, it is generally accepted that PC is a multifactorial disease that occurs in people who have a genetic predisposition, and who are also affected by some external factor. As a rule, the processes of demyelination and inflammation are preceded by biochemical changes, including nitrification and oxidative stress of the mitochondrial proteins of the respiratory complexes, which lead to a decrease in mitochondrial potential and apoptosis of neurons. Myelin-specific T lymphocytes cause damage to mitochondrial macromolecules, thereby breaking off the respiratory chain of mitochondria and reducing ATP synthesis, as well as causing apoptosis [Bernadette Kalman et all. The involvement of mitochondria in the pathogenesis of multiple sclerosis. Journal of Neuroimmunology No. 188, 2007, P. 1-12]. Nitric oxide (NO) is a free radical whose concentration increases during the inflammatory process during the development of multiple sclerosis and plays an important role in the disruption of the BBB, as well as in the process of demyelination and death of oligodendrocytes and axon loss. Myelin is a white matter of the brain that covers the axons of neurons and promotes the effective conductivity of nerve impulses between the brain and other parts of the body. The loss of myelin (i.e., demyelination) or the abnormal composition of myelin may be associated with a decrease in the speed or activity of processes in the nervous system and subsequent deterioration in cognitive function.

The myelin sheath is a special type of cell membrane surrounding the processes of nerve cells, mainly axons in the central nervous system and the central nervous system. The main functions of myelin are: axon nutrition, isolation and acceleration of nerve impulse conduction and preservation of ion fluxes by reducing the membrane capacity, as well as supporting and barrier functions. This is a lipoprotein membrane, consisting of a bimolecular lipid layer located between the monomolecular layers of proteins, spirally twisted around the nerve fiber. Myelins of the central nervous system and PNS differ in their chemical composition. In PNS, myelin is synthesized by Schwann cells. Myelin PNS is noticeably thicker than in the central nervous system. In the central nervous system, myelin is synthesized by oligodendrocytes, with one cell taking part in the myelination of several fibers [Huho F. Neurochemistry: fundamentals and principles: Translated from English. - M: Mir, 1990, 384 p.]. The destruction of myelin is a universal mechanism of reaction of nerve tissue to damage. From the point of view of pathogenesis, PC was considered as an inflammatory demyelinating disease in which the primary targets of the destructive process are the myelin sheath and oligodendrocytes.

Immunological changes in PC are manifested by deviations of cellular and humoral immunity. From the side of cellular reactivity, the following are determined: a decrease in the T-cell content of suppressors, a suppression of the T-cell response to mitogens, a change in the production of interferons, an increase in the cytotoxicity of mononuclear cells, and changes in the system of interleukins. The involvement of multidirectional cytokines in the pathogenesis of PC has been repeatedly shown in experimental studies. Tumor necrosis factor-α (TNF-α) is considered a classic pro-inflammatory cytokine, but it has recently been shown that this cytokine has a significant anti-inflammatory and neuroprotective effect in demyelinating diseases [TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS / MRI Analysis Group // Neurology, 1999, 53,. 457-465] Clinical manifestations of PC are a consequence of the development of demyelinating foci of inflammation in the central nervous system. The autoimmune nature of this disease has both experimental and clinical evidence. In PC, autoimmune aggression can be directed towards the myelin basic protein (MBP), proteolipid protein (PLP, proteolipid protein), myelin glycoprotein (MAG, myelin-associated glycoprotein), myelin oligodendrocyte glycoprotein glycoprotein (MOG) ) and possibly other myelin antigens [Zhang J. T cell vaccination as an immunotherapy for autoimmune diseases. Cell. Mol. Immunol. 2004; 1: P. 321-7]. Pathological foci formed in PC in the white matter of the brain and spinal cord are called plaques. The leading feature of these foci is demyelination. Activation of resident CNS cells — microglia and astroglia — stimulates their secretion of cytokines and chemokines (factors that attract cells to the focus of inflammation). Cells of hematogenous origin migrate to the foci - monocytes / macrophages, T- and B-lymphocytes. So the formation of plaque begins. In the focus of inflammation, cells secrete many active molecules: cytokines, antibodies, oxygen and nitrogen radicals, proteases. These molecules are major factors in damage to oligodendrocytes and myelin. Repeated exacerbation is manifested by inflammation along the periphery of the gliosis zone, the focus increases in size. Along with this, new foci appear, and some may regress. A histological examination of acute foci reveals partial or complete destruction and loss of myelin. Axonal endings generally remain intact. In addition to demyelination, plaques are characterized by a neuroglial reaction and infiltration by mononuclear cells (lymphocytes and macrophages). Chronic lesions are predominantly represented by gliosis [Homes J., Madgwick T., Bates D. The cost of multiple sclerosis. Br J Med Econ 1995; 18: 181-93].

Studies of the last decade have shown that with PC, damage to axons and neurons occurs, the severity of which varies in intensity at different lesions in one patient, as well as when comparing lesions in different patients with PC. [Neurodegenerative process in multiple sclerosis and the possible neuroprotective effect of therapy with β-interferon 1a (Avonex). M.V. Davydovskaya, A.N. Boyko, A.E. Podoprigora, I.N. Pronin, V.N. Kornienko, E.I. Gusev. Journal of Neurology and Psychiatry. No. 9. Vol. 2, 2012, p. 129-135].

The course of PC is very individual - there are no two patients with the same clinical manifestations of the pathological process. In most cases, after a certain period of time, individual for each patient, the remitting course of the PC becomes secondary-progressive with a gradual increase in neurological deficit, a reduction in the periods of clinical stabilization, and disability of patients. In general, the clinical manifestations of PC can be divided into 7 main groups:

1) damage to the pyramidal system with hemi-, para- and tetraparesis with a corresponding increase in tendon reflexes and pathological pyramidal symptoms;

2) damage to the cerebellum and its pathways with the development of static and dynamic ataxia, muscle hypotension;

3) sensory impairment, in the beginning - deep, with the development of sensory ataxia and sensory paresis, and then pain and temperature according to the conductor type;

4) damage to the white matter of the brain stem with various disorders of the cranial innervation, most often with the development of oculomotor symptoms, damage to the facial nerve (peripheral paresis of the muscles of the face);

5) optic neuritis (including retrobulbar neuritis) with a decrease in visual acuity and the appearance of cattle;

6) dysfunctions of the pelvic organs, often by the type of imperative urges, urinary retention, and subsequently until urinary incontinence;

7) neuropsychological changes, weakening of memory, euphoria or depression, characterized by chronic fatigue syndrome.

In most cases, patients have symptoms of damage to both the brain and the spinal cord (cerebrospinal form). In some cases, the symptoms of spinal cord injury (spinal form) or cerebellum (cerebellar or hyperkinetic form) predominate in the clinical picture. In the latter case, intentional trembling can be so pronounced that it reaches a degree of hyperkinesis and makes any targeted movement impossible. Dysmetria, adiadochokinesis, chanted speech, severe ataxia occur. Magnetic resonance imaging (MRI) of the brain and spinal cord is currently one of the most informative research methods. Detection in T2 and proton modes of foci of increased intensity of circular or oval shape, of various sizes (from 3 to 3 cm), located in any areas of the brain, is considered characteristic of DZ.

Other demyelinating diseases also include peripheral nervous system DZ - acute onset (Guillain-Barré syndrome (GBS), occurs at any age, 2 times more often in men. Chronic inflammatory demyelinating polyneuropathy (CID) has two peaks of onset of the disease: in 40 50 years and after 70 years (less pronounced), 3 times more often in men.CVDP is diagnosed with two obligate clinical signs:

1) progressive or recurrent weakness in the limbs lasting more than 6 months;

2) hypo- or areflexia in all four limbs. The distinctive clinical signs of CVD include:

- predominantly distal or mixed (distal and proximal) character of paresis of limbs;

- severe muscular hypotension and hypotrophy of the arms and legs;

- more frequent and persistent sensitive and autonomic disorders in the limbs;

- extremely rare - the addition of respiratory and pelvic disorders.

The prognosis of CVD is less favorable and depends on the type of course (progressive, progressive remitting, regressing, stationary), as well as the possible involvement of the central nervous system structures in the process. After a year, 30-60% of patients lose their ability to work [M. Piradov. // Nevrol. Journal, 2001, No. 2, S. 4-9].

Hereditary motor-sensory polyneuropathy type I (Charcot-Marie disease) is pathomorphologically a demyelinating disease. Polyneuropathy associated with anti-MAG (myelin-associated glycoprotein) monoclonal gammopathy has recently been isolated into an independent nosological form and is clinically manifested in isolation by sensory disturbances in the limbs. [Leger J. - M., Salachas F. // Eur. J. Neurol. 2001, N 8, P. 201-209].

Electroneuromyography reveals signs of myelin destruction and axonal degeneration. The most characteristic changes are a significant decrease in the speed of the impulse along peripheral nerves, an increase in distal latency, a change in the shape of the M-response, and F-wave delay. Using a special technique of sympathetic cutaneous evoked potential allows you to quantify the degree of autonomic disorders in the limbs.

Despite numerous studies, the etiology of the disease is still unclear. Therapy of multiple sclerosis is the timely adequate relief of exacerbations, the appointment of drugs that slow the progression of the disease by preventing exacerbations.

It is known that treatment of PC was reduced to relieving exacerbations of the disease using drugs of the corticosteroid group in order to suppress the activity of the immune system and conduct symptomatic therapy. The most commonly used methylprednisolone is administered intravenously in a dose of 1000-2000 mg per day (per 400-500 ml of saline) for 3-10 days, depending on the severity of the exacerbation [F. Barkhof et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain. - 1997. V. 120. P. 2059-2069].

However, hormonal drugs have a number of side effects. [Bashir K., Buchward L, Coyle R.K. Optimizing immunomodulatory therapy for MS patients // Int. JMCS Care. - 2002. - Vol. 4. - P. 3-7]. Drugs with a cytostatic and antiproliferative effect, as well as general irradiation of lymphocytes, are used, as a rule, in malignant, steadily progressive MS in patients with corticosteroid intolerance. The largest number of studies on the effectiveness of cytostatics for the treatment of multiple sclerosis was carried out using azathioprine. Analysis of controlled studies showed a slight, but statistically significant decrease in the frequency of exacerbations after 2-3 years of therapy, a slight slowdown in patient disability compared with the control placebo group (about 0.2 points on the EDSS scale for 2 years) [A.A. Poryvaeva - On the use of cytostatics in the treatment of multiple sclerosis. Modern high technology. No. 1. 2005. S. 72-73].

However, the use of such cytostatics is associated with the presence of serious side effects of this group of drugs [Bashir K., Buchward L, Coyle P.K. Optimizing immunomodulatory therapy for MS patients // Int. JMCS Care. - 2002. - Vol. 4. - P. 3-7].

In the 90s, preventive drugs of a pathogenetic orientation appeared, which significantly reduce the number of exacerbations of the PC and slow its development, but, unfortunately, do not lead to a complete recovery. These are immunomodulatory agents that have proven themselves in clinical practice.

These include interferons beta (interferon beta-1b, interferon beta-1a) and preparations based on them (betaferon, rebif, avonex) and glatiramer acetate. All these drugs are first-line drugs recommended for prescribing to patients with a remitting form of the course of PC with mild to moderate disability. Possessing completely different mechanisms of action, they lead to a reduction in the frequency of exacerbations by 30-35% [Freedman M., Hughes B., Mikol D. et al. Efficacy of disease-modifying therapies in relapsing-remitting multiple sclerosis: a systematic comparison / Eur. Neurol., 2008. v. 60, p. 1-11].

All of these immunomodulators should be used continuously, injected and have a certain spectrum of adverse events.

However, the most significant adverse event that occurs with the use of interferon beta is a flu-like syndrome with fever, headaches and muscle pain, which occurs after administration of the drug and sometimes lasts quite a long time.

When using glatiramer (copaxone), side effects also occur in the form of systemic post-injection reactions, manifested in the form of autonomic crises, and atrophy of adipose tissue at the injection site. The use of first-line immunomodulators in not all patients leads to the desired result. This is due to a number of reasons, and above all, the genetic characteristics of various patients. In addition, the use of interferon beta in some cases is accompanied by the formation of neutralizing antibodies that reduce the biological activity of drugs [Vartanian T., Sorensen R., Rice G. Impact of neutralizing antibodies on the clinical effect of interferon beta in multiple sclerosis. / J. Neurol., 2004, 251, suppl. 2, 25-30]. A significant factor in the lack of response to therapy is the incomplete adherence to treatment due to fear of injections, "fatigue" from the constant long-term injection of the drug, or intolerable side effects [Gold R. Adherence to treatment: value of patient support / Cl. Trends in Neurol., 2005, v. 1, p. 11-14].

It is known to use the drug fingolimod (Gilenia) manufactured by Novartis, which is used relatively recently. It was approved for use in the United States (2010), Europe (2011), and now in Russia (2010). The drug is a derivative of myriocin and is isolated from the fungus Saria sinclairii, used in traditional herbal treatment. Using sphingosine kinase, it in the liver turns into an active metabolite - fingolimod phosphate. Fingolimod is a modulator of 4 of the 5 known sphingosine phosphate receptors [Dominguez M., Casals D., Sabate M. et al. Prediction of pharmacokinetic / pharmacodynamic behavior in humans of LAS189913, a S1P1 receptors agonist, based on preclinical studies in three animal species / Mult. Scl., 2010, V. 16, suppl. 10, S 150, P 453], which are present in different tissues, but especially widely in lymphocytes, cells of the central and peripheral nervous system.

The number of "autoaggressive" T cells circulating in the blood decreases and the degree of inflammatory changes in the central nervous system decreases. In addition, it was shown that fingolimod, being lipophilic in nature, penetrates the blood-brain barrier into the central nervous system, where phosphate receptors of glia and neurons act on sphingosine-1, having a neuroprotective effect [Osinde M., Mullershausen F., Dev K. Phosphorylated FTY720 stimulates ERK phosphorylation in astrocytes via S1P receptors. / Neuropharm., 2007. v. 52, p. 1210-1218]. However, with its use, adverse side effects are often observed - headache, dyspnea, diarrhea, nausea.

In the first 3-4 months of treatment, the level of liver enzymes may increase. Its normalization occurs after about 2 months. after stopping the drug. Fingolimod has the effect of a “first dose”, resulting in a dose of 0.5 mg to symptomatic bradycardia in about 0.5% of patients, therefore, the use of fingolimod requires monitoring the patient for 6 hours after applying the first dose of the drug. Before prescribing the drug and 3-4 months after the start of its use, an oculist examination is necessary, because taking fingolimod at a dose of 0.5 mg led to the development of edema of the macula of the eye in 0.3% of patients. Patients with diabetes and a history of uveitis require special attention. [Recommendations on the use of new drugs (tisabri, guilenia, movectro) for the pathogenetic treatment of multiple sclerosis. All-Russian Society of Neurologists. Demyelinating Diseases Section. Moscow, 2011].

It is known that bone marrow stem cell transplantation has been proposed for the treatment of PC, but this is associated with the risk of re-autoimmunization of the body, and on the other hand, a higher mortality rate for allotransplantation (15-35%) than for auto-transplantation (3-10%) . Granulocyte-macrophage colony stimulating factor is also proposed for the treatment of PC [Application 2011145434, PCT publication WO No. 2010/1283535, 2010.11.11]. For the treatment of recurrent multiple sclerosis, drugs based on monoclonal antibodies Lemtrada (Lemtrad, alemtuzum) are proposed [Coles A.J. et al. / Alemtuzumab vs interferon beta-1a in early multiple sclerosis. New England Journal of Medicine 2008; 359: 1786-1801]. However, significant side effects appear in the clinic - this is idiopathic thrombocytopenic purpura (ITP) - a disease that disrupts blood coagulation, it was fatal in one case and was noted in 1-3% of participants and impaired thyroid function in 20-30% of patients.

However, given that the PC has been going on for quite some time, these tools and treatments can be very expensive and not available to all patients. So, today the costs of treating patients in a moderate stage in European countries range from € 28,524 to € 43,948 per year [Medical News. 2002, No. 6, S. 3-7].

The closest analogue to the claimed invention is US patent No. 2444356, which proposes the use of polyunsaturated fatty acids for the treatment of dementia. An embodiment of this invention relates to a method for delaying demyelination or reducing the severity of demyelination in an individual. The method comprises administering to the individual a combination of polyunsaturated fatty acids (PUFAs) or their precursors or sources to delay demyelination or reduce the severity of demyelination.

However, polyunsaturated fatty acids can be considered as adjuvants mainly for the prevention of demyelinating conditions, but not for treatment. In addition, polyunsaturated fatty acids and oils in which they are dissolved are usually unstable and transform into a transformation that is already harmful to humans, in particular they increase intraocular pressure in people predisposed to glaucoma. Diet with a higher content of polyunsaturated fats than saturated (animals) often leads to gallstone disease and can cause gallbladder spasms associated with thickening of bile [Mary Den Izz Vitamins and Minerals: A Complete Medical Guide. - 2 ed. - SPb. 1996, 503 pp.]. Therefore, prolonged administration of polyunsaturated fatty acids for the prevention and treatment of demyelinating diseases can be considered as a preventive measure.

Disclosure of invention

The tasks to which the invention is directed are to create a new drug, a new pharmaceutical composition and a new method of treatment, including the prevention of demyelinating diseases.

The technical result of the invention is to obtain a minimal side effect when using a new medicinal product and a new pharmaceutical composition of plant origin, created on the basis of a fundamentally new class of compounds - polyprenols (long chain polyisoprenoid alcohols), in a method of treating demyelinating diseases of a living organism, including the prevention of diseases, including the number of multiple sclerosis and conditions associated with demyelination, and / or symptoms or signs of such Toyan.

The tasks are solved as follows.

Polyprenols of the formula (1)

, где n=8-20

where n = 8-20

were used as an active ingredient in the manufacture of a medicament for the treatment of demyelinating diseases of a living organism.

Polyprenols of the formula (1)

, где n=8-20

where n = 8-20

were used as an active ingredient in the manufacture of a medicament for the prevention of demyelinating diseases of a living organism.

The drug for the treatment of demyelinating diseases of a living organism, including the prevention of the disease, is characterized in that it is a polyprenol of the formula (1)

, где n=8-20.

where n = 8-20.

A pharmaceutical composition for treating demyelinating diseases of a living organism, including disease prevention, is characterized in that it comprises an effective amount of polyprenols of the formula (1)

, где n=8-20.

where n = 8-20.

and pharmaceutically acceptable excipients, including carriers, and / or solvents, additives and / or lubricants.

The pharmaceutical composition may be in the form of a solution, suspension, capsule, tablet, granule, suppository.

A method of treating demyelinating diseases of a living organism, including disease prevention, is characterized in that an effective amount of polyprenols of the formula (1) is introduced into a living organism

, где n=8-20.

where n = 8-20.

in the form of a stand-alone preparation or in the form of a pharmaceutical composition further comprising auxiliary ingredients.

The above polyprenols are isolated from conifers, including pine and spruce, fir, gingko biloba needles from woody green.

The use of polyprenols according to the formula (1) is possible in complex therapy together with a remyelinating agent and an anti-inflammatory agent, which is an adrenocorticotropic hormone, corticosteroid, interferon, glatiramer acetate or a non-steroidal anti-inflammatory drug

The implementation of the invention

The inventors have identified the previously unknown possibility of using polyprenols of the formula (1) for the treatment and prevention in patients with conditions associated with demyelination and / or symptoms or signs of such conditions.

Polyprenols of the formula (1) is a natural mixture of oligomers (isoprenoids) behaves as one substance (Ropren), but can be divided into individual isoprenoids on reversed-phase sorbents. Ropren is obtained from coniferous herbs (pine, spruce, fir) (patent RU No. 20177782). This polyprenol showed antiulcer action [N.A. Skuya et al. Products of woody greens processing - prospects for use in gastroenterology В: Functional diagnostics and treatment of digestive diseases. Vilnius, 1988, part 4, p. 675-676], hepatoprotective (US patent No. 5731357), immunomodulating (patent RU 2137479). The purest fraction of isoprenols - Ropren obtained by the method described in patent PCT / RU No. 2004/000162. The drug stimulates the processes of natural regeneration of the liver (RU No. 2252026), is used as a tool for the treatment of alcoholism and complications associated with it (PCT / RU 2008/000298, RU No. 2323248), as a tool for the treatment of patients with dementia syndrome (PCT / RU Application No. 2008/000297).

However, currently drugs to accelerate the recovery of myelination of nerve endings and accelerate neurogenesis are not used. The use of herbal preparations based on polyprenols is a promising direction.

These include the drug Ropren, which can serve as an exogenous source of isoprenoid units, from which the endogenous product in the body is formed - dolichol. The isoprene units that make up Ropren can be used by the body, both for building cholesterol and for building ubiquinone - vital metabolites for the body. Polyisoprenode alcohols (prenols / dolichols) are metabolites in a living organism that are important, they are present in any living organism - from bacteria to every cell in the human body. They participate in the mevalonate pathway of cholesterol biosynthesis and in violation of this biosynthesis, which can take place both with dolichols and without them, which can lead to impaired lipid metabolism in the body. Another way of biosynthesis, in which polyprenols in the form of phosphorylated derivatives are involved, is the biosynthesis of glycoproteins, where they are involved in the processes of glycosylation of proteins and recognition of glucoprotein on the membrane (for example, as a cofactor in the formation of phosphatidylionisitol (GPI), which, as an anchor, is attached to the membrane and in transmission of a nerve impulse). He also participates in the recognition of antigens on the membrane, regulates the fluidity and viscosity of the membranes, and therefore the opening of ion channels, as well as the passage of a nerve impulse through the membrane. All their functions have not yet been discovered, but based on research, these compounds are of great interest for pharmacology [Surmacz L, Swiezewska E. Polyisoprenoids - Secondary metabolites or physiologically important superlipids, Biochem Biophys Res Commun. 2011, Apr 22; 407 (4): 627-32. doi: 10.1016 / j.bbrc.2011.03.05.059. Epub 2011, Mar 16].

Ropren is a promising drug for the treatment of neurodegenerative diseases such as dementia and Alzheimer's disease (BA) due to its effect on the activity of mitochondrial enzymes Bche and MAO.

As is known, the white matter of the brain in higher organisms consists of more than 50% myelin, therefore, disturbances in the formation of myelin during ontogenesis or changes in the structure of myelin in the developed nervous system lead to demyelinating diseases and severe neuropathies.

There is evidence that polyprenol (dolichol) is found in the black substance of the brain in neuromelanin, and its content is quite high - up to 15%, but its functions are still unknown. [Joshida K., Engel J., Liljequst S. Naunyn. Schmiedebergs Arch. Pharmacol 1982, Oct., 321 (1), 3-74, Investigation of lipid component of neuromelani (NM)]. Typically, proteins predominate in the membranes, but in the case of the myelin sheath of nerves, three quarters of the mass is lipids. Myelin lipids are represented by phospholipids, glycolipids and steroids. Typically, proteins predominate in membranes, but in the case of the myelin sheath of nerves, three quarters of the mass is lipids, with cholesterol of the total lipid mass being 28% and located on the outside of the membrane.

The total lipid content in myelin is 2 times higher - they are approximately 70-85%, and proteins make up to 20% of the dry mass of myelin compared to other plasma membranes. Myelin lipids are represented by phospholipids, glycolipids and steroids. If changes are observed in the lipid composition of myelin, then pathological or genetic disorders occur during myelination. Myelin does not metabolize completely, the half-life of lipids ranges from 5 weeks to 2-4 months in phosphatidylserine and phosphotidylcholine) to 1 year (in cholesterol). For proteins, this period ranges from 2 to 6 weeks (basic protein and proteolipid). However, it is interesting that the half-life is different for each component of the membrane and they are updated independently of each other, i.e. exchange occurs between all layers of the membrane [Huho F. Neurochemistry: fundamentals and principles: Trans. from English M: Mir, 1990, 91-109 p.].

Polyprenols, which are polyisoprene units, like dolichol, exhibit membrane-active properties that affect the fluidity and viscosity of membranes. Apparently, due to the binding of the polyisoprenoid fragment at its a-end to glycoproteins, and then to the protein, the transport of the protein or peptide and the transmission of the nerve impulse are facilitated. The main myelin protein and myelin glycoproteins are the main oligodendrocyte macromolecules. It can be assumed that, when protein synthesis is suppressed in the myelin sheath, polyprenols (Ropren) promote and / or participate in the transfer of myelin proteins, including the myelin basic protein (MBP) and secrete them through the membrane and thereby facilitate the transmission of nerve impulses and protect them from autoimmune aggression. In addition, in each cell in the vesicles, along with cholesterol, dolichol is always contained, which is involved in the biosynthesis of cholesterol. It can be assumed that when, under the influence of various factors, the myelin sheath is damaged, the polyprenols come to the rescue and compensate for the lack of cholesterol, thereby preventing the loss of myelin (i.e., demyelination), and also restoring the speed or activity of processes in the nervous system, which is confirmed new data. Namely, sterols and other lipids (dolichol) involved in cholesterol biosynthesis, are the conductors of the main proteins through the membrane and are involved in the regulation of nerve signal transmission [Friedhelm Schroeder, Barbara P. Atshaves at al-Sterol Carrier Protein-2: New roles in regulating lipid rafts andsignaling / Biochem. Biophys. Acta, 2007, June, 1771 (6), p. 700-718]. Long-chain polyprenols and polyprenyl phosphates are the ubiquitous and major components of cell membranes in all walks of life [Hartley MD1, Imperiali At the membrane frontier: a prospectus on the remarkable evolutionary conservation of polyprenols and polyprenyl-phosphates. Arch Biochem Biophys. 2012 Jan 15; 517 (2): 83-97. doi: 10.1016 / j.abb.2011.10.01.018. Epub 2011 Nov 10]. In addition, polyprenols in membranes can cause intracellular resonance and appear to be involved in signal transduction [Knudsen MJ1, Troy FA. Nuclear magnetic resonance studies of polyisoprenols in model membranes. Chem Phys Lipids. 1989 Nov; 51 (3-4): 205-12].

In an experimental study on animals with cerebral ischemia, it was shown that Ropren has a cerebroprotective effect (Report on the topic “Study of the effect of the drug ropren on energy metabolism in rat brain ischemia. Military Medical Academy, Department of Pharmacology (St. Petersburg)). The use of ropren at a dose of 4.3 mg / kg and 11.3 mg / kg for 7 days after occlusion of the common carotid arteries reduces the severity of neurological disorders in rats and increases their survival in the postischemic period. Ropren in these doses protects the brain from the development of metabolic acidosis and prevents the development of metabolic disorders. Against the background of cerebral ischemia and hypoxia, piracetam only by 46.5%, and ropren 11.6 mg / kg by 62% (that is, almost two-thirds) reduces lactic acidosis. At the same dose, roprene increases the content of creatine phosphate by 73% (piracetam by 60%) and by 173% the content of ATP in the brain tissue. Ropren and the piracetam comparison drug act approximately the same on the ADP level, reducing its level by 40-43%. At the same time, both piracetam and roprene restored to normal the energy charge characterizing the general state of energy metabolism in the brain. The energy-stabilizing effects of roprene are comparable to the effects of piracetam. Shabanov P.D., Zarubina I.V., Sultanov B.C. To the mechanism of action of polyprenols in cerebral ischemia, 2011. V. 11. No. 2. S. 24]. In addition, using the immunohistochemical method, it was shown that Ropren, with cerebral ischemia in the nigrostatum zone, inhibits astrocyte hyperreaction and promotes astrocyte regeneration [Droblenkov AV, Monid MV, Volkovich EI / Early reactive changes of the astrocytes in the midbrain paranigral nucleus after forebrainprotector and Ropren administration in rats] Morfologiia. 2014; 145 (1): 24-7]. Polyprenols have immunomodulatory and antiviral effects [Safatov AS at all, J Aerosol Med. 2005 Spring; 18 (1): 55-62. A prototype prophylactic anti-influenza preparation in aerosol form on the basis of Abies sibirica polyprenols]. Ropren is able to increase the level of INF in the blood and, unlike other drugs (Cycloferon), it has a prolonged effect [Zarubaev V.V., Sultanov B.C., Sukhinin V.P., Roshchin V.I., Nikitina T.V. Study of the dynamics of interferonogenic activity of Ropren preparations and its modified analogue in experiments on white mice. // Materials of the conference “Pasteur’s Ideas in the Fight Against Infections, St. Petersburg, June 2-4, 2008, p. 12]. In addition, when studying the effect of Ropren on the level of TNF-alpha in mice with ascitic and solid Ehrlich carcinoma in the experiment, it was found that in this case, a decrease in the concentration of TNF-alpha in the blood serum is observed (for Ropren by 38% with a solid tumor and 78% - with ascites, and for comparison drug - Glutoxim - by 29 and 75%, respectively (Report of the Research Institute of Influenza RAMS "Research on the antitumor activity and mechanisms of action of the drug" Ropren "on models of solid and ascites forms of Ehrlich carcinoma in white mice, St. Petersburg, 2007). Known that with autoimmune aggression and the development of multiple sclerosis - a decrease in the level of TNF-alpha is a good prognostic factor, reducing inflammation.

The inventors conducted additional studies on the Ropren preparation and revealed a previously unknown property of this compound, namely, a composition based on polyprenols has a double positive effect in demyelinating conditions, namely, it has a remyelinating (restoring) effect, accelerates (increases) the process of neurogenesis, and also has immunomodulatory metabolic action. This new property of Ropren is confirmed by experimental data.

The basis for the use of the compounds of formula (1) for the declared purpose was the identification of a number of new activities previously unknown for this compound.

In an animal experiment, the effect of Ropren on myelination of white and gray matter was studied in a model of multiple sclerosis by cuprizone intoxication. Cuprizone intoxication is an excellent model used worldwide to study pathologies such as multiple sclerosis, epilepsy and schizophrenia. [Preisner A1, Albrecht S, Cui QL, Hucke S - Non-steroidal anti-inflammatory drug indometacin enhances endogenous remyelination. / Acta Neuropathol. 2015 May 6. [Epub ahead of print]. It has been observed that a three-week exposure to cuprizone is sufficient to cause deep demyelination [Oligodendrocytes and ischemic brain injury. Dewar D., Underhill S.M., Goldberg, M.P. J. Cereb. Blood Flow Metab. 23. 2003. P. 263-274]. The introduction of cuprizone causes axonal edema, which occurs due to the redistribution of Na + channels and mitochondrial deficiency, which leads to disruption of sodium and calcium homeostasis. Nevertheless, there are differences - there are no inflamed vessels in the Cuprizon model, and T cells are in a minimal amount [Rossi L., Lombardo M.F., Ciriolo M.R., Rotilio G. Mitochondrial disfunctionin neurodegenerative diseases associated with copper imbalance. Neurochem. Res. 29. 2004. H. 493-504]. Under the action of cuprizone, massive apoptosis of oligodendrocytes occurs on the fourth week of exposure with the participation of the immune system, and by 6 weeks, the oligodendrocyte precursors differentiate into adult cells. Despite the fact that pathologies of neurons are considered rare during demyelination, literary sources indicate the opposite. Early changes occur at the synapse level, where the mediator concentration is impaired due to changes in the activity of synthesizing enzymes. In addition, inhibition of transport protein activity can be observed in demyelinated axon regions, which ultimately leads to axon loss. Most neurons survive during cuprizone intoxication, despite the fact that they are equally or often more vulnerable to metabolic disorders compared to oligodendrocytes. A possible explanation is the metabolic relationship of neurons with astrocytes, which protect them from oxidative stress. During oxidative stress, astrocytes can trigger the glycolysis process, thereby creating a buffer that protects neurons from oxidative stress [Activation of inflammatory response by a combination of growth factors in cuprizone-induced demyelinated brain leads to myelin repair. Biancotti J.C., Kumar S., de Vellis J. Neurochem. Res. 33. 2008. P. 2615-2628].

In accordance with the international classification, 4 main types of PC flow are distinguished. Lucchinetti S., describes 4 main types of multiple sclerosis: types 1 and 2 are considered autoimmune, while in types 3 and 4 oligodendropathy (apoptosis of oligodendrocytes) is considered the primary cause. [Lucchinetti C., Bruck W. et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann. Neurol. 2000, 47, 707-717]. In particular, type 3 multiple sclerosis has many similarities with cuprizone intoxication: actively demyelizing areas with a small participation of lymphocytes, but a large participation of microglia and macrophages, hypoxic tissue damage and signs of oxidative stress, as well as mitochondrial deficiency, it was on this model that we studied the effect Ropren drug. The work was performed on 24 mice of the males of the CD-1 line (age - 8 weeks at the beginning of the experiment) obtained from the nursery of the Research Institute of Pharmacology of the Siberian Branch of the Russian Academy of Medical Sciences.

The studies were carried out in accordance with the rules adopted by the European Convention for the Protection of Vertebrate Animals used for experimental and other scientific purposes. The experimental procedures were approved by the Bioethics Commission of the Institute of Cytology and Genetics SB RAS (Novosibirsk).

Animals were divided into 3 experimental groups: “Control”, “Demyelination” and “Ropren + demyelination”. Animals of the Demyelination and Ropren + demyelination groups received standard food with 0.5% cuprizone for 10 weeks, and Control animals received standard food for 10 weeks. The animals of the Ropren + demyelination group ”were injected with the Ropren drug i.v. at a dose of 12 mg / kg starting from the 6th week of the experiment, the animals of the Control and Demyelination groups were injected with the same dose of the i.v. vegetable olive oil (containing a mixture of polyunsaturated and saturated fatty acids).

After 10 weeks, a brain scan of the mice was performed on a Bruker BioSpec 117 / 16USR magnetic resonance imaging scanner under gas anesthesia using 2% isoflurane.

At the end of the experiment, the animals were killed under ether anesthesia by transcardial perfusion in a large circle of blood circulation with 4% paraformaldehyde. The rat brain was recovered and placed in a 4% formaldehyde solution for 24 hours. After 24 hours, the brain was removed from formalin and placed in a 10% sucrose solution for a day, then it was transferred to a 20% sucrose solution, then it was frozen in liquid nitrogen vapor and placed in a -80 ° C freezer for further immunohistochemical analysis.

The study was conducted using modern methods of magnetic resonance imaging (MRI) of the brain and immunohistochemical analysis of sections of the brain of mice.

Research methods

MRI studies. 10 weeks after the start of the experiment, a brain scan of mice was performed using several sequences (Turbo Rare, T2-weighted image, Study on three-dimensional (3D) protocol for mapping the macromolecular proton fraction (MPF) in the rodent brain with the following parameters: MT- w sequence: TR = 22 ms, TE = 2.5 ms, rotation angle 9 °, spectral bandwidth 125 kHz; for saturation of macromolecular protons an extra-resonant radio frequency pulse of a Gaussian shape with a duration of 10 ms, 6 kHz frequency offset and a nominal rotation angle of 900 °), as well as with the T1-w sequence: TR = 16 ms, TE = 2.5 ms, rotation angle 16 °, spectral bandwidth 125 kHz, as well as PD-w sequence: TR = 16 ms, TE = 2.5 ms, rotation angle 3 °, spectral bandwidth 125 kHz, and also with FieldMap sequence for mapping the field B0 (double echo method): TR = 20 ms, TE1 = 2.4 ms, TE1 = 4.1 ms, rotation angle 8 °, spectral bandwidth 200 kHz., And finally with the AFI sequence for mapping the B1 field (double TR method): TR1 = 12 ms, TR2 = 60 ms, TE = 3.6 ms, rotation angle 60 °, width on the spectral band of 59.5 kHz, the increment of the phase angle is 39 °. Pulse sequences and the method of mapping the macromolecular proton fraction (MPF) were developed by Dr. V.L. Yarny [Yamykh VL. Fast macromolecular proton fraction mapping from a single off-resonance magnetization transfer measurement. Magn Reson Med 2012; 68 (1): 166-178]. Dr. V.L. The vigorous and several independent groups also showed a high correlation of the MPF parameter with the quantitative content of myelin in various areas of the brain [Underhill HR, Rostomily RC, Mikheev AM, Yuan C, Yarnykh VL. Fast bound pool fraction imaging of the in vivo rat brain: Association with myelin content and validation in the C6 glioma model. Neuroimage 2011; 54 (3): 2052-2065 .; Samsonov D Alexander AL, Mossahebi P, Wu YC, Duncan ID, Field AS. Quantitative MR imaging of two-pool magnetization transfer model parameters in myelin mutant shaking pup. Neuroimage 2012; 62: 1390-1398].

Scanning was carried out in axial projection. The geometry parameters, spatial resolution and the number of signal averages were set for the mouse: field of view 20 × 20 × 24 mm, matrix 200 × 200 × 80, resolution 100 × 100 × 300 μm, 4 signal averagings, total scan time 48 minutes. For the sequences of mapping the fields B0 and B1, the resolution in the plane was set half as high as for the remaining sequences due to the smoothness of the spatial changes in the field. Accordingly, a 100 × 100 × 80 matrix was used.

Brain MPF maps were calculated for demyelination mouse and control groups and the degree of demyelination in the structures of white (Corpus callosum, Fornix, Commissura, Capsula interna) and gray (Cortex cerebri, Thalami, Fissure hippocampi, Dentate gyrus, CA1) structures was studied.

For all groups of mice, the area of the corpus callosum was estimated by the sum of the areas of 12-14 sections from the front edge of the olfactory bulb according to T2-weighted images.

The average MPF values in the structures of white (Corpus callosum, Fornix, Commissura, Capsula interna) and gray (Cortex cerebri, Thalami, Fissure hippocampi, Dentate gyrus, CA1) brain substances in demyelinated and control mice were calculated using ImageJ software. An example of an MPF map with a designation of some of the studied brain structures is shown in Fig. 1, which shows a map of the mouse brain with the marks of the structures of white (Corpus callosum, Capsula interna) and gray matter (Cortex cerebri, Thalami, Fissure hippocampi, Dentate gyrus, CA1.)

The area of the white matter of the brain - Corpus callosum (corpus callosum) for control groups, "Demyelination", "Demyelination + Ropren" was measured using ImageJ software using T2-weighted images, which is shown in Fig. 2.

Immunohistochemical studies. Coronary sections of the brain of mice with a thickness of 10 μm were obtained using the NM525 cryotome. Slices were obtained in zones 0.74 ÷ 0.26 and -1.34 ÷ -1.70 from Bregma according to the atlas (G. Paxinos, KBJ Franklin, 2001). The obtained sections were immunohistochemically stained for myelin basic protein (MBP or MBP) and doublecortin (DCX, marker of young neurons) using primary (Goat anti MBP (sc-13914), Goat anti Doublecortin (C-18): sc-8066, Santa Cruz ) and secondary (Donkey anti goat AlexaFlour 488 (705-545-147), Jackson Immunoresearch) antibodies. Photographing was carried out using an Axio Imager Z2 microscope (Carl Zeiss, Germany) and AxioVision 4.8 software (Carl Zeiss, Germany) with a MozaiX module, which allows obtaining ~ 11 mm ² images by combining 20-28 smaller images, depending on the size of the cut . Microphotographs of whole brain sections stained for basic myelin protein (MBP) were evaluated by a method similar to processing MPF cards: the average fluorescence intensity over the area of the studied brain structures was calculated (Corpus callosum, Commissura, Capsula interna, Cortex cerebri, Thalami, Fissure hippocampi, Dentate gy , CA1). The resulting intensity was normalized by the background and average intensity of the whole slice, the obtained values were included in further statistical processing. For each animal, photographs of 10-14 sections of the brain were analyzed.

The number of DCX + (newly formed young neurons) was visually calculated in two main neurogenic zones - the subventricular zone near the lateral ventricles (SVZ) and the subgranular zone of the dentate gyrus of the hippocampus (DG).

The differences between the groups were evaluated using Statistics 6.0 ANOVA software and subsequent post-hoc analysis using the T-test or the non-parametric Mann-Whitney test if the distribution is different from normal. Differences were considered statistically significant at p <0.05.

Example 1. The effect of Ropren on myelination of the brain according to the results of MRI studies

Dispersion analysis of MPF maps showed the significance of the effect of cuprizone administration factor on mouse brain myelination (F (8, 40) = 3.9490, p = 0.00161). Post-hoc analysis confirmed cuprizone demyelination for the main brain structures using the T-test and showed significant demyelination for the white matter of the brain (Corpus callosum, Commissura) and gray matter (Cortex cerebri and Thalami) Thus, a 10-week oral administration cuprizone led to significant demyelination of structures of both white and gray matter, as shown in Fig. 3, where the differences in the MPF parameter of mice with cuprizone demyelination and control animals are visible. ** - p <0.01, * - p <0.05, T-test.

A study was made of the white matter of the brain, namely, the corpus callosum, by mapping the macromolecular proton fraction of MPF, and the area of the corpus callosum was measured. T2-weighted images of mice of the control groups, "Demyelination", "Demyelination + Ropren" are shown in Fig. 4, where the arrows indicate the corpus callosum demyelinated in the mouse with the introduction of cuprizone and without demyelination for the Control and Demyelination + Ropren groups.

A quantitative assessment of the area of the corpus callosum in mice of different groups was carried out, which showed a significant decrease in the area in mice from the introduction of cuprizone, compared with the control group. At the same time, with the introduction of Ropren, the area of the corpus callosum practically did not differ from the control group, despite the introduction of cuprizone, which indicates a protective effect of Ropren on the brain during intoxication with cuprizone, which causes its demyelination. This effect is shown in the diagram in Fig. 5, where the corpus callosum area in mice of the Demyelination group is significantly (P <0.05, T-test) less than the same indicator for the Control and Demyelination + Ropren groups, while there are significant differences between the Control and "Demyelination + Ropren" are absent.

Thus, a 10-week oral administration of cuprizone according to the results of MRI studies leads to a significant demyelination of the brain. When demyelination detected a significant decrease in the area of the corpus callosum. The introduction of Ropren has a protective effect on the white matter of the brain, namely, the corpus callosum in case of cuprizone-induced demyelination, restoring the corpus callosum to control values.

Example 2. The effect of Ropren on myelination of the brain according to the results of immunohistochemical studies

Microphotographs of brain sections stained for the main myelin protein, mice of the Control, Demyelination, Demyelination + Ropren groups are shown in Fig. 6, where the decrease in fluorescence intensity and contrast between the white and gray matter of the brain is clearly observed.

A quantitative analysis of the fluorescence intensity showed a significant decrease in the intensity, reflecting the content of the main MBP myelin protein, for the Demyelination group compared with the control in all the studied brain structures, except Commissura and Capsula interna (Fig. 7), where * - p <0.05, * * - p <0.01, T-test, as well as differences between the Demyelination and Control groups were - p <0.01, T-test, differences between the Demyelination and Demyelination + Ropren groups.

The introduction of Ropren statistically significantly increased myelination in these structures; in terms of structures, myelination was higher than in the control group.

Example 3. The effect of Ropren on neurogenesis in neurogenic zones of the brain according to the results of immunohistochemical studies

The effect of Ropren on neurogenesis in mice was analyzed. In fig. 8 (a, b, c) shows micrographs of brain sections of the subventricular zone near the lateral ventricles for animals of different groups stained for doublecortin (a marker of young neurons is shown in green), where 8a is a micrograph of a section of a mouse brain from the Demyelination group, 8b - from the control group, 8c - from the Demyelination + Ropren group.

It was found that with cuprizone demyelination, the number of young neurons in all major neurogenic zones of the brain decreases compared with the control group (p <0.001). In the subventricular zone (SVZ) in mice treated with a preparation based on polyprenols (Ropren), there is a tendency to an increase in the level of neurogenesis compared to the control group (p = 0.05) and a statistically significant increase in the number of young neurons compared to the Demyelination group, fig. 9.

In the granular layer of cells of the dentate gyrus of the hippocampus (DG), there are no statistically significant differences between the control group and the group of mice that received the preparation based on polyprenols, p> 0.05), while for this group the number of young neurons is higher compared to the Demyelination group "(P <0.001) fig. 10.

The results obtained in experiments on animals on the model of demyelination with cuprizone made it possible to establish with confidence the new properties of Ropren, namely, the drug restores myelination in the structures of the white and gray matter of the brain to the control level, which is confirmed by the results of MRI and immunohistochemical studies. In the cuprizone model of multiple sclerosis, significant demyelination of the structures of both white and gray matter was observed, confirmed by the results of MRI studies using the mapping of the macromolecular proton fraction and immunohistochemical studies. A quantitative assessment of the intensity of staining of brain sections on the main myelin protein showed that Ropren treatment protects the brain from demyelination, restoring the area of the corpus callosum to control values.

The study showed a significant increase under the action of Ropren, the level of neurogenesis in the main neurogenic zones of the brain in mice with demyelination, while the level of neurogenesis during demyelination decreases by 3.6 times.

So, in the granular layer of the dentate gyrus of the hippocampus. Ropren significantly increases - by 4 times the number of young neurons in comparison with demyelination, they become even more than in the control by 15%. The same tendency is observed in another zone - the subgranular zone of the dentate gyrus of the hippocampus (DG): the number of neurons in this region increases by 2.2 times compared with demyelination, and by 37.5% compared with the control. It can be assumed that the effect of polyprenols (Ropren) may be associated with an increase in the production of neurons, for example, through the serotonergic or dopaminergic system (for both neurotransmitters, a regulatory effect on neurogenesis is shown, the most famous fact is the increase in neurogenesis with fluoxetine, an inhibitor of serotonin reuptake)

These new previously unknown properties of Ropren were first clearly shown and proved using MRI and the immunohistochemical method, which makes it possible to use this drug in the treatment of multiple sclerosis and demyelinating diseases.

Clinical experience with the use of Ropren in toxic encephalopolneuropathy with severe demyelination (impaired conduction of both limbs).

Chronic alcoholic polyneuropathy is a primary degenerative process with the breakdown of myelin, the destruction of axial cylinders and the replacement of nervous tissue with connective tissue rich in blood vessels. First of all, the motor nerves are affected: first of all, the radial nerve in the upper limbs and the perineal nerves in the lower extremities. The pectoral and phrenic nerves are involved in the pathological process. The optic nerve and retina are often affected. (Trinitatsky Yu.V., Trinitatsky I.Yu. Treatment of chronic demyelinating polyneuropathies. State. Medical University, Rostov-on-Don, 2003, p. 176). Almost all patients examined by a neurologist were diagnosed with toxic encephalopolneuropathy. In the control group of patients with a diagnosis of polyneuropathy (PUP), there were 25 people, of which 13 patients were diagnosed with toxic encephalopolneuropathy. in the experimental one, 57 people, of which 23 patients were diagnosed with toxic encephalopolneuropathy, out of 60 people observed. Moreover, 50% of them took alcohol substitutes, which led to more persistent disorders in neurological symptoms in connection with the degeneration of myelin.

Legend: Young

From 3-5 points - moderate form of polyneuropathy From 6-8 points - pronounced form of polyneuropathy From 9-10 points - severe form of polyneuropathy Marked in yellow - the number of patients recovered

In the experiment of 23 people with severe and severe forms of PNP during 1 month of treatment with Ropren, there was an improvement in the demyelinating state in patients, which consisted in the transition of PNP to a milder form on the Young scale and only in 2 patients these manifestations were less pronounced . Three patients with this demyelinating disease recovered, and in the control group, no one recovered by the end of treatment. So, in the control group of 14 patients with severe and severe PNP, the effect occurs by the 15th day of treatment, only in 3 patients it is slightly pronounced. It should be noted that the effect of treatment in the experimental group occurred in the majority of patients by the 15th day of treatment. As can be seen from table 1. the effectiveness of treatment with Ropren is most visible with severe forms of PNP, when it is quite difficult to succeed in treating PNP. Such an effect from the use of basic therapy in the treatment of patients with severe forms of PNP, which are related to demyelinating diseases, does not occur even at the end of treatment and their discharge from the hospital.

Improving the condition of patients with demyelinating disease was also noted according to encephalography (EEG) (table 2).

Designations: EnzNPN - encephalopolneuropathy, GM - brain, improvement - improvement, TBI - craniocerebral trauma, +++ - severity of positive dynamics and functional state of the central nervous system according to EEG data (pronounced).

As can be seen from the table, there is a significant regression in focal cerebral and polyneuropathic symptoms associated with demyelination and clearly consistent with pronounced positive dynamics on the EEG. A clear positive dynamics in all indicators is observed in 2 patients with a history of epileptic syndrome and in one patient with Korsakov’s syndrome.

Example 4. Experience. Patient No. 30, 49 years old, disease duration 5 years. Diagnosis: AAS, chronic alcoholism of the 2nd degree, convulsive symptom, toxic encephalopolneuropathy with epileptic syndrome (intensification of seizures last 3 years). Improvement occurred on the 15th day, a decrease in focal cerebral symptoms and polyneurotic prolapse. There were no attacks of epilepsy. By the 30th day of treatment - a marked improvement in focal cerebral symptoms. PNP has passed from a severe to a moderate stage. Regression of neurological status is significant. On the 5th day, AAS was completely stopped. EEG data show a positive trend - increased alpha rhythm.

Example 5. Experience. Patient No. 44, 39 years old, disease duration 10 years. Diagnosis: AAS, chronic alcoholism of the 2nd degree, toxic encephalopolneuropathy. On the 6th day of treatment with Ropren, AAS was completely stopped, in the mental state of the patients on the scale “symptom sheet” and the HADS scale, on the 15th day there is an improvement in symptoms, on the 30th day - the absence of depression. On day 16, a significant regression of focal neurological symptoms: nystagmus disappeared, cerebellar disturbances decreased. By the 30th day, only micro-focal cerebral symptoms persist, a significant regression of PNP (from 10 to 4 points on the Young scale, i.e., from a severe form of PNP went into a moderate form). According to the EEG data, after treatment, there is a positive dynamics in the form of a significant increase in alpha rhythm, a decrease in the severity of the assimilation of photostimulation rhythms (RFUs), and positive dynamics according to the EEG data is noted.

Thus, the results of a study of the effect of a drug and a pharmaceutical composition based on compound (1) in animals on a specific model of multiple sclerosis, which causes demyelination in the brain of mice, as well as in the treatment of patients with toxic encephalopolineuropathy (demyelinating disease) in a clinic on the effectiveness of the treatment of demyelinating diseases, on the restoring (remyelinating) effect, as well as on the acceleration of the formation of new neurons in white and sulfur Ohm substance of the brain and a significant improvement in neurological disorders and / or complete regression of the demyelinating state.

Claims (5)

1. A drug for the treatment of diseases of a living organism associated with inflammatory demyelination, which is a polyprenol derived from coniferous woody general formula

2. A method for treating diseases of a living organism associated with inflammatory demyelination, characterized in that an effective amount of polyprenols of the general formula (1) is introduced into a living organism, enhancing myelination and the formation of young neurons in the white and gray matter of the brain. 3. The method according to p. 2, characterized in that the polyprenols of the general formula (1) are administered as an independent preparation. 4. The method according to p. 2, characterized in that the polyprenols of the General formula (1) are administered in the form of a pharmaceutical composition comprising auxiliary ingredients.

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