[Systematic analysis of the results of fundamental and clinical studies of ethifoxin]. / Sistematizirovannyi analiz rezul'tatov fundamental'nykh i klinicheskikh issledovanii etifoksina.

The main pharmacological use of etifoxine is the treatment of psychosomatic manifestations of anxiety. The purpose of this work is a systematic analysis of fundamental and clinical studies of etifoxine. In addition to the anxiolytic effect, which partially persists even after discontinuation of therapy, etifoxine is characterized by analgesic, neurotrophic and neuroprotective properties. Such a pharmacological profile of etifoxine is due not only to the activation of GABA receptors, but also to the effect on the levels of neurosteroids in the blood and in the brain. Modulation by etifoxine of neurosteroids' metabolism contributes to the manifestation of anxiolytic, anti-inflammatory, neuroprotective and other properties of etifoxine.

[Points of undenatured type II collagen application in musculoskeletal pain syndromes treatment]. / Tochki prilozheniya nedenaturirovannogo kollagena II tipa v terapii skeletno-myshechnykh bolevykh sindromov.

The dominant collagen of the cartilaginous matrix in adults is type II collagen. The amount of type II collagen in the intercellular matrix of cartilage is significantly reduced against the background of musculoskeletal system diseases. The basis of articular cartilage is hyaline cartilage tissue consisting of chondrocytes with tissue-specific antigens that induce the production of antibodies in patients with osteoarthritis (OA). Today, new approaches are being considered in the treatment of OA with the use of udenatured type II collagen (UC-II). Such molecular mechanisms of action of UC-II as the formation of a systemic response through oral tolerance are discussed, since the induction of tolerance is the immune pathway, by default, in the intestine. A number of experimental, preclinical (on volunteers) and clinical studies have shown the effectiveness and safety of the use of UC-II in OA. Standardized extracts of UC-II exhibit anti-inflammatory, immunoregulatory, chondroprotective effects, contributing to the reduction of pain symptoms of OA. Against the background of taking UC-II with induced OA, there is a statistically significant decrease in the level of proinflammatory cytokines, such as interleukin (IL-1ß, IL-6), tumor necrosis factor alpha (TNF), C-reactive protein (CRP) in serum and the level of max proteinases (MMP-3), nucleated factor «kappa-bi¼ (NF-κB) in the knee joint. UC-II significantly inhibits the production of prostaglandin E2 (by 20%) and the expression of genes encoding proinflammatory proteins. In experimental models and in OA patients, a decrease in the severity of pain syndrome, an increase in endurance, mobility and an improvement in the functional state of the joints were noted. Clinically, no changes in the structure of the muscle fiber were detected with increased physical exertion. With OA on the background of UC-II (10-40 mg/s), there was a statistically significant decrease in joint pain according to WOMAC. A promising direction of OA therapy is the combination of UC-II with chondroitin sulfate and glucosamine sulfate.

Direct and Indirect Neurological Signs of COVID-19.

Objective. To systematize the neurological manifestations of COVID-19. Materials and methods. A systematic computerized analysis of all currently available publications on the neurological manifestations of COVID-19 was undertaken (2374 reports in PubMed) by topological data analysis. Results. A set of interactions between infection with SARS-CoV-2, metabolic impairments affecting neurotransmitters (acetylcholine, dopamine, serotonin, and GABA), enkephalins, and neurotrophins, micronutrients, chronic and acute inflammation, encephalopathy, cerebral ischemia, and neurodegeneration (including demyelination) was described. The most typical neurological manifestations of COVID-19 were anosmia/ageusia due to ischemia, neurodegeneration, and/or systematic increases in proinflammatory cytokine levels. COVID-19 provoked ischemic stroke, Guillain-Barré syndrome, polyneuropathy, encephalitis, meningitis, and parkinsonism. Coronavirus infection increased the severity of multiple sclerosis and myopathies. The possible roles of the human virome in the pathophysiology of COVID-19 are considered. A clinical case of a patient with neurological complications of COVID-19 is described. Conclusions. In the long-term perspective, COVID-19 promotes increases in neurodegenerative changes, which requires special neurological rehabilitation programs. Use of cholinergic drugs and antihypoxic agents compatible with COVID-19 therapy is advised.

[Molecular and clinical aspects of the effect of cytidyndiphosphocholine on cognitive functions]. / Molekulyarnye i klinicheskie aspekty deistviya tsitidindifosfokholina na kognitivnye funktsii.

OBJECTIVE: Systematization of the array of publications on cytidyldiphosphocholine (CDP-choline). MATERIAL AND METHODS: Systematic computer analysis of all currently available publications on CDP-choline (1750 publications in PUBMED) using the topological theory of big data analysis. RESULTS: CDP-choline is essential for acetylcholine biosynthesis, phospholipid metabolism, and DNA methylation. The article describes the effects of CDP-choline on acetylcholinergic and other types of neurotransmission, anti-inflammatory, neuroprotective and neurotrophic effects of CDP-choline. Also, the paper presents the effects of the molecule on lipid metabolism and gene expression within the post-genomic paradigm (in particular, an increase in the expression of nicotinic and muscarinic acetylcholine receptors). The results of fundamental and clinical studies of CDP-choline in the treatment of cognitive impairments associated with cerebral ischemia and neurodegeneration are presented. CONCLUSION: The pharmacological effects of CDP-choline are mediated through multiple molecular mechanisms that contribute to the nootropic action of this molecule.

[Comparative chemoreactome analysis of the synergism of vinpocetine, piracetam, and cinnarizine molecules]. / Sravnitel'nyi khemoreaktomnyi analiz sinergizma molekul vinpotsetina, piratsetama i tsinnarizina.

OBJECTIVE: Neuroprotective and nootropic drugs often exhibit complementary, «synergistic¼ effects, the consideration of which is important for choosing the most effective and safe drug combinations. MATERIAL AND METHODS: Chemoinformatic analysis of vinpocetine, piracetam and cinnarizine on neuron cultures, on model organisms (mice, rats) based on modern data mining and machine learning methods. RESULTS: The paper presents the results of the chemoreactom analysis of vinpocetine, piracetam, and cinnarizine. Estimates of various biological activities of molecules on neuronal cultures, on model organisms (mice, rats) and estimates of modulation of the activity of target proteins in rats and humans were obtained. The data obtained made it possible to quantify the value of the synergism score for the combination «vinpocetine + piracetam¼ (54 points) compared with the combination «piracetam + cinnarizine¼ (25 points). CONCLUSIONS: The combination of «vinpocetine + piracetam¼ in the fixed combination (Vinpotropil) is thus more preferable for combined use than for the combination of «piracetam + cinnarizine¼.

[Direct and indirect neurological manifestations of COVID-19]. / O pryamykh i kosvennykh nevrologicheskikh proyavleniyakh COVID-19.

OBJECTIVE: To systemize the neurological manifestations of COVID-19. MATERIALS AND METHODS: A systematic computer analysis of all currently available publications on the neurological manifestations of COVID-19 (2374 publications in PUBMED) using algorithms of topological data analysis was performed. RESULTS: A complex of interactions between SARS-CoV-2 infection, metabolic disorders of neurotransmitters (acetylcholine, dopamine, serotonin and GABA), enkephalins and neurotrophins, micronutrients, chronic and acute inflammation, encephalopathy, cerebral ischemia and neurodegeneration, including demyelination, was described. The most common neurological manifestation of COVID-19 is anosmia/ageusia arising as a result of ischemia, neurodegeneration, and/or systemic elevation of proinflammatory cytokine levels. COVID-19 provokes ischemic stroke, Guillain-Barré syndrome, polyneuropathy, encephalitis, meningitis and parkinsonism. Coronavirus infection significantly aggravates the course of multiple sclerosis and myopathies. Possible roles of the human virome in the neuropathophysiology of COVID-19 are considered. A case of clinical management of a patient with neurological complications of COVID-19 is described. CONCLUSION: In the long term, COVID-19 stimulates neurodegenerative changes, which require specific programs of neurological rehabilitation. It is advisable to use choline drugs and antihypoxants that are compatible with COVID-19 therapy.

[Choice of neuroprotective therapy regimens in patients with chronic cerebral ischemia, taking into account the synergy of drug interactions]. / Vybor neiroprotektivnoi terapii u patsientov s khronicheskoi ishemiei golovnogo mozga s uchetom sinergizma lekarstvennykh vzaimodeistvii.

OBJECTIVE: Optimization of the choice of neuroprotective treatment regimens in patients with chronic cerebral ischemia that takes into account the synergy of drug interactions gives the doctor an opportunity for personalized approach that increases the effectiveness of treatment. MATERIAL AND METHODS: Differential chemoreactomic analysis of the synergism of ethyl methyl hydroxypyridine succinate (EMHPS) and a number of monocomponent neuroprotective agents (piracetam, vinpocetine, citicoline, choline alfoscerate); proteomic analysis of polypeptide neuroprotectors (cerebrolysin, etc.); an expert analysis of multicomponent neuroprotector Cytoflavin. RESULTS: Piracetam, citicoline (Neupilept) and choline alfoscerate (Cereton) effectively enhance the pharmacological properties of EMHPS and vice versa. Expert assessments of the synergism between the properties of EMHPS, polypeptide neuroprotectors (cerebrolysin) and other multicomponent drugs (cytoflavin), which are also used in adjuvant therapy with EMHPS, are presented. CONCLUSION: In real clinical practice, of particular interest is the objectification of the appointment of combined therapy regimens. This study indicates that EMHPS can provide a favorable background for maximizing the effectiveness of therapy when used with other drugs.

[Comprehensive study of the composition of fish fat extracts and quantitative criteria for distinguishing standardized omega-3 polyunsaturated fatty acids extracts].

Background Effects of drugs and biologically active supplements based on omega-3 polyunsaturated fatty acids (ω3 PUFA) considerably depend on the standardized content of eicosatetraenoic acid (EPA), docosahexaenoic acid (DHA), and other fatty acids in the extracts.Material and methods In this study, we comprehensively examined the composition of 10 ω3 PUFA samples with chromatographic measurement of more than 40 metabolites of fatty acids and other compounds. The data on extract composition were analyzed with current methods of intelligent data analysis (metric condensation method; multidimensional scaling; principal component analysis with axis identification; topology-metrical approach to recognition).Results Quantitative markers were obtained, which allowed separating the standardized ω3 PUFA-based samples (Omacor, Solgar omega-3 700, Femibion Natalker-2, Omega-3 concentrate, Omegamama) from less standardized ones (Fish oil-Teva, Omegatrin, Omeganol, etc.) based on results of a chromatographic analysis of fatty acid composition in the studied samples (EPA+DHA marker, ω6+ω11 marker, and standardization coefficient showing conformity of measured ω3 PUFA levels with the content stated by the manufacturer).Conclusions Among the studied samples, the pharmaceutical product Omacor showed the best values of standardization indexes.

[The chemoreactomic analysis of the central mechanisms of action of non-steroidal anti-inflammatory drugs]. / Khemoreaktomnyi analiz tsentral'nykh mekhanizmov nesteroidnykh protivovospalitel'nykh preparatov.

AIM: To perform a chemoreactome modeling of the pharmacological central effects of 4 non-steroidal anti-inflammatory drugs (NSAIDs): dexketoprofen, ketoprofen, aceclofenac, lornoxicam. MATERIAL AND METHODS: An analysis of the pharmacological spectrum of the central action of dexketoprofen, ketoprofen, aceclofenac and lornoxicam was based on the chemoinformatic approach, which compared drug-likeness properties with public and commercial software. RESULTS: The effectiveness of NSAIDs is related to the inhibition of cannabinoid receptors CB-1, the vanilloid receptor TRPV1, NMDA and AMPA receptors and of the GABA reuptake transporter, with dexketoprofen being the most effective inhibitor. The safety of the central effects of NSAID is due to weak interactions of the NSAIDs studied with opioid, adrenergic, serotonin and dopamine receptors. Chemoreactome modeling made it possible to compare the particulars of the effects of the studied NSAIDs on experimental pain and cramps. CONCLUSION: Inhibition of CB-1, TRPV1, NMDA, AMPA, GABA transporter by the NSAID molecules corresponds to a decrease in the intensity of nociceptive signals. A weak intervention of the studied NSAIDs in opioid, adrenergic, serotonin and dopaminergic neurotransmission corresponds to a decrease in the central side-effects of NSAIDs and to a lessened antagonism of these NSAIDs towards exogenous and endogenous opioids.

[Comparative studies of neurotrophic drugs based on brain hydrolysates]. / O sravnitel'nykh éksperimental'nykh issledovaniiakh neirotroficheskikh preparatov na osnove gidrolizatov golovnogo mozga.

The results of the analysis of comparative studies of neurotrophic drugs based on brain hydrolysates (BH) are presented. The most comprehensive comparative study of the BH drugs carried out by Zhang, et al. 2019 investigated the effects of four drugs (cognistar, cerebrolysate, cortexin, cerebrolysin) on a model of ischemic stroke in rats. The study showed that a significant improvement in the neurological outcome compared with placebo was observed only with cerebrolysin. Higher standardization in elemental composition, higher antioxidant activity, and presence of active peptide fragments of neuropeptides of nerve growth factor, enkephalins, orexin and galanin in cerebrolysin explains neurotrophic and neuroprotective effects of the drug.

[An analysis of the peptide composition of a 'light' peptide fraction of cerebrolysin]. / Kompleksnyi proteomnyi analiz 'legkoi' peptidnoi fraktsii preparata Tserebrolizin.

AIM: To analyze the peptide composition of a light peptide fraction of cerebrolysin. MATERIAL AND METHODS: Mass spectrometry (MS) with orbital ion traps and modern de novo MS-sequencing algorithms was performed. RESULTS: The amino acid sequences of 14 635 peptides corresponding to the 1643 porcine proteome neuronal proteins are identified. An analysis of the human proteome annotation shows that these peptides can mimic the corresponding human peptides. In particular, 405 peptide fragments correspond to 300 known biologically active peptides, including fragments of antibacterial peptides (defensins, histatins), immunomodulatory (granulin, manserin) and vasoactive (endothelin, VIP) peptides. At the same time, 8953 of 14 635 peptides can modulate the activity of 275 human signaling proteins, including kinases CDK1, CDK2, TGFBR2, GSK3, MTOR, pro-apoptotic caspases CASP1, CASP3 and CASP6 etc. The results confirm the presence of Leu- and Met-enkephalins, fragments of neuropeptide orexin, neuropeptide VF, galanin and nerve growth factor that have a neurotrophic effect. CONCLUSION: The results of a proteomic study of the peptide composition of cerebrolysin indicate the widest range of molecular mechanisms responsible for the clinical efficacy of this drug.

[Systematic Analysis of the Roles of Trace Elements in the Prevention and Treatment of Chronic Heart Failure].

Systematic analysis of 3 728 publications on the relationship between microelement status and chronic heart failure (CHF) was carried out. Three main areas of research have been identified: 1) magnesium, electrolytes and CHF; 2) the transcriptional and antioxidant effects of zinc, selenium, copper; 3) iron-deficiency anemia and CHF. In this paper, we consider a complex of relationships between the magnesium insufficiency and CHF, the effect of magnesium on vascular tone, mitochondria, heart rhythm and the susceptibility of cardiomyocytes to adrenergic stimulation. Using magnesium orotate for the treatment of CHF is a feasible approach to compensate magnesium insufficiency in patients with CHF.

[Cerebrolysin peptides as mood stabilizers]. / O peptidakh Tserebrolizina, sposobstvuiushchikh normotimii.

AIM: To establish the molecular mechanisms of the mood stabilizing (normothymic) action of the neuroprotector Cerebrolysin. MATERIAL AND METHODS: Mass-spectrometric analysis of the peptide composition of cerebrolysin followed by a complex bioinformatics analysis was utilized. RESULTS: Cerebrolysin contains considerable amounts of Leu- and Met-enkephalins, partial analogues of enkephalins, peptide fragments of beta-lipotropin. These peptides stimulate the endorphinergic system thus contributing to normothymic action and an increase in the levels of the brain-derived neurotrophic factor (BDNF). Specific inhibition of kinases ABL1, PINK1, CDK5 and arginine N-methyltransferase PRMT5 by the peptides of cerebrolysin has a multidirectional effect on the dopaminergic system, also helping to stabilize mood. Cerebrolysin peptides do not directly affect neither the serotonergic, adrenergic, nor GABAergic systems. CONCLUSION: The normothymic effect of Cerebrolysin is due to the stabilization of endorphinergic and dopaminergic neurotransmission.

[Experience with mexidol in neurological practice]. / Opyt primeneniia meksidola v nevrologicheskoi praktike.

Antihypoxic, antioxidant and nootropic effects of mexidol contribute to the improvement of patients with cerebrovascular pathology. The results of clinical studies show that the sequential scheme of using mexidol (first i.v. or i.m., then per os) is effective in the complex therapy of ischemic diseases of the brain, vascular surgery, therapy and rehabilitation of patients with degenerative-dystrophic changes of the spine, treatment of neurodegenerative pathology (including multiple sclerosis, Parkinson's disease and diabetic polyneuropathy), infectious neuropathies (ARVI, herpes, tick-borne encephalitis), neuropsychological and autonomic disorders.

Deficit of Magnesium and States of Hypercoagulation: Intellectual Analysis of Data Obtained From a Sample of Patients Aged 18-50 years From Medical and Preventive Facilities in Russia.

The states characterized by pronounced hypercoagulable components (deep vein thrombosis, cardio- and cerebro-vascular pathologies) are caused by multiple pathophysiological factors, including insufficient supply of magnesium (Mg) and other micronutrients. AIM: to present results of analysis of the Institute of Microelements Data Base (IMDB) performed from point of view of interrelationships of Mg deficit and hypercoagulable states in adults treated in medico-preventive facilities of Central, Northwestern, Northern, and Siberian federal districts of Russia. METHODS: The analysis was realized as analysis of data obtained in a cross-sectional study. In the cohort of patients (n=1453) formed from the IMBD adequacy of Mg supply was assessed by magnesium levels in blood plasma (MgBP) (0.69±0.15 mmol/L) and estimates of daily Mg consumption according to dietary diaries (MgD) (185±90 mg/day). RESULTS: Mg supply was adequate (MgBP >0.80 mmol/L, MgD >300 mg/day) in not more than 6% of patients. Presence of "Hypercoagulation" label in data base was associated with greater number of chronic diseases (2.3±2.1 and 0.83±0.8 with and without this label, respectively, р=0.0006) and elevated risk of the presence on 4 comorbid pathologies (odds ratio [OR] 18, 95% confidence interval [CI] 10-25, р=0.0006). Mg deficit (MgBP.

[Synergistic application of zinc and vitamin C to support memory, attention and the reduction of the risk of the neurological diseases]. / Sinergidnoe primenenie tsinka i vitamina S dlia podderzhki pamiati, vnimaniia i snizheniia riska razvitiia zabolevanii nervnoi sistemy.

Zinc and vitamin C supplementation of the body is important for CNS functioning. Zinc ions are involved in the neurotransmission (signal transmission from acetylcholine, catecholamine, serotonin, prostaglandin receptors) and in ubiquitin-related protein degradation. Zinc deficits are associated with Alzheimer's disease and depression. Zinc supplementation (10-30 mg daily) improves neurologic recovery rate in patients with stroke and brain injury, has a positive impact on memory and reduces hyperactivity in children. Vitamin C, a zinc synergist, maintains antioxidant resources of the brain, synaptic activity and detoxification. Vitamin C in dose 130-500 mg daily should be used to prevent dementia and neurodegenerative pathology.

[A comparative chemoreactome analysis of mexidol]. / Sravnitel'nyi khemoreaktomnyi analiz meksidola.

AIM: To compare mexidol with control molecules (choline alfoscerate, piracetam, glycine, semax) using chemoreactome analysis. MATERIAL AND METHODS: The chemical structure of mexidol was compared to molecule metabolites extracted from the Human Metabolome Database (HMDB) and a drug database. More than 40 000 of metabolites from HMDB were used as a model of human metabolome. RESULTS AND CONCLUSION: The chemoreactome analysis showed that mexidol may be (1) an agonist of acetylcholine and GABA-A receptors; (2) an anti-inflammatory agent, the effects of which are carried out by inhibiting the synthesis of pro-inflammatory prostaglandins; (3) a neurotrophic agent with neuroprotective properties; (4) a coagulation inhibitor; (5) a diabetes medication and (6) a hypolipidemic agent. Compared to 'control' molecules, mexidol has a more pronounced safety profile (a lower impact on serotonin, dopamine and adrenergic receptors, a lesser degree of interaction with the potassium channels of the heart, MAO and P450 cytochromes). The results of modeling allow to specify the mechanisms of action of mexidol at the molecular level.

[A study of the neuroprotective effect of mexidol on the cell model of glutamate stress]. / Izuchenie neiroprotektivnogo deistviia meksidola nakletochnoi modeli glutamatnogo stressa.

AIM: To study a neuroprotective effect of mexidol on the cell model of glutamate stress. MATERIAL AND METHODS: Cytological studies of an effect of glutamate stress on cerebellar granule cells were carried out. RESULTS: Mexidol increased neuronal survival after the addition of glutamate by 8-10% (p<0.05). The effect of mexidol was more pronounced at the stage of neuron culture growth (5 days), cell survivability increased on average by 20%. CONCLUSION: The results of the study confirmed the neuroprotective effect of mexidol in the neuronal culture in glutamate toxicity model.

[Neurotrophic effects of lithium stimulate the reduction of ischemic and neurodegenerative brain damage].

For over 60 years, high doses of lithium (hundreds of milligrams of elemental lithium) have being used to treat bipolar disorder. However, only during the past 20 years the relevant basic and clinical studies have shown that neuroprotective and neurotrophic effects of lithium are possible in much smaller doses ( hundreds of micrograms of elemental lithium). These data indicate a significant potential for the clinical applications of lithium-based drugs in modern neurology for the purposes of prevention and treatment of neurodegenerative and ischemic pathologies. Pharmacological and molecular biology studies indicated that the inhibition of glycogen synthase kinase-syntentase-3 (GSK-3) and induction of brain-derived neurotrophic factors are the main mechanisms of neurotropic actions of lithium. Also, by inhibiting the NMDA receptors, lithium regulates the calcium homeostasis and inhibits the activation of calcium-dependent apotosis. These and other molecular mechanisms of lithium action protect neurons from ischemia and neurodegeneration thus contributing to a significant reduction of neurological deficit in various models of stroke and neurodegenerative diseases.

[Neurotrophic peptides of сerebrolysin as a basis for anticonvulsant effect of the drug]. / Neirotroficheskie peptidy tserebrolizina kak osnova protivosudorozhnogo potentsiala preparata.

AIM: To study an effect of cerebrolysin on the expression and severity of primary-generalized seizures caused by thiosemicarbazide and to analyze the corresponding molecular mechanisms. MATERIAL AND METHODS: The effects of cerebrolysin were studied on the thiosemicarbazide model of convulsions in 144 male rats. Cerebrolysin was introduced intraperitoneally in the dose of 2.5 ml/kg of body mass 5 days a week during 18 days. RESULTS AND CONCLUSION: Cerebrolysin reduces the severity and duration of seizures caused by thiosemicarbazide and increases the survival rate of animals. Cerebrolysin potentiates the anticonvulsant action of gabapentin and sodium valproate. Neurohistological analysis has shown that the thiosemicarbazide model results in the ischemic brain damage. Cerebrolysin substantially minimizes the ischemic injury of neurocytes induced by thiosemicarbazide and contributes to the restoration of brain tissue morphology.