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Mexidol, Cytoflavin, and succinic acid derivatives as antihypoxic, anti-ischemic metabolic modulators, and ergogenic aids in athletes and consideration of their potential as performance enhancing drugs
Abstract
Emoxypine (ethylmethylhydroxypyridine) is a synthetic derivative of vitamin B 6 . Emoxypine succinate is a registered drug in Russia and Ukraine under various trade names including Mexidol, Mexicor, and Armadin Long. Mexidol demonstrates antihypoxic and anti‐ischemic effects and also modulates metabolism. The use of Mexidol by Russian athletes has been confirmed in the past. Current use by athletes is unknown as this drug is not monitored or included in drug testing protocol. Metabotropic and antihypoxic effects of Mexidol were compared to the effects of meldonium or trimetazidine, both of which are included on the World Anti‐Doping Agency (WADA) Prohibited List in category S4.4. Metabolic Modulators. The conjugation of emoxypine with succinate elevates the therapeutic effectiveness of the Mexidol formulation as succinic acid itself has important impacts to consider despite being a common food additive and drug excipient. Other succinic acid salts like ammonium succinate, found as dietary supplement, have been patented as performance enhancers. Available research on healthy subjects suggests that combinations of selected 3‐substituted pyridine derivatives with succinate including Mexidol and a related drug Cytoflavin can enhance the performance of athletes. Cytoflavin is a multi‐component formula containing meglumine sodium succinate, nicotinamide (vitamin B 3 ), inosine (riboxin), and riboflavin. Other related succinate‐based drugs include Remaxol, Reamberin, and Cogitum. Mexidol and Cytoflavin and related substances exhibit similar biological effects as drugs on the WADA Prohibited List, and if they are used for performance enhancement by athletes, they could be worthy of consideration as prohibited substances in sport.
... The possibility of using succinic acid preparations in primary mitochondrial dysfunction is actively discussed, particularly in a patient with MELAS syndrome [257,258]. Combination succinate-containing drugs such as reamberine, cytoflavin, and remaxol have found use in clinical practice [256,[259][260][261]. The bioavailability of succinate is enhanced by combining it with various metabolites (such as citric and malic acids). ...
... Mexidol is used mainly in secondary mitochondrial dysfunctions accompanying chronic cerebral ischemia, CNS damage due to prenatal hypoxia, multiple sclerosis, and working hypoxia [259,279]. In primary mitochondrial dysfunctions, mexidol was used as part of complex therapy of MELAS syndrome and in mitochondrial myopathy [6,280]. ...
The study of mitochondrial dysfunction has become increasingly pivotal in elucidating the pathophysiology of various cerebral pathologies, particularly neurodegener-ative disorders. Mitochondria are essential for cellular energy metabolism, regulation of reactive oxygen species (ROS), calcium homeostasis, and the execution of apoptotic processes. Disruptions in mitochondrial function, driven by factors such as oxidative stress, excitotoxicity, and altered ion balance, lead to neuronal death and contribute to cognitive impairments in several brain diseases. Mitochondrial dysfunction can arise from genetic mutations, ischemic events, hypoxia, and other environmental factors. This article highlights the critical role of mitochondrial dysfunction in the progression of neurodegenera-tive diseases and discusses the need for targeted therapeutic strategies to attenuate cellular damage, restore mitochondrial function, and enhance neuroprotection.
... Мексидол (емоксипін, етилметилгідроксипі-ридин) є синтетичним похідним вітаміну B6, що має антигіпоксичну та антиішемічну дію, а також модулює метаболізм [10]. Результати досліджень показують, що наявність у пацієнтів супутньої патології може мати негативний ефект на процес загоєння ран в щелепно-лицевій хірургії. ...
... У всіх вікових групах переважає генералізована форма стирання над локалізованою [8,9]. Численні електроміографічні дослідження вказують на беззаперечну роль у розвитку підвищеного стирання зубів жувальних та скроневих м'язів, особливо функціональної активності жувальних м'язів [10,11,12]. Проте, жодним чином не згадується вплив медіальних і латеральних крилоподібних м'язів. ...
Odontogenic phlegmon of maxillofacial localisation is one of the most common diseases in the practice of a dental surgeon. The presence of comorbidities, such as coronary heart disease, can negatively impact the course of the underlying condition, complicate diagnosis and treatment, and delay patient recovery. This highlights the need to explore and improve treatment methods for odontogenic phlegmon in patients with coronary heart disease. The aim of this study was to examine the dynamics of regenerative processes in the wound at different stages of the postoperative period after using both classical and novel treatment methods for odontogenic phlegmon of maxillofacial localization in patients with coronary artery disease. Subjects and methods. The study included 80 patients with this pathology, divided into 4 groups. In the first group, quercetin was added to standard therapy, in the second group, quercetin and mexazol were used, and the third group received standard treatment. Patients in these three groups had a history of coronary heart disease. The fourth group (control) had only the underlying disease without comorbidities. Cytological examination was performed using the "surface biopsy" method. The material was collected on days 1, 3, 5, 7, and 9 of the postoperative period and stained using the Romanowsky-Giemsa method. Subsequently, histological specimens were examined. Results. On day 1, the main cellular elements across all groups were erythrocytes. By day 3, lymphocytes and single holonuclear cells were observed in the first group; precollagen fibers appeared in the second group; the third group showed a significant number of polymorphonuclear leukocytes; and the fourth group mainly had holonuclear cells. By day 5, the first group showed progressive development of regenerative processes, while the second group entered the final phase of regeneration. In the third and fourth groups, gradual development of the regenerative process was observed. On day 7, the first group showed signs of the final stage of wound healing, and the second group had completed this process. The third and fourth groups showed signs of the regenerative stage at this point. On day 9, no signs of inflammation were present in the third and fourth groups. Conclusion. The use of quercetin combined with intravenous mexazol injections as part of conservative therapy accelerates regenerative processes in the postoperative period and shortens the duration of the inflammatory reaction.
... The possibility of using succinic acid preparations in primary mitochondrial dysfunction is actively discussed, particularly in a patient with MELAS syndrome [262,263]. Combination succinate-containing drugs such as reamberine, cytoflavin, and remaxol have found use in clinical practice [261,264,265]. The bioavailability of succinate is enhanced by combining it with various metabolites (such as citric and malic acids). ...
... Mexidol is used mainly in secondary mitochondrial dysfunctions accompanying chronic cerebral ischemia, CNS damage due to prenatal hypoxia, multiple sclerosis, working hypoxia [264,288]. In primary mitochondrial dysfunctions mexidol was used as part of complex therapy of MELAS syndrome and in mitochondrial myopathy [6,289]. ...
The study of mitochondrial dysfunction has become increasingly pivotal in elucidating the pathophysiology of various cerebral pathologies, particularly neurodegenerative disorders. Mitochondria are essential for cellular energy metabolism, regulation of reactive oxygen species (ROS), calcium homeostasis, and the execution of apoptotic processes. Disruptions in mitochondrial function, driven by factors such as oxidative stress, excitotoxicity, and altered ion balance, lead to neuronal death and contribute to cognitive impairments in several brain diseases. Mitochondrial dysfunction can arise from genetic mutations, ischemic events, hypoxia, and other environmental factors. This article highlights the critical role of mitochondrial dysfunction in the progression of neurodegenerative diseases and discusses the need for targeted therapeutic strategies to attenuate cellular damage, restore mitochondrial function, and enhance neuroprotection.
Keywords: mitochondrial dysfunction; ROS; cerebral ischemia; HIF-1; HSP 70
... Their changes in different treatment groups may indicate differences in energy metabolism and osmotic regulation. Succinic acid, tartaric acid, and citric acid participate in various metabolic pathways in plants, such as the tricarboxylic acid cycle, and significantly affect fruit flavor [47][48][49]. Their upregulation or downregulation may reflect changes in energy metabolism and fruit quality under different cultivation conditions. Amino acids such as glycine, 4-aminobutyric acid, and beta-alanine are the basic building blocks of proteins and participate in various metabolic pathways in plants [50]. ...
The effects of different shaping methods and loading treatments on the photosynthetic rate, chlorophyll content, fruit yield and quality, and volatile compound composition of the ‘Beibinghong’ grape were studied. In the experiment, 6-year-old ‘Beibinghong’ grapes were selected as the material, and two kinds of shaping methods were adopted: the double main vine upright tree (control) and the inclined horizontal dragon tree. The inclined horizontal dragon tree was treated with different loads. The volatile components in grapes were analyzed by gas chromatography–mass spectrometry (GC-MS). The changes in quality and volatile components of ‘Beibinghong’ grape under different treatments were analyzed by multivariate statistics. The results showed that the inclined horizontal dragon tree significantly increased the net photosynthetic rate and chlorophyll content of leaves, and increased the soluble sugar content and sugar–acid ratio of fruits. The quality of grapes was better than that of the upright tree with double main vine. The results of loading showed that the plants with nine fruit branches had higher net photosynthetic rate and yield, and the best performance in reducing sugar content, titrable acid content and sugar–acid ratio, which was the most suitable loading treatment. The results of metabolomics study showed that 291 volatile metabolites were identified, of which 25 were considered to be the key differential metabolites affecting the flavor of ‘Beibing red’ fruit under different treatments. Further analysis showed that the inclined horizontal draconite tree was superior to the double main draconite tree in improving fruit quality and accumulation of volatile compounds in fruit. This study revealed the regulation mechanism of different shaping methods and loading loads on the growth and fruit quality of ‘Beibinghong’ grapes, which provided theoretical support for optimizing the viticulture management of ‘Beibinghong’ and improving the fruit quality and market competitiveness.
... To date, some drug therapies and surgical interventions have been applied in the treatment of CCI. For example, Mexidol, a kind of emoxypine succinate exhibiting multifaceted pharmacological effect, including anti-hypoxic and anti-ischemic effects [27]. The combination of intravenous administration of Mexidol and oral administration of Mexidol FORTE 250 can alleviate asthenic and emotional disorders, thereby ameliorating cognitive functions in CCI patients [42]. ...
Chronic cerebral ischemia (CCI) is a common neurological disorder, characterized by progressive cognitive impairment. Acupoint catgut embedding (ACE) represents a modern acupuncture form that has shown neuroprotective effects; nevertheless, its effects on CCI and the mechanisms remain largely unknown. Here, we aimed to explore the therapeutic action of ACE in CCI-induced cognitive impairment and its mechanisms. The cognitive function of CCI rats was determined using Morris water maze test, and histopathological changes in the brain were assessed through hematoxylin–eosin (HE) staining. To further explore the molecular mechanisms, the expression levels of oxidative stress markers and the Ang II/AT1R/NOX axis-associated molecules in the hippocampus were evaluated using enzyme-linked immunosorbent assay (ELISA), western blotting, and immunohistochemistry. Here, we observed that ACE treatment alleviated cognitive dysfunction and histopathological injury in CCI rats. Intriguingly, candesartan (an AT1R blocker) enhanced the beneficial effects of ACE on ameliorating cognitive impairment in CCI rats. Mechanistically, ACE treatment blocked the Ang II/AT1R/NOX pathway and subsequently suppressed oxidative stress, thus mitigating cognitive impairment in CCI. Our findings first reveal that ACE treatment could suppress cognitive impairment in CCI, which might be partly due to the suppression of Ang II/AT1R/NOX axis.
The aim of this study was to determine the influence of high-intensity training under extreme conditions (T = 40 °C) on the metabolism and immunological reactions of athletes. Male triathletes (n = 11) with a high level of sports training performed load testing to failure (17 ± 2.7 min) and maximum oxygen consumption (64.1 ± 6.4 mL/min/kg). Blood plasma samples were collected before and immediately after exercise. Mass spectrometric metabolomic analysis identified 30 metabolites and 6 hormones in the plasma, of which 21 and 4 changed after exercise, respectively. Changes in the intermediate products of tricarboxylic and amino acids were observed (FC > 1.5) after exercise. The obtained data can be associated with the effect of physical activity on metabolism in athletes. Therefore, constant monitoring of the biochemical parameters of athletes can help coaches identify individual shortcomings in a timely manner and track changes, especially as the volume of training increases. In addition, it was revealed that the immunological reaction (manifestation of a hyperactive reaction to food components) is personalized in nature. Therefore, it is important for coaches and sports doctors to analyze and control the eating behavior of athletes to identify food intolerances or food allergies in a timely manner and develop an individual elimination diet.
Background and objectives:
In ice hockey, the major physical workload comes from acceleration in all planes of motion and transitions between skating trajectories. Hockey players' anthropometric characteristics correlate with performance. In team sports, the use of ergogenic drugs for recovery is relevant to avoid athletes' overtraining. It is very important to protect athletes' health and allow them to maintain high-performance levels. Cytoflavin is an ergogenic drug whose action is based on the combined effects of its active ingredients (succinic acid, inosine, nicotinamide and riboflavin), which are naturally occurring metabolites that stimulate tissue respiration. The study aimed to assess the 6-week Cytoflavin consumption effects on body composition (body weight, body mass index, body fat percentage and bioimpedance phase angle) and aerobic performance.
Methods:
This study included 60 male professional hockey players (aged 19 to 36 years) divided into two groups of 30 subjects: group I (body weight 87.90 ± 7.44 kg, BMI 25.86 ± 2.04 kg/m2) and group II (body weight 87.04 ± 6.22 kg, BMI 25.52 ± 2.38 kg/m2). Athletes in group I received Cytoflavin, whereas athletes in group II did not.
Results:
In group I, statistically significant reductions in body weight and body mass index were not observed until 14 and 35 days, respectively. In contrast, in group II, both body weight and BMI significantly decreased both times. Aerobic performance significantly increased in both groups, with significantly greater increases in group I.
Conclusions:
Cytoflavin can be considered an ergogenic drug that improves body composition parameters, especially in the control of weight reduction and improvement in aerobic performance.
Traumatic brain injury is the leading cause of symptomatic epilepsy at a young age. Post-traumatic epilepsy (PTE) is the main factor in disabling patients of working age and impairs the quality of life. Comorbid pathology in the form of psychoemotional and cognitive disorders essentially has a single pathogenetic mechanism on the part of traumatic brain disease. There are problems with differential diagnosis between comorbid and direct manifestations of PTE. The above dictates the need to develop modern complex approaches to the treatment of PTE and correction of accompanying and comorbid pathological conditions. Author tries to develop new pathogenetically adequate approaches to the treatment of PTE with correction of the psycho-emotional sphere and cognitive deficit. 44 patients with PTE were examined. The average period of its formation reached 10.3±4.2 years, and the frequency of attacks – 2.4±0.9 per month. Focal attacks prevailed (61.4%). In addition to standard long-term anticonvulsant monotherapy, the main group (32 patients) was prescribed ethylmethylhydroxyperidine succinate and vortioxetine. The control group (12 patients) received only anticonvulsant therapy. When using the proposed complex treatment, the number of people with depression decreased from 25 (56.8%) to 10 (22.7%) cases, that is, by 2.5 times (P <0.05). In the main group, from 59.4% to 21.9%, i.e. 2.7 times (Р<0.05). In the control – from 50.0% to 41.7% (Р>0.05). 37.5% registered positive dynamics in relation to pathological activity on the electroencephalogram. According to the Luria A. R. test, the average values of the obtained data at all stages of word presentation were probably higher than at the beginning of the study. Indicators of long-term memory changed similarly. Thus, the proposed treatment approach has a beneficial effect on the main pathogenetic links of the development of PTE, its course and corrects cognitive deficits, psychoemotional layers, which are comorbid conditions.
A comprehensive analysis of indicators of the state of the body between training and recovery allows a comprehensive evaluation of various aspects of health, athletic performance, and recovery. In this pilot study, an assessment of the metabolomic profile of athletes was performed, and the immunological reaction of the athlete’s body to food before exercise and 48 h after exercise was studied. As a result, 15 amino acids and 3 hormones were identified, the plasma levels of which differed between the training and recovery states. In addition, immunological reactions or hyperreactivity to food allergens were assessed using an enzyme immunoassay. It is likely that for the athletes in the study sample, 48 h is not enough time for the complete recovery of the body.
Test methods in anti‐doping, most of which rely on the most modern mass spectrometric instrumentation, undergo continuous optimization in order to accommodate growing demands as to comprehensiveness, sensitivity, retrospectivity, cost‐effectiveness, turnaround times, etc. While developing and improving analytical approaches is vital for appropriate sports drug testing programs, the combination of today's excellent analytical potential and the inevitable exposure of humans to complex environmental factors, specifically chemicals and drugs at the lowest levels, has necessitated dedicated research, particularly into the elite athlete's exposome. Being subjected to routine doping controls, athletes frequently undergo blood and/or urine tests for a plethora of drugs, chemicals, corresponding metabolic products, and various biomarkers. Due to the applicable anti‐doping regulations, the presence of prohibited substances in an athlete's organism can constitute an anti‐doping rule violation with severe consequences for the individual's career (in contrast to the general population), and frequently the question of whether the analytical data can assist in differentiating scenarios of ‘doping’ from ‘contamination through inadvertent exposure’ is raised. Hence, investigations into the athlete's exposome and how to distinguish between deliberate drug use and potential exposure scenarios have become a central topic of anti‐doping research, aiming at supporting and consolidating the balance between essential analytical performance characteristics of doping control test methods and the mandate of protecting the clean athlete by exploiting new strategies in sampling and analyzing specimens for sports drug‐testing purposes.
Blood transfusion increases red blood cells (RBCs) and significantly improves physical performance. Heterogenous blood transfusion can be tested and detected in the doping labs. However, homologous blood doping is still critical for blood doping laboratories. Many doping labs have been investigating for markers related to homologous blood doping tests.
In the 1st study, we have stored human blood at 4°C in 2 different groups. One group was kept for 3 days, and the other group was kept for 20 days. Later we have collected the storage buffer from both groups and measured the 5-oxoprolinase level by ELISA. In the 2nd experiment, we have stored RBCs at 4°C in a cell stabilizing buffer for 14 days. RBC and buffer samples were collected daily and were stored at -20°C until further analysis. Later, we measured 5-oxoproline, glutamate, GSH concentrations in RBCs by LC-MS/MS, and 5-oxoprolinase level in the buffer stored the RBCs by ELISA.
We found that the 5-oxoprolinase released in cell stabilizing buffer was significantly higher on day 20 than on day 3. In RBC cells, we also found a time kinetic increase of 5-oxoproline and glutamate from day 1 to day 14. On the other hand, the 5-oxoprolinase levels increased significantly in the storage buffer until day 13. The level of increased 5-oxoproline in cells and 5-oxoprolinase in the buffer showed a significant correlation.
We conclude that storage aging has a significant relationship with 5-oxoproline and 5-oxoprolinase levels in RBC. The average human body does not have 5-oxoproline and 5-oxoprolinase at the detectable level. In homologous blood doping, athletes take their preserved RBCs for doping. The intake of storage RBCs in the blood increases 5-oxoproline and 5-oxoprolinase to the detectable level, thus establishing a biomarker for homologous blood doping. Further experiments on humans are needed to confirm these doping markers to include them in daily laboratory detection routines.
Strenuous aerobic work inherent to cyclical sports requires adequate oxygenation of the athletes’ working muscles. One of the ways to improve the oxygen transport function of blood is to optimize the structural and functional state of erythrocytes, for example, by using succinic acid in the form of the medical drug Armadin Long. This pharmacological drug is widespread in clinical practice for treating hypoxic and ischemic conditions, and very little is known about its use for improving the condition of the erythrocytes in the blood of athletes, which determined the relevance of this study.
The objective of the study was to assess the feasibility and effectiveness of using the medical drug Armadine Long to improve the state of the erythrocyte link of the blood oxygen transport system during aerobic exercise.
Materials and Methods. A randomized blinded placebo-controlled trial included 40 male middle-distance runners (aerobic discipline of athletics). The subjects were divided into two subgroups matched for number, age, and anthropometric characteristics (strats). In this work, laboratory methods were used, including hematological tests (in particular, hemoglobin and erythrocytes level measurement and erythrocyte characteristics evaluation), as well as biochemical method: the study of prooxidant and antioxidant balance (activity of lipid peroxidation according to changes in the content of maloniс dialdehyde and antioxidant protection according to changes in the concentration of reduced glutathione) and functional characteristics of erythrocyte membranes (permeability, sorption capacity, sorption capacity of the glycocalyx) as well as evaluation of the main components of lipid and protein composition of red blood cell membranes. Pedagogical research methods were based on the determination of relative aerobic capacity using the generally accepted PWC170 test.
Results of the study. During 21 days of intensive loads, an almost two-fold increase in contents of malonic dialdehyde was observed with a parallel decrease in reduced glutathione content by 23.5 % during aerobic loads. At the same time, there was a deterioration of thefunctional characteristics of erythrocytes and a decrease in the relative
aerobic capacity in comparison with the baseline data.
The use of the medical drug Armadine Long at a dose of 600 mg
per day improved the indicated characteristics of erythrocytes. At the
same time, there were positive changes in the protein and lipid state of
the erythrocyte membranes, and the athletes’ aerobic power increased
by 38.7%. It substantiates the high ergogenic ability of succinic acid,
which is based on the normalization of the lipoperoxidation process
and the improvement of the structural and functional characteristics of
erythrocyte membranes.
Keywords: aerobic loads, succinic acid, oxygen transport function
of blood, erythrocyte membranes, lipid peroxidation.–
Emoxypine and its succinate derivative share a common hydroxypridine structure, which is similar to pyridoxine. These compounds have been utilized therapeutically and industrially, owing to the wide range of properties offered. This includes antihypoxic, neuroprotective and cardioprotective effects, along with pharmacokinetic benefits such as the ability to cross the blood brain barrier (BBB), owing to its relatively small size and low molecular weight. It was observed that emoxypine exhibited iron chelating property in vitro, indicating its usage as a promising therapeutic strategy in the management of neurodegenerative conditions such as Alzheimer's disease (AD), as well as hematologic disorders like thalassemia and hemochromatosis. In addition to this, it has been observed to exert a potent antioxidant effect, therefore, it may be considered for the amelioration of disorders resulting from free radical injury. Studies on its mechanism of action and implications on cellular and molecular levels would help to further the understanding of its benefits, as well as prospects for filing patents for novel applications. The primary focus of this review is to shed light on the broad spectrum of pharmacological properties offered by emoxypine and its succinate derivative, and to highlight the scope for an increased number of pre-clinical and clinical trials to assess its safety and efficacy. In addition to this, the highlights of this article include the recent patents filed and scope for novel applications of these agents.
Introduction:
Antioxidants may have positive impact on diabetic polyneuropathy (DPN), presumably due to alleviation of oxidative stress. We aimed to evaluate the efficacy and safety of combination of antioxidants: succinic acid, inosine, nicotinamide, and riboflavin (SINR) in the treatment of DPN.
Research design and methods:
In a double-blind, placebo-controlled clinical trial, men and women aged 45-74 years with type 2 diabetes and symptomatic DPN, with initial Total Symptom Score (TSS) ˃5, were randomized into experimental (n=109) or placebo (n=107) group. Patients received study medication/placebo intravenously for 10 days, followed by oral administration for 75 days. Statistical significance was defined as a two-tailed p<0.05.
Results:
In SINR group, mean TSS change after 12 weeks was -2.65 (±1.46) vs -1.73 (±1.51) in the placebo group (p<0.0001; t-test). Reduction of symptoms in the SINR group was achieved regardless of hemoglobin A1c levels, but better results were observed in patients with initial TSS <7.5. The analysis of TSS subscores revealed statistically significant between-group differences by dynamics of the intensity of paresthesia and of numbness starting from day 11 (p=0.035 and p=0.001, respectively; mixed model); by day 57, statistically significant between-group differences were detected also by dynamics of burning intensity (p=0.005; mixed model). Study limitations are small effect size, moderate proportion of patients with severe DPN symptoms, subjective assessment of outcomes, exclusion of participants who received injectable glucose-lowering medications other than insulins, and patients with uncontrolled and type 1 diabetes.
Conclusions:
The combination of SINR effectively alleviates DPN symptoms in patients with type 2 diabetes.
Trial registration number:
ClinicalTrials.gov Registry (NCT04649203; Unique Protocol ID: CTF-III-DM-2019).
The term ‘food first’ has been as the within sport nutrition although there is no of this and often of the implications. We propose that food first should mean
come from whole foods and drinks rather than from isolated food components or dietary supplements”. There are many reasons to commend a food first the risk of supplement contamination resulting in anti-doping a few supplements can enhance health and/or performance and therefore a food only approach could be inappropriate. We propose six reasons why a food only approach may not always be optimal for athletes: 1) some nutrients are difficult to obtain in in the diet, or may
intake of other nutrients, 2) some nutrients are abundant only in foods athletes do not eat/like, 3) the nutrient content of some foods with is highly variable, 4) concentrated doses of some nutrients are required to correct deficiencies and/or promote immune tolerance, 5) some foods may be difficult to consume immediately before, during or immediately after exercise and 6) tested supplements could help where there are concerns about food hygiene or contamination. In these situations, it is acceptable for the athlete to that a comprehensive risk is implemented. As a consequence, it is important
to stress that the be “food first but not always food only”.
Aim. To assess the safety and efficacy of Remaxol, solution for infusion, compared with parenteral form of S-adenosyl-L-methionine, in the treatment of patients with intrahepatic cholestasis syndrome accompanying chronic diffuse liver diseases of various etiology.
Materials and methods. In a multicenter open-label comparative study of the safety and efficacy of Remaxol (inosine + meglumine + methionine + nicotinamide + succinic acid) 317 patients aged 18 to 65 years were randomized into 2 groups: patients of the experimental group (n=168) received intravenous Remaxol, solution for infusion, 400 ml, and patients of the control group (n=149) Heptral (S-adenosyl-L-methionine) 800 mg. The duration of treatment was 10 days. The primary efficacy endpoint was the proportion of patients who responded to therapy, as demonstrated by dynamics of laboratory parameters of liver functional status: decrease in gamma glutamyl transpeptidase level by 40%, and/or alkaline phosphatase level by 30%, and/or decrease total bilirubin level by 30% from baseline by the end of the treatment course.
Results. The proportion of responders was 51% in the Remaxol group vs. 44.9% in the Heptral group (p=0.303); the lower limit of the one-sided 95% confidence interval for the difference in the proportions of responders was -4.01%, which exceeds the non-inferiority margin pre-defined by the study protocol, thus, the non-inferiority hypothesis was proven, i.e. Remaxol at a dose of 400 ml/day demonstrates similar efficacy to Heptral at a dose of 800 mg/day in patients with intrahepatic cholestasis syndrome associated with chronic diffuse liver diseases. Similar positive trends in the levels of transaminases, total bilirubin and the severity of pruritus were revealed in both treatment groups. We did not reveal statistically significant between-group differences in the frequency of adverse events definitely related to the study treatment.
Conclusion. Administration of Remaxol as a part of the pathogenetic therapy of patients with intrahepatic cholestasis syndrome who need hepatoprotection is justified.
Endurance training and explosive strength training, with different contraction protein and energy metabolism adaptation in skeletal muscle, are both beneficial for physical function and quality of life. Our previous study found that chronic succinate feeding enhanced the endurance exercise of mice by inducing skeletal muscle fiber-type transformation. The purpose of this study is to investigate the effect of acute succinate administration on skeletal muscle explosive strength and its potential mechanism. Succinate was injected to mature mice to explore the acute effect of succinate on skeletal muscle explosive strength. And C2C12 cells were used to verify the short-term effect of succinate on oxidative phosphorylation. Then the cells interfered with succinate receptor 1 (SUCNR1) siRNA, and the SUCNR1-GKO mouse model was used for verifying the role of SUCNR1 in succinate-induced muscle metabolism and expression and explosive strength. The results showed that acute injection of succinate remarkably improved the explosive strength in mice and also decreased the ratio of nicotinamide adenine dinucleotide (NADH) to NAD⁺ and increased the mitochondrial complex enzyme activity and creatine kinase (CK) activity in skeletal muscle tissue. Similarly, treatment of C2C12 cells with succinate revealed that succinate significantly enhanced oxidative phosphorylation with increased adenosine triphosphate (ATP) content, CK, and the activities of mitochondrial complex I and complex II, but with decreased lactate content, reactive oxygen species (ROS) content, and NADH/NAD⁺ ratio. Moreover, the succinate's effects on oxidative phosphorylation were blocked in SUCNR1-KD cells and SUCNR1-KO mice. In addition, succinate-induced explosive strength was also abolished by SUCNR1 knockout. All the results indicate that acute succinate administration increases oxidative phosphorylation and skeletal muscle explosive strength in a SUCNR1-dependent manner.
Oxidation of succinate by mitochondria can generate a higher protonmotive force (pmf) than can oxidation of NADH-linked substrates. Fundamentally, this is because of differences in redox potentials and gearing. Biology adds kinetic constraints that tune the oxidation of NADH and succinate to ensure that the resulting mitochondrial pmf is suitable for meeting cellular needs without triggering pathology. Tuning within an optimal range is used, for example, to shift ATP consumption between different consumers. Conditions that overcome these constraints and allow succinate oxidation to drive pmf too high can cause pathological generation of reactive oxygen species. We discuss the thermodynamic properties that allow succinate oxidation to drive pmf higher than NADH oxidation, and discuss the evidence for kinetic tuning of ATP production and for pathologies resulting from substantial succinate oxidation in vivo.
Research aim
To study the RBCs functional and metabolic parameters and the microcirculatory brain structure at traumatic brain injury (TBI) under the action of 2-ethyl-6-methyl-3-hydroxypyridine succinate.
Methods
A closed TBI was modeled by the free fall of a load on the parietooccipital regions of head. We made studies of the influence of 2-ethil-6-methil-3-hydroxipiridin succinate on aggregation and electrophoretic mobility of RBCs, catalase activity, malonic dialdehyde concentration, adenosine triphosphate and 2.3-biphosphoglycerate (2.3 – BPG) concentrations in RBCs. The state of parenchyma and microcirculatory brain mainstream in post-traumatic period of TBI have been studied on micro-preparations.
Results
The use of 2-ethyl-6-methyl-3-hydroxypyridine succinate under conditions of head injury leads to a decrease in MDA concentration and in aggregation of RBCs, to an increase in the 2.3—BPG concentration and RBC electrophoretic mobility compared to the control (group value). The most pronounced changes under the action of 2-ethyl-6-methyl-3-hydroxypyridine succinate were observed 3–7 days after the TBI. Significant indicators of the restoration of the microvasculature and brain tissue provoked by the use of 2-ethyl-6-methyl-3-hydroxypyridine succinate of were evident from the 7th day unlike the control group, where the restoration of structural morphological parameters was observed only on the 12th day of the post-traumatic period. Fast recovery of blood flow under the action of 2-ethyl-6-methyl-3-hydroxypyridine succinate ensured effective restoration of neurons and glia in comparison with the control group.
Conclusions
Early and long-term cytoprotective correction intensifies the oxygen transport function of the blood, prevents and / or reduces disorders of microvessels, neurons and glia in the post-traumatic period, thereby provides correction of hypoxic state and drives to the restoration of brain tissues homeostasis.
Lately, the veterinary drug Emidonol® has been discussed as a possible scenario for inadvertent doping in sports. Emidonol® is approved for use in livestock breeding, exhibiting antihypoxic and weak sedative effects. The veterinary drug rapidly dissociates into meldonium, a substance prohibited in sports, and is excreted largely in its unchanged form into urine. To investigate if residues of meldonium in edible produce may result in adverse analytical findings in sports drug testing, a pilot study was conducted with three volunteers consuming a single dose of 100 ml meldonium‐spiked milk at a concentration of 500 ng/ml (Study 1), and multiple doses of 100 ml of meldonium‐spiked milk (500 ng/ml) on five consecutive days (Study 2). In the single dose study, urinary meldonium concentrations peaked between 2 and 6 h post‐administration with maximum values of 7.5 ng/ml, whereas maximum meldonium concentrations of 18.6 ng/ml were determined after multiple doses 4 h post‐administration. All samples were analyzed using an established and validated protocol based on HILIC‐HRMS/MS. The veterinary drug Emidonol® has been discussed as a possible scenario for inadvertent doping in sports. In a recent study, meldonium concentrations determined in raw milk reached up to 701 ng/ml. If consumed, urine collected post‐ingestion can present meldonium residues and adverse analytical findings in doping controls cannot be excluded.
A study has been carried out on the effect of the domestic pharmacological armadin long preparation (2-ethyl-6-methyl-3-hydroxypyridine succinate) on the physical working capacity of athletes under the maximum in-tensity force loads characteristic of modern sports. Since pharmacology in sports is constantly searching for non-toxic drugs of the metabolithotropic origin that would have the ability to promote physical efficiency and slow down fatigue without toxic effects on the body, we have chosen for our research a drug based on succinic acid, which is a natural metabolite of the Krebs cycle. It has been shown that the armadin long preparation, when applied on a course for three weeks, positively affects the parameters of special working capacity associated with the improvement of the oxygen-transport function of blood. The metabolic basis of this phenomenon is the inhibition of a decrease in the pH of the internal environment of the body with the subsequent development of lactate-acidosis and the ability of the armadin long drug to accelerate the processes of angiogenesis, and, accordingly, the transport of oxygen to the athlete’s working muscles. The intensity of the formation of new growth factor (VEGF). Such data substantiate the expediency of the use of succinic acid-based agents to prevent negative metabolic changes and to slow down the onset of fatigue in athletes under intense physical loads
Context: Our goal was to review the current literature regarding the ability of substances that have recently been included in the WADA prohibited list (i.e., meldonium, trimetazidine, xenon, and cobalt) or in the monitoring program (i.e., ecdysterone and bemethyl) to enhance performance in athletes or cause adverse effects. Evidence Acquisition: To find out which studies led to the prohibition of the substances mentioned, we searched the PubMed database using keywords including the substances’ or methods’ names, as well as phrases related to various aspects of sports activities and health assessments of athletes. Results: The results obtained during our systematic literature search clearly indicate that there is a lack of scientific evidence supporting the impact of several substances prohibited by WADA (i.e., meldonium, trimetazidine, xenon, and cobalt) on athletic performance or on health in athletes. Conclusions: There is insufficient evidence that the previously mentioned substances have any performance enhancing potential. If left on the list, meldonium may be classified as a “specified substance” because of its wide availability and due to the fact that this drug that can be easily bought over the counter without a prescription.
Isopropylnorsynephrine (isopropyloctopamine, deterenol, 4‐(1‐hydroxy‐2‐(isopropylamino)ethyl)phenol), a beta‐selective and direct‐acting adrenergic agonist, has been reported in the past as declared as well as non‐declared ingredient of dietary supplements. The proven biological activity and the structural similarity of isopropylnorsynephrine to substances classified as prohibited compounds according to the World Anti‐Doping Agency's (WADA's) regulations could necessitate the inclusion of this sympathomimetic amine into routine doping control analytical assays. Therefore, information on urinary metabolites is desirable in order to allow for an efficient implementation of target compounds into existing multi‐analyte testing procedures, enabling the unequivocal identification of the administration of isopropylnorsynephrine by an athlete. In a pilot study setting, urine samples were collected prior to and after the oral application of ca. 8.7 mg of isopropylnorsynephrine, which were subjected to liquid chromatography‐high resolution/high accuracy (tandem) mass spectrometry. The intact drug, hydroxylated and/or glucurono‐ or sulfo‐conjugated isopropylnorsynephrine were detected up to 48 h post‐administration, with isopropylnorsynephrine sulfate representing the most abundant urinary target analyte. No relevant amounts of the dealkylation product (octopamine) were observed, indicating that merely moderate adaptations of existing test methods (or data evaluation strategies) are required to include isporpoylnorsynephrine in antidoping analytics, if required.
Examination of the patterns of free-radical processes (FRP) and changes of the early screening markers to predict the course of hemorrhagic stroke (HS) and applied pathophysiologically based therapy can be of great practical importance. This study aimed to determine early changes in the parameters of oxidative stress and routine biochemistry blood tests in patients with HS and to assess their relationship with clinical outcome. The effects of early applied cytoflavin were also investigated. The prospective study included 151 patients with HS. Forty-eight percent of patients in the standard conservative therapy were given cytoflavin antioxidant energy therapy from the first day of hospitalization. The neurological status, neuroimaging, biochemical blood tests and FRP were assessed on days 1, 5, 10, and 20 of hospitalization. In patients with HS, an imbalance of all stages of FRP was detected proportionately to the severity of HS. The malondialdehyde concentration above 5.3 μmol/L, the number of leukocytes above 15 800, glucose above 11.9 mmol/L, lactate dehydrogenase above 574 IU/L, and lactate above 2.5 mmol/L, detected on the first day, predetermined a high risk of death. Additional cytoflavin treatment allowed stabilizing the clinical laboratory picture of HS, improved the treatment results, and reduced hospital mortality rate.
A narrative review with an overall aim of indicating the current state of knowledge and the relevance concerning food and supplement contamination and/or adulteration with doping agents and the respective implications for sports drug testing is presented. The identification of a doping agent (or its metabolite) in sports drug testing samples constitutes a violation of the anti-doping rules defined by the World Anti-Doping Agency. Reasons for such Adverse Analytical Findings (AAFs) include the intentional misuse of performance-enhancing/banned drugs; however, also the scenario of inadvertent administrations of doping agents was proven in the past, caused by, amongst others, the ingestion of contaminated dietary supplements, drugs, or food. Even though controversial positions concerning the effectiveness of dietary supplements in healthy subjects exist, they are frequently used by athletes, anticipating positive effects on health, recovery, and performance. However, most supplement users are unaware of the fact that the administration of such products can be associated with unforeseeable health risks and AAFs in sports. In particular anabolic androgenic steroids (AAS) and stimulants have been frequently found as undeclared ingredients of dietary supplements, either as a result of cross-contaminations due to substandard manufacturing practices and missing quality controls or an intentional admixture to increase the effectiveness of the preparations. Cross-contaminations were also found to affect therapeutic drug preparations. While the sensitivity of assays employed to test pharmaceuticals for impurities is in accordance with good manufacturing practice guidelines allowing to exclude any physiological effects, minute trace amounts of contaminating compounds can still result in positive doping tests. In addition, food was found to be a potential source of unintentional doping, the most prominent example being meat tainted with the anabolic agent clenbuterol. The athletes’ compliance with anti-doping rules is frequently tested by routine doping controls. Different measures including offers of topical information and education of the athletes as well as the maintenance of databases summarizing low- or high-risk supplements are important cornerstones in preventing unintentional anti-doping rule violations. Further, the collection of additional analytical data has been shown to allow for supporting result management processes.
2‐(Dimethylamino)ethan‐1‐ol (Deanol) is a widely produced chemical used by both industry and consumers in a variety of applications. Meclofenoxate, a stimulant classified on the World Anti‐Doping Agency Prohibited List, metabolizes into deanol and, presumably, its main metabolite deanol‐ N ‐oxide. Hence, using liquid chromatography–tandem mass spectrometry, a quantitative detection method for deanol‐ N ‐oxide in urine was developed. Subsequently, the urinary excretion of deanol‐ N ‐oxide after oral application of 130 mg of deanol was determined in six volunteers, and urine samples of a cohort of 180 male and female athletes from different sports were analyzed. In addition, urinary deanol‐ N‐ oxide was determined in an exploratory study with one volunteer ingesting 250 mg of meclofenoxate. The developed test method allowed for limits of detection and quantification for deanol‐ N ‐oxide at 0.05 and 0.15 μg/mL, respectively. Urinary deanol‐ N ‐oxide c max levels were found between 100 and 250 μg/mL 2–5 h post‐administration of 130 mg of deanol. Similarly, urine samples collected after the administration of 250 mg of meclofenoxate exhibited c max levels of 115 μg/mL. In contrast, deanol‐ N ‐oxide urine concentrations of pre‐administration specimens and 180 routine doping control urine sample were between 0.3 and 1.3 μg/mL and below limit of quantification and 1.8 μg/mL, respectively. The study suggests that the use of deanol and meclofenoxate results in significantly elevated urinary deanol‐ N ‐oxide levels. Whether or not monitoring deanol‐ N ‐oxide in doping controls can support decision‐making processes concerning the detection of meclofenoxate use necessitates further investigations taking into consideration the elimination kinetics of 4‐chlorophenoxyacetic acid, the main metabolite of meclofenoxate, and deanol‐ N ‐oxide.
Objective:
Study of the effectiveness of monotherapy with potassium N-acetylaminosuccinate (Cogitum) for asthenic syndrome (fatigue) in individuals, uncharacteristic somatic, neurological diseases, anxiety disorders, depression and other diseases that may interfere with asthenia.
Material and methods:
Patients with fatigue scores of 22 or more on the Fatigue Assessment Scale (FAS) were randomly divided into the main group (MG) - 37 people, mean age 22 years [21; 24] and the control group (CG) - 34 people, mean age 21 years [19; 23]. The Trail Making Test (TMT-A and TMT-B), the assessment of general well-being on a visual analogue scale (VAS), where 0 is the worst state of health, 10 is the state of absolute well-being, was assessed. MG patients received a solution of potassium N-acetylaminosuccinate (Cogitum) 750 mg per day in a sterile container, CG patients received sterile water with banana flavor in a sterile container. The duration of the study was 21 days.
Results:
Prior to the start of the study, there were no statistically significant differences in FAS, TMT, and VAS between MG and CG. After 21 days, the FAS score in the MG decreased (p=0.00001), the time of TMT-A (p=0.000012) and TMT-B (p=0.000033) decreased, the VAS score increased (p=0.00024). There were no statistically significant changes in the CG. Placebo effect was noted in 10 patients of the CG (29.4%).
Conclusion:
Potassium aminosuccinate (Cogitum) at a daily dose of 750 mg and a duration of treatment of 21 days effectively eliminates the symptoms of asthenic syndrome (fatigue), while accompanied by an improvement in complex cognitive functions. The results of our study suggest that fatigue (asthenic syndrome) and cognitive impairment may have a common pathogenetic mechanism - a deficiency of systems in which mediators are N-acetylaspartate and N-acetylaspartylglutamate. Cogitum had no side effects and was well tolerated. Cogitum is superior to placebo in the treatment of fatigue (asthenic syndrome).
The first nootropic prohibited in sport was fonturacetam (4-phenylpiracetam, carphedon) in 1998. Presented here 25 years later is a broad-scale consideration of the history, pharmacology, prevalence, regulations, and doping potential of nootropics viewed through a lens of 50 selected dietary supplements (DS) marketed as "cognitive enhancement," "brain health," "brain boosters," or "nootropics," with a focus on unauthorized ingredients. Nootropic DS have risen to prominence over the last decade often as multicomponent formulations of bioactive ingredients presenting compelling pharmacological questions and potential public health concerns. Many popular nootropics are unauthorized food or DS ingredients according to the European Commission including huperzine A, yohimbine, and dimethylaminoethanol; unapproved pharmaceuticals like phenibut or emoxypine (mexidol); previously registered drugs like meclofenoxate or reserpine; EU authorized pharmaceuticals like piracetam or vinpocetine; infamous doping agents like methylhexaneamine or dimethylbutylamine; and other investigational substances and peptides. Several are authorized DS ingredients in the United States resulting in significant global variability as to what qualifies as a legal nootropic. Prohibited stimulants or ß2-agonists commonly used in "pre-workout," "weight loss," or "thermogenic" DS such as octodrine, hordenine, or higenamine are often stacked with nootropic substances. While stimulants and ß2-agonists are defined as doping agents by the World Anti-Doping Agency (WADA), many nootropics are not, although some may qualify as non-approved substances or related substances under catch-all language in the WADA Prohibited List. Synergistic combinations, excessive dosing, or recently researched pharmacology may justify listing certain nootropics as doping agents or warrant additional attention in future regulations.
The article is devoted to infusion therapy with Reamberin 1.5% (Meglumine sodium succinate) in patients with various traumatic injuries. The authors substantiate the relevance and significance of this issue. Specifics and purposes of therapy are considered. The authors reviewed national studies devoted to clinical aspects and determined the main directions of therapy in emergency patients with mechanical injuries, burns, traumatic brain injury and cognitive impairment caused by combat trauma. Moreover, experimental studies of protective properties of Reamberin under combined action of cold, vibration and immobilization, as well as acute massive blood loss are analyzed.
In 2022 Winter Olympics, a 15-year-old star figure skater got into the limelight of a doping scandal after testing positive for trimetazidine along with hypoxen and L-carnitine, raising questions on their role in high performing endurance sports. This editorial explore the potential mechanisms by which these substances work synergistically in enhancing athletic performance under intense hypoxic (oxygen-deprived) conditions. The trimetazidine can reduce the oxygen demand and may help provide energy to the heart muscles, carnitine could help produce more energy, and hypoxen, can help provide that energy even when the tissues are extremely hypoxic (anaerobic conditions). The drugs, however, pose a health and safety risk to athletes, in particular, the adverse effects on cardiac muscles and potential risks of skeletal muscle disorders such as Parkinsonian symptoms. The practitioners in sports nutrition and physical training are, therefore, advised to reflect on current nutritional practices for enhancing endurance and ethical implications of using these supplements in athletes.
Objective:
To assess the efficacy of sequential therapy with Mexidol and Mexidol FORTE 250 in comparison with placebo in patients of different age groups with chronic brain ischemia.
Material and methods:
The study is sub-analysis of data of the international multicenter, randomized, double-blind, placebo-controlled study of sequential therapy in patients with chronic brain ischemia (MEMO), which included 318 patients (25% men) in the age of 40-90 (median 60) years. All subjects were subdivided into 3 age subgroups: 40-60 years (n=163), 61-75 years (n=141) and 76-90 years (n=13). The primary efficacy endpoint was the dynamic of increase of total score by MoCA scale, i.e. the absolute value of difference by MoCA scale at the point of day 75 comparing to values before treatment. As secondary efficacy endpoints results of dynamic by following questionnaires and scales were used: digit symbol substitution test, the Health Survey SF-36, asthenia subjective assessment scale (MFI-20), Vane questionnaire, Beck anxiety scale, Tinetti scale.
Results:
After 75 days of treatment positive dynamic was revealed in cognitive, emotional and motor impairment in patients of 40-60 and 61-75 age subgroups both in groups of Mexidol and placebo, but in group of Mexidol the changes were more prominent which is proved by significantly higher values of median of absolute difference of total score of studied parameters.
Conclusion:
The results of trial showed that in patients of different age-subgroups with chronic brain ischemia the improvement in cognitive, motor impairment and quality of life, as well as decrease in vegetative impairment, asthenia and anxiety are observed after 75 days of treatment both in Mexidol and placebo group, but in Mexidol group these changes are more prominent. The data obtained confirm the expediency of the use of sequential therapy with Mexidol and Mexidol FORTE 250 in patients of different age subgroups with chronic brain ischemia.
The doping control analyses at the XXXII Olympic Games (July 23–August 8, 2021) and the XVI Paralympic Games (August 24–September 5, 2021) held in Tokyo, Japan, after a year of delay due to the COVID‐19 pandemic are summarized in this paper. A new satellite facility at the existing World Anti‐Doping Agency (WADA)‐accredited Tokyo laboratory was established and fully operated by 278 staff, including 33 Tokyo laboratory staff, 49 international experts, and 196 Japanese temporary staff. The numbers of urine samples were 5,081 (Olympics) and 1,519 (Paralympics), and the numbers of blood samples were 1,103 (Olympics) and 500 (Paralympics). The laboratory could prepare for analysis in advance using a paperless chain‐of‐custody system, allowing for faster turnaround time reporting. For the first time, a new polymerase chain reaction method for detecting erythropoietin (EPO) gene doping was used. The laboratory also analyzed blood samples for detecting steroid esters following the spotting of collected venous EDTA blood onto dried blood spot cards. Moreover, full‐scan data acquisition using high‐resolution mass spectrometers was performed for all urine samples, allowing for detecting traces of doping substances, which are not currently analyzed in the subsequent data processing. The presence of some prohibited substances was confirmed, resulting in 8 atypical findings (ATFs) and 11 adverse analytical findings (AAFs), including homologous blood transfusion (2 cases) and recombinant EPO in the blood (1 case), at the Olympics, whereas 2 ATFs and 10 AAFs were reported at the Paralympics.
Objective. To study the efficacy of courses of i.v., Cytoflavin in combination with the standard rehabilitation program for postcovid syndrome for correction of postcovid asthenia. Materials and methods. Follow-up investigations were carried out in 45 patients with postcovid syndrome at the second stage of rehabilitation. Patients were divided into two groups of comparable sex and age. The volume of lung damage was also similar in both groups, at 25-80%. The 24 patients making up the comparison group received standard postcovid rehabilitation: pulsed magnetotherapy, inhalation therapy, aeroionotherapy, infrared laser therapy, courses of aerobic training, rational psychotherapy, and successive drug therapy. The 21 patients of the study group additionally received intravenous Cytoflavin daily for 10 days. The dynamics of increases in scores on the Rehabilitation Routing Scale, the Hamilton Depression Rating Scale (HDRS), the Asthenic Status Scale, and the 6-minute walk test at admission and discharge were also monitored. Results and conclusions. Addition of courses of intravenous Cytoflavin to the complex rehabilitation program for postcovid syndrome significantly improved the general functional state of the body, decreased levels of depression and asthenization, and increased physical exercise tolerance.
The cytochrome c oxidase complex, complex VI (CIV), catalyzes the terminal step of the mitochondrial electron transport chain where the reduction of oxygen to water by cytochrome c is coupled to the generation of a protonmotive force that drive the synthesis of ATP. CIV evolution was greatly accelerated in humans and other anthropoid primates and appears to be driven by adaptive selection. However, it is not known if there are significant functional differences between the anthropoid primates CIV, and other mammals. Comparison of the high-resolution structures of bovine CIV, mouse CIV and human CIV shows structural differences that are associated with anthropoid-specific substitutions. Here I examine the possible effects of these substitutions in four CIV peptides that are known to affect proton pumping: the mtDNA-coded subunits I, II and III, and the nuclear-encoded subunit VIa2. I conclude that many of the anthropoid-specific substitutions could be expected to modulate the rate and/or the efficiency of proton pumping. These results are compatible with the previously proposed hypothesis that the accelerated evolution of CIV in anthropoid primates is driven by selection pressure to lower the mitochondrial protonmotive force and thus decrease the rate of superoxide generation by mitochondria.
Objectives:
To evaluate the efficacy and safety of two dosing regimens of Mexidol film-coated tablets, 125 mg («RPC «PHARMASOFT» LLC Russia), compared with placebo in children with attention deficit hyperactivity disorder (ADHD) aged 6 to 12 years.
Material and methods:
A multicenter randomized, double-blind, placebo-controlled study in 3 parallel groups was conducted in 14 clinical centres of the Russian Federation to assess efficacy and safety of Mexidol film-coated tablets, 125 mg («RPC «PHARMASOFT» LLC Russia) in the treatment of attention deficit hyperactivity disorder (ADHD) in children 6-12 years old with different dosing regimens. The study involved 333 boys and girls aged 6 to 12 years with a confirmed diagnosis of ADHD established in accordance with ICD-10 and DSM-5 criteria. After screening (up to 14 days) the patients were randomised into 3 treatment groups in a 1:1:1: Mexidol 125 mg 2 times daily, Mexidol 125 mg daily+placebo and the placebo group. The duration of treatment in all groups was 42 days. 332 children completed the study. ADHD and comorbid disorders assessment scales were used.
Results:
There were statistically significant changes in the sum of the total scores on the SNAP-IV inattention and hyperactivity/impulsivity subscales after 6 weeks of therapy in all three study groups (p<0.05). There were statistically significant differences between the Mexidol 125 mg and placebo groups and between the Mexidol 125 mg 2 times daily and placebo groups (for the PP population: p=0.000308 and p=0.000024, respectively; for the FAS population: p=0.000198 and p=0.000024, respectively), indicating that Mexidol therapy is superior to placebo. Statistically significant differences (p<0.05) were also obtained for most of the secondary efficacy criteria (average change in SNAP-IV inattention subscale score, average change in SNAP-IV hyperactivity/impulsivity subscale score, average change in SNAP-IV subscale score - Conners index, average change in ADHD-RS-IV score, change in CGI-ADHD-S scores, change in CGI-I score - the Clinical Global Impressions Scale - Improvement) when comparing Mexidol therapy with placebo. The results of statistical analysis of the incidence of adverse events, laboratory values, physical examination show no significant differences between the compared groups in the main safety parameters.
Conclusions:
The regimen of Mexidol, 125 mg film-coated tablets twice daily has been shown to be superior to the regimen of Mexidol, 125 mg film-coated tablets once daily and placebo. The safety profiles of the studied dosing regimens of Mexidol and placebo were comparable.
Objective:
To evaluate the effect of Mexidol on the recovery of cognitive functions in patients after ischemic stroke (IS).
Material and methods:
We examined 70 patients with acute IS, who were randomized into 2 groups by random sampling; The 1st group consisted of patients who, against the background of the main standard therapy for 14 days, received Mexidol intravenously, 500 mg 1 time per day, followed by oral administration of Mexidol FORTE 250, 750 mg per day for 60 days (40 patients; 28 men, 12 women). Group 2 consisted of 30 patients (21 men, 9 women) who received only standard therapy.
Results:
Baseline scores on the MoCA and MMSE scales did not differ between the two groups. Retesting showed that the improvement on these scales was statistically more significant in the 1st group. The analysis of indicators of the evoked potential P300 confirmed a more pronounced positive trend in the 1st group (p<0.01).
Conclusion:
The use of sequential therapy with Mexidol is accompanied by a more complete recovery of cognitive functions in patients who have undergone IS.
Objective:
To assess the efficacy and safety of sequential therapy with Mexidol solution for intravenous and intramuscular administration, 50 mg/ml and Mexidol FORTE 250 film-coated tablets, 250 mg in patients with chronic brain ischemia (CBI).
Material and methods:
An international multicenter, randomized, double-blind, placebo-controlled trial, conducted in 15 clinical centers located in Russian Federation and Republic of Uzbekistan, included 318 patients with CBI aged 40 to 90 years. The patients were randomized into 2 groups, the patients of the 1-st group received Mexidol intravenously 500 mg once daily for 14 days, followed by Mexidol FORTE 250 - 250 mg 3 times a day orally for 60 days; patients of the 2-nd group received a placebo in a similar mode. The primary endpoint was the mean value of difference by MoCA scale at the point of completing the therapy comparing to initial value.
Results:
According to the results of the assessment of the primary endpoint, statistically significant changes in the MoCA scores at the stage of completion of study were revealed when comparing the dynamics between the 1-st and 2-nd groups (p<0.000001). The lower limit of the 95% confidence interval for the difference in the average of the main efficacy endpoint between the 1-st and 2-nd groups was 1.51, which allows to state a higher efficacy of the use of Mexidol. According to the estimates of secondary endpoints, a statistically significant advantage over placebo at the last visit achieved while evaluation by the following scales and tests: digit symbol substitution test, MFI-20 asthenia assessment scale, Beck anxiety scale, Vane questionnaire, Tinetti scale, SF-36 questionnaire (mental component of health), CGI scale. The comparable nature of the safety profile of Mexidol and Placebo was established.
Conclusion:
The validity and expediency of the use of Mexidol and Mexidol FORTE 250 in the treatment of patients with CBI has been demonstrated.
Objective:
To investigate the structure of postcovid syndrome, age and gender characteristics of its course, and to assess the effect of Cytoflavin on the clinical course of neurological disorders in patients who have undergone COVID-19.
Material and methods:
The study included 100 patients, the average age was 40.4±11.7 years, there were statistically more men than women. The duration of the transferred SARS-CoV-2 days is from 30 to 90 days from the date of recovery). By random sampling, the patients were divided into two groups, the main group, received Cytoflavin tablets, a course of 25 days, 2 tablets 2 times a day. Comparison group - other drugs (vitamins, nootropic drugs). All patients were examined on the day of treatment and 25-30 days after the end of therapy. The status was assessed using Asthenia Assessment Scale (MFI-20), Brief Mental Status Assessment Scale (MMSE), Quality-of-Life Questionnaire (EQ-5D), General Health Assessment Scale, and Pittsburgh Sleep Quality Index (PSQI). The analysis of laboratory parameters was carried out retrospectively.
Results and conclusion:
Postcovid syndrome was more common in men, among comorbid conditions arterial hypertension and atherosclerosis prevailed, neurocognitive and autonomic disorders predominated. Appointment of Cytoflavin made it possible to achieve a pronounced anti-asthenic effect with the correction of cognitive impairments, which was reflected in a significantly more significant positive dynamics of indicators of all scales. An additional effect of Cytoflavin was revealed - a decrease in the severity of thrombocytopenia. During the observation period, no patient had any serious adverse events or side effects associated with taking the drug. Prescription of the drug does not require age-related dose adjustment and is well combined with basic therapy for concomitant pathology.
Selective androgen receptor modulators (SARMs) are a class of drugs presenting identical anabolic properties to anabolic steroids in addition to marked reduced androgenic effects. These drugs have emerged in the doping area within the early 2000’s. Ligandrol, ostarine, RAD-140 and andarine are the most popular agents belonging to this class. According to the world anti-doping agency (WADA) prohibited list, SARMs are prohibited at all times (i.e. in and out-of-competition) and are listed under the section S1.2 (other anabolic agents).
The compilation of the WADA testing figures reports from 2015 to 2019 has indicated a regular increase of adverse analytical findings (AAF) due to SARMs, particularly with ostarine and ligandrol. The implementation of highly sensitive chromatographic anti-doping analyses has induced high-profile challenges of anti-doping rules violations as athletes have claimed in numerous occasions that contamination was the reason for their AAF.
Since the early 2000’s, it has been accepted by the Court of Arbitration for Sports (CAS) in Lausanne (Switzerland) that, under some specific circumstances, unusual explanations can be provided to the Panel to explain an AAF. This was the open door for forensic investigations, as it is done in criminal Courts.
A forensic approach can include testing for SARMs in food, drinks, but mostly in dietary supplements. As most anti-doping rules violations are only known several weeks after urine collection, this biological matrix is seldom use for further tests, despite the fact that most SARMs can be detected for several weeks in urine.
Luckily, hair or nail testing can be a complement to document the claim of the athlete but of course, it cannot be considered as an alternative to urinalysis. This is because a negative hair or nail result cannot exclude the use of the detected drug and cannot overrule the urine result.
To date, all methods for SARMs identification in various matrices involve liquid chromatography coupled to tandem mass spectrometry or high-resolution mass spectrometry.
The aim of this paper is to review the scientific literature on the analytical possibilities of testing SARMs in dietary supplements, urine and hair or nail clippings after an AAF to document the claims of an athlete or his/her legal team.
One of the ways to improve the condition of the elderly body is the method of auto-training with biofeedback, as a means of correcting deviations in the functioning of the regulatory apparatus, as well as improving antioxidant protection and eliminating the effects of oxidative stress using Cytoflavin therapy. These methods seem to be a simple and effective means of correcting negative changes in the FS of elderly hockey players after a training cycle and ensuring the possibility of a more complete recovery of their body. The difference in the points of application made it possible to combine the intake of Cytoflavin and biofeedback training into a single complex correctional and restorative technique. Purpose of the research: to consider the organizational and methodological aspects of introducing a comprehensive methodology for correcting the functional state of elderly hockey players into the system of support of their training process. Based on the results of the study, we have obtained convincing data on the positive effect of the inclusion of Cytoflavin and biofeedback training in the system of medical support for the training process of elderly hockey players. The organizational and methodological aspects of introducing a comprehensive methodology for correcting the functional state of older hockey players into the system of support for their training process considered in this article make it possible to solve a number of problems facing medical workers regarding continuous monitoring of the functional state of older hockey players, proactive diagnosis of their negative deviations, as well as a system of reabilitation.
Objective:
To study the features of asthenic syndrome and the possibilities of its therapy in patients in the post-covid period.
Material and methods:
The study included 129 patients with an average age of 49.8±8.9 years who had undergone COVID-19 using a continuous sample method. Patients for the study were selected at the clinical bases of outpatient clinics in Samara (Russia) in July-August 2020. All patients signed an informed consent form prior to enrollment. Patients were randomized into two groups: in the main group (n=64), ethylmethylhydroxypyridine succinate (Neurox) was prescribed 1 tablet (125 mg) 3 times a day for 4 weeks; in the comparison group (n=65), medical drugs (MD) did not contain substances from the pharmacological group related to antihypoxants/antioxidants/nootropics. Three visits (V) were conducted: the first (V1) - the period of inclusion, the second (V2) - after 14 days, the third (V3) - on the 28th day from the start of therapy. The dynamics of the general state (weakness, fatigue, concentration, dizziness, headache, sleep disorders) were evaluated on a visual-analog scale (VAS), the assessment of the subjective feeling of severity of asthenia (fatigue, physical and mental fatigue, decreased motivation and activity) - on Multidimensional Fatigue Inventory (MFI-20), cognitive functions - on Mini-Mental State Examination (MMSE), vegetative tone - according to the Kerdo index.
Results:
At the end of the study (V3), statistically significant changes in indicators (VAS, MFI-20) were obtained only in the main group patients; no statistically significant differences were obtained for the Kerdo index. Analysis of the MMSE data revealed a decrease in cognitive functions in both groups, which may be associated with pseudocognitive deficits due to asthenia.
Conclusions:
We have obtained evidence of a high incidence of asthenic syndrome after COVID-19. Against the background of taking Neurox, there was a decrease in the severity and expression of asthenia symptoms.
The influence of 2-ethyl-6-methyl-3-hydroxypyridine hydrochloride on the in vitro free-radical oxidation and respiration of intact rat liver mitochondria was studied. The drug used at a concentration within the pharmacokinetic range had a modulating effect on lipid peroxidation and oxidative modification of mitochondrial proteins. Emoxypine hydrochloride caused transient accumulation of lipid peroxidation products at relatively high concentrations in the incubation mixture (~10–3 M) and redistribution of free-radical oxidation substrates in favor of proteins with a gradual restriction of oxidative phosphorylation, a decrease in affinity of the respiratory chain to ADP, and an impaired intactness of mitochondrial structures reaching the most significant values at emoxypine hydrochloride concentrations of 10–8 and 10–9 M.
Substandard/counterfeit drugs are a growing global problem. According to the World Health Organisation, counterfeit medicines are medicines that are mislabelled deliberately and fraudulently regarding their identity and/or source. In high income countries, drugs seized are mainly represented by performance and image enhancing drugs (PIEDs). The aim of this study was to present the qualitative and quantitative results of toxicological analyses of pharmaceutical and dietary supplements seized from the black market among bodybuilders in France.
All dietary supplements and pharmaceuticals seized from the black market and addressed to the laboratory for a qualitative and quantitative analysis between January 2016 and December 2019 were included in the study. A screening was carried out by gas chromatography-mass spectrometry and liquid chromatography-high resolution mass spectrometry. Identified compounds were quantified by liquid chromatography-tandem mass spectrometry.
One hundred and ten products were seized and submitted to the laboratory for identification of active compounds and quantification: 75 pharmaceuticals and 35 dietary supplements. This included 39 oily and 3 aqueous solutions for intramuscular injection, 34 tablets, 13 capsules, 14 powders, 4 liquids and 3 lyophilizates. Among the pharmaceuticals, 25/75 (33%) were substandard (dosage not on the acceptable range defined for original products), 24/75 (32%) were counterfeit (qualitative formulation does not match the label) and 14/75 (19%) were original (qualitative formulation and levels of active ingredients fully matches the declared formulation. The analysis of the 12 remaining products revealed a correct qualitative content for 11/75 (15%), but quantitation could not be carried out because of the lack of reference standards at the time of the analysis. Fifty-four pharmaceuticals contained anabolic-androgenic steroids (AAS). Four out of 54 (7.4%) AAS were found as original, 8/54 (15%) could not be quantified (one with wrong active ingredient), corresponding to 43/54 (80%) AAS being non-original. In contrast, only 1/35 dietary supplement (3%) was adulterated, with a doping substance (1,3-dimethylbutylamine, DMBA).
This work allows to show that France is not spared by the trafficking of PIEDs. The use of counterfeit drugs in mainstream population is an underestimated public health issue.
Post-translational modification of proteins is an important biochemical process that occurs at the protein level. Succinylation is a newly discovered post-translational modification with the hallmark of a significant chemical and structural change. Succinylation has many similarities with other modifications, but succinylation may lead to more functional changes. Although the physiological significance of succinylation has not been well characterized, the lysine succinylation modification shows great potentials during disease processes. The discovery of SIRT5 has made great progress in exploring the role of succinylation in energy metabolism, heart disease and tumorigenesis. In this review, we focus on the discovery of succinylation in organisms and mechanism of succinylation. We are also concerned with the metabolic reactions and heart diseases associated with succinylation.
Objective. To study the electroencephalographic signs of the early stages of emotional burnout syndrome (EBS). Materials and methods. Quantitative analysis of the electroencephalogram was carried out in 131 patients with EBS aged 25–45 years. The control group consisted of 143 healthy subjects. Results and conclusions. Patients at different stages of EBS showed increases in dysfunction of the regulatory systems of the brain corresponding to increases in the severity of the clinical signs of this disorder. This indicates an increase in the level of exhaustion of the regulatory systems of the brain and the formation of a stable pathological state.
Hypoxia‐inducible factor (HIF) stabilizer belongs to a novel class of pharmacologically active substances, which are capable of inducing the endogenous erythropoietic system. The transcriptional activator HIF has been shown to significantly increase blood haemoglobin, and is well set for the treatment of chronic kidney disease resulted anaemia. This research work, reports a comprehensive study of the most popular HIF stabilizer roxadustat and its metabolites in thoroughbred horse urine after oral administration. The plausible structures of the detected metabolites were postulated using liquid chromatography‐high resolution mass spectrometry. Under the experimental condition thirteen metabolites (seven phase I, one phase II, and five conjugates of phase I metabolism) were positively detected (M1‐M13). The major phase I metabolites identified were formed by hydroxylation. Dealkylated and hydrolysed phase I metabolites were also observed in this study. In phase II, a glucuronic acid conjugate of roxadustat was detected as the major metabolite. The sulfonic acid conjugates were observed to be formed from phase I metabolites. The characterised in vivo metabolites can potentially serve as target analytes for doping control analysis; hence, the result is an important tool for assessing its use and abuse in competitive sport.
A case of polyorganic insufficiency syndrome associated with coma, convulsive disorder, acute hepato-renal and respiratory dysfunction, hypovolemic shock, and hyperthermal syndrome in a 46 year-old participant ofa marathon competition is reported. The clinical picture was dominated by acute hepatic insufficiency treated with remaxol to activate substrate phosphorylation under effect of exogenous succinate for slowing down the development of energy deficit in mitochondria under condition of oxygen deficit. This case can be regarded as a variant of correction of mitochondrial dysfunction with the use of a mitochondria-targeted medication such as succinate-containing remaxol. This medication reduced AST and ALT activities and utilization of endogenous enzymes for succinate synthesis from alanine and aspartate under hypoxic conditions. Prescription of remaxol as a form of direct substitution therapy was dictated by pathogenetic considerations.
Aim:
To evaluate the efficacy and safety of prolonged sequential therapy with mexidol in the acute and early recovery stages of hemispheric ischemic stroke (IS) across age groups according to the World Health Organization classification.
Material and methods:
The study is an additional analysis across age groups among patients participated in the randomized double blind multicenter placebo-controlled, in parallel groups trial EPICA. All subjects (62 men and 88 women) were subdivided into age groups: younger than 60 years, 60-65 years, 76-90 years. Additionally, all participants were divided into 2 populations: ITT (Intent to treat population, patients who received at least one treatment/placebo dose) and PP (Per protocol population, patients who received treatment per study protocol). Results of Modified Rankin scale (mRs) at the end of treatment period, Barthel index, Beck depression inventory, European Quality of Life Questionnaire were assessed.
Results:
The efficacy of mexidol assessed with all the scales did not differ depending on the age group. By the end of treatment, the mean mRS score was lower in the 76-90 years subgroup (in both populations), compared to placebo (p<0.001). The decrease in mean mRS score (Visit 1-5) was more prominent in patients aged 60-65 years (p=0.025), including patients with diabetes mellitus (DM). Patients aged 76-90 years and patients with DM, compared to placebo, had a decrease of the severity of cognitive-affective depression symptoms (p=0.049 and p=0.02) and an increase in patients without problems with everyday activities (p=0.007 and p=0.02). Patients with DM, compared to placebo, also had the higher levels of everyday activity (p=0.023) and quality of life (p=0.045). There were no statistically significant differences in the frequency of side-effects in patients of all groups.
Conclusion:
It is recommended to include mexidol in therapy of patients with IS in the acute and early rehabilitation stages in all age groups, including patients with DM.
In response to skeletal muscle contraction during exercise, paracrine factors coordinate tissue remodeling, which underlies this healthy adaptation. Here we describe a pH-sensing metabolite signal that initiates muscle remodeling upon exercise. In mice and humans, exercising skeletal muscle releases the mitochondrial metabolite succinate into the local interstitium and circulation. Selective secretion of succinate is facilitated by its transient protonation, which occurs upon muscle cell acidification. In the protonated monocarboxylic form, succinate is rendered a transport substrate for monocarboxylate transporter 1, which facilitates pH-gated release. Upon secretion, succinate signals via its cognate receptor SUCNR1 in non-myofibrillar cells in muscle tissue to control muscle-remodeling transcriptional programs. This succinate-SUCNR1 signaling is required for paracrine regulation of muscle innervation, muscle matrix remodeling, and muscle strength in response to exercise training. In sum, we define a bioenergetic sensor in muscle that utilizes intracellular pH and succinate to coordinate tissue adaptation to exercise.
The purpose of the study. To study the possibility of using the domestic preparation cytoflavin to prevent the transition of the preclinical stage of cardiomyopathy overvoltage to the clinical stage. Material and methods. The study included 45 sportsmen, in whom the examination revealed an increase in myocardial antigen in the blood against the background of lack of clinical and electrocardiographic signs of cardiomyopathy overvoltage. The athletes were divided into 2 groups: 23 sportsmen of the main group took cytoflavin, 22 sportsmen of the control group did not receive the preparation. The level of myocardial antigen was determined in the reactions of passive hemagglutination and inhibition of passive hemagglutination by reducing the antimicrocardial test serum titre. To control the severity of oxidative stress oxLDL in serum was determined by immunoenzyme assay. All athletes were conducted electrocardiography, Holter 24-hour monitoring, echocardiography. Results. In sportsmen of the main group after the course of treatment with cytoflavin a decrease in oxidative stress severity by oxLDL level was established, in sportsmen of the control group oxidative stress severity on the background of decrease in general physical efficiency increased. The examination after 1 month showed that cardiomyopathy overvoltage according to electrocardiography and Holter monitoring data occurred in 16 athletes of the control group and only in 1 athlete of the main group. The efficacy of cytoflavin to prevent the transition of preclinical stage of cardiomyopathy overvoltage to clinical stage was 93.75%. Conclusion. The efficacy of cytoflavin application in sportsmen at the preclinical stage of cardiomyopathy overvoltage is conditioned by its ability to reduce the oxidative stress severity as one of the links in the pathogenesis of cardiomyopathy overvoltage, which significantly reduces the probability of transition of the preclinical stage of the pathology to the clinical stage. It is advisable to use cytoflavin in sports medicine to prevent the transition of preclinical stage of cardiomyopathy overvoltage to clinical stage.
Aim:
To evaluate an effect of long-term sequential therapy with mexidol and mexidol forte on the functional outcome of patients with carotid ischemic stroke.
Material and methods:
The study included 50 patients with newly developed carotid stroke, hospitalized in the stroke unit on the first day from the onset of the disease. Patients of the main group (n=25) received mexidol in a dose of 500 mg intravenously once a day for 14 days, then mexidol forte 250 in tabs 250 mg 3 times a day for 60 days. Patients of the comparison group (n=25) received standard basic therapy. The significance of intergroup differences was assessed using the Mann-Whitney test, Fisher's exact test, and relative risk (OR) calculation. Differences were considered significant at a level of p<0,05.
Results:
After 14 days of therapy, both groups of patients showed a positive trend compared to baseline. At the same time, patients of the mexidol group had a higher MoCA score (U=173,5, p=0,006), a lower score when performing tasks on dynamic praxis (U=214,0, p=0,028) and optical spatial disturbances (U=170,5, p=0,003), better memorization strength (181,5, p = 0,006) and better performance on abstraction MOCA subtest (U=200,5, p=0,014). By the 74th day, the absence of moderate cognitive impairment (MoCA> 26 points) was diagnosed in 17 patients (68%) of the main group and 14 patients (56%) of the comparison group. No significant differences were found. Moreover, patients of the main group had a significantly lower NIHSS score (U=124,0, p<0,001) and a lower degree of disability: a total mRS score 0-2 was achieved in 19 (76%) patients of the main group and only in 12 (48%) patients of the comparison group (OR=3,34, F=0,07, p<0,05). Also, patients receiving long-term sequential therapy with mexidol and mexidol forte 250 had milder spatial disorders than patients of the comparison group.
Conclusion:
Consecutive treatment with mexidol and mexidol forte 250 in the acute and early recovery periods of ischemic stroke positively affects the regression of local neurological symptoms, increases the likelihood of achieving independence in everyday life by 3,34 times, and reduces the severity of optical-spatial, neurodynamic and memory impairments.
Aim:
To evaluate the efficacy of including cytoflavin in rehabilitation measures in the early recovery period of patients with ischemic stroke.
Material and methods:
Results of rehabilitation measures of 100 patients (50 women and 50 men, aged 18 to 85 years) in the early recovery period of ischemic stroke were analyzed. Psychological testing included NIHSS, MMSE, Rankin scale, Rivermead mobility index, exercise tolerance test. Depending on the rehabilitation scheme, patients were divided into the main group (n=50), who received a verticalization course and cytoflavin (intravenously, drip 20.0 ml in 250.0 ml 5% glucose for 14 days). The control group (n=50) included patients who received standard treatment.
Results and conclusion:
Inclusion of cytoflavin in the rehabilitation scheme for patients with ischemic stroke increased the effectiveness of treatment, which was manifested by a decrease in the severity of neurological disorders assessed with NIHSS by 17.6% in the main group versus 10.8% in the control group (p<0.05) and recovery of cognitive functions assessed with MMSE by 5.8% versus 1.6%, respectively (p<0.05). In addition, there was a positive dynamics in the restoration of blood pressure (by 37.1% in the main group versus 30.6% in the control group (p<0.05)).