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The COVID-19 mortality is associated with an increase in interleukin-6 (IL-6) levels. Levilimab is an anti–IL-6 receptor antibody with proven clinical efficacy in patients with severe COVID-19.The aim of the study was to assess the association of COVID-19 severity and levilimab effectiveness with IL-6 levels and to explore the potential for using levilimab in other conditions accompanied by cytokine release syndrome.Materials and methods: the subgroup analysis was based on the data of COVID patients with known baseline IL-6 levels from the CORONA clinical study. Subgroups were formed according to baseline IL-6 levels: ≤5 pg/mL (normal) and >5 pg/mL (elevated). The subgroup analysis included descriptive statistics of the patients and time courses of their clinical and laboratory findings (at screening, on the day of investigational product administration, and further until day 14). In order to compare the percentages of patients who had required rescue therapy, the authors used Fisher's exact test.Results: the subgroup analysis included 91 patients (47 from the levilimab group and 44 from the placebo group). At baseline, the authors observed elevated levels of IL-6 in 31/47 (66%) subjects in the levilimab group and 29/44 (48.4%) subjects in the placebo group. The subjects with elevated IL-6 demonstrated more pronounced clinical signs of pneumonia and abnormalities in inflammatory markers. Elevated baseline IL-6 levels were associated with the need for rescue therapy (OR=3.714; 95% CI: 1.317–9.747; p=0.0183); this association was stronger in the placebo group (OR=8.889; 95% CI: 2.098–33.31; p=0.0036). Also, the placebo group showed long-term abnormalities in the clinical and laboratory findings.Conclusions: IL-6 is one of the key elements in the pathogenesis of cytokine release syndrome related to COVID-19 and other conditions. Elevated IL-6 levels are associated with the severity of COVID-19. Inhibition of IL-6 receptors by levilimab leads to clinical improvement in patients with severe COVID-19, suggesting the effectiveness of levilimab in pathogenesis-oriented therapy for cytokine release syndrome of other aetiologies.

The article presents an overview of publications describing the mechanisms of the development of the pathological process in patients infected with SARS-CoV-2 coronavirus. The authors analysed publications showing that damage to the endothelium and endothelial glycocalyx is the main factor influencing the development of coronavirus COVID-19 infection. It is the endothelium inflammation caused by a virus that leads to the dysfunction of the vascular system and the development of coagulopathy. Using scanning electron microscopy and flow cytofluorimetry, we showed that patients with COVID-19 of moderate severity (CT2) had significant desquamation of endothelial cells (concentration of circulating endothelial cells (CEC) in blood is 300-400 cells/ml whereas the normal range is no more than 10 cells/ ml). Such desquamation should cause exposure of the pro-inflammatory and thrombogenic subendothelial matrix, which, as a results, leads to the development of thrombotic disorders of the circulatory system. Therefore, it is only natural to try to counteract disease progression by protecting the endothelial glycocalyx from damage. Sulodexide, a mixture of fast-moving heparin fraction (80%) and the glycocalyx element dermatan sulfate (20%) obtained from the mucous membrane of the small intestine of pigs, is very promising in this regard. This drug can significantly reduce the inflammatory process, protect the glycocalyx and endothelium from damage, resulting in lowering the degree of thrombus formation in patients with coronavirus COVID-19 infection, which relieves the course of the disease and improves its outcome. The experimental data presented in the review, although obtained in not large enough population of patients, allow us to consider sulodexide a promising drug that protects the endothelium and suppresses thrombosis in COVID-19.

Aim . To compare the kinetics of dissolution (in vitro) and some pharmacodynamic and pharmacokinetic parameters of branded generic preparations of acetylsalicylic acid (ASA) in buffered form in cardioprotective doses [ASA 75 mg+Mg(OH) 2 15.2 mg], which differ in the composition of excipients, with a reference drug. Material and methods . Patients with cardiovascular diseases who had indications for ASA monotherapy (n=75) were included in a one-center open postregistration comparative non-randomized study. Patients were divided into 3 groups for treatment with one of the three studied drugs: Cardiomagnyl® (comparison drug; group 1; n=25), Trombital® (group 2; n=25) and Fazostabil® (group 3; n=25). A study of the kinetics of dissolution of the studied drugs in vitro under conditions of pH 1.2 has been performed. Also, platelet aggregation in response to arachidonic acid, the concentration of salicylic acid and the level of serum thromboxane B 2 were studied in the compared groups. Results . The average release profile of ASA by the 30th minute from Cardiomagnyl® was higher than for Trombital® and Fazostabil® (95.7%, 84.8%, 76.5% respectively). The similarity factor (f 2 ) of ASA release for Trombital® was 39.3, and for Fazostabil® - 34.2. An index of f 2

Arterial thrombosis is a result of complex interaction between blood cells, soluble coagulation factors in plasma and vessel wall. Antiplatelet drugs do not always provide the necessary antithrombotic effect of sufficient strength, because their influence does not extend to all three factors involved in this process. Low doses of direct oral inhibitors of thrombin are able to potentiate antithrombotic effect of antiplatelet therapy. The combination of rivaroxaban in a dose of 2.5 mg and standard double antiplatelet therapy turned out to be the most promising for clinical use, since studies with dabigatran and apixaban at the II and III stages of the trials were found to be unsuccessful due to the unacceptably high frequency of bleeding. Studies of the combination of rivaroxaban at a dose of 2.5 mg and standard antiplatelet therapy conducted in previous years among patients with acute myocardial infarction showed a decrease in the frequency of complications of atherothrombosis associated with their ischemic nature, while at the same time there was a slight increase in hemorrhagic complications. In the COMPASS study the combination of rivaroxaban (2.5 mg) plus aspirin reduced the risk of the primary endpoint (myocardial infarction, ischemic stroke, cardiovascular death) more significantly than aspirin alone in patients with stable ischemic heart disease and ischemic brain disease. The pathophysiological rationales for the use of low doses of rivaroxaban when added to dual antiplatelet therapy are considered, and the significance of recent studies in patients with acute coronary syndrome, stable ischemic heart disease and in the prevention of ischemic stroke is discussed.

Aim. The aim of the study is to evaluate important additional cardiovascular (CV) risk factors of major adverse cardiac events (MACE) in patients with acute coronary syndrome (ACS) during the first 30 days after index event. Materials and methods. Overall 750 patients with ACS were enrolled in the single center prospective registry from 2012-2015yy. 569 patients received dual antiplatelet therapy and in 425 cases platelet function testing (PFT) were performed. Most of the patients characterized as high risk elderly patients with multiple CV risk factors and high comorbidity index. Results. At 30-day follow-up the mortality rate was 10,1%. Singlevariate analysis showed strong association between MACE and age, atrial fibrillation, stroke, chronic kidney disease, low ejection fraction, type 2 myocardial infarction (T2MI). Multivariate analysis showed that high-on-treatment platelet reactivity (PFT> 45%) with odds ratio 4.418 (p=0.0001), chronic kidney disease (OR 6.538 p=0.001) and T2MI (OR 1.925 p=0.0001) were significantly associated with adverse outcome. Conclusion. ACS registry showed high mortality level in real-life practice compared with randomized clinical trials due to the high prevalence of elderly patients with high comorbidity index. Patients with T2MI have significantly more severe prognosis and chronic kidney disease associated with increased MACE. PFT in this category of patients is reasonable for more accurate risk stratification.

Thrombolytic therapy (TLT), as a method of treatment, began to develop in the second half of the 50s of the last century. At that time, there was an accumulation of data on its effectiveness, side effects and contraindications, as well as the development of fibrinolytic drugs, such as fibrinolysin, streptokinase, urokinase, and the conditions for their administration. Official recognition of TLT in regulatory documents began only in the 80s after the development of more effective and safe tissue plasminogen activators. However, on the threshold of an era of development in this area in the treatment of patients with thrombosis of the coronary, carotid, and other peripheral vascular regions, the researchers obtained conflicting data on the results of the use of thrombolytics. There was no concept of a therapeutic window for the use of TLT, there was no data on possible combinations of thrombolytic drugs with anticoagulants, the high probability of bleeding prevented widespread introduction of the method into clinical practice. At that time, vascular imaging and laboratory diagnostics were not sufficiently developed, there was no consensus of the world’s leading experts on the benefits of thrombolysis. The use of TLT in acute arterial thrombosis required not only clinical experience, but also courage and ability to make non-standard decisions. The authors of the article analyze in detail the case of rescuing a patient with progressive thrombotic occlusion of the arteries of the brain stem. Then the pioneer in the field of thrombolytic therapy E. I. Chazov and his colleagues took responsibility for the application in this situation of an insufficiently studied treatment method with uncertain consequences. This decision was not due to the identity of the patient or the threat of an internal investigation. Marshal or soldier – it did not matter for E. I. Chazov and his colleagues. If doctors in this clinical situation relied on recommendations, orders and standards, then such a patient would have to wait thrombolysis for another 30 years.

Thrombocytopenia in blood count may be a reflex of haemostatic problems of different origin – from autoimmune disease to iatrogenic nature. Sometimes, thrombocytopenia may be revealed in patient with coronary heart disease before PCI procedure as well as some hours or days later. Dual antithrombotic therapy and thrombocytopenia have the same main side effect – bleeding. Etiology of disease and details of medical decision before percutаneous coronary intervention (PCI) in CHD patients are discussed.

The article is a critical review of the current literature on the issue of antithrombotic therapy in the acute phase of ischemic stroke. Despite the overall pathogenesis today, there are significant differences in the antithrombotic strategy used in acute coronary syndrome and ischemic stroke. Although reperfusion therapy is the most effective method of treatment of patients with thrombotic occlusion of the arteries of the heart or brain, only about 5% of neurological patients receive intravenous thrombolysis tissue plasminogen activator. In emergency neurology unused opportunities of platelet antiplatelet agents last generations, not appointed anticoagulants. The article examines issues of interdisciplinary collaboration and perspectives of modern antithrombotic strategies in neurology from the point of view of the neurologist, cardiologist and expert on antithrombotic therapy.

Use of antiplatelet therapy in the world indicates real difference in individual drug effect between patients, including the effect on prognosis. Problems of personification of individual approach, concerning antiplatelet therapy, are discussed.

Aim: to assess relation ofhigh functional activity ofplatelets to prognosis ofunfavorable cardiovascular events in patients with Acute Coronary Syndrome (ACS).Materials. The study was based on the data of a single center ACS registry conducted in the Central Clinical Hospital of the Presidential Affairs Department of Russian Federation. Of 529 included patients in 425 without contraindications to double antiplatelet therapy we carried out analysis of dependence of 30 days level of unfavorable events on parameters of functional activity of platelets.Results. High on-treatment platelet reactivity (HTPR) was found to be associated with 3.5 increase of mortality in the group of patients with high cardiovascular risk. Logistic model of prognosis of unfavorable events based on multifactorial analysis of data from patients with measured platelet aggregation included chronic kidney disease, type of myocardial infarction, and degree ofplatelet aggregation >45%. C -statistic was equal to 0.77. We also present in this paper discussion of problems related to studying approaches to individualization of anti-aggregation therapy in real clinical practice and problems of organization ofsimilar studies.Conclusion. The study showed that patients with ACS increased platelet aggregation, as well as chronic kidney disease and type 2 MI are associated with a 30 day prognosis of adverse events.

Endometrial hyperplasia (EH) is one of the most common gynecologic diseases in the world. Different statistical categories implicate an imbalance of estrogens and progestogens in the etiology of this disease. We propose that inflammation also plays a key role in the progression of endometrial hyperplasia.The aim of this study is to evaluate the role of inflammation in the transformation and progression of endometrial hyperplasia, using local inflammatory cytokines and nonspecific protease levels, CD 45(+) expression, and histological examination.The study included 107 patients (ages 29-49 years) with different forms of endometrial hyperplasia. The enrolled patients were randomized into one of the four groups: normal endometrium (n = 18) as the control group, simple hyperplasia (n = 41), complex hyperplasia without atypia (n = 36), complex atypical hyperplasia or endometrioid adenocarcinoma (n = 12).The following were evaluated for patients with different forms of EH: steroid hormone levels in blood serum and uterine flushings, immunohistochemical estrogen and progesterone receptor expression patterns in the endometrial tissue, CD 45(+) (common leukocyte antigen) expression, the levels of the cytokines IL-1β, IL-6, and TNF-α, and nonspecific proteases and their inhibitors.The level of estradiol in blood serum and especially in uterine flushings was elevated dramatically in simple EH as compared to that of controls, but there was no significant difference between estradiol levels among the different forms of EH. The estimation of CD 45(+), the levels of the cytokines IL-1β, IL-6, and TNF-α, and the activity of proteases (elastase-like and trypsin-like activities) and their inhibitors showed that levels of nonspecific inflammatory markers increase with EH progression.We suggest that the initial responsibility for the development of simple endometrial hyperplasia belongs to systemic hyperestrogenemia and, in particular, local hyperestrogenia, but that the role of inflammatory processes increases in complex and atypical EH. Development of inflammatory changes in endometrial hyperplasia may be considered as a factor in the promotion and progression of pathology, as well as an attributed risk factor for malignancy in endometrial hyperplasia. In this study, we have established a role for CD 45(+) expression cells, non-specific proteases, and the inflammatory cytokines IL-1β, IL-6, and TNF-α in endometrial hyperplasia-related inflammation.

Optimal duration of dual antiplatelet therapy (DAPT) after stent implantation is uncertain. Some patients have an extended risk of thrombotic complications including that of very late stent thrombosis after cessation of recommended course of DAPT (6-12 months). On the other hand, there is a real risk of bleeding on DAPT. In this review, we present and discuss results of clinical trials of long-term DAPT and data of their meta-analyses. The review also contains consideration of some aspects of new AHA/ACC recommendations (2016) on duration of DAPT.

Dual antiplatelet therapy, including clopidogrel and aspirin, in a significant share of patients after acute coronary syndrome (ACS) is characterized by high level of platelet reactivity, which is associated with an increased incidence of cardiovascular events. Perhaps it will make reasonable the prescription of new antiplatelet drugs, particularly the combination of ticagrelor with aspirin.Aim. To assess the cost-effectiveness of VerifyNow P2Y12 platelet reactivity testing in patients after ACS.Material and methods. The analysis was performed for patients aged 55 years after ACS by modeling based on the results of the PLATO trial considering Russian epidemiological data. The time horizon of simulation was 5 years. It was assumed that the patients were receiving either generic clopidogrel or ticagrelor for 1 year, or before maintenance treatment VerifyNow P2Y12 assay had been performed, and the patients with platelet reactivity index >230 24-48 hours after ACS were receiving ticagrelor and the remaining patients - generic clopidogrel. It was expected that after 1 year the patients would discontinue treatment with clopidogrel or ticagrelor, and hereafter additional therapeutic effect of their use would be absent. The costs of antiplatelet agents in the reference case corresponded to the weighted average price of public procurement in 2013 in Russia. The costs of treatment of complications corresponded to the compulsory health insurance rates for St. Petersburg in 2014. The cost and life expectancy were discounted at 3.5% per year.Results. The platelet reactivity test and the prescription by its results of the combination of clopidogrel plus aspirin or ticagrelor plus aspirin can prevent 5 myocardial infarction and 6 deaths per 1000 patients additionally as compared with the prescription of clopidogrel plus aspirin combination to all patients. The costs for one additional year of life as compared with the combination of clopidogrel plus aspirin were 376.5 and 373.2 thousand rubles, respectively, the costs for one additional quality adjusted life year (QALY) were 433.8 and 509.8 thousand rubles, respectively. The total predictive value of costs per 1 patient with ACS using the test was 32% lower than in the routine use of ticagrelor in all patients.Conclusion. Assessment of platelets reactivity using VerifyNow P2Y12 assay in patients with ACS and modification of antithrombotic therapy in accordance with the received data can be considered as a cost-effective intervention which can reduce treatment costs as compared with the routine use of new antithrombotic drugs.

The article presents the Perceptron neural network program developed by the authors, which enables assessing in points the quality of the task performed by students in a foreign language. The theoretical basis for the artificial intelligence systems applied in the learning process has been considered. The studies have shown that the online education market has grown in the world, and the trend marked persists. The trends in use of neural networks in learning have been summarized. Analysts noted that the use of artificial intelligence systems has been becoming more widely used in the learning process. It has been hypothesized and proved that a neural network makes it possible to give a grade for the quality of a control text read by a student according to the requirements of competencies using the BI data resulted from processing with an artificial intelligence system. The algorithm proposed by the authors uses the capabilities of the PyPhox mobile application and the Deductor platform. The algorithm is based on the following scheme. The teacher records a piece of a text into a file on the PhyPhox mobile application; its digitized version is then used as a reference to compare the quality of the assignment done by a Master student. The resulting reference file is exported to XL and then imported into the Deductor for further processing. The students do the same; their control files are paired with the reference, combined in XL and imported into the Deductor for processing. In the final, based on the comparison of the coefficients of correlation between the control and reference files, the Perceptron program assigns a score corresponding to the "excellent," "good," "satisfactory" and "not satisfactory" grades. The neural network formed is trained on data sampling, where they add semester points and competence points. The relevance lies in the fact that the program enables automating the learning process and replacing the teacher's work at the stage of the assignment control according to the competencies, which is of practical importance.

Ингибитор ароматазы III поколения Фемара – препарат выбора для лечения больных РМЖ с метастазами в кости в менопаузе. Высокая эффективность и безопасность терапии Фемарой продемонстрированы в многоцентровых международных рандомизированных клинических исследованиях. В силу особенностей механизма действия при назначении больным РМЖ в менопаузе Фемара существенно снижает уровень эстрогенов в сыворотке крови. Но, как известно, снижение уровня эстрогенов в сыворотке крови до 5 мг и ниже у больных РМЖ увеличивает риск переломов на 33%, что в свою очередь ведет к увеличению риска смерти. Поэтому в настоящее время в стандарт лечения больных РМЖ с метастазами в кости входят бисфосфонаты. В клинических исследованиях показано, что использование золедроновой кислоты (Зомета) тормозит развитие остеопороза, ингибирует резорбцию кости и снижает частоту осложнений, обусловленных метастазами в кости. У больных РМЖ в менопаузе при назначении Зометы увеличивалась минеральная плотность костной ткани. Кроме того, золедроновая кислота на этапе доклинического изучения продемонстрировала способность индуцировать апоптоз клеток РМЖ и ингибировать пролиферацию не только костных, но и висцеральных (в легких и печени) метастазов. Учитывая изложенное, использование Фемары в комбинации с Зометой у больных РМЖ с метастазами в кости в менопаузе представляется целесообразным. В 2004–2006 гг. проведено российское многоцентровое исследование по изучению эффективности использования Зометы на фоне эндокринной терапии Фемарой больных РМЖ с метастазами в кости. Цель исследования: улучшение результатов лечения больных РМЖ с метастазами в кости. Оценка эффективности и безопасности терапии Фемарой в комбинации с Зометой в первой/второй линии терапии у больных РМЖ с метастазами в кости. Помимо основной задачи исследования – оценки частоты, характера и продолжительности лечебных эффектов – оценивали такие показатели, как время до прогрессирования, частоту и время до развития костных осложнений, влияние терапии на минеральную плотность костной ткани, продолжительность жизни и общую выживаемость больных. Кроме того, определяли динамику активности пациентов, интенсивности болевого синдрома и качества жизни больных. Оценка безопасности терапии предусматривала оценку характера, частоты и степени выраженности побочных эффектов терапии.Комбинация Фемары и Зометы – эффективный и безопасный режим терапии больных РМЖ с метастазами в кости в менопаузе. Использование этого режима позволяет получить объективные ответы в 25% наблюдений, уменьшить частоту развития осложнений, обусловленных метастатическим поражением костей, включая болевой синдром, патологические переломы, снизить потребность в анальгетиках, лучевой терапии и необходимость хирургических вмешательств на костях.

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent class of medicines which is wide concerning chemical structure and mechanism of action. In the light of contradictory data on efficacy and safety of NSAID in cardiovascular patients selection of most appropriate NSAID (basing on profile of efficacy and safety) in patients receiving continuous therapy with low dose aspirin appears to be a problem. In this paper we discuss peculiarities of drug interaction between cyclooxygenase inhibitors and acetylsalicylic acid, and principles of selection of adequate NSAI.

To evaluate the clinical efficacy, safety, and effects of the nonsteroidal anti-inflammatory drug lornoxicam on inflammatory markers in non-ST-segment elevation acute coronary syndrome (NSTEACS).Eighty-five patients with NSTESCS were enrolled in a prospective randomized study. They were divided into 2 groups: 1) patients received lornoxicam (8 or 12 mg/daily) for 15 days in addition to standard treatment and 2) controls. Cardiovascular outcomes and the levels of C-reactive protein (CRP), IL-6, and IL-10 were determined.The lornoxicam group exhibited a significant reduction in CRP and a decrease in IL-6. There was also a significant increase in IL-10 levels in this group. A 6-month follow-up indicated a significant reduction in the number of cardiovascular events (nonfatal myocardial infarction, unstable angina, coronary death).Lornoxicam reduces the risk of poor cardiovascular outcomes in patients with NSTEACS and the levels of inflammatory markers.

It has been shown that the process of amines new formation in mast cells after the treatment with radioprotectors is less intensive than in other tissues able to synthesize amines. It is proposed that the effect of the mast cells in organism's formation of higher radioresistance is brought to mobilization of the accumulated biogenic amines with their further redistribution in other organs and tissues including radiosensitive ones.

A study was made of the role of calcium ions and some other factors in secretion of biogenic amines from rat mast cells. The data obtained indicate that the radioprotective preparations of indolyl alkylamine and imidazole series can mobilize endogenous radioprotectors. The process of the mediator release from mast cells under the effect of sulfur-containing radioprotective agents is indirect. The molecular mechanisms of mast cell exocytosis are discussed.