Platinum(IV) compounds as potential drugs: a quantitative structure- activity relationship study

Introduction: Machine learning methods, coupled with a tremendous increase in computer power in recent years, are promising tools in modern drug design and drug repurposing.Methods: Machine learning predictive models, publicly available at chemosophia. com, were used to predict the bioactivity of recently synthesized platinum(IV) complexes against different kinds of diseases and medical conditions. Two novel QSAR models based on the BiS algorithm are developed and validated, capable to predict activities against the SARS-CoV virus and its RNA dependent RNA polymerase.Results: The internal predictive power of the QSAR models was tested by 10-fold cross-validation, giving cross-R2 from 0.863 to 0.903. 38 different activities, ranging from antioxidant, antibacterial, and antiviral activities, to potential anti-inflammatory, anti-arrhythmic and anti-malarial activity were predicted for a series of eighteen platinum(IV) complexes.Conclusion: Complexes 1, 3 and 13 have high generalized optimality criteria and are predicted as potential SARS-CoV RNA dependent RNA polymerase inhibitors.

COVID-19 in Russia: Evolution of Views on the Pandemic. Report II

Over the two years of the novel coronavirus infection (COVID-19) pandemic, there has been an evolution of views in various fields of medicine, which has led to a powerful development of scientific research in the field of epidemiology, clinic, diagnosis and therapy of COVID-19. This article discusses the evolution of views and approaches to the study of the clinic and therapy of COVID-19. The symptoms and aggravation of the course of cardiovascular diseases with COVID-19 have been established. The main strategy for organizing surgical care for patients with COVID-19 is indicated. The main criteria for the treatment of COVID-19, the need to prescribe SGCS on an individual basis, and the need to search for new methods of anti-inflammatory therapy for COVID-19, one of which may be the use of alkylating drugs in ultra-low doses, are described. Copyright © 2022 Izdatel'stvo Meditsina. All rights reserved.

COVID-19 in Russia: Evolution of Views on the Pandemic. Report I

Over the two years of the novel coronavirus infection (COVID-19) pandemic, there has been an evolution of views in various fields of medicine, which has led to a powerful development of scientific research in the field of epidemiology, clinic, diagnosis and therapy of COVID-19. The article highlights the evolution of views and approaches to the study of the epidemiology and radiology of COVID-19. The data of molecular genetic studies are shown, which are the most important component of epidemiological surveillance. The study of the manifestations of the COVID-19 epidemic process made it possible to distinguish two stages in the development of the epidemiological situation in the Russian Federation. At the first stage of the epidemic, two rises in the incidence rate of the population were recorded, regulated by social and natural factors. The second stage of the epidemic was due to a change in the biological properties of the SARS-CoV-2 virus, followed by a change in the prevailing genovariants (Alpha, Delta and Omicron). At the second stage of the epidemic, three rises in the incidence of the population were recorded. The general principles for the use of radiodiagnosis methods, which are used primarily to detect lung damage in COVID-19, are given. With the accumulation of experience, a natural change in ideas about the algorithms for the use of visualization technologies has occurred. Copyright © 2022 Izdatel'stvo Meditsina. All rights reserved.

EFFICACY AND SAFETY OF ULTRA-LOW DOSE INHALED MELPHALAN IN THE TREATMENT OF HOSPITALIZED PATIENTS WITH COVID-19

Background. One of the most important components of COVID-19 therapy is the suppression of the hyperergic immune response. There is an urgent need ofcreating the optimaltactics ofefficientandsafe anti-inflammatory therapy. Anew methodoftreatment ofCOVID-19withinhalation ofultra-low (non-cytotoxic)doses of the alkylating drug melphalan is proposed, based on previous experimental, preclinical, and clinical data on its use in severe bronchial asthma. The aim. To evaluate the efficacy and safety of inhalation of ultra-low doses of melphalan in hospitalized patients with COVID-19-associated lung damage. Materials andmethods. A prospective, open, controlled, blindfor the centralexpert study was conducted. Sixty adult patients were included, 30 patients were consecutively admitted to the hospital and received nebulized inhalations of 0.1 mg of melphalan for 7 days. Thirty patients ofthe control group were selectedby an independentexpertretrospectively using the computer algorithm for selecting“close” patients based on the “case-control” principle. The primary endpoints were the dynamics on the WHO Clinical Improvement Scale and the dynamics of dyspnea according to the modified Borg scale, secondary – assessment of adverse events, dynamics of indicators of clinical, biochemical blood tests, lungs computed tomography data from the beginning ofinhalations in the melphalan group andfrom the corresponding day in the control group. Results. Inhalations of melphalan led to a significant improvement in the clinical condition ofpatients according to the WHOscale, decrease in the intensity ofdyspnea on day 7 of treatment and by the time of discharge, a significant anti-inflammatory effect. Adverse events and dynamics of laboratory parameters did not differ from the control group. Conclusion. The method of treatment of COVID-19 by inhalation of ultra-low doses of the alkylating drug melphalan is safe and leads to a significant clinical improvement of hospitalized patients with COVID-19-associated lung damage. © 2022 by the Author(s).

Clinical outcomes of patients with COVID-19 admitted for respiratory support to the intensive care units in Russia

Aim. To evaluate mortality and risk factors for death in patients with COVID-19 who required admission to intensive care units (ICU) for respiratory support in Russia.Material and methods. In a retrospective study, we collected medical records of the consecutive ICU patients submitted by the local COVID-19 hospitals across Russia to the Federal Center at the Sechenov University (Moscow) betweenMarch 16 to May 3, 2020. All patients have completed their hospital stay (death or recovery). Diagnosis of SARS-CoV-2 pneumonia was established both by polymerase chain reaction (PCR) and CT. In patients with inconclusive or negative results of PCR, the SARS-CoV-2 pneumonia was defined as severe acute respiratory infection with typical CT findings and no other obvious aetiology. We used Cox proportional hazards regression model adjusted for age, sex and other risk factors to estimate hazard ratios (HR) and 95% confidence intervals (CI).Results. We studied 1522 ICU patients with SARS-CoV-2 induced acute respiratory distress syndrome (ARDS), including 864 males and 658 females at the median age of 62 years. Nine hundred twenty two records (60.1%) were submitted from Moscow and Moscow province, and 600 records (39.4%) were received from the hospitals located in 70 regions of Russia. SARS-CoV-2 was verified by PCR in 995 (65.4%) patients. Among 1522 patients enrolled in the study,995 patients (65.4%) died, and 527 (34.6%) patients recovered. The most common causes of death were ARDS (93.2%), cardiovascular events (3.7%) and pulmonary embolism (1.0%). The mortality rate was low in patients with less severe pneumonia requiring oxygen therapy (10.1%). However, it increased significantly in patients who were placed on noninvasive or invasive ventilation (36.8% and 76.5%, respectively). Risk of death increased with age, and in males older than 50 years it was significantly higher than in females of similar age. In a unvariate analysis, arterial hypertension, coronary artery disease (CAD), history of stroke, atrial fibrillation, type 2 diabetes, obesity and malignancies were associated with an increased risk of death. However, only CAD (HR1.257, 95% CI 1.064-1.485, p=0.007), type 2 diabetes (HR1.300, 95% CI 1.131-1.494, p<0.0001) and obesity (HR1.347,95% CI 1.166-1.556, p<0.0001) retained statistical signicance in multiple factor analysis.Conclusion. In ICU patients with COVID-19, severity ofARDS (i.e. requirement in mechanical ventilation), age, malegender, CAD, obesity and type 2 diabetes were associatedwith a higher risk of death. Цель. Изучение летальности и факторов рискасмерти больных с COVID-19, госпитализированных для респираторной поддержки в отделения реанимации и интенсивной терапии(ОРИТ) лечебных учреждений Российской Федерации.Материал и методы. Ретроспективноеисследование было выполнено в Федеральномдистанционном консультативном центре анестезиологии и реаниматологии для взрослыхпациентов с COVID-19 на базе Первого МГМУим. И.М. Сеченова. В исследование включаливсех пациентов с известными исходами (смертьот любых причин или выздоровление) SARS-CoV-2 пневмонии, осложнившейся острым респираторным дистресс синдромом (ОРДС),которые были проконсультированы с 16 мартапо 3 мая 2020 г. Факторы риска смерти анализировали с помощью многофакторной регрессионной модели Кокса.Результаты. В исследование были включены 1522 пациента, 864 (56,8%) мужчины и 658(43,2%) женщин. Медиана возраста - 62 года.922 (60,6%) больных находились в ОРИТ стационаров Москвы и Московской области, 600(39,4%) - лечебных учреждений в 70 регионахРоссийской Федерации. У 995 (65,4%) больных диагноз SARS-CoV-2 инфекции был подтвержден с помощью ПЦР. Умерли 995 (65,4%)пациентов, выжили 527 (34,6%). Основнымипричинами смерти были ОРДС (93,2%), сердечно-сосудистые осложнения (3,7%) и тромбоэмболия легочной артерии (1,0%).Летальность была низкой у пациентов, находившихся на оксигенотерапии (10,1%), изначительно повышалась у больных, которыхприходилось переводить на неинвазивную(36,8%) или инвазивную (76,5%) вентиляциюлегких. Риск смерти увеличивался с возрастоми в возрастных группах старше 50 лет у мужчинбыл достоверно выше, чем у женщин. В однофакторных моделях заболеваниями, ассоциировавшимися с развитием летального исхода,были артериальная гипертония, ИБС, инсульт,фибрилляция предсердий, сахарный диабет 2типа, ожирение и солидные опухоли, однако вмногофакторной модели, построенной по всемпризнакам с коррекцией по полу и возрасту,статистическое значение сохранили толькоИБС (отношение рисков [ОР] 1,257, 95% доверительный интервал [ДИ] 1,064-1,485,p=0,007), сахарный диабет 2 типа (ОР 1,300,95% ДИ 1,131-1,494, p<0,0001) и ожирение(ОР 1,347, 95% ДИ 1,166-1,556, p<0,0001).Заключение. Основными факторами рискасмерти больных с COVID-19, переведенных вОРИТ для респираторной поддержки, былитяжесть ОРДС, прежде всего необходимость вИВЛ, пожилой возраст, мужской пол, а такжеИБС, ожирение и сахарный диабет 2 типа.

[Risk factors for the early development of septic shock in patients with severe COVID-19].

AIM: In a retrospective study, we evaluated factors associated with the early development of septic shock in patients with severe COVID-19. MATERIALS AND METHODS: We collected medical records of the intensive care unit patients submitted by the local COVID-19 hospitals across Russia to the Federal Center for the Critical Care at the Sechenov First Moscow State Medical University (Sechenov University). Septic shock in crticially ill patients requiring mechanical ventilation was defined as a need in vasopressors to maintain blood pressure. RESULTS: We studied 1078 patients with severe COVID-19 who were admitted to the intensive care units for respiratory support. There were 611 males and 467 females. The mean age was 61.013.7 years. Five hundred twenty five medical records (48.7%) were received from the Moscow hospitals, 159 (14.7%) from the Moscow region, and 394 (36.5%) from the hospitals located in 58 regions of the Russian Federation. In 613 (56.9%) patients, diagnosis of SARS-CoV-2 infection was confirmed by PCR, and in the other cases it was established on the basis of the clinical picture and the results of the chest CT scan. Septic shock developed in 214 (19.9%) of 1078 patients. In the logistic regression model, the risk of septic shock in patients older than 50 years was higher than in patients of a younger age (OR 2.34; 95% CI 1.533.67; p0.0001). In patients with more severe SARS-CoV-2 infection, there was an increase in the prevalence of cardiovascular diseases, including coronary heart disease and atrial fibrillation, type 2 diabetes and malignant tumors. The risk of septic shock in patients with three or more concomitant diseases was higher than in patients without any concomitant chronic diseases (OR 1.76; 95% CI 1.762.70). CONCLUSION: The risk of septic shock in patients with acute respiratory distress syndrome induced by SARS-CoV-2 is higher in patients older than 50 years with concomitant diseases, although a severe course of the disease is also possible in younger patients without any concomitant disorders.