Meglumine Sodium Succinate to Correct COVID-19-Associated Coagulopathy: the Feasibility Study

Aim of the study: to evaluate the effect of meglumine sodium succinate (MSS) on the efficacy of anticoagulant therapy in patients with severe COVID-19 infection complicated by bilateral community-acquired pneumonia.Materials and methods. Overall efficacy of treatment was analyzed in 12 patients hospitalized to ICU with the diagnosis of severe confirmed COVID-19 coronavirus infection (U07.1) complicated by bilateral multisegmental pneumonia. All patients received prophylactic anticoagulation with unfractionated heparin. The patients were divided into two groups: 7 of them received a multi-electrolyte solution containing MSS 5 ml/kg daily for the entire ICU stay (3-10 days) as a part of therapy; 5 patients received a similar volume of a conventional multi-electrolyte solution containing no metabolically active substrates and comprised a control group. Coagulation parameters were measured in arterial and venous blood of all patients at the following stages: 1) upon admission to the ICU; 2) 2-4 hours after the first dose of heparin; 3) 8-12 hours after the second dose of heparin; 4) 24 hours after the beginning of intensive therapy. On the 28th day of follow-up, mortality, duration of ICU stay, and incidence of thrombotic complications in the groups were evaluated. Nonparametric methods of statistical analysis were used to assess intragroup changes and intergroup differences.Results. The group of patients administered with MSS had significantly fewer thromboembolic events during 28 days of treatment and shorter ICU stay. These patients responded faster to anticoagulant therapy, which was suggested by more distinct changes in coagulation parameters, i.e. increased APTT, persisting viable thrombocyte population, reduced D-dimer and fibrinogen levels.Conclusion. The metabolic action of succinate possibly increases endothelial resistance to damaging factors and reduces its procoagulant activity. The hypothesis requires testing in a larger clinical study with a design including laboratory evaluation of the efficacy of varying doses of the studied drug as well as aiming at elucidation of the mechanisms of its effect on specific pro- and anticoagulation system components

Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment

The community-wide GPCR Dock assessment is conducted to evaluate the status of molecular modeling and ligand docking for human G protein-coupled receptors. The present round of the assessment was based on the recent structures of dopamine D3 and CXCR4 chemokine receptors bound to small molecule antagonists and CXCR4 with a synthetic cyclopeptide. Thirty-five groups submitted their receptor-ligand complex structure predictions prior to the release of the crystallographic coordinates. With closely related homology modeling templates, as for dopamine D3 receptor, and with incorporation of biochemical and QSAR data, modern computational techniques predicted complex details with accuracy approaching experimental. In contrast, CXCR4 complexes that had less-characterized interactions and only distant homology to the known GPCR structures still remained very challenging. The assessment results provide guidance for modeling and crystallographic communities in method development and target selection for further expansion of the structural coverage of the GPCR universe. © 2011 Elsevier Ltd. All rights reserved

The installation for measuring of specific coefficient of force light materials with turn of light effect

The installation for measuring of specific coefficient of candle-power light of returning surfaces on the accordance of ДСТУ 4100-2002 is developed. The construction of installation provides more wide in comparison with analogues range of measuring — from 10–1 to 104 kd/(lk·m2). Limit of the basic assumed relative error of measuring is no more then ±15%

Ligand Binding Pathways of Clozapine and Haloperidol in the Dopamine D₂ and D₃ Receptors

The binding of a small molecule ligand to its protein target is most often characterized by binding affinity and is typically viewed as an on/off switch. The more complex reality is that binding involves the ligand passing through a series of intermediate states between the solution phase and the fully bound pose. We have performed a set of 29 unbiased molecular dynamics simulations to model the binding pathways of the dopamine receptor antagonists clozapine and haloperidol binding to the D₂ and D₃ dopamine receptors. Through these simulations we have captured the binding pathways of clozapine and haloperidol from the extracellular vestibule to the orthosteric binding site and thereby, we also predict the bound pose of each ligand. These are the first long time scale simulations of haloperidol or clozapine binding to dopamine receptors. From these simulations, we have identified several important stages in the binding pathway, including the involvement of Tyr7.35 in a “handover” mechanism that transfers the ligand between the extracellular vestibule and Asp3.32. We have also performed interaction and cluster analyses to determine differences in binding pathways between the D₂ and D₃ receptors and identified metastable states that may be of use in drug design

Первый опыт применения меглюмина натрия сукцината в коррекции COVID-19-ассоциированной коагулопатии

Aim of the study: to evaluate the effect of meglumine sodium succinate (MSS) on the efficacy of anticoagulant therapy in patients with severe COVID-19 infection complicated by bilateral community-acquired pneumonia.Materials and methods. Overall efficacy of treatment was analyzed in 12 patients hospitalized to ICU with the diagnosis of severe confirmed COVID-19 coronavirus infection (U07.1) complicated by bilateral multisegmental pneumonia. All patients received prophylactic anticoagulation with unfractionated heparin. The patients were divided into two groups: 7 of them received a multi-electrolyte solution containing MSS 5 ml/kg daily for the entire ICU stay (3-10 days) as a part of therapy; 5 patients received a similar volume of a conventional multi-electrolyte solution containing no metabolically active substrates and comprised a control group. Coagulation parameters were measured in arterial and venous blood of all patients at the following stages: 1) upon admission to the ICU; 2) 2-4 hours after the first dose of heparin; 3) 8-12 hours after the second dose of heparin; 4) 24 hours after the beginning of intensive therapy. On the 28th day of follow-up, mortality, duration of ICU stay, and incidence of thrombotic complications in the groups were evaluated. Nonparametric methods of statistical analysis were used to assess intragroup changes and intergroup differences.Results. The group of patients administered with MSS had significantly fewer thromboembolic events during 28 days of treatment and shorter ICU stay. These patients responded faster to anticoagulant therapy, which was suggested by more distinct changes in coagulation parameters, i.e. increased APTT, persisting viable thrombocyte population, reduced D-dimer and fibrinogen levels.Conclusion. The metabolic action of succinate possibly increases endothelial resistance to damaging factors and reduces its procoagulant activity. The hypothesis requires testing in a larger clinical study with a design including laboratory evaluation of the efficacy of varying doses of the studied drug as well as aiming at elucidation of the mechanisms of its effect on specific pro- and anticoagulation system components.Цель исследования — оценить влияние меглюмина натрия сукцината на эффективность антикоагулянтной терапии у пациентов с тяжелой формой коронавирусной инфекции COVID-19, осложненной двусторонней внебольничной пневмонией.Материалы и методы. Провели анализ эффективности терапии 12 пациентов, получивших лечение в условиях ОРИТ в связи с диагнозом: «Коронавирусная инфекция COVID-19 (подтвержденная), тяжелая форма U07.1. Осложнение: двусторонняя полисегментарная пневмония. Все пациенты получали профилактическую антикоагулянтную терапию нефракционированным гепарином. Пациентов разделили на две группы: 7 из них получили в составе терапии полиэлектролитный раствор, содержащий меглюмина натрия сукцинат в суточной дозе 5 мл/кг в течение всего срока нахождения в ОРИТ (3-10 дней); 5 пациентов получили аналогичный объем обычного полиэлектролитного раствора, не содержащего метаболически активных субстратов, и составили группу контроля. В артериальной и венозной крови всех пациентов измеряли показатели коагулограммы на этапах:1) при поступлении в ОРИТ; 2) через 2-4 часа после введения первой дозы гепарина; 3) через 8-12 часов после введения повторной дозы гепарина; 4) спустя 24 часа после начала интенсивной терапии. На 28-й день наблюдения оценивали летальность, длительность лечения в ОРИТ и частоту тромботических осложнений в группах. Для оценки внутригрупповой динамики и межгрупповых различий использовали непараметрические методы статистического анализа.Результаты. В группе пациентов, получивших меглюмина натрия сукцинат, отмечали значимое снижение частоты тромбоэмболических событий в течение 28 суток лечения, а также сокращение сроков лечения в ОРИТ. Пациенты данной группы быстрее отвечали на проводимую антикоагулянтную терапию, что выражалось в более отчетливой динамике показателей коагулограммы: прирост АЧТВ, сохранение популяции тромбоцитов, снижение концентрации D-димеров и фибриногена.Заключение. Метаболический эффект сукцината, возможно, повышает устойчивость эндотелия к действию повреждающих факторов и снижает его прокоагулянтную активность. Гипотеза требует проверки в расширенном клиническом исследовании с дизайном, включающем лабораторную оценку эффективности разных курсовых доз исследуемого препарата, а также дифференцирующим механизм воздействия антигипоксанта на конкретные звенья про- и антикоагуляционной систем