The redox transformations and nucleophilic replacements as possible metabolic reactions of the drug “Triazaverin”. The chemical modeling of the metabolic processes

As a model of metabolic transformations of antiviral drug “Triazaverin” and its analogues‑2-alkylthio‑6-nitro‑1,2,4-triazolo[5,1-c][1,2,4]triazine‑7-ones 1a-d examined the oxidation of alkylthio groups to the corresponding sulfoxides 2a-d and sulfones 3a-d, as well as the process of nucleophilic substitution sulfonyloxy group of cysteine and cysteamine with the formation of compounds 5 and 6

ECONOMIC BENEFITS OF LEFT VENTRICULAR HYPERTROPHY REGRESSION IN PATIENTS WITH ARTERIAL HYPERTENSION

Aim. To evaluate by modelling the economic benefits of left ventricular hypertrophy (LVH) regression in patients with arterial hypertension (HT) due to therapy with fixed combination of valsartan/amlodipine.  Material and methods. 20 patients (15 females and 5 males, aged 18 to 70 years) with essential HT accompanied by metabolic syndrome with a history of previous ineffective antihypertensive therapy were included into the study. All patients were treated with fixed combination of amlodipine/valsartan in doses of 5/160 and 10/160 mg depending on blood pressure (BP) level. Treatment duration was 24 weeks. Changes in BP level, LVH regression were assessed. Economic evaluation was performed on the basis of modelling with the specialized software Decision Tree 4.xla. Results. Effect of fixed amlodipine/valsartan combination therapy on LVH was used to estimate treatment effectiveness and to build the model. Patients were distributed according to left ventricular (LV) mass (at baseline and after 24 weeks of therapy). Significant decrease in LV mass from 205.8±50.4 to 181.9±45.1 g (p<0.05) was revealed. The model took into account economic and frequency factors for 10 year prognosis: this therapy prevents 36 deaths, 6 strokes, 24 myocardial infarction per 1000 patients. Absence of need in treatment of these prevented events can save 2 516 772.42 RUR for every 1 000 patients. It would reduce the total costs per patient during 10 years. Conclusion. Treatment with amlodipine/valsartan single pill combination has not only clinical advantages, but also pharmacoeconomic benefits. This combination reduces risk of acute myocardial infarction and death more effectively. Treatment with fixed valsartan/amlodipine combination saves maximum years of life with less cost during 10 years. Despite of higher pharmacotherapy costs, fixed valsartan/amlodipine combination reduces total costs due to prevention of fatal and nonfatal cardiovascular events

Azoloazines as Perspective Antiglycating Agents for Therapy of Diabetes Complications

This work was supported by Russian Federation Ministry of education and science (grant № 4.6351.2017/8.9) and Russian Foundation for Basic Research (grant № 18-03-00787)

Health status of students in the special medical group

To assess the health level of first-year students studying in a special medical group, we researched such indicators as physical development, morbidity, physical training, biological age using the method of V. Sukhov and the health level according to G. L. Apanasenko. The leading positions in the structure of morbidity take diseases of the musculoskeletal system, the nervous system, the eye and its appendage occupy take. 63% of students have a low level of health, more than half of students have a biological age in the range of 31-40 years. Therefore, the training session must be adapted to the state of health.Для оценки уровня здоровья студентов 1 курса, занимающихся в специальной медицинской группе, изучены показатели физического развития, заболеваемости, физической подготовки, биологический возраст по методике В.Сухова, уровень здоровья по Г.Л.Апанасенко. В структуре заболеваемости ведущие позиции занимают болезни костно-мышечной системы, нервной системы, глаза и его придаточного аппарата. Низкий уровень здоровья имеют 63% студентов, более половины студентов имеют биологический возраст в диапазоне 31-40 лет. Поэтому тренировочное занятие должно быть адаптировано с учетом состояния здоровья

The study of the dynamics of clinical and laboratory-instrumental parameters in hypertensive patients with obesity who underwent COVID-19-associated pneumonia

BACKGROUND: According  to the results of the ESSE-RF study, the frequency of obesity in the population  reached 29.7%. Obesity is one of the main risk factors for the development of cardiovascular diseases. Features of the course of COVID-19 in patients with obesity is a very urgent problem.AIM: The aim of the study was a comparative investigation of clinical and laboratory-instrumental parameters in AH patients with or without obesity who had COVID-19 associated pneumonia, to identify the role of obesity as a potential predictor of post-COVID cardiovascular complications 3 months after discharge from the hospital.MATERIALS AND METHODS: Materials and methods. The study included 174 patients with COVID-19-associated pneumonia. Group 1 included 78 patients with AH without obesity, group 2 — 96 patients with AH and obesity. All patients were tested with a blood sample at the time of admission and 3 months after discharge from the hospital. We assessed parameters of general blood test, biochemistry, hemostasis, inflammation biomarkers — concentration of C-reactive protein (CRP), highly sensitive CRP (hs-CRP), homocysteine, IL-6, etc. All patients initially underwent computed tomography  of the chest. In both groups, 24-hour blood pressure monitoring was performed using BPLaB device, according to the standard protocol; echocardiography using  an expert class ultrasound diagnostic  system Vivid S70. The study is registered with the Clinical Trials.gov database Identifier: NCT04501822.RESULTS: Results. The biomarker that significantly distinguished the both groups of patients, as well as subgroups according to the degree of obesity was the concentration of maxCRP and hs-CRP, which was significantly higher in group 2. In addition, the registered maximum values of MPO, NT-proBNP, IL-1,6, TNA-α and NRL parameters in group 2 of patients with 2–3 degrees of obesity, may indicate the highest probability of developing  delayed adverse cardiovascular complications  in this group of patients. Mean systolic blood pressure, variability of systolic and diastolic blood pressure, and heart rate at night were significantly  higher in AH patients with obesity. Numerous correlations of obesity with laboratory and instrumental parameters have been registered, which may indicate an increased likelihood of delayed unwanted cardiovascular complications in this particular group of patients. Multiple regression showed that obesity is an independent predictor of an increase in LDH, hs-CRP and right atrium.CONCLUSION: Dynamic control of the studied parameters in patients with AH and OB registered an increased concentration of CRP at the initial stage and 3 months after treatment, with a general trend towards a decrease in the increased initial structural parameters of ECHO CG. The logistic regression method showed that the presence of OB in patients with AH is an independent factor causing increased levels of immune inflammation (CRP), a marker of tissue destruction (LDH), and load on the right atrium

New antiglycating agents for diabetes therapy

It was shown that azoloazines (1) demonstrated higher antiglycation activity than reference compound, aminoguanidine, and have some potential as dipeptidylpeptidase-4 inhibitors. By given results this class of heterocycles can be considered as candidate for extended studies to develop drugs against complications of T2DM [1-4].The work was supported by the Ministry of Education and Science of Russia (grant №0836-2020-0058)

Современные подходы к введению показателя «Аномальная токсичность»

For over 60 years, the Abnormal Toxicity Test (ATT) has been used as an important tool in safety control of some parenteral and veterinary products made from biological materials. In 2017, some of the members of the Pharmacopoeial Committee of the Eurasian Economic Union (EAEU) proposed not to include the ATT in the draft monographs of the EAEU Pharmacopoeia based on the decision of the European Pharmacopoeia Commission to suppress the test. However, this may not be achieved in Russia at this point, because some production sites that manufacture medicinal products for human and veterinary use have not fully implemented GMP principles yet. The main aim of the ATT is to detect any toxicity above the pre-determined acceptable level. The unacceptable toxicity levels can manifest themselves in higher mortality rates or unexpected intoxication effects in laboratory animals. This test makes it possible to detect abnormal (high) toxicity of a medicinal product which may be associated with degradation products or undesirable impurities resulting from changes of the production technology, which are not mentioned in specification documents related to production, transportation, and storage. In 2016—2017 12 batches of veterinary products, including vaccines and sera, were found to be noncompliant, and the Federal Service for Surveillance in Healthcare rejected 16 batches of medicinal products in 2016—2019. The aim of the study was to analyse current approaches to the ATT in the Russian and foreign pharmacopeias, and to develop a programme for phasing out the ATT use depending on the nature and pharmacological properties of medicinal products. Comparative analysis of the monographs of the world leading pharmacopeias showed that the State Pharmacopoeia of the Russian Federation has the most stringent test conditions. As an alternative to suppressing the ATT the authors suggest a phased approach to reduce the use of this test. They determined groups of medicinal products whose pharmacological properties allow for the suppression of the test. The proposed approach to phasing out the use of ATT will make it possible to use the test effectively and reduce the number of performed tests, but will still ensure drug safety. The suppression of the ATT can not be achieved without a comprehensive detailed research by quality control specialists and further discussion by all interested parties.В течение более 60 лет тест на аномальную токсичность используется как один из важных показателей при контроле качества безопасности парентеральных медицинских и ветеринарных препаратов, получаемых из субстанций биологического происхождения. В 2017 г. на заседании Фармакопейного комитета Евразийского экономического союза (ЕАЭС) было предложено не включать тест на аномальную токсичность в проект Фармакопеи ЕАЭС, основанием для данной дискуссии послужил отказ Европейской фармакопеи от данного испытания. Однако на территории нашей страны в настоящее время подобный шаг не может быть реализован, так как не все производственные площадки для производства медицинских и ветеринарных препаратов полностью отвечают международным требованиям GMP Основной целью проведения теста на аномальную токсичность является выявление токсичности препарата, превышающей установленный ранее допустимый уровень, контролируемый по повышению летальности или по неожидаемым (нерегламентированным) явлениям интоксикации животных. Данное испытание позволяет определить аномальную (повышенную) токсичность лекарственного препарата, которая может возникнуть за счет появления продуктов разложения или нежелательных примесей при изменении процесса производства, не предусмотренных регламентом производства, транспортирования или хранения. Так, в течение 2016—2017 гг. количество выявленных несоответствий ветеринарных препаратов, в том числе вакцин и сывороток, составило 12 серий, а Росздравнадзором за период 2016—2019 гг. забраковано 16 серий лекарственных препаратов. Цель работы — анализ современных подходов к тесту «Аномальная токсичность» в отечественной и зарубежных фармакопеях, разработка программы поэтапного сокращения применения теста в зависимости от природы и фармакологических свойств лекарственных средств. В результате сравнительного анализа монографий ведущих фармакопей мира установлено, что действующие требования Государственной фармакопеи Российской Федерации характеризуются наиболее строгими условиями проведения теста. В качестве альтернативы отказу от испытания на аномальную токсичность авторами предложен поэтапный подход, позволяющий сократить использование теста. Определены группы препаратов, фармакологические свойства которых позволяют исключить показатель. Предложенный поэтапный подход к сокращению использования показателя «Аномальная токсичность» позволит сделать тест более рациональным и сократить количество испытаний, но по-прежнему будет способствовать обеспечению безопасности применения лекарственных препаратов. Исключение испытания на аномальную токсичность не может быть реализовано без всесторонней детальной проработки специалистами в области контроля качества и дальнейшего обсуждения этого вопроса всеми заинтересованными сторонами

Leveraging ligand affinity and properties: discovery of novel benzamide-type cereblon binders for the design of PROTACs

Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide are the most common cereblon (CRBN) recruiters in proteolysis-targeting chimera (PROTAC) design. However, these CRBN ligands induce the degradation of IMiD neosubstrates and are inherently unstable, degrading hydrolytically under moderate conditions. In this work, we simultaneously optimized physiochemical properties, stability, on-target affinity, and off-target neosubstrate modulation features to develop novel nonphthalimide CRBN binders. These efforts led to the discovery of conformationally locked benzamide-type derivatives that replicate the interactions of the natural CRBN degron, exhibit enhanced chemical stability, and display a favorable selectivity profile in terms of neosubstrate recruitment. The utility of the most potent ligands was demonstrated by their transformation into potent degraders of BRD4 and HDAC6 that outperform previously described reference PROTACs. Together with their significantly decreased neomorphic ligase activity on IKZF1/3 and SALL4, these ligands provide opportunities for the design of highly selective and potent chemically inert proximity-inducing compounds

FIXED COMBINATION OF VALSARTAN AND AMLODIPINE: EFFECTS ON THE LEFT VENTRICULAR HYPERTROPHY REGRESSION, ALBUMINURIA REDUCTION AND ENDOTHELIUM FUNCTION IN HYPERTENSIVE PATIENTS WITH METABOLIC SYNDROME

Aim. To study effects of fixed combination of valsartan and amlodipine on of left ventricular hypertrophy (LVH) regression, microalbuminuria reduction and endothelium function in hypertensive patients with metabolic syndrome (MS).Materials and methods. 20 hypertensive patients (15 females and 5 males) with metabolic syndrome and a history of previous ineffective antihypertensive therapy were studied. Combined antihypertensive therapy was applied during 12-24 weeks. Amlodipine and valsartan dose was 5/160 or 10/160 mg/day depending on blood pressure level. Endothelial function, blood pressure level, urinary albumin excretion and LVH regression were estimated.Results. Blood pressure reduction to the target level was revealed. There was a significant reduction in microalbuminuria by -55.3±39.2% (р=0.022) in comparison with the baseline. Endothelium-dependent vasodilation increased in 3.6±7.2% (р=0.05) in comparison with baseline, LVH decreased by -9.1±12.4 g/m2 (р=0.021).Conclusion. Therapy with fixed combination of valsartan and amlodipine results in blood pressure and microalbuminuria reduction, endothelium-dependent vasodilation improvement, LVH regression in hypertensive patients with MS. These findings show that the fixed combination of these antihypertensives has a multifaceted impact on cardiovascular risk

COMPARATIVE EFFICACY OF COMBINED ANTIHYPERTENSIVE THERAPY IN PATIENTS WITH MODERATE ARTERIAL HYPERTENSION ACCOMPANIED BY TYPE 2 DIABETES

Aim. To compare efficacy of different fixed antihypertensive combinations in achievement of the target level of blood pressure (BP), to evaluate the dynamics of endothelium-dependent vasodilation (EDVD) and microalbuminuria (MAU) and to calculate cost-effectiveness ratio (CER). Material and methods. Patients (n=75) with moderate hypertension (HT) accompanied by type 2 diabetes (DM) were studied. The patients were randomized in groups A, B or C. Patients of group A (n=25) received a fixed combination of the original perindopril+indapamide, patients of group B (n=30) — a fixed combination of the generic enalapril+indapamide, patients of group C (n=20) — a fixed combination of the original enalapril+hydrochlorothiazide. Office BP was examined within the 4, 8 and 12 weeks, EDVD and MAU were determined initially and after 12 weeks of therapy. CER was also calculated. Results. The maximal antihypertensive effect was observed in group C (systolic BP (SBP) decreased in 46.6±1.3 mm Hg), followed by group A (SBP decreased in 43.1±0.8 mm Hg) and B (SBP decreased in 40.0±0.8 mm Hg). The groups were distributed as follows (in descending order): according to EDVD rise - group A (Δ4.52%), C (Δ3.14%) B (Δ3%); according to MAU prevalence rate reduction - group A (from 48% to 8%), B (from 40% to 23%) and C (from 40% to 25%). The “C” combination provided the lowest cost of BP reduction (12.33 rubles/mm Hg) and correction of MAU prevalence rate (1 514 rubles/case). According to EDVD improvement combination “A” had the lowest CER (2 805 rubles/case). Conclusion. According to pharmacoeconomic analysis the fixed combination of original enalapril+hydrochlorothiazide and the fixed combination of original perindopril+indapamide should be used in patients with moderate arterial hypertension, endothelial dysfunction and/or MAU