Prerequisites for the creation of an atlas of postcovid inflammation as a way of personalized pharmacotherapy, as well as predicting and preventing organ and systemic dysfunctions

SARS-CoV-2 is a novel coronavirus that has been identified as the cause of the 2019 coronavirus infection (COVID-19), which originated at Wuhan city of PRC in late 2019 and widespread worldwide. As the number of patients recovering from COVID-19 continue to grow, it’s very important to understand what health issues they may keep experiencing. COVID-19 is now recognized as an infectious disease that can cause multiple organ diseases of various localization. It is against this background that a new term was introduced: post-acute post-COVID-19 syndrome characterized by several persistent symptoms inherent in the acute phase of the disease, as well as the occurrence of delayed and (or) long-term complications beyond 4 weeks from the onset of the disease. The work reflected in this article revealed a portrait of a patient with post-COVID-19 syndrome, the most common complications of this period, as well as the mechanisms of their development and the resulting metabolic, cellular, tissue disorders leading to the tissue and organ dysfunctions. A comprehensive biochemical and immunological screening was carried out using the example of three clinical cases to identify the most significant disorders in these patients and to correlate with their clinical status over time. In point of fact, such patients were diagnosed with vascular dysfunction factors (development of endothelial dysfunction), metabolic dysfunction factors (metabolic acidosis, mitochondrial dysfunction, carbohydrate metabolism disorder, insulin resistance, altered branched-chain and aromatic amino acid metabolism), neurological disorder factors (neurotoxicity of the resulting metabolites), immunological disorder factors (decreased efficiency of detoxification systems, secondary immunodeficiency, risk of secondary bacterial infection)

Эффективность и безопасность применения лекарственных средств: значение и возможности клинической фармакологии

Brief description of the opportunities and benefits of applying the methodology of clinical pharmacology and personalized medicine, pharmacokinetics, and pharmacodynamics of medicines, as well as the possibilities of evaluation of metabolic biotransformation and drug interactions to improve the efficacy, safety, therapeutic and pharmacodynamic effects of medicines, is given. These features and techniques should be extensively used for expert evaluation of efficacy and safety of drugs. The introduction of modern methods of diagnostics and treatment in clinical practice will require building a system that could be implemented in the Centres of personalized medicine.Дано краткое описание возможностей и преимуществ применения методологии клинической фармакологии и персонализированной медицины, особенностей фармакокинетики и фармакодинамики лекарственных средств, а также возможности оценки метаболической биотрансформации и взаимодействия лекарственных препаратов для повышения эффективности, безопасности, терапевтических и фармакодинамических эффектов лекарственных средств. Эти возможности и методы необходимо активно использовать при экспертной оценке эффективности и безопасности лекарственных препаратов. Внедрение современных методов диагностики и лечения в клиническую практику потребует выстраивания целой системы, которая могла бы быть реализована в Центрах персонализированной медицины

Механизм действия фоллистатин-подобного белка-1 (FSTL-1)

The paper provides current data on some proteins of the TGF- p family which are potentially capable of exerting a protective effect in diseases of the heart, lungs, placenta, gonads, and pancreas. The study investigated the anti-inflammatory properties of follistatin-like protein-1 (FSTL-1), one of the proteins of this family, at the cellular level. It was demonstrated that FSTL-1 is responsible for heart muscle regeneration in mammals through activation of angiogenic factors. Despite the fact that this protein plays a key role in myocardial regeneration, its concentration in the epicardium decreases immediately after a heart attack, which hampers effective self-repair of the heart. The paper summarises the results of studies of the efficacy of intravenous administration of FSTL-1 in rats with myocardial infarction. However, the administration of a foreign protein can cause allergic reactions, therefore a drug that induces FSTL-1 secretion was chosen instead.The aim of the study was to provide experimental substantiation of the possibility of exogenous regulation of FSTL-1 secretion.Materials and methods: FSTL-1 concentration in rat plasma was assessed by enzyme immunoassay before and after treatment with the antioxidant drug ethyl methyl hydroxypyridine malate. The antioxidant was administered to 15 healthy male Wistar rats subcutaneously 3 times a day at a dose of 6 mg/day for 14 days. A fasting blood sample was obtained on the first day before administration of the drug and on day 15.Results: after the period of treatment with ethyl methyl hydroxypyridine malate the concentration of FSTL-1 in the plasma of the laboratory rats increased significantly (p = 0.0011) to reach 0.92 ± 0.11 ng/mL as compared to the initial concentration of 0.48 ± 0.04 ng/mL.Conclusion: the study provided experimental evidence for new properties of ethyl methyl hydroxypyridine malate, i.e. induction of FSTL-1 in healthy rats. Further studies are encouraged to assess potential use of this drug as an inductor of FSTL-1 in myocardial ischemia.Приведены современные данные о некоторых белках семейства TGF-p, потенциально способных оказывать протективное действие при патологиях сердца, легких, плаценты, половых желез и поджелудочной железы. Были изучены противовоспалительные свойства одного из представителей данного семейства белков — фоллистатин-подобного белка-1 (FSTL-1) на клеточном уровне. Установлено, что FSTL-1 отвечает за регенерацию сердечной мышцы у млекопитающих за счет активации ангиогенных факторов. Несмотря на ведущую роль данного белка в регенерации миокарда, его концентрация в эпикарде сразу после инфаркта уменьшается, что не позволяет сердцу эффективно са-мовосстанавливаться. Приведены данные исследований об эффективности внутривенного введения FSTL-1 у крыс с инфарктом миокарда. Однако поскольку введение чужеродного белка может вызывать аллергические реакции, более рациональным решением стал выбор лекарственного средства, индуцирующего секрецию FSTL-1.Цель работы: экспериментальное обоснование возможности применения экзогенной регуляции секреции фоллистатин-подобного белка-1.Материалы и методы: исследования концентрации FSTL-1 в плазме крыс проводили методом иммуноферментного анализа до и после курса применения антиоксидантного лекарственного средства этилметилгидроксипири-дина малата. Антиоксидант вводили 15 здоровым самцам крыс линии Wistar подкожно 3 раза в сутки в дозе 6 мг/сут, курсом 14 сут. Кровь отбирали из вены натощак в первые сутки до введения препарата и на 15 сут.Результаты: после курса введения этилметилгидроксипиридин малата концентрация FSTL-1 в плазме крови крыс достоверно (р = 0,0011) увеличивалась у экспериментальных животных и составила 0,92 ± 0,11 нг/мл относительно исходного значения 0,48 ± 0,04 нг/мл.Заключение: экспериментально подтверждены новые свойства этилметилгидроксипиридина малата — индукция фоллистатин-подобного белка-1 у здоровых крыс. Предлагается рассмотреть потенциальную возможность применения данного лекарственного средства как индуктора FSTL-1 при ишемии миокарда

Clinical pharmacogenetics of antiaggregants: clinical pharmacologist' point of view

The review is devoted to individual antiaggregant sensitivity issue. According to numerous studies' data, acetylsalicylic acid is ineffective in 5 % of the patients. It might be explained by target molecule (COG-1) gene polymorphism. This phenomenon has important clinical implications, as aspirin-resistant patients have significantly higher risk of thrombotic complications. Another widely used antiaggregant, clopidogrel, is ineffective in more than 15 % of the patients. Clopidogrel effectiveness depends on hepatic iso-enzyme CYP3A activity and ADP receptor gene variant. Many studies demonstrated that clopidogrel resistance worsens prognosis in coronary heart disease patients. Even new antiaggregants, Ilb-IIIa receptor inhibitors, are ineffective in 20 % of the cases, due to glycoprotein receptor gene polymorphism. Therefore, to identify optimal antiaggregant therapy regimen, individual approach is needed, including genetic and pharmacogenetic tests

Clinical pharmacogenetics of angiotensin II receptor blockers: new perspectives of pharmacotherapy individualization

The review focuses on clinical practice perspectives for angiotensin II receptor blockers (ARB). The authors discuss the results of the trials on biotransformation genes (CYP2C9) polymorphism and renin-angiotensin-aldosterone system influence on ARB pharmacokinetics and pharmacodynamics. Pharmacogenetic studies have been performed not only in healthy volunteers, but also in patients with arterial hypertension or chronic heart failure

Standard instructions for medical use of interchangeable drugs: analysis of modern regulatory documents

The article presents a review of modern regulatory and legal framework and draft regulatory documents on circulation of interchangeable drugs with regard to standard instructions for medical use. The analysis included more than 70 documents. There are two slightly different notions in this field: a generic drug and an interchangeable drug. A generic drug is not necessarily an interchangeable drug. The interchangeability of a drug is determined during pre-marketing evaluation. Some differences concerning normative requirements to the content of standard instructions for interchangeable drugs have been observed when comparing the regulatory framework of Russia, CIS countries and the EU. It is necessary to look not only at bioequivalence as an equivalent of interchangeability, but also take into account characteristics of excipients, and therapeutic equivalence based on preclinical and clinical trial results. The analysis of differences in regulatory documents can form the basis for further harmonization of requirements to instructions for medical use of interchangeable drugs

ANTIANGINAL AND ANTI2ISCHEMIC EFFECTIVENESS AND TOLERABILITY OF OXICARDIN IN PATIENTS WITH STABLE ANGINA OF I-III FUNCTIONAL CLASSES: RESULTS OF A RUSSIAN MULTICENTER RUSSIA

Antianginal and anti2ischemic effectiveness and tolerability of oxicardin in patients with stable angina of I-III functional classes: results of a Russian multicenter Russia

Efficacy and safety of medicines: the value and opportunities of clinical pharmacology

Brief description of the opportunities and benefits of applying the methodology of clinical pharmacology and personalized medicine, pharmacokinetics, and pharmacodynamics of medicines, as well as the possibilities of evaluation of metabolic biotransformation and drug interactions to improve the efficacy, safety, therapeutic and pharmacodynamic effects of medicines, is given. These features and techniques should be extensively used for expert evaluation of efficacy and safety of drugs. The introduction of modern methods of diagnostics and treatment in clinical practice will require building a system that could be implemented in the Centres of personalized medicine

The Mechanism of Action of Follistatin-like Protein-1 (FSTL-1)

The paper provides current data on some proteins of the TGF- p family which are potentially capable of exerting a protective effect in diseases of the heart, lungs, placenta, gonads, and pancreas. The study investigated the anti-inflammatory properties of follistatin-like protein-1 (FSTL-1), one of the proteins of this family, at the cellular level. It was demonstrated that FSTL-1 is responsible for heart muscle regeneration in mammals through activation of angiogenic factors. Despite the fact that this protein plays a key role in myocardial regeneration, its concentration in the epicardium decreases immediately after a heart attack, which hampers effective self-repair of the heart. The paper summarises the results of studies of the efficacy of intravenous administration of FSTL-1 in rats with myocardial infarction. However, the administration of a foreign protein can cause allergic reactions, therefore a drug that induces FSTL-1 secretion was chosen instead.The aim of the study was to provide experimental substantiation of the possibility of exogenous regulation of FSTL-1 secretion.Materials and methods: FSTL-1 concentration in rat plasma was assessed by enzyme immunoassay before and after treatment with the antioxidant drug ethyl methyl hydroxypyridine malate. The antioxidant was administered to 15 healthy male Wistar rats subcutaneously 3 times a day at a dose of 6 mg/day for 14 days. A fasting blood sample was obtained on the first day before administration of the drug and on day 15.Results: after the period of treatment with ethyl methyl hydroxypyridine malate the concentration of FSTL-1 in the plasma of the laboratory rats increased significantly (p = 0.0011) to reach 0.92 ± 0.11 ng/mL as compared to the initial concentration of 0.48 ± 0.04 ng/mL.Conclusion: the study provided experimental evidence for new properties of ethyl methyl hydroxypyridine malate, i.e. induction of FSTL-1 in healthy rats. Further studies are encouraged to assess potential use of this drug as an inductor of FSTL-1 in myocardial ischemia