Перепрофилированные противомикробные и противовирусные препараты для лечения COVID-19: безопасность и побочные эффекты в реальной клинической практике (научный обзор)

Леонова М.В. Перепрофилированные противомикробные и противовирусные препараты для лечения COVID-19: безопасность и побочные эффекты в реальной клинической практике (научный обзор). Consilium Medicum. 2022;24(9): DOI: 10.26442/20751753.2022.9.201763

© ООО «КОНСИЛИУМ МЕДИКУМ», 2022 г.

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Leonova MV. Repurposed antimicrobial and antiviral drugs for COVID-19 treatment: safety and side effects in real clinical practice (scientific review): A review. Consilium Medicum. 2022;24(9):
DOI: 10.26442/20751753.2022.9.201763

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Аннотация

Пандемия COVID-19 бросила вызов новым этиотропным средствам, что привело к экстренному перепрофилированию противомикробных и противовирусных препаратов для лечения новой инфекции по результатам экспериментальных исследований in silico, in vitro, in vivo и клинических исследований. Однако вопросам безопасности перепрофилированных препаратов уделялось меньше внимания. Воздействие перепрофилированных препаратов с ограниченными доказательствами соотношения риск-польза при COVID-19 требовало адаптации мониторинга безопасности, что повлияло на полноту и качество отчетов, а проведение оценки причинно-следственных связей стало самой сложной задачей. Представлен обзор накопленных за период пандемии COVID-19 данных о характере нежелательных реакций, связанных с применением перепрофилированных препаратов (гидроксихлорохина, хлорохина, ремдесивира, фавипиравира, лопинавира/ритонавира, рибавирина), используемых в реальной практике. Использовались результаты рандомизированных контролируемых исследований и наблюдательных исследований, систематических обзоров и метаанализов. Согласно систематизированным данным по безопасности применения гидроксихлорохина и хлорохина у пациентов с COVID-19 при краткосрочном лечении (≤14 дней), включая серию метаанализов, риск развития нежелательных эффектов повышен в 1,5–2 раза; основные проявления – удлинение интервала QT и аритмии (до 25%), расстройства со стороны желудочно-кишечного тракта – ЖКТ (до 50%), повышение уровня билирубина (3%) и трансаминаз (до 10%), дерматологические (до 10%) и нейропсихические побочные эффекты (до 21,7%). Большинство побочных эффектов перепрофилированных противовирусных препаратов группы аналогов нуклеозидов связано с их прямым цитотоксическим действием, что проявляется токсическим поражением ЖКТ, гепатотоксичностью, нефротоксичностью, кардиотоксичностью, гематотоксичностью. Наибольшее количество побочных эффектов со стороны ЖКТ и печени наблюдалось для лопинавира/ритонавира в сравнении с другим препаратами. Выявлены новые побочные эффекты для ремдесивира при использовании в условиях пандемии COVID-19 – кардиотоксичность (брадикардия и тяжелая гипотензия) и нефротоксичность, что расценено регуляторными органами как «сигнал безопасности». Для решения задач по оценке причинно-следственной связи потребуются дальнейшие более тщательные исследования и анализы. Накопленная информация в условиях продолжающейся пандемии COVID-19 должна подвергаться постоянному динамическому анализу и публиковаться в медицинских изданиях для оповещения клиницистов.

Ключевые слова: противовирусные препараты, перепрофилированные препараты, COVID-19, безопасность, побочные эффекты

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The COVID-19 pandemic has posed a challenge for new etiotropic agents, leading to an urgent repurposing of antimicrobial and antiviral drugs to treat a new infection based on the results of in silico, in vitro, in vivo experimental studies, and clinical trials. However, less attention has been paid to the safety of repurposed drugs. Exposure to repurposed drugs with limited risk-benefit evidence in COVID-19 required adaptation of safety monitoring, which affected the completeness and quality of reports, and making causality assessments the most difficult task. A review of data accumulated over the period of the COVID-19 pandemic on the nature of adverse reactions associated with the use of repurposed drugs (hydroxychloroquine, chloroquine, remdesivir, favipiravir, lopinavir/ritonavir, ribavirin) used in real practice is presented. The results of RCTs and observational studies, systematic reviews and meta-analyses were used. Systematized data on the safety of the use of hydroxychloroquine and chloroquine in patients with COVID-19 in short-term treatment (≤14 days), including a series of meta-analyses, the risk of adverse effects was increased by 1.5–2 times; the main manifestations are prolongation of the QT interval and arrhythmias (up to 25%), gastrointestinal disorders (up to 50%), increased levels of bilirubin (3%) and transaminases (up to 10%), dermatological (up to 10%) and neuropsychiatric side effects (up to 21.7%). Most of the side effects of repurposed antiviral drugs of the nucleoside analog group are associated with their direct cytotoxic effect, which is manifested by toxic damage to the gastrointestinal tract, hepatotoxicity, nephrotoxicity, cardiotoxicity, and hematotoxicity. The greatest number of side effects from the gastrointestinal tract and liver were observed for lopinavir/ritonavir in comparison with other drugs. New side effects have been identified for remdesivir when used in the context of the COVID-19 pandemic – cardiotoxicity (bradycardia and severe hypotension) and nephrotoxicity, which was regarded by regulatory authorities as a “safety signal”. To solve the problems of assessing the cause-and-effect relationship, further more thorough research and analysis will be required. The accumulated information in the context of the ongoing COVID-19 pandemic should be subject to ongoing dynamic analysis and published in medical journals to alert clinicians.

Keywords: antiviral drugs, repurposed drugs, COVID-19, safety, side effects

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1. Statistics of the spread of coronavirus in the world as of June 15, 2022. Available at: https://coronavirus-monitor.info/. Accessed: 28.06.2022 (in Russian).
2. World Health Organization. 14.9 million excess deaths associated with the COVID-19 pandemic in 2020 and 2021. Published 5 May 2022. Available at: https://www.who.int/news/item/05-05-2022-14.9-million-excess-deaths-were-associated-with-the-covid-1.... Accessed: 28.06.2022
3. Singh TU, Parida S, Lingaraju MC, et al. Drug repurposing approach to fight COVID-19. Pharmacol Rep. 2020;72:1479-508. DOI:10.1007/s43440-020-00155-6
4. Desai MK. Pharmacovigilance and assessment of drug safety reports during COVID 19. Perspect Clin Res. 2020;11(3):128. DOI:10.4103/picr.PICR_171_20
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8. Jankelson L, Karam G, Becker ML, et al. QT prolongation, torsades de pointes, and sudden death with short courses of chloroquine or hydroxychloroquine as used in COVID-19: a systematic review. Heart Rhythm. 2020;17(9):1472-9. DOI:10.1016/j.hrthm.2020.05.008
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DOI:10.3390/jcdd8020018
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24. Nabati M, Parsaee H. Potential cardiotoxic effects of remdesivir on cardiovascular system:a literature review. Cardiovasc Toxicol. 2022;22(3):268-72.
DOI:10.1007/s12012-021-09703-9
25. Silva NAO, Zara ALSA, Figueras A, Melo DO. Potential kidney damage associated with the use of remdesivir for COVID-19: analysis of a pharmacovigilance database. Cad Saude Publica. 2021;37(10):e00077721. DOI:10.1590/0102-311X00077721
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Авторы

М.В. Леонова*

МОО «Ассоциация клинических фармакологов», Волгоград, Россия
*anti23@mail.ru

________________________________________________

Marina V. Leonova*

Association of Clinical Pharmacologists, Volgograd, Russia
*anti23@mail.ru

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