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Фавипиравир как потенциальное средство противодействия при COVID-19
Леонова М.В. Фавипиравир как потенциальное средство противодействия при COVID-19. Consilium Medicum. 2020; 22 (11): 56–60. DOI: 10.26442/20751753.2020.11.200368
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Leonova M.V. Favipiravir as a potential countermeasure for COVID-19. Consilium Medicum. 2020; 22 (11): 56–60. DOI: 10.26442/20751753.2020.11.200368
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Аннотация
Фавипиравир – противовирусный химиопрепарат широкого спектра действия, аналог пуриновых нуклеозидов, одобренный в Японии как лекарство от гриппа. Подобно другим аналогам нуклеозидов, фавипиравир действует как пролекарство, внутриклеточно метаболизируется с образованием активного метаболита фавипиравира рибофуранозил-5'-трифосфата. Метаболит конкурентно ингибирует активность РНК-полимеразы РНК-вирусов и препятствует репликации вируса за счет включения в вирусную РНК, действуя как терминатор цепи. Обладает избирательностью или вирус-специфичностью внутриклеточного действия и низким уровнем цитотоксичности. Фавипиравир как терминатор цепи прекращает удлинение цепи вирусной РНК и дальнейший синтез вирусной РНК, что снижает вероятность образования мутаций и появления резистентных штаммов вирусов. Фавипиравир приводит к значимому снижению уровня провоспалительных цитокинов, что усиливает противовирусный эффект. Фавипиравир продемонстрировал противовирусную активность против широкого спектра РНК-вирусов, таких как вирус гриппа А, В, С, вирусы Эбола, Ласса, бешенства и др. В 2020 г. в рамках скринингового тестирования противовирусных препаратов, включая фавипиравир, показано наличие противовирусной активности против 2019-nCoV в исследовании in vitro на клеточной культуре с показателями эффективности и селективности лучше, чем у рибавирина. Инициировано более 10 клинических исследований по изучению эффективности фавипиравира для лечения COVID-19 легкого и среднетяжелого течения. Применяли фиксированную нагрузочную и поддерживающую дозу 3200/1200 мг и 3600/1600 мг. Результаты показали лучший клинический эффект с более ранней элиминацией коронавируса, регрессом компьютерно-томографических изменений и потребности в искусственной вентиляции легких в группах лечения фавипиравиром в сравнении с лопинавир/ритонавиром, Арбидолом и другими препаратами. В российском клиническом исследовании II/III фазы по изучению эффективности и безопасности фавипиравира (Aвифавир) у пациентов со среднетяжелым течением COVID-19 в дозах 1600/600 мг или 1800/800 мг 2 раза в сутки в сравнении со стандартным лечением показал клиренс вируса у 62,5% пациентов в течение 4 дней, безопасность и хорошую переносимость. Фавипиравир включен в Российские рекомендации по лечению COVID-19 и является единственным одобренным пероральным препаратом для лечения COVID-19 средней степени тяжести на сегодняшний день.
Ключевые слова: COVID-19, фавипиравир, аналог пуриновых нуклеозидов, противовирусная активность, эффективность, безопасность.
Ключевые слова: COVID-19, фавипиравир, аналог пуриновых нуклеозидов, противовирусная активность, эффективность, безопасность.
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Favipiravir is a broad-spectrum antiviral agent, an analogue of purine nucleosides, licensed as an anti-influenza drug in Japan. Like other analogs of nucleosides, favipiravir acts as a prodrug, and undergoes an intracellular phosphoribosylation to be an active form, favipiravir ribofuranosyl-5'-triphosphate. The metabolite competitively inhibits the activity of RNA polymerase of RNA viruses and prevents virus replication by incorporating into the viral RNA, acting as a chain terminator. It possesses selective or virus-specific intracellular action and low cytotoxicity. Favipiravir inhibits viral RNA synthesis by terminating chain elongation, which reduces the likelihood of mutations and the emergence of resistant virus strains. Favipiravir causes a significant decrease in pro-inflammatory cytokines levels, which enhances the antiviral effect. Favipiravir demonstrated antiviral activity against a broad spectrum of RNA viruses, such as influenza A, B and C viruses, Ebola virus, Lassa virus, rabies, etc. In 2020, as part of screening testing of antiviral drugs, including favipiravir, it was shown in vitro antiviral activity against 2019-nCoV with better efficacy and selectivity compared to ribavirin. More than 10 clinical trials have been initiated to study the effectiveness of favipiravir for the treatment of mild to moderate COVID-19. A fixed loading and maintenance dose of 3200/1200 mg and 3600/1600 mg was used. The results showed a better clinical effect with earlier elimination of coronavirus, regression of computed tomographic changes and the need for mechanical ventilation in the favipiravir treatment groups compared with lopinavir/ritonavir, Arbidol and other drugs. In a Russian phase II/III clinical study of efficacy and safety of favipiravir (Avifavir) (1600/600 mg or 1800/800 mg 2 times a day) vs standard treatment in patients with moderate COVID-19, favipiravir showed virus clearance within 4 days in 62,5% of patients, safety and good tolerance. Favipiravir is included in the Russian guidelines for the treatment of COVID-19 and is the only approved oral medication for the treatment of moderate COVID-19 to date.
Key words: COVID-19, favipiravir, purine nucleoside analog, antiviral activity, efficacy, safety
Полный текст
Список литературы
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[Temporary guidelines “Prevention, diagnosis and treatment of new coronavirus infection (COVID-19)”. Ministry of Health of Russia. Version VII. 03.06.2020 (in Russian).]
2. Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID‐19). Drug Discov Ther 2020; 14: 58–60. DOI: 10.5582/ddt.2020.01012
3. Furuta Y, Takahashi K, Kuno-Maekawa M et al. Mechanism of action of T-705 against influenza virus. Antimicrob Agents Chemother 2005; 49 (3): 981–6. DOI: 10.1128/AAC.49.3.981-986.2005
4. Shiraki K, Daikoku T. Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Pharmacol Ther 2020; 209: 107512. DOI: 10.1016/j.pharmthera.2020.107512
5. Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci 2017; 93 (7): 449–63. DOI: 10.2183/pjab.93.027
6. Delang L, Abdelnabi R, Neyts J. Favipiravir as a potential countermeasure against neglected and emerging RNA viruses. Antiviral Res 2018; 153: 85–94. DOI: 10.1016/j.antiviral.2018.03.003
7. Sissoko D, Laouenan C, Folkesson E et al. JIKI Study Group. Experimental treatment with favipiravir for Ebola virus disease (the JIKI trial): a historically controlled, single‐arm proof‐of‐concept trial in Guinea. PLoS Med 2016; 13: e1001967. DOI: 10.1371/journal.pmed.1001967
8. Bai CQ, Mu JS, Kargbo D et al. Clinical and virological characteristics of Ebola virus disease patients treated with favipiravir (T‐705) Sierra Leone, 2014. Clin Infect Dis 2016; 63: 1288–94. DOI: 10.1093/cid/ciw571
9. Lu R, Zhao X, Li J et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 2020; 395: 565–74. DOI: 10.1016/S0140-6736(20)30251-8
10. Wang M, Cao R, Zhang L et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020; 30 (3): 269–71. DOI: 10.1038/s41422-020-0282-0
11. Seneviratne SL, Abeysuriya V, De Mel S et al. Favipiravir in Covid-19. IJPSAT 2020; 19 (2): 143–5. https://www.researchgate.net/publication/340778537_Favipiravir_in_COVID-19
12. Du YX, Chen XP. Favipiravir: Pharmacokinetics and concerns about clinical trials for 2019-nCoV Infection. Clin Pharmacol Ther 2020; 108 (2): 242–7. DOI: 10.1002/cpt.1844
13. Coomes EA, Haghbayan H. Favipiravir, an antiviral for COVID-19? J Antimicrob Chemother 2020; 75 (7): 2013–4. DOI: 10.1093/jac/dkaa171
14. Cai Q, Yang M, Liu D et al. Experimental treatment withfFavipiravir for COVID-19: an open-label control study. Engineering (Beijing) 2020. DOI: 10.1016/j.eng.2020.03.007
15. Chen C, Zhang Y, Huang J et al. Favipiravir versus arbidol for COVID-19: a randomized clinical trial. МedRxiv preprint. DOI: 10.1101/2020.03.17.20037432
16. Rattanaumpawan P, Jirajariyavej S, Lerdlamyong K et al. Real-world experience with favipiravir for treatment of COVID-19 in Thailand: results from a multicenter observational study. МedRxiv preprint. DOI: 10.1101/2020.06.24.20133249
17. Ivashchenko AA, Dmitriev KA, Vostokova NV et al. AVIFAVIR for treatment of patients with moderate COVID-19: interim results of a phase II/III multicenter randomized clinical trial. МedRxiv preprint. DOI: 10.1101/2020.07.26.20154724
18. Zhu R, Gao Yl, Robert SH et al. Systematic review of the registered clinical trials of coronavirus disease2019 (COVID-19). МedRxiv preprint. DOI: 10.1101/2020.03.01.20029611
19. Clinical management of COVID-19. WHO, interim guidance 27 May 2020. https://www.who.int/publications/i/item/clinical-management-of-covid-19.
20. Временные методические рекомендации «Профилактика, диагностика и лечение новой коронавирусной инфекции (COVID-19)». Минздрав России. Версия VII. 03.06.2020.
[Temporary guidelines “Prevention, diagnosis and treatment of new coronavirus infection (COVID-19)”. Ministry of Health of Russia. Version VII. 03.06.2020 (in Russian).]
________________________________________________
1. WHO Director-General's opening remarks at the media briefing on COVID-19 – 11 March 2020.
2. Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID‐19). Drug Discov Ther 2020; 14: 58–60. DOI: 10.5582/ddt.2020.01012
3. Furuta Y, Takahashi K, Kuno-Maekawa M et al. Mechanism of action of T-705 against influenza virus. Antimicrob Agents Chemother 2005; 49 (3): 981–6. DOI: 10.1128/AAC.49.3.981-986.2005
4. Shiraki K, Daikoku T. Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Pharmacol Ther 2020; 209: 107512. DOI: 10.1016/j.pharmthera.2020.107512
5. Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci 2017; 93 (7): 449–63. DOI: 10.2183/pjab.93.027
6. Delang L, Abdelnabi R, Neyts J. Favipiravir as a potential countermeasure against neglected and emerging RNA viruses. Antiviral Res 2018; 153: 85–94. DOI: 10.1016/j.antiviral.2018.03.003
7. Sissoko D, Laouenan C, Folkesson E et al. JIKI Study Group. Experimental treatment with favipiravir for Ebola virus disease (the JIKI trial): a historically controlled, single‐arm proof‐of‐concept trial in Guinea. PLoS Med 2016; 13: e1001967. DOI: 10.1371/journal.pmed.1001967
8. Bai CQ, Mu JS, Kargbo D et al. Clinical and virological characteristics of Ebola virus disease patients treated with favipiravir (T‐705) Sierra Leone, 2014. Clin Infect Dis 2016; 63: 1288–94. DOI: 10.1093/cid/ciw571
9. Lu R, Zhao X, Li J et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 2020; 395: 565–74. DOI: 10.1016/S0140-6736(20)30251-8
10. Wang M, Cao R, Zhang L et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020; 30 (3): 269–71. DOI: 10.1038/s41422-020-0282-0
11. Seneviratne SL, Abeysuriya V, De Mel S et al. Favipiravir in Covid-19. IJPSAT 2020; 19 (2): 143–5. https://www.researchgate.net/publication/340778537_Favipiravir_in_COVID-19
12. Du YX, Chen XP. Favipiravir: Pharmacokinetics and concerns about clinical trials for 2019-nCoV Infection. Clin Pharmacol Ther 2020; 108 (2): 242–7. DOI: 10.1002/cpt.1844
13. Coomes EA, Haghbayan H. Favipiravir, an antiviral for COVID-19? J Antimicrob Chemother 2020; 75 (7): 2013–4. DOI: 10.1093/jac/dkaa171
14. Cai Q, Yang M, Liu D et al. Experimental treatment withfFavipiravir for COVID-19: an open-label control study. Engineering (Beijing) 2020. DOI: 10.1016/j.eng.2020.03.007
15. Chen C, Zhang Y, Huang J et al. Favipiravir versus arbidol for COVID-19: a randomized clinical trial. МedRxiv preprint. DOI: 10.1101/2020.03.17.20037432
16. Rattanaumpawan P, Jirajariyavej S, Lerdlamyong K et al. Real-world experience with favipiravir for treatment of COVID-19 in Thailand: results from a multicenter observational study. МedRxiv preprint. DOI: 10.1101/2020.06.24.20133249
17. Ivashchenko AA, Dmitriev KA, Vostokova NV et al. AVIFAVIR for treatment of patients with moderate COVID-19: interim results of a phase II/III multicenter randomized clinical trial. МedRxiv preprint. DOI: 10.1101/2020.07.26.20154724
18. Zhu R, Gao Yl, Robert SH et al. Systematic review of the registered clinical trials of coronavirus disease2019 (COVID-19). МedRxiv preprint. DOI: 10.1101/2020.03.01.20029611
19. Clinical management of COVID-19. WHO, interim guidance 27 May 2020. https://www.who.int/publications/i/item/clinical-management-of-covid-19.
20. Temporary guidelines “Prevention, diagnosis and treatment of new coronavirus infection (COVID-19)”. Ministry of Health of Russia. Version VII. 03.06.2020 (in Russian).
Авторы
М.В. Леонова*
МОО «Ассоциация клинических фармакологов», Россия
*anti23@mail.ru
МОО «Ассоциация клинических фармакологов», Россия
*anti23@mail.ru
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Marina V. Leonova*
Association of Clinical Pharmacologists, Russia
*anti23@mail.ru
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