Умифеновир и коронавирусные инфекции: обзор результатов исследований и опыта применения в клинической практике - Журнал Терапевтический архив №11 Инфекционные болезни 2020

Умифеновир и коронавирусные инфекции: обзор результатов исследований и опыта применения в клинической практике

Ленева И.А., Пшеничная Н.Ю., Булгакова В.А. Умифеновир и коронавирусные инфекции: обзор результатов исследований и опыта применения в клинической практике. Терапевтический архив. 2020; 92 (11): 91–97.
DOI: 10.26442/00403660.2020.11.000713

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Leneva I.A., Pshenichnaya N.Y., Bulgakova V.A. Umifenovir and coronavirus infections: a review of research results and clinical practice. Therapeutic Archive. 2020; 92 (11): 91–97. DOI: 10.26442/00403660.2020.11.000713

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Аннотация

Коронавирусы – инфекционные агенты, вызывающие острые респираторные заболевания различной степени тяжести. Вопрос противовирусной терапии, в том числе при COVID-19, остается открытым, доказательную базу нельзя считать достаточной, а выбор препаратов для лечения основывается на опыте их применения, данных исследований. Цель – cистематизация, анализ и обобщение доклинических данных, данных результатов клинических исследований и опыта клинического применения умифеновира. Проведен поиск за период с 2004 г. в базах данных Scopus, Web of Science (WoS), РИНЦ, включая результаты 2020 г. в medRxiv. Проведен метаанализ результатов клинических исследований. Умифеновир – противовирусный препарат, ингибирующий процесс слияния вирусов с клеткой. В отношении SARS-CoV-2 механизм действия связан с блокированием этапа фузии, на уровне взаимодействия поверхностного S-белка и рецептора АСЕ2 на поверхности клеток. Доклинические исследования показывают активность умифеновира в отношении ряда коронавирусов, включая SARS-CoV, MERS-CoV, SARS-CoV-2. Умифеновир в комбинациях с другими противовирусными препаратами, симптоматической или традиционной медициной применялся в Китае для лечения пациентов с COVID-19, приводил к снижению смертности, скорости элиминации вируса, частоты развития более тяжелого течения и осложнений при среднем и легком течении. В сравнительных клинических исследованиях умифеновир показывал схожую эффективность с другими противовирусными препаратами, но отличался меньшей частотой развития нежелательных явлений. Терапия, включающая умифеновир, приводила к увеличению доли пациентов с отрицательными результатами ПЦР-тестов на 7–14-е сутки (I2=69,8%, относительный риск 0,48, 95% доверительный интервал 0,19–0,76; p=0,001). Результаты обзора показывают, что при легких и средних формах COVID-19 противовирусная, особенно ранняя, терапия может быть эффективна, но тяжелые формы COVID-19, которые характеризуются иммунопатологией легких, требуют иных подходов к лечению. Результаты первых клинических исследований остаются неоднозначными, требуются дальнейшие исследования для разработки противовирусных препаратов.

Ключевые слова: коронавирусы, SARS-CoV-2, COVID-19, умифеновир, противовирусная терапия, обзор.

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Coronaviruses are known to cause acute respiratory infections. Antiviral therapy, including for COVID-19, is based on clinical practice, experimental data and trial results. The purpose of this review is to: provide and systematize actual preclinical data, clinical trials results and clinical practice for antiviral agent umifenovir (Arbidol). Databases Scopus, Web of Science, RSCI and medRxiv were used for publication searching from 2004. A meta-analysis of clinical trials results was performed. Umifenovir is antiviral agent, it belongs to fusion inhibitors, interacts with SARS-CoV-2 spike protein. Umifenovir the impede the trimerization of spike glycoprotein and inhibit host cell adhesion, at the level of the coronaviruses S-protein of interaction with ACE2 receptor. Preclinical studies in vitro and on animals show umifenovir activity against a number of coronaviruses, including SARS-CoV, MERS-CoV, SARS-CoV-2, and others. Umifenovir, in combination with other antiviral drugs, symptomatic or traditional medicine, was used in China to treat patients with COVID-19, resulting in reduced mortality, virus elimination, the frequency of more severe course and complications in middle severity. However, antiviral therapy for the treatment of severe patients, with ARDS, did not lead to improved outcomes. In comparative clinical studies, umifenovir showed similar effectiveness with other antiviral drugs, and lower frequency of adverse reactions. Therapy with umifenovir, led to an increase percentage of patients with negative results of PCR tests on days 7–14 (I2=69.8%, RR 0.48, 95% CI 0.19–0.76; p=0.001). The efficacy and safety of antivirals against SARS-CoV-2 still requires clinical investigation. Moderate forms of COVID-19 could be effectively treated by antivirals, but severe forms of COVID-19, characterized by pulmonary immunopathology, require different approaches to treatment.

Keywords: coronaviruses, SARS-CoV-2, COVID-19, umifenovir, antiviral therapy, review.

Список литературы

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33. Jun C, Yun L, Xiuhong X, et al. Efficacies of lopinavir/ritonavir and abidol in the treatment of novel coronavirus pneumonia. Chinese J Infect Dis. 2020;38(00):E008-E008. doi: 10.3760/CMA.J.CN311365-20200210-00050
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36. Chen C, Huang J, Cheng Z, et al. Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial. medRxiv. January 2020:2020.03.17.20037432. doi: 10.1101/2020.03.17.20037432
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1. Arabi YM, Balkhy HH, Hayden FG, et al. Middle East Respiratory Syndrome. N Engl J Med. 2017;376(6):584-94. doi: 10.1056/NEJMsr1408795
2. Chan JF-W, Yuan S, Kok K-H, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020;395(10223):514-23. doi: 10.1016/S0140-6736(20)30154-9
3. Channappanavar R, Fehr AR, Vijay R, et al. Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice. Cell Host Microbe. 2016;19(2):181-93. doi: 10.1016/j.chom.2016.01.007
4. Tseng C-TK, Huang C, Newman P, et al. Severe acute respiratory syndrome coronavirus infection of mice transgenic for the human Angiotensin-converting enzyme 2 virus receptor. J Virol. 2007;81(3):1162-73. doi: 10.1128/JVI.01702-06
5. Kim Y-I, Kim S-G, Kim S-M, et al. Infection and Rapid Transmission of SARS-CoV-2 in Ferrets. Cell Host Microbe. April 2020:S1931-3128(20)30187-6. doi: 10.1016/j.chom.2020.03.023
6. Chang D, Mo G, Yuan X, et al. Time Kinetics of Viral Clearance and Resolution of Symptoms in Novel Coronavirus Infection. Am J Respir Crit Care Med. March 2020. doi: 10.1164/rccm.202003-0524LE
7. To KK-W, Tsang OT-Y, Leung W-S, et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis. April 2020. doi: 10.1016/S1473-3099(20)30196-1
8. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5
9. Li G, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov. 2020;19(3):149-50. doi: 10.1038/d41573-020-00016-0
10. Chen X, Zhang Y, Zhu B, et al. Associations of clinical characteristics and antiviral drugs with viral RNA clearance in patients with COVID-19 in Guangzhou, China: a retrospective cohort study. medRxiv. January 2020:2020.04.09.20058941. doi: 10.1101/2020.04.09.20058941
11. Lin L, Lu L, Cao W, Li T. Hypothesis for potential pathogenesis of SARS-CoV-2 infection – a review of immune changes in patients with viral pneumonia. Emerg Microbes Infect. 2020;9(1):727-32. doi: 10.1080/22221751.2020.1746199
12. Channappanavar R, Fehr AR, Vijay R, et al. Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice. Cell Host Microbe. 2016;19(2):181-93. doi: 10.1016/j.chom.2016.01.007
13. Blaising J, Polyak SJ, Pécheur E-I. Arbidol as a broad-spectrum antiviral: An update. Antiviral Res. 2014;107:84-94. doi: 10.1016/j.antiviral.2014.04.006
14. Kadam RU, Wilson IA. Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol. Proc Natl Acad Sci. 2017;114(2):206LP-214. doi: 10.1073/pnas.1617020114
15. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA. April 2020. doi: 10.1001/jama.2020.6019
16. Ge Y, Tian T, Huang S, et al. A data-driven drug repositioning framework discovered a potential therapeutic agent targeting COVID-19. bioRxiv. January 2020:2020.03.11.986836. doi: 10.1101/2020.03.11.986836
17. Kong R, Yang G, Xue R, et al. COVID-19 Docking Server: An interactive server for docking small molecules, peptides and antibodies against potential targets of COVID-19. February 2020. http://arxiv.org/abs/2003.00163
18. Vankadari N. Arbidol: A potential antiviral drug for the treatment of SARS-CoV-2 by blocking the trimerization of viral spike glycoprotein? Int J Antimicrob Agents. 2020:105998. doi: 10.1016/j.ijantimicag.2020.105998
19. Khamitov RA, Loginova SIa, Shchukina VN, et al. Antiviral activity of arbidol and its derivatives against the pathogen of severe acute respiratory syndrome in the cell cultures. Vopr Virusol. 2008;53(4):9-13 (In Russ.) https://elibrary.ru/item.asp?id=11570757
20. Glushkov RG. A drug for the treatment of SARS. RU patent 2 256 451C1. April 21, 2004 (In Russ.)
21. Guan W, Du Q-L, Jiang H-M, et al. Comparison of inhibitory effects of arbidol and Lianhuaqingwen capsules on middle east respiratory syndrome coronavirus in vitro and in vivo. Guangdong Med J. 2018;39(23):3454-58. doi: 10.13820/j.cnki.gdyx.20181221.014
22. Wu C, Liu Y, Yang Y, et al. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm Sin B. 2020. doi: 10.1016/j.apsb.2020.02.008
23. Brooks MJ, Burtseva EI, Ellery PJ, et al. Antiviral activity of arbidol, a broad-spectrum drug for use against respiratory viruses, varies according to test conditions. J Med Virol. 2012;84(1):170-81. doi: 10.1002/jmv.22234
24. Hu L, Chen S, Fu Y, et al. Risk Factors Associated with Clinical Outcomes in 323 COVID-19 Patients in Wuhan, China. medRxiv. January 2020:2020.03.25.20037721. doi: 10.1101/2020.03.25.20037721
25. Lu R, Wang J, Li M, et al. SARS-CoV-2 detection using digital PCR for COVID-19 diagnosis, treatment monitoring and criteria for discharge. medRxiv. January 2020:2020.03.24.20042689. doi: 10.1101/2020.03.24.20042689
26. Shen K-L, Yang Y-H, Jiang R-M, et al. Updated diagnosis, treatment and prevention of COVID-19 in children: experts’ consensus statement (condensed version of the second edition). World J Pediatr. April 2020:1-8. doi: 10.1007/s12519-020-00362-4
27. Wang Z, Yang B, Li Q, et al. Clinical Features of 69 Cases with Coronavirus Disease 2019 in Wuhan, China. Clin Infect Dis. March 2020. doi: 10.1093/cid/ciaa272
28. Liu Q, Fang X, Tian L, et al. The effect of Arbidol Hydrochloride on reducing mortality of Covid-19 patients: a retrospective study of real world date from three hospitals in Wuhan. medRxiv. April 2020:2020.04.11.20056523. doi: 10.1101/2020.04.11.20056523
29. Shi Q, Zhao K, Yu J, et al. Clinical characteristics of 101 COVID-19 nonsurvivors in Wuhan, China: a retrospective study. medRxiv. April 2020:2020.03.04.20031039. doi: 10.1101/2020.03.04.20031039
30. Liu Y, Sun W, Li J, et al. Clinical features and progression of acute respiratory distress syndrome in coronavirus disease 2019. medRxiv. February 2020:2020.02.17.20024166. doi: 10.1101/2020.02.17.20024166
31. Zhu Z, Lu Z, Xu T, et al. Arbidol monotherapy is superior to lopinavir/ritonavir in treating COVID-19. J Infect. April 2020. doi: 10.1016/j.jinf.2020.03.060
32. Deng L, Li C, Zeng Q, et al. Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study. J Infect. March 2020:S0163-4453(20)30113-4. doi: 10.1016/j.jinf.2020.03.002
33. Jun C, Yun L, Xiuhong X, et al. Efficacies of lopinavir/ritonavir and abidol in the treatment of novel coronavirus pneumonia. Chinese J Infect Dis. 2020;38(00):E008-E008. doi: 10.3760/CMA.J.CN311365-20200210-00050
34. Zhou Q, Wei X-S, Xiang X, et al. Interferon-a2b treatment for COVID-19. medRxiv. January 2020:2020.04.06.20042580. doi: 10.1101/2020.04.06.20042580
35. Li Y, Xie Z, Lin W, et al. An exploratory randomized controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI). medRxiv. 2020. doi: 10.1101/2020.03.19.20038984
36. Chen C, Huang J, Cheng Z, et al. Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial. medRxiv. January 2020:2020.03.17.20037432. doi: 10.1101/2020.03.17.20037432
37. Runan W, Nanhong Z, Xiangao J, et al. Early antiviral therapy of abidol combined with lopinavir/ritonavir and recombinant interferon α-2b for patients with COVID-19 in Zhejiang: A multicenter prospective study. Chinese J Clin Infect Dis. 2020;13(01):9-15. doi: 10.3760/CMA.J.ISSN.1674-2397.2020.01.003
38. Shi Q, Zhou Q, Wang X, et al. Potential Effectiveness and Safety of Antiviral Agents in Children with Coronavirus Disease 2019: A Rapid Review and Meta-Analysis. medRxiv. April 2020:2020.04.13.20064436. doi: 10.1101/2020.04.13.20064436

Авторы

И.А. Ленева1, Н.Ю. Пшеничная2, В.А. Булгакова3-5

1 ФГБНУ «Научно-исследовательский институт вакцин и сывороток им. И.И. Мечникова», Москва, Россия;
2 ФГБУ «Национальный медицинский исследовательский центр фтизиопульмонологии и инфекционных заболеваний» Минздрава России, Москва, Россия;
3 ФГАУ «Национальный медицинский исследовательский центр здоровья детей» Минздрава России, Москва, Россия;
4 ФГБОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава России, Москва, Россия;
5 ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия.

________________________________________________

I.A. Leneva1, N.Y. Pshenichnaya2, V.A. Bulgakova3-5

1 Mechnikov Research Institute for Vaccines and Sera, Moscow, Russia;
2 National Medical Research Center for Phthisiopulmonology and Infectious Diseases, Moscow, Russia;
3 National Medical Research Center for Children's Health, Moscow, Russia;
4 Pirogov Russian National Research Medical University, Moscow, Russia;
5 Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia

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