Аннотация
Эпидемия COVID-19, вызываемая коронавирусом человека, привела к абсолютно новым вызовам для клинической фармакологии и системы здравоохранения в целом. К моменту начала распространения инфекции эффективной и безопасной терапии не было. В связи с запросом со стороны общества и медицинских работников клинические исследования и рутинное применение в клинической практике были начаты одновременно. В настоящей публикации приведен клиникофармакологический анализ хорошо известных антималярийных средств, которые стали одними из первых лекарств для лечения COVID-19 практически во всем мире. Представлены фармакодинамические и фармакокинетические показатели. Дано обоснование противовирусной активности, в том числе на коронавирус. Проанализированы основные клинические исследования на июнь 2020 г. Предложены рекомендации и перспективы дальнейших исследований.
ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова» Минздрава России, Санкт-Петербург, Россия
ФГБОУ ВО «Санкт-Петербургский государственный университет», Санкт-Петербург, Россия
-
1.
Mahase E. Covid-19: Coronavirus was first described in The BMJ in 1965. BMJ. 2020;369:m1547.
DOI: 10.1136/bmj.m1547
-
2.
Woo P., Lau S., Huang Yi., Yuen K. Coronavirus diversity, phylogeny and interspecies jumping. Exp Biol Med (Maywood). 2009;234:1117-1127.
DOI: 10.3181/0903-MR-94
-
3.
European Centre for Disease Prevention and Control. Coronavirus disease. Available at: www.ecdc.europa.eu. Accessed 2020.
-
4.
Cheng V., Lau S., Woo P., Yuen K. Severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection. Clin Microbiol Rev. 2007;20:660-694.
DOI: 10.1128/CMR.00023-07
-
5.
Chan J., Lau S., To K., Cheng V., Woo P., Yuen K. Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease. Clin Microbiol Rev. 2015;28:465-522.
DOI: 10.1128/CMR.00102-14
-
6.
Zumla A., Chan J., Azhar E., Hui D., Yuen K. Coronaviruses – drug discovery and therapeutic options. Nat Rev Drug Discov. 2016;15:327-347.
DOI: 10.1038/nrd.2015.37
-
7.
Gierer S., Bertram S., Kaup F., Wrensch F., Heurich A., KrämerKühl A., et al. The spike protein of the emerging betacoronavirus EMC uses a novel coronavirus receptor for entry, can be activated by TMPRSS2, and is targeted by neutralizing antibodies. J Virol. 2013;87:5502-5511.
DOI: 10.1128/JVI.00128-13
-
8.
Qian Z., Dominguez S., Holmes K. Role of the spike glycoprotein of human Middle East respiratory syndrome coronavirus (MERS-CoV) in virus entry and syncytia formation. PLoS One. 2013;8:e76469.
DOI: 10.1371/journal.pone.0076469
-
9.
Wilde A., Jochmans D., Posthuma C., Zevenhoven-Dobbe J., Nieuwkoop S., Bestebroer T., et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother. 2014;58:4875-4884.
DOI: 10.1128/AAC.03011-14
-
10.
Burkard C., Verheije M., Haagmans B., Kuppeveld F., Rottier P., Bosch B., et al. ATP1A1-mediated Src signaling inhibits coronavirus entry into host cells. J Virol. 2015;89:4434-4448.
DOI: 10.1128/JVI.03274-14
-
11.
Wallace D.J. Antimalarials – the ‘real’ advance in lupus. Lupus. 2001;10:385-387.
DOI: 10.1191/096120301678646092
-
12.
Rynes R.I. Antimalarial drugs in the treatment of rheumatological diseases. Br J Rheumatol. 1997;36:799-805.
DOI: 10.1093/rheumatology/36.7.799
-
13.
McChesney E.Q., Fitch C.D. 4-Aminoquinolines. In: Peters W, Richards WHG, editors. Antimalarial drugs II. Current antimalarials and new drug developments. Berlin: Springer; 1984. pp. 3-60.
-
14.
Tzekov R. Ocular toxicity due to chloroquine and hydroxychloroquine: electrophysiological and visual function correlates. Doc Ophthalmol. 2005;110:111-120.
DOI: 10.1007/s10633-005-7349-6
-
15.
Rynes R.I., Parke AL. Introduction to symposium on antimalarial therapy and lupus. Lupus. 1993;2:S1.
-
16.
Ben-Zvi I., Kivity S., Langevitz P., Shoenfeld Y. Hydroxychloroquine: from malaria to autoimmunity. Clin Rev Allergy Immunol. 2012;42:145-153.
DOI: 10.1007/s12016-010-8243-x
-
17.
Canadian rheumatology association Canadian Consensus Conference on hydroxychloroquine. J Rheumatol. 2000;27:29192921. PMID: 11128686
-
18.
Browning D.J. Pharmacology of chloroquine and hydroxychloroquine. hydroxychloroquine and chloroquine retinopathy. Hydroxychloroquine and chloroquine retinopathy. 2014:35-63.
DOI: 10.1007/978-1-4939-0597-3_2
-
19.
Tanenbaum L., Tuffanelli D.L. Antimalarial agents: chloroquine, hydroxychloroquine, and quinacrine. Arch Dermatol. 1980;116:587-591.
DOI: 10.1001/archderm.116.5.587
-
20.
Gustafsson L., Walker O., Alván G., Beermann B., Estevez F., Gleisner L., et al. Disposition of chloroquine in man after single intravenous and oral doses. Br J Clin Pharmacol. 1983;15:471479.
DOI: 10.1111/j.1365-2125.1983.tb01532.x
-
21.
Titus E.O. Recent developments in the understanding of the pharmacokinetics and mechanism of action of chloroquine. Ther Drug Monit. 1989;11:369-379. PMID: 2662478
-
22.
Banks C.N. Melanin: blackguard or red herring? Another look at chloroquine retinopathy. Aust N Z Ophthalmol. 1987;15:365370.
DOI: 10.1111/j.1442-9071.1987.tb00097.x
-
23.
Mackenzie A.H. Dose refinements in long-term therapy of rheumatoid arthritis with antimalarials. Am J Med. 1983;75:4045.
DOI: 10.1016/0002-9343(83)91269-X
-
24.
Bauman J., Tisdale J. Chloroquine and hydroxychloroquine in the era of SARS-CoV2: caution on their cardiac toxicity. Pharmacotherapy. 2020;40(5):387-388.
DOI: 10.1002/phar.2387
-
25.
Ono C., Yamada M., Tanaka M. Absorption, distribution and excretion of 14C-chloroquine after single oral administration in albino and pigmented rats: binding characteristics of chloroquinerelated radioactivity to melanin in-vivo. J Pharm Pharmacol. 2003;55:1647-1654.
DOI: 10.1211/0022357022340
-
26.
Hobbs H.E., Sorsby A., Freedman A. Retinopathy following chloroquine therapy. Lancet. 1959;2:478-480.
DOI: 10.1016/s0140-6736(59)90604-x
-
27.
Bernstein H. Ocular safety of hydroxychloroquine sulfate (Plaquenil) South Med J. 1992;85:274-279.
DOI: 10.1097/00007611199203000-00010
-
28.
Kishimoto M., Deshpande G., Yokogawa N., Buyon J., Okada M. Use of hydroxychloroquine in Japan. J Rheumatol. 2012;39:12961297.
DOI: 10.3899/jrheum.111569
-
29.
COVID-19 and CSRC: Drug Guidance Resources. Available at: https://cardiac-safety.org/covid-19-and-csrc-drug-guidanceresources/. Accessed 2020.
-
30.
Blignaut M., Espach Y., Vuuren M., Dhanabalan K., Huisamen H. Revisiting the cardiotoxic effect of chloroquine. Cardiovasc Drugs Ther. 2019;33(1):1-11.
DOI: 10.1007/s10557-018-06847-9
-
31.
Chatre C., Roubille F., Vernhet H., Jorgensen C., Pers Y. Cardiac complications attributed to chloroquine and hydroxychloroquine: a systematic review of the literature. Drug Saf. 2018;41(10):919931.
DOI: 10.1007/s40264-018-0689-4
-
32.
Savarino A., Boelaert J., Cassone A., Majori G., Cauda R. Effects of chloroquine on viral infections: an old drug against today's diseases. Lancet Infect Dis. 2003;3(11):722-727.
DOI: 10.1016/s1473-3099(03)00806-5
-
33.
Berthet I. Scientific Work of Christian De Duve. Bull Mem Acad R Med Belg. 2007;162(10-12):499-504. PMID: 18557391
-
34.
Ferreira D., Santo M., Rebello M., Rebello M. Weak bases affect late stages of Mayaro virus replication cycle in vertebrate cells. J Med Microbiol. 2000;49:313-318.
DOI: 10.1099/00221317-49-4-313
-
35.
Harley C., Dasgupta A., Wilson D. Characterization of herpes simplex virus-containing organelles by subcellular fractionation: role for organelle acidification in assembly of infectious particles. J Virol. 2001;75:1236-1251.
DOI: 10.1128/JVI.75.3.12361251.2001
-
36.
Randolph V., Winkler G., Stollar V. Acidotropic amines inhibit proteolytic processing of flavivirus prM protein. Virology. 1990;174:450-458.
DOI: 10.1016/0042-6822(90)90099-d
-
37.
Tsai W., Nara P., Kung H., Oroszlan S. Inhibition of human immunodeficiency virus infectivity by chloroquine. AIDS Res Hum Retroviruses. 1990;6:481-489.
DOI: 10.1089/aid.1990.6.481
-
38.
Baughman R., Lower E., Bois R. Sarcoidosis. Lancet. 2003;361:11111118.
DOI: 10.1016/S0140-6736(03)12888-7
-
39.
Jeong J-Y., Jue D-M. Chloroquine inhibits processing of tumor necrosis factor in lipopolysaccharide stimulated RAW 264.7 macrophages. J Immunol. 1997;158:4901-4907. PMID: 9144507
-
40.
Chinese Clinical Trial Registry. Available at: www.chictr.org.cn/. Accessed 2020.
-
41.
Yao X., Ye F., Zhang M., Cui C., Huang B., Niu P., et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020;71(15):732-739.
DOI: 10.1093/cid/ciaa237
-
42.
Gao J., Tian Z., Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020;14(1):72-73.
DOI: 10.5582/bst.2020.01047
-
43.
Gautret P., Lagier J., Parola P., Hoang V., Meddeb L., Mailhe M., et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020;56(1):105949.
DOI: 10.1016/j.ijantimicag.2020.105949
-
44.
Joint ISAC and Elsevier statement on Gautret et al. paper. Available at: www.journals.elsevier.com/international-journal-ofantimicrobial-agents/news/joint-isac-and-elsevier-statement-ongautret-et-al-paper. Accessed 2020.
-
45.
Sanders J., Monogue M., Jodlowski T., Cutrell J. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. JAMA. 2020;323(18):1824-1836.
DOI: 10.1001/jama.2020.6019
-
46.
Information for Clinicians on Investigational Therapeutics for Patients with COVID-19. Available at: www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html. Accessed 2020.
-
47.
Colson P., Rolain J., Lagier J., Brouqui P., Raoult D. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents. 2020;55(4):105932.
DOI: 10.1016/j.ijantimicag.2020.105932
-
48.
Cortegiani A., Ingoglia G., Ippolito M., Giarratano A., Einav S. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. Crit Care. 2020;57:279-283.
DOI: 10.1016/j.jcrc.2020.03.005
-
49.
Clinical Trials Management. Belousov D.Yu., Zyryanov S.K., Kolbin A.S., Eds. 1st Ed. M.: Buki Vedi: OKI Publishing House, 2017. 676 p. Available at: https://clck.ru/Ec85Z. (Управление клиническими исследованиями Под общ. ред. Белоусова Д.Ю., Зырянова С.К., Колбина А.С. 1-е изд. М. : Буки Веди : Издательство ОКИ, 2017. 676 с. Доступно по адресу: https://clck.ru/Ec85Z.)
-
50.
European Union Pharmaceutical Forum, High Level Pharmaceutical Forum 2005-2008. Available at: https://op.europa.eu/en/publication-detail/-/publication/4fddf639-47cc-4f90-9964142757d2515a. Accessed 2020.
-
51.
Millionab M., Gautretac P., Colsona P., Roussel Y., Dubourg G., Chabriereab E., et al. Clinical Efficacy of Chloroquine derivatives in COVID-19 Infection: Comparative meta-analysis between the Big data and the real world. New Microbes and New Infections. Available online 6 June 2020, 100709. In Press, Journal Preproof.
-
52.
Global Coronavirus COVID-19 Clinical Trial Tracker. Available at: www.covid-trials.org/. Accessed 2020.
-
53.
Kolbin A.S. An early assessment of the efficacy of medicines in the treatment of patients with COVID-19. Infekcija i immunitet. 2020;10(2):277-286. Russian. (Колбин А.С. Ранняя оценка эффективности лекарственных средств при лечении больных с COVID-19. Инфекция и иммунитет. 2020;10(2):277-286.)
DOI: 10.15789/2220-7619-AEA-1458
-
54.
Borba M., Almeida Val F., Sampaio V., Alexandre M., Melo G., Brito M., et al. CloroCovid-19 Team. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA Netw Open. 2020;3(4):e208857.
DOI: 10.1001/jamanetworkopen.2020.8857
-
55.
Geleris J., Sun Y., Platt J., Zucker J., Baldwin M., Hripcsak G., et al. Observational study of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med. 2020;382(25):24112418.
DOI: 10.1056/NEJMoa2012410
-
56.
Rosenberg E., Dufort E., Udo T., Wilberschied L., Kumar J., Tesoriero J., et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state. JAMA. 2020;323(24):24932502.
DOI: 10.1001/jama.2020.8630
-
57.
Singh A., Singh A., Singh R., Misra A. Hydroxychloroquine in patients with COVID-19: a systematic review and meta-analysis. Diabetes Metab Syndr. 2020;14(4):589-596.
DOI: 10.1016/j.dsx.2020.05.017
-
58.
Mehra M., Desai S., Ruschitzka F., Patel A. RETRACTED: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020;S0140-6736(20)31180-6.
DOI: 10.1016/S0140-6736(20)31180-6
-
59.
Watson J. Open letter to MR Mehra, SS Desai, F Ruschitzka, and AN Patel, authors of “Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis” (In Lancet. 2020 May 22:S0140-6736(20)31180-6. DOI: 10.1016/S0140-6736(20)31180-6). Available at: https://zenodo.org/record/3862789#.XtOlNJ4zZmD. Accessed 2020
DOI: 10.1016/S0140-6736(20)31180-6
-
60.
Mehra M.R., Ruschitzka F., Patel A. Retraction – Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020;395(10240):1820.
DOI: 10.1016/S01406736(20)31324-6
-
61.
Hernandez A., Roman Y., Pasupuleti V., Barboza J., White M. Hydroxychloroquine or chloroquine for treatment or prophylaxis of COVID-19: a living systematic review. Ann Intern Med. 2020;173(4):287-296.
DOI: 10.7326/M20-2496
-
62.
Boulware D., Pullen M., Bangdiwala A., Pastick K., Lofgren S., Okafor E., et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J Med. 2020;383:517-525.
DOI: 10.1056/NEJMoa2016638
-
63.
Zubair A., McAlpine L., Gardin T., Farhadian S., Kuruvilla D., Spudich S. Neuropathogenesis and neurologic manifestations of the coronaviruses in the age of coronavirus disease 2019. A review. JAMA Neurol. 2020;77(8):1018-1027.
DOI: 10.1001/jamaneurol.2020.2065
-
64.
WHO Official Updates – Coronavirus Disease 2019. Available at: https://www.who.int/emergencies/diseases/novelcoronavirus-2019/global-research-on-novel-coronavirus-2019ncov/solidarity-clinical-trial-for-covid-19-treatments. Accessed 2020.
-
65.
Bauchner H., Fontanarosa P. Randomized clinical trials and COVID-19: managing expectations. JAMA. 2020 May 4.
DOI: 10.1001/jama.2020.8115
-
66.
The Path Forward: Coronavirus Treatment Acceleration Program. Available at: www.fda.gov/news-events/fda-voices-perspectivesfda-leadership-and-experts/path-forward-coronavirus-treatmentacceleration-program. Accessed 2020.
-
67.
Order of the Government of the Russian Federation dated 04.16.2020 No. 1030-p. Available at: http://publication.pravo.gov.ru/Document/View/0001202004160037. Russian. (Распоряжение Правительства Российской Федерации от 16.04.2020 № 1030-р. Доступно по адресу: http://publication.pravo.gov.ru/Document/View/0001202004160037 .)