Repositioning chloroquine as antiviral prophylaxis against COVID-19: potential and challenges

Raymond Chang, Wei-Zen Sun, Raymond Chang, Wei-Zen Sun

Abstract

The Coronavirus Disease 2019 (COVID-19) pandemic is advancing globally, and pharmaceutical prophylaxis is one solution. Here, we propose repositioning chloroquine (CQ) as prophylaxis against COVID-19. CQ blocks viral attachment and entry to host cells and demonstrates efficacy against a variety of viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. Furthermore, CQ is safe, inexpensive, and available. Here, we review the antiviral mechanisms of CQ, its in vitro activity against coronaviruses, its pharmacokinetics (PK) and adverse effects, and why it could be more efficacious as a prophylactic rather than as a therapeutic, given the infection dynamics of SARS-CoV-2. We propose two prophylactic regimens based on efficacy and risk considerations. Although it is largely preclinical data that suggest the potential of CQ, properly planned prophylactic trials and further research are urgently needed.

Copyright © 2020 Elsevier Ltd. All rights reserved.

References

    1. Zhu N. A novel coronavirus from patients with pneumonia in China. N. Engl. J. Med. 2020;382:727–733.
    1. Kuchler H. The $2bn race to find a vaccine. Financial Times. 2020 March 5.
    1. Oxford J.S. Antivirals for the treatment and prevention of epidemic and pandemic influenza. Influenza Other Resp. Viruses. 2007;1:27–34.
    1. Desai M. Recent advances in pre-exposure prophylaxis for HIV. Br. Med. J. 2017;359:j5011.
    1. Hussein I.T.M. The discovery and development of filociclovir for the prevention and treatment of human cytomegalovirus-related disease. Antiviral Res. 2020;176
    1. Rezaee F. Ongoing developments in RSV prophylaxis: a clinician’s analysis. Curr. Opin. Virol. 2017;24:70–78.
    1. Nap R.E. Pandemic influenza and hospital resources. Emerg. Infect. Dis. 2007;13:1714–1719.
    1. Saunders-Hastings P. Assessing the state of knowledge regarding the effectiveness of interventions to contain pandemic influenza transmission: a systematic review and narrative synthesis. PLoS ONE. 2016;11:1–17.
    1. Peters W. Malaria. Chemoprophylaxis and chemotherapy. Br. Med. J. 1971;2:95–98.
    1. White N.J. Malaria. Lancet. 2014;383:723–735.
    1. Coatney G.R. Pitfalls in a discovery: the chronicle of chloroquine. Am. J. Trop. Med. Hyg. 1963;12:121–128.
    1. Al-Bari M.A.A. Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases. J. Antimicrob. Chemother. 2015;70:1608–1621.
    1. Manic G. Chloroquine and hydroxychloroquine for cancer therapy. Mol. Cell. Oncol. 2014;1
    1. Plantone D., Koudriavtseva T. Current and future use of chloroquine and hydroxychloroquine in infectious, immune, neoplastic, and neurological diseases: a mini-review. Clin. Drug. Invest. 2018;38:653–671.
    1. Shimizu Y. Effect of chloroquine on the growth of animal viruses. Arch. Gesamte. Virusforsch. 1972;36:93–104.
    1. Rolain J.M. Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century. Int. J. Antimicrob. Agents. 2007;30:297–308.
    1. Savarino A. Effects of chloroquine on viral infections: an old drug against today’s diseases? Lancet Infect. Dis. 2003;3:722–727.
    1. Al-Bari M.A.A. Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases. Pharmacol. Res. Perspect. 2017;5
    1. Long J. Antiviral therapies against Ebola and other emerging viral diseases using existing medicines that block virus entry. F1000Research. 2015;4:30.
    1. Randolph V.B. Acidotropic amines inhibit proteolytic processing of flavivirus prM protein. Virology. 1990;174:450–458.
    1. Vincent M.J. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol. J. 2005;2:69.
    1. Hoffmann M. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and Is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271–280.
    1. Wang M. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30:269–271.
    1. De Wilde A.H. 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.
    1. Kono M. Inhibition of human coronavirus 229E infection in human epithelial lung cells (L132) by chloroquine: involvement of p38 MAPK and ERK. Antiviral Res. 2008;77:150–152.
    1. Keyaerts E. Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice. Antimicrob. Agents Chemother. 2009;53:3416–3421.
    1. Farias K.J.S. Antiviral activity of chloroquine against Dengue virus type 2 replication in Aotus monkeys. Viral Immunol. 2015;28:161–169.
    1. Li C. Chloroquine, a FDA-approved drug, prevents Zika virus infection and its associated congenital microcephaly in mice. EBioMedicine. 2017;24:189–194.
    1. Madrid P.B. A systematic screen of FDA-approved drugs for inhibitors of biological threat agents. PLoS ONE. 2013;8
    1. Sperber K. Hydroxychloroquine treatment of patients with human immunodeficiency virus type 1. Clin. Ther. 1995;17:622–636.
    1. Kouroumalis E.A., Koskinas J. Treatment of chronic active hepatitis B (CAH B) with chloroquine: a preliminary report. Ann. Acad. Med. Singapore. 1986;15:149–152.
    1. Tricou V. A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults. PLoS Negl. Trop. Dis. 2010;4:e785.
    1. Rana D.R., Dulal S. Therapeutic application of chloroquine and hydroxychloroquine in clinical trials for COVID-19: a systematic review. MedRxiv. 2020;2020 2020.03.22.20040964.
    1. Gao J. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci. Trends. 2020;14:72–73.
    1. Gautret P. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int. J. Antimicrob. Agents. 2020;(Mar)
    1. Gautret P. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: a pilot observational study. Travel Med. Infect. Dis. 2020;34
    1. Chowdhury M.S. A rapid systematic review of clinical trials utilizing chloroquine and hydroxychloroquine as a treatment for COVID-19. Acad. Emerg. Med. 2020;27:493–504.
    1. Krishna S., White N.J. Pharmacokinetics of quinine, chloroquine and amodiaquine - clinical implications. Clin. Pharmacokinet. 1996;30:263–299.
    1. Adelusi S.A., Salako L.A. Tissue and blood concentrations of chloroquine following chronic administration in the rat. J. Pharm. Pharmacol. 1982;34:733–735.
    1. Karunajeewa H.A. Pharmacokinetics and efficacy of piperaquine and chloroquine in Melanesian children with uncomplicated malaria. Antimicrob. Agents Chemother. 2008;52:237–243.
    1. Lee S.J. Chloroquine pharmacokinetics in pregnant and nonpregnant women with vivax malaria. Eur. J. Clin. Pharmacol. 2008;64:987–992.
    1. Wollheim F.A. Chloroquine treatment in rheumatoid arthritis. Scand. J. Rheumatol. 1978;7:171–176.
    1. WHO . 2nd ed. WHO; 1995. WHO Model Prescribing Information: Drugs Used in Parasitic Diseases.
    1. Popert A.J. Chloroquine diphosphate in rheumatoid arthritis. A controlled trial. Ann. Rheum. Dis. 1961;20:18–35.
    1. Meinão I.M. Controlled trial with chloroquine diphosphate in systemic lupus erythematosus. Lupus. 1996;5:237–241.
    1. Ducharme J., Farinotti R. Clinical pharmacokinetics and metabolism of chloroquine. Focus on recent advancements. Clin. Pharmacokinet. 1996;31:257–274.
    1. Rombo L. Chloroquine and desethylchloroquine concentrations during regular long-term malaria prophylaxis. Bull. World Health Org. 1987;65:879–883.
    1. Marques M.M. Plasmodium vivax chloroquine resistance and anemia in the western Brazilian Amazon. Antimicrob. Agents Chemother. 2014;58:342–347.
    1. Salako L.A. Toxicity and side-effects of antimalarials in Africa: a critical review. Bull. World Health Org. 1984;62:63–68.
    1. Mzayek F. Randomized dose-ranging controlled trial of AQ-13, a candidate antimalarial, and chloroquine in healthy volunteers. PLoS Clin. Trials. 2007;2:e6.
    1. Ruiz-Irastorza G. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann. Rheum. Dis. 2010;69:20–28.
    1. Marmor M.F. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision) Ophthalmology. 2016;123:1386–1394.
    1. Chatre C. Cardiac complications attributed to chloroquine and hydroxychloroquine: a systematic review of the literature. Drug Saf. 2018;41:919–931.
    1. Ma L. Coronavirus disease-2019 (COVID-19) and cardiovascular complications. J. Cardiothorac. Vasc. Anesth. 2020;2020 doi: 10.1053/j.jvca.2020.04.041. Published online April 30.
    1. Aggarwal G. Cardiovascular safety of potential drugs for the treatment of coronavirus disease 2019. Am. J. Cardiol. 2020;128:147–150.
    1. Jankelson L. 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;2020 doi: 10.1016/j.hrthm.2020.05.008. Published online May 11.
    1. Borba M.G.S. 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. JAMA Network Open. 2020;3
    1. Mahévas M. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data. Br. Med. J. 2020;369:m1844.
    1. DiMasi J.A. Innovation in the pharmaceutical industry: new estimates of R&D costs. J. Health Econ. 2016;47:20–33.
    1. Mullard A. Drug repurposing programmes get lift off. Nat. Rev. Drug Discov. 2012;11:505–506.
    1. Zepp F. Principles of vaccination. Methods Mol. Biol. 2016;1403:57–84.
    1. Casadevall A., Pirofski L. The Ebola epidemic crystallizes the potential of passive antibody therapy for infectious diseases. PLoS Pathog. 2015;11
    1. Marano G. Convalescent plasma: new evidence for an old therapeutic tool? Blood Transf. 2016;14:152–157.
    1. Li G., De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV) Nat. Rev. Drug Discov. 2020;19:149–150.
    1. De Clercq E. Potential antivirals and antiviral strategies against SARS coronavirus infections. Expert. Rev. Anti-Infect. Ther. 2006;4:291–302.
    1. Liang R. Development of small molecule MERS-CoV inhibitors. Viruses. 2018;10:721.
    1. Jefferson T. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst. Rev. 2014;2014
    1. Strittmatter S.M. Overcoming drug development bottlenecks with repurposing: old drugs learn new tricks. Nat. Med. 2014;20:590–591.
    1. Mercorelli B. Drug repurposing for viral infectious diseases: how far are we? Trends Microbiol. 2018;26:865–876.
    1. de Wilde A.H. Cyclosporin A inhibits the replication of diverse coronaviruses. J. Gen. Virol. 2011;92:2542–2548.
    1. FDA . FDA; 2020. Coronavirus (COVID-19) Update: Daily Roundup March 30, 2020.
    1. Nicholson K.G. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group. Lancet. 2000;355:1845–1850.
    1. Iwanami S. Rethinking antiviral effects for COVID-19 in clinical studies: early initiation is key to successful treatment. MedRxiv. 2020;2020 2020:2020.05.30.20118067.
    1. Chamieh A. Viral dynamics matter in COVID-19 pneumonia: the success of early treatment with hydroxychloroquine and azithromycin in Lebanon. MedRxiv. 2020;2020 2020:2020.05.28.20114835.
    1. Ooi E.E. In vitro inhibition of human influenza A virus replication by chloroquine. Virol. J. 2006;3:39.
    1. Yan Y. Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model. Cell Res. 2013;23:300–302.
    1. Paton N.I. Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial. Lancet Infect. Dis. 2011;11:677–683.
    1. Sourisseau M. Characterization of reemerging chikungunya virus. PLoS Pathog. 2007;3:e89.
    1. De Lamballerie X. On chikungunya acute infection and chloroquine treatment. Vector-Borne Zoonotic Dis. 2008;8:837–840.
    1. Broodman E. From ferrets to mice and marmosets, labs scramble to find right animals for coronavirus studies online. STAT. 2020 March 5.
    1. Lentini G. Covid-19, chloroquine repurposing, and cardiac safety concern: chirality might help. Molecules. 2020;25:1834.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅