COVID-19 prevention and treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology

1. Coatney GR. Pitfalls in a discovery: the chronicle of chloroquine. The American Journal of Tropical Medicine and Hygiene. 1963;12(2):121–128.

2. Berliner RW, Earle DP, Taggart JV, Zubrod CG, Welch WJ, Conan NJ, et al. Studies on the chemotherapy of the human malarias. VI. The physiological disposition, antimalarial activity, and toxicity of several derivatives of 4-aminoquinoline. The Journal of clinical investigation. 1948;27(3):98–107.

3. World Health Organisation Scientific Group on the Chemotherapy of Malaria. Advances in malaria chemotherapy: report of a WHO scientific group. vol. 711. World Health Organization; 1984.

4. CEIC. China CN production. 2020 [cited 2020 May 20]. Available from: https://www.ceicdata.com/en/china/pharmaceutical-production-ytd-antiparasitics-vitamins-and-minerals/cn-production-ytd-hydroxychloroquine.

5. World Health Organization. Guidelines for the treatment of malaria. World Health Organization; 2015.

6. Villegas L, McGready R, Htway M, Paw MK, Pimanpanarak M, Arunjerdja R, et al. Chloroquine prophylaxis against vivax malaria in pregnancy: a randomized, double-blind, placebo-controlled trial. Tropical Medicine & International Health. 2007;12(2):209–218.

7. McGready R, Lee S, Wiladphaingern J, Ashley E, Rijken M, Boel M, et al. Adverse effects of falciparum and vivax malaria and the safety of antimalarial treatment in early pregnancy: a population-based study. The Lancet Infectious Diseases. 2012;12(5):388–396. doi: 10.1016/S1473-3099(11)70339-5 22169409

8. Rynes RI. Hydroxychloroquine treatment of rheumatoid arthritis. The American Journal of Medicine. 1988;85(4):18–22.

9. McChesney EW. Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate. The American Journal of Medicine. 1983;75(1):11–18.

10. Conan NJ. The treatment of hepatic amebiasis with chloroquine. The American journal of medicine. 1949;6(3):309–320. doi: 10.1016/0002-9343(49)90167-9 18112362

11. McChesney EW, Banks WF Jr, Fabian RJ. Tissue distribution of chloroquine, hydroxychloroquine, and desethylchloroquine in the rat. Toxicology and Applied Pharmacology. 1967;10(3):501–513. doi: 10.1016/0041-008x(67)90089-0 6059665

12. McChesney E, Fasco M, Banks W, Kersch TB. The metabolism of chloroquine in man during and after repeated oral dosage. Journal of Pharmacology and Experimental Therapeutics. 1967;158(2):323–331. 6065153

13. Gustafsson L, Walker O, Alvan G, Beermann B, Estevez F, Gleisner L, et al. Disposition of chloroquine in man after single intravenous and oral doses. British Journal of Clinical Pharmacology. 1983;15(4):471–479. doi: 10.1111/j.1365-2125.1983.tb01532.x 6849784

14. Frisk-Holmberg M, Bergqvist Y, Termond E, Domeij-Nyberg B. The single dose kinetics of chloroquine and its major metabolite desethylchloroquine in healthy subjects. European Journal of Clinical Pharmacology. 1984;26(4):521–530. doi: 10.1007/BF00542151 6610555

15. Aderounmu AF, Salako L, Lindstrom B, Walker O, Ekman L. Comparison of the pharmacokinetics of chloroquine after single intravenous and intramuscular administration in healthy Africans. British Journal of Clinical Pharmacology. 1986;22(5):559–564. doi: 10.1111/j.1365-2125.1986.tb02935.x 3790402

16. Looareesuwan S, White N, Chanthavanich P, Edwards G, Nicholl D, Bunch C, et al. Cardiovascular toxicity and distribution kinetics of intravenous chloroquine. British Journal of Clinical Pharmacology. 1986;22(1):31–36. doi: 10.1111/j.1365-2125.1986.tb02876.x 3741724

17. Walker O, Salako L, Alvan G, Ericsson O, Sjoqvist F. The disposition of chloroquine in healthy Nigerians after single intravenous and oral doses. British Journal of Clinical Pharmacology. 1987;23(3):295–301. doi: 10.1111/j.1365-2125.1987.tb03048.x 3567044

18. White N, Watt G, Bergqvist Y, Njelesani E. Parenteral chloroquine for treating falciparum malaria. Journal of Infectious Diseases. 1987;155(2):192–201. doi: 10.1093/infdis/155.2.192 3543146

19. Rombo L, Bergqvist Y, Hellgren U. Chloroquine and desethylchloroquine concentrations during regular long-term malaria prophylaxis. Bulletin of the World Health Organization. 1987;65(6):879. 3501740

20. White NJ, Miller KD, Churchill FC, Berry C, Brown J, Williams SB, et al. Chloroquine Treatment of Severe Malaria in Children. New England Journal of Medicine. 1988;319(23):1493–1500. doi: 10.1056/NEJM198812083192301 3054558

21. Pussard E, Lepers J, Clavier F, Raharimalala L, Le Bras J, Frisk-Holmberg M, et al. Efficacy of a loading dose of oral chloroquine in a 36-hour treatment schedule for uncomplicated Plasmodium falciparum malaria. Antimicrobial Agents and Chemotherapy. 1991;35(3):406–409. doi: 10.1128/aac.35.3.406 2039190

22. Wetsteyn J, De Vries P, Oosterhuis B, Van Boxtel C. The pharmacokinetics of three multiple dose regimens of chloroquine: implications for malaria chemoprophylaxis. British Journal of Clinical Pharmacology. 1995;39(6):696–699. doi: 10.1111/j.1365-2125.1995.tb05731.x 7654492

23. Lee SJ, McGready R, Fernandez C, Stepniewska K, Paw MK, Viladpai-nguen SJ, et al. Chloroquine pharmacokinetics in pregnant and nonpregnant women with vivax malaria. European Journal of Clinical Pharmacology. 2008;64(10):987. doi: 10.1007/s00228-008-0500-z 18594802

24. Pukrittayakamee S, Tarning J, Jittamala P, Charunwatthana P, Lawpoolsri S, Lee SJ, et al. Pharmacokinetic interactions between primaquine and chloroquine. Antimicrobial Agents and Chemotherapy. 2014;58(6):3354–3359. doi: 10.1128/AAC.02794-13 24687509

25. Chairat K, Jittamala P, Hanboonkunupakarn B, Pukrittayakamee S, Hanpithakpong W, Blessborn D, et al. Enantiospecific pharmacokinetics and drug–drug interactions of primaquine and blood-stage antimalarial drugs. Journal of Antimicrobial Chemotherapy. 2018;73(11):3102–3113. doi: 10.1093/jac/dky297 30085149

26. Höglund R, Moussavi Y, Ruengweerayut R, Cheomung A, Äbelö A, Na-Bangchang K. Population pharmacokinetics of a three-day chloroquine treatment in patients with Plasmodium vivax infection on the Thai-Myanmar border. Malaria Journal. 2016;15(1):129.

27. Al-Rawi H, Meggitt S, Williams F, Wahie S. Steady-state pharmacokinetics of hydroxychloroquine in patients with cutaneous lupus erythematosus. Lupus. 2018;27(5):847–852. doi: 10.1177/0961203317727601 28862574

28. Balevic SJ, Green TP, Clowse ME, Eudy AM, Schanberg LE, Cohen-Wolkowiez M. Pharmacokinetics of Hydroxychloroquine in Pregnancies with Rheumatic Diseases. Clinical Pharmacokinetics. 2019;58(4):525–533. doi: 10.1007/s40262-018-0712-z 30255310

29. 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). Clinical Infectious Diseases. 2020; doi: 10.1093/cid/ciaa237 32150618

30. Tett S, Cutler D, Day R, Brown K. A dose-ranging study of the pharmacokinetics of hydroxy-chloroquine following intravenous administration to healthy volunteers. British Journal of Clinical Pharmacology. 1988;26(3):303–313. doi: 10.1111/j.1365-2125.1988.tb05281.x 3179169

31. McLachlan A, Tett S, Cutler D, Day R. Bioavailability of hydroxychloroquine tablets in patients with rheumatoid arthritis. Rheumatology. 1994;33(3):235–239. doi: 10.1093/rheumatology/33.3.235 8156285

32. Furst DE. Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases. Lupus. 1996;5(1_suppl):11–15. doi: 10.1177/096120339600500104 8646219

33. Tett S, Day R, Cutler D. Hydroxychloroquine relative bioavailability: within subject reproducibility. British Journal of Clinical Pharmacology. 1996;41(3):244–246. doi: 10.1111/j.1365-2125.1996.tb00190.x 8866926

34. Tett S, Cutler D, Beck C, Day R. Concentration-effect relationship of hydroxychloroquine in patients with rheumatoid arthritis–a prospective, dose ranging study. The Journal of Rheumatology. 2000;27(7):1656–1660. 10914847

35. Carmichael SJ, Charles B, Tett SE. Population pharmacokinetics of hydroxychloroquine in patients with rheumatoid arthritis. Therapeutic drug monitoring. 2003;25(6):671–681. doi: 10.1097/00007691-200312000-00005 14639053

36. Lim HS, Im JS, Cho JY, Bae KS, Klein TA, Yeom JS, et al. Pharmacokinetics of hydroxychloroquine and its clinical implications in chemoprophylaxis against malaria caused by Plasmodium vivax. Antimicrobial Agents and Chemotherapy. 2009;53(4):1468–1475. doi: 10.1128/AAC.00339-08 19188392

37. Jallouli M, Galicier L, Zahr N, Aumaitre O, Frances C, Le Guern V, et al. Determinants of hydroxychloroquine blood concentration variations in systemic lupus erythematosus. Arthritis & Rheumatology. 2015;67(8):2176–2184.

38. Morita S, Takahashi T, Yoshida Y, Yokota N. Population pharmacokinetics of hydroxychloroquine in Japanese patients with cutaneous or systemic lupus erythematosus. Therapeutic Drug Monitoring. 2016;38(2):259–267. doi: 10.1097/FTD.0000000000000261 26587870

39. Lee JY, Vinayagamoorthy N, Han K, Kwok SK, Ju JH, Park KS, et al. Association of polymorphisms of cytochrome P450 2D6 with blood hydroxychloroquine levels in patients with systemic lupus erythematosus. Arthritis & Rheumatology. 2016;68(1):184–190.

40. Yeon Lee J, Lee J, Ki Kwok S, Hyeon Ju J, Su Park K, Park SH. Factors related to blood hydroxychloroquine concentration in patients with systemic lupus erythematosus. Arthritis Care & Research. 2017;69(4):536–542.

41. Tett SE. Clinical pharmacokinetics of slow-acting antirheumatic drugs. Clinical Pharmacokinetics. 1993;25(5):392–407. doi: 10.2165/00003088-199325050-00005 7904547

42. Cardoso CD, Bonato PS. Enantioselective analysis of the metabolites of hydroxychloroquine and application to an in vitro metabolic study. Journal of Pharmaceutical and Biomedical Analysis. 2005;37(4):703–708. doi: 10.1016/j.jpba.2004.11.048 15797791

43. Fu S, Björkman A, Wåhlin B, Ofori-Adjei D, Ericsson O, Sjöqvist F. In vitro activity of chloroquine, the two enantiomers of chloroquine, desethylchloroquine and pyronaridine against Plasmodium falciparum. British Journal of Clinical Pharmacology. 1986;22(1):93. 3527245

44. Han Y, Pham HT, Xu H, Quan Y, Mesplède T. Antimalarial drugs and their metabolites are potent Zika virus inhibitors. Journal of Medical Virology. 2019;91(7):1182–1190. doi: 10.1002/jmv.25440 30801742

45. Gustafsson L, Bergqvist Y, Ericsson O, Larsson M, Rombo L. Pitfalls in the measurement of chloroquine concentrations. The Lancet. 1983;321(8316):126.

46. Bergqvist Y, Churchill FC. Detection and determination of antimalarial drugs and their metabolites in body fluids. Journal of Chromatography B: Biomedical Sciences and Applications. 1988;434(1):1–20.

47. Mégarbane B, Bloch V, Hirt D, Debray M, Résiére D, Deye N, et al. Blood concentrations are better predictors of chloroquine poisoning severity than plasma concentrations: a prospective study with modeling of the concentration/effect relationships. Clinical Toxicology. 2010;48(9):904–915. doi: 10.3109/15563650.2010.518969 21080867

48. Staiger MA, Nguyen-Dinh P, Churchill FC II. Sensitive high-performance liquid chromatographic analysis for chloroquine in body fluids application to studies of drug resistance in Plasmodium falciparum. Journal of Chromatography B: Biomedical Sciences and Applications. 1981;225(1):139–149.

49. Projean D, Baune B, Farinotti R, Flinois JP, Beaune P, Taburet AM, et al. In vitro metabolism of chloroquine: identification of CYP2C8, CYP3A4, and CYP2D6 as the main isoforms catalyzing N-desethylchloroquine formation. Drug Metabolism and Disposition. 2003;31(6):748–754. doi: 10.1124/dmd.31.6.748 12756207

50. Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today's diseases. The Lancet Infectious Diseases. 2003;3(11):722–727. doi: 10.1016/s1473-3099(03)00806-5 14592603

51. Colson P, Rolain JM, Lagier JC, Brouqui P, Raoult D. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. International Journal of Antimicrobial Agents. 2020;55(4)105932. doi: 10.1016/j.ijantimicag.2020.105932 32145363

52. Gautret P, Lagier JC, Parola P, Meddeb L, Mailhe M, Doudier B, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents. 2020;56(1):105949. doi: 10.1016/j.ijantimicag.2020.105949 32205204

53. Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discovery. 2020;6(1):1–4.

54. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research. 2020;30(3):269–271. doi: 10.1038/s41422-020-0282-0 32020029

55. Fantini J, Chahinian H, Yahi N. Synergistic antiviral effect of hydroxychloroquine and azithromycin in combination against SARS-CoV-2: What molecular dynamics studies of virus-host interactions reveal. International Journal of Antimicrobial Agents. 2020;56(2):106020. https://doi.org/10.1016/j.ijantimicag.2020.106020.

56. Ross LS, Fidock DA. Elucidating mechanisms of drug-resistant Plasmodium falciparum. Cell Host & Microbe. 2019;26(1):35–47.

57. Ginsburg H, Golenser J. Glutathione is involved in the antimalarial action of chloroquine and its modulation affects drug sensitivity of human and murine species of Plasmodium. Redox Report. 2003;8(5):276–279. doi: 10.1179/135100003225002907 14962364

58. Phillips-Howard PA, ter Kuile FO. CNS adverse events associated with antimalarial agents. Drug Safety. 1995;12(6):370–383. doi: 10.2165/00002018-199512060-00003 8527012

59. Huzly D, Schönfeld C, Beuerle W, Bienzle U. Malaria chemoprophylaxis in German tourists: a prospective study on compliance and adverse reactions. Journal of travel medicine. 1996;3(3):148–155. doi: 10.1111/j.1708-8305.1996.tb00729.x 9815443

60. Petersen E, Rønne T, Rønn A, Bygbjerg I, Larsen SO. Reported side effects to chloroquine, chloroquine plus proguanil, and mefloquine as chemoprophylaxis against malaria in Danish travelers. Journal of Travel Medicine. 2000;7(2):79–84. doi: 10.2310/7060.2000.00026 10759574

61. Taylor WRJ, White NJ. Antimalarial drug toxicity. Drug Safety. 2004;27(1):25–61. doi: 10.2165/00002018-200427010-00003 14720085

62. Ponticelli C, Moroni G. Hydroxychloroquine in systemic lupus erythematosus (SLE). Expert Opinion on Drug Safety. 2017;16(3):411–419. doi: 10.1080/14740338.2017.1269168 27927040

63. Supanaranond W, Davis T, Pukrittayakamee S, Nagachinta B, White N. Abnormal circulatory control in falciparum malaria: the effects of antimalarial drugs. European Journal of Clinical Pharmacology. 1993;44(4):325–329. doi: 10.1007/BF00316467 8513843

64. World Health Organization. WHO Evidence Review Group on the Cardiotoxicity of Antimalarial Medicines. 2017.

65. White NJ. Cardiotoxicity of antimalarial drugs. The Lancet Infectious Diseases. 2007;7(8):549–558. doi: 10.1016/S1473-3099(07)70187-1 17646028

66. Sánchez-Chapula JA, Salinas-Stefanon E, Torres-Jácome J, Benavides-Haro DE, Navarro-Polanco RA. Blockade of currents by the antimalarial drug chloroquine in feline ventricular myocytes. Journal of Pharmacology and Experimental Therapeutics. 2001;297(1):437–445. 11259572

67. Sanson C, Schombert B, Filoche-Romme B, Partiseti M, Bohme GA. Electrophysiological and pharmacological characterization of human inwardly rectifying Kir2. 1 channels on an automated patch-clamp platform. Assay and Drug Development Technologies. 2019;17(3):89–99. doi: 10.1089/adt.2018.882 30835490

68. Capel RA, Herring N, Kalla M, Yavari A, Mirams GR, Douglas G, et al. Hydroxychloroquine reduces heart rate by modulating the hyperpolarization-activated current If: Novel electrophysiological insights and therapeutic potential. Heart Rhythm. 2015;12(10):2186–2194. doi: 10.1016/j.hrthm.2015.05.027 26025323

69. Rodrguez-Menchaca AA, Navarro-Polanco RA, Ferrer-Villada T, Rupp J, Sachse FB, Tristani-Firouzi M, et al. The molecular basis of chloroquine block of the inward rectifier Kir2.1 channel. Proceedings of the National Academy of Sciences. 2008;105(4):1364–1368. doi: 10.1073/pnas.0708153105

70. Chen CY, Wang FL, Lin CC. Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia. Clinical Toxicology. 2006;44(2):173–175. doi: 10.1080/15563650500514558 16615675

71. Giudicessi JR, Noseworthy PA, Friedman PA, Ackerman MJ. Urgent guidance for navigating and circumventing the QTc-prolonging and torsadogenic potential of possible pharmacotherapies for coronavirus disease 19 (COVID-19). In: Mayo Clinic Proceedings. vol. 95. Elsevier; 2020. p. 1213–1221. doi: 10.1016/j.mayocp.2020.03.024 32359771

72. Haeusler IL, Chan XHS, Guérin PJ, White NJ. The arrhythmogenic cardiotoxicity of the quinoline and structurally related antimalarial drugs: a systematic review. BMC Medicine. 2018;16(1):200. doi: 10.1186/s12916-018-1188-2 30400791

73. Ursing J, Kofoed PE, Rodrigues A, Bergqvist Y, Rombo L. Chloroquine is grossly overdosed and overused but well tolerated in Guinea-Bissau. Antimicrobial Agents and Chemotherapy. 2009;53(1):180–185. doi: 10.1128/AAC.01111-08 18955514

74. Vicente J, Zusterzeel R, Johannesen L, Ochoa-Jimenez R, Mason JW, Sanabria C, et al. Assessment of Multi-Ion Channel Block in a Phase I Randomized Study Design: Results of the CIPA Phase I ECG Biomarker Validation Study. Clinical Pharmacology & Therapeutics. 2019;105(4):943–953.

75. Szekely Y, Lichter Y, Shrkihe BA, Bruck H, Oster HS, Viskin S. Chloroquine-induced torsade de pointes in a COVID-19 patient. Heart Rhythm. doi: 10.1016/j.hrthm.2020.04.046. Forthcoming 2020. 32380291

76. Chorin E, Wadhwani L, Magnani S, Dai M, Shulman E, Nadeau-Routhier C, et al. QT Interval Prolongation and Torsade De Pointes in Patients with COVID-19 treated with Hydroxychloroquine/Azithromycin. Heart Rhythm. doi: 10.1016/j.hrthm.2020.05.014 Forthcoming 2020. 32407884

77. Food US and Authority Drug. Memorandum Explaining Basis for Revocation of Emergency Use Authorization for Emergency Use of Chloroquine Phosphate and Hydroxychloroquine Sulfate. 2020 [cited 2020 May 20]. Available from: https://www.fda.gov/media/138945/download.

78. Lane JCE, Weaver J, Kostka K, Duarte-Salles T, Abrahao MTF, Alghoul H, et al. Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid wide-spread use for COVID-19: a multinational, network cohort and self-controlled case series study. medRxiv [Preprint]. 2020 [cited 2020 May 20]. doi: 10.1101/2020.04.08.20054551

79. Mehra MR, Desai SS, Ruschitzka F, Patel AN. RETRACTED: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. The Lancet. 2020. doi: 10.1016/S0140-6736(20)31180-6 32450107

80. James Watson on the behalf of 201 signatories. An open letter to Mehra et al and The Lancet (Version 4); 2020 [cited 2020 May 20]. Available from: http://doi.org/10.5281/zenodo.3871094.

81. Chan XHS, Win YN, Mawer LJ, Tan JY, Brugada J, White NJ. Risk of sudden unexplained death after use of dihydroartemisinin–piperaquine for malaria: a systematic review and Bayesian meta-analysis. The Lancet Infectious Diseases. 2018;18(8):913–923. doi: 10.1016/S1473-3099(18)30297-4 29887371

82. Arora R, Sharma V, Madan B. Antiarrhythmics. I. Chloroquine in auricular fibrillation. Indian Journal of Medical Research. 1955;43:659–666. 13278036

83. Sanghvi L. Chloroquine: Clinical and electrocardiographic observations after intravenous administration in two cases of auricular fibrillation. American Heart Journal. 1956;52(6):908–915. doi: 10.1016/0002-8703(56)90159-4 13362096

84. Hess M, Schmidt C. Cardiovascular effects of chloroquine with special reference to its antifibrillatory action. Circulation Research. 1959;7(1):86–92. doi: 10.1161/01.res.7.1.86 13619046

85. Harris L, Downar E, Shaikh N, Chen T. Antiarrhythmic potential of chloroquine: new use for an old drug. The Canadian Journal of Cardiology. 1988;4(6):295–300. 2460205

86. Filgueiras-Rama D, Martins RP, Mironov S, Yamazaki M, Calvo CJ, Ennis SR, et al. Chloroquine terminates stretch-induced atrial fibrillation more effectively than flecainide in the sheep heart. Circulation: Arrhythmia and Electrophysiology. 2012;5(3):561–570. doi: 10.1161/CIRCEP.111.966820 22467674

87. Alkmim Teixeira R, Borba EF, Pedrosa A, Nishioka S, Viana VS, Ramires JA, et al. Evidence for cardiac safety and antiarrhythmic potential of chloroquine in systemic lupus erythematosus. Europace. 2014;16(6):887–892. doi: 10.1093/europace/eut290 24050965

88. Fazekas T, Szekeres L. Effect of chloroquine in experimental myocardial ischaemia. Acta physiologica Hungarica. 1988;72(2):191. 3227859

89. Bourke L, McCormick J, Taylor V, Pericleous C, Blanchet B, Costedoat-Chalumeau N, et al. Hydroxychloroquine Protects against Cardiac Ischaemia/Reperfusion Injury In Vivo via Enhancement of ERK1/2 Phosphorylation. PLoS ONE. 2015;10(12):e0143771. doi: 10.1371/journal.pone.0143771 26636577

90. Chan XHS, Win YN, Haeusler IL, Tan JY, Loganathan S, Saralamba S, et al. Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data. PLoS Med. 2020;17(3):e1003040. doi: 10.1371/journal.pmed.1003040 32134952

91. Bethell DB, Phuong PT, Phuong CXT, Nosten F, Waller D, Davis TM, et al. Electrocardiographic monitoring in severe falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene. 1996;90(3):266–269. doi: 10.1016/s0035-9203(96)90241-2 8758072

92. Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, et al. Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China. JAMA Cardiology. 2020;5(7):802–810. doi: 10.1001/jamacardio.2020.0950 32211816

93. Clemessy JL, Borron S, Baud F, Favier C, Hantson P, Vicaut E, et al. Hypokalaemia related to acute chloroquine ingestion. The Lancet. 1995;346(8979):877–880.

94. Quatraro A, Consoli G, Magno M, Caretta F, Nardozza A, Ceriello A, et al. Hydroxychloroquine in decompensated, treatment-refractory noninsulin-dependent diabetes mellitus: a new job for an old drug? Annals of Internal Medicine. 1990;112(9):678–681. doi: 10.7326/0003-4819-112-9-678 2110430

95. Powrie J, Smith G, Shojaee-Moradie F, Sonksen P, Jones R. Mode of action of chloroquine in patients with non-insulin-dependent diabetes mellitus. American Journal of Physiology-Endocrinology and Metabolism. 1991;260(6):E897–E904.

96. Powrie J, Shojaee-Moradie F, Watts G, Smith G, Sönksen P, Jones R. Effects of chloroquine on the dyslipidemia of non-insulin-dependent diabetes mellitus. Metabolism. 1993;42(4):415–419. doi: 10.1016/0026-0495(93)90096-7 8487662

97. Ajayi AA. Itching, chloroquine, and malaria: a review of recent molecular and neuroscience advances and their contribution to mechanistic understanding and therapeutics of chronic non-histaminergic pruritus. International journal of dermatology. 2019;58(8):880–891. doi: 10.1111/ijd.14252 30362504

98. Percival S, Meanock I. Chloroquine: ophthalmological safety, and clinical assessment in rheumatoid arthritis. British Medical Journal. 1968;3(5618):579–584. doi: 10.1136/bmj.3.5618.579 4875645

99. Rosenthal A, Kolb H, Bergsma D, Huxsoll D, Hopkins J. Chloroquine retinopathy in the rhesus monkey. Investigative Ophthalmology & Visual Science. 1978;17(12):1158–1175.

100. Easterbrook M. Ocular effects and safety of antimalarial agents. The American Journal of Medicine. 1988;85(4):23–29.

101. Pasadhika S, Fishman G. Effects of chronic exposure to hydroxychloroquine or chloroquine on inner retinal structures. Eye. 2010;24(2):340–346. doi: 10.1038/eye.2009.65 19373270

102. Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmology. 2014;132(12):1453–1460. doi: 10.1001/jamaophthalmol.2014.3459 25275721

103. Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology. 2016;123(6):1386–1394. doi: 10.1016/j.ophtha.2016.01.058 26992838

104. Tönnesmann E, Kandolf R, Lewalter T. Chloroquine cardiomyopathy–a review of the literature. Immunopharmacology and Immunotoxicology. 2013;35(3):434–442. doi: 10.3109/08923973.2013.780078 23635029

105. Chatre C, Roubille F, Vernhet H, Jorgensen C, Pers YM. Cardiac complications attributed to chloroquine and hydroxychloroquine: a systematic review of the literature. Drug Safety. 2018;41(10):919–931. doi: 10.1007/s40264-018-0689-4 29858838

106. Beutler E. G6PD deficiency. Blood. 1994;84(11):3613–3636. doi: 10.1182/blood.V84.11.3613.bloodjournal84113613 7949118

107. Cohen RJ, Sachs JR, Wicker DJ, Conrad ME. Methemoglobinemia provoked by malarial chemoprophylaxis in Vietnam. New England Journal of Medicine. 1968;279(21):1127–1131. doi: 10.1056/NEJM196811212792102 5686480

108. Saleh M, Gabriels J, Chang D, Kim BS, Mansoor A, Mahmood E, et al. The Effect of Chloroquine, Hydroxychloroquine and Azithromycin on the Corrected QT Interval in Patients with SARS-CoV-2 Infection. Circulation: Arrhythmia and Electrophysiology. 2020;13(6):e008662. doi: 10.1161/circep.120.008662 32347743

109. Riou B, Barriot P, Rimailho A, Baud FJ. Treatment of severe chloroquine poisoning. New England Journal of Medicine. 1988;318(1):1–6. doi: 10.1056/NEJM198801073180101 3336379

110. Clemessy J, Lapostolle F, Borron S, Baud F. Acute chloroquine poisoning. Presse Medicale (Paris, France: 1983). 1996;25(31):1435–1439.

111. Clemessy JL, Taboulet P, Hoffman JR, Hantson P, Barriot P, Bismuth C, et al. Treatment of acute chloroquine poisoning: a 5-year experience. Critical Care Medicine. 1996;24(7):1189–1195. doi: 10.1097/00003246-199607000-00021 8674334

112. Clemessy JL, Angel G, Borron S, Ndiaye M, Le Brun F, Julien H, et al. Therapeutic trial of diazepam versus placebo in acute chloroquine intoxications of moderate gravity. Intensive Care Medicine. 1996;22(12):1400–1405. doi: 10.1007/BF01709558 8986493

113. Jordan P, Brookes JG, Nikolic G, Le Couteur DG, Le Couteur D. Hydroxychloroquine overdose: toxicokinetics and management. Journal of Toxicology: Clinical Toxicology. 1999;37(7):861–864. doi: 10.1081/clt-100102466 10630270

114. Cheema N, Bryant SM. Hydroxychloroquine and cardiotoxicity: a retrospective review of regional poison center data. Clinical Toxicology. 2013;51(7):712–712.

115. de Olano J, Howland MA, Su MK, Hoffman RS, Biary R. Toxicokinetics of hydroxychloroquine following a massive overdose. The American Journal of Emergency Medicine. 2019;37(12):2264–e5.

116. Ball D, Tagwireyi D, Nhachi C. Chloroquine poisoning in Zimbabwe: a toxicoepidemiological study. Journal of Applied Toxicology: An International Journal. 2002;22(5):311–315.

117. Watson JA, Tarning J, Hoglund RM, Baud FJ, Megarbane B, Clemessy JL, et al. Concentration-dependent mortality of chloroquine in overdose. Elife 2020; 9: e58631. doi: 10.7554/eLife.58631

118. Rombo L, Ericsson O, Alvan G, Lindström B, Gustafsson LL, Sjöqvist F. Chloroquine and desethylchloroquine in plasma, serum, and whole blood: problems in assay and handling of samples. Therapeutic drug monitoring. 1985;7(2):211–215. doi: 10.1097/00007691-198506000-00013 4024216

119. Tett S, Cutler D, Day R, Brown K. Bioavailability of hydroxychloroquine tablets in healthy volunteers. British Journal of Clinical Pharmacology. 1989;27(6):771–779. doi: 10.1111/j.1365-2125.1989.tb03439.x 2757893

120. Borba MGS, Val FFA, Sampaio VS, Alexandre MAA, Melo GC, Brito M, et al. 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 Network Open. 2020;3(4):e208857–e208857. doi: 10.1001/jamanetworkopen.2020.8857

121. Pedrosa TN, Pasoto SG, Aikawa NE, Yuki EF, Borba EF, Filho JCF, et al. Understanding the dynamics of hydroxychloroquine blood levels in lupus nephritis. Lupus. 2020;29(6):560–568. doi: 10.1177/0961203320912832 32192398

122. Mok CC, Penn HJ, Chan KL, Tse SM, Langman LJ, Jannetto PJ. Hydroxychloroquine serum concentrations and flares of systemic lupus erythematosus: a longitudinal cohort analysis. Arthritis Care & Research. 2016;68(9):1295–1302.

123. Durcan L, Clarke WA, Magder LS, Petri M. Hydroxychloroquine blood levels in systemic lupus erythematosus: clarifying dosing controversies and improving adherence. The Journal of Rheumatology. 2015;42(11):2092–2097. doi: 10.3899/jrheum.150379 26428205

124. Geraldino-Pardilla L, Perel-Winkler A, Miceli J, Neville K, Danias G, Nguyen S, et al. Association between hydroxychloroquine levels and disease activity in a predominantly Hispanic systemic lupus erythematosus cohort. Lupus. 2019;28(7):862–867. doi: 10.1177/0961203319851558 31122136

125. Cunha C, Alexander S, Ashby D, Lee J, Chusney G, Cairns TD, et al. Hydroxycloroquine blood concentration in lupus nephritis: a determinant of disease outcome? Nephrology Dialysis Transplantation. 2018;33(9):1604–1610.

126. Keshtkar-Jahromi M, Bavari S. A Call for Randomized Controlled Trials to Test the Efficacy of Chloroquine and Hydroxychloroquine as Therapeutics against Novel Coronavirus Disease (COVID-19). The American Journal of Tropical Medicine and Hygiene. 2020;102(5):932–933. doi: 10.4269/ajtmh.20-0230 32247318

127. Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. New England Journal of Medicine. doi: 10.1056/NEJMoa2016638 Forthcoming 2020. 32492293

128. Cohen MS. Hydroxychloroquine for the Prevention of Covid-19—Searching for Evidence. New England Journal of Medicine. doi: 10.1056/NEJMe2020388 Forthcoming 2020. 32492298

129. Collins R, Bowman L, Landray M, Peto R. The Magic of Randomization versus the Myth of Real-World Evidence. The New England Journal of Medicine. 2020;382(7):674. doi: 10.1056/NEJMsb1901642 32053307

130. Lenzer J. Covid-19: US gives emergency approval to hydroxychloroquine despite lack of evidence. BMJ. 2020;369:m1335. doi: 10.1136/bmj.m1335 32238355

131. Vigdor N. Man Fatally Poisons Himself While Self-Medicating for Coronavirus, Doctor Says. New York Times. 2020 Mar 24. Updated 2020 Apr 24. Available from: https://www.nytimes.com/2020/03/24/us/chloroquine-poisoning-coronavirus.html.

132. Yee TH, Arshad A. Lupus patients hit by run on drug chloroquine after claims it wards against coronavirus. Straits Times. 2020 Mar 25. Available from: https://www.straitstimes.com/asia/se-asia/run-on-drug-chloroquine-despite-unproven-belief-as-ward-against-coronavirus-affecting.

133. Newton PN, Bond KC, Adeyeye M, Antignac M, Ashenef A, Awab GR, et al. COVID-19 and risks to the supply and quality of tests, drugs, and vaccines. The Lancet Global Health. 2020; doi: 10.1016/S2214-109X(20)30136-4 32278364

134. Indian Council for Medical Research. Recommendation for empiric use of hydroxychloroquine for prophylaxis of SARS-CoV-2 infection. 2020 Apr 3.