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Toxicity of chloroquine and hydroxychloroquine following therapeutic use or overdose

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Pages 12-23 | Received 28 Apr 2020, Accepted 24 Aug 2020, Published online: 22 Sep 2020

References

  • Rainsford KD, Parke AL, Clifford-Rashotte M, et al. Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology. 2015;23(5):231–269.
  • Yao X, Ye F, Zhang M, 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.
  • Commissioner of the Emergency Use Authorization. FDA. 2020. [cited 2020 Jun 17]; Available from: https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization.
  • Goodman JL, Borio L. Finding effective treatments for COVID-19: scientific integrity and public confidence in a time of crisis. JAMA. 2020;323(19):1899.
  • Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious diseases society of America guidelines on the treatment and management of patients with COVID-19. Clin Infect Dis. 2020. DOI:10.1093/cid/ciaa1063. Online ahead of print.
  • Information on COVID-19 treatment, prevention and research. COVID-19 treatment guidelines. [cited 2020 Jun 17]. Available from: https://www.covid19treatmentguidelines.nih.gov/.
  • Lalloo DG, Shingadia D, Bell DJ, et al. UK malaria treatment guidelines 2016. J Infect. 2016;72(6):635–649.
  • Hernandez AV, Roman YM, Pasupuleti V, et al. Hydroxychloroquine or chloroquine for treatment or prophylaxis of COVID-19: a living systematic review. Ann Intern Med. 2020;173(4):287–296.
  • Chen Z, Hu J, Zhang Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. Epidemiology; 2020; [cited 2020 Jun 17]. Available from: https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v3
  • Borba MGS, Val FFA, Sampaio VS, 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 Netw Open. 2020;3(4):e208857
  • Ursing J, Kofoed P-E, Rodrigues A, et al. Chloroquine is grossly overdosed and overused but well tolerated in Guinea-bissau. Antimicrob Agents Chemother. 2009;53(1):180–185.
  • Croft AM, Clayton TC, World MJ. Side effects of mefloquine prophylaxis for malaria: an independent randomized controlled trial. Trans R Soc Trop Med Hyg. 1997;91(2):199–203.
  • Jacquerioz FA, Croft AM. Drugs for preventing malaria in travellers. Cochrane Database Syst Rev. 2009;(4):CD006491.
  • Covid-19 living Data [Internet]. [cited 2020 Jun 17]. Available from: https://covid-nma.com/.
  • Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J Med. 2020;383(6):517–525.
  • Nagaraja BS, Ramesh KN, Dhar D, et al. HyPE study: hydroxychloroquine prophylaxis-related adverse events’ analysis among healthcare workers during COVID-19 pandemic: a rising public health concern. J Public Health (Oxf). 2020;42(3):493–503.
  • Huang M, Tang T, Pang P, et al. Treating COVID-19 with chloroquine. J Mol Cell Biol. 2020;12(4):322–325.
  • Zachariah P, Johnson CL, Halabi KC, et al. Epidemiology, clinical features, and disease severity in patients with coronavirus disease 2019 (COVID-19) in a Children’s Hospital in New York City, New York. JAMA Pediatr. 2020;e202430. DOI:10.1001/jamapediatrics.2020.2430. Online ahead of print.
  • Munster T, Gibbs JP, Shen D, et al. Hydroxychloroquine concentration-response relationships in patients with rheumatoid arthritis. Arthritis Rheum. 2002;46(6):1460–1469.
  • Croft AM, Whitehouse DP, Cook GC, et al. Safety evaluation of the drugs available to prevent malaria. Expert Opin Drug Saf. 2002;1(1):19–27.
  • Gevers S, Kwa MSG, Wijnans E, et al. Safety considerations for chloroquine and hydroxychloroquine in the treatment of COVID-19. Clin Microbiol Infect. 2020;26(9):1276–1277.
  • Makin AJ, Wendon J, Fitt S, et al. Fulminant hepatic failure secondary to hydroxychloroquine. Gut. 1994;35(4):569–570.
  • Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369:m1849.
  • Rosenberg ES, Dufort EM, Udo T, 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):2493.
  • Gautret P, Lagier J-C, Parola P, et al. 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;34:101663.
  • Million M, Lagier J-C, Gautret P, et al. Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: a retrospective analysis of 1061 cases in Marseille, France. Travel Med Infect Dis. 2020;35:101738.
  • Falcão MB, Pamplona de Góes Cavalcanti L, Filgueiras Filho NM, et al. Case report: hepatotoxicity associated with the use of hydroxychloroquine in a patient with COVID-19. Am J Trop Med Hyg. 2020;102(6):1214–1216.
  • Cansu DU, Korkmaz C. Hypoglycaemia induced by hydroxychloroquine in a non-diabetic patient treated for RA. Rheumatol Oxf Engl. 2007;47(3):378–379.
  • Riou B, Barriot P, Rimailho A, et al. Treatment of severe chloroquine poisoning. N Engl J Med. 1988;318(1):1–6.
  • Shojania K, Koehler BE, Elliott T. Hypoglycemia induced by hydroxychloroquine in a type II diabetic treated for polyarthritis. J Rheumatol. 1999;26:195–196.
  • Baretić M. Case report of chloroquine therapy and hypoglycaemia in type 1 diabetes: What should we have in mind during the COVID-19 pandemic? Diabetes Metab Syndr. 2020;14(4):355–356.
  • Unübol M, Ayhan M, Guney E. Hypoglycemia induced by hydroxychloroquine in a patient treated for rheumatoid arthritis. J Clin Rheumatol Pract Rep Rheum Musculoskelet Dis. 2011;17:46–47.
  • Infante M, Ricordi C, Fabbri A. Antihyperglycemic properties of hydroxychloroquine in patients with diabetes: risks and benefits at the time of COVID-19 pandemic. J Diabetes. 2020;12(9):659–667.
  • White NJ. Cardiotoxicity of antimalarial drugs. Lancet Infect Dis. 2007;7(8):549–558.
  • Chatre C, Roubille F, Vernhet H, et al. Cardiac complications attributed to chloroquine and hydroxychloroquine: a systematic review of the literature. Drug Saf. 2018;41(10):919–931.
  • Abu-Aisha H, Abu-Sabaa HM, Nur T. Cardiac arrest after intravenous chloroquine injection. J Trop Med Hyg. 1979;82(2):36–37.
  • Scott V. Single intravenous injections of chloroquine in the treatment of falciparum malaria: toxic and immediate therapeutic effects in 110 cases. Am J Trop Med Hyg. 1950;30(4):503–510.
  • Abiose AK, Grossmann M, Tangphao O, et al. Chloroquine-induced venodilation in human hand veins. Clin Pharmacol Ther. 1997;61(6):677–683.
  • Ghigo D, Aldieri E, Todde R, et al. Chloroquine stimulates nitric oxide synthesis in murine, porcine, and human endothelial cells. J Clin Invest. 1998;102(3):595–605.
  • Haeusler IL, Chan XHS, Guérin PJ, et al. The arrhythmogenic cardiotoxicity of the quinoline and structurally related antimalarial drugs: a systematic review. BMC Med. 2018;16(1):200
  • Sánchez-Chapula JA, Salinas-Stefanon E, Torres-Jácome J, et al. Blockade of currents by the antimalarial drug chloroquine in feline ventricular myocytes. J Pharmacol Exp Ther. 2001;297(1):437–445.
  • Rodríguez-Menchaca AA, Navarro-Polanco RA, Ferrer-Villada T, et al. The molecular basis of chloroquine block of the inward rectifier Kir2.1 channel. Proc Natl Acad Sci USA. 2008;105(4):1364–1368.
  • Mzayek F, Deng H, Mather FJ, et al. Randomized dose-ranging controlled trial of AQ-13, a candidate antimalarial, and chloroquine in healthy volunteers. PLoS Clin Trial. 2007;2(1):e6.
  • Morgan ND, Patel SV, Dvorkina O. Suspected hydroxychloroquine-associated QT-interval prolongation in a patient with systemic lupus erythematosus. J Clin Rheumatol Pract Rep Rheum Musculoskelet Dis. 2013;19:286–288.
  • Yogasundaram H, Putko BN, Tien J, et al. Hydroxychloroquine-induced cardiomyopathy: case report, pathophysiology, diagnosis, and treatment. Can J Cardiol. 2014;30(12):1706–1715.
  • [cited 2020. Jun 17]. Available from: https://www.who.int/malaria/mpac/mpac-mar2017-erg-cardiotoxicity-report-session2.pdf.
  • Molina JM, Delaugerre C, Le Goff J, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect. 2020;50(4):384.
  • Perinel S, Launay M, Botelho-Nevers É, et al. Towards optimization of hydroxychloroquine dosing in intensive care unit COVID-19 patients. Clin Infect Dis. 2020. DOI:10.1093/cid/ciaa394. Online ahead of print..
  • Saleh M, Gabriels J, Chang D, et al. Effect of chloroquine, hydroxychloroquine, and azithromycin on the corrected QT interval in patients with SARS-CoV-2 infection. Circ Arrhythm Electrophysiol. 2020;13(6):e008662.
  • Mazzanti A, Briani M, Kukavica D, et al. Association of hydroxychloroquine with QTc interval in patients with COVID-19. Circulation. 2020;142(5):513–515.
  • Mahévas M, Tran V-T, Roumier M, et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ. 2020;369:m1844.
  • van den Broek MPH, Möhlmann JE, Abeln BGS, et al. Chloroquine-induced QTc prolongation in COVID-19 patients. Neth Heart J. 2020;28(7-8):406–409.
  • Cipriani A, Zorzi A, Ceccato D, et al. Arrhythmic profile and 24-hour QT interval variability in COVID-19 patients treated with hydroxychloroquine and azithromycin. Int J Cardiol. 2020. DOI:10.1016/j.ijcard.2020.06.005. Online ahead of print.
  • Hor CP, Hussin N, Nalliah S, et al. Experience of short-term hydroxychloroquine and azithromycin in COVID-19 patients and effect on QTc trend. J Infect. 2020;81(2):e117–e119.
  • Bessière F, Roccia H, Delinière A, et al. Assessment of QT intervals in a case series of patients with coronavirus disease 2019 (COVID-19) infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit. JAMA Cardiol. 2020:e201787. DOI:10.1001/jamacardio.2020.1787. Online ahead of print.
  • Szekely Y, Lichter Y, Shrkihe BA, et al. Chloroquine-induced torsades de pointes in a patient with coronavirus disease 2019. Heart Rhythm. 2020;17(9):1452–1455.
  • Maraj I, Hummel JP, Taoutel R, et al. Incidence and determinants of QT interval prolongation in COVID-19 patients treated with hydroxychloroquine and azithromycin. J Cardiovasc Electrophysiol. 2020;31(8):1904–1907.
  • Chorin E, Wadhwani L, Magnani S, et al. QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin. Heart Rhythm. 2020;17(9):1425–1433.
  • Mercuro NJ, Yen CF, Shim DJ, et al. Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020:e201834. DOI:10.1001/jamacardio.2020.1834. Online ahead of print.
  • Experience with Hydroxychloroquine and Azithromycin in the COVID-19 Pandemic: Implications for QT Interval Monitoring | medRxiv [Internet]. [cited 2020. Jun 17]. Available from: https://www.medrxiv.org/content/10.1101/2020.04.22.20075671v1.
  • Sharma AN, Mesinkovska NA, Paravar T. Characterizing the adverse dermatologic effects of hydroxychloroquine: a systematic review. J Am Acad Dermatol. 2020;83(2):563–578.
  • Phillips-Howard PA, Warwick Buckler J. Idiosyncratic reaction resembling toxic epidermal necrolysis caused by chloroquine and maloprim. Br Med J (Clin Res Ed)). 1988;296(6636):1605.
  • Boffa MJ, Chalmers RJ. Toxic epidermal necrolysis due to chloroquine phosphate. Br J Dermatol. 1994;131(3):444–445.
  • Kanwar AJ, Singh OP. Toxic epidermal necrolysis-drug induced (report of 2 cases). Indian J Dermatol. 1976;21(4):73–77.
  • Barailler H, Milpied B, Chauvel A, et al. Delayed hypersensitivity skin reaction to hydroxychloroquine: successful short desensitization. J Allergy Clin Immunol Pract. 2019;7(1):307–308.
  • Mates M, Zevin S, Breuer GS, et al. Desensitization to hydroxychloroquine–experience of 4 patients. J Rheumatol. 2006;33(4):814–816.
  • Litaiem N, Hajlaoui K, Karray M, et al. Acute generalized exanthematous pustulosis after COVID-19 treatment with hydroxychloroquine. Dermatol Ther. 2020;e13565. DOI:10.1111/dth.13565. Online ahead of print.
  • Robustelli Test E, Vezzoli P, Carugno A, et al. Acute generalized exanthematous pustulosis with erythema multiforme-like lesions in a COVID-19 woman. J Eur Acad Dermatol Venereol. 2020. DOI:10.1111/jdv.16613. Online ahead of print.
  • Grandolfo M, Romita P, Bonamonte D, et al. Drug reaction with eosinophilia and systemic symptoms syndrome to hydroxychloroquine, an old drug in the spotlight in the COVID-19 era. Dermatol Ther. 2020;:e13499. DOI:10.1111/dth.13499. Online ahead of print.
  • Kutlu Ö, Metin A. A case of exacerbation of psoriasis after oseltamivir and hydroxychloroquine in a patient with COVID-19: will cases of psoriasis increase after COVID-19 pandemic? Dermatol Ther. 2020;e13383. DOI:10.1111/dth.13383. Online ahead of print.
  • Schwartz RA, Janniger CK. Generalized pustular figurate erythema: a newly delineated severe cutaneous drug reaction linked with hydroxychloroquine. Dermatol Ther. 2020;33(3):e13380.
  • Herrero-Moyano M, Capusan TM, Andreu-Barasoain M, et al. A clinicopathological study of 8 patients with COVID-19 pneumonia and a late-onset exanthema. J Eur Acad Dermatol Venereol. 2020. DOI:10.1111/jdv.16631. Online ahead of print.
  • Sato K, Mano T, Iwata A, et al. Neuropsychiatric adverse events of chloroquine: a real-world pharmacovigilance study using the FDA Adverse Event Reporting System (FAERS) database. Biosci Trends. 2020;14(2):139–143.
  • Collins KP, Jackson KM, Gustafson DL. Hydroxychloroquine: a physiologically-based pharmacokinetic model in the context of cancer-related autophagy modulation. J Pharmacol Exp Ther. 2018;365(3):447–459.
  • Garg P, Mody P, Lall KB. Toxic psychosis due to chloroquine-not uncommon in children. Clin Pediatr (Phila)). 1990;29(8):448–450.
  • Rab SM. Two cases of chloroquine psychosis. Br Med J. 1963;1(5340):1275.
  • Mustakallio KK, Putkonen T, Pihkanen TA. Chloroquine psychosis?. Lancet Lond Engl. 1962;280(7270):1387–1388.
  • Biswas PS, Sen D, Majumdar R. Psychosis following chloroquine ingestion: a 10-year comparative study from a malaria-hyperendemic district of India. Gen Hosp Psychiatry. 2014;36(2):181–186.
  • Bogaczewicz A, Sobów T. Psychiatric adverse effects of chloroquine. Psychiatr Psychol Klin. 2017;17(2):111–114.
  • Thompson AJ, Lummis SCR. Antimalarial drugs inhibit human 5-HT(3) and GABA(A) but not GABA(C) receptors. Br J Pharmacol. 2008;153(8):1686–1696.
  • 006002s044lbl.pdf [Internet]. [cited 2020. Jun 17]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/006002s044lbl.pdf.
  • 009768s037s045s047lbl.pdf [Internet]. [cited 2020. Jun 17]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/009768s037s045s047lbl.pdf.
  • Nkhoma ET, Poole C, Vannappagari V, et al. The global prevalence of glucose-6-phosphate dehydrogenase deficiency: a systematic review and meta-analysis. Blood Cells Mol Dis. 2009;42(3):267–278.
  • Reference GH. Glucose-6-phosphate dehydrogenase deficiency. Genet. Home Ref. [cited 2020 Jun 17]. Available from: https://ghr.nlm.nih.gov/condition/glucose-6-phosphate-dehydrogenase-deficiency.
  • Mohammad S, Clowse MEB, Eudy AM, et al. Examination of hydroxychloroquine use and hemolytic anemia in G6PDH-deficient patients. Arthritis Care Res (Hoboken). 2018;70(3):481–485.
  • Maillart E, Leemans S, Van Noten H, et al. A case report of serious haemolysis in a glucose-6-phosphate dehydrogenase-deficient COVID-19 patient receiving hydroxychloroquine. Infect Dis (Lond). 2020;52(9):659–661.
  • Kuipers MT, Zwieten R, Heijmans J, et al. G6PD deficiency-associated hemolysis and methemoglobinemia in a COVID-19 patient treated with chloroquine. Am J Hematol. 2020;95(8):E194–E196.
  • Beauverd Y, Adam Y, Assouline B, et al. COVID-19 infection and treatment with hydroxychloroquine cause severe haemolysis crisis in a patient with glucose-6-phosphate dehydrogenase deficiency. Eur J Haematol. 2020;105(3):357–359.
  • Jorge A, Ung C, Young LH, et al. Hydroxychloroquine retinopathy - implications of research advances for rheumatology care. Nat Rev Rheumatol. 2018;14(12):693–703.
  • Tobin DR, Krohel G, Rynes RI. Hydroxychloroquine. Seven-year experience. Arch Ophthalmol. 1982;100(1):81–83.
  • Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol. 2014;132(12):1453–1460.
  • Browning DJ, Lee C. Somatotype, the risk of hydroxychloroquine retinopathy, and safe daily dosing guidelines. Clin Ophthalmol. 2018;12:811–818.
  • Elman A, Gullberg R, Nilsson E, et al. Chloroquine retinopathy in patients with rheumatoid arthritis. Scand J Rheumatol. 1976;5(3):161–166.
  • Bergholz R, Schroeter J, Rüther K. Evaluation of risk factors for retinal damage due to chloroquine and hydroxychloroquine. Br J Ophthalmol. 2010;94(12):1637–1642.
  • Wolfe F, Marmor MF. Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res (Hoboken). 2010;62(6):775–784.
  • Marmor MF, Kellner U, Lai TYY, American Academy of Ophthalmology, et al. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 Revision). Ophthalmology. 2016;123(6):1386–1394.
  • Leung L-SB, Neal JW, Wakelee HA, et al. Rapid onset of retinal toxicity from high-dose hydroxychloroquine given for cancer therapy. Am J Ophthalmol. 2015;160(4):799–805.e1.
  • Browning DJ. Hydroxychloroquine and chloroquine retinopathy: screening for drug toxicity. Am J Ophthalmol. 2002;133(5):649–656.
  • Nika M, Blachley TS, Edwards P, et al. Regular examinations for toxic maculopathy in long-term chloroquine or hydroxychloroquine users. JAMA Ophthalmol. 2014;132(10):1199–1208.
  • Marmor MF, Hu J. Effect of disease stage on progression of hydroxychloroquine retinopathy. JAMA Ophthalmol. 2014;132(9):1105–1112.
  • Mititelu M, Wong BJ, Brenner M, et al. Progression of hydroxychloroquine toxic effects after drug therapy cessation: new evidence from multimodal imaging. JAMA Ophthalmol. 2013;131(9):1187–1197.
  • Inoue S, Hasegawa K, Ito S, et al. Antimelanoma activity of chloroquine, an antimalarial agent with high affinity for melanin. Pigment Cell Res. 1993;6(5):354–358.
  • Grassmann F, Bergholz R, Mändl J, et al. Common synonymous variants in ABCA4 are protective for chloroquine induced maculopathy (toxic maculopathy). BMC Ophthalmol. 2015;15:18.
  • McGhie TK, Harvey P, Su J, et al. Electrocardiogram abnormalities related to anti-malarials in systemic lupus erythematosus. Clin Exp Rheumatol. 2018;36(4):545–551.
  • Costedoat-Chalumeau N, Hulot J-S, Amoura Z, et al. Heart conduction disorders related to antimalarials toxicity: an analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue diseases. Rheumatology (Oxford). 2007;46(5):808–810.
  • Teixeira RA, Borba EF, Pedrosa A, et al. Evidence for cardiac safety and antiarrhythmic potential of chloroquine in systemic lupus erythematosus. Eur Soc Cardiol. 2014;16:887–892.
  • Tönnesmann E, Kandolf R, Lewalter T. Chloroquine cardiomyopathy – a review of the literature. Immunopharmacol Immunotoxicol. 2013;35(3):434–442.
  • Fragasso G, Sanvito F, Baratto F, et al. Cardiotoxicity after low-dose chloroquine antimalarial therapy. Heart Vessels. 2009;24(5):385–387.
  • Costedoat-Chalumeau N, Hulot J-S, Amoura Z, et al. Cardiomyopathy related to antimalarial therapy with illustrative case report. Cardiology. 2007;107(2):73–80.
  • Richter JG, Becker A, Ostendorf B, et al. Differential diagnosis of high serum creatine kinase levels in systemic lupus erythematosus. Rheumatol Int. 2003;23(6):319–323.
  • Siddiqui AK, Huberfeld SI, Weidenheim KM, et al. Hydroxychloroquine-induced toxic myopathy causing respiratory failure. Chest. 2007;131(2):588–590.
  • Estes ML, Ewing-Wilson D, Chou SM, et al. Chloroquine neuromyotoxicity. Clinical and pathologic perspective. Am J Med. 1987;82(3):447–455.
  • Parmar RC, Valvi CV, Kamat JR, et al. Chloroquine induced parkinsonism. J Postgrad Med. 2000;46(1):29–30.
  • Stein M, Bell MJ, Ang LC. Hydroxychloroquine neuromyotoxicity. J Rheumatol. 2000;27(12):2927–2931.
  • Trinkley KE, Page RL, Lien H, et al. QT interval prolongation and the risk of torsades de pointes: essentials for clinicians. Curr Med Res Opin. 2013;29(12):1719–1726.
  • Staikou C, Stamelos M, Stavroulakis E. Impact of anaesthetic drugs and adjuvants on ECG markers of torsadogenicity. Br J Anaesth. 2014;112(2):217–230.
  • Leppert W. CYP2D6 in the metabolism of opioids for mild to moderate pain. Pharmacology. 2011;87(5-6):274–285.
  • McCance-Katz EF, Sullivan LE, Nallani S. Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: a review. Am J Addict. 2010;19(1):4–16.
  • Milberg P, Eckardt L, Bruns H-J, et al. Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdepolarizations and torsade de pointes. J Pharmacol Exp Ther. 2002;303(1):218–225.
  • Fossa AA, Wisialowski T, Duncan JN, et al. Azithromycin/chloroquine combination does not increase cardiac instability despite an increase in monophasic action potential duration in the anesthetized guinea pig. Am J Trop Med Hyg. 2007;77(5):929–938.
  • Mehrzad R, Barza M. Weighing the adverse cardiac effects of fluoroquinolones: a risk perspective. J Clin Pharmacol. 2015;55(11):1198–1206.
  • Hellwig T, Gulseth M. Pharmacokinetic and pharmacodynamic drug interactions with new oral anticoagulants: what do they mean for patients with atrial fibrillation? Ann Pharmacother. 2013;47(11):1478–1487.
  • Rijpma SR, van den Heuvel JJMW, van der Velden M, et al. Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity. Malar J. 2014;13:359.
  • Beach SR, Celano CM, Noseworthy PA, et al. QTc prolongation, Torsades de pointes, and psychotropic medications. Psychosomatics. 2013;54(1):1–13.
  • Beach SR, Celano CM, Sugrue AM, et al. QT prolongation, Torsades de Pointes, and psychotropic medications: a 5-year Update. Psychosomatics. 2018;59(2):105–122.
  • Markowitz JS, Donovan JL, DeVane CL, et al. Effect of St John’s wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. JAMA. 2003;290(11):1500–1504.
  • Brüggemann RJM, Alffenaar J-WC, Blijlevens NMA, et al. Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents. Clin Infect Dis. 2009;48(10):1441–1458.
  • Niwa T, Imagawa Y, Yamazaki H. Drug interactions between nine antifungal agents and drugs metabolized by human cytochromes P450. Curr Drug Metab. 2014;15(7):651–679.
  • Salem M, Reichlin T, Fasel D, et al. Torsade de pointes and systemic azole antifungal agents: analysis of global spontaneous safety reports. Glob Cardiol Sci Pract. 2017;2017(2):11. DOI:10.21542/gcsp.2017.11
  • Devanathan AS, Anderson DJC, Cottrell ML, et al. Contemporary drug-drug interactions in HIV treatment. Clin Pharmacol Ther. 2019;105(6):1362–1377.
  • Fehintola FA, Akinyinka OO, Adewole IF, et al. Drug interactions in the treatment and chemoprophylaxis of malaria in HIV infected individuals in sub Saharan Africa. Curr Drug Metab. 2011;12(1):51–56.
  • Iwuagwu MA, Aloko KS. Adsorption of paracetamol and chloroquine phosphate by some antacids. J Pharm Pharmacol. 1992;44(8):655–658.
  • McElnay JC, Mukhtar HA, D'Arcy PF, et al. The effect of magnesium trisilicate and kaolin on the in vivo absorption of chloroquine. J Trop Med Hyg. 1982;85(4):159–163.
  • Ette EI, Brown-Awala EA, Essien EE. Chloroquine elimination in humans: effect of low-dose cimetidine. J Clin Pharmacol. 1987;27(10):813–816.
  • Tricco AC, Blondal E, Veroniki AA, et al. Comparative safety and effectiveness of serotonin receptor antagonists in patients undergoing chemotherapy: a systematic review and network meta-analysis. BMC Med. 2016;14(1):216.
  • Skinner-Adams T, Davis TM. Synergistic in vitro antimalarial activity of omeprazole and quinine. Antimicrob Agents Chemother. 1999;43(5):1304–1306.
  • Namazi MR. The potential negative impact of proton pump inhibitors on the immunopharmacologic effects of chloroquine and hydroxychloroquine. Lupus. 2009;18(2):104–105.
  • Finielz P, Gendoo Z, Chuet C, et al. Interaction between cyclosporin and chloroquine. Nephron. 1993;65(2):333.
  • Nampoory MR, Nessim J, Gupta RK, et al. Drug interaction of chloroquine with ciclosporin. Nephron. 1992;62(1):108–109.
  • Griffiths N, Lamb JF, Ogden P. The effects of chloroquine and other weak bases on the accumulation and efflux of digoxin and ouabain in HeLa cells. Br J Pharmacol. 1983;79(4):877–890.
  • Leden I. Digoxin-hydroxychloroquine interaction? Acta Med Scand. 1982;211(5):411–412.
  • Goldstein LH, Gabin A, Fawaz A, et al. Azithromycin is not associated with QT prolongation in hospitalized patients with community-acquired pneumonia. Pharmacoepidemiol Drug Saf. 2015;24(10):1042–1048.
  • Alam K, Pahwa S, Wang X, et al. Downregulation of organic anion transporting polypeptide (OATP) 1B1 transport function by lysosomotropic drug chloroquine: implication in OATP-mediated drug-drug interactions. Mol Pharm. 2016;13(3):839–851.
  • Hou LJ, Raju SS, Abdulah MS, et al. Rifampicin antagonizes the effect of choloroquine on chloroquine-resistant Plasmodium berghei in mice. Jpn J Infect Dis. 2004;57(5):198–202.
  • Kjaer K. Effects of an overdose of chloroquine in a pregnant woman. Am J Trop Med Hyg. 1955;4(2):259–262.
  • Graham JD. An overdose of “plaquenil”. Br Med J. 1960;1(5181):1256.
  • Gunja N, Roberts D, McCoubrie D, et al. Survival after massive hydroxychloroquine overdose. Anaesth Intensive Care. 2009;37(1):130–133.
  • Hantson P, Ronveau JL, De Coninck B, et al. Amrinone for refractory cardiogenic shock following chloroquine poisoning. Intensive Care Med. 1991;17(7):430–431.
  • Jordan P, Brookes JG, Nikolic G, et al. Hydroxychloroquine overdose: toxicokinetics and management. J Toxicol Clin Toxicol. 1999;37(7):861–864.
  • Keller T, Schneider A, Lamprecht R, et al. Fatal chloroquine intoxication. Forensic Sci Int. 1998;96(1):21–28.
  • Muhm M, Stimpfl T, Malzer R, et al. Suicidal chloroquine poisoning: clinical course, autopsy findings, and chemical analysis. J Forensic Sci. 1996;41(6):1077–1079.
  • Murphy LR, Maskell KF, Kmiecik KJ, et al. Intravenous lipid emulsion use for severe hydroxychloroquine toxicity. Am J Ther. 2018;25(2):e273–e275.
  • Rajah A. The use of diazepam in chloroquine poisoning. Anaesthesia. 1990;45(11):955–957.
  • Ten Broeke R, Mestrom E, Woo L, et al. Early treatment with intravenous lipid emulsion in a potentially lethal hydroxychloroquine intoxication. Neth J Med. 2016;74:210–214.
  • Ling Ngan Wong A, Tsz Fung Cheung I, Graham CA. Hydroxychloroquine overdose: case report and recommendations for management. Eur J Emerg Med off J Eur Soc Emerg Med. 2008;15:16–18.
  • Yanturali S, Aksay E, Demir OF, et al. Massive hydroxychloroquine overdose. Acta Anaesthesiol Scand. 2004;48(3):379–381.
  • Reddy VG, Sinna S. Chloroquine poisoning: report of two cases. Acta Anaesthesiol Scand. 2000;44(8):1017–1020.
  • Ball DE, Tagwireyi D, Nhachi CFB. Chloroquine poisoning in Zimbabwe: a toxicoepidemiological study. J Appl Toxicol. 2002;22(5):311–315.
  • Marquardt K, Albertson TE. Treatment of hydroxychloroquine overdose. Am J Emerg Med. 2001;19(5):420–424.
  • Isbister GK, Dawson A, Whyte IM. Hydroxychloroquine overdose: a prospective case series. Am J Emerg Med. 2002;20(4):377–378.
  • Clemessy JL, Taboulet P, Hoffman JR, et al. Treatment of acute chloroquine poisoning: a 5-year experience. Crit Care Med. 1996;24(7):1189–1195.
  • de Olano J, Howland MA, Su MK, et al. Toxicokinetics of hydroxychloroquine following a massive overdose. Am J Emerg Med. 2019;37(12):2264.e5–e8.
  • Henderson A, Adamson M, Pond SM. Death from inadvertent chloroquine overdose. Med J Aust. 1994;160(4):231.
  • Chansky PB, Werth VP. Accidental hydroxychloroquine overdose resulting in neurotoxic vestibulopathy. BMJ Case Rep. 2017. DOI:10.1136/bcr-2016-218786. Online ahead of print.
  • Bethlehem C, Jongsma M, Korporaal-Heijman J, et al. Cardiac arrest following chloroquine overdose treated with bicarbonate and lipid emulsion. Neth J Med. 2019;77(5):186–188.
  • Phipps C, Chan K, Teo F, et al. Fatal chloroquine poisoning: a rare cause of sudden cardiac arrest. Ann Acad Med Singap. 2011;40(6):296–297.
  • Stiff G, Robinson D, Cugnoni HL, et al. Massive chloroquine overdose-a survivor. Postgrad Med J. 1991;67(789):678–679.
  • Jaeger A, Sauder P, Kopferschmitt J, et al. Clinical features and management of poisoning due to antimalarial drugs. Med Toxicol Adverse Drug Exp. 1987;2(4):242–273.
  • Mégarbane B, Bloch V, Hirt D, et al. Blood concentrations are better predictors of chioroquine poisoning severity than plasma concentrations: a prospective study with modeling of the concentration/effect relationships. Clin Toxicol Phila Pa. 2010;48(9):904–915.
  • Zaki SA, Mauskar A, Shanbag P. Toxic psychosis due to chloroquine overdose: a case report. J Vector Borne Dis. 2009;46(1):81–82.
  • Ward WQ, Walter-Ryan WG, Shehi GM. Toxic psychosis: a complication of antimalarial therapy. J Am Acad Dermatol. 1985;12(5 Pt 1):863–865.
  • Wilkinson R, Mahatane J, Wade P, et al. Chloroquine poisoning. BMJ. 1993;307(6902):504.
  • Smith ER, Klein-Schwartz W. Are 1-2 dangerous? Chloroquine and hydroxychloroquine exposure in toddlers. J Emerg Med. 2005;28(4):437–443.

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