Review Article

Ototoxic and Vestibulotoxic Effects of Chloroquine/Hydroxychloroquine and Remdesivir in the Treatment of COVID-19: Update Review

Abstract

Introduction: Antiviral drugs have been extensively used as a potential treatment during the COVID-19 pandemic. Based on previous studies, there were concerns about some of these drugs’ ototoxic and vestibulotoxic effects. Still, these concerns were exacerbated by the widespread use of these drugs at the beginning of the COVID-19 pandemic. Therefore, this article was done to comprehensively review the effects of ototoxicity and vestibulotoxicity of chloroquine (CQ)/hydroxychloroquine (HCQ) and remdesivir with different administration models and compare with the COVID-19 treatment guidelines in the world and Iran.
Materials and Methods: This study collected the related published studies in PubMed, Scopus, Google Scholar, and Web of Science with the main keywords “chloroquine”, “hydroxychloroquine”, “remdesivir”, “ototoxicity”, “vestibulotoxicity”, and “COVID-19”.
Results: The dose or duration of used HCQ/CQ drugs that caused ototoxic or vestibulotoxic effects in some diseases was reported mainly more than in COVID-19 guidelines, especially in Iran. These findings align with a recent study on slight HCQ-induced ototoxicity in patients with COVID-19 at low doses and short lengths of use. No evidence of possible cochlear damage after taking remdesivir is reported.
Conclusion: It seems that the concern about the ototoxic effects of some drugs used in the COVID-19 pandemic should be according to some factors that affect the pharmacological effects of drugs, such as dose, length of use, and co-administration of drugs. Therefore, lower dosage and length of use in some administration models in COVID-19 treatment, such as Iran, are associated with limited and reversible ototoxicity effects. However, further studies are needed.

Saghir SAM, AlGabri NA, Alagawany MM, Attia YA, Alyileili SR, Elnesr SS, et al. Chloroquine and hydroxychloroquine for the prevention and treatment of covid-19: A fiction, hope or hype? An updated review. Therapeutics and Clinical Risk Management. 2021; 17:371-87. [DOI:10.2147/TCRM.S301817] [PMID] [PMCID]

Forni G, Mantovani A; COVID-19 Commission of Accademia Nazionale dei Lincei, Rome. COVID-19 vaccines: where we stand and challenges ahead. Cell Death & Differentiation. 2021; 28(2):626-39. [DOI:10.1038/s41418-020-00720-9] [PMID] [PMCID]

COVID-19 Treatment Guidelines Panel. Coronavirus disease 2019 (covid-19) treatment guidelines. Maryland: National Institutes of Health; 2022 . [Link]

Subramaniam V, Vaswani RV. Assessment of short term chloroquine-induced ototoxicity in malaria patients. Global Journal of Medical Research. 2015; 15:14-7. [Link]

Coutinho MB, Duarte I. Hydroxychloroquine ototoxicity in a child with idiopathic pulmonary haemosiderosis. International Journal of Pediatric Otorhinolaryngology. 2002; 62(1):53-7. [DOI:10.1016/S0165-5876(01)00592-4.] [PMID]

Fernandes MRN, Soares DBR, Thien CI, Carneiro S. Hydroxychloroquine ototoxicity in a patient with systemic lupus erythematosus. Anais Brasileiros de Dermatologia. 2018; 93(3):469-470. [PMID]

Johansen PB, Gran JT. Ototoxicity due to hydroxychloroquine: Report of two cases. Clinical and Experimental Rheumatology. 1998; 16(4):472-4. [PMID]

Khalili H, Dastan F, Dehghan Manshadi SA. A case report of hearing loss post use of hydroxychloroquine in a HIV-infected patient. Daru. 2014; 22(1):20. [DOI:10.1186/2008-2231-22-20] [PMID] [PMCID]

Lim SC, Tang SP. Hydroxychloroquine-induced ototoxicity in a child with systemic lupus erythematosus. International Journal of Rheumatic Diseases. 2011; 14(1):e1-2. [DOI:10.1111/j.1756-185X.2010.01582.x] [PMID]

Seçkin Ü, Özoran K, Ikinciogullari A, Borman P, Bostan EE. Hydroxychloroquine ototoxicity in a patient with rheumatoid arthritis. Rheumatology International. 2000; 19(5):203-4. [DOI:10.1007/s002960000054] [PMID]

Food and Drug Administration. Coronavirus (COVID-19) Update: FDA revokes emergency use authorization for chloroquine and hydroxychloroquine. Maryland: Food and Drug Administration; 2020. [Link]

Rahmanzade R, Rahmanzadeh R, Hashemian SM, Tabarsi P. Iran’s Approach to COVID-19: Evolving treatment protocols and ongoing clinical trials. Frontiers in Public Health. 2020; 8:551889. [DOI:10.3389/fpubh.2020.551889] [PMID] [PMCID]

Nicastri E, Petrosillo N, Ascoli Bartoli T, Lepore L, Mondi A, Palmieri F, et al. National Institute for the Infectious Diseases “L. Spallanzani”, IRCCS. Recommendations for COVID-19 clinical management. Infectious Disease Reports. 2020; 12(1):8543. [DOI:10.4081/idr.2020.8543] [PMID] [PMCID]

Prayuenyong P, Kasbekar AV, Baguley DM. Clinical implications of chloroquine and hydroxychloroquine ototoxicity for covid-19 treatment: A mini-review. Frontiers in Public Health. 2020; 8:252. [DOI:10.3389/fpubh.2020.00252] [PMID] [PMCID]

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; 6:16. [DOI:10.1038/s41421-020-0156-0] [PMID] [PMCID]

Chen J, Liu D, Liu L, Liu P, Xu Q, Xia L, et al. [A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19 (Chinese)]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2020; 49(2):215-9. [PMID]

Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, 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] [PMID] [PMCID]

Saghir SAM, AlGabri NA, Alagawany MM, Attia YA, Alyileili SR, Elnesr SS, et al. Chloroquine and hydroxychloroquine for the prevention and treatment of COVID-19: A fiction, hope or hype? An updated review. Therapeutics and Clinical Risk Management. 2021; 17:371-87. [DOI:10.2147/TCRM.S301817] [PMID] [PMCID]

Braga CB, Martins AC, Cayotopa AD, Klein WW, Schlosser AR, da Silva AF, et al. Side effects of chloroquine and primaquine and symptom reduction in malaria endemic area (Mâncio Lima, Acre, Brazil). Interdisciplinary Perspectives on Infectious Diseases. 2015; 2015:346853. [DOI:10.1155/2015/346853] [PMID] [PMCID]

Hadi U, Nuwayhid N, Hasbini AS. Chloroquine ototoxicity: An idiosyncratic phenomenon. Otolaryngology--Head and Neck Surgery: Official Journal of American Academy of Otolaryngology-Head and Neck Surgery. 1996; 114(3):491-3. [DOI:10.1016/S0194-5998(96)70226-7] [PMID]

Sahraei Z, Shabani M, Shokouhi S, Saffaei A. Aminoquinolines against coronavirus disease 2019 (COVID-19): Chloroquine or hydroxychloroquine. International Journal of Antimicrobial Agents. 2020; 55(4):105945. [DOI:10.1016/j.ijantimicag.2020.105945] [PMID] [PMCID]

Ciorba A, Corazzi V, Skarżyński PH, Skarżyńska MB, Bianchini C, Pelucchi S, et al. Don’t forget ototoxicity during the SARS-CoV-2 (Covid-19) pandemic! International Journal of Immunopathology and Pharmacology. 2020; 34:2058738420941754. [DOI:10.1177/2058738420941754] [PMID] [PMCID]

Ciorba A, Skarżyński PH, Pelucchi S, Hatzopoulos S. Ototoxicity prevention during the SARS-CoV-2 (COVID-19) emergency. Journal of Global Antimicrobial Resistance. 2020; 23:263-4. [DOI:10.1016/j.jgar.2020.09.030] [PMID] [PMCID]

Monteiro EMR, Nascimento MFL, Brito TRC, Lima MC, Sefair LR, Pedrosa MM. Chloroquine and COVID-19: Should we care about ototoxicity? International Archives of Otorhinolaryngology. 2020; 24(3):e359-63. [DOI:10.1055/s-0040-1714142] [PMID] [PMCID]

Bernard P. Alterations of auditory evoked potentials during the course of chloroquine treatment. Acta Oto-Laryngologica. 1985; 99(3-4):387-92. [DOI:10.3109/00016488509108928] [PMID]

de Vries FT, Griffiths RI, Bailey M, Craig H, Girlanda M, Gweon HS, et al. Soil bacterial networks are less stable under drought than fungal networks. Nature Communications. 2018; 9(1):3033. [DOI:10.1038/s41467-018-05516-7] [PMID] [PMCID]

Dewar WA, Mann HM. Chloroquine in lupus erythematosus. The Lancet. 1954; 263(6815):780-1. [DOI:10.1016/S0140-6736(54)92747-6]

Matz GJ, Naunton RF. Ototoxicity of chloroquine. Archives of Otolaryngology. 1968; 88(4):370-2. [DOI:10.1001/archotol.1968.00770010372008] [PMID]

Mukherjee DK. Chloroquine ototoxicity-a reversible phenomenon? The Journal of Laryngology and Otology. 1979; 93(8):809-15. [DOI:10.1017/S0022215100087740] [PMID]

Verdel BM, van Puijenbroek EP, Souverein PC, Leufkens HGM, Egberts ACG. Drug-related nephrotoxic and ototoxic reactions: A link through a predictive mechanistic commonality . Drug Safety. 2008; 31(10):877-84. [DOI:10.2165/00002018-200831100-00006] [PMID]

Lanvers-Kaminsky C, Zehnhoff-Dinnesen AA, Parfitt R, Ciarimboli G. Drug‐induced ototoxicity: Mechanisms, pharmacogenetics, and protective strategies. Clinical Pharmacology & Therapeutics. 2017; 101(4):491-500. [DOI:10.1002/cpt.603] [PMID]

WHO. Therapeutics and COVID-19: Living guidelines. Geneva: WHO. [Link]

Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016; 531(7594):381-5. [DOI:10.1038/nature17180] [PMID] [PMCID]

Lamontagne F, Agarwal A, Rochwerg B, Siemieniuk RA, Agoritsas T, Askie L, et al. A living WHO guideline on drugs for covid-19. BMJ. 2020; 370:m3379. [PMID]

Siemieniuk RA, Bartoszko JJ, Zeraatkar D, Kum E, Qasim A, Martinez JPD, et al. Drug treatments for covid-19: living systematic review and network meta-analysis. BMJ. 2020; 370:m2980. [DOI: 10.1136/bmj.m2980] [PMID]

Skarzynska MB, Krol B, Czajka N, Czajka Ł. Ototoxicity of drugs used in the treatment of COVID-19. Journal of Hearing Science. 2020; 10(1):9-20. [Link]

Lamontagne F, Stegemann M, Agarwal A, Agoritsas T, Siemieniuk R, Rochwerg B, et al. A living WHO guideline on drugs to prevent covid-19. BMJ. 2021; 372:n526. [DOI:10.1136/bmj.n526] [PMID]

Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: A randomised, double-blind, placebo-controlled, multicentre trial. The Lancet. 2020; 395(10236):1569-78. [DOI:10.1016/S0140-6736(20)31022-9] [PMID]

Ministry of Health and Medical Education. [Guideline diagnosis and treatment for children and infant with COVID-19 infection, Sixth flowcharts (Persian)]. Tehran: Ministry of Health and Medical Education; 2021. [Link]

Medical Council of Iran. Guideline diagnosis and treatment COVID-19 infection. nine flowchart. Tehran: Medical Council of Iran; 2021. [Link]

Ministry of Health and Medical Education. [Covid-19 patient management guideline, tenth flowchart (Persian)]. Tehran: Ministry of Health and Medical Education; 2021. [Link]

Ministry of Health and Medical Education. [Instructions for taking Remdesivir (Persian)].Tehran: Ministry of Health and Medical Education; 2021. [Link]

Davis SN, Wu P, Camci ED, Simon JA, Rubel EW, Raible DW. Chloroquine kills hair cells in zebrafish lateral line and murine cochlear cultures: Implications for ototoxicity. Hearing Research. 2020; 395:108019. [DOI:10.1016/j.heares.2020.108019] [PMID] [PMCID]

Borba EF, Turrini-Filho JR, Kuruma KA, Bertola C, Pedalini ME, Lorenzi MC, et al. Chloroquine gestational use in systemic lupus erythematosus: Assessing the risk of child ototoxicity by pure tone audiometry. Lupus. 2004; 13(4):223-7. [DOI:10.1191/0961203304lu528oa] [PMID]

Bortoli R, Santiago M. Chloroquine ototoxicity. Clinical Rheumatology. 2007; 26(11):1809-10. [DOI:10.1007/s10067-007-0662-6] [PMID]

Dwivedi GS, Mehra YN. Ototoxicity of chloroquine phosphate: A case report.The Journal of Laryngology and Otology. 1978; 92(8):701-3. [DOI:10.1017/S0022215100085960] [PMID]

Rahimi V, Rouhbakhsh N, Manshadi SAD. Slight high-frequency hearing loss, effect of covid-19 or hydroxychloroquine usage? Otology & Neurotology. 2022; 43(9):e944-50. [DOI:10.1097/MAO.0000000000003649] [PMID] [PMCID]

Hart CW, Naunton RF. The ototoxicity of chloroquine phosphate. Archives of Otolaryngology. 1964; 80(4):407-12. [DOI:10.1001/archotol.1964.00750040419009] [PMID]

FDA. FDA approves first treatment for COVID-19. Maryland: FDA; 2020. [Link]

Taha HR, Keewan N, Slati F, Al-Sawalha NA. Remdesivir: A closer look at its effect in covid-19 pandemic. Pharmacology. 2021; 106(9-10):462-8. [DOI:10.1159/000518440] [PMID] [PMCID]

Mehta HB, An H, Andersen KM, Mansour O, Madhira V, Rashidi ES, et al. Use of hydroxychloroquine, remdesivir, and dexamethasone among adults hospitalized with COVID-19 in the United States: A retrospective cohort study. Annals of Internal Medicine. 2021; 174(10):1395-403. [DOI:10.7326/M21-0857] [PMID] [PMCID]

Amiri M, Hasanalifard M, Delphi M. Impact of COVID-19 on the auditory and vestibular system. Auditory and Vestibular Research Journal. 2021; 30(3):152-9 [DOI:10.18502/avr.v30i3.6528]

Cianfrone G, Pentangelo D, Cianfrone F, Mazzei F, Turchetta R, Orlando MP, et al. Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus: a reasoned and updated guide. European Review for Medical and Pharmacological Sciences. 2011; 15(6):601-36. [PMID]

National Institutes of Healt. Coronavirus disease 2019 (covid-19) treatment guidelines. Maryland: National Institutes of Health; 2019. [Link]

Little C, Cosetti MK. A narrative review of pharmacologic treatments for covid‐19: Safety considerations and ototoxicity. The Laryngoscope. 2021; 131(7):1626-32. [DOI:10.1002/lary.29424] [PMID] [PMCID]

Rossi F, Cuomo V, Biggio G, Ricciardi C. [Farmacologia: Principi di base e applicazioni terapeutiche (Italian)]. Minerva Medica; 2005. [Link]

Ducharme J, Farinotti R. Clinical pharmacokinetics and metabolism of chloroquine. Focus on recent advancements. Clinical Pharmacokinetics. 1996; 31(4):257-74. [DOI:10.2165/00003088-199631040-00003] [PMID]

Jung TTK, Rhee CK, Lee CS, Park YS, Choi DC. Ototoxicity of salicylate, nonsteroidal antiinflammatory drugs, and quinine. Otolaryngologic Clinics of North America. 1993; 26(5):791-810. [DOI:10.1016/S0030-6665(20)30767-2] [PMID]

Hutchison LC, O’Brien CE. Changes in pharmacokinetics and pharmacodynamics in the elderly patient. Journal of Pharmacy Practice. 2007; 20(1):4-12. [DOI:10.1177/0897190007304657]

Roberts J, Turner N. Pharmacodynamic basis for altered drug action in the elderly. Clinics in Geriatric Medicine. 1988; 4(1):127-49. [DOI:10.1016/S0749-0690(18)30769-9] [PMID]

Lien KH, Yang CH. Sex Differences in the triad of acquired sensorineural hearing loss. International Journal of Molecular Sciences. 2021; 22(15):8111. [DOI:10.3390/ijms22158111] [PMID] [PMCID]

Alvan G, Berninger E, Gustafsson LL, Karlsson KK, Paintaud G, Wakelkamp M. Concentration-response relationship of hearing impairment caused by quinine and salicylate: pharmacological similarities but different molecular mechanisms. Basic & Clinical Pharmacology & Toxicology. 2017; 120(1):5-13. [DOI:10.1111/bcpt.12640] [PMID]

Naksuk N, Lazar S, Peeraphatdit TB. Cardiac safety of off-label COVID-19 drug therapy: A review and proposed monitoring protocol. European Heart Journal. Acute Cardiovascular Care. 2020; 9(3):215-21. [DOI:10.1177/2048872620922784] [PMID] [PMCID]

Elsawah HK, Elsokary MA, Abdallah MS, ElShafie AH. Efficacy and safety of remdesivir in hospitalized Covid‐19 patients: Systematic review and meta‐analysis including network meta‐analysis. Reviews in Medical Virology. 2021; 31(4):e2187. [DOI:10.1002/rmv.2187] [PMID]

Aarabi S, Yazdani N, Fakhri J, Rahimi V, Cheraghipour P, Dabiri S. The Relationship between sudden sensorineural hearing loss, vestibular neuritis, and infection with covid-19. Journal of Modern Rehabilitation. 2021; 15(4):239-44. [DOI:10.18502/jmr.v15i4.7744]

Jafari Z, Kolb BE, Mohajerani MH. Hearing loss, tinnitus, and dizziness in COVID-19: A systematic review and meta-analysis. The Canadian Journal of Neurological Sciences. Le Journal Canadien des Sciences Neurologiques. 2022; 49(2):184-95. [DOI:10.1017/cjn.2021.63] [PMID] [PMCID]

Rahimi V, Asiyabar MK, Rouhbakhsh N. Sudden hearing loss and coronavirus disease 2019: The role of corticosteroid intra-tympanic injection in hearing improvement. The Journal of Laryngology & Otology. 2021; 135(5):464-6. [DOI:10.1017/S0022215121001080] [PMID]

Swain SK. Hearing loss and vertigo among COVID-19 patients: A review. International Journal of Research in Medical Sciences. 2021; 9(9):2863-8. [DOI:10.18203/2320-6012.ijrms20213434]

De Luca P, Scarpa A, De Bonis E, Cavaliere M, Viola P, Gioacchini FM, et al. Chloroquine and hydroxychloroquine ototoxicity; potential implications for SARS-CoV-2 treatment. A brief review of the literature. American Journal of Otolaryngology. 2021; 42(5):102640. [DOI:10.1016/j.amjoto.2020.102640] [PMID] [PMCID]

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IssueVol 17 No 3 (2023) QRcode
SectionReview Article(s)
DOI https://doi.org/10.18502/jmr.v17i3.13062
Keywords
Severe acute respiratory syndrome coronavirus (SARS-CoV-2) COVID-19 Ototoxic drugs Hearing loss Antiviral drugs

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1.
Rahimi V, Tavanai E, Khalili ME, Mohammadkhani G. Ototoxic and Vestibulotoxic Effects of Chloroquine/Hydroxychloroquine and Remdesivir in the Treatment of COVID-19: Update Review. jmr. 2023;17(3):219-230.