Abstract

Over 100 drugs and chemicals are associated with permanent hearing loss, tinnitus, and vestibular deficits, collectively known as ototoxicity. The ototoxic potential of drugs is rarely assessed in pre-clinical drug development or during clinical trials, so this debilitating side-effect is often discovered as patients begin to report hearing loss. Furthermore, drug-induced ototoxicity in adults, and particularly in elderly patients, may go unrecognized due to hearing loss from a variety of etiologies because of a lack of baseline assessments immediately prior to novel therapeutic treatment. During the current pandemic, there is an intense effort to identify new drugs or repurpose FDA-approved drugs to treat COVID-19. Several potential COVID-19 therapeutics are known ototoxins, including chloroquine (CQ) and lopinavir-ritonavir, demonstrating the necessity to identify ototoxic potential in existing and novel medicines. Furthermore, several factors are emerging as potentiators of ototoxicity, such as inflammation (a hallmark of COVID-19), genetic polymorphisms, and ototoxic synergy with co-therapeutics, increasing the necessity to evaluate a drug's potential to induce ototoxicity under varying conditions. Here, we review the potential of COVID-19 therapies to induce ototoxicity and factors that may compound their ototoxic effects. We then discuss two models for rapidly detecting the potential for ototoxicity: mammalian auditory cell lines and the larval zebrafish lateral line. These models offer considerable value for pre-clinical drug development, including development of COVID-19 therapies. Finally, we show the validity of in silico screening for ototoxic potential using a computational model that compares structural similarity of compounds of interest with a database of known ototoxins and non-ototoxins. Preclinical screening at in silico, in vitro, and in vivo levels can provide an earlier indication of the potential for ototoxicity and identify the subset of candidate therapeutics for treating COVID-19 that need to be monitored for ototoxicity as for other widely-used clinical therapeutics, like aminoglycosides and cisplatin.

Highlights

  • Drug-induced ototoxicity gained widespread recognition in the 1940’s due to the discovery of hearing loss in patients receiving the -novel aminoglycoside antibiotic streptomycin [1]

  • This strategy should be highly useful when applied to databases of COVID-19 therapeutics, allowing researchers to rapidly identify potential ototoxins based on chemical structure, opportunities to validate these ototoxins in auditory cell lines or the lateral line system

  • We argue that ototoxicity screening should be a required step in the drug development process

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Summary

Introduction

Drug-induced ototoxicity gained widespread recognition in the 1940’s due to the discovery of hearing loss in patients receiving the -novel aminoglycoside antibiotic streptomycin [1]. Both models are highly amenable to moderate- to high-throughput screening for ototoxic potential in new drugs or compound libraries, deciphering the molecular mechanisms of toxicity by known ototoxins, and testing protective therapies [e.g., [7,8,9,10,11]]. It is possible that severe systemic inflammation in COVID-19 patients could increase the risk of drug-induced hearing loss when therapeutics used for treating COVID-19 infections are known or suspected ototoxins.

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