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Neurol."],"abstract":"<jats:p>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<jats:italic>in silico<\/jats:italic>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<jats:italic>in silico, in vitro<\/jats:italic>, and<jats:italic>in vivo<\/jats:italic>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.<\/jats:p>","DOI":"10.3389\/fneur.2021.725566","type":"journal-article","created":{"date-parts":[[2021,8,17]],"date-time":"2021-08-17T13:22:00Z","timestamp":1629206520000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":25,"title":["Detecting Novel Ototoxins and Potentiation of Ototoxicity by Disease Settings"],"prefix":"10.3389","volume":"12","author":[{"given":"Allison 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