Jordaan, Pierre, Abi-Gerges, Najah, Dumotier, Berengere, Ghetti, Andrea, Urban, Laszlo and Miler, Paul (2021) Cardiotoxic Potential of Hydroxychloroquine, Chloroquine and Azithromycin in adult Human Primary Cardiomyocytes. Toxicological Sciences, e-pub (e-pub). pp. 1-13. ISSN 1096-60801096-0929

Abstract

Background
Clinical communications regarding the efficacy and cardiac safety of Hydroxychloroquine (HCQ), Chloroquine (CQ) alone or in combination with Azithromycin (AZ) in patients with Covid-19 provided conflicting evidence. Although these drugs in general have a good safety record, however, if this is true for patients with COVID-19 is unknown.
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Methods
We studied both pro-arrhythmic potential as well as inotropic effect of HCQ, CQ and AZ in paced adult human primary cardiomyocytes in vitro, assessing drug concentrations, the effects of electrolyte changes and elevated temperature that are prevalent risk factors among hospitalized COVID-19 patients.
Results
Concentration-dependent pro-arrhythmia and negative inotropic potential risks of HCQ started within the therapeutic free exposure range (0.1 - 0.3 µM) and were found to be less pronounced compared to CQ. AZ co-administration with HCQ not only altered the pro-arrhythmia profile of HCQ, but also attenuated the negative inotropic effect of HCQ due to mechanisms that need further evaluation. Hypokalemia caused significant indices of pro-arrhythmia at the lower limit of HCQ therapeutic exposure tested, but exposure to high level of Mg2+ significantly reduced all markers of pro-arrhythmia associated with HCQ treatment. When cardiomyocytes were subjected to elevated temperature pro-arrhythmia was observed that was not increased by therapeutic exposure levels of HCQ.
Conclusions
Our data indicate that high exposures levels of HCQ should be avoided. The clinical environment (e.g., elevated temperature, electrolyte changes) associated with severe COVID-19 modulates cardiotoxicity, reinforces the clinical advice to maintain high normal levels of K+ and Mg2+. These results emphasizes the need to assess drugs under the disease-specific conditions.

Item Type:	Article
Date Deposited:	09 Mar 2021 00:45
Last Modified:	09 Mar 2021 00:45
URI:	https://oak.novartis.com/id/eprint/43099