Cardiotoxic Potential of Hydroxychloroquine, Chloroquine and Azithromycin in Adult Human Primary Cardiomyocytes.
Adult
Aged
Aged, 80 and over
Antiviral Agents
/ administration & dosage
Azithromycin
/ administration & dosage
Cardiotoxicity
Chloroquine
/ administration & dosage
Female
Humans
Hydroxychloroquine
/ administration & dosage
Male
Middle Aged
Myocytes, Cardiac
/ drug effects
Risk Assessment
SARS-CoV-2
United States
COVID-19 Drug Treatment
COVID-19
adult human primary cardiomyocyte
contractility
hydroxychloroquine
proarrhythmia risk
translation
Journal
Toxicological sciences : an official journal of the Society of Toxicology
ISSN: 1096-0929
Titre abrégé: Toxicol Sci
Pays: United States
ID NLM: 9805461
Informations de publication
Date de publication:
12 04 2021
12 04 2021
Historique:
pubmed:
24
1
2021
medline:
27
4
2021
entrez:
23
1
2021
Statut:
ppublish
Résumé
Substantial efforts have been recently committed to develop coronavirus disease-2019 (COVID-19) medications, and Hydroxychloroquine alone or in combination with Azithromycin has been promoted as a repurposed treatment. Although these drugs may increase cardiac toxicity risk, cardiomyocyte mechanisms underlying this risk remain poorly understood in humans. Therefore, we evaluated the proarrhythmia risk and inotropic effects of these drugs in the cardiomyocyte contractility-based model of the human heart. We found Hydroxychloroquine to have a low proarrhythmia risk, whereas Chloroquine and Azithromycin were associated with high risk. Hydroxychloroquine proarrhythmia risk changed to high with low level of K+, whereas high level of Mg2+ protected against proarrhythmic effect of high Hydroxychloroquine concentrations. Moreover, therapeutic concentration of Hydroxychloroquine caused no enhancement of elevated temperature-induced proarrhythmia. Polytherapy of Hydroxychloroquine plus Azithromycin and sequential application of these drugs were also found to influence proarrhythmia risk categorization. Hydroxychloroquine proarrhythmia risk changed to high when combined with Azithromycin at therapeutic concentration. However, Hydroxychloroquine at therapeutic concentration impacted the cardiac safety profile of Azithromycin and its proarrhythmia risk only at concentrations above therapeutic level. We also report that Hydroxychloroquine and Chloroquine, but not Azithromycin, decreased contractility while exhibiting multi-ion channel block features, and Hydroxychloroquine's contractility effect was abolished by Azithromycin. Thus, this study has the potential to inform clinical studies evaluating repurposed therapies, including those in the COVID-19 context. Additionally, it demonstrates the translational value of the human cardiomyocyte contractility-based model as a key early discovery path to inform decisions on novel therapies for COVID-19, malaria, and inflammatory diseases.
Identifiants
pubmed: 33483756
pii: 6112009
doi: 10.1093/toxsci/kfaa194
pmc: PMC7928616
doi:
Substances chimiques
Antiviral Agents
0
Hydroxychloroquine
4QWG6N8QKH
Azithromycin
83905-01-5
Chloroquine
886U3H6UFF
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
356-368Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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