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Article

Synergistic Adverse Effects of Azithromycin and Hydroxychloroquine on Human Cardiomyocytes at a Clinically Relevant Treatment Duration

1
Institute of Pharmacology and Toxicology, Technische Universität Dresden, 01307 Dresden, Germany
2
Institute of Clinical Pharmacology, Technische Universität Dresden, 01307 Dresden, Germany
3
QuoData–Quality & Statistics GmbH, 01309 Dresden, Germany
4
Clinic for Cardiology and Pneumology, University Medical Center Göttingen, 37075 Göttingen, Germany
5
German Center for Cardiovascular Research (DZHK), Partner Site Göttingen, 37075 Göttingen, Germany
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
These authors contributed equally to this work.
Academic Editor: Saima Imran
Pharmaceuticals 2022, 15(2), 220; https://doi.org/10.3390/ph15020220
Received: 20 January 2022 / Revised: 7 February 2022 / Accepted: 10 February 2022 / Published: 12 February 2022
(This article belongs to the Special Issue Drug Screening or Drug Designing Based on Stem Cell Models)
Adverse effects of drug combinations and their underlying mechanisms are highly relevant for safety evaluation, but often not fully studied. Hydroxychloroquine (HCQ) and azithromycin (AZM) were used as a combination therapy in the treatment of COVID-19 patients at the beginning of the pandemic, leading to higher complication rates in comparison to respective monotherapies. Here, we used human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to systematically investigate the effects of HCQ, AZM, and their combination on the structure and functionality of cardiomyocytes, and to better understand the underlying mechanisms. Our results demonstrate synergistic adverse effects of AZM and HCQ on electrophysiological and contractile function of iPSC-CMs. HCQ-induced prolongation of field potential duration (FPDc) was gradually increased during 7-day treatment period and was strongly enhanced by combination with AZM, although AZM alone slightly shortened FPDc in iPSC-CMs. Combined treatment with AZM and HCQ leads to higher cardiotoxicity, more severe structural disarrangement, more pronounced contractile dysfunctions, and more elevated conduction velocity, compared to respective monotreatments. Mechanistic insights underlying the synergistic effects of AZM and HCQ on iPSC-CM functionality are provided based on increased cellular accumulation of HCQ and AZM as well as increased Cx43- and Nav1.5-protein levels. View Full-Text
Keywords: hydroxychloroquine; azithromycin; field potential duration; conduction velocity; human induced pluripotent stem cells; cardiomyocytes; drug testing; drug interaction hydroxychloroquine; azithromycin; field potential duration; conduction velocity; human induced pluripotent stem cells; cardiomyocytes; drug testing; drug interaction
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MDPI and ACS Style

Li, W.; Luo, X.; Poetsch, M.S.; Oertel, R.; Nichani, K.; Schneider, M.; Strano, A.; Hasse, M.; Steiner, R.-P.; Cyganek, L.; Hettwer, K.; Uhlig, S.; Simon, K.; Guan, K.; Schubert, M. Synergistic Adverse Effects of Azithromycin and Hydroxychloroquine on Human Cardiomyocytes at a Clinically Relevant Treatment Duration. Pharmaceuticals 2022, 15, 220. https://doi.org/10.3390/ph15020220

AMA Style

Li W, Luo X, Poetsch MS, Oertel R, Nichani K, Schneider M, Strano A, Hasse M, Steiner R-P, Cyganek L, Hettwer K, Uhlig S, Simon K, Guan K, Schubert M. Synergistic Adverse Effects of Azithromycin and Hydroxychloroquine on Human Cardiomyocytes at a Clinically Relevant Treatment Duration. Pharmaceuticals. 2022; 15(2):220. https://doi.org/10.3390/ph15020220

Chicago/Turabian Style

Li, Wener, Xiaojing Luo, Mareike S. Poetsch, Reinhard Oertel, Kapil Nichani, Martin Schneider, Anna Strano, Marcel Hasse, Robert-Patrick Steiner, Lukas Cyganek, Karina Hettwer, Steffen Uhlig, Kirsten Simon, Kaomei Guan, and Mario Schubert. 2022. "Synergistic Adverse Effects of Azithromycin and Hydroxychloroquine on Human Cardiomyocytes at a Clinically Relevant Treatment Duration" Pharmaceuticals 15, no. 2: 220. https://doi.org/10.3390/ph15020220

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