Yoon Seung-Hyun, Lee Hyun-Lee, Jeong Da Un, Lim Ki Moo, Park Seong-Jun, Kim Ki-Suk
R&D Center for Advanced Pharmaceuticals and Evaluation, Korea Institute of Toxicology, Daejeon, Republic of Korea.
College of Veterinary Medicine, Research Institute of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea.
Front Pharmacol. 2023 Aug 15;14:1220796. doi: 10.3389/fphar.2023.1220796. eCollection 2023.
Due to the outbreak of the SARS-CoV-2 virus, drug repurposing and Emergency Use Authorization have been proposed to treat the coronavirus disease 2019 (COVID-19) during the pandemic. While the efficiency of the drugs has been discussed, it was identified that certain compounds, such as chloroquine and hydroxychloroquine, cause QT interval prolongation and potential cardiotoxic effects. Drug-induced cardiotoxicity and QT prolongation may lead to life-threatening arrhythmias such as torsades de pointes (TdP), a potentially fatal arrhythmic symptom. Here, we evaluated the risk of repurposed pyronaridine or artesunate-mediated cardiac arrhythmias alone and in combination for COVID-19 treatment through and investigations using the Comprehensive Proarrhythmia Assay (CiPA) initiative. The potential effects of each drug or in combinations on cardiac action potential (AP) and ion channels were explored using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and Chinese hamster ovary (CHO) cells transiently expressing cardiac ion channels (Nav1.5, Cav1.2, and hERG). We also performed computer simulation using the optimized O'Hara-Rudy human ventricular myocyte model (ORd model) to classify TdP risk. Artesunate and dihydroartemisinin (DHA), the active metabolite of artesunate, are classified as a low risk of inducing TdP based on the torsade metric score (TMS). Moreover, artesunate does not significantly affect the cardiac APs of hiPSC-CMs even at concentrations up to 100 times the maximum serum concentration (C). DHA modestly prolonged at APD (10.16%) at 100 times the C. When considering C, pyronaridine, and the combination of both drugs (pyronaridine and artesunate) are classified as having an intermediate risk of inducing TdP. However, when considering the unbound concentration (the free fraction not bound to carrier proteins or other tissues inducing pharmacological activity), both drugs are classified as having a low risk of inducing TdP. In summary, pyronaridine, artesunate, and a combination of both drugs have been confirmed to pose a low proarrhythmogenic risk at therapeutic and supratherapeutic (up to 4 times) free C. Additionally, the CiPA initiative may be suitable for regulatory use and provide novel insights for evaluating drug-induced cardiotoxicity.
由于严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）病毒的爆发，在疫情期间已提出药物重新利用和紧急使用授权来治疗2019冠状病毒病（COVID-19）。虽然已经讨论了药物的疗效，但已确定某些化合物，如氯喹和羟氯喹，会导致QT间期延长和潜在的心脏毒性作用。药物诱导的心脏毒性和QT延长可能导致危及生命的心律失常，如尖端扭转型室速（TdP），这是一种潜在的致命性心律失常症状。在此，我们通过使用综合致心律失常分析（CiPA）计划进行体外和体内研究，评估了重新利用的咯萘啶或青蒿琥酯单独及联合用于COVID-19治疗时介导的心脏心律失常风险。使用人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）和瞬时表达心脏离子通道（Nav1.5、Cav1.2和hERG）的中国仓鼠卵巢（CHO）细胞，探索了每种药物或其组合对心脏动作电位（AP）和离子通道的潜在影响。我们还使用优化的奥哈拉-鲁迪人心室肌细胞模型（ORd模型）进行了计算机模拟，以分类TdP风险。基于尖端扭转型室速指标评分（TMS），青蒿琥酯及其活性代谢物双氢青蒿素（DHA）被分类为诱导TdP的低风险药物。此外，即使在浓度高达最大血清浓度（Cmax）100倍时，青蒿琥酯对hiPSC-CMs的心脏动作电位也没有显著影响。DHA在100倍Cmax时适度延长动作电位时程（APD）（10.16%）。考虑Cmax时，咯萘啶以及两种药物的组合（咯萘啶和青蒿琥酯）被分类为具有诱导TdP的中度风险。然而，考虑未结合浓度（未与载体蛋白或其他诱导药理活性的组织结合的游离部分）时，两种药物均被分类为具有诱导TdP的低风险。总之，咯萘啶、青蒿琥酯以及两种药物的组合已被证实在治疗和超治疗（高达4倍）游离Cmax时具有低致心律失常风险。此外，CiPA计划可能适用于监管用途，并为评估药物诱导的心脏毒性提供新的见解。
