Assessment of the proarrhythmic effects of repurposed antimalarials for COVID-19 treatment using a comprehensive in vitro proarrhythmia assay (CiPA)
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 a...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-08-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1220796/full |
| _version_ | 1797742371822108672 |
|---|---|
| author | Seung-Hyun Yoon Seung-Hyun Yoon Hyun-Lee Lee Da Un Jeong Ki Moo Lim Seong-Jun Park Ki-Suk Kim |
| author_facet | Seung-Hyun Yoon Seung-Hyun Yoon Hyun-Lee Lee Da Un Jeong Ki Moo Lim Seong-Jun Park Ki-Suk Kim |
| author_sort | Seung-Hyun Yoon |
| collection | DOAJ |
| description | 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 in vitro and in silico investigations using the Comprehensive in vitro 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 in silico 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 (Cmax). DHA modestly prolonged at APD90 (10.16%) at 100 times the Cmax. When considering Cmax, 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 Cmax. Additionally, the CiPA initiative may be suitable for regulatory use and provide novel insights for evaluating drug-induced cardiotoxicity. |
| first_indexed | 2024-03-12T14:39:54Z |
| format | Article |
| id | doaj.art-428570df265441f3902d939e37cacb28 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-12T14:39:54Z |
| publishDate | 2023-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-428570df265441f3902d939e37cacb282023-08-16T09:16:02ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-08-011410.3389/fphar.2023.12207961220796Assessment of the proarrhythmic effects of repurposed antimalarials for COVID-19 treatment using a comprehensive in vitro proarrhythmia assay (CiPA)Seung-Hyun Yoon0Seung-Hyun Yoon1Hyun-Lee Lee2Da Un Jeong3Ki Moo Lim4Seong-Jun Park5Ki-Suk Kim6R&D Center for Advanced Pharmaceuticals and Evaluation, Korea Institute of Toxicology, Daejeon, Republic of KoreaCollege of Veterinary Medicine, Research Institute of Veterinary Medicine, Chungnam National University, Daejeon, Republic of KoreaR&D Center for Advanced Pharmaceuticals and Evaluation, Korea Institute of Toxicology, Daejeon, Republic of KoreaIntelligent Human Twin Research Center, Electronics and Telecommunications Research Institute, Daejeon, Republic of KoreaDepartment of IT Convergence Engineering, Kumoh National Institute of Technology, Gumi, Republic of KoreaCollege of Veterinary Medicine, Research Institute of Veterinary Medicine, Chungnam National University, Daejeon, Republic of KoreaR&D Center for Advanced Pharmaceuticals and Evaluation, Korea Institute of Toxicology, Daejeon, Republic of KoreaDue 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 in vitro and in silico investigations using the Comprehensive in vitro 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 in silico 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 (Cmax). DHA modestly prolonged at APD90 (10.16%) at 100 times the Cmax. When considering Cmax, 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 Cmax. Additionally, the CiPA initiative may be suitable for regulatory use and provide novel insights for evaluating drug-induced cardiotoxicity.https://www.frontiersin.org/articles/10.3389/fphar.2023.1220796/fullCiPAcardiotoxicityCOVID-19electrophysiologyantimalarials |
| spellingShingle | Seung-Hyun Yoon Seung-Hyun Yoon Hyun-Lee Lee Da Un Jeong Ki Moo Lim Seong-Jun Park Ki-Suk Kim Assessment of the proarrhythmic effects of repurposed antimalarials for COVID-19 treatment using a comprehensive in vitro proarrhythmia assay (CiPA) Frontiers in Pharmacology CiPA cardiotoxicity COVID-19 electrophysiology antimalarials |
| title | Assessment of the proarrhythmic effects of repurposed antimalarials for COVID-19 treatment using a comprehensive in vitro proarrhythmia assay (CiPA) |
| title_full | Assessment of the proarrhythmic effects of repurposed antimalarials for COVID-19 treatment using a comprehensive in vitro proarrhythmia assay (CiPA) |
| title_fullStr | Assessment of the proarrhythmic effects of repurposed antimalarials for COVID-19 treatment using a comprehensive in vitro proarrhythmia assay (CiPA) |
| title_full_unstemmed | Assessment of the proarrhythmic effects of repurposed antimalarials for COVID-19 treatment using a comprehensive in vitro proarrhythmia assay (CiPA) |
| title_short | Assessment of the proarrhythmic effects of repurposed antimalarials for COVID-19 treatment using a comprehensive in vitro proarrhythmia assay (CiPA) |
| title_sort | assessment of the proarrhythmic effects of repurposed antimalarials for covid 19 treatment using a comprehensive in vitro proarrhythmia assay cipa |
| topic | CiPA cardiotoxicity COVID-19 electrophysiology antimalarials |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1220796/full |
| work_keys_str_mv | AT seunghyunyoon assessmentoftheproarrhythmiceffectsofrepurposedantimalarialsforcovid19treatmentusingacomprehensiveinvitroproarrhythmiaassaycipa AT seunghyunyoon assessmentoftheproarrhythmiceffectsofrepurposedantimalarialsforcovid19treatmentusingacomprehensiveinvitroproarrhythmiaassaycipa AT hyunleelee assessmentoftheproarrhythmiceffectsofrepurposedantimalarialsforcovid19treatmentusingacomprehensiveinvitroproarrhythmiaassaycipa AT daunjeong assessmentoftheproarrhythmiceffectsofrepurposedantimalarialsforcovid19treatmentusingacomprehensiveinvitroproarrhythmiaassaycipa AT kimoolim assessmentoftheproarrhythmiceffectsofrepurposedantimalarialsforcovid19treatmentusingacomprehensiveinvitroproarrhythmiaassaycipa AT seongjunpark assessmentoftheproarrhythmiceffectsofrepurposedantimalarialsforcovid19treatmentusingacomprehensiveinvitroproarrhythmiaassaycipa AT kisukkim assessmentoftheproarrhythmiceffectsofrepurposedantimalarialsforcovid19treatmentusingacomprehensiveinvitroproarrhythmiaassaycipa |