Assay for evaluation of proarrhythmic effects of herbal products: Case study with 12 Evodia preparations
Guidelines for preclinical drug development reduce the occurrence of arrhythmia-related side effects. Besides ample evidence for the presence of arrhythmogenic substances in plants, there is no consensus on a research strategy for the evaluation of proarrhythmic effects of herbal products. Here, we...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Toxicology Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214750023000471 |
| _version_ | 1797798917478285312 |
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| author | Bozhidar Baltov Stanislav Beyl Igor Baburin Jakob Reinhardt Phillip Szkokan Aleksandra Garifulina Eugen Timin Udo Kraushaar Olivier Potterat Matthias Hamburger Philipp Kügler Steffen Hering |
| author_facet | Bozhidar Baltov Stanislav Beyl Igor Baburin Jakob Reinhardt Phillip Szkokan Aleksandra Garifulina Eugen Timin Udo Kraushaar Olivier Potterat Matthias Hamburger Philipp Kügler Steffen Hering |
| author_sort | Bozhidar Baltov |
| collection | DOAJ |
| description | Guidelines for preclinical drug development reduce the occurrence of arrhythmia-related side effects. Besides ample evidence for the presence of arrhythmogenic substances in plants, there is no consensus on a research strategy for the evaluation of proarrhythmic effects of herbal products. Here, we propose a cardiac safety assay for the detection of proarrhythmic effects of plant extracts based on the experimental approaches described in the Comprehensive In vitro Proarrhythmia Assay (CiPA). Microelectrode array studies (MEAs) and voltage sensing optical technique on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were combined with ionic current measurements in mammalian cell lines, In-silico simulations of cardiac action potentials (APs) and statistic regression analysis. Proarrhythmic effects of 12 Evodia preparations, containing different amounts of the hERG inhibitors dehydroevodiamine (DHE) and hortiamine were analysed. Extracts produced different prolongation of the AP, occurrence of early after depolarisations and triangulation of the AP in hiPSC-CMs depending on the contents of the hERG inhibitors. DHE and hortiamine dose-dependently prolonged the field potential duration in hiPSC-CMs studied with MEAs. In-silico simulations of ventricular AP support a scenario where proarrhythmic effects of Evodia extracts are predominantly caused by the content of the selective hERG inhibitors. Statistic regression analysis revealed a high torsadogenic risk for both compounds that was comparable to drugs assigned to the high-risk category in a CiPA study. |
| first_indexed | 2024-03-13T04:10:52Z |
| format | Article |
| id | doaj.art-fda309defa0a4cfd8025cc81e3d736a8 |
| institution | Directory Open Access Journal |
| issn | 2214-7500 |
| language | English |
| last_indexed | 2024-03-13T04:10:52Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Toxicology Reports |
| spelling | doaj.art-fda309defa0a4cfd8025cc81e3d736a82023-06-21T06:55:11ZengElsevierToxicology Reports2214-75002023-01-0110589599Assay for evaluation of proarrhythmic effects of herbal products: Case study with 12 Evodia preparationsBozhidar Baltov0Stanislav Beyl1Igor Baburin2Jakob Reinhardt3Phillip Szkokan4Aleksandra Garifulina5Eugen Timin6Udo Kraushaar7Olivier Potterat8Matthias Hamburger9Philipp Kügler10Steffen Hering11Division of Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek-Platz 2, 1090 Vienna, Austria; ChanPharm GmbH, Am Kanal 27, 1110 Vienna, AustriaChanPharm GmbH, Am Kanal 27, 1110 Vienna, AustriaChanPharm GmbH, Am Kanal 27, 1110 Vienna, AustriaPharmaceutical Biology, University of Basel, Klingelbergstrasse 50, 4056 Basel, SwitzerlandChanPharm GmbH, Am Kanal 27, 1110 Vienna, AustriaDivision of Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek-Platz 2, 1090 Vienna, AustriaChanPharm GmbH, Am Kanal 27, 1110 Vienna, AustriaNMI Natural and Medical Sciences Institute at the University of Tuebingen, Reutlingen, GermanyPharmaceutical Biology, University of Basel, Klingelbergstrasse 50, 4056 Basel, SwitzerlandPharmaceutical Biology, University of Basel, Klingelbergstrasse 50, 4056 Basel, SwitzerlandUniversity of Hohenheim, Institute of Applied Mathematics and Statistics and Computational Science Hub, 70599 Stuttgart, GermanyDivision of Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek-Platz 2, 1090 Vienna, Austria; ChanPharm GmbH, Am Kanal 27, 1110 Vienna, Austria; Correspondence to: Am Kanal 27,2/3/5–7, 1110 Vienna, Austria.Guidelines for preclinical drug development reduce the occurrence of arrhythmia-related side effects. Besides ample evidence for the presence of arrhythmogenic substances in plants, there is no consensus on a research strategy for the evaluation of proarrhythmic effects of herbal products. Here, we propose a cardiac safety assay for the detection of proarrhythmic effects of plant extracts based on the experimental approaches described in the Comprehensive In vitro Proarrhythmia Assay (CiPA). Microelectrode array studies (MEAs) and voltage sensing optical technique on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were combined with ionic current measurements in mammalian cell lines, In-silico simulations of cardiac action potentials (APs) and statistic regression analysis. Proarrhythmic effects of 12 Evodia preparations, containing different amounts of the hERG inhibitors dehydroevodiamine (DHE) and hortiamine were analysed. Extracts produced different prolongation of the AP, occurrence of early after depolarisations and triangulation of the AP in hiPSC-CMs depending on the contents of the hERG inhibitors. DHE and hortiamine dose-dependently prolonged the field potential duration in hiPSC-CMs studied with MEAs. In-silico simulations of ventricular AP support a scenario where proarrhythmic effects of Evodia extracts are predominantly caused by the content of the selective hERG inhibitors. Statistic regression analysis revealed a high torsadogenic risk for both compounds that was comparable to drugs assigned to the high-risk category in a CiPA study.http://www.sciencedirect.com/science/article/pii/S2214750023000471Evodia rutaecarpaCardiac safetyHERGTdPHiPSC-CMs |
| spellingShingle | Bozhidar Baltov Stanislav Beyl Igor Baburin Jakob Reinhardt Phillip Szkokan Aleksandra Garifulina Eugen Timin Udo Kraushaar Olivier Potterat Matthias Hamburger Philipp Kügler Steffen Hering Assay for evaluation of proarrhythmic effects of herbal products: Case study with 12 Evodia preparations Toxicology Reports Evodia rutaecarpa Cardiac safety HERG TdP HiPSC-CMs |
| title | Assay for evaluation of proarrhythmic effects of herbal products: Case study with 12 Evodia preparations |
| title_full | Assay for evaluation of proarrhythmic effects of herbal products: Case study with 12 Evodia preparations |
| title_fullStr | Assay for evaluation of proarrhythmic effects of herbal products: Case study with 12 Evodia preparations |
| title_full_unstemmed | Assay for evaluation of proarrhythmic effects of herbal products: Case study with 12 Evodia preparations |
| title_short | Assay for evaluation of proarrhythmic effects of herbal products: Case study with 12 Evodia preparations |
| title_sort | assay for evaluation of proarrhythmic effects of herbal products case study with 12 evodia preparations |
| topic | Evodia rutaecarpa Cardiac safety HERG TdP HiPSC-CMs |
| url | http://www.sciencedirect.com/science/article/pii/S2214750023000471 |
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