Human ex-vivo action potential model for pro-arrhythmia risk assessment
| Autor: | Jack Reynolds, Andrea Ghetti, Yannick Miron, Paul Miller, Guido Steiner, Ken Wang, Phachareeya Ratchada, Guy Page, Najah Abi-Gerges, Gary A. Gintant, Andrea Greiter-Wilke, Liudmila Polonchuk, Martin Traebert |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Male 0301 basic medicine Quinidine Action Potentials Dofetilide In Vitro Techniques Signal-To-Noise Ratio 030204 cardiovascular system & hematology Pharmacology Toxicology Models Biological Risk Assessment Article Afterdepolarization Electrocardiography Young Adult 03 medical and health sciences 0302 clinical medicine Predictive Value of Tests Drug Discovery medicine Humans Repolarization business.industry Arrhythmias Cardiac Cardiovascular Agents Heart Middle Aged Electrophysiological Phenomena 030104 developmental biology Data Interpretation Statistical Cardiovascular agent Verapamil Female Risk assessment business Ex vivo medicine.drug |
| Zdroj: | Journal of Pharmacological and Toxicological Methods. 81:183-195 |
| ISSN: | 1056-8719 |
| Popis: | While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2 Hz to quantitatively identify the pro-arrhythmic risk. Each drug was blinded and tested separately with 3 concentrations in triplicate trabeculae from 5 hearts, with one vehicle time control per heart. Electrophysiological stability of the model was not affected by sequential applications of vehicle (0.1% dimethyl sulfoxide). Paracetamol and verapamil did not significantly alter anyone of the AP parameters and were classified as devoid of pro-arrhythmic risk. Dofetilide, d,l-sotalol and quinidine exhibited an increase in the manifestation of pro-arrhythmia markers. The model provided quantitative and actionable activity flags and the relatively low total variability in tissue response allowed for the identification of pro-arrhythmic signals. Power analysis indicated that a total of 6 trabeculae derived from 2 hearts are sufficient to identify drug-induced pro-arrhythmia. Thus, the human ex-vivo AP-based model provides an integrative translational assay assisting in shaping clinical development plans that could be used in conjunction with the new CiPA-proposed approach. |
| Databáze: | OpenAIRE |
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