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An in silico-in vitro pipeline for drug cardiotoxicity screening identifies ionic pro-arrhythmia mechanisms.
Br J Pharmacol
October 2022
Department of Biomedical Engineering, Cornell University, Ithaca, New York, USA.
Background And Purpose: Before advancing to clinical trials, new drugs are screened for their pro-arrhythmic potential using a method that is overly conservative and provides limited mechanistic insight. The shortcomings of this approach can lead to the mis-classification of beneficial drugs as pro-arrhythmic.
Experimental Approach: An in silico-in vitro pipeline was developed to circumvent these shortcomings.
Torsadogenic Action of Cisapride, dl-Sotalol, Bepridil, and Verapamil Analyzed by the Chronic Atrioventricular Block Cynomolgus Monkeys: Comparison With That Reported in the CiPA In Silico Mechanistic Model.
Toxicol Sci
April 2021
Department of Pharmacology, Toho University Graduate School of Medicine, Ota-ku, Tokyo 143-8540, Japan.
In order to bridge the gap of information between the in silico model and human subjects, we evaluated torsadogenic risk of cisapride, dl-sotalol, bepridil and verapamil selected from 12 training compounds in the comprehensive in vitro proarrhythmia assay using the chronic atrioventricular block monkeys. Cisapride (0, 1, and 5 mg/kg, n = 5 for each dose), dl-sotalol (0, 1, 3, and 10 mg/kg, n = 5 for each dose), bepridil (0, 10, and 100 mg/kg, n = 4 for each dose), verapamil (0, 1.5, 15, and 75 mg/kg, n = 4 for each dose) were orally administered to the monkeys in conscious state.
View Article and Find Full Text PDFThree-Dimensional Heart Model-Based Screening of Proarrhythmic Potential by Simulation of Action Potential and Electrocardiograms.
Front Physiol
September 2019
Department of Clinical Pharmacology and Therapeutics, Seoul St. Mary's Hospital, Seoul, South Korea.
The proarrhythmic risk is a major concern in drug development. The Comprehensive Proarrhythmia Assay (CiPA) initiative has proposed the JTpeak interval on electrocardiograms (ECGs) and qNet, an metric, as new biomarkers that may overcome the limitations of the hERG assay and QT interval. In this study, we simulated body-surface ECGs from patch-clamp data using realistic models of the ventricles and torso to explore their suitability as new biomarkers for cardiac safety.
View Article and Find Full Text PDFRecording of multiple ion current components and action potentials in human induced pluripotent stem cell-derived cardiomyocytes via automated patch-clamp.
J Pharmacol Toxicol Methods
March 2020
Dept. Biophysics & Physiology, Faculty of Biology, University of Bucharest, Splaiul Independentei 91-95, 050095 Bucharest, Romania. Electronic address:
Introduction: The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative proposes a three-step approach to evaluate proarrhythmogenic liability of drug candidates: effects on individual ion channels in heterologous expression systems, integrating these data into in-silico models of the electrical activity of human cardiomyocytes, and comparison with experiments on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Here we introduce patch-clamp electrophysiology techniques on hiPSC-CM to combine two of the CiPA steps in one assay.
Methods: We performed automated patch-clamp experiments on hiPSC-CM (Cor.
A Proof-of-Concept Evaluation of JTPc and Tp-Tec as Proarrhythmia Biomarkers in Preclinical Species: A Retrospective Analysis by an HESI-Sponsored Consortium.
Int J Toxicol
December 2019
1 GREPAQ (Groupe de recherche en pharmacologie animale du Québec), Université de Montréal, St-Hyacinthe, Quebec, Canada.
Introduction: Based on the ICH S7B and E14 guidance documents, QT interval (QTc) is used as the primary in vivo biomarker to assess the risk of drug-induced torsades de pointes (TdP). Clinical and nonclinical data suggest that drugs that prolong the corrected QTc with balanced multiple ion channel inhibition (most importantly the l-type calcium, Cav1.2, and persistent or late inward sodium current, Nav1.
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