early afterdepolarization

Last paper published in Toxicology and applied pharmacology (2022)

By On 19/02/2022

Taap 1

 

 

 

 

 

 

 

 

 

 

Occurrence of early afterdepolarization under healthy or hypertrophic cardiomyopathy conditions in the human ventricular endocardial myocyte: in silico study using 109 torsadogenic or non-torsadogenic compounds 

Toxicology and Applied Pharmacology, 438: 115914

https://www.sciencedirect.com/science/article/abs/pii/S0041008X2200059X   PMID: 35150662

read and download for free from the following link provided by Elsevier until April 05, 2022: https://authors.elsevier.com/a/1eb1w_,5zwpSdx

The goal of the CiPA initiative (Comprehensive in vitro Proarrhythmia Assay) was to assess a more accurate prediction of new drug candidate proarrhythmic severe liabilities such as torsades de pointes, for example. This new CiPA paradigm was partly based on in silico reconstruction of human ventricular cardiomyocyte action potential useful to identify repolarization abnormalities such early afterdepolarization (EAD), for example. Using the ToR-ORd algorithm (Tomek-Rodriguez-O'Hara-Rudy dynamic model), the aim of the present work was (i) to identify intracellular parameters leading to EAD occurrence under healthy and hypertrophic cardiomyopathy (HCM) conditions and (ii) to evaluate the prediction accuracy of compound torsadogenic risk based on EAD occurrence using a large set of 109 torsadogenic and non-torsadogenic compounds under both experimental conditions. In silico results highlighted the crucial involvement of Ca++ handling in the ventricular cardiomyocyte intracellular subspace compartment for the initiation of EAD, demonstrated by a higher amplitude of Ca++ release from junctional sarcoplasmic reticulum to subspace compartments (Jrel) measured at EAD take-off voltage in the presence vs. the absence of EAD initiated either by high IKr inhibition or by high enough concentration of a torsadogenic compound under both experimental conditions. Under healthy or HCM conditions, the prediction accuracy of the torsadogenic risk of compound based on EAD occurrence was observed to be 61 or 92%, respectively. This high accuracy under HCM conditions was discussed regarding its usefulness for cardiac safety pharmacology at least at early drug screening/preclinical stage of the drug development process.

https://doi.org/10.1016/j.taap.2022.115914

Last abstract: A risk profile of fenspiride using ion channel data and in silico action potential modeling (2020)

By On 01/12/2020

 

Crumb W.J. Jr  & Christophe B.  (2020)

A risk profile of fenspiride using ion channel data and in silico action potential modeling

Journal of pharmacological and toxicological methods, 105, 106793

https://doi.org/10.1016/j.vascn.2020.106793

Safety Pharmacological Society / Barcelone / September 23-26, 2019

 

Recently, the marketing authorization for fenspiride containing products has been suspended in the EU due to reports of QT prolongation and torsade de pointes. As indicated in the Public Assessment report for Fenspiride, a total of 5 cases of QT prolongation including 3 cases of torsade de pointes were reported since the marketing of fenspiride. Most of these cases were in patients which had known or suspected risk factors for QT prolongation or arrhythmias (eg congenital LQT) or in patients taking other QT prolonging drugs or doses of fenspiride well above therapeutic. The goal of the present study was to characterize the effects of fenspiride on 3 ion channels which are known to play an important role in QT prolongation: hERG, late Nav1. 5, and Cav1. 2. Evaluating drugs against these ion channels and modeling with in silico action potential models is part of the new CiPA paradigm. In addition, we wanted to …