Mag Van Der Heyden

Comparison of the IKr blockers moxifloxacin, dofetilide and E‐4031 in five screening models of pro‐arrhythmia reveals lack of specificity of isolated cardiomyocytes

Drug development requires the testing of new chemical entities for adverse effects. For cardiac safety screening, improved assays are urgently needed. Isolated adult cardiomyocytes (CM) and human embryonic stem cell‐derived cardiomyocytes (hESC‐CM) could be used to identify pro‐arrhythmic compounds. In the present study, five assays were employed to investigate their sensitivity and specificity for evaluating the pro‐arrhythmic properties of IKr blockers, using moxifloxacin (safe compound) and dofetilide or E‐4031 (unsafe compounds).

Robust anti‐arrhythmic efficacy of verapamil and flunarizine against dofetilide‐induced TdP arrhythmias is based upon a shared and a different mode of action

BACKGROUND AND PURPOSE The high predisposition to Torsade de Pointes (TdP) in dogs with chronic AV‐block (CAVB) is well documented. The anti‐arrhythmic efficacy and mode of action of Ca2+ channel antagonists, flunarizine and verapamil against TdP were investigated.

A 2015 focus on preventing drug-induced arrhythmias

ABSTRACT Drug-induced Torsade de Pointes arrhythmia is a life-threatening adverse effect feared by pharmaceutical companies. For the last decade, the cardiac safety guidelines have imposed human ether-a-go-go-related gene channel blockade and prolongation of QT interval as surrogates for proarrhythmic risk propensity of a new chemical entity. Suffering from a lack of specificity, this assessment strategy led to a great amount of false positive outcomes. Therefore, this review will discuss new pharmaceutical strategies: the cardiac safety proposal that recently emerged, the Comprehensive in vitro Proarrhythmia Assay, combining in vitro assays that integrate effects on main cardiac ion channels, with computational models of human ventricular action potential as well as assays using human stem cell-derived cardiomyocytes for an improved prediction of drug’s proarrhythmic liability, alternative pharmacological perspectives as well as the current treatment of drug-induced long QT syndrome.