Mjc Houtman

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.

Structure-activity relationships of pentamidine-affected ion channel trafficking and dofetilide mediated rescue.

Drug interference with normal hERG protein trafficking substantially reduces the channel density in the plasma membrane and thereby poses an arrhythmic threat. The chemical substructures important for hERG trafficking inhibition were investigated using pentamidine as a model drug. Furthermore, the relationship between acute ion channel block and correction of trafficking by dofetilide was studied.