Vanoxerine has been in clinical trials for Parkinsonism, depression and cocaine 
addiction but lacked efficacy. Although a potent blocker of hERG, it produced no 
serious adverse events. We attributed the unexpected result to offsetting 
Multiple Ion Channel Effects (MICE). Vanoxerine's effects were strongly 
frequency-dependent and we repositioned it for treatment of atrial fibrillation 
and flutter. Vanoxerine terminated AF/AFL in an animal model and a dose-ranging 
clinical trial. Reversion to normal rhythm was associated with QT prolongation 
yet absent proarrhythmia markers for Torsade de Pointes (TdP). To understand the 
QT/TdP discordance, we used quantitative profiling and compared vanoxerine with 
dofetilide, a selective hERG-blocking torsadogen used for intractable AF, 
verapamil, a non-torsadogenic MICE comparator and bepridil, a torsadogenic MICE 
comparator. At clinically relevant concentrations, verapamil blocked hCav1.2 and 
hERG, as did vanoxerine and bepridil both of which also blocked hNav1.5. In 
acute experiments and simulations, dofetilide produced early after 
depolarizations (EADs) and arrhythmias, whereas verapamil, vanoxerine and 
bepridil produced no proarrhythmia markers. Of the MICE drugs only bepridil 
inhibited hERG trafficking following overnight exposure. The results are 
consistent with the emphasis on MICE of the CiPA assay. Additionally we propose 
that trafficking inhibition of hERG be added to CiPA.