Sensitivity and Specificity of the In Vitro Guinea Pig Papillary Muscle Action Potential Duration for the Assessment of Drug-Induced Torsades De Pointes Liability in Humans.

The ICH S7B document, which provides guidance for the preclinical cardiovascular evaluation of pharmaceutical new chemical entities (NCE), is essentially focused on drug-induced QT lengthening, a biomarker for the proarrhythmic adverse drug reaction, torsades de pointes (TdP). In 2005, this guidance recommended the IKr assay and the in vivo QT telemetry study as mandatory assays for detecting potential torsades de pointes liability and relegated the cardiac action potential (AP) assay as a follow-up study. The IKr assay has become a mandatory screening tool in the early development and safety assessment process.

I(Ks) blockade in border zone arrhythmias from guinea-pig ventricular myocardium submitted to simulated ischemia and reperfusion.

I(Ks) blockade might be a promising way to treat tachyarrhythmia because of the accumulation of activated potassium channels. However, I(Ks) blockade during ischemia/reperfusion has not been investigated. Thus, the electrophysiological effects of two I(Ks) blockers, chromanol 293B (10 μm) and HMR 1556 (1 μm), were assessed in an in vitro model of border zone between normal and ischemic/reperfused right ventricular myocardium from guinea-pigs, and classic electrophysiological parameters and the incidence of arrhythmias were studied.

I(Kr) vs. I(Ks) blockade and arrhythmogenicity in normoxic rabbit Purkinje fibers: does it really make a difference?

The electrophysiological (standard intracellular microelectrode technique) and pro-arrhythmic (occurrence of early after-depolarization) effects of five class III agents acting on delayed rectifier current (I(K)), rapid (I(Kr)), and/or slow (I(Ks)) components have been studied in rabbit Purkinje fibers taken near the septum and submitted in vitro to reduced stimulation rate (from 1 to 0.5 Hz) in the absence or presence of epinephrine (10 nm) during normoxic conditions. There were two I(Kr) blockers (d-sotalol and dofetilide), two I(Ks) blockers (chromanol 293B and HMR 1556), and a non-selective I(K) blocker (azimilide).

Dexrazoxane protects the heart from acute doxorubicin-induced QT prolongation: a key role for I(Ks).

Introduction: Doxorubicin, an anthracycline widely used in the treatment of a broad range of tumours, causes acute QT prolongation. Dexrazoxane has been shown to prevent the QT prolongation induced by another anthracycline, epirubicin, but has not yet been reported to prevent that induced by doxorubicin. Thus, the present study was designed to test whether the acute QT effects induced by doxorubicin could be blocked by dexrazoxane and to explore the mechanism.

Action potential experiments complete hERG assay and QT-interval measurements in cardiac preclinical studies.

Introduction: The ICHS7B guideline focused on hERG and QT assays, although other factors have also been linked with the induction of severe arrhythmias. Thus, the aim of the present study was to demonstrate that two in vitro action potential recordings constitute convincing models of predictive drug-induced Torsades de pointes (TdP) and re-entry arrhythmias.

Methods: The effects of D,L-sotalol, flecainide and quinidine were investigated on potassium (hERG) and sodium (Na(V)1.

Class III effects of dofetilide and arrhythmias are modulated by [K+]o in an in vitro model of simulated-ischemia and reperfusion in guinea-pig ventricular myocardium.

To evaluate class III effects of clinically relevant concentrations of dofetilide (5 and 10 nmol/l) and the effects of extracellular potassium [K+]o modulation of arrhythmias onset at the level of the "border zone," we used a previously reported in vitro model whereby normoxic and ischemic/reperfused zones were studied. Guinea-pig right ventricular strips (driven at 1 Hz at 36.5+/-0.

Electrophysiological effects of azimilide in an in vitro model of simulated-ischemia and reperfusion in guinea-pig ventricular myocardium.

There are few investigations on azimilide effects during ischemia/reperfusion. We have therefore investigated low concentrations of azimilide (0.1 and 0.

Additive effects of ziprasidone and D,L-sotalol on the action potential in rabbit Purkinje fibres and on the hERG potassium current.

Introduction: Ziprasidone, an atypical antipsychotic has been shown to be devoid of cardiac adverse effects in spite of its propensity to prolong the QT-interval via a hERG current inhibition. However, the effects of ziprasidone on the action potential (AP) parameters have not been published yet. Moreover, very little information is available concerning pharmacodynamic interactions between ziprasidone and other hERG channel blockers.