Search

To characterize in vivo anti-atrial fibrillatory potential and pharmacological safety profile of ranolazine having INa,L plus IKr inhibitory actions in comparison with those of clinically available anti-atrial fibrillatory drugs; namely, dronedarone, amiodarone, bepridil and dl-sotalol in our previous studies, ranolazine dihydrochloride in sub-therapeutic (0.3 mg/kg) and supra-therapeutic (3 mg/kg) doses was intravenously infused over 10 min to the halothane-anesthetized dogs (n = 5). The low dose increased the heart rate, cardiac output and atrioventricular conduction velocity possibly via vasodilator action-induced, reflex-mediated increase of adrenergic tone. Meanwhile, the high dose decreased the heart rate, ventricular contraction, cardiac output and mean blood pressure, indicating that drug-induced direct actions may exceed the reflex-mediated compensation. In addition, it prolonged the atrial and ventricular effective refractory periods, of which potency and selectivity for the former were less great compared with those of the clinically-available drugs. Moreover, it did not alter the ventricular early repolarization period in vivo, but prolonged the late repolarization with minimal risk for re-entrant arrhythmias. These in vivo findings of ranolazine suggest that INa,L suppression may attenuate IKr inhibition-associated prolongation of early repolarization in the presence of reflex-mediated increase of adrenergic tone. Thus, ranolazine alone may be less promising as an anti-atrial fibrillatory drug, but its potential risk for inducing torsade de pointes will be small. These information can be used as a guide to predict the utility and adverse effects of anti-atrial fibrillatory drugs having multi-channel modulatory action. [ABSTRACT FROM AUTHOR]

In order to bridge the gap of information between the in silico model and human subjects, we evaluated torsadogenic risk of cisapride, dl -sotalol, bepridil and verapamil selected from 12 training compounds in the comprehensive in vitro proarrhythmia assay using the chronic atrioventricular block monkeys. Cisapride (0, 1, and 5 mg/kg, n  = 5 for each dose), dl -sotalol (0, 1, 3, and 10 mg/kg, n  = 5 for each dose), bepridil (0, 10, and 100 mg/kg, n  = 4 for each dose), verapamil (0, 1.5, 15, and 75 mg/kg, n  = 4 for each dose) were orally administered to the monkeys in conscious state. Five mg/kg of cisapride, 1, 3, and 10 mg/kg of dl -sotalol and 100 mg/kg of bepridil prolonged ΔΔQTcF, which was not observed by verapamil. Torsade de pointes was induced by 5 mg/kg of cisapride in 2 out of 5 animals, by 10 mg/kg of dl -sotalol in 5 out of 5 and by 100 mg/kg of bepridil in 2 out of 4, which was not induced by verapamil. These torsadogenic doses were normalized by their maximum clinical daily ones to estimate torsadogenic risk. The order of risk was dl -sotalol >bepridil ≥cisapride >verapamil in our study. Since the order was bepridil ≥ dl -sotalol >cisapride >verapamil in comprehensive in vitro proarrhythmia assay (CiPA) in silico mechanistic model validation, sympathetic regulation on the heart may play a pivotal role in the onset of torsade de pointes in vivo. [ABSTRACT FROM AUTHOR]

Lamotrigine has been used for patients with epilepsy and/or bipolar disorder, overdose of which induced the hypotension, elevation of the atrial pacing threshold, cardiac conduction delay, wide complex tachycardia, cardiac arrest and Brugada-like electrocardiographic pattern. To clarify how lamotrigine induces those cardiovascular adverse events, we simultaneously assessed its cardiohemodynamic and electrophysiological effects using the halothane-anesthetized dogs (n = 4). Lamotrigine was intravenously administered in doses of 0.1, 1 and 10 mg/kg/10 min under the monitoring of cardiovascular variables, possibly providing subtherapeutic to supratherapeutic plasma concentrations. The low or middle dose of lamotrigine did not alter any of the variables. The high dose significantly delayed the intra-atrial and intra-ventricular conductions in addition to the prolongation of ventricular effective refractory period, whereas no significant change was detected in the other variables. Lamotrigine by itself has relatively wide safety margin for cardiohemodynamics, indicating that clinically reported hypotension may not be induced through its direct action on the resistance arterioles or capacitance venules. The electrophysiological effects suggested that lamotrigine can inhibit Na+ channel in the in situ hearts. This finding may partly explain the onset mechanism of lamotrigine-associated cardiac adverse events in the clinical cases. In addition, elevation of J wave was induced in half of the animals, suggesting that lamotrigine may have some potential to unmask Brugada electrocardiographic genotype in susceptible patients. [ABSTRACT FROM AUTHOR]

AVE0118, an inhibitor of IKur, Ito and IK,ACh, was in the drug pipeline for atrial fibrillation. To investigate the limitation of AVE0118 as an anti-atrial fibrillatory drug, we studied its electropharmacological effects particularly focusing on the anti-atrial fibrillatory action as reverse translational research. We adopted the chronic atrioventricular block beagle dogs (n = 4), having a pathophysiology of bradycardia-associated, volume overload-induced chronic heart failure, in which the atrial fibrillation was induced by 10 s of burst pacing on atrial septum. AVE0118 in doses of 0.24 and 1.2 mg/kg, i.v. over 10 min hardly altered electrophysiological variables. Meanwhile, AVE0118 in a dose of 6 mg/kg, i.v. over 10 min delayed the inter-atrial conduction in a frequency-dependent manner and prolonged the atrial effective refractory period in a reverse frequency-dependent manner, whereas it did not significantly alter the duration of atrial fibrillation or its cycle length. The increment of atrial effective refractory period was 3.3 times greater compared with that of ventricular one at a basic cycle length of 400 ms. Torsade de pointes was not induced during the experimental period. Thus, AVE0118 may possess a favorable cardiac safety pharmacological profile, but its weak anti-atrial fibrillatory effect would indicate the limitation of atrial repolarization-delaying agents for suppressing atrial fibrillation. [ABSTRACT FROM AUTHOR]