The Potential Mechanisms behind Loperamide-Induced Cardiac Arrhythmias Associated with Human Abuse and Extreme Overdose.

Loperamide has been a safe and effective treatment for diarrhea for many years. However, many cases of cardiotoxicity with intentional abuse of loperamide ingestion have recently been reported. We evaluated loperamide in in vitro and in vivo cardiac safety models to understand the mechanisms for this cardiotoxicity.

I inhibitor JNJ303 prolongs the QT interval and perpetuates arrhythmia when combined with enhanced inotropy in the CAVB dog.

Introduction: Impaired I induced by drugs or due to a KCNQ1 mutation, diagnosed as long QT syndrome type 1 (LQT1) prolongs the QT interval and predisposes the heart to Torsade de Pointes (TdP) arrhythmias. The anesthetized chronic AV block (CAVB) dog is inducible for TdP after remodeling and I inhibitor dofetilide. We tested the proarrhythmic effect of I inhibition in the CAVB dog, and the proarrhythmic role of increased contractility herein.

Electromechanical reciprocity and arrhythmogenesis in long-QT syndrome and beyond.

An abundance of literature describes physiological and pathological determinants of cardiac performance, building on the principles of excitation-contraction coupling. However, the mutual influencing of excitation-contraction and mechano-electrical feedback in the beating heart, here designated 'electromechanical reciprocity', remains poorly recognized clinically, despite the awareness that external and cardiac-internal mechanical stimuli can trigger electrical responses and arrhythmia. This review focuses on electromechanical reciprocity in the long-QT syndrome (LQTS), historically considered a purely electrical disease, but now appreciated as paradigmatic for the understanding of mechano-electrical contributions to arrhythmogenesis in this and other cardiac conditions.

Seizure-induced Torsades de pointes:In a canine drug-induced long-QT1 model.

Introduction: People with epilepsy are at heightened risk of sudden death compared to the general population. The leading cause of epilepsy-related premature mortality is a sudden unexpected death in epilepsy (SUDEP). The mechanism of SUDEP remains largely unresolved and the lack of preclinical models to study the potential mechanism underlying SUDEP is a problem.

Characterization of an anesthetized dog model of transient cardiac ischemia and rapid pacing: a pilot study for preclinical assessment of the potential for proarrhythmic risk of novel drug candidates.

Introduction: Preclinical proarrhythmic risk assessment of drug candidates is focused predominantly on arrhythmias arising from repolarization abnormalities. However, drug-induced cardiac conduction slowing is associated with significant risk of life-threatening ventricular arrhythmias, particularly in a setting of cardiac ischemia. Therefore, we optimized and characterized an anesthetized dog model to evaluate the potential proarrhythmic risk of drug candidates in ischemic heart disease patients.

Interventricular differences in β-adrenergic responses in the canine heart: role of phosphodiesterases.

Background: RV and LV have different embryologic, structural, metabolic, and electrophysiologic characteristics, but whether interventricular differences exist in β-adrenergic (β-AR) responsiveness is unknown. In this study, we examine whether β-AR response and signaling differ in right (RV) versus left (LV) ventricles.

Methods And Results: Sarcomere shortening, Ca(2+) transients, ICa,L and IKs currents were recorded in isolated dog LV and RV midmyocytes.

Diastolic spontaneous calcium release from the sarcoplasmic reticulum increases beat-to-beat variability of repolarization in canine ventricular myocytes after β-adrenergic stimulation.

Rationale: Spontaneous Ca(2+) release (SCR) from the sarcoplasmic reticulum can cause delayed afterdepolarizations and triggered activity, contributing to arrhythmogenesis during β-adrenergic stimulation. Excessive beat-to-beat variability of repolarization duration (BVR) is a proarrhythmic marker. Previous research has shown that BVR is increased during intense β-adrenergic stimulation, leading to SCR.

The fentanyl/etomidate-anesthetized beagle (FEAB) model in safety pharmacology assessment.

This unit describes a procedure for performing safety studies in the anesthetized beagle dog. Detailed are the anesthetic regime, the surgical procedure, and all materials needed to perform cardiovascular, central nervous system, and respiratory safety studies in these animals. An overview of all parameters that can be measured and calculated is provided, as are experimental protocols.

Torcetrapib produces endothelial dysfunction independent of cholesteryl ester transfer protein inhibition.

Objective: Torcetrapib, a prototype cholesteryl ester transfer protein (CETP) inhibitor with potential for decreasing atherosclerotic disease, increased cardiovascular events in clinical trials. The identified hypertensive and aldosterone-elevating actions of torcetrapib may not fully account for this elevated cardiovascular risk. Therefore, we evaluated the effects of torcetrapib on endothelial mediated vasodilation in vivo.

Blockade of the I(Ks) potassium channel: an overlooked cardiovascular liability in drug safety screening?

The problem of drug-induced hERG channel blockade, which can lead to acquired long QT syndrome and potentially fatal arrhythmias, has exercised drug developers and regulatory authorities for over 10 years, and exacting guidelines have been put into place to test for this liability both preclinically (ICH S7B) and clinically (ICH E14). However, the I(Ks) channel, which along with the transient outward current (I(to)) is the other main potassium channel affecting cardiac repolarisation and thus the length of the QT interval, has received little attention, and potent I(Ks) blocking drugs with serious side effects could potentially enter into human testing without being detected by the existing regulatory core battery and standard screening strategies. Here we review the pharmacology of cardiac I(Ks) channel blockade and describe the discovery of a potent I(Ks) blocker whose activity was not detected by standard hERG or invitro action potential screens, but subsequently evoked unprovoked torsades de pointes (TdP) invivo in our anaesthetised dog model.

The fentanyl/etomidate-anaesthetised beagle (FEAB) dog: a versatile in vivo model in cardiovascular safety research.

The purpose of conducting cardiovascular safety pharmacology studies is to investigate the pharmacological profiles of new molecular entities (NMEs) and provide data that can be used for optimization of a possible new drug, and help make a selection of NMEs for clinical development. An anaesthetised dog preparation has been used for more than two decades by our department to measure multiple cardiovascular and respiratory parameters and to evaluate different scientific models, leading to more in-depth evaluation of drug-induced cardiovascular effects. An anaesthetic regime developed in house (induction with lofentanil, scopolamine and succinylcholine, and maintenance with fentanyl and etomidate) gives us a preparation free of pain and stress, with minimal effects on the cardiovascular system.

In vivo mechanisms precipitating torsades de pointes in a canine model of drug-induced long-QT1 syndrome.

Objective: Congenital loss of function and drug-induced inhibition of the slowly-activating delayed-rectifier K(+) current (I(Ks)) cause impaired cardiac repolarization. beta-Adrenergic-receptor stimulation contributes to sympathetically-induced torsades de pointes (TdP). An in vivo model of long-QT1 (LQT1) syndrome and TdP in a species with I(Ks) characteristics relevant to man is lacking.