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Proarrhythmic Potential (proarrhythmic + potential)
Selected AbstractsProarrhythmic potential of halofantrine, terfenadine and clofilium in a modified in vivo model of torsade de pointesBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2002Andrew J Batey This study was designed to compare the proarrhythmic activity of the antimalarial drug, halofantrine and the antihistamine, terfenadine, with that of clofilium a K+ channel blocking drug that can induce torsade de pointes. Experiments were performed in pentobarbitone-anaesthetized, open-chest rabbits. Each rabbit received intermittent, rising dose i.v. infusions of the ,-adrenoceptor agonist phenylephrine. During these infusions rabbits also received increasing i.v. doses of clofilium (20, 60 and 200 nmol kg,1 min,1), terfenadine (75, 250 and 750 nmol kg,1 min,1), halofantrine (6, 20 and 60 ,mol kg,1) or vehicle. Clofilium and halofantrine caused dose-dependent increases in the rate-corrected QT interval (QTc), whereas terfenadine prolonged PR and QRS intervals rather than prolonging cardiac repolarization. Progressive bradycardia occurred in all groups. After administration of the highest dose of each drug halofantrine caused a modest decrease in blood pressure, but terfenadine had profound hypotensive effects resulting in death of most rabbits. The total number of ventricular premature beats was highest in the clofilium group. Torsade de pointes occurred in 6 out of 8 clofilium-treated rabbits and 4 out of 6 of those which received halofantrine, but was not seen in any of the seven terfenadine-treated rabbits. These results show that, like clofilium, halofantrine can cause torsade de pointes in a modified anaesthetized rabbit model whereas the primary adverse effect of terfenadine was cardiac contractile failure. British Journal of Pharmacology (2002) 135, 1003,1012; doi:10.1038/sj.bjp.0704550 [source] Block of HERG-Carried K+ Currents by the New Repolarization Delaying Agent H 345/52JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 6 2003Gregory J. Amos M.D. Ph.D. Introduction: The aim of this study was to analyze the block of HERG-carried membrane currents caused by H 345/52, a new antiarrhythmic compound with low proarrhythmic activity, in transfected mouse fibroblasts. Methods and Results: Using the whole-cell configuration of the voltage patch clamp technique, it was demonstrated that H 345/52 concentration-dependently blocked HERG-carried currents with an IC50 of 230 nM. H 345/52 preferentially bound to the open channel with unusually rapid kinetics and was trapped by channel closure. Voltage-independent behavior of H 345/52 was observed during both square-pulse and action potential clamp protocols. In contrast, the Class III agents dofetilide (10 nM) and almokalant (250 nM) demonstrated significant membrane potential-dependent effects during square-pulse clamp protocols. When using action potential clamp protocols, voltage dependence was seen with dofetilide but not with almokalant. Mathematical simulations of human ventricular action potentials predicted that the different voltage-dependent behaviors would not produce marked variations in action potential duration prolongation patterns. Conclusion: We propose that block of IKr is the principal mechanism by which H 345/52 delays repolarization in human myocardium. The voltage independence of HERG/IKr block is unlikely to underlie the low proarrhythmic potential, and ancillary effects on other membrane currents must be considered. (J Cardiovasc Electrophysiol, Vol. 14, pp. 651-658, June 2003) [source] Adenosine-Induced Ventricular Arrhythmias in Patients with Supraventricular TachycardiasANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 4 2008Cagatay Ertan M.D. Background: Adenosine is widely used for the diagnosis and the termination of supraventricular arrhythmias. There are many case reports and few series about the proarrhythmic potential of adenosine. We sought to evaluate the proarrhythmic potential of adenosine used to terminate the supraventricular arrhythmias. Methods: The records of all patients that received adenosine for the termination of supraventricular tachycardia were reviewed retrospectively and those with a continuous electrocardiographic (ECG) recording during adenosine administration were included to the study. Results: Our search identified 52 supraventricular episodes of 46 patients with a continuous ECG recording during adenosine administration. Following adenosine administration, premature ventricular contraction (PVC) or ventricular tachycardia (VT) developed in 22 (47.8%) patients and in 26 (50%) tachycardia episodes. No patient had a sustained VT. Nonsustained VT developed in eight (17.4%) patients. All VT episodes were polymorphic, short, and self-terminating. When the basal and demographic properties of patients with PVC or VT and those without PVT or VT were compared, there was no significant difference. Conclusions: Adenosine is a quite safe and effective drug for the termination of narrow QRS complex tachycardia but it often induces nonsustained VT or PVC that are clinically insignificant in the absence of other accompanying heart disease. [source] Dog left ventricular midmyocardial myocytes for assessment of drug-induced delayed repolarization: short-term variability and proarrhythmic potentialBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2010Najah Abi-Gerges Background and purpose:, Evaluation of the potential for delayed ventricular repolarization and proarrhythmia by new drugs is essential. We investigated if dog left ventricular midmyocardial myocytes (LVMMs) that can be used as a preclinical model to assess drug effects on action potential duration (APD) and whether in these cells, short-term variability (STV) or triangulation could predict proarrhythmic potential. Experimental approach:, Beagle LVMMs and Purkinje fibres (PFs) were used to record APs. Effects of six reference drugs were assessed on APD at 50% (APD50) and 90% (APD90) of repolarization, STV(APD), triangulation (ratio APD90/APD50) and incidence of early afterdepolarizations (EADs) at 1 and 0.5 Hz. Key results:, LVMMs provided stable recordings of AP, which were not affected by four sequential additions of dimethyl sulphoxide. Effects of dofetilide, d-sotalol, cisapride, pinacidil and diltiazem, but not of terfenadine, on APD in LVMMs were found to be comparable with those recorded in PFs. LVMMs, but not PFs, exhibited a proarrhythmic response to IKr blockers. Incidence of EADs was not related to differences in AP prolongation or triangulation, but corresponded to beat-to-beat variability of repolarization, here quantified as STV of APD. Conclusions and implications:, LVMMs provide a suitable preclinical model to assess the effects of new drugs on APD and also yield additional information about putative indicators of proarrhythmia that add value to an integrated QT/TdP risk assessment. Our findings support the concept that increased STV(APD) may predict drug-induced proarrhythmia. This article is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010 [source] The Novel Antiarrhythmic Drug Dronedarone: Comparison with AmiodaroneCARDIOVASCULAR THERAPEUTICS, Issue 3 2005Sven Kathofer ABSTRACT Dronedarone is a noniodinated benzofuran derivative that has been developed to overcome the limiting iodine-associated adverse effects of the commonly used antiarrhythmic drug, amiodarone. It displays a wide cellular electrophysiological spectrum largely similar to amiodarone, inhibiting the potassium currents Ikr, IKs, IKI, IKACh, and Isus, as well as sodium currents and L-type calcium currents in isolated cardiomyocytes. In addition, dronedarone exhibits antiadrenergic properties. In vivo, dronedarone has been shown to be more effective than amiodarone in several arrhythmia models, particularly in preventing ischemia- and reperfusion-induced ventricular fibrillation and in reducing mortality. However, an increased incidence of torsades de pointes with dronedarone in dogs shows that possible proarrhythmic effects of dronedarone require further evaluation. The clinical trails DAFNE, EURIDIS, and ADONIS indicated safety, antiarrhythmic efficacy and low proarrhythmic potential of the drug in low-risk patients. In contrast, the increased incidence of death in the dronedarone group of the discontinued ANDROMEDA trial raises safety concerns for patients with congestive heart failure and moderate to severe left ventricular dysfunction. Dronedarone appears to be effective in preventing relapses of atrial fibrillation and atrial flutter. Torsades de pointes, the most severe adverse effect associated with amiodarone, has not yet been reported in humans with dronedarone. Unlike amiodarone, dronedarone had little effect on thyroid function and hormone levels in animal models and had no significant effects on human thyroid function in clinical trials. In conclusion, dronedarone could be a useful drug for prevention of atrial fibrillation and atrial flutter relapses in low-risk patients. However, further experimental studies and long-term clinical trials are required to provide additional evidence of efficacy and safety of dronedarone. [source] | ||||||||||