Electrophysiology of O-Demethyl Encainide in a Canine Model of Sustained Ventricular Tachycardia

Roden, Dan M.; Dawson, Albert K.; Duff, Henry J.; Woosley, Raymond L.; Smith, Raymond A.

doi:10.1097/00005344-198407000-00006

Cited by 13 publications

(2 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, growing evidence in animal models of reentrant VT implicates proarrhythmic interaction between cardiac sodium (Na ϩ ) channels, antiarrhythmic drugs, and the remodeled substrate of the ischemic myocardium. [1][2][3] In 1989, the Cardiac Arrhythmia Suppression Trial (CAST) found that therapy with the potent Na ϩ channelblocking drugs flecainide or encainide in patients convalescing from myocardial infarction unexpectedly increased mortality 3-fold. 4 A further analysis of the CAST database indicated that patients whose index myocardial infarction was not transmural (non-Q wave), a subset known to be at higher risk for recurrent myocardial ischemia, exhibited an even greater (8.9-fold) risk with concomitant Na ϩ channel blocker therapy.…”

mentioning

confidence: 99%

Oxidative Mediated Lipid Peroxidation Recapitulates Proarrhythmic Effects on Cardiac Sodium Channels

Fukuda

Davies

Nakajima

et al. 2005

Circulation Research

118

View full text Add to dashboard Cite

Abstract-Sudden cardiac death attributable to ventricular tachycardia/fibrillation (VF) remains a catastrophic outcome of myocardial ischemia and infarction. At the same time, conventional antagonist drugs targeting ion channels have yielded poor survival benefits. Although pharmacological and genetic models suggest an association between sodium (Na ϩ ) channel loss-of-function and sudden cardiac death, molecular mechanisms have not been identified that convincingly link ischemia to Na ϩ channel dysfunction and ventricular arrhythmias. Because ischemia can evoke the generation of reactive oxygen species, we explored the effect of oxidative stress on Na ϩ channel function. We show here that oxidative stress reduces Na ϩ channel availability. Both the general oxidant tert-butyl-hydroperoxide and a specific, highly reactive product of the isoprostane pathway of lipid peroxidation, E 2 -isoketal, potentiate inactivation of cardiac Na ϩ channels in human embryonic kidney (HEK)-293 cells and cultured atrial (HL-1) myocytes. Furthermore, E 2 -isoketals were generated in the epicardial border zone of the canine healing infarct, an arrhythmogenic focus where Na ϩ channels exhibit similar inactivation defects. In addition, we show synergistic functional effects of flecainide, a proarrhythmic Na ϩ channel blocker, and oxidative stress. These data suggest Na ϩ channel dysfunction evoked by lipid peroxidation is a candidate mechanism for ischemia-related conduction abnormalities and arrhythmias.

show abstract

mentioning

confidence: 99%

Oxidative Mediated Lipid Peroxidation Recapitulates Proarrhythmic Effects on Cardiac Sodium Channels

Fukuda

Davies

Nakajima

et al. 2005

Circulation Research

118

View full text Add to dashboard Cite

show abstract

“…In in vitro test systems (Elharrar & Zipes 1982), animal models Duff et al 1983;Roden et al 1982Roden et al , 1984 and most recently patients (Barbey et aI. 1985), both ODE and MODE have been shown to produce pharmacological effects similar to those seen during encainide therapy, including arrhythmia suppression and QRS prolongation.…”

Section: Encainide Disposition In Healthy Subjectsmentioning

confidence: 99%

Clinical Pharmacokinetics of Encainide

Roden

Woosley

1988

Clinical Pharmacokinetics

Self Cite

View full text Add to dashboard Cite

The disposition kinetics of the new antiarrhythmic agent encainide are a function of the genetic polymorphism which also controls debrisoquin 4-hydroxylation. In the majority of subjects (extensive metabolisers) encainide undergoes extensive first-pass hepatic biotransformation to the active metabolites O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (MODE). The plasma concentrations of these metabolites are higher than those of encainide, and pharmacological effects correlate better with plasma metabolite concentrations than they do with those of encainide itself. In poor metabolisers, who make up to 7% of the population, a first-pass effect is absent, encainide clearance is lower, and plasma encainide concentrations are higher than those in extensive metabolisers. In poor metabolisers, plasma concentrations of active metabolites are low or undetectable, and the effects of encainide therapy can be closely correlated with plasma concentrations of the parent drug. Despite the marked differences in encainide disposition between extensive and poor metabolisers, the dosages which produce pharmacological effects (QRS prolongation and arrhythmia suppression) are similar in both groups. Encainide biotransformation is impaired in hepatic disease, but no major dosage changes are required. On the other hand, excretion of encainide and its metabolites is impaired in individuals with renal disease, and starting dosages should be decreased. The time required to achieve steady-state concentrations of metabolites (in extensive metabolisers) and of encainide itself (in poor metabolisers) is similar (3 to 5 days); therefore, the dosage should be increased no more often than every 3 to 5 days.(ABSTRACT TRUNCATED AT 250 WORDS)

show abstract

Effect of Fluosol-DA on infarct morphology and vulnerability to ventricular arrhythmia

Kolodgie¹,

Dawson²,

Roden³

et al. 1986

American Heart Journal

View full text Add to dashboard Cite

Electrophysiology of O-Demethyl Encainide in a Canine Model of Sustained Ventricular Tachycardia

Cited by 13 publications

References 0 publications

Oxidative Mediated Lipid Peroxidation Recapitulates Proarrhythmic Effects on Cardiac Sodium Channels

Oxidative Mediated Lipid Peroxidation Recapitulates Proarrhythmic Effects on Cardiac Sodium Channels

Clinical Pharmacokinetics of Encainide

Effect of Fluosol-DA on infarct morphology and vulnerability to ventricular arrhythmia

Contact Info

Product

Resources

About