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PubMed1988

Encainide.

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Anilides↗
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[Encainide].

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Anilides↗
PubMed1994

Predicting mortality after myocardial infarction from the response of RR variability to antiarrhythmic drug therapy.

OBJECTIVES: This study was designed to test the hypothesis that antiarrhythmic drugs that decrease RR variability will predict all-cause mortality during follow-up after myocardial infarction. BACKGROUND: RR variability, a noninvasive indicator of autonomic nervous system activity, predicts death after acute myocardial infarction independently of other risk predictors and changes substantially in response to some drugs. A previous study in patients with chronic heart disease and frequent ventricular premature complexes reported that flecainide decreased vagal modulation of RR intervals but amiodarone did not. The investigators of that study speculated that changes in RR variability during antiarrhythmic drug therapy predict an increased mortality rate during long-term drug treatment. To explore this hypothesis further, we compared the effects of encainide and flecainide, which increase long-term mortality substantially, on RR variability with the effects of placebo and moricizine, which have no significant effect on mortality during long-term treatment of unsustained ventricular arrhythmias after myocardial infarction. METHODS: The 24-h power spectral density was computed from the baseline electrocardiographic recordings and drug evaluation tapes, and six frequency domain measures of RR variability were calculated: ultra-low frequency (< 0.0033 Hz), very low frequency (0.0033 to < 0.04 Hz), low frequency (0.04 to < 0.15 Hz) and high frequency power (0.15 to < 0.40 Hz), plus total power (< 0.40 Hz) and the ratio of low to high frequency power. Changes in power spectral measures were related to drug treatment and to mortality. RESULTS: In the placebo group, values for RR interval and RR variability increased because of recovery from the effects of acute myocardial infarction. Contrasting placebo treatment with all three active antiarrhythmic drug treatments taken together showed that of all the measures of RR variability, only NN50, pNN50 and low frequency power changed significantly during drug treatment (Bonferroni adjusted p value < 0.025); these variables all decreased during drug therapy. Contrasting encainide and flecainide with moricizine, we found that the encainide and flecainide groups taken together showed a larger decrease in dLF than moricizine, but the difference was of borderline significance (Bonferroni adjusted p value < 0.08). Survival was significantly worse in the groups treated with encainide and flecainide than in the groups treated with placebo or moricizine (relative risk > 2.0, adjusted p < 0.05). The antiarrhythmic drug-induced change in measures of RR variability was not a significant predictor of all-cause mortality during a year of follow-up after myocardial infarction. CONCLUSIONS: Encainide, flecainide and moricizine all caused a decrease in RR variability in patients studied approximately 1 month after acute myocardial infarction. Encainide and flecainide caused a significant increase in mortality rates; placebo and moricizine did not. Baseline measurements of RR variability also predicted all-cause mortality after myocardial infarction. The decrease in RR variability produced by the three antiarrhythmic drugs did not predict mortality during follow-up.

Anti-Arrhythmia Agents↗
PubMed1992

Differential block of cardiac delayed rectifier current by class Ic antiarrhythmic drugs: evidence for open channel block and unblock.

OBJECTIVE: The aim was to compare the effects of the class Ic antiarrhythmic drugs flecainide, encainide, and recainam on the delayed rectifier current, IK. METHODS: Membrane currents were studied using the single suction pipette voltage clamp technique in freshly dissociated cat ventricular myocytes bathed in HEPES buffered physiological saline at 32 degrees C. RESULTS: Flecainide and encainide decreased IK with IC50 values of 2.1 microM and 6 microM, respectively. Recainam (100 microM) reduced IK by only 7 (SEM 3)% after 20-30 min exposure and by 19% after an 80 min exposure (IC50 > 400 microM). None of the compounds blocked the inward rectifier, IK1. Block of IK by flecainide and encainide increased with depolarisation following a voltage dependence similar to that describing channel activation. Flecainide and encainide also slowed the time course of the IK tail currents, consistent with drug dissociating from open channels. CONCLUSIONS: The observed voltage dependence for IK block by flecainide and encainide resembles the interaction reported between these agents and the excitatory sodium channel, ie, depolarisation enhances block while repolarisation leads to removal of block. The results further suggest that the electrophysiological profile of class Ic agents can have a markedly different ionic basis, ie, K+ channel block by flecainide and encainide is balanced by a potent block of sodium channels, while recainam appears to be a weak but relatively specific blocker of sodium channels only. These differences are not readily accommodated by the current Harrison-Vaughan-Williams classification scheme, and suggest the possibility that potentially important drug specific differences can exist within the same antiarrhythmic drug class.

Animals↗
PubMed1991

Phenotypic debrisoquine 4-hydroxylase activity among extensive metabolizers is unrelated to genotype as determined by the Xba-I restriction fragment length polymorphism.

1. The major pathway for 4-hydroxylation of debrisoquine in man is polymorphic and under genetic control. More than 90% of subjects (extensive metabolizers, EMs) have active debrisoquine 4-hydroxylase (cytochrome P450IID6) while in the remainder (poor metabolizers, PMs), cytochrome P450IID6 activity is greatly impaired. 2. Within the EM group, cytochrome P450IID6-mediated metabolism of a range of substrates varies widely. Some of this intra-phenotype non-uniformity may be explained by the presence of two subsets of subjects with different genotypes (heterozygotes and homozygotes). 3. Cytochrome P450IID6 substrates have not differentiated between these two genotypes. However, a restriction fragment length polymorphism (RFLP) which identifies mutant alleles of cytochrome P450IID6 locus has been described and can definitively assign genotype in some heterozygous EM subjects. 4. In this study, we used RFLP analysis and encainide as a model substrate to determine if non-uniformity in cytochrome P450IID6 activity among EMs is related to genotype. We tested the hypothesis that heterozygotes exhibit intermediate metabolic activity and that homozygous dominants exhibit the highest activity. We proposed encainide as a useful substrate for this purpose since cytochrome P450IID6 catalyzes not only its biotransformation to O-desmethyl encainide (ODE) but also the subsequent metabolism of ODE to 3-methoxy-O-desmethyl encainide (MODE). 5. A single 50 mg oral dose of encainide was administered to 139 normal volunteers and 14 PMs were identified. Urinary ratios among encainide, ODE and MODE in the remaining 125 EM subjects revealed a wide range of cytochrome P450IID6 activity. However, Southern blotting of genomic DNA digested with XbaI identified obligate heterozygotes in both extremes of all ratio distributions.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoradiography↗