Treatment of ectopic atrial arrhythmias and premature atrial complexes in adults with encainide.

Few studies of the antiarrhythmic effects of encainide have included patients with primary atrial tachycardias and premature atrial contractions (PACs). In this review, 11 patients with primary atrial tachycardia and 10 patients with symptomatic PACs were abstracted from all studies known to have been performed. These patients had been shown to be highly resistant to prior antiarrhythmic treatments. Intravenous encainide terminated a primary atrial tachycardia in 4 of 4 patients, 3 of whom had an incessant arrhythmia, and oral encainide was effective or partially effective in 6 of 10 patients treated for an average of 2.9 years with a mean dosage of 156 mg/day. Intravenous encainide was effective or partially effective in 8 of 10 patients with symptomatic PACs, and oral encainide was effective or partially effective in 6 of 9 patients treated for an average of 1.8 years with a mean dosage of 114 mg/day. The median number of PACs per hour on Holter recording was reduced from a baseline rate of 1,139/hour to 166/hour at 3 to 5 months of treatment (p = 0.001). Adverse effects were modest. The mechanism of action of encainide in these arrhythmias appears to be depression of ectopic pacemaker activity.

The use of N-acetylcysteine long after an acetaminophen overdose in mice.

N-Acetylcysteine (NAC), given to mice 5 h after an LD50 dose of acetaminophen, decreased 24-h survival to 33%. The reduction in survival observed for late NAC is significantly lower than the survival observed for the LD50 dose alone (53%), and is in sharp contrast to the 100% survival reported for the early use of NAC.

Drug interaction studies and encainide use in renal and hepatic impairment.

The effect of encainide administration on steady-state plasma digoxin levels was evaluated in 17 patients receiving stable doses of digoxin. A paired t test, comparing plasma digoxin levels (mean +/- standard error) before encainide therapy (1.05 +/- 0.14 ng/ml) and after 2 weeks of encainide, 100 mg/day (1.03 +/- 0.11 ng/ml) or 200 mg/day (1.2 +/- 0.2 ng/ml), indicates no significant (p greater than 0.05) change in digoxin levels. These results were confirmed in a second study of 10 patients with severe congestive heart failure. Also, no difference in efficacy of either drug was observed and changes in dosing of digoxin were not required. Plasma concentrations of encainide and its 2 major metabolites, O-demethyl encainide (ODE) and 3-methoxy-O-demethyl encainide, significantly increased by 31.6%, 43.1% and 35.6% after concomitant cimetidine administration in 13 healthy adult men receiving 75 mg/day of encainide. However, a retrospective evaluation of 33 patients receiving both drugs did not reveal any clinically significant interactions. Retrospective evaluation of patients enrolled in clinical studies who received concomitant digoxin (268), antiarrhythmics (118), anticoagulants (78), antidiabetics (40), antipsychotics (23), beta blockers (88), calcium-channel blockers (24) or diuretics (229) did not reveal any clinically significant interactions with encainide. Similarly, in vitro protein binding studies did not reveal any clinically significant interactions with encainide or its major metabolites. Six patients with moderate to severe renal impairment (creatinine clearance 10 to 38 ml/min) received 25 mg of encainide, 3 times/day, for 7 doses. Plasma encainide, ODE and 3-methoxy-O-demethyl concentrations were similar to those observed in normal subjects who had received twice the dose of encainide, and steady-state apparent oral clearance of encainide was reduced by 66% with renal impairment. Based on these data it is recommended that in patients with moderate to severe renal impairment encainide be initiated at one-third the normal dose, or 25 mg once a day. Doses may be elevated in small increments at 1-week intervals if needed for efficacy. The effect of hepatic impairment on the pharmacokinetics of encainide was studied in 7 patients with clinically documented cirrhosis. Compared with normal subjects studied using a similar protocol, the plasma concentrations of encainide were elevated significantly due to a 6-fold decrease in oral clearance. However, since plasma concentrations of the active metabolite ODE were correspondingly lower, specific encainide dosing instructions for patients with hepatic impairment are not indicated.

Relation of blood level and metabolites to the antiarrhythmic effectiveness of encainide.

Encainide is a potent new antiarrhythmic agent with 2 major active metabolites and 2 distinct phenotypes for metabolism, extensive (approximately 92%) and nonextensive (8%). Encainide is an active compound with close correlation of plasma levels with antiarrhythmic effectiveness and electrocardiographic changes in nonextensive metabolizers. Its metabolites, O-demethyl-encainide and 3-methoxy-O-demethyl-encainide, are active against experimental and clinical arrhythmias. They have longer half-lives than and equal or greater potency than the parent compound. All 3 compounds contribute to the antiarrhythmic profile in extensive metabolizers. There is no readily apparent relation between encainide and its metabolites, blood levels and efficacy because of the complexity of the 3 active compounds and individual variation in pharmacokinetic and arrhythmia responsiveness. Encainide has been given for up to 2 years in 140 patients with sustained ventricular tachycardia or ventricular fibrillation. The survival curves are similar to historical control data from patients reported by Graboys and Swerdlow. The survival curves for long-term administration in patients with frequent ventricular premature complexes (greater than 30/min) are comparable to data from Califf. While these data must be viewed cautiously, it seems fair to conclude that encainide is as effective as any combination of drugs for preventing sudden death in patients with life-threatening ventricular arrhythmias.

The effect of alcohol on the toxicity of acetaminophen in mice.

A previous study with human subjects has shown that a low dose of alcohol, consumed prior to the ingestion of a therapeutic dose of acetaminophen, significantly reduced the excretion of acetaminophen-mercapturic acid. This study suggested that alcohol may be of value as an antidote in cases of acetaminophen overdose, by inhibiting the oxidative metabolism of acetaminophen. The present report describes our results in using alcohol as an antidote for acetaminophen overdose in the mouse model. We have observed that 0.2 ml per animal of 19% alcohol, given at 3 - 4 hours after an LD50 dose of acetaminophen, produced a 24 hour survival of 92%. N Acetyl-cysteine produced 100% survival. Changes in either the dose or timing of the alcohol produced smaller increases in survival (75%), and in no case of alcohol treatment was survival less than control levels (50%). Alcohol thus appears to be an effective antidote for acetaminophen overdose in the mouse model, when given at an appropriate time and dose. It remains to be determined whether these results are applicable to human subjects.

The effect of mild alcohol consumption on the metabolism of acetaminophen in man.

Previous studies with human subjects have shown that chronic alcohol consumption increases the risk of hepatotoxic effects from an overdose of acetaminophen (APAP). Recent studies in humans and with animal models have shown, on the other hand, that an acute dose of alcohol inhibits the development of hepatotoxic effects from an APAP overdose. Our studies in human subjects show that low doses of alcohol consumption may also provide some protection from the hepatotoxicity of APAP overdose. Specifically, we observe that a small dose of alcohol (the equivalent of 1 ounce of ethanol), consumed over a period of one hour prior to the ingestion of APAP, leads to a reduction in APAP-mercapturic acid excretion. The reduction in the excretion of this metabolite extends for a period of up to 12 hours after APAP ingestion, which is longer than the half-life of the alcohol consumed. The changes in APAP-mercapturic acid excretion are easily detected by our chromatography system via a colorimetric reaction with diphenylpicrylhydrazyl (DPPH).