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Biomedical subjects

J E Byrne

Publications and source records attributed to J E Byrne.

At least 19 recordsLinked to original sources
PubMed1989

Encainide.

Encainide is a class IC antiarrhythmic agent having little or no effect on action-potential duration or maximum diastolic potential but decreasing the maximum rate of phase O depolarization as well as increasing atrial and ventricular effective refractory periods. In intact animals or humans, encainide increases the AH, PR, QRS, and H-V intervals while not affecting the sinus node cycle length or JT interval. QT interval increases only by the concomitant increase in the QRS interval. Encainide is metabolized to O-demethyl encainide (ODE) and 3-methoxy-ODE (MODE), both of which are also antiarrhythmics with similar pharmacology to encainide. Encainide and its metabolites have little negative inotropic activity and ancillary pharmacology. Consequently, encainide has little or no effect on hemodynamic variables in patients with either normal or compromised cardiac function. The drug is well tolerated, with side effects being mainly those associated with its local anesthetic activity such as blurred vision and dizziness. Encainide is particularly effective in patients with excessive premature ventricular complexes (PVCs) and less so in patients with sustained ventricular tachycardia (VT). Like all antiarrhythmics, encainide may aggravate or precipitate new arrhythmias (proarrhythmia). The overall incidence of proarrhythmia is about 10%, with less occurring in patients with PVCs and more in those with sustained VT; also, the incidence of proarrhythmia is higher in patients with underlying heart disease. Encainide is also effective for the treatment of supra-ventricular arrhythmias, including atrial fibrillation, PSVT (both PAF as well as reentry of the nodal or W-P-W type), and ectopic atrial tachycardia. Its dosage and role in antiarrhythmic therapy are discussed.

Anilides↗
PubMed1986

Electrophysiology, hemodynamic and arrhythmia efficacy model studies on encainide.

Encainide is a class IC agent possessing a broad spectrum of antiarrhythmic actions in a variety of animal models. It increases the ventricular fibrillation threshold of the perfused rabbit heart and in situ dog myocardium. Encainide suppresses atrial fibrillation resulting from topical application of aconitine in the anesthetized dog and ventricular fibrillation induced by chloroform asphyxiation in the mouse. In these latter 2 models, encainide is approximately 7 to 11 and 16 to 18 times more potent, respectively, on a milligram basis than quinidine. In anesthetized dogs encainide converts ouabain-induced tachyarrhythmias to normal sinus rhythm at a mean intravenous dose of 0.67 mg/kg. Single doses of 0.5 mg/kg intravenously or 1 mg/kg orally significantly reduced ventricular ectopy in conscious dogs 18 to 22 hours after 2-stage ligation of the left coronary artery. At doses and plasma concentrations exceeding efficacious therapeutic levels, encainide has no major negative inotropic effects and does not compromise cardiac function or hemodynamics. It is devoid of peripheral autonomic or mediator-evoked responses and, in particular, lacks anticholinergic actions. Encainide is rapidly absorbed by all routes of administration and extensively metabolized by the liver. The major metabolites, O-demethyl encainide and 3-methoxy-O-demethyl encainide, have been shown to have quantitatively different, but qualitatively similar, profiles of pharmacodynamic effects. Subacute and chronic administration of encainide at doses representing 11 times an effective oral human dose have produced no distinct or consistent toxicologic findings. Carcinogenicity and mutagenicity studies were negative.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1986

Comparative antiarrhythmic actions of encainide and its major metabolites.

The local anesthetic, antiarrhythmic, and acute toxicologic properties of the O-demethyl (ODE), 3-methoxy-O-demethyl (MODE) and N-demethyl (NDE) analogs of encainide (E) were compared with those of parent drug in several models. In the mouse chloroform-induced fibrillation model, the order of antiarrhythmic potency was ODE greater than E greater than MODE greater than NDE. The acute LD50 values for ODE, E, MODE and NDE in mice were 22.6, 38.1, 43.6 and 81.1 mg/kg, i.p. Based upon the toxic/therapeutic ratio in mice, ODE appeared to have the greatest margin of safety and MODE the least; E and NDE were intermediate. In dogs with ouabain-induced tachyarrhythmias, the converting doses of encainide, ODE, MODE and NDE were 0.67, 0.15, 0.39 and 1.1 mg/kg, i.v., respectively. The ODE and MODE metabolites thus appear to be more potent on a mg basis, but both have shorter durations of action than the parent compound. Antiarrhythmic activity in this model was best reflected by plasma drug level (Cp) rather than dose of drug administered. Antiarrhythmic onset Cp associated with encainide (244 ng/ml), ODE (77 ng/ml), MODE (164 ng/ml) and NDE (851 ng/ml) have been identified in this anesthetized dog model. In conscious dogs previously subjected to Harris two-stage coronary artery ligation, the minimal effective doses of encainide were 0.5 mg/kg i.v. and 1 mg/kg orally. For ODE and MODE the minimal effective doses were 0.25 and 0.19 mg/kg injected i.v., respectively, and 0.5 and 0.38 mg/kg given orally. By both routes, encainide had the shortest onset, longest duration and most consistent profile of sustained antiarrhythmic effects. Antiarrhythmic activity did not correlate with local anesthetic potency of either encainide or its metabolites. The data are consistent with the hypothesis that the metabolites of encainide may contribute to and/or be responsible, at least in part, for the persistent antiarrhythmic actions observed clinically following chronic administration of the parent drug in patients.

Anesthetics, Local↗
PubMed1982

The antiarrhythmic action of encainide versus ventricular arrhythmias in the conscious dog following coronary artery ligation.

Encainide (MJ 9067) was given intravenously at 1, 2, or 5 mg/kg and orally at 1, 2.5, 5, or 10 mg/kg to conscious dogs 18--23 h after two-stage ligation of the left anterior descending coronary artery. Heart rate and ventricular ectopic rate were lowered in a dose-related manner by 40--70 and 55--158 beats/min, respectively, following drug administration. Ventricular arrhythmia was frequently abolished with doses of 2 mg/kg and above. The onset of antiarrhythmic activity was 1--2 min after intravenous injection and 15--30 min after oral ingestion. The duration of effect was 6--7 h or longer following either route of drug administration. Emesis occurred in 1 of 10 and 1 of 6 dogs, respectively, at the 2 and 5 mg/kg intravenous dose levels. Brief ataxia was also observed in one dog given the latter dose.

Administration, Oral↗
PubMed1982

Differential effects of trazodone and imipramine on intracardiac conduction in the anesthetized dog.

Intra-atrial, ventricular septal and left ventricular free wall conduction rates as well as lead II EKG intervals and heart rate were measured in pentobarbital-anesthetized, open-chest dogs given increasing doses of either trazodone (0.3-30 mg/kg) or imipramine (0.1-10 mg/kg) intravenously. Conduction intervals were measured during periods of spontaneous nodal rhythm or fixed rate (150 b/min) of atrial pacing. Trazodone, at cumulative doses up to 44.3 mg/kg, did not significantly depress any measured index of cardiac conduction but did lower heart rate (36%) and prolong the Q-Tc interval (19%). Imipramine, particularly at doses of 3 and 10 mg/kg, caused bradycardia (32%) and significantly slowed both atrial (23-46%) and ventricular (21-55%) conduction as well as repolarization interval (14-35%). The data indicate the differing effects of these two compounds on the heart and represent suggestive evidence of the potentially greater safety of trazodone as a new and structurally distinct antidepressant drug.

Anesthesia↗
PubMed1980

Cardiovascular effects of bucindolol (MJ 13105) in conscious dogs.

Bucindolol (MJ 13105), administered to conscious, normotensive dogs (a) attenuated the positive chronotropic and diastolic depressor response elicited by isoproterenol, (b) increased heart rate and (c) elevated plasma renin activity (PRA). Repeated daily administration of bucindolol caused a cumulative reduction in isoproterenol-elicited cardiac and vascular responses. The increase in heart rate was not blocked by atropine and only partially attenuated by propranolol. To study the effect of bucindolol on erect blood pressure, dogs were tilted rapidly through 90 degrees from the supine to a head-up erect position, a maneuver that reflexly increases blood pressure. Following the administration of bucindolol, blood pressure in the erect position was lower than before drug but was still higher than blood pressure in the supine position suggesting the compensatory reflex response to this postural change is still functional. Bucindolol had no significant effect on P wave and QRS durations or P-R and corrected Q-T intervals of the EKG.

Administration, Oral↗
PubMed1979

Trazodone and imipramine: comparative effects on canine cardiac conduction.

Lead II EKG and His bundle electrograms were recorded in closed-chest pentobarbital-anesthetized dogs. Trazodone, a structurally distinct, new antidepressant agent, had no effect on His--Purkinje (HV interval) or intraventricular (HS interval) conduction following intravenous injection at graded doses between 1 and 30 mg/kg. In contrast, the tricyclic psychotropic agent imipramine (0.5--5 mg/kg) significantly slowed impulse conduction as indicated by increases in both the HV and HS intervals. Imipramine (5 mg/kg) also slowed impulse transmission across the atrium (PA interval). These responses to imipramine were associated with a concurrent prolongation of both the PR interval and QRS duration. In the anesthetized dog, trazodone administration promoted no evidence of heart block or sign of rhythm disturbances other than slowing in normal sinus rhythm.

Animals↗
PubMed1977

Antiarrhythmic properties of MJ 9067 in acute animal models.

A novel benzanilide derivative, MJ 9067, has been shown to abolish experimental atrial and ventricular arrhythmiase effectively and promote the return of normal sinus rhythm in a variety of animal models. At intravenous dose levels ranging from 0.5 to 3.2 mg/kg, MJ 9067 successfully converted atrial fibrillation induced by either local application of aconitine or electrical stimulation, and ventricular tachycardia elicited by intravenous injection of ouabain or digoxin. The compound was equally effective in vagotomized or nonvagotomized dogs, and in intact cats and monkeys. The ventricular ectopic rate in conscious dogs 18 to 20 hours after two-stage ligation of a coronary artery was also markedly reduced by the drug at 2 mg/kg i.v. At antiarrhythmic dose levels, there were no undesirable effects noted on peripheral blood pressure, heart rate or the configuration of the electrocardiogram.

Aconitine↗