We studied 12 patients receiving either chronic oral (p.o.) maintenance bretylium and/or acute intravenous (i.v.) bretylium to evaluate drug efficacy and pharmacokinetics. All patients were survivors of ventricular tachycardia or fibrillation. A new assay for bretylium was applied, and it proved sensitive and reliable. After single intravenous dosing, bretylium was eliminated from serum with a mean rate constant of lambda iv1 = 0.0515 hr-1 and a corresponding elimination half-life of tiv1/2 = 13.5 hr (7 studies), similar to previous results in normals. Total body clearance averaged 428 ml/min, of which virtually all was accounted for by renal clearance. Seven patients responding to intravenous bretylium were transferred to oral drug. During chronic therapy (mean dose, 41 mg/kg/day bretylium tosylate), mean minimum steady-state concentration of bretylium was 186 ng/ml (range, 72-461) and was accurately predicted, within experimental error, by using the elimination rate constant determined for oral, but not intravenous, drug in normal subjects (lambda po1 = 0.115 hr-1). Determination of average steady-state concentration (Css) yielded similar conclusions. Mean 24 hr urinary excretion of bretylium during oral therapy was 18.3% (range, 9-13%). These results lend validity to earlier observations in normals and suggest route and concentration dependence of disposition. Transfer to oral bretylium allowed continued control of sustained ventricular tachycardia in all 7 patients and of unsustained ventricular tachycardia in 5. Orthostatic hypotension in 4 responded to protriptyline. Six were discharged on bretylium, with a mean follow-up of 12.2 months (range, 1-25.5). Four maintained a favorable response, and 2 died suddenly at 1 and 3 months. We conclude that further evaluation or oral bretylium is justified; attempts should be made to increase steady-state concentrations during oral therapy.

Administration, Oral↗

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Response to encainide of refractory ventricular tachycardia: clinical application of assays for parent drug and metabolites.

To assess the response to encainide in patients with malignant arrhythmias, we treated 22 patients with recurrent ventricular tachycardia (VT) or fibrillation (VF) refractory to an average of 5.7 drugs. Thirteen patients (59%) showed a favorable in-hospital response, and 11 of 22 (50%) maintained a favorable antiarrhythmic response during a median follow-up of 13.5 months (range 0.3--25.5). Encainide was well tolerated. Six (46%) of 13 patients responded to intravenous encainide with suppression of VT by programmed ventricular stimulation or continuous monitoring; oral encainide has maintained arrhythmia control. In six of seven others, cycle length of VT was lengthened. Initial therapy with oral drug yielded five complete and two partial responses, assessed by monitoring, among nine other patients. Of three outpatient failures, only one was an inpatient responder. Proarrhythmic responses were also noted and included spontaneous increases in ectopy (three patients), easier induction of VT spontaneously or at programmed stimulation (three patients), facilitation of exercise VT (one patient), and syncope due to VT/VF (one patient). After intravenous therapy, plasma encainide concentration averaged 773 ng/ml (range 476--1,279, n = 4), with low or negligible metabolites. During chronic oral therapy, encainide concentrations were low and variable, averaging 67.5 ng/ml (less than 10--585; n = 23, 10 patients); metabolite levels were higher and less variable: O-demethyl encainide, mean 198 ng/ml (61--882); 3-methoxy-o-demethyl encainide, mean 128 ng/ml (39--379). Active metabolites(s) may thus be more important than parent drug during chronic therapy. In summary, encainide may provide successful therapy in approximately half of patients with malignant, refractory ventricular arrhythmias. Inpatient response predicts outpatient results. Encainide, like other antiarrhythmics, has proarrhythmic potential, suggesting a carefully monitored initial approach.

Adult↗

PubMedDate not supplied

Urinary androsterone, etiocholanolone, and dehydroepiandrosterone responses to 72-hr. avoidance sessions in the monkey.

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17-Hydroxycorticosteroids↗

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Quantitative characterization of epicardial wave fronts during regional ischemia and elevated extracellular potassium ion concentration.

This study applied zero-delay wave number spectral estimation as a means of quantifying the changes in activation and recovery sequences of propagating plane waves on the epicardial surface of in situ porcine hearts during regional hyperkalemia and ischemia. Unipolar electrograms (104) were recorded from the left ventricular surface of nine hearts using a plaque electrode array with 1 mm spatial sampling intervals. The objectives were (1) to define a set of parameters capable of quantifying the spatial and temporal changes in measured extracellular potentials associated with localized ischemia prior to the onset of conduction block; (2) to elevate regional levels of extracellular potassium ion concentration and quantify potential changes due to this known physiologic manipulation; and (3) to use quantitative parameters to make statistical comparisons in order to distinguish wave fronts during normal, ischemic and hyperkalemic conditions. Results showed that the parameters of wave number and average temporal frequency and the associated power, as determined from the wave number spectrum, provided statistically significant (p<0.05) quantification of changes in wave front features during normal and ischemic or hyperkalemic conditions. The results were consistent with results obtained from conventional time-space domain methods like isochronal mapping and electrograms, with the advantage of a quantitative result enabling simple comparisons and trend analysis for large numbers of heart beats.

Animals↗