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↗

PubMedDate not supplied

Comparative effects of prenalterol and dobutamine in a canine model of acute ischemic heart failure.

The hemodynamic effects of the inotropic agents prenalterol and dobutamine were compared in a canine model of acute ischemic heart failure following two-vessel coronary artery constriction. Intravenous infusions of both inotropic agents resulted in improvement of cardiac output, left ventricular maximum dP/dt, and contractile force in the nonischemic zone and in a decrease in systemic vascular resistance. No significant changes occurred in ischemic zone contractile force or left ventricular end-diastolic pressure following either inotropic agent compared to saline controls. Significant differences between the two inotropic agents consisted of prenalterol's markedly longer duration of action (hemodynamic half life of 3 hr after discontinuation compared to a value of 1.7 min after dobutamine discontinuation) and greater augmentation of cardiac output at high-dose dobutamine due to greater increases in heart rate. However, similar hemodynamic effects were noted with prenalterol and dobutamine at doses which increased nonischemic contractile force 50%. Both inotropic agents were associated with ventricular arrhythmias in the acute ischemic state. Implications regarding the use of prenalterol and dobutamine in clinical acute ischemic low-output states are discussed.

Animals↗

PubMedDate not supplied

The nitroglycerin polymer gel matrix system: a new method for administering nitroglycerin evaluated with plasma nitroglycerin levels.

A new topical dosage form of nitroglycerin has been developed in which nitroglycerin and its vehicle are incorporated in a polymer gel matrix of fixed dimension. Venous plasma nitroglycerin concentrations were measured for 24 h after application of nitroglycerin polymer gel systems measuring 10 cm and containing 2% nitroglycerin (wt/wt) to 10 normal male volunteers. Five of these subjects were subsequently tested with 20-cm2 gel systems of similar composition. With the 10-cm2 nitroglycerin polymer gel system, venous plasma nitroglycerin concentrations were 0.83 +/- 0.26 ng/ml ast 4 h and 0.89 +/- 0.23 ng/ml at 24 h. For the 20-cm2 system, venous plasma nitroglycerin concentrations were 1.83 +/- 0.55 ng/ml at 8 h and 1.81 +/- 0.13 ng/ml at 24 h. The only adverse effect noted was headache, which affected all the subjects tested with the 20-cm2 appliance. The plasma nitroglycerin concentrations obtained with the polymer gel system appear to be in a clinically useful range; thus this new form of topical nitroglycerin should be of benefit to patients in whom sustained plasma nitroglycerin concentrations are desirable, e.g., those patients with chronic congestive heart failure and angina on awakening.

Administration, Topical↗

PubMedDate not supplied

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

Hemodynamic and myocardial metabolic effects of the beta-agonist prenalterol in ischemic left ventricular dysfunction.

Hemodynamic and myocardial metabolic parameters in ischemic left ventricular (LV) dysfunction were evaluated in response to the beta-agonist prenalterol. Twenty micrograms/kg intravenous prenalterol increased resting heart rate and cardiac output and decreased LV filling pressure, systemic vascular resistance, and pulmonary artery pressure. Resting coronary blood flow and myocardial oxygen consumption increased but net myocardial lactate and oxygen extraction did not change significantly. During pacing induced tachycardia (121 +/- 4 beats/min), prenalterol improved cardiac index and stroke work index; whereas, LV filling pressure, systemic vascular resistance, and pulmonary artery pressure decreased. Coronary blood flow and myocardial oxygen extraction did not change significantly. Net myocardial lactate extraction during pacing decreased insignificantly; one patient developed overt lactate production. Thus, prenalterol improves cardiovascular function at rest and during pacing-induced tachycardia in ischemic LV failure, but at the cost of higher resting myocardial oxygen consumption. The majority of subjects had no adverse metabolic response.

Adrenergic beta-Agonists↗

PubMedDate not supplied

Sympathetic inhibition with methyldopa in heart failure.

The hypothesis that withdrawal of increased sympathetic activity may be beneficial in heart failure was tested by administration of the centrally acting adrenergic inhibitor methyldopa. Fourteen subjects with chronic, stable New York Heart Association Functional Class 2 or 3 heart failure receiving digitalis and diuretics were randomized to methyldopa (n = 8) 500-1000 mg daily or placebo (n = 6). Clinical, hemodynamic, neurohumoral, and platelet alpha 2-receptor effects were studied after chronic (3 weeks) administration. Sympathetic inhibition did not alter symptom status or exercise duration but reduced plasma norepinephrine concentration during exercise and permitted the same level of exercise to be attained at a lower pressure-rate product, indicating reduced myocardial oxygen consumption. Left ventricular ejection fraction and stroke volume tended to increase, and systemic vascular resistance tended to decrease during exercise after methyldopa administration, suggesting enhanced vasodilation. Upright plasma renin activity increased from 8.2 +/- 2.2 to 13.3 +/- 3.0 ng/nl/h (p = 0.03) after methyldopa, but plasma antidiuretic hormone concentration changed insignificantly. In a subset of patients, platelet alpha 2-receptor density and affinity were unaltered. Renal function was also unchanged. Thus, sympathetic inhibition induced by methyldopa in selected patients with chronic, stable heart failure does not worsen symptom status or exercise performance, and may produce a beneficial effect by withdrawal of excess sympathetic activity with reduction of plasma norepinephrine levels.

Adult↗