Susan M. Garthwaite

SC-36602, a new antiarrhythmic agent: comparison of its cardiovascular profile with that of other antiarrhythmic drugs.

The cardiovascular profile of SC-36602, a new class 1A/1B antiarrhythmic agent, was compared to those of disopyramide, lidocaine, mexiletine, flecainide, encainide, lorcainide, and quinidine. These drugs were compared at their respective canine antiarrhythmic doses in a hemodynamic evaluation using anesthetized dogs. In another test using anesthetized dogs, the cardiovascular effects of cumulative doses of SC-36602 were assessed. The direct negative inotropic potential of each drug was also determined using isolated cat papillary muscles. In the hemodynamic study, SC-36602 and quinidine did not cause significant myocardial depression, measured as a decrease in the maximal first derivative of the left ventricular pressure. (Heart rate and diastolic filling pressure were not controlled in order to mimic clinical conditions). SC-36602, mexiletine, flecainide, and quinidine increased heart rate. SC-36602 and mexiletine caused a small increase in mean arterial pressure, whereas disopyramide and quinidine decreased it. Disopyramide was the only drug studied that increased left ventricular end-diastolic pressure. SC-36602, quinidine, and mexiletine increased index of cardiac effort. Disopyramide caused a decrease in the latter. Disopyramide, flecainide, encainide, and lorcainide lengthened the ECG intervals. Cumulative intravenous doses of SC-36602 up to 50 mg/kg produced significant decreases in mean arterial pressure, increases in heart rate, and increases in P-R and QRS intervals of the ECG relative to placebo-matched controls. SC-36602 had the least direct negative inotropic action of the drugs studied, as measured in isolated papillary muscles. These data suggest SC-36602, when compared to the other antiarrhythmic drugs studied, has the least amount of hemodynamic side-effects at its antiarrhythmic dose.

The Effect of Bidisomide (SC-40230), a New Class Ia/Ib Antiarrhythmic Agent, on Defihrillation Energy Requirements in Dogs with Healed Myocardial Infarctions

Bidisomide is a Class Ia/Ib antiarrhythmic agent with activity against ventricular and supraventricular arrhythmias. The potential for bidisomide to increase defibrillation threshold (DFT) was tested in anesthetized dogs with healed left ventricular infards (≥ 10 days). Defibrillation patches were attached to each ventricle and shocks were delivered via an external cardioverter/defibrillator. Three groups were studied: placebo (saline), canine therapeutic bidisomide (TB, 2–5 μg/mL plasma concentration) and supratherapeutic bidisomide (STB, 6–14 μg/mL). Each animal received only one treatment. An abbreviated DFT curve was determined before and after treatment. Heart rate, blood pressure, PR, QRS, infarct size, and hematocrit were also measured be/ore and after treatment. DFT was significantly increased (average + 3 to +5 joules [J], P < 0.05) by TB and STB. TB (5/5) did not increase DFT beyond 40 J. In 6/7 experiments, STB did not increase DFT beyond 40 J. Placebo (n = 6) had no significant effect on DFT. Infarct size (x = 11% of the left ventricle) was not significantly different between groups. Heart rate and QRS were not significantly altered but blood pressure was significantly decreased (16%‐31% systolic, 29%‐45% diastolic) and hematocrit was significantly increased (19% to 25%) in oil groups. PR was significantly increased by STB only. Conclusion: therapeutic and supratherapeutic doses of bidisomide slightly but significantly increased DFT (3–5 J) in a canine infarcted heart model.

Efficacy and plasma concentrations of SC-36602 in canine models of ventricular arrhythmia

The antiarrhythmic effectiveness of a new class I agent, SC-36602, was evaluated in two canine models of ventricular arrhythmia. In a Harris coronary ligation-induced arrhythmia model, SC-36602 significantly reduced ectopic rate at doses of 8 mg/kg i.v. and 15, 20 and 30 mg/kg per os. In a ouabain-induced arrhythmia model, a 9 mg/kg i.v. dose of SC-36602 had a sustained (≥60 min) antiarrhythmic effect. The approximate plasma concentration of SC-36602 necessary for measurable antiarrhythmic activity was estimated to be 2–7 μg/ml after either i.v. or oral administration. No adverse cardiovascular or central nervous system effects were observed in conscious or anesthetized dogs in response to SC-36602.

Rapid infusions of bidisomide or disopyramide in conscious dogs : effect of myocardial infarction on acute tolerability

Summary The acute tolerability of rapid infusions of bidisomide or disopyramide was evaluated in normal conscious dogs and in conscious dogs 48 h after the creation of myocardial infarctions (MIs). Both drugs were given in total doses of 15 mg/kg (1.5 × the canine antiarrhythmic dose for each drug). Bidisomide was well tolerated at infusion rates of 3, 5, 11, and 15 mg/kg/min by normal dogs. Disopyramide was well tolerated, except for anticholinergic effects, by normal dogs given infusions at rates of 1.5 and 3 mg/kg/min. Disopyramide caused a ventricular arrhythmia at 4.5 mg/kg/min in one dog, however. Bidisomide (15 mg/kg/min) was well tolerated and antiarrhythmic in dogs with infarctions. Disopyramide (3 and 4.5 mg/kg/min) was lethal in dogs that had myocardial infarctions. A 1 mg/kg/min infusion rate of disopyramide was antiarrhythmic and well tolerated, except for anticholinergic effects, in the post-MI dogs. Both drugs prolonged the ECG lead II P duration, PR interval (bidisomide more so than disopyramide), and QRS duration. Both bidisomide and disopyramide shifted the mean electrical axis of the QRS complex from a right axis deviation to the normal range in dogs with infarctions. The data indicated that the desired cardiac electropharmacologic effects of bidisomide can be achieved in a 1 min infusion. Normal dogs, and especially dogs with infarctions, revealed the potential hazards of rapidly infusing disopyramide.

Simple in vitro method to characterize antiarrhythmic agents.

A simple, nonmicroelectrode method was developed for the in vitro identification and characterization of potential antiarrhythmic agents. To evaluate the method, standard antiarrhythmic agents from three different classifications (I, III, IV) were tested in isolated right ventricular guinea pig papillary muscles for their effect on developed tension (DT), excitability (EX), and effective refractory period (ERP). ERP was measured with the use of paired field stimuli. Depression or reversal of the force frequency relationship was an index of an agents effect on DT. A shift in the stimulus strength-duration relationship was an index of an agents effect on EX. A computer program was developed for data handling and analysis. Disopyramide phosphate (D, 3.0 x 10(-5) M), sotalol (S, 3.0 x 10(-5) M), clofilium phosphate (C, 1.0 x 10(-5) M), and N-acetyl procainamide hydrochloride (N, 3.0 x 10(-5) M) significantly prolonged ERP (+20, +35, +24, +16 ms, respectively), while verapamil (V, 3.0 x 10(-7) M) and the distilled water vehicle (W) did not. D and V significantly decreased DT (-78% and -57% at 1 Hz, respectively) while W, S, C, and N did not. Only D decreased EX. These data correspond well with findings in other models reported in the literature, supporting the use of this simple in vitro method for identification and characterization of potential antiarrhythmic agents.