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Cardiovascular profile of a new anti-arrhythmic agent, SC-40230
L G Frederick1, S J McDonald, S M Garthwaite
1Cardiovascular Diseases Research, Research and Development, GD Searle & Company, Skokie, Illinois 60077.
Insights
SC-40230, a novel anti-arrhythmic drug, demonstrated minimal cardiovascular side effects in preclinical canine and feline studies. Its anti-arrhythmic dose showed limited impact on heart rate and blood pressure, suggesting a potentially improved safety profile compared to existing treatments.
Area of Science:
- Pharmacology
- Cardiovascular Science
- Drug Development
Background:
- Anti-arrhythmic drugs are crucial for managing cardiac rhythm disorders.
- Existing treatments often have significant cardiovascular side effects.
- SC-40230 is a new agent with combined class Ia and Ib anti-arrhythmic properties.
Purpose of the Study:
- To evaluate the cardiac and general haemodynamic effects of SC-40230.
- To compare the inotropic effects of SC-40230 with other anti-arrhythmic agents.
- To assess the potential side effect profile of SC-40230 at its anti-arrhythmic dose.
Main Methods:
- Experiments were conducted using anaesthetised dogs and isolated cat papillary muscles.
- Cardiac and haemodynamic parameters including left ventricular pressure, heart rate, and blood pressure were measured.
- Dose-dependent effects on electrophysiological parameters (P-R interval, QRS duration) and contractility (inotropic effect) were assessed.
Main Results:
- At the effective anti-arrhythmic dose in dogs (9 mg/kg IV), SC-40230 decreased LV dP/dtmax by 20% with minimal effects on heart rate and blood pressure.
- Higher doses were required to induce significant decreases in blood pressure.
- SC-40230 exhibited a weak negative inotropic effect in cat papillary muscles, less potent than disopyramide or mexiletine.
Conclusions:
- SC-40230 appears to possess a favourable cardiovascular and haemodynamic side effect profile within its therapeutic anti-arrhythmic dose range.
- These preclinical findings suggest SC-40230 may offer an improved safety profile compared to established anti-arrhythmic drugs like disopyramide.
- Further clinical studies are warranted to confirm these promising results in human patients.
Abstract:
The cardiac and general haemodynamic effects of SC-40230, a newly developed anti-arrhythmic agent with both class 1a and 1b properties, were assessed in two different types of experiments using anaesthetised dogs, and in experiments using isolated cat papillary muscles. At the canine anti-arrhythmic dose (9 mg.kg-1 intravenously), SC-40230 decreased the maximum rate of rise of the left ventricular pressure (LV dP/dtmax) by 20%. It decreased heart rate slightly, and lowered (greater than 10%) blood pressure only at doses greater than the canine anti-arrhythmic dose. In these experiments there were dose dependent increases in the P-R interval and the QRS duration. In isolated cat papillary muscles, SC-40230 had a weak negative inotropic effect (IC20 = 3.3 X 10(-5) mol.litre-1) which was less than that previously reported for disopyramide phosphate (IC20 = 1.8 X 10(-5) mol.litre-1) or mexiletine (IC20 = 2.1 X 10(-5) mol.litre-1). These findings suggest SC-40230 has a minimal cardiovascular and haemodynamic side effect potential in its anti-arrhythmic dose range. If these results are confirmed in clinical studies, SC-40230 may have an improved side effect profile versus other anti-arrhythmic drugs such as disopyramide.