BETTER ANTIARRHYTHMICS - DEVELOPMENT OF ANTIARRHYTHMIC DRUGS SELECTIVE FOR ISCHEMIA-DEPENDENT ARRHYTHMIAS

RSD1000 is one example of a series of compounds synthesized by Nortran Pharmaceuticals, Inc., to provide selective protection against arrhyt hmias due to myocardial ischaemia and so providing better therapeutic indices than existing drugs. RSD1019 is an analogue of RSD1000, whose therapeutic indices are better than those of RSD1000. The antiarrhythm ic efficacy of RSD1000 and RSD1019 against ventricular arrhythmias ind uced by myocardial ischaemia were investigated in rats. Doses providin g such antiarrhythmic protection were compared with those having effec ts on the ECG and on electrical stimulation variables and induction of ventricular arrhythmias; such actions are indices of ionic current bl ockade in normal myocardium. For RSD1019, additional experiments were performed in rabbits and nonhuman primates to rule out species-specifi c drug actions. The two compounds were also investigated for their eff ects on isolated rat hearts and on sodium and potassium currents in is olated rat cardiac myocytes. Analogous studies were performed on potas sium currents from transfected potassium channels expressed in human e mbrynic kidney cells. Lidocaine was used for comparative purposes in s everal experiments. (C) 1997 Wiley Liss, Inc.