EGIS-7229, the new combined class III antiarrhythmic agent - Lack of EAD inducing effect

EGIS-7229 is a novel antiarrhythmic candidate having multiple mechanisms of action with class III predominance. In this study, the effects of EGIS-722 9 and sotalol on action potential duration (APD) and incidence of early aft erdepolarizations (EADs) were studied and compared in rabbit papillary musc le by using conventional microelectrode techniques. In control bathing solu tion, both drugs increased APD in a concentration-dependent manner; however , the prolongation of APD was greater with sotalol than with EGIS-7229 when the same drug concentrations were compared. EAD developed in 3 of the 11 p reparations (27%) bathed with a solution containing 3.6 mmol/l CsCl + 2 mmo l/l KCl within the first 120 min of superfusion. The addition of 100 mu mol /l sotalol to this superfusate increased the incidence of EAD to 83% (10 fr om 12), whereas the addition of the same concentration of EGIS-7229 prevent ed the development of EAD in all of the 9 preparations studied. These diffe rences in incidence of EAD are likely attributable to differences in drug-i nduced increases of APD-50 in the presence of CsCl. Prolongation of APD-90 showed less correlation with incidence of EAD than changes in APD-50. On th e basis of these in vitro results, high concentrations of EGIS-7229 cannot be expected to be torsadogenic in vivo-in contrast with sotalol-presumably owing to the combined class III + IV activity of the compound. (C) 1999 Els evier Science Inc. All rights reserved.