A Novel Cardioprotective Drug, K201 (JTV519), Induces Prolongation of QT and QTc Intervals, but not Torsades de Pointes

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K201 (JTV-519; 4-[-3{1-(4-benzyl) piperidinyl} propionyl]-7-methoxy-2, 3, 4, 5-tetrahydro-1, 4-ben-zothiazepine), is a multi-channel blocker and a ryanodine receptor stabilizer that exhibits strong cardiopro-tective and antiarrhythmic effects. In this study, we examined how intravenous infusion of K201 without an α-agonist prolongs the QT interval in chloralose-anaesthetized rabbits, and whether the maximum dose of K201 given concomitantly induces torsades de pointes. The QT interval was significantly prolonged in the group receiving 6-hour infusion of K201 at 20 μg/kg/min, but the QTc interval was not prolonged (n=5). With infusion of K201 at 0 (vehicle; n=5), 40 (n=6), 100 (n=6), 200 (n=6) and 400 μg/kg/min (n=5), blood pressure and HR were decreased, and prolongation of PQ, QRS complex, QT and QTc intervals occurred dose-dependently. The QTc interval was significantly prolonged from 211.5±11.9 ms of the baseline to 319.9±31.1 ms at a concentration of 400 μg/kg/min, which is the maximum dose of K201, but tors-ades de pointes was not induced at this dose. These results show that K201, which has a suppressive effect on Ca^<2+> leakage from the sarcoplasmic reticulum and an α_1-adrenoceptor-blocking effect, does not induce torsades de pointes, although it causes prolongation of the QT interval.
2006-03-25