Differential effects of thioridazine enantiomers on action potential duration in rabbit papillary muscle

The antipsychotic drug thioridazine has potential for treatment of multidrug-resistant microbes including tuberculosis but also causes cardiotoxic QT interval prolongation. Both thioridazine enantiomers have potent antimicrobial effects, but the neuroleptic effect primarily resides with (+)-thioridazine. In this study we for the first time investigate the cardiotoxicity of the isolated thioridazine enantiomers and show their effects on ventricular repolarization. The effects of (+)-thioridazine, (-)-thioridazine, and racemate on the rabbit ventricular action potential duration (APD) were investigated in a randomized controlled blinded experiment. Action potentials were measured in papillary muscles isolated from 21 female rabbits, and the chug effect on 90% APD in comparison with control (Delta Delta-APD(90)) was evaluated. Increasing concentrations of (+)-thioridazine and the racemate caused significant dose dependent Delta Delta-APD(90) prolongation, while (-)-thioridazine did not. At 0.5 and 2 Hz pacing, (+)-thioridazine caused 19.5% and 20.1% Delta Delta-APD(90) prolongation, the racemate caused 8.0% and 12.9%, and (-)-thioridazine caused 1.5% and 1.1%. The effect of (-)-thioridazine on APD(90) was significantly less than that of the other drugs at both pacing rates (P < 0.01 in all cases), and there was no significant difference between (-)-thioridazine and control. The results of this study indicate that the APD prolonging effect of thioridazine is primarily due to the (+)-thioridazine enantiomer. If these results are valid in humans, (-)-thioridazine may be a safer drug for treatment of multidrug-resistant tuberculosis and other microbes. (C) 2014 Elsevier B.V. All rights reserved.