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

Abstract
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 drug effect on 90% APD in comparison with control (ΔΔ-APD90) was evaluated. Increasing concentrations of (+)-thioridazine and the racemate caused significant dose-dependent ΔΔ-APD90 prolongation, while (-)-thioridazine did not. At 0.5 and 2Hz pacing, (+)-thioridazine caused 19.5% and 20.1% ΔΔ-APD90 prolongation, the racemate caused 8.0% and 12.9%, and (-)-thioridazine caused 1.5% and 1.1%. The effect of (-)-thioridazine on APD90 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.
AuthorsAsk Schou Jensen, Cristian Pablo Pennisi, Cristian Sevcencu, Jørn Bolstad Christensen, Jette Elisabeth Kristiansen, Johannes Jan Struijk
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 747 Pg. 7-12 (Jan 15 2015) ISSN: 1879-0712 [Electronic] Netherlands
PMID25449032 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier B.V. All rights reserved.
Chemical References
  • Thioridazine
Topics
  • Action Potentials (drug effects)
  • Animals
  • Female
  • Papillary Muscles (drug effects, physiology)
  • Rabbits
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thioridazine (chemistry, pharmacology)
  • Time Factors

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