title: 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.
authors.affiliation: Aalborg University, Fredrik Bajers Vej 5, 9220 Aalborg, Denmark. Electronic address: ask@hst.aau.dk.
authors.forename: Ask Schou
authors.initials: AS
authors.lastname: Jensen
authors.affiliation: Aalborg University, Fredrik Bajers Vej 5, 9220 Aalborg, Denmark.
authors.forename: Cristian Pablo
authors.initials: CP
authors.lastname: Pennisi
authors.affiliation: Aalborg University, Fredrik Bajers Vej 5, 9220 Aalborg, Denmark.
authors.forename: Cristian
authors.initials: C
authors.lastname: Sevcencu
authors.affiliation: University of Copenhagen, Nørregade 10, 1165 Copenhagen, Denmark.
authors.forename: Jørn Bolstad
authors.initials: JB
authors.lastname: Christensen
authors.affiliation: University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark.
authors.forename: Jette Elisabeth
authors.initials: JE
authors.lastname: Kristiansen
authors.affiliation: Aalborg University, Fredrik Bajers Vej 5, 9220 Aalborg, Denmark.
authors.forename: Johannes Jan
authors.initials: JJ
authors.lastname: Struijk
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D005260:Female; D010210:Papillary Muscles / Q000187:drug effects* / Q000502:physiology*; D011817:Rabbits; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013881:Thioridazine / Q000737:chemistry* / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D013881:Thioridazine
keywords: APD prolongation; Isolated papillary muscle; QT prolongation; Reversal of resistance; Thioridazine; Thioridazine hydrochloride (PubChem CID: 66062); Ventricular action potential