Differential effects of thioridazine enantiomers on action potential duration in rabbit papillary muscle
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Differential effects of thioridazine enantiomers on action potential duration in rabbit papillary muscle. / Jensen, Ask Schou; Pennisi, Cristian Pablo; Sevcencu, Cristian; Christensen, Jørn Bolstad; Kristiansen, Jette Elisabeth; Struijk, Johannes Jan.
I: European Journal of Pharmacology, Bind 747, 15.01.2015, s. 7-12.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Differential effects of thioridazine enantiomers on action potential duration in rabbit papillary muscle
AU - Jensen, Ask Schou
AU - Pennisi, Cristian Pablo
AU - Sevcencu, Cristian
AU - Christensen, Jørn Bolstad
AU - Kristiansen, Jette Elisabeth
AU - Struijk, Johannes Jan
PY - 2015/1/15
Y1 - 2015/1/15
N2 - 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 2 Hz 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.
AB - 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 2 Hz 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.
KW - APD prolongation
KW - Isolated papillarymuscle
KW - QT prolongation
KW - Reversalofresistance
KW - Thioridazine
KW - Ventricular actionpotential
U2 - 10.1016/j.ejphar.2014.11.015
DO - 10.1016/j.ejphar.2014.11.015
M3 - Journal article
C2 - 25449032
AN - SCOPUS:84916898704
VL - 747
SP - 7
EP - 12
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
ER -
ID: 261046592