Electrophysiologic Characterization of the Antipsychotic Drug Sertindole in a Rabbit Heart Model of Torsade de Pointes: Low Torsadogenic Potential Despite QT Prolongation

Eckardt, Lars; Breithardt, Günter; Haverkamp, Wilhelm

doi:10.1124/jpet.300.1.64

Cited by 81 publications

(30 citation statements)

References 36 publications

(35 reference statements)

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“…They showed a 15 to 17% prolongation of the QT interval at a perfusion concentration of 1.5 M sertindole without induction of TdP. In the present investigation in anesthetized dogs with normal hearts, 9% prolongation of the QT c interval was observed at 1.3 Ϯ 0.1 M. No TdP was observed, confirming the results from Eckardt et al (2002). Plasma protein binding in vivo and unknown levels of accumulation in cardiac tissue complicate comparisons between these models.…”

Section: Discussionsupporting

confidence: 79%

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Electrophysiological Safety of Sertindole in Dogs with Normal and Remodeled Hearts

Thomsen

Volders

Štengl³

et al. 2003

J Pharmacol Exp Ther

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Inhibition of the potassium current I Kr and QT prolongation are associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. We investigated the cardiac electrophysiological effects of sertindole, an antipsychotic drug reported to prolong the QT interval in schizophrenic patients. In cell cultures, sertindole seemed to be a selective blocker of I HERG over other ion currents. For I HERG , the IC 50 value was 64 Ϯ 7 nM, whereas I SCN5A , I Ca,L , I Ca,T , I KCNQ1/KCNE1 , and I Kv4.3 were blocked in the micromolar range. In canine ventricular myocytes, the IC 50 value for I Kr inhibition by sertindole was 107 Ϯ 21 nM. Action potentials in these cells prolonged in a reverse rate-and concentration-dependent manner at 10 to 300 nM sertindole. In vivo, sertindole was administered to anesthetized dogs at clinically relevant (0.05-0.20 mg/kg) and high doses (1.0 -2.0 mg/kg) i.v. At 0.05 to 0.20 mg/kg sertindole (plasma concentrations 30 -157 nM), QT c was prolonged by 1 to 5% in normal dogs and by 9 to 20% in dogs with remodeled hearts due to chronic atrioventricular block (CAVB). TdP was not induced at these doses in normal dogs or in CAVB dogs with reproducible induction of TdP by dofetilide in previous experiments. At 1.0 to 2.0 mg/kg sertindole (plasma concentrations 0.5-3

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Section: Discussionsupporting

confidence: 79%

“…Reported plasma concentrations from human volunteers receiving dofetilide ranged from 5 to 23 nM (Pfizer, 1999). Eckardt et al (2002) reported a low torsadogenic potential of sertindole in isolated rabbit hearts. They showed a 15 to 17% prolongation of the QT interval at a perfusion concentration of 1.5 M sertindole without induction of TdP.…”

Section: Discussionmentioning

confidence: 99%

Electrophysiological Safety of Sertindole in Dogs with Normal and Remodeled Hearts

Thomsen

Volders

Štengl³

et al. 2003

J Pharmacol Exp Ther

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“…Finally, this result was confirmed with studies on isolated tissues of feline and rabbit (Drici et al 1998;Eckardt et al 2002).…”

Section: Heterogeneous Chemical Classessupporting

confidence: 77%

Drug-induced block of cardiac HERG potassium channels and development of torsade de pointes arrhythmias: the case of antipsychotics

Calderone

Testai

Martinotti

et al. 2005

Journal of Pharmacy and Pharmacology

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The prolongation of the cardiac repolarization process, a result of the blocking of the Human Ether-ago-go Related Gene potassium channel, is an undesired accessory property shared by many pharmacological classes of non-cardiovascular drugs. Often the delayed cardiac repolarization process can be identified by a prolongation of the QT interval of the electrocardiograph. In these conditions, premature action potentials can trigger a dangerous polymorphic ventricular tachyarrhythmia, known as torsade de pointes, which occasionally can result in lethal ventricular fibrillation. In this work, brief descriptions of the electrophysiological basis of torsade de pointes and of the several pharmacological classes of torsadogenic drugs are given. Attention is focused on antipsychotics, with a deeper overview on the experimental and clinical reports about their torsadogenic properties. The cardiac action potentialCardiac action potentials are generated by trans-membrane movements of ion species, flowing principally through specific channels. In a typical human cardiac action potential ( Figure 1A), five different phases can be recognized. Phase 0 is a rapid depolarization process resulting from a massive inward flow of Na þ (current I Na ). The following phase 1 is linked to the inactivation of the I Na current and to a weak and transient repolarization due to an outward flow of K þ (current I to ). Phase 2 reflects an almost iso-electric plateau generated by the simultaneous activation of a depolarizing inward Ca þþ current, a repolarizing outward rapidly activated K þ current (current I Kr ) and a repolarizing outward slowly activated K þ current (current I Ks ). Phase 3 reflects the complete membrane repolarization due to many K þ currents (mainly I Ks and I Kr ), which leads the cell to the recovery of resting membrane potential. Finally, phase 4 is the resting period, ensured by inward rectifier K þ currents (I K1 ), before a new following cardiac cycle. The QT intervalA typical electrocardiograph (ECG) tracing of a human cardiac cycle ( Figure 1B) starts with a P wave (80-110 ms) representing the atrial depolarization. The following iso-electric time (about 100 ms) reflects the propagation of the depolarization through the atrio-ventricular node to the ventricular conduction system. The QRS complex (<120 ms) represents the whole ventricular depolarization, followed by an isoelectric time (about 120 ms) starting from the J point. Finally, the T wave (230-300 ms) represents the final ventricular repolarization and the end of the cycle. Among the various ECG parameters that are useful in analysing the cardiac functions, the QT interval is the most usual one for estimating the ventricular repolarization process. Drug-induced torsade de pointesMany drugs belonging to different pharmacological classes (Table 1) can trigger lifethreatening polymorphic ventricular tachyarrhythmias, such as torsade de pointes. In particular, many non-cardiovascular drugs in common clinical use cause the prolongation

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“…Likewise, lidocaine could decrease significantly the incidence of TdP, but did so without affecting the QTc interval. These results corroborate earlier reports showing that QT prolongation did not correlate to the proarrhythmic liability of repolarization-prolonging drugs in isolated, AVablated rabbit hearts 66,67 .…”

Section: The Applied Repolarization Related Biomarkers Did Not Correlsupporting

confidence: 82%

Comparison of different proarrhythmia biomarkers in isolated rabbit hearts

Orosz

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Electrophysiologic Characterization of the Antipsychotic Drug Sertindole in a Rabbit Heart Model of Torsade de Pointes: Low Torsadogenic Potential Despite QT Prolongation

Cited by 81 publications

References 36 publications

Electrophysiological Safety of Sertindole in Dogs with Normal and Remodeled Hearts

Electrophysiological Safety of Sertindole in Dogs with Normal and Remodeled Hearts

Drug-induced block of cardiac HERG potassium channels and development of torsade de pointes arrhythmias: the case of antipsychotics

Comparison of different proarrhythmia biomarkers in isolated rabbit hearts

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