Electrophysiological safety of sertindole in dogs with normal and remodeled hearts

Morten Bækgaard Thomsen; Paul G A Volders; Milan Stengl; Roel L H M G Spätjens; Jet D M Beekman; Ulrike Bischoff; Morten A Kall; Kristen Frederiksen; Jørgen Matz; Marc A Vos

doi:10.1124/jpet.103.052753

Electrophysiological safety of sertindole in dogs with normal and remodeled hearts

Morten Bækgaard Thomsen, Paul G A Volders, Milan Stengl, Roel L H M G Spätjens, Jet D M Beekman, Ulrike Bischoff, Morten A Kall, Kristen Frederiksen, Jørgen Matz, Marc A Vos

Physiology of circulation, kidney and lung

57 Citationer (Scopus)

Abstract

Inhibition of the potassium current IKr 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 IHERG over other ion currents. For IHERG, the IC50 value was 64 +/- 7 nM, whereas ISCN5A, ICa,L, ICa,T, IKCNQ1/KCNE1, and IKv4.3 were blocked in the micromolar range. In canine ventricular myocytes, the IC50 value for IKr inhibition by sertindole was 107 +/- 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), QTc 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 0.5-3.1 microM), QTc prolonged by 6 to 11% in normal dogs and by 22% in dofetilide-sensitive CAVB dogs. TdP occurred in three of five animals in the latter group. Thus, at high i.v. doses sertindole can pose a serious proarrhythmic risk when electrical remodeling of the ventricles is present. At clinically relevant doses, however, sertindole does not cause TdP in anesthetized dogs with normal or remodeled hearts.

Originalsprog	Engelsk
Tidsskrift	Journal of Pharmacology and Experimental Therapeutics
Vol/bind	307
Udgave nummer	2
Sider (fra-til)	776-84
Antal sider	9
ISSN	0022-3565
DOI	https://doi.org/10.1124/jpet.103.052753
Status	Udgivet - nov. 2003

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10.1124/jpet.103.052753

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title = "Electrophysiological safety of sertindole in dogs with normal and remodeled hearts",

abstract = "Inhibition of the potassium current IKr 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 IHERG over other ion currents. For IHERG, the IC50 value was 64 +/- 7 nM, whereas ISCN5A, ICa,L, ICa,T, IKCNQ1/KCNE1, and IKv4.3 were blocked in the micromolar range. In canine ventricular myocytes, the IC50 value for IKr inhibition by sertindole was 107 +/- 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), QTc 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 0.5-3.1 microM), QTc prolonged by 6 to 11% in normal dogs and by 22% in dofetilide-sensitive CAVB dogs. TdP occurred in three of five animals in the latter group. Thus, at high i.v. doses sertindole can pose a serious proarrhythmic risk when electrical remodeling of the ventricles is present. At clinically relevant doses, however, sertindole does not cause TdP in anesthetized dogs with normal or remodeled hearts.",

keywords = "Action Potentials, Animals, Antipsychotic Agents, Arrhythmias, Cardiac, Dogs, Electrophysiology, Heart, Imidazoles, Indoles, Myocytes, Cardiac, Phenethylamines, Sulfonamides",

author = "Thomsen, {Morten B{\ae}kgaard} and Volders, {Paul G A} and Milan Stengl and Sp{\"a}tjens, {Roel L H M G} and Beekman, {Jet D M} and Ulrike Bischoff and Kall, {Morten A} and Kristen Frederiksen and J{\o}rgen Matz and Vos, {Marc A}",

year = "2003",

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doi = "10.1124/jpet.103.052753",

language = "English",

volume = "307",

pages = "776--84",

journal = "Journal of Pharmacology and Experimental Therapeutics",

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TY - JOUR

T1 - Electrophysiological safety of sertindole in dogs with normal and remodeled hearts

AU - Thomsen, Morten Bækgaard

AU - Volders, Paul G A

AU - Stengl, Milan

AU - Spätjens, Roel L H M G

AU - Beekman, Jet D M

AU - Bischoff, Ulrike

AU - Kall, Morten A

AU - Frederiksen, Kristen

AU - Matz, Jørgen

AU - Vos, Marc A

PY - 2003/11

Y1 - 2003/11

N2 - Inhibition of the potassium current IKr 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 IHERG over other ion currents. For IHERG, the IC50 value was 64 +/- 7 nM, whereas ISCN5A, ICa,L, ICa,T, IKCNQ1/KCNE1, and IKv4.3 were blocked in the micromolar range. In canine ventricular myocytes, the IC50 value for IKr inhibition by sertindole was 107 +/- 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), QTc 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 0.5-3.1 microM), QTc prolonged by 6 to 11% in normal dogs and by 22% in dofetilide-sensitive CAVB dogs. TdP occurred in three of five animals in the latter group. Thus, at high i.v. doses sertindole can pose a serious proarrhythmic risk when electrical remodeling of the ventricles is present. At clinically relevant doses, however, sertindole does not cause TdP in anesthetized dogs with normal or remodeled hearts.

AB - Inhibition of the potassium current IKr 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 IHERG over other ion currents. For IHERG, the IC50 value was 64 +/- 7 nM, whereas ISCN5A, ICa,L, ICa,T, IKCNQ1/KCNE1, and IKv4.3 were blocked in the micromolar range. In canine ventricular myocytes, the IC50 value for IKr inhibition by sertindole was 107 +/- 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), QTc 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 0.5-3.1 microM), QTc prolonged by 6 to 11% in normal dogs and by 22% in dofetilide-sensitive CAVB dogs. TdP occurred in three of five animals in the latter group. Thus, at high i.v. doses sertindole can pose a serious proarrhythmic risk when electrical remodeling of the ventricles is present. At clinically relevant doses, however, sertindole does not cause TdP in anesthetized dogs with normal or remodeled hearts.

KW - Action Potentials

KW - Animals

KW - Antipsychotic Agents

KW - Arrhythmias, Cardiac

KW - Dogs

KW - Electrophysiology

KW - Heart

KW - Imidazoles

KW - Indoles

KW - Myocytes, Cardiac

KW - Phenethylamines

KW - Sulfonamides

U2 - 10.1124/jpet.103.052753

DO - 10.1124/jpet.103.052753

M3 - Journal article

C2 - 12966159

SN - 0022-3565

VL - 307

SP - 776

EP - 784

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

IS - 2

ER -

Electrophysiological safety of sertindole in dogs with normal and remodeled hearts

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