High affinity blockade of the HERG cardiac K+ channel by the neuroleptic pimozide

Kang, Jiesheng; Wang, Lin; Cai, Feng; Rampe, David

doi:10.1016/s0014-2999(00)00123-0

Cited by 86 publications

(43 citation statements)

References 13 publications

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“…Indeed, individual absolute values of the QTcB interval from pre-dose to 6 h after administration of 10 mg / kg of pimozide were from 340 ms to 519 ms, from 330 ms to 407 ms, and from 324 ms to 442 ms, respectively. The results confirm that pimozide prolongs the QTcB interval, and this is supported by previous reports (24,29).…”

Section: Predictability Of Qtcb Prolongation In Cynomolgus Monkeysupporting

confidence: 92%

QT PRODACT: In Vivo QT Assay With a Conscious Monkey for Assessment of the Potential for Drug-Induced QT Interval Prolongation

Ando

Hombo

Kanno³

et al. 2005

J Pharmacol Sci

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Abstract. In safety pharmacology studies, the effects on the QT interval of electrocardiograms are routinely assessed using a telemetry system in cynomolgus monkeys. However, there is a lack of integrated databases concerning in vivo QT assays in conscious monkeys. As part of QT Interval Prolongation: Project for Database Construction (QT PRODACT), the present study examined 10 positive compounds with the potential to prolong the QT interval and 6 negative compounds considered to have no such effect on humans. The experiments were conducted at 7 facilities in accordance with a standard protocol established by QT PRODACT. The vehicle or 3 doses of each test compound were administered orally to male cynomolgus monkeys (n = 3 -4), and telemetry signals were recorded for 24 h. None of the negative compounds prolonged the corrected QT using Bazett's formula (QTcB) interval. On the other hand, almost all of the positive compounds prolonged the QTcB interval, but haloperidol, terfenadine, and thioridazine did not. The failure to detect the QTcB interval prolongation appeared to be attributable for the differences in metabolism between species and / or disagreement with Bazett's formula for tachycardia. In the cynomolgus monkeys, astemizole induced Torsade de Pointes and cisapride caused tachyarrhythmia at lower plasma concentrations than those observed in humans and dogs. These results suggest that in vivo QT assays in conscious monkeys represent a useful model for assessing the risks of drug-induced QT interval prolongation. Supplementary material (Appendix): available only at http://dx

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Section: Predictability Of Qtcb Prolongation In Cynomolgus Monkeysupporting

confidence: 92%

QT PRODACT: In Vivo QT Assay With a Conscious Monkey for Assessment of the Potential for Drug-Induced QT Interval Prolongation

Ando

Hombo

Kanno³

et al. 2005

J Pharmacol Sci

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“…Of the I Kr and / or hERG current inhibitors tested in our study, astemizole (23), cisapride (24), E-4031 (25), flecainide (26), ciprofloxacin (27), pimozide (28), and quinidine (29) have been reported to inhibit I Kr or hERG currents with little or no effect on slowly-activateddelayed-rectifier potassium currents (I Ks ) or I Ks -like KvLQT1 / mink currents. On the other hand, the prolongation of APD and APD induced by cisapride at 1 µmol / L was greater than that of APD 60-90 .…”

Section: Discussionmentioning

confidence: 91%

QT PRODACT: Evaluation of the Potential of Compounds to Cause QT Interval Prolongation by Action Potential Assays Using Guinea-Pig Papillary Muscles

Kii

Hayashi

Tabo³

et al. 2005

J Pharmacol Sci

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Abstract. Certain compounds that prolong QT interval in humans have little or no effect on action-potential (AP) duration used traditionally, but they inhibit rapidly-activated-delayedrectifier potassium currents (I Kr ) and / or human ether-a-go-go-related gene (hERG) currents. In this study using isolated guinea-pig papillary muscles, we investigated whether new parameters in AP assays can detect the inhibitory effects of various compounds on I Kr and / or hERG currents with high sensitivity. The difference in AP duration between 60% and 30% repolarization, 90% and 60% repolarization, and 90% and 30% repolarization (APD 30-60 , APD 60-90 , and APD 30-90 , respectively) were calculated as the new parameters. All the 15 I Kr and / or hERG current inhibitors that have been reported (9 compounds) or not reported (6 compounds) to inhibit calcium currents prolonged APD 30-60 , APD 60-90 , and / or APD 30-90 ; and 8 of the 15 inhibitors prolonged APD 30-60 , APD 60-90 , and / or APD 30-90 more potently than APD 90 . The APD 30-60 , APD 60-90 , and APD 30-90 measurements revealed no difference in sensitivity when evaluating the effects of the I Kr and / or hERG current inhibitors on the three parameters. On the other hand, compounds with little or no effect on hERG currents had no effect on APD 30-60 , APD . Therefore, it is concluded that in AP assays using isolated guinea-pig papillary muscles, APD 30-60 , APD 60-90 , and APD 30-90 are useful indexes for evaluating the inhibitory effects of compounds including mixed ion-channel blockers on I Kr and / or hERG currents. Supplementary material (Appendix): available only at http://dx

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“…Cisapride (Walker et al, 1999) hERG 0.0236 CHO Pimozide (Kang et al, 2000) hERG 0.018 Ibid. Bepridil (Chouabe et al, 1998) hERG 0.55 COS Droperidol (Drolet et al, 1999) I kr hERG 0.0276 0.032…”

Section: Rab-vm Hek293mentioning

confidence: 99%

Drug Screening and Drug Safety Evaluation by Patch Clamp Technique

Long¹,

Li²

2012

Patch Clamp Technique

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High affinity blockade of the HERG cardiac K+ channel by the neuroleptic pimozide

Cited by 86 publications

References 13 publications

QT PRODACT: In Vivo QT Assay With a Conscious Monkey for Assessment of the Potential for Drug-Induced QT Interval Prolongation

QT PRODACT: In Vivo QT Assay With a Conscious Monkey for Assessment of the Potential for Drug-Induced QT Interval Prolongation

QT PRODACT: Evaluation of the Potential of Compounds to Cause QT Interval Prolongation by Action Potential Assays Using Guinea-Pig Papillary Muscles

Drug Screening and Drug Safety Evaluation by Patch Clamp Technique

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