Blinded validation of the isolated arterially perfused rabbit ventricular wedge in preclinical assessment of drug-induced proarrhythmias

Liu, Tengxian; Brown, Barry S.; Wu, Ying; Antzelevitch, Charles; Kowey, Peter R.; Yan, Gan‐Xin

doi:10.1016/j.hrthm.2006.04.021

Cited by 115 publications

(124 citation statements)

References 45 publications

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“…The chest was opened via a left thoracotomy, and the heart was excised and placed in a cardioplegic solution consisting of cold (4°C) normal Tyrode's solution. Transmural wedges with dimensions of approximately 1.5 cm in width and 2 to 3 cm in length were dissected from the left ventricle as described previously (33). The tissue was cannulated via the small branch of the left anterior descending artery and perfused with cardioplegic solution.…”

Section: Methodsmentioning

confidence: 99%

“…The potential torsadogenic risk of DHA, PQP, and their combination was evaluated in a rabbit heart wedge preparation (33), an established experimental model for the prediction of druginduced proarrhythmia (26). In this model, the torsadogenic risk score ranges from Ϫ2 up to 14, with a higher score being worse (33).…”

mentioning

confidence: 99%

“…In this model, the torsadogenic risk score ranges from Ϫ2 up to 14, with a higher score being worse (33). The results with the combination of DHA and PQP were compared to those with chloroquine, artemether combined with lumefantrine, and dofetilide.…”

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confidence: 99%

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In Vitro Cardiovascular Effects of Dihydroartemisin-Piperaquine Combination Compared with Other Antimalarials

Borsini

Crumb²,

Pace

et al. 2012

Antimicrob Agents Chemother

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The in vitro cardiac properties of dihydroartemisinin (DHA) plus piperaquine phosphate (PQP) were compared with those of other antimalarial compounds. Results with antimalarial drugs, chosen on the basis of their free therapeutic maximum concentration in plasma (C max ), were expressed as the fold of that particular effect with respect to their C max . The following tests were used at 37°C: hERG (human ether-à-go-go-related gene) blockade and trafficking, rabbit heart ventricular preparations, and sodium and slow potassium ion current interference (I Na and I Ks , respectively). Chloroquine, halofantrine, mefloquine, and lumefantrine were tested in the hERG studies, but only chloroquine, dofetilide, lumefantrine, and the combination of artemetherlumefantrine were used in the rabbit heart ventricular preparations, hERG trafficking studies, and I Na and I Ks analyses. A proper reference was used in each test. In hERG studies, the high 50% inhibitory concentration (IC 50 ) of halofantrine, which was lower than its C max , was confirmed. All the other compounds blocked hERG, with IC 50 s ranging from 3-to 30-fold their C max s. In hERG trafficking studies, the facilitative effects of chloroquine at about 30-fold its C max were confirmed and DHA blocked it at a concentration about 300-fold its C max . In rabbit heart ventricular preparations, dofetilide, used as a positive control, revealed a high risk of torsades de pointes, whereas chloroquine showed a medium risk. Neither DHA-PQP nor artemether-lumefantrine displayed an in vitro signal for a significant proarrhythmic risk. Only chloroquine blocked the I Na ion current and did so at about 30-fold its C max . No effect on I Ks was detected. In conclusion, despite significant hERG blockade, DHA-PQP and artemether-lumefantrine do not appear to induce potential torsadogenic effects in vitro, affect hERG trafficking, or block sodium and slow potassium ion currents.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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In Vitro Cardiovascular Effects of Dihydroartemisin-Piperaquine Combination Compared with Other Antimalarials

Borsini

Crumb²,

Pace

et al. 2012

Antimicrob Agents Chemother

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“…26,27 Excellent predictive accuracy has been achieved in part by selecting an appropriate species and experimental preparation. The female rabbit left ventricle has a small I Ks , making it particularly sensitive to QT-prolonging agents.…”

Section: Preclinical Assessment Of Drug-induced Qt Liability: Implicamentioning

confidence: 99%

“…As shown in Figure 2, the response of the isolated arterially perfused rabbit ventricular wedge preparation is magnified, allowing discrimination of drugs with no QT effect from those with a weak effect on repolarization. 30 Clinical Assessment of Drug-Induced QT Liability: The Thorough QT Study…”

Section: Preclinical Assessment Of Drug-induced Qt Liability: Implicamentioning

confidence: 99%

Evaluation of Toxicity for Heart Failure Therapeutics

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Yan

Kowey

2010

Circ: Heart Failure

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Predicting Drug‐Induced QT Prolongation and Torsades de Pointes: A Review of Preclinical Endpoint Measures

Townsend

Brown

2013

CP Pharmacology

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Compound-induced prolongation of the cardiac QT interval is a major concern in drug development and this unit discusses approaches that can predict QT effects prior to undertaking clinical trials. The majority of compounds that prolong the QT interval block the cardiac rapid delayed rectifier potassium current, IKr (hERG). Described in this overview are different ways to measure hERG, from recent advances in automated electrophysiology to the quantification of channel protein trafficking and binding. The contribution of other cardiac ion channels to hERG data interpretation is also discussed. In addition, endpoint measures of the integrated activity of cardiac ion channels at the single-cell, tissue, and whole-animal level, including for example the well-established action potential to the more recent beat-to-beat variability, transmural dispersion of repolarization, and field potential duration, are described in the context of their ability to predict QT prolongation and torsadogenicity in humans.

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Blinded validation of the isolated arterially perfused rabbit ventricular wedge in preclinical assessment of drug-induced proarrhythmias

Cited by 115 publications

References 45 publications

In Vitro Cardiovascular Effects of Dihydroartemisin-Piperaquine Combination Compared with Other Antimalarials

In Vitro Cardiovascular Effects of Dihydroartemisin-Piperaquine Combination Compared with Other Antimalarials

Evaluation of Toxicity for Heart Failure Therapeutics

Predicting Drug‐Induced QT Prolongation and Torsades de Pointes: A Review of Preclinical Endpoint Measures

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