HERG-Lite®: A novel comprehensive high-throughput screen for drug-induced hERG risk

Wible, Barbara A.; Hawryluk, Peter; Ficker, Eckhard; Kuryshev, Yuri A.; Kirsch, Glenn E.; Brown, Arthur M.

doi:10.1016/j.vascn.2005.03.008

Cited by 141 publications

(120 citation statements)

References 28 publications

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“…It is worth mentioning that the execution of the hERG trafficking test requires 16 h of incubation with the test compounds. As already reported, chloroquine increased hERG trafficking (50). Thus, it seems that the effect of hERG blockade by the various antimalarial drugs involved increased protein hERG synthesis only by chloroquine.…”

Section: Discussionsupporting

confidence: 72%

“…However, cells in one vial with such a DHA concentration had a mortality rate higher than 75%, and therefore, the result from this vial was not considered. In contrast, chloroquine increased hERG trafficking, as already reported (50). The test system worked properly, as geldanamycin (1 M), the positive-control trafficking inhibitor for WT hERG, produced the expected result with a 50% decrease in WT hERG surface expression (50).…”

Section: Resultssupporting

confidence: 60%

“…The IC 50 s on hERG are similar but somewhat more potent than those previously reported. For example, the IC 50 for halofantrine has been reported to range from 21.6 to 40 nM (35,45), while the present study yielded a value of 18 nM. Chloroquine, mefloquine, and lumefantrine have previously been reported to have IC 50 s of 2.5, 2.6 to 5.6, and 8.1 M, respectively (25,35,45), while the present experiment yielded values of approximately 1.0, 1.0, and 2.6 M, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Dofetilide was used as a positive control because of the numerous reports of TdP associated with this medication (1). Additionally, three in vitro tests were performed with DHA, PQP, and their combination: hERG trafficking (50) and sodium and slow potassium ion current interference (I Na and I Ks , respectively) measurements (11). These tests give additional insights into the possible mechanism of cardiac toxicity.…”

mentioning

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: Discussionsupporting

confidence: 72%

Section: Resultssupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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 cell surface expression of a trafficking deficient mutant human ether-a-go-go (hERG) channel (G601S-hERG) was monitored with a hERG-Lite assay developed by ChanTest (Cleveland, OH) as described by Wible et al (61). Briefly, HEK-293 cells expressing G601S-hERG with an HA epitope in the extracellular loop spanning transmembrane domains S1 and S2 were incubated for 16 h at 37°C with or without test compound.…”

Section: Methodsmentioning

confidence: 99%

Rescue of ΔF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules

Goor

Straley²,

Cao³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

464

556

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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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HERG-Lite®: A novel comprehensive high-throughput screen for drug-induced hERG risk

Cited by 141 publications

References 28 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

Rescue of ΔF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules

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

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