Variability in the measurement of hERG potassium channel inhibition: Effects of temperature and stimulus pattern

Kirsch, Glenn E.; Trepakova, Elena S.; Brimecombe, Jessica C.; Sidach, Serguei S.; Erickson, Hope D.; Kochan, Mary C.; Shyjka, Lisa M.; Lacerda, Antonio E.; Brown, Arthur M.

doi:10.1016/j.vascn.2004.06.003

Cited by 231 publications

(174 citation statements)

References 25 publications

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“…Indeed, the free plasma concentrations of astemizole and desmethylastemizole associated with QTc interval prolongation in this study were 0.3 and 9 nM, respectively, which were close to hERG IC 50 s of 0.9 and 1 nM, respectively (Zhou et al, 1999). On the other hand, dl-sotalol has very weak hERG inhibitory potential with an IC 50 value of 278 μM (Kirsch et al, 2004), but apparently caused QTc interval prolongation at the free plasma concentration of 4.99 μM in common marmosets. dl-Sotalol also prolonged QTc intervals at a free plasma concentration of 7.2 μM in anesthetized dogs (Schnelle and Garrett, 1973;Tabo et al, 2006) and 5.3 μM in humans (Carr et al, 1995;Kimura et al, 1996).…”

Section: Discussionsupporting

confidence: 71%

Prediction of drug-induced QT interval prolongation in telemetered common marmosets

et al. 2008

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-Drug-induced QT interval prolongation is a critical issue in development of new chemical entities, so the pharmaceutical industry needs to evaluate risk as early as possible. Common marmosets have been in the limelight in early-stage development due to their small size, which requires only a small amount of test drug. The purpose of this study was to determine the utility of telemetered common marmosets for predicting drug-induced QT interval prolongation. Telemetry transmitters were implanted in common marmosets (male and female), and QT and RR intervals were measured. The QT interval was corrected for the RR interval by applying Bazett's and Fridericia's correction formulas and individual rate correction. Individual correction showed the least slope for the linear regression of corrected QT (QTc) intervals against RR intervals, indicating that it dissociated changes in heart rate most effectively. With the individual correction method, the QT-prolonging drugs (astemizole, dl-sotalol) showed QTc interval prolongations and the non-QT-prolonging drugs (dl-propranolol, nifedipine) did not show QTc interval prolongations. The plasma concentrations of astemizole and dl-sotalol associated with QTc interval prolongations in common marmosets were similar to those in humans, suggesting that the sensitivity of common marmosets would be appropriate for evaluating risk of drug-induced QT interval prolongation. In conclusion, telemetry studies in common marmosets are useful for predicting clinical QT prolonging potential of drugs in early stage development and require only a small amount of test drug.

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Section: Discussionsupporting

confidence: 71%

Prediction of drug-induced QT interval prolongation in telemetered common marmosets

et al. 2008

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“…Remarkably, EADs were not seen at temperatures lower than 33°C. Although this study did not investigate whether HERG channel block by E-4031 was more potent at higher temperatures, other studies did not find a temperature-dependent change in the potency of E-4031 block of HERG channels (34,35). These data illustrate that the functional implications of I Kr reduction are greater during hyperthermia and support our postulate that failure of mutant HERG current to adequately increase at higher temperatures delays cardiac repolarization.…”

Section: Discussionsupporting

confidence: 62%

Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome

Amin¹,

Herfst²,

Delisle³

et al. 2008

J. Clin. Invest.

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Type 2 congenital long QT syndrome (LQT-2) is linked to mutations in the human ether a-go-go-related gene (HERG) and is characterized by rate-corrected QT interval (QTc) prolongation, ventricular arrhythmias, syncope, and sudden death. Recognized triggers of these cardiac events include emotional and acoustic stimuli. Here we investigated the repeated occurrence of fever-induced polymorphic ventricular tachycardia and ventricular fibrillation in 2 LQT-2 patients with A558P missense mutation in HERG. ECG analysis showed increased QTc with fever in both patients. WT, A558P, and WT+A558P HERG were expressed heterologously in HEK293 cells and were studied using biochemical and electrophysiological techniques. A558P proteins showed a trafficking-deficient phenotype. WT+A558P coexpression caused a dominant-negative effect, selectively accelerated the rate of channel inactivation, and reduced the temperature-dependent increase in the WT current. Thus, the WT+A558P current did not increase to the same extent as the WT current, leading to larger current density differences at higher temperatures. A similar temperature-dependent phenotype was seen for coexpression of the trafficking-deficient LQT-2 F640V mutation. We postulate that the weak increase in the HERG current density in WT-mutant coassembled channels contributes to the development of QTc prolongation and arrhythmias at febrile temperatures and suggest that fever is a potential trigger of life-threatening arrhythmias in LQT-2 patients.

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“…The increased potency in the present study is most likely explained by the use of physiologic temperatures (37°C) versus room temperature in previous studies. Increased potency at elevated temperatures has been reported for other drugs as well, such as erythromycin and sotalol (27,51). The combination of DHA at two concentrations (2.4 and 7.2 M) in the presence of PQP was also evaluated, and hERG blockade by DHA-PQP was less than that by PQP alone.…”

Section: Discussionmentioning

confidence: 99%

“…Previous hERG studies with antimalarials were performed in vitro at room temperature (24,35,45). Under our experimental conditions, the hERG assay was evaluated at 37°C, which provides a more conservative safety evaluation of hERG inhibition (27).…”

mentioning

confidence: 99%

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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Variability in the measurement of hERG potassium channel inhibition: Effects of temperature and stimulus pattern

Cited by 231 publications

References 25 publications

Prediction of drug-induced QT interval prolongation in telemetered common marmosets

Prediction of drug-induced QT interval prolongation in telemetered common marmosets

Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome

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

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