Lengthening of Cardiac Repolarization in Isolated Guinea Pigs Hearts by Sequential or Concomitant Administration of Two IKr Blockers

Hreiche, Raymond; Plante, Isabelle; Drolet, Benoît; Morissette, Pierre; Turgeon, Jacques

doi:10.1002/jps.22437

Cited by 16 publications

(18 citation statements)

References 42 publications

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“…We did not observe any pharmacological antagonism or reversal of I hERG block associated with the administration of low concentrations of erythromycin (≤30 µM) with diverse pore and nonpore hERG blockers. However, we did find, consistent with previous reports (Ducroq et al, 2005; Friemel & Zunkle, 2010; Hreiche et al, 2011; Kornick et al, 2003; Margulis & Sorota, 2008; Wiśniowska et al, 2018), that the paired combination of two hERG inhibitors is associated either with independent or additive/synergistic effects. In our hands, pretreatment with erythromycin was associated with either strong synergism (terfenadine, chloroquine), slightly less than additive effects (dofetilide and thioridazine) or limited effects (ketoconazole and BeKm‐1).…”

Section: Discussionsupporting

confidence: 93%

“…This change to the time constants of deactivation resulted in a crossing‐over of F656V I hERG currents as displayed in Figure 3aii and was observed in all five recordings obtained. Crossing‐over of tail currents on repolarization is typically associated with a “foot in the door” type of blockade (Ducroq, Printemps, & Le Grand, 2005; Hreiche, Plante, Drolet, Morissette, & Turgeon, 2011; Margulis & Sorota, 2008; Sánchez‐Chapula et al, 2002); it indicates that in the case of erythromycin the drug may slow closure of the deactivation gate through interaction with a noncanonical‐binding site.…”

Section: Resultsmentioning

confidence: 99%

“…Despite the fact that drug‐induced QT interval prolongation often occurs clinically with coadministration of >1 QT interval prolonging drug (Hancox et al, 2008; Yap & Camm, 2003), there are only a few in vitro studies examining the effects of the combined administration of multiple hERG blockers on the hERG channel (e.g., Crumb, 2014; Ducroq et al, 2005; Friemel & Zunkle, 2010; Hreiche et al, 2011; Kornick et al, 2003; Margulis & Sorota, 2008; Wiśniowska, Lisowski, Kulig, & Polak, 2018), and reports on the pharmacological antagonism of hERG block are scarce (Crumb, 2014; Hreiche et al, 2011). Prior to the report of a protective effect of macrolides (Crumb, 2014), one study showed that MAPD 90 ‐ prolongation mediated through I Kr block by the concomitant application of single concentrations of erythromycin or ketoconazole with dofetilide was less than the addition of the effects of each drug alone (Hreiche et al, 2011). This would suggest that the combination of two I Kr blockers could lead to pharmacological antagonism.…”

Section: Discussionmentioning

confidence: 99%

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The macrolide drug erythromycin does not protect the hERG channel from inhibition by thioridazine and terfenadine

et al. 2020

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The macrolide antibiotic erythromycin has been associated with QT interval prolongation and inhibition of the hERG‐encoded channels responsible for the rapid delayed rectifier K+ current I(Kr). It has been suggested that low concentrations of erythromycin may have a protective effect against hERG block and associated drug‐induced arrhythmia by reducing the affinity of the pore‐binding site for high potency hERG inhibitors. This study aimed to explore further the notion of a potentially protective effect of erythromycin. Whole‐cell patch‐clamp experiments were performed in which hERG‐expressing mammalian (Human Embryonic Kidney; HEK) cells were preincubated with low to moderate concentrations of erythromycin (3 or 30 µM) prior to whole‐cell patch clamp recordings of hERG current (IhERG) at 37°C. In contrast to a previous report, exposure to low concentrations of erythromycin did not reduce pharmacological sensitivity of hERG to the antipsychotic thioridazine and antihistamine terfenadine. The IC50 value for IhERG tail inhibition by terfenadine was decreased by ~32‐fold in the presence of 3 µM erythromycin (p < .05 vs. no preincubation). Sensitivity to thioridazine remained unchanged (p > .05 vs. no preincubation). The effects of low concentrations of erythromycin were investigated for a series of pore blocking drugs, and the results obtained were consistent with additive and/or synergistic effects. Experiments with the externally acting blocker BeKm‐1 on WT hERG and a pore mutant (F656V) were used to explore the location of the binding site for erythromycin. Our data are inconsistent with the use of erythromycin for the management of drug‐induced QT prolongation.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The macrolide drug erythromycin does not protect the hERG channel from inhibition by thioridazine and terfenadine

et al. 2020

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“…21 In addition, in an isolated perfused heart study, concomitant perfusion of guine pig hearts with two I Kr inhibitors did not produce additive effects on monophasic action potential duration. 22 Further, in a study in a canine model of TdP, the combinations of sotalol and quinidine did not confer a higher risk of TdP than administration of sotalol alone. 23 The influence of concomitant therapy with ≥ 2 QT c interval prolonging drugs on ventricular action potential duration, QT c interval, and risk of TdP requires further study.…”

Section: Discussionmentioning

confidence: 88%

Development and Validation of a Risk Score to Predict QT Interval Prolongation in Hospitalized Patients

Tisdale

Jaynes

Kingery

et al. 2013

Circ: Cardiovascular Quality and Outcomes

325

354

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Background Identifying hospitalized patients at risk for QT interval prolongation could lead to interventions to reduce the risk of torsades de pointes (TdP). Our objective was to develop and validate a risk score for QT prolongation in hospitalized patients. Methods and Results In this study in a single tertiary care institution, consecutive patients (n=900) admitted to cardiac care units comprised the risk score development group (DG). The score was then applied to 300 additional patients in a validation group (VG). Corrected QT (QTc) interval prolongation (defined as QTc > 500 ms and/or an increase of > 60 ms from baseline) occurred in 274 (30.4%) and 90 (30.0%) patients in the DG and VG, respectively. Independent predictors of QTc prolongation included: female (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.1–2.0), diagnosis of myocardial infarction [2.5 (1.6–3.9)], sepsis [2.7 (1.5–4.8)], left ventricular dysfunction [2.7 (1.6–5.0)], administration of a QT-prolonging drug [2.8 (2.0–4.0)], ≥ 2 QT- prolonging drugs [2.6 (1.9–5.6)], or loop diuretic [1.4 (1.0–2.0)], age > 68 years [1.3 (1.0–1.8)], serum K+ < 3.5 mEq/L [2.1 (1.5–2.9)], and admitting QTc > 450 ms [2.3; CI (1.6–3.2)]. Risk scores were developed by assigning points based on Log ORs. Low, moderate and high risk ranges of 0–6, 7–10 and 11–21 points, respectively, best predicted QTc prolongation (C statistic = 0.823). A high risk score > 11 was associated with sensitivity = 0.74, specificity = 0.77, positive predictive value = 0.79 and negative predictive value = 0.76. In the VG, the incidences of QTc prolongation were 15% (low risk); 37% (moderate risk); 73% (high risk). Conclusions A risk score using easily obtainable clinical variables predicts patients at highest risk for QTc prolongation and may be useful in guiding monitoring and treatment decisions.

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“…In addition, the hERG receptor is accessible from the cytoplasm, where intracellular drug disposition was recently shown to be modulated by drug transporters. 43 Because drugs and disease can regulate these transporters, whereas interaction between drugs can alter cytoplasmic drug levels (including for domperidone), 44 marked modulation of drug toxicity can occur.…”

Section: Domperidone Prolongs the Apd Disturbs Triad And Has A Low mentioning

confidence: 99%

Domperidone

Hondeghem

2013

Journal of Cardiovascular Pharmacology

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Lengthening of Cardiac Repolarization in Isolated Guinea Pigs Hearts by Sequential or Concomitant Administration of Two IKr Blockers

Cited by 16 publications

References 42 publications

The macrolide drug erythromycin does not protect the hERG channel from inhibition by thioridazine and terfenadine

The macrolide drug erythromycin does not protect the hERG channel from inhibition by thioridazine and terfenadine

Development and Validation of a Risk Score to Predict QT Interval Prolongation in Hospitalized Patients

Domperidone

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