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Molecular Pharmacology

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Research ArticleArticle

A Common Antitussive Drug, Clobutinol, Precipitates the Long QT Syndrome 2

Chloé Bellocq, Ronald Wilders, Jean-Jacques Schott, Bénédicte Louérat-Oriou, Pierre Boisseau, Hervé Le Marec, Denis Escande and Isabelle Baró
Molecular Pharmacology November 2004, 66 (5) 1093-1102; DOI: https://doi.org/10.1124/mol.104.001065
Chloé Bellocq
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Ronald Wilders
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Jean-Jacques Schott
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Bénédicte Louérat-Oriou
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Pierre Boisseau
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Hervé Le Marec
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Denis Escande
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Isabelle Baró
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Abstract

QT prolongation, a classic risk factor for arrhythmias, can result from a mutation in one of the genes governing cardiac repolarization and also can result from the intake of a medication acting as blocker of the cardiac K+ channel human ether-a-go-go-related gene (HERG). Here, we identified the arrhythmogenic potential of a nonopioid antitussive drug, clobutinol. The deleterious effects of clobutinol were suspected when a young boy, with a diagnosis of congenital long QT syndrome, experienced arrhythmias while being treated with this drug. Using the patch-clamp technique, we showed that clobutinol dose-dependently inhibited the HERG K+ current with a half-maximum block concentration of 2.9 μM. In the proband, we identified a novel A561P HERG mutation. Two others long QT mutations (A561V and A561T) had been reported previously at the same position. None of the three mutants led to a sizeable current in heterologous expression system. When coexpressed with wild-type (WT) HERG channels, the three Ala561 mutants reduced the trafficking of WT and mutant heteromeric channels, resulting in decreased K+ current amplitude (dominant-negative effects). In addition, A561P but not A561V and A561T mutants induced a ≈-11 mV shift of the current activation curve and accelerated deactivation, thereby partially counteracting the dominant-negative effects. A561P mutation and clobutinol effects on the human ventricular action potential characteristics were simulated using the Priebe-Beuckelmann model. Our work shows that clobutinol has limited effects on WT action potential but should be classified as a “drug to be avoided by congenital long QT patients” rather than as a “drug with risk of torsades de pointes”.

  • Received April 2, 2004.
  • Accepted July 27, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 66 (5)
Molecular Pharmacology
Vol. 66, Issue 5
1 Nov 2004
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Research ArticleArticle

A Common Antitussive Drug, Clobutinol, Precipitates the Long QT Syndrome 2

Chloé Bellocq, Ronald Wilders, Jean-Jacques Schott, Bénédicte Louérat-Oriou, Pierre Boisseau, Hervé Le Marec, Denis Escande and Isabelle Baró
Molecular Pharmacology November 1, 2004, 66 (5) 1093-1102; DOI: https://doi.org/10.1124/mol.104.001065

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Research ArticleArticle

A Common Antitussive Drug, Clobutinol, Precipitates the Long QT Syndrome 2

Chloé Bellocq, Ronald Wilders, Jean-Jacques Schott, Bénédicte Louérat-Oriou, Pierre Boisseau, Hervé Le Marec, Denis Escande and Isabelle Baró
Molecular Pharmacology November 1, 2004, 66 (5) 1093-1102; DOI: https://doi.org/10.1124/mol.104.001065
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