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

l'institut du thorax, Institut National de la Sante et de la Recherche Medicale U533, Nantes, France (C.B., J.J.S., B.L.O., H.L.M., D.E., I.B.); Department of Physiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands (R.W.); Laboratoire de Génétique Moléculaire, CHU de Nantes, Nantes, France (P.B.); and Clinique Cardiologique et des Maladies Vasculaires, Centres d'Investigation Clinique Institut National de la Sante et de la Recherche Medicale de Nantes, Nantes, France (H.L.M.)

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".

Address correspondence to: Dr. Isabelle Baró, INSERM U533, Faculté de Médecine, 1, rue Gaston Veil, 44035 Nantes, France. E-mail: isabelle.baro{at}nantes.inserm.fr

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