Key result
Administration of 1 to 10 times the clinically relevant doses of various QT-prolonging drugs induced Torsades de Pointes in chronic atrioventricular block dogs, with the exception of amiodarone.
Why the study?
Do clinically available QT-prolonging drugs induce torsades de pointes in in vivo canine models?
Do clinically available QT-prolonging drugs induce torsades de pointes in in vivo canine models?
In vivo canine models effectively screen for drug-induced torsades de pointes, showing that prolongation of the terminal repolarization period is closely related to proarrhythmic potential.
Validates canine models for QT-prolonging drug screening; leaves open clinical translation of proarrhythmia risk.
The proarrhythmic effects of class III antiarrhythmic agents and non-cardiovascular drugs, which have been shown to prolong QT interval, were assessed using two types of in vivo canine models. First, electrophysiological effects of dofetilide, nifekalant, amiodarone, cisapride, astemizole, sulpiride, haloperidol, and sparfloxacin were assessed using halothane-anesthetized dogs. Each drug prolonged the monophasic action potential (MAP) duration and effective refractory period (ERP) at clinically recommended daily doses. The extent of increase was greater in the refractoriness than in the repolarization only for amiodarone, indicating abbreviation of the terminal repolarization period. The reverse was true for the other drugs. Next, torsadogenic action of sematilide, nifekalant, amiodarone, cisapride, terfenadine, sulpiride, and sparfloxacin was assessed using chronic complete atrioventricular block dogs with Holter ECG monitoring in the conscious state. Oral administration of 1-10 times higher doses than the clinically relevant doses of the drugs induced polymorphic ventricular tachycardia torsades de pointes (TdP), except for amiodarone. These results indicate that the prolongation and backward shift of the terminal repolarization period may be closely related to the drug-induced TdP and suggest that these in vivo models can be used to screen proarrhythmic potential of new drugs.
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Atsushi Sugiyama (2003) studied Drug-induced long QT syndrome and Torsades de Pointes. QT-prolonging drugs (e.g., dofetilide, nifekalant, amiodarone, cisapride) vs. Baseline was evaluated on Induction of Torsades de Pointes (TdP) and changes in terminal repolarization period. Administration of 1 to 10 times the clinically relevant doses of various QT-prolonging drugs induced Torsades de Pointes in chronic atrioventricular block dogs, with the exception of amiodarone.
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