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02.02.2019

Measurement of J–Tpeakc along with QT-Interval Prolongation May Increase the Assay Sensitivity and Specificity for Predicting the Onset of Drug-Induced Torsade de Pointes: Experimental Evidences Based on Proarrhythmia Model Animals

Zeitschrift:
Cardiovascular Toxicology
Autoren:
Ai Goto, Mihoko Hagiwara-Nagasawa, Ryuichi Kambayashi, Koki Chiba, Hiroko Izumi-Nakaseko, Atsuhiko T. Naito, Yasunari Kanda, Atsushi Sugiyama
Wichtige Hinweise
Handling Editor: Yu-Ming Kang.
Ai Goto and Mihoko Hagiwara-Nagasawa have contributed equally to this work.

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Abstract

dl-Sotalol which can block both K+ channel and ß-adrenoceptor has been shown to prolong the J–Tpeakc of electrocardiogram in beagle dogs but tended to shorten it in microminipigs, although the drug prolonged the QT interval in both animals under physiologically maintained experimental condition. In order to estimate how the changes in the J–Tpeakc in the normal hearts would be reflected in the pathologic hearts, we compared proarrhythmic effects of dl-sotalol by using proarrhythmia models of beagle dogs and microminipigs, of which atrioventricular node had been ablated > 2 months and 8–9 weeks before, respectively (n = 4 for each species). dl-Sotalol in an oral dose of 10 mg/kg induced torsade de pointes in three out of four beagle dogs, which degenerated into ventricular fibrillation. In microminipigs, the same dose did not trigger torsade de pointes at all, whereas intermittent ventricular pauses were observed in each animal after the drug treatment. These results indicate that assessment of the J–Tpeakc along with the QT-interval prolongation in healthy subjects may provide reliable information of risk prediction for patients susceptible to the drug-induced torsade de pointes.

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