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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

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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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Acknowledgements

The authors thank Dr. Yuji Nakamura, Dr. Yasuki Akie, Mr. Hiroyuki Saito and Mrs. Yuri Ichikawa for their technical assistance.

Funding

This study was supported in part by Japan agency for medical research and development (AMED Grant #AS2116907E; #18mk0104117j0001) and Japan society for the promotion of science (JSPS KAKENHI Grant Number JP16K08559).

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Author notes

  1. Ai Goto and Mihoko Hagiwara-Nagasawa have contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, Toho University Graduate School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan

    Ai Goto, Koki Chiba, Hiroko Izumi-Nakaseko, Atsuhiko T. Naito & Atsushi Sugiyama

  2. Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan

    Mihoko Hagiwara-Nagasawa, Ryuichi Kambayashi, Hiroko Izumi-Nakaseko, Atsuhiko T. Naito & Atsushi Sugiyama

  3. Division of Pharmacology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa, 210-9501, Japan

    Yasunari Kanda

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  1. Ai Goto
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  2. Mihoko Hagiwara-Nagasawa
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Correspondence to Atsushi Sugiyama.

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The authors indicated no potential conflict of interest.

Ethical Approval

All experiments were planned based upon the rules and regulations of the Committee for Research at Yamanashi Research Center of Clinical Pharmacology (#2009-04) and Toho University Animal Care and User Committee (#17-52-323), and performed in accordance with the Guidelines for the Care and Use of Laboratory Animals of both facilities.

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Handling Editor: Yu-Ming Kang.

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Goto, A., Hagiwara-Nagasawa, M., Kambayashi, R. et al. 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. Cardiovasc Toxicol 19, 357–364 (2019). https://doi.org/10.1007/s12012-019-09506-z

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