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
- 12 Downloads
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.
Keywordsdl-Sotalol J–Tpeakc Torsade de pointes Beagle dogs Microminipigs
The authors thank Dr. Yuji Nakamura, Dr. Yasuki Akie, Mr. Hiroyuki Saito and Mrs. Yuri Ichikawa for their technical assistance.
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).
Compliance with Ethical Standards
Conflict of interest
The authors indicated no potential conflict of interest.
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.
- 3.Cao, X., Nakamura, Y., Wada, T., Izumi-Nakaseko, H., Ando, K., & Sugiyama, A. (2016). Electropharmacological effects of amantadine on cardiovascular system assessed with J-Tpeak and Tpeak-Tend analysis in the halothane-anesthetized beagle dogs. The Journal of Toxicological Sciences, 41, 439–447.CrossRefGoogle Scholar
- 4.Matsukura, S., Nakamura, Y., Hoshiai, K., Hayashi, T., Koga, T., Goto, A., et al. (2018). Effects of moxifloxacin on the proarrhythmic surrogate markers in healthy Filipino subjects: Exposure-response modeling using ECG data of thorough QT/QTc study. Journal of Pharmacological Sciences, 136, 234–241.CrossRefGoogle Scholar
- 5.Vicente, J., Zusterzeel, R., Johannesen, L., Mason, J., Sager, P., Patel, V., et al. (2018). Mechanistic model-informed proarrhythmic risk assessment of drugs: Review of the “CiPA” initiative and design of a prospective clinical validation study. Clinical Pharmacology & Therapeutics, 103, 54–66.CrossRefGoogle Scholar
- 6.Motokawa, Y., Nakamura, Y., Hagiwara-Nagasawa, M., Goto, A., Chiba, K., Lubna, N. J., et al. (2018). In vivo analysis of the anti-atrial fibrillatory, proarrhythmic and cardiodepressive profiles of dronedarone as a guide for safety pharmacological evaluation of antiarrhythmic drugs. Cardiovascular Toxicology, 18, 242–251.CrossRefGoogle Scholar
- 8.Harvey, R. D., & Grant, A. O. (2018). Agents used in cardiac arrhythmias. In B. G. Katzung (Ed.), Basic & clinical pharmacology (14th ed., pp. 212–227). New York: McGraw-Hill Education.Google Scholar
- 9.Yokoyama, H., Nakamura, Y., Saito, H., Nagayama, Y., Hoshiai, K., Wada, T., et al. (2017). Pharmacological characterization of microminipig as a model to assess the drug-induced cardiovascular responses for non-clinical toxicity and/or safety pharmacology studies. The Journal of Toxicological Sciences, 42, 93–101.CrossRefGoogle Scholar
- 12.Katagi, J., Nakamura, Y., Cao, X., Ohara, H., Honda, A., Izumi-Nakaseko, H., et al. (2016). Why can dl-sotalol prolong the QT interval in vivo despite its weak inhibitory effect on hERG K+ channels in vitro? Electrophysiological and pharmacokinetic analysis with the halothane-anesthetized guinea pig model. Cardiovascular Toxicology, 16, 138–146.CrossRefGoogle Scholar
- 15.Verduyn, S. C., Vos, M. A., van der Zande, J., Kulcsàr, A., & Wellens, H. J. (1997). Further observations to elucidate the role of interventricular dispersion of repolarization and early afterdepolarizations in the genesis of acquired torsade de pointes arrhythmias: A comparison between almokalant and d-sotalol using the dog as its own control. Journal of the American College of Cardiology, 30, 1575–1584.CrossRefGoogle Scholar
- 16.Sugiyama, A., Nakamura, Y., Akie, Y., Saito, H., Izumi, Y., Yamazaki, H., et al. (2011). Microminipig, a non-rodent experimental animal optimized for life science research: In vivo proarrhythmia models of drug-induced long QT syndrome: Development of chronic atrioventricular block model of microminipig. Journal of the American College of Cardiology, 115, 122–126.Google Scholar
- 17.Sugiyama, A., Ishida, Y., Satoh, Y., Aoki, S., Hori, M., Akie, Y., et al. (2002). Electrophysiological, anatomical and histological remodeling of the heart to AV block enhances susceptibility to arrhythmogenic effects of QT-prolonging drugs. The Japanese Journal of Pharmacology, 88, 341–350.CrossRefGoogle Scholar
- 18.Takahara, A., Sugiyama, A., Ishida, Y., Satoh, Y., Wang, K., Nakamura, Y., et al. (2006). Long-term bradycardia caused by atrioventricular block can remodel the canine heart to detect the histamine H1 blocker terfenadine-induced torsades de pointes arrhythmias. British Journal of Pharmacology, 147, 634–641.CrossRefGoogle Scholar
- 21.Goto, A., Izumi-Nakaseko, H., Hagiwara-Nagasawa, M., Chiba, K., Ando, K., Naito, A. T., et al. (2018). Analysis of torsadogenic and pharmacokinetic profile of E-4031 in dogs bridging the gap of information between in vitro proarrhythmia assay and clinical observation in human subjects. Journal of Pharmacological Sciences, 137, 237–240.CrossRefGoogle Scholar
- 24.Sugiyama, A., Satoh, Y., Ishida, Y., Yoneyama, M., Yoshida, H., & Hashimoto, K. (2002). Pharmacological and electrophysiological characterization of junctional rhythm during radiofrequency catheter ablation of the atrioventricular node: possible involvement of neurotransmitters from autonomic nervous system. Circulation Journal, 66, 696–701.CrossRefGoogle Scholar