Confounders and Pharmacological Characterization When Using the QT, JTp, and Tpe Intervals in Beagle Dogs
| Autor: | Audrey Sanfacon, Emmanuel Boulay, Ariane Menard, Eric Troncy, Hai Huang, Loïs S. Miraucourt, Michael K. Pugsley, Anne-Marie Downey, Mireille Guerrier, Michael V. Accardi, Wendy Tan, Simon Authier, Michelle Dubuc-Mageau |
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| Rok vydání: | 2020 |
| Předmět: |
Male
medicine.medical_specialty Epinephrine Ranolazine Dofetilide 030204 cardiovascular system & hematology Toxicology 030226 pharmacology & pharmacy Beagle QT interval Body Temperature 03 medical and health sciences Electrocardiography 0302 clinical medicine Dogs Heart Rate Stress Physiological Internal medicine Phenethylamines medicine Animals Sulfonamides Dose-Response Relationship Drug business.industry Confounding Corrected qt Arrhythmias Cardiac Verapamil Cardiology Biomarker (medicine) Female business Anti-Arrhythmia Agents Biomarkers medicine.drug |
| Zdroj: | International journal of toxicology. 39(6) |
| ISSN: | 1092-874X |
| Popis: | Introduction: Corrected QT (QTc) interval is an essential proarrhythmic risk biomarker, but recent data have identified limitations to its use. The J to T-peak (JTp) interval is an alternative biomarker for evaluating drug-induced proarrhythmic risk. The aim of this study was to evaluate pharmacological effects using spatial magnitude leads and DII electrocardiogram (ECG) leads and common ECG confounders (ie, stress and body temperature changes) on covariate adjusted QT (QTca), covariate adjusted JTp (JTpca), and covariate adjusted T-peak to T-end (Tpeca) intervals. Methods: Beagle dogs were exposed to body hyper- (42 °C) or hypothermic (33 °C) conditions or were administered epinephrine to assess confounding effects on heart rate corrected QTca, JTpca, and Tpeca intervals. Dofetilide (0.1, 0.3, 1.0 mg/kg), ranolazine (100, 140, 200 mg/kg), and verapamil (7, 15, 30, 43, 62.5 mg/kg) were administered to evaluate pharmacological effects. Results: Covariate adjusted QT (slope −12.57 ms/°C) and JTpca (−14.79 ms/°C) were negatively correlated with body temperature but Tpeca was minimally affected. Epinephrine was associated with QTca and JTpca shortening, which could be related to undercorrection in the presence of tachycardia, while minimal effects were observed for Tpeca. There were no significant ECG change following ranolazine administration. Verapamil decreased QTca and JTpca intervals and increased Tpeca, whereas dofetilide increased QTca and JTpca intervals but had inconsistent effects on Tpeca. Conclusion: Results highlight potential confounders on QTc interval, but also on JTpca and Tpeca intervals in nonclinical studies. These potential confounding effects may be relevant to the interpretation of ECG data obtained from nonclinical drug safety studies with Beagle dogs. |
| Databáze: | OpenAIRE |
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