Temporal variability of QT interval and changes in T wave morphology in dogs as markers of the clinical risk of drug-induced proarrhythmia.
BACKGROUND
The aim of this experiment was to establish the usefulness of assessing temporal variability of the QT interval and changes in the T wave morphology in dogs as markers of pro-arrhythmic risk in humans. For this purpose, the electrocardiographic effects of astemizole and cisapride, two well known pro-arrhythmic drugs in humans, were assessed in dogs.


METHODS
Astemizole was administered intravenously at single doses of 1 and 3 mg/kg whilst cisapride was administered orally at doses of 1.5 and 6 mg/kg. Electrocardiograms (ECG) were recorded before and after treatment. From each ECG tracing, QT intervals were recorded over 100 beats for calculation of the mean and standard deviation (SD) of QT and mean corrected QT (QTc). The coefficient of variation of QT (CV=SD/mean) was calculated as an indicator of QT temporal variability. The changes in T wave morphology were assessed in precordial lead CV5RL.


RESULTS
Astemizole increased both the QTc interval and the CV of QT. Increases in these parameters also occurred after cisapride, but were less marked than after astemizole. In addition, both compounds produced a notching of the T wave, consisting of the presence of two peaks.


CONCLUSIONS
The effects of astemizole and cisapride on the CV of QT and their propensity to induce of T wave notching are consistent with the blocking of I(Kr) channels and indicate, respectively, an increase in temporal variability of cardiac repolarization and an increased heterogeneity of the repolarization of cardiac cells across the myocardium. These changes are key triggers of arrhythmic events and are thus consistent with the pro-arrhythmic properties of these drugs. This study therefore indicates that the evaluation of CV of QT and T wave morphology in dogs may help in predicting drug-induced pro-arrhythmic risk in humans.
Hanton
G
G
Department of Toxicology and Comparative Medicine, Pfizer Global Research and Development, Amboise Laboratories, France. gilles.hanton@yahoo.fr
Yvon
A
A
Racaud
A
A
D000284:Administration, Oral; D000818:Animals; D016589:Astemizole / Q000633:toxicity; D020117:Cisapride / Q000633:toxicity; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004562:Electrocardiography; D005260:Female; D005765:Gastrointestinal Agents / Q000633:toxicity; D039563:Histamine H1 Antagonists, Non-Sedating / Q000633:toxicity; D007275:Injections, Intravenous; D008133:Long QT Syndrome / Q000139:chemically induced / Q000175:diagnosis / Q000503:physiopathology*; D008297:Male; D011237:Predictive Value of Tests; D013997:Time Factors
D005765:Gastrointestinal Agents; D039563:Histamine H1 Antagonists, Non-Sedating; D016589:Astemizole; D020117:Cisapride