Improved methodology for identifying the teratogenic potential in early drug development of hERG channel blocking drugs.

Drugs blocking the potassium current IKr of the heart (via hERG channel-inhibition) have the potential to cause hypoxia-related teratogenic effects. However, this activity may be missed in conventional teratology studies because repeat dosing may cause resorptions. The aim of the present study was to investigate an alternative protocol to reveal the teratogenic potential of IKr-blocking drugs. The IKr blocker astemizole, given as a single dose (80 mg/kg) on gestation day (GD) 13 to pregnant rats caused digital defects. In whole rat embryo culture (2h) on GD 13, astemizole caused a decrease in embryonic heart rate at 20 nM, and arrhythmias at 200-400 nM. Cetirizine, without IKr-blocking properties, did not affect the rat embryonic heart in vitro. The present study shows that single dose testing on sensitive days of development, together with whole embryo culture, can be a useful methodology to better characterize the teratogenic potential of IKr-blocking drugs.

Temporal variability of QT interval and changes in T wave morphology in dogs as markers of the clinical risk of drug-induced proarrhythmia.

INTRODUCTION: 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. DISCUSSION: 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.

QT prolongation in guinea pigs for preliminary screening of torsadogenicity of drugs and drug-candidates. II.

Experimental approaches on anaesthetised guinea pigs have been shown recently to be satisfactorily predictive of the torsadogenic risk of drugs. This work aimed at obtaining additional data, for a further understanding of the reliability and/or the limits of this model. Clonidine (non-torsadogenic in humans) induced a lengthening of the ECG parameter of RR in anaesthetised guinea pigs, without any corresponding increase of QT (corrected by the algorithms of Bazett and Fridericia). Thus, 'QT correct' prolonging effects produced by drugs torsadogenic in humans, on the guinea pig model are primarily due to inhibition of cardiac repolarisation. The corresponding RR prolongation is a consequence (not the cause) of this primary effect. Astemizole, haloperidol and terfenadine, torsadogenic in humans, produced in Langendorff perfused guinea pig hearts a prolongation of the QT interval. Chlorprotixene (non-torsadogenic) did not produce any significant effect on QT. These results are fully consistent with previous observations in anaesthetised guinea pigs. In Langendorff perfused hearts, pentobarbital does not affect cardiac repolarisation and does not potentiate the QT-prolonging effect of astemizole. Together with the findings reported by many authors, these data suggest that ECG recording in anaesthetised guinea pigs is a reliable model for cardiac safety studies evaluating the influence of drugs on the repolarisation process.

Comparative effects of maternal prenatal and postnatal exposures to astemizole on reproductive parameters of rats.

The prenatal and postnatal effects of administration of a nonsedative antihistamine H1, astemizole (ATZ), were compared. ATZ (10 mg/kg) was injected daily into female Wistar rats throughout pregnancy (prenatal treatment) or during the first 6 days of lactation (postnatal treatment). Neither treatment modified dam body weight. Prenatal exposure reduced offspring body weight and lead to a latter expression of the vaginal opening of female offspring. In addition, a long-term disruption of male reproductive behavior was observed, while female sexual behavior was not modified. The sexual activity index and the intromission frequency were increased in prenatally treated animals. Testes wet weight was reduced, but no modifications were detected in vas deferens or seminal vesicles. Postnatal treatment did not alter offspring body weight, open-field activity, sexual behavior and organ weight as well as did not delay testes descent but reduced the time until vaginal opening. Hypothalamic serotonin (5-HT), dopamine (DA) and noradrenaline (NA) as well as DA and NA metabolites were not modified by both prenatal and postnatal treatments. Increased striatal 3,4-dihydroxyphenylacetic acid (DOPAC) levels were observed after prenatal and postnatal treatments, while only postnatal 5-HT levels were increased. We propose that the present results indicate that prenatal ATZ exposure can have long-lasting organizational effects on reproductive behavior of male rats, while postnatal exposure to this drug did not alter mating behavior. In relation to female rats, prenatal and postnatal exposures to ATZ accelerated puberty but did not alter sexual behavior. Neurochemical data show that both treatments increased striatal dopaminergic system activity, suggesting a central ATZ effect after perinatal exposure.