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Characterisation of the conscious telemetered rat ECG for use in early pre-clinical safety studies Assessment of the effects of new chemical entities (NCE) on electrocardiograms (ECGs) is an important regulatory requirement. Presently, the majority of pre-clinical ECG safety studies are performed at the latter stages of development in large animal models, however, small animal models with higher throughput are being considered for early target derisking. This study assessed the effects, in conscious telemetered rats, of compounds known to cause ECG changes in other species, with the aim of evaluating the utility of the model for early ECG safety studies. Baseline ECG and haemodynamic measurements were recorded in 7 male rats (Sprague-Dawley, 450-650g) over a 23 hr period and then effects of standard agents (propafenone (100, 300, and 600 mg/kg), mexiletine (1, 3 and 10 mg/kg), cisapride (3, 10 and 30 mg/kg), dofetilide (0.2, 1.2 and 4 mg/kg) and milrinone (0.35, 3.5 and 10.5 mg/kg)) were assessed for an additional 23 hrs. The haemodynamic profiles of the compounds were as expected. On ECG, propafenone significantly prolonged (ANOVA, p<0.05) QRS (vehicle (vc): 20.9±0.6 ms; highest dose (hd): 26.0±0.6 ms) and QTc (vc: 73.3±0.6 ms; hd: 77.9±0.8 ms). PR was significantly decreased by milrinone (vc: 47.7±0.2 ms; hd: 43.0±0.2 ms); however, this might be related to the observed increase in heart rate (vc: 323.4±10.4 bpm; hd: 363.3±10.4 bpm). No other significant ECG changes were observed. The effects of propafenone, milrinone and mexiletine are consistent with previous data in other species. However, the known QTc prolonging effects of cisapride and dofetilide due to their effects at the IKr ion channel were not observed. The results of this study highlight the potential of the model for measuring ECG PR and QRS changes. Although its utility is limited when assessing IKr-mediated QT effects, the model might be useful in detecting QT changes induced by other mechanisms.
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