The effect of terfenadine, fexofenadine and E4031 inisolated and perfussed guinea-pig hearts   M. Maginn, O. Åkerlund and J. Matz. Department of Safety Pharmacology. H. Lundbeck A/S. Copenhagen. Denmark.

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Torsade de pointes (TdP) is a rare form of polymorphic ventricular tachycardia (VT) that exhibits a characteristic twisting of QRS complexes around the isoelectric axis. TdP is preceded by a delay in ventricular repolarisation reflected as an increase in the QT interval on the ECG. The mechanism of onset is unknown but terfenadine (TERF) at above therapeutic concentrations prolong QT intervals and are associated with TdP (Monahan et al., 1990). The aim of this study was to compare the effects of TERF and its metabolite fexofenadine (FEXO) in the guinea pig Langendorff heart model with E4031, a potent antagonist for the Ik_r repolarisation current (Follmer and Colatsky, 1990) at various cycle lengths at relevant therapeutic concentrations.

Male guinea-pigs were anaesthetised with sodium pentobarbital (250 mg/kg, i.p.) the hearts were removed and perfused via the aorta with Krebs-Heinselett solution. The hearts were paced at 273 ms CL. Following an equilibration period and a 30 min infusion period of TERF (1.0 µM), FEXO and E4031 (1.0, 3.0 µM) the effects of the cycle length (CL) variation was tested by changing the pacing frequency to a CL of 300 ms and then to 240 ms. Electrocardiograms were digitised and the QT-interval was measured. Drug treatments were compared to the time matched vehicle group at 273 ms. The effect of CL variation was compared within each treatment group. All data are presented as the mean percentage change from baseline ± S.E.M.

The results are shown on Table 1.

Table 1: Effect of TERF, FEXO and E4031 on the QT interval (percentage change from baseline) following a 30 min infusion at CL of 273 ms, 300 ms and 240 ms.

VT=ventricular tachycardia. *p<0.05 (Student t-test, drug treatment vs time matched vehicle group). ^#p<0.05 (Student t-test, drug treatment at 300 ms CL vs drug treatment at 273 ms CL). ^{^}p<0.05 (Student t-test, drug treatment at 300 ms CL vs drug treatment at 273 ms CL).

In conclusion, TERF and E4031 but not FEXO significantly prolonged the QT interval following 30 min incubation at the normal CL. Variation in CL in the TERF group caused increased conduction abnormalities leading to VT. Although E4031 markedly delayed ventricular repolarisation no cardiac arrhythmias were detected.

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Follmer CH. & Colatsky, TJ., (1990). Circulation 82, 289-293.