Effect of Zatebradine, a Novel 'Sinus Node Inhibitor', on Pulmonary Function Compared to Placebo

Summary: Zatebradine, a member of a novel class of drugs called 'sinus node inhibitors', is a specific heart rate lowering drug suitable for the treatment of stable angina pectoris. Animal studies showed that relatively high intravenous doses of zatebradine contracted guinea-pig airways by a histamine-like mechanism. Therefore, the objective of the present study was to assess the bronchopulmonary effects in asthmatic patients who showed a moderate to severe bronchial hyperreactivity towards histamine (PC₂₀ FEV₁ ≤1 mg/ml). Moreover, it had to be established to what extent the bronchial responsiveness to inhaled salbutamol was retained and whether pulmonary effects were related to the severity of bronchial hyperreactivity. By means of a double-blind cross-over design, single oral doses of zatebradine (10 mg) or placebo were administered on two occasions with a washout phase of at least 3 days. Sixteen patients, four female and 12 male, with stable mild to moderate bronchial asthma (FEV₁ less than 80% predicted) were selected. Their mean age was 54 years and the mean FEV₁ was 1.831 (59% predicted). They showed a mean improvement in FEV₁ of 27% 15 min after inhaling 200 μg salbutamol; the mean PC₂₀ was 0.35 mg/ml. Following test drug intake, the respiratory and cardiac effects were assessed at regular time intervals up to 6 h after administration. In comparison to placebo, zatebradine induced small, but significant (P<0.05), mean falls of 128 ml and 168 ml in FEV₁ at 3 h and 6 h after drug intake. A large inter-individual variation in response was noted. In two of the 16 patients a deterioration by more than 20% was observed 6 h after zatebradine intake: 21% and 38% below pre-dose FEV₁ (at 3 h the values were +2% and -14%, respectively). Analysis of the FVC data confirmed the FEV₁ findings. No significant differences were found between zatebradine and placebo for the pulmonary parameters PEF and SG AW. Compared to that on the placebo test day the salbutamol dose-response curve determined 6 h after zatebradine intake did not show a parallel shift to the right; the response to salbutamol was fully retained. No correlation was identified between PC₂₀ and the FEV₁ response observed in the individual patients. One patient reported severe visual disturbances and vomiting, which occurred rather late following zatebradine intake. On both test days no influence on blood pressure was observed, while zatebradine induced a small, but significant, decrease in heart rate at 3 h post-dosing. It is concluded that zatebradine has the potential to cause a deterioration of pulmonary function in asthmatic patients, regardless of the severity of their non-specific bronchial hyperreactivity towards histamine. However, the mean small decrease in pulmonary function as observed in the present study population did fully respond to treatment with a β₂-agonist. Also the patient who showed a deterioration in FEV₁ of 38% following drug intake did fully respond to salbutamol.