Effect of zatebradine, a novel 'sinus node inhibitor', on pulmonary function compared to placebo.
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 < or = 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 micrograms 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Maesen
F P
FP
Department of Pneumology, de Wever Hospital, Heerlen, The Netherlands.
Smeets
J J
JJ
van Noord
J A
JA
Nehmiz
G
G
Wald
F D
FD
Cornelissen
P J
PJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000420:Albuterol / Q000008:administration & dosage / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D001552:Benzazepines / Q000008:administration & dosage / Q000009:adverse effects*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000503:physiopathology; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000009:adverse effects*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D012129:Respiratory Function Tests; D012849:Sinoatrial Node / Q000187:drug effects*
D001552:Benzazepines; D002317:Cardiovascular Agents; D006632:Histamine; D000420:Albuterol; C043636:zatebradine