LONG-TERM CIRCADIAN EFFECTS OF SALMETEROL IN ASTHMATIC-CHILDREN TREATED WITH INHALED CORTICOSTEROIDS

The present study was set up to investigate whether salmeterol in children with asthma already treated with inhaled corticosteroids (ICS) leads to a sustained bronchodilator effect and decreased bronchial responsiveness, both during the day and night. Furthermore, we investigated whether cessation of salmeterol leads to a rebound increase in bronchial responsiveness. Forty children with asthma (aged 7-15 yrs) using ICS participated in a randomized, double-blind, parallel study. They received either twice daily 50 mu g salmeterol or placebo. FEV(1) and provocative concentration of methacholine that caused a 20% fall in FEV(1) (PC20) were measured at 4:00 P.M, and 4:00 A.M. at baseline and after 16 wk. The same measurements were performed at 4:00 P.M. at 8 h after the first dose, and after 1 and 8 wk. After cessation of the study drug, FEV(1) and PC20 Were measured at 12 and 20 h and after 1 wk. Overall mean FEV(1) from 1 to 16 wk of treatment was significantly higher in the salmeterol group than in the placebo group (difference, 4.9 +/- 2.0%, p = 0.01). Evolution in time of FEV(1) did not differ significantly between the two groups (p = 0.09). Overall mean PC20 from 1 to 16 wk of treatment was not significantly higher with salmeterol than with placebo (difference, 0.7 +/- 0.4 doubling dose [DD] p = 0.07); evolution in time of PC20 did not differ significantly between the two groups (p = 0.58). The increase of PC20 8 h after the start of the study was significantly higher with salmeterol than with placebo (1.9 +/-:0.3 DD versus 0.7 +/- 0.3 DD, p < 0.01); significance disappeared at 1 wk. At 16 wk, the circadian variation (day minus night value) in FEV(1) was significantly smaller with salmeterol than with placebo (-0.9 +/- 0.9% versus 2.2 +/- 1.0%, p = 0.03); this was not the case for PC20. No rebound worsening of FEV(1) or PC20 methacholine was observed after cessation of salmeterol. Sixteen weeks of treatment with salmeterol given to children with asthma on regular ICS leads to a sustained bronchodilator effect and improved circadian variation in airway diameter. The initial significant decrease in bronchial responsiveness dropped below significance after 1 wk, and no overall additive beneficial effect of salmeterol on bronchial responsiveness was present. Finally, cessation of salmeterol after 4 mo of treatment does not lead to a rebound increase in bronchial responsiveness in children with asthma treated with inhaled ICS.