Theophylline inhibits the late asthmatic response to nighttime antigen challenge in patients with mild atopic asthma

Background: Inhaled antigen at night causes a more pronounced late asthmatic response (LAR) when compared with daytime challenges. Chronopharmacology with controlled-release theophylline given in the evening leads to a peak serum theophylline concentration (STC) in early morning which coincides with LAR that follows an evening challenge. Objective: To evaluate the effect of controlled-release theophylline given with the evening meal on the immediate asthmatic response (IAR) and LAR following nighttime antigen challenge in patients with mild atopic asthma. Methods: To qualify, subjects underwent antigen bronchoprovocation by graded nebulization until the IAR (fall in FEV1 of greater than or equal to 20%) occurred; spirometry was then measured hourly for 8 hours to establish the presence of LAR (fall in FEV1 greater than or equal to 15%). After 2 weeks of randomized, double-blind crossover treatment with either theophylline (target STC of 10 to 15 mg/L, (56 to 83 mu mol/L)) or placebo, inhaled antigen challenge was performed at 10 PM in each subject. FEV1 values were measured immediately and then hourly for 8 hours following antigen challenge. Results: Twelve subjects completed the study. During the placebo phase, the maximal fall in FEV1 during LAR was 39 +/- 3% (mean +/- SEM) compared with 31 +/- 4% fall during theophylline treatment phase (P = .01). A reduction in LAR occurred despite higher dose (P < .05) of inhaled antigen during theophylline phase, which would have been expected to result in a more pronounced LAR. Serum theophylline concentration at 8 AM on the day following antigen challenge was 9.6 +/- 1.1 mg/L (53 +/- 6 mu mol/L). Conclusion: Nocturnal administration of controlled-release theophylline increases the tolerance to inhaled antigen and reduces severity of LAR. Because the LAR is linked to airway inflammation, these data support the possibility of antiinflammatory effects associated with theophylline use.