EFFECT OF ONCE-DAILY AND TWICE-DAILY SUSTAINED-RELEASE THEOPHYLLINE FORMULATIONS ON DAYTIME VARIATION OF BRONCHIAL HYPERRESPONSIVENESS IN ASTHMATIC-PATIENTS

Background - Previous studies evaluating spirometric values and sympto ms have shown that once daily theophylline administered in the evening produces greater stabilisation of the airway function in asthmatic pa tients than the prototype theophylline given twice a day. The aim of t his study was to compare the effects on bronchial responsiveness to me thacholine of an ultrasustained release theophylline formulation (Diff umal-24, Malesci, Florence, Italy) administered once a day, a sustaine d release theophylline formulation (Theo-Dur, Recordati, Milan, Italy) administered twice a day, and placebo. Methods - The study was perfor med in 12 adult patients with asthma using a randomised, double blind, three phase, crossover design. Each phase lasted seven days and was f ollowed or preceded by at least three days of theophylline washout. Di ffumal-23 was administered once a day at 20.00 hours whereas Theo-Dur was given twice a day at 08.00 hours and 20.00 hours. In each patient the total daily dose of theophylline was the same during both phases. The dose of the two active preparations was titrated to individual nee ds before the beginning of the study and then given in divided or once daily doses. At 08.00, 14.00, and 20.00 hours on day 7 of each phase serum theophylline concentrations were measured and spirometric tests (FEV1) and bronchial challenge with methacholine were also performed. Results - When the administration of Diffumal-24 was compared with tha t of Theo-Dur, a higher serum theophylline concentration of the former was seen in the morning whereas at 20.00 hours the reverse was true. Compared with placebo, at 08.00 hours Diffumal-24 improved FEV1 wherea s Theo-Dur did not (difference between treatments 0.29 1, 95% CI 0.12 to 0.45). At 08.00 hours Diffumal-24 decreased bronchial sensitivity t o methacholine, expressed as a natural logarithm of PD20, to a greater extent than Theo-Dur (difference between treatments 0.54 log units, 9 5% CI 0.016 to 1.08). The morning advantage observed with Diffumal-24 administration was not associated with a deterioration in the state of the airway during the daytime, the protective activity against methac holine during the 12 hours of the monitoring period being constant. Fu rthermore there was no difference in the mean FEV1 between the two tre atments at 14.00 and 20.00 hours. Conclusions - In adults with stable bronchial asthma treatment with a single dose of Diffumal-24 administe red in the evening improved airflow obstruction and reduced bronchial hyperresponsiveness.