The efficacy, as modified by the circadian rhythm of salbutamol administered by different routes

Fourteen asthmatic outpatients participated in a total of 16 trials with salbutamol administered by different routes. Drug dosage was one 4-mg tablet, of two inhalations of 100 mug of salbutamol aerosol or a combination of both, four times daily. During the trial the patients measured their peak expiratory flow (PEF) every day at 1.00 a.m., 7.00 a.m., 10.00 a.m. and 9.30 p.m. The frequency and severity of symptoms and side effects as well as the auxiliary use of isoprenaline inhalation were also recorded. A clear-cut circadian rhythm in bronchial obstruction was observed during both active drug and placebo periods. PEF values during all active periods differed significantly from those during placebo periods at 3 and 2.5 h after drug intake (at 10.00 a.m. and 9.30 p.m.). Moreover, a distinction between the effects of the various active drug forms was possible at 10.00 a.m., salbutamol tablets and the combination of salbutamol tablets and aerosols being then superior to aerosol treatment alone. At night and in the early morning PEF values were generally lower than during the day owing to the circadian rhythm, and bronchodilator response to drugs at these times was also less pronounced. Isoprenaline consumption was highest during placebo periods and lowest during periods of combined active treatment. No serious side effects were seen. Cumulative evidence has shown that this kind of study with outpatients is suitable for comparing the clinical effects of bronchodilator drugs.