DH Yates, SA Kharitonov and PJ Barnes
Department of Thoracic Medicine, National Heart and Lung Institute, London, United Kingdom.

There is increasing evidence for the development of tolerance to the protective effects of inhaled beta 2-agonists against bronchoconstrictor stimuli. Animal studies have suggested that glucocorticoids protect against the down-regulation of beta 2-receptors after chronic exposure to beta 2-agonists. In a double-blind placebo- controlled crossover study in 12 patients with mild asthma, we investigated the effect of inhaled budesonide or identical placebo on the protection conferred by albuterol (200 micrograms) against methacholine-induced bronchoconstriction before and after treatment with the long-acting beta 2-agonist salmeterol. Patients were randomized to be treated for 3 wk with inhaled budesonide (800 micrograms twice a day) or placebo; salmeterol (50 micrograms twice a day) was added during the third week. Airway responsiveness to methacholine was measured 15 min after albuterol, both before and exactly 23 h after the last salmeterol dose. Mean FEV1 increased significantly after 2 wk of budesonide (p < 0.05) and increased further after salmeterol (p < 0.05) compared with placebo. After 2 wk, the bronchoprotective effect of albuterol against methacholine was significantly greater with budesonide than with placebo (3.4 versus 2.4 doubling dilutions; p < 0.05), consistent with an improvement in airway hyperresponsiveness with budesonide therapy. However, regular salmeterol treatment for 1 wk significantly diminished the protection conferred by albuterol against methacholine challenge, both with budesonide and with placebo (-1.1 +/- 0.42 and -1.41 +/- 0.30 doubling dilutions, respectively). There was no significant difference in the loss of bronchoprotection seen with salmeterol between budesonide and placebo treatment periods. Our study suggests that even a high dose of an inhaled glucocorticoid fails to prevent the loss of bronchoprotection produced by regular beta 2-agonist therapy.

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