Comparison of formoterol, salbutamol and salmeterol in methacholine-induced severe bronchoconstriction. M.J. Politiek, M. Boorsma, R. Aalbers. #ERS Journals Ltd 1999. ABSTRACT: The onset of the bronchodilating effect of formoterol (12 mg by Turbuhaler1) was compared with that of salbutamol (50 mg by Turbuhaler), salmeterol (50 mg by Diskhaler1) and placebo in methacholine-induced severe bronchoconstriction.Seventeen subjects with mild-to-moderate asthma completed this randomized, double blind, cross-over, double-dummy study. On four study days, baseline forced expiratory volume in one second (FEV1) was recorded and the subjects were challenged with methacholine until FEV1 fell by at least 30%. Immediately thereafter, the study drugs were inhaled and lung function was assessed for 60 min.The geometric mean time for FEV1 to return to 85% of baseline was 7.2 min with formoterol, 6.5 min with salbutamol, 14.1 min with salmeterol and 34.7 min with placebo (p=0.0001, overall ANOVA). The difference between formoterol and salmeterol was statistically significant (p=0.01); there was no difference between formoterol and salbutamol (p=0.69).In conclusion, formoterol reversed methacholine-induced severe bronchoconstriction as rapidly as salbutamol and more rapidly than salmeterol. Classifying b 2 -agonists as "fast"-and "slow"-acting may be supplemental to "short"-and "long"-acting. Eur Respir J 1999; 13: 988±992.

In a double-blind study of 2 parallel groups of 15 allergic asthmatic patients each, we investigated whether treatment with inhaled budesonide has a dose- and time-dependent effect on the degree of bronchial hyperreactivity. The patients were randomly allocated to treatment with either 200 or 800 micrograms budesonide per day for a period of 8 wk. The active treatment period was preceded by a selection period of 3 wk, and a single-blind placebo period of 2 wk. During these initial 5 wk the maintenance treatment of the patients, including cromolyn sodium and inhaled corticosteroids, was withheld. Spirometry and inhalation provocation tests with methacholine were carried out, and the symptom score was recorded every 2 wk. The methacholine provocation concentrations (geometric mean) causing a decrease in FEV1 of 20% (PC20) in the 200 and 800 micrograms/day treatment groups just before the active treatment period were 0.90 and 0.91 mg/ml, respectively. These values increased significantly to 1.21 and 1.84 mg/ml after 2 wk of treatment (p less than 0.05 and p less than 0.001, respectively) and to 1.55 and 2.74 mg/ml after 8 wk of treatment (p less than 0.01 and p less than 0.001). During the whole study period budesonide in a dosage of 800 micrograms/day induced a significantly larger change in PC20 than in a dosage of 200 micrograms/day. The FEV1 before treatment was 91 +/- 3% (SEM) and 84 +/- 2% of the predicted value in the 200 and 800 micrograms/day treatment groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • In vitro studies with human bronchial epithelial cells have shown that budesonide undergoes rapid, extensive and reversible intracellular esterification, a finding that is believed to contribute to retention and prolonged duration of action. • A case report has suggested retention of budesonide in the lungs of patients undergoing surgical resection. • This study evaluated, for the first time, the esterification (and distribution) of inhaled budesonide and fluticasone propionate in vivo in human lung. WHAT THIS STUDY ADDS • This study has unequivocally shown that budesonide undergoes esterification in human lungs in vivo. • Budesonide was detectable in central and peripheral lung tissue for 10 h, and budesonide oleate up to 43 h after inhalation. • The sustained retention of budesonide esters in the lungs probably contributes to the prolonged duration of action and once‐daily efficacy of budesonide. AIMS Budesonide, unlike fluticasone propionate, undergoes fatty acid esterification in the lungs, and there is a need to characterize fully the distribution and fate of the two drugs after inhalation in humans. METHODS This open‐label, randomized study was performed in adults undergoing whole lung or lobar resection resulting from lung cancer. Patients were given single 1000‐μg doses of both budesonide and fluticasone propionate via dry powder inhalers before surgery. Tissue samples from peripheral and central lung, an ex vivo bronchial brush sample and intercostal muscle, together with plasma samples, were taken during surgery and analysed by liquid chromatography plus tandem mass spectrometry. RESULTS Lung tissue samples were obtained from 22 patients at surgery, 1–43 h after drug dosing. Budesonide was detectable from earliest sampling in central and peripheral lung tissue up to 10 h (in six of 22 samples), fluticasone propionate up to 22 h after inhalation (in 16 of 22 samples), and budesonide oleate up to 43 h after inhalation (in 21 of 22 samples). Budesonide, but not fluticasone propionate, was detected in intercostal muscle for up to 10 h after inhalation. Bronchial brush samples showed the presence of fluticasone propionate for up to 18 h, suggesting the presence of undissolved drug powder particles in the airway lumen. CONCLUSION Sustained retention of esterified budesonide in the lungs supports the prolonged duration of action of budesonide and suitability for once‐daily administration.