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1 Depts of Medical and Surgical Sciences and 2 Preventive and Social Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
CORRESPONDENCE: D.R. Taylor, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. Fax: +6434747641
Keywords: formoterol, long acting beta-agonist, tolerance
Received: March 13, 2000
Accepted August 18, 2000
This work was supported in part, by a GlaxoWellcome Research Fellowship, awarded to S.L. Jones.
Continuous treatment with a short-acting ß2-agonist can lead to reduced bronchodilator responsiveness during acute bronchoconstriction. This study evaluated bronchodilator tolerance to salbutamol following regular treatment with a long-acting ß2-agonist, formoterol. The modifying effect of intravenous corticosteroid was also studied.
Ten asthmatic subjects (using inhaled steroids) participated in a randomised, double-blind, placebo-controlled, cross-over study. Formoterol 12 µg b.i.d. or matching placebo was given for 10–14 days with >2 weeks washout. Following each treatment, patients underwent a methacholine challenge to induce a fall in forced expired volume in one second (FEV1) of at least 20%, then salbutamol 100 µg, 100 µg, and 200 µg was inhaled via a spacer at 5 min intervals, with a further 400 µg at 45 min. After a third single-blind formoterol treatment period, hydrocortisone 200 mg was given intravenously prior to salbutamol. Dose-response curves for change in FEV1 with salbutamol were compared using analysis of covariance to take account ofmethacholine-induced changes in spirometry.
Regular formoterol resulted in a significantly lower FEV1 after salbutamol at each time point compared to placebo (p<0.01). The area under the curves (AUCs) for 15 (AUC0–15) and 45 (AUC0–45) min were 28.8% and 29.5% lower following formoterol treatment (p<0.001). Pretreatment with hydrocortisone had no significant modifying effect within 2 h of administration.
It is concluded that significant tolerance to the bronchodilator effects of inhaled salbutamol occurs 36 h after stopping the regular administration of formoterol. This bronchodilator tolerance is evident in circumstances of acute bronchconstriction.
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