Dose-related effects of formoterol on airway responsiveness to adenosine 5'-monophosphate and histamine.
Inhaled short-acting beta2-agonists provide greater protection against airway responsiveness (AR) to the mast-cell stimulus, adenosine 5'-monophosphate (AMP), than to histamine, a direct spasmogen. Both terbutaline and albuterol exhibit this mast-cell stabilizing property in a dose-dependent manner. A single dose of the long-acting beta2-agonist formoterol has also been reported to have a mast cell-stabilizing effect, whereas salmeterol has not. To explore the dose-related actions of the long-acting beta2-agonist formoterol on AR, the authors compared the acute effects of three doses of formoterol and terbutaline on AR to AMP and histamine. In a double-blind, randomized, placebo-controlled, cross-over study, 25 mild, steroid naive, asthmatic subjects attended on 10 occasions. At each visit, subjects inhaled either a single dose of terbutaline (500 microg), formoterol (6, 12 or 24 microg) or a matched placebo, administered via Turbuhaler, 30 min prior to challenge with both AMP and histamine. Each dose of beta2-agonist reduced AR to AMP and histamine. The bronchoprotective effects of formoterol (6 microg) and terbutaline (500 microg) were similar in magnitude in reducing AR to histamine (mean +/- SD: 3.6 +/- 0.3 and 3.1 +/- 0.3 doubling doses (DD)) and AR to AMP (3.5 +/- 0.5 and 3.3 +/- 0.4 DD, respectively). Overall, formoterol reduced AR to both spasmogens in a dose-dependent manner. In addition, formoterol (12 and 24 microg) provided a significantly greater protective effect against AMP than against histamine challenge. It decreased AR by 5.7 +/- 0.6 and 6.3 +/- 0.7 DD against AMP and 4.3 +/- 0.4 and 4.8 +/- 0.43 DD against histamine, respectively. The results of this study indirectly demonstrated an in vivo dose-dependent mast-cell stabilizing effect of formoterol, in addition to functional antagonism on airway smooth muscle. This property of beta2-agonists may have clinical benefits in asthma management.
Ketchell
R I
RI
Dept of Respiratory Medicine and Allergy, GKT School of Medicine, King's College, London, UK. ian.ketchell@kcl.ac.uk
Jensen
M W
MW
Spina
D
D
O'Connor
B J
BJ
D000249:Adenosine Monophosphate; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage* / Q000494:pharmacology; D000328:Adult; D000403:Airway Resistance / Q000187:drug effects*; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004983:Ethanolamines / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D000068759:Formoterol Fumarate; D006632:Histamine; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000187:drug effects; D013726:Terbutaline
D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D000249:Adenosine Monophosphate; D006632:Histamine; D013726:Terbutaline; D000068759:Formoterol Fumarate