Rapid effect of inhaled fluticasone propionate on airway responsiveness to adenosine 5'-monophosphate in mild asthma.
Inhaled adenosine 5'-monophosphate (AMP) has an "indirect" bronchoconstrictive effect through mast cell degranulation and mediator release, whereas inhaled histamine has a "direct" effect on smooth muscle. Prolonged treatment with inhaled glucocorticosteroids attenuates airway responsiveness (AR) to AMP and histamine. We investigated the early effects of inhaled fluticasone propionate (FP) therapy on AR in 3 consecutive double-blind, randomized, placebo-controlled crossover studies in steroid-naive subjects with mild asthma. In one study, each of 12 subjects received FP 1000 microg or matched placebo for 7 inhalations at 12 hourly intervals; AR to AMP and FEV(1) were measured 2 hours after the 3rd and 7th inhalations. In a second study, each of 12 subjects received FP 100, 250, or 1000 microg or matched placebo for 3 inhalations at 12 hourly intervals; AR to AMP and FEV(1) were measured 2 hours after the 1st and 3rd inhalations. In a third study, each of 8 subjects received a single inhalation of FP 1000 microg or matched placebo; AR to histamine was measured 2 hours later. In the first study, FP 1000 microg significantly attenuated AR to AMP by 2.7 and 2.5 doubling doses after 3 and 7 inhalations, respectively (P < or =.0001). In the second study, FP 100, 250, and 1000 microg significantly attenuated AR to AMP by 1.9, 2.2, and 2.7 doubling doses, respectively, after 1 inhalation and by 2.4, 2.2, and 3.2 doubling doses, respectively, after 3 inhalations (P < or =.0001); a small but significant increase in FEV(1) (>0.15 L) was observed after 3 inhalations but not after 1 inhalation of FP irrespective of dose (P < or =.05). In the third study, a single inhalation of FP 1000 microg had no effect on AR to histamine. We have demonstrated a reduction in AR to AMP but not AR to histamine within 2 hours of a single inhalation of FP. This reflects a rapid, topical anti-inflammatory action of inhaled FP by a mechanism of action that remains unknown.
Ketchell
Robert I
RI
Department of Respiratory Medicine and Allergy, GKT School of Medicine, King's College, Bessemer Road, London SE5 9PJ, UK.
Jensen
Marianne W
MW
Lumley
Philip
P
Wright
Andrew M
AM
Allenby
Mark I
MI
O'connor
Brian J
BJ
D000249:Adenosine Monophosphate / Q000008:administration & dosage / Q000627:therapeutic use*; D000280:Administration, Inhalation; D000328:Adult; D000730:Androstadienes / Q000008:administration & dosage* / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology*; D001980:Bronchi / Q000187:drug effects*; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D000068298:Fluticasone; D005541:Forced Expiratory Volume / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D013997:Time Factors
D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D016085:Bronchoconstrictor Agents; D000249:Adenosine Monophosphate; D006632:Histamine; D000068298:Fluticasone