Differential Effects of Fluticasone Propionate on Allergen-evoked Bronchoconstriction and Increased Urinary Leukotriene E ₄ Excretion

Abstract

Allergen challenge is associated with an increased excretion of urinary leukotriene E4. The source of this increase is unknown, although the lack of effect of inhaled β-agonists and sodium cromoglycate suggests that airway mast cells may not be involved. We investigated this further using a new and topically potent inhaled glucocorticoid, fluticasone propionate (FP). A group of 10 mild atopic asthmatic subjects (6 males; FEV1 > 60% of predicted; PC20 histamine ⩽ 8 mg/ml; and on inhaled β2-agonists only) were studied before and after a 2-wk period of FP (1,000 µg/day) or placebo administered by metered-dose inhalers as two puffs twice per day through a large-volume spacer. Treatments were assigned in a double-blind crossover fashion separated by a 3-wk washout period. The PC20 histamine was measured at the start and end of each treatment when subjects also received a bronchial allergen challenge. Urine was collected for 4 h after allergen challenge for determination of LTE4 using HPLC-RIA, and 2 h later the PC20 histamine measurement was repeated. The 2-wk treatment with FP significantly inhibited both early and late responses to allergen: the maximum % fall in FEV1 during the early (0 to 2 h) and late response (2 to 6 h) was 32.6 ± 3.4 and 19.6 ± 5.2, respectively, following placebo versus 19.5 ± 4.5 and 3.6 ± 2.6 following FP (both p < 0.02). Fluticasone propionate also reduced both the baseline bronchial reactivity (median change in PC20 histamine after placebo was 0.1 [range −0.52 to 0.68] doubling dilutions versus 1.28 [0.49 to 3.88] after FP, p < 0.01) and the allergen-evoked increase in reactivity (median change in PC20 histamine after allergen −1.59 [−2.59 to −0.40] after placebo versus −0.10 [−0.92 to 1.36] after FP, p < 0.01). Despite this, FP had no significant effect on the increased urinary LTE4 excretion following allergen challenge; the geometric mean excretion was 18.4 (95% CI 3.4 to 104.1) ng/mmol creatinine after placebo and 18.7 (3.2 to 109.5) after FP (p > 0.5). Thus, FP behaves like other inhaled glucocorticoids administered chronically, with decreasing bronchial reactivity and inhibition of both the early and late bronchoconstriction to inhaled allergen. The implications of the failure of FP to alter allergen-evoked urinary LTE4 excretion are discussed.