The effect of a single inhaled dose of a VLA-4 antagonist on allergen-induced airway responses and airway inflammation in patients with asthma

Abstract

Adhesion molecule very late antigen-4 (VLA-4) is implicated in the recruitment and activation of inflammatory cells in asthma, including eosinophils, T cells and mast cells. VLA-4 antagonists have been proposed as a new anti-inflammatory treatment modality for asthma. Therefore, we investigated whether a single inhaled dose of VLA-4 antagonist GW559090X could protect against allergen-induced changes in airway responses and airway inflammation in patients with asthma. We performed a randomized, double-blind, three-way crossover study with single inhaled doses of 3 mg of GW559090X, 500 microg of fluticasone propionate (FP) or placebo in 15 patients with mild intermittent asthma, controlled with short-acting beta(2)-agonists only. All patients developed a late asthmatic response (LAR) after allergen inhalation during screening. Study medication was administered 30 min prior to allergen challenge. Pre-dose and 24 h post-dose PC20 methacholine and levels of exhaled nitric oxide (eNO) were determined. At the given dose, VLA-4 antagonist GW559090X did not attenuate the early asthmatic response (EAR) when compared with placebo: mean AUC0-2 h(+/-SEM) (%fall h): 27.2+/-3.7 and 21.9+/-3.0 respectively (P=0.33); nor the LAR: mean AUC3-8 h(+/-SEM) (%fall h): 98.8+/-12.9 and 94.8+/-6.8 respectively (P=0.84). However, pretreatment with FP did attenuate both EAR and LAR when compared with placebo: mean AUC0-2 h11.6+/-3.3 (P=0.024) and mean AUC3-8 h 6.3+/-7.6 (P<0.001). None of these treatments had an effect on allergen-induced changes in airway hyper-responsiveness or eNO levels. These findings suggest that VLA-4 may not play a major role in allergen-induced airway responses and inflammation in asthma.