title: 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.
authors.affiliation: Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: A J
authors.initials: AJ
authors.lastname: Ravensberg
authors.forename: B
authors.initials: B
authors.lastname: Luijk
authors.forename: P
authors.initials: P
authors.lastname: Westers
authors.forename: P S
authors.initials: PS
authors.lastname: Hiemstra
authors.forename: P J
authors.initials: PJ
authors.lastname: Sterk
authors.forename: J W
authors.initials: JW
authors.lastname: Lammers
authors.forename: K F
authors.initials: KF
authors.lastname: Rabe
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000485:Allergens / Q000008:administration & dosage*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D018592:Cross-Over Studies; D004306:Dose-Response Relationship, Immunologic; D004311:Double-Blind Method; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged
chemical_list: D000485:Allergens; D000894:Anti-Inflammatory Agents, Non-Steroidal; D039041:Integrin alpha4beta1