title: Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459.
abstract: CRTH2 (chemoattractant receptor expressed on T-helper (Th) type 2 cells) is a G-protein-coupled receptor expressed by Th2 lymphocytes and eosinophils that mediates prostaglandin (PG)D(2)-driven chemotaxis. We studied the efficacy of the oral CRTH2 antagonist OC000459 in steroid-naïve asthmatic patients. A randomised, double-blind, placebo-controlled, two-way crossover study of 16 days' treatment with OC000459 (200 mg twice daily) on the late (LAR) and early (EAR) asthmatic responses to bronchial allergen challenge was conducted, with 16 subjects completing the study. There was a 25.4% (95% CI 5.1-45.6%) reduction in the LAR area under the curve (AUC) for change in forced expiratory volume in 1 s with OC000459 compared with placebo (p=0.018) but no effect on the EAR. Sputum eosinophil counts at 1 day post-allergen challenge were lower after OC000459 treatment (p=0.002). PGD(2)-induced blood eosinophil shape change ex vivo was assessed at day 7 (n=7). The AUC of eosinophil shift for OC000459 was lower than placebo; the mean difference was -33.6% (95% CI -66.8- -0.4%; p=0.048). OC000459 treatment inhibited LAR and post-allergen increase in sputum eosinophils. This CRTH2 antagonist appears to inhibit allergic inflammation in asthma.
authors.affiliation: Medicines Evaluation Unit, University Hospital of South Manchester Foundation Trust, Wythenshawe, UK.
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
authors.forename: Paul
authors.initials: P
authors.lastname: Cadden
authors.forename: Michael
authors.initials: M
authors.lastname: Hunter
authors.forename: Lisa
authors.initials: L
authors.lastname: Pearce Collins
authors.forename: Mike
authors.initials: M
authors.lastname: Perkins
authors.forename: Roy
authors.initials: R
authors.lastname: Pettipher
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Townsend
authors.forename: Shân
authors.initials: S
authors.lastname: Vinall
authors.forename: Brian
authors.initials: B
authors.lastname: O'Connor
mesh_terms: D000328:Adult; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology*; D001985:Bronchial Provocation Tests; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007210:Indoleacetic Acids / Q000627:therapeutic use*; D008297:Male; D011804:Quinolines / Q000627:therapeutic use*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*
chemical_list: C571151:(5-fluoro-2-methyl-3-quinolin-2-ylmethylindo-1-yl)acetic acid; D007210:Indoleacetic Acids; D011804:Quinolines; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C036293:prostaglandin D2 receptor