title: Effects of a FLAP inhibitor, GSK2190915, in asthmatics with high sputum neutrophils.
abstract: Patients with refractory asthma frequently have neutrophilic airway inflammation and respond poorly to inhaled corticosteroids. This study evaluated the effects of an oral 5-lipoxygenase-activating protein (FLAP) inhibitor, GSK2190915, in patients with asthma and elevated sputum neutrophils. Patients received 14 (range 13-16) days treatment with GSK2190915 100 mg and placebo with a minimum 14 day washout in a double-blind, cross-over, randomised design (N = 14). Sputum induction was performed twice pre-dose in each treatment period to confirm sputum neutrophilia, and twice at the end of each treatment period. The primary endpoint was the percentage and absolute sputum neutrophil count, averaged for end-of-treatment visits. GSK2190915 did not significantly reduce mean percentage sputum neutrophils (GSK2190915-placebo difference [95% CI]: -0.9 [-12.0, 10.3]), or mean sputum neutrophil counts (GSK2190915/placebo ratio [95% CI]: 1.06 [0.43, 2.61]). GSK2190915 resulted in a marked suppression (>90%) of sputum LTB4 and urine LTE4, but did not alter clinical endpoints. There were no safety issues. Despite suppressing the target mediator LTB4, FLAP inhibitor GSK2190915 had no short-term effect on sputum cell counts or clinical endpoints in patients with asthma and sputum neutrophilia.
authors: Institute of Infection, Immunity & Inflammation, University of Glasgow and Respiratory Medicine, Gartnavel General Hospital, Glasgow, UK. Electronic address: Rekha.Chaudhuri@ggc.scot.nhs.uk.
authors: R
authors: R
authors: Chaudhuri
authors: Immuno-Inflammation Therapy Area, GlaxoSmithKline, Stevenage, UK.
authors: V
authors: V
authors: Norris
authors: Clinical Pharmacology Science and Study Operations, GlaxoSmithKline, Uxbridge, UK.
authors: K
authors: K
authors: Kelly
authors: Clinical Statistics, GlaxoSmithKline, Uxbridge, UK.
authors: C-Q
authors: CQ
authors: Zhu
authors: Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Uxbridge, UK.
authors: C
authors: C
authors: Ambery
authors: Institute of Infection, Immunity & Inflammation, University of Glasgow and Respiratory Medicine, Gartnavel General Hospital, Glasgow, UK.
authors: J
authors: J
authors: Lafferty
authors: Institute of Infection, Immunity & Inflammation, University of Glasgow and Respiratory Medicine, Gartnavel General Hospital, Glasgow, UK.
authors: E
authors: E
authors: Cameron
authors: Institute of Infection, Immunity & Inflammation, University of Glasgow and Respiratory Medicine, Gartnavel General Hospital, Glasgow, UK.
authors: N C
authors: NC
authors: Thomson
mesh_terms: D058946:5-Lipoxygenase-Activating Protein Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism*; D010421:Pentanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D013183:Sputum / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C552410:3-(3-tert-butylsulfanyl-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl)-2,2-dimethylpropionic acid; D058946:5-Lipoxygenase-Activating Protein Inhibitors; D007211:Indoles; D010421:Pentanoic Acids
keywords: 5-Lipoxygenase-activating protein (FLAP) inhibitor; Asthma; GSK2190915; Sputum neutrophilia