The effect of GSK2190915, a 5-lipoxygenase-activating protein inhibitor, on exercise-induced bronchoconstriction.
Exercise-induced bronchoconstriction (EIB) describes the condition whereby exercise causes airflow obstruction that lasts for up to 90 minutes without treatment. This double-blind, placebo-controlled, five-way crossover study investigated the dose response and duration of action of a 5-lipoxygenase-activating protein inhibitor, GSK2190915, to inhibit EIB in subjects with asthma. Forty-seven subjects with EIB were enrolled. Exercise challenge testing was scheduled at 2, 9.5, and 24 hours after receiving a single dose of GSK2190915 (10, 50, 100, and 200 mg) or placebo in randomized order. GSK2190915 at 200 and 100 mg significantly attenuated the response to exercise at 2 and 9.5 hours postdose, respectively, compared with placebo. The adjusted mean maximum percentage change from baseline forced expiratory volume at 1 second within 60 minutes postexercise challenge (FEV1 (0-60)) treatment difference for GSK2190915 at 200 mg compared with placebo at 2 hours postdose was 6.30% (95% CI, 3.06, 9.54), corresponding to a 40% attenuation of the placebo response to exercise; the treatment difference between GSK2190915 at 100 mg and placebo at 9.5 hours postdose was 3.49% (95% CI, 1.02, 5.95), corresponding to a 41% attenuation of the placebo response to exercise. No significant effect was seen at 24 hours postdose with any dose; however, investigation of statistically significant treatment-related effects at this time point was limited because of the small fall in adjusted mean FEV1 (0-60) (-7.61%; 95% CI, -10.23, -4.99) after placebo. GSK2190915 may be of benefit in EIB prevention. GSK Clinical Study LPA112025; ClinicalTrials.gov identifier number: NCT00812929.
GlaxoSmithKline, London, UK.
Sandra E
SE
Kent
Jane H
JH
Bentley
David
D
Miller
Richard
R
Sterling
Rogelio
R
Menendez
Martha
M
Tarpay
David S
DS
Pearlman
Virginia
V
Norris
D058946:5-Lipoxygenase-Activating Protein Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000328:Adult; D001249:Asthma; D001982:Bronchial Diseases / Q000188:drug therapy* / Q000209:etiology*; D003251:Constriction, Pathologic; D018592:Cross-Over Studies; D015444:Exercise; D005080:Exercise Test; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D010421:Pentanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
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