The 5-lipoxygenase-activating protein inhibitor, GSK2190915, attenuates the early and late responses to inhaled allergen in mild asthma.

Abstract

BACKGROUND:

GSK2190915, a potent 5-lipoxygenase-activating protein inhibitor, prevents the synthesis of leukotrienes and 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE).

OBJECTIVE:

To assess the effect of GSK2190915 on the allergen-induced asthmatic responses.

METHODS:

Nineteen eligible male subjects with mild asthma were enrolled in and completed this four-centre, double-blind, two-way crossover study (ClinicalTrials.gov NCT00748306). Subjects took GSK2190915 100 mg and placebo orally once daily for 5 days in randomized order. On Day 1 and 4 they had a methacholine challenge, on Day 3 they had an inhaled allergen challenge, and on Days 4 and 6 they had sputum induction.

RESULTS:

GSK2190915 attenuated the early (0-2 h) and late (4-10 h) asthmatic responses to inhaled allergen compared with placebo. There was a statistically significant attenuation of the early asthmatic response (EAR) by GSK2190915; treatment difference of GSK2190915 vs. placebo for the minimum FEV(1) EAR was 0.408 L (0.205, 0.611). There was a statistically significant attenuation of the late asthmatic response (LAR) by GSK2190915; the treatment difference of GSK2190915 vs. placebo for the minimum FEV(1) LAR was 0.229 L (0.041, 0.417). There was a statistically significant attenuation of allergen-induced sputum eosinophil count on Day 4 following GSK2190915: mean treatment difference (95% CI) between GSK2190915 and placebo was -9.95% (-18.15%, -1.77%). Compared with placebo, GSK2190915 100 mg reduced median sputum LTB(4) by > 90% on Days 4 and 6. There was no effect on methacholine PC(20) post allergen. GSK2190915 was generally well tolerated.

CONCLUSION AND CLINICAL RELEVANCE:

GSK2190915 shows potential as a treatment for patients with asthma.

• Authors: S E Kent, M Boyce, Z Diamant, D Singh, B J O'Connor, P S Saggu, V Norris
• Journal: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology (Clin Exp Allergy) Vol. 43 Issue 2 Pg. 177-86 (Feb 2013) ISSN: 1365-2222 [Electronic] England
• PMID: 23331559 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 Blackwell Publishing Ltd.

Chemical References

• 3-(3-tert-butylsulfanyl-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl)-2,2-dimethylpropionic acid
• 5-Lipoxygenase-Activating Protein Inhibitors
• Allergens
• Indoles
• Pentanoic Acids
• Leukotriene B4

Topics

• 5-Lipoxygenase-Activating Protein Inhibitors (pharmacology, therapeutic use)
• Adult
• Allergens (administration & dosage, adverse effects)
• Asthma (drug therapy, immunology)
• Bronchial Provocation Tests
• Humans
• Indoles (administration & dosage, metabolism, therapeutic use)
• Leukotriene B4 (blood, urine)
• Male
• Pentanoic Acids (administration & dosage, metabolism, therapeutic use)
• Respiratory Function Tests
• Sputum (immunology)
• Treatment Outcome
• Young Adult