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A randomized, placebo-controlled study of the effects of the p38 MAPK inhibitor SB-681323 on blood Bbiomarkers of inflammation in COPD patients

Singh, D, Smyth, LJC, Borrill, Z, Sweeney, L and Tal-Singer, R 2010, 'A randomized, placebo-controlled study of the effects of the p38 MAPK inhibitor SB-681323 on blood Bbiomarkers of inflammation in COPD patients' , The Journal of Clinical Pharmacology, 50 (1) , pp. 94-100.

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Abstract

The p38 mitogen-activated protein kinase (MAPK) signaling upregulates inflammation and is known to be increased in chronic obstructive pulmonary disease (COPD). The authors assessed the pharmacology of the novel p38 MAPK inhibitor SB-681323 using blood biomarkers in COPD. Seventeen COPD patients (forced expiratory volume in 1 second 50%-80% predicted) using short-acting bronchodilators participated in a double-blind, double-dummy, randomized, crossover study. Patients received single oral doses of SB-681323 7.5 mg and 25 mg, prednisolone 10 mg and 30 mg, and placebo. Blood was obtained predose and at 1, 2, 6, and 24 hours postdose. Whole-blood sorbitol-induced phosphorylated (p) heat shock protein (HSP) 27 levels as a marker of p38 pathway activation and lipopolysaccharide-induced tumor necrosis factor (TNF)-α production were assessed. Both doses of SB-681323, but not prednisolone, significantly (P < .0001) reduced weighted mean (WM) pHSP27 (0-6 hours) by 58% compared with placebo. WM TNF-α production (0-24 hours) was significantly reduced compared with placebo by SB-681323 25 mg (40%, P = .005) and 7.5 mg (33.4%, P = .02), while prednisolone 30 mg and 10 mg caused 81.5% and 58.2% suppression, respectively (both P < .0001). SB-681323 inhibited the p38 MAPK pathway to a greater degree than prednisolone did. SB-681323 inhibited TNF-α production. SB-681323 is a potent p38 MAPK inhibitor that potentially suppresses inflammation in COPD.

Item Type: Article
Themes: Subjects / Themes > Q Science > QR Microbiology
Subjects outside of the University Themes
Schools: Colleges and Schools > College of Science & Technology
Colleges and Schools > College of Science & Technology > School of Environment and Life Sciences
Journal or Publication Title: The Journal of Clinical Pharmacology
Publisher: Sage Publications
Refereed: Yes
ISSN: 0091-2700
Depositing User: Users 29196 not found.
Date Deposited: 22 Dec 2010 17:02
Last Modified: 20 Aug 2013 17:44
URI: http://usir.salford.ac.uk/id/eprint/12675

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