A randomized, placebo-controlled study of the effects of the p38 MAPK inhibitor SB-681323 on blood biomarkers of inflammation in COPD patients.
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)-alpha 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-alpha 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-alpha production. SB-681323 is a potent p38 MAPK inhibitor that potentially suppresses inflammation in COPD.
Singh
Dave
D
University of Manchester, Medicines Evaluation Unit, South Manchester University Hospitals Trust, Manchester, United Kingdom. e-mail: dsingh@meu.org.uk
Smyth
Lucy
L
Borrill
Zoe
Z
Sweeney
Lisa
L
Tal-Singer
Ruth
R
D000368:Aged; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D054316:Biomarkers, Pharmacological / Q000097:blood*; D005260:Female; D055551:HSP27 Heat-Shock Proteins / Q000097:blood; D006801:Humans; D007249:Inflammation / Q000097:blood*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008875:Middle Aged; D015990:Placebo Effect; D011239:Prednisolone / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood* / Q000188:drug therapy; D011728:Pyridones / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D000893:Anti-Inflammatory Agents; D054316:Biomarkers, Pharmacological; D055551:HSP27 Heat-Shock Proteins; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D011239:Prednisolone; D048051:p38 Mitogen-Activated Protein Kinases; C574213:dilmapimod