title: An oral inhibitor of p38 MAP kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease.
abstract: The aims were to determine the effect of an oral inhibitor of the signaling mediator p38 mitogen-activated protein kinase (GW856553, losmapimod) on sputum neutrophils, pulmonary function, and blood biomarkers of inflammation in chronic obstructive pulmonary disease (COPD). Three hundred and two individuals with GOLD stage II COPD were randomized to oral losmapimod 7.5 mg twice daily, inhaled salmeterol/fluticasone propionate 50 µg/500 µg combination (SFC), or placebo in a 12-week, randomized, double-blind, double-dummy study (MKI102428/NCT00642148). Neither losmapimod nor SFC had an effect on the primary end point of sputum neutrophils. Losmapimod was well tolerated and reduced plasma fibrinogen by 11% (-0.4 g/L, ratio of effect of losmapimod/placebo 0.89; 95% confidence interval, 0.83-0.96; P = .002) with nonsignificant reductions in interleukin-6, interleukin-8, and C-reactive protein. There was evidence of improvement in hyperinflation with losmapimod compared with placebo (overall P = .02). Inhaled SFC significantly improved lung function and reduced serum CC-16 (ratio of effect of SFC/placebo 0.87; 95% confidence interval, 0.82-0.93; P < .001). It was concluded that oral losmapimod significantly reduced plasma fibrinogen in patients with COPD.
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 0XY, UK. dal16@cam.ac.uk
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: David A
authors.initials: DA
authors.lastname: Lipson
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Miller
authors.forename: Lisa
authors.initials: L
authors.lastname: Willits
authors.forename: Oliver
authors.initials: O
authors.lastname: Keene
authors.forename: Helen
authors.initials: H
authors.lastname: Barnacle
authors.forename: Neil C
authors.initials: NC
authors.lastname: Barnes
authors.forename: Ruth
authors.initials: R
authors.lastname: Tal-Singer
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000420:Albuterol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D000730:Androstadienes / Q000008:administration & dosage / Q000627:therapeutic use; D003521:Cyclopropanes / Q000494:pharmacology*; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D005340:Fibrinogen / Q000378:metabolism*; D000068297:Fluticasone-Salmeterol Drug Combination; D006801:Humans; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood* / Q000188:drug therapy* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D013183:Sputum / Q000166:cytology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: C543534:6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide; D000730:Androstadienes; D003521:Cyclopropanes; D004338:Drug Combinations; D000068297:Fluticasone-Salmeterol Drug Combination; D011725:Pyridines; D005340:Fibrinogen; D048051:p38 Mitogen-Activated Protein Kinases; D000420:Albuterol