Oral and inhaled p38 MAPK inhibitors: effects on inhaled LPS challenge in healthy subjects

• Published in: European journal of clinical pharmacology Vol. 71; no. 10; pp. 1175 - 1184
• Main Authors: Singh, Dave, Siew, Leonard, Christensen, Jared, Plumb, Jonathan, Clarke, Graham W., Greenaway, Steve, Perros-Huguet, Christelle, Clarke, Nick, Kilty, Iain, Tan, Lisa
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2015; Springer Nature B.V
• Subjects: Administration, Inhalation; Adolescent; Adult; Anti-Inflammatory Agents - pharmacology; Azabicyclo Compounds - pharmacology; Benzamides - pharmacology; Biomedical and Life Sciences; Biomedicine; Bronchial Provocation Tests; Clinical Trial; Cross-Over Studies; Double-Blind Method; Female; Fluticasone - pharmacology; Humans; Inflammation; Inflammation - metabolism; Inflammation Mediators - metabolism; Lipopolysaccharides - pharmacology; Male; Methylurea Compounds - pharmacology; Middle Aged; Neutrophils - metabolism; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; Pharmaceuticals; Pharmacology; Pharmacology/Toxicology; Pyridones - pharmacology; Respiratory system; Sputum - cytology; Young Adult; p38 MAPK inhibitors; LPS challenge; Induced sputum
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-015-1920-1

Background Inhaled LPS causes neutrophilic airway inflammation in healthy subjects. We compared the effects of p38 MAPK inhibitors and fluticasone propionate on the LPS response. Methods Three randomised, double-blind, placebo-controlled, single dose crossover studies were performed. Active treatments were the oral p38 MAPK inhibitor PH-797804 30 mg (study 1), PH-797804 30 mg and the inhaled p38 MAPK inhibitor PF-03715455 20 mg (study 2) and inhaled fluticasone propionate 500 μg (study 3). The primary endpoint was sputum neutrophil percentage. Results Sputum neutrophil percentage post-LPS challenge was significantly inhibited (15.1 and 15.3 % reduction) by PH-797804 compared to placebo in studies 1 and 2 ( p  = 0.0096 and 0.0001, respectively), and by PF-03715455 (8.0 % reduction, p  = 0.031); fluticasone propionate had no effect. PH-797804 significantly inhibited the increase in inflammatory mediators (IL-6, MCP-1, MIP1β and CC16) in sputum supernatant, while PF-03715455 had no effect. PH-797804 and PF-03715455 both inhibited IL-6, MCP-1, MIP1β, CC16 and CRP levels in plasma, with PH-797804 having greater effects. Fluticasone propionate had no effect on sputum supernatant or plasma biomarkers. Conclusions PH-797804 had the greatest impact on neutrophilic airway inflammation. Oral administration of p38 MAPK inhibitors may optimise pulmonary anti-inflammatory effects.