Oral and inhaled p38 MAPK inhibitors: effects on inhaled LPS challenge in healthy subjects.
Eur J Clin Pharmacol
; 71(10): 1175-84, 2015 Oct.
Article
em En
| MEDLINE
| ID: mdl-26265232
ABSTRACT
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, MIP1ß and CC16) in sputum supernatant, while PF-03715455 had no effect. PH-797804 and PF-03715455 both inhibited IL-6, MCP-1, MIP1ß, 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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piridonas
/
Benzamidas
/
Mediadores da Inflamação
/
Proteínas Quinases p38 Ativadas por Mitógeno
/
Compostos Azabicíclicos
/
Fluticasona
/
Compostos de Metilureia
/
Anti-Inflamatórios
Tipo de estudo:
Clinical_trials
Limite:
Adolescent
/
Adult
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
Eur J Clin Pharmacol
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Reino Unido