Singh Dave, Siew Leonard, Christensen Jared, Plumb Jonathan, Clarke Graham W, Greenaway Steve, Perros-Huguet Christelle, Clarke Nick, Kilty Iain, Tan Lisa
University Of Manchester, Medicines Evaluation Unit, University Hospital of South Manchester Foundation Trust, Manchester, M23 9QZ, UK.
Quintiles Drug Research Unit, Respiratory and Inflammation Early Clinical Development, Quintiles Ltd, London, SE1 1YR, UK.
Eur J Clin Pharmacol. 2015 Oct;71(10):1175-84. doi: 10.1007/s00228-015-1920-1. Epub 2015 Aug 13.
Inhaled LPS causes neutrophilic airway inflammation in healthy subjects. We compared the effects of p38 MAPK inhibitors and fluticasone propionate on the LPS response.
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.
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.
PH-797804 had the greatest impact on neutrophilic airway inflammation. Oral administration of p38 MAPK inhibitors may optimise pulmonary anti-inflammatory effects.
吸入脂多糖可导致健康受试者出现中性粒细胞性气道炎症。我们比较了p38丝裂原活化蛋白激酶（MAPK）抑制剂和丙酸氟替卡松对脂多糖反应的影响。
进行了三项随机、双盲、安慰剂对照、单剂量交叉研究。活性治疗药物分别为口服p38 MAPK抑制剂PH-797804 30毫克（研究1）、PH-797804 30毫克和吸入性p38 MAPK抑制剂PF-03715455 20毫克（研究2）以及吸入性丙酸氟替卡松500微克（研究3）。主要终点为痰液中性粒细胞百分比。
在研究1和2中，与安慰剂相比，PH-797804使脂多糖激发后的痰液中性粒细胞百分比显著降低（分别降低15.1%和15.3%）（p分别为0.0096和0.0001），PF-03715455也使其降低（降低8.0%，p = 0.031）；丙酸氟替卡松无效果。PH-797804显著抑制了痰液上清液中炎症介质（白细胞介素-6、单核细胞趋化蛋白-1、巨噬细胞炎性蛋白1β和CC16）的增加，而PF-03715455无此作用。PH-797804和PF-03715455均抑制血浆中白细胞介素-6、单核细胞趋化蛋白-1、巨噬细胞炎性蛋白1β、CC16和C反应蛋白水平，其中PH-797804作用更强。丙酸氟替卡松对痰液上清液或血浆生物标志物无影响。
PH-７97804对中性粒细胞性气道炎症影响最大。口服p38 MAPK抑制剂可能会优化肺部抗炎效果。
