引用

急性呼吸窘迫综合征(ARDS)与肺血管通透性增加有关。在肺中，瞬时受体电位香草素4 (TRPV4)是一个Ca2+通透性阳离子通道，是内皮通透性和肺水肿的调节因子。我们进行了一项I期、安慰剂对照、双盲、随机、平行组的机制证明研究，利用脂多糖(LPS)诱导的肺炎症模型，研究TRPV4通道阻阻剂GSK2798745对肺-血管屏障通透性的影响。健康受试者随机1:1接受2剂GSK2798745或安慰剂，间隔12小时。第一剂后两小时，参与者接受支气管镜检查和节段性LPS灌注。测量LPS攻毒前和攻毒后24小时采集的支气管肺泡灌洗(BAL)样品中的总蛋白浓度和中性粒细胞计数，分别作为屏障通透性和炎症的标记物。主要终点为LPS刺激后24小时BAL中基线调整的总蛋白浓度。使用贝叶斯框架来估计任何百分比减少的后验概率(GSK2798745相对于安慰剂)。安全性终点包括不良事件发生率、生命体征、12导联心电图、临床实验室和血液学评估以及肺活量测定。47名受试者服用了药物，其中45人完成了研究(22人服用了GSK2798745, 23人服用了安慰剂)。 Overall, GSK2798745 was well tolerated. Small reductions in mean baseline adjusted BAL total protein (~9%) and neutrophils (~7%) in the LPS-challenged segment were observed in the GSK2798745 group compared with the placebo group; however, the reductions did not meet pre-specified success criteria of at least a 95% posterior probability that the percentage reduction in the mean 24-h post LPS BAL total protein level (GSK2798745 relative to placebo) exceeded zero. Median plasma concentrations of GSK2798745 were predicted to inhibit TRPV4 on lung vascular endothelial cells by ~70-85% during the 24 h after LPS challenge; median urea-corrected BAL concentrations of GSK2798745 were 3.0- to 8.7-fold higher than those in plasma. GSK2798745 did not affect segmental LPS-induced elevation of BAL total protein or neutrophils, despite blood and lung exposures that were predicted to be efficacious. CLINICALTRIALS. NCT03511105.