Respiratory Medicine, Barts and the London NHS Trust, London, UK.
Clin Exp Allergy. 2012 Jan;42(1):38-48. doi: 10.1111/j.1365-2222.2011.03813.x. Epub 2011 Jul 15.
CRTH2 is a G-protein-coupled receptor that mediates the activation of Th2 lymphocytes, eosinophils and basophils in response to prostaglandin D(2) and may be involved in the pathogenesis of airway inflammation and dysfunction in asthma.
To evaluate the effects of a potent and selective CRTH2 antagonist, OC000459, on the lung function, symptoms and eosinophilic airway inflammation in a double-blind, parallel group trial in steroid-free subjects with moderate persistent asthma.
Adult subjects were randomized to oral OC000459 200 mg twice daily (N=65) or a placebo (N=67) for 28 days. The primary end-point was the change from baseline in pre-bronchodilator forced expiratory volume in 1 s (FEV(1) ); eosinophilic airway inflammation was assessed by induced sputum differential eosinophil count. The trial was registered on the clinicaltrials.gov database (Identifier NCT01057927).
Data were analysed for both the Full Analysis (FA) population and the Per Protocol (PP) population (55 treated with OC000459 and 52 with placebo), which excluded non-compliant subjects. In the FA population, the mean change in FEV(1) was 7.1% on OC000459 compared with 4.3% on placebo (not significant); in the PP population, the mean changes were 9.2% and 1.8%, respectively (P=0.037). Improvement in quality of life was apparent in both FA and PP populations [difference from the placebo in AQLQ(S) total score of 0.29, P=0.0113 and 0.37, P=0.0022, respectively]. OC000459 also improved the night-time symptom scores (mean reduction of 0.36 vs. 0.11, P=0.008, FA population; 0.37 vs. 0.12, P=0.022, PP population). The geometric mean sputum eosinophil count reduced from 2.1% to 0.7% (P=0.03) after OC000459, but this effect was not significant when compared with the change on placebo (P=0.37). Adverse events on OC000459 were comparable to those on placebo; respiratory infections were notably less common during OC000459 than the placebo treatment.
This study provides the first clinical evidence that CRTH2 receptors contribute to airflow limitation, symptoms and eosinophilic airway inflammation in asthma. OC000459 shows promise as a novel oral treatment for asthma and related disorders.
CRTH2 是一种 G 蛋白偶联受体，介导前列腺素 D2 激活 Th2 淋巴细胞、嗜酸性粒细胞和嗜碱性粒细胞，可能参与哮喘气道炎症和功能障碍的发病机制。
在接受类固醇治疗的中度持续性哮喘患者中，评估一种强效和选择性 CRTH2 拮抗剂 OC000459 对肺功能、症状和嗜酸性粒细胞性气道炎症的影响，采用双盲、平行分组试验。
成年患者随机接受口服 OC000459 200mg，每日 2 次（n=65）或安慰剂（n=67）治疗 28 天。主要终点是支气管扩张剂前用力呼气 1 秒量（FEV1）的基线变化；诱导痰嗜酸性粒细胞计数评估嗜酸性粒细胞性气道炎症。该试验在 clinicaltrials.gov 数据库中注册（标识符 NCT01057927）。
对全分析（FA）人群和协议（PP）人群（OC000459 治疗 55 例，安慰剂治疗 52 例）均进行了数据分析，排除了不依从的患者。在 FA 人群中，OC000459 组 FEV1 的平均变化为 7.1%，安慰剂组为 4.3%（无显著差异）；在 PP 人群中，平均变化分别为 9.2%和 1.8%（P=0.037）。在 FA 和 PP 人群中，生活质量的改善均很明显[与安慰剂相比，AQLQ（S）总分分别改善 0.29（P=0.0113）和 0.37（P=0.0022）]。OC000459 还改善了夜间症状评分（FA 人群中平均减少 0.36 比 0.11，P=0.008；PP 人群中平均减少 0.37 比 0.12，P=0.022）。OC000459 治疗后，痰嗜酸性粒细胞计数的几何均数从 2.1%降至 0.7%（P=0.03），但与安慰剂相比，差异无统计学意义（P=0.37）。OC000459 的不良反应与安慰剂相当；OC000459 治疗期间，呼吸道感染明显少于安慰剂治疗。
本研究首次提供了临床证据，表明 CRTH2 受体参与哮喘的气流受限、症状和嗜酸性粒细胞性气道炎症。OC000459 作为一种新型哮喘和相关疾病的口服治疗药物具有良好的应用前景。
