Diamant Z, Sidharta P N, Singh D, O'Connor B J, Zuiker R, Leaker B R, Silkey M, Dingemanse J
Centre for Human Drug Research, Leiden, The Netherlands.
Clin Exp Allergy. 2014 Aug;44(8):1044-52. doi: 10.1111/cea.12357.
CRTH2 is a G-protein-coupled receptor on T helper2 cells that mediates pro-inflammatory effects of prostaglandin D2 in allergic responses.
To investigate the tolerability and pharmacokinetics of setipiprant (ACT-129968), a selective orally active CRTH2 antagonist, in allergic asthmatics and to assess the protective effects of multiple doses of this drug against allergen-induced airway responses.
In this 3-centre, double-blinded, placebo-controlled, cross-over study, 18 allergic asthmatic males were randomized to setipiprant 1000 mg or matching placebo b.i.d. for 5 consecutive days. Study periods were separated by a washout of ≥ 3 weeks. On study day 4, subjects underwent a standardized allergen challenge and airway response was recorded by FEV1 until 10 h post-allergen. Airway responsiveness to methacholine and exhaled nitric oxide (eNO) were measured pre- and post-dosing. The effects of both treatments on the allergen-induced airway responses were compared by a paired Student's t-test.
Fifteen subjects completed the study per-protocol and were included in the analysis. Overall, setipiprant was well tolerated and no clinically relevant adverse events occurred. Trough plasma concentrations showed a high inter-subject variability. Compared with placebo, setipiprant significantly reduced the allergen-induced late asthmatic response (LAR), inhibiting the area under the response vs. time curve (AUC(3-10 h) ) by on average 25.6% (P = 0.006) and significantly protected against the allergen-induced airway hyperresponsiveness (AHR) to methacholine (P = 0.0029). There was no difference in the early asthmatic response (EAR) or in allergen-induced changes in eNO between treatments.
Setipiprant at multiple oral doses was well tolerated and reduced both the allergen-induced LAR and the associated AHR in allergic asthmatics. Our findings confirm that CRTH2 may be a promising target for the treatment of allergic disorders.
CRTH2是辅助性T细胞2上的一种G蛋白偶联受体，在过敏反应中介导前列腺素D2的促炎作用。
研究选择性口服活性CRTH2拮抗剂西替哌兰特（ACT-129968）在过敏性哮喘患者中的耐受性和药代动力学，并评估多次给药该药物对变应原诱导的气道反应的保护作用。
在这项3中心、双盲、安慰剂对照、交叉研究中，18名过敏性哮喘男性被随机分为接受西替哌兰特1000 mg或匹配安慰剂，每日2次，连续5天。研究周期之间间隔≥3周的洗脱期。在研究第4天，受试者接受标准化变应原激发，通过第1秒用力呼气量（FEV1）记录气道反应直至变应原激发后10小时。在给药前和给药后测量对乙酰甲胆碱的气道反应性和呼出一氧化氮（eNO）水平。通过配对t检验比较两种治疗对变应原诱导的气道反应的影响。
15名受试者按方案完成研究并纳入分析。总体而言，西替哌兰特耐受性良好，未发生临床相关不良事件。谷浓度显示受试者间差异很大。与安慰剂相比，西替哌兰特显著降低变应原诱导的迟发性哮喘反应（LAR），平均抑制反应-时间曲线下面积（AUC(3-10 h)）25.6%（P = 0.006），并显著预防变应原诱导的对乙酰甲胆碱的气道高反应性（AHR）（P = 0.0029）。治疗之间在早发性哮喘反应（EAR）或变应原诱导的eNO变化方面无差异。
多次口服西替哌兰特耐受性良好，可降低过敏性哮喘患者变应原诱导的LAR和相关AHR。我们的研究结果证实CRTH2可能是治疗过敏性疾病的一个有前景的靶点。
