Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial
Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial
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DOI：
10.1111/j.1365-2222.2012.04014.x
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发表时间：
2012-07-01
影响因子：
6.1
通讯作者：
Chanez, P.
中科院分区：
文献类型：
--
作者：
Nair, P.;Gaga, M.;Chanez, P.
背景：据报道，严重哮喘患者气道中中性粒细胞数量增加。目前尚不清楚它们是否导致缺乏控制和严重性。目前还没有通过减少气道中的中性粒细胞数量来研究这一点的策略。目的探讨选择性CXCR 2受体拮抗剂SCH 527123治疗重度哮喘伴痰中性粒细胞增多患者的安全性和有效性。方法采用随机、双盲、平行对照研究方法，将22例痰细胞计数< 10 × 10 6/g、中性粒细胞计数> 40%的重度哮喘患者随机分为SCH 527123组和安慰剂组，每组12例。主要终点是安全性和痰液和血液中性粒细胞计数的变化。次要终点是哮喘控制问卷（ACQ）评分、轻度和重度急性发作、肺功能测定和痰中性粒细胞活化标志物的变化。结果SCH 527123使痰液中性粒细胞百分比平均降低36.3%，而安慰剂组升高6.7%（P = 0.03）。治疗4周后，血中性粒细胞绝对计数平均下降14%，第5周恢复正常。各组间不良事件的总体发生率无差异。轻度急性加重较少（1.3 vs. 2.25，P = 0.05），ACQ评分有改善趋势（组间平均差异为0.42分，P = 0.053）。1秒用力呼气量（FEV 1）、痰液髓过氧化物酶、IL 8和弹性蛋白酶无统计学显著变化。结论SCH 527123对重度哮喘患者的痰液中性粒细胞有降低作用，且安全性好。临床相关性这种新的治疗方法提供了一个机会，以研究中性粒细胞在严重哮喘中的作用，具有潜在的临床效益。需要更长时间的大型研究来评估对哮喘其他结局（包括急性发作）的影响。
Background Increased numbers of neutrophils are reported in the airways of patients with severe asthma. It is not clear if they contribute to the lack of control and severity. There are currently no strategies to investigate this by decreasing neutrophil numbers in the airways. Objective To investigate the safety and efficacy of SCH527123, a selective CXCR2 receptor antagonist, in patients with severe asthma and increased number of neutrophils in sputum. Methods In a randomized, double-blind, parallel study, patients with severe asthma and sputum total cell count < 10 X 106/g and neutrophils > 40% were randomized to SCH527123, 30 mg daily PO (n = 22) or placebo (n = 12) for 4 weeks. Primary end-points were safety and change in sputum and blood neutrophil counts. Secondary end-points were change in asthma control questionnaire (ACQ) score, minor and major exacerbations, spirometry and sputum neutrophil activation markers. Results The SCH 527123 caused a mean reduction of 36.3% in sputum neutrophil percentage compared to a 6.7% increase in the placebo arm (P = 0.03). The mean absolute neutrophil count in blood was reduced by 14% at the end of 4 weeks, but recovered by the 5th week. There were no differences in the overall rates of adverse events among the groups. There were fewer mild exacerbations (1.3 vs. 2.25, P = 0.05) and a trend towards improvement in the ACQ score (mean difference between groups of 0.42 points, P = 0.053). No statistically significant changes were observed in forced expiratory volume in 1 s (FEV 1), sputum myeloperoxidase, IL8 or elastase. Conclusions The SCH527123 is safe and reduces sputum neutrophils in patients with severe asthma. Clinical Relevance This new treatment provides an opportunity to investigate the role of neutrophils in severe asthma with potential clinical benefits. Larger studies of longer duration are needed to evaluate the impact on other outcomes of asthma including exacerbations.