Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Am J Respir Crit Care Med. 2010 Mar 1;181(5):438-45. doi: 10.1164/rccm.200909-1415OC. Epub 2009 Dec 10.
Epidermal growth factor receptor (EGFR) activation is implicated in mucin hypersecretion in chronic obstructive pulmonary disease (COPD).
To investigate the safety and efficacy of an inhaled EGFR antagonist (BIBW 2948) in COPD.
Multicenter, double-blind, placebo-controlled trial of 4 weeks of treatment with two doses of BIBW 2948 (15 and 30 mg twice a day) on safety and mucin-related outcomes in 48 patients with COPD. The effect of BIBW 2948 on EGFR activation in airway epithelial cells was assessed using an ex vivo assay. Efficacy measures included the volume of mucin in the airway epithelium (Vs mu,bala) in bronchial biopsies and the expression of mucin genes in bronchial brushings.
Inhaled BIBW 2948 induced a dose-related inhibition of EGFR internalization (reflecting decreased EGFR activation) in epithelial cells from treated subjects. However, BIBW 2948 was associated with a dose-related increase in adverse events, including reversible liver enzyme elevation (n = 2), and reduction in FEV(1). The changes in mucin stores and mucin gene expression were not significantly different in the pooled BIBW 2948 group versus placebo (volume of mucin per surface area of basal lamina = 0.22 +/- 7.11 vs. 0.47 +/- 8.06 microm(3)/microm(2); P = 0.93). However, in the 30 mg twice a day group, the reduction in epithelial mucin stores was greatest in subjects with the greatest degree of EGFR inhibition (Pearson r = 0.98; 95% confidence interval, 0.71-0.99).
Four-week treatment with BIBW 2948 did not significantly decrease epithelial mucin stores and was poorly tolerated in patients with COPD. Ex vivo analyses suggest that higher doses may be more effective at both EGFR inhibition and decreases in mucin stores but that adverse events should be expected. Clinical trial registered with www.clinicaltrials.gov (NCT00423137).
表皮生长因子受体（EGFR）的激活与慢性阻塞性肺疾病（COPD）中的粘蛋白过度分泌有关。
研究吸入型 EGFR 拮抗剂（BIBW 2948）治疗 COPD 的安全性和疗效。
采用多中心、双盲、安慰剂对照试验，对 48 例 COPD 患者进行为期 4 周的治疗，共使用两种剂量的 BIBW 2948（每日两次，15 和 30mg），评估安全性和粘蛋白相关结果。采用离体试验评估 BIBW 2948 对气道上皮细胞中 EGFR 激活的影响。疗效指标包括支气管活检中气道上皮粘蛋白含量（Vs mu,bala）和支气管刷检中粘蛋白基因的表达。
吸入 BIBW 2948 可使治疗组上皮细胞中的 EGFR 内化呈剂量依赖性抑制（反映 EGFR 激活减少）。然而，BIBW 2948 与剂量相关的不良反应增加相关，包括可逆性肝酶升高（n=2）和 FEV1 下降。与安慰剂相比，联合 BIBW 2948 组的粘蛋白储存和粘蛋白基因表达变化无显著差异（基底膜表面积的粘蛋白体积=0.22+/-7.11 vs. 0.47+/-8.06 µm3/µm2；P=0.93）。然而，在每日两次 30mg 组中，上皮粘蛋白储存的减少在 EGFR 抑制程度最大的患者中最为显著（Pearson r=0.98；95%置信区间，0.71-0.99）。
4 周的 BIBW 2948 治疗并未显著减少上皮粘蛋白储存，且在 COPD 患者中耐受性差。离体分析表明，更高剂量在抑制 EGFR 和减少粘蛋白储存方面可能更有效，但应预期会出现不良反应。临床试验已在 www.clinicaltrials.gov 注册（NCT00423137）。
