Our aim was to determine whether ifetroban, a TP receptor antagonist, attenuates aspirin-induced respiratory symptoms in patients with AERD.
A total of 35 patients with AERD completed a 4-week double-blinded, placebo-controlled trial of ifetroban and underwent an oral aspirin challenge. The primary outcome was change in the provocative dose of aspirin that caused a 2-point increase in Total Nasal Symptom Score. Changes in lung function, eicosanoid levels, and platelet and mast cell activation were assessed. Cultured human nasal fibroblasts were stimulated with or without the TP agonist U46619 and assayed for prostanoid production.
Ifetroban was well tolerated in AERD and did not change the mean 2-point increase in Total Nasal Symptom Score (P = .763). Participants taking ifetroban had greater aspirin-induced nasal symptoms and a greater decline in FEV1 value than did participants receiving placebo (-18.8% ± 3.6% with ifetroban vs -8.4% ± 2.1% with placebo [P = .017]). Four weeks of ifetroban significantly increased urinary leukotriene E4 levels and decreased nasal PGE2 levels compared with placebo. Peak aspirin-induced urinary thromboxane levels correlated with peak urinary leukotriene E4 and prostaglandin D2 metabolite levels in participants taking ifetroban. U46119 significantly potentiated the production of PGE2 by cultured nasal fibroblasts from subjects with AERD but not by cultured nasal fibroblasts from controls without polypoid sinusitis.
Contrary to our hypothesis, TP receptor blockade worsened aspirin-induced reactions in AERD, possibly by exacerbating dysregulation of the eicosanoid system. TP signaling on stromal cells may be critical to maintaining PGE2 production when COX-2 function is low.
目的:确定伊非曲班,TP受体拮抗剂,减轻阿司匹林引起的AERD患者的呼吸道症状。
方法:35例AERD患者完成了为期4周的双盲,ifetroban的安慰剂对照试验,并接受了口服阿司匹林的挑战。主要结果是阿司匹林的挑衅性剂量的变化,使总鼻部症状评分(TNSS)增加2分(PD2)。肺功能的变化,类花生酸,评估血小板和肥大细胞活化。用或不用TP激动剂U46619刺激培养的人鼻成纤维细胞,并测定前列腺素的产生。
结果:伊非曲班在AERD中具有良好的耐受性,并且没有改变平均PD2(P=0.763)。与安慰剂相比,使用伊非曲班的参与者具有更大的阿司匹林诱导的鼻部症状和FEV1下降更大(-18.8%±3.6%伊非曲班vs-8.4%±2.1%安慰剂;P=0.017)。与安慰剂相比,ifetroban的四周显着增加了尿白三烯E4,并降低了鼻PGE2。阿司匹林诱导的尿血栓素峰值水平与伊非曲班参与者的尿白三烯E4和PGD2代谢物峰值水平相关。U46119通过培养的AERD受试者的鼻成纤维细胞显着增强了PGE2的产生,但不是来自非息肉样鼻窦炎的控制。
结论:与我们的假设相反,TP受体阻滞剂使阿司匹林诱导的AERD反应恶化,可能是通过加剧类花生酸系统的失调。当环加氧酶-2功能低时,基质细胞上的TP信号传导对于维持PGE2产生可能是关键的。
结论:在AERD患者中使用伊非曲班抑制TP具有良好的耐受性,但可能会加重阿司匹林诱导的反应,可能是由于伊非曲班对PGE2的抑制和半胱氨酰白三烯的增加。