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Abstract：
Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, recurrent nasal polyposis, and respiratory reactions on ingestion of COX-1 inhibitors. Increased numbers of platelet-leukocyte aggregates are present in the sinus tissue and blood of patients with AERD compared with that of aspirin-tolerant patients, and platelet activation can contribute to aspirin-induced reactions.
We sought to determine whether treatment with prasugrel, which inhibits platelet activation by blocking the type 12 purinergic (P2Y12) receptor, would attenuate the severity of sinonasal and respiratory symptoms induced during aspirin challenge in patients with AERD.
Forty patients with AERD completed a 10-week, double-blind, placebo-controlled crossover trial of prasugrel. All patients underwent oral aspirin challenges after 4 weeks of prasugrel and after 4 weeks of placebo. The primary outcome was a change in the provocative dose of aspirin that would elicit an increase in Total Nasal Symptom Score (TNSS) of 2 points. Changes in lung function, urinary eicosanoids, plasma tryptase, platelet-leukocyte aggregates, and platelet activation were also recorded.
Prasugrel did not significantly change the mean increase in TNSS of 2 points (79 ± 15 for patients receiving placebo and 139 ± 32 for patients receiving prasugrel, P = .10), platelet-leukocyte aggregates, or increases in urinary leukotriene E4 and prostaglandin D2 metabolite levels during aspirin-induced reactions in the study population as a whole. Five subjects (responders) reacted to aspirin while receiving placebo but did not have any reaction to aspirin challenge after the prasugrel arm. In contrast to prasugrel nonresponders (35 subjects), the prasugrel responders had smaller reaction-induced increases in TNSS; did not have significant aspirin-induced increases in urinary leukotriene E4, prostaglandin D2 metabolite, or thromboxane B2 levels; and did not display increases in serum tryptase levels during aspirin reactions on the placebo arm, all of which were observed in the nonresponders.
In the overall study population, prasugrel did not attenuate aspirin-induced symptoms, possibly because it failed to decrease the frequencies of platelet-adherent leukocytes or to diminish aspirin-induced mast cell activation. In a small subset of patients with AERD who had greater baseline platelet activation and milder upper respiratory symptoms during aspirin-induced reactions, P2Y12 receptor antagonism with prasugrel completely inhibited all aspirin-induced reaction symptoms, suggesting a contribution from P2Y12 receptor signaling in this subset.
We sought to determine whether treatment with prasugrel, which inhibits platelet activation by blocking the type 12 purinergic (P2Y12) receptor, would attenuate the severity of sinonasal and respiratory symptoms induced during aspirin challenge in patients with AERD.
Forty patients with AERD completed a 10-week, double-blind, placebo-controlled crossover trial of prasugrel. All patients underwent oral aspirin challenges after 4 weeks of prasugrel and after 4 weeks of placebo. The primary outcome was a change in the provocative dose of aspirin that would elicit an increase in Total Nasal Symptom Score (TNSS) of 2 points. Changes in lung function, urinary eicosanoids, plasma tryptase, platelet-leukocyte aggregates, and platelet activation were also recorded.
Prasugrel did not significantly change the mean increase in TNSS of 2 points (79 ± 15 for patients receiving placebo and 139 ± 32 for patients receiving prasugrel, P = .10), platelet-leukocyte aggregates, or increases in urinary leukotriene E4 and prostaglandin D2 metabolite levels during aspirin-induced reactions in the study population as a whole. Five subjects (responders) reacted to aspirin while receiving placebo but did not have any reaction to aspirin challenge after the prasugrel arm. In contrast to prasugrel nonresponders (35 subjects), the prasugrel responders had smaller reaction-induced increases in TNSS; did not have significant aspirin-induced increases in urinary leukotriene E4, prostaglandin D2 metabolite, or thromboxane B2 levels; and did not display increases in serum tryptase levels during aspirin reactions on the placebo arm, all of which were observed in the nonresponders.
In the overall study population, prasugrel did not attenuate aspirin-induced symptoms, possibly because it failed to decrease the frequencies of platelet-adherent leukocytes or to diminish aspirin-induced mast cell activation. In a small subset of patients with AERD who had greater baseline platelet activation and milder upper respiratory symptoms during aspirin-induced reactions, P2Y12 receptor antagonism with prasugrel completely inhibited all aspirin-induced reaction symptoms, suggesting a contribution from P2Y12 receptor signaling in this subset.
摘要：
阿司匹林加剧的呼吸系统疾病（AERD）的特征是哮喘，复发性鼻息肉,和摄入COX-1抑制剂时的呼吸反应。与阿司匹林耐受患者相比，AERD患者的窦组织和血液中血小板-白细胞聚集体数量增加，血小板活化可导致阿司匹林诱导的反应。
我们试图确定是否用普拉格雷治疗，通过阻断12型嘌呤能（P2Y12）受体来抑制血小板活化，将减轻AERD患者在阿司匹林激发期间引起的鼻窦和呼吸道症状的严重程度。
40名AERD患者完成了为期10周，双盲,普拉格雷的安慰剂对照交叉试验。所有患者在普拉格雷4周后和安慰剂4周后接受口服阿司匹林挑战。主要结果是阿司匹林的激发剂量的变化，这将导致鼻部总症状评分（TNSS）增加2分。肺功能的变化，尿类二十烷酸，血浆类胰蛋白酶,血小板-白细胞聚集体，并记录血小板活化情况.
普拉格雷没有显着改变2分的TNSS平均增加（接受安慰剂的患者为79±15，接受普拉格雷的患者为139±32，P=.10)，血小板-白细胞聚集体，或增加尿白三烯E4和前列腺素D2代谢物水平在阿司匹林诱导的反应在整个研究人群。五名受试者（反应者）在接受安慰剂时对阿司匹林有反应，但在普拉格雷臂后对阿司匹林攻击没有任何反应。与普拉格雷无应答者(35名受试者)相反，普拉格雷反应者有较小的反应诱导的TNSS增加;没有显著的阿司匹林诱导的尿白三烯E4，前列腺素D2代谢物的增加，或血栓素B2水平;并且在安慰剂组的阿司匹林反应期间没有显示血清类胰蛋白酶水平的增加，所有这些都在无应答者中观察到。
在整个研究人群中，普拉格雷没有减轻阿司匹林诱导的症状，可能是因为它不能降低血小板粘附白细胞的频率或减少阿司匹林诱导的肥大细胞活化。在一小部分AERD患者中，在阿司匹林诱导的反应期间，基线血小板活化较高，上呼吸道症状较轻，P2Y12受体拮抗与普拉格雷完全抑制所有阿司匹林诱导的反应症状，表明P2Y12受体信号在该子集中的作用。
我们试图确定是否用普拉格雷治疗，通过阻断12型嘌呤能（P2Y12）受体来抑制血小板活化，将减轻AERD患者在阿司匹林激发期间引起的鼻窦和呼吸道症状的严重程度。
40名AERD患者完成了为期10周，双盲,普拉格雷的安慰剂对照交叉试验。所有患者在普拉格雷4周后和安慰剂4周后接受口服阿司匹林挑战。主要结果是阿司匹林的激发剂量的变化，这将导致鼻部总症状评分（TNSS）增加2分。肺功能的变化，尿类二十烷酸，血浆类胰蛋白酶,血小板-白细胞聚集体，并记录血小板活化情况.
普拉格雷没有显着改变2分的TNSS平均增加（接受安慰剂的患者为79±15，接受普拉格雷的患者为139±32，P=.10)，血小板-白细胞聚集体，或增加尿白三烯E4和前列腺素D2代谢物水平在阿司匹林诱导的反应在整个研究人群。五名受试者（反应者）在接受安慰剂时对阿司匹林有反应，但在普拉格雷臂后对阿司匹林攻击没有任何反应。与普拉格雷无应答者(35名受试者)相反，普拉格雷反应者有较小的反应诱导的TNSS增加;没有显著的阿司匹林诱导的尿白三烯E4，前列腺素D2代谢物的增加，或血栓素B2水平;并且在安慰剂组的阿司匹林反应期间没有显示血清类胰蛋白酶水平的增加，所有这些都在无应答者中观察到。
在整个研究人群中，普拉格雷没有减轻阿司匹林诱导的症状，可能是因为它不能降低血小板粘附白细胞的频率或减少阿司匹林诱导的肥大细胞活化。在一小部分AERD患者中，在阿司匹林诱导的反应期间，基线血小板活化较高，上呼吸道症状较轻，P2Y12受体拮抗与普拉格雷完全抑制所有阿司匹林诱导的反应症状，表明P2Y12受体信号在该子集中的作用。
