Effect of a single dose of the selectin inhibitor TBC1269 on early and late asthmatic responses
Effect of a single dose of the selectin inhibitor TBC1269 on early and late asthmatic responses
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DOI：
10.1111/j.1365-2222.2004.01831.x
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发表时间：
2004-01-01
影响因子：
6.1
通讯作者：
Fahy, JV
中科院分区：
文献类型：
--
作者：
Avila, PC;Boushey, HA;Fahy, JV
背景选择素参与白细胞从循环向炎症组织迁移的初始阶段，并可能在哮喘中炎症细胞流入气道中发挥作用。在羊哮喘模型中，TBC1269，一种泛选择素拮抗剂，将晚期过敏原反应降低了74%。目的探讨单剂量TBC1269是否能抑制支气管扩张剂治疗的特应性哮喘患者的早期（EAR）和晚期（LAR）哮喘反应，以及是否能抑制吸入过敏原攻击后的痰白细胞内流。方法21例哮喘患者（平均+/-SD，年龄=32.5+/-6.7岁，男性8名，预测FEV1 % =84+/-15%）根据筛查吸入过敏原攻击已知晚期哮喘反应，随机分配接受安慰剂（n=11）或TBC1269 （n=10, 30 mg/kg）静脉注射治疗，在筛查过敏原攻击后至少4周立即进行第二次（治疗后）过敏原攻击前15分钟注射。每次激射后监测EAR和LAR 7 h，并在每次激射前1天和后1天诱导痰液。结果与安慰剂组相比，TBC1269没有减弱EAR（1小时内FEV1最大下降为34.1+/-13.9%，TBC1269组和安慰剂组分别为31.8+/-12.2%，P=0.61）或LAR（3 - 7小时FEV1最大下降为39.3+/-15.3%，TBC1269组和安慰剂组分别为32.6+/-13.8%，P=0.24）。TBC1269对过敏原诱导的痰嗜酸性粒细胞增多仅有轻微影响。结论：在过敏原攻击前单次静脉给药TBC1269不会减弱哮喘受试者对过敏原的早期或晚期哮喘反应。
Background Selectins participate in the initial phase of leucocyte migration from circulation to inflamed tissues and may play a role in inflammatory cellular influx into airways in asthma. In the sheep asthma model, TBC1269, a pan-selectin antagonist, reduced late allergen response by 74%.Objective To determine whether a single dose of TBC1269 inhibits early (EAR) and late (LAR) asthmatic responses, and whether it inhibits sputum leucocyte influx after inhalation allergen challenge in atopic asthmatic subjects treated with bronchodilators only.Methods Twenty-one asthmatic subjects (mean+/-SD, age=32.5+/-6.7 years, 8 males, FEV1 percent predicted=84+/-15%) with known late asthmatic response based on a screening inhalation allergen challenge were randomly assigned to receive intravenous treatment with either placebo (n=11) or TBC1269 (n=10, 30 mg/kg) infused over 15 min immediately prior to a second (post-treatment) allergen challenge at least 4 weeks after the screening challenge. After each challenge, EAR and LAR were monitored for 7 h. In addition, sputum was induced 1 day before and 1 day after each allergen challenge.Results TBC1269 did not attenuate the EAR compared with placebo (largest fall in FEV1 within 1 h of 34.1+/-13.9% vs. 31.8+/-12.2% for TBC1269 and placebo groups respectively, P=0.61) or the LAR (largest fall in FEV1 between 3 and 7 h of 39.3+/-15.3% vs. 32.6+/-13.8%, P=0.24). TBC1269 had only minor effects on allergen-induced sputum eosinophilia.Conclusion We conclude that TBC1269 administered before allergen challenge as a single intravenous dose does not attenuate early or late asthmatic responses to allergen in asthmatic subjects.