Project 4: Treatment of mucostasis and airways obstruction in asthma with a novel mucolytic

摘要 项目4的重点是测试新型吸入粘液化合物对哮喘患者的安全性。 (特定目标1)，在轻度粉尘过敏急性加重的过敏原激发模型中测试这些 哮喘患者(特定目标2)，并检测此类化合物对粘液纤毛清除(MCC)和 中度哮喘患者稳定控制治疗2周后的肺功能(特定目标3)。 我们课题组的研究表明，S-S键是哮喘粘液粘度增加的关键因素 并在该tPPG中催化了基于硫醇的哮喘粘解剂的研究。最好的人选是 干预措施是P2176，一种二硫醇粘液剂，它具有很强的降解痰样本中粘蛋白的能力 体外哮喘患者，在动物体内的临床前研究中耐受性良好，目前处于I期研究 一群健康的志愿者。P2176在哮喘患者中的安全性研究将是1-2年内的主要焦点。在2-5年级， 我们将开始筛查粉尘过敏哮喘患者对粉尘变应原的晚期反应性，并开始 追求目标2和目标3。具体目标2将检查P2176对过敏原诱导的晚期阶段的影响 我们已经表明，反应与粘液分泌增加和微血管密度降低有关。成功 SA2可能提示粘液类药物在哮喘急性加重中的作用。《特定目标3》将考察 每日治疗2周对中度哮喘患者微循环的影响。如果成功，这项研究将 提示P2176在长期粘液性哮喘患者的维持治疗中有一定作用 呼吸道阻塞。

Abstract Project 4 is focused on testing the safety of novel inhaled mucolytic compounds in persons with asthma (specific aim 1), testing these in an allergen challenge model of acute exacerbation in mild mite allergic asthmatics (specific aim 2), and examining the effect of such compounds on mucociliary clearance (MCC) and lung function in moderate asthmatics on stable controller therapy over a 2-week period (specific aim 3). Studies from our group indicate that S-S bonds are a key element in increased viscosity of mucus in asthma and have catalyzed the study of thiol based mucolytics for asthma in this tPPG. The best candidate for this intervention is P2176, a di-thiol mucolytic which has robust ability to degrade mucins in sputum samples from asthmatics in vitro, has been well tolerated in animals in pre-clinical studies, and is currently in Phase I studies of healthy volunteers. Safety studies of P2176 in asthmatics will be the major focus in years 1-2. In years 2-5, we will begin to screen mite-allergic asthmatics for late phase responsiveness to mite allergen, and begin to pursue aims 2 and 3. Specific Aim 2 will examine the effect of P2176 on an allergen-induced late phase response, which we have shown is associated with increased mucus secretion and decreased MCC. Success with SA2 would suggest a role for mucolytics in acute exacerbation of asthma. Specific Aim 3 will examine the effect of 2 weeks daily treatment on MCC in volunteers with moderate asthma. If successful, this study would indicate the P2176 has a role in maintenance therapy for asthma in persons with long term mucus-derived airway obstruction.