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

项目 4：用新型粘液溶解剂治疗哮喘粘膜淤积和气道阻塞

• 批准号: 10001602
• 负责人: David B. Peden
• 金额: $ 34.72万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-07 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001602
• 关键词: Acceleration; Acute; Adherence; Adoption; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Adverse event; Agar Gel Electrophoresis; Airway Disease; Allergens; Allergic; Animals; Asthma; Biological; Biological Assay; Biological Markers; Bronchial Spasm; Case Study; Cholinergic Antagonists; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Clinical; Collection; Coughing; Cysteine; Cystic Fibrosis; DNA; Dehydration; Development; Dose; Drug Kinetics; Elements; Exercise; Exhalation; Gel; Health; House Dust Mite Allergens; Hydration status; Hyperactive behavior; IgE; Impairment; In Vitro; Inhalation; Interleukin-13; Interleukin-5; Intervention; Laboratories; Lung diseases; MUC5AC gene; MUC5B gene; Magnetic Resonance Imaging; Maintenance Therapy; Mass Spectrum Analysis; Measurement; Mediator of activation protein; Mites; Modeling; Monitor; Mucins; Mucociliary Clearance; Mucolytics; Mucous body substance; Mus; Obstruction; Obstructive Lung Diseases; Pathologic; Patients; Persons; Pharmaceutical Preparations; Phase; Placebos; Play; Publishing; Pulmonary Cystic Fibrosis; Pulmonary Function Test/Forced Expiratory Volume 1; Randomized; Regimen; Reporting; Research; Respiratory physiology; Rheology; Rodent Model; Role; Safety; Saline; Sampling; Screening procedure; Sheep; Sputum; Sulfhydryl Compounds; Surface; TSLP gene; Testing; Time; Toxic effect; Viscosity; Western Blotting; airway obstruction; allergic response; arm; asthma exacerbation; asthmatic; base; cystic fibrosis patients; disulfide bond; drug inhalation; healthy volunteer; improved; knowledge translation; molecular mass; mucus clearance; neutrophil; novel; phase 1 study; placebo controlled study; preclinical study; pulmonary function; recombinant human DNase; recruit; response; safety study; safety testing; success; therapy development; volunteer; week trial

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.

抽象的 项目 4 的重点是测试新型吸入性粘液溶解化合物对哮喘患者的安全性 （具体目标 1），在轻度螨过敏急性加重的过敏原激发模型中进行测试 哮喘患者（具体目标 2），并检查此类化合物对粘液纤毛清除（MCC）和 两周内接受稳定控制治疗的中度哮喘患者的肺功能（具体目标 3）。 我们小组的研究表明，S-S 键是哮喘粘液粘度增加的关键因素 并在此 tPPG 中催化了基于硫醇的粘液溶解剂治疗哮喘的研究。这方面的最佳人选 干预措施是 P2176，一种二硫醇粘液溶解剂，具有强大的能力，可以降解痰样本中的粘蛋白。 体外治疗哮喘，在临床前研究中在动物中具有良好的耐受性，目前正在进行 I 期研究 健康的志愿者。 P2176 在哮喘患者中的安全性研究将是 1-2 年的主要焦点。在第 2-5 年， 我们将开始筛查螨过敏性哮喘患者对螨过敏原的晚期反应，并开始 追求目标 2 和 3。具体目标 2 将检查 P2176 对过敏原诱导的晚期的影响 我们已经证明，这种反应与粘液分泌增加和 MCC 减少有关。成功 SA2 的结果表明粘液溶解剂在哮喘急性发作中发挥作用。具体目标 3 将检查 每天治疗 2 周对中度哮喘志愿者 MCC 的影响。如果成功的话，这项研究将 表明 P2176 在长期粘液源性哮喘患者的维持治疗中发挥作用 气道阻塞。