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: 9356821
• 负责人: David B. Peden
• 金额: $ 34.93万
• 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/9356821
• 关键词: Acceleration; Acute; Adherence; Adoption; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Adverse event; Agar Gel Electrophoresis; Allergens; Allergic; Animals; Asthma; Biological Assay; Biological Markers; Breathing; Bronchial Spasm; Case Study; Cholinergic Antagonists; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Clinical; Collection; Coughing; Cysteine; DNA; Dehydration; Development; Disease; Dose; Drug Kinetics; Elements; Exercise; Exhalation; Gel; Health; House Dust Mite Allergens; Hydration status; Hyperactive behavior; IgE; Impairment; In Vitro; 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; Placebo Control; Play; Publishing; Pulmonary Cystic Fibrosis; Pulmonary Function Test/Forced Expiratory Volume 1; Randomized; Recruitment Activity; 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; asthmatic; base; cystic fibrosis patients; disulfide bond; drug inhalation; healthy volunteer; improved; knowledge translation; molecular mass; novel; phase 1 study; placebo controlled study; preclinical study; pulmonary function; recombinant human DNase; 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.

摘要 项目4的重点是测试新型吸入粘液溶解化合物在哮喘患者中的安全性 （具体目的1），在轻度螨过敏性疾病急性加重的过敏原激发模型中测试这些。 哮喘（具体目的2），并检查这类化合物对粘膜纤毛清除（MCC）的作用， 在2周内接受稳定控制剂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 并在该tPPG中催化了用于哮喘的基于硫醇的粘液溶解剂的研究。最好的候选人 干预是P2176，一种二硫醇粘液溶解剂，其具有强大的降解痰样品中粘蛋白的能力， 在临床前研究中，在动物中耐受性良好，目前处于I期研究中 健康的志愿者P2176在哮喘患者中的安全性研究将是第1-2年的主要重点。在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对变应原诱导的晚期相的影响 反应，我们已经证明这与粘液分泌增加和MCC减少有关。成功 与SA 2的相关性表明粘液溶解剂在哮喘急性加重中的作用。具体目标3将审查 2周每日治疗对中度哮喘志愿者MCC的影响。如果成功，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