CLINICAL TRIAL: DENUFOSOL TETRASODIUM INHALATION SOLUTION IN PATIENTS WITH MILD

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 囊性纤维化是一种隐性遗传病，以肺和鼻窦疾病以及胃肠道和生殖道功能障碍为特征。这种疾病是由囊性纤维化跨膜调节因子(CFTR)基因突变引起的，CFTR编码一种顶膜上皮蛋白，其功能是c-AMP调节的氯离子通道和其他通道的调节(Boucher，1994)。CFTR缺陷会导致离子转运异常和呼吸道表面液体容量耗尽，粘液纤毛清除减少，并有慢性呼吸道感染的倾向，从而导致炎症、进行性呼吸道损伤和支气管扩张。 基于对疾病病理生理学的洞察，正在开发治疗CF的新疗法。P2Y2受体激动剂代表了一种治疗CF的新方法，该方法试图绕过呼吸道上皮细胞中有缺陷的CFTR，而不是利用这类药物对粘液纤毛清除的综合作用，这些作用不依赖于CFTR。这些药物通过刺激P2Y2受体发挥作用，导致氯离子(Cl-)和液体的分泌，并抑制钠(Na+)的吸收，使呼吸道表面液体层水化，创造更正常的睫状液环境，同时还刺激杯状细胞的粘蛋白分泌，增加纤毛搏动频率。德努福索四钠(INS37217)吸入液是InspirrePharmPharmticals公司正在开发的新型第二代化学稳定的选择性P2Y2受体激动剂。德努福索可能有能力在CF肺部疾病过程的相对早期恢复或维持患者的粘液纤毛清除，这可能保护肺功能，减少不可避免的肺部细菌定植、肺恶化和慢性肺功能下降的重复周期。 本研究的目的是评估雾化吸入60毫克剂量的地那福索与安慰剂相比，在24周内每天三次给药对轻度慢性肺病患者的有效性、安全性和耐受性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cystic fibrosis (CF) is a recessive genetic disease, characterized by pulmonary and sinus disease, and gastrointestinal and reproductive tract dysfunction. The disease is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, which encodes for an apical membrane epithelial protein that functions as a c-AMP-regulated chloride channel and a regulator of other channels (Boucher, 1994). Defective CFTR results in abnormal ion transport and depleted airway surface liquid volume with reduced mucociliary clearance and a propensity for chronic infection of the respiratory tract with resulting inflammation, progressive airway damage and bronchiectasis. New therapies are being developed for the treatment of CF, based on insights into the pathophysiology of the disease. P2Y2 receptor agonists represent a novel approach to the treatment of CF that attempts to bypass defective CFTR in airway epithelia and, instead, take advantage of the integrated actions of this class of agents on mucociliary clearance that are not dependent on CFTR. These agents act by stimulating the P2Y2 receptor, which results in chloride ion (Cl-) and liquid secretion and the inhibition of sodium (Na+) absorption to hydrate the airway surface liquid layer and create a more normal periciliary fluid milieu,while also stimulating mucin secretion from goblet cells and increasing ciliary beat frequency. Denufosol tetrasodium (INS37217) inhalation solution (denufosol) is a novel second generation, chemically stable, selective P2Y2 receptor agonist under development by InspirePharmaceuticals, Inc. Denufosol may have the ability to restore or maintain mucociliary clearance in patients relatively early in the CF lung disease process, which may preserve lung function and lessen the inevitable repeat cycles of pulmonary bacterial colonization, pulmonary exacerbations, and chronic lung function decline. The objective of this study is evaluate the efficacy, safety and tolerability of a 60 mg nebulizer dose of denufosol compared to placebo when administered three times daily over 24 weeks in patients with mild CF lung disease.