LUNG SPECIFIC BIOEFFICACY OF ORAL DMP 777 IN ADULTS W/ CF

尽管在抗生素治疗和支持治疗方面取得了进展，但铜绿假单胞菌慢性肺部感染仍然是囊性纤维化(CF)发病率和死亡率的主要原因。宿主对这种感染的反应以中性粒细胞(PMN)的持续渗透为特征，但这些细胞无法根除感染，实际上可能会造成重大的组织损伤。尽管人们普遍认识到这种过度炎症过程的有害影响，导致了泼尼松和布洛芬等抗炎药的多中心试验，但也可能有理由对PMN的有害产品进行更直接的攻击。中性粒细胞释放过多的无抑制弹性蛋白酶是中性粒细胞参与CF肺损伤的机制之一。不受抑制的弹性蛋白酶改变局部宿主防御，促进粘液分泌，并直接损害CF的呼吸道。当肺中正常存在的蛋白酶抑制剂的抑制能力被CF肺中PMN弹性酶的过度负荷所超过时，就存在未抑制的弹性蛋白酶。这导致了蛋白水解酶-抗蛋白酶系统的不平衡。应用外源性蛋白水解酶抑制剂抑制弹性蛋白酶活性，恢复正常的蛋白水解酶-抗蛋白水解酶平衡，可减轻中性粒细胞对肺组织的损伤。本研究的主要目的是评估口服DMP 777 14天后成人囊性纤维化(CF)患者支气管肺泡灌洗液中人中性粒细胞弹性酶(HNE)抑制活性的大小，并结合全身药代动力学(PK)和药效学(PD)数据，将这种影响与BAL液中观察到的细胞外HNE活性的变化相关联，并评价DMP 777的安全性。

Despite advances in antibiotic therapy and supportive care, chronic pulmonary infection with Pseudomonas aeruginosa continues to be the major cause of morbidity and mortality in cystic fibrosis (CF). The host response to this infection is characterized by persistent infiltration of neutrophils (PMNs), but these cells fail to eradicate the infection and may actually cause significant tissue damage. Although widespread recognition of the deleterious effects of this excessive inflammatory process has led to multicenter trials of anti-inflammatory agents such as prednisone and ibuprofen, a more direct assault on the injurious products of PMNs may also be warranted. An excessive burden of uninhibited elastase from PMNs is one of the proposed mechanisms whereby PMNs contribute to lung injury in CF. Uninhibited elastase alters local host defenses, promotes mucous secretion, and directly damages airways in CF. Uninhibited elastase is present when the inhibitory capacity of protease inhibitors normally present in the lung, is exceeded by the excessive burden of PMN elastase in the CF lung. This results in an imbalance in the protease-antiprotease system. Restoring the normal protease-antiprotease balance by inhibiting active elastase with exogenously administered protease inhibitors may reduce the lung damage caused by PMNs in the CF lung. The primary objectives of this study are to assess the magnitude of extracellular human neutrophil elastase (HNE) inhibitory activity in bronchoalveolar lavage fluid following 14 days of oral DMP 777 administration in adult patients with cystic fibrosis (CF), to correlate this effect with any observed changes in extracellular HNE activity in BAL fluid with systemic pharmacokinetic (PK) and pharmacodynamic (PD) data, and evaluate the safety of DMP 777.