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，但铜绿假单胞菌的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的特征是中性粒细胞（PMN）的持续浸润，但这些细胞不能根除感染，实际上可能导致显著的组织损伤。 虽然这种过度炎症过程的有害影响的广泛认识，导致抗炎药，如泼尼松和布洛芬的多中心试验，对中性粒细胞的有害产物的更直接的攻击也可能是必要的。中性粒细胞释放的弹性蛋白酶过多是导致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中的气道。 当正常存在于肺中的蛋白酶抑制剂的抑制能力被CF肺中PMN弹性蛋白酶的过度负荷超过时，存在未抑制的弹性蛋白酶。 这导致蛋白酶-抗蛋白酶系统的不平衡。 通过外源性蛋白酶抑制剂抑制活性弹性蛋白酶来恢复正常的蛋白酶-抗蛋白酶平衡，可能会减少CF肺中PMN引起的肺损伤。本研究的主要目的是评估囊性纤维化（CF）成人患者口服DMP 777 14天后支气管肺泡灌洗液中细胞外人中性粒细胞弹性蛋白酶（HNE）抑制活性的大小，以将该效应与任何观察到的细胞外HNE活性变化相关联。具有全身药代动力学（PK）和药效学（PD）数据的BAL液中HNE活性，并对777的安全性进行评价。

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.