DMP777 IN ADULT PATIENTS 18 YRS OF AGE AND OLDER WITH CYSTIC FIBROSIS

尽管抗生素治疗和支持性护理取得了进展，但铜绿假单胞菌引起的慢性肺部感染仍然是囊性纤维化患者发病和死亡的主要原因。宿主对这种感染的反应的特点是中性粒细胞（pmn）的持续浸润，但这些细胞不能根除感染，实际上可能导致严重的组织损伤。来自PMNs的不受抑制的弹性蛋白酶的过度负担是PMNs导致CF肺损伤的机制之一。本项目建议评估一种有效的蛋白酶抑制剂DMP-777，用于治疗CF肺部疾病的潜在用途。具体目的是(1)评估多剂量DMP-777的安全性和耐受性，(2)确定多剂量口服DMP-777的药代动力学和药效学特征，以及(3)确定实现持续高水平全身中性粒细胞弹性酶抑制所需的DMP-777剂量水平。迄今为止，已筛选了5名受试者，3名受试者已完成研究。

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. The host response to this infection is characterized by presistent infiltratin of neutrophils (PMNs), but these cells fail to eradicate the infection and may actually cause significant tissue damage. An excessive burden of uninhibited elastase from PMNs is one of the proposed mechanisms whereby PMNs contribute to lung injury in CF. This project proposes to evaluate an potent protease inhibitor, DMP-777, for potential use in the treatment of CF lung disease. The specific aims are (1) to evaluate the safety and tolerability of multiple doses of DMP-777, (2) to determine the pharmacokinetic and pharmacodynamic characteristics of multiple oral doses, and (3) to define the DMP-777 dosage level necessary to achieve sustained high-level systemic neutrophil elastase inhibition. To date, 5 subjects have been screened and 3 have completed the study.