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.
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