Cystic fibrosis, a common genetic disorder, is characterized by abnormally thick mucous secretions in the respiratory and gastrointestinal tracts. Respiratory symptoms predominate and are due to chronic infection, inflammation of the airways, and progressive deterioration of lung function. The secretion of thick mucous in the lungs underlies the chronic infection and inflammation, and these processes result in recruitment of large numbers of white cells into the airway. These cells then release a large amount of an enzyme called elastase, which mediates airway damage directly and also recruits still more white cells and stimulates further mucous production. Alpha-1 antitrypsin (AAT) is a naturally occurring substance which inactivates elastase. Patients with cystic fibrosis have normal concentrations of AAT, but this compound is overwhelmed by the huge amount of neutrophil elastase present in the lungs. A form of AAT has been produced from transgenic sheep, and is designated tg-hAAT, and is identical to naturally occurring AAT with the exception of some slight modifications of sugar molecules attached to AAT. Previous studies have shown that AAT can reduce bronchoalveolar lavage fluid (BALF) elastase concentrations in patients with cystic fibrosis. In this phase II randomized, double-blind, placebo-controlled study, tg-hAAT will be administered to patients with cystic fibrosis via a nebulizer. Two different dose levels will be evaluated over a period of nine weeks. Bronchoalveolar lavage, designed to obtain fluid from the lungs to measure elastase levels and AAT levels, will be performed in the GCRC Research Endoscopy suites. The drug will then be administered (or the placebo) by a nebulizer and a second bronchoalveolar lavage will be done twenty-eight days later. The study assessments include the collection of lung fluid for the measurement of tg-hAAT, total AAT, and biological markers of disease activity.
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