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Intratracheal (i.t.) or intravenous (i.v.) administration of FR901451, a potent inhibitor of human leukocyte elastase (HLE) prevented HLE-induced lung hemorrhage in hamsters with ED50 values of 10.5 micrograms/site and 8.1 mg/kg, respectively. alpha 1-Antitrypsin (alpha 1-AT) also showed inhibitory effect in this model. However, the ED50 value by i.t. injection of FR901451 was 20-fold lower than that of alpha 1-AT. Moreover, FR901451 i.t. significantly modulated porcine pancreas elastase (PPE)-induced changes of the respiratory mechanics in hamsters. The ED50 values were 529 micrograms/site and 244 micrograms/site, which were expressed by static lung compliance (Cst) and vital capacity (VC) of the lungs, respectively. These results suggest that FR901451 could be clinically useful agent for the treatment of the destructive lung disease such as pulmonary emphysema.

FR 901451, a novel inhibitor of human leukocyte elastase from Flexibacter sp. II. Pharmacological effect of FR 901451.