Abstract
We evaluated whether a chymase inhibitor, 2-(5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-[(3,4-dioxo-1-phenyl-7-(2-pyridyloxy))-2-heptyl]acetamide (NK3201), suppressed bleomycin-induced pulmonary fibrosis. Hamsters were orally administered NK3201 (30 mg/kg per day) or placebo, beginning 5 days before intratracheal instillation of bleomycin (10 mg/kg). Four weeks after the instillation of bleomycin, pulmonary chymase activity in placebo-treated hamsters was significantly higher than in control hamsters, whereas the activity in NK3201-treated hamsters was significantly lower than in placebo-treated hamsters. The ratio of fibrotic area to total area in NK3201-treated hamsters was significantly decreased to 54.0% of the ratio in placebo-treated hamsters. Therefore, NK3201 may be useful in the prevention of pulmonary fibrosis.
Copyright 2004 Elsevier B.V.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetamides / administration & dosage
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Acetamides / pharmacokinetics*
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Acetamides / therapeutic use
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Administration, Oral
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Animals
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Bleomycin / adverse effects*
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Chymases
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Collagen Type III / drug effects
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Collagen Type III / genetics
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Cricetinae
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Drug Evaluation, Preclinical / methods
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / pharmacokinetics*
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Enzyme Inhibitors / therapeutic use
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Japan
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Lung / chemistry
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Lung / drug effects
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Lung / enzymology
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Male
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Pulmonary Fibrosis / chemically induced*
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Pulmonary Fibrosis / pathology
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Pulmonary Fibrosis / prevention & control
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Pyrimidines / administration & dosage
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Pyrimidines / pharmacokinetics*
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Pyrimidines / therapeutic use
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RNA, Messenger / chemistry
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RNA, Messenger / drug effects
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RNA, Messenger / genetics
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Serine Endopeptidases / chemistry
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Serine Endopeptidases / drug effects*
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Tissue Extracts / chemistry
Substances
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Acetamides
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Collagen Type III
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Enzyme Inhibitors
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NK3201
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Pyrimidines
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RNA, Messenger
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Tissue Extracts
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Bleomycin
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Serine Endopeptidases
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Chymases