The
cysteine pro-drug Z2196 ((2RS, 4R)-2-methylthiazolidine
carboxylic acid) and two drugs with methyl
esters attached to
Z2196 (
Z2197 and
Z2199) were evaluated for antifibrotic effects in the hamster
bleomycin model of lung
fibrosis. Each
drug or
phosphate-buffered saline (PBS) was given daily (300 mg/kg intraperitoneally) for 2 days before intratracheal instillation of
bleomycin (7.5 units/kg) or saline for an additional 13 days. Lung
collagen measured as
hydroxyproline was significantly increased to 138% of the control groups in the PBS +
Bleomycin treated group, but the
Z2196 +
Bleomycin group was increased to 108% and was not statistically different from controls.
Protein content of bronchoalveolar lavage supernatant in PBS +
Bleomycin treated hamsters was significantly increased to 326% of controls. The
protein content of bronchoalveolar lavage supernatant for all
cysteine pro-drug +
Bleomycin treated hamsters was increased to 160% of PBS +
Bleomycin treated hamsters. All the
Bleomycin treated hamsters had significantly more cells and more neutrophils recovered in bronchoalveolar lavage than controls. The PBS +
Bleomycin treated hamsters had significantly more lymphocytes in bronchoalveolar lavage than all the other treatment groups. The
Z2196 +
Bleomycin and
Z2197 +
Bleomycin hamsters had significantly less monocytes in BALF than PBS +
Bleomycin hamsters. The lung total sulfhydryl and nonprotein sulfhydryl in PBS +
Bleomycin treated hamsters were increased to 210% and 253% of controls, respectively, whereas in
Z2196 +
Bleomycin hamsters they were increased to 152% and 153%, respectively. Histopathology of PBS +
Bleomycin hamsters showed a diffuse mixed mononuclear alveolitis, multifocal
fibrosis and peribronchiolar
fibrosis, whereas
Z2196 +
Bleomycin hamsters showed notably less alveolitis and
fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)