An intrapleural injection of
carrageenan in rats induced
LTB4 and
LTC4/D4/E4 biosynthesis, exudate formation, and cellular influx in the pleural cavity. An injection of
calcium ionophore (
A23187, 100 nmol) 16-18 h after
carrageenan injection augmented
leukotriene biosynthesis and exudate formation, but not cellular influx. The
carrageenan-induced
pleurisy model modifid by
A23187 administration was used to study the oral effect of
CGS 23885 (N-hydroxy-N-[(6-phenoxy-2H-1-
benzopyran-3-yl)-methyl]
urea), a potent
5-lipoxygenase (5-LO) inhibitor, on inflammatory parameters.
CGS 23885 dose-dependently (1 to 30 mg/kg) inhibited the enhanced
LTB4 and
LTC4/D4/E4 (1 to 10 mg/kg) biosynthesis, but had no effect on enhanced exudate formation. An inhibitory effect of
CGS 23885 of small magnitude on cellular influx due to
carrageenan stimulation was seen at 30 mg/kg. The concentrations of
CGS 23885 in the pleural fluid were dose-related, and a positive correlation (r2=0.989) between pleural fluid concentration of
LTB4 and
CGS 23885 was observed. The results confirm that
CGS 23885 is a specific, orally active 5-LO inhibitor which can achieve concentrations in the pleural cavity sufficient to inhibit production of
LTB4 and
LTC4/D4/E4 in an ongoing inflammatory response.