Inhibition of LTB4 biosynthesis in situ by CGS 23885, a potent 5-lipoxygenase inhibitor, correlates with its pleural fluid concentrations in an experimentally induced rat pleurisy model.
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.
Raychaudhuri
A
A
Research Department, Novartis Pharmaceuticals Corporation, Summit, NJ 07901, USA.
Chertock
H
H
Chovan
J
J
Jones
L S
LS
Kimble
E F
EF
Kowalski
T J
TJ
Peppard
J
J
White
D H
DH
Satoh
Y
Y
Roland
D
D
D000818:Animals; D002867:Chromones / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006898:Hydroxylamines / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D010998:Pleurisy / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002867:Chromones; D006898:Hydroxylamines; D016859:Lipoxygenase Inhibitors; C084468:CGS 23885; D007975:Leukotriene B4