LTB4-induced transient neutropenia in the rat: a model for evaluating efficacy and bioavailability of LTB4 receptor antagonists.
An animal model of leukotriene B4- (LTB4) induced neutropenia has been developed to evaluate LTB4 receptor antagonists in vivo. LTB4, a potent chemotactic inflammatory mediator, when administered intravenously, induces a profound, rapid, and transient redistribution of blood neutrophils from the circulating pool to the marginated pool. This phenomenon is applied in the neutropenia model whereby circulating blood neutrophil counts prior to and after intravenous infusion of LTB4 are compared. Kinetics of LTB4-induced neutrophil responses are determined through the use of a Technicon H*1 automated blood cell analyzer. LTB4 receptor antagonists are identified by inhibition of LTB4-induced neutropenia. Standard antiinflammatory compounds including BW-755C, Abbott A-64077 (zileuton), dexamethasone-21-acetate, indomethacin, and naproxen did not affect LTB4-induced neutropenia. A potent LTB4 receptor antagonist, designated "RPR," inhibited LTB4-induced neutropenia following oral administration in a dose-dependent fashion.
Pellas
T C
TC
Ciba-Geigy Corporation, Pharmaceuticals Division, Summit, New Jersey 07901.
Colombo
C
C
Fryer
L R
LR
Pastor
G
G
Haston
W
W
Raychaudhuri
A
A
Kotyuk
B
B
Greenspan
P D
PD
Healy
C
C
DiPasquale
G
G
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D003907:Dexamethasone / Q000031:analogs & derivatives / Q000494:pharmacology; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007958:Leukocyte Count / Q000187:drug effects; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008297:Male; D008954:Models, Biological; D009288:Naproxen / Q000494:pharmacology; D009503:Neutropenia / Q000139:chemically induced* / Q000517:prevention & control*; D009504:Neutrophils / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; D009288:Naproxen; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D003907:Dexamethasone; C018038:dexamethasone acetate; C063449:zileuton; D006918:Hydroxyurea; D007213:Indomethacin