Evaluation of 5-lipoxygenase inhibitors, zileuton, A-78773 and ICI-D-2138 in an ionophore (A-23187)-induced pleural inflammation model in the rat.
Intrapleural injection of A-23187 (10 micrograms), a calcium ionophore, elicited rapid increase in biosynthesis of prostaglandins and leukotrienes in a time-dependent manner. 6-Keto-prostaglandin-F1 alpha (6-KPA) was the principal cyclooxygenase product with modest increases in levels of thromboxane B2 and prostaglandin-E2. Orally administered indomethacin, a selective cyclooxygenase inhibitor, and three selective 5-lipoxygenase inhibitors, zileuton, A-78773 and ICI-D-2138 markedly attenuated respective arachidonate pathways with projected ED50 values of < 1-2 mg/kg. Furthermore, a single oral administration of either ICI-D-2138 or A-78773 (each 20 mg/kg, po) resulted in persistent inhibition of 5-lipoxygenase pathway for up to 24 hr. These results indicate zileuton, A-78773 and ICI-D-2138 to be potent and selective inhibitors of 5-LO and document the utility of A-23187-induced pleural inflammation in evaluating efficacy of inhibitors of arachidonic acid metabolism in vivo.
Inflammatory Diseases Research, Searle Research & Development, c/o Monsanto Company, St. Louis, MO 63198.
T S
TS
Rao
J L
JL
Currie
A F
AF
Shaffer
P C
PC
Isakson
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000001:Calcimycin / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D015777:Eicosanoids / Q000096:biosynthesis; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D015289:Leukotrienes / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D010998:Pleurisy / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology*; D011453:Prostaglandins / Q000096:biosynthesis; D011714:Pyrans / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015777:Eicosanoids; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D011453:Prostaglandins; D011714:Pyrans; D015363:Quinolones; C075799:ICI D2138; C082739:A 78773; D000001:Calcimycin; C063449:zileuton; D006918:Hydroxyurea