title: Simple procedure for measuring the pharmacodynamics and analgesic potential of lipoxygenase inhibitors.
abstract: A model is described for determining the pharmacodynamics of inhibitors of arachidonate metabolism in mice. Bioavailability and selectivity were assessed by ex vivo RIA of TXB2, LTB4, and 12-HETE from ionophore-challenged blood. Inhibition of LTB4 and 12-HETE was measured using a single LTB4 RIA, following extraction and separation of these eicosanoids from plasma. Separation on cyanopropyl mini-columns yielded hexane/ether and methanol fractions, which contained 12-HETE and LTB4, respectively. Analgesic efficacy was measured by inhibition of phenylbenzoquinone-induced abdominal constriction. The NSAIDs, indomethacin ibuprofen, flurbiprofen, and benoxaprofen, were analgesic and selective cyclo-oxygenase inhibitors. BW775C was also analgesic, but inhibited cyclo-oxygenase, 5-lipoxygenase and 12-HETE formation. Other in vitro 5-lipoxygenase inhibitors, NDGA, quercetin, and nafazatrom, were inactive in vivo, although NDGA reduced abdominal constrictions. The results indicate that this model has utility in determining the mechanism/selectivity of action and analgesic potential of 5-lipoxygenase inhibitors.
authors.affiliation: Research Department II, ICI Pharmaceuticals Division, Macclesfield, Cheshire, U.K.
authors.forename: F
authors.initials: F
authors.lastname: Carey
authors.forename: D
authors.initials: D
authors.lastname: Haworth
authors.forename: A E
authors.initials: AE
authors.lastname: Edmonds
authors.forename: R A
authors.initials: RA
authors.lastname: Forder
mesh_terms: D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D000700:Analgesics; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors; D006893:Hydroxyeicosatetraenoic Acids / Q000097:blood; D015289:Leukotrienes / Q000502:physiology; D016859:Lipoxygenase Inhibitors; D009637:Masoprocol / Q000494:pharmacology; D051379:Mice; D010146:Pain / Q000188:drug therapy / Q000209:etiology; D011720:Pyrazoles / Q000494:pharmacology
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D016718:Arachidonic Acid; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D009637:Masoprocol; D001091:Arachidonate Lipoxygenases