Lipoxygenase indomethacin

ML-3000 ((2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl)-acetic acid) is a nonantioxidant dual inhibitor of both cyclooxygenase and 5-lipoxygenase. ML-3000 has been compared to indomethacin in a number of experimental models of inflammation. The analgesic effects of ML-3000 have also been assessed in a number of animal models. Phase II studies have shown a wide range of activities, including anti-inflammatory, analgesic, antiplatelet and antiasthmatic properties (Laufer et al., 1994 Chin and Wallace, 1999). 

When hydroxyacids (11 -HETE and 15-HETE) are produced as byproducts of the cyclooxygenase pathway, inhibition is effected by cyclooxygenase inhibitors as indomethacin and flurbiprofen [159,160]. Indomethacin inhibits formation of thromboxane in platelets effectively at 2.8 X 10 M, while no inhibitory effect was seen on the formation of 12-HETE at 2.8 X 10" M [164]. In leukocytes, however, inhibition of lipoxygenases at an indomethacin concentration of lO " M has been reported [245]. 

The initial product resulting from the action of a lipoxygenase is a hydroperoxy acid. This is quickly followed by reduction to a hydroxyacid by peroxidase. Some common anti-inflammatory drugs have been shown to cause accumulation of 12-HPETE in platelets by inhibition of the enzymatic reduction into 12-HETE [186,188]. Among the drugs showing this effect are aspirin, indomethacin, sodium salicylate and phenylbutazone. 

The phospholipase Aj inhibitor dibromoaceto-phenone, the anti-inflammatory steroid fluocino-lone acetonide or the lipoxygenase inhibitor nordi-hydroguiaretic acid just prior to intraperitoneal injection of 100 ng 12-0-tetradecanoylphorbol-13-acetate into unmanipulated CD-I female mice resulted in a dose-dependent decrease in the number of peritoneal exudate cells producing superoxide anion radical as assessed by the reduction of nitro-blue tetrazolium, while the cycloxygenase inhibitor indomethacin had no effect on the number of formazan-positive peritoneal exudate cells caused by PMA treatment (Czerniecki and Witz 1989). 

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