EFFECTS OF TEPOXALIN, A DUAL INHIBITOR OF CYCLOOXYGENASE 5-LIPOXYGENASE, ON EVENTS ASSOCIATED WITH NSAID-INDUCED GASTROINTESTINAL INFLAMMATION/

Prostaglandins and thromboxanes are products of arachidonic acid metab olism via the cyclooxygenase (GO) enzyme and are responsible for the p ain and swelling common to sites of inflammation. Non-steroidal antiin flammatory drugs (NSAIDs) inhibit the production of these substances a nd are used in the treatment of inflammatory diseases such as arthriti s. However, one of the major side-effects of NSAID therapy is gastric ulceration. It is possible that inhibition of prostaglandin production and a related increase in the formation of leukotrienes via the 5-lip oxygenase (5-LO) enzymatic pathway are responsible for attracting infl ammatory cells, causing local sites of inflammation and producing ulce ration. To determine the effects of 5-LO inhibition on this hypothesis , studies were performed in rats to evaluate the effects of tepoxalin, a dual CO/LO inhibitor on leukotriene B-4 levels in gastric mucosa an d neutrophil adhesion in mesenteric venules. In rats, chronic oral adm inistration of an NSAID, indomethacin (2 mg/kg daily over 4 days), res ulted in 40% mortality, accompanied by intestinal adhesions and perfor ations when evaluated 24 h after the fourth dose of drug. Additionally , neutrophil adhesion was increased in the mesenteric venules and cell infiltration was evident in the mesenteric interstitium. These gastro intestinal side-effects were inhibited in a separate group of rats adm inistered tepoxalin (20 mg/kg, p.o) 30 min prior to each daily indomet hacin treatment. Further studies were performed to determine tepoxalin 's effects on early events associated with NSAID-induced gastrointesti nal inflammation, including neutrophil adhesion, lipid peroxide genera tion and LTB4 production. Indomethacin (100 mg/kg, p.o.) produced elev ated levels of LTB4 in rat gastric mucosa 90 min after administration, Additionally, neutrophil adhesion in mesenteric venules was increased at this dose and with the administration of another NSAID, naproxen. No generation of lipid peroxides was evident in the gastric mucosa at this timepoint. Tepoxalin (up to 400 mg/kg, p.o.) did not have an effe cts on gastric mucosal LTB4 generation and lipid peroxide levels. A de crease in neutrophil adhesion was observed at the highest dose. In ano ther study, pretreatment with tepoxalin (ED50=7.5 mg/kg, p.o.) or the selective 5-LO inhibitor zileuton (100 mg/kg, p.o.) prevented the incr eases in gastric mucosal LTB4 levels and neutrophil adhesion induced b y indomethacin (100 mg/kg, p.o,). These data suggest that LO inhibitio n may play a vital role in the prevention of NSAID-induced gastric inf lammation, providing insight into the lack of ulcerogenicity with tepo xalin and new approaches to anti-inflammatory therapy which may preven t gastric side effects.