A DICLOFENAC DERIVATIVE WITHOUT ULCEROGENIC PROPERTIES

In this study, we assessed the effects of addition of a nitroxybutyl m oiety to diclofenac on its ulcerogenic properties. The diclofenac deri vative, 'nitrofenac', was examined in terms of its ability to induce a cute gastric erosions and chronic-type gastric ulcers in rats and rabb its, respectively. The effects of these compounds on prostaglandin syn thesis in the stomach and at a site of peripheral inflammation were al so assessed, as were their anti-inflammatory properties in a model of acute inflammation. Diclofenac dose-dependently caused acute gastric m ucosal injury in the rat at all doses tested (10-40 mg/kg), that was s ignificantly greater in severity than that observed with the same dose s of nitrofenac. In rabbits, twice-daily administration of diclofenac induced penetrating antral ulcers and small intestinal damage. No dama ge was observed in the stomach or small intestine of rabbits receiving nitrofenac. Diclofenac and nitrofenac exerted similar inhibitory effe cts on prostaglandin E, synthesis in the stomach and in a carrageenan- sponge model of peripheral inflammation. These compounds exerted simil ar inhibitory effects on carrageenan-induced paw edema. Nitrofenac, bu t not diclofenac, caused a significant increase in plasma levels of ni trate/nitrite. These results suggest that the addition of a nitroxybut yl moiety to diclofenac markedly reduces the ulcerogenic properties of this compound without interfering with its ability to inhibit cyclo-o xygenase activity or to reduce acute inflammation.