In this study, we assessed the effects of addition of a nitroxybutyl moiety to
diclofenac on its ulcerogenic properties. The
diclofenac derivative, '
nitrofenac', was examined in terms of its ability to induce acute gastric erosions and chronic-type
gastric ulcers in rats and rabbits, respectively. The effects of these compounds on
prostaglandin synthesis in the stomach and at a site of peripheral
inflammation were also assessed, as were their anti-inflammatory properties in a model of acute
inflammation.
Diclofenac dose-dependently caused acute gastric mucosal injury in the rat at all doses tested (10-40 mg/kg), that was significantly greater in severity than that observed with the same doses of
nitrofenac. In rabbits, twice-daily administration of
diclofenac induced penetrating
antral ulcers and small intestinal damage. No damage was observed in the stomach or small intestine of rabbits receiving
nitrofenac.
Diclofenac and
nitrofenac exerted similar inhibitory effects on
prostaglandin E2 synthesis in the stomach and in a
carrageenan-sponge model of peripheral
inflammation. These compounds exerted similar inhibitory effects on
carrageenan-induced paw
edema.
Nitrofenac, but not
diclofenac, caused a significant increase in plasma levels of
nitrate/
nitrite. These results suggest that the addition of a nitroxybutyl moiety to
diclofenac markedly reduces the ulcerogenic properties of this compound without interfering with its ability to inhibit
cyclo-oxygenase activity or to reduce acute
inflammation.