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INFLAMMATION AND IMMUNOPHARMACOLOGY

Enhanced Anti-Inflammatory Potency of a Nitric Oxide-Releasing Derivative of Flunisolide: Role of Nuclear Factor-B

Mucosal Inflammation Research Group, University of Calgary, Calgary, Alberta, Canada (J.L.W., P.D.S.); Department of Gastroenterology and Hepatology, University of Perugia, Perugia, Italy (G.R., S.F.); and Department of Experimental Pharmacology, University of Naples, Naples, Italy (G.C.)

Glucocorticoids remain among the most commonly used anti-inflammatory drugs, despite significant adverse effects. Other anti-inflammatory drugs, including aspirin, have been coupled through an ester linkage to a nitric oxide-releasing moiety, resulting in an increase in potency and a decrease in adverse effects. Prednisolone has similarly been modified, with marked improvement of its therapeutic index. In the present study, we have evaluated whether a nitric oxide-releasing derivative of another glucocorticoid, flunisolide, would increase its potency as an anti-inflammatory agent and would decrease its systemic toxicity. To evaluate anti-inflammatory potency and efficacy, the carrageenan-airpouch model in the rat was used. Flunisolide and NCX-1024 (flunisolide-21-[4'-(nitrooxymethyl) benzoate]) were compared across a range of doses, with both direct injection into the airpouch and oral administration. The ability of these agents to protect the stomach against indomethacin-induced damage also was assessed. Effects of oral administration of the two drugs on body weight gain and adrenal suppression were also evaluated. With direct application into the airpouch, NCX-1024 was found to be 41 times more potent than flunisolide in reducing leukocyte accumulation and prostaglandin E₂ generation. The increased potency may be related to an enhanced ability of NCX-1024 to prevent nuclear factor-B activation. When given orally, the two compounds exhibited similar potency. However, orally administered NCX-1024 was more potent at protecting against indomethacininduced gastric damage, caused less reduction of body weight, and, unlike flunisolide, did not cause adrenal atrophy. These studies suggest that NCX-1024 may be an attractive alternative to conventional glucocorticoids, particularly for applications involving topical administration.

Address correspondence to: Dr. John L. Wallace, Department of Pharmacology and Therapeutics, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta, T2N 4N1, Canada. E-mail: wallacej{at}ucalgary.ca