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Wallace, John L.; Vergnolle, Nathalie; Muscará, Marcelo N.; Asfaha, Samuel; Chapman, Kevin; McKnight, Webb; Soldato, Piero Del; Morelli, Antonio; Fiorucci, Stefano
Gastroenterology (New York, N.Y. 1943), 09/1999, Letnik: 117, Številka: 3Journal Article
Background & Aims: Nitric oxide (NO)-releasing derivatives of cyclooxygenase inhibitors exhibit enhanced anti-inflammatory activity and greatly reduced gastrointestinal toxicity. We evaluated whether a similar derivatization of mesalamine (5-aminosalicylic acid) would improve its anti-inflammatory activity. Methods: Effects of an NO-releasing derivative of mesalamine (NCX-456; NO-mesalamine) were compared with those of mesalamine itself and 2 other NO donors in a rat model of colitis. These drugs were compared for their ability to inhibit leukocyte adherence to the vascular endothelium in vivo, interleukin (IL)-1β and interferon (IFN)-γ release in vitro (splenocytes and colon), and messenger RNA expression in the inflamed colon. Results: NO-mesalamine was significantly more effective than mesalamine in reducing the severity of colitis (damage and granulocyte infiltration). Unlike mesalamine, NO-mesalamine significantly suppressed leukocyte adherence to the vascular endothelium in vivo. NO-mesalamine inhibited IL-1β and IFN-γ release and caspase 1 activity in splenocytes; such effects were not found in the inflamed colon. Conclusions: These studies show that an NO-releasing derivative of mesalamine has significantly enhanced anti-inflammatory activity, including improved efficacy in a rat model of colitis. The improved efficacy of this derivative is most likely caused by its enhanced ability to suppress leukocyte infiltration and possibly to scavenge peroxynitrite. GASTROENTEROLOGY 1999;117:557-566
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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