Wallace J L, Vergnolle N, Muscará M N, Asfaha S, Chapman K, McKnight W, Del Soldato P, Morelli A, Fiorucci S
Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada.
Gastroenterology. 1999 Sep;117(3):557-66. doi: 10.1016/s0016-5085(99)70448-8.
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.
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)-1beta and interferon (IFN)-gamma release in vitro (splenocytes and colon), and messenger RNA expression in the inflamed colon.
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-1beta and IFN-gamma release and caspase 1 activity in splenocytes; such effects were not found in the inflamed colon.
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.
环氧合酶抑制剂的一氧化氮（NO）释放衍生物具有增强的抗炎活性，且胃肠道毒性大大降低。我们评估了美沙拉嗪（5-氨基水杨酸）的类似衍生化是否会改善其抗炎活性。
在大鼠结肠炎模型中，将美沙拉嗪的一种NO释放衍生物（NCX-456；NO-美沙拉嗪）与美沙拉嗪本身及其他2种NO供体的作用进行比较。比较这些药物在体内抑制白细胞黏附于血管内皮、体外（脾细胞和结肠）抑制白细胞介素（IL）-1β和干扰素（IFN）-γ释放以及在炎症结肠中抑制信使核糖核酸表达的能力。
在减轻结肠炎严重程度（损伤和粒细胞浸润）方面，NO-美沙拉嗪比美沙拉嗪显著更有效。与美沙拉嗪不同，NO-美沙拉嗪在体内能显著抑制白细胞黏附于血管内皮。NO-美沙拉嗪抑制脾细胞中IL-1β和IFN-γ释放以及半胱天冬酶1活性；在炎症结肠中未发现此类作用。
这些研究表明，美沙拉嗪的NO释放衍生物具有显著增强的抗炎活性，包括在大鼠结肠炎模型中疗效更佳。该衍生物疗效的提高很可能是由于其抑制白细胞浸润以及可能清除过氧亚硝酸盐的能力增强。
