糖皮质激素连接物在大鼠胃肠道的转运及其对溃疡性结肠炎的治疗

摘要

目的：研究地塞米松(DX)-右旋糖酐(500 000)连接物(DXD50)在大鼠胃肠道的转运及其对大鼠溃疡性结肠炎的疗效.方法：将DXD50给大鼠ig，监测该DXD50在大鼠胃肠道不同部位释放DX的动力学过程及血药浓度变化.用三硝基苯磺酸诱导大鼠溃疡性结肠炎，以结肠溃疡面积、结肠重量、结肠组织髓过氧化物酶、大鼠外周血淋巴细胞数、胸腺及脾脏重量为指标，观察连接物的疗效.结果：口服连接物后，DX主要分布在盲肠和结肠中.DXD50及DXO.25 μmol·kg-1·d-1可分别使大鼠溃疡面积缩小55.6％和33.3％，同时结肠重量下降17.9％和2.6％.DXD50 0.25 μmol·kg-1·d-1对大鼠外周血淋巴细胞数、胸腺及脾脏重量无影响，而同等剂量的DX可引起大鼠外周血淋巴细胞数、胸腺及脾脏重量明显下降(P＜0.05 vs contro1).结论：DXD50可将DX特异地转运到结肠，它是一种有潜力的治疗炎症性肠病药物.%AIM: To evaluate colonic delivery and therapeutic effecof the newly synthesized dexamethasone (DX)-dextran (500 000) conjugate (DXD50) in the rat. METHODS: The amount of dexamethasone was measured in the contents from different parts of rat gastrointestinal tract and in plasma after ig conjugate.Therapeutic effect of conjugate and DX was tested in trinitrobenzenesulfonic acid-induced colitis in rat. Repair of colitis was assessed by measuring colonic ulceration area, colon weight, and colonic myeloperoxidase (MPO) activity. Systemic immunosuppression of DX was evaluated with weight of thymus and spleen and lymphocyte count in peripheral blood from rat with ulcerative colitis. RESULTS: Dexamethasone released from conjugate was mainly distributed in contents of cecum and colon. When DXD 50 and DX 0.25 μmol· kg- 1 d-1 were used ig to treat ulcerative colitis in rat, the ulcerative area of colon was reduced by 55.6 % and 33.3 %, respectively whereas colon weight was reduced by 17.9 % and 2.6 %, respectively. The conjugate had no effect on lymphocyte count in peripheral blood, spleen weight, and thymus weight of rat which could be reduced markedly by the same dose of DX ( P＜0.05 vs control). CONCLUSION: DXD50, which could specifically deliver DX to large intestine, is a promising agent in the treatment of human inflammatory bowel disease.