Murthy S N, Cooper H S, Shim H, Shah R S, Ibrahim S A, Sedergran D J
Krancer Center for Inflammatory Bowel Disease Research, Department of Medicine, Hahnemann University, Philadelphia, Pennsylvania.
Dig Dis Sci. 1993 Sep;38(9):1722-34. doi: 10.1007/BF01303184.
The use of oral and intravenous cyclosporin represents a significant advance in the therapy of refractory inflammatory bowel diseases (IBD). However, oral administration of cyclosporin is fraught with improper delivery of cyclosporin to the colon for its topical action. Because of unpredictable metabolism by cytochrome P-450 IIIA, the targeted blood level for systemic effect is not reached at low doses. Furthermore, the doses that have been used for therapy of IBD have been shown to induce several adverse side effects. Thus, an alternate method of delivering cyclosporin to the colon is desirable. In this study, the effect of intracolonically administered cyclosporin was tested for its efficacy to heal mucosal erosions in dextran sulfate sodium (DSS)-induced colitis in mice. Both acute and chronic colitis was induced by feeding female Swiss-Webster mice with 5% DSS (30,000-40,000 mol wt) for five or seven days, respectively. Therapy was advocated prophylactically, prophylaxis plus therapy and therapeutically during the acute and chronic phase of the disease and therapeutically during the chronic phase of the disease. Intracolonic cyclosporin given prophylactically showed adverse effects by increasing the damage to the colonic mucosa. However, intracolonic cyclosporin given therapeutically in 2.5, 5, and 10 mg/kg after the induction of colitis resulted in dramatic responses in terms of reducing the disease activity and histologic scores, corroborated by complete histological resolution compared to oral cyclosporin given at identical doses. Intracolonic cyclosporin (5 mg/kg) was also very effective in reducing the chronic inflammation. The results of this study highlight the application of this animal model for therapeutic research. Furthermore, cyclosporin administered as an enema provides a new stratagem for the therapy of IBD because of its rapid onset of action at very low doses without the risk inherent in oral or systemic administration.
口服和静脉注射环孢素在难治性炎症性肠病（IBD）治疗中代表了一项重大进展。然而，口服环孢素存在环孢素难以有效送达结肠发挥局部作用的问题。由于细胞色素P - 450 IIIA的代谢不可预测，低剂量时无法达到产生全身效应的目标血药浓度。此外，已用于IBD治疗的剂量已显示会引发多种不良副作用。因此，需要一种将环孢素送达结肠的替代方法。在本研究中，测试了结肠内给予环孢素对治愈葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎黏膜糜烂的疗效。分别通过给雌性瑞士韦伯斯特小鼠喂食5% DSS（分子量30,000 - 40,000）5天或7天来诱导急性和慢性结肠炎。在疾病的急性和慢性阶段分别提倡预防性、预防加治疗性以及治疗性给药。预防性给予结肠内环孢素会增加结肠黏膜损伤，显示出不良影响。然而，在结肠炎诱导后以2.5、5和10 mg/kg治疗性给予结肠内环孢素，在降低疾病活动度和组织学评分方面产生了显著反应，与相同剂量口服环孢素相比，组织学完全恢复证实了这一点。结肠内环孢素（5 mg/kg）在减轻慢性炎症方面也非常有效。本研究结果突出了该动物模型在治疗研究中的应用。此外，环孢素灌肠给药为IBD治疗提供了一种新策略，因为其在极低剂量下起效迅速，且无口服或全身给药固有的风险。
