Randomized Trial of Rosiglitazone for Ulcerative Colitis

描述（由申请人提供）： 溃疡性结肠炎（UC）是一种慢性炎症性疾病，涉及所有或部分结肠炎。 结肠的一部分目前，几乎没有有效的药物治疗方法， 加州大学此外，由于目前可用的药物的潜在毒性， 因此，非常需要替代疗法来治疗患有这种疾病的患者。 5-阿萨药物治疗难治性UC。 过氧化物酶体增殖物激活受体（PPARs）是核内 转录因子的激素受体超家族，其活性 通过小的亲脂性配体如类固醇的高亲和力结合来调节 荷尔蒙一类新的糖尿病药物，噻唑烷二酮类，已经被 开发为结合PPARs的γ（g）亚型。结肠上皮 细胞表达高水平的PPARg蛋白，并具有产生 炎症细胞因子可能有助于UC的炎症过程。 我们以前已经证明，PPARg配体显著减弱 结肠癌炎症级联反应相关细胞因子基因表达的研究 细胞系此外，我们和其他人已经证明，噻唑烷二酮 PPARg的配体显著降低了小鼠结肠炎模型中的结肠炎症， 溃疡性结肠炎此外，我们在一项试点研究中表明， 50%的轻度至中度活动性UC患者尽管接受了5-阿萨治疗 药物（对于大多数患者，还有皮质类固醇或免疫调节剂药物） 罗格列酮治疗12周内症状改善4 mg，每日两次。因此，我们认为PPARg可能是一个新的靶点， 调节UC中的结肠炎症。 拟开展的研究为多中心、双盲、随机对照试验 罗格列酮与安慰剂治疗轻度至中度活动性溃疡性结肠炎 口服5-阿萨标准治疗难治性结肠炎。176例受试者 将随机分配至罗格列酮4 mg bid或安慰剂组，治疗12周。 主要结局将是疾病活动性的改善， 疾病活动指数最早由萨瑟兰提出。次要结局将 包括临床缓解和生活质量。 我们将使用免疫组织化学技术检测 人结肠组织中的PPARg受体。我们还将使用 免疫组织化学检测在NF-KB活化之前和之后的变化。 安慰剂或罗格列酮治疗后。具体来说，我们将 比较p65和磷酸化IKB-α在结肠组织中的表达， 罗格列酮和安慰剂暴露后。 如果我们的假设是正确的，这项研究将有助于建立配体， 因为PPARg具有调节炎症反应所必需的生物活性， 在完整的人类结肠中的反应。

DESCRIPTION (provided by applicant): Ulcerative colitis (UC) is a chronic inflammatory disease involving all or a portion of the colon. Currently, there are few effective medical therapies for UC. Furthermore, because of the potential toxicity of the currently available agents, there is a great need for alternative therapies to treat patients with UC refractory to therapy with 5-ASA agents. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of transcription factors whose activities are regulated by high affinity binding of small lipophilic ligands such as steroid hormones. A new class of diabetic drugs, the thiazolidinediones, has been developed to bind to the gamma (g) subtype of the PPARs. Colonic epithelial cells express high levels of PPARg protein and have the ability to produce inflammatory cytokines that may contribute to the inflammatory process in UC. We have previously demonstrated that PPARg ligands significantly attenuate cytokine gene expression related to the inflammatory cascade in colon cancer cell lines. Furthermore, we and others have demonstrated that thiazolidinedione ligands for PPARg markedly reduce colonic inflammation in murine models of ulcerative colitis. In addition, we have shown in a pilot study that more than 50% of patients with mild to moderately active UC despite therapy with 5-ASA agents (and corticosteroids or imunomodulator medications for most patients) experienced improved symptoms within 12 weeks of therapy with rosiglitazone 4 mg twice daily. As such, we believe that PPARg may represent a novel target for modulating colonic inflammation in UC. The proposed study is a multi-center, double-blind, randomized controlled trial of rosiglitazone versus placebo for mild to moderately active ulcerative colitis refractory to standard therapy with oral 5-ASA agents. 176 subjects will be randomized to rosiglitazone 4mg bid or placebo for 12 weeks of therapy. The primary outcome will be improvement in disease activity as measured by the Disease Activity Index first described by Sutherland. Secondary outcomes will include clinical remission and quality of life. We will use the techniques of immunohistochemistry to detect expression of PPARg receptors in human colon tissue. We will also use the technique of immunohistochemistry to examine the change in NF-KB activation prior to and following therapy with either placebo or rosiglitazone. Specifically, we will compare expression of p65 and phosphorylated IKB-alpha, in colonic tissue prior to and following exposure to rosiglitazone and placebo. If our hypothesis is correct, this study will serve to establish that ligands for PPARg possess biological activity necessary to modulate the inflammatory response in the intact human colon.