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，累及所有或 结肠的一部分。目前，几乎没有有效的药物疗法来治疗 加州大学。此外，由于目前可用的 代理，非常需要替代疗法来治疗患者 UC对5-ASA类药物治疗无效。 过氧化物酶体增殖物激活受体(PPAR)是核内的一员。 激素受体超家族转录因子，其活性为 受小分子亲脂配体如类固醇的高亲和力结合调节 荷尔蒙。一类新的糖尿病药物，噻唑烷二酮类，已经被 被开发为与PPAR的伽马(G)亚型结合。结肠上皮 细胞表达高水平的PPARg蛋白，并具有产生 炎性细胞因子可能参与UC的炎症过程。 我们之前已经证明了PPARg配体显著地减弱了 结肠癌炎性级联反应相关细胞因子基因的表达 细胞系。此外，我们和其他人已经证明了噻唑烷二酮 PPARg配体可显著减轻结肠炎小鼠模型 溃疡性结肠炎。此外，我们在一项初步研究中表明，超过 尽管接受5-ASA治疗，50%的轻中度UC患者仍有活动 药物(以及大多数患者使用的皮质类固醇或免疫调节剂药物) 罗格列酮4治疗后12周内症状有所改善 每日两次，每次两次。因此，我们认为PPARg可能代表了一个新的靶点 调节UC中的结肠炎。 该研究是一项多中心、双盲、随机对照试验。 罗格列酮与安慰剂治疗轻至中度活动型溃疡的对比研究 口服5-ASA类药物对标准治疗无效的结肠炎。176名受试者 将随机给予罗格列酮4 mg，2次/d或安慰剂治疗12周。 主要结果将是疾病活跃度的改善，由 疾病活动指数最先由萨瑟兰描述。次要结果将是 包括临床缓解和生活质量。 我们将使用免疫组织化学技术来检测 人结肠组织中的PPARG受体。我们还将使用 免疫组织化学方法检测核因子-kB在治疗前后的变化 在接受安慰剂或罗格列酮治疗后。具体来说，我们将 P65和磷酸化IKB-α在结肠组织中的表达比较 在接触罗格列酮和安慰剂后和之后。 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具有调节炎症所必需的生物活性 在完好无损的人体结肠中的反应。

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.