Effects of naltrexone on active Crohn's disease

描述（由申请人提供）： 克罗恩病是一种慢性复发和缓解的条件，造成炎症的肠道。克罗恩病的主要症状包括腹痛、腹泻、胃肠道出血、吸收不良和体重减轻。克罗恩病的病因不明。从克罗恩病受试者的肠中获得的活检显示炎性细胞，表明肠对刺激物有免疫反应，或者胃肠道的内源性免疫系统失去平衡。IBD的治疗一直针对炎症。药物（例如：类固醇或硫唑嘌呤）用于通过抑制宿主免疫系统来降低肠中的炎症反应。最近，克罗恩病的抗肿瘤坏死因子（TNF）策略已经发展，特异性免疫疗法治疗的新时代已经发展。这些药物是嵌合抗体，非常昂贵，并具有潜在的副作用。我们在基础科学实验室的研究涉及研究内源性阿片系统（即，脑啡肽和内啡肽以及阿片受体），以及它们在生长和伤口愈合中的作用。我们已经在患有化学诱导的结肠炎的小鼠中表明，纳洛酮显著降低肠道炎症并改善炎症指数。一项初步研究测试了活动性克罗恩病受试者对口服纳洛酮的临床反应，发现克罗恩病活动指数（CDAI）以及内窥镜下炎症逆转有显著改善。据推测，口服纳洛酮将通过增加活动性克罗恩病受试者的内源性脑啡肽水平来改善肠道炎症。为了检验这一假设，40名活动性克罗恩病受试者将随机接受口服纳洛酮（4.5 mg）或安慰剂，每日一次，持续3个月。将通过CDAI评分、内窥镜检查、组织学和生活质量调查监测受试者的缓解。治疗3个月后，所有受试者将以开放标签的方式接受治疗，以测试缓解的持续时间，并确定6个月的治疗是否优于3个月。将在1个月随访中评价缓解的持久性。该试验基于新颖的创新临床前和临床数据，未来可能会导致更大规模的多中心试验。

DESCRIPTION (provided by applicant): Crohn's disease is a chronic relapsing and remitting condition causing inflammation of the bowel. The major symptoms of Crohn's disease include abdominal pain, diarrhea, gastrointestinal bleeding, malabsorption, and weight loss. The etiology of Crohn's disease is unknown. Biopsies obtained from the bowel in subjects with Crohn's disease reveal inflammatory cells suggesting that the bowel is either reacting immunologically to a stimulus or the endogenous immune system of the gastrointestinal track is off balance. The treatment of IBD always has been directed toward inflammation. Drugs (e.g., steroids or azathioprine) are used to decrease the inflammatory response in the bowel by suppressing the host immune system. Most recently, anti-tumor necrosis factor (TNF) strategies for Crohn's disease have developed, and a new era of treatment with specific immunotherapy has been developed. These medications are chimeric antibodies that are extremely expensive and have potential side effects. Our research in the basic science laboratory has involved studying the endogenous opioid systems (i.e., enkephalins and endorphins, and opioid receptors), and their role on growth and wound healing. We have shown in a mouse with chemically-induced colitis that naltrexone significantly decreases inflammation of the bowel and improves the inflammatory index. A pilot study tested the clinical response to oral naltrexone in subjects with active Crohn's disease and found significant improvement in the Crohn's Disease Activity Index (CDAI) as well as endoscopic reversal of inflammation. It is hypothesized that oral naltrexone will improve inflammation of the bowel by increasing endogenous enkephalin levels in subjects with active Crohn's disease. In order to test this hypothesis, 40 subjects with active Crohn's disease will be randomized to receive either oral naltrexone (4.5 mg) or placebo daily for 3 months. Subjects' response will be monitored by the CDAI scores, endoscopy, histology, and quality of life surveys. After 3 months of therapy all subjects will be treated in an open-labeled fashion to test the longevity of response and determine if 6 months of therapy is better than 3 months. Durability of response will be evaluated in a 1-month follow-up. This trial is based upon novel innovative preclinical and clinical data and may lead to a larger multi-center trial in the future.