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性疾病，会导致肠道发炎。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。克罗恩病的病因尚不清楚。从克罗恩病患者的肠道获得的活检结果显示，炎性细胞表明肠道要么对刺激做出免疫反应，要么胃肠道内源性免疫系统失衡。IBD的治疗一直是针对炎症的。药物(如类固醇或硫唑嘌呤)被用来通过抑制宿主免疫系统来减少肠道的炎症反应。最近，针对克罗恩病的抗肿瘤坏死因子(TNF)策略已被开发出来，并开辟了特异性免疫治疗的新纪元。这些药物是嵌合抗体，极其昂贵，而且有潜在的副作用。我们在基础科学实验室的研究包括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。我们已经在化学诱导的结肠炎小鼠中表明，纳曲酮显著减少肠道炎症，并改善炎症指数。一项试点研究测试了口服纳曲酮对活动期克罗恩病患者的临床反应，发现克罗恩病活动指数(CDAI)以及内窥镜下炎症逆转显著改善。据推测，口服纳曲酮将通过增加活动期克罗恩病受试者的内源性脑啡肽水平来改善肠道炎症。为了验证这一假设，40名活动期克罗恩病患者将被随机分成两组，分别每天服用纳曲酮(4.5毫克)或安慰剂，为期3个月。受试者的反应将通过CDAI评分、内窥镜检查、组织学和生活质量调查进行监测。治疗3个月后，所有受试者都将接受开放标签的治疗，以测试反应的持久性，并确定6个月的治疗是否比3个月的治疗更好。反应的持久性将在1个月的随访中进行评估。这项试验基于创新的临床前和临床数据，并可能在未来导致更大的多中心试验。

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.