TREATMENT OF METABOLIC PRURITIS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。瘙痒是胆汁淤积性肝病的一个显著特征，据估计，20%-50%的黄疸患者和70%-80%的原发性胆汁性肝硬化(PBC)患者会发生瘙痒。瘙痒严重影响生活质量，并可能导致慢性睡眠不足。目前使用的治疗方法往往无效和/或耐受性差。只有几个人在对照试验的背景下进行了检查。美国肝病研究协会发布的实践指南指出，胆汁淤积性瘙痒的一线治疗是胆汁酸结合树脂，如胆碱胺。胆汁酸结合树脂在高达85%的患者中可以部分有效，但依从性往往较差，因为该制剂令人不快。此外，这些树脂热衷于结合并阻止几乎所有其他药物的吸收，严重限制了患者的医疗管理。第二种疗法是利福平，它在几个小型试验中被证明是适度有效的。利福平的主要问题是它会导致血清胆红素水平升高。血清胆红素是预测PBC患者存活率的唯一最重要的指标，因此利福平治疗削弱了医生跟踪患者病程的能力。此外，有报道称利福平导致肝炎，这可能会给已经限制肝功能的患者带来严重问题。三线疗法都被认为是实验性的，因为它们要么有未经证实的疗效，要么严重限制副作用。它们包括：阿片受体阻滞剂，它们导致PBC患者出现阿片类戒断症状，令人不快；苯巴比妥和异丙酚，高度镇静；抗组胺药，它们效果不是很好，而且会加剧80%的PBC患者和许多丙型肝炎患者的口干症；S-腺苷蛋氨酸(作为膳食补充剂)，光疗；抗惊厥药，昂丹西酮，以及血浆置换。在无明显肝细胞衰竭的情况下，顽固性胆汁淤积性瘙痒被认为是肝移植的有效指征，这是一种有效但极端和昂贵的措施。在极少数情况下，患者选择自杀是为了避免无法控制的瘙痒的持续痛苦。该项目的广泛和长期目标是改善引起瘙痒的系统性疾病患者的健康和生活质量。这个项目的假设是基于我们之前的观察，即一些PBC患者在服用舍曲林时他们的瘙痒症状得到了缓解，即舍曲林治疗将改善胆汁淤积性瘙痒的症状。这项特殊的研究旨在作为一项可行性和剂量寻找试点试验，以确定舍曲林作为胆汁淤积性瘙痒治疗的耐受性和有效剂量。预计在这一先导试验之后，将进行一项更大规模的双盲、随机、安慰剂对照试验，以明确评估舍曲林治疗瘙痒的疗效。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Pruritus is a hallmark feature of cholestatic liver diseases and is estimated to occur in 20%-50% of patients with jaundice and 70%-80% of patients with primary biliary cirrhosis (PBC). Pruritus significantly affects quality of life and can lead to chronic sleep deprivation. Currently used therapies are often ineffective and/or poorly tolerated. Only a few have been examined in the setting of controlled trials. Practice guidelines issued by the American Association for the Study of Liver Diseases state that the first line of therapy for cholestatic pruritus is bile acid binding resins such as cholestyramine. Bile acid binding resins can be partially effective in up to 85% of patients, but compliance tends to be poor because the preparation is unpalatable. In addition, these resins avidly bind to and prevent absorption of almost all other medications, severely restricting the medical management of the patients. The second line of therapy is rifampicin, which has been shown to be modestly effective in several small trials. The major problem with rifampicin is that it leads to increases in serum bilirubin levels. Serum bilirubin is the single most important predictor of survival in patients with PBC, and thus rifampicin therapy impairs the physician's ability to follow the patient's course. In addition, there have been reports of rifampicin-induced hepatitis, which could pose a serious problem in patients with already limited liver function. The third line therapies are all considered experimental because they either have unproved efficacy and/or severely limiting side effects. They include: opioid receptor blockers, which are unpleasant because they result in an opioid withdrawal-like syndrome in PBC patients; phenobarbitol and propofol, which are heavily sedating; anti-histamines, which are not very effective and also worsen the xerostomia of sicca syndrome that is present in 80% of patients with PBC and many patients with hepatitis C (HCV); s-adenosylmethionine (SAMe, a dietary supplement), phototherapy; anti-convulsants, ondansetron, and plasmapheresis. Intractable cholestatic pruritus is considered a valid indication for liver transplantation in the absence of overt hepatocellular failure, an effective but drastic and costly measure. In rare cases, patients have opted for suicide in order to avoid the constant distress of unmanageable pruritus. The broad, long-term objective of this project is to improve the health and quality of life of patients with systemic diseases that cause pruritus. The hypothesis of this project, which is based on our previous observation that some patients with PBC have experienced resolution of their pruritus when given sertraline, is that sertraline therapy will improve the symptom of cholestatic pruritus. This particular study is intended to serve as a feasibility and dose-finding pilot trial to determine the tolerability and effective dose of sertraline as a treatment for cholestatic pruritus. It is anticipated that this pilot trial will be followed by a larger, double-blind, randomized, placebo-controlled trial to definitively evaluate the efficacy sertraline therapy for pruritus.