Silymarin for the Treatment of Nonalcoholic Steatohepatitis

描述(申请人提供)：非酒精性脂肪性肝炎(NASH)是肝脏相关疾病的重要原因。鉴于肥胖和2型糖尿病患者面临风险，而且这些过程在美国很常见，旨在寻找治疗方法的研究的影响是深远的。由于其抗氧化性能，水飞蓟素可能有一个看似合理的作用，作为一种有效的治疗NASH，这一过程中已涉及氧化剂损伤。因此，这项研究的广泛目标是确定水飞蓟素治疗NASH患者的安全性、耐受性和有效性，这两种最常见的相关疾病是肥胖和2型糖尿病。第一阶段研究的第一部分是一项剂量发现研究，使用交替分组的肥胖NASH患者的递增剂量序列。本研究设计旨在评估水飞蓟宾在稳态条件下最大耐受量水飞蓟宾的安全性、耐受性和药代动力学。这项研究的主要终点将是不良事件的发生率和AUC的药代动力学参数(0-12小时)。第一阶段的第二部分将评估水飞蓟素在患有NASH的2型糖尿病患者中的安全性和耐受性，由于口服降糖药物的潜在相互作用，该研究与肥胖患者分开进行研究。具体地说，我们将比较患有NASH的肥胖患者和接受口服分泌剂(磺脲类、瑞格列奈、那格列奈、格列美脲)治疗的2型糖尿病NASH患者的AUC药代动力学参数(0-12小时)和不良事件发生率。第二阶段研究将包括一项为期48周的水飞蓟素对照双盲随机试验，用于NASH和肥胖症或2型糖尿病患者。与基线相比，水飞蓟素与安慰剂治疗的患者的主要终点将是肝脏组织学的改善。 与公共健康相关：这项研究解决了美国大部分人口中一个日益普遍的问题；即肥胖和糖尿病患者的脂肪导致的肝脏损伤。水飞蓟素被用于治疗肝病已有数百年的历史，并已被证明是安全的。这项研究将在精心设计的科学试验中证明水飞蓟素对肥胖和糖尿病患者脂肪引起的肝损伤的安全性和有效性。这些结果将允许从业者和患者决定是否在这一特定的疾病过程中使用水飞蓟素。

DESCRIPTION (provided by applicant): Non-alcoholic steatohepatitis (NASH) is an important cause of liver related morbidity. Given that obese and type 2 diabetic patients are at risk and these processes are common in the U.S., the impact of research aimed at finding a therapy is far reaching. By virtue of its antioxidant properties, Silymarin may have a plausible role as an effective therapy for NASH, a process in which oxidant injury has been implicated. Therefore, the broad aims of this research are to establish the safety, tolerability, and efficacy of Silymarin in NASH patients with two of the most commonly associated disorders, obesity and type 2 diabetes. The first part of the Phase I study is a dose-finding study using a sequence of escalating doses with alternating groups of obese patients with NASH. This study design aims to assess the safety, tolerability, and pharmacokinetic profile of silibinin at steady state conditions at a maximally tolerated dose of Silymarin. The primary endpoints of this study will be the incidence of adverse events and the pharmacokinetic parameter of AUC(0-12hr). The second part of phase I will assess the safety and tolerability of Silymarin in type 2 diabetics with NASH, studied separately from the obese patients due to the potential interacting effect of oral hypoglycemics. Specifically, we will compare the pharmacokinetic parameter of AUC(0-12hr) and the incidence of adverse events in obese patients with NASH to type 2 diabetics with NASH who are treated with oral secretagogues (sulfonylureas, repaglinide, nateglinide, glimepiride) with or without insulin. The phase II study will comprise a 48 week placebo controlled double blind randomized trial of Silymarin in patients with NASH and obesity or type 2 diabetes. The primary endpoint will be the improvement in hepatic histology, compared to baseline, in Silymarin versus placebo treated patients. Relevance to Public Health: This research addresses an increasingly common problem in a large segment of the U.S. population; that is, liver injury caused by fat in obese and diabetic patients. Silymarin has been used for many centuries for the treatment of liver diseases and has been shown to be safe. This research will prove the safety and effectiveness of Silymarin for liver injury caused by fat in obese and diabetic patients, in carefully designed scientific trials. These results will allow practitioners and patients to decide whether to use Silymarin in this specific disease process.