Silymarin for the Treatment of Nonalcoholic Steatohepatitis

描述（由申请方提供）：非酒精性脂肪性肝炎（NASH）是肝脏相关疾病的重要原因。考虑到肥胖和2型糖尿病患者有风险，而且这些过程在美国很常见，旨在寻找治疗方法的研究影响深远。由于其抗氧化特性，水飞蓟素可能具有合理的作用，作为NASH的有效治疗方法，这是一个涉及氧化损伤的过程。因此，本研究的主要目的是确定水飞蓟素在NASH患者中的安全性、耐受性和疗效，NASH患者患有两种最常见的相关疾病，肥胖和2型糖尿病。I期研究的第一部分是一项剂量探索研究，采用递增剂量序列，交替分组患有NASH的肥胖患者。本研究设计旨在评估水飞蓟宾在最大耐受剂量的水飞蓟素下在稳态条件下的安全性、耐受性和药代动力学特征。本研究的主要终点为不良事件发生率和药代动力学参数AUC（0- 12 hr）。第一阶段的第二部分将评估水飞蓟素在2型糖尿病伴NASH患者中的安全性和耐受性，由于口服降糖药的潜在相互作用，与肥胖患者分开研究。具体而言，我们将比较伴有NASH的肥胖患者与伴有NASH的2型糖尿病患者的药代动力学参数AUC（0- 12 hr）和不良事件的发生率，后者接受口服促分泌素（磺酰脲类、瑞格列奈、那格列奈、格列美脲）联合或不联合胰岛素治疗。II期研究将包括在NASH和肥胖或2型糖尿病患者中进行的48周安慰剂对照双盲随机试验。主要终点将是水飞蓟素治疗患者与安慰剂治疗患者相比，肝脏组织学较基线的改善。 与公共卫生的相关性：这项研究解决了美国大部分人口中日益普遍的问题;即肥胖和糖尿病患者中脂肪引起的肝损伤。水飞蓟素已被用于治疗肝脏疾病许多世纪，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。这些结果将允许医生和患者决定是否在这种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.