ANTIVIRAL & ANTIFIBROTIC LIVER THERAPY OF HCV+ DRINKERS

抗病毒物质

• 批准号: 6757147
• 负责人: CHARLES S LIEBER
• 金额: $ 4.66万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6757147
• 关键词: alcoholic beverage consumption; chemoprevention; clinical research; combination chemotherapy; fibrogenesis; fibrosis; hepatitis C; hepatitis C virus; human subject; human therapy evaluation; immunotherapy; interferons; liver cirrhosis; liver disorder chemotherapy; phosphatidylcholines; plant extracts; polyenes; ribavirin; soybeans; urinalysis

We plan to evaluate a combined antiviral, antifibrotic and antioxidant treatment in the progression of liver disease of heretofore excluded patients with hepatitis C namely alcohol drinkers. Abstainers or alcohol consumers will be given state- of-the-art antiviral treatment (pegylated interferon + ribavirin) for 24-48 weeks. Another innovative aspect of this proposal is the supplemention with an anti-fibrotic agent, namely polyenylphosphatidylcholine (PPC) extracted from soybeans, or placebo, administered for 3 years (concomitantly with the antiviral treatment and thereafter). Current therapy neglects the fact that what causes the major medical symptoms and eventually the demise of the patient is liver fibrosis, resulting cirrhosis and associated complications, including hepatocellular carcinoma. If the fibrotic process could be stopped or even prevented, the hepatitis C virus would lose much of its impact on health. Available anti-fibrotic agents are too toxic to be used in patients, except for one, namely PPC, which has been shown in various experimental models to have striking anti-fibrotic actions, and which was found recently to be beneficial in HCV+ patients in terms of their circulating levels of transaminases. Fibrosis was not assessed, but documentation of the effects of PPC on fibrosis in HCV+ patients is being proposed here. It is noteworthy that PPC was discovered to have also significant anti- oxidant effects. This may be important in HCV+ patients since various studies have now indicated that HCV is associated with an oxidative stress. Another innovative aspect is the inclusion of drinkers who thus far were excluded from standard antiviral treatment, mainly because of concerns about exacerbation of mental disorders, reliability and compliance. However, the latter objection has now been overcome by the availability of pegylated interferon which can be administered once a week by the therapist in a controlled fashion. For both PPC and ribavirin, compliance will be monitored by incorporation of markers, such as riboflavin, that can be measured in the urine. Spot checks of blood levels of dilinoleoylphosphatidylcholine (DLPC, the main phosphatidylcholine species of PPC) will also be performed. Accordingly, support is requested for a a double-blind, randomized placebo controlled study to assess the efficacy of this novel approach for the treatment of liver disease in HCV+ alcohol consumers or abstainers. Funds are requested for special laboratory tests, study nurses, travel to meetings, patient monitoring expenses and a core office.

我们计划评估联合抗病毒、抗纤维化和抗氧化治疗对迄今为止被排除的丙型肝炎患者（即饮酒者）的肝病进展的影响。 戒酒者或饮酒者将接受最先进的抗病毒治疗（聚乙二醇干扰素+利巴韦林）24-48周。 该提议的另一个创新方面是使用抗纤维化剂，即从大豆中提取的多烯磷脂酰胆碱（PPC）或安慰剂，给药3年（与抗病毒治疗同时进行，此后）。 目前的治疗忽略了这样一个事实，即引起主要医学症状并最终导致患者死亡的是肝纤维化，导致肝硬化和相关并发症，包括肝细胞癌。如果纤维化过程可以停止甚至预防，丙型肝炎病毒将失去对健康的大部分影响。可用的抗纤维化剂毒性太大而不能用于患者，除了一种，即PPC，其已在各种实验模型中显示出具有显著的抗纤维化作用，并且最近发现其在HCV+患者的转氨酶循环水平方面是有益的。未评估纤维化，但本文提出了PPC对HCV+患者纤维化影响的记录。 值得注意的是，发现PPC也具有显著的抗氧化作用。 这在HCV+患者中可能很重要，因为各种研究表明HCV与氧化应激有关。 另一个创新方面是纳入了迄今为止被排除在标准抗病毒治疗之外的饮酒者，主要是因为担心精神障碍的恶化，可靠性和依从性。 然而，后一个反对意见现在已经被聚乙二醇化干扰素的可用性所克服，聚乙二醇化干扰素可以由治疗师以受控的方式每周施用一次。 对于PPC和利巴韦林，将通过掺入可在尿液中测量的标记物（如核黄素）来监测依从性。 还将对二亚油酰磷脂酰胆碱（DLPC，PPC的主要磷脂酰胆碱种类）的血液水平进行抽查。因此，需要支持一项双盲、随机安慰剂对照研究，以评估这种新方法治疗HCV+酒精消费者或戒酒者肝脏疾病的疗效。 要求提供资金用于特殊实验室检查、研究护士、出席会议旅费、病人监测费用和核心办公室。