Sorafenib for Hepatopulmonary Syndrome

索拉非尼治疗肝肺综合征

• 批准号: 8545389
• 负责人: MICHAEL B FALLON
• 金额: $ 106.29万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8545389
• 关键词: Affect; Age; Alveolar; American; Angiogenesis Inhibitors; Animal Model; BAY 54-9085; Biological Markers; Blood Vessels; Cause of Death; Cessation of life; Cirrhosis; Clinical; Clinical Trials; Complication; Data; Disease; Double-Blind Method; Echocardiography; Endostatins; Epidemiologic Studies; Exercise; FDA approved; Focus Groups; Funding; Gases; Genetic; Goals; Hematopoietic stem cells; Hepatopulmonary Syndrome; Home environment; Human; Hypoxemia; Injection of therapeutic agent; Lead; Liver diseases; Lung; Lung diseases; Medical; Outcome; Oxygen; Patients; Pharmaceutical Preparations; Phase; Physiological; Placebo Control; Placebos; Plasma; Population; Primary carcinoma of the liver cells; Principal Investigator; Psyche structure; Public Health; Quality of life; Randomized; Randomized Clinical Trials; Rest; Risk; Role; SF-36; Safety; Saline; Signal Transduction; Stem cells; Testing; Tyrosine; Tyrosine Kinase Inhibitor; United States National Institutes of Health; Variant; Vascular Proliferation; Walking; angiogenesis; cost; double-blind placebo controlled trial; effective therapy; health related quality of life; improved; liver transplantation; monocyte; neovascularization; novel therapeutics; overexpression; patient oriented research; prevent; safety study; treatment effect

DESCRIPTION (provided by applicant): The goal of this application is to determine whether sorafenib may be effective at treating hepatopulmonary syndrome (HPS). Cirrhotic liver disease afflicts nearly 3 million Americans, and complications of cirrhosis are the fourth leading cause of death between ages 45-65. HPS is one such complication which results when pulmonary microvascular dilations lead to an increased alveolar-arterial oxygen gradient (AaPO2) and intrapulmonary transit of bubbles visualized by echocardiography after injection of agitated saline. HPS occurs in 33% of patients evaluated for liver transplantation amounting to hundreds of thousands Americans with HPS. We have shown that HPS worsens quality of life and doubles the already-significantly elevated risk of death of the cirrhotic patient. Unfortunately, te significant public health implications of HPS are magnified by the lack of any medical therapies for this lung disease. The two principal investigators (PIs) of the current application have demonstrated the importance of angiogenesis in HPS in humans and in animal models. Recently, our team has shown that the tyrosine kinase-inhibitor sorafenib prevents aberrant angiogenesis in the lungs, reverses gas exchange abnormalities, and reduces intrapulmonary shunting in the HPS animal model. Sorafenib has been studied extensively in patients with cirrhosis with hepatocellular carcinoma and is FDA-approved in this population. We propose a randomized, double-blind, placebo-controlled parallel trial of 50 patients to determine whether sorafenib affects AaPO2 at three months in patients with HPS. We hypothesize that sorafenib will decrease the AaPO2 compared to placebo. We will also determine the effect of sorafenib on intrapulmonary shunting and biomarkers of angiogenesis, including circulating hematopoietic progenitor cells and other plasma biomarkers. Finally, we will assess the impact of sorafenib on the six-minute walk distance and health-related quality of life of patients with HPS. We will determine the safety and potential efficacy of sorafenib as a novel therapeutic for the treatment of HPS.

描述（由申请人提供）：本申请的目的是确定索拉非尼是否可以有效治疗肝肺综合症（HPS）。肝硬化肝病遭受了近300万美国人，肝硬化并发症是 45-65岁之间的死亡。 HPS是一种这种并发症，当肺微血管扩张导致肺泡 - 氧气梯度（AAPO2）和注射搅动盐水后通过超声心动图可视化的气泡的肺内传发量增加。 HPS发生在33％的评估肝脏移植的患者中，相当于数十万患有HP的美国人。我们已经表明，HPS会使生活质量恶化，并使肝硬化患者死亡的风险增加了一倍。不幸的是，由于缺乏这种肺部疾病的任何医疗疗法，HPS对HP的显着影响都会放大。当前应用的两个主要研究者（PI）证明了人类和动物模型中HPS的血管生成的重要性。最近，我们的团队表明，酪氨酸激酶抑制剂索拉非尼可防止肺部异常的血管生成，逆转气体交换异常，并减少HPS动物模型中的肺内分流。索拉非尼对肝硬化患有肝细胞癌的患者进行了广泛的研究，并在该人群中得到了FDA批准。我们提出了50名患者的一项随机，双盲，安慰剂对照的平行试验，以确定索拉非尼在HPS患者中是否在三个月时影响AAPO2。我们假设与安慰剂相比，索拉非尼将减少AAPO2。我们还将确定索拉非尼对血管生成的肺内分流和生物标志物的影响，包括循环的造血祖细胞和其他血浆生物标志物。最后，我们将评估索拉非尼对HPS患者的六分钟步行距离和与健康相关的生活质量的影响。我们将确定索拉非尼作为治疗HPS的新型治疗方法的安全性和潜在功效。