Sorafenib for Hepatopulmonary Syndrome

描述（由申请人提供）：本申请的目的是确定索拉非尼是否可有效治疗肝病综合征（HPS）。肝硬化肝病困扰着近300万美国人，肝硬化并发症是肝硬化的第四大原因。 45-65岁之间死亡。HPS是一种这样的并发症，当肺微血管扩张导致肺泡-动脉氧分压差（AaPO 2）增加和在注射搅拌盐水后通过超声心动图可视化的气泡的肺内转运时导致。在接受肝移植评估的患者中，有33%发生HPS，这相当于数十万美国人患有HPS。我们已经证明HPS提高了患者的生活质量，并使已经显着升高的死亡风险增加了一倍。不幸的是，HPS的重大公共卫生影响由于缺乏对这种肺部疾病的任何药物治疗而被放大。本申请的两名主要研究者（PI）已经证明了人类和动物模型中HPS血管生成的重要性。最近，我们的研究小组已经证明，酪氨酸激酶抑制剂索拉非尼可以预防肺血管异常生成，逆转气体交换异常，并减少HPS动物模型中的肺内分流。索拉非尼已在肝硬化伴肝细胞癌患者中进行了广泛研究，并已获得FDA批准用于该人群。我们提出了一个随机，双盲，安慰剂对照平行试验50例患者，以确定索拉非尼是否影响AaPO 2在3个月的HPS患者。我们假设与安慰剂相比，索拉非尼将降低AaPO 2。我们还将确定索拉非尼对肺内分流和血管生成生物标志物的影响，包括循环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6分钟步行距离和健康相关生活质量的影响。我们将确定索拉非尼作为治疗HPS的新疗法的安全性和潜在疗效。

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.