Sorafenib for Hepatopulmonary Syndrome

描述(申请人提供)：本申请的目的是确定索拉非尼是否可以有效地治疗肝肺综合征(HPS)。肝硬化性肝病困扰着近300万美国人，而肝硬变并发症是导致肝炎的第四大原因。 死亡年龄在45-65岁之间。HPS是这样一种并发症，当注射搅动盐水后超声心动图显示肺微血管扩张导致肺泡-动脉血氧梯度(AaPO2)增加和肺内气泡通过时，HPS就是其中之一。在接受肝移植评估的患者中，33%发生了HPS，总计有数十万美国HPS患者。我们已经证明，HPS会恶化生活质量，使本已显著增加的肝硬变患者死亡风险加倍。不幸的是，由于缺乏任何治疗这种肺部疾病的药物，HPS对公众健康的重大影响被放大了。目前应用的两个主要研究人员(PI)已经证明了血管生成在人类和动物模型的HPS中的重要性。最近，我们的团队在HPS动物模型中证明了酪氨酸激酶抑制剂索拉非尼可以防止肺中异常的血管生成，逆转气体交换异常，并减少肺内分流。索拉非尼已在肝硬变合并肝细胞癌患者中进行了广泛的研究，并已在该人群中获得FDA批准。我们建议对50名患者进行随机、双盲、安慰剂对照的平行试验，以确定索拉非尼对HPS患者三个月后的AaPO2是否有影响。我们假设与安慰剂相比，索拉非尼将降低AaPO2。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一种治疗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.