Aromatase Inhibitors in Pulmonary Vascular Complications of Liver Disease

史蒂文·M·考特，医学博士，硕士，加州大学医学和流行病学副教授 宾夕法尼亚医学院(宾夕法尼亚大学)，他致力于研究和护理病人 患有肺血管疾病(PVD)。他对这个领域的兴趣在他的训练早期就开始了，并指导了他的 从那以后的发展。他领导着一个联邦资助的研究项目，该项目基于流行病学和 室间隔缺损和右心功能不全的治疗。他还指导了29多名学员 以患者为中心的研究(POR)的成功，导致了出版物和资金的发展 自己的独立。 卡武特？S博士最近被招募到宾夕法尼亚大学领导肺血管疾病计划，创造了一个 这是扩大他的研究计划以及培训和指导年轻研究人员的重要机会。 在宾夕法尼亚大学，心血管研究所、肺科、过敏科和 重症监护科，临床流行病学和生物统计中心提供给候选人和 他的实习生。这些资源包括最先进的临床研究和实验室资源。候选人S 在这个奖项中，近期和长期的职业目标是获得临床试验技能 在罕见的PVD和发展他的指导能力。宾夕法尼亚大学的环境非常适合开发 作为导师的应聘者，并促进被辅导者在这些领域的学术成长。 4%-8%的门脉高压患者(称为 门静脉高压症(PPHTN)。PPHTN没有已知的致病机制，有限的，非特异性的 治疗，并可能极大地复杂化、延迟或阻止肝移植。肝肺综合征 (HPS)以肺微血管扩张和气体交换障碍为特征，可见于 30%的患者接受肝移植评估。HPS的发展机制是 同样神秘。 Kawut博士最近进行了一项由NIH资助的研究，重点是临床和遗传决定因素 PPHTN和HPS。这些研究表明，1)女性是PPHTN的强烈危险因素，2)遗传 雌激素受体的变异与HPS的发生有关，3)基因变异。 芳香酶与较高的血浆雌二醇(E2)水平和较高的PPHTN风险相关。这些 数据有力地表明，雌激素是治疗和预防这些疾病的潜在治疗靶点。 门脉高压的肺血管后遗症。 阿那曲唑(AN)是FDA批准的一种芳香酶抑制剂，可显著降低外周血流量 男性和绝经后女性的雌激素产生。因此，我们建议进行两项原则证明 随机临床试验(RCT)开始雌激素抑制的研究，用于治疗 PPHTN和HPS。我们的目标是：1)确定安与安慰剂在三个月内对患者的影响 通过PPHTN和2)确定安慰剂与安慰剂在HPS患者三个月内的疗效。 终点将包括雌二醇水平、经胸超声心动图检查、肺泡-动脉血氧分压、 功能状态、安全性和耐受性。 如果建议的好处，结果可以用来规划和推动多中心的第二阶段或第三阶段的随机对照试验 在这两个PVD中的一个或两个。这项研究将为年轻的调查人员提供理想的培训场所 对PVD的POR感兴趣，希望研究治疗孤儿疾病的新疗法。

Steven M. Kawut, MD, MS is an Associate Professor of Medicine and Epidemiology at the University of Pennsylvania School of Medicine (Penn) who has committed his career to the research and care of patients with pulmonary vascular disease (PVD). His interest in this area began early in his training and has guided his development since then. He heads a federally-funded research program based on the epidemiology and treatment of PVD and right ventricular dysfunction. He has also mentored more than twenty-nine trainees to success in patient-oriented research (POR), resulting in publications and funding as they develop towards their own independence. Dr. Kawut¿s recent recruitment to Penn to direct the Pulmonary Vascular Disease Program has created a significant opportunity to expand his research program as well as to train and mentor young investigators. There are outstanding resources at Penn housed in the Cardiovascular Institute, the Pulmonary, Allergy, and Critical Care Division, and the Center for Clinical Epidemiology and Biostatistics available to the candidate and his trainees. These include state-of-the-art clinical research and laboratory resources. The candidate¿s immediate- and long-term career goals during this award center on acquiring skills in performing clinical trials in rare PVDs and developing his mentorship abilities. The environment at Penn is ideal to develop the applicant as a mentor and to foster the academic growth of mentees in these areas. Pulmonary arterial hypertension occurs in 4-8% of patients with portal hypertension (termed portopulmonary hypertension (PPHTN)). PPHTN has no known disease mechanism, limited, non-specific therapies, and may greatly complicate, delay, or prevent liver transplantation. Hepatopulmonary syndrome (HPS) is characterized by pulmonary microvascular dilations and impaired gas exchange and is found in up to 30% of patients being evaluated for liver transplantation. The mechanism for the development of HPS is similarly cryptic. Dr. Kawut recently performed a NIH-funded study focused on the clinical and genetic determinants of PPHTN and HPS. These studies showed that 1) female gender was a strong risk factor for PPHTN, 2) genetic variation in estrogen receptor β was associated with the occurrence of HPS , and 3) genetic variation in aromatase was associated with both higher plasma estradiol (E2) levels and a higher risk of PPHTN. These data strongly suggest estrogen as a potential therapeutic target in treatment and prevention of these pulmonary vascular sequelae of portal hypertension. Anastrozole (AN) is an FDA-approved aromatase inhibitor which dramatically decreases peripheral estrogen production in men and post-menopausal women. We therefore propose to conduct two ¿proof-ofprinciple¿ randomized clinical trials (RCTs) to begin the study of estrogen inhibition with AN for the treatment of PPHTN and HPS. We aim: 1) To determine the effects of AN versus placebo over three months in patients with PPHTN and 2) To determine the effects of AN versus placebo over three months in patients with HPS. End points will include E2 levels, transthoracic echocardiology measures, alveolar-arterial oxygen gradient, functional status, safety, and tolerability. If suggestive of benefit, the results could be used to plan and power multicenter Phase II or III RCTs of AN in one or both of these PVDs. This research would provide the ideal training ground for young investigators interested in POR in PVD who wish to study novel therapeutics for ¿orphan¿ diseases.