Aromatase Inhibitors in Pulmonary Vascular Complications of Liver Disease

芳香酶抑制剂治疗肝病肺血管并发症

• 批准号: 8662302
• 负责人: Steven M Kawut
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662302
• 关键词: Adverse effects; Affect; Alveolar; Area; Aromatase; Aromatase Inhibitors; Attention; Award; Basic Science; Biochemical; Biometry; Blood Vessels; Cardiovascular system; Cessation of life; Cirrhosis; Clinical; Clinical Research; Clinical Trials; Collaborations; Commit; Critical Care; Data; Development; Disease; Environment; Epidemiology; Estradiol; Estrogen Receptors; Estrogens; FDA approved; Female; Fostering; Funding; Future; Gases; Gender; Genetic Determinism; Genetic Variation; Goals; Growth; Head; Hepatology; Hepatopulmonary Syndrome; Housing; Hypersensitivity; Hypertension; Hypertrophy; Industry; Institutes; Laboratories; Liver; Liver diseases; Lung; Measures; Medial; Mediator of activation protein; Medical; Medicine; Mentors; Mentorship; Methodology; Morbidity - disease rate; Muscle; Oxygen; Patient Care; Patients; Pennsylvania; Peripheral; Phase; Physiological; Placebos; Plasma; Portal Hypertension; Postmenopause; Prevention; Production; Publications; Pulmonary Hypertension; Pulmonary artery structure; Randomized Clinical Trials; Rare Diseases; Research; Research Personnel; Resources; Right Ventricular Dysfunction; Risk; Risk Factors; Safety; Signal Transduction; Time; Training; United States National Institutes of Health; Universities; Vascular Diseases; Walking; Woman; alternative treatment; anastrozole; base; career; clinical epidemiology; design; functional status; high risk; interest; liver transplantation; malignant breast neoplasm; medical schools; medical specialties; men; mortality; neglect; novel therapeutics; patient oriented research; patient population; prevent; professor; programs; pulmonary arterial hypertension; research study; screening; skills; success; therapeutic target; treatment strategy

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.

史蒂文·M·库特（Steven M. Kawut），医学博士，MS是大学医学和流行病学副教授 宾夕法尼亚州医学院（PENN），他的职业生涯从事患者的研究和护理 肺血管疾病（PVD）。他对这一领域的兴趣开始于他的培训初期，并指导了他 从那以后的发展。他负责基于流行病学的联邦资助研究计划 PVD和右心室功能障碍的治疗。他还指导了29多名学员 以患者为导向的研究（POR）的成功，从而获得了出版物和资金 自己的独立性。 Kawut博士最近招募宾夕法尼亚州指导肺血管疾病计划创造了一个 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。 在心血管研究所，肺部，过敏和 重症监护司，以及可供候选人提供的临床流行病学和生物统计学中心以及 他的学员。其中包括最先进的临床研究和实验室资源。候选人 该奖项中心的立即和长期职业目标是获取临床试验技能的 在罕见的PVD和发展他的指导能力中。宾夕法尼亚州的环境非常适合开发 申请人是一种心理，并在这些领域促进月经的学术增长。 肺动脉高压发生在4-8％的门户高血压患者中（称为） 波经肺高血压（PPHTN））。 PPHTN没有已知的疾病机制，有限，非特异性 疗法，可能会大大补充，延迟或预防肝移植。肝肺综合症 （HPS）的特征是肺微血管膨胀和气体交换受损，可在 30％的患者正在评估肝移植。 HPS开发的机制是 同样是加密。 Kawut博士最近进行了一项NIH资助的研究，重点是 PPHTN和HPS。这些研究表明，1）女性是PPHTN的强大风险因素，2）遗传 雌激素受体β的变异与HP的发生有关，3）遗传变异 芳香酶与较高的血浆雌二醇（E2）水平和PPHTN风险更高有关。这些 数据强烈建议雌激素是治疗和预防的潜在治疗靶点 门户高血压的肺血管后遗症。 Anastrozole（AN）是FDA批准的芳香酶抑制剂，大大减少了外围 男性和绝经后女性的雌激素产生。因此，我们建议进行两次`证明原则证明 随机临床试验（RCT）开始研究雌激素抑制作用 PPHTN和HPS。我们的目的：1）确定三个月内安慰剂与安慰剂的影响 使用PPHTN和2）在三个月内确定安慰剂与安慰剂的影响。 终点将包括E2水平，经胸膜超声心动学测量，肺泡 - 氧气梯度， 功能状态，安全性和耐受性。 如果暗示福利，则可以使用结果来计划和动力多中心II期或III级或III RCT 在这两个PVD中。这项研究将为年轻调查人员提供理想的培训理由 对希望学习新颖疗法的孤儿疾病的PVD感兴趣。