Mentored Patient-Oriented Research Career Development Aw

指导以患者为中心的研究职业发展Aw

• 批准号: 6639888
• 负责人: Ivan M Robbins
• 金额: $ 12.48万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6639888
• 关键词: ACE inhibitors; angiography; antihypertensive agents; cardiovascular disorder chemotherapy; career; clinical research; clinical trials; combination chemotherapy; cooperative study; disease /disorder etiology; drug screening /evaluation; hemodynamics; human subject; human therapy evaluation; pathologic process; pharmacokinetics; placebos; plasminogen activator inhibitors; prostacyclins; prostaglandins; pulmonary circulation; pulmonary hypertension; renin angiotensin system; scleroderma; thromboxanes

(Adapted from the applicant's abstract): PPH is a disease of high morbidity and mortality occurring predominately in young adult women. The etiology of this illness remains unknown, but increased production of thromboxane A(2) [TxA(2)] and decreased synthesis of prostacyclin [prostaglandin I] provide clues to the pathogenesis. Over the past decade, intravenous epoprostenol, the synthetic analogue of prostacyclin, has emerged as the most effective treatment of PPH. However, tolerance to the effects of epoprostenol occurs in the majority of patients necessitating progressive dose escalation to maintain efficacy. Furthermore, only 70% of patients benefit from treatment. Preliminary data derived from clinical studies of patients with PPH demonstrate that epoprostenol increases circulating levels of angiotensin II (AII), a potent vasoconstrictor and smooth muscle mitogen, which can stimulate production of both plasminogen activator inhibitor 1 (PAI- 1), a procoagulant protein, and vascular endothelial growth factor (VEGF), permeability and angiogenic growth factor. This proposal will explore two hypotheses: 1) activation of the renin- angiotensin system (RAS) during chronic administration of epoprostenol is the cause of increasing dose requirements; 2) direct and indirect effects of RAS activation and persistent TxA(2) production limit the clinical efficacy of epoprostenol. To evaluate these hypotheses, the applicant will: a) delineate the relationship between epoprostenol-induced RAS activation and compare biochemical changes with hemodynamic data obtained during right heart catheterization; b) delineate clinical data obtained from measurement of distance walked in six minutes, and structural changes obtained by wedge angiography of pulmonary circulation; and c) determine, in a collaborative study with other medical centers, whether concomitant treatment with and angiotensin converting enzyme inhibitor will improve the clinical efficacy of epoprostenol and prevent the need for chronic dose escalation. These studies will advance our knowledge of the mechanism of action of epoprostenol and pulmonary hypertension.

（改编自申请人的摘要）：PPH 是一种高发疾病 发病和死亡主要发生在年轻成年妇女中。 这 这种疾病的病因尚不清楚，但增加了 血栓素 A(2) [TxA(2)] 和前列环素合成减少 [前列腺素I]为发病机制提供线索。 在过去的十年里， 静脉注射依前列醇（前列环素的合成类似物）已出现 作为治疗 PPH 最有效的方法。 然而，对影响的耐受性 大多数患者需要进行依前列醇治疗 剂量递增以维持疗效。 此外，只有 70% 的患者 从治疗中受益。 来自临床研究的初步数据 PPH 患者证明依前列醇可增加循环水平 血管紧张素 II (AII)，一种有效的血管收缩剂和平滑肌有丝分裂原， 它可以刺激纤溶酶原激活剂抑制剂 1 (PAI- 1)、促凝血蛋白和血管内皮生长因子（VEGF）， 通透性和血管生成生长因子。 该提案将探讨两个假设：1）肾素激活 长期服用依前列醇期间的血管紧张素系统（RAS）是 剂量需求增加的原因； 2）RAS的直接和间接影响 激活和持续的 TxA(2) 产生限制了临床疗效 依前列醇。 为了评估这些假设，申请人将： a) 描述 依前列醇诱导的 RAS 激活之间的关系及比较 右心期间获得的血流动力学数据的生化变化 导管插入术； b) 描绘从测量中获得的临床数据 六分钟步行距离，楔形获得的结构变化 肺循环血管造影； c) 共同确定 与其他医疗中心研究，是否同时治疗和 血管紧张素转换酶抑制剂可提高临床疗效 依前列醇并防止需要长期剂量递增。 这些研究 将增进我们对依前列醇作用机制的了解 肺动脉高压。