Molecular and Clinical Pharmacology of Retinopathy of Prematurity

早产儿视网膜病变的分子和临床药理学

• 批准号: 8246596
• 负责人: JACOB V ARANDA
• 金额: $ 80.66万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8246596
• 关键词: Molecular; Clinical; Pharmacology; Retinopathy; Prematurity

DESCRIPTION (provided by applicant): Retinopathy of prematurity (ROP) occurs in 50 to 80% of preterm babies born weighing less than 1250 grams. The NYPD-PRC (New York Pediatric Developmental Pharmacology Research Consortium) was formed as a unique multidisciplinary research team of neonatal pharmacologist, retina investigators, neonatologists and pharmaceutical scientists to define the molecular events leading to ROP and to develop effective and safe pharmacologic strategies to prevent it. The overarching hypothesis is that repeated hyperoxic/hypoxic episodes promoting aberrant ocular VEGF signaling, dysregulated angiogenesis and vasoproliferation can be modulated or prevented by synergistic interventions of caffeine and systemic ibuprofen or ocular NSAID local drops. Using novel intervention strategies and unique approaches, three distinct but highly inter-related study proposals will test various hypotheses and specific aims in newborn rats, retinal endothelial tip cell cultures and in preterm newborn infants born <28 weeks or weighing <1250 grams. Protocol 1 will determine the efficacy and safety of ocular ibuprofen or ketorolac with systemic caffeine as well as the critical timing of intervention for the prevention of oxygen induced retinopathy in newborn rat model of OIR. Protocol II will examine the behavior of retinal endothelial tip cells and their dynamic relationship with astrocytes in the setting of oxidative stress (hyperoxia/hypoxia cycling); and to determine whether ibuprofen co-administered with caffeine will preserve tip cell quiescence. Once studies on additional safety, efficacy and critical timing of intervention (vasoobliterative or vaso-proliferative phase) are completed, Protocol III will be implemented in preterm newborns weighing <1250 grams, to test the safety, efficacy, pharmacodynamics and pharmacogenomics of systemic caffeine with or without IV ibuprofen or with or without local NSAID eye drops (ketorolac) in a multicenter, randomized, open label study to prevent ROP (all stages). Unique pharmacometric analyses of all 3 protocols provide novel data on ocular drug transport and action during development. The NYPD-PRC will surely elevate the level of scientific inquiry on molecular and clinical pharmacology of ROP to hasten its prevention and avert life-long blindness. PUBLIC HEALTH RELEVANCE: Retinopathy of Prematurity or ROP occurs in 2 out of 3 small babies born prematurely and treated with oxygen. ROP is the most common cause of blindness in children. Understanding the molecular events leading to ROP and providing novel, effective and safe drug interventions will avert a lifetime of blindness, disability and darkness.

描述（由申请人提供）： 50% 至 80% 的出生体重低于 1250 克的早产儿患有早产儿视网膜病变 (ROP)。 NYPD-PRC（纽约儿科发育药理学研究联盟）是一个由新生儿药理学家、视网膜研究人员、新生儿学家和药学科学家组成的独特的多学科研究团队，旨在确定导致 ROP 的分子事件，并制定有效且安全的药理学策略来预防 ROP。总体假设是，反复的高氧/缺氧事件会促进异常的眼部 VEGF 信号传导、血管生成失调和血管增殖，可以通过咖啡因和全身布洛芬或眼部 NSAID 局部滴剂的协同干预来调节或预防。使用新颖的干预策略和独特的方法，三个不同但高度相关的研究提案将测试 新生大鼠、视网膜内皮尖端细胞培养物和出生 <28 周或体重 <1250 的早产新生儿的各种假设和具体目标 克。方案 1 将确定眼部布洛芬或酮咯酸与全身用药的有效性和安全性 咖啡因以及预防氧诱导性视网膜病变的干预的关键时机 OIR新生大鼠模型。方案 II 将检查视网膜内皮尖端细胞的行为及其 氧化应激（高氧/缺氧循环）下与星形胶质细胞的动态关系；并确定布洛芬与咖啡因共同给药是否会保持尖端细胞静止。一旦完成额外安全性、有效性和干预关键时机（血管闭塞期或血管增殖期）的研究，方案 III 将在体重 <1250 克的早产新生儿中实施，以测试全身咖啡因联合或不联合静脉注射布洛芬或联合或不联合局部 NSAID 滴眼剂（酮咯酸）的安全性、有效性、药效学和药物基因组学。 预防 ROP 的多中心、随机、开放标签研究（所有阶段）。对所有 3 个方案的独特药理学分析提供了开发过程中眼部药物转运和作用的新数据。 NYPD-PRC必将提高ROP分子和临床药理学的科学探究水平，以加快其预防并避免终身失明。 公共卫生相关性：每 3 个接受吸氧治疗的早产小婴儿中就有 2 个会发生早产儿视网膜病变或 ROP。 ROP 是儿童失明的最常见原因。了解导致 ROP 的分子事件并提供新颖、有效和安全的药物干预措施将避免终生失明、残疾和黑暗。