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: 8473232
• 负责人: JACOB V ARANDA
• 金额: $ 70.94万
• 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/8473232
• 关键词: Area; Astrocytes; Awareness; Behavior; Blindness; Caffeine; Cell Culture Techniques; Cells; Child; Childhood; Clinical; Clinical Pharmacology; Communities; Darkness; Data; Development; Drops; Drug Transport; Drug effect disorder; Drug usage; Event; Eye; Eyedrops; General Population; Health; Hyperoxia; Hypoxia; Ibuprofen; Interdisciplinary Study; Intervention; Ketorolac; Life; Modeling; Molecular; Neonatal; New York; Newborn Infant; Non-Steroidal Anti-Inflammatory Agents; Oxidative Stress; Oxygen; Performance; Perinatal; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenomics; Pharmacologic Substance; Pharmacology; Phase; Premature Infant; Prevention; Preventive Intervention; Protocols documentation; Randomized; Rattus; Research; Research Activity; Research Personnel; Retina; Retinal; Retinal Diseases; Retinopathy of Prematurity; Safety; Scientist; Signal Transduction; Staging; Testing; Time; Training; Training Programs; Translational Research; Vascular Endothelial Growth Factors; angiogenesis; career development; disability; multidisciplinary; novel; open label; pediatric pharmacology; prevent; programs; safety testing

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.

描述（由申请人提供）：早产儿视网膜病变（ROP）发生在50%至80%出生时体重低于1250克的早产儿中。NYPD-PRC（纽约儿科发育药理学研究联合会）是由新生儿药理学家、视网膜研究者、眼科医生和药学家组成的独特的多学科研究小组，其目的是确定导致ROP的分子事件，并开发有效和安全的药理学策略来预防ROP。失调的血管生成和血管增生可以通过咖啡因和全身布洛芬或眼用NSAID局部滴剂的协同干预来调节或预防。使用新的干预策略和独特的方法，三个不同的，但高度相关的研究建议将测试 在新生大鼠、视网膜内皮尖端细胞培养物和出生<28周或体重<1250的早产新生儿中的各种假设和具体目标 克.方案1将确定眼用布洛芬或酮咯酸与全身给药的疗效和安全性。 咖啡因以及干预的关键时间，以预防氧诱导的视网膜病变， 方案II将检查视网膜内皮尖端细胞的行为及其在OIR的新生大鼠模型中的作用。 在氧化应激（高氧/缺氧循环）的情况下与星形胶质细胞的动态关系;以及确定布洛芬与咖啡因共同给药是否将保持尖端细胞静止。关于额外安全性、有效性和关键干预时间的研究（血管闭塞或血管增生期）完成后，将在体重<1250克的早产新生儿中实施方案III，以测试全身性咖啡因联合或不联合IV布洛芬或联合或不联合局部NSAID滴眼液的安全性、有效性、药效学和药物基因组学。在一项多中心、随机、开放标签研究中，使用酮咯酸（酮咯酸）预防ROP（所有阶段）。所有3种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将提高ROP分子和临床药理学的科学研究水平，以加速其预防和避免终身失明。