Molecular and Clinical Pharmacology of Retinopathy of Prematurity

描述(申请人提供)：早产儿视网膜病变(ROP)发生在50%到80%的早产儿出生时体重小于1250克。NYPD-PRC(纽约儿科发展药理学研究联盟)是由新生儿药理学家、视网膜研究人员、新生儿科学家和药剂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，并开发有效和安全的药理学策略来预防ROP。最重要的假设是，重复的高氧/低氧事件促进了眼部血管内皮生长因子信号的异常、调节失调的血管生成和血管增殖，可以通过咖啡因和全身布洛芬或眼部非甾体抗炎药局部滴注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，将测试三个截然不同但高度相关的研究建议 在新生大鼠、视网膜内皮细胞培养和出生28周或体重1250的早产儿中的各种假说和特定目的 奶奶。方案1将确定布洛芬或酮咯酸眼用全身性的有效性和安全性 咖啡因以及预防氧源性视网膜病变的关键干预时机 新生大鼠OIR模型。方案II将检查视网膜内皮细胞的行为和它们的 在氧化应激(高氧/低氧循环)环境中与星形胶质细胞的动态关系；以及确定布洛芬与咖啡因联合应用是否能保持TIP细胞的静止。一旦关于额外的安全性、有效性和干预的关键时机(血管闭塞期或血管增生期)的研究完成，第三项方案将在体重为1250克的早产儿身上实施，以在一项旨在预防ROP的多中心、随机、开放标签研究中测试全身咖啡因与静脉注射布洛芬或与或不与局部非甾体抗炎药滴眼液(酮咯酸)联合使用的安全性、有效性、药效学和药物基因组学。对所有3种方案的独特的药物计量分析为眼部药物在开发过程中的转运和作用提供了新的数据。NYPD-PRC必将提高ROP的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。

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.