OCULAR NSAIDs/CAFFEINE POTENTIATION IN OXYGEN-INDUCED RETINOPATHY

早产儿视网膜病变（ROP）是一种血管增殖性视网膜疾病，高达50%的极低胎龄新生儿（elgan, <1250g/<28周）患有此病，其中约5%的人终生失明。咖啡因和非甾体抗炎药已被证明可以降低elgan患者发生严重ROP的风险。然而，给药途径和药物干预的时间仍然存在争议。我们提出了一种新的方法，将局部布洛芬或酮罗拉酸与全身咖啡因联合使用，以优化其预防氧诱导视网膜病变（OIR）的疗效。本研究的主要目的是研究局部布洛芬或酮罗拉酸加全身咖啡因是否能降低暴露于频繁、短暂、聚集性高氧-低氧循环的新生大鼠OIR的发生率和/或严重程度。我们的具体目标有三个方面：1)确定高氧/缺氧发作的临界次数，这将导致负责异常血管生成和严重OIR的基因上调。我们假设存在一个临界数量的高氧/缺氧周期，超过这个周期，发育中的视网膜将无法发育

Retinopathy of prematurity (ROP) is a vasoproliferative retinal disease that afflicts as much as 50% of all extremely low gestational age neonates (ELGANs, <1250g/<28 weeks) with approximately 5% condemned to a lifetime of blindness. Caffeine and NSAIDs have been shown to decrease the risk of severe ROP in ELGANs. However, the routes of administration and the timing of drug intervention remain debatable. We propose a novel approach combining topical ibuprofen or ketorolac with systemic caffeine to optimize their efficacy for prevention of oxygen-induced retinopathy (OIR). The overarching goal of this proposal is to investigate whether topical ocular ibuprofen or ketorolac potentiated with systemic caffeine decreases the incidence and/or severity of OIR in neonatal rats exposed to frequent, brief, clustered hyperoxia-hypoxia cycling. Our specific aims are three-fold: 1) To identify the critical number of hyperoxic/hypoxic episodes that will result in upregulation of genes responsible for abnormal angiogenesis and severe OIR. We hypothesize that there is a critical number of hyperoxia/hypoxia cycles beyond which the developing retina will not recover; 2) Using optimized preparations, we will determine if ibuprofen (Neoprofen) or a new preparation of ketorolac (Acuvail) administered topically as eye drops, with or without systemic caffeine citrate (Cafcit) exert protective effects on the retina at risk for severe OIR. We will also determine the dose-response of ibuprofen. We hypothesize that topical ibuprofen or ketotolac potentiated with systemic caffeine will provide long term efficacy and safety for prevention of OIR; and 3) To examine whether the protective effects of ibuprofen or ketorolac eye drops, potentiated with caffeine, are determined by timing of administration of the drug. We hypothesize that timing of drug administration in relation to the disease phase (vasoobliterative versus proliferative) is a major determinant of drug efficacy. We believe that once activated in the immature retina, the mechanisms for neovascularization are irreversible. Early identification and prevention is vital. Our proposed studies will aid in early identification of infants at risk.