OCULAR NSAIDs/CAFFEINE POTENTIATION IN OXYGEN-INDUCED RETINOPATHY

早产儿视网膜病变（ROP）是一种血管增生性视网膜疾病，其折磨多达50%的所有极低胎龄新生儿（ELGAN，<1250 g/<28周），其中约5%注定终身失明。咖啡因和NSAID已被证明可以降低ELGAN中严重ROP的风险。然而，给药途径和药物干预的时机仍然存在争议。我们提出了一种新的方法，结合局部布洛芬或酮咯酸与全身咖啡因，以优化其预防氧诱导性视网膜病变（OIR）的疗效。本提案的总体目标是研究局部眼用布洛芬或酮咯酸与全身性咖啡因联合使用是否可降低暴露于频繁、短暂、聚集性高氧-缺氧循环的新生大鼠OIR的发生率和/或严重程度。我们的具体目标有三个方面：1）确定导致异常血管生成和严重OIR的基因上调的高氧/缺氧事件的临界数量。我们假设存在一个临界数量的高氧/缺氧周期，超过这个数量，发育中的视网膜将不会发生异常血管生成和严重OIR。 恢复; 2）使用优化的制剂，我们将确定布洛芬（Neoprofen）或酮咯酸的新制剂（Acuvail）作为滴眼剂局部给药，与或不与全身性柠檬酸咖啡因（Cafcit）一起使用，是否对处于严重OIR风险中的视网膜产生保护作用。我们还将确定布洛芬的剂量反应。我们假设，局部布洛芬或酮咯酸与全身性咖啡因增强将提供长期的疗效和安全性，用于预防OIR;和3）检查布洛芬或酮咯酸滴眼液的保护作用，与咖啡因增强，是否由药物的给药时间决定。我们假设，与疾病阶段（血管闭塞性与增殖性）相关的给药时间是药物疗效的主要决定因素。我们认为，一旦在未成熟的视网膜中激活，新生血管形成的机制是不可逆的。早期识别和预防至关重要。 我们提出的研究将有助于早期识别处于危险中的婴儿。

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.