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，高达50%的极低胎龄新生儿(早产儿，1250g/&lt；28周)患有此病，其中约5%会终身失明。咖啡因和非甾体抗炎药已被证明可以降低伊尔甘人严重ROP的风险。然而，药物干预的给药途径和时机仍然存在争议。我们提出了一种新的方法，将局部应用布洛芬或酮咯酸与全身咖啡因相结合，以优化它们预防氧源性视网膜病变(OIR)的疗效。这项建议的主要目标是调查局部眼部布洛芬或酮咯酸与全身咖啡因联合使用是否能降低暴露于频繁、短暂、群集性高氧-低氧循环的新生大鼠OIR的发生率和/或严重性。我们的具体目标有三个：1)确定导致异常血管生成和严重OIR的基因上调的高氧/低氧发作的临界数量。我们假设存在一个临界数量的高氧/低氧循环，超过这个循环，发育中的视网膜将不会 恢复；2)使用优化的制剂，我们将确定布洛芬(新洛芬)或新剂型的酮咯酸(Acuvail)作为滴眼液局部应用，与或不联合全身柠檬酸咖啡因(Cafcit)对严重OIR风险的视网膜是否具有保护作用。我们还将测定布洛芬的剂量反应。我们假设，局部应用布洛芬或酮咯酸并辅以全身性咖啡因将为预防OIR提供长期的有效性和安全性；3)检查布洛芬或酮咯酸滴眼液加咖啡因的保护作用是否由给药时机决定。我们假设，与疾病阶段(血管闭塞与增生期)相关的给药时机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被激活，新生血管的机制就是不可逆转的。及早识别和预防至关重要。我们建议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.