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.

Public Health Relevance

These proposed studies will use topical, non-invasive, NSAIDs (ibuprofen and ketorolac) complemented with systemic caffeine citrate to preserve normal retinal growth and development during oxidative stress in order to protect the immature retina. Data from these studies will form the rationale for a future clinical trial to prevent ROP, the most common cause of childhood blindness. ROP is the leading cause of childhood blindness and the epidemic is increasing. Current medications, such as intravitreal Avastin is highly invasive, causes retinal hemorrhage, retinal detachment, choroidal ruptures, etc., and may have adverse effects on associated retinal cells such as astrocyges and microglia. The need for other potential therapies is vital. The unique strategy proposed in these studies will provide an alternate approach and form the rationale for a future clinical trial.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Suny Downstate Medical Center
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