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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Special Emphasis Panel (ZHD1-DSR-A)
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Suny Downstate Medical Center
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Tu, Chengjian; Li, Jun; Shen, Shichen et al. (2016) Performance Investigation of Proteomic Identification by HCD/CID Fragmentations in Combination with High/Low-Resolution Detectors on a Tribrid, High-Field Orbitrap Instrument. PLoS One 11:e0160160
Beharry, Kay D; Valencia, Gloria B; Lazzaro, Douglas R et al. (2016) Pharmacologic interventions for the prevention and treatment of retinopathy of prematurity. Semin Perinatol 40:189-202
Inayat, Musaddaq; Bany-Mohammed, Fayez; Valencia, Arwin et al. (2015) Antioxidants and Biomarkers of Oxidative Stress in Preterm Infants with Symptomatic Patent Ductus Arteriosus. Am J Perinatol 32:895-904
An, Bo; Zhang, Ming; Johnson, Robert W et al. (2015) Surfactant-aided precipitation/on-pellet-digestion (SOD) procedure provides robust and rapid sample preparation for reproducible, accurate and sensitive LC/MS quantification of therapeutic protein in plasma and tissues. Anal Chem 87:4023-9
Shen, Xiaomeng; Nair, Bindukumar; Mahajan, Supriya D et al. (2015) New Insights into the Disease Progression Control Mechanisms by Comparing Long-Term-Nonprogressors versus Normal-Progressors among HIV-1-Positive Patients Using an Ion Current-Based MS1 Proteomic Profiling. J Proteome Res 14:5225-39
Jivabhai Patel, Shamin; Bany-Mohammed, Fayez; McNally, Lois et al. (2015) Exogenous Superoxide Dismutase Mimetic Without Scavenging H2O2 Causes Photoreceptor Damage in a Rat Model for Oxygen-Induced Retinopathy. Invest Ophthalmol Vis Sci 56:1665-77
Tu, Chengjian; Beharry, Kay D; Shen, Xiaomeng et al. (2015) Proteomic profiling of the retinas in a neonatal rat model of oxygen-induced retinopathy with a reproducible ion-current-based MS1 approach. J Proteome Res 14:2109-20
Tu, Chengjian; Sheng, Quanhu; Li, Jun et al. (2015) Optimization of Search Engines and Postprocessing Approaches to Maximize Peptide and Protein Identification for High-Resolution Mass Data. J Proteome Res 14:4662-73
Kamisoglu, Kubra; Sukumaran, Siddharth; Nouri-Nigjeh, Eslam et al. (2015) Tandem analysis of transcriptome and proteome changes after a single dose of corticosteroid: a systems approach to liver function in pharmacogenomics. OMICS 19:80-91
Lott, Kaylen; Mukhopadhyay, Shreya; Li, Jun et al. (2015) Arginine methylation of DRBD18 differentially impacts its opposing effects on the trypanosome transcriptome. Nucleic Acids Res 43:5501-23

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