Using Advanced Bioinformatics Tools to Identify Novel Therapeutic Candidates for Proliferative Vitreoretinopathy.

Purpose: Proliferative vitreoretinopathy (PVR) is the dreaded cause of failure following retinal detachment repair; however, no cures or preventative therapies exist to date. The purpose of this study was to use bioinformatics tools to identify drugs or compounds that interact with biomarkers and pathways involved in PVR pathogenesis that could be eligible for further testing for the prevention and treatment of PVR. Methods: We queried PubMed to compile a comprehensive list of genes described in PVR to date from human studies, animal models, and genomic studies found in the National Center for Biotechnology Information database. Gene enrichment analysis was performed using ToppGene on PVR-related genes against drug-gene interaction databases to construct a pharmacome and estimate the statistical significance of overrepresented compounds. Compounds with no clinical indications were filtered out from the resulting drug lists. Results: Our query identified 34 unique genes associated with PVR. Out of 77,146 candidate drugs or compounds in the drug databases, our analysis revealed multiple drugs and compounds that have significant interactions with genes involved in PVR, including antiproliferatives, corticosteroids, cardiovascular agents, antioxidants, statins, and micronutrients. Top compounds, including curcumin, statins, and cardiovascular agents such as carvedilol and enalapril, have well-established safety profiles and potentially could be readily repurposed for PVR. Other significant compounds such as prednisone and methotrexate have shown promising results in ongoing clinical trials for PVR. Conclusions: This bioinformatics approach of studying drug-gene interactions can identify drugs that may affect genes and pathways implicated in PVR. Predicted bioinformatics studies require further validation by preclinical or clinical studies; however, this unbiased approach could identify potential candidates among existing drugs and compounds that could be repurposed for PVR and guide future investigations. Translational Relevance: Novel repurposable drug therapies for PVR can be found using advanced bioinformatics models.

Intravitreal 5-Fluorouracil and Heparin to Prevent Proliferative Vitreoretinopathy: Results from a Randomized Clinical Trial.

PURPOSE: Proliferative vitreoretinopathy (PVR) is the major cause for surgical failure after primary rhegmatogenous retinal detachment (RRD). So far, no therapy has been proven to prevent PVR. Promising results for 5-fluorouracil (5-FU) and low-molecular weight heparin (LMWH) in high-risk eyes have been reported previously. The objective of this trial was to examine the effect of adjuvant intravitreal therapy with 5-FU and LMWH compared with placebo on incidence of PVR in high-risk patients with primary RRD. DESIGN: Randomized, double-blind, controlled, multicenter, interventional trial with 1 interim analysis. PARTICIPANTS: Patients with RRD who were considered to be at high risk for PVR were included. Risk of PVR was assessed by noninvasive aqueous flare measurement using laser flare photometry. METHODS: Patients were randomized 1:1 to verum (200 mg/ml 5-FU and 5 IU/ml dalteparin) and placebo (balanced salt solution) intravitreally applied during routine pars plana vitrectomy. MAIN OUTCOME MEASURES: Primary end point was the development of PVR grade CP (full-thickness retinal folds or subretinal strands in clock hours located posterior to equator) 1 or higher within 12 weeks after surgery. For grading, an end point committee assessed fundus photographs. Secondary end points included best-corrected visual acuity and redetachment rate. A group sequential design with 1 interim analysis was applied using the O'Brien and Fleming boundaries. Proliferative vitreoretinopathy grade CP incidence was compared using a Mantel-Haenszel test stratified by surgeon. RESULTS: A total of 325 patients in 13 German trial sites had been randomized (verum, n = 163; placebo, n = 162). In study eyes, mean laser flare was 31 ± 26 pc/ms. No significant difference was found in PVR rate. Primary analysis in the modified intention-to-treat population results were: verum 28% vs. placebo 23% (including not assessable cases as failures); odds ratio [OR], 1.25; 95% confidence interval [CI], 0.76-2.08; P = 0.77. Those in the per-protocol population were: 12% vs. 12%; OR, 1.05; 95% CI, 0.47-2.34; P = 0.47. None of the secondary end points showed any significant difference between treatment groups. During the study period, no relevant safety risks were identified. CONCLUSIONS: Rate of PVR did not differ between adjuvant therapy with 5-FU and LMWH and placebo treatment in eyes with RRD.

Doxycycline Ameliorates the Severity of Experimental Proliferative Vitreoretinopathy in Mice.

After successful surgeries for patients with rhegmatogenous retinal detachment, the most common cause of retinal redetachment is proliferative vitreoretinopathy (PVR), which causes severe vision impairment and even blindness worldwide. Until now, the major treatment for PVR is surgical removal of the epiretinal membrane, while effective treatment to prevent PVR is still unavailable. Therefore, we investigated the potential of doxycycline, an antibiotic in the tetracycline class, to treat PVR using a mouse model. We used the human retinal pigment epithelial cell line, ARPE-19, for in vitro and in vivo studies to test doxycycline for PVR treatment. We found that doxycycline suppressed the migration, proliferation, and contraction of ARPE-19 cells with reduced p38 MAPK activation and total MMP activity. Intravitreal doxycycline and topical tetracycline treatment significantly ameliorated the PVR severity induced by ARPE-19 cells in mice. PVR increased the expression of MMP-9 and IL-4 and p38 MAPK phosphorylation and modestly decreased IL-10. These effects were reversed by doxycycline and tetracycline treatment in the mouse retina. These results suggest that doxycycline will be a potential treatment for PVR in the future.

TRActional DIabetic reTInal detachment surgery with co-adjuvant intravitreal dexamethasONe implant: the TRADITION STUDY.

AIM: Main failure of diabetic tractional retinal detachment (TRD) surgery is the development of proliferative vitreoretinopathy (PVR), causing higher re-detachment rates. We investigated whether the use of dexamethasone (DEX) implant at the end of pars plana vitrectomy (PPV) with silicone oil tamponade might have an impact on these outcomes. DESIGN: Comparative, nonrandomized, retrospective study. PARTICIPANTS: A total of 148 eyes from 148 patients that underwent PPV with silicone oil tamponade for diabetic TRD (with DEX implant, n = 52; without DEX implant, n = 96). METHODS: Consecutive patients' records were reviewed for time between TRD diagnosis and surgery; lens status before surgery and after 6, 12, and 24 months; retina attachment rate after primary PPV; change in postoperative PVR severity; rate of re-detachment at 6, 12, and 24 months; use of IOP lowering treatment after 6, 12, and 24 months; surgery details; intra- and postoperative complications. Correlations between outcome measures, postoperative PVR severity, and re-detachment rates were analyzed. MAIN OUTCOME MEASURES: Change in postoperative PVR severity and retinal re-detachment rates with and without the adjuvant use of DEX implant. RESULTS: Retinal re-detachment rates were significantly higher in the group of patients that did not receive DEX implant [11/96 (11.5%) vs. 0/52 (0%), p = 0.049; 11/84 (12.9%) vs. 4/52 (7.7%), p = 0.007; 14/71 (19.7%) vs. 5/52 (10%) p < 0.001 at 6, 12, and 24 months, respectively]. PVR severity correlated with retinal status at 12 and 24 months (p = 0.018 and p = 0.027, respectively). The difference in PVR severity between the two groups was statistically significant at 6, 12, and 24 months (p < 0.001). CONCLUSIONS: DEX implant at the end of PPV in patients with diabetic TRD improves PVR severity and decreases re-detachment rates. This should be considered as an option in the customized treatment of TRD.

Plumbagin induces RPE cell cycle arrest and apoptosis via p38 MARK and PI3K/AKT/mTOR signaling pathways in PVR.

BACKGROUND: This study aimed to explore the effects of plumbagin (PLB) on ARPE-19 cells and underlying mechanism. METHODS: Cultured ARPE-19 cells were treated with various concentrations (0, 5, 15, and 25 µM) of PLB for 24 h or with 15 µM PLB for 12, 24 and 48 h. Then cell viability was evaluated by MTT assay and DAPI staining, while apoptosis and cell cycle progression of ARPE cells were assessed by flow cytometric analysis. Furthermore, the level of main regulatory proteins was examinated by Western boltting and the expression of relative mRNA was tested by Real-Time PCR. RESULTS: PLB exhibited potent inducing effects on cell cycle arrest at G2/M phase and apoptosis of ARPE cells via the modulation of Bcl-2 family regulators in a concentration- and time-dependent manner. PLB induced inhibition of phosphatidylinositol 3-kinase (PI3K) and p38 mitogen-activated protein kinase (p38 MAPK) signaling pathways contributing to the anti-proliferative activities in ARPE cells. CONCLUSIONS: This is the first report to show that PLB could inhibit the proliferation of RPE cells through down-regulation of modulatory signaling pathways. The results open new avenues for the use of PLB in prevention and treatment of proliferative vitreoretinopathy.

Cytokine profiling in the sub-silicone oil fluid after vitrectomy surgeries for refractory retinal diseases.

Silicone oil (SO) is an intraocular surgical adjuvant that reduces the surgical complications in refractory retinal diseases, although membrane and cellular proliferation is often seen even in SO-filled eyes. We hypothesised that the fluid in the space between the SO and the retina, named the "sub-silicone oil fluid (SOF)", enhances these biological responses. We proposed a safe method for SOF extraction. We also analysed inflammatory cytokine expressions and SOF osmotic pressures from eyes with rhegmatogenous retinal detachment (RRD), proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy (PVR) and macular hole-associated retinal detachment (MHRD). Interleukin (IL)-10, IL-12p40, IL-6, monocyte chemotactic protein-1, and vascular endothelial growth factor (VEGF) in the SOF with PVR were significantly higher than in those with RRD or MHRD. Fibroblast growth factor-2, IL-10, IL-12p40, IL-8, VEGF, and transforming growth factor beta 1 levels in eyes with exacerbated PDR indicated a significantly higher expression than those with simple PDR. IL-6 and tumour necrosis factor alpha in eyes with exacerbated PVR demonstrated a significantly higher expression than in those with simple PVR. However, there was no difference in SOF osmotic pressure between group of each disease. These studies indicate that disease-specific SOF is a significant reflection of disease status.

Epigallocatechin gallate & curcumin prevent transforming growth factor beta 1-induced epithelial to mesenchymal transition in ARPE-19 cells.

Background & objectives: Proliferative vitreoretinopathy (PVR) is characterized by the presence of epiretinal membrane (ERM), which exerts traction and detaches the retina. Epithelial to mesenchymal transition (EMT) of the retinal pigment epithelial (RPE) cells underlies ERM formation. Adjuvant therapies aimed at preventing recurrence of PVR after surgery mostly failed in clinical trials. This study was aimed to evaluate the anti-EMT properties of bio-active compounds epigallocatechin gallate (EGCG), curcumin and lycopene as inhibitors of EMT induced by transforming growth factor beta 1 (TGF-ß1) in cultured ARPE-19 cells. Methods: ARPE-19 cells were treated with TGF-ß1 alone or co-treated with EGCG (1-50 µM), lycopene (1-10 µM) and curcumin (1-10 µM). The mRNA and protein expression of EMT markers, alpha-smooth muscle actin, vimentin, zonula occludens-1 and matrix metalloproteinase-2 (MMP-2), were assessed by reverse transcription polymerase chain reaction/quantitative polymerase chain reaction and immunofluorescence/enzyme linked immunosorbent assay. Activity of MMP-2 was assessed by zymography. Functional implications of EMT were assessed by proliferation assay (MTT assay) and migration assay (scratch assay). Western-blot for phosphorylated Smad-3 and total Smad-3 was done to delineate the mechanism. Results: EGCG and curcumin at 10 µM concentration reversed EMT, inhibited proliferation and migration through Smad-3 phosphorylation, when induced by TGF-ß1 in ARPE-19 cells. Lycopene did not prevent EMT in ARPE-19 cells. Interpretation & conclusions: EGCG and curcumin are potent in preventing EMT induced by TGF-ß1 in ARPE-19 cells and therefore, proposed as potential molecules for further pre-clinical evaluation in PVR management.

Effect of Guibi-Tang, a Traditional Herbal Formula, on Retinal Neovascularization in a Mouse Model of Proliferative Retinopathy.

Ocular pathologic angiogenesis is an important causative risk factor of blindness in retinopathy of prematurity, proliferative diabetic retinopathy, and neovascular macular degeneration. Guibi-tang (GBT) is a frequently used oriental herbal formula in East Asian countries, and is also called Qui-pi-tang in Chinese and Kihi-To in Japanese. In the present study, we investigated the preventive effect of GBT on retinal pathogenic neovascularization in a mouse model of oxygen-induced retinopathy (OIR). C57BL/6 mice were exposed to 75% hyperoxia for five days on postnatal day 7 (P7). The mice were then exposed to room air from P12 to P17 to induce ischemic proliferative retinopathy. GBT (50 or 100 mg/kg/day) was intraperitoneally administered daily for five days (from P12 to P16). On P17, Retinal neovascularization was measured on P17, and the expression levels of 55 angiogenesis-related factors were analyzed using protein arrays. GBT significantly decreased retinal pathogenic angiogenesis in OIR mice, and protein arrays revealed that GBT decreased PAI-1 protein expression levels. Quantitative real-time PCR revealed that GBT reduced vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), and plasminogen activator inhibitor 1 (PAI-1) mRNA levels in OIR mice. GBT promotes potent inhibitory activity for retinal neovascularization by decreasing VEGF, FGF2, and PAI-1 levels.

A Novel Approach of Daunorubicin Application on Formation of Proliferative Retinopathy Using a Porous Silicon Controlled Delivery System: Pharmacodynamics.

PURPOSE: Proliferative vitreoretinopathy (PVR) is the most common cause of poor visual outcomes in association with retinal detachment surgeries and ocular trauma. Daunorubicin (DNR) has shown the strongest efficacy in proliferation inhibition in vitro. However, clinical studies have shown only mild effect owing to limitations of narrow therapeutic window and short vitreous half-life. METHODS: Three milligrams of DNR-loaded particles were intravitreally injected into 18 pigmented rabbits, and vitreous samples were collected up to 84 days for analysis. Thirty-seven rabbits were used for a dose-escalation (1, 3, 6 mg) safety and efficacy study in a rabbit PVR model using a pretreatment design. RESULTS: Loading efficiency of DNR was 108.55 ± 12 µg per 1 mg particles. Eighty-four days of follow-up did not reveal any adverse reaction. Pharmacokinetic analysis demonstrated a vitreous half-life of 29 days with a maximum DNR concentration of 178 ng/mL and a minimum concentration of 29 ng/mL at day 84. Daunorubicin-loaded porous silicon (pSi) particles were dosed 8 to 9 weeks before PVR induction, and PVR severity score was dose dependent (Spearman ρ = -0.25, P = 0.0005). Proliferative vitreoretinopathy with tractional retinal detachment was 88% in the control group, 63% in the low-dose group, 14% in the medium-dose group, and 0% in the high-dose group (Cochran-Armitage Trend Test, Z = 8.99, ρ = -0.67, P < 0.0001). CONCLUSIONS: Daunorubicin-loaded pSi particles can safely reside in the vitreous for at least 3 months. The pSi-based delivery expanded the therapeutic window of DNR by a factor of 862 and drove down the minimum effective concentration by a factor of 175.

Ozurdex (a slow-release dexamethasone implant) in proliferative vitreoretinopathy: study protocol for a randomised controlled trial.

BACKGROUND: Proliferative vitreoretinopathy (PVR) is the commonest cause of late anatomical failure in rhegmatogenous retinal detachment. Visual and anatomical outcomes remain poor despite advances in vitreoretinal surgical techniques with reported primary failure rates of up to nearly 50%. Numerous adjunctive medications have been evaluated in clinical trials with no agent gaining widespread acceptance and use.This study was designed to investigate the benefits of using a slow-release dexamethasone implant delivered intra-operatively in patients undergoing vitrectomy surgery for retinal detachment with established PVR. METHODS/DESIGN: For the study, 140 patients requiring vitrectomy surgery with silicone oil for retinal detachment with established PVR will be randomised to receive either standard treatment or study treatment in a 1:1 treatment allocation ratio. Both groups will receive the standard surgical treatment appropriate for their eye condition and routine peri-operative treatment and care, differing only in the addition of the supplementary adjunctive agent in the treatment group. The investigated primary outcome measure is stable retinal reattachment with removal of silicone oil without additional vitreoretinal surgical intervention at 6 months. DISCUSSION: This is the first randomised controlled clinical trial to investigate the use of an adjunctive slow-release dexamethasone implant in patients undergoing vitrectomy surgery for retinal detachments with proliferative vitreoretinopathy. TRIAL REGISTRATION: EudraCT No: 2011-004498-96.

Curcumin, a potential therapeutic candidate for retinal diseases.

Curcumin, the major extraction of turmeric, has been widely used in many countries for centuries both as a spice and as a medicine. In the last decade, researchers have found the beneficial effects of curcumin on multiple disorders are due to its antioxidative, anti-inflammatory, and antiproliferative properties, as well as its novel function as an inhibitor of histone aectyltransferases. In this review, we summarize the recent progress made on studying the beneficial effects of curcumin on multiple retinal diseases, including diabetic retinopathy, glaucoma, and age-related macular degeneration. Recent clinical trials on the effectiveness of phosphatidylcholine formulated curcumin in treating eye diseases have also shown promising results, making curcumin a potent therapeutic drug candidate for inflammatory and degenerative retinal and eye diseases.

[Densiron-68 heavy silicone oil in cases of PVR. Anatomic and functional outcomes]. / Schweres Silikonöl bei PVR. Anatomische und funktionelle Ergebnisse.

PURPOSE: To evaluate the safety and efficacy of Densiron-68 heavy silicone oil in the clinical management of complex retinal detachments with proliferative vitreoretinopathy (PVR). METHODS: We present a prospective, interventional noncomparative case series of 80 eyes of 79 consecutive patients. The primary end point was anatomical reattachment of the retina, defined as retinal reattachment in the absence of any tamponade agent. The secondary end point was to record the visual function and surgical complications. Inclusion criteria were PVR stages B-CA4, including posterior or inferior retinal breaks and the patient's inability to posture. RESULTS: Patients were 59.1 (+/-18.1) years old, male:female =48:32, R:L=40:40. Fifty-six patients (70%) had previous unsuccessful retinal surgery, and 24 (30%) received heavy silicone oil at their first procedure. The extent of the detachments was 2.46 quadrants (+/-0.83) with macular involvement in 49 cases (61%). Fifty-six (67.5%) patients achieved retinal reattachment with one retinal operation and no tamponade, 64 (80%) achieved retinal reattachment with more than one operation and no tamponade, and 72 (90%) achieved a flat retina with tamponade in situ. Visual acuity rose from 1.48 LogMar (+/-0.91) to 1.12 (+/-0.82; p=0.009). Densiron was removed after 126 days (+/-55.1). CONCLUSION: The treatment of PVR remains challenging. No tamponade agent can provide simultaneous support for the superior as well as the inferior retina; therefore, a tamponade agent that "sinks" is a welcome new tool for the surgeon. We regard the use of heavy as well as conventional silicone oil as complementary to each other.

[Pharmacological adjuvants for surgical treatment of proliferative vitreoretinopathy]. / Adjuvants pharmacologiques du traitement chirurgical de la prolifération vitréorétinienne.

Proliferative vitreoretinopathy (PVR) is the major cause of retinal detachment surgery failure. Many adjuvants were studied in vitro and on animals, some were studied on humans. Daunomycin seems to reduce PVR recidivism. 5-FU and steroids are nontoxic but their efficacy is not clear. Heparin reduced postoperative inflammation and seems to reduce PVR recidivism when associated with 5-FU. Associating heparin and steroids seems to reduce PVR in some groups of patients (aphakic, anterior PVR). Colchicine and retinoic acid per os are ineffective, silicone oil is effective as an internal tamponade but not as an adjuvant of PVR. Currently, no molecule has proven efficacy as an adjunctive treatment of PVR.

[Experimental study of nimodipine and vascular endothelial growth factor in proliferative retinopathy].

OBJECTIVE: To study the therapeutic effect of the calcium channel antagonist nimodipine on the proliferative retinopathy and it's interaction with vascular endothelial growth factor (VEGF). METHODS: A proliferative retinopathy model (OIR) of newborn Sprague-Dawley (SD) rats was induced by hyperoxia. Different dosages of nimodipine were injected to the rats through retrobulbar or intraperitoneal routes. Both eyeballs of newborn rats were enucleated for performing pathological sections and were studied by immunohistochemical method, in order to count the nuclei of proliferative retinal vessels and to investigate the expression of VEGF in the retina. RESULTS: The number of nuclei of proliferative retinal vessels and the expression of VEGF in non-treatment group increased significantly as compared with normal control group (P < 0.01). Both parameters decreased significantly in high dosage and medium dosage of retrobulbar injection group as compared with the non-treatment group (P < 0.01) and there was no significant decrease in low dosage group (P > 0.05). In each dosage group of intraperitoneal injection, there was a significant decrease of the expression of VEGF (P > 0.01). CONCLUSION: VEGF can induce cell proliferation by activating the calcium channel in cell membrane through which the influx of calcium is increased. The calcium channel antagonist nimodipine can inhibit proliferative retinopathy by blocking the influx of calcium. Nimodipine can inhibit the expression of VEGF at certain degrees.

Triamcinolone-assisted pars plana vitrectomy for proliferative vitreoretinopathy.

PURPOSE: To determine whether triamcinolone acetonide (TAAC) staining facilitates posterior hyaloid and epiretinal membrane (ERM) removal in patients undergoing pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment (RRD) with proliferative vitreoretinopathy (PVR). METHODS: Ten consecutive pseudophakic patients (10 eyes) underwent PPV for RRD with PVR. After a core PPV, a few drops of a commercially available TAAC aqueous suspension (40 mg/mL) with vehicle were injected into the mid vitreous cavity to visualize the posterior hyaloid, thus allowing a complete posterior hyaloidectomy. Next, 0.1 to 0.2 mL of TAAC was applied on the retinal surface to visualize and peel the ERMs. The tamponading agent was silicone oil (1,300 cs) in eight eyes and perfluropropane (C3F8 14%) in two eyes. The minimal follow-up period in all patients was 4 months. RESULTS: In all patients, intraoperative staining with TAAC consistently improved direct visualization and delineation of the posterior hyaloid and ERMs and facilitated their removal. No adverse reaction related to the use of TAAC was observed immediately postoperatively or 4 months after surgery. CONCLUSIONS: Intravitreal TAAC may be an important adjuvant tool in the delineation of posterior hyaloid and ERMs, allowing for a more complete and safer ERM removal in the surgical management of PVR complicating RRD. It is well tolerated with all its vehicle if used at low concentration and rapidly removed during surgery.

The effect of prinomastat (AG3340), a potent inhibitor of matrix metalloproteinases, on a subacute model of proliferative vitreoretinopathy.

PURPOSE: To determine the efficacy of prinomastat (AG3340), a synthetic inhibitor of matrix metalloproteinase, in the treatment of experimental proliferative vitreoretinopathy (PVR) induced by intravitreal dispase injection. METHODS: One eye each of 53 New Zealand white rabbits was injected in the vitreous cavity with 0.07 unit of dispase to induce PVR. One week after PVR induction, 53 rabbits were randomized (27:26) to receive 0.5 mg prinomastat or the vehicle of the drug (acidified water) intravitreally every two weeks. The scores of PVR severity (scale of 1-5) were graded to compare the prinomastat-treated animals with the control group. RESULTS: The average PVR scores in the treatment and control groups were 2.62 and 3.57 respectively (p = 0.038; Wilcoxon rank sum). Clinically significant PVR with retinal detachment (PVR > or = grade 3) developed in 76% of rabbits in the control group versus 51% of rabbits treated with prinomastat. CONCLUSIONS: Intravitreally administered prinomastat decreased development of PVR in an experimental model which made use of dispase to induce PVR.

Effects of EGb761 and superoxide dismutase in an experimental model of retinopathy generated by intravitreal production of superoxide anion radical.

BACKGROUND: A study was carried out to investigate the effect of two antioxidants--Ginkgo biloba extract (EGb761) and superoxide dismutase (SOD)--in an experimental model of vitreoretinopathy obtained by direct production of oxygen free radicals in the vitreous cavity. METHODS: Twenty-eight pigmented rabbits were used. Vitreoretinopathy was induced by intravitreal injection of 50 microliters of a mixture composed of 40 nmol of xanthine and 0.001 IU of xanthine oxidase. Rabbits were randomly distributed into four groups: Group 1 (n = 8) did not receive any treatment and served as a positive control. Groups 2 (n = 8) and 3 (n = 8) received for 1 month EGb761 given orally at a dose of 100 mg/kg/day, respectively 1 day after and 1 week before induction of retinopathy. Group 4 (n = 4) was treated by three intramuscular injections of 15,000 IU/kg of SOD, 24 h before induction and 24 and 48 h thereafter. Clinical evaluations and electroretinograms (ERG) were repeatedly performed until the animals were killed at day 28. Histological examinations and immunohistological procedures were performed to ascertain the origin and characteristics of the cellular proliferation and to compare vitreoretinal structures in the four groups. RESULTS: Intravitreal injection of xanthine-xanthine oxidase produced a strong inflammatory response with vitreous infiltrates and epiretinal membrane formation, inconstantly associated with retinal detachment. ERG showed a decrease of the a-, b- and c-waves beginning within a few hours after injection. Histologic evaluation found an intravitreal and epiretinal infiltration by leukocytes and epithelial-derived cells, dense vitreoretinal membranes and retinal detachments with occasional neovascularization. In the treated groups (groups 2-4), all clinical, electric and histologic data were significantly improved compared to the control group. However, no difference could be found among the three treated groups. CONCLUSION: This study demonstrates the strong pathologic effects of free radical production on the retina and the close relationships between free radicals, inflammatory pathways and vitreoretinal proliferative disorders. It also confirms the pharmacological interest of prevention by antioxidants and free radical scavengers.

Adjunctive daunorubicin in the treatment of proliferative vitreoretinopathy: results of a multicenter clinical trial. Daunomycin Study Group.

PURPOSE: To assess the efficacy and safety of adjunctive daunorubicin during vitrectomy surgery in eyes with idiopathic proliferative vitreoretinopathy (PVR). METHODS: Two hundred eighty-six eyes (286 patients) with stage C2 (Retina Society Classification, 1983) or more advanced preoperative PVR in which surgery with silicone oil was planned were enrolled in a multicenter, prospective, randomized, controlled clinical trial. Standardized surgery plus adjunctive daunorubicin perfusion was compared with surgery alone. Outcomes assessed were retinal attachment without additional vitreoretinal surgery 6 months after standardized surgery, number of and time until vitreoretinal reoperations within 1 year of standardized surgery, and change in visual acuity 1 year after standardized surgery, evaluated by photodocumentation, number of reoperations, and measurement of best-corrected visual function. Outcomes were determined 6 months after operation and reevaluated after 1 year of follow-up. RESULTS: Six months after standardized surgery, complete retinal reattachment without additional vitreoretinal surgery was achieved in 62.7% (89/142) of eyes in the daunorubicin group vs 54.1% (73/135) in the control group (P = .07, one-sided). However, in the daunorubicin group, significantly fewer vitreoretinal reoperations were performed within 1 year postoperatively (P = .005, one-sided) to achieve the same overall 1-year retinal reattachment rate (80.2% [105/131] vs 81.8% [103/126]). The rate of patients with no vitreoretinal reoperations was 65.5% (95/145) in the daunorubicin group vs 53.9% (76/141) in the control group. There was no difference in the best-corrected visual acuity. No severe adverse effect related to daunorubicin was identified. CONCLUSIONS: Although the rate of anatomic success after 6 months failed to show significance, some benefit of the adjunctive treatment exists, especially a tendency toward increased rate of reattachment and a significant reduction in the number of reoperations. This shows that human PVR is amenable to pharmacologic treatment.

Vitamin E inhibits retinal pigment epithelium cell proliferation in vitro.

Retinal pigment epithelium (RPE) cells migrating through the damaged retina play an important role in the pathogenesis of proliferative vitreoretinopathy (PVR). We found that alpha-tocopherol (vitamin E) inhibits proliferation of human RPE in culture without exerting cytotoxic effects. Maximal inhibition was achieved with 100 microM alpha-tocopherol. Our result could explain the observation that vitamin E supplements have an adverse effect on light-damaged retina and on the course of retinitis pigmentosa. Since it has been shown that supplemental oral administrations of vitamin E can raise the RPE concentration of alpha-tocopherol well above 100 microM and supplementation is not associated with any clinical relevant adverse effect, we believe that vitamin E could be beneficial in the treatment of PVR.