Review Article | Open Access
Golnaz Javey, Stephen G. Schwartz, Harry W. Flynn, "Emerging Pharmacotherapies for Diabetic Macular Edema", Journal of Diabetes Research, vol. 2012, Article ID 548732, 12 pages, 2012. https://doi.org/10.1155/2012/548732
Emerging Pharmacotherapies for Diabetic Macular Edema
Diabetic macular edema (DME) remains an important cause of visual loss in patients with diabetes mellitus. Although photocoagulation and intensive control of systemic metabolic factors have been reported to achieve improved outcomes in large randomized clinical trials (RCTs), some patients with DME continue to lose vision despite treatment. Pharmacotherapies for DME include locally and systemically administered agents. We review several agents that have been studied for the treatment of DME.
Diabetic macular edema (DME) is one of the most common causes of visual loss in patients with diabetes mellitus . The pathophysiology of DME involves dilated capillaries, retinal microaneurysms, and loss of pericytes, with eventual impairment of the blood-retinal barrier (BRB) . Breakdown of the BRB results in fluid leakage into the extracellular space, which disrupts macular structure and function on a cellular level [3, 4]. A technique for visualizing molecules leaked through the outer BRB in a diabetic rodent model has recently been described, which should increase our understanding of this process .
This leakage may be analyzed in terms of physical forces . Starling’s Law states that the net flow of fluid across a vessel wall is increased by hydrostatic pressure within the lumen of the vessel and decreased by oncotic pressure within the lumen. In diabetic patients, hydrostatic pressure may be increased because of systemic hypertension and retinal ischemia, increasing the likelihood of exudation. This problem is exacerbated because increased hydrostatic pressure may lead to dilatation and tortuosity of retinal arterioles, capillaries, and venules, which increases vessel wall tension and further disruption of the BRB according to LaPlace’s Law . Other factors may also contribute to this edema, such as osmotic stress leading to Muller cell swelling, such as that reported with retinal detachment .
The pathogenesis of DME is at this time poorly defined, but is believed to involve angiogenesis, inflammation, and oxidative stress . Hyperglycemia is reported to lead to capillary endothelial damage and alterations in leukocyte function . In addition, hyperglycemia has been reported to activate oxidative stress agents, such as advanced glycation endproducts and the protein kinase C (PKC) pathway . Various inflammatory mediators appear to play a role in promoting DME, including vascular endothelial growth factor (VEGF) , placental growth factor (PlGF) , and hepatocyte growth factor (HGF) .
The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) reported that approximately 14% of patients with type 2 diabetes developed DME over a 10-year period . More recently, the 10-year incidence of DME in a Spanish population of patients with type 1 diabetes was reported as approximately 11% . Reported risk factors for diabetic retinopathy and DME include duration of diabetes, as well as the severity of hyperglycemia, hypertension, and hyperlipidemia .
Intensive control of systemic factors, including blood sugar, blood pressure, and serum lipids, has been reported to reduce complications of diabetic retinopathy in patients with type 1  and type 2  diabetes. Macular photocoagulation was demonstrated as a treatment for clinically significant macular edema (CSME) by the Early Treatment Diabetic Retinopathy Study (ETDRS) in 1985 . Newer clinical trials using intravitreal pharmacotherapies have reported many favorable outcomes. The current paper will review the literature and various randomized clinical trials (RCTs) on emerging pharmacotherapies for the treatment of DME.
2. Ocular Agents
Corticosteroids may have multiple mechanisms of action in the treatment of DME. In addition to their anti-inflammatory properties, corticosteroids have been reported to reduce the activity of VEGF . Intravitreal triamcinolone acetonide (IVTA) has been reported for the treatment of DME (Figure 1) (Table 1). Currently, there are at least four preparations reported in clinical studies: Kenalog-40 (Bristol-Myers Squibb, Princeton, NJ, USA); preservative-free triamcinolone acetonide from compounding pharmacies; Triesence (Alcon, Fort Worth, TX, US); and Trivaris (Allergan, Irvine, CA, USA).
The Diabetic Retinopathy Clinical Research Network (DRCR) protocol B compared two doses (1 and 4 mg) of IVTA versus photocoagulation for DME . For most patients, photocoagulation produced more favorable outcomes than did IVTA at 24 months of followup. Similar results were reported at 3-year followup . The most common complications of IVTA are cataract formation  and increased intraocular pressure (IOP) . Pseudoendophthalmitis  and infectious endophthalmitis occur much less commonly. The rate of infectious endophthalmitis after IVTA is low in reported series. For example, in an analysis of two large RCTs (from the DRCR network and the Standard Care Versus Corticosteroid for Retinal Vein Occlusion (SCORE) trials), the rate of endophthalmitis after IVTA was 0.05% .
A triamcinolone-eluting intravitreal implant (I-vation, SurModics, Inc., MN, USA) for the treatment of DME was suspended in a phase 2b RCT after the publication of the DRCR network results showing a benefit of laser photocoagulation over IVTA in treatment of DME .
In order to reduce the risk of complications associated with IVTA, the use of peribulbar triamcinolone was investigated. In a single-center, prospective trial, peribulbar triamcinolone demonstrated lesser efficacy than did IVTA . The DRCR reported that peribulbar triamcinolone did not significantly benefit patients with mild DME and visual acuity of 20/40 or better .
To reduce the need for repeated intravitreal injections, several extended-release corticosteroid delivery systems have been studied. A fluocinolone-acetonide- (FA-) eluting intravitreal implant (Retisert, Bausch and Lomb, NY, USA) has received FDA approval for the treatment of chronic, noninfectious posterior segment uveitis . This is a nonbiodegradable device that releases 0.59 μg/day of FA into the vitreous cavity. It must be implanted in an operating room or similar setting. In an RCT, the effects of the device versus photocoagulation for DME were studied. At one year, DME was resolved by clinical examination and optical coherence tomography (OCT) in 57% of patients with the FA implant versus 20% of patients with photocoagulation. There were no statistically significant differences in final visual acuity between the two groups . At 3 years, patients randomized to receive the FA implant had persistent treatment of macular edema, but 95% of phakic eyes developed significant cataract, and about one-third of eyes had IOP above 30 mm Hg .
A smaller fluocinolone acetonide-eluting device (Iluvien, Alimera Sciences, Alpharetta, GA, USA) may be administered through a 25-gauge device in a clinic setting. The Famous (Pharmacokinetic and Efficiency Study of Fluocinolone Acetonide Inserts in Patients with DME) study compared 0.2 versus 0.5 μg/day fluocinolone injection devices in patients with persistent DME despite at least one previous focal/grid laser therapy . There was a mean improvement of 5 letters in visual acuity in both groups at 3-month followup. The number of patients in the trial was too small to determine whether there were clinically meaningful differences in results obtained from the two doses.
The Fluocinolone Acetonide for Macular Edema (FAME) study comprised 2 phase 3 RCTs assessing the efficacy and safety of 0.2 μg/day (low dose) and 0.5 μg/day (high dose) inserts in patients with DME with persistent edema despite at least one macular laser treatment . The primary study endpoint was defined as improvement in visual acuity by 15 or more letters at 2 years. At 24 months, the primary endpoint was achieved in 28.7% and 28.6% of low- and high- dose insert groups compared with 16.2% in the sham group. Elevated intraocular pressure requiring incisional surgery occurred in 3.7%, 7.6%, and 0.5% of the low-dose, high-dose, and sham groups, respectively.
The dexamethasone drug delivery system (DDS) [Ozurdex, Allergan, Irvine, California] is a biodegradable, sustained-release device approved by the US FDA for the treatment of macular edema associated with retinal vein occlusion and noninfectious posterior segment uveitis. A phase 2 RCT in patients with persistent macular edema secondary to various etiologies, including DME, showed that the dexamethasone DDS produced improvements in visual acuity, macular thickness, and fluorescein leakage that were sustained for up to 6 months . In an RCT, the safety and efficacy of the dexamethasone DDS in the treatment of DME was studied . Patients with persistent macular edema (at least 90-day duration) were randomized to treatment with 700 μg or 350 μg of dexamethasone DDS or observation. At 3 months, visual acuity improved by 10 letters or more in 30% of eyes in the 700 μg group, 20% of eyes in the 350 μg group, and 12% of eyes in the observation group. A more recent study reported that the dexamethasone DDS improved visual acuity and macular edema in previously vitrectomized eyes with diffuse DME .
2.2. Vascular Endothelial Growth Factor Antagonists
VEGF appears to play an important role in the pathogenesis of diabetic retinopathy . In animal models, injection of VEGF causes breakdown of the BRB , and elevated levels of VEGF cause macular edema . An oral nonselective blocker of VEGF receptor was found to reduce DME, suggesting that VEGF antagonists may provide benefit in treatment of DME . Four intravitreal anti-VEGF agents are currently available commercially, although none is FDA-approved for the treatment of DME (Table 2).
Pegaptanib (Macugen, Eyetech Pharmaceuticals, Palm Beach Gardens, FL, USA) is a pegylated aptamer that targets the VEGF165 isoform. Pegaptanib is approved by the FDA for the treatment of neovascular age-related macular degeneration (AMD) and was the first anti-VEGF medication reported to have efficacy in the treatment of DME. The Macugen Diabetic Retinopathy Study Group conducted a phase 2 RCT of pegaptanib for fovea-involving DME . After 36 weeks of followup, the pegaptanib-treated eyes had better visual acuity, more reduction in central retinal thickness, and less need for laser photocoagulation compared to the sham group. More recently, a phase 2/3 RCT reported that pegaptanib therapy was associated with improved visual outcomes in patients with DME for up to 2 years .
Bevacizumab (Avastin, Genentech, Inc., South San Francisco, CA, US) is a full-length recombinant humanized antibody against all isoforms of VEGF-A. Bevacizumab is approved by the FDA for the systemic treatment of metastatic colorectal cancer, metastatic breast cancer, and nonsmall cell lung cancer . The agent is used commonly as an off-label intravitreal injection (Figure 2). The DRCR network conducted a randomized study of 121 eyes with DME over a 12-week period . There were five treatment arms: focal photocoagulation, 2 consecutive 1.25 mg bevacizumab injections, 2 consecutive 2.5 mg bevacizumab injections, 1.25 mg bevacizumab followed by sham injection, and combination of photocoagulation with 2 consecutive 1.25 mg bevacizumab injections. The groups that received two bevacizumab injections without laser had a significant improvement in visual acuity over the laser-only group. There were no detectable differences between the 1.25 mg and 2.5 mg doses. The single injection group had no advantage over the laser-only group. The combination of laser and bevacizumab had comparable results to the laser-only group with a trend toward worse short-term vision than eyes that received two bevacizumab injections. The DRCR is currently planning an RCT to compare bevacizumab to ranibizumab in the treatment of DME.
In the BOLT (Bevacizumab Or Laser Therapy in the Management of DME) study, repeated intravitreal bevacizumab injections were compared with modified ETDRS photocoagulation in patients with persistent DME. A total of 80 patients with center-involving DME and at least one prior photocoagulation without evidence of advanced macular ischemia were included. Patients were randomized to 2 arms: intravitreal bevacizumab (injections at baseline, 6- and 12-week followup with subsequent injections every 6 weeks based on OCT-guided retreatment protocol) or photocoagulation (at baseline with subsequent retreatment every 4 months if clinically indicated by ETDRS guidelines). At 12 months, bevacizumab had a greater treatment effect than did photocoagulation. The bevacizumab arm gained a median of 8 ETDRS letters, whereas the photocoagulation group lost a median of 0.5 ETDRS letters. Approximately 31% of patients in the bevacizumab arm versus 7.9% of patients in the laser arm gained ≥10 ETDRS letters (). The decrease in central macular thickness was significantly more in the bevacizumab group compared to the photocoagulation group . There was no progression of macular ischemia in either treatment group .
Ranibizumab (Lucentis, Genentech, Inc. South San Francisco, CA, USA) is a recombinant humanized monoclonal antibody fragment that binds all isoforms of VEGF-A with high affinity. Ranibizumab is FDA-approved for the treatment of neovascular AMD and retinal vascular occlusion [48–51]. The Ranibizumab for Edema of the Macula in Diabetes (READ-2) study randomized 126 eyes with DME to 3 groups: ranibizumab only (injection at baseline, months 1, 3, and 5); photocoagulation (at baseline and at 3 months if needed); combined ranibizumab and photocoagulation (photocoagulation and ranibizumab at baseline, and ranibizumab at 3 months if needed) . Patients randomized to ranibizumab only showed a significantly better visual outcome at 6 months compared with the other 2 groups. For patients with data available at 6 months, improvement of 3 lines or more in vision occurred in 22% of patients in the ranibizumab-only arm, none in the photocoagulation-only arm, and 8% in combined arm. At 24 months, the study reported that intravitreal ranibizumab provided persistent treatment benefits .
DRCR protocol I evaluated ranibizumab and IVTA in combination with photocoagulation by randomizing patients into four arms: ranibizumab with prompt (within one week) photocoagulation, IVTA with prompt photocoagulation, sham injection with prompt photocoagulation, and ranibizumab with photocoagulation deferred for at least 24 weeks . The treatment protocol included a baseline treatment followed by intravitreal study medication or sham injection retreatments every 4 weeks through the 12-week visit. After the 16-week visit, retreatment was at the investigator’s discretion according to web-based predetermined criteria. Ranibizumab with prompt or deferred photocoagulation resulted in more favorable visual acuity and central macular thickness outcomes compared with photocoagulation alone at 1 and 2 years of followup. In ranibizumab-treated eyes, the results were similar whether photocoagulation was given with the first injection or deferred for at least 24 weeks. IVTA combined with photocoagulation did not result in better visual outcomes compared with photocoagulation alone. In pseudophakic eyes, the IVTA with prompt photocoagulation group had similar visual outcomes to the 2 ranibizumab groups, suggesting that cataract formation may have affected the visual acuity outcomes in phakic eyes treated with IVTA. Two-year visual outcomes were similar to 1-year results and reinforced the conclusion that ranibizumab with prompt or deferred photocoagulation should be considered for patients with vision impairment of worse than 20/32 secondary to DME . This study utilized a web-based algorithm to determine treatment decisions; in clinical practice, this may not be feasible, but the general approach may be emulated .
The RESTORE phase 3 study reported that ranibizumab monotherapy or combined with laser photocoagulation provided superior visual acuity gain over standard photocoagulation in the treatment of DME . The one-year results showed that 37% of patients treated with ranibizumab 0.5 mg alone, and 43% of those treated with ranibizumab plus laser therapy, gained vision improvement of 10 letters or more compared to 16% of patients treated with laser alone. At one year, no difference was detected between the ranibizumab and ranibizumab plus laser arms.
A recent study showed that the addition of one IVTA injection or two ranibizumab injections to eyes receiving focal laser treatment for DME and panretinal photocoagulation is associated with significantly better visual acuity and decreased macular edema by 14 weeks . However, these improvements were not maintained when study subjects were followed for 56 weeks for safety outcomes.
Two additional phase 3 RCTs (RISE and RIDE) were conducted to evaluate the efficacy, durability, and long-term safety of monthly ranibizumab injections in patients with center-involving DME. The primary efficacy outcome was the proportion of subjects who gained more than 15 letters in visual acuity compared with baseline at 24 months. Patients were randomized 1 : 1 : 1 to receive monthly injections of 0.3 mg ranibizumab, 0.5 mg ranibizumab, or sham. These studies were not designed to compare the two doses of ranibizumab, but each dose against the sham injection. At 24 months, RISE met its primary endpoint with statistically significant improvements in vision in ranibizumab-treated patients compared to sham injections .
The safety and efficacy of 2 concentrations of intravitreal ranibizumab in the treatment of DME were compared in the RESOLVE phase 2 trial . Subjects were randomized to receive 3 monthly injections with either 0.3 or 0.5 mg ranibizumab or placebo. Treatment was then administered on an as-needed basis, depending on the response to initial treatment. If edema persisted, then the dose of ranibizumab was doubled after 1 month. Photocoagulation after 3 injections was given if needed. When the pooled data from the double-dose ranibizumab group () were compared with the sham group (), there were statistically significant improvements in vision and central macular thickness.
In contrast to intravitreal corticosteroids, cataract progression associated with intravitreal VEGF antagonists has not been identified. Some patients do sustain IOP elevation following repeated injections of VEGF antagonists , but this effect does not appear to be as strong as that associated with intravitreal corticosteroids. In most published series, the rate of endophthalmitis following treatment with intravitreal anti-VEGF injections is about 0.03% per injection [62–64]. The incidence and severity of systemic and ocular adverse events that are associated with repeated intravitreal injections of two doses of ranibizumab (0.5 mg versus 2.0 mg) in subjects with DME are being investigated in READ-3 study.
Aflibercept, or VEGF trap-eye, (Eylea, Regeneron, Tarrytown, NY, USA), is a recombinant fusion protein with activity against all VEGF-A isoforms and PlGF that is FDA-approved for the treatment of neovascular AMD and has been shown to have short-term efficacy in the treatment of DME . The DA-VINCI study assessed the efficacy and safety of intravitreal aflibercept versus laser photocoagulation in the treatment of DME. Patients were randomized to one of the following treatment arms: 0.5 mg aflibercept every 4 weeks, 2 mg aflibercept every 4 weeks, 2 mg aflibercept every 8 weeks, 2 mg aflibercept as needed, or photocoagulation. At 24 weeks, the mean change in BCVA for aflibercept arms ranged from +8.5 to +11.4 letters compared to the mean change of +2.5 letters in the laser-treated eyes (). There was no statistical significant difference between the aflibercept arms. Anatomic effects (mean change in central retinal thickness) ranged from −127 μm to −195 μm in aflibercept arms compared to −68 μm in laser-treated eyes at 24 weeks (). At 52 weeks, the mean change in BCVA for aflibercept arms ranged from +9.7 to +13.1 letters compared to the mean change of −1.3 letters in the laser-treated eyes () . In this study population, intravitreal aflibercept produced significant improvements in visual acuity and retinal thickness as compared to laser photocoagulation at both 24 and 52 weeks. At this time, aflibercept is not approved by the US FDA for the treatment of DME.
The vitreous has been implicated as a cause of DME by several mechanical and physiological mechanisms, including macular traction and concentration of vasopermeable factors in the macular region . A recent prospective trial by DRCR network evaluated visual and anatomical outcomes of pars plana vitrectomy (PPV) without concomitant cataract surgery for DME in eyes with moderate vision loss and vitreomacular traction. Retinal thickening was improved in most eyes, but visual acuity results were less consistent with improvement of ≥10 letters in 38%, and worsening by ≥10 letters in 22% at 6 months . In a subsequent analysis, the DRCR reported that better visual outcomes were associated with worse baseline visual acuity and in eyes in which an epiretinal membrane was removed .
Enzymatic vitreolysis with or without PPV has been studied in the treatment of DME. Intravitreal hyaluronidase (Vitrase, ISTA Pharmaceuticals, Irvine, CA, USA) has shown evidence of safety and efficacy in reducing vitreous hemorrhage secondary to different etiologies, including proliferative diabetic retinopathy (PDR), although it has not received FDA approval for this indication [70, 71].
Induction of a posterior vitreous detachment (PVD) may be beneficial in the treatment of DME . Enzymes that may have efficacy in creating a PVD include hyaluronidase, plasmin, chondroitinase, and dispase . Autologous plasmin has been used by itself or as adjunct to PPV in the treatment of DME [74, 75]. Microplasmin is a recombinant human protein derived from the yeast Pichiapastoris. It is a truncated form of the human protein plasmin with intact protease activity. The Microplasmin Intravitreous Injection (MIVI) trial was a phase 2 RCT that evaluated the safety and efficacy of intravitreal microplasmin in facilitating the creation of a total PVD in patients scheduled for PPV . The study showed that microplasmin injection at a dose of 125 μg led to a greater likelihood of induction of PVD than placebo. Patients receiving microplasmin were significantly more likely to have resolution of vitreomacular traction and not to require PPV.
2.4. Other Ocular Agents
Other ocular agents have been studied as treatments for DME (Table 3). Animal models have demonstrated an important role for inflammation in diabetic retinopathy . In early stages of diabetic retinopathy, there is upregulation of cyclo-oxygenase-2 (COX-2) that leads to elevated prostaglandin production and increased expression of VEGF with increased risk of vascular leakage and retinal neovascularization . High doses of aspirin and intermediate doses of COX-2 inhibitors (celecoxib) have shown to be beneficial in early stages of experimental diabetic retinopathy . Periocular celecoxib-containing microparticles have shown to inhibit elevation of VEGF for as long as 60 days in animal models . A recent multicenter clinical trial failed to show any visual function benefits with celecoxib treatment in DME, although, there was a suggestive effect of celecoxib in reducing fluorescein leakage .
Nepafenac (Nevanac, Alcon, Ft. Worth, TX, USA), an FDA-approved topical nonsteroidal anti-inflammatory drug (NSAID), is a prodrug that is converted to amfenac in the anterior chamber . In a pilot study, nepafenac has shown some efficacy in the treatment of DME . The DRCR is currently beginning a phase 2 RCT studying the use of topical nepafenac to treat nonclinically significant DME.
Etanercept (Enbrel, Amgen, Inc. Thousand Oaks, CA, USA and Wyeth, Madison, NJ, USA), a recombinant fusion protein with activity against TNF-α, is FDA-approved for the treatment of psoriatic disease . Intravitreal etanercept has shown some evidence of efficacy against refractory DME .
Infliximab (Remicade, Centocor, Horsham, PA, USA) is another TNF-α antagonist that is FDA-approved for the treatment of Crohn’s disease . A pilot study showed benefits from systemic infliximab in treatment of DME . A pilot study of intravitreal infliximab is continuing.
Stimulation of nicotinic acetylcholine (nACh) receptors on vascular endothelial cells promotes angiogenesis and vascular permeability in animal models [88, 89]. A recent multicenter phase 1/2 clinical trial evaluated the safety and bioactivity of topical mecamylamine, an antagonist of nACh receptors, in patients with DME . Mecamylamine drops were well tolerated. The study suggested that administration of topical mecamylamine may have heterogeneous effects in patients with DME. The heterogeneous response may be secondary to variable expression of nACh receptor subtypes on endothelial cells.
A pilot study has reported a short-term positive response to intravitreal erythropoietin in a group of patients with chronic DME unresponsive to other therapies .
3. Systemic Agents
Various systemic agents have been studied in the treatment of DME (Table 4). Activation of protein kinase C (PKC) may play an important role in the development and progression of diabetic retinopathy [92–98]. Ruboxistaurin (Arxxant, Eli Lilly and Company, Indianapolis, IN, USA) is a selective antagonist of PKC βI and PKC βII . The PKC-Diabetic Retinopathy Study (PKC-DRS) reported that ruboxistaurin was associated with a reduced incidence of moderate visual loss (doubling of the visual angle) . The PKC-DRS 2 reported that ruboxistaurin was associated with a reduced incidence of sustained moderate visual loss (for 6 months) . The PKC-DME Study (PKC-DMES) reported some evidence that ruboxistaurin was associated with reduced progression of DME, although this was a secondary endpoint . Ruboxistaurin has not received approval from the USA FDA.
Fenofibrate is a fibric acid derivative with pleiotropic effects that is used as a lipid-modifying agent . The fenofibrate intervention and event lowering in diabetes (FIELD) study, a large RCT, showed that treatment with fenofibrate reduces the need for laser treatment in patients with PDR and DME .
Rosiglitazone (Avandia, GlaxoSmith Klein, Research Triangle Park, NC, US) is a peroxisome proliferator-activated γ ligand that is used in the treatment of type 2 diabetes . Treatment with rosiglitazone has been shown to reduce the rate of progression to PDR , however, in some patients, it may be associated with increased risk of DME .
4. Summary Statement
For decades, standard treatments for DME have included tighter control of systemic metabolic factors, as well as photocoagulation. However, some patients continue to lose vision despite these therapies, which has led to the investigation of various pharmacotherapies for DME. At this time, both intravitreal corticosteroids and intravitreal anti-VEGF agents are widely used in clinical settings. The role of combination therapies (both various medications with each other as well as medications with photocoagulation) is yet to be determined. As we continue to collect data from current and future RCTs, management strategies for DME will continue to evolve.
This work was partially supported by NIH Center Grant P30-EY014801 and by an unrestricted grant to the University of Miami from Research to Prevent Blindness, NY, NY, USA. S. G. Schwartz is a consultant for Alimera Sciences and Bausch + Lomb, and holds intellectual property licensed to IC Labs. H. W. Flynn, Jr. is a consultant for Alcon Laboratories, Allergan, Pfizer, and Santen.
- R. Klein, M. D. Knudtson, K. E. Lee, R. Gangnon, and B. E. K. Klein, “The Wisconsin Epidemiologic Study of diabetic retinopathy XXIII: the twenty-five-year incidence of macular edema in persons with type 1 diabetes,” Ophthalmology, vol. 116, no. 3, pp. 497–503, 2009.
- T. A. Ciulla, A. G. Amador, and B. Zinman, “Diabetic retinopathy and diabetic macular edema: pathophysiology, screening, and novel therapies,” Diabetes Care, vol. 26, no. 9, pp. 2653–2664, 2003.
- S. T. Knudsen, T. Bek, P. L. Poulsen, M. N. Hove, M. Rehling, and C. E. Mogensen, “Macular edema reflects generalized vascular hyperpermeability in type 2 diabetic patients with retinopathy,” Diabetes Care, vol. 25, no. 12, pp. 2328–2334, 2002.
- T. G. Rotsos and M. M. Moschos, “Cystoid macular edema,” Journal of Clinical Ophthalmology, vol. 2, pp. 919–930, 2008.
- H. Z. Xu and Y. Z. Le, “Significance of outer blood-retina barrier breakdown in diabetes and ischemia,” Investigative Ophthalmology & Visual Science, vol. 52, pp. 2160–2164, 2011.
- T. W. Gardner, D. A. Antonetti, A. J. Barber, K. F. LaNoue, and S. W. Levison, “Diabetic retinopathy: more than meets the eye,” Survey of Ophthalmology, vol. 47, supplement 2, pp. S253–S262, 2002.
- J. K. Kristinsson, M. S. Gottfredsdóttir, and E. Stefánsson, “Retinal vessel dilatation and elongation precedes diabetic macular oedema,” British Journal of Ophthalmology, vol. 81, no. 4, pp. 274–278, 1997.
- A. Wurm, T. Pannicke, I. Iandiev et al., “Changes in membrane conductance play a pathogenic role in osmotic glial cell swelling in detached retinas,” American Journal of Pathology, vol. 169, no. 6, pp. 1990–1998, 2006.
- R. Ehrlich, A. Harris, T. A. Ciulla, N. Kheradiya, D. M. Winston, and B. Wirostko, “Diabetic macular oedema: physical, physiological and molecular factors contribute to this pathological process,” Acta Ophthalmologica, vol. 88, no. 3, pp. 279–291, 2010.
- M. Morigi, S. Angioletti, B. Imberti et al., “Leukocyte-endothelial interaction is augmented by high glucose concentrations and hyperglycemia in a NF-kB-dependent fashion,” Journal of Clinical Investigation, vol. 101, no. 9, pp. 1905–1915, 1998.
- M. Brownlee, “The pathobiology of diabetic complications: a unifying mechanism,” Diabetes, vol. 54, no. 6, pp. 1615–1625, 2005.
- N. Shams and T. Ianchulev, “Role of vascular endothelial growth factor in ocular angiogenesis,” Ophthalmology Clinics of North America, vol. 19, no. 3, pp. 335–344, 2006.
- N. Miyamoto, Y. de Kozak, J. C. Jeanny et al., “Placental growth factor-1 and epithelial haemato-retinal barrier breakdown: potential implication in the pathogenesis of diabetic retinopathy,” Diabetologia, vol. 50, no. 2, pp. 461–470, 2007.
- W. Cai, S. L. Rook, Z. Y. Jiang, N. Takahara, and L. P. Aiello, “Mechanisms of hepatocyte growth factor-induced retinal endothelial cell migration and growth,” Investigative Ophthalmology and Visual Science, vol. 41, no. 7, pp. 1885–1893, 2000.
- R. Klein, B. E. K. Klein, S. E. Moss, and K. J. Cruickshanks, “The Wisconsin epidemiologic study of diabetic retinopathy XV: the long term incidence of macular edema,” Ophthalmology, vol. 102, no. 1, pp. 7–16, 1995.
- P. Romero-Aroca, M. Baget-Bernaldiz, J. Fernandez-Ballart et al., “Ten-year incidence of diabetic retinopathy and macular edema. Risk factors in a sample of people with type 1 diabetes,” Diabetes Research and Clinical Practice, vol. 94, no. 1, pp. 126–132, 2011.
- M. Rodriguez-Fontal, J. B. Kerrison, D. V. Alfaro, and E. P. Jablon, “Metabolic control and diabetic retinopathy,” Current Diabetes Reviews, vol. 5, no. 1, pp. 3–7, 2009.
- Diabetes Control and Complication Trial Research Group, “The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus,” The New England Journal of Medicine, vol. 329, pp. 977–986, 1993.
- UK Prospective Diabetes Study Group, “Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. UKPDS 33,” Lancet, vol. 352, pp. 837–853, 1998.
- Early Treatment Diabetic Retinopathy Study Research Group, “Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1,” Archives of Ophthalmology, vol. 103, pp. 1796–1806, 1985.
- M. Nauck, M. Roth, M. Tamm et al., “Induction of vascular endothelial growth factor by platelet-activating factor and platelet-derived growth factor is downregulated by corticosteroids,” American Journal of Respiratory Cell and Molecular Biology, vol. 16, no. 4, pp. 398–406, 1997.
- Diabetic Retinopathy Clinical Research Network, “A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema,” Ophthalmology, vol. 115, pp. 1447–1449, 2008.
- R. W. Beck, A. R. Edwards, L. P. Aiello et al., “Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema,” Archives of Ophthalmology, vol. 127, no. 3, pp. 245–251, 2009.
- Y. K. Chu, E. J. Chung, O. W. Kwon, J. H. Lee, and H. J. Koh, “Objective evaluation of cataract progression associated with a high dose intravitreal triamcinolone injection,” Eye, vol. 22, no. 7, pp. 895–899, 2008.
- L. M. Smithen, M. D. Ober, L. Maranan, and R. F. Spaide, “Intravitreal triamcinolone acetonide and intraocular pressure,” American Journal of Ophthalmology, vol. 138, no. 5, pp. 740–743, 2004.
- D. M. Moshfeghi, P. K. Kaiser, S. J. Bakri et al., “Presumed sterile endophthalmitis following intravitreal triamcinolone acetonide injection,” Ophthalmic Surgery Lasers and Imaging, vol. 36, no. 1, pp. 24–29, 2005.
- A. R. Bhavsar, M. S. Ip, and A. R. Glassman, “The risk of endophthalmitis following intravitreal triamcinolone injection in the DRCRnet and SCORE clinical trials,” American Journal of Ophthalmology, vol. 144, no. 3, pp. 454–456, 2007.
- M. A. Bonini-Filho, R. Jorge, J. C. Barbosa, D. Calucci, J. A. Cardillo, and R. A. Costa, “Intravitreal injection versus sub-tenon's infusion of triamcinolone acetonide for refractory diabetic macular edema: a randomized clinical trial,” Investigative Ophthalmology and Visual Science, vol. 46, no. 10, pp. 3845–3849, 2005.
- E. Chew and S. Trauber, “Diabetic Retinopathy Clinical Research Network, triamcinolone acetonide with and without focal photocoagulation for mild diabetic macular edema: a pilot study,” Ophthalmology, vol. 114, pp. 1190–1196, 2007.
- G. J. Jaffe, D. Martin, D. Callanan, P. A. Pearson, B. Levy, and T. Comstock, “Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis. Thirty-four-week results of a multicenter randomized clinical study,” Ophthalmology, vol. 113, no. 6, pp. 1020–1027, 2006.
- “Fluocinolone acetonide ophthalmic- Bausch & Lomb: fluocinolone acetonide envision TD implant,” Drugs RD, vol. 6, no. 2, pp. 116–119, 2005.
- J. A. Montero and J. M. Ruiz-Moreno, “Intravitreal inserts of steroids to treat diabetic macular edema,” Current Diabetes Reviews, vol. 5, no. 1, pp. 26–32, 2009.
- P. A. Campochiaro, G. Hafiz, S. M. Shah et al., “Sustained ocular delivery of fluocinolone acetonide by an intravitreal insert,” Ophthalmology, vol. 117, no. 7, pp. 1393–1399, 2010.
- P. A. Campochiaro, D. M. Brown, A. Pearson et al., “Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema,” Ophthalmology, vol. 118, no. 4, pp. 626–635, 2011.
- B. D. Kuppermann, M. S. Blumenkranz, J. A. Haller et al., “Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema,” Archives of Ophthalmology, vol. 125, no. 3, pp. 309–317, 2007.
- J. A. Haller, B. D. Kuppermann, M. S. Blumenkranz et al., “Randomized controlled trial of an intravitreous dexamethasone drug delivery system in patients with diabetic macular edema,” Archives of Ophthalmology, vol. 128, no. 3, pp. 289–296, 2010.
- D. S. Boyer, D. Faber, S. Gupta et al., “Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients,” Retina, vol. 31, no. 5, pp. 915–923, 2011.
- S. A. Vinores, A. L. Youssri, J. D. Luna et al., “Upregulation of vascular endothelial growth factor in ischemic and non-ischemic human and experimental retinal disease,” Histology and Histopathology, vol. 12, no. 1, pp. 99–109, 1997.
- N. L. Derevjanik, S. A. Vinores, W. H. Xiao et al., “Quantitative assessment of the integrity of the blood-retinal barrier in mice,” Investigative Ophthalmology and Visual Science, vol. 43, no. 7, pp. 2462–2467, 2002.
- H. Ozaki, H. Hayashi, S. A. Vinores, Y. Moromizato, P. A. Campochiaro, and K. Oshima, “Intravitreal sustained release of VEGF causes retinal neovascularization in rabbits and breakdown of the blood-retinal barrier in rabbits and primates,” Experimental Eye Research, vol. 64, no. 4, pp. 505–517, 1997.
- P. A. Campochiaro, “Reduction of diabetic macular edema by oral administration of the kinase inhibitor PKC412,” Investigative Ophthalmology and Visual Science, vol. 45, no. 3, pp. 922–931, 2004.
- E. T. Cunningham Jr., A. P. Adamis, M. Altaweel et al., “A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema,” Ophthalmology, vol. 112, no. 10, pp. 1747–1757, 2005.
- M. B. Sultan, D. Zhou, J. Loftus, T. Dombi, and K. S. Ice, “A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema,” Ophthalmology, vol. 118, no. 6, pp. 1107–1118, 2011.
- J. C. Yang, L. Haworth, R. M. Sherry et al., “A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer,” New England Journal of Medicine, vol. 349, no. 5, pp. 427–434, 2003.
- Diabetic Retinopathy Clinical Research Network, “A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema,” Ophthalmology, vol. 114, pp. 1860–1867, 2007.
- M. Michaelides, A. Kaines, R. D. Hamilton et al., “A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study). 12-month data: report 2,” Ophthalmology, vol. 117, no. 6, pp. 1078–1086, 2010.
- M. Michaelides, S. Fraser-Bell, R. Hamilton et al., “Macular perfusion determined by fundus fluorescein angiography at the 4-month time point in a prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (bolt study): report 1,” Retina, vol. 30, no. 5, pp. 781–786, 2010.
- P. J. Rosenfeld, D. M. Brown, J. S. Heier et al., “Ranibizumab for neovascular age-related macular degeneration,” New England Journal of Medicine, vol. 355, no. 14, pp. 1419–1431, 2006.
- D. M. Brown, P. K. Kaiser, M. Michels et al., “Ranibizumab versus verteporfin for neovascular age-related macular degeneration,” New England Journal of Medicine, vol. 355, no. 14, pp. 1432–1444, 2006.
- P. A. Campochiaro, J. S. Heier, L. Feiner et al., “Ranibizumab for macular edema following branch retinal vein occlusion. Six-month primary end point results of a phase III study,” Ophthalmology, vol. 117, no. 6, pp. 1102–1112, 2010.
- D. M. Brown, P. A. Campochiaro, R. P. Singh et al., “Ranibizumab for macular edema following central retinal vein occlusion. Six-month primary end point results of a phase III study,” Ophthalmology, vol. 117, no. 6, pp. 1124–1133, 2010.
- Q. D. Nguyen, S. M. Shah, J. S. Heier et al., “Primary end point (six months) results of the ranibizumab for edema of the mAcula in diabetes (READ-2) study,” Ophthalmology, vol. 116, no. 11, pp. 2175–2181, 2009.
- Q. D. Nguyen, S. M. Shah, A. A. Khwaja et al., “Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study,” Ophthalmology, vol. 117, no. 11, pp. 2146–2151, 2010.
- Diabetic Retinopathy Clinical Research Network, M. J. Elman, L. P. Aiello et al., “Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema,” Ophthalmology, vol. 117, no. 6, pp. 1064–1077, 2010.
- M. J. Elman, N. M. Bressler, H. Qin et al., “Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema,” Ophthalmology, vol. 118, no. 4, pp. 609–614, 2011.
- L. P. Aiello, R. W. Beck, N. M. Bressler et al., “Rationale for the diabetic retinopathy clinical research network treatment protocol for center-involved diabetic macular edema,” Ophthalmology, vol. 118, no. 12, pp. e5–e14, 2011.
- P. Mitchell, F. Bandello, U. Schmidt-Erfurth et al., “The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema,” Ophthalmology, vol. 118, no. 4, pp. 615–625, 2011.
- J. Googe, A. J. Brucker, N. M. Bressler et al., “Randomized trial evaluating short-term effects of intravitreal ranibizumab or triamcinolone acetonide on macular edema after focal/grid laser for diabetic macular edema in eyes also receiving panretinal photocoagulation,” Retina, vol. 31, no. 6, pp. 1009–1027, 2011.
- D. M. Brown, Q. D. Nguyen, R. G. Rubio et al., “Ranibizumab for diabetic macular edema (DME): 24-month efficacy and safety results of RISE—a phase 3 randomized controlled trial,” ARVO abstract 6647, 2011.
- P. Massin, F. Bandello, J. G. Garweg et al., “Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE study): a 12-month, randomized, controlled, double-masked, multicenter phase II study,” Diabetes Care, vol. 33, no. 11, pp. 2399–2405, 2010.
- T. J. Good, A. E. Kimura, N. Mandava, and M. Y. Kahook, “Sustained elevation of intraocular pressure after intravitreal injections of anti-VEGF agents,” British Journal of Ophthalmology, vol. 95, no. 8, pp. 1111–1114, 2011.
- S. G. Schwartz, H. W. Flynn Jr., and I. U. Scott, “Endophthalmitis after intravitreal injections,” Expert Opinion on Pharmacotherapy, vol. 10, no. 13, pp. 2119–2126, 2009.
- A. A. Moshfeghi, P. J. Rosenfeld, H. W. Flynn Jr. et al., “Endophthalmitis after intravitreal anti-vascular endothelial growth factor antagonists: a six-year experience at a university referral center,” Retina, vol. 31, no. 4, pp. 662–668, 2011.
- C. A. McCannel, “Meta-analysis of endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents: causative organisms and possible prevention strategies,” Retina, vol. 31, no. 4, pp. 654–661, 2011.
- D. V. Do, Q. D. Nguyen, S. M. Shah et al., “An exploratory study of the safety, tolerability and bioactivity of a single intravitreal injection of vascular endothelial growth factor Trap-Eye in patients with diabetic macular oedema,” British Journal of Ophthalmology, vol. 93, no. 2, pp. 144–149, 2009.
- D. V. Do, U. Schmidt-Erfurth, V. H. Gonzalez et al., “The da VINCI study: phase 2 primary results of VEGF trap-eye in patients with diabetic macular edema,” Ophthalmology, vol. 118, no. 9, pp. 1819–1826, 2011.
- J. W. Harbour, W. E. Smiddy, H. W. Flynn Jr., and P. E. Rubsamen, “Vitrectomy for diabetic macular edema associated with a thickened and taut posterior hyaloid membrane,” American Journal of Ophthalmology, vol. 121, no. 4, pp. 405–413, 1996.
- Diabetic Retinopathy Clinical Research Network Writing Committee, J. A. Haller, and H. Qin, “Vitrectomy outcomes in eyes with diabetic macular edema and vitreomacular traction,” Ophthalmology, vol. 117, pp. 1087–1093, 2010.
- C. J. Flaxel, A. R. Edwards, L. P. Aiello et al., “Factors associated with visual acuity outcomes after vitrectomy for diabetic macular edema: diabetic retinopathy clinical research network,” Retina, vol. 30, no. 9, pp. 1488–1495, 2010.
- B. D. Kuppermann, E. L. Thomas, M. D. De Smet, and L. R. Grillone, “Pooled efficacy results from two multinational randomized controlled clinical trials of a single intravitreous injection of highly purified ovine hyaluronidase (Vitrase) for the management of vitreous hemorrhage,” American Journal of Ophthalmology, vol. 140, no. 4, pp. 573–584, 2005.
- B. D. Kuppermann, E. L. Thomas, M. D. De Smet, and L. R. Grillone, “Safety results of two phase III trials of an intravitreous injection of highly purified ovine hyaluronidase (Vitrase) for the management of vitreous hemorrhage,” American Journal of Ophthalmology, vol. 140, no. 4, pp. 585–597, 2005.
- F. Lopez-Lopez, M. Rodriguez-Blanco, F. Gómez-Ulla, and J. Marticonera, “Enzymatic vitreolysis,” Current Diabetes Reviews, vol. 5, no. 1, pp. 57–62, 2009.
- A. Gandorfer, “Enzymatic vitreous disruption,” Eye, vol. 22, no. 10, pp. 1273–1277, 2008.
- M. Diaz-Llopis, P. Udaondo, F. Arevalo et al., “Intravitreal plasmin without associated vitrectomy as a treatment for refractory diabetic macular edema,” Journal of Ocular Pharmacology and Therapeutics, vol. 25, no. 4, pp. 379–384, 2009.
- C. Azzolini, A. D'Angelo, G. Maestranzi et al., “Intrasurgical plasmin enzyme in diabetic macular edema,” American Journal of Ophthalmology, vol. 138, no. 4, pp. 560–566, 2004.
- M. S. Benz, K. H. Packo, V. Gonzalez et al., “A placebo-controlled trial of microplasmin intravitreous injection to facilitate posterior vitreous detachment before vitrectomy,” Ophthalmology, vol. 117, no. 4, pp. 791–797, 2010.
- E. I. M. Johnson, M. E. Dunlop, and R. G. Larkins, “Increased vasodilatory prostaglandin production in the diabetic rat retinal vasculature,” Current Eye Research, vol. 18, no. 2, pp. 79–82, 1999.
- L. P. Aiello, R. L. Avery, P. G. Arrigg et al., “Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders,” New England Journal of Medicine, vol. 331, no. 22, pp. 1480–1487, 1994.
- A. M. Joussen, V. Poulaki, N. Mitsiades et al., “Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression,” The FASEB Journal, vol. 16, no. 3, pp. 438–440, 2002.
- A. C. Amrite, S. P. Ayalasomayajula, N. P. S. Cheruvu, and U. B. Kompella, “Single periocular injection of celecoxib-PLGA microparticles inhibits diabetes-induced elevations in retinal PGE2, VEGF, and vascular leakage,” Investigative Ophthalmology and Visual Science, vol. 47, no. 3, pp. 1149–1160, 2006.
- E. Y. Chew, J. Kim, H. R. Coleman et al., “Preliminary assessment of celecoxib and microdiode pulse laser treatment of diabetic macular edema,” Retina, vol. 30, no. 3, pp. 459–467, 2010.
- D. A. Gamache, G. Graff, M. T. Brady, J. M. Spellman, and J. M. Yanni, “Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced ocular inflammation: I. Assessment of anti- inflammatory efficacy,” Inflammation, vol. 24, no. 4, pp. 357–370, 2000.
- S. M. Hariprasad, D. Callanan, S. Gainey, Y. G. He, and K. Warren, “Cystoid and diabetic macular edema treated with nepafenac 0.1%,” Journal of Ocular Pharmacology and Therapeutics, vol. 23, no. 6, pp. 585–590, 2007.
- E. Ducharme and J. M. Weinberg, “Etanercept,” Expert Opinion on Biological Therapy, vol. 8, no. 4, pp. 491–502, 2008.
- M. K. Tsilimbaris, T. D. Panagiotoglou, S. K. Charisis, A. Anastasakis, T. S. Krikonis, and E. Christodoulakis, “The use of intravitreal etanercept in diabetic macular oedema,” Seminars in Ophthalmology, vol. 22, no. 2, pp. 75–79, 2007.
- S. R. Targan, S. B. Hanauer, S. J. H. van Deventer et al., “A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn's Disease,” New England Journal of Medicine, vol. 337, no. 15, pp. 1029–1035, 1997.
- P. P. Sfikakis, N. Markomichelakis, G. P. Theodossiadis, V. Grigoropoulos, N. Katsilambros, and P. G. Theodossiadis, “Regression of sight-threatening macular edema in type 2 diabetes following treatment with the anti-tumor necrosis factor monoclonal antibody infliximab,” Diabetes Care, vol. 28, no. 2, pp. 445–447, 2005.
- A. C. Villablanca, “Nicotine stimulates DNA synthesis and proliferation in vascular endothelial cells in vitro,” Journal of Applied Physiology, vol. 84, no. 6, pp. 2089–2098, 1998.
- C. Heeschen, J. J. Jang, M. Weis et al., “Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis,” Nature Medicine, vol. 7, no. 7, pp. 833–839, 2001.
- P. A. Campochiaro, S. M. Shah, G. Hafiz et al., “Topical mecamylamine for diabetic macular edema,” American Journal of Ophthalmology, vol. 149, no. 5, pp. 839–851, 2010.
- W. Li, S. H. Sinclair, and G. T. Xu, “Effects of intravitreal erythropoietin therapy for patients with chronic and progressive diabetic macular edema,” Ophthalmic Surgery Lasers and Imaging, vol. 41, no. 1, pp. 18–25, 2010.
- J. Y. Park, N. Takahara, A. Gabriele et al., “Induction of endothelin-1 expression by glucose an effect of protein kinase C activation,” Diabetes, vol. 49, no. 7, pp. 1239–1248, 2000.
- C. W. Park, J. H. Kim, J. W. Lee et al., “High glucose-induced intercellular adhesion molecule-1 (ICAM-1) expression through an osmotic effect in rat mesangial cells is PKC-NF-χB-dependent,” Diabetologia, vol. 43, no. 12, pp. 1544–1553, 2000.
- P. Xia, T. Inoguchi, T. S. Kern, R. L. Engerman, P. J. Oates, and G. L. King, “Characterization of the mechanism for the chronic activation of diacylglycerol-protein kinase C pathway in diabetes and hypergalactosemia,” Diabetes, vol. 43, no. 9, pp. 1122–1129, 1994.
- L. P. Aiello, “The potential role of PKC β in diabetic retinopathy and macular edema,” Survey of Ophthalmology, vol. 47, supplement 2, pp. S263–S269, 2002.
- R. Donnelly, I. Idris, and J. V. Forrester, “Protein kinase C inhibition and diabetic retinopathy: a shot in the dark at translational research,” British Journal of Ophthalmology, vol. 88, no. 1, pp. 145–151, 2004.
- Y. Nishizuka, “The molecular heterogeneity of protein kinase C and its implications for cellular regulation,” Nature, vol. 334, no. 6184, pp. 661–665, 1988.
- L. P. Aiello, S. E. Bursell, A. Clermont et al., “Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective β-isoform-selective inhibitor,” Diabetes, vol. 46, no. 9, pp. 1473–1480, 1997.
- M. R. Jirousek, J. R. Gillig, C. M. Gonzalez et al., “(S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21- dimetheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene- 1,3(2H)-dione (LY333531) and related analogues: isozyme selective inhibitors of protein kinase Cβ,” Journal of Medicinal Chemistry, vol. 39, no. 14, pp. 2664–2671, 1996.
- The PKC-DRS Study Group, “The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy: initial results of the protein kinase C β inhibitor diabetic retinopathy study (PKC-DRS) multicenter randomized clinical trial,” Diabetes, vol. 54, no. 7, pp. 2188–2197, 2005.
- PKC-DRS2 Group, L. P. Aiello, M. D. Davis et al., “Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy,” Ophthalmology, vol. 113, no. 12, pp. 2221–2230, 2006.
- The PKC-DMES Study Group, “Effect of ruboxistaurin in patients with diabetic macular edema: thirty-month results of the randomized PKC-DMES clinical trial,” Archives of Ophthalmology, vol. 125, no. 3, pp. 318–324, 2007.
- G. M. Keating and K. F. Croom, “Fenofibrate: a review of its use in primary dyslipidaemia, the metabolic syndrome and type 2 diabetes mellitus,” Drugs, vol. 67, no. 1, pp. 121–153, 2007.
- A. Keech, P. Mitchell, P. Summanen et al., “Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial,” Lancet, vol. 370, no. 9600, pp. 1687–1697, 2007.
- J. J. Nolan, N. P. Jones, R. Patwardhan, and L. F. Deacon, “Rosiglitazone taken once daily provides effective glycaemic control in patients with Type 2 diabetes mellitus,” Diabetic Medicine, vol. 17, no. 4, pp. 287–294, 2000.
- L. Q. Shen, A. Child, G. M. Weber, J. Folkman, and L. P. Aiello, “Rosiglitazone and delayed onset of proliferative diabetic retinopathy,” Archives of Ophthalmology, vol. 126, no. 6, pp. 793–799, 2008.
- E. H. Ryan Jr., D. P. Han, R. C. Ramsay et al., “Diabetic macular edema associated with glitazone use,” Retina, vol. 26, no. 5, pp. 562–570, 2006.
Copyright © 2012 Golnaz Javey et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.