Nonsteroidal anti-inflammatory drugs (NSAIDs) are used extensively in ophthalmology for pain and photophobia after photorefractive surgery and to reduce miosis, inflammation, and cystoid macular edema following cataract surgery. In recent years, the US Food and Drug Administration has approved new topical NSAIDs and previously approved NSAIDs have been reformulated. These changes may allow for greater drug penetration into the retina and thereby offer additional therapeutic advantages. For example, therapeutic effects on diabetic retinopathy and age-related macular degeneration may now be achievable. We provide an updated review on the scientific rationale and clinical use of NSAIDs for retinal disease. 1. Introduction Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly prescribed classes of medications and are routinely employed for their analgesic, antipyretic, and anti-inflammatory properties. NSAIDs are potent inhibitors of cyclooxygenase (COX) enzymes and thereby the synthesis of pro-inflammatory prostaglandins (PGs). In ophthalmology, topical NSAIDs are used to stabilize pupillary dilation during intraocular surgery and to treat allergic conjunctivitis and postoperative inflammmation, pain and cystoid macular edema (CME) [1]. The therapeutic efficacy of topical NSAIDs for these aforementioned conditions has been well established [1, 2]. There is also increasing evidence that PGs play a role in the pathogenesis of diabetic retinopathy and age-related macular degeneration (AMD) and recent years have seen more studies examining the therapeutic role of NSAIDs for these disorders [1]. The intent of this paper is to focus on the potential application of NSAIDs to treat retinal disease. 2. Nonsteroidal Anti-Inflammatory Drugs NSAIDs are a class of medications that lack a steroid nucleus and inhibit COX enzymes [1]. COX enzymes catalyze the production of five classes of PGs: PGE2, PGD2, PGF2α, PGI2, and Thromboxane A2. Two main isoforms of COX, COX-1 and COX-2, exist [3], and a third (COX-3) remains largely uncharacterized [4]. COX-1 contributes to normal physiological processes and is expressed in the gastrointestinal tract, kidneys, platelets, and vascular endothelium [1]. COX-2 is an inducible enzyme that is upregulated during pain, fever, and inflammatory responses, but is also expressed in some systems under normal conditions. COX-2 is the predominate isoform in retinal pigment epithelium (RPE) cells and is up-regulated in the presence of proinflammatory cytokines [5]. COX-2 has an important role in angiogenesis and has been
References
[1]
S. J. Kim, A. J. Flach, and L. M. Jampol, “Nonsteroidal anti-inflammatory drugs inophthalmology,” Survey of Ophthalmology, vol. 55, no. 2, pp. 108–133, 2010.
[2]
H. N. Shelsta and L. M. Jampol, “Pharmacologic therapy of pseudophakic cystoid macular edema: 2010 update,” Retina, vol. 31, no. 1, pp. 4–12, 2011.
[3]
D. L. Simmons, R. M. Botting, and T. Hla, “Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition,” Pharmacological Reviews, vol. 56, no. 3, pp. 387–437, 2004.
[4]
N. M. Davies, R. L. Good, K. A. Roupe, and J. A. Yá？ez, “Cyclooxygenase-3: axiom, dogma, anomaly, enigma or splice error?—not as easy as 1, 2, 3,” Journal of Pharmacy and Pharmaceutical Sciences, vol. 7, no. 2, pp. 217–226, 2004.
[5]
M. S. Chin, C. N. Nagineni, L. C. Hooper, B. Detrick, and J. J. Hooks, “Cyclooxygenase-2 gene expression and regulation in human retinal pigment epithelial cells,” Investigative Ophthalmology and Visual Science, vol. 42, no. 10, pp. 2338–2346, 2001.
[6]
S. Shinomiya, H. Naraba, A. Ueno et al., “Regulation of TNFα and interleukin-10 production by prostaglandins I2 and E2: studies with prostaglandin receptor-deficient mice and prostaglandin E-receptor subtype-selective synthetic agonists,” Biochemical Pharmacology, vol. 61, no. 9, pp. 1153–1160, 2001.
[7]
T. Cheng, W. Cao, R. Wen, R. H. Steinberg, and M. M. LaVail, “Prostaglandin E2 induces vascular endothelial growth factor and basic fibroblast growth factor mRNA expression in cultured rat Muller cells,” Investigative Ophthalmology and Visual Science, vol. 39, no. 3, pp. 581–591, 1998.
[8]
R. Reddy and S. J. Kim, “Critical appraisal of ophthalmic ketorolac in the treatment of pain and inflammation following cataract surgery,” Clinical Ophthalmology, vol. 5, pp. 751–758, 2011.
[9]
M. Ahuja, A. S. Dhake, S. K. Sharma, and D. K. Majumdar, “Topical ocular delivery of NSAIDs,” The AAPS Journal, vol. 10, no. 2, pp. 229–241, 2008.
[10]
D. Riendeau, S. Charleson, W. Cromlish, J. A. Mancini, E. Wong, and J. Guay, “Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, using sensitive microsomal and platelet assays,” Canadian Journal of Physiology and Pharmacology, vol. 75, no. 9, pp. 1088–1095, 1997.
[11]
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.
[12]
L. D. Waterbury, D. Silliman, and T. Jolas, “Comparison of cyclooxygenase inhibitory activity and ocular anti-inflammatory effects of ketorolac tromethamine and bromfenac sodium,” Current Medical Research and Opinion, vol. 22, no. 6, pp. 1133–1140, 2006.
[13]
T. Walters, M. Raizman, P. Ernest, J. Gayton, and R. Lehmann, “In vivo pharmacokinetics and in vitro pharmacodynamics of nepafenac, amfenac, ketorolac, and bromfenac,” Journal of Cataract and Refractive Surgery, vol. 33, no. 9, pp. 1539–1545, 2007.
[14]
P. P. Ellis, D. S. Pfoff, D. C. Bloedow, and M. Riegel, “Intraocular diclofenac and flurbiprofen concentrations in human aqueous humor following topical application,” Journal of Ocular Pharmacology, vol. 10, no. 4, pp. 677–682, 1994.
[15]
M. Attar, R. Schiffman, L. Borbridge, Q. Farnes, and D. Welty, “Ocular pharmacokinetics of 0.45% ketorolac tromethamine,” Clinical Ophthalmology, vol. 4, no. 1, pp. 1403–1408, 2010.
[16]
F. A. Bucci Jr., L. D. Waterbury, and L. M. Amico, “Prostaglandin E2 inhibition and aqueous concentration of ketorolac 0.4% (Acular LS) and nepafenac 0.1% (Nevanac) in patients undergoing phacoemulsification,” American Journal of Ophthalmology, vol. 144, no. 1, pp. 146–147, 2007.
[17]
J. S. Heier, C. C. Awh, B. G. Busbee et al., “Vitreous nonsteroidal antiinflammatory drug concentrations and prostaglandin E2 levels in vitrectomy patients treated with ketorolac 0.4%, bromfenac 0.09%, and nepafenac 0.1%,” Retina, vol. 29, no. 9, pp. 1310–1313, 2009.
[18]
S. R. Irvine, “A newly defined vitreous syndrome following cataract surgery,” American Journal of Ophthalmology, vol. 36, no. 5, pp. 499–619, 1953.
[19]
S. J. Kim, R. Equi, and N. M. Bressler, “Analysis of macular edema after cataract surgery in patients with diabetes using optical coherence tomography,” Ophthalmology, vol. 114, no. 5, pp. 881–889, 2007.
[20]
C. L. Lobo, P. M. Faria, M. A. Soares, R. C. Bernardes, and J. G. Cunha-Vaz, “Macular alterations after small-incision cataract surgery,” Journal of Cataract and Refractive Surgery, vol. 30, no. 4, pp. 752–760, 2004.
[21]
P. G. Ursell, D. J. Spalton, S. M. Whitcup, and R. B. Nussenblatt, “Cystoid macular edema after phacoemulsification: relationship to blood- aqueous barrier damage and visual acuity,” Journal of Cataract and Refractive Surgery, vol. 25, no. 11, pp. 1492–1497, 1999.
[22]
K. A. Warren, H. Bahrani, and J. E. Fox, “NSAIDs in combination therapy for the treatment of chronic pseudophakic cystoid macular edema,” Retina, vol. 30, no. 2, pp. 260–266, 2010.
[23]
S. M. Hariprasad, L. Akduman, J. A. Clever, M. Ober, F. M. Recchia, and W. F. Mieler, “Treatment of cystoid macular edema with the new-generation NSAID nepafenac 0.1%,” Clinical Ophthalmology, vol. 3, no. 1, pp. 147–154, 2009.
[24]
A. J. Flach, R. C. Stegman, J. Graham, and L. P. Kruger, “Prophylaxis of aphakic cystoid macular edema without corticosteroids: a paired-comparison, placebo-controlled double-masked study,” Ophthalmology, vol. 97, no. 10, pp. 1253–1258, 1990.
[25]
K. Miyake, K. Masuda, S. Shirato et al., “Comparison of diclofenac and fluorometholone in preventing cystoid macular edema after small incision cataract surgery: a multicentered prospective trial,” Japanese Journal of Ophthalmology, vol. 44, no. 1, pp. 58–67, 2000.
[26]
J. R. Wittpenn, S. Silverstein, J. Heier, K. R. Kenyon, J. D. Hunkeler, and M. Earl, “A randomized, masked comparison of topical ketorolac 0.4% plus steroid vs. steroid alone in low-risk cataract surgery patients,” American Journal of Ophthalmology, vol. 146, no. 4, pp. 554–560, 2008.
[27]
S. J. Kim and N. M. Bressler, “Optical coherence tomography and cataract surgery,” Current Opinion in Ophthalmology, vol. 20, no. 1, pp. 46–51, 2009.
[28]
A. J. Flach, M. C. Kraff, D. R. Sanders, and L. Tanenbaum, “The quantitative effect of 0.5% ketorolac tromethamine solution and 0.1% dexamethasone sodium phosphate solution on postsurgical blood-aqueous barrier,” Archives of Ophthalmology, vol. 106, no. 4, pp. 480–483, 1988.
[29]
S. J. Kim, W. R. Lo, G. B. Hubbard et al., “Topical ketorolac in vitreoretinal surgery: a prospective, randomized, placebo-controlled, double-masked trial,” Archives of Ophthalmology, vol. 126, no. 9, pp. 1203–1208, 2008.
[30]
S. D. Schoenberger, D. M. Miller, M. R. Petersen, R. E. Foster, C. D. Riemann, and R. A. Sisk, “Nepafenac for epiretinal membrane surgery,” Ophthalmology, vol. 118, no. 7, pp. 1482.e1–1482.e3, 2011.
[31]
P. Naithani, S. Puranik, N. Vashisht, S. Khanduja, S. Kumar, and S. Garg, “Role of topical nepafenac in prevention and treatment of macular edema after vitreoretinal surgery,” Retina, vol. 32, no. 2, pp. 250–255, 2012.
[32]
D. S. Friedman, B. J. O’Colmain, B. Munoz, et al., “Prevalence of age-related macular degeneration in the United States,” Archives of Ophthalmology, vol. 122, no. 4, pp. 564–572, 2004.
[33]
G. C. Brown, M. M. Brown, S. Sharma et al., “The burden of age-related macular degeneration: a value-based medicine analysis,” Transactions of the American Ophthalmological Society, vol. 103, pp. 173–186, 2005.
[34]
J. C. Folk and E. M. Stone, “Ranibizumab therapy for neovascular age-related macular degeneration,” New England Journal of Medicine, vol. 363, no. 17, pp. 1648–1655, 2010.
[35]
P. A. Yourey, S. Gohari, J. L. Su, and R. F. Alderson, “Vascular endothelial cell growth factors promote the in vitro development of rat photoreceptor cells,” Journal of Neuroscience, vol. 20, no. 18, pp. 6781–6788, 2000.
[36]
M. A. Zarbin, “Current concepts in the pathogenesis of age-related macular degeneration,” Archives of Ophthalmology, vol. 122, no. 4, pp. 598–614, 2004.
[37]
M. Patel and C. C. Chan, “Immunopathological aspects of age-related macular degeneration,” Seminars in Immunopathology, vol. 30, no. 2, pp. 97–110, 2008.
[38]
S. C. Maloney, B. F. Fernandes, E. Castiglione et al., “Expression of cyclooxygenase-2 in choroidal neovascular membranes from age-related macular degeneration patients,” Retina, vol. 29, no. 2, pp. 176–180, 2009.
[39]
Y. Monnier, J. Zaric, and C. Rüegg, “Inhibition of angiogenesis by non-steroidal anti-inflammatory drugs: from the bench to the bedside and back,” Current Drug Targets: Inflammation and Allergy, vol. 4, no. 1, pp. 31–38, 2005.
[40]
S. Gately and R. Kerbel, “Therapeutic potential of selective cyclooxygenase-2 inhibitors in the management of tumor angiogenesis,” Progress in Experimental Tumor Research, vol. 37, pp. 179–192, 2003.
[41]
W. K. K. Wu, J. J. Sung, C. W. Lee, J. Yu, and C. H. Cho, “Cyclooxygenase-2 in tumorigenesis of gastrointestinal cancers: an update on the molecular mechanisms,” Cancer Letters, vol. 295, no. 1, pp. 7–16, 2010.
[42]
S. E. Yanni, J. M. Barnett, M. L. Clark, and J. S. Penn, “The role of PGE2 receptor EP4 in pathologic ocular angiogenesis,” Investigative Ophthalmology and Visual Science, vol. 50, no. 11, pp. 5479–5486, 2009.
[43]
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.
[44]
K. Takahashi, Y. Saishin, Y. Saishin et al., “Topical nepafenac inhibits ocular neovascularization,” Investigative Ophthalmology and Visual Science, vol. 44, no. 1, pp. 409–415, 2003.
[45]
S. J. Kim, H. S. Toma, J. M. Barnett, and J. S. Penn, “Ketorolac inhibits choroidal neovascularization by suppression of retinal VEGF,” Experimental Eye Research, vol. 91, no. 4, pp. 537–543, 2010.
[46]
S. J. Kim and H. S. Toma, “Inhibition of choroidal neovascularization by intravitreal ketorolac,” Archives of Ophthalmology, vol. 128, no. 5, pp. 596–600, 2010.
[47]
K. A. Rezaei, H. S. Toma, J. Cai, J. S. Penn, P. Sternberg, and S. J. Kim, “Reduced choroidal neovascular membrane formation in cyclooxygenase-2 null mice,” Investigative Ophthalmology and Visual Science, vol. 52, no. 2, pp. 701–707, 2011.
[48]
W. Hu, M. H. Criswell, A. Ottlecz et al., “Oral administration of lumiracoxib reduces choroidal neovascular membrane development in the rat laser-trauma model,” Retina, vol. 25, no. 8, pp. 1054–1064, 2005.
[49]
H. Takahashi, Y. Yanagi, Y. Tamaki, S. Uchida, and K. Muranaka, “COX-2-selective inhibitor, etodolac, suppresses choroidal neovascularization in a mice model,” Biochemical and Biophysical Research Communications, vol. 325, no. 2, pp. 461–466, 2004.
[50]
P. L. McGeer and J. Sibley, “Sparing of age-related macular degeneration in rheumatoid arthritis,” Neurobiology of Aging, vol. 26, no. 8, pp. 1199–1203, 2005.
[51]
H. L. Wilson, D. M. Schwartz, H. R. F. Bhatt, C. E. McCulloch, and J. L. Duncan, “Statin and aspirin therapy are associated with decreased rates of choroidal neovascularization among patients with age-related macular degeneration,” American Journal of Ophthalmology, vol. 137, no. 4, pp. 615–624, 2004.
[52]
J. J. Wang, P. Mitchell, W. Smith, M. Gillies, F. Billson, and Blue Mountains Eye Study, “Systemic use of anti-inflammatory medications and age-related maculopathy: the Blue Mountains Eye Study,” Ophthalmic Epidemiology, vol. 10, no. 1, pp. 37–48, 2003.
[53]
S. A. Zweifel, M. Engelbert, S. Khan, and K. B. Freund, “Retrospective review of the efficacy of topical bromfenac (0.09%) as an adjunctive therapy for patients with neovascular age-related macular degeneration,” Retina, vol. 29, no. 10, pp. 1527–1531, 2009.
[54]
E. Chen, M. S. Benz, R. H. Fish et al., “Use of nepafenac (Nevanac)in combination with intravitreal anti-VEGF agents in the treatment of recalcitrant exudative macular degeneration requiring monthly injections,” Clinical Ophthalmology, vol. 4, no. 1, pp. 1249–1252, 2010.
[55]
Adjunctive Diclofenac with Verteporfin (ADD-V) Study Group, D. S. Boyer, P. M. Beer et al., “Effect of adjunctive diclofenac with verteporfin therapy to treat choroidal neovascularization due to age-related macular degeneration: phase II study,” Retina, vol. 27, no. 6, pp. 693–700, 2007.
[56]
C. A. Grant, “Combination therapy: lucentis (ranibizumab injection) and xibrom (bromfenac ophthalmic solution) 0. 09% in the treatment of chroidal neovascular membrane secondary to age-related macular degeneration,” Investigative Ophthalmology & Visual Science, vol. 49, 2008, E-abstract 563.
[57]
C. Flaxel, M. B. Schain, S. C. Hamon, and P. J. Francis, “Prospective randomized controlled trial of combination ranibizumab (Lucentis) and bromfenac (Xibrom) for neovascular age-related macular degeneration,” Retina, vol. 32, no. 3, pp. 417–423, 2012.
[58]
F. Gomi, M. Sawa, M. Tsujikawa, and K. Nishida, “Topical bromfenac as an adjunctive treatment with intravitreal ranibizumab for exudative age-related macular degeneration,” Retina, vol. 32, no. 9, pp. 1804–1810, 2012.
[59]
D. A. Antonetti, R. Klein, and T. W. Gardner, “Diabetic retinopathy,” New England Journal of Medicine, vol. 366, no. 13, pp. 1227–1239, 2012.
[60]
N. Bhagat, R. A. Grigorian, A. Tutela, and M. A. Zarbin, “Diabetic macular edema: pathogenesis and treatment,” Survey of Ophthalmology, vol. 54, no. 1, pp. 1–32, 2009.
[61]
“Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial. Diabetes Control and Complications Trial Research Group,” Ophthalmology, vol. 102, no. 4, pp. 647–661, 1995.
[62]
“Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. United Kingdom Prospective Diabetes Study Group,” British Medical Journal, vol. 317, no. 7160, pp. 703–713, 1998.
[63]
A. P. Adamis and A. J. Berman, “Immunological mechanisms in the pathogenesis of diabetic retinopathy,” Seminars in Immunopathology, vol. 30, no. 2, pp. 65–84, 2008.
[64]
C. A. Lange, P. Stavrakas, U. F. Luhmann, et al., “Intraocular oxygen distribution in advanced proliferative diabetic retinopathy,” American Journal of Ophthalmology, vol. 152, no. 3, pp. 406–412, 2011.
[65]
Y. Suzuki, M. Nakazawa, K. Suzuki, H. Yamazaki, and Y. Miyagawa, “Expression profiles of cytokines and chemokines in vitreous fluid in diabetic retinopathy and central retinal vein occlusion,” Japanese Journal of Ophthalmology, vol. 55, no. 3, pp. 256–263, 2011.
[66]
J. Zhou, S. Wang, and X. Xia, “Role of intravitreal inflammatory cytokines and angiogenic factors in proliferative diabetic retinopathy,” Current Eye Research, vol. 37, no. 5, pp. 416–420, 2012.
[67]
S. D. Schoenberger, S. J. Kim, J. Sheng, K. A. Rezaei, M. Lalezary, and E. Cherney, “Increased prostaglandin E2 (PGE2) levels in proliferative diabetic retinopathy and correlation with VEGF and inflammatory cytokines,” Investigative Ophthalmology & Visual Science, vol. 53, no. 9, pp. 5906–5911, 2012.
[68]
T. Cheng, W. Cao, R. Wen, R. H. Steinberg, and M. M. LaVail, “Prostaglandin E2 induces vascular endothelial growth factor and basic fibroblast growth factor mRNA expression in cultured rat Muller cells,” Investigative Ophthalmology and Visual Science, vol. 39, no. 3, pp. 581–591, 1998.
[69]
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.
[70]
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.
[71]
T. S. Kern, C. M. Miller, Y. Du et al., “Topical administration of nepafenac inhibits diabetes-induced retinal microvascular disease and underlying abnormalities of retinal metabolism and physiology,” Diabetes, vol. 56, no. 2, pp. 373–379, 2007.
[72]
S. P. Ayalasomayajula and U. B. Kompella, “Celecoxib, a selective cyclooxygenase-2 inhibitor, inhibits retinal vascular endothelial growth factor expression and vascular leakage in a streptozotocin-induced diabetic rat model,” European Journal of Pharmacology, vol. 458, no. 3, pp. 283–289, 2003.
[73]
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.
[74]
E. D. Powell and R. Field, “Diabetic retinopathy and rheumatoid arthritis,” The Lancet, vol. 284, no. 7349, pp. 17–18, 1964.
[75]
“Effects of aspirin treatment on diabetic retinopathy. ETDRS report number 8. Early Treatment Diabetic Retinopathy Study Research Group,” Ophthalmology, vol. 98, no. 5, supplement, pp. 757–765, 1991.
[76]
“Effect of aspirin alone and aspirin plus dipyridamole in early diabetic retinopathy. A multicenter randomized controlled clinical trial. The DAMAD Study Group,” Diabetes, vol. 38, no. 4, pp. 491–498, 1989.
[77]
Y. Hattori, K. Hashizume, K. Nakajima, Y. Nishimura, M. Naka, and K. Miyanaga, “The effect of long-term treatment with sulindac on the progression of diabetic retinopathy,” Current Medical Research and Opinion, vol. 23, no. 8, pp. 1913–1917, 2007.
[78]
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.
[79]
N. M. Bressler, A. R. Edwards, R. W. Beck et al., “Exploratory analysis of diabetic retinopathy progression through 3 years in a randomized clinical trial that compares intravitreal triamcinolone acetonide with focal/grid photocoagulation,” Archives of Ophthalmology, vol. 127, no. 12, pp. 1566–1571, 2009.
[80]
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. 585–589, 2007.
[81]
D. Callanan and P. Williams, “Topical nepafenac in the treatment of diabetic macular edema,” Clinical Ophthalmology, vol. 2, no. 4, pp. 689–692, 2008.
[82]
July 2012, http://clinicaltrials.gov/ct2/show/NCT01331005.
[83]
M. Soheilian, S. Karimi, A. Ramezani, and G. A. Peyman, “Pilot study of intravitreal injection of diclofenac for treatment of macular edema of various etiologies,” Retina, vol. 30, no. 3, pp. 509–515, 2010.
[84]
A. M. Elbendary and M. M. Shahin, “Intravitreal diclofenac versus intravitreal triamcinolone acetonide in the treatment of diabetic macular edema,” Retina, vol. 31, no. 10, pp. 2058–2064, 2011.
[85]
C. Reis Ado, R. N. Vianna, R. S. Reis, and G. P. Cardoso, “Intravitreal injection of ketorolac tromethamine in patients with diabetic macular edema refractory to retinal photocoagulation,” Arquivos Brasileiros de Oftalmologia, vol. 73, no. 4, pp. 338–342, 2010.
[86]
R. M. Maldonado, R. N. G. Vianna, G. P. Cardoso, A. V. de Magalh？es, and M. N. Burnier Jr., “Intravitreal injection of commercially available ketorolac tromethamine in eyes with diabetic macular edema refractory to laser photocoagulation,” Current Eye Research, vol. 36, no. 8, pp. 768–773, 2011.
