Aging Disorders of the Eye: Challenges and Approaches for Their Treatment

  • Shruti Hazare
  • Rongbing Yang
  • Smita Chavan
  • Mala D. MenonEmail author
  • Mahavir B. ChouguleEmail author


The proportion of the global population aged 60 years and over is steadily increasing and projected to increase to almost 30 % in 2050. Among the various health problems, eye and vision problems are serious issues in the elderly. These may be manifested as basic functional disabilities or a decline in the receptive, storage, and analytical capacities of the central visual system. The major eye disorders of aging are cataract, age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy. Although there are treatment methods (e.g., medications and surgical interventions) for these conditions, they are still very challenging areas due to the delicate and critical nature of the eye tissues. Compared with drug delivery to other parts of the body, drug delivery to the eye has met with significant challenges posed by various ocular barriers, which are inherent and unique to the ocular anatomy. In addition, in the case of the aging population, there are added difficulties due to multiple diseases and health problems, the several medications being taken together and the physical and psychological difficulties, including disabilities, dependence, fears, and apprehensions: opening packages, swallowing oral medication and/or reading leaflet information, fear of surgery, and device insertion and removal.

This chapter discusses:
  1. (a)

    Brief of anatomy of the eye and aging changes in the eye

  2. (b)

    The major age-related eye problems, including cataract, AMD, diabetic retinopathy, and glaucoma

  3. (c)

    The current treatment methods, novel drug delivery systems, and approaches being investigated for each of abovementioned eye problems


Maintaining good vision is an important part of “active aging,” a concept promoted by the WHO. Active aging means continued health, security, and participation in society as people age, in order to ensure a good quality of life in later years. Nations and communities have to gear up to this challenge to ensure that good quality eye care and therapies are available to this group.


Aging disorders of the eye Cataract Diabetic retinopathy Age-related macular degeneration Glaucoma 



The authors acknowledge the support given by the following funding agencies:

(a) National Institute of General Medical Science of the National Institutes of Health (award number SC3 SC3GM109873, 2011); (b) Hawaii Community Foundation, Honolulu, HI, USA, for research support on asthma and mesothelioma research (Leahi Fund) 2013; (c) The 2013 George F. Straub Trust and Robert C. Perry Fund of the Hawaii Community Foundation, Honolulu, HI, USA, for research support on lung cancer; (d) Seed grant from the Research Corporation of the University of Hawaii at Hilo, HI, USA, and University of Hawaii at Hilo, the Daniel K Inouye College of Pharmacy for providing start-up financial support to our research group; (e) University Grants Commission, India – Major Research Project funding titled “Studies in the Development of Mucoadhesive Systems for Ocular and Nasal Delivery of Drugs” (Sanction No. F-7-11/99-SR, Aug 2000–2003); (f) Amrut Mody research fund (AMRF) for project titled “Studies in the development of novel enzyme delivery systems” (Year 2007–2010).


  1. 1.
    Abdullah KN, Abdullah MT (2002) Management and planning for primary eye care of the elderly: the need to create public awareness of age-related cataract in Pakistan. Community Eye Health 15(43):45PubMedPubMedCentralGoogle Scholar
  2. 2.
    Control Centers for Disease (2006) Improving the nation’s vision health: a coordinated public health approach. Centre for disease control, AtlantaGoogle Scholar
  3. 3.
    Evans J (2008) Eye care for older people. Community Eye Health J 21(66):21–23Google Scholar
  4. 4.
    Nobili A, Garattini S, Mannucci PM (2011) Multiple diseases and polypharmacy in the elderly: challenges for the internist of the third millennium. J Comorbidity 1(1):28–44CrossRefGoogle Scholar
  5. 5.
    Team Ve-r (2010) Vision 2020 e-resource for eye care management worldwide. Vision 2020 e-resource team.
  6. 6.
    Wong TY, Loon SC, Saw SM (2006) The epidemiology of age related eye diseases in Asia. Br J Ophthalmol 90(4):506–511PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Gentry LR (1998) Anatomy of the orbit. Neuroimaging Clin N Am 8(1):171–194PubMedGoogle Scholar
  8. 8.
    Hughes MS (1991) Dictionary of eye terminology. Arch Ophthalmol 109(9):1208CrossRefGoogle Scholar
  9. 9.
    Alm A, Nilsson SFE (2009) Uveoscleral outflow – A review. Exp Eye Res 88(4):760–768Google Scholar
  10. 10.
    Hayreh SS (1975) Segmental nature of the choroidal vasculature. Br J Ophthalmol 59(11):631–648Google Scholar
  11. 11.
    Oyster CW (1999) The human eye: structure and function. Sinauer Associates, Inc., SunderlandGoogle Scholar
  12. 12.
    Hubel DH (1995) Eye, brain, and vision. Scientific American Library series (Issue 22), Henry Holt and Company, New YorkGoogle Scholar
  13. 13.
    Forrester J, Dick A, McMenamin P, Lee W (1996) The eye: basic sciences in practice. WB Saunders Company Ltd, LondonGoogle Scholar
  14. 14.
    Venes D (2013) Taber’s cyclopedic medical dictionary. FA Davis, PhiladelphiaGoogle Scholar
  15. 15.
    Baerveldt G (2000) Method and apparatus for inserting a glaucoma implant in an anterior and posterior segment of the eye. Google patentsGoogle Scholar
  16. 16.
    Kronfeld P (1962) Gross anatomy and embryology of the eye. Eye 1:1–66Google Scholar
  17. 17.
    Salvi SM, Akhtar S, Currie Z (2006) Ageing changes in the eye. Postgrad Med J 82(971):581–587Google Scholar
  18. 18.
    Van Haeringen NJ (1997) Aging and the lacrimal system. Br J Ophthalmol 81(10):824–826PubMedCrossRefGoogle Scholar
  19. 19.
    Faragher RGA, Mulholland B, Tuft SJ, Sandeman S, Khaw PT (1997) Aging and the cornea. Br J Ophthalmol 81(10):814–817PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Duncan G, Wormstone IM, Davies P (1997) The aging human lens: structure, growth, and physiological behaviour. Br J Ophthalmol 81(10):818–823PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Le Goff MM, Bishop PN (2008) Adult vitreous structure and postnatal changes. Eye 22(10):1214–1222PubMedCrossRefGoogle Scholar
  22. 22.
    Grunwald JE, Metelitsina TI, DuPont JC, Ying G-S, Maguire MG (2005) Reduced foveolar choroidal blood flow in eyes with increasing AMD severity. Invest Ophthalmol Vis Sci 46(3):1033–1038PubMedCrossRefGoogle Scholar
  23. 23.
    Grunwald JE, Piltz J, Patel N, Bose S, Riva CE (1993) Effect of aging on retinal macular microcirculation: a blue field simulation study. Invest Ophthalmol Vis Sci 34(13):3609–3613PubMedGoogle Scholar
  24. 24.
    Brian G, Taylor H (2001) Cataract blindness: challenges for the 21st century. Bull World Health Organ 79(3):249–256PubMedPubMedCentralGoogle Scholar
  25. 25.
    Rao GN, Sadasivudu B, Cotlier E (1983) Studies on glutathione S-transferase, glutathione peroxidase and glutathione reductase in human normal and cataractous lenses. Ophthalmic Res 15(4):173–179PubMedCrossRefGoogle Scholar
  26. 26.
    Beers MH, Berkow R (1999) The Merck manual of diagnosis and therapy. Merck and Co. Inc., Whitehouse StationGoogle Scholar
  27. 27.
    Cejková J, Stípek S, Crkovska J, Ardan T, Platenik J, Cejka C, Midelfart A (2004) UV rays, the prooxidant/antioxidant imbalance in the cornea and oxidative eye damage. Physiol Res 53:1–10PubMedGoogle Scholar
  28. 28.
    Cumming RG, Mitchell P (1997) Alcohol, smoking, and cataracts: the Blue Mountains eye study. Arch Ophthalmol 115(10):1296–1303PubMedCrossRefGoogle Scholar
  29. 29.
    Auricchio G, Libondi T (1982) The physiologic and pharmacologic factors protecting the lens transparency and the update approach to the prevention of experimental cataracts: a review. Metab Pediatr Syst Ophthalmol 7(2):115–124Google Scholar
  30. 30.
    Spector A, Garner WH (1981) Hydrogen peroxide and human cataract. Exp Eye Res 33(6):673–681PubMedCrossRefGoogle Scholar
  31. 31.
    Wakamatsu TH, Dogru M, Tsubota K (2008) Tearful relations: oxidative stress, inflammation and eye diseases. Arq Bras Oftalmol 71(6):72–79PubMedCrossRefGoogle Scholar
  32. 32.
    Brown L, Rimm EB, Seddon JM, Giovannucci EL, Chasan-Taber L, Spiegelman D, Willett WC, Hankinson SE (1999) A prospective study of carotenoid intake and risk of cataract extraction in US men. Am J Clin Nutr 70(4):517–524PubMedGoogle Scholar
  33. 33.
    Gritz DC, Srinivasan M, Smith SD, Kim U, Lietman TM, Wilkins JH, Priyadharshini B, John RK, Aravind S, Prajna NV (2006) The antioxidants in prevention of cataracts study: effects of antioxidant supplements on cataract progression in South India. Br J Ophthalmol 90(7):847–851PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Jacques PF, Chylack LT (1991) Epidemiologic evidence of a role for the antioxidant vitamins and carotenoids in cataract prevention. Am J Clin Nutr 53(1):352S–355SPubMedGoogle Scholar
  35. 35.
    Calladine D, Evans JR, Shah S, Leyland M (2012) Multifocal versus monofocal intraocular lenses after cataract extraction. Cochrane Database Syst Rev 9Google Scholar
  36. 36.
    Leung TG, Lindsley K, Kuo IC (2014) Types of intraocular lenses for cataract surgery in eyes with uveitis. Cochrane Database Syst Rev 3:Cd007284Google Scholar
  37. 37.
    Chanalet L, Lapalus P (1994) Drugs designed to maintain the transparence of the ocular lens. Fundam Clin Pharmacol 8(4):322–341PubMedCrossRefGoogle Scholar
  38. 38.
    Testa M, Iuliano G, Marino E, Buongiovanni C, Paolercio F, Trapanese A, Mortow P (1986) Bendazac and benzydamine for treatment of cataract: individualized therapy by the “BLOA test”. J Ocul Pharmacol Ther 2(3):251–266CrossRefGoogle Scholar
  39. 39.
    Toh TY, Morton J, Coxon J, Elder MJ (2007) Medical treatment of cataract. Clin Experiment Ophthalmol 35(7):664–671PubMedCrossRefGoogle Scholar
  40. 40.
    Balfour JA, Clissold SP (1990) Bendazac lysine. Drugs 39(4):575–596PubMedCrossRefGoogle Scholar
  41. 41.
    Testa M, Iuliano G, Morton P, Longoni A (1987) Topical benzyl alcohol reduces cataract surgery need: two long-term double blind studies. J Ocul Pharmacol Ther 3(3):211–225CrossRefGoogle Scholar
  42. 42.
    Hu C-C, Liao J-H, Hsu K-Y, Lin IL, Tsai M-H, Wu W-H, Wei T-T, Huang Y-S, Chiu S-J, Chen H-Y (2011) Role of pirenoxine in the effects of catalin on in vitro ultraviolet-induced lens protein turbidity and selenite-induced cataractogenesis in vivo. Mol Vis 17:1862PubMedPubMedCentralGoogle Scholar
  43. 43.
    Kociecki J, Załecki K, Wasiewicz-Rager J, Pecold K (2003) Evaluation of effectiveness of Catalin eyedrops in patients with presenile and senile cataract. Klinika oczna 106(6):778–782Google Scholar
  44. 44.
    Angra SK, Mohan M, Saini JS (1983) Medical therapy of cataract (evaluation of Catalin). Indian J Ophthalmol 31(1):5PubMedGoogle Scholar
  45. 45.
    Hockwin O, Laser H, De Gregorio M, Carrieri MP (1989) Bendazac lysine in selected types of human senile cataract. Ophthalmic Res 21(3):141–154PubMedCrossRefGoogle Scholar
  46. 46.
    Leuschen J, Mortensen EM, Frei CR, Mansi EA, Panday V, Mansi I (2013) Association of statin use with cataracts: a propensity score-matched analysis. JAMA Ophthalmol 131(11):1427–1434PubMedCrossRefGoogle Scholar
  47. 47.
    Bonnefont-Rousselot D (2000) Antioxidant and anti-AGE therapeutics: evaluation and perspectives. J Soc Biol 195(4):391–398Google Scholar
  48. 48.
    Babizhayev MA, Deyev AI, Yermakova VN, Semiletov YA, Davydova NG, Doroshenko VS, Zhukotskii AV, Goldman IM (2002) Efficacy of N-acetylcarnosine in the treatment of cataracts. Drugs R&D 3(2):87–103CrossRefGoogle Scholar
  49. 49.
    Stankiewicz A, Poppe E, Stasiewicz B, Gołebiowska-Hrycukowa A (1990) Evaluation of the effectiveness of Quinax in the prevention of the development of senile cataract. Klinika oczna 92(3–4):52–54PubMedGoogle Scholar
  50. 50.
    Ito Y et al (1999) Correlation between prevention of cataract development by disulfiram and fates of selenium in selenium-treated rats. Curr Eye Res 18(4):292–299Google Scholar
  51. 51.
    Zhang J, Guan P, Wang T, Chang D, Jiang T, Wang S (2009) Freeze-dried liposomes as potential carriers for ocular administration of cytochrome c against selenite cataract formation. J Pharm Pharmacol 61(9):1171–1178PubMedCrossRefGoogle Scholar
  52. 52.
    Grama CN, Suryanarayana P, Patil MA, Raghu G, Balakrishna N, Kumar MNVR, Reddy GB (2013) Efficacy of biodegradable curcumin nanoparticles in delaying cataract in diabetic rat model. PLoS One 8(10), e78217PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Sunkireddy P, Jha SN, Kanwar JR, Yadav SC (2013) Natural antioxidant biomolecules promises future nanomedicine based therapy for cataract. Colloids Surf B Biointerfaces 112:554–562PubMedCrossRefGoogle Scholar
  54. 54.
    Ito Y, Nagai N, Cai H, Takeda M, Koizumi Y (2006) Preventive effect of eye drops of liposomes containing disulfiram and cefmetazole on selenite-induced cataract in rat pups. J Oleo Sci 55(1):15–22CrossRefGoogle Scholar
  55. 55.
    Hazare SA (2010) Studies in the development of novel carrier systems for enzymes. University of Mumbai, MumbaiGoogle Scholar
  56. 56.
    Ramos D, Carretero A, Navarro M, Mendes-Jorge L, Rodriguez-Baeza A, Nacher V, Ruberte J (2014) Mouse models of diabetic retinopathy. Drug Discov Today Dis Models. doi: 10.1016/j.ddmod.2014.02.002 Google Scholar
  57. 57.
    Macleod S, Forrester JV (2002) Diabetic retinopathy. Medicine 30(2):41–44. doi: 10.1383/medc. CrossRefGoogle Scholar
  58. 58.
    Scanlon PH (2010) Diabetic retinopathy. Medicine 38(12):656–660. doi: 10.1016/j.mpmed.2010.08.010 CrossRefGoogle Scholar
  59. 59.
    Alghadyan AA (2011) Diabetic retinopathy – an update. Saudi J Ophthalmol 25(2):99–111. doi: 10.1016/j.sjopt.2011.01.009 PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Fante RJ, Durairaj VD, Oliver SC (2010) Diabetic retinopathy: an update on treatment. Am J Med 123(3):213–216. doi: 10.1016/j.amjmed.2009.09.020 PubMedCrossRefGoogle Scholar
  61. 61.
    National Eye Institute (2003) Diabetic retinopathy: what you should know. National Eye Institute, BethesdaGoogle Scholar
  62. 62.
    Laatikainen L (1977) Preliminary report on effect of retinal panphotocoagulation on rubeosis iridis and neovascular glaucoma. Br J Ophthalmol 61(4):278–284PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Turner R, Holman R (1995) Lessons from UK prospective diabetes study. Diabetes Res Clin Pract 28:S151–S157PubMedCrossRefGoogle Scholar
  64. 64.
    Cunha-Vaz J (1978) Pathophysiology of diabetic retinopathy. Br J Ophthalmol 62(6):351–355PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Tarr JM, Kaul K, Chopra M, Kohner EM, Chibber R (2013) Pathophysiology of diabetic retinopathy. ISRN Ophthalmol.
  66. 66.
    Dagher Z, Park YS, Asnaghi V, Hoehn T, Gerhardinger C, Lorenzi M (2004) Studies of rat and human retinas predict a role for the polyol pathway in human diabetic retinopathy. Diabetes 53(9):2404–2411PubMedCrossRefGoogle Scholar
  67. 67.
    Lorenzi M (2007) The polyol pathway as a mechanism for diabetic retinopathy: attractive, elusive, and resilient. Exp Diabetes Res 2007:61038. doi:  10.1155/2007/61038 Google Scholar
  68. 68.
    Van den Enden MK, Nyengaard JR, Ostrow E, Burgan JH, Williamson JR (1995) Elevated glucose levels increase retinal glycolysis and sorbitol pathway metabolism. Implications for diabetic retinopathy. Invest Ophthalmol Vis Sci 36(8):1675–1685PubMedGoogle Scholar
  69. 69.
    Hammes H-P, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D (2003) Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 9(3):294–299PubMedCrossRefGoogle Scholar
  70. 70.
    Kern TS, Kowluru RA, Engerman RL (1994) Abnormalities of retinal metabolism in diabetes or galactosemia: ATPases and glutathione. Invest Ophthalmol Vis Sci 35(7):2962–2967PubMedGoogle Scholar
  71. 71.
    Robison W, Nagata M, Laver N, Hohman T, Kinoshita J (1989) Diabetic-like retinopathy in rats prevented with an aldose reductase inhibitor. Invest Ophthalmol Vis Sci 30(11):2285–2292PubMedGoogle Scholar
  72. 72.
    Hotta N, Akanuma Y, Kawamori R, Matsuoka K, Oka Y, Shichiri M, Toyota T, Nakashima M, Yoshimura I, Sakamoto N (2006) Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy the 3-year, multicenter, comparative aldose reductase inhibitor-diabetes complications trial. Diabetes Care 29(7):1538–1544PubMedCrossRefGoogle Scholar
  73. 73.
    Sun W, Oates PJ, Coutcher JB, Gerhardinger C, Lorenzi M (2006) A selective aldose reductase inhibitor of a new structural class prevents or reverses early retinal abnormalities in experimental diabetic retinopathy. Diabetes 55(10):2757–2762PubMedCrossRefGoogle Scholar
  74. 74.
    Amano S, S-i Y, Kato N, Inagaki Y, Okamoto T, Makino M, Taniko K, Hirooka H, Jomori T, Takeuchi M (2002) Sorbitol dehydrogenase overexpression potentiates glucose toxicity to cultured retinal pericytes. Biochem Biophys Res Commun 299(2):183–188PubMedCrossRefGoogle Scholar
  75. 75.
    Stitt AW (2003) The role of advanced glycation in the pathogenesis of diabetic retinopathy. Exp Mol Pathol 75(1):95–108PubMedCrossRefGoogle Scholar
  76. 76.
    Stitt AW, Li YM, Gardiner TA, Bucala R, Archer DB, Vlassara H (1997) Advanced glycation end products (AGEs) co-localize with AGE receptors in the retinal vasculature of diabetic and of AGE-infused rats. Am J Pathol 150(2):523PubMedPubMedCentralGoogle Scholar
  77. 77.
    Grossin N, Wautier MP, Mes T, Guillausseau PJ et al (2008) Severity of diabetic microvascular complications is associated with low soluble RAGE level. Diabetes Metab 34:392–395Google Scholar
  78. 78.
    Zong H, Ward M, Stitt AW (2011) AGEs, RAGE, and diabetic retinopathy. Curr Diab Rep 11(4):244–252PubMedCrossRefGoogle Scholar
  79. 79.
    Ahmed N, Thornalley P (2007) Advanced glycation end products: what is their relevance to diabetic complications? Diabetes Obes Metab 9(3):233–245PubMedCrossRefGoogle Scholar
  80. 80.
    Thallas-Bonke V, Lindschau C, Rizkalla B, Bach LA, Boner G, Meier M, Haller H, Cooper ME, Forbes JM (2004) Attenuation of extracellular matrix accumulation in diabetic nephropathy by the advanced glycation end product cross-link breaker ALT-711 via a protein kinase C-α-dependent pathway. Diabetes 53(11):2921–2930PubMedCrossRefGoogle Scholar
  81. 81.
    Koya D, King GL (1998) Protein kinase C activation and the development of diabetic complications. Diabetes 47(6):859–866PubMedCrossRefGoogle Scholar
  82. 82.
    Aiello LP, Bursell S-E, Clermont A, Duh E, Ishii H, Takagi C, Mori F, Ciulla TA, Ways K, Jirousek M (1997) 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 46(9):1473–1480PubMedCrossRefGoogle Scholar
  83. 83.
    Aiello LP, Clermont A, Arora V, Davis MD, Sheetz MJ, Bursell S-E (2006) Inhibition of PKC β by oral administration of ruboxistaurin is well tolerated and ameliorates diabetes-induced retinal hemodynamic abnormalities in patients. Invest Ophthalmol Vis Sci 47(1):86–92PubMedCrossRefGoogle Scholar
  84. 84.
    Strøm C, Sander B, Klemp K, Aiello LP, Lund-Andersen H, Larsen M (2005) Effect of ruboxistaurin on blood–retinal barrier permeability in relation to severity of leakage in diabetic macular edema. Invest Ophthalmol Vis Sci 46(10):3855–3858PubMedCrossRefGoogle Scholar
  85. 85.
    Klein BE, Knudtson MD, Tsai MY, Klein R (2009) The relation of markers of inflammation and endothelial dysfunction to the prevalence and progression of diabetic retinopathy: Wisconsin epidemiologic study of diabetic retinopathy. Arch Ophthalmol 127(9):1175–1182PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Tang J, Kern TS (2011) Inflammation in diabetic retinopathy. Prog Retin Eye Res 30(5):343–358. doi: 10.1016/j.preteyeres.2011.05.002 PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Chibber R, Ben-Mahmud BM, Mann GE, Zhang JJ, Kohner EM (2003) Protein kinase C β2-dependent phosphorylation of core 2 GlcNAc-T promotes leukocyte-endothelial cell adhesion a mechanism underlying capillary occlusion in diabetic retinopathy. Diabetes 52(6):1519–1527PubMedCrossRefGoogle Scholar
  88. 88.
    Gillies MC, Sutter FK, Simpson JM, Larsson J, Ali H, Zhu M (2006) Intravitreal triamcinolone for refractory diabetic macular edema: two-year results of a double-masked, placebo-controlled, randomized clinical trial. Ophthalmology 113(9):1533–1538PubMedCrossRefGoogle Scholar
  89. 89.
    Kuppermann BD, Blumenkranz MS, Haller JA, Williams GA, Weinberg DV, Chou C, Whitcup SM (2007) Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthalmol 125(3):309–317PubMedCrossRefGoogle Scholar
  90. 90.
    Baynes JW, Thorpe SR (1999) Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 48(1):1–9PubMedCrossRefGoogle Scholar
  91. 91.
    Mohammad G, Kowluru RA (2011) Novel role of mitochondrial matrix metalloproteinase-2 in the development of diabetic retinopathy. Invest Ophthalmol Vis Sci 52(6):3832–3841PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Kowluru RA (2003) Effect of reinstitution of good glycemic control on retinal oxidative stress and nitrative stress in diabetic rats. Diabetes 52(3):818–823PubMedCrossRefGoogle Scholar
  93. 93.
    Haskins K, Bradley B, Powers K, Fadok V, Flores S, Ling X, Pugazhenthi S, Reusch J, Kench J (2003) Oxidative stress in type 1 diabetes. Ann N Y Acad Sci 1005(1):43–54PubMedCrossRefGoogle Scholar
  94. 94.
    Hueber A, Wiedemann P, Esser P, Heimann K (1997) Basic fibroblast growth factor mRNA, bFGF peptide and FGF receptor in epiretinal membranes of intraocular proliferative disorders (PVR and PDR). Int Ophthalmol 20(6):345–350CrossRefGoogle Scholar
  95. 95.
    Haurigot V, Villacampa P, Ribera A, Llombart C, Bosch A, Nacher V, Ramos D, Ayuso E, Segovia JC, Bueren JA (2009) Increased intraocular insulin-like growth factor-I triggers blood-retinal barrier breakdown. J Biol Chem 284(34):22961–22969PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Rangasamy S, Srinivasan R, Maestas J, McGuire PG, Das A (2011) A potential role for angiopoietin 2 in the regulation of the blood–retinal barrier in diabetic retinopathy. Invest Ophthalmol Vis Sci 52(6):3784–3791PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Brooks HL, Caballero S, Newell CK, Steinmetz RL, Watson D, Segal MS, Harrison JK, Scott EW, Grant MB (2004) Vitreous levels of vascular endothelial growth factor and stromal-derived factor 1 in patients with diabetic retinopathy and cystoid macular edema before and after intraocular injection of triamcinolone. Arch Ophthalmol 122(12):1801–1807PubMedCrossRefGoogle Scholar
  98. 98.
    Lev-Ran A, Hwang DL, Miller JD, Josefsberg Z (1990) Excretion of epidermal growth factor (EGF) in diabetes. Clin Chim Acta 192(3):201–206PubMedCrossRefGoogle Scholar
  99. 99.
    Ie D, Gordon LW, Glaser BM, Pena RA (1994) Transforming growth factor-beta 2 levels increase following retinal laser photocoagulation. Curr Eye Res 13(10):743–746PubMedCrossRefGoogle Scholar
  100. 100.
    Praidou A, Klangas I, Papakonstantinou E, Androudi S, Georgiadis N, Karakiulakis G, Dimitrakos S (2009) Vitreous and serum levels of platelet-derived growth factor and their correlation in patients with proliferative diabetic retinopathy. Curr Eye Res 34(2):152–161PubMedCrossRefGoogle Scholar
  101. 101.
    Eckardt K-U (2009) Erythropoietin and microvascular diabetic complications. Nephrol Dial Transplant 24(2):388–390PubMedCrossRefGoogle Scholar
  102. 102.
    Awata T, Inoue K, Kurihara S, Ohkubo T, Watanabe M, Inukai K, Inoue I, Katayama S (2002) A common polymorphism in the 5′-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes. Diabetes 51(5):1635–1639PubMedCrossRefGoogle Scholar
  103. 103.
    Boulton M, Foreman D, Williams G, McLeod D (1998) VEGF localisation in diabetic retinopathy. Br J Ophthalmol 82(5):561–568PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Joussen AM, Poulaki V, Qin W, Kirchhof B, Mitsiades N, Wiegand SJ, Rudge J, Yancopoulos GD, Adamis AP (2002) Retinal vascular endothelial growth factor induces intercellular adhesion molecule-1 and endothelial nitric oxide synthase expression and initiates early diabetic retinal leukocyte adhesion in vivo. Am J Pathol 160(2):501–509PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Ray D, Mishra M, Ralph S, Read I, Davies R, Brenchley P (2004) Association of the VEGF gene with proliferative diabetic retinopathy but not proteinuria in diabetes. Diabetes 53(3):861–864PubMedCrossRefGoogle Scholar
  106. 106.
    Park Y, Freedman B, Lee E, Park S, Jameson J (2003) A dominant negative PPARγ mutant shows altered cofactor recruitment and inhibits adipogenesis in 3T3-L1 cells. Diabetologia 46(3):365–377PubMedCrossRefGoogle Scholar
  107. 107.
    Estacio R, Jeffers B, Gifford N, Schrier R (2000) Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care 23:B54–B64PubMedGoogle Scholar
  108. 108.
    Rassam S, Patel V, Kohner E (1995) The effect of experimental hypertension on retinal vascular autoregulation in humans: a mechanism for the progression of diabetic retinopathy. Exp Physiol 80(1):53–68PubMedCrossRefGoogle Scholar
  109. 109.
    Suzuma I, Hata Y, Clermont A, Pokras F, Rook SL, Suzuma K, Feener EP, Aiello LP (2001) Cyclic stretch and hypertension induce retinal expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 potential mechanisms for exacerbation of diabetic retinopathy by hypertension. Diabetes 50(2):444–454PubMedCrossRefGoogle Scholar
  110. 110.
    DPS Group (2005) The DIabetic REtinopathy Candesartan Trials (DIRECT) programme: baseline characteristics. J Renin Angiotensin Aldosterone Syst 6(1):25–32CrossRefGoogle Scholar
  111. 111.
    Corneli HM, Zorc JJ, Mahajan P, Shaw KN, Holubkov R, Reeves SD, Ruddy RM, Malik B, Nelson KA, Bregstein JS (2007) A multicenter, randomized, controlled trial of dexamethasone for bronchiolitis. New Engl J Med 357(4):331–339PubMedCrossRefGoogle Scholar
  112. 112.
    Makadia HK, Siegel SJ (2011) Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier. Polymers 3(3):1377–1397PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Boyer DS, Faber D, Gupta S, Patel SS, Tabandeh H, Li X-Y, Liu CC, Lou J, Whitcup SM, OCS Group (2011) Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. Retina 31(5):915–923PubMedCrossRefGoogle Scholar
  114. 114.
    Pacella E, Vestri AR, Muscella R, Carbotti MR, Castellucci M, Coi L, Turchetti P, Pacella F (2013) Preliminary results of an intravitreal dexamethasone implant (Ozurdex®) in patients with persistent diabetic macular edema. Clin Ophthalmol 7:1423PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Pearson P, Levy B, Comstock T, Group FAIS (2006) Fluocinolone acetonide intravitreal implant to treat diabetic macular edema: 3-year results of a multi-center clinical trial. Invest Ophthalmol Vis Sci 47(5):5442Google Scholar
  116. 116.
    Pearson PA, Comstock TL, Ip M, Callanan D, Morse LS, Ashton P, Levy B, Mann ES, Eliott D (2011) Fluocinolone acetonide intravitreal implant for diabetic macular edema: a 3-year multicenter, randomized, controlled clinical trial. Ophthalmology 118(8):1580–1587PubMedCrossRefGoogle Scholar
  117. 117.
    Campochiaro PA, Brown DM, Pearson A, Ciulla T, Boyer D, Holz FG, Tolentino M, Gupta A, Duarte L, Madreperla S (2011) Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology 118(4):626–635. e622PubMedCrossRefGoogle Scholar
  118. 118.
    Chew EY, Kim J, Coleman HR, Aiello LP, Fish G, Ip M, Haller JA, Figueroa M, Martin D, Callanan D (2010) Preliminary assessment of celecoxib and microdiode pulse laser treatment of diabetic macular edema. Retina 30(3):459PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Ayalasomayajula SP, Kompella UB (2005) Subconjunctivally administered celecoxib-PLGA microparticles sustain retinal drug levels and alleviate diabetes-induced oxidative stress in a rat model. Eur J Pharmacol 511(2):191–198PubMedCrossRefGoogle Scholar
  120. 120.
    Felinski EA, Antonetti DA (2005) Glucocorticoid regulation of endothelial cell tight junction gene expression: novel treatments for diabetic retinopathy. Curr Eye Res 30(11):949–957PubMedCrossRefGoogle Scholar
  121. 121.
    Kompella UB, Bandi N, Ayalasomayajula SP (2003) Subconjunctival nano-and microparticles sustain retinal delivery of budesonide, a corticosteroid capable of inhibiting VEGF expression. Invest Ophthalmol Vis Sci 44(3):1192–1201PubMedCrossRefGoogle Scholar
  122. 122.
    Prasad PS, Schwartz SD, Hubschman J-P (2010) Age-related macular degeneration: current and novel therapies. Maturitas 66(1):46–50PubMedCrossRefGoogle Scholar
  123. 123.
    Swaroop A, Branham KEH, Chen W, Abecasis G (2007) Genetic susceptibility to age-related macular degeneration: a paradigm for dissecting complex disease traits. Hum Mol Genet 16(R2):R174–R182PubMedCrossRefGoogle Scholar
  124. 124.
    Friedman DS, O’Colmain BJ, Munoz B, Tomany SC, McCarty C, De Jong PT, Nemesure B, Mitchell P, Kempen J (2004) Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 122(4):564–572PubMedCrossRefGoogle Scholar
  125. 125.
    Kowluru RA, Zhong Q (2011) Beyond AREDS: is there a place for antioxidant therapy in the prevention/treatment of eye disease? Invest Ophthalmol Vis Sci 52(12):8665–8671PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Evans JR (2001) Risk factors for age-related macular degeneration. Prog Retin Eye Res 20(2):227–253PubMedCrossRefGoogle Scholar
  127. 127.
    Seddon JM, Reynolds R, Rosner B (2010) Associations of smoking, body mass index, dietary lutein, and the LIPC gene variant rs10468017 with advanced age-related macular degeneration. Mol Vis 16:2412PubMedPubMedCentralGoogle Scholar
  128. 128.
    Vingerling JR, Hofman A, Grobbee DE, De Jong PTVM (1996) Age-related macular degeneration and smoking: the Rotterdam study. Arch Ophthalmol 114(10):1193–1196PubMedCrossRefGoogle Scholar
  129. 129.
    Chakravarthy U, Augood C, Bentham GC, de Jong P, Rahu M, Seland J, Soubrane G, Tomazzoli L, Topouzis F, Vingerling JR (2007) Cigarette smoking and age-related macular degeneration in the EUREYE Study. Ophthalmology 114(6):1157–1163PubMedCrossRefGoogle Scholar
  130. 130.
    Seddon JM, George S, Rosner B, Klein ML (2006) CFH gene variant, Y402H, and smoking, body mass index, environmental associations with advanced age-related macular degeneration. Hum Hered 61(3):157–165PubMedCrossRefGoogle Scholar
  131. 131.
    Francis PJ, George S, Schultz DW, Rosner B, Hamon S, Ott J, Weleber RG, Klein ML, Seddon JM (2007) The LOC387715 gene, smoking, body mass index, environmental associations with advanced age-related macular degeneration. Hum Hered 63(3–4):212–218PubMedGoogle Scholar
  132. 132.
    Schmidt S, Hauser MA, Scott WK, Postel EA, Agarwal A, Gallins P, Wong F, Chen YS, Spencer K, Schnetz-Boutaud N (2006) Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration. Am J Hum Genet 78(5):852–864PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Algvere PV, Marshall J, Seregard S (2006) Age related maculopathy and the impact of blue light hazard. Acta Ophthalmol Scand 84(1):4–15PubMedCrossRefGoogle Scholar
  134. 134.
    Cruickshanks KJ, Klein R, Klein BEK (1993) Sunlight and age-related macular degeneration: the Beaver Dam eye study. Arch Ophthalmol 111(4):514–518PubMedCrossRefGoogle Scholar
  135. 135.
    Darzins P, Mitchell P, Heller RF (1997) Sun exposure and age-related macular degeneration: an Australian case-control study. Ophthalmology 104(5):770–776PubMedCrossRefGoogle Scholar
  136. 136.
    Delcourt C, Carriere I, Ponton-Sanchez A, Fourrey S, Lacroux A, Papoz L (2001) Light exposure and the risk of age-related macular degeneration: the Pathologies Oculaires Liees a l’Age (POLA) study. Arch Ophthalmol 119(10):1463–1468PubMedCrossRefGoogle Scholar
  137. 137.
    McCarty CA, Mukesh BN, Fu CL, Mitchell P, Wang JJ, Taylor HR (2001) Risk factors for age-related maculopathy: the visual impairment project. Arch Ophthalmol 119(10):1455–1462PubMedCrossRefGoogle Scholar
  138. 138.
    Pham TQ, Rochtchina E, Mitchell P, Smith W, Wang JJ (2009) Sunlight-related factors and the 10-year incidence of age-related maculopathy. Ophthalmic Epidemiol 16(2):136–141PubMedCrossRefGoogle Scholar
  139. 139.
    Taylor HR, West S, Muñoz B, Rosenthal FS, Bressler SB, Bressler NM (1992) The long-term effects of visible light on the eye. Archives Ophthalmol 110(1):99–04CrossRefGoogle Scholar
  140. 140.
    Tomany SC, Cruickshanks KJ, Klein R, Klein BEK, Knudtson MD (2004) Sunlight and the 10-year incidence of age-related maculopathy: the Beaver Dam eye study. Arch Ophthalmol 122(5):750–757PubMedCrossRefGoogle Scholar
  141. 141.
    Whitehead AJ, Mares JA, Danis RP (2006) Macular pigment: a review of current knowledge. Arch Ophthalmol 124(7):1038–1045PubMedCrossRefGoogle Scholar
  142. 142.
    Fletcher AE, Bentham GC, Agnew M, Young IS, Augood C, Chakravarthy U, de Jong PTVM, Rahu M, Seland J, Soubrane G (2008) Sunlight exposure, antioxidants, and age-related macular degeneration. Arch Ophthalmol 126(10):1396–1403PubMedCrossRefGoogle Scholar
  143. 143.
    Johnson EJ (2005) Obesity, lutein metabolism, and age-related macular degeneration: a web of connections. Nutr Rev 63(1):9–15PubMedCrossRefGoogle Scholar
  144. 144.
    Klein R, Klein BEK, Tomany SC, Cruickshanks KJ (2003) The association of cardiovascular disease with the long-term incidence of age-related maculopathy: the Beaver Dam eye study. Ophthalmology 110(4):636–643PubMedCrossRefGoogle Scholar
  145. 145.
    Krishnaiah S, Das T, Nirmalan PK, Nutheti R, Shamanna BR, Rao GN, Thomas R (2005) Risk factors for age-related macular degeneration: findings from the Andhra Pradesh eye disease study in South India. Invest Ophthalmol Vis Sci 46(12):4442–4449PubMedCrossRefGoogle Scholar
  146. 146.
    Cugati S, Mitchell P, Rochtchina E, Tan AG, Smith W, Wang JJ (2006) Cataract surgery and the 10-year incidence of age-related maculopathy: the Blue Mountains eye study. Ophthalmology 113(11):2020–2025PubMedCrossRefGoogle Scholar
  147. 147.
    Ho L, Boekhoorn SS, van Duijn CM, Uitterlinden AG, Hofman A, de Jong PTVM, Stijnen T, Vingerling JR (2008) Cataract surgery and the risk of aging macula disorder: the Rotterdam study. Invest Ophthalmol Vis Sci 49(11):4795–4800PubMedCrossRefGoogle Scholar
  148. 148.
    Kaiserman I, Kaiserman N, Elhayany A, Vinker S (2007) Cataract surgery is associated with a higher rate of photodynamic therapy for age-related macular degeneration. Ophthalmology 114(2):278–282PubMedCrossRefGoogle Scholar
  149. 149.
    Klein R, Klein BEK, Wong TY, Tomany SC, Cruickshanks KJ (2002) The association of cataract and cataract surgery with the long-term incidence of age-related maculopathy: the Beaver Dam eye study. Arch Ophthalmol 120(11):1551–1558PubMedCrossRefGoogle Scholar
  150. 150.
    Pham TQ, Cugati S, Rochtchina E, Mitchell P, Maloof A, Wang JJ (2006) Early age-related maculopathy in eyes after cataract surgery. Eye 21(4):512–517PubMedGoogle Scholar
  151. 151.
    Pollack A, Marcovich A, Bukelman A, Oliver M (1996) Age-related macular degeneration after extracapsular cataract extraction with intraocular lens implantation. Ophthalmology 103(10):1546–1554PubMedCrossRefGoogle Scholar
  152. 152.
    Wang JJ, Klein R, Smith W, Klein BEK, Tomany S, Mitchell P (2003) Cataract surgery and the 5-year incidence of late-stage age-related maculopathy: pooled findings from the Beaver Dam and Blue Mountains eye studies. Ophthalmology 110(10):1960–1967PubMedCrossRefGoogle Scholar
  153. 153.
    Jarrett SG, Boulton ME (2012) Consequences of oxidative stress in age-related macular degeneration. Mol Aspects Med 33(4):399PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Group A-REDSR (2001) A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no 8. Arch Ophthalmol 119(10):1417CrossRefGoogle Scholar
  155. 155.
    Macular Photocoagulation Study Group (1991) Argon laser photocoagulation for neovascular maculopathy: five-year results from randomized clinical trials. Arch Ophthalmol 109(8):1109CrossRefGoogle Scholar
  156. 156.
    Bressler NM (2002) Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization-verteporfin in photodynamic therapy report 2. Am J Ophthalmol 133(1):168–169PubMedCrossRefGoogle Scholar
  157. 157.
    Treatment of Age-Related Macular Degeneration with Photodynamic Therapy Study Group (1999) Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials – TAP report 1. Arch Ophthalmol 117(10):1329CrossRefGoogle Scholar
  158. 158.
    Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, Sy JP, Schneider S (2006) Ranibizumab versus verteporfin for neovascular age-related macular degeneration. New Engl J Med 355(14):1432–1444PubMedCrossRefGoogle Scholar
  159. 159.
    Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY (2006) Ranibizumab for neovascular age-related macular degeneration. New Engl J Med 355(14):1419–1431PubMedCrossRefGoogle Scholar
  160. 160.
    Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, Griffing S, Bergsland E (2003) Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21(1):60–65PubMedCrossRefGoogle Scholar
  161. 161.
    Fong DS, Custis P, Howes J, Hsu J-W (2010) Intravitreal bevacizumab and ranibizumab for age-related macular degeneration: a multicenter, retrospective study. Ophthalmology 117(2):298–302PubMedCrossRefGoogle Scholar
  162. 162.
    Landa G, Amde W, Doshi V, Ali A, McGevna L, Gentile RC, Muldoon TO, Walsh JB, Rosen RB (2009) Comparative study of intravitreal bevacizumab (Avastin) versus ranibizumab (Lucentis) in the treatment of neovascular age-related macular degeneration. Ophthalmologica 223(6):370–375PubMedCrossRefGoogle Scholar
  163. 163.
    Thomas L, Berenberg MD, Ying GS et al (2012) The association between Drusen extent and foveolar choroidal blood flow in AMD. Retina 32(1):25–31Google Scholar
  164. 164.
    Abrishami M, Ghanavati SZ, Soroush D, Rouhbakhsh M, Jaafari MR, Malaekeh-Nikouei B (2009) Preparation, characterization, and in vivo evaluation of nanoliposomes-encapsulated bevacizumab (avastin) for intravitreal administration. Retina 29(5):699–703PubMedCrossRefGoogle Scholar
  165. 165.
    Honda M, Asai T, Umemoto T, Araki Y, Oku N, Tanaka M (2011) Suppression of choroidal neovascularization by intravitreal injection of liposomal SU5416. Arch Ophthalmol 129(3):317–321PubMedCrossRefGoogle Scholar
  166. 166.
    Katanasaka Y, Ida T, Asai T, Shimizu K, Koizumi F, Maeda N, Baba K, Oku N (2008) Antiangiogenic cancer therapy using tumor vasculature-targeted liposomes encapsulating 3-(3, 5-dimethyl-1H-pyrrol-2-ylmethylene)-1, 3-dihydro-indol-2-one, SU5416. Cancer Lett 270(2):260–268PubMedCrossRefGoogle Scholar
  167. 167.
    Wang C-H, Lu D-W, Chiang C-H (2010) Gene therapy using SiRNA for treatment of ocular neovascularization. J Med Sci 30(3):79–84Google Scholar
  168. 168.
    Li F, Hurley B, Liu Y, Leonard B, Griffith M (2012) Controlled release of bevacizumab through nanospheres for extended treatment of age-related macular degeneration. Open Ophthalmol J 6:54PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Kadam RS, Tyagi P, Edelhauser HF, Kompella UB (2012) Influence of choroidal neovascularization and biodegradable polymeric particle size on transscleral sustained delivery of triamcinolone acetonide. Int J Pharm 434(1):140–147PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Suen W-LL, Chau Y (2013) Specific uptake of folate-decorated triamcinolone-encapsulating nanoparticles by retinal pigment epithelium cells enhances and prolongs antiangiogenic activity. J Control Release 167(1):21–28PubMedCrossRefGoogle Scholar
  171. 171.
    Mo Y, Barnett ME, Takemoto D, Davidson H, Kompella UB (2007) Human serum albumin nanoparticles for efficient delivery of Cu, Zn superoxide dismutase gene. Mol Vis 13:746PubMedPubMedCentralGoogle Scholar
  172. 172.
    Jayaraman MS, Bharali DJ, Sudha T, Mousa SA (2012) Nano chitosan peptide as a potential therapeutic carrier for retinal delivery to treat age-related macular degeneration. Mol Vis 18:2300PubMedPubMedCentralGoogle Scholar
  173. 173.
    Iezzi R, Guru BR, Glybina IV, Mishra MK, Kennedy A, Kannan RM (2012) Dendrimer-based targeted intravitreal therapy for sustained attenuation of neuroinflammation in retinal degeneration. Biomaterials 33(3):979–988Google Scholar
  174. 174.
    Molokhia SA, Sant H, Simonis J, Bishop CJ, Burr RM, Gale BK, Ambati BK (2010) The capsule drug device: novel approach for drug delivery to the eye. Vision Res 50(7):680–685PubMedCrossRefGoogle Scholar
  175. 175.
    Geltzer A, Turalba A, Vedula SS (2007) Surgical implantation of steroids with antiangiogenic characteristics for treating neovascular age-related macular degeneration. Cochrane Database Syst Rev 4, 2013 Jan 31;1:CD005022. doi:  10.1002/14651858.CD005022.pub3
  176. 176.
    Cantor LB (2006) Brimonidine in the treatment of glaucoma and ocular hypertension. Ther Clin Risk Manag 2(4):337PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Pickering MC, Cook HT, Warren J, Bygrave AE, Moss J, Walport MJ, Botto M (2002) Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H. Nat Genet 31(4):424–428PubMedGoogle Scholar
  178. 178.
    Nozaki M, Raisler BJ, Sakurai E, Sarma JV, Barnum SR, Lambris JD, Chen Y, Zhang K, Ambati BK, Baffi JZ (2006) Drusen complement components C3a and C5a promote choroidal neovascularization. Proc Natl Acad Sci 103(7):2328–2333PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Johnson LV, Ozaki S, Staples MK, Erickson PA, Anderson DH (2000) A potential role for immune complex pathogenesis in drusen formation. Exp Eye Res 70(4):441–449PubMedCrossRefGoogle Scholar
  180. 180.
    Mullins RF, Russell SR, Anderson DH, Hageman GS (2000) Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J 14(7):835–846PubMedGoogle Scholar
  181. 181.
    Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, Hageman JL, Stockman HA, Borchardt JD, Gehrs KM (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci 102(20):7227–7232PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Johnson LV, Leitner WP, Staples MK, Anderson DH (2001) Complement activation and inflammatory processes in drusen formation and age related macular degeneration. Exp Eye Res 73(6):887–896PubMedCrossRefGoogle Scholar
  183. 183.
    Coffey PJ, Gias C, McDermott CJ, Lundh P, Pickering MC, Sethi C, Bird A, Fitzke FW, Maass A, Chen LL (2007) Complement factor H deficiency in aged mice causes retinal abnormalities and visual dysfunction. Proc Natl Acad Sci 104(42):16651–16656PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Ufret-Vincenty RL, Aredo B, Liu X, McMahon A, Chen PW, Sun H, Niederkorn JY, Kedzierski W (2010) Transgenic mice expressing variants of complement factor H develop AMD-like retinal findings. Invest Ophthalmol Vis Sci 51(11):5878–5887PubMedCrossRefGoogle Scholar
  185. 185.
    Cashman SM, Desai A, Ramo K, Kumar-Singh R (2011) Expression of complement component 3 (C3) from an adenovirus leads to pathology in the murine retina. Invest Ophthalmol Vis Sci 52(6):3436–3445PubMedCrossRefGoogle Scholar
  186. 186.
    Mélik-Parsadaniantz S, Rostène W (2008) Chemokines and neuromodulation. J Neuroimmunol 198(1):62–68Google Scholar
  187. 187.
    Hollyfield JG, Bonilha VL, Rayborn ME, Yang X, Shadrach KG, Lu L, Ufret RL, Salomon RG, Perez VL (2008) Oxidative damage-induced inflammation initiates age-related macular degeneration. Nat Med 14(2):194–198PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Hollyfield JG, Perez VL, Salomon RG (2010) A hapten generated from an oxidation fragment of docosahexaenoic acid is sufficient to initiate age-related macular degeneration. Mol Neurobiol 41(2–3):290–298PubMedCrossRefGoogle Scholar
  189. 189.
    Hahn P, Qian Y, Dentchev T, Chen L, Beard J, Harris ZL, Dunaief JL (2004) Disruption of ceruloplasmin and hephaestin in mice causes retinal iron overload and retinal degeneration with features of age-related macular degeneration. Proc Natl Acad Sci 101(38):13850–13855PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Crabb JW, Miyagi M, Gu X, Shadrach K, West KA, Sakaguchi H, Kamei M, Hasan A, Yan L, Rayborn ME (2002) Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc Natl Acad Sci 99(23):14682–14687PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Imamura Y, Noda S, Hashizume K, Shinoda K, Yamaguchi M, Uchiyama S, Shimizu T, Mizushima Y, Shirasawa T, Tsubota K (2006) Drusen, choroidal neovascularization, and retinal pigment epithelium dysfunction in SOD1-deficient mice: a model of age-related macular degeneration. Proc Natl Acad Sci 103(30):11282–11287PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Justilien V, Pang J-J, Renganathan K, Zhan X, Crabb JW, Kim SR, Sparrow JR, Hauswirth WW, Lewin AS (2007) SOD2 knockdown mouse model of early AMD. Invest Ophthalmol Vis Sci 48(10):4407–4420PubMedCrossRefGoogle Scholar
  193. 193.
    Pennesi ME, Neuringer M, Courtney RJ (2012) Animal models of age related macular degeneration. Mol Aspects Med 33(4):487–509PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Majji AB, Cao J, Chang KY, Hayashi A, Aggarwal S, Grebe RR, de Juan E (2000) Age-related retinal pigment epithelium and Bruch’s membrane degeneration in senescence-accelerated mouse. Invest Ophthalmol Vis Sci 41(12):3936–3942PubMedGoogle Scholar
  195. 195.
    Weber BHF, Lin B, White K, Kohler K, Soboleva G, Herterich S, Seeliger MW, Jaissle GB, Grimm C, Reme C (2002) A mouse model for Sorsby fundus dystrophy. Invest Ophthalmol Vis Sci 43(8):2732–2740PubMedGoogle Scholar
  196. 196.
    Mata NL, Weng J, Travis GH (2000) Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration. Proc Natl Acad Sci 97(13):7154–7159PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Karan G, Lillo C, Yang Z, Cameron DJ, Locke KG, Zhao Y, Thirumalaichary S, Li C, Birch DG, Vollmer-Snarr HR (2005) Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice: a model for macular degeneration. Proc Natl Acad Sci 102(11):4164–4169PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Marmorstein LY, McLaughlin PJ, Peachey NS, Sasaki T, Marmorstein AD (2007) Formation and progression of sub-retinal pigment epithelium deposits in Efemp1 mutation knock-in mice: a model for the early pathogenic course of macular degeneration. Hum Mol Genet 16(20):2423–2432PubMedCrossRefGoogle Scholar
  199. 199.
    Dobi ET, Puliafito CA, Destro M (1989) A new model of experimental choroidal neovascularization in the rat. Arch Ophthalmol 107(2):264–269PubMedCrossRefGoogle Scholar
  200. 200.
    Ryan S (1979) The development of an experimental model of subretinal neovascularization in disciform macular degeneration. Trans Am Ophthalmol Soc 77:707PubMedPubMedCentralGoogle Scholar
  201. 201.
    Shen D, Wen R, Tuo J, Bojanowski CM, Chan CC (2006) Exacerbation of retinal degeneration and choroidal neovascularization induced by subretinal injection of Matrigel in CCL2/MCP-1-deficient mice. Ophthalmic Res 38(2):71–73PubMedCrossRefGoogle Scholar
  202. 202.
    Tobe T, Ortega S, Luna JD, Ozaki H, Okamoto N, Derevjanik NL, Vinores SA, Basilico C, Campochiaro PA (1998) Targeted disruption of the FGF2 gene does not prevent choroidal neovascularization in a murine model. Am J Pathol 153(5):1641–1646PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Qiu G, Stewart JM, Sadda S, Freda R, Lee S, Guven D (2006) A new model of experimental subretinal neovascularization in the rabbit. Exp Eye Res 83(1):141–152PubMedCrossRefGoogle Scholar
  204. 204.
    Baffi J, Byrnes G, Chan CC, Csaky KG (2000) Choroidal neovascularization in the rat induced by adenovirus mediated expression of vascular endothelial growth factor. Invest Ophthalmol Vis Sci 41(11):3582–3589PubMedGoogle Scholar
  205. 205.
    Grossniklaus HE, Ling JX, Wallace TM, Dithmar S, Lawson DH, Cohen C, Elner VM, Elner SG, Sternberg P Jr (2002) Macrophage and retinal pigment epithelium expression of angiogenic cytokines in choroidal neovascularization. Mol Vis 8(8):119–126PubMedGoogle Scholar
  206. 206.
    Tamai K, Spaide RF, Ellis E, Iwabuchi S, Ogura Y, Armstrong D (2002) Lipid hydroperoxide stimulates subretinal choroidal neovascularization in the rabbit. Exp Eye Res 74(2):301–308PubMedCrossRefGoogle Scholar
  207. 207.
    Lyzogubov VV, Tytarenko RG, Liu J, Bora NS, Bora PS (2011) Polyethylene glycol (PEG)-induced mouse model of choroidal neovascularization. J Biol Chem 286(18):16229–16237PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Goldberg MF (1976) Bruch’s membrane and vascular growth. Invest Ophthalmol Vis Sci 15(6):443–446Google Scholar
  209. 209.
    Kiilgaard JF, Andersen MVN, Wiencke AK, Scherfig E, La Cour M, Tezel TH, Prause JU (2005) A new animal model of choroidal neovascularization. Acta Ophthalmol Scand 83(6):697–704PubMedCrossRefGoogle Scholar
  210. 210.
    Glaucoma Research Foundation (2014) Types of glaucoma. Glaucoma Research Foundation. Accessed Sept 2014Google Scholar
  211. 211.
    Kumarasamy NA, Lam FS, Wang AL, Theoharides TC (2006) Glaucoma: current and developing concepts for inflammation, pathogenesis and treatment. Eur J Inflamm 4(3):129CrossRefGoogle Scholar
  212. 212.
    Lavik E, Kuehn MH, Kwon YH (2011) Novel drug delivery systems for glaucoma. Eye 25(5):578–586PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Monem AS, Ali FM, Ismail MW (2000) Prolonged effect of liposomes encapsulating pilocarpine HCl in normal and glaucomatous rabbits. Int J Pharm 198(1):29–38PubMedCrossRefGoogle Scholar
  214. 214.
    De Campos AM, Sánchez A, Gref R, Calvo P, Alonso MJ (2003) The effect of a PEG versus a chitosan coating on the interaction of drug colloidal carriers with the ocular mucosa. Eur J Pharm Sci 20(1):73–81PubMedCrossRefGoogle Scholar
  215. 215.
    Date RD (1999) Studies in the development of new drug delivery systems- mucoadhesive systems. University of Mumbai, MumbaiGoogle Scholar
  216. 216.
    Gaikwad DD (2000) New drug delivery systems: mucoadhesive opthalmic formulations. University of Mumbai, MumbaiGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of PharmaceuticsBombay College of PharmacyMumbaiIndia
  2. 2.The Daniel K. Inouye College of PharmacyUniversity of Hawaii at HiloHiloUSA

Personalised recommendations