Ординатура / Офтальмология / Английские материалы / Diabetes and Ocular Disease Past, Present, and Future Therapies 2nd edition_Scott, Flynn, Smiddy_2009

424 Diabetes and Ocular Disease

exists for the use of peribulbar/retrobulbar steroid injections in nondiabetic cystoid macular edema due to conditions such as uveitis and following cataract extraction. For diabetic macular edema, one case series of six eyes with persistent diabetic macular edema demonstrated that treatment with 12 mg of posterior subtenon’s TA applied after vitrectomy improved visual acuity in three eyes [155].

A phase II pilot study performed by the DRCR.net in 32 centers nationwide has recently reported 34-week follow-up primary endpoint data [156]. In this study, neither anterior (20 mg) nor posterior (40 mg) peribulbar injection of Kenalog, either in combination with laser therapy or alone, was more effective than focal/ grid laser. Thus, the DRCR.net is not pursuing further peribulbar steroid injection studies at this time.

CURRENT STATUS OF NOVEL THERAPEUTIC AGENTS

IN CLINICAL TRIAL

Advances in the development and clinical testing of antiangiogenic and antipermeability agents continue to accelerate remarkably. Significant mechanistic discoveries, initiation of clinical investigations, and new data from controlled clinical trials are now forthcoming each year. Most large pharmaceutical and biotechnology companies currently have active programs devoted to the identification, development, and testing of novel approaches applicable to diabetic macular edema and/ or diabetic retinopathy [157]. Indeed, many agents that are being investigated as potential therapies for various vascular cancers and pathologic permeability have clear implications for the treatment of diabetic eye disease. Soon to be initiated or currently ongoing clinical trials in diabetic retinopathy and macular edema include studies of bevacizumab (phase III); dexamethasone, fluocinolone acetonide, pegaptanib (III); ranibizumab (phase III); ruboxistaurin (phase III); triamcinolone acetonide (including preservative-free preparations in phase III investigation); and VEGF trap among others. A variety of other therapeutic approaches are in early stages of development, including gene therapy, anti-inflammatory agents, receptor tyrosine kinase inhibitors, integrin blockers, advanced glycation end product inhibitors, and vitreoretinal interface disruptors such as microplasmin.

CHALLENGES FOR ANTIANGIOGENIC THERAPY

OF DIABETIC RETINOPATHY

Although the data supporting the human use of antiangiogenic and antipermeability agents for the treatment of PDR and macular edema are compelling, there are several as-yet unresolved issues that will be important to clarify if these approaches are to achieve routine and highly effective clinical application. The method of drug delivery and the duration of action will become critical issues. Local delivery would presumably have fewer side effects than systemic administration, but achieving adequate concentrations of these agents at the retina is difficult using a topical or peribulbar approach. Indeed, as discussed above, recent evaluation of peribulbar Kenalog with and without additional laser showed that

this approach was not more effective than laser alone [156]. Intravitreal injections allow for delivery of high intraocular concentrations of an agent, but frequent repeated intravitreal injections for the treatment of a life-long chronic disease such as diabetic retinopathy are suboptimal because of physician and patient inconvenience and the cumulative risks of endophthalmitis, retinal detachment, and potential toxicity. This drawback is especially notable for the treatment of diabetic retinopathy in light of the remarkable effectiveness of current laser photocoagulation, a noninvasive and relatively well-tolerated intervention [158,159]. Thus, evolution of therapies with duration of action substantially longer than the 4- to 6-week period required for current anti-VEGF therapies, or clear demonstration that duration of therapy will be self-limited rather than life-long, will be necessary for achieving optimal care.

Regardless of systemic or local therapy, it is not known whether excessive inhibition of VEGF in the adult will lead to side effects resulting from a physiological requirement for basal expression of VEGF in the eye or other tissues. Indeed, VEGF has neuroprotective properties that may be important for normal retinal function [160–162]. Thus, especially with a long duration of treatment, careful titration of the extent of VEGF inhibition might be necessary and the therapeutic window could be smaller than initially assumed. This consideration is of particular concern in the neonatal eye, in which VEGF directs appropriate retinal vascular development [61,66]. Antiangiogenic agents would be expected to cause developmental defects if administered systemically during embryogenesis and, thus, their use during pregnancy is likely to be problematic.

Even if a well-tolerated, easily administered antiagiogenic agent with limited toxicity was available, there are likely to be instances where a normal neovascular response would be desired in the patient, and the angio-suppressive action of retinopathy treatment might be detrimental. Although local drug delivery might obviate a part of this problem, systemic administration could be challenging when extensive wound healing or vascular collateralization is required. In patients with diabetes, this scenario might commonly arise following significant trauma, in the presence of concomitant nonhealing ulcers or following myocardial infarction. Increased systemic levels of VEGF may be beneficial in these cases. Indeed, direct myocardial gene transfer of VEGF in five patients with symptomatic myocardial ischemia resulted in reduced symptoms and improved myocardial perfusion [163]. Antiangiogenic agents that can be rapidly reversed or have short half-lives might permit prompt return of angiogenic capabilities in patients when required.

Results from numerous future clinical trials will be necessary to determine the optimal manner in which these agents will contribute to our therapeutic options for treatment of diabetic retinopathy and macular edema. Various therapeutic scenarios include antiangiogenic monotherapy, antiangiogenic therapy prior to laser, concurrent use with laser, or perhaps application only if laser therapy is ineffective. Mounting evidence suggests that, especially in the case of diabetic macular edema, multiple molecules and various pathways are likely to be involved [164], thus suggesting that combination therapies (as proven effective in cancer and AIDS) may provide a powerful approach to the treatment of diabetic eye disease [165].

426 Diabetes and Ocular Disease

SUMMARY

For over six decades, there has been an excellent appreciation of the fundamental processes underlying the ocular complications of diabetes. Only recently, however, has an extraordinary series of scientific advances provided a detailed understanding of the molecular mechanisms involved in the evolution of diabetic retinopathy. These observations have suggested novel interventional approaches that hold promise as potentially efficacious, noninvasive, and nondestructive treatments of both diabetic retinopathy and diabetic macular edema. Several of these novel therapeutic modalities now have data derived from clinical trials, are currently under clinical trial evaluation, or will soon be evaluated in clinical trials. Ultimately, it is the results of these randomized clinical investigations that will help resolve the remaining unanswered clinical issues and determine whether any of these approaches may yet prove to be sufficiently effective and adequately free of side effects to have a substantial impact on the clinical care of diabetic retinal disease. Indeed, antiangiogenic agents are now of proven benefit in the treatment of cancer and AMD [124,127,166]. It is enlightening to remember that more than 20 years before the discovery of insulin, Dr Elliot P. Joslin routinely advised his diabetic patients to “Live, so that you may profit from some new discovery.” The scientific progress achieved in the past few years, and the information soon to become available from ongoing clinical trials continue to provide validation of this advice, and a new ophthalmic frontier of pharmacologic therapy will continue to evolve with substantial benefits for our patients with diabetes.

REFERENCES

1.The Eye Disease Prevalence Research Group. The prevalence of diabetic retinopathy among adults in the United States. Arch Ophthalmol. 2004;122:552–563.

2.Zhang X, Gregg EW, Cheng YJ, et al. Diabetes mellitus and visual impairment. National Health and Nutrition Examination Survey, 1999–2004. Arch Ophthalmol. 2008;126:1421–1427.

3.Ferris FL. How effective are treatments for diabetic retinopathy? JAMA. 1993;269:1290–1291.

4.Greene DA, Sima AA, Stevens MJ, et al. Aldose reductase inhibitors: an approach to the treatment of diabetic nerve damage. Diabetes Metab.Rev. 1993;9:189–217.

5.Brownlee M. The pathological implications of protein glycation. Clin Invest Med. 1995;18:275–281.

6.Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications. A new perspective on an old paradigm. Diabetes. 1999;48:1–9.

7.Koya D, King GL. Protein kinase C activation and the development of diabetic complications. Diabetes. 1998;47:859–866.

8.Horton MA. The alpha v beta 3 integrin vitronectin receptor. Int J Biochem Cell Biol. 1997;29:721–725.

9.King GL, Shiba T, Oliver J, Inoguchi T, Bursell SE. Cellular and molecular abnormalities in the vascular endothelium of diabetes mellitus. Annu Rev Med. 1994;45:179–188.

10.Gartner S, Henkind P. Neovascularization of the iris (rubeosis iridis). Surv Ophthalmol. 1978;22:291–312.

11.Henkind P. Ocular neovascularization. The Krill memorial lecture. Am J Ophthalmol. 1978;85:287–301.

12.The Early Treatment Diabetic Retinopathy Study Research Group. Fluorescein angiographic risk factors for progression of diabetic retinopathy: ETDRS report number 13. Ophthalmology. 1991;98:834–840.

13.The Early Treatment Diabetic Retinopathy Study Research Group. Classification of diabetic retinopathy from fluorescein angiograms: ETDRS report number 11. Ophthalmology. 1991;98:807–822.

14.Anonymous. Argon laser scatter photocoagulation for prevention of neovascularization and vitreous hemorrhage in branch vein occlusion. A randomized clinical trial. Branch Vein Occlusion Study Group. Arch Ophthalmol. 1986;104:34–41.

15.Aiello LM, Wand M, Liang G. Neovascular glaucoma and vitreous hemorrhage following cataract surgery in patients with diabetes mellitus. Ophthalmology. 1983;90:814–820.

16.Michaelson IC. The mode of development of the vascular system of the retina, with some observations on its significance for certain retinal diseases. Trans Ophthalmol Soc UK. 1948;68:137–180.

17.Ashton N. Retinal neovascularization in health and disease. Am J Ophthalmol. 1957;44:7–24.

18.Friedlander M, Theesfeld CL, Sugita M, et al. Involvement of integrins alpha v beta 3 and alpha v beta 5 in ocular neovascular diseases. Proc Natl Acad Sci USA. 1996;93:9764–9769.

19.O’Reilly MS, Holmgren L, Shing Y, et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma [see comments]. Cell. 1994;79:315–328.

20.O’Reilly MS, Boehm T, Shing Y, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997;88:277–285.

21.Grant MB, Caballero S, Tarnuzzer RW, et al. Matrix metalloproteinase expression in human retinal microvascular cells. Diabetes. 1998;47:1311–1317.

22.De La Paz MA, Itoh Y, Toth CA, Nagase H. Matrix metalloproteinases and their inhibitors in human vitreous. Invest Ophthalmol Vis Sci. 1998;39:1256–1260.

23.Brown D, Hamdi H, Bahri S, Kenney MC. Characterization of an endogenous metalloproteinase in human vitreous. Curr Eye Res. 1994;13:639–647.

24.Burgess WH, Maciag T. The heparin-binding (fibroblast) growth factor family of proteins. Annu Rev Biochem. 1989;58:575–606.

25.Vlodavsky I, Folkman J, Sullivan R, et al. Endothelial cell-derived basic fibroblast growth factor: synthesis and deposition into subendothelial extracellular matrix. Proc Natl Acad Sci USA. 1987;84:2292–2296.

26.Abraham JA, Mergia A, Whang JL, et al. Nucleotide sequence of a bovine clone encoding the angiogenic protein, basic fibroblast growth factor. Science. 1986;233: 545–548.

27.Kandel J, Bossy-Wetzel E, Radvanyi F, Klagsbrun M, Folkman J, Hanahan D. Neovascularization is associated with a switch to the export of bFGF in the multistep development of fibrosarcoma. Cell. 1991;66:1095–1104.

28.McNeil PL, Muthukrishnan L, Warder E, D’Amore PA. Growth factors are released by mechanically wounded endothelial cells. J Cell Biol. 1989;109:811–822.

29.Gao H, Hollyfield JG. Basic fibroblast growth factor (bFGF) immunolocalization in the rodent outer retina demonstrated with an anti-rodent bFGF antibody. Brain Res. 1992;585:355–360.

428 Diabetes and Ocular Disease

30.Sivalingam A, Kenney J, Brown GC, Benson WE, Donoso L. Basic fibroblast growth factor levels in the vitreous of patients with proliferative diabetic retinopathy. Arch Ophthalmol. 1990;108:869–872.

31.Ozaki H, Okamoto N, Ortega S, et al. Basic fibroblast growth factor is neither necessary nor sufficient for the development of retinal neovascularization [see comments]. Am J Pathol. 1998;153:757–765.

32.Asahara T, Bauters C, Zheng LP, et al. Synergistic effect of vascular endothelial growth factor and basic fibroblast growth factor on angiogenesis in vivo. Circulation. 1995;92:II365–II371.

33.Goto F, Goto K, Weindel K, Folkman J. Synergistic effects of vascular endothelial growth factor and basic fibroblast growth factor on the proliferation and cord formation of bovine capillary endothelial cells within collagen gels [see comments]. Lab Invest. 1993;69:508–517.

34.Pepper MS, Ferrara N, Orci L, Montesano R. Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem Biophys Res Commun. 1992;189:824–831.

35.LeRoith D, Roberts CT. Insulin-like growth factors. Ann N Y Acad Sci. 1993;692:1–9.

36.Poulsen J. Diabetes and anterior pituitary insufficiency. Final course and postmortem study of a diabetic patient with Sheehan’s syndrome. Diabetes. 1966;15:73–77.

37.Poulsen JE. The Houssay phenomenon in man. Recovery from retinopathy in a case of diabetes with Simmonds’ disease. Diabetes. 1953;2:7–12.

38.Sharp P, Fallon T, Brazier O, Sandler L, Joplin G., Kohner E. Long-term follow-up of patients who underwent Yttrium-90 pituitary implantation for treatment of proliferative diabetic retinopathy. Diabetologia. 1987;30:199–207.

39.Smith LE, Kopchick JJ, Chen W, et al. Essential role of growth hormone in ischemiainduced retinal neovascularization. Science. 1997;276:1706–1709.

40.Mallet B, Vialettes B, Haroche S, et al. Stabilization of severe proliferative diabetic retinopathy by long-term treatment with SMS 201-995. Diabetes Metab. 1992;18: 438–444.

41.Grant MB, Mames RN, Fitzgerald C, et al. The efficacy of octreotide in the therapy of severe nonproliferative and early proliferative diabetic retinopathy: a randomized controlled study. Diabetes Care. 2000;23:504–509.

42.Boehm BO, Lang GK, Jehle PM, et al. Octreotide reduces vitreous hemorrhage and loss of visual acuity risk in patients with high-risk proliferative diabetic retinopathy. Horm Metab Res. 2001;33:300–306.

43.Growth Hormone Antagonist for Proliferative Diabetic Retinopathy Study Group. The effect of a growth hormone receptor antagonist drug on proliferative diabetic retinopathy. Ophthalmology. 2001;108:2266–2272.

44.Novartis media release, http://cws.huginonline.com/N/134323/PR/200604/1046164_5. html. Last accessed February 25, 2009.

45.Grant MB, Caballero S Jr. The potential role of octreotide in the treatment of diabetic retinopathy. Treat Endocrinol. 2005;4(4):199–203.

46.Katsura Y, Okano T, Noritake M, et al. Hepatocyte growth factor in vitreous fluid of patients with proliferative diabetic retinopathy and other retinal disorders. Diabetes Care. 1998;21:1759–1763.

47.Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983;219:983–985.

48.Keck PJ, Hauser SD, Krivi G, et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989;246:1309–1312.

49.Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246:1306–1309.

50.Ferrara N, Houck KA, Jakeman LB, Winer J, Leung DW. The vascular endothelial growth factor family of polypeptides. J Cell Biochem. 1991;47:211–218.

51.Williams B. Vascular permeability/vascular endothelial growth factors: a potential role in the pathogenesis and treatment of vascular diseases. Vasc Med. 1996;1:251–258.

52.Miller JW, Adamis AP, Aiello LP. Vascular endothelial growth factor in ocular neovascularization and proliferative diabetic retinopathy. Diabetes Metab Rev. 1997; 13:37–50.

53.Aiello LP. Clinical implications of vascular growth factors in proliferative retinopathies. Curr Opin Ophthalmol. 1997;8:19–31.

54.Aiello LP. Vascular endothelial growth factor. 20th-century mechanisms, 21st-century therapies. Invest Ophthalmol Vis Sci. 1997;38:1647–1652.

55.Thieme H, Aiello LP, Takagi H, Ferrara N, King GL. Comparative analysis of vascular endothelial growth factor receptors on retinal and aortic vascular endothelial cells. Diabetes. 1995; 44:98–103.

56.Aiello LP, Northrup JM, Keyt BA, Takagi H, Iwamoto MA. Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch Ophthalmol. 1995;113: 1538–1544.

57.De Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science. 1992;255: 989–991.

58.Millauer B, Wizigmann-Voos S, Schnurch H, et al. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell. 1993;72:835–846.

59.Simorre-Pinatel V, Guerrin M, Chollet P, et al. Vasculotropin-VEGF stimulates retinal capillary endothelial cells through an autocrine pathway. Invest Ophthalmol Vis Sci. 1994;35:3393–3400.

60.Dorey CK, Aouididi S, Reynaud X, Dvorak HF, Brown LF. Correlation of vascular permeability factor/vascular endothelial growth factor with extraretinal neovascularization in the rat [see comments] [published erratum appears in Arch Ophthalmol. February 1997;115(2):192]. Arch Ophthalmol. 1996;114:1210–1217.

61.Stone J, Chan-Ling T, Pe’er J, Itin A, Gnessin H, Keshet E. Roles of vascular endothelial growth factor and astrocyte degeneration in the genesis of retinopathy of prematurity. Invest Ophthalmol Vis Sci. 1996;37:290–299.

62.Smith LE, Wesolowski E, McLellan A, et al. Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci. 1994;35:101–111.

63.Donahue ML, Phelps DL, Watkins RH, LoMonaco MB, Horowitz S. Retinal vascular endothelial growth factor (VEGF) mRNA expression is altered in relation to neovascularization in oxygen induced retinopathy. Curr Eye Res. 1996;15:175–184.

64.Miller JW, Adamis AP, Shima DT, et al. Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am J Pathol. 1994;145:574–584.

65.Pierce EA, Avery RL, Foley ED, Aiello LP, Smith LE. Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. Proc Natl Acad Sci USA. 1995;92:905–909.

66.Pierce EA, Foley ED, Smith LE. Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity [see comments] [published erratum appears in Arch Ophthalmol. March 1997;115(3):427]. Arch Ophthalmol. 1996;114:1219–1228.

430 Diabetes and Ocular Disease

67.Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders [see comments]. N Engl J Med. 1994;331:1480–1487.

68.Adamis AP, Miller JW, Bernal MT, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol. 1994;118:445–450.

69.Burgos R, Simo R, Audi L, et al. Vitreous levels of vascular endothelial growth factor are not influenced by its serum concentrations in diabetic retinopathy. Diabetologia. 1997;40:1107–1109.

70.Funatsu H, Yamashita H, Nakamura S, et al. Various levels of pigmentepitheliumderived factor and vascular endothelial growth fact are related to diabetic macular edema. Ophthalmology. February 2006;113(2):294–301.

71.Patel JI, Tombran-Tink J, Hykin PG, Gregor ZJ, Cree IA. Vitreous and aqueous concentrations of proangiogenic, antiangiogenic factors and other cytokines in diabetic retinopathy patients with macular edema: implications for structural differences in macular profiles. Exp Eye Res. May 2006;82(5):798–806.

72.Pe’er J, Folberg R, Itin A, Gnessin H, Hemo I, Keshet E. Upregulated expression of vascular endothelial growth factor in proliferative diabetic retinopathy. Br J Ophthalmol. 1996;80:241–245.

73.Armstrong D, Augustin AJ, Spengler R, et al. Detection of vascular endothelial growth factor and tumor necrosis factor alpha in epiretinal membranes of proliferative diabetic retinopathy, proliferative vitreoretinopathy and macular pucker. Ophthalmologica. 1998;212:410–414.

74.Chen YS, Hackett SF, Schoenfeld CL, Vinores MA, Vinores SA, Campochiaro PA. Localisation of vascular endothelial growth factor and its receptors to cells of vascular and avascular epiretinal membranes. Br J Ophthalmol. 1997;81:919–926.

75.Frank RN, Amin RH, Eliott D, Puklin JE, Abrams GW. Basic fibroblast growth factor and vascular endothelial growth factor are present in epiretinal and choroidal neovascular membranes. Am J Ophthalmol. 1996;122:393–403.

76.Malecaze F, Clamens S, Simorre-Pinatel V, et al. Detection of vascular endothelial growth factor messenger RNA and vascular endothelial growth factor-like activity in proliferative diabetic retinopathy. Arch Ophthalmol. 1994;112:1476–1482.

77.Tang S, Le-Ruppert KC, Gabel VP. Proliferation and activation of vascular endothelial cells in epiretinal membranes from patients with proliferative diabetic retinopathy. An immunohistochemistry and clinical study. Ger J Ophthalmol. 1994;3:131–136.

78.Schneeberger SA, Hjelmeland LM, Tucker RP, Morse LS. Vascular endothelial growth factor and fibroblast growth factor 5 are colocalized in vascular and avascular epiretinal membranes. Am J Ophthalmol. 1997;124:447–454.

79.Tolentino MJ, Miller JW, Gragoudas ES, Chatzistefanou K, Ferrara N, Adamis AP. Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman primate. Arch Ophthalmol. 1996;114:964–970.

80.Tobe T, Okamoto N, Vinores MA, et al. Evolution of neovascularization in mice with overexpression of vascular endothelial growth factor in photoreceptors. Invest Ophthalmol Vis Sci. 1998;39:180–188.

81.Okamoto N, Tobe T, Hackett SF, et al. Transgenic mice with increased expression of vascular endothelial growth factor in the retina: a new model of intraretinal and subretinal neovascularization [see comments]. Am J Pathol. 1997;151:281–291.

82.Senger DR, Connolly DT, Van de Water L, Feder J, Dvorak HF. Purification and NH2-terminal amino acid sequence of guinea pig tumorsecreted vascular permeability factor. Cancer Res. 1990;50:1774–1778.

83.Murata T, Ishibashi T, Khalil A, Hata Y, Yoshikawa H, Inomata H. Vascular endothelial growth factor plays a role in hyperpermeability of diabetic retinal vessels. Ophthalmic Res. 1995;27:48–52.

84.Murata T, Nakagawa K, Khalil A, Ishibashi T, Inomata H, Sueishi K. The relation between expression of vascular endothelial growth factor and breakdown of the blood-retinal barrier in diabetic rat retinas. Lab Invest. 1996;74:819–825.

85.Tolentino MJ, Miller JW, Gragoudas ES, et al. Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology. 1996;103:1820–1828.

86.Aiello LP, Bursell SE, Clermont A, et al. Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor. Diabetes. 1997;46:1473–1480.

87.Antonetti DA, Barber AJ, Khin S, Lieth E, Tarbell JM, Gardner TW. Vascular permeability in experimental diabetes is associated with reduced endothelial occludin content: vascular endothelial growth factor decreases occludin in retinal endothelial cells. Penn State Retina Research Group. Diabetes. 1998;47:1953–1959.

88.Kevil CG, Payne DK, Mire E, Alexander JS. Vascular permeability factor/vascular endothelial cell growth factor-mediated permeability occurs through disorganization of endothelial junctional proteins. J Biol Chem. 1998;273:15099–15103.

89.Gerhardinger C, Brown LF, Roy S, Mizutani M, Zucker CL, Lorenzi M. Expression of vascular endothelial growth factor in the human retina and in nonproliferative diabetic retinopathy. Am J Pathol. 1998;152:1453–1462.

90.Boulton M, Foreman D, Williams G, McLeod D. VEGF localisation in diabetic retinopathy. Br J Ophthalmol. 1998;82:561–568.

91.Amin RH, Frank RN, Kennedy A, Eliott D, Puklin JE, Abrams GW. Vascular endothelial growth factor is present in glial cells of the retina and optic nerve of human subjects with nonproliferative diabetic retinopathy. Invest Ophthalmol Vis Sci. 1997;38:36–47.

92.Clermont AC, Aiello LP, Mori F, Aiello LM, Bursell SE. Vascular endothelial growth factor and severity of nonproliferative diabetic retinopathy mediate retinal hemodynamics in vivo: a potential role for vascular endothelial growth factor in the progression of nonproliferative diabetic retinopathy. Am J Ophthalmol. 1997;124:433–446.

93.Aiello LP, Pierce EA, Foley ED, et al. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGFreceptor chimeric proteins. Proc Natl Acad Sci USA. 1995;92:10457–10461.

94.Adamis AP, Shima DT, Tolentino MJ, et al. Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate. Arch Ophthalmol. 1996;114:66–71.

95.Robinson GS, Pierce EA, Rook SL, Foley E, Webb R, Smith LE. Oligodeoxynucleotides inhibit retinal neovascularization in a murine model of proliferative retinopathy. Proc Natl Acad Sci USA. 1996;93:4851–4856.

96.Oshima Y, Sakaguchi H, Fumi Gomi F, Yasuo T. Regression of iris neovascularization after intravitreal injection of bevacizumab in patients with proliferative diabetic retinopathy. Am J Ophthalmol. 2006;142:155–158.

97.Spaide RF, Fisher YL. Intravitreal bevacizumab (Avastin) treatment of proliferative diabetic retinopathy complicated by vitreous hemorrhage. Retina. 2006;26:275–278.

432Diabetes and Ocular Disease

98.Avery RL, Joel Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology. 2006;113: 1695–1715.

99.Fischer S, Sharma HS, Karliczek GF, Schaper W. Expression of vascular permeability factor/vascular endothelial growth factor in pig cerebral microvascular endothelial cells and its upregulation by adenosine. Brain Res Mol Brain Res. 1995;28: 141–148.

100.Fischer S, Knoll R, Renz D, Karliczek GF, Schaper W. Role of adenosine in the hypoxic induction of vascular endothelial growth factor in porcine brain derived microvascular endothelial cells [In Process Citation]. Endothelium. 1997;5:155–165.

101.Hashimoto E, Kage K, Ogita T, Nakaoka T, Matsuoka R, Kira Y. Adenosine as an endogenous mediator of hypoxia for induction of vascular endothelial growth factor mRNA in U-937 cells. Biochem Biophys Res Commun. 1994;204:318–324.

102.Lutty GA, Mathews MK, Merges C, McLeod DS. Adenosine stimulates canine retinal microvascular endothelial cell migration and tube formation. Curr Eye Res. 1998;17:594–607.

103.Takagi H, King GL, Robinson GS, Ferrara N, Aiello LP. Adenosine mediates hypoxic induction of vascular endothelial growth factor in retinal pericytes and endothelial cells. Invest Ophthalmol Vis Sci. 1996;37:2165–2176.

104.Bontemps F, Vincent MF, Van den Berghe G. Mechanisms of elevation of adenosine levels in anoxic hepatocytes. Biochem J. 1993;290:671–677.

105.Stavri GT, Zachary IC, Baskerville PA, Martin JF, Erusalimsky JD. Basic fibroblast growth factor upregulates the expression of vascular endothelial growth factor in vascular smooth muscle cells. Synergistic interaction with hypoxia. Circulation. 1995;92:11–14.

106.Milanini J, Vinals F, Pouyssegur J, Pages G. p42/p44 MAP kinase module plays a key role in the transcriptional regulation of the vascular endothelial growth factor gene in fibroblasts. J Biol Chem. 1998;273:18165–18172.

107.Hata Y, Rook S, Aiello LP. Basic f ibroblast growth factor induces expression of VEGF receptor KDR through a protein kinase C and p44/p42 mitogen-activated protein kinase-dependent pathway. Diabetes. 1999;48:1145–1155.

108.Zucker S, Mirza H, Conner CE, et al. Vascular endothelial growth factor induces tissue factor and matrix metalloproteinase production in endothelial cells: conversion of prothrombin to thrombin results in progelatinase A activation and cell proliferation. Int J Cancer. 1998;75:780–786.

109.Mandriota SJ, Pepper MS. Vascular endothelial growth factor-induced in vitro angiogenesis and plasminogen activator expression are dependent on endogenous basic fibroblast growth factor. J Cell Sci. 1997;110:2293–2302.

110.Benezra M, Vlodavsky I, Ishai-Michaeli R, Neufeld G, Bar-Shavit R. Thrombininduced release of active basic fibroblast growth factor-heparan sulfate complexes from subendothelial extracellular matrix. Blood. 1993;81:3324–3331.

111.Witte L, Hicklin DJ, Zhu Z, et al. Monoclonal antibodies targeting the VEGF recep- tor-2 (Flk1/KDR) as an anti-angiogenic therapeutic strategy. Cancer Metastasis Rev. 1998;17:155–161.

112.Zhu Z, Rockwell P, Lu D, et al. Inhibition of vascular endothelial growth fac- tor-induced receptor activation with anti-kinase insert domain-containing receptor singlechain antibodies from a phage display library. Cancer Res. 1998;58: 3209–3214.

113.Ruckman J, Green LS, Beeson J, et al. 2’-Fluoropyrimidine RNA-based aptamers to the 165-amino acid form of vascular endothelial growth factor (VEGF165). Inhibition

of receptor binding and VEGF-induced vascular permeability through interactions requiring the exon 7-encoded domain. J Biol Chem. 1998;273:20556–20567.

114.Goldman CK, Kendall RL, Cabrera G, et al. Paracrine expression of a native soluble vascular endothelial growth factor receptor inhibits tumor growth, metastasis, and mortality rate. Proc Natl Acad Sci USA. 1998;95:8795–8800.

115.Siemeister G, Schirner M, Reusch P, Barleon B, Marme D, Martiny-Baron G. An antagonistic vascular endothelial growth factor (VEGF) variant inhibits VEGFstimulated receptor autophosphorylation and proliferation of human endothelial cells. Proc Natl Acad Sci USA. 1998;95:4625–4629.

116.Kong HL, Hecht D, Song W, et al. Regional suppression of tumor growth by in vivo transfer of a cDNA encoding a secreted form of the extracellular domain of the flt-1 vascular endothelial growth factor receptor. Hum Gene Ther. 1998;9: 823–833.

117.Strawn LM, McMahon G, App H, et al. Flk-1 as a target for tumor growth inhibition. Cancer Res. 1996;56:3540–3545.

118.Xia P, Inoguchi T, Kern TS, Engerman RL, Oates PJ, King GL. Characterization of the mechanism for the chronic activation of diacylglycerol-protein kinase C pathway in diabetes and hypergalactosemia. Diabetes. 1994;43:1122–1129.

119.Mazure NM, Chen EY, Laderoute KR, Giaccia AJ. Induction of vascular endothelial growth factor by hypoxia is modulated by a phosphatidylinositol 3-kinase/Akt signaling pathway in Ha-ras-transformed cells through a hypoxia inducible factor-1 transcriptional element. Blood. 1997;90:3322–3331.

120.Williams B, Gallacher B, Patel H, Orme C. Glucose-induced protein kinase C activation regulates vascular permeability factor mRNA expression and peptide production by human vascular smooth muscle cells in vitro. Diabetes. 1997;46:1497–1503.

121.Gerber HP, McMurtrey A, Kowalski J, et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3’-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem. 1998;273:30336–30343.

122.Xia P, Aiello LP, Ishii H, et al. Characterization of vascular endothelial growth factor’s effect on the activation of protein kinase C, its isoforms, and endothelial cell growth. J Clin Invest. 1996;98:2018–2026.

123.Danis RP, Bingaman DP, Jirousek M, Yang Y. Inhibition of intraocular neovascularization caused by retinal ischemia in pigs by PKCbeta inhibition with LY333531.

Invest Ophthalmol Vis Sci. 1998;39:171–179.

124.Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR; VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. December 30, 2004;351(27):2805–2816.

125.Macugen Diabetic Retinopathy Study Group. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology. 2005;112:1747–1757.

126.Adamis AP, Altaweel M, Bressler NM, et al. Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology. January 2006;113(1):23–28.

127.Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. October 5, 2006;355(14):1419–1431.

128.Chun DW, Heier JS, Topping TM, Duker JS, Bankert JM. A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema. Ophthalmology. 2006;113:1706–1712.