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Effect of multiple injections of small divided doses vs single injection of intravitreal bevacizumab on retinal neovascular model in rabbits

  • Retinal Disorders
  • Published:
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Abstract

Background

To compare effects of multiple injections of small divided doses of intravitreal bevacizumab vs a single injection using a retinal neovascular model in rabbits.

Methods

We assigned 12 pigmented rabbits to four groups of three each. All groups received an intravitreal injection of vascular endothelial growth factor (VEGF, 10 μg) on the first day. Group A received an intravitreal loading dose of bevacizumab (0.5 mg) on day 3, followed by five smaller injections (0.15 mg), one every third day. Those in groups B and C received a single intravitreal injection of bevacizumab (1.25 mg) on day 3, followed by five injections of sham, one every third day in group C. Group D received only intravitreal VEGF. Follow-up examinations were performed for 26 days.

Results

In groups A and B, vascular changes associated with VEGF injection decreased substantially in the first 3 days, and continued to show gradual regression during each follow-up interval. No statistically significant differences were found between the changes of mean retinal thicknesses in groups A and B in both areas. In group C, the extra sham injections did not lead to any further vascular changes. The mean retinal thickness in groups B and C did not have a statistically significant difference during the follow-up period. In group D, vascular changes resolved more gradually than in other groups. The difference in retinal thickness between group D and the other groups was statistically significant on day 6 in both groups (medullary and inferior part; p = 0.0003) and in medullary wing on day 12 (p = 0.03).

Conclusions

Frequent smaller doses of bevacizumab can control VEGF-induced vascular changes as well as the currently utilized model of single large monthly injections. Dividing of currently used single injection (1.25 mg) of bevacizumab to multiple small doses can control VEGF-induced vascular changes as effectively as one large injection.

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References

  1. Rahimi N (2006) Vascular endothelial growth factor receptors: molecular mechanisms of activation and therapeutic potentials. Exp Eye Res 83:1005–1016

    Article  CAS  PubMed  Google Scholar 

  2. 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 122:564–572

    Article  PubMed  Google Scholar 

  3. Kempen JH, O'Colmain BJ, Leske MC, Haffner SM, Klein R, Moss SE, Taylor HR, Hamman RF (2004) The prevalence of diabetic retinopathy among adults in the United States. Arch Ophthalmol 122:552–563

    Article  PubMed  Google Scholar 

  4. Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE et al (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487

    Article  CAS  PubMed  Google Scholar 

  5. Wells JA, Murthy R, Chibber R, Nunn A, Molinatti PA, Kohner EM, Gregor ZJ (1996) Levels of vascular endothelial growth factor are elevated in the vitreous of patients with subretinal neovascularisation. Br J Ophthalmol 80:363–366

    Article  CAS  PubMed  Google Scholar 

  6. Adamis AP, Shima DT (2005) The role of vascular endothelial growth factor in ocular health and disease. Retina 25:111–118

    Article  PubMed  Google Scholar 

  7. Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J (2000) Vascular-specific growth factors and blood vessel formation. Nature 407:242–248

    Article  CAS  PubMed  Google Scholar 

  8. Bhisitkul RB (2006) Vascular endothelial growth factor biology: clinical implications for ocular treatments. Br J Ophthalmol 90:1542–1547

    Article  CAS  PubMed  Google Scholar 

  9. Fuh G, Wu P, Liang WC, Ultsch M, Lee CV, Moffat B, Wiesmann C (2006) Structure-function studies of two synthetic anti-vascular endothelial growth factor Fabs and comparison with the Avastin Fab. J Biol Chem 281:6625–6631

    Article  CAS  PubMed  Google Scholar 

  10. Avery RL (2006) Regression of retinal and iris neovascularization after intravitreal bevacizumab (Avastin) treatment. Retina 26:352–354

    Article  PubMed  Google Scholar 

  11. Cordero Coma M, Sobrin L, Onal S, Christen W, Foster CS (2007) Intravitreal bevacizumab for treatment of uveitic macular edema. Ophthalmology 114:1574–1579

    Article  PubMed  Google Scholar 

  12. Davidorf FH, Mouser JG, Derick RJ (2006) Rapid improvement of rubeosis iridis from a single bevacizumab (Avastin) injection. Retina 26:354–356

    Article  PubMed  Google Scholar 

  13. Finger PT (2007) Anti-VEGF bevacizumab (Avastin) for radiation optic neuropathy. Am J Ophthalmol 143:335–338

    Article  CAS  PubMed  Google Scholar 

  14. Haritoglou C, Kook D, Neubauer A, Wolf A, Priglinger S, Strauss R, Gandorfer A, Ulbig M, Kampik A (2006) Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema. Retina 26:999–1005

    Article  PubMed  Google Scholar 

  15. Jorge R, Costa RA, Calucci D, Scott IU (2007) Intravitreal bevacizumab (Avastin) associated with the regression of subretinal neovascularization in idiopathic juxtafoveolar retinal telangiectasis. Graefes Arch Clin Exp Ophthalmol 245:1045–1048

    Article  CAS  PubMed  Google Scholar 

  16. Mason JO 3rd, Albert MA Jr, Vail R (2006) Intravitreal bevacizumab (Avastin) for refractory pseudophakic cystoid macular edema. Retina 26:356–357

    Article  PubMed  Google Scholar 

  17. Rosenfeld PJ, Fung AE, Puliafito CA (2005) Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for macular edema from central retinal vein occlusion. Ophthalmic Surg Lasers Imaging 36:336–339

    PubMed  Google Scholar 

  18. Rosenfeld PJ, Moshfeghi AA, Puliafito CA (2005) Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 36:331–335

    PubMed  Google Scholar 

  19. Siqueira RC, Costa RA, Scott IU, Cintra LP, Jorge R (2006) Intravitreal bevacizumab (Avastin) injection associated with regression of retinal neovascularization caused by sickle cell retinopathy. Acta Ophthalmol Scand 84:834–835

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  21. Algvere PV, Steen B, Seregard S, Kvanta A (2007) A prospective study on intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration of different durations. Acta Ophthalmol 86:482–489. [pii] AOS1113 doi:10.1111/j.1600-0420.2007.01113.x

    PubMed  Google Scholar 

  22. Wu L, Martinez-Castellanos MA, Quiroz-Mercado H, Arevalo JF, Berrocal MH, Farah ME, Maia M, Roca JA, Rodriguez FJ (2008) Twelve-month safety of intravitreal injections of bevacizumab (Avastin(R)): results of the Pan-American Collaborative Retina Study Group (PACORES). Graefes Arch Clin Exp Ophthalmol 246:81–87

    Article  CAS  PubMed  Google Scholar 

  23. Arevalo JF, Maia M, Flynn HW Jr, Saravia M, Avery RL, Wu L, Eid Farah M, Pieramici DJ, Berrocal MH, Sanchez JG (2008) Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy. Br J Ophthalmol 92:213–216

    Article  CAS  PubMed  Google Scholar 

  24. Meyer CH, Mennel S, Eter N (2007) Incidence of endophthalmitis after intravitreal Avastin injection with and without postoperative topical antibiotic application. Ophthalmologe 104:952–957

    Article  CAS  PubMed  Google Scholar 

  25. Shima C, Sakaguchi H, Gomi F, Kamei M, Ikuno Y, Oshima Y, Sawa M, Tsujikawa M, Kusaka S, Tano Y (2008) Complications in patients after intravitreal injection of bevacizumab. Acta Ophthalmol 86:372–376

    Article  PubMed  Google Scholar 

  26. Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T (2009) Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study. Ophthalmology 116:57–65

    Article  PubMed  Google Scholar 

  27. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355:1419–1431

    Article  CAS  PubMed  Google Scholar 

  28. Simo R, Hernandez C (2008) Intravitreous anti-VEGF for diabetic retinopathy: hopes and fears for a new therapeutic strategy. Diabetologia 51:1574–1580

    Article  CAS  PubMed  Google Scholar 

  29. Avery RL, Pearlman J, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ, Wendel R, Patel A (2006) Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology 113:1695

    Article  PubMed  Google Scholar 

  30. Li P-Y, Shih J, Lo R, Saati S, Agrawal R, Humayun MS, Tai Y-C, Meng E (2008) An electrochemical intraocular drug delivery device. Sens Actuators A Phys 143:41–48

    Article  Google Scholar 

  31. Caldwell RB, Bartoli M, Behzadian MA, El-Remessy AE, Al-Shabrawey M, Platt DH, Caldwell RW (2003) Vascular endothelial growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. Diabetes Metab Res Rev 19:442–455

    Article  CAS  PubMed  Google Scholar 

  32. Pournaras CJ, Rungger-Brandle E, Riva CE, Hardarson SH, Stefansson E (2008) Regulation of retinal blood flow in health and disease. Prog Retin Eye Res 27:284–330

    Article  CAS  PubMed  Google Scholar 

  33. Maurice DM (1987) Flow of water between aqueous and vitreous compartments in the rabbit eye. Am J Physiol 252:F104–F108

    CAS  PubMed  Google Scholar 

  34. Aiello LP, Brucker AJ, Chang S, Cunningham ET Jr, D'Amico DJ, Flynn HW Jr, Grillone LR, Hutcherson S, Liebmann JM, O'Brien TP, Scott IU, Spaide RF, Ta C, Trese MT (2004) Evolving guidelines for intravitreous injections. Retina 24:S3–S19

    Article  PubMed  Google Scholar 

  35. Ameri H, Chader GJ, Kim JG, Sadda SR, Rao NA, Humayun MS (2007) The effects of intravitreous bevacizumab on retinal neovascular membrane and normal capillaries in rabbits. Invest Ophthalmol Vis Sci 48:5708–5715

    Article  PubMed  Google Scholar 

  36. Agrawal RN, He S, Spee C, Cui JZ, Ryan SJ, Hinton DR (2007) In vivo models of proliferative vitreoretinopathy. Nat Protoc 2:67–77

    Article  CAS  PubMed  Google Scholar 

  37. Peters S, Heiduschka P, Julien S, Ziemssen F, Fietz H, Bartz-Schmidt KU, Schraermeyer U (2007) Ultrastructural findings in the primate eye after intravitreal injection of bevacizumab. Am J Ophthalmol 143:995–1002

    Article  CAS  PubMed  Google Scholar 

  38. Bakri SJ, Snyder MR, Reid JM, Pulido JS, Singh RJ (2007) Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology 114:855–859

    Article  PubMed  Google Scholar 

  39. Mintz-Hittner HA, Kuffel RR Jr (2008) Intravitreal injection of bevacizumab (Avastin) for treatment of stage 3 retinopathy of prematurity in zone I or posterior zone II. Retina 28:831–838

    Article  PubMed  Google Scholar 

  40. Zhu Q, Ziemssen F, Henke-Fahle S, Tatar O, Szurman P, Aisenbrey S, Schneiderhan-Marra N, Xu X, Grisanti S (2008) Vitreous levels of bevacizumab and vascular endothelial growth factor-A in patients with choroidal neovascularization. Ophthalmology 115:1750–1755

    Article  PubMed  Google Scholar 

  41. Bakri SJ, Pulido JS, Mukherjee P, Marler RJ, Mukhopadhyay D (2008) Absence of histologic retinal toxicity of intravitreal nanogold in a rabbit model. Retina 28:147–149

    Article  PubMed  Google Scholar 

  42. Feiner L, Barr EE, Shui YB, Holekamp NM, Brantley MA Jr (2006) Safety of intravitreal injection of bevacizumab in rabbit eyes. Retina 26:882–888

    Article  PubMed  Google Scholar 

  43. Manzano RP, Peyman GA, Khan P, Kivilcim M (2006) Testing intravitreal toxicity of bevacizumab (Avastin). Retina 26:257–261

    Article  PubMed  Google Scholar 

  44. Shahar J, Avery RL, Heilweil G, Barak A, Zemel E, Lewis GP, Johnson PT, Fisher SK, Perlman I, Loewenstein A (2006) Electrophysiologic and retinal penetration studies following intravitreal injection of bevacizumab (Avastin). Retina 26:262–269

    Article  PubMed  Google Scholar 

  45. Avci B, Avci R, Inan UU, Kaderli B (2009) Comparative evaluation of apoptotic activity in photoreceptor cells after intravitreal injection of bevacizumab and pegaptanib sodium in rabbits. Invest Ophthalmol Vis Sci 50:3438–3446. [pii] iovs.08-2871 doi:10.1167/iovs.08-2871

    Article  PubMed  Google Scholar 

  46. Inan UU, Avci B, Kusbeci T, Kaderli B, Avci R, Temel SG (2007) Preclinical safety evaluation of intravitreal injection of full-length humanized vascular endothelial growth factor antibody in rabbit eyes. Invest Ophthalmol Vis Sci 48:1773–1781

    Article  PubMed  Google Scholar 

  47. Alikacem N, Yoshizawa T, Nelson KD, Wilson CA (2000) Quantitative MR imaging study of intravitreal sustained release of VEGF in rabbits. Invest Ophthalmol Vis Sci 41:1561–1569

    CAS  PubMed  Google Scholar 

  48. Ozaki H, Hayashi H, Vinores SA, Moromizato Y, Campochiaro PA, Oshima K (1997) Intravitreal sustained release of VEGF causes retinal neovascularization in rabbits and breakdown of the blood-retinal barrier in rabbits and primates. Exp Eye Res 64:505–517

    Article  CAS  PubMed  Google Scholar 

  49. Wong CG, Rich KA, Liaw LH, Hsu HT, Berns MW (2001) Intravitreal VEGF and bFGF produce florid retinal neovascularization and hemorrhage in the rabbit. Curr Eye Res 22:140–147

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by Biomimetic Micro-Electronic Systems-Engineering Research Center, National Science Foundation EEC-0310723, and also in part by NIH core grant EY03040 and an unrestricted grant by Research to Prevent Blindness.

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Authors and Affiliations

  1. Doheny Retina Institute, Doheny Eye Institute, 1450 San Pablo St., Los Angeles, CA, 90033, USA

    Saloomeh Saati, Rajat N. Agrawal, Gerald J. Chader & Mark S. Humayun

  2. Department of Ophthalmology, Keck School of Medicine, University of Southern California, 1450 San Pablo St., Los Angeles, CA, 90033, USA

    Rajat N. Agrawal, Gerald J. Chader & Mark S. Humayun

  3. Department of Pharmacy, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA, 90033, USA

    Stan Louie

  4. Doheny Eye Institute, 1450 San Pablo St., DVRC 124, Los Angeles, CA, 90033, USA

    Rajat N. Agrawal

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  1. Saloomeh Saati
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  3. Stan Louie
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Correspondence to Rajat N. Agrawal.

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None of the authors have any proprietary interest in the work presented. All the authors have full control of all primary data, and they agree to allow Graefe's Archive for Clinical and Experimental Ophthalmology to review their data upon request.

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Saati, S., Agrawal, R.N., Louie, S. et al. Effect of multiple injections of small divided doses vs single injection of intravitreal bevacizumab on retinal neovascular model in rabbits. Graefes Arch Clin Exp Ophthalmol 248, 457–466 (2010). https://doi.org/10.1007/s00417-009-1153-z

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  • DOI: https://doi.org/10.1007/s00417-009-1153-z

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