Structural and Functional Criteria of Neuroprotection Effectiveness after Anti-VEGF Therapy in Patients with Neovascular Age-Related Macular Degeneration

Purpose. Estimate of clinical efficacy of combined use of aflibercept and meldonium at tachyphylaxis of neovascular age-related macular degeneration (nAMD) to ranibizumab.

Patients and methods. Comparative analysis of treatment results of nAMD in 25 eyes (25 patients) aged from 52 to 79 years was carried out. Main criterion for the patients inclusion was presence of nAMD resistant to intravitreal injections (IVI) of VEGF inhibitor ranibizumab with visual acuity values of not less than 0.1. Patients with different ophthalmologic pathology, accompanied by development of macular edema, with glaucoma and after any eye operations, performed during study period, were excluded from study. Before using aflibercept, all patients were treated with ranibizumab for 1.5–2 years (from 5 to 7 injections). The lack of persistent positive result was cause for change of course treatment of this patients on aflibercept (3 monthly injections) for enhance anti-vasoproliferative effect. The patients were divided into two groups — main and comparison, comparable by sex, age, visual acuity and type of choroidal neovascularization. In the main group, 3 aflibercept IVI were supplemented parabulbar injections of 0.5 ml of meldonium (with concentration of 500 mg / 5 ml) daily for 10 days. Patients of the comparison group did not receive meldonium.

Results. The supplement of meldonium in the main group, relative to the comparison group, led to increase in 1.5 times of best corrected visual acuity, in 1.2 times of b-wave amplitude of the electroretinogram, preservation of the neuro- and pigment epithelium of retina, complete regression of neovascularization.

Conclusion. Findings results evidence about clinically advisable to use meldonium in course treatment in patients with nAMD, resistant to ranibizumab, with aflibercept IVI for increase visual functions and stabilize the degenerative changes in neurosensory retina, pigment epithelium and choriocapillary layer.

1. Libman E.S., Kaleeva E.V., Ryazanov D.P. Comprehensive characteristics of disability due to ophthalmic pathology in the Russian Federation. Russian ophthalmology online = Rossijskaya oftalmologiya onlajn. 2012;5 URL: http://www.eyepress.ru/article.aspx?10314 (available to October 30, 2018). (In Russ.)

2. Stahl A. Anti-angiogenic therapy in ophthalmology. Germany: Springer; 2016. 193 p.

3. Bikbov M.M., Fayzrakhmanov R.R., Yarmukhametova A.L. Agerelated macular degeneration. Moscow: April; 2013. 196 p. (In Russ.)

4. Boiko E.V., Zhuravleva L.V., Sosnovsky S.V. Age-related macular degeneration (risk factors, classification, diagnosis, prevention, treatment). Moscow; 2009. 44 p. (In Russ.)

5. Egorov E.A., Romanenko I.A. Age-related macular degeneration. Issues of pathogenesis, diagnosis and treatment. Russian Medical Journal. Clinical Ophthalmology = Rossijskij medicinskij zhurnal. 2009;10(1):42–45 (In Russ.)

6. Zenkov N.K., Lankin V.Z., Menshchikova E.B. Oxidative stress: biochemical and pathophysiological aspects. Moscow; 2001. 343 p. (In Russ.)

7. Das A., Friberg T. Therapy for ocular angiogenesis: principles and practice. Philadelphia: LWW; 2011. 377 p.

8. Stewart M.W. The expanding role of vascular endothelial growth factor inhibitors in ophthalmology. Mayo Clin. Proc. 2012;87(1):77–88. DOI: 10.1016/j.mayocp.2011.10.001

9. Panova I.E., Tonkikh N.A., Prokopieva M.Yu., Bukhtiyarova N.V. Ages central degeneration with neovascular answer: peculiarities of clinical course, characteristics of cellular immunity. Annals of Orenburg State University = Vestnik Orenburgskogo gosudarstvennogo universiteta. 2004;38:246–248 (In Russ.)

10. Miller J.W., Adamis A.P., Shima D.T. Vascular endothelial growth factor/vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am. J. Pathol. 1994;145(3):574–584.

11. Rakic J.M., Lambert V., Devy L., et al. Placental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization. Invest Ophthalmol Vis Sci. 2003;44(7):3186–3193. DOI: 10.1167/iovs.02-1092

12. Hoeben A., Landuyt B., Highley M.S. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004;56(4):549–580. DOI: 10.1124/pr.56.4.3

13. VEGF Trap-Eye (aflibercept ophthalmic solution) briefing document — Ophthalmologic Drugs Advisory Committee. 2011 (updated June 17, 2011; available to October 30, 2018). URL: https://www.retina3000.it/nuoveterapie_eylea_uk.html

14. Papadopoulos N., Martin J., Ruan Q., et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis. 2012;15(2):171–185. DOI: 10.1007/s10456-011-9249-6

15. Stewart M.W. Pharmacokinetics, pharmacodynamics and preclinical characteristics of ophthalmic drugs that bind VEGF. Expert Rev Clin Pharmacol. 2014;7(2):167–180. DOI: 10.1586/17512433.2014.884458

16. Young M., Chui L., Fallah N., et al. Exacerbation of choroidal and retinal pigment epithelial atrophy after antivascular endothelial growth factor treatment in neovascular age-related macular degeneration. Retina. 2014;34(7):1308–1315. DOI: 10.1097/IAE.0000000000000081

17. Egorov E.A., Astakhov Yu.S., Stavitskaya T.V. Ophthalmopharmacology. Moscow: GEOTAR-Media; 2009. 592 p. (In Russ.)

18. Zhajvoronok N.S., Smoliakova G.P., Danilova L.P., Emanova L.P., Povalyaeva D.A. Long-term results of antiangiogenic therapy of neovascular age-related macular degeneration. Modern technologies in ophthalmology = Sovremennye tekhnologii v oftal’mologii. 2017;2:198–200 (In Russ.)