Oral Doxycycline Reduces the Total Number of Intraocular Bevacizumab Injections Needed to Control Neovascular Age-related Macular Degeneration

Ahmad Mirshahi, Pourya Azimi, Ali Abdollahi, Romina Mirshahi, Mahnaz Abdollahian


Tetracyclines, especially doxycycline, play a role in the regulation of inflammation, immunomodulation, cell proliferation, and angiogenesis. Treatment of corneal angiogenesis or choroidal neovascularization with tetracyclines has been shown to be effective in animal models. The aim of this study was to evaluate the efficacy of oral doxycycline in reducing the total number of intraocular injections needed for controlling neovascular age-related macular degeneration in human patients. In this interventional case series, 28 random consecutive patients with neovascular age-related macular degeneration from Farabi Hospital, Tehran, Iran were treated for 4 months with 200 mg doxycycline once a day after the first intravitreal bevacizumab injection in addition to standard therapy in agreement with as-needed regimen. After 12 months of follow-up, total number of injections, foveal thickness and visual acuity were compared to those at baseline and of similar studies. Similar to standard treatment, co-treatment with doxycycline was able to control active disease (intraretinal or subretinal collection or leakage, new-onset of macular hemorrhage, and depletion of visual acuity more than 5 letters based on Early Treatment Diabetic Retinopathy Study [ETDRS] charts) yet with fewer injections (for current study and standard treatment, respectively 3.14 vs. 5.92, P < 0.001). Furthermore, while better control of the foveal thickness was achieved (P < 0.001), vision improvement was similar to that achieved with standard therapy (P > 0.05). If confirmed in larger studies, the findings of this interventional case series could provide a strategy to control neovascular age-related macular degeneration with fewer intraocular bevacizumab injections by co-administering a well-known oral agent—doxycycline.



Eandi CM, Alovisi C, De Sanctis U, Grignolo FM. Treatment for neovascular age related macular degeneration: The state of the art. Eur J Pharmacol. 2016;787:78-83. DOI: 10.1016/j.ejphar.2016.03.002 PMID: 26948315

Mantel I. [Age-related macular degeneration - a challenge for public health care]. Ther Umsch. 2016;73(2):79-83. DOI: 10.1024/0040-5930/a000760 PMID: 26982646

Frennesson C, Nilsson UL, Peebo BB, Nilsson SE. Significant improvements in near vision, reading speed, central visual field and related quality of life after ranibizumab treatment of wet age-related macular degeneration. Acta Ophthalmol. 2010;88(4):420-5. DOI: 10.1111/j.1755-3768.2009.01 576.x PMID: 19678811

Agosta E, Lazzeri S, Orlandi P, Figus M, Fioravanti A, Di Desidero T, et al. Pharmacogenetics of antiangiogenic and antineovascular therapies of age-related macular degeneration. Pharmacogenomics. 2012;13(9):1037-53. DOI: 10.2217/pgs.12.77 PMID: 22838951

Gilbertson-Beadling S, Powers EA, Stamp-Cole M, Scott PS, Wallace TL, Copeland J, et al. The tetracycline analogs minocycline and doxycycline inhibit angiogenesis in vitro by a non-metalloproteinase-dependent mechanism. Cancer Chemother Pharmacol. 1995;36(5):418-24. DOI: 10.1007/BF0068 6191 PMID: 7543375

Comparison of Age-related Macular Degeneration Treatments Trials Research G, Martin DF, Maguire MG, Fine SL, Ying GS, Jaffe GJ, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388-98. DOI: 10.1016/j .ophtha.2012.03.053 PMID: 22555112

Freund KB, Korobelnik JF, Devenyi R, Framme C, Galic J, Herbert E, et al. TREAT-AND-EXTEND REGIMENS WITH ANTI-VEGF AGENTS IN RETINAL DISEASES: A Literature Review and Consensus Recommendations. Retina. 2015;35(8):1489-506. DOI: 10.1097/IAE.00000 00000000627 PMID: 26076215

Scott AW, Bressler SB. Long-term follow-up of vascular endothelial growth factor inhibitor therapy for neovascular age-related macular degeneration. Curr Opin Ophthalmol. 2013;24(3):190-6. DOI: 10.1097/ICU.0b013e32835fefee PMID: 23492430

Kim LN, Mehta H, Barthelmes D, Nguyen V, Gillies MC. Metaanalysis of Real-World Outcomes of Intravitreal Ranibizumab for the Treatment of Neovascular Age-Related Macular Degeneration. Retina. 2016;36(8):1418-31. DOI: 10.1097/IAE.00000000000 01142 PMID: 27388744

Santarelli M, Diplotti L, Samassa F, Veritti D, Kuppermann BD, Lanzetta P. Advances in pharmacotherapy for wet age-related macular degeneration. Expert Opin Pharmacother. 2015;16(12):1769-81. DOI: 10.1517/14656566.2015. 1067679 PMID: 26165696

Wan MJ, Hooper PL, Sheidow TG. Combination therapy in exudative age-related macular degeneration: visual outcomes following combined treatment with photodynamic therapy and intravitreal bevacizumab. Can J Ophthalmol. 2010;45(4):375-80. DOI: 10.3129 /i10-011 PMID: 20648087

Mendez CA, Ehlers JP. Radiation therapy: age-related macular degeneration. Dev Ophthalmol. 2013;52:75-84. DOI: 10.1159/000351061 PMID: 23989128

Patel S. Combination therapy for age-related macular degeneration. Retina. 2009;29(6 Suppl):S45-8. DOI: 10.1097/IAE.0b013e3181ad22d5 PMID: 19553801

Tao Y, Jonas JB. Intravitreal bevacizumab combined with intravitreal triamcinolone for therapy-resistant exudative age-related macular degeneration. J Ocul Pharmacol Ther. 2010;26(2):207-12. DOI: 10.1089/jop .2009.0131 PMID: 20415625

Soheilian M, Movaseghi M, Ramezani A, Peyman GA. Pilot study of safety and effect of combined intravitreal bevacizumab and methotrexate for neovascular age-related macular degeneration. Eur J Ophthalmol. 2011;21(1):77-82. PMID: 20872362

Oshima Y, Oshima S, Nambu H, Kachi S, Hackett SF, Melia M, et al. Increased expression of VEGF in retinal pigmented epithelial cells is not sufficient to cause choroidal neovascularization. J Cell Physiol. 2004;201(3):393-400. DOI: 10.1002/jcp.20110 PMID: 15389527

Samtani S, Amaral J, Campos MM, Fariss RN, Becerra SP. Doxycycline-mediated inhibition of choroidal neovascularization. Invest Ophthalmol Vis Sci. 2009;50(11):5098-106. DOI: 10.1167/iovs.08-3174 PMID: 19516001

Roychoudhury J, Herndon JM, Yin J, Apte RS, Ferguson TA. Targeting immune privilege to prevent pathogenic neovascularization. Invest Ophthalmol Vis Sci. 2010;51(7):3560-6. DOI: 10.1167/iovs.09-3890 PMID: 20164456

Fainaru O, Adini I, Benny O, Bazinet L, Pravda E, D'Amato R, et al. Doxycycline induces membrane expression of VE-cadherin on endothelial cells and prevents vascular hyperpermeability. FASEB J. 2008;22(10):3728-35. DOI: 10.1096/fj.08-110494 PMID: 18606869

Debrah AY, Mand S, Specht S, Marfo-Debrekyei Y, Batsa L, Pfarr K, et al. Doxycycline reduces plasma VEGF-C/sVEGFR-3 and improves pathology in lymphatic filariasis. PLoS Pathog. 2006;2(9):e92. DOI: 10.1371/journal.ppat.0020092 PMID: 17044733

Pimenta SP, Baldi BG, Acencio MM, Kairalla RA, Carvalho CR. Doxycycline use in patients with lymphangioleiomyomatosis: safety and efficacy in metalloproteinase blockade. J Bras Pneumol. 2011;37(4):424-30. PMID: 21881731

Pimenta SP, Baldi BG, Kairalla RA, Carvalho CR. Doxycycline use in patients with lymphangioleiomyomatosis: biomarkers and pulmonary function response. J Bras Pneumol. 2013;39(1):5-15. PMID: 23503480

Peyman GA, Kazi AA, Riazi-Esfahani M, Aydin E, Kivilcim M, Sanders DR. The effect of combinations of flurbiprofen, low molecular weight heparin, and doxycycline on the inhibition of corneal neovascularization. Cornea. 2006;25(5):582-5. DOI: 10.1097/01.ico.0000220767.73660.3a PMID: 167831 47

Dan L, Shi-long Y, Miao-li L, Yong-ping L, Hong-jie M, Ying Z, et al. Inhibitory effect of oral doxycycline on neovascularization in a rat corneal alkali burn model of angiogenesis. Curr Eye Res. 2008;33(8):653-60. DOI: 10.1080/02713680802245772 PMID: 18696340

Cox CA, Amaral J, Salloum R, Guedez L, Reid TW, Jaworski C, et al. Doxycycline's effect on ocular angiogenesis: an in vivo analysis. Ophthalmology. 2010;117(9):1782-91. DOI: 10.1016/j.ophtha.2010.01. 037 PMID: 20605212

Su W, Li Z, Li Y, Lin M, Yao L, Liu Y, et al. Doxycycline enhances the inhibitory effects of bevacizumab on corneal neovascularization and prevents its side effects. Invest Ophthalmol Vis Sci. 2011;52(12):9108-15. DOI: 10.1167/iovs.11-7255 PMID: 22039247

Sivaprasad S, Patra S, DaCosta J, Adewoyin T, Shona O, Pearce E, et al. A pilot study on the combination treatment of reduced-fluence photodynamic therapy, intravitreal ranibizumab, intravitreal dexamethasone and oral minocycline for neovascular age-related macular degeneration. Ophthalmologica. 2011;225(4):200-6. DOI: 10.1159/000322363 PMID: 21293163

Robert MC, Saab M, Rezende FA. Presumed choroidal neovascularization secondary to Bartonella henselae. Can J Ophthalmol. 2012;47(4):e9-10. DOI: 10.1016 /j.jcjo.2012.03.010 PMID: 22883856

Carneiro AM, Mendonca LS, Falcao MS, Fonseca SL, Brandao EM, Falcao-Reis FM. Comparative study of 1+PRN ranibizumab versus bevacizumab in the clinical setting. Clin Ophthalmol. 2012;6:1149-57. DOI: 10.2147/OPTH.S33017 PMID: 22973087

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