Dobesilate for dry age-related macular degeneration

Pedro Cuevas, Luis A. Outeiriño, Carlos Azanza, Javier Angulo, Guillermo Giménez-Gallego

Departamento de Estructura y Función de Proteínas, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.
Departamento de Investigación, IRYCIS, Hospital Universitario Ramón y Cajal, Madrid, Spain.
Departamento de Oftalmología, Hospital de Día Pío XII, Madrid, Spain.

DOI: 10.4236/jbise.2013.610A2002                

Abstract

We have evaluated the effects of intravitreal dobesilate, a synthetic fibroblast growth factor inhibitor, in patients with dry age-related macular degeneration, an inflammatory-related retinal disease without available treatment up to date. 36 eyes from 36 patients with dry age-related macular degeneration were treated with a single intravitreal dobesilate injection. The end points were the improvement from baseline visual acuity and normalization of retinal histology at one month. Intravitreal dobesilate injection resulted in a significant improvement in functional and anatomical outcomes at one month after injection. Our results suggest that intravitreal dobesilate may increase the chance of visual acuity gain in dry age-related macular degeneration, even in cases with initial low vision. This study supports the findings of previously published case reports, regarding the short-term improvement in visual acuity by intravitreal dobesilate injection in different degenerative retinal diseases.

Keywords

Dry Age-Related Macular Degeneration; Fibroblast Growth Factor Inhibition; Intravitreal Dobesilate

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Ambati, J., Ambati, B.K., Yoo, S.H., Ianchulev, S. and Adamis, A.P. (2003) Age-related macular degeneration: Etiology, pathogenesis, and therapeutic strategies. Survey of Ophthalmology, 48, 257-293. http://dx.doi.org/10.1016/S0039-6257(03)00030-4
[2]	van Leeuwen, R., Klaver, C.C., Vingerling, J.R., Hofman, A. and de Jong, P.T. (2003) Epidemiology of age-related maculopathy: A review. European Journal of Epidemiology, 18, 845-854. http://dx.doi.org/10.1023/A:1025643303914
[3]	Klein, R., Klein, B.E., Knudtson, M.D., Meuer, S.M., Swift, M. and Gangnon, R.E. (2007) Fifteen-year cumulative incidence of age-related macular degeneration: The beaver dam eye study. Ophthalmology, 114, 253-262. http://dx.doi.org/10.1016/j.ophtha.2006.10.040
[4]	Rodrigues, E.B. (2007) Inflammation in dry age-related macular degeneration. Ophthalmologica, 221, 143-152. http://dx.doi.org/10.1159/000099293
[5]	Nowak, J.Z. (2006) Age-related macular degeneration (AMD): Pathogenesis and therapy. Pharmacological Reports, 58, 353-363.
[6]	Patel, M. and Chan, C.C. (2008) Immunopathological aspects of age-related macular degeneration. Seminars in Immunopathology, 30, 97-110. http://dx.doi.org/10.1159/000099293
[7]	Hollyfield, J.G., Bonilha, V.L., Rayborn, M.E., Yang, X., Shadrach, K.G., Lu, L., Ufret, R.L, Salomon, R.G. and Perez, V.L. (2008) Oxidative damage-induced inflammation initiates age-related macular degeneration. Nature Medicine, 14, 194-198. http://dx.doi.org/10.1038/nm1709
[8]	Buschini, E., Piras, A., Nuzzi, R. and Vercelli, A. (2011) Age related macular degeneration and drusen: Neuroinflammation in the retina. Progress in Neurobiology, 95, 14-25. http://dx.doi.org/10.1016/j.pneurobio.2011.05.011
[9]	Telander, D.G. (2011) Inflammation and age-related macular degeneration (AMD). Seminars in Ophthalmology, 26, 192-197. http://dx.doi.org/10.1016/j.pneurobio.2011.05.011
[10]	Byrd, V.M., Ballard, D.W., Miller, G.G. and Thomas, J.W. (1999) Fibroblast growth factor-1 (FGF-1) enhances IL-2 production and nuclear translocation of NF-kappaB in FGF receptor-bearing Jurkat T cells. Journal of Immunology, 162, 5853-5859.
[11]	Meij, J.T., Sheikh, F., Jiménez, S.K., Nickerson, P.W., Kardami, E. and Cattini, P.A. (2002) Exacerbation of myocardial injury in transgenic mice overexpressing FGF-2 is T cell dependent. American Journal of Physiology— Heart and Circulatory Physiology, 282, H547-H555.
[12]	Rossini, M., Cheunsuchon, B., Donnert, E., Ma, L.J., Thomas, J.W., Neilson, E.G. and Fogo, A.B. (2005) Immunolocalization of fibroblast growth factor-1 (FGF-1), its receptor (FGFR-1), and fibroblast-specific protein-1 (FSP-1) in inflammatory renal disease. Kidney International, 68, 2621-2628. http://dx.doi.org/10.1111/j.1523-1755.2005.00734.x
[13]	Zittermann, S.I. and Issekutz, A.C. (2006) Basic fibroblast growth factor (bFGF, FGF-2) potentiates leukocyte recruitment to inflammation by enhancing endothelial adhesion molecule expression. American Journal of Pathology, 168, 835-846. http://dx.doi.org/10.2353/ajpath.2006.050479
[14]	Andrés, G., Leali, D., Mitola, S., Coltrini, D., Camozzi, M., Corsini, M., Belleri, M., Hirsch, E., Schwendener, R.A., Christofori, G., Alcami, A. and Presta, M. (2009) A pro-inflammatory signatura mediates FGF2-induced angiogenesis. Journal of Cellular and Molecular Medicine, 13, 2083-2108. http://dx.doi.org/10.1111/j.1582-4934.2008.00415.x
[15]	Strowig, T., Henao-Mejía, J., Elinav, E. and Flawell, R. (2012) Inflammosomes in health and disease. Nature, 481, 278-296. http://dx.doi.org/10.1038/nature10759
[16]	Stewart, M.W. (2012) The expanding role of vascular endothelial growth factor inhibitors in ophthalmology. Mayo Clinic Proceedings, 87, 77-88. http://dx.doi.org/10.1016/j.mayocp.2011.10.001
[17]	Lee, M., Kang, Y., Suk, K., Schwab, C., Yu, S. and McGeer, P.L. (2011) Acidic fibroblast growth factor (FGF) potentiates glial-mediated neurotoxicity by activating FGFR2 IIIb protein. Journal of Biological Chemistry, 286, 41230-41245. http://dx.doi.org/10.1074/jbc.M111.270470
[18]	Aiello, L.P., Brucker, A.J., Chang, S., Cunningham Jr, E.T., D’Amico, D.J., Flynn Jr., H.W., Grillote, L.R., Hutcherson, S., Liebmann, J.M., O’Brien, T.P., Scout, I.U., Spaide, R.F., Ta, C. and Trese, M.T. (2004) Evolving guidelines for intravitreous injections. Retina, 24, S3-S19. http://dx.doi.org/10.1097/00006982-200410001-00002
[19]	Verma, L., Sinha, R., Venkatesh, P. and Tewari, H.K. (2004) Comparative evaluation of diode laser versus argon laser photocoagulation in patients with central serous retinopathy: A pilot, randomized controlled trial [ISRC-TN84128484]. BMC Ophthalmology, 4, 15. http://dx.doi.org/10.1186/1471-2415-4-15
[20]	Sarks, J.P., Sarks, S.H. and Killingsworth, M.C. (1988) Evolution of geographic atrophy of the retinal pigment epithelium. Eye (Lond), 2, 552-577. http://dx.doi.org/10.1038/eye.1988.106
[21]	Chappelow, A.V. and Kaiser, P.K. (2008) Neovascular age-related macular degeneration: Potential therapies. Drugs, 68, 1029-1036. http://dx.doi.org/10.1038/eye.1988.106
[22]	Fernández, I.S., Cuevas, P., Angulo, J., López-Navajas, P., Canales-Mayordomo, A., Lozano, R.M., Valverde, S., Jiménez-Barbero, J., Romero, A. and Giménez-Gallego, G. (2010) Gentisic acid, a compound associated with plant defence and a metabolite of aspirin, heads a new class of in vivo FGF inhibitor. The Journal of Biological Chemistry, 285, 1714-1729. http://dx.doi.org/10.1074/jbc.M109.064618
[23]	Cuevas, P., Outeirino, L.A., Azanza, C. and Giménez-Gallego, G. (2012) Intravitreal dobesilate in the treatment of choroidal neovascularization associated with age-related macular degeneration. Report of two cases. British Medical Journal (BMJ) Case Reports.
[24]	Cuevas, P., Outeirino, L.A., Azanza, C., Angulo, J. and Giménez-Gallego, G. (2012) Short-term efficacy of intravitreal dobesilate in central serous chorioretinopathy. European Journal of Medical Research, 17, 22. http://dx.doi.org/10.1186/2047-783X-17-22
[25]	Cuevas, P., Outeirino, L.A., Angulo, J. and Giménez-Gallego, G. (2012) Chronic cystoid macular oedema treated with intravitreal dobesilate. British Medical Journal (BMJ) Case Reports.
[26]	Cuevas, P., Outeirino, L.A., Angulo, J. and Giménez-Gallego, G. (2012) Treatment of dry age-related macular degeneration with dobesilate. British Medical Journal (BMJ) Case Reports.
[27]	Cuevas, P., Outeirino, L.A., Angulo, J. and Giménez-Gallego, G. (2012) Treatment of Stargardt disease with dobesilate. British Medical Journal (BMJ) Case Reports.
[28]	Thomas, K.A. and Giménez-Gallego, G. (1986) Fibroblast growth factors: Broad spectrum mitogens with potent angiogenic activity. Trends in Biochemical Sciences, 11, 81-84. http://dx.doi.org/10.1016/0968-0004(86)90271-9
[29]	Cuevas, P., Carceller, F., Ortega, S., Zazo, M., Nieto, I. and Giménez-Gallego, G. (1991) Hypotensive activity of fibroblast growth factor. Science, 254, 1208-1210. http://dx.doi.org/10.1126/science.1957172
[30]	Galan, J.M., Cuevas, B., Dujovny, N., Giménez-Gallego, G. and Cuevas, P. (1996) Sleep promoting effects of intravenously administered acidic fibroblast growth factor. Neurological Research, 18, 567-569.
[31]	Cuevas, P., Angulo, J. and Giménez-Gallego, G. (2011) Topical treatment of contact dermatitis by pine processionary caterpillar. British Medical Journal (BMJ) Case Reports. http://casereports.bmj.com/content/2011/bcr.06.2011.4351.full.pdf
[32]	Hanai, K., Oomura, Y., Kai, Y., Nishikawa, K., Shimizu, N., Morita, H. and Plata-Salamán, C.R. (1989) Central action of acidic fibroblast growth factor in feeding regulation. American Journal of Physiology, 256, R217-R223.
[33]	Bame, K.J. (2001) Heparanases: Endoglycosidases that degrade heparan sulfate proteoglycans. Glycobiology, 11, 91R-98R. http://dx.doi.org/10.1093/glycob/11.6.91R
[34]	Yuan, K., Hong, T.M., Chen, J.J., Tsai, W.H. and Lin, M.T. (2004) Syndecan-1 up-regulated by ephrinB2/EphB4 plays dual roles in inflammatory angiogenesis. Blood, 104, 1025-1033. http://dx.doi.org/10.1182/blood-2003-09-3334
[35]	Chen, G., Wang, D., Vikramadithyan, R., Yagyu, H., Saxena, U., Pillarisetti, S. and Goldberg, I.J. (2004) Inflammatory cytokines and fatty acids regulate endothelial cell heparanase expression. Biochemistry, 43, 4971-4977. http://dx.doi.org/10.1021/bi0356552