Due to its low price, bevacizumab, which binds vascular endothelial growth factor, is currently used off-label for the treatment of over 50 different eye diseases and has been adopted worldwide despite the absence of serious preclinical data. This study examines the effects of intravitreal bevacizumab on monkey eyes with particular focus on choroidal and retinal vessels.
Cynomolgus monkeys received an intravitreal injection of 1.25 mg bevacizumab with or without (125)I labeling. The eyes were enucleated between 1 and 14 days after injection and were investigated by electron microscopy, immunocytochemistry, histochemistry or autoradiography. Untreated and phosphate buffered saline (PBS)-injected monkeys were used as controls.
Bevacizumab locally accumulated at high concentration within individual blood vessels. It formed electron-dense deposits inside retinal veins and between red and white blood cells, activated thrombocytes and induced retinal vein thrombosis. Retinal cells like Müller cells, astrocytes and microglia were also activated. High amounts of bevacizumab were found in retinal and choroidal vessels which may interfere with blood flow.
The deposits on the retinal vein walls may provide a mechanistic basis for the observed retinal blood flow alterations after bevacizumab treatment in patients.
[Show abstract][Hide abstract] ABSTRACT: Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world. With an ageing population, it is anticipated that the number of AMD cases will increase dramatically, making a solution to this debilitating disease an urgent requirement for the socioeconomic future of the European Union and worldwide. The present paper reviews the limitations of the current therapies as well as the socioeconomic impact of the AMD. There is currently no cure available for AMD, and even palliative treatments are rare. Treatment options show several side effects, are of high cost, and only treat the consequence, not the cause of the pathology. For that reason, many options involving cell therapy mainly based on retinal and iris pigment epithelium cells as well as stem cells are being tested. Moreover, tissue engineering strategies to design and manufacture scaffolds to mimic Bruch's membrane are very diverse and under investigation. Both alternative therapies are aimed to prevent and/or cure AMD and are reviewed herein.
Journal of Ophthalmology 01/2014; 2014(5):510285. DOI:10.1155/2014/510285 · 1.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Since there is evidence that the Fc domain of antivascular endothelial growth factor drugs may cause unexpected consequences in retinal and choroidal vessels, the effects of intravitreal ranibizumab and aflibercept on monkey eyes were investigated.
Four cynomolgus monkeys were intravitreally injected with 0.5 mg of ranibizumab and another four with 2 mg of aflibercept. Two untreated monkeys served as controls. Funduscopy, fluorescein angiography (FA), spectral-domain-optical coherence tomography (SD-OCT) and measurement of intraocular pressure (IOP) were performed. The eyes were inspected by light, fluorescence and electron microscopy. The diameter of the choriocapillaris (CC) was measured by morphometry, and the areas of the CC with free haemoglobin, CC fenestrations and endothelial thickness were quantified.
Analysis showed ranibizumab permeated the retina via intercellular clefts, whereas aflibercept was taken up by ganglion cells, cells of the inner and outer retinal layers and the retinal pigment epithelium (RPE). Stasis and haemolysis in the choriocapillaris and choroidal vessels were more frequent after aflibercept treatment, which caused hypertrophy and death of individual RPE cells. The area of the CC was significantly reduced after both drugs compared with controls, but the reduction of the CC endothelium thickness, number of fenestrations and the areas with haemolysis were more pronounced after aflibercept.
Ranibizumab permeated the retina through intercellular spaces, whereas aflibercept was taken up by neuronal and RPE cells. Aflibercept induced protein complex formation and more haemolysis in the choriocapillaris, leading to individual RPE cell death. The clinical significance and relation of these findings to the Fc domain or to other characteristics of aflibercept remain to be investigated.
The British journal of ophthalmology 01/2014; 98(6). DOI:10.1136/bjophthalmol-2013-304019 · 2.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A retrospective chart review of patients with persistent subretinal and/or intraretinal fluid, despite previous treatment with intravitreal ranibizumab (0.5 mg), who were switched to aflibercept injections, was performed. Treatment was three monthly aflibercept (2 mg) injections followed by dosing on pro re nata basis. Main outcome measures included changes in best corrected visual acuity (BCVA), 1 mm central subfield (CSF) retinal thickness, the height of the pigment epithelial detachment (PED), and subfoveal choroidal thickness on optical coherence tomography at 6 months. Thirty-one eyes of 30 patients were analyzed. The mean number of injections before aflibercept conversion was 34.4 ± 11.9. After an average of 4.5 aflibercept injections (range 3 to 6) over 6 months, no significant change in BCVA was observed (P > 0.05). Compared with baseline, there was a significant reduction of the CSF retinal thickness (449 ± 179 versus 269 ± 145 μ m, P < 0.001), maximum PED height (262 ± 134 versus 183 ± 100 μ m, P < 0.001), and choroidal thickness (192 ± 67 versus 167 ± 51 μ m, P < 0.01). Stable visual acuity and anatomical improvement were obtained for up to 6 months after aflibercept conversion. However, choroidal thinning related to treatment was observed.
BioMed Research International 05/2014; 2014:273754. DOI:10.1155/2014/273754 · 3.17 Impact Factor
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