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1.
Invest Ophthalmol Vis Sci ; 65(4): 10, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38573620

RESUMO

Purpose: In a previous study, we documented that the Intravitreal injections (IVIs) of bevacizumab in rats caused a retinal inflammatory response. We now study whether the IVI of other humanized anti-VEGF: ranibizumab and aflibercept also cause an inflammatory reaction in the rat retina and if it depends on the dose administered. Finally, we study whether this reaction affects retinal ganglion cell (RGC) survival. Methods: Albino Sprague-Dawley rats received a single IVI of 5 µL of PBS or ranibizumab or aflibercept at the concentration used in clinical practice (10 µg/µL or 40 µg/µL) or at a lower concentration (0.38 µg/µL and 1.5 µg/µL) calculated to obtain within the rat eye the same concentration as in the human eye in clinical practice. Others received a single 5 µL IVI of a polyclonal goat anti-rat VEGF (0.015 µg/µL) or of vehicle (PBS). Animals were processed 7 days or 1 month later. Retinal whole mounts were immunolabeled for the detection of microglial, macroglial, RGCs, and intrinsically photosensitive RGCs (ipRGCs). Fluorescence and confocal microscopy were used to examine retinal changes, and RGCs and ipRGCs were quantified automatically or semiautomatically, respectively. Results: All the injected substances including the PBS induced detectable side effects, namely, retinal microglial cell activation and retinal astrocyte hypertrophy. However, there was a greater microglial and macroglial response when the higher concentrations of ranibizumab and aflibercept were injected than when PBS, the antibody anti-rat VEGF and the lower concentrations of ranibizumab or aflibercept were injected. The higher concentration of ranibizumab and aflibercept resulted also in significant RGC death, but did not cause appreciable ipRGC death. Conclusions: The IVI of all the substances had some retinal inflammatory effects. The IVI of humanized anti-VEGF to rats at high doses cause important side effects: severe inflammation and RGC death, but not ipRGC death.


Assuntos
Fatores de Crescimento Endotelial , Células Ganglionares da Retina , Humanos , Ratos , Animais , Injeções Intravítreas , Ranibizumab/toxicidade , Fator A de Crescimento do Endotélio Vascular , Ratos Sprague-Dawley , Cabras , Neuroglia
2.
Toxicol Pathol ; 49(3): 663-672, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33205714

RESUMO

The Port Delivery System with ranibizumab (PDS) is an investigational drug delivery system designed to provide continuous intravitreal release of ranibizumab for extended durations. The PDS consists of a permanent, surgically placed, refillable intraocular implant; a customized formulation of ranibizumab; and ancillary devices to support surgery and refill procedures. A toxicology program was conducted to evaluate the ocular toxicology and biocompatibility of the PDS to support its clinical development program and product registrational activities. PDS safety studies included a 6-month chronic toxicology evaluation in minipigs as well as evaluation of nonfunctional surrogate implants (comprised of the same implant materials but without ranibizumab) in rabbits. Biocompatibility of the implant and ancillary devices was evaluated in both in vitro and in vivo studies. Implants and extracts from implants and ancillary devices were nongenotoxic, noncytotoxic, nonsensitizing, and nonirritating. Ocular findings were comparable between implanted and sham-operated eyes, and no systemic toxicity was observed. The results of this nonclinical toxicology program demonstrated that the PDS was biocompatible and that intravitreal delivery of ranibizumab via the PDS did not introduce any new toxicology-related safety concerns relative to intravitreal injections, supporting ongoing PDS clinical development and product registrational evaluation.


Assuntos
Degeneração Macular , Ranibizumab , Inibidores da Angiogênese , Animais , Injeções Intravítreas , Degeneração Macular/tratamento farmacológico , Coelhos , Ranibizumab/uso terapêutico , Ranibizumab/toxicidade , Suínos , Porco Miniatura , Tomografia de Coerência Óptica
3.
BMC Ophthalmol ; 18(1): 316, 2018 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-30537942

RESUMO

BACKGROUND: Ingrowth of newly formed blood and lymph vessels (angiogenesis) from the limbus region into the cornea can be treated successfully by subconjunctival application of antiangiogenic agents. Currently, there are several angiogenesis inhibitors from various manufacturers available, such as vascular endothelial growth factor (VEGF) antibodies. The aim of the study was to investigate potential cytotoxic effects of two anti-VEGF agents, ranibizumab (Lucentis®) and bevacizumab (Avastin®) on the human corneal endothelium. METHODS: Human donor corneas, not suitable for corneal transplantation, were organ-cultured in the presence of either ranibizumab (Lucentis®) or bevacizumab (Avastin®) at different concentrations (group 1: 250 µg / ml, group 2: 25 µg / ml, group 3: 2.5 µg / ml) for a period of up to 4 weeks. Microscopic imaging for endothelial cell counting, detection of morphologic alterations of the endothelium, and molecular biology testing (Enzyme-linked Immunosorbent Assay [ELISA]) for metabolic changes was performed. RESULTS: Background-corrected results showed neither a significant lactate dehydrogenase (LDH) change with increasing culturing time nor a significant difference between ranibizumab (Lucentis®) and bevacizumab (Avastin®) treatment. The endothelial cell density revealed also no statistically significant difference between the two treatment groups with ranibizumab (Lucentis®) and bevacizumab (Avastin®) at all concentrations tested in this study. CONCLUSIONS: In this study, the anti-angiogenic agents ranibizumab (Lucentis®) and bevacizumab (Avastin®) demonstrated no cytotoxic effects on the corneal endothelium of human organ-cultured donor corneas over the limited study time period of 4 weeks. However, based on the study design (in-vitro) and the limited follow-up period, no conclusions on potential long-term effects can be drawn.


Assuntos
Inibidores da Angiogênese/toxicidade , Bevacizumab/toxicidade , Células Endoteliais/efeitos dos fármacos , Endotélio Corneano/efeitos dos fármacos , Ranibizumab/toxicidade , Idoso , Idoso de 80 Anos ou mais , Contagem de Células , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
4.
Biochem Pharmacol ; 103: 129-39, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26793998

RESUMO

We assessed the effect of single and repeated doses of bevacizumab, ranibizumab, and aflibercept on cell viability, proliferation, permeability, and apoptosis of ARPE-19 cells. MTT and BrdU assays were used to determine viability and proliferation after single or repeated doses of anti-VEGF drugs under normal and oxidative stress conditions. Caspase-3 expression after single and repeated doses of the 3 drugs was assessed using immunofluorescence. Transepithelial-electrical-resistance (TER) was measured to study the effect of anti-VEGFs on retinal pigment epithelium (RPE) permeability under normal and oxidative stress conditions. Flow cytometry was used to detect intracellular accumulation of the drugs. Finally, a wound healing assay was performed to investigate the effect of the drugs on RPE cell migration. Single and multiple doses of anti-VEGF drugs had no effect on cell viability and proliferation. The oxidative effect of H2O2 decreased cell viability and proliferation; however, no difference was observed between anti-VEGF treatments. Immunofluorescence performed after single and repeated doses of the drugs revealed some caspase-3 expression. Interestingly, anti-VEGFs restored the increased permeability induced by H2O2. The 3 drugs accumulated inside the cells and were detectable 5 days after treatment. Finally, none of the drugs affected migration. In conclusion, no measureable toxic effect was observed after single or repeated doses of VEGF antagonists under normal and oxidative stress. Intracellular accumulation of the drugs does not seem to be toxic or affect cell functions. Our study suggests that anti-VEGFs could have a preventive effect on the maintenance of the RPE barrier under oxidative stress.


Assuntos
Bevacizumab/toxicidade , Estresse Oxidativo , Ranibizumab/toxicidade , Receptores de Fatores de Crescimento do Endotélio Vascular/toxicidade , Proteínas Recombinantes de Fusão/toxicidade , Epitélio Pigmentado da Retina/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Bevacizumab/metabolismo , Caspase 3/metabolismo , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Impedância Elétrica , Humanos , Espaço Intracelular/metabolismo , Ranibizumab/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/metabolismo
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