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1.
Pharm Res ; 41(6): 1247-1256, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38839719

RESUMEN

PURPOSE: Wet age-related macular degeneration (AMD) is a blinding retinal disease. Monthly intravitreal anti-VEGF antibody injections of bevacizumab (off-label) and ranibizumab (FDA approved) are the standard of care. Antibody aggregation may interfere with ocular absorption/distribution. This study assessed topical delivery of dilute antibodies to the posterior segment of rabbit eyes using a novel anti-aggregation formula (AAF). METHODS: Bevacizumab, or biosimilar ranibizumab was diluted to 5 mg/ml in AAF. All rabbits were dosed twice daily. Substudy 1 rabbits (bevacizumab, 100 µl eye drops): Group 1 (bevacizumab/AAF, n = 6); Group 2 (bevacizumab/PBS, n = 7) and Vehicle control (AAF, n = 1). Substudy 2 rabbits (ranibizumab biosimilar/AAF, 50 µl eye drops): (ranibizumab biosimilar/AAF, n = 8). At 14.5 days, serum was drawn from rabbits. Aqueous, vitreous and retina samples were recovered from eyes and placed into AAF aliquots. Tissue analyzed using AAF as diluent. RESULTS: Bevacizumab in AAF permeated/accumulated in rabbit aqueous, vitreous and retina 10 times more, than when diluted in PBS. AAF/0.1% hyaluronic acid eye drops, dosed twice daily, provided mean tissue concentrations (ng/g) in retina (29.50), aqueous (12.34), vitreous (3.46), and serum (0.28 ng/ml). Additionally, the highest concentration (ng/g) of ranibizumab biosimilar was present in the retina (18.0), followed by aqueous (7.82) and vitreous (1.47). Serum concentration was negligible (< 0.04 ng/ml). No irritation was observed throughout the studies. CONCLUSIONS: Bevacizumab and ranibizumab, in an AAF diluent eye drop, can be delivered to the retina, by the twice daily dosing of a low concentration mAb formulation. This may prove to be an adjunct to intravitreal injections.


Asunto(s)
Bevacizumab , Soluciones Oftálmicas , Ranibizumab , Retina , Animales , Ranibizumab/administración & dosificación , Ranibizumab/farmacocinética , Conejos , Bevacizumab/administración & dosificación , Bevacizumab/farmacocinética , Soluciones Oftálmicas/administración & dosificación , Retina/metabolismo , Retina/efectos de los fármacos , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/farmacocinética , Cuerpo Vítreo/metabolismo , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inyecciones Intravítreas , Biosimilares Farmacéuticos/administración & dosificación , Biosimilares Farmacéuticos/farmacocinética , Degeneración Macular Húmeda/tratamiento farmacológico
2.
Proc Natl Acad Sci U S A ; 112(5): 1565-70, 2015 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-25605911

RESUMEN

Accumulation of protein- and lipid-containing deposits external to the retinal pigment epithelium (RPE) is common in the aging eye, and has long been viewed as the hallmark of age-related macular degeneration (AMD). The cause for the accumulation and retention of molecules in the sub-RPE space, however, remains an enigma. Here, we present fluorescence microscopy and X-ray diffraction evidence for the formation of small (0.5-20 µm in diameter), hollow, hydroxyapatite (HAP) spherules in Bruch's membrane in human eyes. These spherules are distinct in form, placement, and staining from the well-known calcification of the elastin layer of the aging Bruch's membrane. Secondary ion mass spectrometry (SIMS) imaging confirmed the presence of calcium phosphate in the spherules and identified cholesterol enrichment in their core. Using HAP-selective fluorescent dyes, we show that all types of sub-RPE deposits in the macula, as well as in the periphery, contain numerous HAP spherules. Immunohistochemical labeling for proteins characteristic of sub-RPE deposits, such as complement factor H, vitronectin, and amyloid beta, revealed that HAP spherules were coated with these proteins. HAP spherules were also found outside the sub-RPE deposits, ready to bind proteins at the RPE/choroid interface. Based on these results, we propose a novel mechanism for the growth, and possibly even the formation, of sub-RPE deposits, namely, that the deposit growth and formation begin with the deposition of insoluble HAP shells around naturally occurring, cholesterol-containing extracellular lipid droplets at the RPE/choroid interface; proteins and lipids then attach to these shells, initiating or supporting the growth of sub-RPE deposits.


Asunto(s)
Envejecimiento/metabolismo , Durapatita/metabolismo , Ojo/metabolismo , Epitelio Pigmentado de la Retina/metabolismo , Humanos , Microscopía Fluorescente , Difracción de Rayos X
3.
Cureus ; 13(9): e18192, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34722017

RESUMEN

Purpose This is a retrospective study of primary open-angle glaucoma patients treated with the immunosuppressor FK506 (tacrolimus) after an organ transplant. We assessed whether FK506 might be a potential neuroprotector adjuvant in glaucoma therapy. Patients and methods Organ transplant patients treated with FK506 for one or more years between 2006 and 2017 at the University of Texas Medical Branch (UTMB) were enrolled. Those selected were patients older than or equal to 50 years of age and had an ophthalmological eye examination with or without diagnostic tests for primary open-angle glaucoma (POAG). Sixty-one eligible subjects were included in the study and matched with the non-FK506 control group for age, gender, race, and follow-up visits. Results A lower incidence of POAG was noted in the FK506-treated patients (15%) when compared to the non-FK506 group (22%), though not significant (p=0.34). Among POAG subjects, the average retinal nerve fiber layer (RNFL) thickness decreased at a rate of 1.4 µm per year (p=0.0001) in the non-FK506 control patients versus 0.4 µm per year (p=0.34) in the FK506 patients. The superior and inferior RNFL quadrants in the control non-FK506 group had a thinning of 2.2 µm and 2.3 µm per year, respectively, (p=0.003 and p=0.0001), while in the FK506 patients, there was no significant loss. In addition, RNFL thinning in nasal and temporal quadrant also showed less reduction in FK506-treated subjects but was not statistically significant (p=0.68 and p=0.93). Conclusion FK506 therapy offers a new promising avenue for neuroprotection in POAG patients and needs to be investigated further for use in conjunction with conventional glaucoma treatments.

4.
Transl Vis Sci Technol ; 10(3): 6, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-34003940

RESUMEN

Purpose: Chemical burns due to alkalis cause extensive damage to the ocular surface leading to blindness. Assessment of ocular burn could be challenging due to severe opacity, inflammation, and angiogenesis. Anterior segment optical coherence tomography (AS-OCT) and OCT angiography (OCTA) may provide fast, non-invasive deep tissue visualization of pathology with high sensitivity in conjunction with slit-lamp analysis. Methods: C57-BL/6J mice were anesthetized with ketamine/dexmedetomidine, and corneal alkali burn was induced (n = 6) by placing filter paper soaked in 1-M sodium hydroxide for 30 seconds on the right eye while the left eye was kept as control. Longitudinal imaging was done with AS-OCT/OCTA and fluorescein angiography at various time intervals for 14 days. Results: AS-OCT showed characteristic pathological changes in alkali-burned eyes with high sensitivity. Although OCT/OCTA showed three-dimensional and cross-sectional views of the anterior chamber and angiogenesis, fluorescein angiography showed nascent vessels with active leakage. Corneal swelling progressively increased by 125.26% on day 12 with a high prevalence of epithelial bullae, stromal cysts, stromal splitting, and Descemet's membrane detachment. Neovascularization was noted as early as day 4 in the burned eyes by both methods. Severe corneal opacity and anterior chamber inflammation were also detected by AS-OCT/OCTA. Conclusions: AS-OCT/OCTA is a promising, noninvasive, high-resolution imaging modality that can provide both qualitative and quantitative information regarding deep tissue pathology at a structural level. Translational Relevance: Noninvasive AS-OCT/OCTA and fluorescein methods show promise in clinical pathology evaluation for ocular injury management and prognostic indications, as the early presence of Descemet's membrane detachment and corneal swelling appears to be correlated with the severity and localization of corneal neovascularization.


Asunto(s)
Álcalis , Tomografía de Coherencia Óptica , Animales , Córnea/diagnóstico por imagen , Estudios Transversales , Angiografía con Fluoresceína , Ratones
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