RESUMEN
Subretinal injection (SR injection) is a commonly used method of ocular drug delivery and has been mainly applied for the treatment of neovascular age-associated macular degeneration (nAMD) and sub-macular hemorrhage (SMH) caused by nAMD, as well as various types of hereditary retinopathies (IRD) such as Stargardt's disease (STGD), retinitis pigmentosa (RP), and a series of fundus diseases such as Leber's congenital dark haze (LCA), choroidal defects, etc. The commonly used carriers of SR injection are mainly divided into viral and non-viral vectors. Leber's congenital amaurosis (LCA), choroidal agenesis, and a series of other fundus diseases are also commonly treated using SR injection. The commonly used vectors for SR injection are divided into two categories: viral vectors and non-viral vectors. Viral vectors are a traditional class of SR injection drug carriers that have been extensively studied in clinical treatment, but they still have many limitations that cannot be ignored, such as poor reproduction efficiency, small loading genes, and triggering of immune reactions. With the rapid development of nanotechnology in the treatment of ocular diseases, nanovectors have become a research hotspot in the field of non-viral vectors. Nanocarriers have numerous attractive properties such as low immunogenicity, robust loading capacity, stable structure, and easy modification. These valuable features imply greater safety, improved therapeutic efficacy, longer duration, and more flexible indications. In recent years, there has been a growing interest in nanocarriers, which has led to significant advancements in the treatment of ocular diseases. Nanocarriers have not only successfully addressed clinical problems that viral vectors have failed to overcome but have also introduced new therapeutic possibilities for certain classical disease types. Nanocarriers offer undeniable advantages over viral vectors. This review discusses the advantages of subretinal (SR) injection, the current status of research, and the research hotspots of gene therapy with viral vectors. It focuses on the latest progress of nanocarriers in SR injection and enumerates the limitations and future perspectives of nanocarriers in the treatment of fundus lesions. Furthermore, this review also covers the research progress of nanocarriers in the field of subretinal injection and highlights the value of nanocarrier-mediated SR injection in the treatment of fundus disorders. Overall, it provides a theoretical basis for the application of nanocarriers in SR injection.
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Portadores de Fármacos , Humanos , Animales , Portadores de Fármacos/química , Inyecciones Intraoculares , Retina , Enfermedades de la Retina/terapia , Enfermedades de la Retina/tratamiento farmacológico , Nanopartículas/química , Sistemas de Liberación de Medicamentos/métodos , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Degeneración Macular/terapiaRESUMEN
Purpose: To investigate the intraocular concentration profiles of stem cell factor (SCF)/c-KIT, galectin-1 (GAL-1), and vascular endothelial growth factor (VEGF)-A with regard to retinal disease and treatment response. Methods: The study group included 13 patients with dry age-related macular degeneration (AMD), 196 with neovascular AMD (nAMD), 21 with diabetic macular edema (DME), 10 with retinal vein occlusion (RVO), and 34 normal subjects with cataracts. Aqueous humor levels of SCF, c-KIT, GAL-1, and VEGF-A were analyzed by immunoassay according to disease group and treatment response. Results: Increased aqueous levels of SCF, c-KIT, and GAL-1 were observed in eyes with nAMD (2.67 ± 3.66, 296.84 ± 359.56, and 3945.61 ± 5976.2 pg/mL, respectively), DME (1.64 ± 0.89, 238.80 ± 265.54, and 3701.23 ± 4340.54 pg/mL, respectively), and RVO (4.62 ± 8.76, 509.63 ± 647.58, and 9079.60 ± 11909.20 pg/mL, respectively) compared with controls (1.13 ± 0.24, 60.00 ± 0.00, and 613.27 ± 1595.12 pg/mL, respectively). In the eyes of nAMD, the levels of all three cytokines correlated positively with VEGF-A levels. After intravitreal injections of anti-VEGF agents, the levels of GAL-1 and VEGF-A decreased significantly, whereas those of SCF and c-Kit showed no significant change. Eyes of nAMD patients with improved vision after treatment had significantly lower levels of c-KIT, GAL-1, and VEGF-A at baseline. Conclusions: The intraocular levels of cytokines were significantly elevated in eyes with nAMD, DME, and RVO compared to the controls and they showed different response to anti-VEGF treatment. With this result and their known association with angiogenesis, these cytokines may be potential therapeutic targets for future research.
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Galectina 1 , Proteínas Proto-Oncogénicas c-kit , Factor de Células Madre , Factor A de Crecimiento Endotelial Vascular , Humanos , Galectina 1/metabolismo , Factor de Células Madre/metabolismo , Masculino , Anciano , Femenino , Proteínas Proto-Oncogénicas c-kit/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Persona de Mediana Edad , Humor Acuoso/metabolismo , Anciano de 80 o más Años , Enfermedades de la Retina/metabolismo , Enfermedades de la Retina/tratamiento farmacológico , Edema Macular/metabolismo , Edema Macular/tratamiento farmacológico , Oclusión de la Vena Retiniana/metabolismo , Oclusión de la Vena Retiniana/tratamiento farmacológico , Retinopatía Diabética/metabolismo , Retinopatía Diabética/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Degeneración Macular/metabolismo , Degeneración Macular/tratamiento farmacológico , Inyecciones IntravítreasRESUMEN
BACKGROUND: Topical non-steroidal anti-inflammatory drugs have the potential to reduce treatment burden and improve outcomes of anti-VEGF therapy for a number of retinal disorders, including neovascular age-related macular degeneration, diabetic macular edema, and retinal vein occlusions. In this review, we focused on the advantages of topical bromfenac as an adjunct to intravitreal anti-VEGF therapy in VEGF-driven maculopathies. METHODS: Cochrane Library, PubMed, and EMBASE were systematically reviewed to identify the relevant studies of neovascular age-related macular degeneration, diabetic macular edema, macular edema associated with retinal vein occlusion, myopic choroidal neovascularization, and radiation maculopathy which reported changes in central retinal thickness, visual acuity, and the number of anti-VEGF injections needed when anti-VEGF therapy was combined with topical bromfenac. RESULTS: In total, ten studies evaluating bromfenac as an adjunct to anti-VEGF therapy were identified. Five studies were included in meta-analysis of the number of injections and five studies were included in the analysis of changes in central retinal thickness. A statistically significantly lower number of intravitreal injections (p = 0.005) was required when bromfenac was used as an adjunct to anti-VEGF therapy compared to anti-VEGF monotherapy with pro re nata regimen. At the same time, eyes receiving bromfenac as an adjunct to anti-VEGF therapy demonstrated non-inferior outcomes in central retinal thickness (p = 0.07). Except for one study which reported better visual outcomes with combined treatment, no difference in visual acuity or clinically significant adverse effects were reported. CONCLUSIONS: This literature review and meta-analysis showed that topical bromfenac can be considered as a safe adjunct to anti-VEGF therapy with a potential to reduce the treatment burden with anti-VEGF drugs requiring frequent injections without compromising improvement of central retinal thickness or visual acuity.
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Inhibidores de la Angiogénesis , Antiinflamatorios no Esteroideos , Benzofenonas , Bromobencenos , Factor A de Crecimiento Endotelial Vascular , Humanos , Administración Tópica , Inhibidores de la Angiogénesis/administración & dosificación , Antiinflamatorios no Esteroideos/administración & dosificación , Benzofenonas/administración & dosificación , Bromobencenos/administración & dosificación , Inyecciones Intravítreas , Edema Macular/tratamiento farmacológico , Soluciones Oftálmicas/administración & dosificación , Enfermedades de la Retina/tratamiento farmacológico , Enfermedades de la Retina/fisiopatología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Agudeza VisualRESUMEN
Retinal injury may be exacerbated by iron overload. Astragaloside IV (AS-IV) has potential applications in the food and healthcare industry to promote eye health. We sought to determine the mechanisms responsible for the protective effects of AS-IV on photoreceptor and retinal pigment epithelium cell death induced by iron overload. We conducted in vitro and in vivo experiments involving AS-IV pretreatment. We tested AS-IV for its ability to protect iron-overload mice from retinal injury. In particular, we analyzed the effects of AS-IV on iron overload-induced ferroptosis in 661W and ARPE-19 cells. AS-IV not only attenuated iron deposition and retinal injury in iron-overload mice but also effectively reduced iron overload-induced ferroptotic cell death in 661W and ARPE-19 cells. AS-IV effectively prevented ferroptosis by inhibiting iron accumulation and lipid peroxidation. In addition, inhibiting nuclear factor erythroid 2-related factor 2 (Nrf2) eliminated the protective effect of AS-IV against ferroptosis. The results suggest that ferroptosis might be a significant cause of retinal cell death associated with iron overload. AS-IV provides protection from iron overload-induced ferroptosis, partly by activating the Nrf2 signaling pathway.
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Ferroptosis , Sobrecarga de Hierro , Ratones Endogámicos C57BL , Epitelio Pigmentado de la Retina , Saponinas , Triterpenos , Ferroptosis/efectos de los fármacos , Animales , Triterpenos/farmacología , Triterpenos/uso terapéutico , Saponinas/farmacología , Sobrecarga de Hierro/metabolismo , Sobrecarga de Hierro/tratamiento farmacológico , Ratones , Epitelio Pigmentado de la Retina/efectos de los fármacos , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/patología , Modelos Animales de Enfermedad , Peroxidación de Lípido/efectos de los fármacos , Humanos , Enfermedades de la Retina/prevención & control , Enfermedades de la Retina/metabolismo , Enfermedades de la Retina/patología , Enfermedades de la Retina/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/metabolismo , Western Blotting , Masculino , Hierro/metabolismoRESUMEN
Retinal ischemia-reperfusion (RIR) injury can lead to various retinal diseases. Oxidative stress is considered an important pathological event in RIR injury. Here, we designed and synthesized 34 ocotillol derivatives, then examined their antioxidant and anti-inflammatory capacities; we found that compounds 7 (C24-R) and 8 (C24-S) were most active. To enhance their water solubility, sustained release, and biocompatibility, compounds 7 and 8 were encapsulated into liposomes for in vivo activity and mechanistic studies. In vivo studies indicated that compounds 7 and 8 protected normal retinal structure and physiological function after RIR injury, reversed damage to retinal ganglion cells, and the S-configuration exhibited significantly stronger activity compared with the R-configuration. Mechanistic studies showed that compound 8 exerted a therapeutic effect on RIR injury by activating the Keap1/Nrf2/ARE signaling pathway; compound 7 did not influence this pathway. We also demonstrated that differential isomerization at the C-24 position influenced protection against RIR injury.
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Proteína 1 Asociada A ECH Tipo Kelch , Factor 2 Relacionado con NF-E2 , Daño por Reperfusión , Transducción de Señal , Factor 2 Relacionado con NF-E2/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Animales , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Transducción de Señal/efectos de los fármacos , Antioxidantes/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Retina/efectos de los fármacos , Retina/metabolismo , Retina/patología , Masculino , Ratones , Elementos de Respuesta Antioxidante/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Enfermedades de la Retina/tratamiento farmacológico , Enfermedades de la Retina/metabolismo , Enfermedades de la Retina/patología , Ratones Endogámicos C57BL , HumanosRESUMEN
The vasculature of the retina is exposed to systemic and local factors that have the capacity to induce several retinal vascular diseases, each of which may lead to vision loss. Prostaglandin signaling has arisen as a potential therapeutic target for several of these diseases due to the diverse manners in which these lipid mediators may affect retinal blood vessel function. Previous reports and clinical practices have investigated cyclooxygenase (COX) inhibition by nonsteroidal anti-inflammatory drugs (NSAIDs) to address retinal diseases with varying degrees of success; however, targeting individual prostanoids or their distinct receptors affords more signaling specificity and poses strong potential for therapeutic development. This review offers a comprehensive view of prostanoid signaling involved in five key retinal vascular diseases: retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, retinal occlusive diseases, and uveitis. Mechanistic and clinical studies of these lipid mediators provide an outlook for therapeutic development with the potential to reduce vision loss in each of these conditions.
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Prostaglandinas , Enfermedades de la Retina , Transducción de Señal , Humanos , Prostaglandinas/metabolismo , Enfermedades de la Retina/metabolismo , Enfermedades de la Retina/tratamiento farmacológico , Animales , Vasos Retinianos/metabolismo , Vasos Retinianos/patologíaRESUMEN
Intravitreal injection of biodegradable implant drug carriers shows promise in reducing the injection frequency for neovascular retinal diseases. However, current intravitreal ocular devices have limitations in adjusting drug release rates for individual patients, thereby affecting treatment effectiveness. Accordingly, we developed mesoporous silica nanoparticles (MSNs) featuring a surface that reverse its charge in response to reactive oxygen species (ROS) for efficient delivery of humanin peptide (HN) to retinal epithelial cells (ARPE-19). The MSN core, designed with a pore size of 2.8 nm, ensures a high HN loading capacity 64.4% (w/w). We fine-tuned the external surface of the MSNs by incorporating 20% Acetyl-L-arginine (Ar) to create a partial positive charge, while 80% conjugated thioketal (TK) methoxy polyethylene glycol (mPEG) act as ROS gatekeeper. Ex vivo experiments using bovine eyes revealed the immobilization of Ar-MSNs-TK-PEG (mean zeta potential: 2 mV) in the negatively charged vitreous. However, oxidative stress reversed the surface charge to -25 mV by mPEG loss, facilitating the diffusion of the nanoparticles impeded with HN. In vitro studies showed that ARPE-19 cells effectively internalize HN-loaded Ar-MSNs-TK, subsequently releasing the peptide, which offered protection against oxidative stress-induced apoptosis, as evidenced by reduced TUNEL and caspase3 activation. The inhibition of retinal neovascularization was further validated in an in vivo oxygen-induced retinopathy (OIR) mouse model.
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Nanopartículas , Especies Reactivas de Oxígeno , Neovascularización Retiniana , Dióxido de Silicio , Animales , Dióxido de Silicio/química , Especies Reactivas de Oxígeno/metabolismo , Humanos , Nanopartículas/química , Bovinos , Neovascularización Retiniana/tratamiento farmacológico , Línea Celular , Porosidad , Sistemas de Liberación de Medicamentos , Portadores de Fármacos/química , Ratones , Polietilenglicoles/química , Ratones Endogámicos C57BL , Apoptosis/efectos de los fármacos , Enfermedades de la Retina/tratamiento farmacológicoRESUMEN
PURPOSE: Bietti crystalline dystrophy (BCD) is an inherited retinal degeneration disease caused by mutations in the CYP4V2 gene. Currently, there is no clinical therapy approach available for BCD patients. Previous research has suggested that polyunsaturated fatty acids (PUFAs) may play a significant role in the development of BCD, implicating the involvement of ferroptosis in disease pathogenesis. In this work, we aimed to investigate the interplay between ferroptosis and BCD and to detect potential therapeutic strategies for the disease. METHODS: Genetic-edited RPE cell line was first established in this study by CRISPR-Cas9 technology. Cyp4v3 (the homologous gene of human CYP4V2) knock out (KO) mice have also been used. Lipid profiling and transcriptome analysis of retinal pigment epithelium (RPE) cells from Cyp4v3 KO mice have been conducted. Ferroptosis phenotypes have been first investigated in BCD models in vitro and in vivo, including lipid peroxidation, mitochondrial changes, elevated levels of reactive oxygen species (ROS), and altered gene expression. Additionally, an iron chelator, deferiprone (DFP), has been tested in vitro and in vivo to determine its efficacy in suppressing ferroptosis and restoring the BCD phenotype. RESULTS: Cyp4v3 KO mice exhibited progressive retinal degeneration and lipid accumulation, similar to the BCD phenotype, which was exacerbated by a high-fat diet (HFD). Increased levels of PUFAs, such as EPA (C22:5) and AA (C20:4), were observed in the RPE of Cyp4v3 KO mice. Transcriptome analysis of RPE in Cyp4v3 KO mice revealed changes in genes involved in iron homeostasis, particularly an upregulation of NCOA4, which was confirmed by immunofluorescence. Ferroptosis-related characteristics, including mitochondrial defects, lipid peroxidation, ROS accumulation, and upregulation of related genes, were detected in the RPE both in vitro and in vivo. Abnormal accumulation of ferrous iron was also detected. DFP, an iron chelator administration suppressed ferroptosis phenotype in CYP4V2 mutated RPE. Oral administration of DFP also restored the retinal function and morphology in Cyp4v3 KO mice. CONCLUSION: This study represented the first evidence of the substantial role of ferroptosis in the development of BCD. PUFAs resulting from CYP4V2 mutation may serve as substrates for ferroptosis, potentially working in conjunction with NCOA4-regulated iron accumulation, ultimately leading to RPE degeneration. DFP administration, which chelates iron, has demonstrated its ability to reverse BCD phenotype both in vitro and in vivo, suggesting a promising therapeutic approach in the future.
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Distrofias Hereditarias de la Córnea , Ferroptosis , Ratones Noqueados , Epitelio Pigmentado de la Retina , Animales , Ferroptosis/genética , Ferroptosis/efectos de los fármacos , Distrofias Hereditarias de la Córnea/genética , Distrofias Hereditarias de la Córnea/patología , Distrofias Hereditarias de la Córnea/metabolismo , Distrofias Hereditarias de la Córnea/tratamiento farmacológico , Humanos , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/patología , Epitelio Pigmentado de la Retina/efectos de los fármacos , Ratones , Especies Reactivas de Oxígeno/metabolismo , Enfermedades de la Retina/genética , Enfermedades de la Retina/patología , Enfermedades de la Retina/metabolismo , Enfermedades de la Retina/tratamiento farmacológico , Familia 4 del Citocromo P450/genética , Ratones Endogámicos C57BL , Línea Celular , Peroxidación de Lípido/efectos de los fármacosRESUMEN
BackgroundRetinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare, autosomal dominant, universally fatal disease without effective treatment options. This study explores the safety and preliminary efficacy of crizanlizumab, a humanized monoclonal antibody against P-selectin approved for the prevention of sickle cell crises, in slowing retinal nonperfusion and preserving vision in patients with RVCL-S.METHODSEleven patients with RVCL-S with confirmed exonuclease 3 prime repair exonuclease 1 (TREX1) mutations received monthly crizanlizumab infusions over 2 years. The study measured the nonperfusion index within 3 retinal zones and the total retina with fluorescein angiography, visual acuity, intraocular pressure (IOP), and optical coherence tomography central subfield thickness (CST) at baseline, 1 year, and 2 years. A mixed repeated-measures analysis was performed to assess the progression rates and changes from baseline.RESULTSEleven participants received crizanlizumab infusions. All of the participants tolerated crizanlizumab well, with 8 of 11 (72.7%) reporting mild adverse effects such as nausea, fatigue, and gastrointestinal symptoms. The change in total retinal nonperfusion was 7.22% [4.47, 9.97] in year 1 and -0.69% [-4.06, 2.68] in year 2 (P < 0.001). In the mid periphery, the change in nonperfusion was 10.6% [5.1, 16.1] in year 1 and -0.68% [-3.98, 5.35] in year 2 (P < 0.01), demonstrating a reduction in progression of nonperfusion in the second year of treatment. Visual acuity, IOP, and CST remained stable.CONCLUSIONCrizanlizumab has an acceptable safety profile. These results show promising potential for examining crizanlizumab in larger studies of RVCL-S and similar small-vessel diseases and for using the retina as a biomarker for systemic disease.Trial registrationClinicalTrials.gov NCT04611880.FUNDINGThe Clayco Foundation; DeNardo Education and Research Foundation Grant; Jeffrey T. Fort Innovation Fund; Siteman Retina Research Fund; unrestricted grant from Research to Prevent Blindness Inc.; National Heart,Lung, and Blood Institute (NHLBI), NIH (R01HL129241); National Institute of Neurological Disorders and Stroke (NINDS), NIH (RF1NS116565).
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Anticuerpos Monoclonales Humanizados , Humanos , Masculino , Femenino , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Persona de Mediana Edad , Leucoencefalopatías/tratamiento farmacológico , Exodesoxirribonucleasas/genética , Enfermedades de la Retina/tratamiento farmacológico , FosfoproteínasRESUMEN
INTRODUCTION: SB11 (Byooviz™; Samsung Bioepis Co., Ltd.) is a ranibizumab (Lucentis®; Genentech, Inc.) biosimilar targeting vascular endothelial growth factor A for the treatment of retinal diseases. The pre-filled syringe (PFS) presentation of SB11 offers an alternative administration method to the vial, with the potential for enhanced safety and efficient syringe preparation. The objective of this study was to assess the ability of healthcare professionals (HCPs) to follow the instructions for use to prepare and administer SB11 PFS intravitreal (IVT) injections to patients with neovascular age-related macular degeneration (nAMD) or macular edema secondary to retinal vein occlusion (RVO). METHODS: This study was an open-label, single-arm, single-dose clinical study to evaluate the usability of the SB11 PFS in patients with nAMD or macular edema secondary to RVO. Four HCPs prepared and administered 0.5 mg SB11 PFS IVT injections to 34 patients. Product use task completion (12 tasks in total) was assessed by independent observers. Safety was assessed up to 7 days after injection of the investigational product. RESULTS: A total of 34 patients were enrolled and completed the study. All 12 tasks were successfully completed in 34 (100%) patients without a use-related failure. Most patients (32 patients, 94.1%) experienced no adverse events (AEs), whereas 2 (5.9%) patients experienced three treatment-emergent AEs (TEAEs) which were mild to moderate in severity. There were no severe or serious TEAEs reported during the study. CONCLUSIONS: This study showed that HCPs were able to successfully prepare and administer the SB11 PFS via IVT injection. No unexpected safety issues were identified. The SB11 PFS is a promising alternative for therapeutic administration of SB11 in patients with retinal disease. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT06176963; EudraCT number 2021-003566-12.
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Inyecciones Intravítreas , Edema Macular , Ranibizumab , Oclusión de la Vena Retiniana , Jeringas , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/efectos adversos , Biosimilares Farmacéuticos/uso terapéutico , Biosimilares Farmacéuticos/administración & dosificación , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/complicaciones , Edema Macular/tratamiento farmacológico , Edema Macular/etiología , Ranibizumab/administración & dosificación , Ranibizumab/uso terapéutico , Enfermedades de la Retina/tratamiento farmacológico , Oclusión de la Vena Retiniana/tratamiento farmacológico , Oclusión de la Vena Retiniana/complicacionesRESUMEN
Importance: Anti-vascular endothelial growth factor (VEGF) intravitreal injections, a mainstay of treatment for many retinal diseases to optimize visual outcomes, have been included in prior authorization (PA) initiatives. However, if clinicians are extremely accurate in their use of anti-VEGF medications, such administrative burdens may need reconsideration. Objective: To quantify PA for anti-VEGF medications (aflibercept, ranibizumab, and bevacizumab) that were approved and determine associated administrative burdens experienced by retina practices. Design, Setting, and Participants: Prospective multicenter quality improvement study conducted from January 2022 through June 2022, and participants were 9 private retina practices across the US. Main Outcomes and Measures: Overall rate of approval of PA requests, reasons for requesting PA, and overall rate of delay of care resulting from PA procedures. Results: In total, 2365 PA requests were recorded, 2225 of which met inclusion criteria. Overall, 2140 (96.2%) requests were approved. The most common reason for requesting PA, at 64% (1423 of 2225 requests), was reauthorization for a previously utilized medication. Of the 2140 approvals, 59.6% (1277) resulted in a delay in care greater than 24 hours, and 40% (863) were given on the date of service. In a granular analysis of a subset of delayed approvals, 23.9% (173 of 725) were approved within 1 day, 15.9% (115 of 725) were approved within 2 to 3 days, 21.5% (156 of 725) were approved within 4 to 7 days, 26.3% (191 of 725) were approved within 8 to 31 days, and 12.4% (90 of 725) were approved within more than 31 days. Overall, PA denial for step therapy was 2.9% (65 of 2225) of requests and uncovered diagnoses was 0.9% (20 of 2225) of requests. The median staff time spent to obtain a single PA was 100 (range, 0-200) minutes. Conclusions and Relevance: In this study, PA requests were almost always approved but led to a delay in patient care in most patients. The current study suggests that the PA process may not be effective for retina specialists if these results can be generalized to other practices in the US and if less burdensome and less costly approaches could result in similar approval rates. Potential short-term solutions may include eliminating the PA process for bevacizumab and reauthorizations for established patients.
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Inhibidores de la Angiogénesis , Bevacizumab , Inyecciones Intravítreas , Autorización Previa , Ranibizumab , Receptores de Factores de Crecimiento Endotelial Vascular , Proteínas Recombinantes de Fusión , Enfermedades de la Retina , Factor A de Crecimiento Endotelial Vascular , Humanos , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Bevacizumab/uso terapéutico , Bevacizumab/administración & dosificación , Estudios Prospectivos , Proteínas Recombinantes de Fusión/uso terapéutico , Ranibizumab/uso terapéutico , Ranibizumab/administración & dosificación , Enfermedades de la Retina/tratamiento farmacológico , Autorización Previa/estadística & datos numéricos , Mejoramiento de la Calidad , Estados UnidosRESUMEN
The complement cascade is a vital system in the human body's defense against pathogens. During the natural aging process, it has been observed that this system is imperative for ensuring the integrity and homeostasis of the retina. While this system is critical for proper host defense and retinal integrity, it has also been found that dysregulation of this system may lead to certain retinal pathologies, including geographic atrophy and diabetic retinopathy. Targeting components of the complement system for retinal diseases has been an area of interest, and in vivo, ex vivo, and clinical trials have been conducted in this area. Following clinical trials, medications targeting the complement system for retinal disease have also become available. In this manuscript, we discuss the pathophysiology of complement dysfunction in the retina and specific pathologies. We then describe the results of cellular, animal, and clinical studies targeting the complement system for retinal diseases. We then provide an overview of complement inhibitors that have been approved by the Food and Drug Administration (FDA) for geographic atrophy. The complement system in retinal diseases continues to serve as an emerging therapeutic target, and further research in this field will provide additional insights into the mechanisms and considerations for treatment of retinal pathologies.
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Proteínas del Sistema Complemento , Enfermedades de la Retina , Humanos , Enfermedades de la Retina/tratamiento farmacológico , Enfermedades de la Retina/fisiopatología , Enfermedades de la Retina/inmunología , Proteínas del Sistema Complemento/fisiología , Animales , Inactivadores del Complemento/uso terapéutico , Inactivadores del Complemento/farmacología , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/fisiopatología , Retina/efectos de los fármacos , Retina/inmunologíaRESUMEN
PURPOSE: To report a case of progressive ischemic retinopathy and optic neuropathy in a patient with heavy chain deposition disease (HCDD), a rare form of monoclonal immunoglobulin deposition disease (MIDD). OBSERVATIONS: Our case describes a 74-year-old woman diagnosed with IgG1 lambda HCDD. After treatment with daratumumab and intravenous IVIG therapy, the patient developed worsening ischemic retinopathy and optic neuropathy, neovascular glaucoma, and bilateral sequential vitreous hemorrhages, necessitating surgical intervention. We present multimodal imaging from the onset of ischemic retinopathy to end-stage maculopathy illustrated by optical coherence tomography (OCT) angiography. Despite discontinuing treatment with daratumumab and providing maximal ocular interventions to control the complications of neovascular disease, the patient's condition progressed, resulting in profound vision loss. CONCLUSIONS AND IMPORTANCE: Our case illustrates the potential for HCDD to cause end-organ disease, including ischemic retinopathy and optic neuropathy, possibly worsened by the patient's underlying cardiovascular risk factor status and medications. Daratumumab, a humanized IgG1 kappa monoclonal antibody that binds to CD38 used to treat specific blood cancers, has been reported to cause disturbances in retinal blood flow, including retinal artery and vein occlusions. It remains to be determined whether careful patient selection or dose adjustments and timing of HCDD treatments could protect vision by reducing the risk of these rare yet severe ocular complications.
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Angiografía con Fluoresceína , Enfermedades de la Retina , Tomografía de Coherencia Óptica , Humanos , Femenino , Anciano , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/tratamiento farmacológico , Neuropatía Óptica Isquémica/diagnóstico , Neuropatía Óptica Isquémica/tratamiento farmacológico , Neuropatía Óptica Isquémica/etiología , Inmunoglobulina G/sangre , Isquemia/diagnóstico , Isquemia/tratamiento farmacológico , Agudeza Visual , Fondo de Ojo , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Enfermedad Relacionada con Inmunoglobulina G4/complicaciones , Enfermedad Relacionada con Inmunoglobulina G4/tratamiento farmacológico , Enfermedades del Nervio Óptico/diagnóstico , Enfermedades del Nervio Óptico/tratamiento farmacológico , Enfermedades del Nervio Óptico/etiología , Anticuerpos Monoclonales/uso terapéuticoRESUMEN
OBJECTIVE: Aim: To showcase a rare retinal lesion and the results of contemporary diagnostic and treatment of interferon-induced retinopathy. PATIENTS AND METHODS: Materials and Methods: We describe a case of a 36-year-old patient with interferon-induced retinopathy, with hepatitis C, that received prolonged interferon treatment. Clinical signs, examination and combined laser and pharmacologic treatment were showcased in the study. RESULTS: Results: As a result of pharmacologic and laser treatment, the patient's visual acuity increased from 0.1 to 1.0 through the duration of 3 months after treatment. The patients` condition remained stable under dynamic observation. CONCLUSION: Conclusions: Because interferon-induced retinopathy is a rare occurrence in routine ophthalmologic practice, combined laser therapy can be used for treatment of preretinal hemorrhage, which leads to improvement of visual functions and stabilization of the retinal processes. This case is an addition to the few described cases of interferon-induced retinopathy.
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Enfermedades de la Retina , Humanos , Adulto , Enfermedades de la Retina/inducido químicamente , Enfermedades de la Retina/tratamiento farmacológico , Masculino , Agudeza Visual , Antivirales/efectos adversos , Antivirales/uso terapéutico , Interferones/efectos adversos , Interferones/uso terapéutico , Resultado del Tratamiento , Hepatitis C/tratamiento farmacológico , Hepatitis C/complicacionesRESUMEN
Recent studies have highlighted the indispensable role of oxidized lipids in inflammatory responses, cell death, and disease pathogenesis. Consequently, inhibitors targeting oxidized lipids, particularly lipid-derived radicals critical in lipid peroxidation, which are known as radical-trapping antioxidants (RTAs), have been actively pursued. We focused our investigation on nitroxide compounds that have rapid second-order reaction rate constants for reaction with lipid-derived radicals. A novel screening system was developed by employing competitive reactions between library compounds and a newly developed profluorescence nitroxide probe with lipid-derived radicals to identify RTA compounds. A PubMed search of the top hit compounds revealed their wide application as repositioned drugs. Notably, the inhibitory efficacy of methyldopa, selected from these compounds, against retinal damage and bilateral common carotid artery stenosis was confirmed in animal models. These findings underscore the efficacy of our screening system and suggest that it is an effective approach for the discovery of RTA compounds.
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Antioxidantes , Peroxidación de Lípido , Animales , Humanos , Antioxidantes/farmacología , Antioxidantes/química , Peroxidación de Lípido/efectos de los fármacos , Enfermedades de la Retina/tratamiento farmacológico , Enfermedades de la Retina/metabolismo , Trastornos Cerebrovasculares/tratamiento farmacológico , Trastornos Cerebrovasculares/metabolismo , Radicales Libres/metabolismo , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Ratones , Lípidos/químicaRESUMEN
INTRODUCTION: Retinal drug delivery has witnessed significant advancements in recent years, mainly driven by the prevalence of retinal diseases and the need for more efficient and patient-friendly treatment strategies. AREAS COVERED: Advancements in nanotechnology have introduced novel drug delivery platforms to improve bioavailability and provide controlled/targeted delivery to specific retinal layers. This review highlights various treatment options for retinal diseases. Additionally, diverse strategies aimed at enhancing delivery of small molecules and antibodies to the posterior segment such as implants, polymeric nanoparticles, liposomes, niosomes, microneedles, iontophoresis and mixed micelles were emphasized. A comprehensive overview of the special technologies currently under clinical trials or already in the clinic was provided. EXPERT OPINION: Ideally, drug delivery system for treating retinal diseases should be less invasive in nature and exhibit sustained release up to several months. Though topical administration in the form of eye drops offers better patient compliance, its clinical utility is limited by nature of the drug. There is a wide range of delivery platforms available, however, it is not easy to modify any single platform to accommodate all types of drugs. Coordinated efforts between ophthalmologists and drug delivery scientists are necessary while developing therapeutic compounds, right from their inception.
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Sistemas de Liberación de Medicamentos , Enfermedades de la Retina , Humanos , Enfermedades de la Retina/tratamiento farmacológico , Animales , Nanotecnología , Disponibilidad Biológica , Soluciones Oftálmicas/administración & dosificación , Administración Oftálmica , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones de Acción Retardada , NanopartículasRESUMEN
BACKGROUND: Retinal diseases significantly contribute to the global burden of visual impairment and blindness. The occurrence of retinal diseases is often accompanied by destruction of the bloodâretinal barrier, a vital physiological structure responsible for maintaining the stability of the retinal microenvironment. However, detailed summaries of the factors damage the bloodâretinal barrier and treatment methods involving natural plant medications are lacking. PURPOSE: To comprehensively summarize and analyze the protective effects of active substances in natural plant medications on damage to the blood-retina barrier that occurs when retinal illnesses, particularly diabetic retinopathy, and examine their medicinal value and future development prospects. METHODS: In this study, we searched for studies published in the ScienceDirect, PubMed, and Web of Science databases. The keywords used included natural plant medications, plants, natural herbs, blood retinal barrier, retinal diseases, diabetic retinopathy, age-related macular degeneration, and uveitis. Chinese herbal compound articles, non-English articles, warning journals, and duplicates were excluded from the analysis. RESULTS: The bloodâretinal barrier is susceptible to high glucose, aging, immune responses, and other factors that destroy retinal homeostasis, resulting in pathological changes such as apoptosis and increased vascular permeability. Existing studies have shown that the active compounds or extracts of many natural plants have the effect of repairing blood-retinal barrier dysfunction. Notably, berberine, puerarin, and Lycium barbarum polysaccharides exhibited remarkable therapeutic effects. Additionally, curcumin, astragaloside IV, hesperidin, resveratrol, ginsenoside Rb1, luteolin, and Panax notoginseng saponins can effectively protect the bloodâretinal barrier by interfering with distinct pathways. The active ingredients found in natural plant medications primarily repair the bloodâretinal barrier by modulating pathological factors such as oxidative stress, inflammation, pyroptosis, and autophagy, thereby alleviating retinal diseases. CONCLUSION: This review summarizes a series of plant extracts and plant active compounds that can treat retinal diseases by preventing and treating bloodâretinal barrier damage and provides reference for the research of new drugs for treating retinal diseases.
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Barrera Hematorretinal , Enfermedades de la Retina , Barrera Hematorretinal/efectos de los fármacos , Humanos , Animales , Enfermedades de la Retina/tratamiento farmacológico , Retinopatía Diabética/tratamiento farmacológico , Fitoterapia , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Plantas Medicinales/químicaRESUMEN
PURPOSE: This review investigates the therapeutic benefits of interferons (IFNs) in vitreoretinal diseases, focusing on their regulatory roles in innate immunological reactions and angiogenesis. The study aims to categorize the clinical outcomes of IFN applications and proposes a molecular mechanism underlying their action. METHODS: A systematic review was conducted using MEDLINE/PubMed, Web of Science, EMBASE, and Google Scholar databases to identify randomized clinical trials, case series, and case-control studies related to IFNs' impact on vitreoretinal diseases (1990-2022). The data synthesis involved an in-depth analysis of the anti-inflammatory and anti-angiogenesis effects of IFNs across various studies. RESULTS: Our findings indicate that IFNs exhibit efficacy in treating inflammation-associated vitreoretinal disorders. However, a lack of sufficient evidence exists regarding the suitability of IFNs in angiogenesis-associated vitreoretinal diseases like choroidal neovascularization and diabetic retinopathies. The synthesis of data suggests that IFNs may not be optimal for managing advanced stages of angiogenesis-associated disorders. CONCLUSION: While IFNs emerge as promising therapeutic candidates for inflammation-related vitreoretinal diseases, caution is warranted in their application for angiogenesis-associated disorders, especially in advanced stages. Further research is needed to elucidate the nuanced molecular pathways of IFN action, guiding their targeted use in specific vitreoretinal conditions.
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Interferones , Humanos , Interferones/uso terapéutico , Enfermedades de la Retina/tratamiento farmacológico , Cuerpo VítreoRESUMEN
Increased cellular senescence burden contributes in part to age-related organ dysfunction and pathologies. In our study, using mouse models of natural aging, we observed structural and functional decline in the aged retina, which was accompanied by the accumulation of senescent cells and senescence-associated secretory phenotype factors. We further validated the senolytic and senomorphic properties of procyanidin C1 (PCC1) both in vitro and in vivo, the long-term treatment of which ameliorated age-related retinal impairment. Through high-throughput single-cell RNA sequencing (scRNA-seq), we comprehensively characterized the retinal landscape after PCC1 administration and deciphered the molecular basis underlying the senescence burden increment and elimination. By exploring the scRNA-seq database of age-related retinal disorders, we revealed the role of cellular senescence and the therapeutic potential of PCC1 in these pathologies. Overall, these results indicate the therapeutic effects of PCC1 on the aged retina and its potential use for treating age-related retinal disorders.