Dose-Related Side Effects of Intravitreal Injections of Humanized Anti-Vascular Endothelial Growth Factor in Rats: Glial Cell Reactivity and Retinal Ganglion Cell Loss.

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.

Switching to the aflibercept (3 mg) therapy for treatment-resistant wet age-related macular degeneration: 1-year outcomes.

This study aimed to elucidate 1-year outcomes following switching to the aflibercept (3 mg) therapy for treatment-resistant wet age-related macular degeneration (wAMD). In this prospective, open-label, non-controlled clinical trial, 18 patients with wAMD who had multiple recurrences or persistent exudation despite intravitreal injections of anti-vascular endothelial growth factor agents (except aflibercept) received a 3-mg intravitreal aflibercept injection every 4 weeks. Each patient received 3 to 8 injections. The central retinal thickness and fibrovascular pigment epithelial detachment height decreased significantly at 1 month after initiation of the aflibercept injection, and the values were 146 and 163.2 µm, respectively, at the final visit. The morphological improvement was sustained. The intraretinal and subretinal fluid was completely absorbed at the end of the follow-up. The logMAR vision increased from baseline 0.68 to 0.59 (P < .05). No ocular or systemic adverse events occurred. The intravitreal injection of 3-mg aflibercept seems to be feasible in the treatment of wAMD unresponsive to other anti-vascular endothelial growth factor agents.

High-fat diet promotes coagulation and endothelial activation in Sprague Dawley rats: Short-term effects of combined oral contraceptives / Dieta alta en grasas promueve la coagulación y la activación endotelial en ratas Sprague Dawley: efectos a corto plazo de los anticonceptivos orales combinados

Background Combined oral contraceptives (COCs), use in individuals are associated with increased risk of thrombotic events. This highlights the significance of assessing the impact of COC on promoting coagulation and endothelial activation in high-fat diet (HFD)-fed Sprague Dawley rats. Methods Twenty (20) five-weeks-old female Sprague Dawley rats weighing between 150 and 200g were subjected to both LFD and HFD-feeding for 8-weeks to determine its influence on basic metabolic status, hemostatic profile, hemodynamic parameters (blood pressure and heart rate), as well as selected biomarkers of coagulation (tissue factor and D-dimer) and endothelial activation (Von Willebrand factor and nitric oxide). Thereafter HFD-fed animals were treated with receive high dose combined oral contraceptive (HCOC) and low dose combine oral contraceptive (LCOC) for 6 weeks. Results Our results showed that beyond weight gain, HFD-feeding was associated with hyperglycemia, increased mean arterial pressure, and reduced nitric oxide levels when compared with LFD group (p<0.05). Interestingly, treatment with high dose of COC for 6-weeks did not significantly alter atherothrombotic markers (p>0.05). However, this study is not without limitation as regulation of these markers remains to be confirmed within the cardiac tissues or endothelial cells of these animals. Conclusion HFD-feeding orchestrate the concomitant release of pro-coagulants and endothelial activation markers in rats leading to haemostatic imbalance and endothelial dysfunction. Short-term treatment with COC shows no detrimental effects in these HFD-fed rats. Although in terms of clinical relevance, our findings depict the notion that the risk of CVD in association with COC may depend on the dosage and duration of use among other factors especially in certain conditions. ... (AU)

Antecedentes El uso de anticonceptivos orales combinados (AOC) en individuos se asocia con un mayor riesgo de eventos trombóticos. Esto resalta la importancia de evaluar el impacto de los AOC en la promoción de la coagulación y la activación endotelial en ratas Sprague Dawley alimentadas con una dieta alta en grasas (HFD). Métodos Veinte (20) ratas Sprague Dawley hembra de 5semanas de edad con un peso entre 150-200g fueron tratadas mediante una alimentación con dieta baja en grasas (LFD) y alta en grasas (HFD) durante 8 semanas para determinar su influencia en el estado metabólico básico, perfil hemostático, parámetros hemodinámicos (presión arterial y frecuencia cardíaca), así como biomarcadores seleccionados de coagulación (factor tisular y D-dímero) y activación endotelial (factor de von Willebrand y óxido nítrico). Posteriormente, los animales alimentados con HFD fueron tratados con dosis alta de anticonceptivo oral combinado (AOC-AL) y dosis baja de anticonceptivo oral combinado (AOC-BL) durante 6 semanas. Resultados Nuestros resultados mostraron que, además del aumento de peso, la alimentación con HFD se asoció con hiperglucemia, aumento de la presión arterial media y niveles reducidos de óxido nítrico en comparación con el grupo LFD (p<0,05). Curiosamente, el tratamiento con dosis alta de AOC durante 6 semanas no alteró significativamente los marcadores aterotrombóticos (p>0,05). Sin embargo, este estudio no está exento de limitaciones, ya que la regulación de estos marcadores aún debe confirmarse en los tejidos cardíacos o las células endoteliales de estos animales. Conclusión La alimentación con HFD orquesta la liberación concomitante de procoagulantes y marcadores de activación endotelial en ratas, lo que conduce a un desequilibrio hemostático y disfunción endotelial. El tratamiento a corto plazo con AOC no muestra efectos perjudiciales en estas ratas alimentadas con HFD. ... (AU)

Association between the response of intravitreal antivascular endothelial growth factor injection and systemic factors of diabetic macular edema.

BACKGROUND: This study investigated the effects of systemic factors in response to intravitreal injections in patients with macular edema due to non-proliferative diabetic retinopathy (NPDR). METHODS: We retrospectively reviewed the medical records of patients treated with intravitreal injections for macular edema secondary to NPDR between January 2018 and January 2021. The patients were divided into three groups according to the injection response. When patients with diabetic macular edema showed 20µ or more reduction in central retinal thickness compared to baseline, they were classified as responsive group, and if not, they were classified as refractory group. The responsive group was further divided into the complete and incomplete response groups. Patients with complete disappearance of edema at seven months were classified as the complete response group, whereas those in which edema did not disappear were classified as the incomplete response group. The clinical characteristics of each group, including medical history, ophthalmic examination results, and laboratory examination results at the time of diagnosis, were analyzed. RESULTS: Of the 112 eyes (91 patients) that satisfied the inclusion criteria, 89 (77 patients) in the responsive group and 23 (14 patients) in the refractory group were included in the analysis. The responsive group was further divided into the complete (51 eyes) and incomplete (38 eyes) response groups. The refractory group had significantly higher glycated hemoglobin levels and significantly lower estimated glomerular filtration rates than the responsive group (p = 0.026 and p = 0.012, respectively). In the multivariate logistic regression analysis, both factors were found to be significant in predicting the degree of response (all p < 0.05). No factor showed a significant difference between the incomplete and complete response groups(all p > 0.05). CONCLUSIONS: In macular edema caused by NPDR, low glomerular filtration rates and high glycated hemoglobin levels may be used as predictors of poor response to intravitreal injection therapy. In addition to blood glucose control, education should be provided regarding the need for the continuous monitoring of renal function.

The role of endothelial growth factor and tear levels in diabetic retinopathy in type 2 diabetes.

PURPOSE: To evaluate the tear level of VEGF and the quantity of tear film in type 2 diabetic patients. METHODS: Thirty patients with diabetic retinopathy (DR group) and 30 patients with no DR (NDR group), and 30 healthy subjects with age and gender matching were enrolled in this prospective comparative study. The tear samples were collected using the Schirmer strips, and the amount of moisture absorbed by the strips was used to determine the quantitative level of the tear film. The concentration of VEGF in the tear samples was measured using the enzyme-linked immunosorbent assay method. The variables were compared with an independent t-test and covariance analysis. RESULTS: Mean tear level of VEGF was significantly higher in DR group (235.42 pg/ml) compared to NDR (75.11 pg/ml) and control (58.77 pg/ml) groups (P ≤ 0.001). There was no significant difference in the mean of VEGF between NDR and control patients (P = 1.00). Mean quantitative tear film levels were 7.15%, 9.72%, and 15.11% in DR, NDR, and healthy subjects, respectively (P < 0.05). The pairwise analysis showed significant differences in the level of VEGF between DR and both NDR (P = 0.001) and normal (P = 0.017) groups. However, there was no significant difference observed between NDR and normal eyes (P = 0.743). CONCLUSION: The VEGF level in tear was higher in diabetic patients with DR, independent of tear volume. The tear VEGF measurement can be used as a valuable predictor to prevent DR in diabetic patients.

Long-term outcomes of anti-vascular endothelial growth factor therapy with and without posterior scleral reinforcement on myopic maculopathy in myopic choroidal neovascularization eyes.

BACKGROUND: Anti-vascular endothelial growth factor (anti-VEGF) therapy is used for myopic choroidal neovascularization (mCNV). Patchy chorioretinal atrophy (pCRA) enlargement has been reported in mCNV cases associated with vision loss. Our aim was to compare the long-term effectiveness of anti-VEGF therapy alone versus anti-VEGF followed by posterior scleral reinforcement (PSR) in controlling myopic maculopathy in mCNV eyes. METHODS: We performed a retrospective review of the medical records of 95 high myopia patients (refractive error ≥ 6.00 diopters, axial length ≥ 26.0 mm) with mCNV. Patients were treated with anti-VEGF alone (group A) or anti-VEGF followed by PSR (group B). The following data were collected: refractive error, best corrected visual acuity (BCVA), ophthalmic fundus examination, ocular coherence tomography and ocular biometry at 12 and 24 months pre- and postoperatively. The primary outcomes were changes in pCRA and BCVA. RESULTS: In 26 eyes of 24 patients, the mean pCRA size significantly increased from baseline (0.88 ± 1.69 mm2) to 12 months (1.57 ± 2.32 mm2, t = 3.249, P = 0.003) and 24 months (2.17 ± 2.79 mm2, t = 3.965, P = 0.001) postoperatively. The increase in perilesional pCRA in group B (n = 12) was 98.2% and 94.2% smaller than that in group A (n = 14) at 12 and 24 months (Beta 0.57 [95% CI 0.01, 191 1.13], P = 0.048). In group B, 7 eyes (58.3%) gained more than 2 lines of BCVA compared with only 4 eyes (28.6%) in group A at 24 months. CONCLUSION: Anti-VEGF therapy followed by PSR achieved better outcomes than anti-VEGF therapy alone in controlling the development of myopic maculopathy in mCNV and may constitute a better treatment option by securing a better long-term VA outcome.

Subthreshold micropulse diode laser treatment in diabetic macular edema: biological impact, therapeutic effects, and safety.

PURPOSE: To introduce the treatment of diabetic macular edema (DME) with subthreshold micropulse diode laser (SMPL), to summarize the biological impact, therapeutic effects, and safety of this treatment, and to discuss the response to DME when SMPL is combined with anti-vascular endothelial growth factor (anti-VEGF) or steroid. METHODS: The literature search was performed on the PubMed database, with a selection of English-language articles published from 2000 to 2023 with the following combinations of search terms: diabetes macular (o) edema, micropulse laser or subthreshold micropulse laser, anti-vascular endothelial growth factor, and steroid. RESULTS: SMPL is a popular, invisible retinal laser phototherapy that is inexpensive, safe, and effective in the treatment of DME. It can selectively target the retinal pigment epithelium, reduce the expression of pro-inflammatory factors, promote the absorption of macular edema, and exert a similar and lasting clinical effect to traditional lasers. No significant difference was found in the therapeutic effects of SMPL between different wavelengths. However, HbA1c level and pretreatment central macular thickness (CMT) may affect the therapeutic outcomes of SMPL. CONCLUSION: SMPL has a slow onset and produces lasting clinical effects similar to conventional photocoagulation. It has been reported that SMPL combined with the intravitreal anti-VEGF injection can significantly reduce the number of injections without influencing the therapeutic effect, which is essential for clinical applications and research. Although 577 nm SMPL is widely used clinically, there are no standardized protocols for SMPL. Additionally, some important problems regarding the treatment of SMPL require further discussion and exploration.

Enhanced durability and evolution of retreatment criteria of intravitreal antivascular endothelial growth factor agents for diabetic macular edema.

PURPOSE OF REVIEW: The increasing prevalence of diabetic macular edema (DME) necessitates an updated review of treatment modalities. While the shift from laser to anti-vascular endothelial growth factor (anti-VEGF) therapy has transformed patient outcomes, benefits of these agents are not fully realized in real-world implementation relative to the setting of controlled clinical trials. This review outlines the evolution of intravitreal anti-VEGF treatment extension protocols for DME that reflect efforts to address treatment adherence challenges while optimizing visual outcomes. RECENT FINDINGS: Recent studies highlight the efficacy of extended-interval dosing with anti-VEGF agents in managing DME. Trials such as RISE/RIDE, VISTA/VIVID, and LUCIDATE have established the foundation of these regimens by demonstrating sustained visual gains with continuous treatment. However, newer trials including PROTOCOL T, KESTREL/KITE, YOSEMITE/RHINE, and PHOTON have furthered this concept, revealing that less frequent dosing of various anti-VEGF agents can maintain similar visual acuity and anatomical outcomes to traditional monthly injections. SUMMARY: The reviewed findings suggest a paradigm shift in DME treatment toward less frequent anti-VEGF injections. This has significant implications for clinical practice, potentially leading to greater adherence to treatment regimens and sustained visual function in patients, while minimizing treatment burden and healthcare costs. Further investigation into the long-term effects of extended dosing intervals is required.

The mechanism of EGFL7 regulating neovascularization in diabetic retinopathy through the PI3K/AKT/VEGFA pathway.

Diabetic retinopathy (DR) is a blinding disease caused by diabetes, characterized by neovascularization of the retina. The aim of this study was to investigate the roles of epidermal growth factor-like structural domain 7 (EGFL7) on human retinal vascular endothelial cells (HRECS) and retinas from rats with DR. An in vitro model of DR was established through culturing HRECS in high glucose. The in vivo model of DR was established by injecting SD rats with streptozotocin (STZ) to induce diabetes. The differences in the expressed levels of EGFL7, PI3K, AKT, P-AKT and VEGFA in high-glucose cultured cells and retinal tissues of diabetic rats were detected in compared to those in the control group. Stable EGFL7 knockdown cell lines were generated by transfecting HRECS with lentiviral vectors and the effects of EGFL7 knockdown on angiogenesis, cell migration and proliferation were investigated. The results showed that EGFL7, PI3K, P-AKT and VEGFA was increased in cells and tissues under high glucose conditions. Knockdown of EGFL7 downregulated the proliferation, migration and angiogenesis capacity of HRECS, and blocked the PI3K/AKT/VEGFA signaling pathway. Furthermore, overexpression of PI3K reversed the effects of EGFL7 inhibition. These findings provide new ideas for the treatment of neovascularisation in DR.

FGF2, LIF, and IGF-1 supplementation improves mouse oocyte in vitro maturation via increased glucose metabolism†.

Chemically defined oocyte maturation media supplemented with FGF2, LIF, and IGF-1 (FLI medium) enabled significantly improved oocyte quality in multiple farm animals, yet the molecular mechanisms behind such benefits were poorly defined. Here, we first demonstrated that FLI medium enhanced mouse oocyte quality assessed by blastocyst formation after in vitro fertilization and implantation and fetal development after embryo transfer. We then analyzed the glucose concentrations in the spent media; reactive oxygen species concentrations; mitochondrial membrane potential; spindle morphology in oocytes; and the abundance of transcripts of endothelial growth factor-like factors, cumulus expansion factors, and glucose metabolism-related genes in cumulus cells. We found that FLI medium enabled increased glucose metabolism through glycolysis, pentose phosphate pathway, and hexosamine biosynthetic pathway, as well as more active endothelial growth factor-like factor expressions in cumulus cells, resulting in improved cumulus cell expansion, decreased spindle abnormality, and overall improvement in oocyte quality. In addition, the activities of MAPK1/3, PI3K/AKT, JAK/STAT3, and mTOR signaling pathways in cumulus cells were assessed by the phosphorylation of MAPK1/3, AKT, STAT3, and mTOR downstream target RPS6KB1. We demonstrated that FLI medium promoted activations of all these signaling pathways at multiple different time points during in vitro maturation.

Sodium-glucose co-transporter 2 inhibitor therapy reduces the administration frequency of anti-vascular endothelial growth factor agents in patients with diabetic macular oedema with a history of anti-vascular endothelial growth factor agent use: A cohort study using the Japanese health insurance claims database.

AIM: We assessed the effectiveness of sodium-glucose co-transporter 2 inhibitors (SGLT2is) in reducing the administration frequency of anti-vascular endothelial growth factor (VEGF) agents in patients with diabetic macular oedema (DMO) using a health insurance claims database. MATERIALS AND METHODS: This retrospective cohort study analysed health insurance claims data covering 11 million Japanese patients between 2005 and 2019. We analysed the frequency and duration of intravitreal injection of anti-VEGF agents after initiating SGLT2is or other antidiabetic drugs. RESULTS: Among 2412 matched patients with DMO, the incidence rates of anti-VEGF agent injections were 230.1 per 1000 person-year in SGLT2i users and 228.4 times per 1000 person-year in non-users, respectively, and the risk ratio for events was unchanged in both groups. Sub-analysis of each baseline characteristic of the patients showed that SGLT2is were particularly effective in patients with a history of anti-VEGF agent use [p = .027, hazard ratio (HR): 0.44, 95% confidence interval (CI): 0.22-0.91]. SGLT2is reduced the risk for the first (p = .023, HR: 0.45, 95% CI: 0.22-0.91) and second (p = .021, HR: 0.39, 95% CI: 0.17-0.89) anti-VEGF agent injections. CONCLUSIONS: There was no difference in the risk ratio for the addition of anti-VEGF therapy between the two treatment groups. However, the use of SGLT2is reduced the frequency of anti-VEGF agent administration in patients with DMO requiring anti-VEGF therapy. Therefore, SGLT2i therapy may be a novel, non-invasive, low-cost adjunctive therapy for DMO requiring anti-VEGF therapy.

Characteristics of macular edema associated with retinal vein occlusion showing poor anatomic response to three loading anti-vascular endothelial growth factor injections: an optical coherence tomography analysis.

PURPOSE: To analyze the clinical features of refractory cystoid macular edema related to retinal vein occlusion associated with the response to three consecutive loading doses of anti-vascular endothelial growth factor. METHODS: A retrospective chart review was performed on retinal vein occlusion patients treated by three anti-vascular endothelial growth factor injections. They were divided into a group according to resolution of macular edema in optical coherence tomography (Group 1) and with persistent macular edema (Group 2). We analyzed qualitative and quantitative morphologic features of optical coherence tomography. RESULTS: We enrolled a total of 120 eyes from 120 patients (Group 1: n = 54, Group 2: n = 66). The baseline choroidal thickness differed significantly between groups 1 and 2 (290.70 ± 19.58 µm and 311.06 ± 17.87 µm P < 0.001). The presence of Hyperreflective foci (16.70% vs. 36.40% P < 0.001), Disorganization of the retinal inner layers (14.80% vs. 87.90%) and external limiting membrane disruption (16.60% vs. 39.3% P < 0.001) differed significantly. Logistic regression analysis showed that the initial central macular thickness (B = 0.012; P = 0.006), baseline choroidal thickness (B = 0.232; P = 0.016) and presence of hyperreflective foci (B = 1.050; P = 0.019), disorganization of the retinal inner layers (B = 1.132; P = 0.001) and external limiting membrane disruption (B = 1.575; P = 0.012) significantly affected the anti-vascular endothelial growth factor treatment response. CONCLUSION: A thicker sub-fovea choroid and the presence of hyperreflective foci, disruption of the external limiting membrane and disorganization of the retinal inner layers associated with a poorer response to three loading anti-vascular endothelial growth factor injections in macular edema associated retinal vein occlusion.

Intravitreal Injection of Anti-Vascular Endothelial Growth Factors Combined with Corticosteroids for the Treatment of Macular Edema Secondary to Retinal Vein Occlusion: A Systematic Review and Meta-Analysis.

PURPOSE: To evaluate the efficacy and safety of intravitreal anti-vascular endothelial growth factor (anti-VEGF) and corticosteroid combination therapy for the management of treatment-naïve or recurrent/refractory macular edema caused by retinal vein occlusion (RVO) in comparison with anti-VEGF monotherapy. METHODS: In this systematic review and meta-analysis study, the data from publications in the electronic databases including PubMed, Embase, Cochrane Library Central Register of Controlled Trials, ISI and Scopus from January 1, 2007, through November 20, 2020, were compiled. Heterogeneity was statistically quantified by the I2 statistic, and meta-analysis was performed using a random-effects model. RESULTS: Twenty-four related studies were identified, including a total of 1280 eyes, which consisted of 685 and 507 patients with central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO), respectively. This study demonstrated a greater improvement in best-corrected visual acuity (BCVA) in the combination group compared to anti-VEGF monotherapy for both CRVO and BRVO cases at 6 months after initiating therapy. The improvement in vision was more notable in BRVO cases than in CRVO cases. However, the changes in central macular thickness (CMT) did not differ significantly between the different treatment approaches, and the results were inconclusive. Including all cases with RVO, there was no inferiority in terms of BCVA improvement and CMT reduction in the triamcinolone subgroup compared with the slow-release dexamethasone implant subgroup. A greater improvement was noticed in terms of BCVA in the sequentially treated subgroup compared to the simultaneous treatment subgroup, while there was a greater reduction in CMT in the simultaneous subgroup with the highest reduction recorded at 1 month after treatment. CONCLUSIONS: This study suggests that combination therapy with intravitreal anti-VEGF and corticosteroid (such as intravitreal or subtenon triamcinolone or dexamethasone implant) has a slightly better effect on improving BCVA in cases with BRVO or CRVO at 6 months compared to monotherapy.

Honokiol Attenuates Choroidal Neovascularization by Inhibiting the Hypoxia-Inducible Factor-α/Vascular Endothelial Growth Factor Axis via Nuclear Transcription Factor-Kappa B Activation.

PURPOSE: Honokiol is a lignan isolated from Magnolia officinalis and exhibits anti-angiogenic properties. This study was conducted to investigate the role of honokiol in choroidal neovascularization. METHODS: C57BL/6 mice were treated with honokiol at 10-20 mg/kg by daily intraperitoneal injection from day 1 to 6 after laser photocoagulation. ARPE-19 cells were cultured under hypoxic conditions with or without the presence of honokiol. After laser photocoagulation and honokiol treatment, hematoxylin and eosin staining, immunofluorescence and fundus fluorescein angiography were used to analyze the effect of honokiol on choroidal neovascularization formation. Quantitative real-time PCR, western blot, enzyme-linked immunosorbent assay, immunofluorescence, luciferase assay, and chromatin immunoprecipitation were performed to explore the mechanism of honokiol in the pathological process of choroidal neovascularization. Finally, the role of honokiol on the human choroidal vascular endothelial cells was detected by using 5-ethynyl-20-deoxyuridine assay, Transwell and Tube formation assays. RESULTS: The results of hematoxylin and eosin staining and immunofluorescence suggested that honokiol reduced the thickness, length, and area of choroidal neovascularization lesions in laser-induced choroidal neovascularization mouse model. Fundus fluorescein angiography showed that choroidal neovascularization leakage was reduced in honokiol group and the concentration of 20 mg/kg showed better effects. Mechanism studies have shown that honokiol exerted inhibitory effects on choroidal neovascularization by inactivating hypoxia-inducible factor-1α/vascular endothelial growth factor axis through the nuclear transcription factor-kappa B signaling pathway. The same results were obtained in ARPE-19 cells under hypoxic conditions. Furthermore, the conditional medium of retinal pigmented epithelial cells promoted the proliferation, migration, and tube formation of human choroidal vascular endothelial cells, while honokiol reversed these. CONCLUSION: We demonstrated that honokiol attenuated choroidal neovascularization formation by inactivating the hypoxia-inducible factor-1α/vascular endothelial growth factor axis through nuclear transcription factor-kappa B signaling pathway.

Exudative age-related macular degeneration lesion components predicting microperimetric retinal sensitivity during anti-vascular endothelial growth factor treatment.

PURPOSE: To analyse the effect of exudative age-related macular degeneration (eAMD) lesion components on retinal sensitivity during anti-vascular endothelial growth factor treatment. METHODS: Visual acuity, fluorescein and indocyanine green (ICG) angiographies, autofluorescence images, microperimetries and optical coherence tomographies (OCTs) of 24 eyes of 24 patients were prospectively analysed in a 2-year study of pro-re-nata bevacizumab treatment for eAMD. Microperimetries were aligned with the OCTs, angiographies and autofluorescence images. Thicknesses of the neuroretina, pigment epithelial (RPE) elevation, neuroepithelial detachment (NED), subretinal tissue (SRT) and cystic intraretinal fluid were measured under each stimulus site, and areas of type 1 and type 2 macular neovascularizations (MNVs), ICG plaque, haemorrhage and RPE atrophy were identified. The effects and predictive values of lesion components on retinal sensitivity were analysed with multivariate mixed linear models for repeated measurements. RESULTS: The overall microperimetric retinal sensitivity increased during the first year (from 10.1 dB at baseline to 11.9 dB at 1 year; p = 0.021, Wilcoxon signed ranks), but remained the same during the second year (11.5 dB, p = 0.301). The baseline lesion components most strongly predicting deteriorated sensitivity at 1 year were RPE atrophy, the area of Type 2 MNV, intraretinal cysts, haemorrhage, Type 1 MNV and retinal thickening >350 µm. NED and RPE elevation had only small effects. At 2 years, the predictive values of the baseline lesion components remained quite unchanged. CONCLUSION: The most powerful predictors of retinal sensitivity loss during 2 years of treatment were RPE atrophy, areas of haemorrhage, the area of MNVs, intraretinal cysts and SRT. RPE elevation and NED had lesser effects.

Anti-vascular endothelial growth factor therapy and retinal non-perfusion in diabetic retinopathy: A meta-analysis of randomised trials.

PURPOSE: Retinal non-perfusion (RNP) is fundamental to disease onset and progression in diabetic retinopathy (DR). Whether anti-vascular endothelial growth factor (anti-VEGF) therapy can modify RNP progression is unclear. This investigation quantified the impact of anti-VEGF therapy on RNP progression compared with laser or sham at 12 months. METHODS: A systematic review and meta-analysis of randomised controlled trials (RCTs) were performed; Ovid MEDLINE, EMBASE and CENTRAL were searched from inception to 4th March 2022. The change in any continuous measure of RNP at 12 months and 24 months was the primary and secondary outcomes, respectively. Outcomes were reported utilising standardised mean differences (SMD). The Cochrane Risk of Bias Tool version-2 and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines informed risk of bias and certainty of evidence assessments. RESULTS: Six RCTs (1296 eyes) and three RCTs (1131 eyes) were included at 12 and 24 months, respectively. Meta-analysis demonstrated that RNP progression may be slowed with anti-VEGF therapy compared with laser/sham at 12 months (SMD: -0.17; 95% confidence interval [CI]: -0.29, -0.06; p = 0.003; I2 = 0; GRADE rating: LOW) and 24-months (SMD: -0.21; 95% CI: -0.37, -0.05; p = 0.009; I2 = 28%; GRADE rating: LOW). The certainty of evidence was downgraded due to indirectness and due to imprecision. CONCLUSION: Anti-VEGF treatment may slightly impact the pathophysiologic process of progressive RNP in DR. The dosing regimen and the absence of diabetic macular edema may impact this potential effect. Future trials are needed to increase the precision of the effect and inform the association between RNP progression and clinically important events. PROSPERO REGISTRATION: CRD42022314418.

The efficacy of different anti-vascular endothelial growth factor agents, and dexamethasone implant therapy in patients with serous retinal detachment caused by Irvine-Gass syndrome.

PURPOSE: The aim of this study is to compare the efficacy of intravitreal aflibercept (IVA), bevacizumab (IVB), ranibizumab (IVR), and dexamethasone implant (IVDI) in the treatment of serous retinal detachment (SRD) caused by Irvine-Gass syndrome (IGS). DESIGN: Retrospective cohort, comparative study. METHODS AND MATERIALS: The medical records of 128 eyes with no previous history of intravitreal agents in 128 IGS patients with SRD that received IVA, IVB, IVR, and IVDI monotherapy were retrospectively reviewed. The patients were divided into 4 groups, according to treatment. Patients with recurrence and/or were unresponsive following a course of topical steroids and non-steroidal anti-inflammatory drugs (NSAIDs) were included in the study. Best corrected visual acuity (BCVA), central macular thickness (CMT), subfoveal choroidal thickness (SFCT), and SRD were compared between the 4 treatment groups at baseline, at follow-up months 1, 3, 6, and 12, and at the final follow-up visit. RESULTS: Serous retinal detachment completely resolved in 74%, 45.7%, 66.4%, and 40.8% of the eyes at month 1 (P = 0.042), 87%, 50.9%, 75.8%, and 80.9% at month 3 (p = 0.031), 88.9%, 50.4%, 75.7%, 80.2% at month 6 (p = 0.028), 81.7%, 72.8%, 68.7%, 80.1% at month 12 (p = 0.580), and 100%, 66.4%, 87.9%, 93.2% (p = 0.478) at final follow-up visit in the IVA, IVB, IVR, and IVDI groups, respectively. BCVA was significantly better in the IVA group at all follow-up time points (month 1: p < 0.001; month 3: p < 0.001; month 6: p = 0.002; month 12: p = 0.009, final follow-up visit: p < 0.001). CMT was significantly lower in the IVA group at months 3 (p = 0.008), 6 (p = 0.011), and 12 (p = 0.010), and at the final follow-up visit (p < 0.001). Recurrence was observed after a longer period of time and fewer injections were needed in the IVDI and IVA groups (p < 0.05). Resolution of CME was most rapid in the IVA group (p = 0.032). CONCLUSION: All intravitreal agents were effective in terms of visual results in the SRD patients; however, eyes treated with IVA and IVDI required fewer injections, as compared to the eyes treated with IVB and IVR. Furthermore, SRD entirely resolved in all eyes in the IVA group at the final follow-up visit.