Anti-vascular Endothelial Growth Factor Drugs Research Articles

Nonclinical Similarity of the Biosimilar Candidate ABP 938 with Aflibercept Reference Product.

ABP 938 is being developed as a biosimilar to Eylea® (aflibercept reference product [RP]), an anti-vascular endothelial growth factor (VEGF) drug used in the management of retinal diseases. Previously, a comparative analytical similarity assessment demonstrated that ABP 938 and aflibercept RP have the same amino acid sequence and exhibit similar higher-order structure and biological activity. The nonclinical studies described here were designed to assess the in vitro pharmacology and the in vivo pharmacokinetics (PK), toxicokinetics (TK), and safety profiles of ABP 938 compared to aflibercept RP. In vitro target-binding kinetics and affinity for VEGF-A and placental growth factor (PIGF) isoforms were evaluated using surface plasmon resonance (SPR). Effector functions were assessed by cell-based assays. PK was evaluated in a nonterminal intravitreal (IVT) ocular distribution study in rabbits. Safety was assessed in a 1-month IVT study in cynomolgus monkeys. SPR results demonstrated that ABP 938 is similar to aflibercept RP in binding kinetics and affinity for VEGF-A111, VEGF-A121, VEGF-A165, VEGF-A189, PlGF-1, and PlGF-2 isoforms. No antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, or complement-dependent cytotoxicity was observed with ABP 938 and aflibercept RP. Results from thenonterminal ocular distribution study in rabbits indicated that there were no meaningful differences in the distribution kinetics between intravitreally injected ABP 938 and aflibercept RP. Additionally, there was no evidence of ocular or systemic toxicity associated with IVT administration of ABP 938 in a repeat-dose, 1-month toxicology study in cynomolgus monkeys; toxicokinetic and toxicology profiles were similar to aflibercept RP. This integrated assessment of results from the in vitro pharmacology assessment and in vivo PK and TK/toxicology profiles formed the nonclinical portion of the totality of evidence demonstrating ABP938 is a biosimilar to aflibercept RP.

Repeated treatment with VEGF receptor inhibitors induces phenotypic changes in endothelial cells and pericytes in the rat retina

Abnormal ocular angiogenesis is a major cause of visual impairment and vision loss in neovascularization-related diseases. Currently, anti-vascular endothelial growth factor (VEGF) drugs are used to treat ocular neovascularization, but repeated injections are needed to maintain their therapeutic effects. However, repeated injection of anti-VEGF drugs may affect the retinal blood vessel phenotype and diminish therapeutic effects. In this study, we aimed to investigate the phenotypic changes in endothelial cells and pericytes caused by the repeated interruption of the VEGF receptor signaling pathway in neonatal rats. KRN633 (10 mg/kg), a VEGF receptor tyrosine kinase inhibitor, was subcutaneously administered on postnatal day (P)-7 and P8 (first round), P14 and P15 (second round), and P21 and P22 (third round). The rat eyes were collected on P7, P9, P14, P16, P21, P23, P28, and P35. Using retinal flat-mount specimens stained with specific markers for vascular endothelial cells, basement membranes, and pericytes, the arteriolar tortuosity, capillary area density, and distribution of pericytes were evaluated. Significant loss of capillaries was observed the day after the first round of KRN633 treatment, after which aggressive angiogenesis occurred, leading to the formation of tortuous arterioles. Rats that completed second and third rounds of KRN633 treatment showed more severe abnormalities in the retinal vasculature than those that only completed first round treatment. Repeated treatment with KRN633 decreased the anti-angiogenic effects but increased the immunoreactivity of α-smooth muscle actin in the pericytes on veins and capillaries. α-Smooth muscle actin expression was inversely correlated to anti-angiogenic effects. Overall, these results revealed that repeated interruption of VEGF receptor signaling pathway altered the phenotypes of endothelial cells and pericytes and induced anti-VEGF drug resistance. Therefore, careful follow-up is necessary when using anti-VEGF drugs to treat abnormal angiogenesis-associated ocular diseases.

Pharmacokinetics of intravitreal anti-VEGF drugs in vitrectomized eyes

Neovascular retinal diseases pose a significant burden, often resulting in visual impairment. Intravitreal injection of anti-vascular endothelial growth factor (VEGF) drugs serves as the primary therapeutic approach. Nonetheless, certain patients necessitate continued anti-VEGF treatment post-vitrectomy or other ocular surgeries. Emerging evidence suggests that variations in surgical techniques and postoperative vitreous cavity management may induce distinct intraocular pharmacokinetics (PK) of anti-VEGF agents following vitrectomy, prompting potential adjustments in therapeutic strategies. This review offers a thorough examination of the pharmacokinetic determinants impacting anti-VEGF drugs and their intraocular dynamics post-vitrectomy.

The toxic effects of polystyrene microplastic/nanoplastic particles on retinal pigment epithelial cells and retinal tissue.

The increasing use of contact lenses, artificial tears, and anti-vascular endothelial growth factor (anti-VEGF) drug injections for age-related macular degeneration has heightened the likelihood of eye exposure to microplastic particles. Extensive research has established that microplastic particles can induce oxidative stress on the ocular surface, resulting in damage. However, the impact of these particles on the retina remains unclear. Therefore, this study investigated whether microplastics/nanoplastics (MPs/NPs) cause retinal damage. In vitro human retinal pigment epithelial (RPE) cells were exposed to polystyrene MPs and NPs for 48h. Assessment of cell viability using WST-8; evaluation of TNF-α and IL-1β expression; observation of cell morphology and particle invasion via TEM; measurement of ROS levels using the DCFDA reagent; and western blot analysis of SOD2, FIS1, Drp1, and LC3B expression were conducted. In vivo experiments involved intravitreal injection of MPs/NPs in rats, followed by retinal H&E staining 24h later and evaluation of TNF-α and IL-1β expression. Results indicated that exposure to MPs did not significantly alter RPE cell viability, whereas exposure to NPs led to a noticeable decrease. TEM images revealed NPs' penetration into cells, causing increased oxidative stress (SOD2), mitochondrial fission (FIS1, Drp1), and mitochondrial autophagy (LC3B). In vivo experiments demonstrated an increase in inflammatory cells in retinal tissues exposed to NPs, along with elevated levels of TNF-α and IL-1β. Conclusively, both MPs and NPs impact the retina, with NPs displaying greater toxicity. NPs significantly elevate ROS levels in the retina and induce mitochondrial fission and mitophagy in RPE cells compared to MPs.

Intravitreal Dexamethasone Implant Switch after Anti-VEGF Treatment in Patients Affected by Retinal Vein Occlusion: A Review of the Literature.

Nowadays, retinal vein occlusion (RVO) is the second most prevalent cause of vision loss associated with retinal vascular disease. Intravitreal injections are currently known as a major advancement in ophthalmology, particularly in the treatment of RVO and other retinal disorders. Particularly, the first line of therapy is usually anti-vascular endothelial growth factor (VEGF) drugs. Notably, for RVO eyes that have not responded to anti-VEGF therapy, an intravitreal dexamethasone (DEX) implant 0.7 mg (Ozurdex®, AbbVie Inc., North Chicago, IL, USA) is considered a suitable therapeutical substitute. Actually, investigations carried out in the real world and clinical trials have shown the safety and the efficacy of intravitreal DEX implants for treating this retinal disease. For this reason, choosing patients carefully may thus be essential to reduce the number of injections that clinics and hospitals have to do to manage RVO and its complications. The primary aim of this review is to summarize the pathophysiology of this retinal vascular disease, as well as the clinical and ocular imaging features that may support a switch from prior anti-VEGF treatment to intravitreal DEX implant, to provide the RVO patients with the best possible treatment to ensure maximum visual recovery.

Summary of the Therapeutic Options for Patients with Dry and Neovascular AMD.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness worldwide and a severe medical and social problem. The steadily increasing number of patients is related to the aging of the population. So far, many factors affecting the development of AMD have been identified, which can be divided into non-modifiable, including genetic factors, age, and sex, and modifiable or environmental factors, such as smoking, poor diet, and hypertension. Early stages of age-related macular degeneration are characterized by fundus drusen and abnormalities in the retinal pigment epithelium. In late stages, geographic atrophy and choroidal neovascularization (CNV) are observed. The treatment of AMD, especially its advanced forms, is very challenging. Intensive research has made it possible to treat advanced stages of the dry form of AMD with pegcetacoplan and avacincaptad pegol, new drugs approved for use in the US. Pegcetacoplan targets the C3 and avacincaptad pegol targets the C5, the pivotal proteins of the complement cascade. The drugs are administered by intravitreal injection. The gold standard for neovascular AMD (nAMD) consists of intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) drugs such as bevacizumab, ranibizumab, aflibercept, brolucizumab, and faricimab. Treatment can be administered according to the fixed, pro-re-nata, and treat-and-extend regimens. The latter seems to have the best effect on improving visual acuity (VA) and the maximum therapeutic benefit. The search continues for the best ways to deliver intravitreal drugs. Current methods include sustained-release implants and hydrogel platforms for drug release, while the most promising future pathways for treating dry and nAMD are stem cell and gene therapy.

Aflibercept 8 mg/0.07 mL (Eylea HD)

CADTH recommends that aflibercept 8mg/ 0.07 mL (Eylea HD) be reimbursed by public drug plans for treating diabetic macular edema (DME) if certain conditions are met. Eylea HD should only be covered to treat adult patients with DME due to type 1 or 2 diabetes mellitus, with a central retinal thickness (CRT) of 300 µm or more (or 320 µm or more on the Spectralis scan) and a score of 78 to 24 letters in the eye with decreased vision primarily due to DME according to the early treatment diabetic retinopathy study (ETDRS) scoring system. Eylea HD should only be reimbursed if it is prescribed by an ophthalmologist with experience managing DME, it is used in combination with other antivascular endothelial growth factor (VEGF) drugs, and the cost of Eylea HD is not more than the least costly anti-VEGF drug covered by the public drug plans for the treatment of DME. Eylea HD should only be authorized for reimbursement for 12 months the first time it is used. Eylea HD should no longer be reimbursed if injections need to be given more frequently than every 12 weeks or if the patient experiences > 10 letter loss in best-corrected visual acuity (BCVA) from week 12 in association with persistent or worsening DME and > 50 μm increase in CRT from week 12.

The matricellular protein CCN5 prevents anti-VEGF drug-induced epithelial-mesenchymal transition of retinal pigment epithelium

Age-related macular degeneration (AMD) is one of the major causes of blindness in the elderly worldwide. Anti-vascular endothelial growth factor (VEGF) drugs have been widely used to treat the neovascular type of AMD (nAMD). However, VEGF acts not only as a pro-angiogenic factor but also as an anti-apoptotic factor in the eyes. In this study, we found that anti-VEGF drugs, including bevacizumab (Bev), ranibizumab (Ran), and aflibercept (Afl), induced epithelial-mesenchymal transition (EMT) in ARPE-19 cells in vitro, accompanied by the induction of CCN2, a potent pro-fibrotic factor. Similarly, intravitreal injection of Afl into mouse eyes resulted in EMT in the retinal pigmented epithelium (RPE). Co-treatment with CCN5, an anti-fibrotic factor that down-regulates CCN2 expression, significantly attenuated the adverse effects of the anti-VEGF drugs both in vitro and in vivo. Inhibition of the VEGF signaling pathway with antagonists of VEGF receptors, SU5416 and ZM323881, induced EMT and up-regulated CCN2 in ARPE-19 cells. Additionally, knock-down of CCN2 with siRNA abolished the adverse effects of the anti-VEGF drugs in ARPE-19 cells. Collectively, these results suggest that anti-VEGF drugs induce EMT in RPE through the induction of CCN2 and that co-treatment with CCN5 attenuates the adverse effects of anti-VEGF drugs in mouse eyes.

The factors associated with retinal pigment epithelium tear development in the early phase after treatment initiation for age-related macular degeneration.

This study aimed to evaluate the factors associated with retinal pigment epithelium (RPE) tear development in the early phase after anti-vascular endothelial growth factor (VEGF) drug initiation in eyes with neovascular age-related macular degeneration (nAMD) and retinal pigment epithelial detachment (PED). Treatment-naive eyes with nAMD and PED for which anti-VEGF drug injections had been initiated and followed up for at least 3months after the 1st anti-VEGF drug injection, were retrospectively investigated. Baseline characteristics of the PEDs, including type, height, and area, were evaluated using fundus photographs, fluorescein angiography, and optical coherence tomography images. The association between patient age, sex, medical history, PED characteristics, and the development of RPE tears within 3months of starting anti-VEGF therapy was examined. This study included 244 eyes (230 patients; mean age 75.0years, 159 males and 71 females). RPE tears occurred in 13 eyes (5.3%) within 3months of the start of anti-VEGF therapy. Multivariate analysis showed an association of the development of RPE tears with PED height (every 100µm, odds ratio [OR]: 1.50, 95% confidence interval [CI]: 1.07-2.12, p = 0.019), PED area (every 10 mm2, OR: 3.02, CI: 1.22-7.46, p = 0.016), and the presence of fibrovascular PED (OR: 59.22, CI: 4.12-850.59, p = 0.002). Eyes with cleft (the hypo-reflective space beneath the fibrovascular PED) were more likely to develop an RPE tear (p = 0.01, χ-square test). Fibrovascular PED, large PED area, high PED height, and the cleft finding are independent risk factors for the development of RPE tears early after the administration of anti-VEGF drugs.

Novel CCR3-targeted cyclic peptides as potential therapeutic agents for age-related macular degeneration via inhibiting angiogenesis and reducing retinal photoreceptor damage

The prolonged intravitreal administration of anti-vascular endothelial growth factor (VEGF) drugs is prone to inducing aberrant retinal vascular development and causing damage to retinal neurons. Hence, we have taken an alternative approach by designing and synthesizing a series of cyclic peptides targeting CC motif chemokine receptor 3 (CCR3). Based on the binding mode of the N-terminal region in CCR3 protein to CCL11, we used computer-aided identification of key amino acid sequence, conformational restriction through different cyclization methods, designed and synthesized a series of target cyclic peptides, and screened the preferred compound IB-2 through affinity. IB-2 exhibits excellent anti-angiogenic activity in HRECs. The apoptosis level of 661W cells demonstrated a significant decrease with the escalating concentration of IB-2. This suggests that IB-2 may have a protective effect on photoreceptor cells. In vivo experiments have shown that IB-2 significantly reduces retinal vascular leakage and choroidal neovascularization (CNV) area in a laser-induced mouse model of CNV. These findings indicate the potential of IB-2 as a safe and effective therapeutic agent for AMD, warranting further development.

Proteomic study of vitreous in proliferative diabetic retinopathy patients after treatment with aflibercept: a quantitative analysis based on 4D label-free technique.

To identify different metabolites, proteins and related pathways to elucidate the causes of proliferative diabetic retinopathy (PDR) and resistance to anti-vascular endothelial growth factor (VEGF) drugs, and to provide biomarkers for the diagnosis and treatment of PDR. Vitreous specimens from patients with diabetic retinopathy were collected and analyzed by Liquid Chromatography-Mass Spectrometry (LC-MS/MS) analyses based on 4D label-free technology. Statistically differentially expressed proteins (DEPs), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway representation and protein interactions were analyzed. A total of 12 samples were analyzed. The proteomics results showed that a total of 58 proteins were identified as DEPs, of which 47 proteins were up-regulated and 11 proteins were down-regulated. We found that C1q and tumor necrosis factor related protein 5 (C1QTNF5), Clusterin (CLU), tissue inhibitor of metal protease 1 (TIMP1) and signal regulatory protein alpha (SIRPα) can all be specifically regulated after aflibercept treatment. GO functional analysis showed that some DEPs are related to changes in inflammatory regulatory pathways caused by PDR. In addition, protein-protein interaction (PPI) network evaluation revealed that TIMP1 plays a central role in neural regulation. In addition, CD47/SIRPα may become a key target to resolve anti-VEGF drug resistance in PDR. Proteomic analysis is an approach of choice to explore the molecular mechanisms of PDR. Our data show that multiple proteins are differentially changed in PDR patients after intravitreal injection of aflibercept, among which C1QTNF5, CLU, TIMP1 and SIRPα may become targets for future treatment of PDR and resolution of anti-VEGF resistance.

Molecular mechanism and intervention measures of microvascular complications in diabetes.

In this article, the epidemiology, molecular mechanism of occurrence and development, risk factors, and treatment of diabetic microvascular complications such as diabetic nephropathy, diabetic retinopathy, and diabetic peripheral neuropathy were discussed, providing the theoretical basis for more accurate elucidation of the pathogenesis and treatment of diabetic microvascular complications. The electronic database of PubMed was searched, and retrieved papers were screened for eligibility by two independent reviewers. Data were extracted using a standardized data extraction form and the quality of included papers was assessed. Thirty-eight articles were included. Diabetes nephropathy, diabetes peripheral neuropathy, and diabetes retinopathy are the most common and serious microvascular complications of diabetes in clinical patients. Renin-angiotensin system blockers, beta drugs, statins, antivascular endothelial growth factor drugs, and antioxidants can inhibit the occurrence of microvascular complications in diabetes. However, there has been no breakthrough in the treatment of diabetic microvascular complications. Therefore, prevention of diabetic microvascular complications is more important than treatment.

Clinical effects of atorvastatin combined with conbercept in the treatment of patients with macular edema secondary to retinal vein occlusion and carotid plaque: study protocol for a prospective randomized controlled trial.

Intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) drugs have been widely used in patients with macular edema (ME) secondary to retinal vein occlusion (RVO); however, recurrence is a major concern. This study aims to observe the clinical effects of atorvastatin and intravitreal therapy in the treatment of patients with branch or central RVO-ME and coexistent carotid plaques (CP). A prospective randomized controlled clinical trial will be conducted. Sixty-four patients diagnosed with branch or central RVO-ME and coexistent CP will be enrolled and randomly allocated in a 1:1 ratio to the control and experimental groups. The control group will be treated with intravitreal conbercept monthly for 3 months, followed by monthly evaluation and injection of pro re nata (PRN) for 12 months, while the experimental group will be treated with oral atorvastatin 20 mg daily combined with the control group treatment. If a drop of best-corrected visual acuity (BCVA) is more than five Early Treatment Diabetic Retinopathy Study (ETDRS) letters (one line) or an increment in central subfield thickness (CSFT) of 100 μm (or a 10% increment from the previous visit), intravitreal re-treatment will be performed. Outcome measurements include CSFT, BCVA, number of injections, and incidence of adverse events during the 12-month follow-up period. Differences between groups will be evaluated using Student's t-test, and comparisons between groups will be evaluated using repeated-measures analysis of variance. The study has been approved by the Institutional Review Board of Nanjing Lishui People's Hospital, Nanjing, China (approval number 2023KY0418-12, dated 18 April 2023), and has been registered on chictr.org.cn. Written informed consent will be collected from each patient and the results of this trial will be submitted to a peer-reviewed journal. Chinese Clinical Trial Registry ChiCTR2300071359. Registered on 12 May 2023.

Management after cataract surgery for patients with diabetic retinopathy: a systematic review and meta-analysis.

To evaluate the safety and effectiveness of various treatment modalities in patients with diabetic retinopathy (DR) who underwent cataract surgery. A comprehensive search for randomized controlled trials (RCTs) was conducted using the PubMed, Embase, Cochrane Library, and CNKI databases up to December 22, 2021. The safety and efficacy of treatment modalities were assessed using the risk ratio (RR) to compare the progression of DR and the mean difference to evaluate the best corrected visual acuity (BCVA) and macular thickness (MT). The meta-analysis of the RCTs revealed that anti-VEGF (anti-vascular endothelial growth factor) drugs significantly reduced the progression of DR [RR: 0.37 (95%CI 0.19, 0.70), P = 0.002] and improved BCVA [mean difference = -0.06 (-0.12, -0.01), P = 0.03] in patients with pre-existing DR who underwent cataract surgery. Steroid drugs also showed a significant reduction in macular thickness [mean difference = -55.63 (-90.73, -20.53), I2 = 56%, P = 0.002] in DR patients two weeks after cataract surgery compared to the control group. The safety profiles of different management options did not differ significantly. The present meta-analysis suggests that anti-VEGF drugs can effectively slow down the progression of diabetic retinopathy, improve BCVA, and reduce MT in DR patients who underwent cataract surgery. Steroid drugs also show promise in reducing MT. However, further studies with larger sample sizes are required to compare the efficacy and safety of different management options in a multi-center clinical setting.

Anti–Vascular Endothelial Growth Factor Drugs Compared With Panretinal Photocoagulation for the Treatment of Proliferative Diabetic Retinopathy: A Cost-Effectiveness Analysis

ObjectivesThis study aimed to evaluate the cost-effectiveness of anti–vascular endothelial growth factor drugs (anti-VEGFs) compared with panretinal photocoagulation (PRP) for treating proliferative diabetic retinopathy (PDR) in the United Kingdom. MethodsA discrete event simulation model was developed, informed by individual participant data meta-analysis. The model captures treatment effects on best corrected visual acuity in both eyes, and the occurrence of diabetic macular edema and vitreous hemorrhage. The model also estimates the value of undertaking further research to resolve decision uncertainty. ResultsAnti-VEGFs are unlikely to generate clinically meaningful benefits over PRP. The model predicted anti-VEGFs be more costly and similarly effective as PRP, generating 0.029 fewer quality-adjusted life-years at an additional cost of £3688, with a net health benefit of −0.214 at a £20 000 willingness-to-pay threshold. Scenario analysis results suggest that only under very select conditions may anti-VEGFs offer potential for cost-effective treatment of PDR. The consequences of loss to follow-up were an important driver of model outcomes. ConclusionsAnti-VEGFs are unlikely to be a cost-effective treatment for early PDR compared with PRP. Anti-VEGFs are generally associated with higher costs and similar health outcomes across various scenarios. Although anti-VEGFs were associated with lower diabetic macular edema rates, the number of cases avoided is insufficient to offset the additional treatment costs. Key uncertainties relate to the long-term comparative effectiveness of anti-VEGFs, particularly considering the real-world rates and consequences of treatment nonadherence. Further research on long-term visual acuity and rates of vision-threatening complications may be beneficial in resolving uncertainties.

Potential Mechanism of Platelet GPIIb/IIIa and Fibrinogen on Retinal Vein Occlusion

Purpose To explore the role of coagulation and fibrinolytic factors, and the potential mechanism of platelet aggregation in the pathogenesis of retinal vein occlusion. Methods Coagulation and fibrinolytic parameters in patients with retinal vein occlusion were determined using hemagglutinin and HISCL-5000. Relationships between these elevated parameters and factors representing typical clinical manifestations of retinal vein occlusion were examined, and these parameters were analyzed using a STRING database to indicate the potential role of platelet aggregation. Platelet glycoprotein IIb/IIIa (GPIIb/IIIa) levels were evaluated by flow cytometry after antiplatelet treatment in patients and mouse models. Furthermore, the GPIIb/IIIa ligand fibrinogen in peripheral blood and retina of mouse models was assessed by the turbidimetric method and real-time PCR, respectively. Results In patients, significant increases in peripheral blood fibrinogen and GPIIb/IIIa levels were observed (p = 0.0040, p < 0.0001, respectively). A positive correlation was observed between macular thickness (MT) and both fibrinogen and GPIIb/IIIa (r = 0.4528, p = 0.0063; r = 0.3789, p = 0.0427, respectively). After intravitreal injections of anti-vascular endothelial growth factor drugs, a significant reduction in fibrinogen levels was observed (p = 0.0072). In addition, the use of antiplatelet drugs resulted in a significant decrease in GPIIb/IIIa (p < 0.0001). In a mouse model, antiplatelet therapy significantly reduced both peripheral blood and retina fibrinogen levels and the overall rate of vein occlusion 3 days after occlusion (p < 0.0005). In addition, the reduction in GPIIb/IIIa levels after antiplatelet therapy was remarkable. Conclusion Fibrinogen and GPIIb/IIIa may be involved in retinal vein occlusion and blocking platelet aggregation may be a new therapeutic approach for retinal vein occlusion.

Kavain Alleviates Choroidal Neovascularization Via Decreasing the Activity of the HIF-1α/VEGF-A/VEGFR2 Signaling Pathway and Inhibiting Inflammation.

Neovascular age-related macular degeneration (nAMD) is a prevalent cause of blindness in the elderly. Standard treatment includes anti-vascular endothelial growth factor (anti-VEGF) drugs, such as aflibercept. However, anti-VEGF drugs may have limited efficacy and cause drug resistance. This study explores whether Kavain, an anti-inflammatory molecule from Piper methysticum, can treat choroidal neovascularization (CNV). Various experiments were conducted to assess the Kavain's toxicity. The impact of Kavain on in vitro cultured endothelial cells was examined through 5-ethynyl-20-deoxyuridine (EdU) assays, transwell migration assays, and tube formation assays. The therapeutic effects of Kavain on CNV were investigated using a laser-induced CNV mice model. To elucidate the mechanism of Kavain, network pharmacology analysis, molecular docking, and western blots were performed. Kavain exhibited no apparent toxicity both in vitro and in vivo. Kavain significantly decreased endothelial cell viability, proliferation, migration, and tube formation ability in a dose-dependent manner compared to the hypoxia groups (P<0.05). Kavain alleviated CNV in the laser-induced CNV mouse model compared to the control groups (P<0.05). These effects were statistically significantly enhanced in the Kavain plus aflibercept groups (P<0.05). Following Kavain administration, the expression levels of various inflammatory factors were markedly reduced in retinal pigment epithelium (RPE)/choroid complexes (P<0.05). Mechanistically, Kavain decreased the activity of the hypoxia-inducible factor 1α (HIF-1α)/VEGF-A/ VEGF receptor 2 (VEGFR2) signaling pathway. Our study is the first to demonstrate Kavain's potential as a promising treatment for nAMD, owing to its dual effects of anti-inflammation and anti-angiogenesis.

Recent Advances in Nanomedicine for Ocular Fundus Neovascularization Disease Management.

As an indispensable part of the human sensory system, visual acuity may be impaired and even develop into irreversible blindness due to various ocular pathologies. Among ocular diseases, fundus neovascularization diseases (FNDs) are prominent etiologies of visual impairment worldwide. Intravitreal injection of anti-vascular endothelial growth factor drugs remains the primary therapy but is hurdled by common complications and incomplete potency. To renovate the current therapeutic modalities, nanomedicine emerged as the times required, which is endowed with advanced capabilities, able to fulfill the effective ocular fundus drug delivery and achieve precise drug release control, thus further improving the therapeutic effect. This review provides a comprehensive summary of advances in nanomedicine for FND management from state-of-the-art studies. First, the current therapeutic modalities for FNDs are thoroughly introduced, focusing on the key challenges of ocular fundus drug delivery. Second, nanocarriers are comprehensively reviewed for ocular posterior drug delivery based on the nanostructures: polymer-based nanocarriers, lipid-based nanocarriers, and inorganic nanoparticles. Thirdly, the characteristics of the fundus microenvironment, their pathological changes during FNDs, and corresponding strategies for constructing smart nanocarriers are elaborated. Furthermore, the challenges and prospects of nanomedicine for FND management are thoroughly discussed.

Multiple Choroidal Neovascularizations in Choroidal Osteoma Treated with Anti-VEGF Injections: A 6-Year Follow-Up Case Report.

To report a case of multiple choroidal neovascularizations (CNVs) secondary to choroidal osteoma injected with a total of 13 anti-vascular endothelial growth factor (VEGF) drugs over a long-term follow up of 6-year period. Case report. A 29-year-old female presented with a peripapillary choroidal osteoma in her left eye with the best-corrected visual acuity (BCVA) of 20/25. After 2 years of follow-up, two foci of CNV (one was at the infra-nasal of the optic disc, and the other was near the sub-temporal vascular arch), and massive subretinal hemorrhage developed overlying the osteoma, causing decreased BCVA of 20/33. The patient was treated with four consecutive intravitreal injections of conbercept and the two CNVs regressed with BCVA recovered to 20/25. While 17 months later, the third CNV lesion locating at the fovea appeared and nine more injections of aflibercept were given during which repeated recurrence of it occurred. At last follow-up, 6 years from baseline, all the three CNV foci were controlled, with final BCVA of 20/33. Multiple CNVs may appear simultaneously at different locations in one osteoma and prompt treatment with intravitreal anti-VEGF may be a good option to control the progression and recurrence of these CNVs. Long-term follow-up and multimodal imaging are vital in the management of CO-associated CNV.

BROLUCIZUMAB FOR WET-AGED RELATED MACULAR DEGENERATION PATIENTS : TOO GOOD TO BE TRUE

Introduction &amp; Objective: Brolucizumab is the newest anti-vascular endothelial growth factor (anti-VEGF) drug. It showed superior anatomic outcomes compared to other anti-VEGF and noniferiority best corrected visual acuity (BCVA) results for Wet-Aged Related Macular Degeneration (Wet-AMD) patients. In Yogyakarta, its been only used in few patients and we want to report the Effectiveness and safety of brolucizumab in Wet-AMD patients in Yogyakarta. Method: In this retrospective study, all neovascular AMD (nAMD) Patients who underwent brolucizumab intravitreal injections between December 2021 and January 2023 at YAP Eye Hospital were studied. Patient’s demographic data, before and after intravitreal brolucizumab injections (central subfield thickness, intraocular pressure and BCVA) were assessed. Result :This study included 6 eyes of 6 patients ( 3 women) with a mean age of 69.5 years old. The mean follow- up period was 27 ± 10.1 weeks after the first injection of brolucizumab. Three patients were naïve nAMD patient, never got any intravitreal injections and three anti-VEGF experienced nAMD patients with ranibizumab or aflibercept injections prior to brolucizumab. Mean BCVA at baseline (before brolucizumab injection) was 0.12 decimal (6/48) and was 0.29 decimal (6/20) at the last follow-up. Five out of six patients visual acuity were improved,one patient had constant bcva. Four out of six patient central subfield thickness were reduced, none of the patient intraocular pressure increased over 21 mmhg. None of the patient reported any signs of inflammation, vasculitis, or any other ocular or systemic adverse effects. Conclusion :This limited data demonstrated that brolucizumab was safe and effective in stabilizing BCVA for both of nAMD patients who had undergone previous treatment with other anti-VEGFs agents and naive. Future larger multicenter collaborative studies are warranted.