Effects of switching from intravitreal injection of aflibercept to faricimab on ocular blood flow in patients with diabetic macular edema.

We assessed the short-term effects of switching from intravitreal aflibercept (IVA) to intravitreal faricimab (IVF) on ocular blood flow in patients with treatment-resistant diabetic macular edema (DME). The medical records of 15 patients with DME who had received IVA injection ≥ 3 months before were retrospectively reviewed. The best-corrected visual acuity, central macular thickness (CMT) on optical coherence tomography, and mean blur rate (MBR) of all disc areas on laser speckle flowgraphy were measured before, 1 week after, and 4 weeks after IVA and IVF, respectively. The changes in visual acuity showed no significant difference after switching from IVA to IVF (P = 0.732). The mean CMT decreased significantly during the follow-up period (both P < 0.001). MBR showed no significant difference during the follow-up period (P = 0.26). However, it decreased significantly 4 weeks after IVF (P = 0.01) compared with the baseline value, but not 4 weeks after IVA (P = 0.074). A significant association was observed between decreased MBR and decreased CMT in patients who received IVF (correlation coefficient: 0.501, P = 0.005) but not in those who received IVA (P = 0.735). Thus, IVF maintained ocular blood flow reduction, although no significant differences in visual acuity and CMT changes were observed compared to IVA.

Inhibition of choroidal neovascularization by blocking vascular endothelial growth factor receptor tyrosine kinase.

PURPOSE: To investigate the role played by receptors of vascular endothelial growth factors, Flt-1 and KDR/Flk-1, on an experimental model of choroidal neovascularization (CNV). METHODS: The vascular endothelial growth factor-A (VEGF-A) receptor-specific tyrosine kinase inhibitor SU5416 was administered to a laser-induced mouse model of CNV. The formation of CNV and the degree of vascular permeability in Flt-1 tyrosine kinase domain-deficient mice were also investigated. RESULTS: SU5416 reduced vascularity and vascular endothelial cell proliferation, and promoted endothelial cell apoptosis within CNV. Furthermore, the formation of CNV and the degree of vascular permeability were significantly reduced in Flt-1 tyrosine kinase domain-deficient mice, and this effect was enhanced by the administration of SU5416. CONCLUSIONS: Both Flt-1 and KDR/Flk-1 have a significant role in CNV formation. Suppression of apoptosis may be involved in the process.

Effects of peroxisome proliferator-activated receptor gamma and its ligand on blood-retinal barrier in a streptozotocin-induced diabetic model.

PURPOSE: To clarify whether endogenous peroxisome proliferator-activated receptor gamma (PPARgamma) and its ligand, rosiglitazone, affect retinal leukostasis and the associated vascular leakage using an experimental diabetic model. METHODS: Diabetes was induced in heterozygous PPARgamma+/- mice and Brown Norway rats with an intraperitoneal streptozotocin (STZ) injection. Retinal leukostasis and leakage, quantified by concanavalin A (Con A) lectin perfusion labeling combined with a fluorophotometric dextran leakage assay, were investigated at 120 days in diabetic PPARgamma+/- and wild-type mice and at 21 days in diabetic rats receiving rosiglitazone or the vehicle. The retinal protein expression levels of vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-alpha, and the intercellular adhesion molecule (ICAM)-1 were investigated by means of the ELISA assay. RESULTS: In the diabetic PPARgamma+/- mice, retinal leukostasis and leakage were greater than in the diabetic wild-type mice. In addition retinal leukostasis and leakage were suppressed by treatment with rosiglitazone in experimental diabetic rats. ELISA analysis revealed that the upregulated ICAM-1 expression in the diabetic rat retina was reduced by rosiglitazone treatment. CONCLUSIONS: An endogenous pathway involving PPARgamma provides protection against retinal leukostasis and retinal leakage in diabetes and treatment with PPARgamma specific ligands inhibits retinal leukostasis and retinal leakage in diabetic rats.

Suppression of laser-induced choroidal neovascularization by oral administration of SA3443 in mice.

The effect of a synthetic cyclic disulfide compound, SA3443, on neovascularization was investigated. In vitro, enzyme-linked immunosorbent assay and RT-PCR demonstrated that SA3443 suppressed the expression of the hypoxia-induced vascular endothelial growth factor (VEGF) at both protein and mRNA levels in ARPE-19 cells. In vivo, the administration of SA3443 to mice with laser-induced choroidal neovascularization (CNV) suppressed the leakage from the lesions and reduced their size. Furthermore, the expression level of VEGF protein was significantly reduced by the administration of SA3443. Taken together, our results demonstrate that SA3443 suppresses VEGF production and reduces vascular leakage and the growth of mouse experimental CNV.

COX-2-selective inhibitor, etodolac, suppresses choroidal neovascularization in a mice model.

Cyclooxygenases (COXs) are involved in choroidal neovascularization (CNV). However, the relative contribution of COX-1 and -2 to CNV has not been determined. In this study, the expression of COX-2 was investigated in CNVs in a murine laser-induced model. Subsequently, we found that experimental CNV expressed COX-2, most remarkably around the highly vascularized lesions. To examine the effect of COX-2 inhibition on CNV, etodolac, a non-steroidal anti-inflammatory drug with a high COX-2 selectivity, was tested on murine CNV model. The results demonstrated that the intensity of fluorescein leakage from the photocoagulated lesions decreased significantly compared to the control eyes following etodolac administration. The area of CNV lesions, as examined using histological sections and choroidal flatmounts at day 7, demonstrated that the average size of the CNV lesions was significantly reduced in the etodolac-treated eyes compared to the control eyes. Together, our results demonstrated that selective COX-2 inhibition suppresses CNV.

Contribution of bone-marrow-derived cells to choroidal neovascularization.

We investigated the involvement of bone-marrow derived cells to experimental choroidal neovascularization (CNV) in mice, whose bone marrow was reconstituted by either unfractionated bone-marrow cells or Lin-c(-)Kit(+)Sca-1+ enriched presumable hematopoietic stem cells from the green fluorescent protein (GFP) transgeneic mice. Immunohistochemical analysis demonstrated the presence of GFP-positive cells in the CNV lesion after unfractionated bone-marrow transplantation, as well as Lin-c(-)Kit(+)Sca-1+ cell transplantation. Some of the GFP-expressing cells also expressed CD-31 and PanEC antigen, markers of vascular endothelial cells. Our results suggest that bone-marrow derived cells may contribute endothelial cells in CNV.

Subconjunctival doxifluridine administration suppresses rat choroidal neovascularization through activated thymidine phosphorylase.

PURPOSE: Doxifluridine (5'-deoxy 5-fluorouridine) is an oral anticancer drug with antiangiogenic effects, with vasoclastic action that is enhanced by a major member of the pyrimidine phosphorylases, thymidine phosphorylase (TP). Previous studies have demonstrated that TP is upregulated in the lesions where pathologic angiogenesis occurs and TP itself promotes angiogenesis. To investigate the possible role of TP and doxifluridine in choroidal neovascularization (CNV), the expression level of TP was measured and the effect of doxifluridine was investigated in rat eyes with experimental CNV. METHODS: CNV was induced in rat eyes by diode laser photocoagulation. The expression level of TP in the laser-treated and control eyes was examined with high-performance liquid chromatography (HPLC). For the evaluation of CNV activity, the intensity of fluorescein leakage from the photocoagulated lesions was scored, and the areas of CNV lesions were measured histologically in the control eyes and eyes treated with a subconjunctival injection of doxifluridine 14 days after photocoagulation. RESULTS: The expression level of TP was higher in the laser-treated eyes than in the control eyes. Fluorescein leakage from the CNV lesions significantly decreased in the eyes given a subconjunctival injection of doxifluridine compared with the control. Histologic analysis demonstrated that both the areas of CNV lesions and the degree of vascular formation in the subretinal membrane were reduced in the doxifluridine-treated eyes compared with the control eyes. CONCLUSIONS: TP may be involved in the formation of CNV. Subconjunctival injection of doxifluridine significantly reduced experimental CNV activity without apparent adverse effects. These results suggest the possibility that doxifluridine can be beneficial in treating CNV.

Subconjunctival administration of bucillamine suppresses choroidal neovascularization in rat.

PURPOSE: Bucillamine is an antirheumatic drug with antiangiogenic properties that is currently used in clinical practice. Because bucillamine inhibits the production of VEGF, it is possible that this drug may inhibit choroidal neovascularization (CNV). Thus, the effect of bucillamine on the eyes of rats with experimental CNV was investigated in vivo by subconjunctival injection or oral intake. METHODS: CNV was induced in rat eyes by diode laser photocoagulation. The intensity of fluorescein leakage from the photocoagulated lesions was studied 7 and 14 days after photocoagulation. The areas of CNV lesions were measured histologically and studied immunohistochemically at days 4, 7, and 14. In addition, the concentration of the drug in ocular tissue and blood was measured by high-performance liquid chromatography-tandem mass spectrometry after the drug was delivered orally or subconjunctivally. RESULTS: After subconjunctival injection, fluorescein leakage from the CNV lesions decreased significantly compared with the control eyes throughout the study period. Histologic and immunohistochemical analyses 4, 7, and 14 days after photocoagulation demonstrated that the average size of the CNV lesions was reduced in the bucillamine-treated eyes compared with the control eyes. Subconjunctival injection maximized the ocular drug concentration while minimizing the blood concentration of the drug compared with oral intake. CONCLUSIONS: Subconjunctival injection of bucillamine significantly reduced the leakage and size of experimental CNV. These results suggest that bucillamine may be beneficial in treating CNV and that further studies can be considered to evaluate this possibility.