This retrospective exploratory study examines the visual acuity outcomes following a retinal vasculitis (RV) event possibly associated with intravitreal (IVT) biological drugs using a large ophthalmic registry, to gain a better understanding of RV's impact on vision in real-world clinical settings. An ophthalmic registry was used in a retrospective exploratory analysis and focused on subjects who received IVT anti-VEGF and anticomplement therapies. We excluded eyes with RV in the visual acuity analysis that had received more than one IVT biological drug within 2 months before the diagnosis of RV to increase confidence that a single biological drug was possibly associated with the RV event. A total of 1,998,399 subjects received IVT injections of biological drugs, and 2,115 subjects were diagnosed with RV in at least 1 eye. A total of 436 subjects (531 eyes total) were coded as having RV. There was a 78% increase in eyes that became legally blind (≤20/200 Snellen equivalent) and 46% increase in eyes reading 0 letters (≤count fingers vision) following the RV event. In the real world, the number of legally blind eyes substantially increased following the RV diagnosis. Given the retrospective and exploratory nature of this study, all interpretations should be made cautiously, including any suggested association between biological therapy and the occurrence of RV, and prospective studies are necessary to confirm these associations. Further research is indicated to improve the safety of biological therapies for retinal diseases and minimize the risk of serious complications such as RV.

To evaluate the efficacy and safety of subliminal subthreshold laser (SubCyclo) in reducing peak intraocular pressure (IOP) using the water-drinking test (WDT) in patients with refractory glaucoma. This prospective interventional study included 50 eyes of 49 patients with moderate-to-advanced refractory glaucoma treated with SubCyclo using a standardized protocol. WDT was performed at baseline, 1, 3, and 6 months postoperatively. Surgical success was defined as: Criterion A, IOP < 21 mmHg or ≥ 20% reduction from baseline; and Criterion B, IOP < 21 mmHg and ≥ 20% reduction. The number of medications, reasons for patient exclusion, and sensitivity analyses comparing patients with ≥ 3 months versus < 3 months follow-up were assessed. Safety outcomes included complications and hypotony. Mean baseline basal and peak IOP was 23.2 ± 8.9 mmHg and 27.8 ± 11.1 mmHg, respectively. At 6 months, basal IOP was 20.1 ± 8.6 mmHg (13.5% reduction, P = 0.18), and peak IOP was 25.8 ± 10.3 mmHg (7.2% reduction, P = 0.73). Surgical success at 6 months was 38% (criterion A) and 20% (criterion B). Kaplan-Meier analysis showed cumulative failure rates of 64.8% and 81.5%, respectively. Mean medications decreased from 4.1 ± 1.02 to 3.72 ± 1.40 (P = 0.34) at 6 months. No hypotony, vision-threatening complications, or persistent inflammation were observed. SubCyclo showed a favorable safety profile, but did not significantly reduce peak IOP as measured by WDT in refractory glaucoma. These findings highlight the need to refine treatment parameters and identify subgroups most likely to benefit.

A supplement, OPTIADE® DE, containing specific lactic acid bacteria, Enterococcus faecium WB2000, has been shown to provide significant ameliorative effects in patients. However, the mechanism of the supplement has not been elucidated. In this study, we investigated the mechanism of the supplement on dry eye symptoms using an air stress-induced dry eye mice. Stress-induced dry eye in mice was produced by exposing the mice to an air stream. OPTIADE® DE was administered for 5 days during the daily exposure to the air stress, and then the tear volume and the expression of specific mRNA were measured. Furthermore, the effects of WB2000 and the other nutritional ingredients were also investigated, respectively. The contribution of peroxisome proliferator-activated receptor α (PPARα) to the regulation of tear secretion was investigated by an inhibitor of PPARα. Exposure of the mice to air stress displayed a remarkable decrease in the tear volume with a concomitant reduction in the PPARα expression in the lacrimal gland. OPTIADE® DE significantly inhibited the decrease in the tear volume and the expression of the PPARα. WB2000 and the other nutritional ingredients additively inhibited the decrease in the tear volume. Inhibition of PPARα completely canceled the effects of the OPTIADE® DE and WB2000 without influencing the effect of the mixture of other nutritional ingredients on the tear volume. These results suggest that both the PPARα-dependent pathway and the independent pathway contributed to the ameliorative effect of OPTIADE® DE in the dry eye mice.

This study aimed to develop a porcine eye model used to predict corneal endothelial cell loss (ECL) associated with anterior chamber paracentesis (ACP) in a healthy adult human cornea. To assess the average wound area and ECL created by needle punctures, a 27-gauge (27G) needle was inserted at the limbus of a porcine eye through the clear cornea and into the anterior chamber. Needle-punctured areas were immediately collected, stained, and photographed with a digital light microscope. The wound areas were quantified in square millimeters (mm2) and then extrapolated to predict ECL in a healthy adult human cornea. The average wound area of the puncture sites was 0.274 ± 0.122 mm2. The needle punctures created a larger area of ECL than the observed cross-sectional area of the needle (0.12 mm2). Extrapolating these data to the ECL that would occur in healthy adult human corneas, each 27G corneal needle puncture would damage 685 cells, or 0.21% of the corneal endothelial cell layer. The predicted wound areas for 28G, 30G, and 33G needles were 0.234 mm2, 0.163 mm2, and 0.072 mm2, respectively. The predicted cell loss for a 28G, 30G, and 33G needle stick corresponded to a loss of 586 cells (0.18% of the corneal endothelium), 407 cells (0.13% of the corneal endothelium), and 181 cells (0.06% of the corneal endothelium), respectively. Frequent ACPs following intravitreal injections may be associated with clinically significant ECL; thus, caution is advised, particularly in patients with compromised corneas and low endothelial cell counts.

Purpose: Rho-associated kinase (ROCK) regulates fibrosis and angiogenesis. This study evaluated the effects of the topical ROCK inhibitor HA1077 (fasudil) to attenuate corneal fibrosis and corneal neovascularization (CNV) invivo. Methods: Primary human corneal stromal fibroblasts (hCSF) and New Zealand White rabbits (n = 12) were used. Corneal fibrosis and CNV invivo were provoked by alkali injury. Immediately post-injury, eyes received topical balanced salt solution (BSS) or HA1077 (3 nM twice/day for 3 days). Clinical slit-lamp biomicroscopy and stereomicroscopy gauged corneal haze/fibrosis (Fante's score) and CNV (morphometric score) in live rabbits. Post-euthanasia, H&E, immunofluorescence, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays analyzed α-smooth muscle actin (α-SMA), filamentous actin (F-actin), endoglin, CD11b, and apoptotic cells. Results: HA1077 treatment to hCSF did not alter viability, morphology, and proliferation ability at 3 nM or lower doses. Topical HA1077 (3 nM) treatment significantly reduced corneal haze/fibrosis (P < 0.0001) and CNV (P < 0.0001) invivo at days 7 and 14 compared with the corresponding controls. Histological H&E analysis revealed retrieval of overall corneal health with a remarkable decrease in fibrotic (myofibroblasts), angiogenic (neovessels), and immune cell infiltration in rabbit corneas treated with HA1077 than the control corneas. HA1077 therapy significantly reduced α-SMA+, F-actin+, and endoglin+ cells, markers of fibrosis and CNV. Intraocular pressure (IOP) remained within the normal physiological range of eyes with HA1077. TUNEL assay revealed the tolerability of the examined HA1077 regimen invivo. Conclusions: The tested HA1077 dosage regimen is effective and tolerable to rabbit eyes in abrogating corneal fibrosis and CNV triggered by alkali injury invivo without major adverse effects. ROCK inhibition represents a promising therapeutic strategy for vascularized and fibrotic corneal wounds but warrants additional dose-response invivo studies.

Purpose: Cetalkonium chloride (CKC) is a cationic agent used in ophthalmical emulsions. Despite its growing application in ocular drug delivery, its safety profile on corneal endothelial cells remains unclear. This study evaluated the in vitro cytotoxic effects of CKC on human corneal endothelial cells (HCEnCs). Methods: HCEnCs were exposed to CKC at concentrations ranging from 0.03125 to 4.0 × 10-4% (w/v) for 24-72 h. Cell viability was assessed using Cell Counting Kit-8 and lactate dehydrogenase (LDH) assays. Live/dead cell staining was performed for morphological confirmation. Reactive oxygen species (ROS) production and mitochondrial function were evaluated using DCFDA and MitoTracker assays. Western blot analysis was conducted to examine CKC-induced changes in cell survival pathways, including mammalian target of rapamycin (mTOR), protein kinase B (Akt), extracellular signal-regulated kinase (ERK), Bcl-2-associated X protein (BAX), and B-cell lymphoma-extra-large (Bcl-xL). Results: CKC induced dose- and time-dependent cytotoxicity in HCEnCs. Exposure to CKC at concentrations ≥0.25 × 10-4 % for over 48 h significantly reduced cell viability and increased LDH release and ROS production. At concentrations ≥1.0 × 10-4 %, cell viability was reduced by more than 50% at both 48 and 72 h. In surviving cells, mitochondria showed minimal structural alterations. CKC exposure inhibited cell survival pathways such as mTOR, Akt, Bcl-xL, and ERK, while the proapoptotic pathway marker BAX was upregulated. Conclusion: CKC exhibits dose- and time-dependent toxicity in HCEnCs, mediated by oxidative stress and the modulation of survival and apoptotic signaling pathways. However, it is challenging to directly extrapolate laboratory conditions to the clinical setting. Therefore, these findings should be interpreted with caution, particularly in scenarios where direct exposure of the corneal endothelium to CKC-containing formulations is anticipated.

Purpose: To study the ability of five kinin peptides to relax phenylephrine-contracted bovine posterior ciliary artery (PCA; major retinal blood supplier) and carbachol-contracted ciliary muscle (CM) (involved in accommodation and aqueous humor drainage) in vitro. Methods: Isolated bovine CM strips and PCA rings were mounted in small organ baths and perfused with oxygenated Krebs' solution containing 3 µM flurbiprofen. The tissues were then contracted with 10 µM carbachol (for CM) and 10 µM phenylephrine (for PCA), and the relaxant effects of kinins (0.3 nM to 10 µM) were determined. Results: All tested kinin peptides concentration-dependently relaxed precontracted CM and PCA in a biphasic manner. The concentrations of the peptides (BK [bradykinin], Hyp3-BK, Lys-BK, Met-Lys-BK, and Des-Arg9-BK) yielding half-maximal relaxation (EC50) of PCA via the high potency receptor site ranged between 0.1 nM and 9.0 nM (n = 5-6). Precontracted PCA relaxation by the same kinins via the low potency receptor site occurred with EC50 values of 39.5-399 nM (n = 5-6). In contrast, EC50 values for these peptides relaxing the precontracted CM strips were 0.25-30 nM (high potency receptor site) and 100-3,000 nM (low potency receptor site) (n = 3-6). Precontracted PCA rings were significantly (generally P < 0.005-0.05) more sensitive to the relaxant activity of the kinin peptides than precontracted CM strips. Conclusions: The tissue relaxant agonist profile of the kinins in both precontracted CM strips and PCA rings, as judged by the 2-site-fit data, indicated the involvement of both B1- and B2-receptor subtypes.

Purpose: This study aimed to elucidate the contribution of EP3 receptor agonism to the intraocular pressure (IOP)-lowering effects of sepetaprost, a novel dual agonist of FP and EP3 receptors, in monkeys. Methods: The agonistic activities of ONO-AG-367 (the active metabolite of sepetaprost) and latanoprost acid toward FP and EP3 receptors were assessed using a cell-based assay. The IOP-lowering effects of sepetaprost and latanoprost were compared in ocular normotensive monkeys. The involvement of EP3 receptor activation in sepetaprost-induced IOP reduction was evaluated by intracameral administration of an EP3 antagonist followed by topical sepetaprost. Aqueous humor dynamics (AHD) were assessed via fluorophotometry in ocular hypertensive monkeys. Outflow facility was measured by tonography in ocular normotensive monkeys. Additionally, the IOP-lowering efficacy of sepetaprost was examined in latanoprost low-responder monkeys. Results: ONO-AG-367 exhibited potent agonistic activity at both FP and EP3 receptors, whereas latanoprost acid selectively activated the FP receptor. Sepetaprost elicited greater and longer-lasting IOP reduction than latanoprost. Pretreatment with an EP3 antagonist significantly attenuated the IOP-lowering effect of sepetaprost at 26 h. In the AHD study, sepetaprost enhanced outflow facility and uveoscleral outflow. Tonographic assessment confirmed a significant increase in outflow facility following sepetaprost treatment. Sepetaprost also effectively reduced IOP in latanoprost low-responder monkeys. Conclusions: EP3 receptor agonism contributes to the longer-lasting IOP-lowering effect of sepetaprost in monkeys. These findings suggest that sepetaprost enhances uveoscleral outflow and improves facility in the trabecular outflow pathway, and may provide effective IOP lowering when there is a suboptimal response to latanoprost.

Purpose: To compare the performance of two preservative-free artificial tears with sodium hyaluronate (SH) in patients with moderate-to-severe dry eye: a 0.24% SH eye drop with carbomer (CB) and triglycerides (TGs) as lipids (SH-CB-TG), and a comparator with 0.18% SH (C-SH). Methods: Relief of Eye Surface by Triple Action (RESTA), a multicenter, investigator-masked, noninferiority study (NCT03368404) assessed patients with moderate-to-severe dry eye (N = 79). Patients were randomized 1:1 to receive drops containing SH, CB, and medium-chain TGs [0.24% SH, 0.0625% CB, and 0.2% TGs; SH-CB-TG (Artelac® Complete); n = 45] versus an SH-only drop (0.18%; C-SH; n = 34) instilled 3-6 times daily for 90 days. The primary endpoint was change from baseline to Day 28 in total ocular surface fluorescein staining (OSFS) with noninferiority defined as a between-group 95% confidence interval (CI) upper bound <2 grades. Secondary endpoints included global OSFS at Day 90, individual OSFS component scores, dry eye symptoms, tear film break-up time, Schirmer's test, quality of life (QoL) measures, and instillation frequency. Results: At Day 28, mean OSFS score in the SH-CB-TG group decreased by 2.07 ± 1.67 versus 1.50 ± 1.64 for C-SH; the 95% CI upper limit was 0.13, confirming noninferiority. Dry eye signs, symptoms, and QoL measures improved continuously in both groups, with the SH-CB-TG group showing significantly improved QoL globally at Day 90 (P = 0.0306) and across several individual QoL parameters, plus an acceptable safety profile. Conclusions: Including medium-chain TGs in dry eye drops provides noninferior improvements of dry eye signs and symptoms versus viscosity agent-only drops and may enhance patient QoL.