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Introduction: Neovascular glaucoma is characterized by neovascularization of the iris and the anterior angle chamber. Intravitreal anti-vascular endothelial growth factor agents may improve intraocular pressure (IOP) and neovascularization. Methods: The VEGA trial assessed the efficacy and safety of intravitreal aflibercept (IVT-AFL) in patients with neovascular glaucoma in a 13-week, randomized, double-masked, sham-controlled, phase 3 study performed at multiple sites in Japan that enrolled patients with anterior segment neovascularization and IOP > 25 mmHg. Patients received background therapy plus IVT-AFL (2 mg) or sham injection at baseline. Patients were re-treated if presenting with IOP > 21 mmHg and incomplete regression of iris neovascularization, receiving additional sham or IVT-AFL injections at week 1 and IVT-AFL injections at weeks 5 and/or 9. Double-masking was maintained throughout. The primary endpoint was change in IOP from baseline to week 1. Results: Fifty-four patients were randomly assigned (full analysis set); the per-protocol set comprised 52 patients. At week 1, the least squares mean change in IOP was −9.9 mmHg for IVT-AFL versus −5.0 mmHg for sham [full analysis set: difference −4.9 mmHg (95% confidence interval −10.2 to 0.3; P = 0.06); per-protocol set: −5.5 mmHg (95% CI −10.8 to −0.2; P = 0.04)]. At week 1, a greater proportion of patients administered IVT-AFL versus sham achieved IOP ≤ 21 mmHg and had improved neovascularization grades. Patients in the sham group who met re-treatment criteria and received IVT-AFL at week 1 [n = 22 (81.5%)] had an additional mean IOP decrease of 9.2 mmHg by week 2, and the proportion with improvement in neovascularization grades increased from 11.5% to 69.2%. Increases in the proportion of patients with improved neovascularization grades and the proportion who achieved IOP control (≤ 21 mmHg) were also observed by week 2 in this group. Overall, 77.8% and 74.1% of patients treated with IVT-AFL and sham/IVT-AFL, respectively, received a single IVT-AFL injection. The most common ocular treatment-emergent adverse event was punctate keratitis (9.3%: 7.4% and 11.1% in the IVT-AFL and sham/IVT-AFL groups, respectively). Conclusions: IVT-AFL was associated with clinically meaningful improvements in IOP control, indicating that IVT-AFL may be a potential treatment option for patients with neovascular glaucoma. Trial Registration: Clinicaltrials.gov identifier, NCT02396316. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate some clinically important features of benzalkonium chloride (BAK) toxicity by comparing tafluprost with 0.001% BAK and travoprost preserved with SofZia applied to the ocular surface of the eyes with glaucoma. Methods: This was a prospective, randomized, observer unmasked, multicenter crossover trial. A total of 195 patients were randomized and 174 patients completed the study at 19 clinics between November 2011 and August 2012. Topical BAK-preserved tafluprost or SofZia-preserved travoprost was newly administered or continued. Superficial punctate keratopathy (SPK), tear break-up time (BUT), the conjunctival hyperemia score, and intraocular pressure (IOP) were compared at the baseline visit, 4, and 12 weeks after the start of therapy. The eye drops were switched to another eye drop after 12 weeks of observation. Results: The total SPK and conjunctival hyperemia scores were significantly lower in the tafluprost compared with those in the travoprost phase (both P=0.038). There were no significant differences in the SPK scores of the superior area ( P=0.679), central area ( P=0.089), inferior area ( P=0.090), and tear BUT ( P=0.271). The IOP-lowering effects were similar ( P=0.155). Conclusions: SPK, hyperemia score, and tear BUT while using tafluprost with 0.001% BAK were not inferior compared with those caused by travoprost with SofZia. [ABSTRACT FROM AUTHOR]

Background/aims Scarring and contraction of the conjunctiva are common complications of many ocular diseases. We investigated the effects of all-trans-retinoic acid (ATRA) on the contractility of human Tenon's capsule fibroblasts (HTFs) cultured in a three-dimensional collagen gel. Methods HTFs were cultured in a three-dimensional gel of type I collagen and in the absence or presence of transforming growth factor (TGF)-β, ATRA, or an inhibitor of matrix metalloproteinases (MMPs). Collagen gel contraction was evaluated by measurement of gel diameter. The release of MMPs and tissue inhibitors of metalloproteinases (TIMPs) into culture supernatants was assessed by immunoblot analysis and gelatin zymography. The release of lactate dehydrogenase activity from HTFs was measured with a colorimetric assay kit. Results ATRA inhibited TGF-β-induced collagen gel contraction mediated by HTFs in a concentration- and timedependent manner. TGF-β induced the release of MMP-1, MMP-2 and MMP-3 by HTFs, and ATRA inhibited these effects of TGF-β on MMP-1 and MMP-3 release. ATRA also stimulated TIMP-1 release from HTFs in the presence of TGF-β. Furthermore, TGF-β-induced collagen gel contraction was blocked by the MMP inhibitor GM6001. ATRA did not exhibit cytotoxicity for HTFs. Conclusions ATRA inhibited TGF-β-induced collagen gel contraction mediated by HTFs, likely in part by attenuating the production of MMP-1 and MMP-3 and by stimulating the production of TIMP-1. ATRA may therefore prove to be of clinical value for inhibition of scar formation in the conjunctiva. [ABSTRACT FROM AUTHOR]

Aim: To investigate the efficacy of ripasudil, a Rho kinase inhibitor, in reducing intraocular pressure (IOP) and medication scores of anti-glaucoma drugs in patients with ocular hypertension with inflammation and corticosteroid., Methods: The study included 11 patients diagnosed with ocular hypertension with inflammation and corticosteroid, all of whom were prescribed ripasudil eye drops and followed up for at least 2y after the initiation of treatment. IOP was measured using a non-contact tonometer before enrollment and at each follow-up visit. The medication score of glaucoma eye drops was calculated for each patient., Results: The mean IOP (26.4±2.9 mm Hg before treatment) significantly decreased after ripasudil therapy (13.7±3.3 mm Hg at 3mo) and remained stable in the low-teens during the 2-year follow-up period ( P <0.0001). A significant decrease in the medication score was observed at 12mo or later after the initiation of ripasudil therapy ( P <0.05). Both baseline medication scores and glaucomatous optic disc change rates were significantly higher in the five eyes that required glaucoma surgery during the 2-year observation period than the 10 eyes that did not require surgery., Conclusion: Our results demonstrate the efficacy of ripasudil, in reducing IOP and the medication score over a 2-year treatment period in patients with ocular hypertension with inflammation and corticosteroid. Our findings also suggest that ripasudil could reduce the IOP in uveitic glaucoma patients with both lower baseline medication score and lower glaucomatous optic disc change rate., (International Journal of Ophthalmology Press.)

Purpose: Scar formation is most frequently responsible for the failure of glaucoma filtration surgery. Retinoic acids are vitamin A derivatives that play diverse roles in development, immunity, and tissue repair. The effects of the retinoic acid receptor (RAR) γ agonist R667 on the contractility of human Tenon fibroblasts (HTFs) cultured in a three-dimensional collagen gel as well as on intraocular pressure (IOP) in a rat model of glaucoma filtration surgery were investigated., Methods: HTFs were cultured in a type I collagen gel, the contraction of which was evaluated by measurement of the gel diameter. The release of matrix metalloproteinases (MMPs) into culture supernatants was assessed with immunoblot analysis and gelatin zymography. Phosphorylation of focal adhesion kinase (FAK) was examined with immunoblot analysis, and production of fibronectin and type I collagen was measured with immunoassays., Results: R667 inhibited transforming growth factor-β1 (TGF-β1)-induced collagen gel contraction mediated by HTFs in a concentration- and time-dependent manner, whereas an RARα agonist inhibited this process to a lesser extent and an RARβ agonist had no effect. TGF-β1-induced MMP-1 and MMP-3 release, FAK phosphorylation, and fibronectin and type I collagen production in HTFs were also attenuated by R667. Furthermore, R667 lowered IOP in rats after glaucoma filtration surgery., Conclusions: R667 inhibited TGF-β1-induced contraction and extracellular matrix synthesis in HTFs. Such effects might have contributed to the lowering of IOP by R667 in a rat model of glaucoma filtration surgery. RARγ agonists might thus prove effective for inhibition of scar formation after such surgery.

Purpose: To investigate the effects of preservative-free eyedrops containing betamethasone sodium phosphate (BSP) on the development of corneal epithelial disorders after penetrating keratoplasty (PKP)., Methods: The records of 48 patients who underwent unilateral PKP and were followed for 6 months postoperatively were reviewed retrospectively. Twenty-four patients were treated with BSP eyedrops containing preservatives and the other 24 patients with preservative-free BSP eyedrops four times daily. Patients in the two groups were matched for age and sex. Corneal epithelial disorders and other complications were examined with a slitlamp biomicroscope at 1, 3, and 6 months after surgery., Results: None of the patients developed corneal erosion or corneal epithelial defects. The incidence of superficial punctate keratopathy in the preservative-free group (2 of 24 eyes) was significantly reduced compared with that in the preservative group (9 of 24 eyes) 1 month after surgery. The SPK score in the preservative-free group (0.17 +/- 0.56 points) was also significantly smaller than that in the preservative group (1.04 +/- 1.46 points) at 1 month. There was no significant difference in other postoperative complications between the two groups., Conclusions: Preservative-free BSP eyedrops are effective for preventing the development of corneal epithelial disorders after PKP.

Purpose: The corneal epithelium provides a barrier that is both important for corneal homeostasis and dependent on tight junctions (TJs) between adjacent epithelial cells. The authors examined the effects of tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, on barrier function and the expression of TJ proteins in simian virus 40-transformed human corneal epithelial (HCE) cells., Methods: The barrier function of cultured HCE cells was evaluated by measurement of transepithelial electrical resistance (TER). The subcellular distribution of the TJ proteins zonula occludens-1 (ZO-1) and occludin and that of the p65 subunit of nuclear factor-kappaB (NF-kappaB) were determined by immunofluorescence staining. The expression of ZO-1 and occludin and the phosphorylation and degradation of the NF-kappaB inhibitory protein IkappaB-alpha were examined by immunoblot analysis., Results: TNF-alpha induced a decrease in the TER of HCE cells in a concentration- and time-dependent manner. It also induced the disappearance of ZO-1 from the interfaces of neighboring HCE cells without affecting the localization of occludin. The abundance of neither ZO-1 nor occludin was affected by TNF-alpha. TNF-alpha induced the phosphorylation and downregulation of IkappaB-alpha and the translocation of the p65 subunit of NF-kappaB to the nucleus. The NF-kappaB inhibitor curcumin blocked the effects of TNF-alpha on TER and the subcellular localization of ZO-1 at late phase., Conclusions: TNF-alpha disrupted the barrier function of HCE cells, apparently by affecting the localization of ZO-1 at TJs in a manner dependent on NF-kappaB at late phase. This action of TNF-alpha may contribute to the loss of corneal epithelial barrier function associated with ocular inflammation.