[Multikinase inhibitors as a new approach in neovascular age-related macular degeneration (AMD) treatment: in vitro safety evaluations of axitinib, pazopanib and sorafenib for intraocular use]. / Multikinase-inhibitoren als therapeutischer ansatz bei neovaskulärer AMD: in-vitro-evaluation der sicherheit von axitinib, pazopanib und sorafenib zur intraokularen anwendung.

BACKGROUND: Multikinase inhibitors (MKI) interfere effectively at different levels of the neovascularisation cascade. Early clinical and experimental data suggest that MKIs represent a promising novel approach for the treatment of neovascular age-related macular degeneration (AMD). However, so far little is known about the biocompatibility of MKIs regarding human ocular cells. This in vitro study investigates and compares the biocompatibility of three MKIs, axitinib, pazopanib, and sorafenib regarding ocular cells of the anterior and posterior segments, as well as organ-cultured donor corneas. METHODS: Primary human optic nerve head astrocytes (ONHA), trabecular meshwork cells (TMC), and retinal pigment epithelium (RPE), human corneal endothelial and lens epithelial cells (CEC and LEC) were treated with different concentrations of axitinib, pazopanib, or sorafenib (0.1 to 100 µg/mL). To simulate oxidative stress, the cells were additionally co-incubated with 400 µM hydrogen peroxide. Induction of cell death and cellular viability were examined by live-dead assay and tetrazolium dye reduction assay (MTT). In addition, the influence of the three substances on human corneal endothelium was evaluated in seropositive donor corneas in organ culture by phase contrast microscopy. RESULTS: Up to a concentration of 7.5 mg/mL of the substances tested in any cell type examined, no toxic effects were found. Even after 10 days of incubation of organ-cultured donor corneas with 7.5 µg/mL, axitinib, pazopanib, or sorafenib, no evidence for endothelial toxicity was found. CONCLUSION: All three MKIs tested, axitinib, pazopanib, and sorafenib showed a good biocompatibility on the investigated ocular cells. Even under conditions of oxidative stress, there were no toxic effects up to a concentration of 7.5 µg/mL. Only at higher concentrations, there was a dose-dependent decrease in cellular viability and pronounced induction of cell death. These effects on cellular viability and induction of cell death appeared to be stronger with pazopanib, followed by sorafenib, than with axitinib.

[Improvement of fixation in diabetic macular oedema patients under intravitreal ranibizumab treatment]. / Verbesserung des Fixationsverhaltens bei Patienten mit diabetischem Makulaödem unter Therapie mit Ranibizumab.

BACKGROUND: The aim of this study was to evaluate the fixation and other functional and morphological alterations in patients with diabetic macular oedema (DMO) under intravitreal ranibizumab therapy. PATIENTS AND METHODS: Thirty patients (39 eyes) with DMO with central involvement were included in this prospective study. Morphological (fluorescein angiography, OCT) as well as functional (visual acuity, microperimetry including fixation) parameters were analysed before and after three monthly intravitreal applications of ranibizumab. RESULTS: Best-corrected mean visual acuity (BCVA) increased significantly by 6.85 + 6.45 letters from 26.15 ± 13.83 to 33.03 ± 13.31 letters. Mean central retinal thickness and mean central retinal volume decreased significantly from 503.72 ± 143.78 µm, respectively (p < 0.001) before treatment to 387.05 ± 122.02 µm after the third intravitreal injection with ranibizumab. Mean retinal sensitivity obtained with microperimetry did not change significantly over the course of treatment. Mean fixation within 2° (4°) improved from 64.15 % (85.7 %) before treatment significantly to 70.15 % (91.5 %) after three intravitreal injections with ranibizumab. Mean fixation stability within 2° improved from 43.9 % before treatment significantly to 58.5 % after three intravitreal injections. CONCLUSION: DMO improved both morphologically with a significant reduction of central retinal thickness and volume and a significantly improved BCVA as well as fixation and fixation stability over the course of three monthly intravitreal injections with ranibizumab. Retinal sensitivity obtained in microperimetry did not change significantly over the course. Based on our observations we interpret and suggest fixation and fixation stability as an early functional parameter and prior to microperimetrically detectable changes of retinal sensitivity additional to BCVA during treatment of diabetic macular edema.

[Navigated focal retinal laser therapy using the NAVILAS® system for diabetic macula edema]. / Navigierte fokale retinale Lasertherapie mit dem NAVILAS®-System bei diabetischem Makulaödem.

PURPOSE: The aim of this study was to investigate the accuracy of a navigated laser photocoagulator in clinically significant macular edema (CSME). METHODS: Focal laser treatment for diabetic macular edema (DME) in 36 patients was digitally planned on fundus images and performed with navigation using NAVILAS® (OD-OS, Teltow, Germany). Treatment intensity was controlled visually during treatment so the laser spots applied were barely directly visible after treatment. Using color images (CI) and optical coherence tomography (OCT) 4,137 laser spots (mean 115 per eye) were analyzed at 1 month follow-up and accuracy of spot placement was determined. RESULTS: In total 79% of laser spots were visible on CI of which 96% were within 100 µm of the planned target position. On an intention-to-treat (ITT) basis, 76% of the laser spots were placed and visible within the 100 µm target and OCT confirmed that laser effects were limited to the outer retina. The mean time for focal treatment was < 7 min (±3 min). CONCLUSIONS: After NAVILAS treatment for DME a high percentage of laser effects could be visualized on post-treatment color images and the location showed high concordance with the preplanning target.

Sorafenib prevents human retinal pigment epithelium cells from light-induced overexpression of VEGF, PDGF and PlGF.

BACKGROUND: Cumulative light exposure is significantly associated with progression of age-related macular degeneration (AMD). Inhibition of vascular endothelial growth factor is the main target of current antiangiogenic treatment strategies in AMD. However, other growth factors, such as platelet-derived growth factor (PDGF) and placenta growth factor (PlGF), have a substantial impact on development of AMD. Previous reports indicate that sorafenib, an oral multikinase inhibitor, might have beneficial effects on exudative AMD. This study investigates the effects of sorafenib on light-induced overexpression of growth factors in human retinal pigment epithelial (RPE) cells. METHODS: Primary human RPE cells were exposed to white light and incubated with sorafenib. Viability, expression, and secretion of VEGF-A, PDGF-BB, and PlGF and their mRNA were determined by reverse transcription-polymerase chain reactions, immunohistochemistry and enzyme-linked immunosorbent assays. RESULTS: Light exposure decreased cell viability and increased expression and secretion of VEGF-A, PDGF-BB and PlGF. These light-induced effects were significantly reduced when cells were treated with sorafenib at a dose of 1 µg/ml. CONCLUSION: The results show that sorafenib has promising properties as a potential antiangiogenic treatment for AMD.

Sorafenib protects human optic nerve head astrocytes from light-induced overexpression of vascular endothelial growth factor, platelet-derived growth factor, and placenta growth factor.

OBJECTIVES: Growth factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and placenta growth factor (PlGF) are key players in the development of diabetic retinopathy, age-related macular degeneration, and other retinal neovascular diseases. Glial cells provide a significant source of retinal growth factor production under physiologic and pathologic conditions. Cumulative light exposure has been linked to increased retinal growth factor expression. Previous reports indicate that sorafenib, an oral multikinase inhibitor, might have a beneficial effect on retinal neovascularization. This study was designed to investigate the effects of sorafenib on light-induced overexpression of growth factors in human retinal glial cells. METHODS: Primary human optic nerve head astrocytes (ONHAs) were exposed to white light and incubated with sorafenib. Viability, expression, and secretion of VEGF-A, PDGF-BB, and PlGF and their mRNA were determined by reverse transcription-polymerase chain reaction, immunohistochemistry, and enzyme-linked immunosorbent assay. RESULTS: Light exposure decreased cell viability and increased VEGF-A, PDGF-BB, and PlGF expression and secretion. These light-induced effects were significantly reduced when cells were treated with sorafenib at a concentration of 1 microg/ml. CONCLUSION: Sorafenib significantly reduced light-induced overexpression of VEGF-A, PDGF-BB, and PlGF in primary human ONHAs. Sorafenib has promising properties as a potential supportive treatment for retinal neovascularization.

[Intracameral moxifloxacin: a safe option for endophthalmitis prophylaxis? In vitro safety profile for intraocular application]. / Moxifloxacin intrakameral: Eine sichere Option zur Endophthalmitisprophylaxe? In-vitro-Sicherheitsprofil zur intraokularen Anwendung.

BACKGROUND: Moxifloxacin (Vigamox), a 4th-generation fluoroquinolone, covers most isolates causing endophthalmitis. It is safe and effective for systemic and topical use; however, only very limited data are available on prophylactic intracameral administration to prevent endophthalmitis. This study investigated the safety of Vigamox for intracameral application in a cell-culture model. METHODS: The endothelial toxicity of moxifloxacin (Vigamox) was evaluated in cultured human corneas. Primary human retinal pigment epithelium cells (RPEs), trabecular meshwork cells (TMCs), lens epithelium cells (LECs), and corneal endothelial cells (CECs) were treated with concentrations of Vigamox. Toxic effects were evaluated after 24 h (MTT assay and live-dead assay). By treating TMC, CEC, and RPE cells either with oxidative stress or tumor necrosis factor-alpha (TNF-a), lipopolysaccharide (LPS), and interleukin-6 (IL-6), the effects of moxifloxacin on cellular viability under conditions of inflammation were investigated. RESULTS: No corneal endothelial toxicity could be detected after 30 days of treatment with moxifloxacin 500 microg/ml. Primary RPEs, TMCs, LECs, and CECs showed adverse effects on proliferation and viability only at concentrations higher than 150 microg/ml moxifloxacin. After preincubation with TNF-a, LPS, and IL-6 for 24 h and subsequent treatment with moxifloxacin at concentrations of 10-150 microg/ml for 24 h, no significant decrease in proliferation or viability was observed. H2O2 exposure did not increase cellular toxicity CONCLUSION: Vigamox did not show significant toxicity on primary RPEs, TMCs, LECs, CECs, or human corneal endothelium at concentrations up to 150 microg/ml. The MIC90 of moxifloxacin for pathogens commonly encountered in endophthalmitis is known to be in the range of 0.25-2.5 microg/ml. Therefore, intracameral use of Vigamox at concentrations up to 150 microg/ml may be safe and effective for preventing endophthalmitis after intraocular surgery.