Photoelectric Dye, NK-5962, as a Potential Drug for Preventing Retinal Neurons from Apoptosis: Pharmacokinetic Studies Based on Review of the Evidence

NK-5962 is a key component of photoelectric dye-based retinal prosthesis (OUReP). In testing the safety and efficacy, NK-5962 was safe in all tests for the biological evaluation of medical devices (ISO 10993) and effective in preventing retinal cells from death even under dark conditions. The long-term implantation of the photoelectric dye-coupled polyethylene film in the subretinal space of hereditary retinal dystrophic (RCS) rats prevented neurons from apoptosis in the adjacent retinal tissue. The intravitreous injection of NK-5962 in the eyes of RCS rats, indeed, reduced the number of apoptotic cells in the retinal outer nuclear layer irrespective of light or dark conditions. In this study, we reviewed the in vitro and in vivo evidence of neuroprotective effect of NK-5962 and designed pharmacokinetic experiments. The in vitro IC50 of 1.7 μM, based on the protective effect on retinal cells in culture, could explain the in vivo EC50 of 3 μM that is calculated from concentrations of intravitreous injection to prevent retinal neurons from apoptosis. Pharmacokinetics of NK-5962 showed that intravenous administration, but not oral administration, led to the effective concentration in the eye of rats. NK-5962 would be a candidate drug for delaying the deterioration of retinal dystrophy, such as retinitis pigmentosa.

Concentration Distribution of Anti-VEGF Drugs Injected Into the Vitreous Cavity of Vitrectomy and Non-vitrectomy Eyes

Objective: To study the difference of retinal drug concentration distribution of anti-VEGF drugs injected into the vitreous cavity of vitrectomy and non-vitrectomy eyes.Methods: This article reviews the related studies on the distribution of retinal drugs after vitrectomy and non-vitrectomy eyes after IVI of anti-VEGF drugs. Results: There were few studies on retinal drug concentration after vitrectomy and non-vitrectomy eyes after vitreous injection of anti-VEGF drugs. Pharmacokinetics plays an important role in drug tissue distribution and onset time. A faster drug clearance rate can theoretically explain that the shorter retention time of anti-VEGF drugs in the vitreous cavity after intraocular injection of anti-VEGF drugs after vitrectomy, the lower concentration of anti-VEGF drugs in the vitreous cavity at the same time point, which can explain the reason for the poor efficacy of anti-VEGF treatment in the eyes after vitrectomy. Therefore, we have reason to believe that there is a difference in retinal drug concentration after vitrectomy and non-vitrectomy eyes after intravitreous injection of anti-VEGF drugs. Previous research results may have some deficiencies, which need to be verified by further research. Conclusion: There are differences in retinal drug concentration between vitrectomy eyes and non-vitrectomy eyes after vitreous injection of anti-VEGF drugs. There may be some deficiencies in the previous research results, which need to be verified by further research.

In Vitro and In Vivo Evaluation of Three Newly Isolated Bacteriophage Candidates, phiEF7H, phiEF14H1, phiEF19G, for Treatment of Enterococcus faecalis Endophthalmitis

Post-operative endophthalmitis caused by Enterococcus spp. progresses rapidly and often results in substantial and irreversible vision loss. Therefore, novel alternative treatments that are effective against enterococcal endophthalmitis are required. Bacteriophage therapy has the potential to be an optional therapy for infectious diseases. Therefore, we investigated the therapeutic potential of three newly isolated enterococcal phages, phiEF7H, phiEF14H1, and phiEF19G, in E. faecalis-induced endophthalmitis. These phages could lyse the broad-range E. faecalis, including strains derived from endophthalmitis and vancomycin-resistant E. faecalis in vitro, as determined by the streak test. Morphological and genomic analyses revealed that these phages were classified into the Herelleviridae genus Kochikohdavirus. The whole genomes of these phages contained 143,399, 143,280, and 143,400 bp, respectively. Endophthalmitis was induced in mice by injection of three strains of E. faecalis derived from post-operative endophthalmitis or vancomycin-resistant strains into the vitreous body. The number of viable bacteria and infiltration of neutrophils in the eye were both decreased by intravitreous injection of phiEF7H, phiEF14H1, and phiEF19G 6 h after injection of all E. faecalis strains. Thus, these results suggest that these newly isolated phages may serve as promising candidates for phage therapy against endophthalmitis.

Emodin protected against retinal ischemia insulted neurons through the downregulation of protein overexpression of β-catenin and vascular endothelium factor

Background Emodin has been proved to have an anti-ischemic effect on the brain, however little research has been done on its effect on vision-threatening retinal ischemia. Thus, an investigation was carried out into the hypothetical efficacy of emodin against retinal ischemia and the role of β-catenin/VEGF in its therapeutic mechanism. Methods Retinal ischemia, followed by reperfusion (IR), was inducted by raising the intraocular pressure of a Wistar rat’s eye to 120 mmHg for 60 min. Additionally, pre-ischemic/post-ischemic intravitreous injections of emodin (4, 10 and 20 μM) or vehicle were carried out on the eye with retinal ischemia. MTT assay, electroretinograms, cresyl violet staining retinal thickness measurements, and fluorogold retrograde labelling of retinal ganglion cells (RGCs) as well as Western blotting were carried out. Results Cultured RGC-5 cells subjected to oxygen glucose deprivation (OGD) were used to confirm the effective concentrations of emodin (administered 1 h pre-OGD, pre-OGD emodin). The most effective and significant (P = 0.04) dose of pre-OGD emodin was observed at 0.5 μM (cell viability: 47.52 ± 3.99%) as compared to pre-OGD vehicle treatment group (38.30 ± 2.51%). Furthermore, pre-ischemic intravitreous injection of 20 μM emodin (Emo20 + IR = 0.99 ± 0.18, P < 0.001) significantly attenuated the ischemia induced reduction in ERG b-wave amplitude, as compared to pre-ischemic intravitreous vehicle (Vehicle+IR = 0.04 ± 0.02). Post-ischemic intravitreous 20 μM emodin also significantly (P < 0.001) attenuated the ischemia associated b-wave reduction (IR + Em20 = 0.24 ± 0.09). Compared with pre-ischemic intravitreous vehicle (Vehicle+IR; whole retina thickness = 71.80 ± 1.08 μm; inner retina thickness = 20.97 ± 0.85 μm; RGC =2069.12 ± 212.82/0.17mm2), the significant (P < 0.001) protective effect was also present with pre-ischemic administration of emodin. This was shown by observing cresyl violet stained retinal thickness (Emo20 + IR: whole retina = 170.10 ± 0.10 μm; inner retina = 70.65 ± 2.06 μm) and retrograde fluorogold immunolabeled RGC density (4623.53 ± 179.48/0.17mm2). As compared to the normal control (the ratio of β-catenin/VEGF to β-actin was set as 1 in the Sham group), the β-catenin/VEGF protein level significantly (P < 0.001) increased after retinal ischemia and when pre-ischemic intravitreous vehicle (Vehicle+IR = 1.64 ± 0.14/7.67 ± 2.57) was carried out. However, these elevations were significantly (P = 0.02) attenuated by treatment with emodin 20 μM (Emo20 + IR = 1.00 ± 0.19/1.23 ± 0.44). Conclusions The present results suggest that emodin might protect against retinal ischemia insulted neurons such as RGCs by significantly downregulating the upregulation of β-catenin/VEGF protein that occurs during ischemia.

Ghost cell glaucoma after intravitreous injection of ranibizumab in proliferative diabetic retinopathy

BACKGROUND: The development of ghost cell glaucoma in patients with PDR after intravitreous injection (IV) was rare. Here we reported a series of patients with PDR who received Intravitreous Ranibizumab (IVR) and developed ghost cell glaucoma and analyzed the potential factors that might be related to the development of ghost cell glaucoma. METHODS: Retrospective case series study. The medical records of 71 consecutive eyes of 68 PDR patients who received vitrectomy after IVR from January 2015 to January 2017 were reviewed. The development of ghost cell glaucoma after IVR was recorded. Characteristics of enrolled patients were retrieved from their medical charts. Factors associated with ghost cell glaucoma were compared between eyes with the development of ghost cell glaucoma and eyes without the development of ghost cell glaucoma. Variables were further enrolled in a binary backward stepwise logistic regression model, and the model that had the lowest AIC was chosen. RESULTS: There were 8 out of 71 eyes of the PDR patients developed ghost cell glaucoma after they received IVR. The interval between detection of elevation of intraocular pressure ( IOP ) and IV ranged from 0 to 2 days. Among them, after IVR, there were two eyes had IOP greater than 30mmHg within 30 minutes, four eyes showed normal IOP at 30 min, and then developed ghost cell glaucoma within 1 day, two eyes developed ghost cell glaucoma between 24 and 48 hours. The mean IOP was 46.5±8.0 mmHg. All patients gained normal IOP after vitrectomy without medicine for lowering IOP. The presence of ghost cell glaucoma was associated with tractional retinal detachment (RR=4.60 [2.02~8.48], p=0.004) and fibrovascular membrane involving disk (RR=-3.57 [-7.59~-0.92], p=0.03) (AIC= 39.23，AUC=0.88) in a logistic regression model. CONCLUSION: Attention to postoperative IOP should be paid to patients with PDR undergoing vitrectomy who receive a preoperative IV of anti-VEGF agents. PDR patients with tractional retinal detachment or fibrovasucular membrane involving optic disc are more likely to develop ghost cell glaucoma after IV.

Ghost cell glaucoma after intravitreous injection of ranibizumab in proliferative diabetic retinopathy

BACKGROUND: The development of ghost cell glaucoma in patients with PDR after intravitreous injection was rare. Here we reported a series of patients with PDR who received Intravitreous Ranibizumab (IVR) and developed ghost cell glaucoma and analyzed the potential factors that might be related to the development of ghost cell glaucoma.METHODS: Retrospective case series study. The medical records of 71 consecutive eyes of 68 PDR patients who received vitrectomy after IVR from January 2015 to January 2017 were reviewed. The development of ghost cell glaucoma after IVR was recorded. Characteristics of enrolled patients were retrieved from their medical charts. Factors associated with ghost cell glaucoma were compared between eyes with the development of ghost cell glaucoma and eyes without the development of ghost cell glaucoma. Variables were further enrolled in a binary backward stepwise logistic regression model, and the model that had the lowest AIC was chosen. RESULTS: There were 8 out of 71 eyes of the PDR patients developed ghost cell glaucoma after they received IVR. The interval between detection of elevation of intraocular pressure ( IOP ) and intravitreous injection ranged from 0 to 2 days. Among them, After IVR, there were two eyes had IOP greater than 30mmHg within 30 minutes, four eyes showed normal IOP at 30 min, and then developed ghost cell glaucoma within 1 day, two eyes developed ghost cell glaucoma between 24 and 48 hours. The mean maximum IOP was 46.5±8.0 mmHg. All patients gained normal IOP after vitrectomy without medicine for lowering IOP. The presence of ghost cell glaucoma was associated with tractional retinal detachment (RR= 4.60 [2.02~8.48], p= 0.004) and fibrovascular membrane involving disk (RR=-3.57 [-7.59~-0.92], p=0.03) (AIC= 39.23，AUC=0.88) in a logistic regression model.CONCLUSION: Attention to postoperative IOP should be paid to patients with PDR undergoing vitrectomy who receive a preoperative intravitreous injection of anti-VEGF agents. PDR patients with tractional retinal detachment or fibrovasucular membrane involving optic disc are more likely to develop ghost cell glaucoma after IVR.