Preclinical Efficacy and Safety of VEGF-Grab, a Novel Anti-VEGF Drug, and Its Comparison to Aflibercept.

Purpose: VEGF-Grab is a novel anti-vascular endothelial growth factor (VEGF) candidate drug with higher affinity to both VEGF and placental growth factor (PlGF) compared to aflibercept. We investigated the preclinical efficacy of VEGF-Grab for ophthalmic therapy and compared it to that of aflibercept. Methods: The in vitro anti-VEGF efficacy of VEGF-Grab was determined using VEGF-induced cell proliferation/migration and tube formation assays. The in vivo antiangiogenic efficacy of intravitreal injection of either VEGF-Grab or aflibercept was evaluated using murine models of ocular angiogenesis: mouse oxygen-induced retinopathy (OIR) and rat laser-induced choroidal neovascularization (CNV). The in vivo retinal toxicity in the mouse eye resulting from the injection of either drug was evaluated with light and electron microscopy. Results: VEGF-Grab showed greater inhibition of VEGF-induced cell proliferation/migration than aflibercept, but it showed comparable inhibition of tube formation in vitro. In the in vivo OIR model, VEGF-Grab showed a comparable suppression of retinal neovascularization compared to aflibercept. Additionally, VEGF-Grab showed an efficacy similar to that of aflibercept in terms of CNV inhibition in the laser-induced CNV model. Histology and transmission electron microscopy showed no significant signs of toxicity in the mouse retina at 7 and 30 days following the intravitreal injection of VEGF-Grab or aflibercept. Conclusions: Compared to aflibercept, VEGF-Grab presented comparable in vivo antiangiogenic efficacy and superior in vitro anti-VEGF activity. The retinal safety profiles were comparable for the two drugs. Considering its known higher binding affinity to VEGF and PlGF compared to aflibercept, VEGF-Grab could be a potential candidate drug for neovascular retinal diseases and an alternative to aflibercept.

Five-year nationwide incidence of macular hole requiring surgery in Korea.

BACKGROUND/AIMS: To estimate the incidence and demographics of macular hole (MH) requiring surgery in Korea. METHODS: Patients who underwent surgery for MH in Korea from 2011 to 2015 with the diagnostic code for MH and the surgical code for vitrectomy were retrospectively identified using the Korean national health claims database. The average incidence rate of MH during the 5-year study period was estimated by applying the direct method of standardisation using the 2015 census data as a reference population. RESULTS: A total of 7301 patients with MH requiring surgery were identified. The average incidence of MH requiring surgery was 3.14 (95 % CI, 3.07 to 3.21) per 100 000 person-years . The incidence in women (4.29 per 100 000 person-years; 95% CI, 4.17 to 4.40) was significantly higher than that in men (2.00 per 100 000 person-years; 95% CI, 1.92 to 2.07; p<0.001). The incidence rate of MH increased exponentially with increasing age between the ages of 35 years and 69 years and was highest among patients aged 65-69 years. The female-to-male ratio for the incidence of MH was 2.15:1. CONCLUSIONS: This study represents the largest nationwide population-based investigation of the incidence of MH, using a database that covers the entire population of South Korea. MH is the disease of elderly peaked 70 years old and more common in women.

Risk and Risk Periods for Stroke and Acute Myocardial Infarction in Patients with Central Retinal Artery Occlusion.

PURPOSE: To investigate the risk of stroke and acute myocardial infarction (AMI) in patients with incident central retinal artery occlusion (CRAO). DESIGN: A self-controlled case series (SCCS) study. PARTICIPANTS: Patients with incident CRAO from the entire Korean population of 48 million individuals. METHODS: We used the Korean national claim database (2007-2011) for analyses. After identifying patients with incident CRAO, the relative incidence rate ratios (IRRs) for stroke and AMI in risk periods were measured in these patients using a SCCS method. MAIN OUTCOME MEASURES: The IRRs of stroke and AMI by risk periods. RESULTS: Of 1655 patients with incident CRAO in 2009-2010, 165 had stroke/AMI (ischemic stroke in 139, hemorrhagic stroke in 13, and AMI in 15) in the observation period spanning 365 days before and after the occurrence of CRAO. The IRR of stroke/AMI 1 to 30 days after CRAO occurrence significantly increased (14.0; 95% confidence interval [CI], 8.90-22.00); the IRR peaked during the 1 to 7 days after CRAO occurrence (44.51; 95% CI, 27.07-73.20), and the increased risk was present for the first 30 days. The IRR of stroke/AMI also significantly increased 1 to 30 days (6.82; 95% CI, 4.01-11.60) and 31 to 90 days (2.86; 95% CI, 1.66-4.93) before CRAO occurrence. Subanalysis for only ischemic stroke showed similar, magnified IRRs in the risk periods compared with all events. The IRRs were not significantly different between sexes or age groups (<65 vs. ≥65 years). CONCLUSIONS: Patients with incident CRAO are at increased risk of ischemic stroke just after CRAO occurrence, and the risk is particularly increased during the first week immediately after the CRAO occurrence. The results suggest that patients with incident CRAO require immediate neurologic evaluation and preventive treatment to reduce mortality and morbidity.

The effect of lithospermic acid, an antioxidant, on development of diabetic retinopathy in spontaneously obese diabetic rats.

BACKGROUND: Lithospermic acid B (LAB), an active component isolated from Salvia miltiorrhiza radix, has been reported to have antioxidant effects. We examined the effects of LAB on the prevention of diabetic retinopathy in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes. METHODS AND FINDINGS: LAB (10 or 20 mg/kg) or normal saline were given orally once daily to 24-week-old male OLETF rats for 52 weeks. At the end of treatment, fundoscopic findings, vascular endothelial growth factor (VEGF) expression in the eyeball, VEGF levels in the ocular fluid, and any structural abnormalities in the retina were assessed. Glucose metabolism, serum levels of high-sensitivity C-reactive protein (hsCRP), monocyte chemotactic protein-1 (MCP1), and tumor necrosis factor-alpha (TNFα) and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels were also measured. Treatment with LAB prevented vascular leakage and basement membrane thickening in retinal capillaries in a dose-dependent manner. Insulin resistance and glucose intolerance were significantly improved by LAB treatment. The levels of serum hsCRP, MCP1, TNFα, and urinary 8-OHdG were lower in the LAB-treated OLETF rats than in the controls. CONCLUSIONS: Treatment with LAB had a preventive effect on the development of diabetic retinopathy in this animal model, probably because of its antioxidative effects and anti-inflammatory effects.

Nationwide incidence of clinically diagnosed retinal vein occlusion in Korea, 2008 through 2011: preponderance of women and the impact of aging.

OBJECTIVE: This study aimed at defining the incidence and demographics of clinically diagnosed retinal vein occlusion (RVO) in Korea. DESIGN: Nationwide population-based retrospective study using data entered into the Korean national health claims database from 2007 through 2011. PARTICIPANTS: Data of the entire population of Korea (n = 47,990,761, based on the 2010 census) were analyzed. METHODS: The Korean national health claims database was analyzed to identify patients with RVO. Incident cases included individuals with no RVO claims in 2007, but with RVO claims in the years 2008 through 2011. The incidence rate of RVO was estimated for the entire Korean population. MAIN OUTCOME MEASURES: The person-time incidence rates of clinically diagnosed RVO in Korea, including the age- and gender-specific incidence rates, were estimated. RESULTS: A total of 92 730 RVO cases (56.4% in women) were identified. The incidence rate of clinically diagnosed RVO during the study period was 48.31 per 100,000 person-years (95% confidence interval [CI], 48.00-48.62). The incidence rate among men and women was 42.40 (95% CI, 41.99-42.81) and 54.14 (95% CI, 53.67-54.60) per 100,000 person-years, respectively (P < 0.001). The highest incidence of 214.92 per 100,000 person-years (95% CI, 211.29-218.56) was observed in the age group of 70 to 74 years (186.62 [95% CI, 181.46-191.78] and 236.25 [95% CI, 231.21-241.29] per 100,000 person-years for men and women aged 70 to 74 years, respectively). The incidence rate of RVO increased as the age of the population increased-more than doubling approximately every 10 years from the second to the seventh decade of life. Retinal vein occlusion occurred more often in men 30 to 54 years of age and in men older than 85 years, but was more common in women 55 to 84 years of age. CONCLUSIONS: This study reports the population-based RVO incidence in Korea. The RVO incidence increased exponentially as the age of the population increased, and the RVO incidence in women was 1.28 times higher than that in men.

A case of atypical progressive outer retinal necrosis after highly active antiretroviral therapy.

This is a report of an atypical case of progressive outer retinal necrosis (PORN) and the effect of highly active antiretroviral therapy (HAART) on the clinical course of viral retinitis in an acquired immunodeficiency syndrome (AIDS) patient. A 22-year-old male patient infected with human immunodeficiency virus (HIV) presented with unilaterally reduced visual acuity and a dense cataract. After cataract extraction, retinal lesions involving the peripheral and macular areas were found with perivascular sparing and the mud-cracked, characteristic appearance of PORN. He was diagnosed as having PORN based on clinical features and was given combined antiviral treatment. With concurrent HAART, the retinal lesions regressed, with the regression being accelerated by further treatment with intravenous acyclovir and ganciclovir. This case suggests that HAART may change the clinical course of PORN in AIDS patients by improving host immunity. PORN should be included in the differential diagnosis of acute unilateral cataract in AIDS patients.