Cytidine 5'-Diphosphocholine (Citicoline): Evidence for a Neuroprotective Role in Glaucoma

Glaucoma, a heterogeneous set of progressively degenerative optic neuropathies characterized by a loss of retinal ganglion cells (RGCs) and typical visual field deficits that can progress to blindness, is a neurodegenerative disease involving both ocular and visual brain structures. Although elevated intraocular pressure (IOP) remains the most important modifiable risk factor of primary open-angle glaucoma (POAG) and is the main therapeutic target in treating glaucoma, other factors that influence the disease course are involved and reaching the optimal IOP target does not stop the progression of glaucoma, as the visual field continues to narrow. In addition to a managed IOP, neuroprotection may be beneficial by slowing the progression of glaucoma and improving the visual defects. Citicoline (cytidine 5'-diphosphocholine) is a naturally occurring endogenous compound that has been investigated as a novel therapeutic agent for the management of glaucoma. Citicoline has demonstrated activity in a range of central neurodegenerative diseases, and experimental evidence suggests a it performs a neuromodulator and neuroprotective role on neuronal cells, including RGCs, associated with improvement in visual function, extension of the visual field and central benefits for the patient. This review aims to critically summarize the current evidence for the neuroprotective properties of citicoline in glaucoma

Therapeutic benefit of idebenone in patients with Leber hereditary optic neuropathy: The LEROS nonrandomized controlled trial

Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to rapid and severe bilateral vision loss. Idebenone has been shown to be effective in stabilizing and restoring vision in patients treated within 1 year of onset of vision loss. The open-label, international, multicenter, natural history-controlled LEROS study (ClinicalTrials.gov NCT02774005) assesses the efficacy and safety of idebenone treatment (900 mg/day) in patients with LHON up to 5 years after symptom onset (N = 199) and over a treatment period of 24 months, compared to an external natural history control cohort (N = 372), matched by time since symptom onset. LEROS meets its primary endpoint and confirms the long-term efficacy of idebenone in the subacute/dynamic and chronic phases; the treatment effect varies depending on disease phase and the causative mtDNA mutation. The findings of the LEROS study will help guide the clinical management of patients with LHON

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Assessing the Impact of Long-Term Idebenone Treatment in Chronic Leber's Hereditary Optic Neuropathy: Results from the LEROS Study

Preservation and/or recovery of functional visual acuity (VA) are desirable outcomes for patients with Leber's hereditary optic neuropathy (LHON). In LEROS, VA outcomes following 24 months of idebenone treatment were compared to an external, matched, natural history (NH) cohort. Here, we report VA outcome results from LEROS in the chronic phase

Early response to the treatment of choroidal neovascularization complicating central serous chorioretinopathy: a OCT-angiography study

PURPOSE: To analyze the quantitative and qualitative early changes of choroidal neovascularization (CNV) associated with chronic central serous chorioretinopathy (CSC) after treatment using optical coherence tomography-angiography (OCT-A). METHODS: Charts of consecutive patients with diagnosis of chronic CSC complicated by CNV were retrospectively reviewed. Included patients were divided in photodynamic therapy (PDT) or aflibercept group on the basis of the treatment received (half-fluence PDT or aflibercept 2.0\u2009mg/0.05\u2009ml intravitreal injection). Main outcome measures included the changes between baseline and 1-month follow-up in CNV vessel density (VD) and area on OCT-A images after thresholding and binarization. RESULTS: A total of 30 eyes of 26 Caucasian patients were included: 17 eyes of 15 patients in PDT group (mean age 53\u2009\ub1\u200911 years) and 13 eyes of 11 patients in aflibercept group (mean age 58\u2009\ub1\u20098 years [p\u2009=\u20090.196]). In both PDT and aflibercept groups, best-corrected visual acuity improved at 1 month, and central macular thickness and subretinal fluid significantly decreased. VD did not change after the treatment in both groups (p\u2009=\u20090.502 and p\u2009=\u20090.086) although CNV area decreased significantly (from 0.586\u2009\ub1\u20090.449\u2009mm2 to 0.553\u2009\ub1\u20090.453\u2009mm2 [0.041]) in the PDT group, and nonsignificantly (from 0.767\u2009\ub1\u20090.466\u2009mm2 to 0.733\u2009\ub1\u20090.472\u2009mm2 [p\u2009=\u20090.095]) in the aflibercept group. The same results were confirmed in the subanalysis of the 18 treatment-na\uefve eyes. CONCLUSIONS: We demonstrated that, despite all patients showed a favorable clinical response, VD of CNVs complicating chronic CSC did not change after treatment. These findings support the idea that arteriogenesis is the main driving force of CNV in pachychoroid-related macular disorders

Retinal arterial dilation is impaired in eyes with drusen and reticular pseudodrusen

Purpose: To analyze static characteristics and dynamic functionality of retinal vessels in eyes with drusen and reticular pseudodrusen (RPD) using dynamic vessel analyzer.Methods:Patients with clinical diagnosis of isolated RPD or medium-large drusen and healthy controls were enrolled in the study between July 2016 and May 2018. Participants underwent complete ophthalmologic examination, including enhanced depth imaging structural optical coherence tomography, dynamic retinal vessel analysis, and static retinal vessel analysis.Results:Twenty-eight eyes of 23 patients with drusen (9 men, mean age 77 ± 6 years), 22 eyes of 16 patients with RPD (7 men, mean age: 76 ± 6 years), and 22 eyes of 22 control subjects (11 men, mean age of 75 ± 6 years) were enrolled. Static retinal vessel analysis did not show any significant difference between the three groups for the central retinal artery equivalent (P = 0.11), the central retinal vein equivalent (P = 0.27), and the arteriovenous ratio (P = 0.30). Dynamic vessel analysis showed significantly reduced arterial dilation in eyes with drusen (P = 0.0001) and RPD (P = 0.015) compared with control subjects. No significant difference was seen between drusen and RPD groups (P = 0.32). Dynamic vessel analysis of retinal veins showed no differences between the three groups (P = 0.10).Conclusion:Dynamic vessel analysis in eyes with drusen and RPD revealed an impaired retinal arterial dilation in response to flicker light stimulation, which further supports the relationship between cardiovascular risk and age-related macular degeneration