Improving medication dispensing and counselling for patients with vision impairment: a qualitative study of pharmacist-reported barriers and facilitators.

BACKGROUND: People with vision impairment encounter many difficulties when it comes to medicines use. However, evidence indicates that there are major gaps in pharmaceutical care service provision worldwide and limited research on interventions to optimise medication use for this patient population. The Theoretical Domains Framework (TDF) provides a method for theoretically understanding individuals' behaviour and informing development of interventions. The aim of this research was to (a) identify the barriers and facilitators to the provision of medication dispensing and counselling services by pharmacists to patients with vision impairment, and (b) identify key TDF domains to be targeted in a future intervention. METHODS: Semi-structured interviews were conducted with pharmacists from different pharmacy practice settings/areas in Saudi Arabia. The 14-domain TDF was utilised as the theoretical lens through which pharmacists' behaviours were examined. Interviews were conducted in Arabic or English, either face-to-face or over the telephone based on the participant's preference. Following transcription, interviews conducted in Arabic were translated into English before analysis. Data analysis involved using the framework method and content analysis to identify important barriers and facilitators to the provision of dispensing and counselling services to those with vision impairment. Key TDF domains that could be targeted in a future intervention were then identified using a consensus-based approach. RESULTS: Twenty-six pharmacists were interviewed. Pharmacists' experience in pharmacy practice ranged from two to 28 years. A range of barriers and facilitators were highlighted as important in providing services to those with vision impairment. Eight domains were identified as 'key domains' including: 'Knowledge', 'Skills', 'Beliefs about capabilities', 'Goals', 'Memory, attention, and decision processes', 'Environmental context and resources', 'Social influences', and 'Behavioural regulation'. CONCLUSIONS: Barriers and facilitators identified by pharmacists will inform the development of an intervention to ensure its applicability to everyday practice. Future research will focus on the process of developing the proposed intervention through targeting key TDF domains to improve medication dispensing and counselling by pharmacists to patients with vision impairment.

SEVERE VISUAL LOSS DURING ANTI-VEGF INTRAVITREAL INJECTIONS IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: TIMING, PROGNOSIS, AND OPTICAL COHERENCE TOMOGRAPHY FINDINGS.

PURPOSE: Intravitreal injection (IVI) of anti-vascular endothelial growth factor (VEGF) is the standard of care for neovascular age-related macular degeneration (nAMD). However, a small subgroup of patients still experience severe visual impairment, which may be related to the number of IVI administered. METHODS: This retrospective observational study analyzed data from patients with sudden severe visual decline (≥15 Early Treatment Diabetic Retinopathy Study [ETDRS] letters loss between two consecutive IVIs) during anti-VEGF treatment for nAMD. Best-corrected visual acuity examination, optical coherence tomography (OCT), and OCT angiography (OCTA) were performed before every IVI and central macular thickness (CMT) and drug injected were collected. RESULTS: 1,019 eyes received anti-VEGF IVI for nAMD from December 2017 to March 2021. Severe VA loss occurred in 15.1% after a median of 6 (range 1-38) IVI. Ranibizumab was injected in 52.8% and aflibercept in 31.9% of cases. Functional recovery after 3 months was significant, without further improvement at 6 months. Visual prognosis relative to the percentage of CMT change showed better visual outcome in eyes with no substantial change in CMT compared with an increase of >20% or a decrease of >5%. CONCLUSION: In this first real-life study exploring severe VA loss during anti-VEGF treatment in patients with nAMD, it was found that it was not unusual for a ≥15 ETDRS letters loss to occur between two consecutive IVIs, often within 9 months of diagnosis and 2 months after the last IVI. Close follow-up and a proactive regimen should be preferred, at least in the first year.

Long-Term Outcomes of High-Dose Conbercept Treatment for Myopic Choroidal Neovascularization and Idiopathic Choroidal Neovascularization.

INTRODUCTION: The aim of the study was to report 2-year outcomes of intravitreal injection of high-dose conbercept (1 mg 2 + PRN scheme) for subjects with myopic choroidal neovascularization (mCNV) and idiopathic choroidal neovascularization (iCNV) by optical coherence tomography angiography follow-up. METHODS: A total of 38 subjects (38 eyes) were enrolled in this retrospective study, which were divided into group A (mCNV, 20 subjects, 20 eyes) and group B (iCNV, 18 subjects, 18 eyes). All subjects received 1.0 mg of conbercept intravitreally at diagnosis and again 35 days later. Additional conbercept injection was administered upon findings of decreased best-corrected visual acuity (BCVA); metamorphosis aggravation, macular hemorrhage, or edema; increased central retinal thickness (CRT); or leakage observed by fluorescein angiography. The BCVA, CRT, and CNV areas of the two groups were evaluated at baseline and at 1, 2, 4, 6, 12, and 24 months after surgery. RESULTS: The BCVA of group A improved from 0.31 ± 0.16 logMAR at baseline to 0.12 ± 0.03 logMAR at the final follow-up (p < 0.001), while in group B the corresponding improvement was from 0.33 ± 0.16 logMAR at baseline to 0.12 ± 0.03 logMAR at the final follow-up (p < 0.001). Visual acuity improved in 17 subjects in group A and 15 in group B, while it remained stable in 3 subjects in each of groups A and B. CRT decreased from 311.83 ± 30.95 µm in group A and 351.17 ± 37.09 µm in group B preoperation to 229.56 ± 5.75 µm and 227.67 ± 4.98 µm at 24-month follow-up, respectively (p < 0.001 in groups A and B). Metamorphopsia was improved in subjects in groups A and B. CNV had disappeared in the two groups at the last postoperative visit. The BCVA, CRT, and CNV areas showed no statistical differences between the two groups at 6-, 12-, and 24-month follow-up (p > 0.05). CONCLUSION: Intravitreal injection of conbercept (1 mg 2 + PRN scheme) is effective for treating patients with mCNV or iCNV, which can improve and stabilize vision as well as dramatically alleviate metamorphopsia.

Real-World Outcomes of Ranibizumab Treatment in French Patients with Visual Impairment due to Macular Edema Secondary to Retinal Vein Occlusion: 24-Month Results from the BOREAL-RVO Study.

INTRODUCTION: Information about real-world ranibizumab use is needed to optimize treatment of macular edema secondary to retinal vein occlusion (RVO). The BOREAL-RVO study assessed treatment use, effectiveness, and safety of 24-month treatment with ranibizumab 0.5 mg in patients with visual impairment due to macular edema secondary to RVO in a real-world setting. METHODS: This was a multicenter, post-authorization, observational study in France, including patients starting ranibizumab for RVO. Primary endpoint was mean change from baseline in best-corrected visual acuity (BCVA) at month 6. Secondary endpoints were mean changes from baseline in BCVA at month 24 and central retinal thickness (CRT) at months 6 and 24, and treatment use in real-world setting. RESULTS: 226 branch RVO (BRVO) and 196 central RVO (CRVO) patients were enrolled; 71.7% and 70.9% completed the 24-month follow-up, respectively. In BRVO, mean (SD) baseline BCVA was 55.2 (18.7) letters, with gains of 14.3 (13.7), 14.1 (16.5), 13.0 (17.5), and 11.4 (20.1) letters at months 3, 6, 12, and 24, respectively. In CRVO, mean (SD) baseline BCVA was 40.4 (25.6) letters, with gains of 16.0 (21.2), 9.5 (25.4), 9.2 (27.7), and 8.3 (23.8) letters at months 3, 6, 12, and 24, respectively. At month 24, 52% of BRVO and 41% of CRVO patients had gains of 15 or more letters. In BRVO, mean (SD) CRT values at baseline and months 3, 6, 12, and 24 were 550 (175), 315 (104), 343 (122), 335 (137), and 340 (105) µm. In CRVO, mean (SD) CRT values at baseline and months 3, 6, 12, and 24 were 643 (217), 327 (152), 400 (203), 379 (175), and 348 (161) µm. On average, BRVO patients had 3.8 injections for 6.9 visits by month 6, and 7.2 injections for 19.7 visits by month 24. CRVO patients had 2.7 injections for 4.2 visits by month 6 and 7.1 injections for 21.1 visits by month 24. Factors predictive of better BCVA gain at month 6 were age under 60 at baseline, lower baseline BCVA and BCVA gain at month 3. There were no new safety findings. CONCLUSION: Major improvements in BCVA and CRT were observed at month 3 after the induction phase and then were sustained up to month 24, with a slight decrease, probably due to under-treatment. This study demonstrated ranibizumab to be a safe and effective treatment for BRVO and CRVO in the real-world setting, although more regular or proactive treatment could further improve outcomes.

Four-Year Visual Outcomes in the Protocol W Randomized Trial of Intravitreous Aflibercept for Prevention of Vision-Threatening Complications of Diabetic Retinopathy.

Importance: Anti-vascular endothelial growth factor (VEGF) injections in eyes with nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) reduce development of vision-threatening complications from diabetes over at least 2 years, but whether this treatment has a longer-term benefit on visual acuity is unknown. Objective: To compare the primary 4-year outcomes of visual acuity and rates of vision-threatening complications in eyes with moderate to severe NPDR treated with intravitreal aflibercept compared with sham. The primary 2-year analysis of this study has been reported. Design, Setting, and Participants: Randomized clinical trial conducted at 64 clinical sites in the US and Canada from January 2016 to March 2018, enrolling 328 adults (399 eyes) with moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study [ETDRS] severity level 43-53; range, 0 [worst] to 100 [best]) without CI-DME. Interventions: Eyes were randomly assigned to 2.0 mg aflibercept (n = 200) or sham (n = 199). Eight injections were administered at defined intervals through 2 years, continuing quarterly through 4 years unless the eye improved to mild NPDR or better. Aflibercept was given in both groups to treat development of high-risk proliferative diabetic retinopathy (PDR) or CI-DME with vision loss. Main Outcomes and Measures: Development of PDR or CI-DME with vision loss (≥10 letters at 1 visit or ≥5 letters at 2 consecutive visits) and change in visual acuity (best corrected ETDRS letter score) from baseline to 4 years. Results: Among participants (mean age 56 years; 42.4% female; 5% Asian, 15% Black, 32% Hispanic, 45% White), the 4-year cumulative probability of developing PDR or CI-DME with vision loss was 33.9% with aflibercept vs 56.9% with sham (adjusted hazard ratio, 0.40 [97.5% CI, 0.28 to 0.57]; P < .001). The mean (SD) change in visual acuity from baseline to 4 years was -2.7 (6.5) letters with aflibercept and -2.4 (5.8) letters with sham (adjusted mean difference, -0.5 letters [97.5% CI, -2.3 to 1.3]; P = .52). Antiplatelet Trialists' Collaboration cardiovascular/cerebrovascular event rates were 9.9% (7 of 71) in bilateral participants, 10.9% (14 of 129) in unilateral aflibercept participants, and 7.8% (10 of 128) in unilateral sham participants. Conclusions and Relevance: Among patients with NPDR but without CI-DME at 4 years treatment with aflibercept vs sham, initiating aflibercept treatment only if vision-threatening complications developed, resulted in statistically significant anatomic improvement but no improvement in visual acuity. Aflibercept as a preventive strategy, as used in this trial, may not be generally warranted for patients with NPDR without CI-DME. Trial Registration: ClinicalTrials.gov Identifier: NCT02634333.

[Diagnostic and Therapeutic Management of Episcleritis and Scleritis]. / Diagnostisches und therapeutisches Management der Episkleritis und Skleritis.

While episcleritis is a benign disease only affecting the episclera, scleritis is an ocular inflammation with typically severe pain and not rarely affecting adjacent tissue.Scleritis is classified into anterior and posterior forms. Anterior scleritis is further subdivided into diffuse, nodular, necrotizing with inflammation, and necrotizing scleritis without inflammation (scleromalacia perforans). A systemic disease such as rheumatoid arthritis or granulomatosis with polyangiitis is associated with up to 50% of all patients with scleritis or episcleritis, consequently a systemic work-up with blood sampling and imaging as well as collaboration with internists are necessary.Differentiating these two entities is of high importance for planning the treatment: episcleritis has a self-limited course, whereas treatment of scleritis is obligatory to protect patients from irreversible visual loss, organ damage, and furthermore reduce the risk of mortality.Treatment depending of subtype and associated systemic disease may involve non-steroidal anti-inflammatory drugs, corticosteroids, and disease-modifying anti-rheumatic drugs.

A CONSENSUS ON RISK MITIGATION FOR BROLUCIZUMAB IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: Patient Selection, Evaluation, and Treatment.

PURPOSE: Brolucizumab has high efficacy in retinal fluid resolution and provides the possibility for longer dosing intervals in the treatment of neovascular age-related macular degeneration. However, brolucizumab has been associated with events of retinal vasculitis and retinal vascular occlusion typically in the presence of other signs of intraocular inflammation (IOI). The purpose of this report is to provide guidance on the use of brolucizumab for neovascular age-related macular degeneration to a global audience. METHODS: A literature review was conducted on adverse events related to IOI after administration of brolucizumab in eyes with neovascular age-related macular degeneration. RESULTS: Possible risk factors for IOI and retinal vascular occlusion after brolucizumab should be considered before administering brolucizumab. Patients who receive brolucizumab should be educated on the symptoms, signs, and time course of IOI after brolucizumab. Before each injection of brolucizumab, physicians should assess the eye for any signs of inflammation and not treat with brolucizumab if inflammation is detected. Treatment of IOI should be prompt and provided with particular attention to the posterior segment. CONCLUSION: Careful patient selection, patient education, assessment for inflammation, and intensive treatment of possible inflammation are important when using brolucizumab in patients with neovascular age-related macular degeneration.

A randomized phase 2 clinical trial of phentolamine mesylate eye drops in patients with severe night vision disturbances.

PURPOSE: Dim light vision disturbances (DLD) comprise a wide range of symptoms affecting the quality of vision at low illumination including glare, halos, and starbursts. This exploratory study investigated 1.0% phentolamine mesylate ophthalmic solution (PMOS) as a treatment to improve vision and image quality for patients with DLD. METHODS: In this placebo-controlled, randomized, double-masked clinical trial, 24 adult patients with severe DLD were randomized in a 2:1 ratio to receive either one dose of PMOS or placebo. Subjects were eligible if they reported experiencing severe night vision difficulty that was not eliminated by distance spectacle correction and scored ≥0.3 log units below the normal range of contrast sensitivity assessed under mesopic conditions with glare at ≥2 spatial frequencies. Key efficacy outcomes were change from baseline in pupil diameter, contrast sensitivity, and visual acuity. Safety measures including intraocular pressure, conjunctival hyperemia, and systemic effects were also assessed. RESULTS: Eight subjects were randomized to placebo (63% female; mean age 47 years) and 16 were randomized to PMOS (75% female; mean age 42 years). Mean (SD) pupil diameter of PMOS-treated subjects decreased significantly - 1.3 mm (0 to - 2.8 mm) with p < 0.0001. Mean contrast sensitivity with glare in PMOS-treated subjects improved significantly post-treatment at spatial frequencies 3, 6, 12, and 18 cycles per degree (p ≤ 0.03). PMOS also demonstrated improvements in the numbers of letters read for mesopic and photopic, high- and low-contrast visual acuity (LCVA). Importantly, a statistically greater proportion of PMOS-treated eyes registered mesopic LCVA 5 letter (69% vs. 31%, p = 0.029) and 10 letter (34% vs. 6%, p = 0.04) improvement, with a trend at 15 letters (19% vs. 0%, p = 0.16). PMOS was well tolerated with the only reported side effect being a mild increase in conjunctival hyperemia. CONCLUSION: PMOS was well tolerated and effectively reduced pupil size with improvements in contrast sensitivity and visual acuity in adults with severe DLD. Future Phase 3 studies should be conducted to further evaluate its potential to treat DLD. TRIAL REGISTRATION: The trial registration number is NCT04004507 (02/07/2019). Retrospectively registered.

Real-World Outcomes after 36-Month Treatment with Ranibizumab 0.5 mg in Patients with Visual Impairment due to Diabetic Macular Edema (BOREAL-DME).

PURPOSE: To assess the efficacy, safety, and follow-up of 36-month treatment with ranibizumab in patients with diabetic macular edema (DME) in real-life setting. METHODS: This is a prospective phase 4 observational study. Between December 2013 and April 2015, 84 ophthalmologists enrolled a total of 290 adult patients initiating ranibizumab for visual impairment due to DME and treated them according to their routine practice. The primary outcome (mean change in best-corrected visual acuity [BCVA] after 12 months) was previously reported. Here, we present outcomes after 36 months of follow-up for BCVA and change in central subfield thickness (CSFT) and report how participating ophthalmologists treated DME over a 3-year period (number of visits and injections and evolution of treatment strategy). RESULTS: Of the 290 patients enrolled, 187 (64.5%) completed the 36 months of the study (entire cohort). In the entire cohort, 97 patients were treated exclusively with ranibizumab throughout the study, and 90 patients switched to other intravitreal treatments. Mean BCVA was 64.2 (20.1) letters, representing a gain of +4.1 (19.9) letters from baseline to month 36 (M36). CSFT improved over the study, and by M36 had decreased by 127 (138) µm compared to baseline. Over the 36 months of follow-up, patients in the entire cohort paid their ophthalmologists a mean of 30.9 (12.2) visits and had a mean of 7.6 (5.2) any injections. Results for quality of life questionnaires NEI-VFQ25 and HUI-3 remained stable throughout the study. Multivariate analysis on the 145 patients with evaluable BCVA data at M36 found that male gender and milder baseline DME characteristics (BCVA ≥59 and CSFT <500 µm) were predictive factors for achieving a BCVA of ≥70 letters at M36. This study did not find any new safety signals, compared to the known profile of ranibizumab. CONCLUSIONS: Gains in BCVA in this real-life study were lower than those observed in randomized clinical trials with ranibizumab, mainly due to undertreatment. Safety analysis of ranibizumab did not yield any new safety concerns.

Aptamers as Therapeutics.

Aptamers are single-stranded nucleic acid molecules that bind to and inhibit proteins and are commonly produced by systematic evolution of ligands by exponential enrichment (SELEX). Aptamers undergo extensive pharmacological revision, which alters affinity, specificity, and therapeutic half-life, tailoring each drug for a specific clinical need. The first therapeutic aptamer was described 25 years ago. Thus far, one aptamer has been approved for clinical use, and numerous others are in preclinical or clinical development. This review presents a short history of aptamers and SELEX, describes their pharmacological development and optimization, and reviews potential treatment of diseases including visual disorders, thrombosis, and cancer.

Case Report: Posterior Uveitis after Divalent Human Papillomavirus Vaccination in an Asian Female.

SIGNIFICANCE: Vaccine-associated uveitis has appeared in recent years because of various vaccines, whereas cases for human papillomavirus (HPV) vaccination were rarely reported. With more and more females becoming aware of its importance and choosing HPV vaccination, much more attention should be paid on the adverse effects of it. PURPOSE: The purpose of this study was to report a rare case of posterior uveitis after divalent HPV vaccination in an Asian female. CASE REPORT: A 29-year-old woman presented with acute vision loss accompanied by symptoms of headache, tinnitus, and myalgia after the third injection of HPV vaccination. The best-corrected visual acuity dropped to 20/500 for both eyes, and optical coherence tomography revealed bilateral multifocal submacular fluid. A short course of oral prednisone as well as Ozurdex intravitreal injection resulted in the reversal of all signs and symptoms. CONCLUSIONS: Although this case resembled Harada disease, we diagnosed it as vaccine-induced uveitis rather than coincidental autoimmune disease based on the rapid response to a short course of systemic corticosteroids. Because vaccine-induced uveitis is rare and difficult to distinguish from coincidental autoimmune disease, our case reminds eye care providers to be aware of the possible association between vaccination and a Harada-like reaction and to ask appropriately directed questions when obtaining history from young patients with uveitis. Based on this case, we also suggest Ozurdex intravitreal injection as a potential therapeutic choice, especially for patients with contraindication or personal concern to systemic corticosteroid.

A 5-Year Review of Acanthamoeba Keratitis Related to Wearing Contact Lenses in Korea.

PURPOSE: To investigate the presentation, clinical characteristics, and outcomes of Acanthamoeba keratitis (AK) in Busan, South Korea, over a 5-year period. METHODS: This retrospective study involved a review of the medical records of 16 patients (19 eyes in total) who were diagnosed with AK, related to wearing contact lenses, at the tertiary hospital, Pusan National University Hospital at Busan City, from December 2013 to December 2018. RESULTS: Nineteen eyes of 16 patients with a diagnosis of AK were identified. The average age of the patients was 21.1±12.6 years; there were 2 men and 14 women. The mean period from the onset of the first symptoms to diagnosis was 7.0±6.5 days. The average initial visual acuity was 0.78±0.37 (tested on a logarithm of the minimum angle of resolution chart), and the final visual acuity after treatment was 0.07±0.07, indicating a significant improvement (P=0.001). A variety of corneal lesions were identified. Early diagnosis of AK was associated with a significantly better final visual acuity. CONCLUSION: The average therapeutic period for AK, when a surface epithelial lesion of the cornea was identified, was 4 months compared with an average period of over 6 months for a deeper stromal lesion. Therefore, this study highlights the fundamental importance of early diagnosis, preventing deeper layers of the cornea from being affected, and appropriate management to ensure a favorable outcome.

A Novel Eye Drop Candidate for Age-Related Macular Degeneration Treatment: Studies on its Pharmacokinetics and Distribution in Rats and Rabbits.

Age-related macular degeneration (AMD) is wearing down of macula of retina, causing a blur or loss of vision in the center of the visual field. It can be categorized into dry or wet AMD. Until now, medical treatments for dry AMD have not been developed yet. The aim of this study was to evaluate pharmacokinetics (PKs) and tissue distribution of CK41016, a novel candidate for dry AMD, after intravenous (IV) or eye drop administration in rats and rabbits. In addition, a simple and sensitive bioanalytical method for CK41016 using ultra performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) was developed. PK parameters were estimated by compartmental analysis using a WinNonlin® software version 8.1 (a Certara™ company). A PK model of CK41016 was well-described by the two-compartment model. The tissue-to-plasma partition coefficient (Kp) of CK41016 was the highest in the vitreous humor of rats and the cornea of rabbits after eye drop administration. In addition, the Caco-2 cell transporter assay confirmed that CK41016 was not an active substrate for the efflux transporter. In summary, the PKs and tissue distribution of CK41016 were successfully evaluated and investigated whether this drug was a substrate of efflux transporters.

A Randomized, Double-Masked, Multicenter, Phase III Study Assessing the Efficacy and Safety of Brolucizumab versus Aflibercept in Patients with Visual Impairment due to Diabetic Macular Edema (KITE).

BACKGROUND: Brolucizumab is a single-chain variable antibody fragment (scVF) that specifically binds to VEGF-A. The results of two large phase III, multicentre, randomized clinical trials comparing intravitreal treatment with Brolucizumab and Aflibercept in neovascular age-related degeneration demonstrated its potency in the treatment of neovascular age-related macular degeneration (nAMD). METHODS: The currently tested injected dose of 6 mg Brolucizumab results in a 11.2 - 13.3 times higher equivalent molar dose compared to Aflibercept 2 mg. Thus, it is conceivable that the effect of Brolucizumab in DME exceeds that of other currently used anti-VEGF agents with regards to effect durability; this was confirmed for nAMD in a phase I/II study. RESULTS: Approved anti-VEGF drugs have shown unprecedented success compared to laser treatment with regards to restoration of visual acuity and improvement of diabetic retinopathy severity scores for up to 5 years. The visual gains were sustained after the loading phase and a reduced number of injections were required after the first year independent of the treatment strategy. Compared to pan-retinal laser photocoagulation, the time to progression of DRP was markedly extended and was proven by better preservation of the visual field, prevention of severe vision loss, hemorrhagic complications, and the need for intraocular surgery. CONCLUSIONS: The ongoing prospective, randomized, phase III clinical studies in DME, KITE, and KESTREL aim to confirm the non-inferiority of Brolucizumab 6 mg compared to Aflibercept 2 mg on a functional and morphological level as well as durability effect over 2 years.

Amelioration of visual deficits and visual system pathology after mild TBI with the cannabinoid type-2 receptor inverse agonist SMM-189.

Mild TBI is often accompanied by visual system dysfunction and injury, which is at least partly caused by microglial neuroinflammatory processes initiated by the injury. Using our focal cranial blast mouse model of closed-skull mild TBI, we evaluated the ability of the cannabinoid type-2 (CB2) receptor inverse agonist SMM-189, which biases microglia from the harmful M1 state to the beneficial M2 state, to mitigate visual system dysfunction and injury after TBI. Male C57BL/6 or Thy1-EYFP reporter mice received a closed-head blast of either 0-psi (sham) or 50-psi to the left side of the cranium. Blast mice received vehicle or 6 mg/kg SMM-189 daily beginning 2 h after blast. Sham mice received vehicle. In some mice, retina and optic nerve/tract were assessed morphologically at 3-7 days after blast, while other mice were assessed functionally by Optomotry 30 days after blast and morphologically at ≥30 days after blast. Mice sacrificed at 3-7 days were treated daily until sacrificed, while those assessed ≥30 days after blast were treated daily for 2 weeks post blast. Axon damage was evident in the left optic nerve and its continuation as the right optic tract at 3 days post blast in vehicle-treated blast mice in the form of swollen axon bulbs, and was accompanied by a significant increase in the abundance of microglia. Testing at 30 days post blast revealed that the contrast sensitivity function was significantly reduced in both eyes in vehicle-treated blast mice compared to vehicle-treated sham blast mice, and axon counts at ≥30 days after blast revealed a ∼10% loss in left optic nerve in vehicle-treated blast mice. Left optic nerve axon loss was highly correlated with the left eye deficit in contrast sensitivity. Immunolabeling at 30 days post blast showed a significant increase in the abundance of microglia in the retinas of both eyes and in GFAP + Müller cell processes traversing the inner plexiform layer in the left eye of vehicle-treated blast mice. SMM-189 treatment reduced axon injury and microglial abundance at 3 days, and mitigated axon loss, contrast sensitivity deficits, microglial abundance, and Müller cell GFAP upregulation at ≥30 days after blast injury. Analysis of right optic tract microglia at 3 days post blast for M1 versus M2 markers revealed that SMM-189 biased microglia toward the M2 state, with this action of SMM-189 being linked to reduced axonal injury. Taken together, our results show that focal left side cranial blast resulted in impaired contrast sensitivity and retinal pathology bilaterally and optic nerve loss ipsilaterally. The novel cannabinoid drug SMM-189 significantly mitigated the functional deficit and the associated pathologies. Our findings suggest the value of combatting visual system injury after TBI by using CB2 inverse agonists such as SMM-189, which appear to target microglia and bias them away from the pro-inflammatory M1 state, toward the protective M2 state.

OLIMPIC: a 12-month study on the criteria driving retreatment with ranibizumab in patients with visual impairment due to myopic choroidal neovascularization.

PURPOSE: To evaluate criteria driving retreatment with ranibizumab in Italian patients with myopic choroidal neovascularization (mCNV). METHODS: OLIMPIC was a 12-month, phase IIIb, open-label study. Patients with active mCNV were treated with ranibizumab 0.5 mg according to the European label. The study assessed local criteria in Italy driving retreatment decisions with ranibizumab; and the efficacy, safety, and tolerability of ranibizumab. RESULTS: The mean (standard deviation [SD]) age of treated patients (N = 200) was 61.8 (12.7) years; range 22-85 years. The multivariate regression model indicated that presence of active leakage (odds ratio [OR] 95% confidence interval [CI]: 11.30 [1.03-124.14]), presence of intraretinal fluid (OR [95%CI]: 28.21 [1.55-513.73]), and an improvement in best-corrected visual acuity (BCVA) from baseline < 10 letters (OR [95%CI]: 17.60 [1.39-222.75]) were the factors with the greatest effect on retreatment with ranibizumab. The mean (SD) BCVA gain from baseline to month 12 was 8.4 (12.8) letters (P < 0.0001). The mean (SD) number of injections was 2.41 (1.53); range 1-9. Ocular and non-ocular adverse events were reported in 41 (20.5%) and 30 (15.0%) patients, respectively. CONCLUSIONS: Individualized treatment with ranibizumab was effective in improving BCVA in patients with mCNV over 12 months. Both anatomical and functional variables had significant effects on causing retreatment. There were no new safety findings. TRIAL REGISTRATION: www.ClinicalTrials.Gov (NCT No: NCT02034006).

Efficacy and safety of ranibizumab 0.5 mg in Chinese patients with visual impairment due to diabetic macular edema: results from the 12-month REFINE study.

PURPOSE: To demonstrate the efficacy and safety of ranibizumab 0.5 mg pro re nata (PRN) versus laser photocoagulation for the treatment of Chinese patients with visual impairment due to diabetic macular edema (DME). METHODS: REFINE was a phase III, 12-month, double-masked, multicenter, laser-controlled study in patients (aged ≥ 18 years) with DME. Patients were randomized 4:1 to receive either ranibizumab 0.5 mg or laser dosing regimen. Efficacy was evaluated as mean average change in best-corrected visual acuity (BCVA) from Months 1 to 12 versus baseline (primary endpoint), anatomical outcomes, treatment exposure, and safety were also assessed. RESULTS: Ranibizumab was statistically superior (p < 0.001) to laser treatment, with a mean average BCVA gain of 6.8 letters (ranibizumab) over 12 months versus 1.1 letters (laser). At Month 12, mean BCVA gain was 7.8 letters (ranibizumab) and 2.5 letters (laser) from baseline. Patients in the ranibizumab arm received a mean number of 7.9 intravitreal injections, whereas those in the laser arm received a mean of 2.1 treatments. There were no new safety signals. CONCLUSION: Ranibizumab 0.5 mg PRN demonstrated a statistically significant and clinically meaningful treatment effect versus laser and was well tolerated in Chinese patients with visual impairment due to DME over 12 months.

LONG-TERM VISUAL CHANGES IN INITIALLY STRONGER FELLOW EYES IN PATIENTS WITH UNILATERAL TYPE 3 NEOVASCULARIZATION.

PURPOSE: To evaluate long-term visual changes in initially stronger fellow eyes in patients with unilateral Type 3 neovascularization. METHODS: This retrospective study included 102 patients who were newly diagnosed with unilateral Type 3 neovascularization and in whom the best-corrected visual acuity (BCVA) of the fellow eye was initially better than that of the involved eye. All patients were treated with intravitreal anti-vascular endothelial growth factor injections. The BCVAs were compared at diagnosis, 12 months, 24 months, and the final visit. In patients who experienced ≥3 lines of visual deterioration in the BCVA of the fellow eye, the reason for visual deterioration was also verified. RESULTS: The patients were followed for 45.9 ± 18.5 months after diagnosis. At diagnosis, the fellow-eye BCVA was better than that of the initially involved eye in all 102 patients. However, the fellow-eye visual acuity was the same or worse than that of the initially involved eye in 13 patients (12.7%) at 12 months, in 20 patients (19.6%) at 24 months, and in 24 patients (23.5%) at the final visit. At the final visit, 53 patients (51.9%) had experienced ≥3 lines of deterioration in the BCVA of the fellow eye. Fellow-eye neovascularization occurred in 42 patients, and geographic atrophy involving the fovea was noted in the remaining 11 patients. CONCLUSION: Deterioration of the visual acuity of the fellow eye is frequently noted in unilateral Type 3 neovascularization. As a result of this deterioration, the initially stronger fellow eye did not remain stronger in 23.5% of the patients, suggesting the need for long-term strict treatment of the initially involved eye even when the visual acuity of the fellow eye is good.

INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR TREATMENT AT 2-MONTH INTERVALS REDUCES FOVEAL AVASCULAR ZONE ENLARGEMENT AND VISION LOSS IN RADIATION MACULOPATHY: A Pilot Study.

PURPOSE: To evaluate, in eyes with radiation maculopathy, the effect of 2-month-interval anti-vascular endothelial growth factor therapy on best-corrected visual acuity and foveal avascular zone (FAZ) enlargement using optical coherence tomography angiography. METHODS: Consecutive treatment-naive patients with radiation maculopathy after proton beam irradiation for choroidal melanoma were retrospectively included. Clinical and optical coherence tomography angiography data at baseline and the 6-month visit were recorded. Two independent observers measured FAZ area manually on 3 × 3-mm optical coherence tomography angiography images of the superficial capillary plexus and deep capillary plexus. Patients were encouraged to follow strictly a 2-month-interval intravitreal anti-vascular endothelial growth factor treatment by either bevacizumab or ranibizumab. Findings were analyzed based on the adherence to the treatment scheme. RESULTS: According to the adherence to the bimonthly anti-vascular endothelial growth factor treatment protocol, patients were categorized into 3 groups: treatment protocol (n = 19, strict adherence), variable intervals (n = 11, intervals other than 2 months), and no treatment (n = 11). The estimated radiation dose to the foveola in each group was 49 ± 16, 46 ± 17, and 46 ± 18 cobalt gray equivalent, respectively (P = 0.85). For the entire cohort, best-corrected visual acuity loss (P < 0.02) and FAZ enlargement (P < 0.0001) were observed over 6 months. Best-corrected visual acuity loss was significantly less pronounced in the treatment-protocol group than in the variable-interval and no-treatment groups (P = 0.007 and P = 0.004). The FAZ enlargement was lower in the treatment-protocol group compared with the variable-interval group for both superficial capillary plexus (P = 0.029) and deep capillary plexus (P = 0.03), and to the no-treatment group for the deep capillary plexus only (P = 0.016). CONCLUSION: Decrease in best-corrected visual acuity and FAZ enlargement on optical coherence tomography angiography occurred over 6 months in eyes with radiation maculopathy and were significantly reduced under 2-month-interval anti-vascular endothelial growth factor therapy.

Inhibitors of the Neutral Amino Acid Transporters ASCT1 and ASCT2 Are Effective in In Vivo Models of Schizophrenia and Visual Dysfunction.

The N-methyl-d-aspartate receptor coagonist d-serine is a substrate for the neutral amino acid transporters ASCT1 and ASCT2, which may regulate its extracellular levels in the central nervous system (CNS). We tested inhibitors of ASCT1 and ASCT2 for their effects in rodent models of schizophrenia and visual dysfunction, which had previously been shown to be responsive to d-serine. L-4-fluorophenylglycine (L-4FPG), L-4-hydroxyPG (L-4OHPG), and L-4-chloroPG (L-4ClPG) all showed high plasma bioavailability when administered systemically to rats and mice. L-4FPG showed good brain penetration with brain/plasma ratios of 0.7-1.4; however, values for L-4OHPG and L-4ClPG were lower. Systemically administered L-4FPG potently reduced amphetamine-induced hyperlocomotion in mice, whereas L-4OHPG was 100-fold less effective and L-4ClPG inactive at the doses tested. L-4FPG and L-4OHPG did not impair visual acuity in naive rats, and acute systemic administration of L-4FPG significantly improved the deficit in contrast sensitivity in blue light-treated rats caused by retinal degeneration. The ability of L-4FPG to penetrate the brain makes this compound a useful tool to further evaluate the function of ASCT1 and ASCT2 transporters in the CNS.