Sex as a risk factor regarding presbyopia in the rhesus monkey.

PURPOSE: To determine the effect of sex as a risk factor regarding presbyopia. METHODS: Maximum accommodation was pharmacologically induced (40% cabachol corneal iontophoresis) in 97 rhesus monkeys (49 males and 48 females) ranging in age from 8 to 36 years old. Accommodation was measured by Hartinger coincidence refractometry. RESULTS: Accommodative amplitude measured refractometrically decreased with age, and the rate of change was not different between males and females (p = 0.827). CONCLUSIONS: Presbyopia is essentially sex neutral, and no one is spared. There may be modest variations between different populations for various reasons, but essentially it is monotonously predictable. At present there is no biological therapeutic.

Accommodative movements of the choroid in the optic nerve head region of human eyes, and their relationship to the lens.

The ciliary muscle (CM) powers the accommodative response, and during accommodation the CM pulls the choroid forward in the region of the ora serrata. Our goal was to elucidate the accommodative movements of the choroid in the optic nerve region in humans and to determine whether these movements are related to changes in the lens dimensions that occur with aging, in the unaccommodated and accommodated state. Both eyes of 12 human subjects (aged 18-51 yrs) were studied. Homatropine (1 drop/5%) was used to relax the ciliary muscle (unaccommodated or "resting" eye) and pilocarpine was used to induce the maximum accommodative response (2 drops/4%) (accommodated eye). Images of the fundus and choroid were collected in the region of the optic nerve (ON) via Spectralis OCT (infrared and EDI mode), and choroidal thickness was determined. Ultrasound biomicroscopy (UBM; 50 MHz, 35 MHz) images were collected in the region of the lens/capsule and ciliary body. OCT and UBM images were collected in the resting and accommodated state. The unaccommodated choroidal thickness declined significantly with age (p = 0.0073, r = 0.73) over the entire age range of the subjects studied (18-51 years old). The choroidal thickness was significantly negatively correlated with lens thickness in the accommodated (p = 0.01) and the unaccommodated states (p = 0.005); the thicker the lens the thinner the choroid. Choroid movements around the optic nerve during accommodation were statistically significant; during accommodation the choroid both thinned and moved centrifugally (outward/away from the optic nerve head). The accommodative choroid movements did not decline significantly with age and were not correlated with accommodative amplitude. Measurement of the choroidal thickness is possible with the Spectralis OCT instrument using EDI mode and can be used to determine the accommodative changes in choroidal thickness. The choroidal thickness decreased with age and during accommodation. It may be that age-related choroidal thinning is due to changes in the geometry of the accommodative apparatus to which it is attached (i.e., ciliary muscle/lens complex) such that when the lens is thicker, the choroid is thinner. Accommodative decrease in choroidal thickness and stretch of the retina/choroid may indicate stress/strain forces in the region of the optic nerve during accommodation and may have implications for glaucoma.

Intraocular accommodative movements in monkeys; relationship to presbyopia.

Our goal was to quantify the age-related changes in the dynamic accommodative movements of the vitreous and aqueous humor in iridic, aniridic, phakic and aphakic primate eyes. Six bilaterally iridic and four bilaterally iridectomized rhesus monkeys, ranging in age from 6 to 25 years, received a stimulating electrode in the midbrain Edinger-Westphal nucleus to induce accommodation, measured by a Hartinger coincidence refractometer. One of the four iridectomized monkeys underwent unilateral extracapsular and another monkey underwent intracapsular lens extraction. Eyes were imaged utilizing specialized techniques and contrast agents to resolve intraocular structures. During accommodation the anterior hyaloid membrane and the posterior lens capsule bowed backward. Central vitreous fluid and structures/strands moved posteriorly toward the optic nerve region as peripheral vitreous, attached to the vitreous zonule, was pulled forward by ciliary muscle contraction. Triamcinolone particles injected intravitreally were also observed in the anterior chamber and moved from the anterior chamber toward the cleft of the anterior hyaloid membrane and then further posteriorly into the vitreous-filled cleft between the vitreous zonule and the ciliary body pars plana. These accommodative movements occurred in all eyes, and declined with age. There are statistically significant accommodative movements of various intravitreal structures. The posterior/anterior fluid flow between the anterior chamber and the vitreous compartments during accommodation/disaccommodation represents fluid displacement to allow/facilitate lens thickening. The posterior accommodative movement of central vitreous fluid may result from centripetal compression of the anterior tips of the cistern-like structure attached to the vitreous zonule, and posterior displacement of the central trunk of the cistern during ciliary muscle contraction and centripetal muscle movement. The findings may have implications for presbyopia.

Consensus Recommendation for Mouse Models of Ocular Hypertension to Study Aqueous Humor Outflow and Its Mechanisms.

Due to their similarities in anatomy, physiology, and pharmacology to humans, mice are a valuable model system to study the generation and mechanisms modulating conventional outflow resistance and thus intraocular pressure. In addition, mouse models are critical for understanding the complex nature of conventional outflow homeostasis and dysfunction that results in ocular hypertension. In this review, we describe a set of minimum acceptable standards for developing, characterizing, and utilizing mouse models of open-angle ocular hypertension. We expect that this set of standard practices will increase scientific rigor when using mouse models and will better enable researchers to replicate and build upon previous findings.

Report: The effects of topical pleurotus tuberregium (PT) aqueous extract on intraocular pressure in monkeys.

PURPOSE: In earlier experiments in Nigeria, aqueous extract of Pleurotus tuber-regium (PT) had been shown to lower intra ocular pressure (IOP) in a feline model. The aim of the current study was to determine whether PT had the same or a similar IOP-lowering effect in ocularly normal non-human primates. METHODS: Four monkeys were treated twice daily for 4 days with 2 x 20 µl drops of 50 mg/ml PT (pH = 4.3). The monkeys were sedated with 5-10 mg/kg ketamine HCl IM. PT was administered to the right eye and BSS to the left eye. Baseline IOP was measured just prior to beginning treatment, and on day 5 before treatment and then hourly for 3 hours, beginning 1 hour after treatment. SLEs were performed at baseline and on day 5 pre- and 3 hours post-treatment. RESULTS: There was no significant difference between IOP in treated vs control eyes in the protocol. There were no adverse effects or toxicity as seen by SLE. CONCLUSIONS: The inability of the extract to lower IOP in monkeys, in contrast to ocular hypertensive cats in an earlier study, could be due to species differences or duration of treatment. Since no adverse effects were observed in the monkeys, further studies with varying durations and dosages are recommended.

Deconstructing aqueous humor outflow - The last 50 years.

Herein partially summarizes one scientist-clinician's wanderings through the jungles of primate aqueous humor outflow over the past ~45 years. Totally removing the iris has no effect on outflow facility or its response to pilocarpine, whereas disinserting the ciliary muscle (CM) from the scleral spur/trabecular meshwork (TM) completely abolishes pilocarpine's effect. Epinephrine increases facility in CM disinserted eyes. Cytochalasins and latrunculins increase outflow facility, subthreshold doses of cytochalasins and epinephrine given together increase facility, and phalloidin, which has no effect on facility, partially blocks the effect of both cytochalasins and epinephrine. H-7, ML7, Y27632 and nitric oxide - donating compounds all increase facility, consistent with a mechanosensitive TM/SC. Adenosine A1 agonists increase and angiotensin II decrease facility. OCT and optical imaging techniques now permit visualization and digital recording of the distal outflow pathways in real time. Prostaglandin (PG) F2α analogues increase the synthesis and release of matrix metalloproteinases by the CM cells, causing remodeling and thinning of the interbundle extracellular matrix (ECM), thereby increasing uveoscleral outflow and reducing IOP. Combination molecules (one molecule, two or more effects) and fixed combination products (two molecules in one bottle) simplify drug regimens for patients. Gene and stem cell therapies to enhance aqueous outflow have been successful in laboratory models and may fill an unmet need in terms of patient compliance, taking the patient out of the delivery system. Functional transfer of genes inhibiting the rho cascade or decoupling actin from myosin increase facility, while genes preferentially expressed in the glaucomatous TM decrease facility. In live NHP, reporter genes are expressed for 2+ years in the TM after a single intracameral injection, with no adverse reaction. However, except for one recent report, injection of facility-effective genes in monkey organ cultured anterior segments (MOCAS) have no effect in live NHP. While intracameral injection of an FIV. BOVPGFS-myc.GFP PGF synthase vector construct reproducibly induces an ~2 mmHg reduction in IOP, the effect is much less than that of topical PGF2⍺ analogue eyedrops, and dissipates after 5 months. The turnoff mechanism has yet to be defeated, although proteasome inhibition enhances reporter gene expression in MOCAS. Intracanalicular injection might minimize off-target effects that activate turn-off mechanisms. An AD-P21 vector injected sub-tenon is effective in 'right-timing' wound healing after trabeculectomy in live laser-induced glaucomatous monkeys. In human (H)OCAS, depletion of TM cells by saponification eliminates the aqueous flow response to pressure elevation, which can be restored by either cultured TM cells or by IPSC-derived TM cells. There were many other steps along the way, but much was accomplished, biologically and therapeutically over the past half century of research and development focused on one very small but complex ocular apparatus. I am deeply grateful for this award, named for a giant in our field that none of us can live up to.

Early adoption of the fluocinolone acetonide (FAc) intravitreal implant in patients with persistent or recurrent diabetic macular edema (DME).

Objective: To assess long-term outcomes for effectiveness, safety, and treatment burden after injection of 0.2 µg/day fluocinolone acetonide [FAc] intravitreal implant (ILUVIEN®) in patients with persistent or recurrent diabetic macular edema (DME) and 6-18 months of follow-up. Methods: Retrospective case series in 18 eyes (13 patients) treated with the FAc implant. Prior to the implant, eyes were treated with an anti-VEGF therapy, dexamethasone implant, or focal or panretinal photocoagulation. Effectiveness outcomes included changes in visual acuity and macular edema. Safety outcomes included intraocular pressure (IOP) changes, IOP drugs, and IOP-related surgeries/interventions. Treatment burden was assessed by comparing the number of DME treatments before and after FAc implantation. Results: The FAc implant reduced macular volume in 16/18 (89%) eyes, with a statistically significant mean change of -1.33 mm3 (p=0.001). The average central retinal thickness reduction for all 18 eyes was statistically significant, decreasing from 444 µm at baseline to 359 µm after the FAc implant (p<0.001). In 90% of eyes, visual acuity was stable throughout the follow-up period, with increases or no worsening in Early Treatment Diabetic Retinopathy Study letter score. Although mean IOP was statistically higher after treatment, it was within the normal range at all timepoints, and most (83.3%) eyes remained in the IOP category 0-22 mmHg, and the number of IOP treatments required did not increase and no patients required IOP-lowering surgery. Treatment burden for DME was reduced after the implant was administered, with 56% of eyes not requiring any additional treatment. The average number of treatments was 1.3 in the 6 months after the FAc implant versus 4.6 in the 12 months preceding the implant. Conclusion: The FAc implant is an appropriate option to incorporate earlier in the DME treatment process, leading to positive long-term outcomes with an acceptable safety profile, and a reduced treatment burden for patients, and reduced clinical staff time.

SB772077B, A New Rho Kinase Inhibitor Enhances Aqueous Humour Outflow Facility in Human Eyes.

We investigated the effect of a new Rho kinase inhibitor, SB772077B (SB77) on aqueous outflow facility (OF) in human eyes using human organ-cultured anterior segment (HOCAS). IOP was monitored for 24 h post-treatment with either SB77 (0.1/10/50 µM) or vehicle after a stable baseline pressure. The hydrodynamic pattern of aqueous outflow was analysed by labelling outflow pathway with red fluorescent microspheres. The effect of SB77 on cell morphology, actin stress fibers, focal adhesions, ECM, status of RhoA activation and myosin light chain phosphorylation (p-MLC) were evaluated and compared with Y27632, by immunostaining using primary human trabecular meshwork (HTM) cells. Following 24 h treatment, SB77 increased OF by 16% at 0.1 µM (N = 6), 29% at 10 µM (N = 8; p = 0.018) and 39% at 50 µM (N = 8; p = 0.004) in human eyes. There was an overall increase in tracer quantity and in area along inner wall of Schlemm's canal. Treatment with SB77 showed no evidence of cytotoxicity and caused a significant reduction in the expression of fibrotic markers compared to Y27632. The present findings indicate that SB77 treatment was effective in enhancing OF and reducing fibrotic markers in an ex vivo model. Thus SB77 may be a potential clinical candidate for the management of glaucoma.

Effects of Lentivirus-Mediated C3 Expression on Trabecular Meshwork Cells and Intraocular Pressure.

Purpose: We evaluated the effects of lentivirus-mediated exoenzyme C3 transferase (C3) expression on cultured primary human trabecular meshwork (HTM) cells in vitro, and on rat intraocular pressure (IOP). Methods: HTM cells were cultured and treated with lentivirus vectors expressing either green fluorescent protein (GFP) only (LV-GFP) or GFP and C3 together (LV-C3-GFP). Changes in cell morphology and actin stress fibers were assessed. The vectors were also injected into the anterior chamber of rats, and GFP expression was visualized by a Micron III Retinal Imaging Microscope in vivo and a fluorescence microscope ex vivo. Changes in rat IOP were monitored by using a rebound tonometer and the eyes were evaluated by slit lamp. Results: LV-mediated C3 expression induced morphologic changes in HTM cells. The cells became retracted and rounded. GFP expression in the anterior chamber angle of rats was observed in vivo from 8 days to 48 days after injection of LV-C3-GFP or LV-GFP. IOP was significantly decreased in the LV-C3-GFP group starting 3 days post injection, and lasting for at least 40 days, when compared to either the contralateral control eyes (the LV-GFP group) or the ipsilateral baseline before injection (P < 0.05). No obvious inflammatory signs were observed in either the LV-C3-GFP or LV-GFP groups. Conclusions: LV-mediated C3 expression induced changes in morphology of cultured HTM cells. Intracameral injection of LV-C3-GFP lowered rat IOP for at least 40 days. No significant inflammatory reactions were observed in either the LV-C3-GFP or LV-GFP groups. This study supports the possible use of C3 gene therapy for the treatment of glaucoma.

Glaucoma Drugs in the Pipeline.

Glaucoma is a chronic disease that can be challenging to treat for both patients and physicians. Most patients will require more than 1 medication over time to maintain their intraocular pressure (IOP) at a physiologically benign level. Patients may become refractory to existing compounds and many struggle with adherence to multiple topical drop regimens. The field of glaucoma therapeutics has been advancing rapidly with an emphasis on compounds comprising multiple molecules/mechanisms of action that offer additivity and are complementary to current therapeutics. Several new topical drop compounds directly targeting the trabecular meshwork (TM)/Schlemm canal/conventional outflow pathway to reduce outflow resistance have obtained US Food and Drug Administration approval in the past year. These include rho kinase inhibitors and nitric oxide donating compounds. Alternative therapies that offer long-term IOP lowering while removing the patient from the drug delivery system are moving forward in development. These include gene therapy and stem cell strategies, which could ease or eliminate the burden of topical drop self-administration for several years. Additionally, a variety of novel formulations and devices are in development that aim for controlled, steady state delivery of therapeutics over periods of months. The future of glaucoma therapy is focusing on an increase in specificity for the individual patient: their type of glaucoma; underlying mechanisms; genetic make-up; comorbid conditions; and rate of progression. Maintaining functional vision and improving patient outcomes remains the goal in glaucoma therapeutics. The current collection of novel therapeutics offers an expanded set of tools to achieve that goal.

Medical Management of Glaucoma in Exfoliation Syndrome.

The treatment of glaucoma in exfoliation syndrome is similar to primary open-angle glaucoma. Frequently, exfoliation glaucoma (XFG) patients require early polytherapy with topical medications. Little emphasis has been placed on tailoring treatment specifically to XFG. New outflow enhancing agents with novel mechanisms of action, such as Rho Kinase inhibition, NO signaling (both recently FDA-approved drugs) and adenosine α1-receptor stimulation, act directly on the trabecular meshwork. These agents may prove to be effective in lowering intraocular pressure and perhaps altering the pathogenesis of XFG aid in the long-term management of this disease.

Consensus recommendations for trabecular meshwork cell isolation, characterization and culture.

Cultured trabecular meshwork (TM) cells are a valuable model system to study the cellular mechanisms involved in the regulation of conventional outflow resistance and thus intraocular pressure; and their dysfunction resulting in ocular hypertension. In this review, we describe the standard procedures used for the isolation of TM cells from several animal species including humans, and the methods used to validate their identity. Having a set of standard practices for TM cells will increase the scientific rigor when used as a model, and enable other researchers to replicate and build upon previous findings.

Proteasome Inhibition Increases the Efficiency of Lentiviral Vector-Mediated Transduction of Trabecular Meshwork.

Purpose: To determine if proteasome inhibition using MG132 increased the efficiency of FIV vector-mediated transduction in human trabecular meshwork (TM)-1 cells and monkey organ-cultured anterior segments (MOCAS). Methods: TM-1 cells were pretreated for 1 hour with 0.5% dimethyl sulfoxide (DMSO; vehicle control) or 5 to 50 µM MG132 and transduced with FIV.GFP (green fluorescent protein)- or FIV.mCherry-expressing vector at a multiplicity of transduction (MOT) of 20. At 24 hours, cells were fixed and stained with antibodies for GFP, and positive cells were counted, manually or by fluorescence-activated cell sorting (FACS). Cells transduced with FIV.GFP particles alone were used as controls. The effect of 20 µM MG132 treatment on high- and low-dose (2 × 107 and 0.8 × 107 transducing units [TU], respectively) FIV.GFP transduction with or without MG132 was also evaluated in MOCAS using fluorescence microscopy. Vector genome equivalents in cells and tissues were quantified by quantitative (q)PCR on DNA. Results: In the MG132 treatment groups, there was a significant dose-dependent increase in the percentage of transduced cells at all concentrations tested. Vector genome equivalents were also increased in TM-1 cells treated with MG132. Increased FIV.GFP expression in the TM was also observed in MOCAS treated with 20 µM MG132 and the high dose of vector. Vector genome equivalents were also significantly increased in the MOCAS tissues. Increased transduction was not seen with the low dose of virus. Conclusions: Proteasome inhibition increased the transduction efficiency of FIV particles in TM-1 cells and MOCAS and may be a useful adjunct for delivery of therapeutic genes to the TM by lentiviral vectors.

Latanoprostene Bunod 0.024% in Subjects With Open-angle Glaucoma or Ocular Hypertension: Pooled Phase 3 Study Findings.

PURPOSE: To compare the diurnal intraocular pressure (IOP)-lowering effect of latanoprostene bunod (LBN) 0.024% with timolol maleate 0.5% in subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT). PATIENTS AND METHODS: Pooled analysis of two phase 3, randomized, multicenter, double-masked, parallel-group, noninferiority trials (APOLLO and LUNAR), each with open-label safety extension phases. Adults with OAG or OHT were randomized 2:1 to double-masked treatment with LBN once daily (qd) or timolol twice daily (bid) for 3 months followed by open-label LBN treatment for 3 (LUNAR) or 9 (APOLLO) months. IOP was measured at 8 AM, 12 PM, and 4 PM at week 2, week 6, and months 3, 6, 9, and 12. RESULTS: Of the 840 subjects randomized, 774 (LBN, n=523; timolol crossover to LBN, n=251) completed the efficacy phase, and 738 completed the safety extension phase. Mean IOP was significantly lower with LBN versus timolol at all 9 evaluation timepoints during the efficacy phase (P<0.001). A significantly greater proportion of LBN-treated subjects attained a mean IOP ≤18 mm Hg and IOP reduction ≥25% from baseline versus timolol-treated subjects (P<0.001). The IOP reduction with LBN was sustained through the safety phase; subjects crossed over from timolol to LBN experienced additional significant IOP lowering (P≤0.009). Both treatments were well tolerated, and there were no safety concerns with long-term LBN treatment. CONCLUSIONS: In this pooled analysis of subjects with OAG and OHT, LBN 0.024% qd provided greater IOP-lowering compared with timolol 0.5% bid and maintained lowered IOP through 12 months. LBN demonstrated a safety profile comparable to that of prostaglandin analogs.

Effects of Vitrectomy and Lensectomy on Older Rhesus Macaques: Oxygen Distribution, Antioxidant Status, and Aqueous Humor Dynamics.

Purpose: The purpose of this study is to evaluate effects of vitrectomy (PPV) and lens extraction with intraocular lens implantation (PE/IOL) on molecular oxygen (pO2) distribution, aqueous humor antioxidant-oxidant balance, aqueous humor dynamics, and histopathologic changes in the trabecular meshwork (TM) in the older macaque monkey. Methods: Six rhesus monkeys underwent PPV followed by PE/IOL. pO2, outflow facility, and intraocular pressure (IOP) were measured. Aqueous and vitreous humor specimens were analyzed for antioxidant status and 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative damage. TM specimens were obtained for immunohistochemical and quantitative PCR analysis. Results: pO2 at baseline revealed steep gradients in the anterior chamber and low levels in the posterior chamber (PC) and around the lens. Following PPV and PE/IOL, pO2 significantly increased in the PC, around the IOL, and angle. IOP increased following both surgical interventions, with no change in outflow facility. Histopathologic analysis did not show changes in TM cell quantification, but there was an increase in 8-OHdG. Quantitative PCR did not reveal significant differences in glaucoma-related gene expression. Aqueous and vitreous humor analysis revealed decreased ascorbate and total reactive antioxidant potential and increased 8-OHdG in the aqueous humor only in the surgical eyes. Conclusions: Oxygen distribution in the older rhesus monkey is similar to humans at baseline and following surgical interventions. Our findings of histopathologic changes of TM oxidative damage and alterations in the oxidant-antioxidant balance suggest a potential correlation of increased oxygen exposure with oxidative stress/damage and the development of open angle glaucoma.

Change in Diabetic Retinopathy Through 2 Years: Secondary Analysis of a Randomized Clinical Trial Comparing Aflibercept, Bevacizumab, and Ranibizumab.

Importance: Anti-vascular endothelial growth factor (anti-VEGF) therapy for diabetic macular edema (DME) favorably affects diabetic retinopathy (DR) improvement and worsening. It is unknown whether these effects differ across anti-VEGF agents. Objective: To compare changes in DR severity during aflibercept, bevacizumab, or ranibizumab treatment for DME. Design, Setting, and Participants: Preplanned secondary analysis of data from a comparative effectiveness trial for center-involved DME was conducted in 650 participants receiving aflibercept, bevacizumab, or ranibizumab. Retinopathy improvement and worsening were determined during 2 years of treatment. Participants were randomized in 2012 through 2013, and the trial concluded on September 23, 2015. Interventions: Random assignment to aflibercept, 2.0 mg; bevacizumab, 1.25 mg; ranibizumab, 0.3 mg, up to every 4 weeks through 2 years following a retreatment protocol. Main Outcomes and Measures: Percentages with retinopathy improvement at 1 and 2 years and cumulative probabilities for retinopathy worsening through 2-year without adjustment for multiple outcomes. Results: A total of 650 participants (495 [76.2%] nonproliferative DR [NPDR], 155 proliferative DR [PDR]) were analyzed; 302 (46.5%) were women and mean (SD) age was 61 (10) years; 425 (65.4%) were white. At 1 year, among 423 NPDR eyes, 44 of 141 (31.2%) treated with aflibercept, 29 of 131 (22.1%) with bevacizumab, and 57 of 151 (37.7%) with ranibizumab had improvement of DR severity (adjusted difference: 11.7%; 95% CI, 2.9% to 20.6%; P = .004 for aflibercept vs bevacizumab; 8.9%; 95% CI, 1.7% to 16.1%; P = .01 for ranibizumab vs bevacizumab; and 2.9%; 95% CI, -5.7% to 11.4%; P = .51 for aflibercept vs ranibizumab). At 2 years, 33 eyes (24.8%) in the aflibercept group, 25 eyes (22.1%) in the bevacizumab group, and 40 eyes (31.0%) in the ranibizumab group had DR improvement; no treatment group differences were identified. For 93 eyes with PDR at baseline, 1-year improvement rates were 75.9% for aflibercept, 31.4% for bevacizumab, and 55.2% for ranibizumab (adjusted difference: 50.4%; 95% CI, 26.8% to 74.0%; P < .001 for aflibercept vs bevacizumab; 20.4%; 95% CI, -3.1% to 44.0%; P = .09 for ranibizumab vs bevacizumab; and 30.0%; 95% CI, 4.4% to 55.6%; P = .02 for aflibercept vs ranibizumab). These rates and treatment group differences appeared to be maintained at 2 years. Despite the reduced numbers of injections in the second year, 66 (59.5%) of NPDR and 28 (70.0%) of PDR eyes that manifested improvement at 1 year maintained improvement at 2 years. Two-year cumulative rates for retinopathy worsening ranged from 7.1% to 10.2% and 17.2% to 26.4% among anti-VEGF groups for NPDR and PDR eyes, respectively. No statistically significant treatment differences were noted. Conclusions and Relevance: At 1 and 2 years, eyes with NPDR receiving anti-VEGF treatment for DME may experience improvement in DR severity. Less improvement was demonstrated with bevacizumab at 1 year than with aflibercept or ranibizumab. Aflibercept was associated with more improvement at 1 and 2 years in the smaller subgroup of participants with PDR at baseline. All 3 anti-VEGF treatments were associated with low rates of DR worsening. These data provide additional outcomes that might be considered when choosing an anti-VEGF agent to treat DME.

Latanoprostene bunod ophthalmic solution 0.024% for IOP lowering in glaucoma and ocular hypertension.

INTRODUCTION: Intraocular pressure (IOP)-lowering has been demonstrated to slow the progression or onset of visual field loss in open-angle glaucoma (OAG) or ocular hypertension (OHT). Pharmacological lowering of IOP is the most common initial intervention in patients with OAG or OHT, however, many patients will require more than one therapy to achieve target IOP. Latanoprostene bunod is a novel nitric oxide (NO)-donating prostaglandin F2α analog for the reduction of IOP. Areas covered: Current knowledge concerning the mechanism of action of latanoprostene bunod is presented. Additionally, clinical safety and efficacy data from published Phase 1 (KRONUS), Phase 2 (VOYAGER, CONSTELLATION) and Phase 3 (APOLLO, LUNAR, JUPITER) studies are reviewed. Expert opinion: Latanoprostene bunod is a dual mechanism, dual pathway molecule, consisting of latanoprost acid, which is known to enhance uveoscleral (unconventional) outflow by upregulating matrix metalloproteinase expression and remodeling of the ciliary muscle's extracellular matrix, linked to an NO-donating moiety, which enhances trabecular meshwork/Schlemm's canal (conventional) outflow by inducing cytoskeletal relaxation via the soluble guanylyl cyclase-cyclic guanosine monophosphate (sGC-cGMP) signaling pathway. Latanoprostene bunod 0.024% solution applied topically once daily appears more effective in reducing IOP in OHT and OAG subjects than either latanoprost or timolol, with a side effect profile similar to that of latanoprost.