Identifying Baseline Predictors of Selective Laser Trabeculoplasty Effectiveness: An Alternative Mathematical Approach.

BACKGROUND: Selective laser trabeculoplasty (SLT) emerges as a first-line treatment for newly diagnosed open-angle glaucoma and ocular hypertension. However, the interindividual response to SLT considerably varied. Large-scale clinical investigations concerning predictive factors for SLT effectiveness are limited. This study aimed to identify baseline predictors of the percentage intraocular pressure (IOP)-lowering effectiveness of SLT using an alternative mathematical approach. METHODS: Mathematical equations of IOP under the steady state of aqueous humour flow were formulated. The conclusive equation integrates physiological variables, including trabecular outflow facility, uveoscleral outflow fraction, plasma protein concentration, albumin/globulin ratio, mean arterial pressure, episcleral venous pressure, and plasma osmolarity. The equation was employed to estimate the percentage of IOP reduction following SLT and subsequently subjected to global sensitivity analysis to determine significant predictors of the IOP-lowering effect of SLT using the Monte Carlo simulation of 8,192 samples. RESULTS: In the current model, a 50% improvement in the trabecular outflow facility impacted by SLT is associated with a mean percentage IOP reduction of 16.6%. Lower baseline trabecular outflow facilities were the strongest predictors, showing a correlation with greater effectiveness of SLT in terms of percentage of IOP reduction. The second most influential factor includes baseline uveoscleral outflow fraction, followed by baseline episcleral venous pressure. Specifically, lower baseline uveoscleral outflow fraction and episcleral venous pressure were found to be correlated with increased effectiveness of SLT. Baseline levels of plasma protein concentration, albumin/globulin ratio, mean arterial pressure, and plasma osmolarity have minimal impact on SLT success or failure. CONCLUSION: This study identifies baseline trabecular outflow facilities as the strongest predictor of SLT effectiveness. The results suggested that pre-SLT medical treatment that augments uveoscleral outflow and/or trabecular outflow facilities could compromise the effectiveness of subsequent SLT in terms of percentage IOP reduction compared to those who never received pre-SLT medication.

Comparing the effect of benzalkonium chloride-preserved, polyquad-preserved, and preservative-free prostaglandin analogue eye drops on cultured human conjunctival goblet cells.

PURPOSE: To investigate the effect of benzalkonium chloride (BAK)-preserved latanoprost and bimatoprost, polyquad (PQ)-preserved travoprost, and preservative-free (PF) latanoprost and tafluprost, all prostaglandin analogues (PGAs), on human conjunctival goblet cell (GC) survival. Furthermore, to investigate the effect of BAK-preserved and PF latanoprost on the cytokine secretion from GC. METHODS: Primary human conjunctival GCs were cultivated from donor tissue. Lactate dehydrogenase (LDH) and tetrazolium dye colorimetric (MTT) assays were used for the assessment of GC survival. A cytometric bead array was employed for measuring secretion of interleukin (IL)-6 and IL-8 from GC. RESULTS: BAK-preserved latanoprost and bimatoprost reduced cell survival by 28% (p = 0.0133) and 20% (p = 0.0208), respectively, in the LDH assay compared to a negative control. BAK-preserved latanoprost reduced cell proliferation by 54% (p = 0.003), BAK-preserved bimatoprost by 45% (p = 0.006), PQ-preserved travoprost by 16% (p = 0.0041), and PF latanoprost by 19% (p = 0.0001), in the MTT assay compared to a negative control. Only PF tafluprost did not affect the GCs in either assay. BAK-preserved latanoprost caused an increase in the secretion of pro-inflammatory IL-6 and IL-8 (p = 0.0001 and p = 0.0019, respectively) compared to a negative control, which PF latanoprost did not. CONCLUSION: BAK-preserved PGA eye drops were more cytotoxic to GCs than PQ-preserved and PF PGA eye drops. BAK-preserved latanoprost induced an inflammatory response in GC. Treatment with PF and PQ-preserved PGA eye drops could mean better tolerability and adherence in glaucoma patients compared to treatment with BAK-preserved PGA eye drops.

Pregnancy outcomes in the medical management of glaucoma: An international multicenter descriptive survey.

PURPOSE: To determine if glaucoma medications are associated with pregnancy and/or postnatal complications. METHODS: Multicenter descriptive survey. Subjects were female patients 18-45 years who were previously pregnant with a diagnosis of glaucoma or ocular hypertension prior to pregnancy. Chart review queried diagnosis, glaucoma severity, and race. Survey questions were asked for each pregnancy and queried pregnancy age, medications used, and pregnancy outcomes/complications. RESULTS: 114 pregnancies of 56 patients (mean 2.0 pregnancies per patient) were included. Three pregnancies with therapeutic abortion were excluded from further analysis. Mean age during pregnancy was 29.1 ± 5.7 years. Of the 111 pregnancies, 20 (18.0%) used no medications and 91 (82.0%) used at least one medication. Medications were topical carbonic anhydrase inhibitors (n = 45), beta-blockers (n = 55), alpha-agonists (n = 56), and prostaglandin analogues (n = 28). Outcomes were: preterm contractions/labour (6.3%), miscarriage (4.5%), stillbirth (4.5%), induction of labour (11.9%), emergency/unplanned caesarean delivery (13.9%), neonatal intensive care unit (NICU) stay (15.8%), congenital anomalies (8.1%), and low birth weight (10.9%). Fisher exact test assessed outcome associations with individual agents, use of any agent, and different number of agents. Alpha-agonist use was associated with NICU stay: 25.5% rate (p = 0.012) in alpha-agonist use. Most of the alpha-agonist use NICU stays occurred in pregnancies with third trimester use. All other associations were not statistically significant. CONCLUSIONS: The data from this survey suggest an overall favourable safety profile for topical glaucoma medications in pregnancy, but further investigation is needed. Caution should be employed regarding third trimester alpha-agonist use owing to association with NICU stay.

Improvement of Prostaglandin-Associated Periorbitopathy after Discontinuing Treatment.

Objectives: To report that the periorbital changes induced by prostaglandin analogue (PGA) eye drops are partially reversible after discontinuing treatment. Materials and Methods: Nine patients with prostaglandin-associated periorbitopathy seen in a referral oculoplastic practice were included in this study, eight with unilateral glaucoma and one with bilateral open-angle glaucoma. All of them had been treated with topical PGA for at least one year, before the treatment was discontinued for cosmetic reasons. Results: In all cases, there were evident periocular differences between the treated eye and the fellow eye, consisting mainly of deepening of the upper eyelid sulcus and eyelid fat pad reduction. One year after discontinuing the PGA eye drops, improvement of these features was observed. Conclusion: Clinicians and patients should be aware of the side effects of topical PGA therapy on periorbital tissues, and that these side effects can partially regress after discontinuation of the medication.

Trends in development and quality assessment of pharmaceutical formulations - F2α analogues in the glaucoma treatment.

The ocular delivery route presents a number of challenges in terms of drug administration and bioavailability. The low bioavailability following topical ophthalmic administration shows that there is a clear need for in-depth research aimed at finding both more efficacious molecules and formulations precisely targeted at the site of action. Continuous technological development will eventually result in improved bioavailability, lower dosages, reduced toxicity, fewer adverse effects, and thus better patient compliance and treatment efficacy. Technological development, as well as increasingly stringent quality requirements, help stimulate analytical progress. This is also clearly evident in the case of medicinal products used in the treatment of glaucoma, which are the subject of this review. Impurity profiling of PGF2α analogues, either in the pure substance or in the finished formulation, is a crucial step in assessing their quality. The development of specific, accurate and precise stability-indicating analytical methods for determining the content and related substances seems to be an important issue in relation to this tasks. A total of 27 official and in-house analytical methods are presented that are used for the analysis of latanoprost, travoprost and bimatoprost. The conditions for chromatographic separation with UV or MS/MS detection and the available results obtained during method validation are described. In addition, several aspects are discussed, with particular emphasis on the instability of the analogues in aqueous solution and the phenomenon of isomerism, which affects a potentially large number of degradation products.

Newer advances in medical management of glaucoma.

The burden of irreversible vision loss from Glaucoma continues to rise. While the disease pathogenesis is not well understood, intraocular pressure (IOP) is the only modifiable risk factor identified to prevent glaucomatous vision loss. Medical management remains the first-line of treatment in most adult glaucomas and the evolution of medical therapy for glaucoma has followed an exponential curve. This review tracks the rapid development of new medications and drug delivery systems in the recent years. Introduction of Rho kinase inhibitors with an entirely new mechanism of action from that of the currently used anti glaucoma medications has been a significant milestone. Latanoprostene Bunod is a novel, single molecule which provides two active metabolites that work through two different pathways for reducing intra ocular pressure. Bimatoprost implants and travoprost punctum plugs attempt to ease chronic medication use in glaucoma patients. Nanotechnology is an evolving route of drug delivery. Role of cannabinoids in medical management of glaucoma remain equivocal. The relatively short term effect on IOP, the risks of developing tolerance and side effects impacting patients' neurocognitive health greatly outweigh the potential benefit. Research on Latrunculin B, Adenosine receptor agonists, Specific gene silencing and Stem cell therapy are poised to make an impact on glaucoma treatment. While there is some evidence to support the role of Brimonidine in neuroprotection, further research is needed to clarify the role of Memantine and Neurotrophins. Evidence for benefit from dietary supplementation with Alpha lipoic acid, Forskolin , and Ginko Biloba is limited.

Switching to Preservative-Free Tafluprost/Timolol Fixed-Dose Combination in the Treatment of Open-Angle Glaucoma or Ocular Hypertension: Subanalysis of Data from the VISIONARY Study According to Baseline Monotherapy Treatment.

INTRODUCTION: The VISIONARY study demonstrated statistically significant intraocular pressure (IOP) reductions with the preservative-free fixed-dose combination of tafluprost 0.0015% and timolol 0.5% (PF tafluprost/timolol FC) in open-angle glaucoma (OAG) or ocular hypertension (OHT) patients, sub-optimally controlled with topical prostaglandin analogue (PGA) or beta-blocker monotherapy. Current subanalyses have examined these data according to the baseline monotherapy. METHODS: A European, prospective, observational study included adults (aged ≥ 18 years) with OAG or OHT, who were switched to the PF tafluprost/timolol FC from PGA or beta-blocker monotherapy. Treatment outcomes were reported according to prior monotherapy subgroup: beta-blocker, preserved latanoprost, PF-latanoprost, bimatoprost, tafluprost, and travoprost. Endpoints included the mean change from baseline regarding IOP, conjunctival hyperemia, and corneal fluorescein staining (CFS) at Week 4 and Week 12, and at Month 6. RESULTS: The subanalysis included 577 patients. All prior monotherapy subgroups demonstrated statistically significant IOP reductions from baseline at Week 4, that were maintained through Month 6 (p < 0.001). Mean (SD) IOP change at Month 6 was 6.6 (4.16), 6.3 (4.39), 5.6 (3.67), 4.9 (2.97), 4.6 (4.39), and 4.7  (3.64) mmHg for prior beta-blocker, preserved latanoprost, PF-latanoprost, tafluprost, bimatoprost, and travoprost subgroups, respectively. The largest IOP change was observed in the preserved latanoprost subgroup for each of the ≥ 20%, ≥ 25%, ≥ 30%, and ≥ 35% IOP reduction categories at Month 6, demonstrating respective reductions of 8.06, 9.20, 10.64, and 11.55 mmHg. CFS was significantly reduced at Month 6 in the prior bimatoprost subgroup (p = 0.0013). Conjunctival hyperemia severity was significantly reduced at each study visit for prior preserved latanoprost users (p < 0.001). CONCLUSION: PF tafluprost/timolol FC therapy provided statistically and clinically significant IOP reductions from Week 4 over the total 6-month period, in patients with OAG/OHT, regardless of the type of prior PGA or beta-blocker monotherapy used. Conjunctival hyperemia severity and CFS decreased significantly in prior bimatoprost and preserved latanoprost users, respectively. CLINICAL STUDY NUMBER: European Union electronic Register of Post-Authorization Studies (EU PAS) register number: EUPAS22204.

Comparative effects of latanoprost and latanoprostene bunod on intraocular pressure and pupil size in ophthalmologically normal Beagle dogs.

OBJECTIVE: To compare effects of latanoprost, a topical prostaglandin analogue (PGA) commonly used to treat glaucoma and lens instability in dogs, and latanoprostene bunod, a novel PGA with a nitric oxide-donating moiety, on intraocular pressure (IOP) and pupil diameter (PD). ANIMALS STUDIED: Ten ophthalmologically normal Beagle dogs. PROCEDURES: Dogs were treated twice a day for 5 days in a randomly selected eye with either latanoprost or latanoprostene bunod. After a 6-week washout period, dogs were treated with the opposite drug. IOP and PD were measured at treatment times, at midday on days 1 and 5, and for 6 days post-treatment. RESULTS: Both drugs significantly decreased IOP and PD. At midday on day 5 of treatment, mean IOP in eyes treated with latanoprost was 4.5 mmHg lower than the fellow eye and 3.0 mmHg lower than the same eye at baseline, while mean IOP in eyes treated with latanoprostene bunod was 5.5 mmHg lower than the fellow eye and 3.6 mmHg lower than baseline. Mean PD was 0.94 mm in eyes treated with latanoprost and 0.76 mmHg in eyes treated with latanoprostene bunod. There was no significant difference between the two drugs for either parameter at that time point (p = .372 and .619, respectively, for IOP relative to control and to baseline; p = .076 for PD) or when analyzed longitudinally. Significant diurnal variation in PD was noted and may have implications for treatment of lens' instability. CONCLUSIONS: Latanoprost and latanoprostene bunod produce similar IOP reduction and miosis in normal canine eyes.

Effect of Topical Prostaglandin Analogue Therapy on Central Corneal Thickness: A Systematic Review.

To investigate whether prostaglandin analogue (PGA) eyedrops have a significant effect on central corneal thickness (CCT), we conducted a systematic search of literature published from 2000 to 2021. Among the studies conducted on topical PGA therapy in open-angle glaucoma or ocular hypertension patients over 18 years old, prospective studies with CCT change as an outcome were included. A single-arm meta-analysis was conducted to assess the overall effect on CCT, and subgroup analysis according to exposure time of PGA eyedrops was also performed. We counted the number of articles that reported on severe events (CCT reduction of 25 µm or more) and obtained their proportion. The methodological quality was assessed by the McHarm tool. Twenty-two reports of prospective studies were selected. The results of the single-arm meta-analysis showed very high heterogeneity. Still, in subgroup analysis, when PGA was used for more than 6 months, heterogeneity was low, and a significant decrease in CCT was observed. Severe events were reported in two reports and occurred in 3.8% to 14.8% of participants. PGA eyedrop use may cause a clinically significant CCT decrease, requiring CCT follow-up.

Differential impact of prostaglandin analogues on agreement of intraocular pressure measurements obtained by Goldmann applanation, rebound, and noncontact tonometry.

BACKGROUND: To evaluate the effect of topical prostaglandin analogues on agreement of IOP measurements obtained by Goldmann applanation tonometry (GAT), rebound tonometry (RBT), and noncontact tonometry (NCT) in eyes with primary open- angle glaucoma (POAG). METHODS: Intraocular pressure measurements were obtained using GAT, RBT, and NCT in patients with POAG with or without prostaglandin analogues. The agreement between each tonometry was analysed using Bland-Altman analyses in those with or without prostaglandin analogues. The effect of average IOP on IOP differences was also evaluated. RESULTS: Among a total of 86 subjects included in the study, 44 patients were using prostaglandin analogues. The difference in IOP measured by GAT and RBT was marginally greater in those with (GAT-RBT: - 0.94 ± 1.63 mmHg) prostaglandin analogues than in those without (- 0.33 ± 1.22 mmHg, P = 0.06). The difference in IOP measured by GAT and NCT was significantly greater in the prostaglandin group (GAT-NCT: 2.40 ± 2.89 mmHg) than in the group without prostaglandin analogues (0.41 ± 1.63 mmHg, P < 0.01). While there was no significant relationship between the average of all tonometries and the difference between tonometries in those without prostaglandin analogues, both RBT and NCT underestimated IOP relative to GAT at higher IOP in those using prostaglandin analogues. CONCLUSION: Intraocular pressure measured by RBT and NCT was similar to that measured by GAT in those without prostaglandin analogues. RBT overestimated and NCT underestimated IOP compared to GAT in those using prostaglandin analogues.

Comparison of the Safety and Efficacy between Preserved and Preservative-Free Latanoprost and Preservative-Free Tafluprost.

In this study, we investigated the effect of preservative-free (PF) 0.0015% tafluprost (TA), to the preservative containing (PC) and the PF 0.005% latanoprost (LA) in Korean subjects. This study was conducted as a multi-center, randomized, investigator-blind, active controlled, parallel-group, clinical trial in adult patients (≥19 years) with open-angle glaucoma (OAG) and ocular hypertension (OHT). After a washout period, patients with an IOP between 15 and 35 mmHg were enrolled and evaluated the efficacy, safety, and compliance at 4, 8 and 12 weeks after the first administration. A total of 137 OAG and OHT patients were randomized. Statistically significant reductions in IOP were observed in all groups. Twelve weeks after each eye drop instillation, the mean IOP reduction was -4.59 ± 2.70 mmHg (-24.57 ± 13.49%) in the PC-LA group, -4.52 ± 2.17 mmHg (-24.41 ± 11.38%) in the PF-LA, and -3.14 ± 2.83 mmHg (-17.22 ± 14.57%) in the PF-TA group. The PF-LA showed significantly better responsiveness than did PF-TA. PF-LA was better tolerated than was PC-LA. There were no adverse events that led to cessation of eye drop use in any of the groups. In conclusion, IOP decreased similarly across the groups. PF-LA may provide a good choice for OAG patients with ocular surface diseases.

Headaches related to latanoprost in open-angle glaucoma.

Clinical relevance: The existing notion that topical latanoprost can lead to symptoms of headaches by reporting three cases of headache symptoms that developed following instillation of latanoprost prescribed as first-line therapy for newly diagnosed primary open-angle glaucoma (POAG) is explored in this case series.Background: Prostaglandin analogues (PGAs) are often used as first-line treatment in the treatment of POAG. An uncommon and infrequently reported side effect of PGAs is headaches.Methods: A retrospective review of patient records was conducted on patients seen at the Centre for Eye Health between April 2016 and August 2017. Clinical findings, including outcomes following interventions such a punctal occlusion, as well as the proposed pharmacological mechanism underlying this phenomenon are presented and discussed.Results: Case 1 is a 62-year-old Caucasian male diagnosed with POAG and prescribed latanoprost in both eyes. At the follow-up visit, he reported waking up in with a dull throbbing headache following instillation of the eye drops the night before. Case 2 is a 58-year-old Asian male with POAG prescribed latanoprost to both eyes. Within a week, he developed symptoms of recurrent progressively worsening headaches post-instillation which persisted into the morning. Case 3 is a 75-year-old Caucasian male with POAG prescribed latanoprost for both eyes. He developed latanoprost sensitivity as well as headache symptoms associated with the eye drops which resolved followed its cessation. All patients reported initial symptoms of headaches associated with latanoprost use however the headaches were not persistent with intermittent punctal occlusion (cases 1 and 2) or intra-class drug rechallenge (case 3).Conclusion: Although there may be a yet-undiscovered link between a headache response and latanoprost, these cases call to question the pharmacological relationship between latanoprost and headache symptoms. A systemic approach to critically examine the pathophysiological link between pharmacological therapy and potential adverse effects is proposed.

A randomized comparative study of the efficacy of topical latanoprost versus topical betamethasone diproprionate lotion in the treatment of localized alopecia areata.

BACKGROUND: Topical corticosteroids are the standard therapy for the treatment of alopecia areata. Recently, topical latanoprost has been found effective in the treatment of eyelash alopecia areata. OBJECTIVES: The objective of this study was to compare the efficacy of topical latanoprost ophthalmic solution (group 1) with that of topical betamethasone diproprionate lotion (group 2) in the treatment of localized alopecia areata. METHODS: This was a single-centre, randomized, two-armed, parallel-group efficacy trial. Fifty consecutive patients with localized alopecia areata were randomized in a 1:1 ratio to receive either topical latanoprost 0.005% ophthalmic solution or topical betamethasone diproprionate 0.05% lotion. Of these 50 patients, 44 patients (21 in group 1 and 23 in group 2) completed the treatment protocol. RESULTS: The percentage reduction in area involved with alopecia areata at 16 weeks (primary outcome) was lower in latanoprost vs. betamethasone group (median [interquartile range], 11.1 [0-99.1] vs. 100% [13.6-100], P = 0.02). Significantly lesser patients in the latanoprost group had a complete response to treatment as compared to the betamethasone group (6 [24%] vs. 14 [56%], P = 0.02). The median (interquartile range) hair regrowth score was significantly lower in the latanoprost vs. the betamethasone group (1 [0-4.5] vs. 5 [1-5], P = 0.02). Subjects in the betamethasone group showed a more rapid reduction in the involved area. LIMITATIONS: Short duration of treatment and follow-up were limitations of this study. CONCLUSION: Our results suggest that topical latanoprost 0.005% ophthalmic solution is less effective but safer than topical betamethasone dipropionate 0.05% lotion in the treatment of localized alopecia areata (clinicaltrials.gov: NCT02350023).

The changes of corneal biomechanical properties with long-term treatment of prostaglandin analogue measured by Corvis ST.

BACKGROUND: To investigate the corneal biomechanical changes in primary open angle glaucoma (POAG) patients treated with long-term prostaglandin analogue (PGA). METHODS: One hundred eleven newly diagnosed POAG patients, including 43 high tension glaucoma (HTG) and 68 normal tension glaucoma (NTG), were measured by Corvis ST to obtain intraocular pressure (IOP), central corneal thickness (CCT) and corneal biomechanical parameters at baseline and at each follow-up visit after initiation of PGA treatment. The follow-up measurements were analyzed by the generalized estimate equation model with an exchangeable correlation structure. Restricted cubic spline was employed to estimate the dose-response relation between follow-up time and corneal biomechanics. RESULTS: The mean follow-up time was 10.3 ± 7.02 months. Deformation amplitude (ß = -0.0015, P = 0.016), the first applanation velocity (AV1, ß = -0.0004, P = 0.00058) decreased and the first applanation time (AT1, ß = 0.0089, P < 0.000001) increased statistically significantly with PGA therapy over time after adjusting for age, gender, axial length, corneal curvature, IOP and CCT. In addition, AT1 was lower (7.2950 ± 0.2707 in NTG and 7.5889 ± 0.2873 in HTG, P = 0.00011) and AV1 was greater (0.1478 ± 0.0187 in NTG and 0.1314 ± 0.0191 in HTG, P = 0.00002) in NTG than in HTG after adjusting for confounding factors. CONCLUSIONS: Chronic use of PGA probably influences the corneal biomechanical properties directly, which is to make cornea less deformable. Besides, corneas in NTG tended to be more deformable compared to those in HTG with long-term treatment of PGA.

Effect of Prostaglandin Analogues on Central Corneal Thickness: 3-Year Follow-up Results.

PURPOSE: To evaluate the effects of each subgroup of prostaglandin analogues (PGAs) on central corneal thickness (CCT) in patients with normal tension glaucoma (NTG). METHODS: We retrospectively reviewed 55 eyes of 55 patients with NTG who were receiving PGA therapy. Patients who were treated with 0.005% latanoprost (16 eyes), 0.0015% tafluprost (16 eyes), or 0.004% travoprost (23 eyes) monotherapy were included. CCT assessments were performed at baseline and 1, 2, and 3 years after initiation of treatment. RESULTS: In the NTG group, the mean CCT showed a decreasing trend, and there was a significant difference in mean CCT at 1, 2, and 3 years compared with baseline (baseline, 538.16 ± 32.14; 1 year, 526.55 ± 37.30 µm [p = 0.00]; 2 years, 521.67 ± 36.79 µm [p = 0.00]; 3 years, 520.43 ± 36.88 µm [p = 0.00]). The reduction of CCT was confirmed by subgroup analysis. In the 0.005% latanoprost group, mean CCT was decreased at 1 year (p = 0.11), 2 years (p = 0.00), and 3 years (p = 0.02). In the 0.0015% tafluprost group and the 0.004% travoprost group, mean CCT was also significantly decreased at all years (p = 0.00). No statistical difference was observed between the NTG subgroups (p = 0.06). CONCLUSIONS: Topical therapy with PGAs appeared to cause a significant decrease in CCT reduction in patients with NTG. A long-term follow-up study including more participants is needed.

Distribution of 14C-Latanoprost Following a Single Intracameral Administration Versus Repeated Topical Administration.

PURPOSE: To qualitatively evaluate the ocular and periocular distribution of 14C-latanoprost following a single intracameral administration or repeated topical ocular administration in beagle dogs and cynomolgus monkeys. METHODS: In the dog study, three animals received an intracameral dose of 14C-latanoprost bilaterally and were euthanized at 1, 2, and 4 h post dose; three control animals received topical 14C-latanoprost bilaterally once daily for 5 days and were euthanized at 1, 4, and 24 h post final dose. Sagittal 40-µm sections of eyes with surrounding tissues were collected and processed for autoradiography. Methods in the monkey study were similar; two animals received a unilateral intracameral dose of 14C-latanoprost. RESULTS: After intracameral dosing in dogs, radioactivity was concentrated in the cornea, iris, ciliary body, and anterior chamber with no radioactivity detected in the eyelids or other periorbital tissues. After topical dosing, radioactivity was distributed in the bulbar conjunctiva, cornea, anterior chamber, iris, ciliary body, upper and lower eyelids, and periorbital tissues (fat/muscle). After intracameral dosing in monkeys, radioactivity was concentrated in the anterior chamber, cornea, iris, ciliary body, and posteriorly along the uveoscleral outflow pathway; there was no radioactivity in the eyelids or periorbital tissues aside from signal in the nasolacrimal duct, likely from reflux of 14C-latanoprost into the tear film. CONCLUSIONS: Intracameral delivery resulted in more selective target tissue drug exposure. Intracameral drug delivery has potential to reduce ocular surface and periocular adverse effects associated with topical administration of prostaglandin analogues, such as eyelash growth and periorbital fat atrophy.

[Long-term use of latanoprost in the treatment of glaucoma]. / Dolgosrochnoe primenenie latanoprosta v lechenii glaukomy.

Glaucoma is the main cause of irreversible blindness in the world. Latanoprost - an ester prodrug of prostaglandin F2α (PGF2α) - was the first prostaglandin analogue used in the treatment of glaucoma. The present review shows that latanoprost is the most balanced prostaglandin analogue in terms of efficacy-safety. Its use improves the quality of life of glaucoma patients, provides reliable IOP reduction, has high patient compliance, and helps with the long-term preservation of visual functions. The review also reveals the possibility of long-term (more than five years) use of the drug, as well as effective combined treatment using latanoprost and beta-blockers, considers the pediatric use of latanoprost, and discusses its neuroprotective properties.

Fixed-Dose Combination of Netarsudil and Latanoprost in Ocular Hypertension and Open-Angle Glaucoma: Pooled Efficacy/Safety Analysis of Phase 3 MERCURY-1 and -2.

INTRODUCTION: New open-angle glaucoma (OAG) and ocular hypertension (OHT) therapies that reduce treatment burden and improve outcomes relative to currently available agents are needed. Netarsudil, a novel Rho kinase inhibitor approved by the US Food and Drug Administration, reduces intraocular pressure (IOP) by increasing trabecular outflow. Two phase 3 superiority studies compared a fixed-dose combination (FDC) of netarsudil and the prostaglandin latanoprost with each active component for IOP-lowering efficacy. METHODS: Pooled efficacy and safety data were analyzed from MERCURY-1 and -2 studies in patients with OAG or OHT. Patients instilled one drop of netarsudil (0.02%)/latanoprost (0.005%) FDC (n = 483), netarsudil (0.02%, n = 499), or latanoprost (0.005%, n = 486) into each eye once-daily between 20:00 and 22:00. IOP was measured at 08:00, 10:00, and 16:00 at weeks 2, 6, and the primary endpoint at month 3. RESULTS: Baseline mean diurnal IOP was 23.6, 23.6, and 23.5 mmHg in netarsudil/latanoprost FDC, netarsudil, and latanoprost groups, respectively. Mean diurnal IOP in each group was 15.3, 18.1, and 17.5 mmHg at week 2, 15.7, 18.4, and 17.4 mmHg at week 6, and 15.8, 18.4, and 17.3 mmHg at week 12. The netarsudil/latanoprost FDC met criteria for superiority compared with each active component (p < 0.0001 for all nine time points). At month 3, among patients randomized to netarsudil/latanoprost FDC or latanoprost, 58.4% vs 37.3% (p < 0.0001) achieved IOP ≤ 16 mmHg. Among patients randomized to netarsudil/latanoprost FDC or netarsudil or latanoprost, 30.9% vs 5.9% (p < 0.0001) vs 8.5% (p < 0.0001) achieved at least a 40% reduction from baseline in mean diurnal IOP. Pooled safety results were consistent with individual MERCURY studies. CONCLUSION: Once-daily netarsudil/latanoprost FDC produced statistically significant and clinically relevant reductions in mean IOP that were statistically superior to IOP reductions achieved by netarsudil and latanoprost monotherapy. Results of the pooled efficacy and safety analyses were consistent with the individual studies. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT02558400 and NCT02674854.

In patients with open-angle glaucoma (OAG) or ocular hypertension (OHT), treatment to lower intraocular pressure (IOP) is needed to prevent optic nerve damage and vision loss. Many patients do not achieve sufficient IOP lowering with a single drug. The use of multiple IOP-lowering agents, which may have different dose regimens, can be complex and reduce patient adherence. Combination treatments that incorporate multiple agents are available, but until recently none included a prostaglandin analogue, the most widely prescribed first-line therapy. A once-daily, fixed-dose combination (FDC) therapy (ROCKLATAN^®) has been approved in the USA that contains the prostaglandin analogue latanoprost and netarsudil, a novel Rho kinase inhibitor. The netarsudil/latanoprost FDC demonstrated efficacy and safety in lowering IOP among patients with OAG and OHT in the 12-month MERCURY-1 and the 3-month MERCURY-2 clinical trials. To better characterize efficacy and safety, we pooled and analyzed the data from each trial. The pooled data support the findings of the individual studies:Efficacy: 1. Netarsudil/latanoprost FDC demonstrated statistical superiority to the individual components netarsudil and latanoprost in decreasing IOP at all time points assessed over 3 months. 2. Nearly twice as many patients receiving FDC achieved at least a 30% reduction from baseline in IOP, as recommended by the American Academy of Ophthalmology for a first-line treatment, compared to the IOP reduction achieved by netarsudil and latanoprost monotherapy.Safety: No new safety signals were identified. Netarsudil/latanoprost FDC was associated with no treatment-related serious adverse events, minimal systemic adverse events, and manageable ocular adverse events.

Evaluating the Effects of an Ophthalmic Solution of Coenzyme Q10 and Vitamin E in Open-Angle Glaucoma Patients: A Study Protocol.

INTRODUCTION: The CoQun® study is a multicenter, controlled trial aimed to evaluate the neuroprotective effects of Coqun®, an ophthalmic solution of Coenzyme q10 (CoQ10) and Vitamin E (VitE), in patients affected by primary open-angle glaucoma (POAG). Pre-clinical studies and small non-controlled clinical trials have previously shown a potential role of CoQ10 and VitE in glaucoma neuroprotection, both in vitro and in vivo. METHODS: Randomized, parallel arm, multicenter, double-blind study. POAG patients with an IOP ranging from 17 to 21 mm Hg on monotherapy with a prostaglandin analogue (PGA) will be considered for study enrollment. Inclusion criteria will be visual field (VF) mean deviation between - 4 and - 10 dB and VF Pattern Standard Deviation between 4 and 10 dB. Eligible patients will be randomized to receive CoQun® (Arm A) or placebo (Arm B), in addition to PGA monotherapy. PLANNED OUTCOMES: Primary outcome will be time to progression, defined as the time between the baseline visit and the visit with confirmed VF progression. A total of 612 patients are planned to be enrolled, to detect a hazard ratio of 0.65, with a power of 80% and an alpha error of 0.05 (two-sided). For study power calculation, 10% non-evaluable patients are assumed. This is the first study investigating, in a randomized, double-blind and controlled fashion, the neuroprotective effects of CoQ10 and VitE in POAG patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03611530.

Prophylactic treatment of intraocular pressure elevation after uncomplicated cataract surgery in nonglaucomatous eyes - a systematic review.

The purpose of this systematic review was to evaluate the literature regarding prophylactic treatment of intraocular pressure (IOP) elevation after uncomplicated cataract surgery to provide an evidence-based guideline for cataract surgeons. The relevant literature was identified in EMBASE and PubMed. The risk of bias was assessed according to the 'Cochrane Handbook for Systematic Reviews of Interventions' and the ROBINS-I tool. The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) criteria were used to rate the quality of evidence, and relevant data were systematically extracted to evaluate the pressure-lowering effect of the active substances. The primary outcomes for this systematic review were the absolute and relative pressure-lowering effect of the different drugs after 3-8 hr and 1 day after surgery. In total, 23 randomized controlled trials and one nonrandomized controlled study consisting of 45 treatment arms with 14 different active substances were included in the qualitative synthesis. According to the GRADE criteria, nine trials were graded as 'high' quality of evidence, 12 trials as 'moderate', while three trials were given the grade 'low' quality of evidence. The primary outcomes showed most consistency between the trials, which studied the effect of timolol, and presented a relative effect from 18.6% to 29.6% at 3-8 hr and 9.8% to 23.6% at day 1. This systematic review indicates that timolol, latanoprost and travoprost alone or medications containing timolol as an additive active substance, such as dorzolamide + timolol, brinzolamide + timolol and brimonidine + timolol, are characterized by a good relative IOP-lowering effect, which can be gained by a single dose postoperatively.