IOP-lowering Efficacy Research Articles

Travoprost Intracameral Implant Demonstrates Superior IOP Lowering Versus Topical Prostaglandin Analog Monotherapy in Patients with Open-Angle Glaucoma or Ocular Hypertension.

This study was conducted to analyze and compare the intraocular pressure (IOP) treatment effect of the slow-eluting (SE) travoprost intracameral implant to the IOP treatment effect of topical prostaglandin analog (PGA) monotherapy in a subgroup of subjects who were on pre-study PGA monotherapy prior to enrollment in the two pivotal phase 3 trials of the travoprost intracameral implant. A combined study population of 133 subjects from two phase 3 trials, who were on topical PGA monotherapy at screening, subsequently underwent a washout period from their topical PGA, and then were randomized and administered an SE travoprost intracameral implant. The subjects were analyzed for the IOP treatment effects of the pre-study topical PGA monotherapy and the in-study SE travoprost intracameral implant. Paired t-tests were used to compare the difference in screening minus post-washout baseline IOP versus month 3 minus post-washout baseline IOP. The IOP-lowering efficacy in eyes administered an SE travoprost intracameral implant was compared to the IOP lowering in the same eyes while on a topical PGA monotherapy prior to study entry. Pre-study topical PGA monotherapy and the SE travoprost intracameral implant demonstrated IOP treatment effects of -5.76mmHg and -7.07 mmHg, respectively. The IOP-lowering treatment effect was significantly greater by 1.31mmHg for the SE travoprost intracameral implant relative to pre-study PGA monotherapy (95% confidence interval: -2.01, -0.60; P = 0.0003). The SE travoprost intracameral implant demonstrated superior IOP-lowering treatment effect versus pre-study topical PGA monotherapy with a superiority margin that was both statistically significant and clinically meaningful. The greater IOP reduction from baseline while on the SE implant versus pre-study topical PGA monotherapy may be a reflection of the optimized adherence and continuous elution of PGA therapy into the anterior chamber achieved with the SE travoprost intracameral implant. ClinicalTrials.gov identifiers, NCT03519386 and NCT03868124.

Sustained release of brimonidine from conjunctival sac insert to reduce intraocular pressure for glaucoma treatment

ABSTRACT Background Glaucoma is one of the major irreversible blinding eye diseases in the world. Reducing intraocular pressure (IOP) is the primary treatment option, and taking eye drops daily is the common method. However, short drug duration and poor bioavailability of eye drops may lead to unsatisfied therapeutic effects and inadequate patient compliance. Methods A brimonidine-loaded silicone rubber insert (BRI@SR@PT) was prepared by loading brimonidine into a surface-modified silicone rubber ring, followed by polydopamine/thermoplastic polyurethane coatings. The physical properties, in vitro cytocompatibility and drug release of BRI@SR@PT were investigated. The BRI@SR@PT was administrated in the conjunctival sac of rabbit eyes, and its in vivo drug release, IOP-lowering efficacy and biosafety were assessed. Results The BRI@SR@PT presented great thermal stability and excellent elasticity. The BRI@SR@PT was able to release BRI sustainably for 28 days with little toxicity in vitro. Compared to BRI eye drops, the BRI@SR@PT effectively lowered IOP for 21 days based on the sustained BRI release with great biosafety when administrated in conjunctival sac of rabbit eyes in a noninvasive fashion. Conclusions The conjunctival sac insert (BRI@SR@PT), as a promising drug-delivery platform, may provide a sustained IOP-lowering treatment for patients with ocular hypertension or glaucoma, without the need for invasive procedures.

Phase 3 Randomized Clinical Trial of the Safety and Efficacy of Travoprost Intraocular Implant in Patients with Open-Angle Glaucoma or Ocular Hypertension

PurposeEvaluate the safety and intraocular pressure (IOP)-lowering efficacy of two models of the travoprost intraocular implant (fast-eluting [FE-implant] and slow eluting [SE-implant]) from one of two pivotal trials (GC-010). DesignPhase 3, multicenter, randomized, double-masked, sham-controlled, non-inferiority trial. ParticipantsSubjects with open-angle glaucoma or ocular hypertension, using 0 to 3 IOP-lowering medications at screening and having an unmedicated baseline mean diurnal IOP (average of 8AM, 10AM and 4PM timepoints) of ≥ 21 mmHg, and an unmedicated baseline IOP of ≤ 36 mmHg at each timepoint in the study eye. MethodsStudy eyes were randomized to the travoprost intraocular implant (FE-implant [n=200] or SE-implant [n=197] model) plus twice-daily (BID) placebo eye drops, or to sham procedure plus timolol ophthalmic solution, 0.5% BID (n=193). Main Outcome MeasuresThe primary outcome was mean change from baseline IOP in the study eye at 8AM and 10AM, at each of day 10, week 6, and month 3. Safety outcomes included adverse events (AEs), corneal endothelial cell counts, visual acuity, and conjunctival hyperemia assessment. ResultsMean IOP reduction from baseline over the 6 timepoints ranged from 6.6 to 8.4 mmHg for the FE-implant group, from 6.6 to 8.5 mmHg for the SE-implant group, and from 6.5 to 7.7 mmHg for the timolol group. The primary efficacy endpoint was met; the upper limit of the 95% confidence interval of the difference between the implant groups and the timolol group was < 1 mmHg at all 6 timepoints. Study eye AEs, most of mild or moderate severity, were reported in 21.5%, 27.2% and 10.8% of subjects in the FE-implant, SE-implant and timolol groups, respectively. The most common AEs included iritis (FE-implant, 0.5%; SE-implant, 5.1%), ocular hyperaemia (FE-implant, 3.0%; SE-implant, 2.6%), visual acuity reduced (FE-implant, 1.0%; SE-implant, 4.1%; timolol, 0.5%), and IOP increased (FE-implant, 3.5%; SE-implant, 2.6%; timolol, 2.1%). There was one serious study eye AE (endophthalmitis). ConclusionsThe travoprost intraocular implant demonstrated robust IOP reduction over the 3-month primary efficacy evaluation period following a single administration. The IOP-lowering efficacy of both implant groups was statistically and clinically non-inferior to the timolol group, with a favorable safety profile.

Omidenepag Isopropyl Versus Timolol in Patients With Glaucoma or Ocular Hypertension: Two Randomized Phase 3 Trials (SPECTRUM 4 and 3)

The SPECTRUM 4 and 3 studies assessed the intraocular pressure (IOP)-lowering efficacy and safety of omidenepag isopropyl (OMDI) 0.002% vs timolol 0.5% in patients with glaucoma or ocular hypertension (OHT). Phase 3, randomized, controlled, double-masked, noninferiority studies. Multicenter studies in the US. Inclusion criteria for adults ≥ 18 years (SPECTRUM 4 [N = 409] and 3 [N = 413]) were open-angle glaucoma or OHT, and IOP ≥ 22 mm Hg and ≤ 34 mm Hg; and for pediatric patients < 18 years (N = 13, SPECTRUM 3) were pediatric glaucoma or OHT. The primary objective in both studies was OMDI noninferiority to timolol in reducing IOP (3 months). SPECTRUM 3 included an additional 9 months of OMDI treatment. Safety evaluations were of ocular/non-ocular adverse events (AEs). The IOP-lowering range of OMDI remained consistent in SPECTRUM 4 and 3 (-5.6 to -5.9 vs -5.3 to -5.7 mm Hg, respectively); however, timolol efficacy varied (-5.4 to -6.1 vs -6.4 to -7.0 mm Hg, respectively). OMDI noninferiority was achieved in SPECTRUM 4. Efficacy was maintained with 12-month treatment in SPECTRUM 3. Both studies reported more ocular AEs with OMDI, but lower rates of appearance-altering AEs vs timolol. No new safety concerns were identified. Rates of macular edema in pseudophakic patients increased with prolonged OMDI exposure. SPECTRUM 4 and 3 demonstrated consistent 3-month IOP-lowering efficacy and safety of OMDI vs timolol in patients with glaucoma or OHT. The 12-month data from SPECTRUM 3 suggest OMDI may have long-term benefits in patients with glaucoma or OHT.

Postoperative Management of Kahook Dual Blade Goniotomy with Phacoemulsification Cataract Extraction.

To review the efficacy and safety of two common postoperative regimens following Kahook Dual Blade goniotomy with phacoemulsification cataract extraction (KDB-CE). This is a retrospective review of eyes undergoing KDB-CE from May 2016 to 2018 by a single surgeon. Almost 12-month follow-up data were assessed for two common postop regimens-treatment with (1) topical prednisolone acetate 1% with pilocarpine 1% (pred-pilo) or (2) difluprednate 0.05% postoperatively. Postoperative results were compared to each respective baseline intraocular pressure (IOP) levels. There were 53 eyes in the difluprednate group and 25 eyes in the pred-pilo group. In the difluprednate group, the IOP decreased at postoperative day 1 (POD1) [16 ± 5 baseline vs 15 ± 5 POD1, mean ± standard deviation (SD) in mm Hg, and p = 0.321], but increased at postoperative week 1 (POW1) due to a 15% rate of IOP-spikes (19 ± 9, p = 0.099). The number of IOP-lowering drops decreased from baseline (2 ± 1 drops) to 1 ± 1 drops at POD1 (p < 0.0001), and remained at 1 ± 1 drops through postoperative month 12 (POM12) (p < 0.0001). In the pred-pilo group, there was a statistically significant decrease in mean IOP at POW1 (16 ± 4 POW1 vs 18 ± 6 baseline, p = 0.044), which persisted through POM6. The number of IOP-lowering drops was not statistically significantly lower from baseline at POM3 (2 ± 1 at POM3, p = 0.188). Spikes in IOP, corneal edema, and hyphema were the most common complications. Both postoperative regimens were effective following KDB-CE at reducing IOP at 12 months. The difluprednate group was likely to experience an IOP-spike at POW1 but used fewer IOP-lowering drops 12 months after KDB goniotomy. In the pred-pilo group, the number of IOP-lowering drops was equivalent to baseline levels at POM3. Aside from IOP spikes, there were similar complication rates observed between the two postoperative regimens. Due to demographic differences, it was not possible to compare relative IOP-lowering efficacy between the two postoperative regimens. It is efficacious and safe to use either postoperative regimen following KBD-CE. Postoperative trajectories may differ with respect to the postoperative regimen, but further randomized controlled trials are needed to compare various topical steroid medications for postoperative regimens following KDB-CE. Birnbaum F, Wakil S, Vu DM, et al. Postoperative Management of Kahook Dual Blade Goniotomy with Phacoemulsification Cataract Extraction. J Curr Glaucoma Pract 2023;17(4):169-174.

Fabrication of Anti-glaucoma Nanofibers as Controlled-Release Inserts for Ophthalmic Delivery of Brimonidine Tartrate: In Vivo Evaluation in Caprine Eye.

Chronic ailments usually decrease the quality of life due to the requirement for repetitive administration of drugs. Glaucoma is a chronic eye disease occurred because of increased intraocular pressure (IOP). Controlled-release inserts can overcome this challenge by a gradual release of the antiglaucoma drugs. This study aimed to fabricate ocular inserts of brimonidine tartrate (BMD) for the management of glaucoma. Different polymers including poly (D, L-lactide), polycaprolactone, cellulose acetate, and Eudragit RL100® were used to develop the BMD-loaded nanofibrous inserts by electrospinning technique. The inserts were characterized. The morphology and drug-polymer compatibility were examined by scanning electron microscopy (SEM), and Fourier-transform infrared (FTIR) spectroscopy and in vitro drug release in PBS. The IOP-lowering efficacy and irritancy of optimized formulation were assessed in the caprines. SEM images demonstrated nanofibers with uniform morphology and a mean diameter<300 nm were fabricated. The nanofibers were high-strength and flexible enough to be placed in the conjunctival sac. FTIR showed drug-polymer compatibility. In vitro release study indicated a sustained-release profile of the drug during 6 days for inserts. In vivo evaluation indicated that the optimized formulation is capable of maintaining the IOP in a non-glaucomatous range for an extended duration of 6 days. In addition, the formulation was non-irritant to the caprine eye. Due to the prolonged IOP-lowering efficiency, BMD-loaded nanofibrous inserts can be considered suitable for the controlled release of drugs and thus enhance patient compliance by reducing the frequency of administration.

One-year experience with latanoprostene bunod ophthalmic solution 0.024% in clinical practice: A retrospective observational study.

We evaluated the IOP-lowering efficacy and safety of latanoprostene bunod (LBN) ophthalmic solution 0.024% (Vyzulta®), the first topical nitric oxide-donating prostaglandin analog (PGA), in clinical practice. A retrospective medical chart review from July 2021 to July 2023 of patients with open-angle glaucoma receiving LBN with at least 1 year follow-up was conducted. All included patients received LBN 0.024% as a replacement for a PGA, with examinations at 1-, 3-, 6-and 12-months follow-up. Main outcome measures were IOP, retinal nerve fiber layer thickness, visual fields before/after LBN use and adverse effects. Subgroup analysis with glaucoma types and PGA use were performed for additional IOP reduction after LBN use. Among 78 included patients, 47 patients (81 eyes), 60% with open-angle glaucoma (OAG) remained on LBN throughout 12-month follow-up. Baseline IOP was 18.2±4.2 mm Hg, and Prostaglandin analog (PGA)-IOP was 14.4 ± 3.0 mm Hg (21% mean IOP reduction). After switched to LBN, mean additional IOP reduction was 1.0 mm Hg at month 1, and the greatest reduction was 1.6 mm Hg (8.8% additional mean IOP reduction) at month 12 (P<0.0001). Subgroup analysis (NTG, 73%) showed that mean additional IOP reduction at month 12 was 1.3±2.0 mm Hg in NTG group and 2.1±3.2 mm Hg in POAG group (7.7% vs. 8.7% additional IOP reduction rates, P = 0.23). Subgroup analysis of PGA use at month 12 was 1.8±2.3 mm Hg in tafluoprost group and 0.5±1.7 mm Hg in travoprost group (9.5% vs.2.6% additional IOP reduction rates, P = 0.02). Tolerable ocular adverse effects included irritation (n = 16, 19.8%), mild conjunctival hyperemia (n = 11, 13.6%), dark circles (n = 4, 4.9%) and blurred vision (n = 2, 2.5%). There were no significant visual field and retinal nerve fiber layer thickness changes after 12 months of treatment with LBN 0.024%. Although high intolerable adverse effects including conjunctival hyperemia and eye irritation happened in the first month, remaining sixty percent of patients exhibited statistically significant additional IOP reductions in the replacement of other PGAs during 12 months of clinical use of LBN 0.024%.

A novel reverse micelle based cationic double nanoemulsion as a potential nanoplatform for enhancing the anitglucomal activity of betaxolol hydrochloride; formulation, in vitro characterization, ex vivo permeation and in vivo pharmacodynamic evaluation in glaucomatous rabbits’ eyes

Glaucoma is one of the most common causes of irreversible vision loss worldwide. The hydrophilic nature of the anti-glaucoma drug Betaxolol hydrochloride (BH) limits its ocular permeation necessitating repeated dosing. This can reduce patient compliance and increase the risk of experiencing adverse side effects. Our research is the first to encapsulate BH into reverse micelle-based cationic double W1/O/W2 nanoemulsions (RM-CDNEs) as a new platform capable of enhancing both the corneal permeability and IOP lowering efficacy of this drug. BH-loaded RM-CDNEs were prepared by a modified two-step emulsification method using sonication technique and applying 24 full factorial design to assess the impact of formulation variables and select the optimal delivery system. The in vitro drug-release, ex vivo permeation and in vivo performance of this novel nanocarrier were also assessed. The optimal delivery system (RM-CDNE 10) has mean DS, PDI, ZP and entrapment efficiency of 46.53 ± 1.30 nm, 0.217 ± 0.02, +40.9 ± 5.04 mV and 95.1 ± 2.44 %, respectively. A 90.77 % of drug was released over 7h. RM-CDNE 10 showed 2.5-fold increase in ex vivo corneal BH permeation with a prolonged IOP reduction of 58.77 % ± 1.18 % and AUC0-48 of 2537.82 ± 12.8%h. While, the marketed product (Epitaxol®) had only 33.63 ± 1.54 % IOP reduction with AUC0–48 h of 823.14 ± 3.67%h when tested in rabbits (P ≤ 0.05). Histopathological and Draize irritation studies confirmed that RM-CDNEs were non-irritant. These findings proved that the novel BH-loaded RM-CDNEs system improved the outcomes for patients suffering from glaucoma and thus decreasing the liability for disease progression into blindness.

Single Administration of Bimatoprost Implant: Effects on 24-Hour Intraocular Pressure and 1-Year Outcomes

To evaluate the effects of a single bimatoprost implant administration on 24-hour intraocular pressure (IOP) lowering at 8 weeks, and 1-year IOP-lowering efficacy and safety outcomes. Multicenter, open-label, 12-month, phase 3b study (NCT04285580). Adults with open-angle glaucoma or ocular hypertension. Participants (n=31) received 10-μg bimatoprost implant in the study eye on day 1; IOP (sitting and/or supine) was measured with pneumatonometry every 2 hours throughout a 24-hour period at baseline and week 8. IOP was measured by Goldmann applanation tonometry (GAT) at hour 0 (8 am±1 hour) at baseline, weeks 8 and 16, and months 6, 9, and12. The primary endpoint was the week-8 hour-matched change from baseline in habitual position IOP over 24 hours assessed with pneumatonometry. Hour 0 IOP change from baseline measured with GAT in study eyes that received no additional (rescue) IOP-lowering treatment, treatment-emergent adverse events (TEAEs), and central corneal endothelial cell density (CECD) were evaluated through 12 months. The mean (standard deviation [SD]) baseline IOP at hour 0 was 24.2 (2.70) mmHg and 25.3 (7.15) mmHg by GAT and pneumatonometry, respectively. Pneumatonometer measurements of IOP taken over 24 hours at week 8 with the participant in habitual position (sitting from 8 am to 10 pm, supine from 12 am to 6 am) showed consistent IOP lowering through the day and night and reduced fluctuation in IOP. The range in IOP measurements over 24 hours was reduced from baseline by a mean (SD) of-1.6 (2.98) mmHg. All 31 bimatoprost implant-treated participants completed the 12-month study; 23 (74%) required no rescue IOP-lowering treatment. The mean (SD) IOP reduction from baseline at month 12 in nonrescued eyes was-4.3 (3.35) mmHg. The most common TEAE was conjunctival hyperemia (incidence 35.5%, 11/31). No implant-treated eye had a ≥ 15% loss in CECD from baseline. A single intracameral administration of the bimatoprost implant lowered IOP in the habitual position consistently throughout the day and night at week 8. The majority of participants continued to have reduced IOP for 1 year without additional therapy. The 1-year safety profile was favorable. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

MINIMALLY INVASIVE GLAUCOMA SURGERY (MIGS): COMPARISON OF TRABECULAR VERSUS SUPRACHOROIDAL ROUTE

Introduction: Because of the high rate of complications associated with traditional glaucoma filtering surgery, various research were launched to develop a new device, such as drainage channels, such as Glaucoma Drainage Devices. Objective: To compare the efficacy and safety of trabecular route and suprachoroidal MIGS in eyes with mild to moderate glaucoma with and without cataract extraction of these two devices. Methods: Literature search was conducted using online database such as Google Scholar, Pubmed, Survey of Ophtalmology, and Clinical Key. Result: Since the IOP-lowering efficacy of these treatments is restricted by episcleral venous pressure, MIGS targeting the trabecular outflow system may be the best option for patients with mild-to-moderate open-angle glaucoma. Conclusion: The implantation of trabecular iStents resulted in a considerable reduction in IOP, particularly in mild and moderate POAG. Both MIGS versions have good efficacy and safety profiles, with only minor problems like microscopic hyphema and stent blockage. Keywords: glaucoma, Minimally Invasive Glaucoma Surgery (MIGS), iStents, cypass

Ophthalmic prostaglandin analogs revisited - A systematic review of commonly used formulations

Aim: To systematically review the randomized control trials (RCTs) of the various prostaglandin(PG) analogues, comparing the effectiveness in treating glaucomas, safety and adverse effects of the individual agents. Methods: Articles were searchedusing the following key words “PG analogues”, “Latanoprost”, “ Bimatoprost”, “Travoprost”, “ Tafluprost”, “Unoprostone”, “ophthalmology”, “randomized controlled trial”, either singly or variably combined. Databases searched included Pubmed, Embase, Cochrane library, and Science direct. The search strategy was to identify randomized control trials (RCTs), either singly or variably combined. Results: 24 Randomised control trials that had evaluated the efficacy and adverse effects of different PG analogue agents were selected and were used in this review Average JADAD value of the researches was found to be 2.83. Bimatoprost was found to be the most effective agent in IOP lowering efficacy but it had the maximal incidence of local adverse effects. Latanoprost, Travoprost and Tafluprost had similar efficacy. Latanoprost had the best tolerability. Unoprostone had weaker antiglaucoma action, compared to the other agents. Conclusions: Bimatoprost is probably one of the best antiglaucoma medications available at present. Its tolerability could be improved by using preservative free formulations. Latanoprost is a well tolerated agent with reasonably good antiglaucoma action.

Critical Evaluation of Multifunctional Betaxolol Hydrochloride Nanoformulations for Effective Sustained Intraocular Pressure Reduction.

Glaucoma is a chronic disease that requires long-term adherence to treatment. Topical application of conventional eye drops results in substantial drug loss due to rapid tear turnover, with poor drug bioavailability being a major challenge for efficient glaucoma treatment. We aimed to prepare the anti-glaucoma drug betaxolol hydrochloride (BH) as a novel nano-delivery system that prolonged the retention time at the ocular surface and improved bioavailability. We constructed multifunctional nanoparticles (MMt-BH-HA/CS-ED NPs) by ion cross-linking-solvent evaporation method. The particle size, zeta potential, encapsulation efficiency and drug loading of MMt-BH-HA/CS-ED NPs were physicochemically characterized. The structure of the preparations was characterized by microscopic techniques of SEM, TEM, XPS, XRD, FTIR and TGA, and evaluated for their in vitro release performance as well as adhesion properties. Its safety was investigated using irritation assays of hemolysis experiment, Draize test and histopathology examination. Precorneal retention was examined by in vivo fluorescence tracer method and pharmacokinetics in tear fluid was studied. A model of high IOP successfully induced by injection of compound carbomer solution was used to assess the IOP-lowering efficacy of the formulation, and it was proposed that micro-interactions between the formulation and the tear film would be used to analyze the behavior at the ocular surface. The positively charged MMt-BH-HA/CS-ED NPs were successfully prepared with good two-step release properties, higher viscosity, and slower pre-corneal diffusion rate along with longer precorneal retention time compared to BH solution. The micro-interactions between nanoparticles and tear film converted the drug clearance from being controlled by fast aqueous layer turnover to slow mucin layer turnover, resulting in higher drug concentration on the ocular surface, providing more durable and stable IOP-lowering efficacy. The novel multifunctional MMt-BH-HA/CS-ED NPs can effectively reduce IOP and are suitable for the treatment of chronic disease glaucoma.

Reviewing the evidence surrounding preservative-free tafluprost/timolol fixed-dose combination therapy in open-angle glaucoma and ocular hypertension management: a focus on efficacy, safety, and tolerability

ABSTRACT Introduction Elevated intraocular pressure (IOP) is the most important modifiable risk factor for irreversible sight loss in open-angle glaucoma (OAG). The topical fixed-dose combination (FC) of preservative-free (PF) tafluprost (0.0015%) and timolol (0.5%) (tafluprost/timolol) is among the second-line IOP-lowering options for OAG and ocular hypertension (OHT). Areas covered PubMed searches identified publications reporting key evidence from randomized controlled trials (RCTs) and real-world studies examining the safety, tolerability, and IOP-lowering efficacy of PF tafluprost/timolol FC therapy in OAG/OHT management. Expert opinion Glaucoma patients are more likely to have ocular surface disease, and treatment should be individualized so that target response may be achieved while considering tolerability and quality of life, according to European Glaucoma Society guidelines. PF FC therapies, such as PF tafluprost/timolol FC, avoid ocular surface exposure to toxic preservative agents and reduce the required number of treatment administrations. These properties may enhance treatment tolerability and adherence, resulting in improved IOP-lowering efficacy and disease control. Treatment outcomes from RCTs and real-world studies examining PF tafluprost/timolol FC therapy support this hypothesis, with significant IOP reductions and/or improvements in tolerability parameters demonstrated, regardless of the prior topical therapy used and even when switched directly to PF tafluprost/timolol FC treatment (without washout).

Ionic Liquid Pilocarpine Analog as an Antiglaucoma Drug Candidate.

Ionic liquid pilocarpine analog [Pilo-OEG]Cl, the first-of-its-kind ionic liquid antiglaucoma drug candidate, is synthesized and reported. To synthesize [Pilo-OEG]Cl, pilocarpine was reacted with the oligo-polyethylene glycol chloride, 2-[2-(2-chloroethoxy)ethoxy] ethanol, to form an ionic liquid molecule with an imidazole cation and a chloride anion. The chemical structure of [Pilo-OEG]Cl was confirmed with 1H NMR spectroscopy. Compared with pilocarpine (Pilo) and pilocarpine hydrochloride (PiloHCl), [Pilo-OEG]Cl has improved structural stability according to pH measurements and LC-MS analysis. The corneal permeability coefficient of [Pilo-OEG]Cl is 2-fold higher than that of Pilo and 8-fold higher than that of PiloHCl. [Pilo-OEG]Cl does not show apparent toxicity to human corneal epithelial cells over a broad range of concentrations up to 50 mM. The in vivo efficacy of PiloHCl and [Pilo-OEG]Cl was tested in normotensive adult Brown Norway female rats. [Pilo-OEG]Cl is found to be more potent than PiloHCl in lowering the intraocular pressure (IOP). [Pilo-OEG]Cl is more cytocompatible than PiloHCl based on the in vitro ELISA and hemolysis tests and in vivo histological analysis. Taken together, [Pilo-OEG]Cl has enhanced stability, corneal permeability, better IOP-lowering efficacy, and improved biocompatibility, thus making it a promising new drug candidate for antiglaucoma therapy. Transforming old antiglaucoma drugs to pharmaceutically active ionic liquids represents an innovative approach to developing glaucoma medications.

Preliminary Surgical Outcomes of a Trimmed-Plate Aurolab Aqueous Drainage Implant (AADI) in Eyes at High Risk of Hypotony

PurposeWe describe the technique of trimming the 350 mm2 AADI glaucoma shunt plate and report preliminary results that test the hypothesis that the IOP-lowering efficacy of the trimmed AADI glaucoma shunt is comparable to the Baerveldt 250 mm2 glaucoma drainage implant with a comparable safety profile to the standard AADI implant.MethodsConsecutive patients who had received the modified trimmed-plate AADI, standard AADI and Baerveldt 250 mm2 were included in the study. This included patients with refractory or primary or secondary glaucoma of all ages and eyes with and without previous glaucoma surgery. The decision for trimming the AADI plate was made according to the surgeon’s perceived risk of hypotony. Pre-operative, intraoperative and post-operative data were collected from the hospital electronic medical record system. Surgical success was defined as IOP ≥5 mmHg and ≤21 mmHg on two consecutive visits after 3 months, whilst maintaining at least LP vision and avoiding re-operation for glaucoma.ResultsThe sample consisted of 69 eyes (19 with trimmed-plate AADI implant; 36 eyes with the standard AADI implant and 14 eyes who received a BGI-250). The mean IOP reduction at 1 year was 15 mmHg for the Baerveldt-250, 10 mmHg for the AADI and 13 mmHg for the trimmed-plate AADI. The surgical success rate of the implants over 1 year was 85.7% (95% CI, 53.9–96.2%) for BGI-250, 81.5% (62.6–91.5%) for standard AADI and 78.2% (51.7–91.3%) for the trimmed AADI.ConclusionTrimming the plate of the AADI manually may provide a safe and low-cost method of obtaining a successful surgical outcome in eyes at high risk of hypotony.

Treatment of open-angle glaucoma and ocular hypertension with preservative-free tafluprost/timolol fixed-dose combination therapy: 6 case reports and clinical outcomes

BackgroundTreatment of open angle glaucoma (OAG) and/or ocular hypertension (OHT) focuses on achievement of target intraocular pressure (IOP), with the objective of slowing disease progression. However, ocular surface health is an important consideration in the optimization of treatment. We report 6 patient cases in which enhanced IOP control was achieved following appropriate management of ocular surface inflammation and a therapeutic switch to the preservative-free (PF) tafluprost (0.0015%)/timolol (0.5%) fixed-dose combination (FC).Case presentationSix patient cases, aged 48–74 years, presented with OAG or OHT. Each patient had signs and symptoms of ocular surface disease (OSD). Cases 1–3 were each receiving maximal medical therapy for OAG; regimens comprising prostaglandin analogue (PGA), β-blocker, carbonic anhydrase inhibitor (CAI) and α-2 agonist agents (including treatments containing preservative agent). Cases 1 and 2 reported IOP values ≥23 mmHg in each eye, and wide IOP fluctuations were identified when reviewing patient data concerning case 3 (11–20 mmHg). Maximal therapy was ceased and PF tafluprost/timolol FC was initiated, after which the signs and symptoms of OSD were improved and IOP was reduced (≤18 mmHg for cases 1–3) and stabilized. Cases 4 and 5 were diagnosed with OAG and case 6 had OHT. Each had symptoms and signs of OSD and were treated with a preserved PGA monotherapy (latanoprost 0.005% or bimatoprost 0.03%). At presentation, IOP was 24 mmHg in both eyes (case 4), ≥18 mmHg (case 5) and ≥ 22 mmHg (case 6). Following a switch to the PF tafluprost/timolol FC, OSD symptoms were improved and IOP was 14 mmHg (both eyes; case 4), ≤14 mmHg (case 5) and 16 mmHg (both eyes; case 6).ConclusionsIn addition to IOP-lowering efficacy, approaches to the management of OAG and OHT should consider the impact of treatment tolerability and the susceptibility of these patients to OSD. The presence of ocular surface inflammation appears to be detrimental to adherence and therefore to the effectiveness of topical medications. Addressing OSD through the use of PF FC formations, such as the PF tafluprost/timolol FC, reduces exposure to potentially toxic agents and facilitates improvements in IOP control.

Treatment of Open-Angle Glaucoma and Ocular Hypertension with Preservative-Free Tafluprost/Timolol Fixed-Dose Combination Therapy: Results from the VISIONARY Study Population in Spain.

Purpose:Data are presented from ophthalmology clinics in Spain participating in the VISIONARY study, examining the effectiveness, tolerability, and safety of the preservative-free tafluprost (0.0015%) and timolol (0.5%) fixed-dose combination (PF tafluprost/timolol FC) in the treatment of OAG and OHT.Methods:An observational, multicenter prospective study examined treatment outcomes following a switch to PF tafluprost/timolol FC in adult OAG/OHT patients demonstrating insufficient response to beta-blocker or prostaglandin analog (PGA) monotherapy. Primary end point was mean change in intraocular pressure (IOP) from baseline at month 6. Changes in the severity of ocular signs and symptoms were also assessed.Results:Overall, 92 patients (51.1% female) were included. Mean (standard deviation) age was 68.3 (12.1) years. Mean IOP was reduced from 21.9 mmHg at baseline to 16.7 mmHg at month 6 (22.3% decrease; P < 0.0001). Significant IOP reductions were observed at weeks 4 and 12 (P < 0.0001). Baseline PGA and beta-blocker users demonstrated mean month 6 IOP reductions of 5.5 mmHg (23.5%; P < 0.001) and 3.5 mmHg (14.6%; P = 0.029), respectively. Severity of conjunctival hyperemia, dry eye, irritation, itching, foreign body sensation, and eye pain was significantly reduced. Three treatment-related adverse events were reported, all were nonserious and mild/moderate in severity.Conclusion:In real-world clinical practice, PF tafluprost/timolol FC treatment provided significant IOP reductions over 6 months and was well tolerated among OAG/OHT patients showing poor response to PGA or beta-blocker monotherapy. IOP-lowering efficacy and improvements in ocular signs and symptoms were evident from week 4 and maintained over the 6-month study period. Trial Registration: European Union electronic Register of Post-Authorisation Studies (EU PAS) register number EUPAS22204.

Phase 2b, Randomized, 3-Month, Dose-Finding Study of Sepetaprost in Patients with Primary Open-Angle Glaucoma or Ocular Hypertension: The ANGEL Study.

Purpose:This phase 2b, randomized, observer-masked, placebo- and active-controlled, parallel-group, multinational (USA and Japan), multicenter study (NCT03216902) assessed the optimal dose of sepetaprost ophthalmic solution in patients with primary open-angle glaucoma or ocular hypertension.Methods:After washout, patients ≥18 years (USA) or ≥20 years of age (Japan) received once-daily sepetaprost for 3 months [0.0005% (n = 43); 0.001% (n = 43); 0.002% (n = 44); and 0.003% (n = 45)], latanoprost 0.005% (n = 44) or placebo until week 6, followed by sepetaprost 0.003% until month 3 (n = 22). Safety assessments included adverse event (AE) occurrence.Results:Baseline mean diurnal intraocular pressure (IOP) was 24.3 mmHg for latanoprost and ranged between 24.1 and 24.5 mmHg for the sepetaprost groups. Sepetaprost 0.002% had the lowest IOP at each month 3 time point (9:00 AM; 1:00 PM; 5:00 PM) of all sepetaprost concentrations (mean ± standard error: 17.6 ± 0.5; 17.4 ± 0.4; 16.7 ± 0.4 mmHg); similar values were observed with latanoprost (18.1 ± 0.6; 17.3 ± 0.5; 17.2 ± 0.5 mmHg). A positive dose–response relationship was observed with the 3 lower sepetaprost doses; sepetaprost 0.002% had numerically greater IOP-lowering effects than sepetaprost 0.003%. All sepetaprost doses had statistically significantly greater IOP reductions from baseline versus placebo at week 6 (P < 0.0001). This IOP-lowering effect was consistent between Japan- and USA-based patients. Most AEs were mild and occurred numerically less frequently with sepetaprost 0.002% (34.1%) versus latanoprost (50.0%). The most frequently reported AE was conjunctival hyperemia.Conclusion:In this study, sepetaprost 0.002% was the optimal concentration, showing comparable IOP-lowering efficacy and safety with latanoprost 0.005%. Most AEs were mild; occurrence was numerically lower with sepetaprost 0.002% than latanoprost 0.005%.

Tie2 Activation via VE-PTP Inhibition With Razuprotafib as an Adjunct to Latanoprost in Patients With Open Angle Glaucoma or Ocular Hypertension.

PurposeTo evaluate the ocular hypotensive efficacy and safety of razuprotafib, a novel Tie2 activator, when used as an adjunct to latanoprost in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT).MethodsSubjects with OAG or OHT and an unmedicated IOP from ≥22 mm Hg to <36 mm Hg were randomized to one of three treatment arms: razuprotafib every day (QD) + latanoprost; razuprotafib twice daily (BID) + latanoprost; or latanoprost monotherapy. The primary endpoint was change in mean diurnal IOP from baseline at day 28.ResultsA total of 194 subjects were randomized, and 193 (99.5%) completed the study. Razuprotafib BID + latanoprost resulted in a significantly larger reduction in diurnal IOP than latanoprost alone (7.95 ± 0.26 mmHg vs. 7.04 ± 0.26 mm Hg, P < 0.05). A smaller improvement was observed after 14 days of treatment (7.62 ± 0.26 mm Hg vs. 7.03 ± 0.26 mm Hg, P = 0.11). Razuprotafib QD dosing did not demonstrate additional IOP lowering compared to latanoprost alone. Conjunctival hyperemia on Day 28 increased by 1.1 units on the four-point Efron scale two hours post dose from a baseline value of 0.6 units, and decreased thereafter.ConclusionsTopical ocular razuprotafib as an adjunct to latanoprost therapy was well tolerated and significantly reduced IOP in patients with OAG/OHT.Translational RelevanceThese data support the IOP lowering efficacy of targeting Tie2 activation in Schlemm's canal in the relevant patient population.

Comparison of the efficacy of latanoprost versus dorzolamide/timolol fixed combination therapy in patients with pseudoexfoliative glaucoma according to glaucoma stage.

Only a few trials have compared the intraocular pressure-lowering effects of prostaglandin analogs to carbonic anhydrase inhibitor plus beta-blocker fixed-dose combination therapy in patients with pseudoexfoliative glaucoma. Furthermore, the influence of the glaucoma stage on the intraocular pressure-lowering effects of these drug types has not been studied. The purpose of this study was to compare the IOP-lowering efficacy of latanoprost, a prostaglandin analog versus dorzolamide/timolol fixed combination, a carbonic anhydrase inhibitor plus beta-blocker fixed-dose combination therapy, in patients with pseudoexfoliative glaucoma based on glaucoma stage. The data of 32 eyes (32 patients) diagnosed with uniocular pseudoexfoliative glaucoma and treated with topical latanoprost (Group 1) or dorzolamide/timolol fixed combination (Group 2) were retrospectively assessed. The groups were subdivided into early and moderate-advanced stages. Patients' demographics, baseline intraocular pressure, final intraocular pressure, and intraocular pressure difference (the difference between the baseline and final intraocular pressure) were determined from medical records and compared between groups and according to glaucoma stage. The mean drug use duration was 17.7 ± 13.5 months. No significant differences in mean baseline intraocular pressure, mean final intraocular pressure and mean intraocular pressure difference between Groups 1 and 2. In Group 2, the mean intraocular pressure difference was significantly greater in patients with early versus moderate-advanced stage glaucoma (p=0.015). The difference, however, was not detected in Group 1. The mean intraocular pressure difference in early-stage glaucoma was significantly greater in Group 2 versus 1 (p=0.033). Latanoprost and dorzolamide/timolol fixed combination are effective treatments for newly diagnosed pseudoexfoliative glaucoma. In early-stage pseudoexfoliative glaucoma, greater intraocular pressure reduction was noted with dorzolamide/timolol fixed combination than with latanoprost; thus, dorzolamide/timolol fixed combination should be considered when a significant decrease in intraocular pressure is desired in early-stage glaucoma.