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Precis: We retrospectively reviewed records of patients prescribed latanoprostene bunod 0.024% (LBN) to assess its efficacy and safety in a real-world clinical setting. LBN was efficacious in lowering intraocular pressure (IOP) and had a favorable safety profile., Purpose: The aim of this study was to evaluate the usage of LBN, the first topical nitric oxide-donating prostaglandin analog (PGA) for reducing IOP, in clinical practice., Patients and Methods: Retrospective review identified patients prescribed LBN by 5 glaucoma specialists at an academic center from January 2018 to November 2019. Fifty-six patients (102 eyes) met inclusion criteria of an IOP measured at the visit LBN was prescribed and at 2 visits ≥7 days after beginning treatment, with no surgeries, lasers or medication changes during follow-up. Main outcome measures were IOP, number of ocular medications, and adverse effects., Results: IOP (mean±SD, mm Hg) at the visit LBN was prescribed was 16.2±4.3 on 3.2±1.5 glaucoma medications. IOP at most recent visit was 13.7±3.8 on 3.2±1.6 medications. Mean IOP reduction was 2.1±3.5 (P<0.0001) at first follow-up, after 38.7±36.5 days, and 2.5±3.3 (P<0.0001) at last follow-up, after 235.9±160.8 days. Pressure decreased ≥2 mm Hg in 60%, ≥3 mm Hg in 46%, and ≥4 mm Hg in 34% of eyes. All patients received LBN as replacement for a PGA or latanoprost/netarsudil fixed-dose combination. Forty-three patients remained on LBN throughout the follow-up period. Seven were discontinued for insufficient pressure control, 4 for adverse effects including pain and itching, and 2 for financial reasons., Conclusions: In 2 years of clinical use of LBN, patients exhibited IOP reductions that were statistically significant overall and clinically meaningful in 60% of patients. LBN was well-tolerated and may be more efficacious than traditional PGAs., Competing Interests: Disclosure: J.B.S.: Consultant—Aerie Pharmaceuticals, Allergan, Bausch and Lomb, Qlaris Bio; Speaker—Aerie Pharmaceuticals, Bausch and Lomb. J.C.T.: Consultant—Eyenovia, ReNetX Bio, Smartlens. The remaining authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

PRéCIS:: To assess the after-visit summary (AVS) as a tool for glaucoma medication recall. Medication recall was associated with level of education and complexity of medication regimen. Receiving an AVS was not associated with better medication recall., Purpose: The purpose of this study was to determine whether patients given the AVS have better or worse glaucoma medication recall., Materials and Methods: Observational clinical study. Adults on ≥1 glaucoma medications examined between June 30, 2017 and August 2, 2017., Data Collection: in-person questionnaire and retrospective chart review. Self-reported glaucoma medications compared with prescribed glaucoma medication regimen verified by electronic medical record. Medication recall assessed using 3-point scoring: 1 point each for; (1) name or color of bottle or cap; (2) treatment eye(s); and (3) dosing regimen., Data Analysis: 2-sample Welch t test, 2-proportion z-test, analysis of variance, univariate, and multivariate regression., Results: A total of 118 patients enrolled: age 69.7±12.9 years (mean±SD), 55.9% of patients had received an AVS at the previous visit. Of these, 33.3% reported receiving an AVS, 51.2% reported not receiving one (15.1% did not recall or respond). Patients who had received AVSs had lower medication recall scores than those who did not (2.4±1.0 vs. 2.7±0.6, P=0.04). Receipt of an AVS was associated with having Nisha Chadha as their provider (P=0.01), fewer days since prior visit (P=0.0001), and medication regimen change at prior visit (P<0.0001). Multivariate analysis revealed completion of associate's degree or higher and fewer prescribed medications to be independent predictors of higher recall score (P=0.0002 and 0.002)., Conclusions: AVSs were conceived to enhance patient care. This study indicates this goal is not achieved consistently. Less education and more complex medication regimens were identified as barriers to medication recall. Additional investigations should explore if modifying this document and enhanced explanation of its use will impact medication recall and health outcomes.

Purpose: To compare the ocular hypotensive efficacy and safety of a fixed-dose combination (FDC) of the Rho kinase inhibitor netarsudil and latanoprost vs monotherapy with netarsudil or latanoprost., Design: Three-month primary endpoint analysis of a randomized, double-masked, phase 3 clinical trial., Methods: Adults with open-angle glaucoma or ocular hypertension (unmedicated intraocular pressure [IOP] >20 and <36 mm Hg at 8:00 AM) were randomized to receive once-daily netarsudil/latanoprost FDC, netarsudil 0.02%, or latanoprost 0.005% for up to 12 months. The primary efficacy endpoint was mean IOP at 8:00 AM, 10:00 AM, and 4:00 PM at week 2, week 6, and month 3., Results: Mean treated IOP ranged from 14.8-16.2 mm Hg for netarsudil/latanoprost FDC, 17.2-19.0 mm Hg for netarsudil, and 16.7-17.8 mm Hg for latanoprost. Netarsudil/latanoprost FDC met the criteria for superiority to each active component at all 9 time points (all P < .0001), lowering IOP by an additional 1.8-3.0 mm Hg vs netarsudil and an additional 1.3-2.5 mm Hg vs latanoprost. At month 3, the proportion of patients achieving mean diurnal IOP ≤15 mm Hg was 43.5% for netarsudil/latanoprost FDC, 22.7% for netarsudil, and 24.7% for latanoprost. No treatment-related serious adverse events were reported; treatment-related systemic adverse events were minimal. The most frequent ocular adverse event was conjunctival hyperemia (netarsudil/latanoprost FDC, 53.4%; netarsudil, 41.0%; latanoprost, 14.0%), which led to treatment discontinuation in 7.1% (netarsudil/latanoprost FDC), 4.9% (netarsudil), and 0% (latanoprost) of patients., Conclusions: Once-daily netarsudil/latanoprost FDC demonstrated IOP reductions that were statistically and clinically superior to netarsudil and latanoprost across all 9 time points through month 3, with acceptable ocular safety., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

The fixed-dose combination (FDC) of netarsudil 0.02%/ latanoprost 0.005% was approved by the United States Food and Drug Administration (FDA) on March 12, 2019, for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma (OAG) and ocular hypertension (OHT). Netarsudil is a Rho kinase (ROCK) inhibitor and latanoprost is a prostaglandin analogue (PGA). Once-daily administration of this FDC reduces IOP by enhancing aqueous outflow through both the trabecular pathways (ROCK inhibition) and uveoscleral pathways (PGA). Two phase III clinical trials, MERCURY-1 and MERCURY-2, confirmed significantly greater efficacy of the FDC than the individual components, with IOP reductions of 30% or greater observed in 59-65% of subjects treated with FDC compared with 29-37% of subjects treated with latanoprost alone and 21-29% of subjects treated with netarsudil alone. The FDC was well tolerated with mostly mild ocular side effects and limited systemic side effects. This paper will review the work leading to FDA approval and the clinical indications for the use of this combination., (Copyright 2019 Clarivate Analytics.)

Purpose: To compare the intraocular pressure (IOP)-lowering efficacy and safety of netarsudil once daily (QD) and timolol twice daily (BID)., Design: Double-masked, randomized, phase 3, noninferiority study., Methods: Patients with open-angle glaucoma or ocular hypertension (unmedicated baseline IOP >20 to <30 mm Hg at 8:00 AM) were randomized to netarsudil ophthalmic solution 0.02% QD (PM) or timolol ophthalmic solution 0.5% BID. The primary endpoint was mean IOP at 8:00 AM, 10:00 AM, and 4:00 PM at week 2, week 6, and month 3 in patients with baseline IOP <25 mm Hg (per-protocol population). Safety was recorded over the 6-month treatment period., Results: A total of 186 patients from each treatment arm were included in the primary efficacy analysis. Netarsudil QD met the criteria for noninferiority to timolol BID. Mean treated IOP ranged from 16.3 to 17.9 mm Hg for netarsudil and 16.7 to 17.6 for timolol, with mean reductions from baseline of 3.9 to 4.7 mm Hg and 3.8 to 5.2 mm Hg, respectively. In prespecified secondary analyses, netarsudil demonstrated noninferiority to timolol in patients with baseline IOP <27 mm Hg and <30 mm Hg. The IOP-lowering effects of netarsudil were sustained over 6 months of treatment. No treatment-related serious adverse event (AE) was reported for either study drug. However, statistically significant reductions in mean heart rate were recorded at all study visits for the timolol group. The most frequent ocular AE among netarsudil-treated patients was conjunctival hyperemia (47.9%), which was predominately mild., Conclusions: Netarsudil QD (PM), a first-in-class IOP-lowering medication, was noninferior to timolol BID and was associated with tolerable ocular AEs., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate netarsudil 0.02% ophthalmic solution in patients with open-angle glaucoma (OAG) and ocular hypertension (OHT)., Design: Double-masked, randomized, multicenter, parallel-group, noninferiority clinical study., Methods: After a washout of all prestudy ocular hypotensive medications, 756 eligible patients with elevated IOP were randomized to receive netarsudil 0.02% once a day (q.d.) (251); netarsudil 0.02% twice a day (b.i.d.) (254); or timolol 0.5% b.i.d. (251) for 12 months, as well as a noninterventional Corneal Observation Study (COS) for patients manifesting cornea verticillata., Results: On treatment, mean IOP at 8:00 AM decreased from a baseline IOP of 22.5-22.6 mm Hg to 17.9-18.8 mm Hg, 17.2-18.0 mm Hg, and 17.5-17.9 mm Hg for netarsudil q.d., netarsudil b.i.d., and timolol, respectively, over 12 months. The most frequently reported adverse events (AEs) were ocular, with the most frequent ocular AE being conjunctival hyperemia, with an incidence of 61%, 66%, and 14%, respectively. The next most frequent AEs were corneal deposits (corneal verticillata), with an incidence of 26%, 25%, and 1%, respectively, and conjunctival hemorrhage (typically petechial), with an incidence of 20%, 19%, and 1%, respectively. All 3 AEs were generally scored as mild, with conjunctival hyperemia and/or hemorrhage appearing sporadically during the study. In the observational follow-up component of this study, there was no clinically meaningful impact of corneal verticillata on visual function in affected patients., Conclusions: In this randomized, double-masked trial, once-daily dosing of netarsudil 0.02% was effective, consistently lowering IOP through 12 months, and was tolerated by the majority of patients., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the efficacy and ocular and systemic safety of netarsudil 0.02% ophthalmic solution, a rho-kinase inhibitor and norepinephrine transporter inhibitor, in patients with open-angle glaucoma and ocular hypertension., Design: Double-masked, randomized noninferiority clinical trials: Rho Kinase Elevated IOP Treatment Trial 1 and 2 (ROCKET-1 and ROCKET-2)., Methods: After a washout of all pre-study ocular hypotensive medications, eligible patients were randomized to receive netarsudil 0.02% once daily (q.d.), timolol 0.5% twice a day (b.i.d.), and (ROCKET-2 only) netarsudil 0.02% b.i.d. Data through 3 months from both studies are provided in this report., Results: Enrolled into the 2 studies were 1167 patients. Treatment with netarsudil q.d. produced clinically and statistically significant reductions from baseline intraocular pressure (P < .001), and was noninferior to timolol in the per-protocol population with maximum baseline IOP < 25 mm Hg in both studies (ROCKET-2, primary outcome measure and population, ROCKET-1, post hoc outcome measure). Netarsudil b.i.d. was also noninferior to timolol (ROCKET-2). The most frequent adverse event was conjunctival hyperemia, the incidence of which ranged from 50% (126/251, ROCKET-2) to 53% (108/203, ROCKET-1) for netarsudil q.d., 59% (149/253, ROCKET-2) for netarsudil b.i.d., and 8% (17/208, ROCKET-1) to 11% (27/251, ROCKET-2) for timolol (P < .0001 for netarsudil vs timolol)., Conclusions: In 2 large, randomized, double-masked trials reported here, once-daily dosing of netarsudil 0.02% was found to be effective and well tolerated for the treatment of patients with ocular hypertension and open-angle glaucoma. The novel pharmacology and aqueous humor dynamic effects of this molecule suggest it may be a useful addition to the armamentarium of ocular hypotensive medications., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess pharmacodynamic and safety profiles of ONO-9054 following single and multiple day dosing in subjects with ocular hypertension or open-angle glaucoma., Materials and Methods: This was a phase I, single-center, randomized, double-masked, placebo-controlled dose-escalation study. Nine subjects were randomized to each of ONO-9054 3, 10, 20, 30 μg/mL and 12 to placebo. Subjects received a single drop to each eye at 07:00±30 minutes (single dose). Following a 4-day no-treatment period, subjects were dosed once daily for 14 consecutive days (multiple day dosing). Intraocular pressure (IOP) was measured regularly and compared with baseline measurements. Ocular examinations assessed safety and tolerability., Results: Mean IOP decreased dose dependently. Following single dosing, IOP decreased from 22.9±4.0 to 15.9±2.3 mm Hg (ONO-9054, 30 μg/mL) at peak effect 9 hours postdose; the reduction in placebo-treated subjects was from 22.3±2.4 to 21.5±3.3 mm Hg. Following multiple day dosing, the greatest reduction in IOP occurred 1 hour postdose on day 18, from 23.3±0.6 to 15.1±2.4 mm Hg (ONO-9054, 10 μg/mL); the smallest reduction at this time was from 23.9±0.8 to 18.6±2.0 mm Hg (ONO-9054, 3 μg/mL). Pressures remained reduced on day 19, 25 hours after the last dose, when the lowest measurement was 15.8±2.1 mm Hg (ONO-9054, 10 μg/mL). Anterior uveitis and vitreous detachment were each reported in 2 subjects and considered moderate by the Investigator. Ocular hyperemia and tolerability symptoms were generally mild and transient., Conclusions: ONO-9054 was well-tolerated and elicited dose-dependent reductions in IOP, which were sustained for at least 24 hours following 2 weeks of consecutive daily dosing.

Purpose: To assess the ability of latanoprost-eluting contact lenses to lower the intraocular pressure (IOP) of glaucomatous eyes of cynomolgus monkeys., Design: Preclinical efficacy study of 3 treatment arms in a crossover design., Participants: Female cynomolgus monkeys with glaucoma induced in 1 eye by repeated argon laser trabeculoplasty., Methods: Latanoprost-eluting low-dose contact lenses (CLLO) and high-dose contact lenses (CLHI) were produced by encapsulating a thin latanoprost-polymer film within the periphery of a methafilcon hydrogel, which was lathed into a contact lens. We assessed the IOP-lowering effect of CLLO, CLHI, or daily latanoprost ophthalmic solution in the same monkeys. Each monkey consecutively received 1 week of continuous-wear CLLO, 3 weeks without treatment, 5 days of latanoprost drops, 3 weeks without treatment, and 1 week of continuous-wear CLHI. On 2 consecutive days before initiation of each study arm, the IOP was measured hourly over 7 consecutive hours to establish the baseline IOP. Two-tailed Student t tests and repeated-measures analysis of variance were used for statistical analysis., Main Outcome Measures: Intraocular pressure., Results: Latanoprost ophthalmic solution resulted in IOP reduction of 5.4±1.0 mmHg on day 3 and peak IOP reduction of 6.6±1.3 mmHg on day 5. The CLLO reduced IOP by 6.3±1.0, 6.7±0.3, and 6.7±0.3 mmHg on days 3, 5, and 8, respectively. The CLHI lowered IOP by 10.5±1.4, 11.1±4.0, and 10.0±2.5 mmHg on days 3, 5, and 8, respectively. For the CLLO and CLHI, the IOP was statistically significantly reduced compared with the untreated baseline at most time points measured. The CLHI demonstrated greater IOP reduction than latanoprost ophthalmic solution on day 3 (P = 0.001) and day 5 (P = 0.015), and at several time points on day 8 (P < 0.05)., Conclusions: Sustained delivery of latanoprost by contact lenses is at least as effective as delivery with daily latanoprost ophthalmic solution. More research is needed to determine the optimal continuous-release dose that would be well tolerated and maximally effective. Contact lens drug delivery may become an option for the treatment of glaucoma and a platform for ocular drug delivery., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the mechanism by which topically applied AR-13324, a rho kinase inhibitor, and an inhibitor of the norepinephrine transporter, reduces intraocular pressure (IOP) in normotensive monkey eyes., Methods: Seven normotensive monkeys were used. Tonographic outflow facility (C) was measured before drug administration and repeated 6 hours after administration of 50 µL (25 µL×2) of 0.04% AR-13324 to 1 eye and an equal volume of vehicle to the contralateral control eye. Baseline aqueous humor flow rates (F) were measured hourly for 6 hours beginning at 10:00 AM on day 1. On day 2, 50 µL (25 µL×2) of 0.04% AR-13324 was applied to 1 eye of each animal and vehicle to the fellow eye at 8:00 AM. Aqueous humor flow rates were measured at the same times as on the baseline day beginning 2 hours after dosing., Results: Six hours after a single dose of 0.04% AR-13324 to 7 normal monkey eyes, C was increased (P<0.05) by 53% in drug-treated eyes compared with either contralateral vehicle-treated control eyes or baseline measurements. The IOP measured by pneumatonometer in treated eyes was reduced (P<0.005) by 25% when compared with baseline measurements and by 24% when compared with contralateral vehicle-treated eyes. For 6 hours after a single dose of 0.04% AR-13324, F was reduced (P<0.05) by 20% and 23% when compared with contralateral vehicle-treated eyes and baseline values, respectively., Conclusions: AR-13324 reduces IOP in normotensive monkey eyes. A dual mechanism of action, increase in tonographic outflow facility, and decrease of aqueous humor flow rates, accounts for the IOP reduction in normotensive monkey eyes.

The effect of topical application of SPP 635, a renin inhibitor, on intraocular pressure (IOP) was evaluated in the eyes of monkeys with laser induced unilateral glaucoma. A multiple-dose study was performed in 8 glaucomatous monkey eyes with 3 concentrations of SPP 635, 0.2%, 0.3% and 0.4%. IOP was measured hourly for 6 h on each day of the study beginning at 9:30 a.m. Following one baseline day (untreated) and one vehicle-treated day (50 μl drop of vehicle to the glaucomatous eye at 9:30 a.m.), a 50 μl drop (25 μl × 2) of SPP 635, 0.2%, 0.3% or 0.4%, was topically applied to the glaucomatous eye at 9:30 a.m. and 3:30 p.m. for 5 consecutive days. Twice daily administration of each of the 3 concentrations of SPP 635 for 5 days significantly (p < 0.05) reduced IOP. The maximum reduction in IOP occurred 3 or 4 h after morning dosing and was 4.3 ± 0.8 (mean ± SEM) mmHg (14%) for 0.2% SPP 635, 5.3 ± 1.0 mmHg, (19%) for 0.3% SPP 635, and 8.0 ± 1.3 mmHg (25%) for 0.4% SPP 635. The longest duration of IOP reduction was for 6 h with 0.2% or 0.3% SPP 635, and was for at least 18 h with 0.4% concentration. Compared to 0.2% or 0.3% concentrations, 0.4% SPP 635 produced a greater (p < 0.05) and longer duration of IOP reduction (18 vs. 6 h). Mild conjunctival discharge appeared in 2 of 8 eyes, and hyperemia appeared in 2 eyes with the 0.3% and 0.4% concentrations on treatment days 3 and 5. Topically applied SPP 635, a new renin inhibitor, reduces IOP in glaucomatous monkeys in a dose-dependent manner. Renin inhibitors, are a novel class of compounds which may have potential for the treatment of glaucoma., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

This study examined relationships between indoor air, breath, and blood tetrachloroethylene (perc) levels and visual contrast sensitivity (VCS) among adult and child residents of buildings with or without a colocated dry cleaner using perc. Decreasing trends in proportions of adults or children with maximum VCS scores indicated decreased VCS at a single spatial frequency (12 cycles per degree [cpd]) among children residing in buildings with colocated dry cleaners when indoor air perc level averaged 336 μg/m³; breath perc level averaged 159.5 μg/m³; and blood perc level averaged 0.51 μg/L. Adjusted logistic regression indicated that increases in indoor air, breath, and blood perc levels among all child participants significantly increased the odds for decreased VCS at 12 cpd. Adult VCS was not significantly decreased by increasing indoor air, breath, or blood perc level. These results suggest that elevated residential perc exposures may alter children's VCS, a possible subclinical central nervous system effect.

Purpose: To evaluate the effect of topical application of avosentan (SPP 301), endothelin receptor type A antagonist, on intraocular pressure (IOP) in monkey eyes with laser-induced unilateral glaucoma., Materials and Methods: A multiple-dose study was performed in eight glaucomatous monkey eyes that were topically treated with SPP 301 by applying a 50 µl drop (25 µl × 2) at 9:30 a.m. and 3:30 p.m. for 5 consecutive days at three concentrations (0.003%, 0.03%, or 0.3%). IOP was measured hourly for 6 hrs on each day of the study beginning at 9:30 a.m. for one baseline day, one vehicle-treated day, and treatment days 1, 3, and 5., Results: Twice daily administration of each of the three concentrations of SPP 301 for 5 days significantly (p < 0.05) reduced IOP. The maximum reduction in IOP occurred 2 or 3 hrs after morning dosing and was 1.8 ± 0.8 (mean ± SEM) mmHg (6%) for 0.003% SPP 301, 4.1 ± 0.7 mmHg (13%) for 0.03% SPP 301, and 7.1 ± 1.3 mmHg (21%) for 0.3% SPP 301. The longest duration of IOP reduction was for 2 hrs with 0.003% SPP 301, and was for at least 6 hrs with 0.03% and 0.3% concentrations. Compared to 0.03% or 0.003% concentrations, 0.3% SPP 301 produced a greater (p < 0.05) IOP reduction. IOP was reduced in fellow untreated normal eyes 2 hr after morning dosing with 0.3% SPP 301, maximum reduction in IOP (11%) occurred on day 1. Of the eyes treated with 0.3% SPP 301, one eye demonstrated mild conjunctival discharge and one eye was closed for 5 min after dosing., Conclusion: Topically applied SPP 301, an endothelin antagonist, reduced IOP in glaucomatous monkey eyes in a dose-dependent manner. Endothelin antagonists, a novel class of compound, may have potential for the treatment of glaucoma.

Purpose: To assess effectiveness of selective laser trabeculoplasty (SLT) in lowering intraocular pressure (IOP) in patients with steroid-induced elevated IOP., Methods: Retrospective review of 7 patients (7 eyes) with IOP elevation after intravitreal triamcinolone acetonide (4.0 mg/0.1 mL) injections for macular edema (6 patients) or central retinal vein occlusion (1 patient). Three patients had preexisting open angle glaucoma; 2 patients had preexisting ocular hypertension. Time between intraocular corticosteroid injection and subsequent increased IOP ranged from 5 to 29 weeks. After unsuccessful maximum tolerated medical therapy, patients underwent unilateral SLT between April 2003 and June 2005. IOP was measured 4 weeks prelaser; on the day of laser; within 3 weeks, and at 1, 3, and 6 months postlaser. Two-sample t test was used for analysis., Results: The pre-SLT and post-SLT IOP measurements were the major outcome measures used to define the relative success of the SLT procedure. Seven patients were taking 4.0+/-0.8 ocular hypotensive medications before SLT. Preoperative IOP (mm Hg+/-SD) 38.4+/-7.3 decreased postoperative to 25.6+/-7.1 within 3 weeks (P<0.003), 25.9+/-8.8 at 1 month (P<0.007), 23.9+/-10.6 at 3 months (P<0.006), and 15.7+/-2.2 at 6 months (P<0.001). Four patients underwent a second SLT procedure. Two patients failed after the 3-month visit. IOP in fellow eyes of all patients was unchanged (P>0.080)., Conclusions: SLT lowered (P<0.007) IOP in 5 eyes of 7 patients with steroid-induced increased IOP from 3 weeks to 6 months postoperative. Two patients required additional surgical procedures. Repeat SLT treatments may be necessary. SLT is a temporizing procedure to consider in patients with steroid-induced elevated IOP.

Objective: To examine resource consumption and the direct costs of treating glaucoma at different disease severity levels., Design: Observational, retrospective cohort study based on medical record review., Participants: One hundred fifty-one records of patients with primary open-angle or normal-tension glaucoma, glaucoma suspect, or ocular hypertension (age > or =18 years) were randomly selected from 12 sites in the United States and stratified according to severity based on International Classification of Diseases, Ninth Revision, Clinical Modification codes. Patients had to have been followed up for a minimum of 5 years. Patients with concomitant ocular disease likely to affect glaucoma treatment-related resource consumption were excluded., Methods: Glaucoma severity was assessed and assigned using a 6-stage glaucoma staging system, modified from the Bascom Palmer (Hodapp-Anderson-Parrish) system. Clinical and resource use data were collected from the medical record review. Resource consumption for low-vision care and vision rehabilitation was estimated for patients with end-stage disease based on specialist surveys. For each stage of disease, publicly available economic data were then applied to assign resource valuation and estimate patient-level direct costs from the payer perspective., Main Outcome Measures: Average annual resource use and estimated total annual direct cost of treatment were calculated at the patient level and stratified by stage of disease. Direct costs by specific resource types, including ophthalmology visits, glaucoma surgeries, medications, visual field examinations, and other glaucoma services, were also assessed., Results: Direct ophthalmology-related resource use, including ophthalmology visits, glaucoma surgeries, and medication use, increased as disease severity worsened. Average direct cost of treatment ranged from $623 per patient per year for glaucoma suspects or patients with early-stage disease to $2511 per patient per year for patients with end-stage disease. Medication costs composed the largest proportion of total direct cost for all stages of disease (range, 24%-61%)., Conclusions: The study results suggest that resource use and direct cost of glaucoma management increase with worsening disease severity. Based on these findings, a glaucoma treatment that delays the progression of disease could have the potential to significantly reduce the health economic burden of this chronic disease over many years.

Purpose: To determine whether intraocular pressure (IOP) in the early postoperative period after trabeculectomy or combined phacoemulsification-trabeculectomy, augmented with antimetabolite, correlates with IOP at one year in surgeries considered to be successful at that time point., Design: Retrospective case series., Methods: A chart review of antimetabolite-augmented surgical procedures done by DJG and JBS between January 1994 and November 2000 identified 82 primary or secondary trabeculectomies and 53 combined phacoemulsification-trabeculectomies with at least one year of follow-up. The success rate for each surgical subgroup was calculated and IOP on postoperative days (POD +/- SD) 1, 7 (+/-2), 30 (+/-5), 90 (+/-10), and 180 (+/-20) was correlated with IOP at one year (POY 1, between month 12 and 15) using linear regression. IOP at each time point was compared among eyes that achieved success at one year with and without the use of IOP-lowering agents., Results: Of the 82 eyes having undergone antimetabolite-augmented trabeculectomies and the 53 eyes having undergone combined surgeries with at least one year of follow-up, the surgical success rates at POY 1 were 87.8% (72 of 82 eyes) and 92.5% (49 of 53 eyes). Of these, 42 eyes (58.3%) from 39 patients in the trabeculectomy group and 27 eyes (55.1%) from 24 patients in the combined surgery group did not require glaucoma medications at one year postsurgically, and were considered complete surgical successes. Mean preoperative IOP mm Hg +/- SD was 26.0 +/- 8.5 for the trabeculectomy group and 18.2 +/- 4.5 for the phaco-trabeculectomy group. Postoperative IOP at POD 1, POD 7, POD 30, POD 90, POD 180, and POY 1 respectively for the eyes undergoing trabeculectomy were 13.9 +/- 10.4, 9.5 +/- 6.2, 12.0 +/- 5.5, 12.0 +/- 5.2, 12.8 +/- 5.9, and 12.1 +/- 4.3, and for the combined surgery group were 20.8 +/- 12.5, 9.7 +/- 5.7, 12.2 +/- 5.4, 11.1 +/- 3.4, 11.6 +/- 4.6, and 10.3 +/- 4.3. Intraocular pressure on postoperative day one correlated poorly with intraocular pressure at POY 1 for the trabeculectomy group (R2 = 0.0788), and not at all for the combined procedures group (R2 = 0.018). The correlation was slightly better for intraocular pressure at postoperative day 90 for the trabeculectomy group (R2 = 0.546), and at postoperative day 180 for the combined group (R2 = 0.37), but still rather low. Eyes requiring glaucoma medication use at POY 1 in the trabeculectomy group had higher (P < 0.009) intraocular pressure at POD 30 and at all subsequent visits than eyes not requiring these medications. Eyes requiring glaucoma medication use at POY 1 in the phaco-trabeculectomy group had higher (P < 0.0025) intraocular pressure at POD 30, POD 180, and POY 1 than eyes not requiring these medications., Conclusion: Intraocular pressure in the early postoperative period correlates very poorly with intraocular pressure one year after successful antimetabolite-augmented trabeculectomy or combined cataract extraction and trabeculectomy. Starting one month after glaucoma surgery, intraocular pressure is substantially lower in eyes that will ultimately not require the use of ocular hypotensive agents to achieve clinical success one year postoperatively.

Purpose: To determine if the intraocular pressure (IOP) effect of pilocarpine at various concentrations is additive to that of bimatoprost and to assess the tolerability of this combination., Methods: This was a randomized, prospective trial of patients with IOP > 21 mm Hg following appropriate medication washout. For all visits IOP was measured at 9:00 AM and 11:00 AM. Following baseline visit (#1), bimatoprost 0.03% was instilled qhs OU through visit 6. Following visits 2, 3, and 4 pilocarpine (2%, 4%, 6%) was instilled qid in one randomly selected eye. Pilocarpine was discontinued after visit 5 and bimatoprost after visit 6. Two-tailed, paired t test was used to compare treated and contralateral eyes for their IOP, IOP change, percentage IOP change from baseline, and to compare IOP in the same eye at 9:00 AM and 11:00 AM (before and after pilocarpine administration). IOPs using bimatoprost alone or in combination with various pilocarpine concentrations were compared using single variant Analysis of Variance (ANOVA)., Results: Seventeen patients were enrolled and 13 patients completed the study. Bimatoprost reduced IOP 28.7% to 30.5% (P < 0.0001) from baseline to visit 2. IOPs in eyes treated with bimatoprost alone or with bimatoprost and various pilocarpine concentrations were similar (P > 0.81, ANOVA). The IOP (P > 0.17) and percentage IOP change from baseline (P > 0.10) was similar in treated and contralateral eyes with all three strengths of pilocarpine. IOP values at 9:00 AM and 11:00 AM, before and after pilocarpine administration, were similar (P > 0.22)., Conclusion: Bimatoprost alone reduces IOP substantially. Pilocarpine added to bimatoprost at concentrations of 2%, 4%, or 6% was neither additive nor antagonistic to the ocular hypotensive efficacy of bimatoprost.

Purpose: To determine if laser iridotomy altered the anterior segment anatomy of patients with plateau iris configuration., Methods: Twenty eyes of 9 female and 1 male patients were imaged using an ultrasound biomicroscope within 19 weeks before and 52 weeks after laser iridotomy. Measurements obtained included the anterior chamber depth (ACD), trabecular-ciliary process distance (TCPD), iris thickness (IT), angle opening distance at 500 micrometers (AOD), iridozonular distance (IZD), and trabecular-iris angle (TIA). Comparisons of the pre- and post- iridotomy measurements were made using a two-tailed paired t test., Results: Laser iridotomy elicited no statistically significant change in ACD, TCPD, IT, AOD, or TIA. However, IZD was decreased (P < 0.05) in both eyes after laser iridotomy. Configuration of the irides was flat before and after laser iridotomies., Conclusion: This study suggests that laser iridotomy did not alter anterior segment anatomy, probably because of the fixed anterior insertion of the iris and ciliary body in plateau iris configuration. The decrease in IZD distance may be the result of a small posterior movement of the iris due to a reduction in relative pupillary block, secondary to laser iridotomy. The small reduction in relative papillary block in plateau iris configuration does not alter the width of the anterior chamber angle as measured by AOD and TIA.

Purpose: 5-MCA-NAT, a putative melatonin MT3 receptor agonist, reduced intraocular pressure (IOP) in ocular normotensive rabbit eyes. This study evaluates the effect of topical application of 5-MCA-NAT on IOP in monkey eyes with laser-induced unilateral glaucoma., Methods: A multiple-dose study was performed in 8 glaucomatous monkey eyes. One 25-microL drop of 5-MCA-NAT (2%) was applied topically to the glaucomatous eye at 9:30 am and 3:30 pm for 5 consecutive days. IOP was measured hourly for 6 hours beginning at 9:30 am for one baseline day, one vehicle-treated day, and treatment days 1, 3, and 5 with 5-MCA-NAT., Results: Compared with vehicle treatment, twice daily administration of 5-MCA-NAT for 5 days reduced (P < 0.05) IOP from 1 hour to 5 hours after the first dose, and the IOP-lowering effects were shown to last at least 18 hours following administration, based on IOP measurements made after the fourth and eighth doses. The ocular hypotensive effect of 5-MCA-NAT was enhanced with repeated dosing. The maximum reduction (P < 0.001) of IOP occurred at 3 hours after each morning dose, and was 4.0 +/- 0.5 (mean +/- SEM) mm Hg (10%) on day 1, 5.6 +/- 0.8 mm Hg (15%) on day 3, and 7.0 +/- 1.1 mm Hg (19%) on day 5. Adverse ocular or systemic side effects were not observed during the 5 days of treatment., Conclusions: 5-MCA-NAT, a putative melatonin MT3 receptor agonist, reduces IOP in glaucomatous monkey eyes. Melatonin agonists with activity on the putative MT3 receptor may have clinical potential for treating elevated IOP.

Purpose: To compare the effect of pilocarpine, an agent that reduces uveoscleral outflow, on the ocular hypotensive efficacy of latanoprost and 8-iso prostaglandin E2 (PGE2)., Methods: Each of the two treatment groups was composed of the same eight monkeys with unilateral laser-induced glaucoma. Intraocular pressure (IOP) was measured hourly for 6 hours beginning at 9:00 AM on the baseline day (Thursday before treatment week) and on treatment days 1, 3, and 5 (Monday, Wednesday, and Friday). On all five treatment days, one drop of pilocarpine 4% was administered at 9:00 AM and 3:00 PM and one drop of latanoprost 0.005% or 25 microL of 8-iso PGE2 0.1% was administered at 10:00 AM and 4:00 PM., Results: One hour after pilocarpine instillation on day 1, the reduction of IOP was similar (P > 0.90) in both treatment groups, 7.6 +/- 1.1 mm Hg (mean +/- standard error of the mean ) in the latanoprost group and 7.4 +/- 0.8 mm Hg in the 8-iso PGE2 group. However, the IOP effects of the two treatment groups became significantly different (P < 0.05) beginning 2 hours after dosing with latanoprost or 8-iso PGE, on day 1. A difference (P < 0.05) between the two groups persisted at all subsequent measurements. The reduction of IOP lessened with repeated dosing in the latanoprost and 8-iso PGE2 groups. Three hours after dosing with pilocarpine and two hours after dosing with the prostanoids, the IOP reduction was 8.3 +/- 0.9 mm Hg in the latanoprost group and 9.9 +/- 0.6 mm Hg in the 8-iso PGE2 group on day 1, and 2.1 +/- 1.0 mm Hg in the latanoprost group and 7.3 +/- 0.9 mm Hg in the 8-iso PGE1 group on day 5., Conclusions: The smaller reductions in IOP with pilocarpine and latanoprost than with pilocarpine and 8-iso PGE2 show that pilocarpine blocks much more of the ocular hypotensive effect of latanoprost than of 8-iso PGE2. The results also indicate that pilocarpine and latanoprost are mutually antagonistic. Enhancement of uveoscleral outflow appears to account for most of the ocular hypotensive effect of latanoprost and for much less of the ocular hypotensive effect of 8-iso prostaglandin E2.

Purpose: To investigate the additive ocular hypotensive effect of brimonidine, dorzolamide, latanoprost, or artificial tears to timolol in monkey eyes with laser-induced unilateral glaucoma., Methods: Eight monkeys were used and each animal received all four combinations of drugs in a randomized fashion during the study. The washout period between each combination was at least 2 weeks. Intraocular pressure (IOP) was measured at 8:30 AM, 11:00 AM, 1:00 PM, and 3:30 PM on day 1 (untreated baseline), day 2 (timolol treatment alone), and days 3 through 5 (combination therapy with two drugs). One drop of 0.5% timolol was topically applied at 3:45 PM on day 1 and at 8:45 AM and 3:45 PM on days 2 through 5. One drop of 0.2% brimonidine or 2% dorzolamide or artificial tears was added on day 2 at 4:00 PM and at 9:00 AM and 4:00 PM on days 3 through 5, or latanoprost was added at 9:00 AM on days 3 through 5., Results: Compared with timolol alone, the maximal additive reduction in IOP which occurred on day 5 was 4.8 +/- 0.8 mm Hg (mean +/- standard error of the mean) with timolol plus brimonidine, 5.6 +/- 1.0 mm Hg with timolol plus dorzolamide, 4.3 +/- 1.0 mm Hg with timolol plus latanoprost, and 2.0 +/- 0.5 mm Hg with timolol plus artificial tears (P < 0.01). At all measurements, timolol plus brimonidine, timolol plus dorzolamide, and timolol plus latanoprost caused greater (P < 0.05) IOP reductions than did timolol plus artificial tears. The additive IOP-lowering effect was similar (P > 0.60) when comparing timolol plus brimonidine and timolol plus dorzolamide, timolol plus brimonidine and timolol plus latanoprost, timolol plus dorzolamide and timolol plus latanoprost at all measurements, but timolol plus dorzolamide caused a greater (P < 0.05) reduction of IOP than did timolol plus latanoprost at 0 hours on day 5., Conclusions: The addition of brimonidine, dorzolamide, or latanoprost to timolol caused similar additional reductions of IOP in glaucomatous monkey eyes.

Objective: To evaluate the possible additivity of the effects of latanoprost and 8-iso prostaglandin E2 (8-iso PGE2) on intraocular pressure (IOP) in monkey eyes with laser-induced glaucoma., Methods: The IOP was measured hourly for 6 hours beginning at 9:30 AM on day 1 (baseline day), days 6 and 7 (single-agent therapy), and days 13 and 14 (combination therapy with both agents). Following 1 day of baseline measurement, 4 monkeys with unilateral glaucoma received monotherapy) twice daily with either 1 drop of 0.005% latanoprost, or 0.1% 8-iso PGE2, 25 microL, at 9:30 AM and 3:30 PM from days 2 through 7. From days 8 through 14, both agents were applied twice daily 5 minutes apart., Results: The maximum reduction of IOP (mean +/- SEM) was 8.8 +/- 1.9 mmHg (26%) (P<.05) with latanoprost alone and 6.5 +/- 1.0 mmHg (21%) (P<.0l) with 8-iso PGE2 alone, 2 hours after the morning dosing on day 7. A further reduction of IOP of 4.0 +/- 0.6 mm Hg was produced when 8-iso PGE2 was added to latanoprost and of 3.0 +/- 0.7 mm Hg was produced when latanoprost was added to 8-iso PGE2 on day 13 before the morning dosing. Combination therapy with both agents caused maximum IOP reductions from baseline of 11.3 +/- 3.0 mm Hg (33%) (P<.05) (latanoprost with 8-iso PGE2 added) and of 9.8 +/- 1.3 mm Hg (31%) (P<.01) (8-iso PGE2 with latanoprost added) on day 14., Conclusion: Latanoprost and 8-iso PGE2 have an additive effect on IOP in glaucomatous monkey eyes., Clinical Relevance: At least 50% of patients are treated with more than 1 ocular hypotensive medication. Thus, the determination of the additive effects on IOP of glaucoma medications will help to define optimum treatment regimens.

Objective: To evaluate the effects of 8-iso prostaglandin E2 (8-iso PGE2; prosta-5,13-dien-1-oic acid,11,15-dihydroxy-9-oxo-,[5Z,8beta-11X,13E,15 S]-) on the intraocular pressure (IOP), outflow facility, and aqueous humor flow rates in normal monkeys and monkeys with glaucoma., Methods: The IOP was measured before and as long as 6 hours after the topical application of 8-iso PGE2 to 1 eye of 6 normal monkeys and to the glaucomatous eye of 8 monkeys with unilateral laser-induced glaucoma. The pupil diameter was measured at the same times as the IOP measurements in the normal monkeys. Tonographic outflow facility and fluorophotometric flow rates of aqueous humor were measured in 6 normal monkeys before and after drug treatment., Results: In normal monkeys, a single dose of 0.1% 8-iso PGE2 reduced (P<.01) the IOP for 4 hours in the treated eyes with a maximum (mean +/- SEM) reduction of 3.2 +/- 0.2 mm Hg, compared with the contralateral control eyes. The pupil size was smaller (P<.01) in the treated eyes by as much as 1.0 +/- 0.2 mm for 4 hours. In 8 glaucomatous monkey eyes, the application of 0.05% and 0.1% 8-iso PGE2 reduced the IOP (P<.01) for as long as 2 and 5 hours, respectively. The maximum reduction in the IOP was 4.6 +/- 0.8 mm Hg (0.05%) and 6.0 +/- 0.8 mm Hg (0.1%) compared with baseline measurements. The magnitude and duration of the ocular hypotensive effect were enhanced with twice-a-day administration for 5 consecutive days. Outflow facility in normal monkey eyes was increased (P<.05) by 48% in the treated eyes, and aqueous humor flow was unchanged (P>.10), compared with vehicle-treated contralateral control eyes. Mild eyelid edema, conjunctival edema, hyperemia, and discharge appeared in some eyes treated with the 0.1% drug concentration., Conclusions: The use of 8-iso PGE2 reduces the IOP in both normal and glaucomatous monkey eyes. An increase in outflow facility appears to account for most of the IOP reduction in normal monkeys., Clinical Relevance: The application of 8-iso PGE2 may have potential for the treatment of glaucoma as an outflow facility-increasing drug.

Latanoprost (PhXA41, Xalatan) and isopropyl unoprostone (UF-021, unoprostone, Rescula) two new prostanoid derivatives, have been shown to reduce intraocular pressure (IOP) significantly in patients with glaucoma or ocular hypertension. This study was designed to compare the ocular hypotensive effects of latanoprost and unoprostone in cynomologus monkeys with glaucoma and characterizes the prostanoid's mechanisms of action in normal cynomolgus monkey eyes. Intraocular pressure was measured daily at 0, 0.5, and 1 hour and hourly for 5 additional hours during 1 baseline day, 1 vehicle-treated day, and 5 days of therapy with either 0.005% latanoprost or 0.12% unoprostone applied twice daily, at 9:30 AM and 3:30 PM, to the glaucomatous eye of eight monkeys with unilateral laser-induced glaucoma. Outflow facility was measured in six normal monkeys 3 hours prior to dosing and 1 hour after unilateral dosing with either drug. Aqueous humor flow rates were measured in six normal monkeys hourly for 4 hours on 1 baseline day and on 1 treatment day beginning 1 hour after administration of either drug to one eye. Intraocular pressure was significantly (P < 0.005) reduced after the first application for 4 hours with latanoprost and for 2 hours with unoprostone, up to 5.4 +/- 0.8 mm Hg (mean +/- SEM) (latanoprost) and 3.8 +/- 0.5 mm Hg (unoprostone). Intraocular pressure was significantly (P < 0.005) reduced for at least 18 hours following each PM dose of latanoprost. Intraocular pressure was not reduced (P > .05) 18 hours after each PM dose of unoprostone. An enhancement of the ocular hypotensive effect was observed from day 1 to day 5 with repeated dosing of either drug. Latanoprost produced a greater magnitude of IOP reduction for a longer duration of time than unoprostone after each application. Neither drug altered outflow facility or aqueous humor flow rates. Latanoprost and unoprostone appear to reduce IOP in monkeys by enhancing uveoscleral outflow. Latanoprost appears to be more efficacious and potent than unoprostone in reducing IOP in glaucomatous monkey eyes.

Purpose: To create an experimental glaucoma monkey model using high-power diode laser photocoagulation of the trabecular meshwork, and to compare this with the experimental glaucoma monkey model induced by argon laser photocoagulation of the trabecular meshwork., Methods: One eye each of eight adult cynomolgus monkeys underwent repeated application of diode laser photocoagulation of the trabecular meshwork until sustained intraocular pressure (IOP) elevation was achieved. 50 to 120 spots were applied to midtrabecular meshwork for 360 degrees; spot size, 75 microns; power, 1.2 W; duration, 0.5 seconds. Intraocular pressure, tonographic outflow facility, and ophthalmoscopically and photographically documented optic nerve head evaluations were carried out before and after treatment. Data were compared retrospectively with similar data from an experimental glaucoma monkey model after argon laser photocoagulation of the trabecular meshwork (n = 10)., Results: The average number of laser treatments to achieve stable IOP elevation was 3.0 with both diode and argon laser trabecular treatments (p > 0.99). On week 4 after initial pressure elevation, peak IOP was greater--(p < 0.05) 43.0 mmHg +/- 2.4 mmHg (mean +/- SEM) and 37.4 mmHg +/- 1.3 mmHg--in the diode laser-induced than in the argon laser-induced glaucomatous eyes, respectively. Outflow facility (microliter/min/mmHg) was reduced (p < 0.001) in both diode (0.09 +/- 0.01 microliter/min/mmHg) and argon (0.10 +/- 0.01 microliter/min/mmHg) laser-induced glaucomatous eyes compared with untreated fellow eyes. Both the diode and argon laser techniques produced the earliest signs of optic nerve head excavation within about one month of IOP elevation., Conclusions: Repeat diode laser photocoagulation of the trabecular meshwork produced higher (p < 0.05) IOP elevation than argon laser photocoagulation of the trabecular meshwork in this study. No significant differences in outflow facility and optic nerve head change were observed between these two laser techniques. The experimental glaucoma monkey model can be created with either the diode or argon laser photocoagulation of the trabecular meshwork.

Purpose: To evaluate the effects of 5-methylurapidil (5-MU) on intraocular pressure (IOP) and aqueous humor dynamics in female cynomolgus monkeys and albino rabbits., Methods: IOP was measured by pneumatonometer prior to and up to 6 hours after AM administration of 5-MU to one eye of each of 8 normal monkeys and to the laser-induced glaucomatous eye of 8 monkeys. During single-dose and 5-day multiple-dose testing, pupillary diameter (PD) was measured at the same time and same intervals as IOP measurements in the normal monkeys. Outflow facility and aqueous humor flow rates were measured in 8 normal monkeys before and after treatment. Uveoscleral outflow was measured in 8 rabbits before and after treatment., Results: In normal monkeys, unilateral topical application of 2 x 25 microliters of 1% or 2% 5-MU significantly (p < 0.05) reduced pupil size and IOP bilaterally as compared to baseline measurements. The reduction in IOP (mean +/- SEM, mmHg) was up to 2.8 +/- 0.7 (1% 5-MU) and 4.4 +/- 0.5 (2% 5-MU) in the treated eyes, and 2.3 +/- 0.8 (1%) and 3.0 +/- 0.7 (2%) in the contralateral eyes. In glaucomatous monkeys, the maximum reduction in IOP was 6.5 +/- 1.0 mmHg (1%) and 7.5 +/- 0.8 mmHg (2%). The ocular hypotensive effect increased over time with twice-daily administration for 5 days. Compared with baseline values, outflow facility and aqueous flow rates in the treated eyes of normal monkeys were increased (p < 0.01) by 51% and by 11%, respectively. Uveoscleral outflow was unaltered (p > 0.3) in rabbits compared with baseline values. Mild corneal edema, corneal punctate erosions, and conjunctival discharge occurred in some eyes treated with either 1% or 2% 5-MU., Conclusions: 5-Methylurapidil, an antagonist at the alpha 1A-adrenergic receptor subtype and an agonist at the 5-HT1A receptor subtype, lowers IOP predominantly by increasing outflow facility and may have potential for the therapy of glaucoma.

The safety and ocular hypotensive efficacy of twice-daily administration of brimonidine 0.2% solution or betaxolol 0.25% suspension were compared in subjects with open-angle glaucoma or ocular hypertension. A total of 206 adult patients were enrolled in a prospective, 3-month, multicentered, randomized, double-masked, parallel-group study. Both drugs significantly (p < 0.001) reduced peak and trough intraocular pressure (IOP) at every scheduled follow-up visit over the 3-month study. At peak, the overall mean decrease from baseline IOP was greater (p = 0.004) in the brimonidine-treated group (5.8 mm Hg) than in the betaxolol-treated group (3.8 mm Hg). At trough, the overall mean decrease from baseline (p < 0.001) was 3.9 mm Hg in the brimonidine-treated group and 3.2 mm Hg in the betaxolol-treated group. The IOP-lowering effect of brimonidine was sustained throughout the 3-month study period. Terminations from the study due to lack of efficacy included 2.9% (3/103) of patients in the brimonidine group and 4.2% (4/96) of those in the betaxolol group. The overall incidence of adverse events was similar in both treatment groups, with the only significant (p = 0.027) between-group difference being that ocular blurring was reported more often by patients receiving betaxolol suspension than by those receiving brimonidine treatment. Instillation of drug was reported to be comfortable (p = 0.036) by more brimonidine-treated patients than betaxolol-treated patients. Overall, brimonidine 0.2% solution was well-tolerated, safe and clinically and statistically more effective than betaxolol 0.25% suspension in lowering intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

Glaucoma is a potentially blinding disease. The goal of glaucoma therapy is to reduce intraocular pressure to a predetermined target level. There are currently 5 classes of compounds used for the medical management of glaucoma. Four classes that appear promising for the long term management of glaucoma are in different phases of clinical investigation, and include the topically active carbonic anhydrase inhibitors, selective alpha 2-adrenergic agonists, prostaglandins and ethacrynic acid. The topically active carbonic anhydrase inhibitor dorzolamide (MK-507) is effective and well tolerated in clinical trials of up to 1 year's duration. Animal studies have demonstrated that this drug lowers intraocular pressure by reducing aqueous humour formation. The selective alpha 2-adrenergic agonists, brimonidine and apraclonidine, have been shown to be effective in reducing intraocular pressure in the short term. Long term effectiveness of these agents is under investigation. Prostaglandins (PG) of the PGF2-alpha isopropylester series caused marked reductions of intraocular pressure in laboratory and clinical trials. The newest prostaglandin analogue, latanoprost (PhXA41), effectively lowered intraocular pressure and was well tolerated in clinical trials of up to 4 weeks' duration. Prostaglandins reduce intraocular pressure by enhancing uveoscleral outflow. Ethacrynic acid enhanced traditional outflow facility and lowered intraocular pressure when applied topically or intracamerally in laboratory studies and clinical trials. Corneal adverse effects of ethacrynic acid have been noted. Reformulation of ethacrynic acid ointment may resolve this problem. These 4 classes of compounds will enhance our options for the medical management of glaucoma. They may be used instead of or in combination with some of the drugs currently in use, and may be better tolerated.

Objective: To evaluate the long-term effects of ethacrynic acid (ECA) ointment, compared with timolol maleate on intraocular pressure (IOP) in cynomolgus monkey eyes with argon laser-induced glaucoma., Methods: In a 5-day study, IOP was measured for 7 hours after once-daily topical applications of ECA ointment to four glaucomatous monkey eyes. For this study, ECA ointment was given in 0.5%, 1.0%, 1.5%, or 2.5% concentrations. In a separate 30-day study, IOP was measured after once-daily topical applications of ECA ointment in concentrations of 0.75% or 1.5%. The results were compared with IOP after the application of 0.5% timolol maleate administered twice daily on weekdays and once daily on weekends., Results: In the 5-day study, 2.5% ECA ointment had the greatest effect on lowering IOP, with a maximum reduction of 8.5 +/- 2.9 mm Hg (mean +/- SEM). A more pronounced reduction in IOP was observed on the fifth day of treatment for each of the four concentrations. In the 30-day study, 1.5% ECA ointment or 0.5% timolol maleate reduced IOP as much as 11.5 +/- 3.7 mmHg and 14.0 +/- 4.5 mmHg, respectively. With repetitive dosing, the effect on IOP after using 1.5% ECA ointment increased with time. Mild eyelid edema, conjunctival hyperemia, and discharge were observed in some eyes treated with the highest concentrations. One eye of four treated with 1.5% ECA ointment for 30 days developed a superficial corneal erosion in the 30-day study., Conclusions: The ECA ointment reduced IOP in glaucomatous monkey eyes. This reduction was evident by the fifth day of treatment with all the concentrations tested. The reduction in IOP produced by once-daily treatment with 1.5% ECA ointment was comparable with that of 0.5% timolol maleate administered twice daily. Therefore, drugs in this class of compound may prove to be useful in glaucoma therapy.

Objective: To evaluate the ocular effects of oxymetazoline hydrochloride, an alpha 2 agonist, in cynomolgus monkeys and albino rabbits., Methods: Intraocular pressure was measured before and for 6 hours after application to glaucomatous monkey eyes. Outflow facility and aqueous flow rates were measured in normal monkey eyes. Uveoscleral outflow was measured in rabbit eyes. Ocular peak pulse volume was determined with the ocular blood flow system in normal and glaucomatous monkey eyes., Results: Single applications of ozymetazoline reduced (P < .001) intraocular pressure up to 6.0 +/- 1.0 mm Hg (mean +/- SEM). Enhancement of the ocular hypotensive effect was observed with 5-day twice-daily administration. Outflow facility was unaltered; aqueous flow rate was decreased (P < .001) by 39% in the treated eyes compared with baseline values; and uveoscleral outflow was increased (P < .005) by 56% in the treated eye. Peak pulse volume was unchanged., Conclusion: Oxymetazoline reduces intraocular pressure by decreasing aqueous humor flow rates and increasing uveoscleral outflow. Oxymetazoline may have clinical potential as an ocular hypotensive drug.

In a randomized, double-masked, parallel study, one drop of 0.003% (1 microgram; n = 9) or 0.01% (3 micrograms; n = 10) PhXA34, a new phenyl-substituted prostaglandin F2 alpha analogue (13,14-dihydro-15[R,S]-17-phenyl-18,19,20-trinor-prostaglandin F2 alpha-1-isopropyl ester), or its vehicle (n = 10) was applied topically twice daily for 6 days to one eye in each of 29 patients with ocular hypertension. Compared with either baseline, contralateral, or vehicle control values, PhXA34 caused a significant (P < .001) dose-dependent reduction of intraocular pressure. The reduction lasted at least 12 hours after each drop and 24 to 48 hours after the last drop, with a significant (P < .0001) mean +/- SEM reduction of as much as 10 +/- 1 mm Hg (40%). Conjunctival hyperemia was not produced by 0.003% PhXA34, but was noted in some eyes treated with 0.01% PhXA34, and after repeated tonometry with either concentration. The prostaglandin analogue did not produce clinically obvious miosis, anterior chamber flare or cellular response, or any subjective adverse effects. PhXA34 is a potent, effective, and well-tolerated ocular hypotensive agent based on our results in this small, short-term study. Its potential as a new drug for glaucoma therapy warrants further investigation in long-term, larger studies.

Ocular hypertensive patients were enrolled in a 6-week double-masked safety study of 2% MK-927 (27 patients), a topically active carbonic anhydrase inhibitor, administered bilaterally b.i.d.; 9 additional patients received 0.5% timolol as the control agent. Intraocular pressure (IOP) was measured weekly prior to a.m. drug administration; twelve hour diurnal curves were performed prestudy and at 3 and 6 weeks. The mean reduction of IOP prior to a.m. drug administration ranged from 1.2 +/- 4.4 mm Hg (SD) to 3.0 +/- 4.2 mm Hg with MK-927 and from 4.7 +/- 3.9 mm Hg to 8.8 +/- 0.6 mm Hg with timolol. Mean outflow facility measured tonographically prestudy and on days 33 to 42 four hours after a.m. drug administration was unchanged in both groups. Corneal sensitivity (Cochet-Bonnet), corneal thickness (ultrasound pachymetry), Schirmer tear testing, and extensive ophthalmologic and medical examinations, and hematologic studies were not substantially altered throughout the study. In this longest chronic administration study to date, MK-927 did not cause adverse ocular or systemic side effects.

In randomized, double-masked fashion, 24 volunteers with ocular hypertension received 0.3% or 0.6% metipranolol, a noncardioselective beta blocker; or placebo twice daily to both eyes for six weeks. Intraocular pressure (mean +/- SEM) was reduced (P = .01) in the metipranolol-treated patients (baseline measurement, 25.9 +/- 0.5 mm Hg to 18.1 +/- 1.2 mm Hg at six weeks, 0.6% concentration; baseline measurement, 27.1 +/- 0.4 mm Hg to 21.6 +/- 1.5 mm Hg at six weeks, 0.3% concentration). Intraocular pressure was not markedly changed in placebo-treated patients. Outflow facility was unaltered two hours after instillation of metipranolol at study week 2 compared to baseline measurement. Aqueous humor flow rates were reduced (P = .02) 20% after 0.6% or 0.3% metipranolol instillation and were unchanged after placebo administration compared to baseline measurement. Mean systolic blood pressure, diastolic blood pressure, and pulse rate were not markedly altered. Metipranolol reduces intraocular pressure by suppressing aqueous humor flow rates.

An investigation was carried out to determine the mechanism by which MK-507 (L-671,152), a water-soluble inhibitor of human carbonic anhydrase II in vitro, reduces intraocular pressure when applied topically to monkey eyes. Intraocular pressure, tonographically measured outflow facility, and fluorophotometrically determined aqueous humor flow were measured before and after therapy in eight normal cynomolgus monkeys. Fifty microliters of 2% MK-507 was instilled in one eye and diluent in the contralateral eye. Baseline values for intraocular pressure, outflow facility, and aqueous humor flow were similar in the drug-treated and diluent-treated control eyes. After therapy, intraocular pressure was significantly (P less than .05) reduced from 1 to 7 hours (eg, 14.0 +/- 1.0 and 15.9 +/- 0.9 mm Hg [mean +/- SEM], treated and control eyes, respectively, at 3 hours). Outflow facility was not significantly (P greater than .40) changed at 3 hours, and aqueous humor flow measured over 5 hours was significantly (P less than .05) reduced (38%) in treated (0.9 +/- 0.1 microL/min) as compared with control eyes (1.5 +/- 0.1 microL/min). The results suggest that MK-507 reduces intraocular pressure by decreasing aqueous humor production.

Selective alpha 2-adrenergic agonists UK14304-18 and B-HT 920 were evaluated in the eyes of cynomolgus monkeys. In normal monkeys, unilateral topical application of 0.3%, 0.5%, or 1% UK14304-18 or B-HT 920 reduced (P less than .05) intraocular pressure bilaterally up to 9.9 +/- 1.2 mm Hg (mean +/- SEM) and 8.4 +/- 1.4 mm Hg in treated and contralateral eyes, respectively. Five-day twice-daily 0.5% UK14304-18 administration reduced (P less than .05) intraocular pressure up to 49% in eight glaucomatous monkeys. In eight normal monkeys, 0.5% B-HT 920 and 0.5% UK14304-18 produced no alterations in outflow facility. Following unilateral application of 0.5% B-HT 920 or 0.5% UK14304-18, fluorophotometrically measured aqueous humor production was reduced (P less than .05) bilaterally up to 67% compared with baseline values. Also, 0.5% UK14304-18 reduced (P less than .025) systolic and diastolic blood pressure. UK14304-18 and B-HT 920 seem to reduce intraocular pressure by decreasing aqueous production. They are potential new agents for the treatment of glaucoma.

We investigated the dose-response and reproducibility of the intraocular pressure-lowering effect of MK-927 in ocular hypertensive patients. Patients were enrolled until at least 8 "marked responders" (peak reduction in intraocular pressure comparing the MK-927-treated eye with the placebo-treated eye greater than or equal to 6 mm Hg) and 7 "mild responders" (peak reduction in intraocular pressure comparing the MK-927-treated eye with the placebo-treated eye less than or equal to 3 mm Hg) were identified. In part A, 27 patients received one drop of 2% MK-927 in one eye (baseline mean +/- SEM intraocular pressure, 28.0 +/- 1.0 mm Hg) and placebo in the contralateral eye. Intraocular pressure was measured at baseline and 1, 2, 3, 4, and 6 hours. Maximum reduction in intraocular pressure was 4.0 +/- 0.8 mm Hg at 3 hours, with a duration of 4 hours. Ten patients were identified as marked responders and 7 as mild responders. In part B, 8 of the marked responders entered a four-period crossover study and received 2%, 0.5%, and 0.125% MK-927 and placebo in the same treated eye as in part A, and placebo in the contralateral eye. The 7 mild responders in part C received 2% MK-927 in a similar fashion as in part A. MK-927 in concentrations of 0.125% and 0.5% had little or no effect on intraocular pressure in patients with a marked response to 2% MK-927. Within-patient variability in peak response to single doses of 2% MK-927 was substantial (coefficient of variation of 0.3 and 0.5 for marked responder and mild responder groups, respectively.

L-671,152, a new potent water-soluble inhibitor of human carbonic anhydrase II in vitro, was applied topically to cynomolgus monkey eyes in which glaucoma had been produced by argon laser photocoagulation of the trabecular mesh-work. Intraocular pressure was measured at 0 hours, 0.5 hours, and hourly for 8 hours in eight eyes for 2 baseline days, 1 day receiving the vehicle and 5 days receiving therapy with 2% L-671,152 twice a day, after initial single-dose trials of various concentrations. Intraocular pressure was not significantly different comparing baseline and vehicle-treated days. Significant intraocular pressure reductions occurred from 1 to 8 hours after the first dose, and lasted for at least 16 hours after the second dose. The reduction in intraocular pressure became more pronounced from day 1 to day 5 at each time interval. The mean (+/- SEM) maximum reduction in intraocular pressure was 7.8 +/- 2.1 mm Hg on day 1 and 10.1 +/- 2.4 mm Hg on day 5 at 3 hours after administration, comparing the intraocular pressure in drug-treated and vehicle-treated eyes. L-671,152 has a longer duration of action than does previously studied MK-927 in glaucomatous monkeys. It appears to have great clinical potential.

MK-927 is a water soluble, potent inhibitor of human carbonic anhydrase (CA) II in vitro. Topical administration of MK-927 reduces intraocular pressure (IOP) in rabbits. Elevated IOP was produced in cynomolgus monkey eyes by argon laser photocoagulation of the trabecular meshwork. IOP was measured at 0 hr, 0.5 hr and hourly for 8 hrs in 8 eyes for two baseline days, one day on vehicle and five days of therapy with 2% MK-927 b.i.d., after initial single-dose trials of various concentrations. IOP was not significantly different comparing baseline and vehicle treated days. Significant (p less than 0.05) reductions of IOP occurred for five days lasting at least 8 hrs after each dosing. At 3 hrs after treatment with vehicle the IOP was 31.6 +/- 3.4 (SE) mm Hg. Maximum reduction of IOP occurred at 3 hrs after application of MK-927, the IOP decreasing from day 1 (19.9 +/- 1.0 mm Hg) to day 5 (16.5 +/- 1.6 mm Hg). MK-927 appears to have great clinical potential.

In a randomized, double-masked, placebo-controlled study, 0.25 microgram (n = 11) or 0.5 microgram (n = 13) of prostaglandin F2 alpha-1-isopropyl ester (PGF2 alpha-IE) was applied topically twice daily for 8 days to one eye of ocular hypertensive or chronic open-angle glaucoma patients. Compared with contralateral, vehicle-treated eyes, PGF2 alpha-IE significantly (P less than 0.05) reduced intraocular pressure (IOP), beginning 4 hours after the first 0.5-microgram dose and lasting at least 12 hours after the fourteenth dose, with a significant (P less than 0.005) mean reduction of 4 to 6 mmHg maintained throughout the last day of therapy with either dose. A contralateral effect was not observed. Mean tonographic outflow facility was significantly (P less than 0.05) higher in PG-treated compared with vehicle-treated eyes (0.17 +/- 0.02 versus 0.12 +/- 0.01 microliter/minute/mmHg, respectively; +/- standard error of the mean) for the 0.5 microgram dose. Conjunctival hyperemia reached a maximum at 30 to 60 minutes after PGF2 alpha-IE application. Some patients reported mild irritation lasting several minutes after some doses. Visual acuity, accommodative amplitude, pupillary diameter, aqueous humor flare, anterior chamber cellular response, Schirmer's test, pulse rate, and blood pressure were not significantly altered. Our findings show that PGF2 alpha-IE is a potent ocular hypotensive agent and a promising drug for glaucoma therapy.

Topical administration of 50 microliter of 1% Na3VO4 caused a significant fall in intraocular pressure (IOP) in the rabbit eye at 90 min. Assay of ATPase of the iris and ciliary body in vitro at 90 min posttreatment showed no differences between control and treated (Na+, K+)ATPase, ouabain sensitive ATPase or vanadate sensitive ATPase. Accumulation of 48V-labelled orthovanadate in iris and ciliary body reached a plateau of 12 pmoles/mg dry tissue weight 4 hr after a single 25-microliter topical dose of 1% orthovanadate. In vitro inhibition of Na+ sensitive ATPase by sodium metavanadate had an IC50 of 1.8 mM, whereas a 1.8-fold stimulation of adenylate cyclase in iris-ciliary body (ICB) membranes in vitro occurred at 10 mM but not at 10 microM Na metavanadate. These results indicate that the vanadate content of the iris and ciliary body at the time of lowered intraocular pressure is too small to inhibit a significant fraction (greater than 10%) of (Na+, K+)ATPase, or cause a significant stimulation of adenylate cyclase, and that other cellular mechanisms are likely to be involved in the ocular hypotensive response to vanadate.

A single drop, dose-response, double-masked study of the effect corynanthine, a selective alpha 1 adrenergic antagonist, on intraocular pressure (IOP) was carried out in 10 symmetrically ocular hypertensive patients. Corynanthine 1% had no significant pressure lowering effect. Topical application of a 2% solution significantly (P less than 0.05) reduced IOP for at least eight hours; at five hours, mean IOP (+/- SEM) was 20.6 +/- 2.0 mmHg and 26.0 +/- 4.9 mmHg, comparing treated and control eyes, respectively. The 5% solution caused a significant (P less than 0.05) bilateral reduction in IOP, comparing treated and control eyes to baseline IOP respectively. Two percent corynanthine applied topically two or three times daily for one, two, or three weeks to seven patients with symmetrical ocular hypertension did not reduce IOP. Alpha adrenergic antagonists may have a role in the treatment of glaucoma.

The effects of corynanthine tartrate, a selective alpha 1-adrenergic receptor antagonist, were studied on intraocular pressure by pneumatonometry, outflow facility by tonography, and aqueous humor flow by fluorophotometry in laboratory animals. Unilateral topical administration of 5% corynanthine significantly lowered mean IOP (+/- SEM) in rabbits for at least six hours, in ten awake monkeys for six hours, and in ten monkeys anesthetized with ketamine for four hours. The maximum effect in awake monkeys occurred two hours after drug administration, from 15.8 +/- 0.5 mm Hg to 12.7 +/- 0.5 mm Hg, with no substantial change in control eyes. No change in outflow facility was demonstrated in 11 monkeys two hours after 5% corynanthine administration. Aqueous humor flow rates did not change in 12 monkeys up to three hours after drug administration. Corynanthine may act by increasing uveoscleral outflow.

Topical administration of nylidrin hydrochloride lowered intraocular pressure in both albino rabbits and cynomologus monkeys. The maximum decrease occurred two hours following drug application and was unilateral. The response lasted four hours in monkeys and at least six hours in rabbits. Outflow facility, episcleral venous pressure, and aqueous humor flow measured by fluorophotometry were unaltered in both species. In rabbits in the treated eyes, ocular blood flow was increased, and anterior and posterior chamber ascorbate concentrations were unchanged. The mechanism of IOP reduction appears to be increased aqueous humor outflow via uveoscleral outflow routes that are not pressure dependent.

A need exists for new ocular hypotensive agents that are more efficacious and that have fewer side effects than those now clinically used. Laser-induced glaucoma in monkeys is an excellent model to test potential new drugs that lower intraocular pressure (IOP). A variety of agents that act through secondary messenger systems or via enzymes to lower IOP are being investigated in primates. Several alpha-adrenergic agonists and antagonists are effective ocular hypotensive agents in monkeys and humans. Para-aminoclonidine, an alpha2 agonist, inhibits the transient post-laser rise of IOP in humans. Prostaglandin F2 alpha-1-isopropyl ester significantly reduces IOP when tested in multiple dose fashion in glaucomatous monkey eyes and glaucoma patients. Modified carbonic anhydrase inhibitors, designed to enhance intraocular penetration, reduce IOP in the monkey model and in ocular hypertensive patients in single-dose studies when given topically. Studies show that forskolin and vanadate are less promising agents for glaucoma therapy.

Sixteen patients enrolled in the PERK study were evaluated by fluorophotometry 24 hours or six months following radial keratotomy. A comparison of eyes operated and not operated upon showed that endothelial permeability was not significantly altered 24 hours and six months after surgery. Aqueous humour flow rates and anterior chamber elimination coefficients were significantly higher 24 hours after surgery in the eyes operated on than in those not operated on. Six months after surgery there was no longer a significant difference in these factors. The increase in aqueous humour flow rates 24 hours after surgery may represent a subclinical breakdown in the blood-aqueous barrier.

The effects of multiple dosing with 0.5% timolol maleate, 2% epinephrine hydrochloride, 4% pilocarpine hydrochloride, 1% vanadate, 1% forskolin (nonproprietary name, colforsin), or 0.5% prostaglandin F2 alpha on intraocular pressure (IOP) were each tested on eight cynomolgus monkey eyes in which glaucoma was induced by photocoagulating the trabecular meshwork with the argon laser. The week prior to drug therapy, baseline IOP measurements were carried out at hourly intervals from 9:30 am to 3:30 pm on three days. One to two days later, therapy was initiated. Each drug was applied topically to both eyes of each monkey twice daily for at least four days. The IOP was measured with a calibrated pneumatonometer at the same hourly intervals on treatment days as on the baseline days. The IOP at each time of day on treatment days was compared with the average baseline IOP measured at the corresponding time of day. Topical application of timolol, epinephrine, pilocarpine, vanadate, and prostaglandin F2 alpha significantly reduced IOP without evidence of tolerance or tachyphylaxis during the course of therapy. Forskolin did not significantly decrease IOP after the second day of treatment.