Netarsudil/latanoprost fixed-dose combination for the treatment of open-angle glaucoma or ocular hypertension.

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.

Effect of pilocarpine 4% in combination with latanoprost 0.005% or 8-iso prostaglandin E2 0.1% on intraocular pressure in laser-induced glaucomatous monkey eyes.

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.

Comparison of the ocular hypotensive effect of brimonidine, dorzolamide, latanoprost, or artificial tears added to timolol in glaucomatous monkey eyes.

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.

Effect of latanoprost or 8-iso prostaglandin E2 alone and in combination on intraocular pressure 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.

Effect of 8-iso prostaglandin E2 on aqueous humor dynamics in monkeys.

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.

A comparative study of latanoprost (Xalatan) and isopropyl unoprostone (Rescula) in normal and glaucomatous monkey eyes.

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.

A comparison of argon laser and diode laser photocoagulation of the trabecular meshwork to produce the glaucoma monkey model.

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.

Effect of 5-methylurapidil, an alpha 1a-adrenergic antagonist and 5-hydroxytryptamine1a agonist, on aqueous humor dynamics in monkeys and rabbits.

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.

A comparison of the safety and efficacy of twice daily brimonidine 0.2% versus betaxolol 0.25% in subjects with elevated intraocular pressure. The Brimonidine Study Group III.

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.

Pharmacological advances in the treatment of glaucoma.

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.

Studies of the ocular pulse in primates.

Ocular pulse amplitude (OPA) and intraocular pressure (IOP) were measured in groups of human subjects with primary open-angle glaucoma (POAG), ocular hypertension (OHT), low-tension glaucoma (LTG), retinal degenerations (RD), in OHT volunteers treated with single doses of 2% epinephrine, 4% pilocarpine, 0.5% timolol or 1% p-amino-clonidine, and in normal subjects before and after exercise. Compared to normal controls, OHT subjects showed significantly higher IOP and OPA, while OPA was significantly lower in ocular normotensive LTG and RD subjects groups. All drug treatments lowered IOP in OHT subjects, but did not change OPA significantly. Exercise in normal volunteers increased calculated ocular perfusion pressure by 22.5%, lowered IOP by 32%, but showed no significant change in OPA. When IOP was elevated > or = 5 mmHg in lasered monkey eyes peak pulse volume (PPV) was increased significantly in the unlasered eyes. Epinephrine 2% or 1% p-aminoclonidine lowered IOP moderately with no change in PPV, while treatment with 4% pilocarpine or 0.5% timolol reduced IOP and increased PPV significantly. The findings suggest that LTG may be associated with an ocular vascular abnormality. OPA in OHT or normal human subjects did not change when IOP was decreased by antiglaucoma drug treatments or exercise, respectively. These results indicate that OPA may be physiologically autoregulated in human subjects with IOPs in the 11-21 mmHg range. However, laser-induced glaucomatous monkey eyes with higher IOP (30-35 mmHg) did not autoregulate, but showed a low peak pulse volume, which increased when IOP was reduced 5 mmHg or more by means of antiglaucoma drug treatment.

Effects of topical ethacrynic acid ointment vs timolol on intraocular pressure in glaucomatous monkey eyes.

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.

Effect of oxymetazoline on aqueous humor dynamics and ocular blood flow in monkeys and rabbits.

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.

Intraocular pressure reduction with PhXA34, a new prostaglandin analogue, in patients with ocular hypertension.

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.

Six week safety study of 2% MK-927 administered twice daily to ocular hypertensive volunteers.

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.

MK-507 (L-671,152), a topically active carbonic anhydrase inhibitor, reduces aqueous humor production in monkeys.

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.

A clinical trial of metipranolol, a noncardioselective beta-adrenergic antagonist, in ocular hypertension.

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.

Selective alpha 2-adrenergic agonists B-HT 920 and UK14304-18. Effects on aqueous humor dynamics in monkeys.

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.