Janet B. Serle

Maintained reduction of intraocular pressure by prostaglandin F2α-1-isopropyl ester applied in multiple doses in ocular hypertensive and glaucoma patients

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, Schirmers 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.

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 prostanoids 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.

Effect of 5-mca-nat, a Putative Melatonin Mt3 Receptor Agonist, on Intraocular Pressure in Glaucomatous Monkey Eyes

Purpose5-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. MethodsA multiple-dose study was performed in 8 glaucomatous monkey eyes. One 25-μL 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. ResultsCompared 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. Conclusions5-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.

The Effect of Topically Administered Carbonic Anhydrase Inhibitors on Aqueous Humor Dynamics in Rabbits

Repeated topical administration of 2.5% trifluormethazolamide, a halogenated derivative of methazolamide, resulted in a unilateral decrease in intraocular pressure in rabbits. Mean (+/- S.E.M.) baseline intraocular pressure (19.8 +/- 2.1 mm Hg) was significantly (P less than .05) decreased 30 minutes (16.1 +/- 2.2 mm Hg) and 60 minutes (15.8 +/- 2.7 mm Hg) after drug administration. Trifluormethazolamide did not alter outflow facility. Aqueous humor flow calculated from the tonographic data was reduced 44% and flow measured by fluorophotometry was reduced 29%. Topical delivery of trifluormethazolamide decreased the level of carbon dioxide in the aqueous humor in the treated eye in a manner similar to that observed after systemic administration of carbonic anhydrase inhibitors. Topical administration of 10% acetazolamide did not decrease intraocular pressure. However, topical administration of either trifluormethazolamide or acetazolamide before oral administration of water resulted in a blunting of the water-induced ocular hypertensive response.

The Use of Dorzolamide and Pilocarpine as Adjunctive Therapy to Timolol in Patients with Elevated Intraocular Pressure

PURPOSE To report the results of two studies on the use of dorzolamide as adjunctive therapy to timolol in patients with elevated intraocular pressure (IOP). In the larger study, the additive effect of dorzolamide administered twice daily also was compared with 2% pilocarpine. METHODS Both studies were parallel, randomized, double-masked, placebo-controlled comparisons. In the pilot study, 32 patients received 0.5% timolol twice daily plus either 2% dorzolamide twice daily or placebo twice daily for 8 days. In the Pilocarpine Comparison Study, 261 patients received 0.5% timolol twice daily plus 0.7% dorzolamide twice daily, 2% dorzolamide twice daily, 2% pilocarpine four times daily, or placebo (twice daily or 4 times daily) for 2 weeks. Patients then entered a 6-month extension period and received 0.5% timolol twice daily plus either 0.7% dorzolamide twice daily, 2% dorzolamide twice daily, or 2% pilocarpine four times daily. RESULTS In the pilot study, after 8 days, additional mean percent reductions in IOP for 2% dorzolamide and placebo were 17% and 3% at morning trough and 19% and 2% at peak, respectively. In the Pilocarpine Comparison Study, after 6 months, additional mean percent reductions in IOP (morning trough) were 9%, 13%, and 10% for 0.7% dorzolamide, 2% dorzolamide, and 2% pilocarpine, respectively. Patients receiving 2% pilocarpine had the highest rate of discontinuation due to a clinical adverse experience, and the use of dorzolamide was not associated with systemic side effects commonly observed with the use of oral carbonic anhydrase inhibitors. CONCLUSION Dorzolamide twice daily was effective and well tolerated by the patients in these studies as adjunctive therapy to timolol. The larger study demonstrated that both concentrations of dorzolamide produce similar IOP-lowering effects to 2% pilocarpine.

Krupin Eye Valve with Disk for Filtration Surgery

PURPOSE The authors evaluate a long posterior tube shunt device with a pressure sensitive valve for filtration surgery in eyes with recalcitrant glaucoma. METHODS The device consisted of an anterior chamber tube connected to an oval (13 x 18 mm) episcleral explant. The explant was designed to maximize the area of surrounding encapsulation while still allowing implantation within one quadrant. A pressure-sensitive and unidirectional slit valve in the tube provided resistance to aqueous humor flow. One-stage implantation without the use of restrictive sutures was performed in 50 eyes with various types of glaucoma unresponsive to prior glaucoma surgery. RESULTS Mean (+/- standard error of the mean) preoperative intraocular pressure (IOP) of 36.4 +/- 1.6 mmHg was reduced significantly (P < 0.001) to 8.3 +/- 1.3 mmHg on the first postoperative day. Mean anterior chamber depth (scale, 0-4+) was 3.4 +/- 0.1. Mean IOP 1 month after surgery was 14.1 +/- 1.3 mmHg. The implant was removed from four eyes due to IOP failure (1 eye), external erosion (2 eyes), or endophthalmitis (1 eye). A suprachoroidal hemorrhage occurred in one eye on the first postoperative day. Diplopia developed in one eye after surgery. Mean IOP at last follow-up examination (mean, 25.4 +/- 2.4 months; range, 16-36 months) was 13.1 +/- 1.3 mmHg. Intraocular pressure was 19 mmHg or lower in 80% of the eyes, 59% of which were without adjunctive antiglaucoma medications. CONCLUSIONS Design features of the Krupin Eye Valve with Disk result in a large area of encapsulation in a single ocular quadrant which functions as an external reservoir for passage of aqueous humor. The valve portion facilitates maintenance of anterior chamber depth during the early postoperative interval. This new therapeutic device can be effective in the long-term control of IOP in glaucomatous eyes not responsive to prior filtration surgery with adjunctive antimetabolite therapy.

A Long Krupin-Denver Valve Implant Attached to a 180° Scleral Explant for Glaucoma Surgery

Abstract A long glaucoma valve implant attached to an external scleral explant was used during filtration surgery in 72 eyes: 39 eyes with neovascular glaucoma and 33 eyes with other types of secondary glaucomas or with primary glaucoma in which prior filtration surgery had failed. The implant consisted of an open Silastic tube (outside diameter, 0.64 mm), which was placed into the anterior chamber. The external end of the tube contained a pressure-sensitive (opening pressure, 11 mmHg) and unidirectional slit-valve, and was sutured within the groove of a #220 Silastic explant. The 180° explant was placed beneath three rectus muscles and then sutured so that the grooved side was against the sclera, with the anterior edge 8 to 12 mm posterior to the limbus. The long glaucoma valve implant resulted in a large, posterior bleb extending over the area of the Silastic explant. The mean preoperative intraocular pressure (IOP) of 43.9 mmHg in the eyes with neovascular glaucoma was reduced to 17.4 mmHg after a mean follow-up of 20.2 months. The mean preoperative IOP of 38.1 mmHg in the eyes after failure of previous filtration surgery was reduced to 17.6 mmHg at a mean follow-up of 21.0 months. Postoperative IOP was less than 21 mmHg in 77% of eyes with neovascular glaucoma (47% required additional medication) and in 82% of eyes with previous failure of filtration surgery (56% required additional medication).

The effect of selective laser trabeculoplasty on intraocular pressure in patients with intravitreal steroid-induced elevated intraocular pressure.

PurposeTo assess effectiveness of selective laser trabeculoplasty (SLT) in lowering intraocular pressure (IOP) in patients with steroid-induced elevated IOP. MethodsRetrospective 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. ResultsThe 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). ConclusionsSLT 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.

Effect of 0.04% AR-13324, a ROCK, and norepinephrine transporter inhibitor, on aqueous humor dynamics in normotensive monkey eyes.

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.

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°; spot size, 75 μm; 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 (μl/min/ mmHg) was reduced (p < 0.001) in both diode (0.09 ± 0.01 μl/min/mmHg) and argon (0.10 ± 0.01 μl/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.