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 on intraocular pressure during 24 hours after repeated administration of the fixed combination of latanoprost 0.005% and timolol 0.5% in patients with ocular hypertension

PURPOSE: To measure the effect on intraocular pressure (IOP) for 24 hours after repeated administration of the fixed combination of latanoprost 0.005% and timolol 0.5%. METHODS: A randomized, double-masked placebo-controlled crossover study including 20 patients with ocular hypertension was carried out. Patients were randomized to treatment with the fixed combination of latanoprost and timolol or with placebo. The eyedrop was taken at 8 AM. After 2 weeks of treatment, the patients were hospitalized, and the IOP was measured at 8 AM, and thereafter every other hour until midnight, and also at 3 AM, 6 AM, and 8 A.M. After a washout period of 4 weeks, they switched to the other eyedrop, and after 2 weeks of treatment were hospitalized and the IOP measurements were repeated at the same intervals. RESULTS: The mean 24-hour IOP was 14.7 +/- 0.3 mm Hg (mean +/- standard error of the mean) for latanoprost and timolol and 19.4 +/- 0.3 mm Hg for placebo. This corresponds to a significant IOP difference of 4.7 +/- 0.4 mm Hg (95% confidence interval 3.8-5.8; P < 0.001) between the two treatments in favor of the combination. At all measured time points, except at 3 AM, the mean IOP was lower with latanoprost and timolol than with placebo. During daytime measurements the mean IOP was 13.9 +/- 0.7 mm Hg for the fixed combination and 19.5 +/- 0.7 mm Hg for the placebo. Corresponding figures at nighttime were 16.1 +/- 0.7 mm Hg and 19.2 +/- 0.7 mmHg, respectively. CONCLUSIONS: The fixed combination of latanoprost and timolol significantly reduced IOP after administration once daily for 2 weeks in patients with ocular hypertension. A reduction of IOP during a 24-hour period was seen, with a greater IOP reduction during daytime compared with nighttime. The fixed combination applied once daily could be a convenient alternative to concomitant therapy with its individual components.     

Potential mechanism for the additivity of pilocarpine and latanoprost

PURPOSE: To determine the ocular hypotensive mechanism underlying the additivity of latanoprost and pilocarpine. METHODS: This randomized, double-masked study included 30 patients with ocular hypertension on no ocular medications for at least 3 weeks. On each of six visits to the clinic, measurements were taken of aqueous flow and outflow facility by fluorophotometry, intraocular pressure by tonometry, and episcleral venous pressure by venomanometry. Uveoscleral outflow was calculated. Clinic visits were scheduled on baseline day; on day 8 of four times daily pilocarpine (2%) to one eye and vehicle to the other; on day 8 of continued pilocarpine/vehicle treatment plus latanoprost (0.005%) once daily to both eyes; after a 3-week washout period; on day 8 of once-daily latanoprost to one eye and vehicle to the other; and on day 8 of continued latanoprost/vehicle treatment plus pilocarpine four times a day to both eyes. Drug-treated eyes were compared with contralateral vehicle-treated eyes and with baseline day by paired t tests. Combined pilocarpine and latanoprost-treated eyes were compared with individual drug-treated eyes and with baseline day using the Bonferroni test. RESULTS: Compared with baseline, pilocarpine reduced intraocular pressure from 18.9 to 16.2 mm Hg (P =.001) and increased outflow facility from 0.18 to 0.23 microl per minute per mm Hg (P =.03). No other parameters were affected. Adding latanoprost further reduced intraocular pressure to 13.7 mm Hg (P <.001) and increased uveoscleral outflow from 0.82 to 1.36 microl per minute (P =.02). Latanoprost alone reduced intraocular pressure from 17.6 to 14.3 mm Hg (P <.0001) and increased uveoscleral outflow from 0.89 to 1.25 microl per minute (P =.05). Adding pilocarpine to the latanoprost treatment further reduced intraocular pressure to 12.7 mm Hg (P <.001) and increased outflow facility from 0.21 to 0.30 microl per minute per mm Hg (P =.03). CONCLUSIONS: Latanoprost and pilocarpine predominantly increase uveoscleral outflow and outflow facility, respectively, when given alone. These drugs are additive because pilocarpine does not inhibit the uveoscleral outflow increase induced by latanoprost.     

Latanoprost or brimonidine as treatment for elevated intraocular pressure: multicenter trial in the United States

PURPOSE: To compare the efficacy and tolerability of latanoprost or brimonidine in patients with elevated intraocular pressure (IOP). MATERIALS AND METHODS: This prospective, randomized, masked-evaluator, parallel-group, multicenter study in the United States included patients with primary open angle glaucoma or ocular hypertension. Patients received latanoprost 0.005% once daily (8:00 AM; n = 152) or brimonidine tartrate 0.2% twice daily (8:00 AM and 8:00 PM; n = 151). Patients underwent evaluation at screening, baseline (randomization), and after 0.5, 3, and 6 months of treatment. IOP was measured at 8:00 AM, 10:00 AM, noon, and 4:00 PM at baseline and the months 3 and 6 visits, and at 8:00 AM only at week 2. The main outcome measure was the difference in diurnal IOP change from baseline to month 6 between treatment groups. Adverse events were recorded at each visit. RESULTS: Baseline mean diurnal IOP levels were similar between groups. At month 6, the adjusted mean (+/- SEM) diurnal IOP reduction was 5.7 +/- 0.3 mm Hg in the latanoprost group and 3.1 +/- 0.3 mm Hg in patients receiving brimonidine (P < 0.001). The mean difference in diurnal IOP reduction was 2.5 +/- 0.3 mm Hg (95% CI: 1.9, 3.2; P < 0.001). Five times more patients receiving brimonidine than latanoprost were withdrawn from the study due to adverse events. CONCLUSION: Latanoprost instilled once daily is more effective and better tolerated than brimonidine administered twice daily for the treatment of patients with glaucoma or ocular hypertension. During therapy, the range of daily fluctuation of IOP is less for latanoprost compared with brimonidine.     

Effects of travoprost on aqueous humor dynamics in monkeys

PURPOSE: To determine the mechanism by which travoprost, a prodrug of a prostaglandin F2alpha analog, reduces intraocular pressure (IOP) in cynomolgus monkey eyes. METHODS: One eye each of 12 monkeys was treated with laser burns to the trabecular meshwork to elevate IOP. At least 4 months later (Baseline Day), IOP was measured by pneumatonometry (9:00 AM and 11:45 AM), and aqueous flow and outflow facility were determined by a fluorophotometric method. Uveoscleral outflow was calculated. Both eyes were treated with travoprost 0.004% at 9:00 AM and 5:00 PM for two days and at 9:30 AM on the third day (Treatment Day), when measurements were repeated as on Baseline Day. Statistical analyses were performed using two-tailed, paired t tests. RESULTS: On Treatment Day compared with Baseline Day, IOP in hypertensive eyes was reduced at 2.25 hours (25.8 +/- 11.2 vs 33.7 +/- 13.2 mm Hg; mean +/- standard error of the mean [SEM]; P = 0.02) and 16 hours (26.3 +/- 10.2 vs 35.1 +/- 13.6 mm Hg; P = 0.02) after treatment. The increase in uveoscleral outflow was not significant. In normotensive eyes, IOP was reduced at 2.25 hours (19.0 +/- 3.7 vs 23.0 +/- 4.0 mm Hg; P = 0.03) and 16 hours (20.7 +/- 5.4 vs 23.4 +/- 5.3 mm Hg; P = 0.01) after treatment, and uveoscleral outflow was significantly (P = 0.02) increased (1.02 +/- 0.43 vs 0.35 +/- 0.72 microL/min). CONCLUSION: Travoprost reduces IOP in normotensive monkey eyes by increasing uveoscleral outflow. The IOP reduction in hypertensive eyes is probably via the same mechanism, although the increased uveoscleral drainage did not reach statistical significance. Travoprost had no effect on aqueous flow or outflow facility.     

The effects of prostaglandin analogues on IOP in prostanoid FP-receptor-deficient mice

PURPOSE: This study was designed to clarify the involvement of the prostanoid FP receptor in the intraocular pressure (IOP)-lowering effects of latanoprost, travoprost, bimatoprost, and unoprostone with the use of FP-receptor-deficient (FPKO) mice. METHODS: FPKO and wild-type (WT) mice were bred and acclimatized under a 12-hour light-dark cycle. IOP was measured under general anesthesia by a microneedle METHOD: To evaluate the effects of each drug, a single drop (3 muL) of each drug solution was topically applied in a masked manner to a randomly selected eye. IOP reduction was evaluated by the difference in IOP between the treated eye and the untreated contralateral eye in the same mouse. First, the diurnal variation and baseline IOP in WT and FPKO mice were measured. Then, to determine the window feasible for demonstrating the most marked ocular hypotensive effect, 0.005% latanoprost was applied to WT mice during the day or at night. The time when the ocular hypotensive effect was larger was selected for further studies to evaluate the effects of latanoprost (0.005%), travoprost (0.004%), bimatoprost (0.03%), and unoprostone (0.12%). In addition, bunazosin (0.1%) was also applied to demonstrate functional uveoscleral outflow in FPKO mice. All experiments were conducted under a masked study design. RESULTS: The baseline IOP (mean +/- SEM) in WT and FPKO mice was 15.0 +/- 0.2 and 15.0 +/- 0.3 mm Hg, respectively, during the day, and 18.9 +/- 0.4 and 19.2 +/- 0.4 mm Hg, respectively, at night. In WT mice, latanoprost significantly lowered IOP both during the day and at night, at 2 to 6 hours and 1 to 6 hours after application, respectively. Maximal IOP reduction was observed at 3 hours after drug instillation both during the day (10.9 +/- 1.8%) and at night (23.2 +/- 1.1%). At 3 hours after instillation, latanoprost (10.9 +/- 1.8% and 23.2 +/- 1.1%, daytime and nighttime, respectively), travoprost (15.9 +/- 1.4% and 26.1 +/- 1.2%) and bimatoprost (8.8 +/- 2.0 and 19.8 +/- 1.5%) significantly lowered IOP in WT mice both during the day and at night; isopropyl unoprostone significantly lowered IOP at night (13.7 +/- 1.9%) but not during the day (5.3 +/- 3.2%). In FPKO mice, latanoprost, travoprost, bimatoprost, and unoprostone showed no significant IOP-lowering effect. Bunazosin significantly lowered IOP in both WT (22.1 +/- 1.6%) and FPKO mice (22.2 +/- 2.1%). CONCLUSIONS: A single application of latanoprost, travoprost, bimatoprost, or unoprostone had no effect on IOP in FPKO mice with presumed functional uveoscleral outflow pathways. The prostanoid FP receptor plays a crucial role in the mechanism of early IOP lowering of all commercially available prostaglandin analogues.     

Interaction of pilocarpine with latanoprost in patients with glaucoma and ocular hypertension.

PURPOSE: To study any interaction between pilocarpine and latanoprost when administered together, and to determine the optimal timing of dosage to maximize reduction of intraocular pressure (IOP). METHODS: Nineteen adult patients with either primary open-angle glaucoma or ocular hypertension participated in a single-center, prospective case study with masked observer. After a baseline measurement of IOP during treatment with latanoprost was obtained, initial treatment with pilocarpine three times daily was added without bedtime administration. This was followed by three different dose regimens in which pilocarpine was administered four times daily, altering the bedtime pilocarpine dose to precede the latanoprost dose by 1 hour, or to follow it by 10 minutes or 1 hour. Intraocular pressure was measured at 8:00 AM and 75 minutes after administration of the morning dose of pilocarpine. RESULTS: Comparison of IOP at 8:00 AM with baseline showed no significant change when pilocarpine was taken three times daily, or when pilocarpine was taken four times daily when the bedtime dose preceded administration of latanoprost by 1 hour. There were significant decreases in IOP versus baseline when the bedtime dose of pilocarpine was taken simultaneously with or 1 hour after administration of latanoprost. Application of pilocarpine immediately after the 8:00 AM IOP measurement revealed a significant additional decrease in pressure. There were no significant differences between dosage schedules in the magnitude of the additional reduction in IOP. CONCLUSION: The order and timing of administration of pilocarpine and latanoprost can significantly alter their ocular hypotensive activity. Pilocarpine is most effective when administered four times daily, and when the bedtime dose is administered 1 hour after administration of latanoprost.     

Randomized clinical trial of latanoprost and unoprostone in patients with elevated intraocular pressure

PURPOSE: To compare the intraocular pressure (IOP)-lowering effect and safety of latanoprost 0.005% once daily with that of unoprostone 0.15% twice daily for patients with primary open-angle glaucoma or ocular hypertension. DESIGN: Randomized clinical trial. METHODS: In a prospective, 8-week, investigator-masked, parallel-group study conducted at numerous centers in the United States, 165 previously treated patients with IOP >or= 25 mm Hg in one or both eyes after washout were randomly assigned to receive either latanoprost 0.005% once daily in the evening or unoprostone 0.15% twice daily. Observations procedures were Goldmann applanation tonometry, best-corrected visual acuity, slit lamp biomicroscopy, and ophthalmoscopy. The main outcome measure was change in the mean of the IOPs measured at 8:00 AM, 12 noon, and 4:00 PM between baseline (before treatment) and after 8 weeks of treatment. RESULTS: The change in the mean +/- SD of the IOPs measured at 8:00 AM, 12 noon, and 4:00 PM was -7.2 +/- 3.2 mm Hg (28%) for latanoprost (25.3 +/- 2.8 mm Hg at baseline to 18.2 +/- 2.8 mm Hg at 8 weeks) and -3.9 +/- 2.6 mm Hg (15%) for unoprostone (25.5 +/- 3.3 mm Hg at baseline to 21.6 +/- 4.0 mm Hg; P 相似文献   

Comparison of the intraocular pressure lowering effect of latanoprost and carteolol-pilocarpine combination in newly diagnosed glaucoma

PURPOSE: To evaluate the comparative efficacy of latanoprost monotherapy versus combined carteolol and pilocarpine therapy in patients with newly diagnosed glaucoma. METHODS: Masked randomized prospective trial. This study included 51 patients (64 eyes) with newly diagnosed glaucoma or ocular hypertension. The cases were randomly divided into two treatment groups for administration of latanoprost 0.005% once daily, or of carteolol 2% twice daily and pilocarpine 2% twice daily. Mean diurnal intraocular pressure (IOP) was measured at baseline, week 2, week 4, and month 3 after the beginning of treatment. Changes in mean IOP from baseline to the 3-month visit were determined by an analysis of variance. RESULTS: Mean diurnal IOP values were 25.1 +/- 3.1 mm Hg and 25.5 +/- 2.5 mm Hg at baseline in the latanoprost monotherapy group and in the carteolol-plus-pilocarpine group, respectively. Diurnal IOP was significantly decreased from baseline to 3 months in both groups (P <.001). At this time point, latanoprost monotherapy had reduced mean diurnal IOP by 7.2 +/- 2.5 mm Hg (28.7%) and carteolol plus pilocarpine had reduced mean diurnal IOP by 7.4 +/- 2.7 mm Hg (29%). There was no difference between the groups in terms of their IOP reduction effect (P =.51). Decreased visual acuity and twilight vision, blurred vision, and headache were more frequent in the carteolol-plus-pilocarpine group than in the latanoprost group (P <.05). CONCLUSIONS: We concluded that latanoprost monotherapy was at least as effective as the carteolol-pilocarpine combination therapy in reducing mean diurnal IOP in newly diagnosed glaucoma or ocular hypertension.     

The efficacy and safety of latanoprost 0.005% once daily versus brimonidine 0.2% twice daily in open-angle glaucoma or ocular hypertension

PURPOSE: To evaluate the efficacy and safety of latanoprost 0.005% given topically every evening versus brimonidine 0.2% given topically twice daily in primary open-angle glaucoma or ocular hypertensive patients. METHODS: This was a multicenter, crossover, double-masked comparison. After a 28-day treatment-free period, patients with primary open-angle glaucoma or ocular hypertension were randomized for 6 weeks to brimonidine or latanoprost and then crossed over to the opposite treatment. At baseline and after each treatment period, patients underwent intraocular pressure measurements every 2 hours from 08:00 to 20:00. RESULTS: In 33 patients the mean baseline trough (08:00) was 23.2 +/- 2.1 mm Hg and the diurnal curve pressure was 19.8 +/- 2.7 mm Hg. The trough and diurnal intraocular pressures for brimonidine were 19.6 +/- 3.4 mm Hg and 17.6 +/- 2.2 mm Hg, respectively. Brimonidine statistically reduced the pressure from baseline at each time point except hours 10 and 12 (P =.14 and P =.21, respectively). For latanoprost, the trough and diurnal pressures were 16.2 +/- 2.9 mm Hg and 15.4 +/- 2.5 mm Hg, respectively, and the pressure was statistically reduced at each time point (P <.001) and for the diurnal curve (P <.001). When compared directly, the intraocular pressure level for latanoprost was lower than brimonidine for the diurnal pressure and at each time point (P <.05). One patient was discontinued early from latanoprost treatment because of eyelid swelling; also, latanoprost caused more hyperemia than brimonidine (P =.04). CONCLUSION: This study suggests latanoprost dosed daily in the evening statistically reduces intraocular pressure more during daytime and evening hours than brimonidine dosed twice daily. Brimonidine may not consistently decrease the pressure 10 and 12 hours past dosing from nontreated levels.     

Effect of 15-keto latanoprost on intraocular pressure and aqueous humor dynamics in monkey eyes

PURPOSE: To compare the ocular hypotensive effects of 15-keto latanoprost (KL) with the commercial preparation of latanoprost (Xalatan; Pfizer, New York, NY) in monkey eyes with laser-induced unilateral glaucoma and to evaluate the effects of topical 0.005% KL on aqueous humor dynamics in normal monkey eyes. METHODS: Intraocular pressure (IOP) was measured hourly for 6 hours beginning at 9:30 AM on day 1 (untreated baseline); day 2 (vehicle only); and treatment days 1, 3, and 5 (topical, 30 microL of study drug) in the glaucomatous eyes of four to eight monkeys with unilateral laser-induced glaucoma. KL concentrations of 0.0001%, 0.001%, and 0.01% and latanoprost at 0.005% were studied separately, with a minimum washout period of 2 weeks between studies. Tonographic outflow facility (C) and fluorophotometric aqueous humor flow rates (F) were measured in nine normal monkeys before and after a single topical dose of 0.005% KL in one eye, with a vehicle-only control in the fellow eye. RESULTS: When applied once daily to glaucomatous monkey eyes, all three concentrations of KL and a 0.005% concentration of latanoprost produced significant (P < 0.05) reductions in IOP, with the maximum reduction on treatment day 5, regardless of the drug or concentration studied. The maximum reduction (P < 0.001) from vehicle-only baseline IOP was (mean +/- SEM) 3.0 +/- 0.3 mm Hg (9%) for 0.0001% KL, 7.6 +/- 0.6 mm Hg (23%) for 0.001% KL, 6.3 +/- 0.4 mm Hg (18%) for 0.01% KL, and 6.6 +/- 0.6 mm Hg (20%) for 0.005% latanoprost. After application of a single dose of 0.005% KL in nine normal monkey eyes, neither C nor F was altered (P > 0.80) when compared with untreated baseline values or vehicle-treated control eyes. CONCLUSIONS: The reduction in IOP produced by 0.001% KL was equivalent to, and at some measured time points, greater than the effect produced by 0.005% latanoprost. The IOP reduction by KL in normal monkeys appeared to have no effect on aqueous humor production or tonographic outflow facility and may thus indicate a drug-induced increase in uveoscleral outflow.     

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 randomized double-masked crossover study comparing latanoprost 0.005% with unoprostone 0.12% in patients with primary open-angle glaucoma and ocular hypertension

PURPOSE: To compare the intraocular pressure)-lowering effect and side effects of latanoprost 0.005% once daily with unoprostone 0.12% twice daily. METHODS: Sixty patients with primary open-angle glaucoma or ocular hypertension were randomized to receive either latanoprost once daily in the evening and placebo once daily in the morning, or unoprostone twice daily in the morning and evening. The study was double masked and followed a crossover design with two treatment periods of 1 month separated by a 3-week washout period. The intraocular pressure was measured at 9 AM and 5 PM on the baseline and day 28 visits, and at 9 AM on day 2 and day 14 visits of each treatment period. The 9 AM measurement was taken 2 hours and 13 hours after the last drop of unoprostone and latanoprost, and the 5 PM measurement was at 10 and 21 hours, respectively. The mean of the measurements was calculated. Safety parameters were also recorded. RESULTS: Fifty-six patients completed both treatment periods and had intraocular pressure data available for evaluation. After 1 month of treatment, latanoprost significantly reduced intraocular pressure (mean +/- SEM) by 6.1 +/- 0.5 mm Hg (P <.001) and unoprostone by 4.2 +/- 0.4 mm Hg (P <.001) adjusted from an overall baseline of 22.3 +/- 0.5 mm Hg and 23.2 +/- 0.4 mm Hg, respectively. The difference of 1.9 mm Hg between treatments was statistically significant in favor of latanoprost [P =.003, analysis of covariance (ANCOVA)]. Unadjusted analysis of responders using the percentage decrease in intraocular pressure showed that the proportion of responders in the latanoprost-treated group was greater than in the unoprostone-treated group. Adverse ocular symptoms and findings were mild in both treatment groups. Eye redness and ocular irritation were the most frequently reported events. CONCLUSIONS: Latanoprost once daily was significantly more effective in reducing intraocular pressure compared with unoprostone twice daily after 1 month of treatment in patients with primary open-angle glaucoma and ocular hypertension. Both drugs were well tolerated with few ocular adverse events.     

Diurnal intraocular pressure reduction with latanoprost 0.005% compared to timolol maleate 0.5% as monotherapy in subjects with exfoliation glaucoma

AIMS: To compare the diurnal intraocular pressure (IOP) efficacy and safety of timolol vs latanoprost in subjects with exfoliation glaucoma (XFG). METHODS: A 3-month prospective, single-masked, active-controlled, parallel comparison performed in six centres in Greece that randomized subjects in a 1 : 1 ratio to either latanoprost in the evening (2000 hours) and placebo in the morning (0800 hours), or timolol twice daily (0800 and 2000 hours). RESULTS: In all, 103 subjects completed the study. After 3 months of chronic dosing, the latanoprost group exhibited a trend to a greater diurnal IOP reduction from an untreated baseline (24.9+/-3.2-17.4+/-2.9) compared with timolol (24.7+/-2.8-18.3+/-1.9 mmHg) (P=0.07). Latanoprost showed a significantly greater IOP reduction at 0800 hours (-8.5 vs -6.0 mm Hg for timolol, P<0.0001) whereas no difference was observed between the two medications at 1000, 1400, and 2000 hours after a Bonferroni Correction. In addition, latanoprost demonstrated a narrower range of diurnal IOP (2.4) than timolol (3.2 mmHg)(P=0.0017). Safety was similar between groups, except there was more conjunctival hyperaemia with latanoprost (n=8) than timolol (n=1)(P=0.01). CONCLUSIONS: This study suggests that latanoprost provides a statistically lower 08:00-hour IOP and better range of IOP than timolol in the treatment of XFG glaucoma.     

A comparison of the fixed combination of latanoprost and timolol with the unfixed combination of brimonidine and timolol in patients with elevated intraocular pressure. A six month, evaluator masked, multicentre study in Europe

PURPOSE: To compare the intraocular pressure (IOP) reducing effect and safety of fixed combination (FC) latanoprost/timolol with unfixed combination (UFC) brimonidine/timolol in patients with increased IOP. METHODS: In this 6 month, randomised, evaluator masked, parallel group European study, patients with glaucoma or ocular hypertension and IOP > or =21 mm Hg on monotherapy or >16 mm Hg on dual therapy received either FC latanoprost/timolol at 8:00AM or UFC brimonidine/timolol at 8:00AM and 8:00PM. The primary outcome was the difference from baseline to month 6 in mean diurnal IOP reduction. RESULTS: 325 of 334 randomised patients were included in intent to treat analyses (FC latanoprost/timolol, 163; UFC brimonidine/timolol, 162). Baseline diurnal IOP levels were similar: FC latanoprost/timolol, 26.4 (SD 2.7) mm Hg; UFC brimonidine/timolol, 26.5 (SD 2.8) mm Hg (p = 0.851). At month 6, levels were 16.9 (SD 2.8) mm Hg in FC latanoprost/timolol patients and 18.2 (SD 3.1) mm Hg in UFC brimonidine/timolol patients (p<0.001). No adverse events were reported by 76.4% and 75.5% of patients receiving FC latanoprost/timolol versus UFC brimonidine/timolol, respectively. Larger proportions of brimonidine/timolol treated patients reported study medication related adverse events (18.6% v 7.3%) and discontinued study participation because of this (10.8% v 1.8%). CONCLUSION: Fixed combination latanoprost/timolol administered once daily is both more effective and better tolerated than twice daily dosing with UFC brimonidine/timolol.     

Comparison of 24-hour intraocular pressure reduction with two dosing regimens of latanoprost and timolol maleate in patients with primary open-angle glaucoma.

PURPOSE: To compare the 24-hour diurnal ocular hypotensive efficacy of two dosing regimens of latanoprost, once daily (8 AM or 10 PM), vs timolol maleate, twice daily. METHODS: We measured six diurnal intraocular pressure curves (6 AM, 10 AM, 2 PM, 6 PM, 10 PM, and 2 AM) in one randomly selected eye of 34 Greek patients newly diagnosed with primary open-angle glaucoma. The first diurnal curve was an untreated baseline. Patients began taking timolol 0.5%, twice daily, for 2 months. Patients were randomly assigned to latanoprost 0.005% given at 8 AM or 10 PM for 1 month and then changed to the other dosing regimen for 1 month. A diurnal curve was performed after each dosing period. RESULTS: The baseline diurnal pressure for all 34 subjects was 23.1 +/- 3.7 mm Hg. The average intraocular pressures at 6 AM for patients who were given latanoprost in the evening (17.9 +/- 2.9 mm Hg) was statistically lower than that in patients given timolol solution (20.1 +/- 2.5 mm Hg, P = .003); however, patients who were given timolol demonstrated a similar diurnal intraocular pressure (19.1 +/- 2.8 mm Hg) to both morning (18.8 +/- 3.7 mm Hg) and evening doses (18.8 +/- 3.6 mm Hg) of latanoprost (P =.329). When the two latanoprost dosages were compared directly, evening administration provided a statistically lower intraocular pressure at 10 AM (P = .0001) and morning administration at 10 PM (P = .0001). This study had an 80% power to exclude a 1.2-mm Hg difference between groups. CONCLUSIONS: This study indicates that in a small population, both latanoprost and timolol are effective in lowering intraocular pressure throughout a 24-hour period; however, latanoprost is most effective in the 12-hour to 24-hour period after administration.     

Additive efficacy of unoprostone isopropyl 0.12% (rescula) to latanoprost 0.005%

PURPOSE: To evaluate the safety and efficacy of adding unoprostone isopropyl 0.12% vs placebo both given twice daily to latanoprost 0.005% given every evening. METHODS: We treated 41 patients with primary open-angle glaucoma or ocular hypertension with latanoprost 0.005% for 1 month and then randomized each to either placebo or unoprostone isopropyl 0.12% for 8 weeks. Diurnal intraocular pressures were measured at 08:00, 10:00, 12:00, 18:00, and 20:00 hours, both at baseline (time of randomization) and after 8 weeks of treatment. RESULTS: Twenty patients were treated in the placebo group and 21 in the unoprostone isopropyl group. After 8 weeks of treatment in the placebo group, the trough intraocular pressure at 08:00 and the diurnal pressure were 20.4 +/- 3.2 and 19.1 +/- 2.2 mm Hg, respectively. In the unoprostone isopropyl group the pressures were 19.4 +/- 3.3 and 18.0 +/- 1.7 mm Hg (P =.22 and P =.042), respectively. However, eyes with a baseline pressure of 22 mm Hg or greater on latanoprost had an average 3.3 mm Hg greater reduction at trough (P <.01) and a 2.1 mm Hg greater decrease in diurnal pressure (P =.030) after adding unoprostone isopropyl (n = 14 eyes) compared with placebo (n = 16 eyes; P <.001). In addition, the range of the pressures throughout the diurnal curve was reduced from 2.7 mm Hg on latanoprost alone to 1.4 mm Hg after adding unoprostone isopropyl. Adverse events were similar between groups, and no patients were discontinued because of safety reasons. CONCLUSIONS: This study suggests that unoprostone isopropyl can safely improve the diurnal curve characteristics in patients who continue to have an elevated pressure on latanoprost 0.005% alone.     

Effect of latanoprost on outflow facility in the mouse

PURPOSE: To assess the early effect of latanoprost on outflow facility and aqueous humor dynamics in the mouse. METHODS: Aqueous humor dynamics in NIH Swiss White mice were assessed with an injection and aspiration system, using fine glass microneedles. A single 200-ng (4 microL) dose of latanoprost was applied to one eye 2 hours before measurement. The fellow eye served as a control. Intraocular pressure (IOP) was measured by using an established microneedle procedure. Outflow facility (C) was determined by constant-pressure perfusion measurements obtained at two different IOPs. Aqueous humor flow (Fa) was determined by a dilution method using rhodamine-dextran. Conventional and uveoscleral outflow (Fc and Fu) were calculated by the Goldmann equation. RESULTS: Average IOP, Fa, and C of control eyes were 15.7 +/- 1.0 mm Hg, 0.144 +/- 0.04 microL/min (mean +/- SD, n = 8), and 0.0053 +/- 0.0014 microL/min per mm Hg (n = 21), respectively. Average IOP, Fa, and C of treated eyes were 14.0 +/- 0.8 mm Hg, 0.138 +/- 0.04 microL/min (n = 8 for each), and 0.0074 +/- 0.0016 microL/min per mm Hg (n = 21), respectively. The differences between treated and control eyes were significant for IOP and total outflow facility only. CONCLUSIONS: These data indicate that the early hypotensive effect of latanoprost in the mouse eye is associated with a significant increase in total outflow facility. Alterations in the aqueous dynamics induced by latanoprost can be measured reproducibly in the mouse and may provide a useful model for further determining the mechanism by which latanoprost reduces IOP and alters outflow facility.     

Aqueous humor dynamics in monkeys after topical 8-iso PGE(2)

PURPOSE: To determine in normotensive cynomolgus monkeys, the effects of topical 8-iso prostaglandin (PG)E(2) on intraocular pressure (IOP), aqueous humor formation (AHF), uveoscleral outflow (Fu), and total and trabecular outflow facility. METHODS: IOP was measured by Goldmann applanation tonometry under ketamine anesthesia after single or twice-daily topical treatments with 8-iso PGE(2). With animals under pentobarbital anesthesia, AHF and flow to blood (equated to trabecular outflow) were determined by anterior chamber perfusion with radioactively labeled albumin solution. Fu and trabecular outflow facility were calculated from these measurements. Total outflow facility was measured by two-level, constant-pressure perfusion. RESULTS: IOP was not significantly changed after single or multiple 10- micro g doses of 8-iso PGE(2). The 25- micro g dose significantly decreased IOP by 2 to 3 mm Hg compared to the contralateral vehicle-treated control 4 to 6 hours after a single dose and by 3 to 5 mm Hg within 1.5 hours after twice-daily treatments for 4 to 5 days. Total outflow facility corrected for control eye washout was increased by an apparent 37% (P < 0.02, n = 7) from 2 to 3.5 hours after the ninth dose, largely due to outlier values obtained in one monkey. Isotope studies performed after twice-daily treatments totaling 9 to 29 doses showed no change in AHF, trabecular outflow facility, or total outflow facility. Relative to AHF, trabecular outflow was significantly decreased, and the calculated Fu was significantly increased when all data were analyzed. CONCLUSIONS: The present findings are consistent with lowering of IOP by 8-iso PGE(2), primarily by increasing Fu. A direct effect on the trabecular meshwork was not indicated by these in vivo studies.     

Effects of topical hypotensive drugs on circadian IOP, blood pressure, and calculated diastolic ocular perfusion pressure in patients with glaucoma

PURPOSE: To compare the short-term effects of timolol 0.5%, brimonidine 0.2%, dorzolamide 2%, and latanoprost 0.005% on intraocular pressure (IOP), blood pressure (BP), and diastolic ocular perfusion pressure (DOPP), calculated as the difference between the diastolic blood pressure (DBP) and IOP. METHODS: According to a 4 x 4 Latin squares design for repeated measures, 27 untreated patients and patients with newly diagnosed primary open-angle glaucoma (POAG) were treated with timolol 0.5% at 8 AM and 8 PM; brimonidine 0.2% at 8 AM and 8 PM; dorzolamide 2% at 8 AM, 2 PM, and 8 PM; and latanoprost 0.005% at 8 PM. The duration of each treatment course was 6-weeks, with a 4-week washout between each treatment. IOP and BP were measured at baseline and at the end of each treatment period. IOP was measured every 2 hours throughout a 24-hour period. Sitting IOP was measured from 8 AM to 10 PM by Goldmann applanation tonometry. Supine IOP was assessed from 12 to 6 AM by means of a handheld electronic tonometer (TonoPen XL; Mentor, Norwell, MA). BP monitoring was performed by means of an automated portable device (TM-2430; A & D Co., Saitama, Japan). RESULTS: All the drugs tested decreased the IOP significantly at all time points in comparison with baseline pressure. The mean 24-hour IOP after latanoprost administration (16.62+/-0.98 mm Hg) was significantly lower than that after timolol, brimonidine, or dorzolamide (P=0.0001). During the 24-hour period, brimonidine induced a significant decrease in systolic BP (SBP) and DBP at all time points when compared with baseline measurements and with those after administration of the other drugs (P<0.0001). Timolol caused a significant decrease in DBP and SBP at all the 24-hour time points when compared with the baseline and with the dorzolamide- and latanoprost-induced changes (P<0.0001). The mean 24-hour DOPPs were 50.7+/-5.9 mm Hg at baseline, 53+/-5.5 mm Hg with timolol, 46.2+/-5.4 mm Hg with brimonidine, 55.9+/-4.6 mm Hg with dorzolamide, and 56.4+/-4.9 mm Hg with latanoprost. Brimonidine induced a significant decrease in the mean 24-hour DOPP compared with that at baseline (P<0.0001), whereas dorzolamide and latanoprost induced a significant increase (P<0.0001). CONCLUSIONS: Latanoprost seemed to induce a uniform reduction in IOP during the 24-hour period, although timolol was as effective as latanoprost during the daytime, and dorzolamide are as effective as latanoprost at night. SBP and DBP were significantly decreased by either timolol or brimonidine. In this study of patients with newly diagnosed POAG, only dorzolamide and latanoprost significantly increased mean 24-hour DOPP.