Effects of latanoprost and timolol-XE on hydrodynamics in the normal eye

PURPOSE: To compare the effects of latanoprost and timolol-XE on ocular pressure and perfusion in healthy adults, with respect to episcleral venous pressure. METHODS: A double-masked, placebo-controlled crossover study of weeklong bedtime treatment with one drop of drug, with placebo contralaterally, followed by a 3-week washout and alternate-drug/contralateral-placebo repeat. Intraocular pressure was measured by applanation and by pneumotonometry, providing pulsatile ocular circulatory estimates. Measurements of episcleral venous pressure were obtained (Friberg method). RESULTS: Twenty subjects participated (five men, 15 women; mean age, 39 years (range, 21 to 55 years); mean baseline intraocular pressure, 13.4 mm Hg). A greater decrease in intraocular pressure was seen among these subjects the morning after initiating treatment with latanoprost (-2.0 mm Hg; P <.0001) than with timolol-XE (-0.9 mm Hg; P =.051) (latanoprost versus timolol DeltaP =.008). This ocular hypotensive effect remained significant that evening with latanoprost (-3.2 mm Hg; P <.0001) but not with timolol XE (-1.0 mm Hg; P =.2). By the morning of day 8, mean intraocular pressure remained 3.2 mm Hg below baseline with latanoprost and 2.3 mm Hg below baseline with timolol-XE (P <.0001 for both drugs). Neither drug altered episcleral venous pressure. Among a subgroup of nine subjects with comparable intraocular pressure reductions with the two drugs, latanoprost treatment was associated with a 16.7% increase in mean pulsatile ocular blood flow (P =.04) through the weeklong treatment interval, consistently higher than during timolol-XE treatment of the same subjects. CONCLUSION: Latanoprost caused an overnight decrease in intraocular pressure in normotensive normal eyes, and both drugs significantly reduced intraocular pressure within 1 week. Intraocular pressure remained higher than episcleral venous pressure throughout treatment with both drugs. Latanoprost was associated with enhanced pulsatile ocular perfusion not seen with timolol-XE treatment.     

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.     

Latanoprost and cholinergic agonists in combination

Latanoprost, a prodrug of a prostaglandin F(2alpha) analog, is a potent ocular hypotensive agent, reducing intraocular pressure (IOP) primarily by increasing aqueous humor drainage through the uveoscleral outflow pathway. Initial assessments in animals found that high concentrations of cholinergic agonists reduced drainage through this pathway and attenuated the effects of a PGF(2alpha) analog. This raised the question of whether latanoprost would be effective when added to the treatment regimen of patients on pilocarpine or strong miotics. In published clinical studies, latanoprost was additive to the maximally tolerated medical therapy (which included cholinergic agonists) of glaucoma patients. Multiple doses of physostigmine in healthy volunteers did not block the effect of a single drop of latanoprost during a 1-day study. One study attempting to find the optimal timing of administration of latanoprost and pilocarpine claimed to show that additivity was best when pilocarpine was given one hour after latanoprost in the evening. Two other studies found that the timing of the doses was not important. To explain the additivity of latanoprost and pilocarpine, aqueous humor dynamics were assessed in ocular hypertensive patients treated for 1 week with each drug alone and then for one week in combination. The results showed that latanoprost increased uveoscleral outflow, pilocarpine increased outflow facility, and pilocarpine did not block or attenuate the uveoscleral outflow effect of latanoprost. The result was greater IOP reduction when these drugs were used in combination than when either drug was used alone. All available evidence demonstrates that addition of latanoprost to the treatment regime of patients already taking cholinergic agonists is an effective, although not necessarily the preferred, combination of medications for the treatment of elevated IOP.     

Effects of brinzolamide on aqueous humor dynamics in monkeys and rabbits.

This study examines the mechanisms by which brinzolamide reduces intraocular pressure (IOP) in healthy rabbits and in monkeys with unilateral ocular hypertension. Intraocular pressures were measured by pneumatonometry and aqueous flow was determined by fluorophotometry before and after three twice-daily drops of 1% brinzolamide to both eyes per monkey and after similar treatment to one eye per rabbit. In monkeys, outflow facility was determined by fluorophotometry and uveoscleral outflow was calculated. In rabbits, outflow facility was determined by two-level constant pressure infusion and uveoscleral outflow was measured by an intracameral tracer technique. Compared with contralateral vehicle-treated rabbit eyes, IOP was reduced in brinzolamide-treated eyes by 2.5 +/- 1.9 mmHg (mean +/- standard deviation; p =.006) at four hours after the second dose. Aqueous flow was reduced by 0.50 +/- 0.65 microl/min (p =.02). This effect was found in rabbits previously treated with brinzolamide but not in naive rabbits. Treated hypertensive eyes of monkeys had a reduction in IOP of 7.3 +/- 8.8 mmHg (p = 0.01) and aqueous flow of 0.69 +/- 1.10 microL/min (p = 0.05) when compared with baseline. Brinzolamide did not affect outflow facility or uveoscleral outflow in either rabbits or monkeys. It is concluded that, in normotensive eyes of rabbits and hypertensive eyes of monkeys, brinzolamide reduces IOP by reducing aqueous flow and not by affecting aqueous humor drainage.     

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.     

Comparative effects of latanoprost (Xalatan) and unoprostone (Rescula) in patients with open-angle glaucoma and suspected glaucoma

PURPOSE: To compare, in paired eyes of open-angle glaucoma patients and glaucoma suspects, hydrodynamic and visual changes after 1 month of topical latanoprost in one eye and unoprostone in the other.DESIGN: Single-center, institutional randomized clinical trial.METHODS: After completing a washout period off all topical medication, 25 adults (mean age 54 +/- SEM 2 years) with bilateral open-angle glaucoma or glaucoma suspect status underwent morning (8 to 10 AM) and afternoon (1 to 3 PM) measurements of intraocular pressure (IOP), pulsatile ocular blood flow (POBF), contrast, sensitivity, frequency doubling technology, and Humphrey 10-2 perimetry (HVFA II) in both eyes. Each then started unoprostone 0.15% (Rescula) in one randomly assigned eye and latanoprost 0.005% (Xalatan) in the other. Unoprostone was administered at 8 AM and 8 PM and latanoprost at 8 PM with placebo at 8 AM, both from masked bottles. After 28 days, differences were determined for each measured variable by two-tailed paired t test.RESULTS: Starting from similar baseline IOP levels, after 1 month of treatment, the mean morning IOP values differed according to the topical agent received (16.2 +/- SEM 0.6 mm Hg for latanoprost vs 17.9 +/- 0.7 mm Hg for unoprostone; P =.001). These morning pressures were 2.6 mm Hg lower than baseline in the eyes receiving latanoprost (P <.0001), and 1.6 mm Hg lower in unoprostone-treated eyes (P =.02). Afternoon values were 3.1 +/- SEM 0.6 lower than corresponding baseline in eyes receiving latanoprost, and 2.4 +/- SEM 0.6 mm Hg in unoprostone-treated eyes (P <.0001 from baseline for both medications; interdrug mean IOP difference; P =.04). Eyes receiving unoprostone showed a 1.7-db improvement in frequency doubling mean deviation (P =.03), the only significant visual function change observed. Pulsatile ocular blood flow increased 30% relative to baseline in eyes receiving latanoprost, (P <.0001) and 16% in eyes receiving unoprostone (P =.05) by the morning of day 28. That afternoon, mean POBF had increased 30% (P <.0001) relative to afternoon baseline values among eyes receiving latanoprost and 18% (P =.03) among those receiving unoprostone (interdrug change difference, P =.05). Humphrey perimetry and contrast sensitivity remained stable with both prostanoids.CONCLUSIONS: Both latanoprost and unoprostone produced significant reductions in IOP and increases in POBF, with stable central and perimacular visual function. Latanoprost once daily produced IOP reduction and POBF increases nearly twofold greater than those obtained with unoprostone twice daily. These differences in IOP and POBF change between unoprostone and latanoprost were statistically significant.     

A comparison of intraocular pressure-lowering effect of prostaglandin F2 -alpha analogues, latanoprost, and unoprostone isopropyl.

PURPOSE: To compare the intraocular pressure-lowering effect of unoprostone isopropyl (unoprostone) 0.12% and latanoprost 0.005%. A correlation between the intraocular pressure-lowering effect of unoprostone and latanoprost was also evaluated. METHODS: A single-masked randomized study included 18 patients between 49 and 68 years (mean, 60.7 +/- 5.1 years) with an intraocular pressure of both eyes from 21 to 27 mm Hg. The patients were prospectively randomized to receive latanoprost in the right eye and unoprostone in the left eye, or unoprostone in the right eye and latanoprost in the left eye. The patients were followed up for 8 weeks. This study evaluated the intraocular pressure-lowering effect and incidence of drug-related side effects. RESULTS: Mean baseline intraocular pressure was 22.8 +/- 1.2 mm Hg in latanoprost-treated eyes and 22.4 +/- 1.0 mm Hg in unoprostone-treated eyes; there was no statistically significant difference between these groups. Mean intraocular pressure at 8 weeks after the start of the administration was 16.7 +/- 2.0 mm Hg in latanoprost-treated eyes and 19.0 +/- 1.5 mm Hg in unoprostone-treated eyes. Patients in the latanoprost-treated group showed a greater intraocular pressure reduction compared with those in the unoprostone-treated group. Mean intraocular pressure changes in latanoprost-treated eyes were significantly greater at every visit (P < 0.0001). A change of intraocular pressure at 8 weeks in the latanoprost-treated eyes was significantly correlated with that in the contralateral unoprostone-treated eyes (r = 0.665, P = 0.0013) (Figure). There was no significant difference in the rate of ocular side effects between latanoprost- and unoprostone-treated eyes. CONCLUSIONS: Latanoprost appears to have a more beneficial effect for intraocular pressure control compared with unoprostone. An intraocular pressure reduction in the latanoprost-treated eyes was significantly correlated with that in the contralateral unoprostone-treated eyes. There was no significant difference in the incidence of ocular side effects between both drugs. Further investigation using more cases and longer follow-up periods are needed.     

Acute effect of latanoprost on pulsatile ocular blood flow in normal eyes

PURPOSE: To determine the effect of an acute dose of 0.005% latanoprost on intraocular pressure and pulsatile ocular blood flow in normal eyes. METHODS: Nineteen volunteers received a single dose (two drops) of latanoprost 0.005% in one eye and placebo in the fellow control eye, randomized and masked to the observer. Intraocular pressure, perfusion pressure, pulsatile ocular blood flow, and systemic circulatory parameters were measured before and 8 hours after dosing. RESULTS: The mean (+/- SE) intraocular pressure, perfusion pressure, and pulsatile ocular blood flow before treatment were 17 +/- 1 mm Hg, 46 +/- 3 mm Hg, and 13 +/- 1 microl per second, respectively, in both the treated and control eyes. The mean intraocular pressure reduction was 4.9 and 2.1 mm Hg (28% and 12%) in the treated and fellow eye, respectively. The mean perfusion pressure increase was 5.6 and 2.8 mm Hg (12% and 6%) in the treated and fellow eye, respectively. The mean pulsatile ocular blood flow increase was 2.7 and 0.2 microl per second (20% and 1%) in the treated and fellow eye, respectively. The treated eye change in pulsatile ocular blood flow was not correlated to the change in perfusion pressure. Simultaneous reduction of intraocular pressure and increase or no significant change in pulsatile ocular blood flow occurred in 15 of 19 (79%) of the treated eyes. The systemic blood pressure and pulse rates remained in normal ranges over the 8-hour period. CONCLUSION: In this study, topical latanoprost significantly reduces intraocular pressure and increases ocular blood flow in normal eyes 8 hours after dosing. These effects of latanoprost may be beneficial in the management of glaucoma patients.     

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.     

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.