Effect of flunarizine, a calcium channel blocker, on intraocular pressure and aqueous humor dynamics in monkeys

PURPOSE: To evaluate the effects of flunarizine, a nonselective calcium channel blocker, on intraocular pressure (IOP) in monkeys with laser-induced unilateral glaucoma and on aqueous humor dynamics in normal monkeys. METHODS: The IOP was measured before and hourly for 6 hours after single-dose administration of 0.5%, 1%, or 2% flunarizine to the glaucomatous eye of 8 monkeys with unilateral laser-induced glaucoma. In a separate multiple-dose study, 0.5% flunarizine was applied twice daily for 5 consecutive days to the glaucomatous eye of the same 8 monkeys. IOP was measured at untreated baseline, after treatment with vehicle only, and on treatment days 1, 3, and 5. Tonographic outflow facility and fluorophotometric flow rates of aqueous humor were measured in 7 normal monkeys before and after the fifth dose of twice-daily treatment with 0.5% flunarizine. RESULTS: Unilateral application of 50 microL of 0.5%, 1%, or 2% flunarizine reduced IOP bilaterally. In the treated glaucomatous eyes, flunarizine reduced the IOP for 2, 3, or 5 hours, with a maximum reduction of 2.5+/-0.5 (mean+/-SEM) mm Hg (9%), 3.0+/-0.4 mm Hg (10%), and 5.0+/-0.8 mm Hg (18%) following the 0.5%, 1%, and 2% concentrations, respectively (P<0.01). The maximum reductions in IOP in the contralateral untreated eyes were 1.3+/-0.5 mm Hg, 1.5+/-0.3 mm Hg, and 2.9+/-0.7 mm Hg following the 0.5%, 1%, and 2% concentrations, respectively (P<0.05). Both the magnitude and duration of the ocular hypotensive effect of 0.5% flunarizine were enhanced with twice-daily administration for 5 days. Outflow facility in normal monkey eyes was increased (P<0.05) by 39% in the treated eyes compared with vehicle-treated contralateral eyes and by 41% compared with baseline values, and aqueous humor flow rates were unchanged (P>0.30). CONCLUSIONS: Flunarizine reduces IOP in a dose-dependent manner when administered to glaucomatous monkey eyes, but also has an ocular hypotensive effect on the contralateral untreated eyes. An increase in tonographic outflow facility seems to account for the IOP reduction in normal monkey eyes.     

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.     

Effect of topical pergolide on aqueous dynamics in normal and glaucomatous monkeys

The effects of pergolide mesylate, an ergoline derivative, were studied on intraocular pressure (IOP), outflow facility, aqueous humor flow, and pupil size in monkeys. Unilateral topical administration of two 20-microliters drops of 0.1% pergolide significantly lowered IOP in the treated- and contralateral eye in both normal- and glaucomatous monkeys. In 12 normal monkeys, the baseline IOP of 18.3 +/- 0.4 mmHg [mean +/- S.E.(M.)] was maximally reduced to 14.4 +/- 0.7 mmHg in the treated eye (P less than 0.001) and 14.6 +/- 0.6 mmHg in the contralateral eye (P less than 0.001) at 2 hr after drug administration. In 10 monkeys made bilaterally glaucomatous by argon laser treatment of the trabecular meshwork, the baseline IOP of 33.9 +/- 3.0 mmHg [mean +/- S.E.(M.)] in the treated eyes and 31.7 +/- 3.3 mmHg in the untreated eyes maximally decreased to 23.9 +/- 2.2 mmHg (P less than 0.05) and 26.2 +/- 3.3 mmHg (P less than 0.005), respectively, at 5 hr. No significant change (P greater than 0.7) in outflow facility occurred in either eye of 11 normal monkeys 2 hr after unilateral 0.1% pergolide treatment. In six normal monkeys, the baseline aqueous humor flow of 1.58 +/- 0.20 microliter min-1 in treated eyes and 1.44 +/- 0.18 microliter min-1 in untreated eyes was reduced to 0.92 +/- 0.08 microliter min-1 (P less than 0.02) and 1.09 +/- 0.11 microliter min-1 (P greater than 0.10), respectively, from 0.5- to 3.5 hr after drug administration. A mydriatic response was observed in both eyes after unilateral treatment from 1- to 2 hr in eight normal monkeys. By the third day of treatment, bilateral twice a day 0.1% pergolide drops in eight glaucomatous monkey eyes no longer significantly (P greater than 0.05) decreased IOP.     

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.     

Effects of latanoprost and unoprostone when used alone or in combination for open-angle glaucoma

PURPOSE: To evaluate the effects of latanoprost and unoprostone on the intraocular pressure (IOP) and on the tonographic outflow facility in glaucoma patients when used alone or in combination. DESIGN: Open label randomized clinical study. METHODS: Fifty-two patients (52 eyes) with primary open-angle glaucoma were randomly divided into two groups. One group initially received only latanoprost 0.005% once daily and the other group, only unoprostone 0.12% twice daily. The study period was 12 weeks: in the first 6 weeks, latanoprost or unoprostone was given as monotherapy, and in the last 6 weeks, patients received both drugs. IOP was measured every 2 weeks by one investigator masked to the medication received by patients during the study period in the same hour as on the baseline day. At Weeks 0, 6, and 12, the coefficient of aqueous outflow was measured by tonography. RESULTS: With latanoprost monotherapy, the baseline IOP of 22.9 +/- 2.4 mm Hg (mean +/- SD) decreased to 16.9 +/- 2.1 mm Hg (P<.01). When unoprostone was added to latanoprost, the IOP remained at 16.7 +/- 2.5 mm Hg. With unoprostone monotherapy, the baseline IOP of 22.7 +/- 2.1 mm Hg decreased to 19.4 +/- 2.4 mm Hg (P<.01). When latanoprost was added to unoprostone, the IOP decreased to 16.8 +/- 1.7 mm Hg (P<.01). There was no significant change in the coefficient of aqueous outflow with monotherapy or the combined use of the drugs. CONCLUSIONS: The combination of latanoprost and unoprostone does not result in a more potent hypotensive effect than latanoprost alone.     

The prostanoid EP2 receptor agonist butaprost increases uveoscleral outflow in the cynomolgus monkey

PURPOSE: To investigate the ocular hypotensive effect of the prostanoid EP2 receptor agonist butaprost and to establish its mechanism of action. METHODS: All experiments were performed in cynomolgus monkeys after topical application of butaprost (0.1%). The effects of butaprost on aqueous humor flow were determined by fluorophotometry. Total outflow facility was measured by the two-level, constant-pressure perfusion method, and uveoscleral outflow was determined by perfusion of FITC-labeled dextran through the anterior chamber. Effects on ocular morphology were studied after tissue fixation with transcardial perfusion by paraformaldehyde and immersion fixation of the globe, in animals subjected to long-term treatment with butaprost. Conscious ocular normotensive monkeys and monkeys with unilateral ocular hypertension were used for intraocular pressure (IOP) studies. RESULTS: Butaprost had no significant effect on aqueous humor flow or total outflow facility in ocular normotensive monkeys. Uveoscleral outflow was significantly higher in the butaprost treated eyes than in vehicle treated eyes, 1.03 +/- 0.20 vs. 0.53 +/- 0.18 microL.min(-1). After a 1-year treatment with butaprost, the morphology of the ciliary muscle was changed, showing increased spaces between ciliary muscle bundles and the apparent formation of new outflow channels. In many instances, changes were observed in the trabecular meshwork as well. Butaprost, in a single 0.1% dose, decreased IOP significantly in ocular normotensive monkeys and reduced IOP in laser-induced glaucomatous monkey eyes to the same level as that in the ocular normotensive contralateral eyes. CONCLUSIONS: The prostanoid EP2 receptor agonist butaprost appears to lower IOP by increasing uveoscleral outflow, according to both physiological and morphologic findings. Although the prostanoid EP2 receptor is structurally and functionally distinct from the FP receptor, the effects of EP2 and FP receptor stimulation on aqueous humor outflow are similar.     

Effect of bimatoprost on intraocular pressure in prostaglandin FP receptor knockout mice

PURPOSE: To determine the effect of bimatoprost on intraocular pressure in the prostaglandin FP receptor knockout mouse. METHODS: The IOP response to a single 1.2-microg (4 microL) dose of bimatoprost was measured in the treated and untreated fellow eyes of homozygote (FP+/+, n = 9) and heterozygote (FP+/-, n = 10) FP-knockout mice, as well as in wild-type C57BL/6 mice (FP+/+, n = 20). Serial IOP measurements were also performed after topical bimatoprost in a separate generation of homozygous FP-knockout mice and wild-type littermate control animals (n = 4 per group). Aqueous humor protein concentrations were measured to establish the state of the blood-aqueous barrier. Tissue, aqueous humor and vitreous concentrations of bimatoprost, latanoprost, and their C-1 free acids were determined by liquid chromatography and tandem mass spectrometry. RESULTS: A significant reduction in IOP was observed in the bimatoprost-treated eye of wild-type mice at 2 hours, with a mean difference and 95% confidence interval (CI) of the difference in means of -1.33 mm Hg (-0.81 to -1.84). Bimatoprost did not lead to a significant reduction in IOP in either the heterozygous knockout -0.36 mm Hg (-0.82 to +0.09) or homozygous FP-knockout mice 0.25 mm Hg (-0.38 to +0.89). The lack of an IOP response in the FP-knockout mice was not a consequence of blood-aqueous barrier breakdown, as there was no significant difference in aqueous humor protein concentration between treated and fellow eyes. Tissue and aqueous humor concentrations of bimatoprost, latanoprost, and their C-1 free acids indicate that latanoprost, but not bimatoprost, is hydrolyzed in the mouse eye after topical administration. CONCLUSIONS: An intact FP receptor gene is critical to the IOP response to bimatoprost in the mouse eye.     

Efficacy of latanoprost in reducing intraocular pressure in patients with primary angle-closure glaucoma

Two independent, prospective trials were recently conducted to assess the efficacy of latanoprost in reducing intraocular pressure (IOP) in patients with primary angle-closure glaucoma (PACG). The first study was a 2-week, randomized, double-masked comparison of latanoprost treatment and timolol treatment in patients with PACG. Patients were randomized to one of two parallel treatment groups, receiving either placebo in the morning and latanoprost 0.005% in the evening, or timolol 0.5% twice daily. The mean IOP reduction in latanoprost group was 8.8 +/- 1.1 mm Hg (mean +/- SEM, p < 0.001; 34.2%) from a mean baseline IOP of 25.7 +/- 0.9 mm Hg, and the corresponding figures for the timolol group were 5.7 +/- 0.9 mm Hg (p < 0.001; 22.6%) from a mean baseline IOP of 25.2 +/- 1.1 mm Hg. A significantly greater IOP reduction of 3.1 +/- 1.5 mm Hg (95% confidence interval: 0.1 to 6.0) was achieved in the latanoprost group compared to the timolol treatment group (p = 0.04). In the second study, latanoprost 0.005% once a day was added adjunctively to PACG patients with persistently elevated IOP after iridectomy, despite treatment with beta-blockers and pilocarpine. The IOP decreased by about 21% during the first 3 months, and showed a reduction of about 36% at the end of 1 year. At the 1-year follow-up, IOP was <20 mm Hg in all eyes. In both studies, latanoprost was well tolerated with few adverse events. These results demonstrate that latanoprost is effective in reducing IOP in patients with PACG.     

Replacing maximum-tolerated medications with latanoprost versus adding latanoprost to maximum-tolerated medications: a two-center randomized prospective trial

PURPOSE: To compare the replacement of every drug with latanoprost 0.005% once a day in glaucomatous eyes with poorly controlled intraocular pressure upon combination therapy, versus addition of latanoprost to the pre-existing treatment. PATIENTS AND METHODS: Study design: prospective, investigator-masked, two-center, randomized clinical trial lasting 3 months. Eligibility criteria: open-angle glaucoma; IOP > or = 21 mm Hg upon the combination of a non-selective beta-blocker with pilocarpine or dorzolamide or both; no previous bulbar surgery; and prior glaucoma therapy lasting at least 2 years. Two treatment arms: (1) addition of latanoprost 0.005% QD to the pre-existing therapy [group A]; (2) substitution with latanoprost alone [group B]. RESULTS: One hundred thirty-six eyes (68 eyes/treatment group) were randomized according to intraocular pressure level and the number of adjunctive medications to beta blocker. Both treatments provided a significant IOP decrease over baseline (from 23.5 +/- 1.4 to 19.7 +/- 1.9 mm Hg in group A, (P < 0.001); from 23.2 +/- 1.3 to 20.1 +/- 2.2 mm Hg in group B (P < 0.001), paired Student t test). At the end of the follow-up period, group A showed a higher number of intraocular readings less than or equal to 18 mm Hg than group B (42.6% vs. 30.8%; Fisher exact test: P = 0.018). CONCLUSIONS: In eyes showing an intraocular pressure greater than 21 mm Hg upon combination therapy, the substitution of the pre-existing treatment with latanoprost can provide a significant IOP decrease. However, adding latanoprost to the pre-existing therapy is more likely to achieve a target intraocular pressure less than or equal to 18 mm Hg.     

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.     

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.     

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 5-MCA-NAT, a putative melatonin MT3 receptor agonist, on intraocular pressure in glaucomatous monkey eyes

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

Peak pressures: crossover study of timolol and latanoprost

PURPOSE: To compare the diurnal efficacy and action on peak intraocular pressures (IOP) of 0.005% latanoprost and 0.5% timolol as primary therapy in 60 eyes having dark brown irides with primary open angle glaucoma (POAG). METHODS: A prospective, comparative, observer-masked, crossover, interventional trial including the mean of both eyes of 30 patients with POAG who were randomly started on either latanoprost once daily or timolol twice daily. Three months after treatment with one drug, the second drug was substituted. A masked observer carried out diurnal assessments of IOP before the start of therapy and at 3 and 7 months. The fourth month was the washout period for the first drug. RESULTS: The average baseline IOP was 23.36 +/- 2.14 mm Hg, which was reduced by 8.8 +/- 2.2 mmHg with latanoprost (p < 0.01) and by 6.75 +/- 1.9 mm Hg with timolol (p = 0.01). The reduction was greater for latanoprost (p < 0.005). The average peak IOP at baseline was 27.6 +/- 2.22 mmHg. The effective fall in IOP at the time of new peaks in subsequent diurnal recordings of IOP compared to the baseline diurnal curve was 8.9 mm Hg with latanoprost (p < 0.005) and 5.77 mm Hg with timolol (p < 0.01). This difference in IOP reduction between the two drugs was statistically significant (p < 0.01). Latanoprost had a lower efficacy in peak IOP reduction in eyes with evening peak of IOP than in those with morning peak (p < 0.005). The efficacy of timolol was lower overall compared to latanoprost, but was similar in all circadian rhythms. The shift in timing of IOP peak was greater with latanoprost compared to timolol (4.34 hours vs -0.72 hours, p < .01). A total of 90% of patients on latanoprost and 33.3% on timolol achieved a reduction of > 30% in baseline mean IOP. The average of the trough IOP recorded in each of the individual baseline IOP curves was 19.05 +/- 2.05 mm Hg. CONCLUSIONS: Greater mean and peak IOP reduction was achieved with latanoprost compared to timolol. Dampening of the circadian rhythm was better with latanoprost. Latanoprost appears to be more effective than timolol at all points in time with greater efficacy in eyes with morning peaks compared to evening peaks.     

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.     

Prostaglandin analogs and blood-aqueous barrier integrity: a flare cell meter study

PURPOSE: To study, with an objective method, inflammation of the anterior segment of the glaucomatous eye after treatment with latanoprost, travoprost and bimatoprost. MATERIALS AND METHODS: Sixty patients with chronic open-angle glaucoma aged between 38 and 76 years (mean 64.0 +/- 12.2) were randomly assigned to latanoprost 0.005, travoprost 0.004 and bimatoprost 0.03%. The study period lasted 6 months. Intraocular pressure (IOP) was measured every 2 weeks. We studied the intraocular inflammation before and after 3 and 6 months of therapy with an instrument composed of a He-Ne laser beam system, a photomultiplier mounted on a slitlamp microscope and a computer. This flare meter allows objective determination of the flare and the number of cells in the aqueous of the anterior chamber. RESULTS: At the baseline, IOP was 26.4 +/- 3.6 mm Hg. After 3 months of treatment, mean IOP in the latanoprost group was 17.9 +/- 0.3 mm Hg (p < 0.001) with a mean cellularity of 12.638 +/- 3.284 photons/ms (p < 0.001). The travoprost group had an IOP of 17.2 +/- 0.3 mm Hg (p < 0.001) with a cellularity of 9.719 +/- 1.927 photons/ms (0.001). Finally, IOP in the bimatoprost group was 17.6 +/- 0.5 mm Hg (p < 0.001) with a cellularity of 6.138 +/- 1.475 photons/ms (p < 0.032). After 6 months of treatment, IOP in the latanoprost group was 18.1 +/- 0.3 (p < 0.001), in the travoprost group 17.3 +/- 0.3 (p < 0.001) and in the bimatoprost group 17.7 +/- 0.5 mm Hg (p < 0.001), whereas cellularity was 11.838 +/- 3.218 (p < 0.001), 8.950 +/- 3.692 (p < 0.001) and 7.617 +/- 2.603 photons/ms (p < 0.001), respectively. After 3 months, the travoprost (p < 0.013) and the bimatoprost groups (p < 0.001) had less flare compared with the latanoprost group and this remained so even at 6 months. When we compared the travoprost group with the bimatoprost group, we found significantly less flare at 3 months in the bimatoprost group (p < 0.001) but not at 6 months (p < 0.246). CONCLUSIONS: The flare meter analysis shows that the eyes treated with bimatoprost and travoprost have a less significantly broken blood-aqueous barrier and their anterior chamber is also significantly less inflamed.     

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.     

Effects of topical administration of y-39983, a selective rho-associated protein kinase inhibitor, on ocular tissues in rabbits and monkeys

PURPOSE: To elucidate the intraocular pressure (IOP)-lowering effects and associated characteristics of Y-39983, a selective Rho-associated coiled coil-forming protein kinase (ROCK) inhibitor derived from Y-27632, in animal eyes. METHODS: Y-39983 was compared with Y-27632 for selectivity of ROCK inhibition by biochemical assay. The IOP was monitored by pneumatonometer in albino rabbits and cynomolgus monkeys that were given topically administered Y-39983. The total outflow facility and uveoscleral outflow were measured by two-level constant-pressure perfusion and perfusion technique using fluorescein isothiocyanate-dextran, respectively, at 2 hours after topical administration of Y-39983 in albino rabbits. The ocular toxicologic effects of topical administration of Y-39983 were observed in albino rabbits and cynomolgus monkeys. RESULTS: A biochemical assay showed that Y-39983 inhibited ROCK more potently than Y-27632. In rabbits, topical administration of Y-39983 significantly increased conventional outflow by 65.5%, followed by significant, dose-dependent reduction in IOP. Maximum IOP reduction was 13.2 +/- 0.6 mm Hg (mean +/- SE) at 0.1% Y-39983 in rabbits. In monkeys, at 3 hours after topical administration of 0.05% Y-39983, maximum reduction of IOP was 2.5 +/- 0.8 mm Hg. No serious side effects were observed in ocular tissues except sporadic punctate subconjunctival hemorrhage during long-term topical administration of Y-39983 four times a day (at 2-hour intervals) in rabbits or monkeys. However, punctate subconjunctival hemorrhage was not observed with administration twice daily (at a 6-hour interval) or three times a day (at 5-hour intervals). CONCLUSIONS: Y-39983 causes increased outflow facility followed by IOP reduction. Y-39983 ophthalmic solution may be a candidate drug for lowering of IOP, since it increases conventional outflow and produces relatively few side effects.     

Circadian variation of aqueous dynamics in young healthy adults

PURPOSE: Recent research indicates that intraocular pressure (IOP) does not decrease significantly during the nocturnal period, although aqueous humor flow decreases by 50% or more at night. This study was undertaken to investigate whether changes in outflow facility, episcleral venous pressure, or uveoscleral flow at night could account for the nocturnal IOP. METHODS: Sixty-eight eyes of 34 healthy subjects (age, 18-44 years; mean, 29) were studied. Aqueous humor flow rate, IOP, and outflow facility were measured with pneumatonometry, anterior chamber fluorophotometry, and Schiotz tonography respectively, in each eye during the mid-diurnal (2-4 PM) and mid-nocturnal (2-4 AM) periods. Nocturnal IOP, flow rate, and outflow facility were compared to the same variables during the diurnal period. Mathematical models based on the modified Goldmann equation were used to assess the conditions under which these results could be reconciled. RESULTS: Supine IOP decreased slightly from 18.9 +/- 2.7 mm Hg in the mid-diurnal period to 17.8 +/- 2.5 mm Hg in the mid-nocturnal period (mean +/- SD, P = 0.001). Aqueous flow rate decreased from 2.26 +/- 0.73 to 1.12 +/- 0.75 microL/min (mean +/- SD, P < 0.001). There was a nonsignificant trend toward a nocturnal decrease of outflow facility (diurnal, 0.27 +/- 0.11 microL/min/mm Hg; nocturnal, 0.25 +/- 0.08 microL/min/mm Hg; mean +/- SD, P = 0.13). CONCLUSIONS: Outflow facility measured by tonography does not decrease enough during the nocturnal period to compensate for the decreased aqueous humor flow rate. Modeling results indicate that the experimental results could be reconciled only if nocturnal changes in episcleral venous pressure and/or uveoscleral flow occurred.     

Tonometric changes of latanoprost-induced intraocular pressure reduction after photorefractive keratectomy

PURPOSE: To assess whether tonometric measurements of the drop in intraocular pressure (IOP) induced by 0.005% latanoprost are modified after photorefractive keratectomy (PRK). METHODS: Data from 24 randomly selected eyes of 24 patients (12 men and 12 women, mean age +/- SD: 31.7 +/- 6.2 years) who were undergoing bilateral PRK for myopia (-6.38 +/- 2.26 D) were obtained. Objective refraction, central corneal thickness (CCT), anterior radius of corneal curvature (R), and IOP measurements at baseline and 24 hours after 1 drop of 0.005% latanoprost, were performed before and 6 months after PRK. All measured IOPs were recalculated by a correction factor for CCT and R and expressed as true IOP (IOPT) measurements. RESULTS: The mean CCT +/- SD was 544.58 +/- 36.03 and 463.21 +/- 38.59 micro m, and the anterior radius of corneal curvature was 7.73 +/- 0.26 and 8.33 +/- 0.37 mm, before and after PRK, respectively. The mean IOP at baseline was 15.8 +/- 2.92 and 12.23 +/- 2.37 mm Hg, and after latanoprost administration was 12.54 +/- 1.97 and 10.19 +/- 1.47 mm Hg, before and after PRK, respectively. The mean IOPT at baseline was 15.46 +/- 1.08 and 16.18 +/- 2.31 mm Hg, and after latanoprost administration was 11.85 +/- 1.56 and 12.96 +/- 1.71 mm Hg, before and after PRK, respectively. The mean IOP and IOPT reductions after latanoprost administration were, respectively, 3.25 +/- 1.66 and 3.61 +/- 1.7 mm Hg before PRK, and 2.03 +/- 1.42 and 3.22 +/- 1.79 mm Hg after PRK. Pre- and postoperative IOP reduction significantly differed (P < 0.001), but not IOPT. CONCLUSIONS: The effect of hypotensive drugs on IOP readings may be underestimated because of measurement errors due to CCT reduction and R increase after PRK for myopia. Misdiagnosis of reduced pharmacologic efficacy may be avoided if the measured IOP is corrected by a proper nomogram.