Aqueous humor dynamics during the day and night in volunteers with ocular hypertension.

OBJECTIVE: To evaluate the differences in aqueous humor dynamics between nighttime and daytime in participants with ocular hypertension. METHODS: Thirty participants (mean [SD] age, 59.2 [11.1] years) with ocular hypertension were enrolled in the study, which included 1 daytime and 1 nighttime visit. During each visit, measurements included central cornea thickness by ultrasound pachymetry, intraocular pressure (IOP) by pneumatonometry, aqueous flow by fluorophotometry, outflow facility by tonography, and blood pressure by sphygmomanometry. Uveoscleral outflow was calculated using the Goldmann equation. Daytime measurements were made only of episcleral venous pressure by venomanometry, anterior chamber depth by A-scan, and outflow facility by fluorophotometry. Repeated-measures analysis of variance and 2-tailed t tests were used for statistical comparisons. RESULTS: Compared with daytime seated IOP (21.3 [3.5] mm Hg), nighttime seated IOP (17.2 [3.7] mm Hg) was reduced (P < .001) and nighttime supine IOP (22.7 [4.6] mm Hg) was increased (P = .03). Central cornea thickness was increased at night from 570 (39) µm to 585 (46) µm (P < .001). There was a 48% nocturnal reduction in aqueous flow from 2.13 (0.71) µL/min during the day to 1.11 (0.38) µL/min at night (P < .001). Uveoscleral outflow was significantly reduced (P = .03) by 0.61 µL/min at night when using supine IOP, tonographic outflow facility, and episcleral venous pressure adjusted for postural changes in the Goldmann equation. All other measurements had no significant changes. CONCLUSIONS: Significant ocular changes occur at night in individuals with ocular hypertension, including a reduction in seated IOP but an increase in habitual IOP, thickening of the cornea, and decreases in aqueous flow and uveoscleral outflow. Outflow facility does not change significantly at nighttime.

Aqueous humor dynamics during the day and night in healthy mature volunteers.

OBJECTIVES: To investigate the daytime vs nighttime differences in intraocular pressure (IOP), aqueous humor dynamics, central cornea thickness, and blood pressure among a cohort of healthy volunteers. METHODS: Thirty healthy volunteers (mean [SD] age, 57.0 [8.6] years) were enrolled in the study. Individuals underwent 1 daytime visit and 1 nighttime visit for the measurement of aqueous humor dynamics. Measurements included IOP by pneumatonometry, aqueous flow by fluorophotometry, outflow facility by fluorophotometry and tonography, uveoscleral outflow by mathematical calculation, central cornea thickness by pachymetry, and blood pressure by sphygmomanometry. Results between visits were compared by appropriate t test. Dependence of the pneumatonometer probe results on position was tested in enucleated rabbit eyes at set pressures and probe positions. RESULTS: Compared with daytime seated IOP, nighttime seated IOP was reduced by 16%, whereas nighttime supine IOP was increased by 17% (P < .001 for both). The IOP changes were independent of the pneumatonometer probe position. Central cornea thickness was increased at nighttime from a mean (SD) of 560 (37) µm to a mean (SD) of 574 (37) µm (P < .001). Compared with daytime aqueous flow, nighttime aqueous flow was reduced by 49% (P < .001). During the night, fluorophotometric outflow facility was reduced by 45% (P = .05), and tonographic outflow facility was reduced by 17% (P < .01). Uveoscleral outflow at night was decreased when calculated using tonographic outflow facility but not fluorophotometric outflow facility in the Goldmann equation. All other measurements were unchanged. CONCLUSIONS: Significant changes in aqueous humor dynamics at night in healthy mature humans include reductions in aqueous flow, outflow facility, and possibly uveoscleral outflow. Nocturnal changes in IOP are independent of the pneumatonometer probe position and are dependent on an individual's posture during the measurement.

Correlations between parameters of aqueous humor dynamics and the influence of central corneal thickness.

PURPOSE: The individual parameters of aqueous humor dynamics may influence each other to maintain intraocular pressure (IOP) homeostasis. Central corneal thickness (CCT) is known to be associated with onset and progression of glaucoma and can potentially influence the individual parameters of aqueous humor dynamics that maintain IOP. This study investigates the correlation between parameters of aqueous humor dynamics and the influence of CCT in healthy volunteers and compares it with the correlations seen in patients with ocular hypertension. METHODS: Aqueous humor dynamics (aqueous flow, outflow facility, and uveoscleral outflow), IOP, and pachymetry data from 94 healthy ocular normotensive (ONT) volunteers and 63 ocular hypertensive (OHT) patients was analyzed retrospectively. Linear correlations between individual aqueous humor dynamics parameters and pachymetry were evaluated using scatter plots and the Spearman correlation coefficient where appropriate. RESULTS: In both groups, a significant (P < 0.05) negative correlation was found between corneal thickness and aqueous flow (ONT, R(2) = 0.14; OHT, R(2) = 0.10) and between corneal thickness and uveoscleral outflow (ONT and OHT, R(2) = 0.10). A significant (P < 0.05) positive correlation was found between aqueous flow and outflow facility (ONT, R (2) = 0.24; OHT, R(2) = 0.10). In healthy controls, but not OHT patients, a significant (P < 0.001) positive correlation was found between aqueous flow and uveoscleral outflow (R(2) = 0.15). CONCLUSIONS: Thicker corneas may be associated with lower aqueous production and lower uveoscleral outflow. The interplay between parameters of aqueous humor dynamics suggests possible autoregulatory mechanisms in the eye. OHT may differ from ONT subjects in their inability to increase the uveoscleral outflow with increases in aqueous inflow.

Aqueous humor dynamics in pigment dispersion syndrome.

OBJECTIVE: To assess aqueous humor dynamics in pigment dispersion syndrome (PDS). METHODS: Four groups of age-matched participants included 2 experimental groups with PDS (PDS with ocular hypertension [PDS-OHT], 17 eyes; PDS without ocular hypertension [PDS-ONT], 18 eyes) and 2 control groups without PDS (OHT, 18 eyes; ONT, 18 eyes). Assessments included intraocular pressure measured by pneumatonometry, episcleral venous pressure by venomanometry, aqueous flow and outflow facility by fluorophotometry, corneal thickness and anterior chamber depth by pachymetry, and uveoscleral outflow by mathematical calculation. Comparisons were made by analysis of variance and 2-tailed unpaired t tests. RESULTS: The PDS-OHT group had higher intraocular pressures than the ONT and PDS-ONT groups (P < .001) and higher episcleral venous pressure (P = .04) and lower outflow facility (P = .01) than the ONT group. Anterior chamber volume was larger in the PDS-OHT group than in the other groups (P < .05 for all). No other comparisons between the PDS-OHT group and the other groups yielded statistically significant differences at a significance level of less than .05. CONCLUSIONS: The elevated intraocular pressure in PDS is caused by reduced outflow facility. This differs from OHT without PDS, in which reductions in uveoscleral outflow and outflow facility have been reported.

Duration of anesthesia affects intraocular pressure, but not outflow facility in mice.

PURPOSE: The study of aqueous humor dynamics (AHD) in mice is becoming more prevalent as more strains with elevated intraocular pressure (IOP) are developed. High IOP is usually associated with reduced outflow facility making this one of the more important AHD parameters to evaluate. Ocular measurements in mice require anesthesia that has profound effects on IOP but unknown effects on outflow facility. This study evaluates the effects of anesthesia duration and latanoprost treatment on outflow facility and IOP in BALB/c mice. METHODS: IOPs were measured in conscious and anesthetized mice by tonometry. Outflow facility was evaluated in 15-min intervals at three pressure levels over two 45-min periods. Comparisons were made between latanoprost-treated eyes and untreated contralateral eyes. To determine the effect of anesthesia duration on IOP, a microneedle method was used to follow IOP for 120 min in separate mice. RESULTS: IOP was 9.7 +/- 0.3 mmHg (mean +/- SEM) in conscious mice and 7.1 +/- 0.02 within 10 min of anesthesia initiation (p < 0.01). IOP changed significantly between but not within assessment periods. IOP at 75 min was significantly (p = 0.004) reduced compared to IOP at 15 min after initial anesthesia. In control eyes, outflow facility did not change between the two 45-min assessment periods during the 120 min test (p = 0.80). In latanoprost-treated eyes, outflow facility increased compared with control eyes during both assessment periods (p = 0.03). A test of filters in series with known resistance found that the method was sensitive enough to detect a change in outflow facility of 0.001 microl/min/mmHg. CONCLUSIONS: Administration of ketamine/xylazine anesthesia for 120 min did not alter outflow facility or lessen the effect of latanoprost on outflow facility in mice as determined by a new analysis system. Accurate IOP measurements must be made within minutes of anesthesia administration but outflow facility measurements can be made with less haste.

Efficacy and mechanisms of intraocular pressure reduction with latanoprost and timolol in participants with ocular hypertension: a comparison of 1 and 6 weeks of treatment.

PURPOSE: To investigate whether the intraocular pressure (IOP) reduction and mechanism of action of timolol and latanoprost change between 1 and 6 weeks of treatment. PATIENTS AND METHODS: Thirty participants on no ocular medications completed this double-masked, 6-visit, crossover study. At each visit IOP was determined by pneumatonometry, aqueous flow by fluorophotometry, and outflow facility by fluorophotometry and tonography. Separate values of uveoscleral outflow were calculated using the Goldmann equation, an episcleral venous pressure of 11 mm Hg, and each of the 2 outflow facility values. In a randomized fashion, both eyes were treated for 6 weeks with latanoprost 0.005% once daily or timolol 0.5% twice daily. Measurements were repeated at 1 and 6 weeks of dosing. After 6 weeks of washout, the second drug was administered in a crossover manner. One and 6 weeks of treatment were compared with appropriate baselines using 1-way analyses of variance (ANOVA). RESULTS: Timolol reduced aqueous flow by 27% at week 1 (P<0.001) and 16% at week 6 (P=0.03). Latanoprost increased uveoscleral outflow several fold at each visit (P<0.05). Neither drug altered outflow facility. Neither drug showed a detectable change in aqueous humor dynamics at week 6 compared with week 1. Both drugs significantly (P<0.001) reduced IOP at 1 and 6 weeks of treatment. CONCLUSIONS: Timolol and latanoprost significantly reduce IOP by different mechanisms. Timolol reduces aqueous flow whereas latanoprost increases uveoscleral outflow. Continued treatment with timolol or latanoprost for 6 weeks did not alter effects on aqueous humor dynamics. Outflow facility changes sometimes reported with prostaglandin analogues were not detected in this study.

Aqueous humor dynamics during the day and night in juvenile and adult rabbits.

PURPOSE: To determine the day and night differences in intraocular pressure (IOP), aqueous flow, outflow facility, uveoscleral outflow, and central corneal thickness (CCT) in juvenile and adult rabbits. METHODS: Studies were performed on twelve 3-month-old and ten 12-month-old male New Zealand White rabbits. Daytime measurements were made between 9 AM (3 hours after lights on) and 3 PM, and nighttime measurements were made between 11 PM and 5 AM. IOP was measured by pneumotonometry and aqueous flow by fluorophotometry. Outflow facility was determined by both fluorophotometry and tonography. Uveoscleral outflow was calculated by the Goldmann equation. CCT was measured by ultrasound pachymetry. Repeated-measures ANOVAs and Student's two-tailed t-tests were used for statistical comparisons. RESULTS: When nighttime versus daytime readings were compared, IOP, aqueous flow and uveoscleral outflow were higher, fluorophotometric outflow facility was lower, and CCT was thinner in both age groups. When the juvenile rabbits were compared to adult rabbits, IOP was lower, aqueous flow and uveoscleral outflow were higher, and fluorophotometric outflow facility and CCT were not different during the day or night. Tonographic outflow facility did not change in a 24-hour period in the juvenile rabbits. CONCLUSIONS: The increased IOP at night in rabbits can be explained mainly by a decrease in outflow facility. An increase in aqueous flow at night is counterbalanced by an increase in uveoscleral outflow. Although the rates of aqueous flow and uveoscleral outflow slow with maturity, their relative day/night differences remain the same.

PRDX6 attenuates oxidative stress- and TGFbeta-induced abnormalities of human trabecular meshwork cells.

Oxidative stress and TGFbeta-induced disturbance of cells and tissues are implicated in initiation and progression of pathophysiology of cells/tissues. Using primary human trabecular meshwork (TM) cells from normal and glaucomatous subjects, this study demonstrated that peroxiredoxin (PRDX) 6, an antioxidant, offsets the deleterious effects of oxidative stress on TM cells by optimizing ROS and TGFbeta levels. An analysis of glaucomatous TM cells revealed a reduced expression of PRDX6 mRNA and protein. Biochemical assays disclosed enhanced levels of ROS, as well as high levels of TGFbetas and these cells expressed elevated extracellular matrix (ECM) and Tsp1 proteins with reduced MMP2; conditions implicated in the pathophysiology of glaucoma. Non-glaucomatous TM cells exposed to TGFbetas/ROS showed similar features as in glaucomatous cells. The abnormalities induced were reversed by delivery of PRDX6. The data provide evidence that oxidative stress-induced abnormality in TM may be related to reduced PRDX6 expression and provide a foundation for antioxidant-based therapeutics for treating glaucoma.

Cabergoline: Pharmacology, ocular hypotensive studies in multiple species, and aqueous humor dynamic modulation in the Cynomolgus monkey eyes.

The aims of the current studies were to determine the in vitro and in vivo ocular and non-ocular pharmacological properties of cabergoline using well documented receptor binding, cell-based functional assays, and in vivo models. Cabergoline bound to native and/or human cloned serotonin-2A/B/C (5HT(2A/B/C)), 5HT(1A), 5HT(7), alpha(2B), and dopamine-2/3 (D(2/3)) receptor subtypes with nanomolar affinity. Cabergoline was an agonist at human recombinant 5HT(2), 5HT(1A) and D(2/3) receptors but an antagonist at 5HT(7) and alpha(2) receptors. In primary human ciliary muscle (h-CM) and trabecular meshwork (h-TM) cells, cabergoline stimulated phosphoinositide (PI) hydrolysis (EC(50)=19+/-7 nM in TM; 76 nM in h-CM) and intracellular Ca(2+) ([Ca(2+)](i)) mobilization (EC(50)=570+/-83 nM in h-TM; EC(50)=900+/-320 nM in h-CM). Cabergoline-induced [Ca(2+)](i) mobilization in h-TM and h-CM cells was potently antagonized by a 5HT(2A)-selective antagonist (M-100907, K(i)=0.29-0.53 nM). Cabergoline also stimulated [Ca(2+)](i) mobilization more potently via human cloned 5HT(2A) (EC(50)=63.4+/-10.3 nM) than via 5HT(2B) and 5HT(2C) receptors. In h-CM cells, cabergoline (1 microM) stimulated production of pro-matrix metalloproteinases-1 and -3 and synergized with forskolin to enhance cAMP production. Cabergoline (1 microM) perfused through anterior segments of porcine eyes caused a significant (27%) increase in outflow facility. Topically administered cabergoline (300-500 microg) in Dutch-belted rabbit eyes yielded 4.5 microMM and 1.97 microM levels in the aqueous humor 30 min and 90 min post-dose but failed to modulate intraocular pressure (IOP). However, cabergoline was an efficacious IOP-lowering agent in normotensive Brown Norway rats (25% IOP decrease with 6 microg at 4h post-dose) and in conscious ocular hypertensive cynomolgus monkeys (peak reduction of 30.6+/-3.6% with 50 microg at 3h post-dose; 30.4+/-4.5% with 500 microg at 7h post-dose). In ketamine-sedated monkeys, IOP was significantly lowered at 2.5h after the second topical ocular dose (300 microg) of cabergoline by 23% (p<0.02) and 35% (p<0.004) in normotensive and ocular hypertensive eyes, respectively. In normotensive eyes, cabergoline increased uveoscleral outflow (0.69+/-0.7 microL/min-1.61+/-0.97 microL/min, n=13; p<0.01). However, only seven of the eleven ocular hypertensive monkeys showed significantly increased uveoscleral outflow. These data indicate that cabergoline's most prominent agonist activity involves activation of 5HT(2), 5HT(1A), and D(2/3) receptors. Since 5HT(1A) agonists, 5HT(7) antagonists, and alpha(2) antagonists do not lower IOP in conscious ocular hypertensive monkeys, the 5HT(2) and dopaminergic agonist activities of cabergoline probably mediated the IOP reduction observed with this compound in this species.

Commercially available prostaglandin analogs for the reduction of intraocular pressure: similarities and differences.

Over the last 12 years, the pharmacological management of glaucoma and ocular hypertension has significantly changed with the introduction of the prostaglandin analogs, specifically, latanoprost, bimatoprost, and travoprost. Their ability to effectively reduce intraocular pressure with once-per-day dosing, their comparable ocular tolerability with timolol, and their general lack of systemic side effects have made them the mainstay of pharmacological therapy for glaucoma and ocular hypertension in most parts of the world. A review of their pharmacology reveals that they are all prodrugs that are converted to their respective free acids within the eye to activate the prostanoid FP receptor and to reduce intraocular pressure by enhancing the uveoscleral and the trabecular meshwork outflow pathways. A review of numerous prospective, randomized comparative studies indicates that no clinically significant differences exist among these agents regarding their ability to lower intraocular pressure.

Aqueous humor dynamics in exfoliation syndrome.

OBJECTIVE: To examine how aqueous humor dynamics are affected by exfoliation syndrome (XFS) with or without elevated intraocular pressure (IOP). METHODS: Eighty participants were divided into 4 groups: (1) those with XFS and ocular normotension (n = 25), (2) controls with ocular normotension without XFS, age-matched to group 1 (n = 25), (3) those with XFS and ocular hypertension (n = 15), and (4) controls with ocular hypertension without XFS, age-matched to group 3 (n = 15). Following washout of glaucoma medications, assessments were made of IOP, episcleral venous pressure, aqueous flow, outflow facility, and uveoscleral outflow. Differences were analyzed by group mean comparisons and linear regression analyses. RESULTS: Uveoscleral outflow was significantly decreased in individuals with XFS compared with age-matched controls and was independent of IOP. Patients with ocular hypertension (with or without XFS) exhibited decreased outflow facility compared with those with ocular normotension (with or without XFS). Aqueous flow was not affected by the level of IOP or the presence of XFS. CONCLUSIONS: Exfoliation syndrome in normotensive and hypertensive eyes is associated with a decrease in uveoscleral outflow, whereas in hypertensive but not normotensive eyes, it is associated with reduced outflow facility.

Effects of central corneal thickness on the efficacy of topical ocular hypotensive medications.

PURPOSE: To determine the effect of central corneal thickness (CCT) on the efficacy of intraocular pressure (IOP)-reducing drugs in patients with ocular hypertension (OHT). METHODS: This retrospective study analyzed research records of 115 OHT patients and 97 ocular normotensive (ONT) volunteers. CCT was measured by slit-lamp pachymetry and IOP by pneumatonometry. The OHT patients were divided into Thick (>540 microm, n=52) and Thin (

Bacterial DNA confers neuroprotection after optic nerve injury by suppressing CD4+CD25+ regulatory T-cell activity.

PURPOSE: Protective autoimmunity attenuates secondary degeneration after central nervous system (CNS) injury. Such neuroprotection is achieved via activation of autoimmune CD4(+)CD25(-) effector T cells (Teffs) or suppression of naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs). In this study the ability of bacterial DNA, characterized by unmethylated CpG islands, to downregulate Treg activity and therefore, to confer neuroprotection was investigated. METHODS: The effects of CpG on suppressive activity of mouse Tregs were studied by coculturing Tregs with Teffs and measuring proliferation by radiolabeled thymidine. The neuroprotective effects of CpG-mediated Treg suppression was examined in rats after optic nerve crush. RESULTS: Teff proliferation in response to T-cell receptor stimuli was significantly reduced when the Teffs were cocultured with Tregs, compared with Teff activation when cultured alone. Treating Tregs with CpG reduced their suppressive activity and restored Teff proliferation to baseline levels. CpG injection in rats with optic nerve crush conferred significant neuroprotection compared with that in untreated control rats (118 +/- 8 cells/mm(2) vs. 69 +/- 5 cells/mm(2), respectively; mean +/- SEM; P < 0.05). CpG-mediated neuroprotection was accompanied by significantly increased T-cell infiltration at the injury site. Similar CpG treatment of athymic nude rats yielded no neuroprotection, further suggesting a T-cell-dependent mechanism of CpG action. CONCLUSIONS: These findings strongly support the notion that alleviation of Treg suppression after injury benefits neuronal survival. Bacterial DNA attenuation of Treg suppressive activity may represent an evolutionary adaptation that curbs the amplified infection risk after CNS trauma, due to blood-brain barrier breakdown. This study may prompt development of new neuroprotective therapies aimed at the immune system, to benefit the injured CNS.

Effects of travoprost on aqueous humor dynamics in patients with elevated intraocular pressure.

PURPOSE: To determine the mechanism by which travoprost 0.004% reduces intraocular pressure (IOP) in patients with ocular hypertension or primary open angle glaucoma. DESIGN: This is a randomized, double-masked, placebo-controlled, single center study of 26 patients scheduled for 3 visits (baseline, day 15, and days 17 to 18) following screening. METHODS: After appropriate washout of all ocular medications, baseline IOPs were taken and travoprost 0.004% was administered once-daily in the evening for 17 consecutive doses to 1 eye and its vehicle to the fellow eye in a randomized, masked fashion. On day 15, beginning 12 hours after the 14th consecutive dose, IOP was measured by pneumatonometry, aqueous flow and outflow facility by fluorophotometry, and episcleral venous pressure by venomanometry. Uveoscleral outflow was determined by mathematical calculation. Two days later, the last drop of drug/vehicle was given at 2000 hours. Fluorophotometry and tonometry measurements were repeated between 2200 and 0600 hours. Treated eyes were compared with contralateral control eyes or baseline measurements, and daytime measurements were compared with nighttime measurements using paired t tests. RESULTS: Travoprost-treated eyes showed a significant (P<0.001) decrease in daytime IOP compared with baseline (26%) or to vehicle-treated eyes (22%), and an increase in daytime outflow facility (P=0.001; 64%). The increase in uveoscleral outflow was not statistically significant. At night, the IOPs of travoprost-treated eyes remained 21% to 24% below baseline daytime values. Seated and supine IOPs in control eyes were significantly (P<0.04) lower at 2200 hours than 1700 hours (P<0.04). Supine IOPs were higher than seated IOPs in both control and treated eyes (P<0.001). Aqueous flow was significantly (P<0.001) reduced at night in both travoprost (30%) and vehicle-treated (25%) eyes when compared with daytime values. No other comparisons were statistically significant. CONCLUSIONS: Travoprost seems to lower IOP by increasing trabecular outflow facility. An effect on uveoscleral outflow cannot be ruled out.

Effects of a prostaglandin DP receptor agonist, AL-6598, on aqueous humor dynamics in a nonhuman primate model of glaucoma.

This study examines, in 11 cynomolgus monkeys with unilateral laser-induced glaucoma, the ocular hypotensive mechanism of action of AL-6598, partial agonist at the DP and EP prostanoid receptors. In a crossover fashion, both eyes of each monkey were dosed twice daily with 25 microL of either AL-6598 0.01% or vehicle for 2 days and on the morning of the 3rd day. Measurements were made on day 3 of each treatment. Alternative treatments were separated by at least 2 weeks. Intraocular pressures (IOPs) were measured by pneumatonometry and aqueous flow and outflow facility by fluorophotometry. Uveoscleral outflow was calculated mathematically. In the normotensive eyes, compared to vehicle treatment, AL-6598 decreased IOP from 22.5 +/- 0.7 to 18.7 +/- 0.9 mmHg (P = 0.006), increased uveoscleral outflow from 0.47 +/- 0.17 to 1.22 +/- 0.17 microL/min (P = 0.03), and increased aqueous flow from 1.49 +/- 0.10 to 1.93 +/- 0.13 microL/min (P = 0.01). No measurement in AL-6598-treated hypertensive eyes was significantly different from vehicle treatment. It is concluded that AL-6598 reduces IOP by increasing uveoscleral outflow in normotensive eyes of ketamine-sedated monkeys, despite an increase in aqueous flow. This effect is different from that of PGD(2), which decreases aqueous flow, and of the selective DP receptor agonist, BW245C, which increases both outflow facility and uveoscleral outflow in addition to decreasing aqueous flow.

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.

Increase in outflow facility with unoprostone treatment in ocular hypertensive patients.

OBJECTIVE: To determine the mechanism by which 0.15% unoprostone isopropyl reduces intraocular pressure (IOP) by studying 33 patients with ocular hypertension or primary open-angle glaucoma. METHODS: At baseline, IOP was determined by pneumatonometry, aqueous flow and outflow facility by fluorophotometry, episcleral venous pressure by venomanometry, and uveoscleral outflow by mathematical calculation. Unoprostone was administered to one eye and placebo to the fellow eye of each patient twice daily in a randomized masked fashion. In patients who demonstrated an IOP reduction of 3 mm Hg or more in either eye on day 5 +/- 1 (n = 29), determinations were repeated on that day and on day 28 +/- 2. Treated eyes were compared with control eyes, and treatment days were compared with baseline by paired t tests. RESULTS: Compared with baseline, unoprostone significantly (P<.001) reduced IOP by a mean +/- SEM of 5.6 +/- 0.4 mm Hg and 4.8 +/- 0.6 mm Hg on days 5 and 28, respectively. The change from baseline with unoprostone was significantly (P<.001) greater than with placebo by 2.8 +/- 0.4 mm Hg on day 5 and by 3.2 +/- 0.5 mm Hg on day 28. Compared with baseline, unoprostone significantly (P