Shan Fan

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

PurposeTo determine the mechanism by which travoprost 0.004% reduces intraocular pressure (IOP) in patients with ocular hypertension or primary open angle glaucoma. DesignThis 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. MethodsAfter 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. ResultsTravoprost-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. ConclusionsTravoprost seems to lower IOP by increasing trabecular outflow facility. An effect on uveoscleral outflow cannot be ruled out.

A novel Schlemm's Canal scaffold increases outflow facility in a human anterior segment perfusion model.

PURPOSE An intracanalicular scaffold (Hydrus microstent) designed to reduce intraocular pressure as a glaucoma treatment was tested in human anterior segments to determine changes in outflow facility (C). METHODS Human eyes with no history of ocular disease or surgeries were perfused within 49 hours of death. The anterior segments were isolated and connected to a perfusion system. Flow rates were measured at pressures of 10, 20, 30, and 40 mm Hg. The scaffold was inserted into Schlemms canal of the experimental eye, while a control eye underwent a sham procedure. Flow rate measurements were repeated at the four pressure levels. Individual C values were computed by dividing the flow rate by its corresponding pressure, and by averaging the four individual C measurements. The change in C between control and experimental eyes was assessed by the ratio of the baseline and second C measurement. In two eyes, the placement of the scaffold was evaluated histologically. RESULTS After scaffold implantation in the experimental eyes, the average C increased significantly from baseline (n = 9, P < 0.05). Ratios of C at all pressure levels, except for 10 mm Hg, were significantly higher in experimental eyes (n = 9) than control eyes (P < 0.05, n = 7). Histologically, the scaffold dilated Schlemms canal with no visible damage to the trabecular meshwork. CONCLUSIONS The Hydrus Microstent provided an effective way to increase outflow facility in human eyes ex vivo.

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.

Rebound tonometry in conscious, conditioned mice avoids the acute and profound effects of anesthesia on intraocular pressure.

AIMS The aims of this study were to evaluate the accuracy, repeatability, and safety of multiple intraocular pressure (IOP) measurements by a commercially available rebound tonometer in conscious, conditioned mice, and to characterize the acute and profound effects of anesthesia on IOP in mice. METHODS To test the accuracy of the tonometer, IOPs of CD-1 mice under ketamine/xylazine anesthesia were experimentally set and monitored with a water manometer/transducer system following transcorneal cannulation while simultaneously performing tonometry. The long- and short-term repeatability of the tonometer was tested in conscious, restrained mice, as measurements were taken once-daily in the afternoon for 4 consecutive days. On day 5, IOPs were measured in the same mice once every 4 min for 32 min. On 2 separate days, mice were administered ketamine/xylazine or 2,2,2-tribromoethanol anesthesia, in a crossover design, and IOPs were measured once every 2 min for 32 min. Rebound tonometry was performed in conscious mice before and 1 hour after 1 drop of timolol maleate (10 microL of 0.5%) application to 1 eye. RESULTS IOP measurements by rebound tonometry correlated well with manometry for pressures between 8 and 38 mmHg (y = 0.98x - 0.32, R(2) = 0.94; P < 0.001). The average tonometric IOP was invariant over 4 days (range, 11.7-13.2 mmHg). IOPs dropped significantly ( P < or = 0.05) within 6 min (ketamine/xylazine) or 10 min (2,2,2-tribromoethanol) postadministration of anesthesia but not with conscious restraint. Timolol significantly (P < 0.001) lowered IOP from 12.8 +/- 0.3 (mean +/- standard error of the mean) to 10.1 +/- 0.6 mmHg, as measured by the tonometer. CONCLUSIONS Rebound tonometry can be used to obtain accurate IOP measurements in conscious, restrained mice while avoiding the rapid and profound ocular hypotensive effects of general anesthesia. Small changes in IOP with an aqueous-flow suppressant are readily detectable with conscious restraint that may be missed with chemical restraint.

A Novel 8-mm Schlemm's Canal Scaffold Reduces Outflow Resistance in a Human Anterior Segment Perfusion Model

PURPOSE To study the effect on outflow facility and outflow resistance of a nitinol microstent implanted into Schlemms canal. METHODS Using a constant pressure perfusion method, outflow facility and outflow resistance were measured in 26 pairs of dissected anterior segments from donated human eyes. Measurements were made at perfusion pressures of 10, 20, 30 and 40 mm Hg. The Hydrus Microstent was placed in Schlemms canal of one eye and the contralateral eye underwent a sham procedure. Outflow facility and outflow resistance were measured again after the microstent implantation or sham procedure. RESULTS The Hydrus Microstent significantly increased outflow facility from 0.33 ± 0.17 μL/min/mm Hg to 0.52 ± 0.19 μL/min/mm Hg (P < 0.001). Outflow resistance was significantly reduced from 4.38 ± 3.03 mm Hg/μL/min at baseline to 2.34 ± 1.04 mm Hg/μL/min (P < 0.001) with the microstent. There was a linear correlation between outflow resistance at baseline and decrease in outflow resistance with the microstent (R(2) = 0.89, P < 0.0001). CONCLUSIONS The increase in outflow facility and decrease in resistance supports the potential use of the Hydrus Microstent as a surgical option to reduce intraocular pressure (IOP). The IOP-lowering effect may be higher in eyes with higher outflow resistance (and IOP) as compared with eyes with lower outflow resistance (and IOP).

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 individuals posture during the measurement.

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 μl/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.

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

PurposeTo determine the effect of central corneal thickness (CCT) on the efficacy of intraocular pressure (IOP)-reducing drugs in patients with ocular hypertension (OHT). MethodsThis 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 μm, n=52) and Thin (≤540 μm, n=63) Cornea groups. Measurements in the OHT group were made after washout of all IOP-lowering drugs and at 1 week of treatment with latanoprost 0.005%, dorzolamide 2%, brimonidine 0.2%, apraclonidine 0.5%, pilocarpine 2%, or unoprostone 0.15% to 1 eye and vehicle contralaterally. ONT volunteers also were divided into Thick (n=34) and Thin (n=63) Cornea groups. Results were compared between groups using unpaired t tests or nonparametric Wilcoxon tests and within groups using linear regression analyses. ResultsBaseline IOPs were not different between CCT groups of OHT patients or of ONT volunteers. After 1 week of drug treatment, IOP was significantly (P=0.02) lower in the OHT Thin Cornea group (16.0±3.0 mm Hg, mean±SD) than the OHT Thick Cornea group (17.4±2.8 mm Hg). There was a positive correlation between IOP and CCT (R2=0.06, P=0.007) in OHT drug-treated eyes, but not OHT vehicle-treated or ONT untreated eyes. The final IOP was significantly lower in the Thin than the Thick Cornea group treated with brimonidine (P=0.02) but not with latanoprost (P=0.91). ConclusionsWhen dosed with IOP lowering drugs, eyes with thinner corneas had lower IOPs than eyes with thicker corneas. This suggests a reduced efficacy of some glaucoma medications in ocular hypertensive patients with thick corneas.

Diurnal and Nocturnal Variations in Aqueous Humor Dynamics of Patients With Ocular Hypertension Undergoing Medical Therapy

OBJECTIVE To evaluate the interaction of intraocular pressure(IOP)–lowering medications with physiologic day and night changes in aqueous humor dynamics in participants with ocular hypertension. METHODS Thirty participants were enrolled in thisdouble-masked, randomized, crossover study. Each participant underwent aqueous humor dynamics measurements at baseline and at 2 weeks of dosing in random order with latanoprost in the evening and placebo in the morning, timolol maleate twice daily, and dorzolamide hydrochloride twice daily. Measurements included central corneal thickness by ultrasound pachymetry, anterior chamber depth by A-scan, seated and habitual IOP by pneumatonometry, blood pressure by sphygmomanometry,episcleral venous pressure by venomanometry,and aqueous flow by fluorophotometry. Outflow facility was assessed by fluorophotometry and by tonography. Uveoscleral outflow was mathematically calculated using the Goldmann equation. RESULTS Latanoprost use significantly decreased IOP during the day and night. It increased daytime uveoscleral outflow by a mean (SD) of 0.90 (1.46) μL/min (P=.048), but a nighttime increase of 0.26 (1.10) μL/min (P=.47)did not reach statistical significance. Timolol use decreased IOP during the day by reducing aqueous flow by 25%. Dorzolamide use lowered IOP only at the noon measurement and reduced daytime aqueous flow by 16%. Neither dorzolamide nor timolol use added to the physiologic 47% reduction in nighttime aqueous flow. CONCLUSIONS The daytime IOP-lowering effects of latanoprost are mediated by an increase in uveoscleral outflow,and those of timolol and dorzolamide are mediated by aqueous flow suppression. Nighttime physiologic changes in uveoscleral outflow limit the nighttime pharmacodynamic efficacy of latanoprost. Aqueous flow suppression with timolol and dorzolamide was ineffective in obtaining IOP lowering at night.

Improvement in Outflow Facility by Two Novel Microinvasive Glaucoma Surgery Implants

PURPOSE To determine improvement in outflow facility (C) in human anterior segments implanted with a novel Schlemms canal scaffold or two trabecular micro-bypasses. METHODS Human anterior segments were isolated from 12 pairs of eyes from donors with no history of ocular disease and then perfused at 50, 40, 30, 20, and 10 mm Hg pressures for 10 minutes each. Baseline C was calculated from perfusion pressures and flow rates. The scaffold was implanted into Schlemms canal of one anterior segment, and two micro-bypasses were implanted three clock-hours apart in the contralateral anterior segment. Outflow facility and resistance were compared at various standardized perfusion pressures and between each device. RESULTS Compared to baseline, C increased by 0.16 ± 0.12 μL/min/mm Hg (74%) with the scaffold, and 0.08 ± 0.12 μL/min/mm Hg (34%) with two micro-bypasses. The scaffold increased C at perfusion pressures of 50, 40, 30, and 20 mm Hg (P < 0.005). Two micro-bypasses increased C at a perfusion pressure of 40 mm Hg (P < 0.05). CONCLUSIONS Both implants effectively increased C in human eyes ex vivo. The scaffold increased C by a greater percentage (73% vs. 34%) and at a greater range of perfusion pressures (20 to 50 mm Hg vs. 40 mm Hg) than the two micro-bypasses, suggesting that the 8-mm dilation of Schlemms canal by the scaffold may have additional benefits in lowering the outflow resistance. The Hydrus Microstent scaffold may be an effective therapy for increasing outflow facility and thus reducing the IOP in patients with glaucoma.