Aqueous humor dynamics in mice

PURPOSE: To assess aqueous humor dynamics in mouse eyes. METHODS: Aqueous humor dynamics of NIH Swiss White mouse were assessed with an injection and aspiration system, using fine glass microneedles. Intraocular pressure (IOP) was measured by a microneedle connected to a pressure transducer. Episcleral venous pressure (EVP) was measured by gradually lowering intracameral pressure until blood reflux into Schlemm's canal was observed. Outflow facility (C) was determined based on constant pressure perfusion measurements obtained at two different IOPs. Aqueous volume (V(a)) was determined by direct measurement of aspirated aqueous humor. Aqueous humor production (F(a)) was measured by the dilution method with rhodamine-dextran. Conventional and uveoscleral outflow (F(c) and F(u), respectively), as well as the turnover rate of aqueous humor, were also calculated. RESULTS: IOP and EVP were 15.7 +/- 2.0 and 9.5 +/- 1.2 mm Hg, respectively (n = 20). F(a) was 0.18 +/- 0.05 microL/min (mean +/- SD; n = 8). C was 0.0051 +/- 0.0006 microL/min per mm Hg (n = 8). Estimated F(c) and F(u) were 0.032 and 0.148 microL/min, respectively. F(c) was 18% of F(a). F(u) was 82% of F(a). V(a) was 5.9 +/- 0.5 microL (n = 8). The calculated turnover rate of aqueous humor was 2.5%. CONCLUSIONS: The mouse eye has similar aqueous production and aqueous humor turnover rate as the human eye. The presence of both conventional and uveoscleral outflow suggests that the mouse is a useful model system for further investigations of the biology of aqueous dynamics.     

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.     

Aqueous humor dynamics in ocular hypertensive patients

PURPOSE: To evaluate the mechanism of the intraocular pressure (IOP) elevation in ocular hypertension (OHT), aqueous humor dynamics were compared in patients with OHT versus age-matched ocular normotensive (NT) volunteers. METHODS: In this retrospective study, one group included patients diagnosed with OHT (IOPs > 21 mm Hg, n = 55) for at least six months. All eye medications were discontinued for at least three weeks before the study visit. A second group included age-matched NT subjects (n = 55) with no eye diseases. The study visit included measurements of IOP by pneumatonometry, aqueous flow and outflow facility by fluorophotometry, anterior chamber depth and corneal thickness by pachymetry and episcleral venous pressure by venomanometry. Uveoscleral outflow and anterior chamber volume were calculated mathematically. RESULTS: Significant differences in the OHT versus the NT groups were as follows: increased IOP (21.4 +/- 0.6 versus 14.9 +/- 0.3 mm Hg, respectively; P < 0.0001), reduced uveoscleral outflow (0.66 +/- 0.11 versus 1.09 +/- 0.11 microL/min; P = 0.005) and reduced fluorophotometric outflow facility (0.17 +/- 0.01 versus 0.27 +/- 0.02 microL/min/mm Hg; P < 0.0001). With respect to age, anterior chamber volume decreased in both groups at a rate of 2.4 +/- 0.3 microL/year (r(2) = 0.5, P <.001) and aqueous flow decreased at a rate of 0.013 +/- 0.005 microL/min/year (r(2) = 0.07, P = 0.005). CONCLUSIONS: The increased IOP in ocular hypertensive patients is caused by a reduction in trabecular outflow facility and uveoscleral outflow. Aqueous flow remains normal. When both ocular normotensive and hypertensive groups are combined, aqueous flow and anterior chamber volume decrease slightly with age.     

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.     

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.     

Evaluation of aqueous outflow facility in patients with high intraocular pressure after cataract surgery.

BACKGROUND AND OBJECTIVE: To study whether patients with a marked elevation of intraocular pressure (IOP) the day after cataract surgery may have a chronically impaired aqueous outflow. PATIENTS AND METHODS: In 128 consecutive patients, IOP was measured both preoperatively and the day after phacoemulsification and intraocular lens implantation. In the late postoperative period, aqueous outflow facility (C-value) was measured with pneumatonography in patients (n = 7) who experienced a postoperative IOP increase of at least 20 mm Hg and in patients (n = 11) with a difference between preoperative and postoperative IOP of not more than 2 mm Hg. RESULTS: Aqueous outflow facility was normal in both groups. Mean C-value was 0.32 +/- 0.18 microL/min/ mm Hg in the hypertensive group and 0.23 +/- 0.10 microL/ min/mm Hg in the normotensive group. The difference was not statistically significant (P = .20). CONCLUSIONS: Patients with marked IOP elevation the day after cataract surgery do not seem to have a chronically impaired aqueous outflow facility compared with normotensive patients.     

Effect of Healon and Viscoat on outflow facility in human cadaver eyes

PURPOSE: To compare the acute effects of Healon (sodium hyaluronate) and Viscoat (sodium chondroitin sulfate-sodium hyaluronate) on outflow facility in human cadaver eyes and determine which viscoelastic agent is least likely to cause an intraocular pressure (IOP) spike after cataract surgery. SETTING: The Glaucoma Research Lab, University of Toronto, Ontario, Canada. METHODS: In this prospective paired study, 15 pairs of human cadaver eyes were used. Following the construction of a 3.0 mm scleral tunnel, 0.25 cc of Healon was injected into the anterior chamber of 1 eye and 0.25 cc of Viscoat was injected into the contralateral eye. The viscoelastic agents were removed from both eyes in a standardized fashion and the scleral tunnels closed. The eyes were then perfused at a constant IOP of 8.0 mm Hg, corresponding to 16.0 mm Hg in vivo. Outflow facility (microL/minute [min]/mm Hg) was recorded every 15 minutes for 24 hours using standard methods. RESULTS: Outflow facility in the Viscoat-treated eyes decreased appreciably for the first 3 hours, then recovered somewhat after 12 hours; facility in the Healon-treated eyes showed less of an overall decrease. Over the 24 hour perfusion period, mean outflow facility was 0.037 microL/min/mm Hg +/- 0.015 (SD) in the Viscoat-treated eyes and 0.060 +/- 0.012 microL/min/mm Hg in the Healon-treated eyes. Healon reduced outflow facility significantly less than Viscoat between 3.25 and 10.50 hours postoperatively (P < .05, 2-tailed t test). CONCLUSIONS: Healon reduced outflow facility less than Viscoat between 3.25 and 10.50 hours postoperatively.     

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 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.     

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.     

Aqueous humor dynamics in monkeys after topical R-DOI

PURPOSE: To determine the effects of R-DOI, a selective 5-HT2 agonist, on intraocular pressure (IOP) and aqueous humor dynamics in monkeys. METHODS: Normotensive cynomolgus monkeys (n = 8) were treated topically once daily with four 5-muL drops of 0.5% R-DOI in one eye, vehicle in the opposite eye. The 6-hour IOP response (Goldmann applanation tonometry) was determined before the drug application and on the third day of treatment. Aqueous humor formation, or flow (AHF, measured by fluorophotometry), was measured from hours 3 to 8 after the third dose. Beginning 3.5 hours after the fourth or fifth dose, AHF was measured by dilution of radio-iodinated monkey albumin perfused through the anterior chamber and flow to blood by accumulation of albumin in the general circulation. Uveoscleral outflow (Fu) was calculated. Flow to blood was determined at spontaneous and elevated pressures, allowing calculation of trabecular outflow facility. Total outflow facility was determined by two-level constant pressure perfusion from 3.5 to 5 hours and from 5.5 to 6.25 hours after R-DOI treatment. RESULTS: Reduction of IOP in treated eyes was compared to the opposite control eyes corrected for the 6-hour IOP baseline before the first dose. After the third dose of R-DOI, IOP was significantly (P < 0.01, n = 7) decreased by 1.4 to 4.7 mm Hg over the 6 hours. AHF (by fluorophotometry) increased by 13% (P < 0.05, n = 8) in treated compared with control eyes corrected for baseline. AHF (isotope dilution) increased by 30% (P < 0.01, n = 8), flow to blood decreased by 28% (n = 5), and Fu increased by 241% (P < 0.05, n = 5). Total and trabecular outflow facility were unchanged. CONCLUSIONS: R-DOI caused a small but significant increase in AHF and lowered IOP in normotensive monkeys primarily by increasing Fu.     

Relationship between aqueous humor protein level and outflow facility in patients with uveitis

PURPOSE: To determine whether there is a relationship between the aqueous humor protein level and outflow facility in patients with uveitis. METHODS: Aqueous humor protein levels were determined by laser flare photometry, and outflow facility was determined by Schiotz tonography. RESULTS: Thirty patients with uveitis and 10 control subjects were studied. Outflow facility was lower in patients with uveitis (0.21 +/- 0.12 microl/min x mm Hg) than in control subjects (0.33 +/- 0.05 microl/min x mm Hg, P < 0.001). Patients with uveitis and laser flare photometry results (flare) more than 20 photon units/msec (n = 21) had a lower outflow facility (0.17 +/- 0.07 microl/min x mm Hg) than patients with uveitis and flare less than 20 photon units/msec (n = 9, 0.32 +/- 0.14 microl/min x mm Hg, P = 0.004). Furthermore, no difference was identified between outflow facility in patients with active uveitis (those who had anterior chamber cells) and flare less than 20 photon units/msec and outflow in control subjects. In patients with uveitis, there was a linear correlation between flare and outflow facility (r = -0.50, P = 0.005). There was no relationship between flare measurements and either intraocular pressure or aqueous humor cell levels when scored with a clinical, semiquantitative system. CONCLUSIONS: Outflow facility is significantly reduced in patients with uveitis who have high aqueous humor protein levels. Outflow facility appears to be normal in patients with active uveitis whose flare levels are low, and therefore the association between flare and outflow facility does not appear to be an indirect reflection of elevated anterior chamber cells. It is possible that elevated aqueous humor protein levels contribute to the development of uveitic glaucoma in some individuals by decreasing aqueous humor outflow facility, although a causal relationship cannot be established on the basis of this study.     

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.     

Reliable measurement of mouse intraocular pressure by a servo-null micropipette system.

PURPOSE. To develop a reliable technique for measuring intraocular pressure (IOP) in the mouse. METHODS. An electrophysiologic approach-the servo-null micropipette system (SNMS)-for measuring hydrostatic pressure was adapted for the mouse eye. Fine-tipped (5 microm in diameter) micropipettes were advanced across the cornea with a piezoelectric micromanipulator, and the IOP was continuously monitored for up to 46 minutes. RESULTS. The micropipette tip was visualized in the anterior chamber. With the SNMS, the IOP of black Swiss outbred mice under ketamine anesthesia was 17.8 +/- 0.4 mm Hg, higher than values previously estimated in inbred mouse strains by a larger bore microneedle manometric technique. After withdrawal of the micropipette, a second penetration led to a similar level of IOP. Hypotonic solutions increased and hypertonic solutions decreased IOP. Drugs that decrease inflow (acetazolamide, timolol) or increase outflow facility (pilocarpine, latanoprost) in primates and humans lowered steady state IOP in the mouse. The transient initial increase in IOP produced by pilocarpine reported in other animals was also observed in the mouse. Xylazine-ketamine anesthesia lowered IOP substantially in comparison with systemic anesthesia with either ketamine or tribromoethanol alone. CONCLUSIONS. The SNMS is the first reliable, reproducible method for measuring mouse IOP. The mouse IOP is sensitive not only to drugs known to reduce aqueous humor inflow but also to drugs that increase aqueous humor outflow facility in the eyes of primates and humans. The development of the SNMS is an enabling step in the use of the mouse for glaucoma research, including molecular genetics, molecular pharmacology, and the search for novel antiglaucoma drugs.     

Time dependent effects of sympathetic denervation on aqueous humor dynamics and choroidal blood flow in rabbits

PURPOSE: This study investigates the time-dependent effects of superior cervical ganglionectomy (SCGx) on aqueous humor dynamics and ocular blood flow in rabbits. METHODS: Measurements were made at various times between 24 hours and 12 months after SCGx. Intraocular pressure (IOP) was measured by pneumatonometry, aqueous flow by fluorophotometry and outflow facility by tonography. Uveoscleral outflow was determined by an intracameral tracer infusion technique and blood flow to the choroid was evaluated with fluorescent microspheres. Values in denervated eyes were compared with the contralateral, normally-innervated eyes using a paired Student's two-tailed t-test. RESULTS: At 24 hours after SCGx, IOP in denervated eyes was less than in normally-innervated eyes (14.6 +/- 0.8 vs 20.1 +/- 1.5 mmHg, 27%, p < 0.002). At one month, IOPs were not different between eyes. Compared with normally-innervated eyes at 10-12 months, IOP in denervated eyes was greater (20.4 +/- 0.7 vs 17.2 +/- 0.9 mmHg, 19%, p < 0.001), outflow facility was less (0.15 +/- 0.02 vs 0.21 +/- 0.01 microl/min/mmHg, 29%, p < 0.01) and blood flow to the choroid was less (12.1 +/- 5.0 vs 16.2 +/- 6.0 ml/min/gm tissue, 25%, p < 0.05). Aqueous humor flow was not significantly altered by SCGx at any time. CONCLUSIONS: The reduction in IOP at 24 hours after SCGx was not due to any change in aqueous flow or uveoscleral outflow (current study) but rather to an increase in outflow facility (previous studies). At 10-12 months, IOP was elevated because outflow facility was significantly reduced. The reduction in choroidal blood flow at 10-12 months may have occurred because of the increased IOP.     

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.     

Aqueous dynamics in experimental ab externo trabeculectomy

PURPOSE: This study assessed the decrease in intraocular pressure (IOP), the residual outflow resistance of the trabeculum and the filtration site by histology in enucleated pig and human eyes after ab externo trabeculectomy. METHOD: Measurement of the resistance to aqueous outflow was performed using the constant pressure method before and after ab externo trabeculectomy. RESULTS: The outflow facility was 0.31 +/- 0.13 microl/min/mm Hg in pig eyes and 0.24 +/- 0.08 microl/min/mm Hg in human eyes before surgery, and 79.0 +/- 47. 6 microl/min/mm Hg in pig eyes and 6.33 +/- 6.67 microl/min/mm Hg in human eyes after ab externo trabeculectomy. On histological examinations the aqueous outflow pathway was seen to be at the level of the residual trabecular meshwork. CONCLUSION: This study showed that ab externo trabeculectomy significantly lowers IOP and improves outflow facility in enucleated pig and human eyes.     

Effect of dorzolamide and latanoprost on intraocular pressure after small incision cataract surgery

PURPOSE: To evaluate the effect of dorzolamide 2% and latanoprost 0.005% on intraocular pressure (IOP) after small incision cataract surgery. SETTING: Department of Ophthalmology, University of Vienna, Vienna, Austria. METHODS: This prospective study comprised 102 eyes of 102 consecutive patients scheduled for small incision cataract surgery. The patients were assigned preoperatively to 1 of 3 groups of 34 each: dorzolamide, latanoprost, and control (no treatment). One drop of the assigned medication was instilled immediately after surgery. Intraocular pressure was measured preoperatively and 6 and 20 to 24 hours postoperatively. RESULTS: Six hours after surgery, the mean increase in IOP was 1.9 mm Hg +/- 3.9 (SD) in the dorzolamide group (P = .004 versus control), 2.2 +/- 3.0 mm Hg in the latanoprost group (P = .005 versus control), and 4.8 +/- 5.2 mm Hg in the control group. Twenty to 24 hours postoperatively, IOP decreased a mean of -0.9 +/- 3.5 mm Hg in the dorzolamide group (P = .012 versus control) and increased a mean of 0.3 +/- 3.6 mm Hg in the latanoprost group (P = 0.24 versus control) and 1.3 +/- 4.2 mm Hg in the control group. One eye in the dorzolamide group, 1 eye in the latanoprost group, and 4 eyes in the control group had an IOP of 30 mm Hg or higher 6 hours postoperatively. CONCLUSION: Six hours postoperatively, dorzolamide and latanoprost were effective in reducing the IOP increase after small incision cataract surgery; however, at 20 to 24 hours, only dorzolamide was effective. Neither drug prevented IOP spikes of 30 mm Hg or higher.     

Effect of latanoprost on intraocular pressure in mice lacking the prostaglandin FP receptor

PURPOSE: To determine whether latanoprost lowers IOP in prostaglandin FP receptor knockout mice. METHODS: Mean IOP difference between treated and untreated fellow eyes was measured on three separate occasions, 2 hours after a 200-ng dose of latanoprost to the right eye of homozygous (n = 9) and heterozygous (n = 15) FP knockout mice. C57BL/6 (n = 10) and NIH Swiss white mice (n = 17), which have normal FP receptor expression, provided the control population. The investigator was masked to the genotype of the FP knockout mice at the time of IOP measurement. RESULTS: Latanoprost had no effect on IOP in the homozygous FP knockout mice, with an average difference in IOP between treated and untreated fellow eyes of +0.25 mm Hg and a 95% confidence interval (CI) for the difference between means of -0.019 to +0.69. In contrast, latanoprost reduced IOP in the treated eye of the heterozygous FP knockout, C57BL/6, and Swiss white mice with mean differences and 95% CI of the difference in means of -0.52 (-0.91 to -0.14), -1.38 (-2.1 to -0.70), and -1.29 (-1.78 to -0.79) mm Hg, respectively. CONCLUSIONS: FP receptor signaling plays a crucial role in the early IOP response to latanoprost in the mouse eye.     

Effect of latanoprost on intraocular pressure in steroid-induced glaucoma

PURPOSE: To study the effect of monotherapy with latanoprost 0.005% on intraocular pressure (IOP) in a prospective nonrandomized clinical trial of patients newly diagnosed with steroid-induced secondary open-angle glaucoma. PATIENTS AND METHODS: Eight patients (16 eyes) with newly diagnosed steroid-associated secondary open-angle glaucoma were prescribed latanoprost 0.005% once a day in each eye. The initial IOP before treatment served as an internal control for each eye. Intraocular pressure was remeasured after 1 month of monotherapy with latanoprost. Investigators (WJS) were blinded to initial IOP at the time of remeasurement. After discontinuation of steroids, IOP was rechecked. If IOP was stable, latanoprost was discontinued. Intraocular pressure was rechecked 2 to 4 weeks later to confirm an association with steroid use. RESULTS: Intraocular pressure was significantly decreased after treatment with latanoprost (18.3 +/- 2.8 mm Hg) compared with initial IOP (25.3 +/- 9.1 mm Hg). This change represented a 28% decrease in IOP compared with baseline levels. Average IOP after discontinuation of steroids and latanoprost (17.3 +/- 1.4 mm Hg) did not differ from IOP measured during treatment with latanoprost, but it was significantly less than the initial IOP before treatment. No adverse effects were noted. CONCLUSIONS: Monotherapy with latanoprost is safe and effective in patients with steroid-induced glaucoma. Advantages include lack of systemic side effects and convenient once-daily dosing.