Acute effects of insulin on aqueous humor flow in patients with type 1 diabetes.

PURPOSE: Previous studies reported reduced aqueous humor flow through the anterior segment of the eye in patients with type 1 diabetes. This study investigates whether reduced flow is the result of the diabetic state or of alterations in glucose or insulin concentrations. METHODS: A cross-sectional study, involving patients with type 1 diabetes and healthy controls, measured aqueous flow at different insulin concentrations. Eleven patients with type 1 diabetes (hemoglobin A1C = 7.0 +/- 0.3% [mean +/- SEM], normal < 6.5) with no microvascular complications and 17 controls were prospectively studied. Controls were studied fasting and during a hyperinsulinemic-euglycemic clamp (insulin 2 mU/kg per minute). Patients with type 1 diabetes were similarly studied during two euglycemic clamp procedures (insulin 0.5 and 2.0 mU/kg per minute). Aqueous flow was measured by fluorophotometry. Pulsatile ocular blood flow and intraocular pressure were measured with a Langham flow probe. RESULTS: Control subjects had no change in aqueous flow during fasting and hyperinsulinemic conditions (3.0 +/- 0.1 vs 2.8 +/- 0.1 microl per minute). In the patients with type 1 diabetes, aqueous flow was not decreased with hyperinsulinemia, compared with the low insulin state (P =.7). Compared with control subjects, patients with type 1 diabetes had lower aqueous flow during hyperinsulinemia (2.4 +/- 0.1 microl per minute, P =.03) and at lower insulin conditions (2.6 +/- 0.1 microl per minute, P <.05). No differences in intraocular pressure or pulsatile ocular blood flow were noted between groups or between insulin states within groups. CONCLUSIONS: Aqueous flow is decreased in patients with type 1 diabetes under euglycemic conditions of high and relatively low insulin concentrations, despite the absence of microvascular complications.

Potential mechanism for the additivity of pilocarpine and latanoprost.

PURPOSE: To determine the ocular hypotensive mechanism underlying the additivity of latanoprost and pilocarpine. METHODS: This randomized, double-masked study included 30 patients with ocular hypertension on no ocular medications for at least 3 weeks. On each of six visits to the clinic, measurements were taken of aqueous flow and outflow facility by fluorophotometry, intraocular pressure by tonometry, and episcleral venous pressure by venomanometry. Uveoscleral outflow was calculated. Clinic visits were scheduled on baseline day; on day 8 of four times daily pilocarpine (2%) to one eye and vehicle to the other; on day 8 of continued pilocarpine/vehicle treatment plus latanoprost (0.005%) once daily to both eyes; after a 3-week washout period; on day 8 of once-daily latanoprost to one eye and vehicle to the other; and on day 8 of continued latanoprost/vehicle treatment plus pilocarpine four times a day to both eyes. Drug-treated eyes were compared with contralateral vehicle-treated eyes and with baseline day by paired t tests. Combined pilocarpine and latanoprost-treated eyes were compared with individual drug-treated eyes and with baseline day using the Bonferroni test. RESULTS: Compared with baseline, pilocarpine reduced intraocular pressure from 18.9 to 16.2 mm Hg (P =.001) and increased outflow facility from 0.18 to 0.23 microl per minute per mm Hg (P =.03). No other parameters were affected. Adding latanoprost further reduced intraocular pressure to 13.7 mm Hg (P <.001) and increased uveoscleral outflow from 0.82 to 1.36 microl per minute (P =.02). Latanoprost alone reduced intraocular pressure from 17.6 to 14.3 mm Hg (P <.0001) and increased uveoscleral outflow from 0.89 to 1.25 microl per minute (P =.05). Adding pilocarpine to the latanoprost treatment further reduced intraocular pressure to 12.7 mm Hg (P <.001) and increased outflow facility from 0.21 to 0.30 microl per minute per mm Hg (P =.03). CONCLUSIONS: Latanoprost and pilocarpine predominantly increase uveoscleral outflow and outflow facility, respectively, when given alone. These drugs are additive because pilocarpine does not inhibit the uveoscleral outflow increase induced by latanoprost.

Effect of scleral expansion band on ocular hypertension: Canadian phase 1 study.

A prospective, nonrandomized, controlled, phase 1 clinical trial was conducted to evaluate use of the scleral expansion band for lowering elevated intraocular pressure (IOP) in patients with ocular hypertension or primary open-angle glaucoma. The procedure lowered IOP by increasing outflow.

Aqueous humor dynamics in monkeys with laser-induced glaucoma.

This study determines the effects of laser-induced glaucoma on aqueous humor dynamics of 18 cynomolgus monkeys. Baseline measurements of 12 monkeys included intraocular pressure (IOP) by pneumatonometry, aqueous flow by fluorophotometry and outflow facility by tonography. Beginning 4 to 14 days later, the trabecular meshwork of one eye was treated repeatedly with laser photocoagulation until elevated IOP was induced. Thirty-six to 75 days after the last laser treatment, all measurements were repeated. Between 1.7 and 11.4 years after laser treatment, the same 12 monkeys plus 6 additional monkeys underwent IOP and aqueous flow measurements. In addition, outflow facility was determined with fluorophotometry, and uveoscleral outflow was both calculated (n=18) and measured with an intracameral tracer (n=7). In glaucoma eyes compared to control eyes (n=12), IOP was increased (p<0.04) by at least 8 mmHg at Time 1 (1 to 3 months) or Time 2 (3 to 4 years) after laser treatment; aqueous flow was reduced (p=0.0007) by 46% at Time 1 but returned to baseline levels at Time 2; tonographic outflow facility was reduced (p=0.0008) by 71% at Time 1. In lasered eyes compared to control eyes, fluorophotometric outflow facility was reduced (p=0.0008; n=18) by 63%, and uveoscleral outflow was increased (p<0.05), whether calculated or measured with tracers at least 1 year after laser treatment. The increased IOP in monkeys with laser-induced glaucoma was caused by a sustained reduction in outflow facility. The uveoscleral outflow increase was not enough to prevent the rise in IOP.

Acute versus chronic effects of brimonidine on aqueous humor dynamics in ocular hypertensive patients.

PURPOSE: To report the acute vs chronic effects of brimonidine, a selective alpha2-adrenergic receptor agonist, on aqueous humor dynamics in ocular hypertensive patients. METHODS: Brimonidine 0.2% was given topically twice daily for 29 days to one eye each of 28 ocular hypertensive volunteers in a randomized double-masked study. The fellow eye was similarly treated with vehicle. Aqueous flow (Fa) and outflow facility (Cfl) were determined with fluorophotometry. Intraocular pressure, outflow facility (Cton), and episcleral venous pressure (Pev) were measured with pneumatonometry, tonography, and venomanometry, respectively. Uveoscleral outflow (Fu) was calculated from intraocular pressure, Fa, Pev, and Cfl values. All measurements were taken on baseline day, day 8, and day 29 of treatment. Intraocular pressure and Fa only were measured after instillation of 1 drop of brimonidine on day 1. RESULTS: When measured 3 hours after instillation on days 1, 8, and 29 of treatment, brimonidine significantly (P < .001) reduced intraocular pressure by at least 5.0 +/- 0.7 mm Hg (mean +/- SEM) compared with baseline day, and by 2.7 +/- 0.5 mm Hg compared with the vehicle-treated contralateral control eyes. The greatest decrease (6.0 +/- 0.6 mm Hg) was observed at 3 hours after the first drop. Aqueous flow was reduced by 29% (P < .001) after the first application but was not significantly different from baseline when measured at day 29 of treatment. Uveoscleral outflow was increased 60% at day 8 (P < .06) and day 29 (P < .05) compared with baseline. There was no significant difference in outflow facility or episcleral venous pressure at day 8 or day 29 of treatment. CONCLUSIONS: The brimonidine-induced reduction in intraocular pressure in humans is associated initially with a decrease in aqueous flow, and after chronic treatment with an increase in uveoscleral outflow.

Effects of topical epinephrine on aqueous humor dynamics in the cat.

The purpose of this study was to investigate, in cats, the effects of topical epinephrine on aqueous humor dynamics as measured by the non-invasive method of fluorophotometry and by other methods. Measurements were carried out on 12 cats before and after one week of twice daily treatment with 2% epinephrine hydrochloride to one eye. Aqueous flow and outflow facility were determined using fluorophotometry. Uveoscleral outflow was calculated from these results and was evaluated with anterior chamber perfusion of FITC-dextran. Outflow facility also was measured by tonography. Epinephrine-treated eyes, compared with their baseline values, showed a 31% reduction in intraocular pressure (P<0.001), a 23% reduction in aqueous flow (P<0.05), a 60% increase in fluorophotometric outflow facility (P<0.05), and a 43% increase in tonographic outflow facility (P<0.05). Treated eyes, compared with contralateral control eyes, showed a 27% reduction in IOP (P<0.005), a 25% reduction in aqueous flow (P<0.005), a 38% increase in fluorophotometric outflow facility (P<0.05), and a 34% increase in tonographic outflow facility. When evaluated by both fluorophotometry and FITC-dextran tracer methods, epinephrine had no significant effect on uveoscleral outflow. It was concluded that, in cats treated with topical epinephrine twice daily for a week, a reduction in intraocular pressure is induced by an increase in outflow facility and decrease in aqueous flow.

Aqueous humor dynamics in the aging human eye.

PURPOSE: Healthy subjects were recruited to identify normal, age-associated changes in intraocular pressure and aqueous humor dynamics. METHODS: Normal healthy subjects from two age groups were enrolled in the study: (1) those from 20 to 30 years of age (n = 51) and (2) those 60 years of age and older (n = 53). Intraocular pressure was measured by pneumatonometry, tonographic outflow facility by pneumatonography, and episcleral venous pressure by venomanometry. Aqueous flow and outflow facility were determined by a fluorophotometric technique. Uveoscleral outflow and anterior chamber volume were calculated. Results from the older group were compared with those from the younger group by means of unpaired, two-tailed t tests. RESULTS: Compared with the younger group, the older group showed significant differences as follows: smaller anterior chamber volume (160+/-39 vs. 247+/-39 microl; mean +/- SD; P< .00001), reduced aqueous flow (2.4+/-0.6 vs. 2.8+/-0.8 microl/minute; P = .002), and reduced uveoscleral outflow (1.10+/-0.81 vs. 1.52+/-0.81 microl/minute; P = .009). CONCLUSIONS: In the healthy aging eye, there is a reduction in the production of aqueous humor and a reduction in its drainage through the uveoscleral outflow pathway.

Bunazosin reduces intraocular pressure in rabbits by increasing uveoscleral outflow.

The mechanism of the ocular hypotensive effect of bunazosin hydrochloride (an alpha1-adrenergic antagonist) and the possible intermediary role of prostaglandins were studied in New Zealand albino rabbits. Aqueous flow, outflow facility and uveoscleral outflow were determined by fluorophotometry, and intraocular pressure (IOP) was measured by pneumatonometry on the fourth day of twice daily topical treatment with 0.1% bunazosin. Uveoscleral outflow was measured with a tracer infusion technique at 1 to 2 hours after one dose of 0.1% bunazosin. Total outflow facility was measured by a two-level constant-pressure infusion method before and at one hour after one dose of 0.1% bunazosin. The effect of topically applied cyclooxygenase inhibitors, including 0.25% indomethacin and 0.03% flurbiprofen, on the IOP reduction after bunazosin was evaluated. At 3 hours after the seventh consecutive dose given twice-daily, bunazosin significantly (P<0.001) reduced IOP to 13.4+/-0.8 mm Hg (mean +/- SEM) from a baseline of 19.6+/-1.1 mm Hg. Indomethacin significantly inhibited the IOP reduction after one dose of bunazosin, whereas flurbiprofen did not (repeated measures ANOVA). Bunazosin significantly increased uveoscleral outflow (P<0.05) and total outflow facility (P<0.02), but not fluorophotometric outflow facility or aqueous flow. It is concluded that, in rabbits, 0.1% bunazosin reduces IOP predominantly by increasing uveoscleral outflow. The role of prostaglandins in this effect is equivocal.

Effects of exogenous prostaglandins on aqueous humor dynamics and blood-aqueous barrier function.

Topical prostaglandins (PGs) are very effective at reducing intraocular pressure (IOP) in a variety of animals and in humans with relatively few side effects. The mechanisms of action of several PGs, their prodrugs and analogues have been studied in rabbits, cats, monkeys and humans. PGF2 alpha and its analogues evaluated in monkeys include PGF2 alpha-tromethamine salt, PGF2 alpha -isopropylester (-IE), S-1033, PhXA34, PhDH100A and latanoprost (PhXA41). Aqueous flow and outflow facility are either increased or remain unchanged by these agents. PGF2 alpha-IE, PHXA34, PhDH100A and latanoprost increase uveoscleral outflow, accounting for most of the IOP reduction. PGA2 in cats increases aqueous flow and outflow facility, but it reduces IOP primarily by stimulating uveoscleral outflow. The PGD2 analogue BW245C is unique in that it is the only PG that decreases aqueous flow. Mechanistic studies in humans have been performed with PGF2 alpha -IE, unoprostone, PhXA34 and latanoprost. In two clinical studies with latanoprost, a significant increase in uveoscleral outflow was found which, as in animals, accounts for most of the IOP reduction. A slight but inconsistent increase in outflow facility may also be involved. The doses tested had minimal effects on the permeability of the blood-aqueous barrier (BAB). In vitro studies of human tissue have been conducted to elucidate the PG effect on outflow facility and uveoscleral outflow. Studies of isolated human anterior segment preparations show that PGE2 increases outflow facility whereas PGF2 alpha has no measurable effect on this parameter. Studies of human ciliary muscle cells in tissue culture indicate that PGs may directly modulate extracellular matrix metabolism, which may be related to the increased uveoscleral drainage. This review summarizes in vitro and in vivo studies of the effects of PGs on aqueous humor dynamics and BAB integrity in humans, cats and monkeys.

Predicting long-term results of trabeculectomy from early postoperative intraocular pressure levels.

BACKGROUND AND OBJECTIVES: The authors retrospectively examined the potential for early postoperative intraocular pressure to predict the long-term results of initial trabeculectomies. PATIENTS AND METHODS: The records of 173 patients (207 consecutive eyes) who underwent initial trabeculectomies, which were performed by one of the authors between 1983 and 1991, with a minimum follow-up of 150 days were reviewed. Cases of trabeculectomy combined with cataract extraction were excluded. RESULTS: The intraocular pressure during postoperative week 1 was the same for patients with successful initial trabeculectomies (success group) as it was for patients with unsuccessful trabeculectomies (failure group). However, the intraocular pressure during the second, third, and fourth weeks was significantly higher in the failure group (P < .001). Laser suture lysis and 5-fluorouracil had no influence on the fact that high intraocular pressure during the first postoperative week had no prognostic significance. CONCLUSION: Positive results on postoperative Seidel tests did not predict a poor prognosis. However, high intraocular pressure after the first week may require intervention because it predicts a poor prognosis.

Effects of brimonidine on aqueous humor dynamics in human eyes.

OBJECTIVE: To evaluate the mechanism by which brimonidine, a selective alpha 2-adrenergic agonist, lowers intraocular pressure (IOP) in humans. SUBJECTS: Twenty-one volunteers with ocular hypertension. METHODS: Brimonidine tartrate (0.2%) was given topically twice daily for 1 week to one eye in a randomized, double-masked study. The fellow eye was similarly treated with brimonidine vehicle. Before (baseline) and after 1 week (day 8) of dosing, IOP, aqueous flow, episcleral venous pressure, and tonographic outflow facility were directly measured. Fluorophotometric outflow facility and uveoscleral outflow were calculated. Brimonidine-treated eyes were compared with vehicle-treated contralateral control eyes and with baseline measurements after 1 week of dosing. RESULTS: Brimonidine significantly (P < .001, Student's two-tailed t test) reduced IOP mean +/- SE of 4.7 +/- 0.7 and 4.2 +/- 0.4 mm Hg compared with the baseline day and with the vehicle-treated contralateral control eyes, respectively. Compared with the baseline day, aqueous flow was reduced by 20% (P = .002) and uveoscleral outflow was increased (P = .04). A slight contralateral decrease in IOP of 1.2 +/- 0.6 mm Hg (P = .05) and in aqueous flow of 12% (P = .05) was noted. No significant difference was seen in the outflow facility values or episcleral venous pressure compared with the baseline day or with the contralateral control eye. CONCLUSIONS: The brimonidine-induced reduction in IOP in humans is associated with a decrease in aqueous flow and an increase in uveoscleral outflow. The decrease in IOP and aqueous flow in the contralateral control eye on day 8 compared with the baseline day suggests a mild contralateral effect.

Prostaglandin A2 increases uveoscleral outflow and trabecular outflow facility in the cat.

Prostaglandins (PG) are very effective ocular hypotensive agents. It is generally agreed that these drugs reduce intraocular pressure primarily by increasing uveoscleral outflow. They may also increase trabecular outflow facility though available evidence is less convincing. It has been hypothesized that PGs may increase facility of uveoscleral outflow in addition to their other mechanisms, but this has not yet been tested. To help clarify the ocular hypotensive mechanism of action of a derived PG of the A type, cats were treated twice daily for one week with PGA2 (0.01%) to one eye and vehicle to the other. Measurements were made of aqueous flow and outflow facility with fluorophotometry and of intraocular pressure with pneumatonometry. From these values, uveoscleral outflow was calculated. In addition, total outflow facility, uveoscleral outflow, and uveoscleral outflow facility were determined with invasive methods. PGA2 significantly reduced IOP by a mean of at least 4.7 mmHg in all experiments with all P-values less than 0.01. Compared with contralateral vehicle-treated control eyes, uveoscleral outflow in the treated eye was significantly (P < 0.05) increased by at least 50% using two different methods of measurement. Compared with baseline day, PGA2 significantly (P < or = 0.05) increased aqueous flow by 1.8 microliters min-1, fluorophotometric outflow facility by 0.36 microliter min-1 mmHg-1 and fluorophotometric uveoscleral outflow by 2.0 microliters min-1. Total outflow facility was not significantly different comparing treated with contralateral control eyes. Facility of uveoscleral outflow was < or = 0.02 microliters min-1 mmHg-1 for both control and treated eyes. It is concluded that PGA2 decreases IOP in cats by increasing uveoscleral outflow and trabecular outflow facility as measured with fluorophotometry. A significant increase in aqueous flow reduces the ocular hypotensive effect.

A retrospective study of the effects of laser suture lysis on the long-term results of trabeculectomy.

We retrospectively examined the effects of laser suture lysis on the long-term results of initial trabeculectomies in 130 consecutive eyes that had an intraocular pressure greater than 21 mm Hg during the first 4 postoperative weeks. After the high intraocular pressure was noted, 46 eyes underwent laser suture lysis; the other 84 did not. The 2-year cumulative probability of success in the laser suture lysis group was .84 and, in the control group, .82 (P > .05). Intraocular pressures in the two groups 1 and 2 years after trabeculectomy were similar. Laser suture lysis had no discernible effect on the long-term success rate of trabeculectomy in these patients.

Effects of apraclonidine on aqueous humor dynamics in human eyes.

PURPOSE: The mechanism by which apraclonidine, an alpha 2-adrenergic agonist, lowers intraocular pressure (IOP) was evaluated in humans. METHODS: In a randomized, double-masked, placebo-controlled study, 0.5% apraclonidine was given topically twice daily for 1 week to one eye in each of 21 ocular hypertensive volunteers. The other eye was treated similarly with vehicle. Before and after 1 week of treatment, aqueous flow, uveoscleral outflow, fluorophotometric outflow facility, intraocular pressure, tonographic outflow facility, episcleral venous pressure, and outflow pressure were either directly measured or mathematically calculated. Values were compared in treated versus contralateral control eyes and on baseline versus day 8 of treatment. RESULTS: When compared with both contralateral control eyes and baseline day, fluorophotometric outflow facility in the apraclonidine-treated eyes increased by 0.09 to 0.10 microliter/minute/mmHg (P < 0.04), IOP decreased by 3.1 to 5.2 mmHg (P < 0.0001), and outflow pressure decreased by 3.3 to 4.2 mmHg (P < 0.0001). When compared with baseline day only, aqueous flow in the apraclonidine-treated eyes decreased by 0.3 microliter/minute (P < 0.04), and episcleral venous pressure decreased by 1.0 mmHg (P < 0.001). Episcleral venous pressure also decreased in the control eyes compared with baseline day by 1.3 mmHg (P < 0.001). When compared with contralateral control eyes only, uveoscleral outflow in the apraclonidine-treated eyes decreased by 0.47 microliter/minute (P < 0.03). Tonographic outflow facility showed no change when compared with either contralateral control eyes or baseline values. CONCLUSIONS: The apraclonidine-induced reduction in intraocular pressure was associated with an increase in fluorophotometric outflow facility, decrease in aqueous flow and decrease in episcleral venous pressure compared to baseline. The lack of a significant difference in aqueous flow and episcleral venous pressure between treated and contralateral control eyes may represent a contralateral drug effect.

Effects of PhXA41, a new prostaglandin F2 alpha analog, on aqueous humor dynamics in human eyes.

PURPOSE: PhXA41, a new phenyl-substituted analog of a prostaglandin F2 alpha (PGF2 alpha) prodrug (13,14-dihydro-17-phenyl-18,19,20-trinor-prostaglandin F2 alpha-1-isopropyl ester), is an effective ocular hypotensive agent in patients with glaucoma. To understand its mechanism of action, various components of aqueous humor dynamics were examined after topical application to human eyes. METHODS: In a randomized, double-masked, placebo-controlled study, PhXA41 (0.006%) was given topically twice daily for 1 week to one eye each of 22 volunteers with normotension or ocular hypertension. The other eye was similarly treated with vehicle. Intraocular pressure (IOP) was measured by pneumatonometry and tonographic outflow facility by pneumatonography. Aqueous flow and outflow facility were determined either directly or indirectly by a fluorophotometric technique, and uveoscleral outflow was calculated secondarily. Comparison of values obtained in treated versus contralateral control eyes and on baseline versus day 8 of treatment were made. RESULTS: Compared with baseline measurements, PhXA41 significantly (P < 0.001) reduced IOP by 5.5 +/- 0.6 mmHg (mean +/- standard error of the mean) as measured 3 hours after the last dose on the eighth day of treatment. Aqueous flow, tonographic outflow facility, and fluorophotometric outflow facility were not changed by PhXA41. However, uveoscleral outflow was significantly greater in the PhXA41-treated eyes (0.87 +/- 0.22 microliter/minute) compared with either the contralateral vehicle-treated eyes (0.14 +/- 0.30; P < 0.02) or baseline measurements (0.39 +/- 0.20 microliter/minute; P < 0.05). CONCLUSIONS: PhXA41 decreases IOP in humans by increasing uveoscleral outflow without significantly affecting other parameters of aqueous humor dynamics.

Posttrabeculectomy anterior subcapsular cataract formation induced by anterior chamber air.

We retrospectively examined the effect of air, as contrasted with balanced salt solution (BSS), sodium hyaluronate, or no substance at all, used to reform the anterior chamber at the end of trabeculectomy on subsequent cataract formation in 141 consecutive patients (173 phakic eyes). The minimum follow up was 120 days. The use of air increased the incidence of anterior subcapsular cataract formation significantly. Also, the eyes that had a large air bubble on postoperative day 1 had a higher incidence of anterior subcapsular cataract than the eyes with less air on that day. We suggest that the toxicity to the lens of the oxygen in the air increased the incidence of anterior subcapsular cataract in the eyes in which air was used. We recommend that BSS or sodium hyaluronate be used instead of air to reform the anterior chamber following trabeculectomy.