Mechanism of action of bimatoprost (Lumigan).

Bimatoprost is a new ocular hypotensive agent that lowers intraocular pressure (IOP) in normal, ocular hypertensive, and glaucomatous eyes. Its mechanism of action has been studied in normal human subjects. Bimatoprost mildly stimulates the rate of aqueous humor flow during the day (13%) and at night (14%). Its ocular hypotensive action is due primarily to a 26% reduction in the tonographic resistance to outflow. Thus, bimatoprost enhances the pressure-sensitive outflow pathway. Additional beneficial effects may include an increase in the rate of flow via the pressure-insensitive outflow pathway (sometimes called the "uveoscleral outflow pathway") and a lowering of the extraocular recipient pressure (sometimes called "episcleral venous pressure"). Reduction of tonographic resistance to aqueous humor outflow reduces steady-state IOP, an effect that is beneficial for the treatment of glaucoma. In addition to its effect on steady-state IOP, reduction of resistance allows the eye to recover more quickly from transient IOP elevations. The former effect is common to all ocular hypotensive drugs, but the latter effect is an exclusive property of drugs that reduce outflow resistance, such as bimatoprost.

Effects of AGN 192024, a new ocular hypotensive agent, on aqueous dynamics.

PURPOSE: To determine the mechanism of intraocular pressure lowering for the Ocular Hypotensive Lipid, AGN 192024 (Allergan, Inc, Irvine, California). METHODS: Twenty-five normal human volunteers between the ages of 21 and 48 took part in a randomized, double-masked, placebo-controlled, paired-comparison study in which intraocular pressure, aqueous humor flow, and tonographic resistance to outflow were studied. Measurements of aqueous flow were made during the day and at night while subjects slept. Intraocular pressure was measured with the Goldmann tonometer, and resistance to outflow was measured by electronic recording Schiötz tonography. RESULTS: Intraocular pressure was decreased by 20% on day 3 in AGN 192024-treated eyes in comparison with placebo-treated eyes in normal subjects (P <.001). Aqueous humor flow was stimulated 13% during the day (P =.007) and 14% at night (P =.014) by the drug. Tonographic resistance to outflow was decreased 26% by AGN 192024 (P <.001), and apparent resistance to outflow (the ratio of intraocular pressure to aqueous flow) was decreased 31% (P <.001). Assuming that AGN 192024 does not cause prolonged lowering of episcleral venous pressure, the results show that pressure-insensitive outflow is enhanced by 50%, whereas tonographic facility of outflow (reciprocal of resistance) was enhanced 35%. CONCLUSIONS: AGN 192024 is an ocular hypotensive agent that works by enhancing both pressure-sensitive and pressure-insensitive aqueous humor outflow without diminishing aqueous humor formation.

Ascorbic acid content of human corneal epithelium.

PURPOSE: To measure the concentration of ascorbic acid in the human corneal epithelium. METHODS: Corneal epithelium was removed from postmortem eyes 4 to 16 hours after death and ascorbate measured by high-performance liquid chromatography. RESULTS: The concentration of ascorbate was 1.33 +/- 0.48 mg/gm wet weight (mean +/- SD), estimated to be 14 times its concentration in the aqueous humor. CONCLUSIONS: Ascorbate can protect the basal layer of the epithelium by absorption of incident ultraviolet radiation.

Comparison of the efficacy of betaxolol-brinzolamide and timolol-dorzolamide as suppressors of aqueous humor flow in human subjects.

OBJECTIVE: To compare the efficacy of combinations of betaxolol-brinzolamide and timolol-dorzolamide as suppressors of aqueous humor flow and ocular hypotensive agents. DESIGN: Placebo-controlled, masked comparison of the two drug combinations. PARTICIPANTS: Twenty-five normal human volunteers with the fellow eye serving as control. METHODS OR TESTING: Fluorophotometric measurement of aqueous humor flow and pneumatonometric measurement of intraocular pressure. MAIN OUTCOME MEASURES: Aqueous humor flow and intraocular pressure. RESULTS: The betaxolol-brinzolamide combination lowered aqueous flow 39% to 44%, and the timololdorzolamide combination lowered aqueous flow 51%. The betaxolol-brinzolamide combination lowered intraocular pressure 14% to 19%, and the timolol-dorzolamide combination lowered it 18% to 24%. CONCLUSIONS: Both drug combinations were effective; the timolol-dorzolamide combination appeared to be the more effective of the two after short-term exposure (24 hours).

Effect of brinzolamide and dorzolamide on aqueous humor flow in human eyes.

PURPOSE: To measure the relative efficacy of brinzolamide hydrochloride 1% ophthalmic suspension, a new carbonic anhydrase inhibitor, compared with the currently used dorzolamide hydrochloride 2% ophthalmic solution as suppressors of aqueous humor flow in human eyes, and to study the difference of effect during the day and at night. METHODS: A randomized, double-masked, placebo-controlled study of 25 normal human subjects was carried out at Mayo Clinic. The daytime rate of aqueous humor flow was measured every 2 hours from 8 AM to 4 PM by means of fluorophotometry. Likewise, the night-time rate of aqueous humor flow was measured every 2 hours from 12 AM to 6 AM. Intraocular pressure was measured at 4 PM and 6 AM. RESULTS: Brinzolamide reduced aqueous flow by 0.47+/-0.20 microl per min (mean+/-SD) during the day, whereas dorzolamide reduced flow by 0.34+/-0.20 microl per min. Brinzolamide reduced aqueous flow by 0.16+/-0.12 microl per min during the night, whereas dorzolamide reduced flow by 0.10+/-0.13 microl per min. Brinzolamide reduced afternoon intraocular pressure by 1.5+/-1.1 mm Hg, and dorzolamide reduced afternoon intraocular pressure by 1.1+/-1.0 mm Hg. Brinzolamide reduced the morning awakening intraocular pressure by 0.3+/-1.6 mm Hg, and dorzolamide reduced it by 0.8+/-1.0 mm Hg. CONCLUSIONS: Our data support the idea that brinzolamide is at least as efficacious as dorzolamide as a suppressor of aqueous humor flow in normal human eyes and that there is probably not a clinically significant difference between the two drugs in this efficacy. Clinicians who prescribe brinzolamide should expect similar ocular hypotensive responses from brinzolamide and dorzolamide.

A family of mammalian Na+-dependent L-ascorbic acid transporters.

Vitamin C (L-ascorbic acid) is essential for many enzymatic reactions, in which it serves to maintain prosthetic metal ions in their reduced forms (for example, Fe2+, Cu+), and for scavenging free radicals in order to protect tissues from oxidative damage. The facilitative sugar transporters of the GLUT type can transport the oxidized form of the vitamin, dehydroascorbic acid, but these transporters are unlikely to allow significant physiological amounts of vitamin C to be taken up in the presence of normal glucose concentrations, because the vitamin is present in plasma essentially only in its reduced form. Here we describe the isolation of two L-ascorbic acid transporters, SVCT1 and SVCT2, from rat complementary DNA libraries, as the first step in investigating the importance of L-ascorbic acid transport in regulating the supply and metabolism of vitamin C. We find that SVCT1 and SVCT2 each mediate concentrative, high-affinity L-ascorbic acid transport that is stereospecific and is driven by the Na+ electrochemical gradient. Despite their close sequence homology and similar functions, the two isoforms of the transporter are discretely distributed: SVCT1 is mainly confined to epithelial systems (intestine, kidney, liver), whereas SVCT2 serves a host of metabolically active cells and specialized tissues in the brain, eye and other organs.

Comparison of the early effects of brimonidine and apraclonidine as topical ocular hypotensive agents.

OBJECTIVE: To compare the mechanism of action of short-term administration of brimonidine tartrate and apraclonidine hydrochloride as topical ocular hypotensive agents. SUBJECTS AND METHODS: Two randomized, double-masked, placebo-controlled studies of 19 normal human subjects were carried out. The first study compared brimonidine with apraclonidine in timolol maleate-treated eyes, and the second study compared latanoprost with placebo in timolol-treated eyes. The rate of aqueous flow and intraocular pressure were measured in both studies. The topical drug combinations were instilled the night before and repeated the morning before the measurements. Aqueous humor flow was measured by the rate of disappearance of topically applied fluorescein. Intraocular pressure was measured by pneumatonometry every 2 hours from 8:15 AM to 4:15 PM. RESULTS: Both brimonidine and apraclonidine further reduced aqueous flow in timolol-treated eyes from 1.23 +/- 0.21 microL/min to 0.96 +/- 0.16 microL/min and 0.98 +/- 0.17 microL/min, respectively. Consistent reductions were observed in intraocular pressure, with average reductions of 19% with brimonidine and 17% with apraclonidine. Latanoprost had no effect on aqueous flow in timolol-treated eyes (P = .15), but showed an average reduction in intraocular pressure of 13%. CONCLUSIONS: Brimonidine and apraclonidine are similar in their effects on the aqueous system. Both reduce intraocular pressure in the timolol-treated eye, primarily, if not exclusively, by further suppressing aqueous flow. In contrast, latanoprost reduces intraocular pressure in the timolol-treated eye without affecting aqueous flow.

Comparison of effects of topical ibopamine and epinephrine on the circadian rhythm of intraocular pressure of the rabbit eye as measured by telemetry.

The purpose of this study was to measure the effect of topical ibopamine and epinephrine on intraocular pressure in undisturbed rabbits. Six pigmented rabbits were outfitted with a telemetric transducer system connected via catheter to the vitreous cavity of one eye for continuous monitoring of intraocular pressure. After entrainment to a 12 hour light, 12 hour dark cycle and after stabilization of the circadian rhythm of intraocular pressure, the animals were tested with 2% ibopamine and 2% epinephrine. Each drug was instilled during the light phase and during the dark phase of the circadian cycle. When administered during the light phase, both drugs caused a transient pressure rise followed by prolonged hypotension. When administered during the dark phase, neither drug caused a pressure rise but both drugs caused prolonged hypotension. It was concluded that ibopamine and epinephrine cause identical intraocular pressure changes in the normal rabbit eye. The effect was dependent on the timing of administration during the circadian cycle. Since ibopamine is a pro-drug of deoxyepinephrine (N-methyl dopamine, epinine), its effects are assumed to be due to this metabolite, a metabolite that is structurally similar to epinephrine.

Measurement of aqueous humor flow by fluorophotometry in the presence of a dilated pupil.

PURPOSE: To determine by means of fluorophotometry whether pharmacologic dilation of the pupil can interfere with the measurement of aqueous flow. METHODS: Ten normal human volunteers underwent dilation with tropicamide, phenylephrine, and a combination of the two drugs. Before and after dilation, the rate of aqueous flow was measured by the rate of disappearance of fluorescein from the cornea and the anterior chamber. RESULTS: Dilation of the pupil with tropicamide alone had no effect on the rate of clearance of fluorescein. Dilation with phenylephrine increased the rate of clearance of fluorescein by 40% and caused a small increase in the variability among subjects. Dilation with a combination of tropicamide and phenylephrine caused clearance of fluorescein at more than double the normal rate and a marked increase in variability among subjects. CONCLUSIONS: When the pupil is dilated sufficiently to permit mixing of aqueous humor in the posterior and anterior chambers, fluorescein can leave the system by a posterior route, and its rate of clearance may not be an accurate measure of the net rate of aqueous humor flow through the anterior chamber.

Additive effect of dorzolamide on aqueous humor flow in patients receiving long-term treatment with timolol.

OBJECTIVE: To determine the additive effect on aqueous humor flow of short-term dorzolamide treatment in patients with glaucoma receiving long-term treatment with timolol. SUBJECTS AND METHODS: Thirty-nine patients with glaucoma, 19 at Mayo Clinic, Rochester, Minn, and 20 at the University of Uppsala, Uppsala, Sweden, who had been receiving timolol treatment in both eyes for at least 1 year were studied. Aqueous flow was measured with fluorophotometry and intraocular pressure with tonometry. The effect of dorzolamide was compared with placebo when added to the long-term treatment regimen with timolol. RESULTS: Dorzolamide reduced aqueous humor flow by 24% +/- 11% (mean +/- SD). The intraocular pressure as compared with placebo in the US cohort was reduced by 10% +/- 6% and in the Swedish cohort by 18% +/- 9%. CONCLUSIONS: Dorzolamide, a carbonic anhydrase inhibitor, has additive effects as an ocular hypotensive agent with timolol, a beta-adrenergic antagonist, even though both drugs are suppressors of aqueous humor flow. Dorzolamide's effect on flow in these patients is the same as reported previously in normal subjects who are not taking a beta-adrenergic antagonist.

Comparison of the efficacy of apraclonidine and brimonidine as aqueous suppressants in humans.

OBJECTIVE: To measure and compare the effect of apraclonidine hydrochloride and brimonidine tartrate on the rate of aqueous humor flow in human subjects. SUBJECTS AND METHODS: Forty normal human subjects were given apraclonidine or brimonidine by topical instillation. Aqueous humor flow was measured by the rate of disappearance of topically applied fluorescein. Intraocular pressure was measured by applanation tonometry. RESULTS: Apraclonidine suppressed aqueous humor flow between 39% and 44% and lowered intraocular pressure between 20% and 23%. Brimonidine suppressed aqueous humor flow between 44% and 48% and lowered intraocular pressure between 19% and 22%. CONCLUSION: No statistically significant differences were found between the effects of the 2 drugs on aqueous humor dynamics in normal subjects.

Measuring oxygen tension in the anterior chamber of rabbits.

PURPOSE: Measuring the concentration of oxygen in the aqueous humor without penetrating the eye would provide a new dimension in understanding aqueous humor and corneal dynamics. In this study a preinvasive method was developed for determining the cameral oxygen concentration in anesthetized rabbits by measuring the excited-state lifetime of a phosphorescent dye. METHODS: A scanning ocular fluorometer was designed to excite phosphorescence with a brief flash of light and to measure the decay of luminescence for as long as 1000 microsec after excitation. The measurement window was scanned through the depth of the anterior chamber or fixed at the mid-anterior chamber. A depot of the phosphorescent dye Pd-uroporphyrin was injected into the vitreous of eight pigmented rabbits, and within a few days the dye was measurable in the anterior chamber. The excited-state lifetime of this dye is inversely correlated to oxygen concentration and was calibrated by measuring the lifetime of dye in cuvettes equilibrated with oxygen-nitrogen mixtures. Oxygen tensions were determined from lifetimes measured in the open eye, under a polymethylmethacrylate (PMMA) contact lens, under two oxygen-permeable contact lenses, and immediately after lid closure. RESULTS: Oxygen tension in the mid-anterior chamber before placing a PMMA contact lens was 23 +/- 3 mm Hg (mean +/- SD; n = 6). After 20 minutes of PMMA lens wear, oxygen tension decreased to 4 +/- 2 mm Hg. When the focal diamond was scanned through the anterior chamber, oxygen tension was 24 +/- 5 mm Hg near the corneal endothelium and decreased to 17 +/- 8 mm Hg near the crystalline lens. Under the PMMA contact lens this gradient reversed: Oxygen tensions near the endothelium and lens were 3 +/- 2 mm Hg and 6 +/- 2 mm Hg, respectively. Lid closure for 10 minutes or longer decreased the mid-anterior chamber oxygen tension from 21 +/- 2 mm Hg (n = 19 measurements from seven animals) to 10 +/- 3 mm Hg (n = 15 measurements from five animals). CONCLUSIONS: Measuring excited-state lifetime of phosphorescent dyes in the anterior chamber provides a useful method for determining oxygen concentration in vivo, without penetrating the eye. Cameral oxygen tension under PMMA contact lenses are significantly lower than in the uncovered eye. The profile of oxygen tension through the anterior chamber suggests that oxygen is supplied transcorneally to the aqueous humor.

Combined effect of dorzolamide and latanoprost on the rate of aqueous humor flow.

PURPOSE: To determine whether latanoprost, an ocular hypotensive agent believed to enhance uveoscleral outflow of aqueous humor, augments the aqueous-suppressing effect of dorzolamide, a topical carbonic anhydrase inhibitor. METHODS: Twenty-four normal subjects underwent measurement of aqueous humor flow by fluorophotometry to determine the flow with placebo, with dorzolamide, and with a combination of dorzolamide and latanoprost. RESULTS: The flow of aqueous humor was suppressed 13% by dorzolamide but not by latanoprost. Latanoprost did not augment the effect of dorzolamide on aqueous humor flow; latanoprost and dorzolamide had additive ocular hypotensive effects. CONCLUSIONS: The uveoscleral flow effect of latanoprost does not improve the aqueous-suppressing effect of dorzolamide, but the two drugs have additive ocular hypotensive effects.

Aqueous humor flow in sleeping humans is unaffected by norepinephrine infusion.

PURPOSE: Intravenous administration of the catecholamine epinephrine is known to have a stimulatory effect on aqueous humor flow in sleeping human subjects, an effect that is augmented by plasma corticosteroids. This study was performed to determine whether the closely related catecholamine norepinephrine has a similar effect on aqueous humor flow. METHODS: Twenty normal subjects were studied. Aqueous flow was measured by fluorophotometry. At night during sleep, norepinephrine or placebo was infused intravenously (i.v.) between midnight and 6 AM. The rate of aqueous flow during the norepinephrine infusion was compared with the rate of flow during placebo infusion, with each subject serving as his/her own control. The urinary excretions of epinephrine and norepinephrine were measured at the end of each infusion period. RESULTS: The norepinephrine infusion caused an 8% increase in systolic blood pressure (P < 0.001), a 15% increase in diastolic blood pressure (P < 0.001), and a 9% decrease in heart rate (P=0.003) compared with the placebo. The rate of aqueous humor flow during sleep from 12 AM to 6 AM was unchanged by norepinephrine. The rate was 1.27+/-0.31 microl/min (mean+/-SD) during i.v. infusion of placebo and 1.30+/-0.27 microl/min during infusion of norepinephrine (P=0.63). CONCLUSIONS: An infusion of norepinephrine during sleep that causes measurable changes in cardiovascular parameters has no measurable effects on the rate of aqueous humor flow. The lack of a measurable effect of a norepinephrine infusion contrasts to the stimulatory effect of an epinephrine infusion.

The effect of dorzolamide on aqueous humor dynamics in normal human subjects during sleep.

OBJECTIVE: The purpose of the study was to measure the effect of the topical carbonic anhydrase inhibitor, 2% dorzolamide hydrochloride, on the rate of aqueous humor flow in sleeping humans. DESIGN: A randomized, double-masked, placebo-controlled study. PARTICIPANTS: Twenty-five normal human subjects. INTERVENTION: Topical instillation of 2% dorzolamide hydrochloride versus topical placebo. MAIN OUTCOME MEASURES: Rate of aqueous humor flow in sleeping humans and intraocular pressure immediately after awakening from sleep. RESULTS: The rate of flow in sleeping subjects at night (12 AM to 6 AM) was 1.28 +/- 0.30 microliters/min (mean +/- standard deviation; n = 25) in placebo-treated eyes, whereas the nighttime flow in dorzolamide-treated eyes was 1.17 +/- 0.38 microliters/min (P = < 0.001), resulting in a nighttime reduction of 9% (P = 0.032). In contrast, the daytime (8 AM to 4 PM) rate of flow in ambulatory subjects was 2.97 +/- 0.64 microliters/min in placebo-treated eyes and 2.60 +/- 0.63 microliters/min (P = 0.032) in dorzolamide-treated eyes, resulting in a daytime reduction of 13% (P = < 0.001). CONCLUSIONS: Topically administered dorzolamide hydrochloride is effective for reducing the rate of aqueous humor flow in normal human eyes during the day and at night during sleep. The efficacy of dorzolamide at these two times is approximately half that of systematically administered acetazolamide.

Long-term outcome of patients who undergo tonometry as part of a general physical examination.

OBJECTIVE: To determine the value of including tonometry as part of a general physical examination. MATERIAL AND METHODS: Between Feb. 14, 1977, and Dec. 31, 1980, 849 residents of Rochester, Minnesota, underwent measurement of intraocular pressure by trained ophthalmic technicians at the request of a nonophthalmologist physician as part of a general physical examination. In 1995 and 1996, these cases were reviewed to determine how many patients in this study cohort had subsequently been diagnosed as having glaucoma. The outcome was derived from the examination of medical records and from the responses to mailed questionnaires and telephone interviews with study patients and their physicians. RESULTS: In patients whose intraocular pressures were less than 16 mmHg at baseline, the risk of being diagnosed as having glaucoma within 10 years was 1% (95% confidence interval [CI], 0 to 2%) and within 15 years was 2% (95% CI, 0 to 4%). In patients whose pressure in the higher-pressure eye was 16 to 21 mmHg at baseline, the risk of having glaucoma in 10 years was 3% (95% CI, 2 to 5%) and in 15 years was 5% (95% CI, 3 to 7%). Twenty-four patients were found at baseline to have an intraocular pressure of 22 mmHg or higher in at least one eye or a difference of 5 mmHg or more between the two eyes. In this group, the risk of having glaucoma in 10 years was 17% (95% CI, 0 to 31%) and in 15 years was 26% (95% CI, 6 to 43%). CONCLUSION: When included as part of a general physical examination of older persons, tonometry and a few simple questions provide information that can be used to help the clinician determine the advisability of more detailed ophthalmic examinations.