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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.

Animals↗

Effect of ifenprodil on aqueous humor dynamics and optic nerve head circulation in rabbits.

The purpose of this study was to study the effects of ifenprodil, a cerebral vasodilator with alpha and N-methyl-D-aspartate (NMDA) receptor antagonistic activities, on aqueous humor dynamics and optic nerve head (ONH) circulation in rabbits. Experiments were performed during the dark phase in rabbits conditioned to a schedule of alternating 12-hr periods of light and dark. Effects on blood-aqueous barrier permeability (K(d)), aqueous flow rate (F), outflow facility to general blood circulation (C(gen)), and uveoscleral outflow (F(u) were determined fluorophotometrically. Effects on ONH tissue circulation were estimated using the laser speckle method. Unilateral topical administration of 0.5% ifenprodil solution decreased intraocular pressure (IOP) with a maximum reduction of 3.4 mmHg and an effect duration of 3 hr without effects on the contralateral eye. A single instillation of 0.5% ifenprodil had no significant effect on K(d), F, or C(gen), whereas it substantially increased F(u). Twenty-day, twice-daily unilateral 0.5% ifenprodil instillation significantly increased tissue blood velocity in the ONH only in the treated eye.

Administration, Topical↗

Penetration of tobramycin sulfate in the aqueous humor of the rabbit.

The intraocular penetration of tobramycin sulfate, a new aminoglycoside antibiotic, was evaluated in rabbits following subconjunctival injection. The mean tobramycin sulfate concentration in the aqueous humor 60 minutes after a single 5-mg dose was 5.5 mug/ml, as compared to a mean concentration of 6.7 mug/ml following a single 10-mg dose. These levels exceed the minimal inhibitory concentration (MIC) for most Pseudomonas species and a variety of other Gram-negative bacilli recovered from clinical infection. No anterior segment changes that may be attributed to the antibiotic could be demonstrated in the injected eye.

Animals↗

The effects of body immersion on aqueous humor dynamics in rabbits.

Rabbits subjected to free-floating body immersion demonstrated decreases in intraocular pressure followed by later increases. These intraocular pressure alterations were associated with parallel changes in aqueous humor production. Episcleral venous pressure was elevated during immersion but outflow facility was unaltered. The decrease in intraocular pressure could be partially blocked by pretreatment with vasopressin or desoxycorticosterone acetate. In cross-circulation studies between an immersed and non-immersed rabbit, a decrease in intraocular pressure was observed in both animals. This observation further supported the involvement of humoral factors in the body-immersion induced intraocular pressure response.

Animals↗

Correlation of aqueous humor ascorbate with intraocular pressure and outflow facility in hereditary buphthalmic rabbits.

The hypotensive effect of ascorbate on intraocular pressure has been reported following topical application, oral administration, or anterior chamber infusion in animals. The present report describes the correlation of aqueous humor ascorbate concentration with intraocular pressure as well as outflow facility in vivo. Low aqueous ascorbate level was seen in buphthalmic eyes with high intraocular pressure and low outflow facility. The opposite correlation was observed in normal eyes. Ascorbate concentration in the anterior chamber of the rabbit eye is apparently related to the alteration of outflow facility and the movement of fluid in the anterior chamber.

Animals↗

Availability of 0.3% ofloxacin ointment and solution in human conjunctiva and aqueous humor.

Ofloxacin 0.3% ophthalmic solution or ointment was administered preoperatively to 13 patients undergoing cataract surgery. Mean drug concentrations in conjunctival biopsies were 2.62 and 6.55 micrograms/gm and in aqueous humor samples were 0.36 micrograms/mL and 0.43 micrograms/mL, for ointment and solution respectively. Mean conjunctival concentrations of ofloxacin achieved MIC90 values for 419 gram-positive and gram-negative organisms previously analyzed.

Aged↗

The relationship between aqueous humor flow and anterior chamber protein concentration in rabbits.

PURPOSE: Protein concentration in the anterior chamber of noninflamed eyes is determined by three factors: the rate of protein entry into the aqueous humor (AH), the removal rate by bulk flow of AH, and the anterior chamber volume. On the basis of observations by previous investigators and the authors' computational modeling, it was hypothesized that a direct reciprocal relationship exists between aqueous flare and AH flow. This relationship was studied in pigmented rabbits, under several conditions, to determine the validity of the hypothesis that changes in aqueous flare intensity reflect variations in AH flow rate. METHODS: Aqueous flare and AH flow were measured in rabbits entrained to a 12 hr light: 12 hr dark cycle, starting at 6 AM, which subsequently was phase-shifted 6 hr earlier to allow measurements over the light-to-dark transition period. AH flow rates were determined fluorophotometrically using the clearance method after corneal deposition of fluorescein. A Kowa FC1000 cell/flare meter was used to measure aqueous flare. Predictions of anterior chamber protein concentration were made using a computer model of plasma-derived protein diffusion into AH. The response to changes primarily of AH flow were evaluated by concurrently determining flare and flow before and after administration of intravenous acetazolamide. RESULTS: Aqueous flare decreased 40% during constant light and 47% over the light-dark transition in a parallel, monophasic manner. AH flow did not change significantly under either condition. In contrast, acetazolamide-induced changes in AH flow resulted in reciprocal changes in flare that could be simulated with the computer model through flow parameter changes alone. CONCLUSIONS: Anterior chamber protein concentration in rabbits appears to be modulated both by factors affecting AH flow and protein entry into the aqueous. Thus, in rabbits, changes in aqueous flare do not necessarily reflect AH flow changes.

Acetazolamide↗

Aqueous humor penetration of ciprofloxacin in the human eye.

Two doses of ciprofloxacin were administered intravenously, 200 mg every 12 hours, to 25 patients undergoing cataract surgery. Plasma and aqueous humor were obtained at 1, 3, 5, 7, and 9 hours after the administration of the second dose of the drug. Peak intraocular concentrations (mean +/- SD), 0.21 +/- 0.1 mg/L, were detected at one hour following ciprofloxacin administration. A time-dependent decrease of the penetration was observed, and by nine hours after the administration, ciprofloxacin levels were 0.05 mg/L. These results illustrate that ciprofloxacin may be an effective antimicrobial agent for prophylactic use in ophthalmologic surgery and also for the treatment of intraocular infections due to susceptible organisms.

Aged↗

Concentrations of serum albumin and nonesterified fatty acids in bovine aqueous humor with regard to the fatty acid sensitivity of bovine lens epithelial cells.

Concentrations of albumin and nonesterified fatty acids (FAs) have been determined in bovine serum and aqueous humor (AH) with regard to the FA-to-albumin molar ratio, which has been proved decisive for the FA cytotoxicity to bovine lens epithelial cells as described previously. In 6- to 7-month-old female calves the average albumin level was reduced 309-fold from 638 micromol/l in serum to 2.00 micromol/l in AH, in 72- to 84-month-old cows 405-fold from 632 to 1. 56 micromol/l, and in 12- to 18-month-old bulls 395-fold from 553 to 1.40 micromol/l. In 64% of the animals the albumin concentration in AH differed significantly between both eyes. The serum albumin values resulted in a Gaussian curve, but the frequency distribution for AH albumin values skewed to the right. Using an enzymatic method the concentrations of nonesterified FAs were determined in serum as well as in concentrated AH samples. In all animals investigated the molar FA-to-albumin ratio was higher in AH than in serum. The results are discussed in view of the assumption that unsaturated nonesterified FAs might be cataractogenic risk factors.

Aging↗

[An experimental study of gentamycin delivery into cornea and aqueous humor from the collagen corneal shield].

Collagen corneal shields immersed in 13.33 mg/ml gentamycin solution for 5 minutes were placed in rabbit eyes and the gentamycin concentrations in the cornea and aqueous humor were determined with radioimmunoassay. The results were compared with those achieved by soft contact lens, subconjunctival injection, and frequent instillations. It was found that (1) 1 and 3 hours after application, the collagen corneal shield produced significantly higher concentration of gentamycin in the aqueous than did the other methods, and in the cornea than did the contact lens or instillations; and (2) 6 hours after application, the antibiotic level in the cornea dropped lower than that by subconjunctival injection, but still 15-30 times higher than the bactericidal concentration.

Administration, Topical↗

The effects of ascorbate, 3-aminotriazole, and 1,3-bis-(2-chloroethyl)-1-nitrosourea on hydrogen peroxide levels in the rabbit aqueous humor.

3-aminotriazole (3-AT), a catalase inhibitor, given to pigmented rabbits in 0.2% drinking solution for 43 days, produced cataractous changes and over a 50% reduction in iris and ciliary process catalase activity. Aqueous H2O2 levels were suppressed by 60% which correlated with a 77% reduction in aqueous ascorbate concentration. Intravenous 3-AT at 1.0 g/kg body weight had no effect on either aqueous ascorbate or H2O2 levels. BCNU (1,3-bis-(2-chloroethyl)-1-nitrosourea) was given intravitreally to rabbits: 3.0 mg suppressed iris glutathione reductase activity by 80%, but only increased the oxidized glutathione/total glutathione ratio to 26% from 18%. Both aqueous ascorbate and H2O2 levels were unaltered at 48 hours. Buthionine sulfoximine (BSO) was given intravitreally; at 48 hours after 4.0 mg BSO, iris-ciliary body total glutathione levels were reduced by 80%, aqueous ascorbate levels were reduced by 53%, and aqueous H2O2 levels were unaltered. A direct correlation seems to exist between aqueous humor ascorbate and H2O2 concentrations, even during suppression of tissue catalase activity. Changes in glutathione status cause peroxide levels to be greater than predicted from the aqueous ascorbate concentration.

Amitrole↗

Effects of a cyclic AMP phosphodiesterase inhibitor, 8'-pivaloyloxymethyl ester of griseolic acid, on aqueous humor dynamics in rabbits.

The mechanism by which pivaloyloxymethyl (POM) ester of griseolic acid (GA), a potent cyclic AMP-phosphodiesterase inhibitor, lowers intraocular pressure (IOP) in albino rabbits was studied. The rate of aqueous flow, measured by fluorophotometry, was significantly lower in GA POM ester-treated eyes (2.36 +/- 0.24 microliters/min) than in control eyes (3.02 +/- 0.24 microliters/min). Topically applied GA POM ester did not alter tonographic outflow or uveoscleral outflow. No differences in aqueous humor protein concentrations between GA POM ester-treated and control eyes were observed. It was thought that the GA POM ester lowered the IOP by decreasing the aqueous inflow. Topical application of this compound caused no inflammatory response in the eye or changes in the blood aqueous barrier.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

Levofloxacin disposition over time in aqueous humor of patients undergoing cataract surgery.

The ocular disposition of levofloxacin in patients receiving two 500-mg oral doses 10 h apart before cataract surgery was assessed with the intent of defining drug ocular exposure over time. The mean aqueous humor concentrations persisted above 1.5 mg/liter between 1.5 and 6.0 h after the second dose, with average aqueous-to-plasma ratios ranging between 0.33 and 0.57. This favorable ocular disposition provides support for trials of systemic levofloxacin for prophylaxis of postoperative endophthalmitis in selected patients or as adjunctive therapy for the treatment of this potentially devastating infective complication.

Aged↗

Effects of D-timolol on intraocular pressure (IOP), beta blocking activity, and the dynamic changes of drug concentrations in aqueous humor.

L-timolol has been used successfully in the treatment of glaucoma. Because of its powerful beta blocking activity, however, more and more side effects have been reported. D-timolol, an optic isomer of L-timolol with much less beta blocking activity, was noted to have similar ocular hypotensive effects through inhibition of aqueous production as L-timolol. Thus, it is expected that D-timolol may reduce the side effects considerably if it is used in the clinics. In this study, we observed the ocular hypotensive effect of 0.5% D-timolol in normotensive and water-loaded rabbits as well as in patients with glaucoma or ocular hypertension. A significant reduction of intraocular pressure (IOP) which lasted at least six hours was observed. No side effects, either locally or systemically, were found. The concentration of D-timolol was traced in rabbits' aqueous humor after topical administration. The drug quickly appeared in the aqueous 30 minutes after instillation of 100 microliters 1% D-timolol. The peak concentration was 1916.5 ng/ml. It declined to a minimum in four hours, although the hypotensive effect could last at least six hours. For estimating the beta blocking potency of D-timolol, radioligand binding assay was employed to calculate the Ki value from isolated cell membrane of rabbits' lung. It showed that the beta blocking potency of D-timolol was much less than that obtained from L-timolol. It is concluded that D-timolol may be a valuable antiglaucoma agent comparable to L-timolol in lowering the IOP. The side effects induced by beta blocking agents we are using currently might be considerably reduced with D-timolol.

Adolescent↗

Vanadate and aqueous humor dynamics. Proctor Lecture.

Topical administration of 0.5% vanadate lowers intraocular pressure in monkey and rabbit eyes. This appears to be a consequence of a reduction in the rate of aqueous humor secretion, probably resulting from the inhibition of ciliary epithelium membrane. NaK ATPase. The ubiquitous vanadate and its interactions with catecholamines and ascorbate may play a role in regulating the sodium pump of the ciliary epithelium. Adrenergic blocking agents may also lower intraocular pressure by inhibiting the NaK ATPase of the ciliary epithelium.

Adrenergic beta-Antagonists↗