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Oxidative stress and TGFbeta-induced disturbance of cells and tissues are implicated in initiation and progression of pathophysiology of cells/tissues. Using primary human trabecular meshwork (TM) cells from normal and glaucomatous subjects, this study demonstrated that peroxiredoxin (PRDX) 6, an antioxidant, offsets the deleterious effects of oxidative stress on TM cells by optimizing ROS and TGFbeta levels. An analysis of glaucomatous TM cells revealed a reduced expression of PRDX6 mRNA and protein. Biochemical assays disclosed enhanced levels of ROS, as well as high levels of TGFbetas and these cells expressed elevated extracellular matrix (ECM) and Tsp1 proteins with reduced MMP2; conditions implicated in the pathophysiology of glaucoma. Non-glaucomatous TM cells exposed to TGFbetas/ROS showed similar features as in glaucomatous cells. The abnormalities induced were reversed by delivery of PRDX6. The data provide evidence that oxidative stress-induced abnormality in TM may be related to reduced PRDX6 expression and provide a foundation for antioxidant-based therapeutics for treating glaucoma.

Uno de los mayores rubros que se comercializa en la era de las Telecomunicaciones es la venta de “tiempo aire” por medio de minutos, ya sea a través de operadoras de telefonía fija, telefonía celular o Internet, con diferentes destinos a partir de los cuales dependen los precios. Para que las compañías telefónicas o revendedoras de minutos puedan tener control sobre la cantidad de “tiempo aire” vendido necesitan de un sistema de control que realice un conteo y una tarifación acorde al destino llamado y al tiempo utilizado. El presente trabajo presenta el diseño e implementación de un prototipo de Sistema de Tarifación Telefónico para Locutorios. Este dispositivo está basado en microcontroladores de mediana escala de integración, utiliza un software destinado para el control y almacenamiento de información en una base de datos, para ejercer acciones de control de forma automática. Es un sistema electrónico y de computación que permite la tarifación en tiempo real segundo a segundo y la facturación de las llamada telefónicas, a través de un módulo de tarifación diseñado para centros de servicios de telecomunicaciones. El sistema permite al operador del sistema ver el estado de cada una de las cabinas y a su vez el cliente puede observar en el display de tarifación: los números telefónicos, duración de la llamada y su valor total por minutos; todo en tiempo real.

A decade has passed since the first topical prostaglandin analog was prescribed to reduce intraocular pressure (IOP) for the treatment of glaucoma. Now four prostaglandin analogs are available for clinical use around the world and more are in development. The three most efficacious of these drugs are latanoprost, travoprost, and bimatoprost, and their effects on IOP and aqueous humor dynamics are similar. A consistent finding is a substantial increase in uveoscleral outflow and a less consistent finding is an increase in trabecular outflow facility. Aqueous flow appears to be slightly stimulated as well. Prostaglandin receptors and their associated mRNAs have been located in the trabecular meshwork, ciliary muscle, and sclera, providing evidence that endogenous prostaglandins have a functional role in aqueous humor drainage. Earlier evidence found that topical PG analogs release endogenous prostaglandins. One well-studied mechanism for the enhancement of outflow by prostaglandins is the regulation of matrix metalloproteinases and remodeling of extracellular matrix. Other proposed mechanisms include widening of the connective tissue-filled spaces and changes in the shape of cells. All of these mechanisms alter the permeability of tissues of the outflow pathways leading to changes in outflow resistance and/or outflow rates. This review summarizes recent (since 2000) animal and clinical studies of the effects of topical prostaglandin analogs on aqueous humor dynamics and recent cellular and molecular studies designed to clarify the outflow effects.

Objective To examine how aqueous humor dynamics are affected by exfoliation syndrome (XFS) with or without elevated intraocular pressure (IOP). Methods Eighty participants were divided into 4 groups: (1) those with XFS and ocular normotension (n = 25), (2) controls with ocular normotension without XFS, age-matched to group 1 (n = 25), (3) those with XFS and ocular hypertension (n = 15), and (4) controls with ocular hypertension without XFS, age-matched to group 3 (n = 15). Following washout of glaucoma medications, assessments were made of IOP, episcleral venous pressure, aqueous flow, outflow facility, and uveoscleral outflow. Differences were analyzed by group mean comparisons and linear regression analyses. Results Uveoscleral outflow was significantly decreased in individuals with XFS compared with age-matched controls and was independent of IOP. Patients with ocular hypertension (with or without XFS) exhibited decreased outflow facility compared with those with ocular normotension (with or without XFS). Aqueous flow was not affected by the level of IOP or the presence of XFS. Conclusions Exfoliation syndrome in normotensive and hypertensive eyes is associated with a decrease in uveoscleral outflow, whereas in hypertensive but not normotensive eyes, it is associated with reduced outflow facility.

The aims of this study were to evaluate the accuracy, repeatability, and safety of multiple intraocular pressure (IOP) measurements by a commercially available rebound tonometer in conscious, conditioned mice, and to characterize the acute and profound effects of anesthesia on IOP in mice.To test the accuracy of the tonometer, IOPs of CD-1 mice under ketamine/xylazine anesthesia were experimentally set and monitored with a water manometer/transducer system following transcorneal cannulation while simultaneously performing tonometry. The long- and short-term repeatability of the tonometer was tested in conscious, restrained mice, as measurements were taken once-daily in the afternoon for 4 consecutive days. On day 5, IOPs were measured in the same mice once every 4 min for 32 min. On 2 separate days, mice were administered ketamine/xylazine or 2,2,2-tribromoethanol anesthesia, in a crossover design, and IOPs were measured once every 2 min for 32 min. Rebound tonometry was performed in conscious mice before and 1 hour after 1 drop of timolol maleate (10 microL of 0.5%) application to 1 eye.IOP measurements by rebound tonometry correlated well with manometry for pressures between 8 and 38 mmHg (y = 0.98x - 0.32, R(2) = 0.94; P0.001). The average tonometric IOP was invariant over 4 days (range, 11.7-13.2 mmHg). IOPs dropped significantly ( Por = 0.05) within 6 min (ketamine/xylazine) or 10 min (2,2,2-tribromoethanol) postadministration of anesthesia but not with conscious restraint. Timolol significantly (P0.001) lowered IOP from 12.8 +/- 0.3 (mean +/- standard error of the mean) to 10.1 +/- 0.6 mmHg, as measured by the tonometer.Rebound tonometry can be used to obtain accurate IOP measurements in conscious, restrained mice while avoiding the rapid and profound ocular hypotensive effects of general anesthesia. Small changes in IOP with an aqueous-flow suppressant are readily detectable with conscious restraint that may be missed with chemical restraint.

Publisher Summary Intraocular pressure (IOP) is maintained by the dynamics of ocular aqueous humor that involves its secretion, circulation throughout the anterior chamber, and drainage into the iridocorneal angle. The measurable components of aqueous humor dynamics include aqueous flow, outflow facility, uveoscleral outflow, and episcleral venous pressure. Multiple methods are available to assess these components. Interpretation of data collected by these methods requires an understanding of the inherent assumptions and limitations of each method applicable to the species of animal under investigation. Despite the inevitable problems associated with each method, invaluable information has been collected regarding normal circadian rhythms and interspecies differences in aqueous humor dynamics. Additionally, studies of animal models of spontaneous and induced glaucoma have enhanced the understanding of human glaucoma and facilitated the design of improved pharmacological treatments and surgical procedures. This chapter describes various methods to assess aqueous humor dynamics and summarizes findings from the animal species that have contributed the most to the understanding of aqueous humor dynamics.

Publisher Summary A stable rate of production and drainage of aqueous humor is essential for the health of the eye and maintenance of normal visual function. This chapter reviews the contributions of aqueous humor dynamics in normal and pathological conditions affecting intraocular pressure (IOP). IOP remains relatively stable throughout one's lifetime but subtle changes do occur in the outflow pathways that could increase IOP and the risk for glaucoma. Abnormalities in aqueous humor dynamics have been found in various clinical syndromes that affect IOP. Most of the abnormalities have been localized to the aqueous humor outflow pathways. Surprisingly, aqueous humor production remains relatively stable in all of these conditions and ranges of IOPs. Some older drugs to treat elevated IOP work by reducing aqueous humor production, theoretically, placing the avascular lens and cornea at risk for damage from limited nutrients and accumulation of toxic metabolites. The recently approved drugs and the ones currently under development for future glaucoma therapy are those that target the outflow pathways. From a physiological perspective, this is a logical approach because this is the location of the pathology in glaucoma and the region in need of repair. These drugs and their effects on aqueous humor dynamics also are discussed in this chapter.

Most patients with invasive squamous cell carcinoma of the penis do not have inguinal node metastasis at the time of diagnosis and 50% of those having palpable nodes are inflammatory. Penis cancer (PC) treatment implies resection of the primary tumor and inguinal lymphadenectomy; nevertheless, morbidity related to this procedure is high and its usefulness may be questioned in patients without metastasis in dissected nodes. Lymphatic mapping with sentinel node biopsy (LMSNB) is a valid alternative, useful in other neoplasias. The objective of this study is to determine if it is possible to identify a sentinel node (SN) in patients with PC. Patients with T1-2 PC without palpable nodes (N0) were included. LMSNB was carried out with the combined technique (blue dye and radiocolloid). All patients underwent an elective bilateral inguinal lymphadenectomy. Sensitivity and false negative index were calculated. SNs were sent for transoperative study with imprint technique and, definitively, with serial cuts and hematoxylin/eosin staining. Nine patients showed results with 32 lymph carrier zones and SN was identified in all of them, 4 regions had metastasis, in 3 the SN was metastatic and in one patient was metastasis-negative (false negative); sensitivity = 80%; false negatives index = 20%. Seven patients (77%) did not have node metastasis. LMSNB is an alternative for staging PC patients and could prevent unnecessary inguinal lymphadenectomies. A larger number of patients is required to validate the sturdy. The combined technique offers a high rate of success in SN identification.

To determine the mechanism by which travoprost 0.004% reduces intraocular pressure (IOP) in patients with ocular hypertension or primary open angle glaucoma.This is a randomized, double-masked, placebo-controlled, single center study of 26 patients scheduled for 3 visits (baseline, day 15, and days 17 to 18) following screening.After appropriate washout of all ocular medications, baseline IOPs were taken and travoprost 0.004% was administered once-daily in the evening for 17 consecutive doses to 1 eye and its vehicle to the fellow eye in a randomized, masked fashion. On day 15, beginning 12 hours after the 14th consecutive dose, IOP was measured by pneumatonometry, aqueous flow and outflow facility by fluorophotometry, and episcleral venous pressure by venomanometry. Uveoscleral outflow was determined by mathematical calculation. Two days later, the last drop of drug/vehicle was given at 2000 hours. Fluorophotometry and tonometry measurements were repeated between 2200 and 0600 hours. Treated eyes were compared with contralateral control eyes or baseline measurements, and daytime measurements were compared with nighttime measurements using paired t tests.Travoprost-treated eyes showed a significant (P0.001) decrease in daytime IOP compared with baseline (26%) or to vehicle-treated eyes (22%), and an increase in daytime outflow facility (P=0.001; 64%). The increase in uveoscleral outflow was not statistically significant. At night, the IOPs of travoprost-treated eyes remained 21% to 24% below baseline daytime values. Seated and supine IOPs in control eyes were significantly (P0.04) lower at 2200 hours than 1700 hours (P0.04). Supine IOPs were higher than seated IOPs in both control and treated eyes (P0.001). Aqueous flow was significantly (P0.001) reduced at night in both travoprost (30%) and vehicle-treated (25%) eyes when compared with daytime values. No other comparisons were statistically significant.Travoprost seems to lower IOP by increasing trabecular outflow facility. An effect on uveoscleral outflow cannot be ruled out.

La mayoría de los pacientes con carcinoma epidermoide invasor de pene no tiene metástasis ganglionares inguinales al momento del diagnóstico; en 50 % de los ganglios palpables la causa es inflamatoria. El tratamiento del cáncer peneano implica resección del tumor primario y linfadenectomía inguinal, sin embargo, la morbilidad derivada del procedimiento es alta y la utilidad cuestionable en pacientes sin metástasis en ganglios disecados. El mapeo linfático con biopsia del ganglio centinela (MLBGC) es una alternativa útil en otras neoplasias. El objetivo de la presente investigación es conocer si es posible identificar un ganglio centinela en pacientes con cáncer de pene, para lo cual se analizaron pacientes con esta neoplasia estadios T1 o T2 sin ganglios palpables, a quienes se realizó MLBGC con técnica combinada (colorante y radiocoloide) y linfadenectomía inguinal bilateral electiva. Se calculó índice de falsos negativos y sensibilidad; los ganglios centinela fueron estudiados en el transoperatorio con impronta, y en definitivo con cortes seriados y hematoxilina-eosina. Se trató de nueve pacientes con 32 zonas linfoportadoras; en todos se identificó ganglio centinela; hubo metástasis en cuatro regiones, en tres el ganglio centinela fue metastásico y en uno fue negativo (falso negativo). La sensibilidad fue de 80 % y el índice de falsos negativos de 20 %. Siete pacientes (77 %) no tuvieron metástasis ganglionares. El MLBGC es una opción para la estadificación en pacientes con cáncer peniano y podría evitar linfadenectomías inguinales innecesarias; se requiere un mayor número de pacientes para validar el estudio. La técnica combinada ofrece una elevada tasa de éxito en la identificación del ganglio centinela.

To study the effects of 3 prostaglandin analogs, bimatoprost, latanoprost, and travoprost, on aqueous dynamics in the same subjects and to compare techniques of assessing outflow facility.Experimental study (double-masked, placebo-controlled, randomized paired comparison, 4-period crossover).Thirty healthy adult subjects.Bimatoprost, latanoprost, travoprost, or a placebo was administered to the left eye once a day in the evening for 7 days, after a minimum 4-week washout period between each session. Tonographic outflow facility was measured by Schiøtz tonography and pneumatonography on day 7. On day 8, the aqueous humor flow rate and fluorophotometric outflow facility were measured by fluorophotometry. Uveoscleral outflow was calculated from the aqueous humor flow rate and outflow facility using the Goldmann equation.Facility of outflow, aqueous humor flow rate, intraocular pressure (IOP), and calculation of uveoscleral outflow.All medications lowered IOP relative to a placebo. None of the drugs affected aqueous humor production. All medications increased outflow facility compared with placebo when measured by Schiøtz and 2-minute pneumatonography (Por =0.02); the apparent increase of outflow facility measured with fluorophotometry and 4-minute pneumatonography did not reach statistical significance. In contrast, uveoscleral outflow was significantly increased by all medications when calculated from 4-minute pneumatonography data, and fluorophotometry and Schiøtz data at higher episcleral venous pressures. The apparent increase found with 2-minute pneumatonography did not reach statistical significance. These differing results in the same patients indicate that differences in measurement techniques, and not differences in mechanism of action, explain previous conflicting published reports on the mechanism of action of the prostaglandins.Bimatoprost, latanoprost, and travoprost have similar mechanisms of action. All 3 drugs reduce IOP without significantly affecting the aqueous production rate. All drugs increase aqueous humor outflow, either by enhancing the pressure-sensitive (presumed trabecular) outflow pathway or by increasing the pressure-insensitive (uveoscleral) outflow, but the assessment of the amount of flow through each pathway depends upon the measurement technique.

PURPOSE. To investigate the ocular hypotensive effect of the prostanoid EP2 receptor agonist butaprost and to establish its mechanism of action. METHODS. All experiments were performed in cynomolgus monkeys after topical application of butaprost (0.1%). The effects of butaprost on aqueous humor flow were determined by fluorophotometry. Total outflow facility was measured by the two-level, constant-pressure perfusion method, and uveoscleral outflow was determined by perfusion of FITC-labeled dextran through the anterior chamber. Effects on ocular morphology were studied after tissue fixation with transcardial perfusion by paraformaldehyde and immersion fixation of the globe, in animals subjected to long-term treatment with butaprost. Conscious ocular normotensive monkeys and monkeys with unilateral ocular hypertension were used for intraocular pressure (IOP) studies. RESULTS. Butaprost had no significant effect on aqueous humor flow or total outflow facility in ocular normotensive monkeys. Uveoscleral outflow was significantly higher in the butaprost treated eyes than in vehicle treated eyes, 1.03 ± 0.20 vs. 0.53 ± 0.18 μL · min-1. After a 1-year treatment with butaprost, the morphology of the ciliary muscle was changed, showing increased spaces between ciliary muscle bundles and the apparent formation of new outflow channels. In many instances, changes were observed in the trabecular meshwork as well. Butaprost, in a single 0.1% dose, decreased IOP significantly in ocular normotensive monkeys and reduced IOP in laser-induced glaucomatous monkey eyes to the same level as that in the ocular normotensive contralateral eyes. CONCLUSIONS. The prostanoid EP2 receptor agonist butaprost appears to lower IOP by increasing uveoscleral outflow, according to both physiological and morphologic findings. Although the prostanoid EP2 receptor is structurally and functionally distinct from the FP receptor, the effects of EP2 and FP receptor stimulation on aqueous humor outflow are similar. Copyright © Association for Research in Vision and Ophthalmology.

The second annual ARVO/Pfizer Ophthalmic Research Institute conference was held Friday and Saturday, April 28 and 29, 2006, at the Fort Lauderdale Grande Hotel and Yacht Club, Fort Lauderdale, Florida. The conference, funded by The ARVO Foundation for Eye Research through a grant from Pfizer Ophthalmics, provided an opportunity to gather experts from within and outside ophthalmology to develop strategies to improve research and clinical care in areas of ophthalmology related to preventable vision loss and blindness. This year’s conference focused on aqueous humor outflow. A working group of 31 researchers on aqueous outflow, 8 scientists working on interests other than aqueous humor outflow but with expertise in areas relevant to the field, and 11 observers from ARVO, Pfizer, and clinical and basic ophthalmic research convened on April 28, 2006, to evaluate the current understanding of the aqueous humor outflow pathway. The goals were to compare similarities between ocular aqueous humor outflow and fluid flow in other tissues of the body, to critique conventional ideas, to identify the most important scientific questions, and to discuss strategies to answer these questions. The meeting format emphasized discussion and concentrated on questions within four general areas of outflow research: Session I: Conventional Outflow: Cell Function in the Aqueous Humor Outflow Pathway Session II: Conventional Outflow: Role of the Extracellular Matrix Session III: Uveoscleral Outflow: The Other Pathway Session IV: Normal Versus Primary Open Angle Glaucoma (POAG): What Is the Cause of Elevated Pressure? Each session began with a 10-minute overview by an outflow researcher followed by a 30-minute talk by one of the outside experts. Parallels between their fields of expertise and the eye were included in these talks. Invited outside experts covered several areas of research, including vascular endothelial cell biology (Peter Davies, PhD, University of Pennsylvania, Philadelphia), matricellular proteins (Paul Bornstein, MD, University of Washington, Seattle), renal and lymphatic biology (Donatscho Kerjaschki, MD, University of Vienna, Austria, and David Zawiega, PhD, Texas A & M University, College Station, Texas), oxidative damage mechanisms (James Mitchell, PhD, National Institutes of Health, Bethesda, Maryland), advanced glycation end-products and aging (Alan Stitt, PhD, Queens University, Belfast, Northern Ireland), cell adhesion (Benjamin Geiger, PhD, Weizmann Institute of Science, Rehovot, Israel), and cellular tight junctions (Eveline Schneeberger, MD, Massachusetts General Hospital, Boston, Massachusetts). The remainder of each session was used to discuss questions pertinent to the main topic and provided an opportunity for attendees to voice their opinions and work together to define questions that are still unanswered. The lively discussions were successful in defining old and new ideas that are essential to a better understanding of aqueous humor outflow. This conference summary highlights the ideas discussed and introduces areas that need further exploration.

To determine the mechanism by which 0.15% unoprostone isopropyl reduces intraocular pressure (IOP) by studying 33 patients with ocular hypertension or primary open-angle glaucoma.At baseline, IOP was determined by pneumatonometry, aqueous flow and outflow facility by fluorophotometry, episcleral venous pressure by venomanometry, and uveoscleral outflow by mathematical calculation. Unoprostone was administered to one eye and placebo to the fellow eye of each patient twice daily in a randomized masked fashion. In patients who demonstrated an IOP reduction of 3 mm Hg or more in either eye on day 5 +/- 1 (n = 29), determinations were repeated on that day and on day 28 +/- 2. Treated eyes were compared with control eyes, and treatment days were compared with baseline by paired t tests.Compared with baseline, unoprostone significantly (P.001) reduced IOP by a mean +/- SEM of 5.6 +/- 0.4 mm Hg and 4.8 +/- 0.6 mm Hg on days 5 and 28, respectively. The change from baseline with unoprostone was significantly (P.001) greater than with placebo by 2.8 +/- 0.4 mm Hg on day 5 and by 3.2 +/- 0.5 mm Hg on day 28. Compared with baseline, unoprostone significantly (P/=.001) increased outflow facility by 0.05 +/- 0.01 and 0.08 +/- 0.02 microL.min(-1).mm Hg(-1) on days 5 and 28, respectively. The baseline-adjusted between-treatment differences were significant (P/=.04) on day 28 (0.06 +/- 0.02 microL.min(-1).mm Hg(-1)). Other measures were not different from placebo.In responsive patients, unoprostone decreased IOP by increasing outflow facility.

Purpose To determine whether bimatoprost is hydrolyzed to its free acid after topical application in humans in vivo. Design Prospective, masked, and vehicle controlled. Participants Thirty-one eyes of 31 patients with cataracts. Methods Beginning 7 days before scheduled cataract surgery, one eye of each patient was treated with bimatoprost 0.03% or vehicle once daily, with the last drop administered 2 to 12 hours before anterior chamber paracentesis before cataract surgery. In a masked fashion, aqueous humor specimens were assayed for bimatoprost and its free acid by high-pressure liquid chromatography and mass spectrometry. Main outcome measure Detection of the free acid of bimatoprost in aqueous humor. Results Aqueous humor concentrations of the free acid of bimatoprost were 22.0±7.0 nmol/l (mean ± standard error of the mean, n = 12) and 7.0±4.6 nmol/l (n = 8) at 2 and 12 hours, respectively, and below the limit of detection after vehicle (n = 10). Concentrations of bimatoprost (amide) were 5.7±1.4 and 1.1±0.4 nmol/l at 2 and 12 hours, respectively, and undetectable after vehicle. Conclusion After topical application of bimatoprost in humans, a sufficient concentration of its free acid, a potent FPprostanoid receptor agonist, is found in the aqueous humor to account for its ability to reduce intraocular pressure.

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.

PURPOSE Unoprostone isopropyl ester (unoprostone) -induced iris color darkening was evaluated in a rabbit model using a cyclooxygenase inhibitor, an alpha(1)-adrenergic antagonist, and sympathetic denervation. MATERIALS AND METHODS Dutch-belted rabbits were divided into five groups based on type of surgery and eyedrop treatment to both eyes: (1) sham surgery (n = 7); (2) bilateral superior cervical ganglionectomy (SCGx, n = 7); (3) SCGx plus flurbiprofen 0.03% (n = 7); (4) SCGx plus thymoxamine 0.5% (n = 6); and (5) SCGx plus flurbiprofen and thymoxamine (n = 6). All rabbits were treated with unoprostone 0.12% to one eye and its vehicle to the contralateral eye twice daily for 43 weeks after SCGx. Periodic color photographs of paired eyes were scored for difference in eye color. Iris melanin and aqueous humor protein were measured at week 43. RESULTS Twenty-three of the 26 rabbits with bilateral SCGx and unilateral unoprostone treatment demonstrated a darker iris color on the unoprostone-treated side. The average scores (demonstrating difference in iris color) comparing photographs of treated versus control eyes in the four SCGx groups were higher than those in the sham surgery group (P < 0.03), and higher than at week 0 (P < 0.001). The group pretreated with flurbiprofen and thymoxamine had the highest score of all groups. The aqueous humor protein in unoprostone-treated eyes was higher (P < or = 0.0001) than in vehicle-treated eyes. The melanin content of irides of the denervated groups was higher (P < or = 0.01) in unoprostone-treated than in vehicle-treated eyes. CONCLUSION Unoprostone produced iris color darkening in pigmented rabbit eyes with sympathetic denervation. Pretreatment with flurbiprofen and thymoxamine appeared to enhance this effect but this was not statistically demonstrated by the study.

This study investigates the time-dependent effects of superior cervical ganglionectomy (SCGx) on aqueous humor dynamics and ocular blood flow in rabbits.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.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%, p0.002). 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%, p0.001), outflow facility was less (0.15 +/- 0.02 vs 0.21 +/- 0.01 microl/min/mmHg, 29%, p0.01) and blood flow to the choroid was less (12.1 +/- 5.0 vs 16.2 +/- 6.0 ml/min/gm tissue, 25%, p0.05). Aqueous humor flow was not significantly altered by SCGx at any time.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.

Topical treatments with certain prostaglandins (PGs), including FP receptor agonists, lower intraocular pressure by increasing uveoscleral outflow. Although the precise mechanism for the increased uveoscleral outflow is not known, there appears to be activation of a molecular transduction cascade and an increase in the biosynthesis of certain metalloproteinases. This leads to reduction of extracellular matrix components within the ciliary muscle, iris root, and sclera. It is possible that this reduction of extracellular matrix present within portions of the uveoscleral pathway may contribute to the mechanism of increased uveoscleral outflow. Additional mechanisms that may contribute to the PG-mediated increase of uveoscleral outflow include relaxation of the ciliary muscle, cell shape changes, cytoskeletal alteration, or compaction of the extracellular matrix within the tissues of the uveoscleral outflow pathway. Future studies should clarify the importance of these various responses that may contribute to increased uveoscleral outflow. At present, there is no compelling evidence for a substantial facility-increasing effect on the trabecular meshwork outflow for any of these compounds.

Latanoprost, a prodrug of a prostaglandin F 2α analog, is a potent ocular hypotensive agent, reducing intraocular pressure (IOP) primarily by increasing aqueous humor drainage through the uveoscleral outflow pathway. Initial assessments in animals found that high concentrations of cholinergic agonists reduced drainage through this pathway and attenuated the effects of a PGF 2α analog. This raised the question of whether latanoprost would be effective when added to the treatment regimen of patients on pilocarpine or strong miotics. In published clinical studies, latanoprost was additive to the maximally tolerated medical therapy (which included cholinergic agonists) of glaucoma patients. Multiple doses of physostigmine in healthy volunteers did not block the effect of a single drop of latanoprost during a 1-day study. One study attempting to find the optimal timing of administration of latanoprost and pilocarpine claimed to show that additivity was best when pilocarpine was given one hour after latanoprost in the evening. Two other studies found that the timing of the doses was not important. To explain the additivity of latanoprost and pilocarpine, aqueous humor dynamics were assessed in ocular hypertensive patients treated for 1 week with each drug alone and then for one week in combination. The results showed that latanoprost increased uveoscleral outflow, pilocarpine increased outflow facility, and pilocarpine did not block or attenuate the uveoscleral outflow effect of latanoprost. The result was greater IOP reduction when these drugs were used in combination than when either drug was used alone. All available evidence demonstrates that addition of latanoprost to the treatment regime of patients already taking cholinergic agonists is an effective, although not necessarily the preferred, combination of medications for the treatment of elevated IOP.

Bimatoprost (Lumigan [Allergan, Inc, Irvine CA]) and travoprost (Travatan [Alcon, Ft Worth, TX]) are two new intraocular pressure (IOP)-lowering drugs for use in patients with glaucoma and ocular hypertension. This review evaluates recent studies comparing these new drugs with timolol and with latanoprost. In each study, the statistical analyses support the conclusion that these agents were more effective than timolol and as effective as latanoprost in terms of their ability to reduce IOP. The side effect profiles for bimatoprost, latanoprost, and travoprost were similar, but with statistically higher occurrences of hyperemia and eyelash growth for bimatoprost or travoprost versus latanoprost or timolol.

Adjunctive intraocular pressure (IOP)-lowering therapy is widely used today, as one-third of all patients being treated for glaucoma need additional therapy to reach and maintain healthy IOPs. Timolol, latanoprost, and pilocarpine are three potent drugs that have been used in combination to reduce IOP. Timolol reduces the production rate of aqueous humor to achieve the IOP decrease. Latanoprost and pilocarpine both affect aqueous outflow, although by different mechanisms. The IOP efficacy of combined therapy with timolol and pilocarpine compared with timolol and latanoprost or with latanoprost alone has been investigated in three multicenter, randomized, clinical trials in Europe. This is a review of those published trials. In 2 of the 3 studies, the additional IOP lowering effect of latanoprost 0.005% administered once daily was compared with pilocarpine 2% administered 3 times daily in patients with primary open-angle glaucoma (POAG) or ocular hypertension currently on monotherapy with timolol 0.5% twice daily. These 6-month studies found that the timolol and latanoprost combination reduced IOP more and was better tolerated with fewer side-effects than the timolol and pilocarpine combination. At 6 months, there was no evidence of long-term drift in IOP with timolol and latanoprost. This combined therapy provides an effective and safe option for lowering IOP in glaucoma patients. These results suggest that the timolol/latanoprost combination is preferable to the timolol/pilocarpine combination not only with regard to side effects but also to the magnitude of IOP reduction. Two of the 3 studies compared latanoprost monotherapy with timolol and pilocarpine combined therapy in patients with POAG, various other glaucomas, or ocular hypertension. Treatment was for 6 weeks or 6 months. In both studies, latanoprost was more effective and better tolerated than the combination of timolol and pilocarpine. These results suggest that latanoprost alone should be tried before the addition of pilocarpine to timolol therapy is considered. The convenience of daily administration of a single drop of latanoprost versus multiple drops of timolol and pilocarpine should improve patient compliance.

Numerous studies have provided conflicting evidence to explain the ocular hypotensive mechanism of action of epinephrine. Although epinephrine has been shown consistently to increase outflow facility, its effects on aqueous flow and uveoscleral outflow are not as clear. The purpose of this study was to clarify the effects of multiple doses of topical epinephrine on aqueous humor dynamics in human eyes. This was done by evaluating the four main parameters that determine steady state intraocular pressure. These parameters were assessed at baseline and after a week of twice-daily treatment of epinephrine hydrochloride 2% to one eye. Twenty-six human volunteers were enrolled in the study. Intraocular pressure was measured by pneumatonometry, aqueous flow and trabecular outflow facility by fluorophotometry, episcleral venous pressure by venomanometry and uveoscleral outflow by mathematical calculation. In epinephrine-treated eyes compared to baseline, intraocular pressure and aqueous flow were reduced from 21.2 +/- 0.3 to 17.1 +/- 0.2 mmHg (19%, p = .01) and 3.3 +/- 0.2 to 2.9 +/- 0.2 microl/min (12%, p = .03), respectively. Trabecular outflow facility obtained by fluorophotometry was increased from 0.18 +/- 0.02 to 0.26 +/- 0.03 microl/min/mmHg (44%, p = .02). Topical epinephrine did not significantly affect uveoscleral outflow or episcleral venous pressure. In conclusion, multiple topical doses of epinephrine lowered intraocular pressure in human volunteers by reducing aqueous humor formation and increasing trabecular outflow facility. The increase in uveoscleral outflow suggested by other studies was not observed.

With the advent of several new topically active medications for glaucoma therapy, intraocular pressure (IOP) can be reduced to target levels in more patients before resorting to surgery. Some of these newer agents have a number of advantages over some of the older medications, several of which are seldom used now. The topically active carbonic anhydrase inhibitors are better tolerated than oral formulations, which are infrequently used despite their greater efficacy compared with the topical formulations. The alpha2-adrenergic agonists effectively reduce IOP with few systemic adverse effects. The prostaglandin analogues are even more effective and well tolerated when applied once daily without known systemic adverse effects. The variety of glaucoma medications forces the physician to be selective with various combinations before proceeding with surgery. This article critically reviews the literature pertaining to the newer glaucoma medications, thereby providing guidelines to make rational choices from among the available options.

To report the acute vs chronic effects of brimonidine, a selective alpha2-adrenergic receptor agonist, on aqueous humor dynamics in ocular hypertensive patients.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.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.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.

Healthy subjects were recruited to identify normal, age-associated changes in intraocular pressure and aqueous humor dynamics.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.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).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.

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

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 (P0.001) 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 (P0.05) and total outflow facility (P0.02), 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.