The effect of topically administered carbonic anhydrase inhibitors on aqueous humor dynamics in rabbits

Repeated topical administration of 2.5% trifluormethazolamide, a halogenated derivative of methazolamide, resulted in a unilateral decrease in intraocular pressure in rabbits. Mean (+/- S.E.M.) baseline intraocular pressure (19.8 +/- 2.1 mm Hg) was significantly (P less than .05) decreased 30 minutes (16.1 +/- 2.2 mm Hg) and 60 minutes (15.8 +/- 2.7 mm Hg) after drug administration. Trifluormethazolamide did not alter outflow facility. Aqueous humor flow calculated from the tonographic data was reduced 44% and flow measured by fluorophotometry was reduced 29%. Topical delivery of trifluormethazolamide decreased the level of carbon dioxide in the aqueous humor in the treated eye in a manner similar to that observed after systemic administration of carbonic anhydrase inhibitors. Topical administration of 10% acetazolamide did not decrease intraocular pressure. However, topical administration of either trifluormethazolamide or acetazolamide before oral administration of water resulted in a blunting of the water-induced ocular hypertensive response.     

Acidosis, alkalosis, and aqueous humor dynamics in rabbits

Systemic acidosis induced by intravenous administration of hydrochloric acid lowered intraocular pressure in unanesthetized rabbits. Aqueous humor flow was reduced by approximately 50%, as measured by the iodide method and as calculated from tonographic data. Outflow facility, episcleral venous pressure, plasma osmolality, blood pressure, pulse, and body temperature were not altered by systemic acidosis. Systemic alkalosis induced by intravenously administered sodium bicarbonate was associated with an increased intraocular pressure. Aqueous humor flow following systemic alkalosis was increased by approximately 100%, as measured by the iodide method and as calculated from tonographic data. Alkalosis was not associated with alterations in outflow facility, episcleral venous pressure, plasma osmality, blood pressure, pulse, or rectal temperature.     

The effect of melatonin on aqueous humor flow in humans during the day

BACKGROUND: Aqueous humor flow through the anterior chamber of the eye undergoes a circadian cycle. The rate of flow during the day is twice as high as the rate of flow at night. The pineal hormone, melatonin, also undergoes a circadian cycle. Melatonin levels are high at night, whereas aqueous humor flow is low. The authors studied the effect of oral melatonin on aqueous humor flow in humans. METHODS: The effect of melatonin on aqueous humor flow was evaluated in 19 healthy human volunteers in a randomized, masked crossover study with a placebo control. The hormone or placebo was administered orally during the day when endogenous levels of melatonin are low. Aqueous flow was measured by fluorophotometry for 8 hours. RESULTS: The mean rate of flow during melatonin treatment was 2.71 +/- 0.64 microliters/minute (+/- standard deviation). The rate of flow during placebo treatment was 2.80 +/- 0.66 microliters/minute. There is no statistically significant difference between these two rates (P = 0.4). With a sample size of 19, the study has a power of 92% to detect at least a 15% difference in the rate of flow under the two conditions. Measurement of plasma concentration of melatonin in five subjects confirmed that concentrations after oral dosage reached peaks comparable with the normal endogenous nocturnal peaks. CONCLUSIONS: The authors conclude that melatonin concentrations during the day, comparable with plasma concentrations that occur spontaneously during sleep, do not suppress aqueous humor formation. The authors find no support for the idea that plasma melatonin, per se, can suppress aqueous formation or that the circadian rhythm of plasma melatonin is primarily responsible for the circadian rhythm of aqueous humor flow.     

Effect of 8-iso prostaglandin E2 on aqueous humor dynamics in monkeys

OBJECTIVE: To evaluate the effects of 8-iso prostaglandin E2 (8-iso PGE2; prosta-5,13-dien-1-oic acid,11,15-dihydroxy-9-oxo-,[5Z,8beta-11X,13E,15 S]-) on the intraocular pressure (IOP), outflow facility, and aqueous humor flow rates in normal monkeys and monkeys with glaucoma. METHODS: The IOP was measured before and as long as 6 hours after the topical application of 8-iso PGE2 to 1 eye of 6 normal monkeys and to the glaucomatous eye of 8 monkeys with unilateral laser-induced glaucoma. The pupil diameter was measured at the same times as the IOP measurements in the normal monkeys. Tonographic outflow facility and fluorophotometric flow rates of aqueous humor were measured in 6 normal monkeys before and after drug treatment. RESULTS: In normal monkeys, a single dose of 0.1% 8-iso PGE2 reduced (P<.01) the IOP for 4 hours in the treated eyes with a maximum (mean +/- SEM) reduction of 3.2 +/- 0.2 mm Hg, compared with the contralateral control eyes. The pupil size was smaller (P<.01) in the treated eyes by as much as 1.0 +/- 0.2 mm for 4 hours. In 8 glaucomatous monkey eyes, the application of 0.05% and 0.1% 8-iso PGE2 reduced the IOP (P<.01) for as long as 2 and 5 hours, respectively. The maximum reduction in the IOP was 4.6 +/- 0.8 mm Hg (0.05%) and 6.0 +/- 0.8 mm Hg (0.1%) compared with baseline measurements. The magnitude and duration of the ocular hypotensive effect were enhanced with twice-a-day administration for 5 consecutive days. Outflow facility in normal monkey eyes was increased (P<.05) by 48% in the treated eyes, and aqueous humor flow was unchanged (P>.10), compared with vehicle-treated contralateral control eyes. Mild eyelid edema, conjunctival edema, hyperemia, and discharge appeared in some eyes treated with the 0.1% drug concentration. CONCLUSIONS: The use of 8-iso PGE2 reduces the IOP in both normal and glaucomatous monkey eyes. An increase in outflow facility appears to account for most of the IOP reduction in normal monkeys. Clinical Relevance: The application of 8-iso PGE2 may have potential for the treatment of glaucoma as an outflow facility-increasing drug.     

Effects of adenosine agonists on intraocular pressure and aqueous humor dynamics in cynomolgus monkeys

The effects of single or multiple topical doses of the relatively selective A1 adenosine receptor agonists (R)-phenylisopropyladenosine (R-PIA) and N6-cyclohexyladenosine (CHA) on intraocular pressure (IOP), aqueous humor flow (AHF) and outflow facility were investigated in ocular normotensive cynomolgus monkeys. IOP and AHF were determined, under ketamine anesthesia, by Goldmann applanation tonometry and fluorophotometry, respectively. Total outflow facility was determined by anterior chamber perfusion under pentobarbital anesthesia. A single unilateral topical application of R-PIA (20-250 micrograms) or CHA (20-500 micrograms) produced ocular hypertension (maximum rise = 4.9 or 3.5 mmHg) within 30 min, followed by ocular hypotension (maximum fall = 2.1 or 3.6 mmHg) from 2-6 hr. The relatively selective adenosine A2 antagonist 3,7-dimethyl-1-propargylxanthine (DMPX, 320 micrograms) inhibited the early hypertension, without influencing the hypotension. Neither 100 micrograms R-PIA nor 500 micrograms CHA clearly altered AHF. Total outflow facility was increased by 71% 3 hr after 100 micrograms R-PIA. In conclusion, the early ocular hypertension produced by topical adenosine agonists in cynomolgus monkeys is associated with the activation of adenosine A2 receptors, while the subsequent hypotension appears to be mediated by adenosine A1 receptors and results primarily from increased outflow facility.     

Changes of some physicochemical parameters of gas exchange in aqueous humor of rabbits during treatment of experimental uveitis

PURPOSE: To evaluate the usefulness of some parameters of the aqueous humor: pH, pO2 (oxygen pressure), pCO2 (carbon dioxide pressure) and HCO3- concentration in the diagnosis of uveitis. Changes of these parameters following conventional treatment and cryotherapy have also been investigated. MATERIAL AND METHOD: We used 40 grey rabbits (weighing 2.5-3.0 kg). Uveitis was evoked by intravitreal injection of 5 mg of animal albumin. Cryotherapy was performed by transconjunctival, quintuple cryoapplication (30 s) over ciliary body. Samples of aqueous humor were collected 6, 12, 24 and 48 hours after albumin injection. pH, pO2, pCO2 values and HCO3- concentration were determined using Astrup microanalyser. RESULTS: Parameters of aqueous humor, especially pH, pCO2 and HCO3- turned out to be fairly sensitive indicators reflecting the natural history of experimental uveitis. Cryotherapy characteristically modulates the pH, pCO2 and HCO3- values in the anterior chamber. CONCLUSIONS: We came to the conclusion that monitoring of these parameters may give some important information about the intensity of the course of uveitis and the influence of the treatment. Normalisation of the values usually parallels clinical improvement.     

The effect of motivation arousal on humor preferences.

"The present experiment was designed to test the hypothesis that the arousal of different types of motivations would produce differences in humor preferences. It was predicted that in a hostility-arousing situation subjects would prefer humorous material of a hostile and aggressive nature, while subjects placed in a sexually arousing situation would prefer humor material with a sexual theme. This prediction was confirmed… [and] an explanation of the results was offered in terms of suppression." (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Physostigmine increases aqueous humor production in human eyes

PURPOSE: To investigate if part of the progressive reduction of intraocular pressure (IOP), seen when physostigmine is applied on alternate hours, is due to a reduced aqueous flow. METHODS: In a randomized, open study, one drop of physostigmine salicylate, 8 mg/ml, was instilled at 7 AM in one randomly assigned eye in each of twenty healthy volunteers. Instillations were repeated on alternate hours throughout the day. Each subject's untreated eye served as control. Fluorophotometry of the anterior segment was performed hourly between 7 Am and 8 PM and aqueous flow was calculated. Subsequently, the subjects underwent tomography and tonometry. The change in anterior chamber depth and volume induced by physostigmine was assessed separately. RESULTS: The mean aqueous flow during the day was 25-28% higher in the physostigmine-treated eye than in the control eye. The difference was statistically significant from 9 AM (p < 0.05-p < 0.001). Each dose caused a further increase. The mean outflow facility increased by 0.14 microliters/min/mm Hg with 95% confidence interval (CI) 0.09-0.18. Although the increase in outflow facility was small, there was a marked reduction of IOP with a mean difference between treated and untreated eye of 3.2 mm Hg (95% CI: 2.3-4.0). CONCLUSIONS: Repeated administrations of physostigmine increase the aqueous flow and outflow facility. The combined effect is a marked reduction of IOP.     

Effects of topical nipradilol, a beta-blocking agent with alpha-blocking and nitroglycerin-like activities, on aqueous humor dynamics and fundus circulation

PURPOSE: To study the effects of nipradilol, a nonselective beta-blocker with alpha 1-blocking activity and nitroglycerin-like activity, on aqueous humor dynamics and optic nerve head (ONH) circulation in albino rabbits. METHODS: Experiments were carried out during the dark phase, in conscious rabbits conditioned to a schedule of alternating 12-hour periods of light and dark. The blood-aqueous barrier permeability and the aqueous flow rate were determined fluorophotometrically. The effect on outflow to general blood circulation and uveoscleral outflow were determined by using the fluorophotometric Diamox technique, and the effect on the uveoscleral outflow was further assessed by using the anterior chamber perfusion method. The ONH circulation was estimated by using the laser speckle method. RESULTS: Unilateral topical administration of 0.25% nipradilol solution lowered intraocular pressure (IOP) with relatively weak contralateral effects in a dose-dependent manner with a maximum reduction of 6 mm Hg and an effect duration of 6 hours. Twice-daily instillation for 14 days showed no attenuation of the effects. Single instillation of 0.25% nipradilol showed no significant effect on blood-aqueous barrier permeability and decreased aqueous flow rate in the treated eye (17%; P < 0.01) and in the contralateral eye (9%, P < 0.05). Nipradilol produced no significant effect on outflow facility to general blood circulation, whereas it substantially increased uveoscleral outflow. Twice-daily 0.25% nipradilol instillation increased ONH tissue blood velocity by 13% (P < 0.01), which was probably attributable to locally penetrating drug. CONCLUSIONS: Because of its ability to lower IOP and to increase uveoscleral outflow and optic nerve head circulation in rabbits, further studies are warranted to determine whether nipradilol has potential as an antiglaucoma agent in humans.     

The aqueous humor is capable of generating and degrading H2O2

PURPOSE: To determine the ability of the aqueous humor to generate and degrade H2O2, the effect of environmental factors such as oxygen tension and temperature, and the constituents contributing to the observed results. METHODS: Aqueous humor was carefully removed from bovine eyes within 3 hours of death. Standard and new techniques were used to follow H2O2 degradation and formation. Catalase activity was measured by H2O2 decomposition, usually at 100 microM and 10 mM H2O2, and in some cases by O2 generation. RESULTS: Bovine aqueous humor generated and degraded H2O2. The generation of H2O2 was minimal at 0 degrees C but increased as temperature increased, so that at 37 degrees C at 3 hours, approximately 90 microM H2O2 was observed. Degradation was more complex. At 0 degrees C, only a slow rate of degradation was observed. At 25 degrees C, it was more rapid, and a steady state between generation and degradation was observed at approximately 30 microM. However, at 37 degrees C, starting with 100 microM H2O2, degradation was initially rapid, but then generation became predominant and H2O2, concentration increased to more than 100 microM in 3 hours. No H2O2 was generated in the absence of O2, and H2O2 production increased with increasing O2 tension. Both low and high molecular weight components contributed to the degradation, but synthesis was completely dependent on low molecular weight constituents. Ascorbic acid and metal ions such as Cu+ made a major contribution to H2O2 production. Catalase may be the macromolecular component responsible for aqueous H2O2 decay, as evidenced by H2O2 degradation, inhibition by boiling or 3-aminotriazole, and the approximate correspondence between oxygen generation and H2O2 degradation. CONCLUSIONS: The results indicate that the aqueous humor is capable of producing levels of H2O2 that have been shown previously to cause cataract in organ culture. Changes in aqueous humor metal ion content and concentration of oxygen level have profound effects on H2O2 concentration and may effect lens viability. The variation in published H2O2 levels may in part be the result of the conditions under which the aqueous humor was obtained, stored, and used for assay. The observed steady state H2O2 concentration of 1 microM in fresh aqueous from bovine eyes must be maintained by the metabolism of surrounding tissues as well as intrinsic components capable of degrading H2O2.     

Human hepatocyte growth factor (HGF) in the aqueous humor

Previous studies have demonstrated that individuals with cystinosis, an inherited metabolic disorder, have difficulty processing visual information, and may be selectively impaired in the ability to mentally rotate figures, despite having normal IQs and normal primary sensory function. In our novel task-the 'Black Box'-subjects identified objects solely by feeling the contours. Twenty-three subjects with cystinosis, aged 4 to 34 years, were individually matched with controls on age, sex, handedness, and test form. Subjects with cystinosis performed significantly worse in identifying objects than did controls. In addition, when only subjects over 7 years of age were included, those with cystinosis took significantly longer to correctly identify objects than did controls. Our findings suggest that individuals with cystinosis have difficulty with tactile recognition of common objects. These results support the hypothesis that a genetic disorder may have specific behavioral correlates.     

Penetration of oral and topical ciprofloxacin into human aqueous humor

PURPOSE: This study was planned to investigate the penetration of ciprofloxacin into aqueous humor following oral and topical application as a prophylactic antimicrobial agent. METHODS: Forty-six patients undergoing cataract surgery were randomly divided into two groups. In the first group, the patients received 500 mg oral ciprofloxacin eight hours before surgery and in the second, 5 drops of 0.3% ciprofloxacin were applied to the patients every twenty minutes, starting 100 minutes before the surgery. By paracentesis, aqueous samples were taken just before the operation so the interval between the first topical application and paracentesis was 100 minutes. RESULTS: The mean concentration of ciprofloxacin in aqueous humor was 0.63+/-0.29 microg/ml in the first group. The concentration was 0.69+/-0.30 microg/ml in the second group. Both of these mean concentrations were higher than the levels of MIC90 of S.aureus , S. epidermidis, P. aeruginosa and Gram (-) bacteriae. CONCLUSION: As a result, both topically and orally applied ciprofloxacin achieved a significant aqueous concentration. Each route studied might be suitable for surgical prophylaxis or treatment of infections.     

The effect of neutralizing agents on aqueous parachlorophenol

The effect of possible neutralizing agents on aqueous parachlorophenol were studied. Results indicated that saline, EDTAC, dentin, saliva, prolonged light exposure, and thermal extremes do not appreciably affect the antibacterial properties of aqueous parachlorophenol. The presence of blood and necrotic tissue demonstrated a marked inhibitory effect.     

Aqueous humor dynamics in beagle dogs with caffeine-induced ocular hypertension

In order to investigate the possible mechanisms for caffeine-induced ocular hypertension, the intraocular pressure (IOP) and the outflow through the trabecular meshwork were measured in beagle dog eyes after dosing with intravenous caffeine (30 mg/kg) alone or in combination with the topical beta-blocker befunolol [applied as 100 microliters of a 1% (w/v) solution] which inhibits aqueous humor formation in the ciliary body. Intravenous injections of caffeine significantly increased the IOP at 0.25 and 1 hr after a single dose. The ocular hypertension recovered within 2 hr following dosing. Over time, there were no differences in the outflow between the caffeine and control groups. The instillation of befunolol lowered outflow and produced ocular hypotension. The levels of the IOP and outflow in dogs treated with caffeine and befunolol in combination were almost the same as those in dogs treated with befunolol alone. Single-dose and combination-dose studies demonstrate that intravenous caffeine increases the IOP in normal beagle dogs possibly by increasing aqueous humor formation and not by the inhibition of aqueous humor drainage through the trabecular meshwork.     

The effect of phacoemulsification on aqueous outflow facility

OBJECTIVE: Although control of intraocular pressure (IOP) after cataract extraction may be of critical importance, little is known regarding changes in facility of outflow in the early postoperative period. The effect of phacoemulsification and conjunctival peritomy size on the coefficient of aqueous outflow facility (C) and IOP was studied. DESIGN: Participants were assigned randomly to one of two treatment groups. PARTICIPANTS: Seventy-four patients with cataract and without evidence of glaucoma were studied. INTERVENTION: Patients were randomized to receive either single- or two-quadrant conjunctival peritomy and phacoemulsification. MAIN OUTCOME MEASURES: Tonometry and tonography were assessed before surgery and at 1 day, 1 week, 6 weeks, and 1 year after surgery by a masked observer. RESULTS: Fifty patients with a mean of 11.4 months' (range, 10-13 months) follow-up were analyzed. Patients with reduced preoperative facility of outflow (as defined by C < or = 0.28 microliter/min/mmHg) showed a significant improvement from a mean preoperative value of 0.24 +/- 0.04 microliter/min/mmHg to 0.41 +/- 0.22 microliter/min/mmHg at 1 year (P = 0.002, N = 19). Among all patients, there was no significant change between mean preoperative C and last follow-up (0.39 +/- 0.23 vs. 0.46 +/- 0.38 microliter/min/mmHg, not significant [ns], N = 50). Furthermore, there was no significant change between mean preoperative and final IOP (23.7 +/- 4.1 vs. 23.3 +/- 3.9 mmHg, ns, N = 50). There was a significant elevation of mean IOP on postoperative day 1 to 27 +/- 6.2 mmHg (P = 0.001, N = 50). Patients with IOP elevations greater than 8 mmHg on postoperative day 1 had significantly elevated IOP at 1 year compared to preoperative values (P = 0.02, N = 12). There were no significant differences detected regarding C or IOP between single- or two-quadrant peritomy groups. CONCLUSIONS: Outflow facility improves after phacoemulsification in patients with a reduced preoperative coefficient of aqueous outflow. Postoperative day 1 IOP is significantly elevated after phacoemulsification. Conjunctival peritomy size does not appear to play a role in aqueous outflow facility or IOP after surgery.     

Photoreceptor outer segments in aqueous humor from dogs with rhegmatogenous retinal detachments

OBJECTIVE: To determine whether photoreceptor outer segments can be found in aqueous humor from dogs with rhegmatogenous retinal detachment (RRD). DESIGN: Case series. ANIMALS: 4 dogs with unilateral RRD, 2 dogs with bilateral RRD, 1 dog with unilateral non-RRD, and 1 dog with glaucoma without retinal detachment. PROCEDURE: Aqueous humor samples were fixed in 2% glutaraldehyde and examined by means of transmission electron microscopy. RESULTS: Outer segments were found in aqueous humor from 7 of 8 eyes with RRD but were not found in aqueous humor from dogs with non-RRD or glaucoma. CLINICAL IMPLICATIONS: Photoreceptor outer segments may move into the anterior chamber of eyes with RRD.     

Short-term clinical study on a new aqueous humor drainage implant for refractory glaucoma

Alkaline phosphatase-conjugated oligonucleotide probes were developed to detect the gene coding for Vero toxin 1 (VT1) and Vero toxin 2 (VT2). Using these probes, 3 hr was enough to detect VT genes when suspicious colonies of enterohaemorrhagic Escherichia coli (EHEC) were obtained on an agar plate. The results of a hybridization test with 144 isolates of EHEC O157 and one isolate of Shigella dysenteriae Type 1 agreed exactly with the immunological detection, reversed passive latex agglutination (RPLA) test, of VTs in their culture supernatants. The sensitivity levels of these probes for the detection of VT genes were 100%. The specificity of these probes were also tested with a total of 1,002 strains of Escherichia coli other than EHEC and 8 strains of Shigella sp. other than Shigella dysenteriae Type 1; the results showed 100% specificity.