Characterization of ocular hypertension induced by adenosine agonists

PURPOSE: Previous studies have shown that adenosine agonists may induce a rise in intraocular pressure (IOP), a reduction in IOP, or both. Although the reduction in IOP results from the activation of adenosine A1 receptors, the mechanisms responsible for the rise in IOP have not been investigated. This study examines the receptors and mechanisms responsible for the adenosine agonist-induced rise in IOP. METHODS: The ocular effects of the nonselective adenosine agonist NECA, the relatively selective adenosine A2 agonist CV-1808, the A2a agonist CGS-21680, and the A1 agonist R-PIA were evaluated. RESULTS: The topical administration of CV-1808 produced a rapid rise in IOP, with a maximum increase of 15.6 +/- 1.6 mm Hg. Dose-response curves demonstrated that each agonist produced a dose-related rise in IOP with the following rank order of potency: NECA > CV-1808 > > R-PIA = CGS-21680. At times corresponding to the rise in IOP, the administration of high doses of CV-1808 (165 micrograms) produced a significant increase in aqueous humor flow and protein concentration. Increases in IOP and aqueous humor protein levels induced by CV-1808 were blocked by pretreatment with the adenosine A2 antagonist DMPX. In vitro studies demonstrated that CV-1808 did not alter cyclic adenosine monophosphate production in the rabbit iris-ciliary body. In cats, topical administration of CV-1808 produced a rapid rise in IOP, with a maximum increase of 8.1 +/- 2.4 mm Hg and an ED50 of 73 +/- 2.9 micrograms. This rise in IOP was blocked by DMPX pretreatment. CONCLUSIONS: These data demonstrate that adenosine receptor agonists can induce an acute rise in IOP in rabbits and cats. On the basis of pharmacologic characteristics, the rise in IOP is consistent with the activation of ocular adenosine A2 receptors. Functional studies indicate that at high doses, this rise in IOP involves an increase in aqueous flow and the breakdown of the blood-aqueous barrier.     

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.     

epsilon-Aminocaproic acid does not inhibit outflow resistance washout in monkeys

PURPOSE: To determine whether the anti-fibrinolytic agent epsilon-aminocaproic acid (EACA) inhibits the washout of resistance to aqueous humor outflow during anterior chamber perfusion in cynomolgus monkeys, as it does in rabbits. METHODS: Nine adult ocular normotensive cynomolgus monkeys underwent bilateral anterior chamber perfusion with Bárány solution, containing 3.8 mM EACA unilaterally. Total outflow facility was determined in both eyes simultaneously for approximately 4 hours by the two-level constant pressure method. The data were analyzed using a linear regression model that tested treated versus control eye differences over time against a slope and intercept of 0.0. RESULTS: Outflow facility increased and resistance decreased significantly over time similarly in both EACA-treated and control eyes; i.e., neither the slopes nor the intercepts for facility or resistance, respectively, differed between the eyes over the entire 4-hour measurement period or for the initial 90 minutes considered separately. The facility increase and resistance decrease as functions of perfusion volume also were similar in EACA-treated and control eyes. CONCLUSIONS: EACA at this dose does not prevent resistance washout in the cynomolgus monkey, in contrast to the rabbit. This species difference may relate to the vastly different anatomy and physiology of their outflow pathways.     

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.     

Biologic effects of nonsteroidal anti-inflammatory drugs

Experimental glaucoma was induced in 1 eye of 6 cynomolgus monkeys by laser treatment of the trabecular meshwork. In 5 of the 6 monkeys the increased intraocular pressure (IOP) caused marked glaucomatous damage in the experimental eye. Ocular blood flow was determined with labeled microspheres 4 years after the laser treatment. IOP was regulated with an external reservoir. With the same perfusion pressure in both eyes no statistically significant difference was observed between the 2 eyes for total ocular blood flow or for blood flow through any of the ocular tissues. Total ocular blood flow was 343.5 +/- 61.4 mg/min (mean +/- SEM) in the control eye and 385.3 +/- 107.7 mg/min in the experimental eye.     

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.     

Effect of DMSO and exchange volume on outflow resistance washout and response to pilocarpine during anterior chamber perfusion in monkeys

PURPOSE: To determine the dependence of outflow resistance washout on anterior chamber (AC) fluid exchange volume (EV); the minimum EV required for complete AC mixing, and the effect of 0.01-5% DMSO in the exchange solution on outflow resistance. METHODS: Total outflow facility was determined in 63 pentobarbital-anesthetized cynomolgus monkeys, before and after AC exchange, for 10 min, with 1, 2, and 4 ml of Bárány's perfusand, containing 0.01-5% DMSO or containing 1 microgram/ml or 5 micrograms/ml pilocarpine HCL (pilo), each volume. RESULTS: Post-exchange facility increased by 21% (p < 0.05) vs. baseline for both the 1 and 2 ml Bárány's volumes and by 50% (p < 0.001) for the 4-ml volume. Washout-corrected post-exchange facility was unchanged from baseline, following 1 or 2 ml exchange with 1 microgram/ml pilo; 5 micrograms/ml pilo increased facility by 130 +/- 41% and 174 +/- 40% respectively, relative to baseline. Exchange with 4 ml of 1 microgram/ml pilo increased facility 72% more than the 2 ml (p < 0.029) and 100% more than the 1 ml (p < 0.014) volumes. When corrected for their respective baselines, 2 ml of 5 micrograms/ml pilo increased facility 12.7 +/- 4.4% more than the 1 ml volume (p < 0.05). Post exchange facility was not significantly increased over baseline in eyes exchanged with 2 ml of 0.01-4% DMSO or in eyes exchanged with Bárány's alone. When corrected for their respective baselines, post-exchange facility was significantly lower in eyes exchanged with 5% DMSO vs. Bárány's (p = 0.022). CONCLUSIONS: One- and 2-ml EVs preserve outflow resistance equally well, and substantially better than 4 ml. Two ml is the minimum volume necessary for adequate mixing of AC drug solutions, to achieve the full facility effect. Concentrations of DMSO up to 4% in a 2-ml EV can solubilize compounds without additionally decreasing outflow resistance.     

Psychiatry and bioethics. An exploration of the relationship

The purpose of this study was to determine glucocorticoid modulation of ocular pressure to epinephrine applied topically to rabbit eyes that were pretreated with dexamethasone. Rabbit eyes were pretreated with five applications of topical 0.07% dexamethasone (0.1% dexamethasone phosphate) or saline drops, administered at ten minute intervals. The eyes were then treated with epinephrine bitartrate drops at concentrations of free base epinephrine of 1.1%, 0.27%, 0.05%, 0.027%, 0.005% or 0.0005%. An additional group of rabbits received dexamethasone pretreatment only. Intraocular pressure (IOP) was measured for the next four hours. Enhanced lowering of intraocular pressure was observed with dexamethasone pretreatment. Rabbits receiving the smaller dose of epinephrine with dexamethasone had the largest decrease in IOP at 135 minutes after instillation of the epinephrine drops (0.005% epinephrine, mean difference +/- standard error of mean = 5.4 +/- 1.1 mmHg). Similarly, the duration of significant decrease of the IOP was prolonged in the groups receiving the lower concentrations of epinephrine (0.005% epinephrine, 255 minutes after administration of epinephrine). The synergism between glucocorticoids and adrenergic agonists in lowering IOP may be potentially useful in the therapy of ocular hypertension and glaucoma.     

The nerve fibre layer in ocular hypertension. Preliminary results

A group of healthy subjects (IOP < 22 mmHg) and a simple ocular hypertension group (IOP > or = 22 mmHg) were examined with a view to checking if there were any differences between their nerve fibre layers. Results indicate thinner fibres in the ocular hypertensives significantly correlative with pressure increase. Among the two groups, some corresponding fibre thicknesses were found.     

Hemodynamic response to induction and intubation. Propofol/fentanyl interaction

BACKGROUND: When given as an intravenous bolus for induction of anesthesia, propofol can decrease postintubation hypertension but can also create moderate to severe postinduction, preintubation hypotension. The addition of fentanyl usually decreases the postintubation hypertension but can increase the propofol-induced preintubation hypotension. The goal of the study was to determine the relation between propofol and fentanyl doses and the hemodynamic changes post-induction, preintubation and postintubation. METHODS: Twelve groups of 10 patients, ASA physical status 1 or 2, first received fentanyl 0, 2, or 4 micrograms.kg-1 and then 5 min later received propofol 2.0, 2.5, 3.0, or 3.5 mg.kg-1 as an intravenous bolus for induction of anesthesia. Arterial blood pressure was continuously monitored. The trachea was intubated 4 min after propofol administration. RESULTS: The mean decrease in systolic blood pressure after propofol was 28 mmHg when no fentanyl was given, 53 mmHg after 2 microgram.kg-1 of fentanyl (P < 0.05 vs. no fentanyl), and 50 mmHg after 4 micrograms.kg-1 (P < 0.05 vs. no fentanyl; no statistically significant difference 4 vs. 2 micrograms.kg-1). There was no statistically significant difference in hemodynamic response to intubation relative to propofol dose. Hemodynamic response to intubation was decreased by the administration of fentanyl; the mean increase of systolic blood pressure after intubation was 65 mmHg from preintubation value without fentanyl, 50 mmHg after 2 micrograms.kg-1, and 37 mmHg after 4 micrograms.kg-1 (P < 0.05 for 2 and 4 micrograms.kg-1 vs. no fentanyl and for 4 vs. 2 micrograms.kg-1). Hemodynamic changes postintubation were not statistically different with increasing doses of propofol. CONCLUSIONS: Hemodynamic changes after induction with propofol or propofol/fentanyl, pre- or postintubation, are not modified when the propofol dose is increased from 2 to 3.5 mg.kg-1. Maximal hypotension preintubation occurs with a fentanyl dose of 2 micrograms.kg-1, whereas the magnitude of postintubation hypertension is significantly decreased with an increase in the fentanyl dose to 4 micrograms.kg-1.     

H-7 disrupts the actin cytoskeleton and increases outflow facility

OBJECTIVES: To determine the effects of the serine-threonine kinase inhibitor H-7 on (1) cell junctions and the attached actin-based cytoskeleton in cultured bovine aortic endothelial cells, and (2) outflow facility in living monkeys. METHODS: Bovine aortic endothelial cells were cultured by standard techniques. The architecture and distribution of actin filaments, vinculin, and beta-catenin in bovine aortic endothelial cells were studied by immunolabeling before and after exposure to H-7 at various concentrations and durations. Outflow facility (perfusion) and intraocular pressure (Goldmann tonometer) were determined before and after the intracameral or topical administration of H-7 or a vehicle. RESULTS: In bovine aortic endothelial cells, exposure to H-7 produced a reversible time- and concentration-dependent disruption of actin microfilaments and an alteration in the organization of cell-cell and cell-matrix adhesions. In monkeys, intracameral and topical administration of H-7 dose dependently and reversibly doubled facility, and topical H-7 reduced intraocular pressures. CONCLUSION: H-7 increases outflow facility in monkeys, probably by inhibiting cell contractility, cytoskeletal support, and cell-cell adhesions in the trabecular meshwork.     

Increase in aqueous humor production following D1 receptors activation by means of ibopamine

BACKGROUND: Topically administered 2% ibopamine (a dopaminergic agonist) induces a transitory ocular hypertension in 92% of patients with primary open-angle glaucoma and in 52% of patients with normal tension glaucoma. In normal eyes, ibopamine has no effect on IOP. PURPOSE: The aim of the present study was to verify, by means of fluorophotometric techniques, which hydrodynamic changes could be induced in normal and glaucomatous eyes, stimulating the D1 receptor with 2% ibopamine administered topically. In addiction, we wanted to evaluate if ibopamine could modify IOP before and after an experimentally induced outflow system impairment in rabbits. METHODS: In study 1 we performed a measurement of aqueous humor flow in 6 healthy volunteers and in 6 glaucomatous patients, before and after 2% ibopamine administration. In study 2 the alteration of outflow pathways was induced by means of Laminaria Digitata in 10 rabbits. RESULTS: After 2% ibopamine administration we found a significant increase in aqueous humor production, both in glaucomatous (P = 0.035) and normal eyes (P = 0.004). In rabbits, we found no significant change in IOP at basal conditions. After experimentally induced outflow system impairment by laminaria, we observed a marked increase in IOP (+ 13.5 mmHg SD 7.2; P < = 0.001) following ibopamine administration. CONCLUSIONS: These experimental data have a diagnostic value in glaucoma, since they show how an intraocular hypertensive response due to ibopamine in normotensive eyes is a sign of initial outflow impairment. Moreover, the possibility to increase the aqueous humor production sets new trends in the treatment of post surgical ocular hypotony.     

The cyclopentolate provocative test in suspected or untreated open-angle glaucoma. V. Statistical analysis of 431 eyes

The mydriasis provocative test with 1% cyclopentolate (CPT) was performed on 431 eyes with suspected or untreated open-angle glaucoma. Tonography was performed both before and during CPT to study the changes in aqueous dynamics during the test. Statistical analysis of the results yielded the following mean trends and correlations at a highly significant level (P less than 0.001) in the alterations: Intraocular pressure (IOP) rose (deltaP +/- SD) (+ 1.4 +/- 2.9 mmHg) and aqueous outflow facility decreased (deltaC) (-10%) during CPT. The distribution of deltaP and deltaC did not follow the normal Gaussian distribution. The change in deltaP deviated from the Gaussian distribution in 5-10% of the eyes. The deviating values concur with those of the responder eyes in which IOP rose greater than or equal to 8 mmHg during CPT. deltaP was linearly dependent on the initial IOP level Po and the absolute change was always almost constant, approximately +1.4 mmHg. Both the total series and the responder eyes displayed the same trend for the change in aqueous outflow facility in relation to the initial C value (Co): low Co values changed less on average and high Co values changed more and diminished. It is not known why the deltaC change was different depending on the Co value. The change in IOP correlated statistically highly significantly in the initial C value (Co). The loqwe the Co value, the higher was the mean IOP elevation during CPT. In contrast, the change in aqueous outflow (deltaC) did not corrrelate (N.S.) with the initial IOP level (Po) before CPT.     

Basal concentrations of various steroids in the nonobese diabetic (NOD) mouse and effect of immobilization stress

Psychiatric patients receiving phenothiazine, tricyclic antidepressant and antiparkinsonian drugs for prolonged periods, occasionally develop mydriasis and angle closure glaucoma. Suxamethonium, usually given to modify the convulsion of electroconvulsive therapy (ECT) increases intraocular pressure (IOP) by about 7-8 mmHg, the increase being maximal and having returned to baseline 2 min and 6 mins after injection, respectively. We studied the effects on IOP of an electrically induced convulsion following induction of anesthesia using methohexitone 1 mg.kg(-1) and suxamethonium 0.5 mg.kg(-1) in 21 consecutive cooperative psychiatric patients, all receiving antipsychotropic drugs. IOP was recorded sequentially from before induction of anesthesia to after resumption of spontaneous respiration. Their mean IOP was 15.3 (SD 3.7) mmHg prior to induction of anesthesia, 13.5 (SD 3.5) mmHg after loss of eyelash reflex following injection of methohexitone, 16.1 (SD 2.4) mmHg after cessation of muscle fasciculations induced by suxamethonium, 19.2 (SD 5.6) mmHg after cessation of convulsion and 15.5 (SD 4.4) mmHg following resumption of regular spontaneous respiration. The successive stepwise changes in the mean IOP were all statistically significant (p < 0.001 each change compared with the preceding pressure; paired 't' tests). These data reveal that the reduction in IOP produced by methohexitone is reversed by the increase in IOP produced by suxamethonium. Collated with the time course of the effects of barbiturates and suxamethomium on IOP, the increase in IOP observed following the induced convulsion was not greater than that expected after suxamethonium alone, suggesting that the induced convulsion during ECT does not pose an ocular hazard to psychiatric patients receiving medications which have iatrogenic glaucomatous potential.     

Adenosine A1 receptor-mediated inhibition of evoked glutamate release is coupled to calcium influx decrease in goldfish brain synaptosomes

Binding of [3H]cyclohexyladenosine (CHA) to the cellular fractions and P2 subfractions of the goldfish brain was studied. The A1 receptor density was predominantly in synaptosomal membranes. In goldfish brain synaptosomes (P2), 30 mM K+ stimulated glutamate, taurine and GABA release in a Ca(2+)-dependent fashion, whereas the aspartate release was Ca(2+)-independent. Adenosine, R-phenylisopropyladenosine (R-PIA) and CHA (100 microM) inhibited K(+)-stimulated glutamate release (31%, 34% and 45%, respectively). All of these effects were reversed by the selective adenosine A1 receptor antagonist, 8-cyclopentyltheophylline (CPT). In the same synaptosomal preparation, K+ (30 mM) stimulated Ca2+ influx (46.8 +/- 6.8%) and this increase was completely abolished by pretreatment with 100 nM omega-conotoxin. Pretreatment with 100 microM R-PIA or 100 microM CHA, reduced the evoked increase of intra-synaptosomal Ca2+ concentration, respectively by 37.7 +/- 4.3% and 39.7 +/- 9.0%. A possible correlation between presynaptic A1 receptor inhibition of glutamate release and inhibition of calcium influx is discussed.     

Expanding role of alpha adrenoceptor blockade in the treatment of benign prostatic hyperplasia

PURPOSE: To evaluate the efficacy and safety of timolol hemihydrate once daily versus timolol maleate gel forming solution once daily in patients with primary open-angle glaucoma or ocular hypertension. METHODS: We prospectively randomized patients with primary open-angle glaucoma or ocular hypertension to receive either timolol hemihydrate 0.5% solution or timolol maleate gel forming solution 0.5% every morning. The primary efficacy variable was the 8:00 AM trough intraocular pressure (IOP) 24 hours after administration. RESULTS: Three months after initiation of therapy, baseline IOP had decreased from 23.6 +/- 1.9 mmHg to 18.3 +/- 2.8 mmHg in the group taking timolol hemihydrate (n = 22) and from 23.7 +/- 2.2 mmHg to 18.4 +/- 3.1 mmHg in the group receiving timolol maleate gel (n = 21) at the 24-hour trough level. This was not a significant difference between groups at 3 months. Also, no difference was observed between groups in the 2-hour post instillation IOP. Visual acuity was decreased in the group receiving timolol maleate gel compared with those receiving timolol hemihydrate one minute after instillation of study medicine at month 3. Otherwise, ocular and systemic safety were similar between groups. No differences between groups in cardiac pulse or systolic and diastolic blood pressure were observed. CONCLUSION: Timolol hemihydrate 0.5% solution given once a day appears to be as efficacious and safe in decreasing IOP as timolol maleate gel 0.5% given once a day.     

The effects of unoprostone isopropyl 0.12% and timolol maleate 0.5% on diurnal intraocular pressure

PURPOSE: To compare the effect of unoprostone isopropyl 0.12% to that of timolol maleate 0.5% solution given twice daily on the diurnal curve of intraocular pressure (IOP) in patients with primary open-angle glaucoma or ocular hypertension. METHODS: In this investigator-masked, single-center, parallel-group comparison, 36 patients with primary open-angle glaucoma or ocular hypertension were randomized in a 2:1 ratio to receive either unoprostone isopropyl 0.12% or placebo/timolol maleate 0.5% solution, respectively. A placebo-controlled diurnal curve on day 0 and active-controlled diurnal curves at weeks 2 and 4 were performed at 0, 2, 4, 6, 8, 10, 12, and 24 hours. At week 2, administration of unoprostone isopropyl twice daily was compared with administration of timolol maleate twice daily. At week 4, administration of unoprostone isopropyl three times daily was compared with administration of timolol maleate twice daily. RESULTS: At the 24-hour 8:00 AM trough at week 2, administration of unoprostone isopropyl twice daily decreased IOP from 23.4 +/- 2.0 mmHg at baseline to 19.3 +/- 4.4 mmHg, and timolol maleate reduced IOP from 24.4 +/- 2.6 mmHg to 17.5 +/- 2.9 mmHg. At the 8:00 AM trough at week 4, unoprostone isopropyl given three times daily produced an IOP of 19.6 +/- 3.3 mmHg and timolol maleate resulted in an IOP of 19.4 +/- 3.0 mmHg. No statistical differences between groups were observed at any time point during either diurnal curve. Safety was similar in the two treatment groups, with no differences between groups in conjunctival hyperemia, anterior segment inflammation, or iris color change. CONCLUSION: Results of this short-term pilot trial indicate that unoprostone isopropyl may be safe and effective in reducing IOP from baseline when given twice or three times daily.     

Effect of intravenous fenoldopam on intraocular pressure in ocular hypertension

Intravenous fenoldopam, a selective dopamine-1 receptor agonist, was compared with placebo in this randomized, double-blind, two-period crossover study to evaluate its effects on intraocular pressure, aqueous dynamics, and macular blood flow in patients with elevated intraocular pressure or primary open-angle glaucoma. Doses of fenoldopam were titrated up to a maximum of 0.5 microgram/kg/min. Intraocular pressure, measured by pneumotonometry, was the primary outcome variable. Other outcomes included macular blood flow assessed by blue field examination, visual field examined by automated perimetry, aqueous outflow facility measured by tonography, and aqueous humor production determined by fluorophotometry. During infusions of fenoldopam, intraocular pressure increased from a mean baseline level of 29.2 mmHg to a mean maximum level of 35.7 mmHg. During the placebo infusions, pressure increased from a mean baseline of 28.4 mmHg to a mean of 29.0 mmHg at the time point that corresponded to the mean maximum intraocular pressure on the day intravenous fenoldopam was administered, to yield a mean difference in pressure between study days of 6.7 mmHg (P < 0.05). There were no apparent changes in macular blood flow, visual fields, or production or outflow of aqueous humor associated with fenoldopam infusion. The increase in intraocular pressure seen in this population of patients with ocular hypertension during infusions of fenoldopam is consistent with fenoldopam-associated increases in intraocular pressure reported in previous studies of healthy volunteers and of patients with accelerated systemic hypertension. These results further suggest that dopamine-1 receptors play a role in the regulation of intraocular pressure.     

Measuring sexual harassment: development and validation of the Sexual Harassment Inventory

Recent studies have suggested that intravenous infusion of fenoldopam, a selective dopamine-1 receptor agonist, elevates intraocular pressure (IOP) in man. This study evaluated the effect of intravenous fenoldopam on IOP, aqueous humor outflow facility and gonioscopy in 12 healthy human subjects. Three doses (0.2, 0.5 and 1.0 microg/kg/min) were infused for 120 minutes in a double masked, placebo controlled, four-way crossover design. IOP was measured every 20 minutes in the supine position and every 40 minutes while sitting during the drug and placebo infusions. Tonography and gonioscopy were performed at baseline and after 120 minutes of infusion. Compared to placebo, IOP increased by 3.5 mm Hg (32%) for the lowest dose, 5.8 mm Hg (46%) for the intermediate dose, and 6.9 mm Hg (55%) for the highest dose (p<0.05 for all three doses). IOP returned to baseline within 30 minutes of stopping the infusion. The outflow facility decreased from baseline by 26% after 120 minutes of infusion for all drug doses. In contrast, outflow facility increased from baseline by 11% during placebo infusion. Compared to placebo, the fenoldopam induced changes in outflow were statistically significant (p<0.05). There was no change in the gonioscopic appearance of the anterior chamber angle during the infusion. This study shows that systemic administration of a selective dopamine-1 receptor agonist causes a significant dose-dependent increase in IOP that can be explained in part by diminished outflow facility. These results support a role for the dopamine-1 receptor in the modulation of IOP in general and suggest modulation of aqueous humor outflow by dopaminergic receptors.     

Effect of spinal cord stimulation on tactile hypersensitivity in mononeuropathic rats is potentiated by simultaneous GABA(B) and adenosine receptor activation

In rats with abnormally low withdrawal thresholds ('allodynia') in one hindpaw induced by a photochemical sciatic lesion, an intrathecal catheter was inserted to the lumber enlargement and an epidural electrode was implanted at T11. I.t. administration of GABA(B) or adenosine A1 receptor agonists (baclofen, R(-)-N6-(2-phenylisopropyl)adenosine (R-PIA)) suppressed allodynia in a dose-dependent fashion. When the two agonists were given together, each in an ineffective dose, there was a normalization of the thresholds. Rats, in which spinal cord stimulation (SCS) could not suppress the allodynia (non-responders), were transformed into SCS-responders by injection of baclofen and R-PIA in low, ineffective doses, combined with SCS. In SCS responding rats, combination of a selective GABA(B) and an adenosine A1 receptor antagonist (CGP 55845, CPT) in low, ineffective doses abolished the SCS-induced threshold normalization. These results indicate that GABAergic and adenosine-dependent mechanisms are involved in the SCS effect and further suggest a strategy for enhancing the therapeutic efficacy of SCS.