Pharmacokinetic and pharmacodynamic profile of donepezil HCl following multiple oral doses.

AIM: The aim of this study was to characterize the pharmacokinetics and pharmacodynamics of donepezil HCl, a new, chemically distinct and specific acetylcholinesterase (AChE) inhibitor for the treatment of Alzheimer's disease, following multiple-dose administration. METHODS: This was a double-blind, randomized, placebo-controlled, multiple-dose study in healthy male volunteers (n=27). Three dose levels were investigated in sequential order: 1, 3 and 5 mg. Each dose was administered orally, once a day, for 21 consecutive days. Donepezil concentrations in plasma were quantified by HPLC. Pharmacodynamic activity was determined by the radioenzymatic measurement of erythrocyte membrane acetylcholinesterase (rbc-AChE) inhibition. RESULTS: The pharmacokinetic disposition of donepezil was observed to be dose proportional. The mean terminal disposition half-life was 79.5+/-19.0 h which resulted in a slow approach to steady state (14-21 days). A four- to sixfold increase in donepezil plasma concentration was observed during this time; however, no further increase was evident after achievement of steady state. The mean donepezil plasma concentration at steady state (Css) was 14.2 ng ml(-1). Neither the rate of accumulation nor the rate of clearance was dose dependent. Inhibition of rbc-AChE was directly correlated with donepezil concentration over a wide concentration range, with the higher concentrations showing the expected hyperbolic relationship. Donepezil was well tolerated by all subjects with no clinically significant changes in laboratory or physical parameters observed at any dose. CONCLUSIONS: The pharmacokinetics of donepezil were found to be dose proportional following the administration of multiple doses to healthy volunteers. A predictable relationship was also observed between plasma donepezil concentrations and rbc-AChE inhibition. The half-life of donepezil makes it suitable for once-daily dosing.

Intraoperative mitomycin-C for glaucoma associated with ocular inflammation.

BACKGROUND AND OBJECTIVE: The authors studied the efficacy and complications of intraoperative mitomycin-C in glaucoma associated with ocular inflammation. PATIENTS AND METHODS: The authors retrospectively reviewed the medical records of 24 consecutive patients (24 eyes) with glaucoma and ocular inflammation who had been treated with trabeculectomy and intraoperative mitomycin-C. Patient ages ranged from 10 to 83 years (mean 43 years). All patients were observed for at least 6 months. RESULTS: With a mean follow-up time of 14.6 months, 18 of the 24 patients (75%) retained vision and had an intraocular pressure of 21 mm Hg or lower with or without medications (range 4 to 21 mm Hg; mean 13.4 mm Hg). Fifteen of 24 patients (62%) had an intraocular pressure of 21 mm Hg or lower with no medications. Three patients required tube shunt implants. One patient had a retinal detachment and lost light perception. One patient had endophthalmitis 14 months after surgery. Seven of 24 patients lost two or more lines of Snellen acuity. CONCLUSION: Trabeculectomy with mitomycin-C can control intraocular pressure in glaucoma associated with ocular inflammation, but complications are frequent.

Intermediate-term outcome of variable dose mitomycin C filtering surgery.

PURPOSE: Trabeculectomy with adjunctive mitomycin C is associated with high success rates in studies with follow-up of less than 1 year. This report evaluates the visual and intraocular pressure (IOP) outcome in eyes after trabeculectomy with adjunctive mitomycin C 1 to 3 years after surgery in a predominantly white group (98.1%). METHODS: The records of 157 eyes of 157 consecutive patients, aged 18 or older, who underwent mitomycin C trabeculectomies for uncontrolled glaucoma of various causes were reviewed. All surgeries were performed between April 1991 and June 1993. The concentration of mitomycin C varied from 0.2 to 0.5 mg/ml and was applied for 30 seconds to 5 minutes (only one patient received 0.2 mg/ml). Of the 157 eyes, 110 eyes were at high risk for failure (previous surgeries or inflammatory glaucoma). Thirty-nine eyes had preoperative IOP < or = 21 mmHg. RESULTS: The mean preoperative IOP was 29.4 +/- 10.3 mmHg. This was reduced to 13.0 +/- 7.6 mmHg at 1 year, 11.5 +/- 6.4 mmHg at 2 years, and 13.4 +/- 7.3 mmHg at 3 years. Cumulative survival rate by life-table analysis was 94.2% +/- 1.9% at 1 year, 92.1% +/- 2.4% at 2 years, and 88.7% +/- 4.0% at 3 years, where failure was defined as reoperation for control of IOP. Complications included cataract formation-progression (n = 31), hyphema (n = 26), choroidal detachment (n = 21), hypotony maculopathy (n = 5), and endophthalmitis (n = 2). Vision deteriorated in 29 eyes and improved by 2 or more Snellen visual acuity lines in 29 eyes. CONCLUSION: The IOP reduction after mitomycin C filtering surgery is sustained in the intermediate-term, 1 to 3 years, follow-up period.

A case of orbital emphysema as an ocular emergency.

Orbital emphysema is radiologically apparent in 50% of cases of orbital fractures, but it is generally a benign, self-limited condition. However, visual loss may occur if a fracture produces orbital compression via a ball-valve effect, allowing air to enter but not leave the orbit. A case of compressive orbital emphysema complicated by ischemic optic neuropathy is reported. Intraorbital needle aspiration relieved the compression with improvement of visual acuity and normalization of intraocular pressure.

Glaucoma. A primer for primary care physicians.

Glaucoma is best detected by examination of the optic disk, since intraocular pressure is not always elevated in patients with the condition. A large, vertically oval cup within the optic disk is strong evidence for glaucoma. Open-angle glaucoma, the most common form of the disorder, often is not detected until the disease is advanced. It can usually be treated successfully with topical medications, but systemic absorption of these can result in serious side effects. If medical treatment fails, laser therapy or filtering surgery may be helpful. Acute angle-closure glaucoma has a sudden onset marked by alarming elevations in intraocular pressure. It is treated immediately with topical pilocarpine and systemic osmotic agents, and an iridectomy should be performed as soon as possible. Congenital glaucoma can be cured with goniotomy.

Extravascular albumin concentration of the uvea.

The hypothesis that uveal vessels absorb fluid was tested by measuring the albumin in extravascular uveal tissues and in plasma. From these results the effective albumin concentration was calculated in both rabbits and monkeys. Three separate methods were used to measure uveal albumin, and the results of these were compared. In method 1, the intravenous fluorescein isothiocyanate (FITC)-albumin concentration found in the uvea 5 min after injection (intravascular tracer) was subtracted from that found 2 hr after injection (intravascular plus extravascular tracer) to determine the extravascular albumin concentration. In method 2, intravenous FITC-albumin was followed by vascular washout after a 2-hr equilibration period to determine extravascular uveal albumin. In method 3, the endogenous extravascular albumin concentration of uveal tissues was measured with an enzyme-linked immunosorbent assay (ELISA) after vascular washout. The effective albumin concentration was determined by dividing the data in methods 1, 2, and 3 by the extravascular albumin space volume. The effective albumin concentration in monkey (as percentage of plasma) was, for methods 1, 2, and 3: iris 2, 3, and 4%; pars plicata 14, 12, and 7%; pars plana 2, 10, and 12%; and choroid 2, 12, and 10%, respectively. In rabbit, the extravascular albumin concentrations were: iris 10, 21, and 7%; pars plicata 69, 26, and 39%; pars plana 41, 46, and 10%; and choroid 88, 30, and 26%, respectively. These findings are lower than previously reported in rabbits, yet are consistent with previous estimates in monkeys. These results support the hypothesis that uveal vessels are capable of fluid absorption, since a large colloid osmotic gradient exists across the vessel wall.

Hydrostatic pressure of the suprachoroidal space.

The hydrostatic pressure of the suprachoroidal space was measured in 18 cynomolgus monkey eyes by one of two methods: (1) direct cannulation, or (2) silicone sponge implantation. The intraocular pressure (IOP) and suprachoroidal pressure were monitored simultaneously with the IOP being held at various levels between 5 and 60 mm Hg. In eyes with direct cannulation, at an IOP of 15 mm Hg, the pressure in the anterior suprachoroidal (supraciliary) space was 0.8 +/- 0.2 mm Hg (n = 6, mean +/- SE) below the IOP, but the posterior suprachoroidal pressure was 3.7 +/- 0.4 mm Hg (n = 8) below the IOP. The suprachoroidal pressure in eyes with silicone sponge implant was 4.7 +/- 0.6 (n = 7) mm Hg below the IOP. A change in IOP produced a corresponding change in the supraciliary space pressure. However, the pressure difference between the anterior chamber and the posterior suprachoroidal space increased at higher IOP. This pressure differential is the driving force for uveoscleral outflow.

Volume flow across the isolated retinal pigment epithelium of cynomolgus monkey eyes.

The retinal pigment epithelium (RPE)-choroid was isolated from cynomolgus monkey eyes with experimental retinal detachments and the volume flow was determined in vitro using Ussing-type chambers. With zero pressure difference across the membrane, retina-to-choroid volume flow was 5.0 microliter/hr/cm2 in eyes with subacute retinal detachments (1-2 weeks). In eyes with chronic retinal detachment (8-20 months), the flow was 7.3 microliter/hr/cm2. Volume flow was not affected by the elimination of ambient bicarbonate. Transepithelial potential difference and resistance were 8.9 mV, retinal side positive, and 339 ohm-cm2, respectively, in chronic retinal detachments. It is concluded that there is a posteriorly directed flow of fluid across the RPE in cynomolgus monkey eyes with chronic retinal detachments.

Effect of plasma osmolality and intraocular pressure on fluid movement across the blood-retinal barrier.

The inward permeability of the blood-retinal barrier to carboxyfluorescein was determined in monkey eyes with and without rhegmatogenous retinal detachment (RD). In the absence of changes in the diffusional permeability of the retinal pigment epithelium (RPE), inward permeability changes reflect changes in fluid flow across the RPE. Intravenous injection of mannitol resulted in a 15 mosmol/kg increase in plasma osmolality which decreased inward permeability 37% in eyes with RD and 21% in eyes with vitrectomy alone. When the intraocular pressure was raised 20 mm Hg above normal, inward permeability decreased 29% in eyes with RD and 32% in normal eyes. It is concluded that fluid flow across the blood-retinal barrier is influenced by both plasma osmolality and intraocular pressure.

Functional recovery of retinal pigment epithelial damage in experimental retinal detachment.

The integrity of the RPE barrier function in retinal detachment was studied in vitro. The retinal pigment epithelium (RPE)-choroid tissue was isolated from cynomolgus monkey eyes with acute (less than 1 hr), subacute (1-2 weeks), and chronic (8-20 months) retinal detachments, and clamped between Ussing-type chambers. Electrical characteristics and choroid-to-retina permeability to carboxyfluorescein were determined. In the HEPES-buffered bathing solution, transepithelial potential difference and resistance in eyes with acute retinal detachments (0.2 mV and 134 ohm-cm2, respectively) were significantly lower than subacute (7.9 and 350) and chronic (10.4 and 348) retinal detachments. Furthermore, the permeability was increased five-fold in acute retinal detachments with respect to subacute and chronic retinal detachments, indicating a breakdown of the RPE barrier in acute retinal detachment. No statistical difference was found between subacute and chronic retinal detachments. In this animal model, RPE barrier function is destroyed at the onset of retinal detachment, but recovers in a week or two, and is maintained in the chronic stage. Histological examination revealed that RPE recovery was accomplished by RPE proliferation and hyperplasia.

Uveoscleral outflow using different-sized fluorescent tracers in normal and inflamed eyes.

Sodium fluorescein and fluorescinated dextrans (FD) of selected molecular weights were combined and perfused into the anterior chamber of normal and inflamed eyes of cynomolgus monkeys. The eyes were dissected into iris, anterior and posterior uvea, anterior and posterior sclera, retina and intraocular fluids (excluding aqueous). Each tissue was homogenized and centrifuged and the supernatant was run through a gel-filtration column to separate the fluorescent tracers. Each of the resultant peaks was quantitated and facility of uveoscleral outflow was determined. In control eyes the calculated facility of uveoscleral outflow was very similar with all tracers (from 0.047-to 0.052 microliter min-1 mmHg-1) and each tracer was found in highest concentration in the anterior sclera and anterior uvea. In inflamed eyes the calculated facility of uveoscleral outflow increased two- to five-fold with each tracer (0.12-; 0.17-; 0.29-; and 0.24 microliter min-1 mmHg-1 with fluorescein, and the fluorescinated dextrans of MWs 4000, 40,000 and 150,000, respectively). Each tracer was found in the anterior sclera and uvea in inflamed eyes whereas the posterior sclera and uvea contained predominantly the higher molecular-weight tracers (MWs 40,000 and 150,000). It is concluded that iridocyclitis causes an increase in uveoscleral outflow by increasing the permeability of the anterior uvea to all tracers and fluid. Small tracers may then diffuse into uveal blood vessels or across the sclera, yielding lower values for uveoscleral outflow. Of the four tracers studied, the optimal tracer size for studying uveoscleral outflow in either normal or inflamed eyes is MW 40,000.

Uveoscleral outflow: diffusion or flow?

Shallow peripheral ciliochoroidal detachments with 10(-4) M fluorescein isothiocyanate dextran 70 were created in cynomolgus monkey eyes. Anterior chamber fluorophotometric readings were taken for 6 hr. From the anterior chamber fluorescence values, the rate of tracer movement from the supraciliary space into the anterior chamber was calculated. The rate of movement was 0.003 microliter/min, expressed in equivalent volumes of tracer solution. This value is more than 200 times lower than the rate of tracer movement from the anterior chamber to the supraciliary space. It is concluded that tracer movement from the anterior chamber to the supraciliary space (uveoscleral route) results from fluid flow rather than diffusion.

Aqueous humor dynamics in experimental iridocyclitis.

Ocular inflammation was induced by intravitreal bovine serum albumin (BSA) injection in one eye of each of six cynomolgus monkeys. The fellow eyes were injected with sterile saline alone. The intraocular pressure decreased by 12.2 +/- 1.3 mmHg (mean +/- SE) 2 days after BSA injection and 4.0 +/- 1.1 mmHg after saline injection. Aqueous flow and uveoscleral outflow were determined with fluorescein isothiocyanate (FITC) dextran 70. Aqueous flow in inflamed eyes averaged 0.32 +/- 0.04 ul/min, less than half the rate of control eyes (0.77 +/- 0.08 ul/min, P = 0.01). The facility of uveoscleral outflow in inflamed eyes was four times that of control eyes (0.2 +/- 0.03 vs 0.05 +/- 0.01 ul/min/mmHg, respectively, P = 0.009). Fluorescence microscopic examination revealed intense fluorescence of the edematous ciliary body muscle and of the suprachoroidal space extending to the posterior pole. These findings indicate that BSA-induced ocular inflammation causes a simultaneous reduction in aqueous humor flow and an increase in uveoscleral outflow, resulting in ocular hypotony.

Acetazolamide effect on the inward permeability of the blood-retinal barrier to carboxyfluorescein.

The inward permeability of the blood-retinal barrier to carboxyfluorescein was determined in 12 cynomolgus monkeys. Probenecid (175 mg/kg), an inhibitor of active outward transport of carboxyfluorescein, did not affect the inward permeability, indicating that the inward permeability is independent of the active outward transport system. However, acetazolamide (20 mg/kg), which causes increased outward fluid movement across the retinal pigment epithelium (RPE), significantly reduced the inward permeability. Thus, inward diffusion of carboxyfluorescein interacts with outward fluid flow across the RPE. Since carboxyfluorescein has low lipid solubility and remains extracellular, it is concluded that the pathway of fluid movement and carboxyfluorescein diffusion across the RPE is paracellular.

Permeability of the blood-retinal barrier to carboxyfluorescein in eyes with rhegmatogenous retinal detachment.

Outward and inward permeability of carboxyfluorescein across the blood-retinal barrier were measured fluorophotometrically in seven cynomolgus monkey eyes with experimental rhegmatogenous retinal detachment. Probenecid was used to inhibit outward transport of carboxyfluorescein. The outward permeability was 1.98 +/- 0.31 microliter/min in eyes with retinal detachment and 0.84 +/- 0.15 microliter/min in control eyes with vitrectomy alone (P less than 0.01). The inward permeability, determined separately following intravenous injection, was significantly lower than the outward permeability: 0.14 +/- 0.02 microliter/min for eyes with retinal detachment and 0.04 +/- 0.01 microliter/min for control eyes. Since the outward permeability minus the inward permeability in the presence of probenecid represents that fraction of tracer moving due to fluid flow, it may be concluded that outward flow of fluid across the blood-retinal barrier is a substantial contributor to carboxyfluorescein loss from the vitreous cavity following intravitreal injection.

Permeability of the isolated dog retinal pigment epithelium to carboxyfluorescein.

Outward (retina to choroid) and inward (choroid to retina) permeabilities of carboxyfluorescein and fluorescein in the isolated dog retinal pigment epithelium (RPE)-choroid were determined. Outward permeability was 9 and 47 times larger than inward permeability for carboxyfluorescein and fluorescein, respectively. The outward permeability of carboxyfluorescein was seven times lower than that of fluorescein, whereas there was no statistical difference between the inward permeabilities. Carboxyfluorescein is thus distinguished from fluorescein by its low affinity to the outwardly directed organic anion transport system. 10(-4) M probenecid caused greater than 98% inhibition of the outward transport of 6 X 10(-5) M carboxyfluorescein and 6 X 10(-6) M fluorescein.

Experimental retinal detachment. XI. Furosemide-inhibitable fluid absorption across retinal pigment epithelium in vivo.

Rhegmatogenous retinal detachments were created in one eye of each of six cynomolgus monkeys. Total vitrectomy alone was performed in the fellow eyes. The rate of disappearance of fluorescein sodium injected into the vitreous cavity was measured with kinetic vitreous fluorophotometry. Intravitreal 10(-4)M probenecid was used to inhibit active outward transport of fluorescein. In eyes with retinal detachment, the rate of fluorescein loss from the vitreous cavity was decreased 44% and 22% following intravitreal injection of 10(-4) and 10(-5)M furosemide (Lasix), respectively. Intravitreal 10(-4)M furosemide decreased the rate of fluorescein loss in fellow eyes by 35%. The rate of fluorescein loss via the anterior chamber accounted for only 1% to 8% of the total rate of vitreous fluorescein loss. Thus, it is concluded that intravitreal absorption across the retinal pigment epithelium.

Ocular hypotony.

In hypotony, where the intraocular pressure is lower than the episcleral venous pressure, aqueous humour outflow must be via unconventional channels, such as uveoscleral outflow pathways. The level of intraocular pressure will be determined by the rate of aqueous humour production and the facility of unconventional outflow. The facility of unconventional outflow has been shown to be increased in eyes with experimentally-induced hypotony from cyclodialysis, ciliochoroidal detachment, iridocyclitis, or retinal detachment. Aqueous humour production is reduced in eyes with hypotony during the acute phase following cyclodialysis, and in eyes with iridocyclitis or rhegmatogenous retinal detachment. Chronic cyclodialysis or ciliochoroidal detachment does not lead to reduced aqueous humour production, if unassociated with iridocyclitis. Detachment of the ciliary body in hypotony is often associated with, but does not appear to cause, reduced aqueous humour formation. Apart from treatment of the specific cause of hypotony, reduction of the accompanying inflammatory response is essential for normalisation of aqueous dynamics and intraocular pressure.

Effect of intraocular pressure on uveoscleral outflow following cyclodialysis in the monkey eye.

Cyclodialysis was performed in both eyes of five cynomolgus monkeys. Two days later the intraocular pressure (IOP) had fallen from 17.7 +/- 0.8 to 7.1 +/- 1.4 mm Hg (P less than 0.001). At that time, both eyes were perfused for 30 min with fluorescein-isothiocyanate (FITC) dextran (MW 70,000), one at 35 mm Hg and the other at 4 mm Hg. Four pairs of control eyes (without cyclodialysis) were perfused in the same manner. At 4 mm Hg, uveoscleral outflow was 0.02 +/- 0.02 microliter/min in control eyes and 0.05 +/- 0.04 microliter/min in eyes following cyclodialysis. However, at 35 mm Hg, uveoscleral outflow in eyes with cyclodialysis increased to 2.13 +/- 0.47 microliters/min compared to 0.32 +/- 0.10 microliter/min in control eyes. Thus the "facility" of uveoscleral outflow in control eyes is 0.01 microliter/min/mm Hg and in eyes following cyclodialysis is 0.07 microliter/min/mm Hg. It is concluded that cyclodialysis results in a pressure-dependent increase in uveoscleral outflow.