Journal of ocular pharmacology最新文献

Retinal vessel changes in 36-month 30% galactose-fed beagles treated with or without aldose reductase inhibitors were quantified using an Olympus Cue-3 color image analysis system. Individual maps of the intact retinal vasculature, isolated by trypsin-digestion, were divided into 24 distinct subregions and measurements of either the endothelial cell to pericyte (E/P) ratio or cell densities, expressed as pericytes per mm capillary length or endothelial cells per mm capillary length, were conducted in 0.1 mm2 areas surrounding the midpoints of 12 subregions associated with the highest incidence of microaneurysms. Significantly increased E/P ratios and decreased pericyte densities were observed with the duration of galactose-feeding. These retinal changes were reduced by aldose reductase inhibitor treatment. Correlations between the E/P ratio and either number of microaneurysms or cataract severity were also observed. These data support the dose-dependent effects of aldose reductase inhibitors in preventing pericyte degeneration and subsequent formation of microaneurysms (Archives Ophthalmol. 108:1301, 1990).

Ab interno pulsed dye laser sclerostomy uses a gonioscopic approach to form a limbal fistula for the treatment of glaucoma. This procedure requires a full thickness penetration of stain in sclera for adequate absorption of the visible light energy. Iontophoresis is a technique using an electrical current to noninvasively deliver Reactive Black 5 (RB5) stain into sclera. This project determined the stability of RB5 stain as well as the optimal parameters for iontophoresis (probe tip surface area, current, and duration) in a rabbit model. RB5 stain was stable over time (72 hr) as well as after exposure to extreme heat (120 degrees C), scleral constituents (namely collagen), high concentrations of oxidants (1.5% H2O2), and laser light energy. Ideal parameters for iontophoresis included a probe tip surface area between 0.1 and 0.7 mm2, a current of 0.5 mA, and a duration of 5 min. The maximum concentration of RB5 stain achieved in sclera was 0.15%. The threshold of ablation for RB5 using an energy of 250 mJ was 0.001%. Iontophoresis can effectively deliver RB5 stain into sclera and may be a viable adjunct to ab interno pulsed dye laser sclerostomy procedures in the eye.

The effects of cholecystokinin (CCK) and calcitonin gene-related peptide (CGRP) on ocular blood flow were studied in monkeys using the labelled microsphere method. Intracameral administration of 800 pmole CGRP increased the blood flow significantly in the conjunctiva, ciliary body and sclera. There was no significant change in the choroid and retina. CCK-33 (800 pmole) caused no significant effects on the blood flow in the tissues examined, when compared to the control eyes. A miotic response was however noted, consistent with previous results. Neither peptide caused significant changes in the intraocular pressure. These results suggest that CGRP has a vasodilatory effect in some parts of the monkey eye, whereas CCK-33 is a miotic with no marked effect on ocular blood flow.

In experimental immunogenic keratitis, provoked in rabbits by intracorneal injection of 20 microliters of human serum albumin (HSA), various anti-inflammatory agents were studied in their effects on corneal edema, neovascularisation and leukocyte infiltration. Prophylactic treatment with a corticosteroid completely prevented the occurrence of keratitis. Nonsteroidal anti-inflammatory drugs such as a cyclooxygenase inhibitor partly prevented neovascularisation and corneal edema, a lipoxygenase inhibitor, a leukotriene antagonist or platelet-activating factor (PAF)-antagonist BN 52021 partially prevented mainly leukocyte infiltration. Prophylactic topical treatment with the poly-unsaturated fatty acids eicosapentaenoic acid and columbinic acid or a dietary supplement with fish oil showed less symptoms of keratitis in all respects.

A series of amphiphilic esters of timolol malonate (octanoyl, decanoyl, dodecanoyl, myristoyl and palmitoyl timolol) were tested in rabbits for their capacity to antagonise the isoproterenol-induced ocular hypotension, using timolol maleate as reference standard. The most active prodrug, palmitoyl timolol malonate (PTM) was also evaluated for its capacity: (a) to decrease IOP in a model of bethamethasone-induced ocular hypertension, and (b) to permeate "in vitro" through rabbit corneal tissues. PTM, the prodrug with the longest aliphatic chain and therefore the greatest amphiphilic/lipophilic character, showed "in vivo" significant activity differences with respect to timolol maleate: the beta-antagonism was more important at earlier and later experimental times, and the IOP decrease was more marked at longer times. The prodrug, however, showed "in vitro" an inferior corneal permeability when compared with timolol maleate. The significant differences observed for the beta-antagonism of PTM at earlier times of the test might be attributed to transscleral absorption, due to the physicochemical characteristics of the prodrug, while the prolonged action (also observed in the IOP-depression test) might be due to sustained release, resulting from accumulation of the prodrug in the corneal epithelium. The present preliminary results are indicative of the potentiality of amphiphilic properties in a prodrug molecule.

3H-DTG (1.3-di(2-[5-3H]tolyl)guanidine) or 3H-haloperidol was added to sigma-receptors (25 nM) in the presence of 25 nM spiperone and incubated with increasing concentrations of bromhexine derivatives (phenylalkylamines; 10(-9) to 10(-2)M) in membrane homogenate suspensions. IC50 values for two derivatives ranged from 3.2 to 8.8 nM for both radioligands. A preferred derivative, 7A (N,N'-dimethyl-2-phenyl-ethylamine), yielded an IC50 of 7.8 nM for 3H-haloperidol but showed much less affinity in displacing 3H-DTG (IC50 = 900 nM). Applying the technic of Bromberg [Exp. Eye Res., 40:313-320, 1985], in vitro protein secretion rates were measured following stimulation of either lacrimal gland slices or isolated, intact lacrimocytes with the compounds. In vitro protein secretion rates exhibit a dose-response relationship with increases in protein release up to a concentration of 10(-8) to 10(-4) M for various derivatives of bromhexine and 10(-4) M for carbachol. By means of Schirmer strips, tear fluid was collected over a five minute period at 10 and 60 minutes post-dosing following the topical application (50 microliters) to the right eye of New Zealand white rabbits (n = 20-24) of 7A at various concentrations. Incubation of lacrimocytes with 7A alone (10(-4) M), with haloperidol (10(-4) M) alone or in combination show that 7A is acting as an agonist to stimulate protein release, whereas haloperidol is acting as an antagonist to inhibit release. In vivo protein secretion rates also show a dose-response curve (at both 10 and 60 minutes post-dosing) for 7A that reach a statistically significant maximum in the dosed eye at a concentration of 0.15% w/v. Analysis of protein extracts using size exclusion HPLC shows an increase in secretory proteins, particularly tear-specific prealbumin.

The primary route into the eye for many drugs is transcorneal permeation. A better understanding of the mechanisms involved in transcorneal permeation could lead to improvements in drug dosage forms or the development of drug delivery devices which enhance the ocular bioavailability of drugs. A corneal permeation model has been developed which can be used to study the mechanisms involved in corneal permeation. The model uses five compartments in series to simulate the tear film, epithelium, stroma, endothelium and aqueous humour. These tissues were assumed to be adequately represented by plane sheet barriers of physiological thickness. The tear film was assumed to be perfectly mixed and the stroma completely stagnant. Due to inadequate knowledge of the hydrodynamics of the aqueous humour, both stagnant and perfectly mixed extremes were studied. The four routes of drug loss which were considered the most significant and therefore included in the model were lacrimal drainage, conjunctival absorption, aqueous drainage and iris-ciliary body absorption. The equilibrium that can exist between the ionic and non-ionic forms of a drug was found to be an important step in the mechanism of transcorneal permeation. Including the equilibrium condition in the model resulted in aqueous humour drug levels that were over 50 times higher than the levels predicted by a model which did not use the equilibrium mechanism. A relationship between the lipophilicity of each of the two drug forms and its permeability in each layer of the cornea was used in the model. The model was used to predict aqueous humour drug concentrations resulting from a constant release of timolol into the tear film or from the application of timolol, levobunolol and pilocarpine eyedrops. The model produced transient aqueous humour drug levels that closely followed experimental in vivo data from literature. Using the model, it was also possible to predict the amount of instilled drug that is lost through each of the four elimination routes of the eye.

To locate suitable candidates to study the intraocular pressure (IOP) effects of new ocular steroids, healthy volunteers must be challenged with topically applied steroids to verify that such individuals are indeed high "steroid responders"; that is, they respond with IOP elevations of at least 5 mmHg during a 4- to 6-week challenge with the topically applied steroid. We used first-degree offspring of individuals with primary open-angle glaucoma to develop a model to identify high steroid responders to topical ophthalmic prednisolone. We conducted a prospective, randomized, open-label, placebo-controlled study of prednisolone phosphate 1.0% in which 13 subjects received either topical prednisolone phosphate 4 times daily to the right eye and placebo to the left eye, or vice versa. Baseline evaluations occurred on study Day 0, and follow-up examinations were on Days 7, 14, 21, 28, 35, and 42. The medications were administered continuously for 6 weeks or until the IOP rose > or = 10 mmHg. After the effect of diurnal variation in IOP was taken into account, 4 of the 13 subjects (31%) had a maximum elevation in IOP of 4 mmHg or less, 7 subjects (54%) showed maximum elevations in IOP of 5 to 9 mmHg, and 2 subjects (15%) had a maximum IOP elevation of > or = 10 mmHg. Thus, a cumulative total of 9 subjects (69%) had IOP elevations of at least 5 mmHg and could be classified as moderate to high steroid responders. This model should become useful as a productive source of subjects for studies evaluating the effect on IOP of new ocular steroids.

Topically administered beta blockers are the preferred medical therapy for glaucoma. These agents reduce intraocular pressure (IOP), thereby preventing damage to the optic nerve and the subsequent loss of vision. Timolol, betaxolol, levobunolol, metipranolol, and carteolol are the topical beta blockers available in the U.S. They have similar IOP-lowering efficacy, but differ in other pharmacological properties. Topically administered beta blockers are generally well tolerated. They undergo systemic absorption, however, and can adversely affect cardiovascular and bronchopulmonary function in patients with existing diseases such as heart failure, sinus bradycardia, chronic obstructive airways disease, or asthma. Betaxolol, which is beta 1-selective, and carteolol, which has intrinsic sympathomimetic activity (ISA), may have systemic tolerability profiles superior to the traditional nonselective, non-ISA beta blockers. These hypotheses require confirmation in controlled clinical trials. Local adverse effects associated with beta blockers include stinging, burning, red eye, itching, tearing and loss of corneal sensitivity. Stinging upon instillation is a particularly frequent finding with betaxolol (up to 30% to 40% of patients). Preliminary evidence suggests that carteolol has the best local tolerability profile of these drugs.

The objective of this study was to determine the relative efficacy of various formulations in maximizing the ratio of ocular to systemic absorption of topically applied atenolol following solution instillation in the pigmented rabbit. Formulations of various pH's and tonicities and containing various preservatives and polymers were tested. Ocular absorption was determined by monitoring atenolol concentrations in various anterior segment tissues at 30 min following solution instillation, while systemic absorption was determined by monitoring the time course of atenolol concentration over 480 min. Reversed phase HPLC was the analytical methodology. All formulations except those containing 0.025% benzalkonium chloride or 0.5% EDTA showed similar drug concentration vs. time profiles in plasma, attaining a peak concentration of 30-50 ng/ml at about 100 min. For benzalkonium chloride and EDTA, there was an undesirable increase in systemic absorption, although ocular absorption was also increased. By contrast, lowering the solution tonicity to 80 mOsm/kg increased the ratio of aqueous humor to plasma peak concentrations 2 times and the ratio of iris-ciliary body to plasma peak concentrations 3 times. Incorporation of 3.75% poly(vinyl alcohol) into the formulation afforded yet a larger increase in the iris-ciliary body to plasma drug concentration ratio (52 times.) It may therefore be concluded that, for a hydrophilic drug like atenolol, formulation changes that increase membrane permeability and/or enhance noncorneal drug access may be more promising than those that increase drug residence in the conjunctival sac with respect to maximizing the ratio of ocular to systemic drug absorption.