Journal of ocular pharmacology最新文献

The penetration into the eye of fluorescein from a normal drop was found to increase with age and averaged twelve times more in the elderly than in the young. Examination of the literature suggests that this is a result of a greater contact time with the cornea rather than a rise in epithelial permeability.

Opacification of the posterior lens capsule, (secondary cataract), is one of the major complications of extracapsular cataract extraction. The lens epithelial cells remaining after surgery migrate and proliferate along posterior capsule, and give rise to structures such as pearls and cells with contractile properties, which considerably hamper vision. One pharmacological approach aimed at limiting this phenomenon would be to stop this cell migration, thus inhibiting their proliferation. It has been shown that cells adhere and migrate on their support via adhesion molecules such as integrins. Generally, the tripeptide sequence Arg-Gly-Asp (RGD) is the recognition motif for these receptors. In this study, cell adhesion inhibition in the presence of RGD peptides and derivatives was measured on extracellular matrix and lens capsule. One of these compounds, the [N alpha-acetyl-NG(H+)-arginyl]-glycyl-[C beta (H)-C alpha -benzyl]-aspartamid- HCl] (LCM 1910), significantly inhibited cell migration at millimolar concentrations, and could be of interest in prevention of secondary cataract.

Loteprednol etabonate (LE) is a novel steroid with a low tendency to raise IOP. It is metabolized in the eye to an inactive metabolite. The current study was undertaken to assess the intra-ocular anti-inflammatory activity of LE in two models of experimental uveitis in rabbits. In the endotoxin induced rabbit model, LE was effective at reducing measures of inflammation, but less so that either fluorometholone (FML) or dexamethasone. In the Freunds adjuvant chronic uveitis model, FML was also very effective with LE and dexamethasone showing similar activity. The data demonstrate that LE is effective at reducing intra-ocular inflammation.

An overview of the ocular hypotensive actions of some alpha 2-agonists with imidazoline structures is presented. These agents inhibit isoproterenol-stimulated adenylate cyclase (AC) activity in ciliary process membrane through a Na+ and GTP-dependent mechanism. Receptor binding studies with the alpha 2-agonist radioligand [125I] p-iodoclonidine ([125I]PIC) in rabbit ciliary body membranes indicate that the alpha 2-receptor subtype is alpha 2A. Gpp(NH)p and NaCl dose-dependently decreased the number of [125I]PIC binding sites by shifting the receptor-G protein complexes from the high affinity state to the low affinity state for agonist binding. This is consistent with the observations that inhibition of AC was Na+ and GTP dependent. The NaCl and Gpp(NH)p effects on binding appeared to be through different mechanisms. The alpha 2-receptor in ciliary process thus appears to be an alpha 2A-receptor that is negatively coupled to the AC-cAMP generating system.

1) Moxonidine (MOX), injected icvt into the anterior lateral ventricle of NZW rabbits, induced bilateral, ocular hypotension (> 7.0 mmHg) that persisted for two hrs. 2) Oxymetazoline (OXY), injected icvt into the anterior lateral ventricle of NZW rabbits, induced bilateral ocular hypotension (> 7.0 mmHg) that peaked at two hrs. 3) Unilateral topical application of OXY induced maximal, bilateral ocular hypotension (> 12 mmHg), at 3 hrs, in both the contralateral and ipsilateral eyes, that persisted more than 12 hrs. 4) The putative imidazoline (I1) antagonist, efaroxan, injected icvt into the anterior lateral ventricle, inhibited significantly the ocular hypotension produced by icvt MOX, icvt OXY, and unilateral topical OXY. 5) Imidazoline (I1) receptors, located in the CNS, play a role in MOX- and OXY-induced ocular hypotension, as suggested by the ability of the putative imidazoline (I1) receptor antagonist efaroxan, to inhibit icvt MOX-, icvt OXY- and topical OXY-induced ocular hypotension.

Agents that elevate intracellular cyclic AMP (cAMP) have been found to enhance the synaptic discharge of norepinephrine (NE) from sympathetic nerve terminals in the rabbit iris-ciliary body and other peripheral tissues. We explored the hypothesis that prejunctional alpha 2-adrenergic receptors that mediate feedback inhibition of NE release may be coupled to adenylyl cyclase inhibition. To indirectly monitor cAMP changes in sympathetic axon terminals, we analyzed the cAMP-mediated activation of tyrosine hydroxylase, a sympathetic marker protein that undergoes acute phosphorylation and activation by cAMP-dependent protein kinase A. Tyrosine hydroxylase activity was assayed in situ by incubation of rabbit iris-ciliary body tissue segments in buffered Krebs-Ringer solution containing the substrate tyrosine (100 microM) and the DOPA decarboxylase inhibitor brocresine (30 microM). Intraneuronal DOPA accumulation was quantified by HPLC with electrochemical detection. Tyrosine hydroxylase activity was increased approximately 2 fold by incubation with forskolin (10 microM) plus IBMX (0.5 mM) or with 8-Bromo-cAMP (3 mM). Simultaneous addition of the alpha 2-adrenergic agonist clonidine (1 microM) attenuated the response to forskolin/IBMX, but had no effect on the response to 8-Br-cAMP. Clonidine-mediated inhibition of the forskolin/IBMX response was abolished by treatment of tissues with N-ethylmaleimide (NEM), an alkylating agent that inactivates pertussis toxin-sensitive G proteins (Gi) that couple receptors to adenylyl cyclase inhibition. These findings suggest that prejunctional alpha 2-adrenoceptors in the rabbit iris-ciliary body are negatively coupled to adenylyl cyclase. This mechanism may contribute to autofeedback regulation of NE biosynthesis and release.

Flurbiprofen Na and diclofenac Na, two ocular antiinflammatory agents, were investigated to determine the aqueous humor concentrations in the human eye following topical application. One hundred sixty-five patients undergoing cataract surgery received a single drop of either diclofenac Na or flurbiprofen Na at selected times prior to the surgical procedure. Aqueous humor samples were aspirated at the beginning of surgery and a sensitive high-performance liquid chromatographic assay was used to determine the concentration of the antiinflammatory agent in the ocular fluid. Samples were obtained between 10 min and 24 hrs after a single instillation of the drug onto the cornea. The highest average concentration of diclofenac was 82 ng/ml at 2.4 hrs after instillation; concentrations remained above 20 ng/ml for over 4 hrs. Thereafter, between 3 and 16 ng/ml diclofenac could be assayed through 24 hrs. The highest average concentration of flurbiprofen, 60 ng/ml, was found at 2.0 hrs. The last detectable flurbiprofen concentration was measured at 7.25 hrs after instillation.

To determine the minimum effective concentration of insulin eyedrops for human use, insulin eyedrops at 0.01%, 0.05%, and 0.25% plus 0.5% Brij-78 were instilled into rabbit eyes. Brij-78 (0.5%) eyedrops were instilled as control. It was found that very low concentrations of insulin such as 0.05% plus 0.5% Brij-78 can reduce the blood glucose effectively in rabbits. The 0.05% insulin with 0.5% Brij-78 seems to be the best choice. Assuming the human body weight is approximately 25 times that of the rabbit, the concentration of insulin to be used for human patients would be 1.25% insulin (0.05% x 25), which is equivalent to 1.25 mg insulin/75 kg body weight. Because the absorption rate of insulin eyedrops plus Brij-78 is approximately 60-70%, 1.25% insulin plus Brij-78 would easily reach the therapeutic dose of insulin by injection (0.4-0.5 mg/75 kg). These results indicate that it is feasible to use insulin eyedrops to lower the blood glucose in humans. There was no statistical difference in blood glucose levels between animals instilled with 0.5% Brij-78 alone as control and those instilled with 0.01% insulin plus 0.5% Brij-78.

Pilocarpine, a widely used antiglaucoma drug, was incorporated into a newly developed submicron emulsion (pilocarpine emulsion) suitable for local ocular administration. Pilocarpine-Emulsion effect on the intraocular pressure (IOP) was studied following a single dose application in normotensive rabbits. Membrane filtration (steam autoclaving) was found not to affect particle size distribution, zeta potential or pH of the pilocarpine emulsion preparation. A single dose application of pilocarpine emulsion 1.7% (equivalent to 2% pilocarpine hydrochloride) induced a prolonged progressive decrease in IOP in normotensive rabbits, which started at eleven hours post instillation and reached its maximal value of 6.0 +/- 0.2 mmHg at 29 hours. The pressure decreasing effect induced by pilocarpine emulsion treatment followed a pattern different from that generated by generic pilocarpine (Pilocarpine Hydrochloride 2% eye drops); In the latter group, IOP reduction (starting at two hours) persisted during the initial five hours post-instillation, while in the former, the hypotensive effect started at a later stage, and was maintained during a twenty nine hour follow-up causing a greater IOP decrease than in the generic group (% delta IOP of 28.5% and 18%, respectively). In the contralateral eyes of Pilocarpine Emulsion treated rabbits, an ocular hypotensive effect was noted late after application (11 hours through 29 hours post-instillation), while this effect was negligible in rabbits-treated with aqueous pilocarpine. Our findings point to the possibility that the novel preparation of pilocarpine incorporated into submicron emulsion might serve as a long-acting form of pilocarpine which might require a single daily application. Further studies are required to elucidate the mechanism and action of this preparation.

The antihistaminic agent, emedastine, was tested for its ability to compete for [3H]pyrilamine, [3H]tiotidine and [3H]N-methyl histamine binding to rodent brain H1, H2 and H3 histamine receptors, respectively. Emedastine exhibited the highest affinity for H1-receptors (dissociation constant, Ki = 1.3 +/- 0.1 nM), and was considerably weaker at H2- (K1 = 49,067 +/- 11,113 nM) and H3-receptors (Ki = 12,430 +/- 1,282 nM). These data yielded ratios of 37744, 9562 and 4 for H2:H1, H3:H1 and H2:H3 receptor affinities, respectively, thus making emedastine a very selective H1-receptor antagonist. The H1-selectivity of emedastine was considerably superior to that of pyrilamine (H2:H1, H3:H1 and H2:H3 ratios of 11887, 12709 and 1, respectively). Similarly, the respective receptor affinity ratios for ketotifen (858, 1752, 0.5), levocabastine (420, 82, 5), pheniramine (430, 312, 1), chlorpheniramine (5700, 2216, 3) and antazoline (1163, 1110, 1) showed these antihistamines to be also markedly less H1-selective than emedastine. The potency of emedastine (IC50 = 1.44 +/- 0.3 nM) for antagonizing histamine-induced phosphoinositide turnover in human trabecular meshwork cells compared well with its binding affinity at the H1-receptor. These data indicate emedastine to be a high affinity and high potency histamine antagonist with the highest selectivity for the H1-histamine receptor.