Journal of ocular pharmacology最新文献

Carnitine plays an important role in the metabolism of fatty acids. Its presence is considerable in tissues that use fatty acids as an important source of energy, such as the heart and skeletal muscle. Free carnitine and acid soluble acylcarnitines are present in various tissues of the rabbit eye. The lowest concentration of carnitine was observed in the vitreous humor and the highest in the lens. The ratio, acid soluble acylcarnitine/free carnitine, was lower in the cornea, aqueous humor, vitreous humor and lens, than in iris, ciliary body and choroid-retina. The topical administration of carnitine increased both free carnitine and acetylcarnitine in cornea, and only free carnitine in aqueous humor and choroid retina. Only after intravenous administration, did the levels of free and acyl-carnitine increase in the iris and ciliary body. Neither of the two carnitine species was changed in vitreous humor. The determination of the activity of carnitine acetyltransferase in the eye showed that in the ciliary body the values of activity were three times higher than those in the iris and choroid-retina. The elevated ratio of acid soluble acylcarnitines with respect to free carnitine in iris, ciliary body, choroid-retina as well as the higher activity of carnitine acetyltransferase in the ciliary body, suggest that carnitine plays an important role in those tissues of the eye where cells of a muscular nature are present and may represent, after esterification, an important energy reserve.

Animal studies have shown that insulin eyedrops containing an absorption-enhancing agent can have a significant effect on blood glucose levels. When formulated as a topical solution, insulin might potentially be used to treat or augment the treatment of diabetes mellitus in humans. We sought to investigate the feasibility of using insulin eyedrops in humans by studying the local toxicity and efficacy of insulin administered without surfactant to the eyes of healthy volunteers. A prospective, randomized, placebo-controlled, single-masked study was conducted in which 8 subjects were given 50 microliters of sterile normal saline containing varying insulin concentrations randomized to one eye, and 50 microliters of placebo (sterile normal saline) to the fellow eye. Subjective ocular irritation was evaluated, and the eyelids, conjunctiva, cornea, and anterior chamber were examined objectively with slit lamp biomicroscopy. Subjects were evaluated for 2 hours following administration of a single dose of insulin. There was no statistically significant difference (P > 0.05) in toxicity observed by any parameter evaluated between eyes receiving insulin and placebo. No systemic absorption of insulin was observed; blood glucose levels and serum immunoreactive insulin levels were unchanged. The results of this study suggest that single-dose insulin in concentrations up to 100 U/ml formulated in saline has no detectable clinical toxicity to the anterior structures of the human eye.

Ocular blood flow in the retina, choroid and optic nerve head should be measured in addition to the intraocular pressure (IOP) in order to better diagnose glaucoma disease and to better evaluate the efficacy of antiglaucoma drugs. It was found that beta-adrenergic blockers, the most widely used antiglaucoma drugs, reduced ocular blood flow in animals and worsened glaucoma disease in some patients, even though the IOP was reduced to the normal range. Therefore, their use for glaucoma treatment requires careful re-evaluation. On the other hand, most dopamine antagonists were found to reduce the IOP and increase the blood flow to the retina, choroid, iris and ciliary muscle. Therefore, these agents could be used for glaucoma treatment. Further, dopamine antagonists were found to improve retinal function after ischemia and, thus, also could be used for the treatment of ischemic retinopathy.

Adenosine is a potent modulator of various physiological functions. Although adenosine receptors have been demonstrated in the retina, little is known about their functional role. This study determined the effects of relatively selective adenosine agonists on K+ depolarization-induced release of dopamine and retinal arteriolar tone. For dopamine release studies, bovine retinas were isolated and endogenous synaptosomal stores were loaded with [3H] dopamine. Retinas were then transferred to a superfusion chamber and the spontaneous and K+ depolarization-induced release of dopamine were determined. Cyclopentyladenosine (CPA) did not significantly alter the spontaneous release of dopamine; however, CPA produced a dose-related inhibition of K+ depolarization-evoked release of dopamine. This CPA-induced suppression of dopamine release was reversed by pretreatment with the adenosine A1 antagonist cyclopentyltheophylline. In retinal vasculature studies, adenosine and its agonists injected intravitreally dilated retinal arterioles and venules, in newborn pigs, with a potency profile indicative of mediation by A2 adenosine receptors. Intravitreal injections of drugs inhibiting the metabolism of endogenous adenosine also induced an arteriolar vasodilation which was inhibited by co-administration of an adenosine receptor antagonist. Intravitreally administered adenosine antagonists also attenuated the vasodilative response to both systemic hypoxia and systemic hypotension in the newborn pig, indicating that endogenously produced adenosine is important in retinal blood flow regulation.

There is an expectation that ocular inserts, regardless of the nature of the polymer, will faithfully reduce systemic drug absorption. This may not necessarily be so, however, since not all polymers would release drug at the same rate and to the same extent. The objective of the present study was to determine how drug release rate from various polymeric ocular inserts may influence systemic timolol absorption in the pigmented rabbit. The inserts tested were made of polyvinyl alcohol (PVA), hydroxypropylcellulose (HPC), or partial ethyl ester of poly(vinyl methyl ether/maleic anhydride) (PVMMA), approximately 89.4% w/w in all cases. Some polyvinyl alcohol inserts contained timolol in salt form with Carbopol 940 (PVA-C940), 8.6% w/w. The time course of timolol in plasma over 6 hr was monitored using reversed phase HPLC. While all inserts reduced the peak timolol concentration in plasma (Cmax), only the PVA and HPC inserts, which released timolol rapidly in vitro, reduced the extent of systemic timolol absorption (AUC). On the other hand, both PVA-C940 and PVMMA inserts, which released timolol relatively slowly in vitro, increased the extent of systemic timolol absorption. Moreover, the time at which peak timolol concentration was achieved in the plasma was much delayed, raising the possibility of delayed timolol absorption until discharge of the presumably viscous and/or mucoadhesive solutions of PVA-C940 and PVMMA inserts into the nasal cavity. It may be concluded that not all polymeric ocular inserts reduce systemic timolol absorption. Whether an insert would do so depends on the interplay of residence time in the conjunctival sac and rate of drug release from the insert.

Because of rapid developments in biotechnology, numerous peptides are now available for clinical treatment of various diseases. In order to avoid parenteral injections, alternative routes of drug administration have been investigated. Among them, the ocular route seemed to be the most feasible one because a) it could deliver precise doses of drugs just like injections; b) it was much easier and less expensive to administer eyedrops than an injection; c) the rate of systemic absorption through the ocular route was as fast as an injection; d) eye tissues were much less sensitive to the development of immunological reactions than other tissues; e) the drug absorbed via the ocular route would avoid the first passage through hepatic circulation to reach the sites of action before liver metabolism; and f) no tolerance and ocular side effects could be detected after long-term (three months) daily administration of insulin eyedrops.

Insulin administered in eyedrop from with a surfactant agent has been shown to be clinically effective in treating diabetes in animal models. Concentrations of insulin as high as 100 U/ml in saline were shown to produce no detectable clinical toxicity to human eyes in single-dose administration. We sought to investigate the local toxicity of insulin in human eyes during long-term, multidose administration. A prospective, randomized, placebo controlled, double-masked study was conducted involving eight healthy volunteers. Subjects were given 50 microliters sterile saline containing 100 U/ml crystalline porcine insulin randomized to one eye and 50 microliters placebo (sterile saline) to the fellow eye administered twice daily for 8 weeks. Subjective ocular irritation and visual acuity and objective assessment of the eyelids, conjunctiva, cornea, anterior chamber, crystalline lens, pupil size, and intraocular pressure were evaluated. Blood D-glucose levels were monitored to assess glycemic levels. There was no statistically significant difference (p > 0.05) observed between insulin-treated and placebo-treated eyes. Eyedrops containing insulin were subjectively as comfortable and objectively as clinically innocuous as sterile saline alone. The results of this study demonstrate that insulin (100 U/ml) in saline is nontoxic to the human eye after long-term, multi-dose exposure. Topical administration of insulin combined with an absorption-promoting agent may be a practical and feasible alternative to multiple daily subcutaneous injections or implanted pump devices currently used in the long-term treatment of diabetes mellitus if a nonirritating absorption-promoting agent can be identified.(ABSTRACT TRUNCATED AT 250 WORDS)

The iris is innervated by nerves of the sympathetic, parasympathetic, and sensory nervous systems. The terminal nerve fibres are endowed with prejunctional receptors which modulate neurotransmitter release. Activation or blockade of prejunctional receptors by drugs may have an influence on iris smooth muscle tone. Several findings are in favour of the hypothesis that prejunctional receptors may be involved in regulation of iris smooth muscle tone and/or pathophysiological events. (i). Release of acetylcholine from parasympathetic nerves of guinea-pig iris sphincter evoked by electrical stimulation is subject to autoinhibition via prejunctional M2 muscarinic receptors, and the release can be enhanced by M2 selective antagonists such as methoctramine or gallamine. Concomitantly with the increased neurotransmitter release, the sphincter contraction is enhanced in the presence of M2 antagonists, since the postjunctional muscarinic receptors (presumably M3, or at least not M2) are not simultaneously blocked. Unlike the non-selective blocker atropine, M2 antagonists are not expected to cause mydriasis but rather miosis. (ii). Sensory nerves are involved in pathophysiological events following ocular irritation. Release of substance P and/or neurokinin A from sensory nerves of rabbit iris is followed by a non-adrenergic-non-cholinergic iris sphincter contraction (mediated by NK1 and NK3 receptors) which can be used to estimate sensory neurotransmitter release. Exocytotic release of the sensory neurotransmitters is inhibited by activation of alpha 2B-adrenoceptors and probably also via putative prejunctional imidazoline receptors. Alpha-adrenoceptors are stimulated by oxymetazoline and other imidazoline derivatives (which are agonists at imidazoline receptors) leading to a reduction of sensory neurotransmitter release, as evident from a decrease in evoked sphincter contraction. Imidazolines in eye drops may not only cause relief in ocular inflammation due to postjunctional vasoconstriction but also possibly due to a prejunctional effect, a reduction of sensory neurotransmitter release. Reinforcement of inflammation due to release of sensory neurotransmitters may thus be prevented.

To avoid the side effects of systemic administration of ganciclovir (GCV) for the treatment of cytomegalovirus (CMV) retinitis, we studied transscleral iontophoresis of GCV into rabbit eyes. After a single application with 20% (w/w) aqueous solution of GCV at 1.0 mA for 15 min gave a vitreal/retinal level of GCV at 74 +/- 17 micrograms/ml at 2 hours as determined by HPLC. At 24 hours after iontophoresis the vitreal/retinal level was above therapeutic level at 4.2 +/- 0.6 micrograms/ml. At 72 hours, there was still detectable level in the vitreous/retina. Hence, transscleral iontophoresis is able to deliver effective dose of GCV into the vitreous. Multiple applications of iontophoresis should be examined as a possible means of CMV treatment.

Microsomal fractions from porcine ocular tissues synthesized 12(S)-5,8,10,14-hydroxyeicosatetraenoic acid [12(S)-HETE] from arachidonic acid by a membrane-bound lipoxygenase and 12(R)-HETE by the cytochrome P450-dependent monooxygenase system. Both activities were the highest in corneal microsomes. The 12(R)-HETE synthesizing activity of corneal microsomes was dependent on NADPH and inhibited by 0.1 mM SKF-525A, an inhibitor of P450 enzymes. The activity to form 12(R)-enantiomer was significantly enhanced by treatment of corneal epithelium with 3-methylcholanthrene or clofibrate. The induced activity was suppressed by cycloheximide, indicating that the induction of enzyme activities involved a translational process. The effect of these inducers on 12(R)-HETE synthesizing activity appeared to be additive. The activity to form 12(S)-enantiomer was markedly stimulated by 3 mM CaCl2. The 12-lipoxygenase of corneal microsomes was capable of oxygenating linoleic acid in addition to arachidonic acid, a characteristic of 12-lipoxygenases of the leukocyte type. 12(R)-HETE at 10(-6) M inhibited almost completely the Na,K-ATPase of corneal epithelium but had little or no effect on ciliary epithelial enzymic activity. 12(S)-HETE at 10(-6) M also inhibited corneal enzymic activity but to a lesser extent, and had no significant effect on ciliary epithelial Na,K-ATPase activity.