Journal of ocular pharmacology最新文献

In melanocytes, the biosynthesis of L-dopa derived indole polymer, melanin, is accelerated by tyrosinase and related enzymes. The brown to black pigment is characterized by a stable free-radical property. In humans, a pigment dependent slow onset of ocular actions of ephedrine, atropine, cocaine, pilocarpine and related medications was observed. Extensive accumulation of drugs by melanin appears to be the most important factor governing the long term therapeutic/toxicological activities. Drugs crossing placental circulation are localized in the mouse fetal eye. Thus, drugs exhibit a high binding capacity for melanin containing tissues. Studies on synthetic melanin and melanin granules also indicated a high binding capacity of many therapeutic classes of drugs, including psychotropics. In addition to the liposoluble property of the molecule, there is a definite relationship between chemical structure and the affinity of drugs for melanin. For example, the affinity of chlorpromazine for melanin is higher than that of chlorprothixene. NMR studies, with soluble melanins indicate that there is a steric preference among ephedrine enantiomers. A high binding capacity indicates that more than two molecules of (-)-ephedrine may complex with one indole unit of melanin. Ocular drug development calls for the study of qualitative and quantitative aspects of drug-melanin interaction.

The corneal epithelium of several species, has the capacity to metabolize arachidonic acid (arachidonic acid) via an NADPH-dependent cytochrome P450 mechanism. The major metabolites are 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) and 12-hydroxy-5,8,14-eicosatrienoic acid (12-HETrE), both of which exist in stereoisomeric configurations. However, the R enantiomers are predominantly produced by this enzyme system and exhibit potent biological activities. 12(R)-HETE inhibits Na-K-ATPase, increases corneal thickness and reduces intraocular pressure. 12(R)-HETrE causes vasodilation, neutrophil chemoattraction and angiogenesis. The formation of these metabolites is unaffected by cyclooxygenase and lipoxygenase inhibitors (indomethacin, diclofenac and BW755C) but inhibited by cytochrome P450 enzyme inhibitors such as carbon monoxide, SKF-525A and clotrimazole. The capacity of the normal corneal epithelium to metabolize arachidonic acid via cytochrome P450 is very low although under certain conditions this enzymatic pathway may become greatly induced. Corneal epithelial hypoxia in response to contact lens wear results in the time-dependent formation of NADPH-cytochrome P450-dependent arachidonate metabolites, 12(R)-HETE and 12(R)-HETrE. Under this condition, metabolite production correlates strongly with the in situ inflammatory response and inhibition of their formation significantly attenuates inflammation. It is evident that the cytochrome P450 arachidonate metabolites should be added to the realm of cyclooxygenase and lipoxygenase-derived eicosanoids as possible inflammatory mediators. Therefore, studies to evaluate eicosanoid involvement in inflammation should examine inhibitors of this pathway in addition to the classically studied non-steroidal antiinflammatory drugs (NSAIDs).

Various classes of anti-inflammatory compounds like steroids (dexamethasone), cyclooxygenase inhibitors (indomethacin and flurbiprofen), 5-lipoxygenase inhibitors (BWA 218C and BWA 4C), immunosuppressive drugs (cyclosporin and rapamycin) and cod liver oil were tested for their antiinflammatory activities in endotoxin-induced uveitis model in rabbits. Intraocular inflammation was assessed in terms of two inflammatory responses i.e. breakdown of blood-aqueous barrier (BAB) and leukocyte infiltration into aqueous humor and iris ciliary body (ICB). Prostaglandin (PG) E2 and leukotriene (LT) B4 release into aqueous humor was also measured. Indomethacin significantly inhibited PGE2 release without affecting leukocyte or BAB response. Flurbiprofen prevented leukocyte, PGE2 and LTB4 release into aqueous humor but not ICB chemotaxis. BWA 218C and BWA 4C also significantly inhibited leukocyte and LTB4 release but not BAB responses. Dexamethasone (2mg/kg, i.m.) and cyclosporin A (25 mg/kg i.m.) significantly inhibited leukocyte infiltration into aqueous humor and ICB, and PGE2 release but they failed to inhibit breakdown of BAB and LTB4 release. On the other hand, rapamycin (10mg/kg i.m.) and cod liver oil (1 ml daily i.m. up to 15 days) significantly prevented leukocyte and BAB response. Cod liver oil also significantly inhibited PGE2 and LTB4 release but rapamycin affected only PGE2 release into aqueous humor. It is concluded that arachidonic acid metabolites may not play a vital role in this uveitis model and additional proinflammatory mediators like cytokines may be involved.

Studies in vitro and in vivo were conducted to investigate the effect of pilocarpine on ocular absorption of levobunolol when both drugs were formulated in one solution dosage. The ocular absorption of levobunolol is pH-dependent. Due to the large buffering capacity of pilocarpine at pH 5.5, the ocular absorption of levobunolol from pilocarpine-containing solutions was reduced by approximately four-fold as compared to a non-pilocarpine-containing formulation at pH 7.2. The ocular absorption of levobunolol in the presence of pilocarpine at acidic pH was enhanced by the use of sulfosuccinates, specifically Schercopol CMS.

Docosahexaenoic acid (22:6n-3, DHA) is derived in vertebrate animals from n-3 fatty acids present in the diet (i.e., alpha-linolenic acid, 18:3n-3 and/or other n-3-long chain polyunsaturated fatty acids) and is found in very high concentrations in phospholipids from membranes of the central nervous system. Disk membranes of photoreceptor outer segments and synaptic terminals display a preferential enrichment in DHA-phospholipids that appears to be necessary for normal excitable membrane functions. Because of the relevance of adequate DHA-phospholipid synthesis and sorting toward new assembled disk membranes and synaptic terminals, as well as the pathophysiological implications of abnormal DHA metabolism (including its synthesis, delivery to the retina, and incorporation into lipids by de novo and turnover pathways), we reviewed recent studies of: a) the preferential uptake and retention of DHA by photoreceptors and its metabolism as it is activated to DHA-CoA and incorporated preferentially into phospholipids; b) pharmacological manipulations using amphiphilic cationic drugs (i.e., propranolol) to show an active esterification of DHA into lipids via de novo synthesis; and c) perturbations in DHA metabolism in retinas from dogs with progressive rod-cone degeneration (prcd).

In developing chick embryos, hydrocortisone induces cataract formation following a decrease in lens glutathione content but an increase in lipid peroxide content in lens, blood and liver. The preventive effects of ascorbic acid 2-O-alpha-glucoside (AA-2G) on these parameters were compared on cataract formation with those of ascorbic acid (AsA) and ascorbic acid 2-O-phosphate (AA-2P). In these tissues, AA-2G inhibited a decrease in glutathione content and an increase in lipid peroxide content more effectively than either AsA or AA-2P. Various tissues including lens and liver have alpha-glucosidase activity, strongly suggesting that AsA is enzymatically liberated from AA-2G in these tissues. In summary, these results suggest that AA-2G exerts a potent anti-cataract activity via a reduction in oxidative damage through AsA release.

The effect of systemic low dose cyclosporin-A (5 mg/kg/day as initial dose) combined with 0.2 to 0.6 mg/kg/day prednisolone (when necessary) in clinical course of 22 patients suffering from severe forms of Behçet's disease are reviewed. All the patients had received other drugs previously and had either no response to them or developed intolerable side effects, therefore, pre treatment visual acuity (VA) was compared to post treatment VA as "self control". The average age of our patients was 30.6 years (range 19-51 years). The average duration of our therapy was 19.5 months (range 4-32 months). Improvement or stabilization of vision was achieved in 21 patients (95%). The intraocular inflammation was controlled in all of the eyes and most of the non-ocular signs and symptoms were also improved. Serious side effects included rise in creatinine in 10 (45%) of the patients, rise in bilirubin in 6 (27%) and hypertension in 1 (4.5%). These side effects disappeared as the dose of cyclosporin-A was tapered. We believe this form of therapy is of great value in the management of severe forms of Behçet's disease.

The present study was undertaken to determine the effects of direct administration of the selective alpha 2-adrenoceptor stimulant, B-HT 933, on choroidal blood flow, intraocular pressure and pupil size in anesthetized cats. Anterior segment choroidal blood flow was measured using laser-Doppler flowmetry. B-HT 933 administered by intra-arterial, topical and intracameral routes produced a significant depression of ocular blood flow which was largely abolished by pretreatment with rauwolscine. B-HT 933 did not lower IOP in any of these preparations. The largest doses of B-HT 933 caused a modest mydriasis when given intracamerally. However, this pupillary dilation was not blocked by rauwolscine. These results demonstrate that alpha 2-adrenoceptor activation can produce pronounced depression of anterior segment choroidal blood flow but does not cause a concomitant lowering of IOP or mydriasis in anesthetized cats.

A chronic administration of three ganciclovir gels (0.2%, 0.05%, 0.0125%) was compared with a placebo gel and a 3% acyclovir ophthalmic ointment in the treatment of HSV-1 rabbit keratitis. All the ganciclovir gels showed a clinical efficacy: a significant reduction of the corneal ulcer area, clouding and vascularization (p < 0.05) and a fast inhibition of HSV isolates into tear film with the 0.2% and 0.05% ganciclovir gels. However the efficacy was slower than using acyclovir ointment. No significant difference could be shown between the 0.2% and 0.05% ganciclovir gels or the 0.05% ganciclovir gel and the acyclovir treatment on viral isolation, when it was performed on pooled samples. The distribution of ganciclovir and acyclovir into the rabbit eyes (HPLC methods), were similar but markedly higher in solid tissues than ocular fluids. It might explain the recovery from tissue damages. The mean corneal ganciclovir concentrations were largely higher than ED 50 of ganciclovir for HSV-1. No toxicity was expected, due to very limited systemic availability. This study suggests a comparable activity on HSV-1 superficial keratitis between 0.05%, 0.2% ganciclovir gels and 3% acyclovir ointment. Higher concentration of ganciclovir gels are probably necessary in order to treat the HSV-1 kerato-uveitis.

The b-wave of electroretinogram (ERG) was used as an indicator of the retinal function in this research to study the facilitation of retinal function recovery by some natural products isolated from medicinal plants. The retinal ischemia was induced by occlusion of the central retinal artery. It was found that the recovery of b-waves was limited to approximately 30-37% in control animals, whereas the b-wave recovery was doubled by natural products, including scoparone, corylifolinin and EGCG (epigallocatechin-3-0-gallate). Lespedeza flavanone A had biphasic action by suppressing the b-wave recovery below control level initially, then enhancing the b-wave recovery over the control rate later. These results indicate that some natural products could be used for the treatment of ischemic retinopathy.