Journal of ocular pharmacology最新文献

New non-steroidal anti-inflammatory agents (NSAIAs) were tested on lens protein-, endotoxin- and interleukin-1-induced ocular inflammation. It was found that most NSAIAs, including REV 5901, mefenamic acid, indomethacin, CK-17 and CK-102, inhibited lens protein-induced inflammation. Endotoxin induced inflammation indirectly through the release of IL-1 which was inhibited by fewer agents, including CK-17, CK-102 and prednisolone. However, the direct effect of IL-1 can only be suppressed by CK-17 and prednisolone. Therefore, CK-17 could become an important NSAIA which acts similarly to corticosteroids yet produces no steroidal side effects. CK-17 was different from most NSAIAs as it affected little, if any, arachidonate metabolism. Most importantly, CK-17 was found to be 2-fold more potent than prednisolone in inhibiting IL-1-induced uveitis, while no side effects were noted at doses tested to date.

Adenosine receptors have been shown to modulate a variety of physiological functions; however, little is known about the role these receptors play in the modulation of ocular function. To investigate the potential role of adenosine receptors in modulating intraocular pressure (IOP), the A1 agonist N6-cyclopentyladenosine (CPA), the nonselective adenosine agonist 5'-N-ethylcarboxamideadenosine (NECA) and the A2 agonist 8-phenylaminoadenosine (CV-1808) were evaluated. Topical administration of NECA produced a dose-related reduction in IOP. However, an initial ocular hypertension of 1 to 2 hours was also observed in rabbits treated with NECA. The administration of CPA (165 micrograms) resulted only in a reduction in IOP, while the administration of CV-1808 produced only an initial ocular hypertension. As adenosine A1 receptors have been shown to be negatively coupled to adenylate cyclase in several systems, CPA was evaluated for its ability to suppress cAMP formation in the isolated iris/ciliary body. CPA produced a dose-related suppression of cAMP accumulation induced by 10(-6) M forskolin (EC50 = 3.2 nM). These results indicate that selected adenosine agonists can modulate IOP. The ocular hypotension induced by adenosine agonists is consistent with the activation of adenosine A1 receptors and may involve the modulation of cAMP levels in the iris/ciliary body.

A new novel delivery system for ophthalmic drugs was developed using an antiglaucoma agent Betaxolol Hydrochloride as a model. The new delivery system involved both the binding and release of drug from ion exchange resin particles. Betaxolol was studied in-vitro via a release model analysis. The ocular comfort of Betaxolol was greatly enhanced by reducing the availability of free drug molecules in the precorneal tear film. The amount of resin concentration was selected to obtain optimum binding of the drug. The zeta potential of suspended particles was adjusted to produce flocculated suspension. Drug resin particles were then incorporated into the structured vehicle, containing Carbomer 934P as a polymer, to enhance the physical stability and ease of resuspendability of the product. This delivery system also optimized the bioavailability of Betaxolol, reducing the total drug concentration in half to 0.25% Betaxolol in 0.25% BETOPTIC S Ophthalmic Suspension as compared with 0.5% Betaxolol in BETOPTIC 0.5% Sterile Ophthalmic Solution dosage form. Increased comfort of 0.25% BETOPTIC S Ophthalmic Suspension, as well as its bioequivalency data in animal models (rabbits), was confirmed in actual clinical trials of the product 0.25% BETOPTIC S Ophthalmic Suspension. The 0.25% BETOPTIC S Ophthalmic Suspension product has been approved gamma FDA and is marketed in U. S. since February 1990. The 0.25% BETOPTIC S Ophthalmic Suspension formulation has an increased bioavailability (equivalent to BETOPTIC 0.5% Sterile Ophthalmic Solution at half the concentration of drug); and pharmaceutically, is an elegant suspension product which settles slowly providing uniform dosage and increased ocular comfort.

The use of natural prostaglandins (PG), such as PGD2, PGE2, PGF2 alpha, and PGI2, for treating glaucoma is limited by their ocular side effects. One approach to achieve the required separation of ocular hypotensive activity from side effects is to employ ester prodrugs. From a novel series of 11- and 15-mono and 11,15-diacyl esters of PGF2 alpha we identified prodrugs where PGF2 alpha formation rates in the iris-ciliary body exceeded those in the conjunctiva, sclera, and corneal endothelium. Compared to PGF2 alpha-1-isopropyl ester the ocular tissue hydrolysis rates of the 11-monopivaloyl, the 11,15-dipivaloyl ester and the 1,11-lactone were up to 1000 fold less. Despite this large disparity in hydrolysis rates, the pivaloyl esters and the 1,11-lactone were potent ocular hypotensives in our animal models. In studying prostaglandin analogs, we found that a diverse variety of prostanoid receptor selective agonists lowered intraocular pressure in dogs and/or monkeys. These included DP-, EP1-, EP2-, EP3-, and FP-receptor selective compounds. These findings were surprising and prompted us to re-examine the receptor selectivity of these agonists by radioligand binding studies. Using radiolabelled PGE2, 17-phenyl PGF2 alpha, and sulprostone we were able to confirm the selectivity of the agonists currently used for receptor characterization directly by radioligand binding competition studies. It appears that multiple prostanoid receptor subtypes may be involved in regulating intraocular pressure.

There are two major novel metabolism-based drug design concepts which have significant advantages when used in the design of safe, specific ophthalmic drugs. One is based on predictable enzymatic activation processes by enzymes found exclusively or preferentially at the site of action--in this case, within the eye, primarily in the iris-ciliary body. The second major retrometabolic design technique involves soft drug approaches. Among the various soft drug design strategies, it was found that the "inactive metabolite" and the "soft analog" approaches are the most useful for designing safe and selective ophthalmic drugs. In the first case, the design process starts with a known (or predicted) inactive metabolite (Mi) of the drug (D). This Mi is then structurally modified in the "chemical activation" stage to the soft drug (SD), which is isosteric and/or isoelectronic with D to produce activity at the target receptors, similar to that of D. By design, however, SD is also subject to a facile, predictable (generally hydrolytic) metabolism leading in one step to the starting inactive Mi. As this deactivation takes places everywhere in the body, the desired activities are produced virtually exclusively at the target site at or near the place of application. Successful use of this general concept has led to soft beta-blockers as safe antiglaucoma agents, soft anticholinergics as short acting mydriatic agents, and soft corticosteroids as a type of novel, safe anti-inflammatory agents, which due to their unique design, do not elevate intraocular pressure IOP and do not produce other systemic and local side effects.

We determined the concentration dependent effects of arachidonic acid between 0.3 and 30 x 10(-6) M on corneal epithelial migration, in an organ culture system of the rabbit cornea. With 3 x 10(-6) M arachidonic acid, corneal epithelial migration was maximally stimulated by 51%. The cyclooxygenase inhibitors, indomethacin, ketoprofen, flurbiprofen and diclofenac sodium also all had a tendency to stimulate corneal epithelial migration at low concentrations (0.1 or 1 x 10(-6) M). However, the inhibitory effect of epithelial migration was observed at higher concentration (100 x 10(-6) M) of these compounds. On the other hand, the selective 5-lipoxygenase inhibitor, AA-861 over a concentration range from 0.1 to 10 x 10(-6) M maximally inhibited corneal epithelial migration by 25%. These results suggest that during wound healing some of the increased release of arachidonic acid may be derived from a metabolite of the 5-lipoxygenase pathway which may in turn hasten wound closure.

Systemic absorption of insulin delivered via eyedrops has been studied in rats made transiently hyperglycemic by anesthesia with xylazine/ketamine. Insulin at a concentration of 2 mg/ml was not absorbed significantly when saline alone was used as the formulation for the eyedrops (0.04 ml). When various emulsant agents were added to the eyedrop formulation, systemic insulin levels were increased and concomitantly, blood D-glucose levels were decreased. Saponin, Brij-78, BL-9 and several alkylglycosides all increased the systemic absorption of insulin following delivery in eyedrops. Not all surfactant agents were effective in promoting systemic insulin absorption from eyedrops, as evidenced by the failure of some non-ionic surfactants to increase insulin absorption. Similar results were obtained when nosedrops containing insulin plus non-ionic surfactants were administered to rats. In conclusion, systemic insulin absorption was greatly accelerated by the addition of certain emulsants to the eyedrop formulation and physiologically important levels of insulin could be delivered systemically following eyedrop administration.

The efficacy of naloxone (NL), a broad spectrum opioid antagonist, on retinal ischemia, was evaluated in a rat model of retinal ischemia with histopathologic and morphometric criteria. Two intraperitoneal injections of naloxone 3 mg/kg given immediately and 6 hr after reperfusion showed beneficial effects to the retina as evaluated at 2, 7, and 14 days after reperfusion. Morphologically, the naloxone-treated group showed better-preserved ganglion cells, nerve fiber layer, and inner nuclear layer. Morphometrically, in the treated groups, inner retinal thickness at all three time points and ganglion cell counts at 7 days showed higher values than vehicle controls. This beneficial effect of naloxone was dose-dependent with a minimal effective total dose of 6 mg/kg. A possible role of opiate receptors in retinal ischemia is suggested.

It is well known that corticosteroids are potent anti-inflammatory agents, yet they produce serious side effects. Although arachidonate metabolite blockers have been developed for the treatment of inflammation, they are much less potent than corticosteroids. Furthermore, they still process serious side effects. In search of potent and safe non-steroidal anti-inflammatory agents (NSAIA), interleukin-1 (IL-1) blockers have been developed. Among 121 CK-analogs studied, CK-17, CK-101A and CK103A have been identified as promising anti-inflammatory agents as potent as prednisolone in inhibiting lens proteins-induced inflammation and twice as potent as prednisolone in inhibiting endotoxin-and IL-1-induced uveitis. No serious side effects could be noticed with the doses of these compounds tested to date. These results indicate that the development of potent NSAIAs is feasible. Moreover, these compounds are not related to arachidonate metabolites.

A series of polyanionic natural or semi-synthetic polymers (polygalacturonic acid, hyaluronic acid, carboxymethylamylose, carboxymethylchitin, chondroitin sulfate, heparan sulfate and mesoglycan) were evaluated as potential mucoadhesive carriers for ophthalmic drugs. Solutions containing cyclopentolate (CY) or pilocarpine (PI) as salts (or polyanionic complexes) with the acidic polymers, all showing a low viscosity, were tested for miotic (resp. mydriatic) activity in albino rabbits. In the case of some polymeric complexes, small but significant increases of the areas under the activity vs. time curves (AUC) over reference cyclopentolate hydrochloride (CYHC1) or pilocarpine nitrate (PINO3) vehicles, and significant AUC decreases after removal of precorneal mucin by treatment with N-acetylcysteine were observed. A correlation was found between these data, considered indicative of the occurrence of a mucoadhesive interaction "in vivo", and "in vitro" viscometric data expressing the polymers-mucin force of interaction. The advantages and limitations of the mucoadhesive non-viscous approach in the formulation of ophthalmic vehicles are presented and discussed.