Showing papers in "Journal of Ocular Pharmacology and Therapeutics in 1994"
TL;DR: It is demonstrated that aqueous compositions that reversibly gel in response to simultaneous variations in at least two physical parameters, such as temperature, pH, and ionic strength, can be formed by appropriate combinations of macromolecular polymers which exhibit reversible gelation properties.
Abstract: Poor bioavailability of ophthalmic solutions caused by dilution and drainage from the eye can be overcome by using in situ-forming ophthalmic drug delivery systems prepared from polymers that exhibit reversible phase transitions. Joshi et al. (1), have demonstrated that aqueous compositions that reversibly gel in response to simultaneous variations in at least two physical parameters, such as temperature, pH, and ionic strength, can be formed by appropriate combinations of macromolecular polymers which exhibit reversible gelation properties. In the present study, the rheological characterization of such a system, prepared by a combination of Carbopol® (C) and methyl cellulose (MC), was carried out at two different pH (4.0 and 7.4) and temperatures (25 and 37°C) by rotational cone and plate viscometry. The shear stress (τ) vs. shear rate (D) flow curves of the aqueous polymer solutions indicated a pseudoplastic behavior, with a yield point. An increase in pH from 4.0 to 7.4, or temperature from 25...
123 citations
TL;DR: This review aims to educate the reader regarding the essential features of this procedure and to discuss the past and future role of iontophoresis in ocular drug delivery.
Abstract: Iontophoresis has been utilized in the field of ophthalmology for many years. Present application of this technique has diminished considerably and few clinicians are currently familiar with its use. This review aims to educate the reader regarding the essential features of this procedure and to discuss the past and future role of iontophoresis in ocular drug delivery.
76 citations
TL;DR: A correlation was found between data, considered indicative of the occurrence of a mucoadhesive interaction "in vivo", and "in vitro" viscometric data expressing the polymers-mucin force of interaction.
Abstract: 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 (CYHCl) 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 f...
74 citations
TL;DR: A new novel delivery system for ophthalmic drugs was developed using an antiglaucoma agent Betaxolol Hydrochloride as a model, which optimized the bioavailability and physical stability and ease of resuspendability of the product.
Abstract: 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 BETOP...
72 citations
TL;DR: The in vitro and in vivo studies have shown that this dosage form holds great promise for sustained drug release in the eye, however, several formulation challenges, including production of stable suspensions, uniform dose per unit volume, efficient drug entrapment, reproducible and large scale manufacturing, uniform particle size, etc., have to be addressed.
Abstract: Microparticulates are drug-containing small polymeric particles (erodible, non-erodible or ion-exchange resins) that are suspended in a liquid carrier medium. Upon administration of particle suspension in the eye, the particles reside at the delivery site (cul-de-sac, sub conjunctiva or vitreous cavity) and the drug is released from the particles through diffusion, chemical reaction, polymer degradation, or ion-exchange mechanism. Several distinct approaches have been used to formulate drugs in microparticulate dosage form for intraocular and topical application. These include erodible microparticulates, swelling mucoadhesive particulates, pH responsive microparticulates, nanoparticles/latex systems, ion-exchange resins, etc. Injection of bioerodible microparticulates in the vitreous for treating infections of posterior segment and the release of acceptable levels of drug up to two weeks has been demonstrated. Both corneal and non-corneal routes of drug entry in the eye from topical instillations are postulated. The in vitro and in vivo studies have shown that this dosage form holds great promise for sustained drug release in the eye. However, several formulation challenges, including production of stable suspensions, uniform dose per unit volume, efficient drug entrapment, reproducible and large scale manufacturing, uniform particle size, etc., have to be addressed. Fruitful resolution of technological challenges will result in a superior dosage form for both topical and intraocular ophthalmic application. Recent developments and future challenges of microparticulate ophthalmic drug delivery system are discussed in this review.
70 citations
TL;DR: Ocular drug development calls for the study of qualitative and quantitative aspects of drug-melanin interaction, and studies on synthetic melanin and melanin granules indicated a high binding capacity of many therapeutic classes of drugs, including psychotropics.
Abstract: 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 ...
70 citations
TL;DR: The findings point to the possibility that the novel preparation of pilocarpine incorporated into submicron emulsion might serve as a long-acting form of pilokarpine which might require a single daily application.
Abstract: 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 initi...
65 citations
TL;DR: Improve drug delivery by chemically modifying the collagen molecule to slow diffusion of the drug from the Collasome matrix, as well as varying the amount of cetyl alcohol and combining it with modified collagen in Lacrisomes to maximize comfort in patients with dry eyes.
Abstract: For patients with conditions requiring chronic rather than acute therapy, the advantages of collagen shields in providing high and sustained levels of drugs and/or lubricants to the cornea are outweighed by the difficulty of insertion of the shield and the problem of blurred vision. We have developed a delivery system in which collagen pieces suspended in a viscous vehicle can be instilled into the lower forniceal space, thereby simplifying application and reducing blurring of vision. The collagen pieces (Collasomes) can be formulated with various constituents such as antibiotics or cyclosporine, or with chemical alterations such as the inclusion of a lipid (Lacrisomes) for the treatment of dry eyes. In the normal eyes of volunteers, Collasomes hydrated in a solution of sodium fluorescein and suspended in a methylcellulose vehicle as a model for delivery of water-soluble drugs produced fluorescein concentrations 17 to 42 times higher in the cornea and 6 to 8 times higher in the aqueous humor, com...
64 citations
TL;DR: Data indicate emedastine to be a high affinity and high potency histamine antagonist with the highest selectivity for the H1-histamine receptor.
Abstract: 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.
59 citations
TL;DR: Results lead to the assumption that LMW-HS could be used in ophthalmology to inhibit corneal neovascularization and the distribution of basic fibroblast growth factor (bFGF) in the cauterized cornea was evaluated by using an immunohistochemical method.
Abstract: Vascularization of the cornea occurs in many pathological conditions and can result in loss of visual acuity. It is also thought that vascularization predisposes the cornea to reject grafts by facilitating the detection of foreign antigens in donor material. A rat corneal assay for angiogenesis was adopted in the present study to evaluate the possible angiostatic activity of a low molecular weight heparan sulphate (LMW-HS). Corneal lesions were induced by chemical cauterization at 2 mm from the corneoscleral limbus. Rats were randomized to receive two drops/eye four times daily, for 6 days, of a solution of LMW-HS in vehicle (2.5% carboxymethylcellulose), heparin, heparin plus hydrocortisone, or vehicle alone. After a 6 day-treatment period, the eyes were perfused with india ink and the degree of neovascularization was evaluated. In rats treated with vehicle alone a dense vascular network extending from the corneoscleral limbus to the cauterized site was observed; on the contrary, a markedly redu...
50 citations
TL;DR: Topical treatment of infected eyes with the two anti-inflammatory drugs, prednisolone or quercetin, resulted in higher ocular bacterial levels throughout the infection, with an immediate release of peak levels of IL-1 alpha within 24 hours after infection which did not begin to approach baseline until 9 to 11 days after infection.
Abstract: In order to characterize the inflammatory response to corneal infection by Pseudomonas aeruginosa, ocular cytokine and arachidonic acid metabolite levels were determined in the C57BL/6J strain of mice. The effects of topical anti-inflammatory drugs on the ability of the mice to clear viable P. aeruginosa from the eyes during the 12 day infection period was also examined. Ocular IL-1 alpha, IL-6, and TNF-alpha were detected over an 11 day time period. Little or no bacteria, as determined by quantitative plate counts, was detected after this time period. The kinetics of the cytokine production varied from one another, with an immediate release of peak levels of IL-1 alpha within 24 hours after infection which did not begin to approach baseline until 9 to 11 days after infection. Five to ten-fold lower concentrations of IL-6 and TNF-alpha were detected. IL-6 levels were induced at 24 hours after infection but there was essentially no distinct peak time-point. Peak levels of TNF-alpha were detected at 6 days post-infection. The kinetics of arachidonic acid metabolite release from infected eyes were also examined. Peak levels of PGE2 and TxB2 were observed at 6 days post-infection whereas peak LTB4 levels were determined at 3 days post-infection. Topical treatment of infected eyes with the two anti-inflammatory drugs, prednisolone or quercetin, resulted in higher ocular bacterial levels throughout the infection.
TL;DR: Emedastine has potential as a topical ocular anti-histamine for treating allergic conjunctivitis and failed to significantly attenuate either serotonin or platelet-activating-factor induced vascular permeability changes indicating high selectivity for the histamine H1 receptor.
Abstract: Emedastine [1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)-benzimidazole difumarate] was evaluated for topical ocular anti-histaminic activity in histamine and antigen stimulated conjunc...
TL;DR: A comparable activity on HSV-1 superficial keratitis between 0.05%, 0.2% ganciclovir gels and 3% acyclovir ointment is suggested, which might explain the recovery from tissue damages.
Abstract: 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.
TL;DR: Patients undergoing cataract surgery received a single drop of either diclofenac Na or flurbiprofen Na at selected times prior to the surgical procedure to determine the aqueous humor concentrations in the human eye following topical application.
Abstract: 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.
TL;DR: 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, this work reviewed recent studies of the preferential uptake and retention of DHA by photoreceptors.
Abstract: Docosahexaenoic acid (22:6n-3, DHA) is derived in vertebrate animals from n-3 fatty acids present in the diet (i.e., α-linolenic acid, 18:3n-3 and/or other n-3-long chain polyunsaturated f...
TL;DR: The results indicate that selected adenosine agonists can modulate intraocular pressure and may involve the modulation of cAMP levels in the iris/ciliary body.
Abstract: 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 μg) 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 p...
TL;DR: The effect of systemic low dose cyclosporin-A 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 and it is believed this form of therapy is of great value in the management of severe forms.
Abstract: 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 fro...
TL;DR: Transscleral iontophoresis is able to deliver effective dose of GCV into the vitreous into rabbit eyes to avoid the side effects of systemic administration of ganciclovir for the treatment of cytomegalovirus retinitis.
Abstract: 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 ug/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 ug/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.
TL;DR: 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.
Abstract: 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 μ1 of sterile normal saline containing varying insulin concentrations randomized to one eye, and 50 μl 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 wa
TL;DR: The low affinity of tropicamide for muscarinic receptors and its negligible receptor occupancy in plasma can explain the low incidence of systemic side-effects of Tropicamide eyedrops.
Abstract: We studied the plasma levels and systemic anticholinergic activity of tropicamide after ocular administration in eight women. Two 40 μl drops of 0.5 % tropicamide were instilled into the l...
TL;DR: 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 carnitines acetyltransferase in the ciliaryBody 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.
Abstract: 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.
TL;DR: 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.
Abstract: 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 en...
TL;DR: No tolerance and ocular side effects could be detected after long-term daily administration of insulin eyedrops and the ocular route seemed to be the most feasible one.
Abstract: 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.
TL;DR: Intravitreally administered adenosine antagonists also attenuated the vasodilative response to both systemic hypoxia and systemic hypotension in the newborn pig, indicating that endogenously produced adenosines is important in retinal blood flow regulation.
Abstract: 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.
TL;DR: In studying prostaglandin analogs, it was found that a diverse variety of prostanoid receptor selective agonists lowered intraocular pressure in dogs and/or monkeys.
Abstract: The use of natural prostaglandins (PG), such as PGD2, PGF2, PGF2α, and PGI2, for treating glaucoma is limited by their ocular side effects. One approach to achieve the required separation ...
TL;DR: It is evident that the cytochrome P450 arachidonate metabolites should be added to the realm of cyclo oxygengenase and lipoxygenase-derived eicosanoids as possible inflammatory mediators and studies to evaluate eicOSanoid involvement in inflammation should examine inhibitors of this pathway in addition to the classically studied non-steroidal antiinflammatory drugs (NSAIDs).
Abstract: 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).
TL;DR: The data demonstrate that LE is effective at reducing intra-ocular inflammation and at reducing measures of inflammation in rabbits.
Abstract: 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.
TL;DR: Results indicate that an M3-like receptor subtype is essential in mediating the muscarinic agonists-induced functional changes, such as PLC activation or muscle contraction, in the ciliary muscle.
Abstract: Muscarinic agonist-induced contraction of the ciliary muscle is generally believed to increase aqueous outflow facility and effect accommodation. We used cultured human ciliary muscle cells as a model to study the muscarinic receptor subtype(s) involved in the contractile response of the muscle. Thus, a single cell contraction assay for these muscle cells was developed. And since agonist-induced contraction of smooth muscles is expected to involve the activation of phospholipase C (PLC), we also monitored the PLC activity in these cells. Carbachol caused contraction of the muscle cells in a dose-dependent and time-dependent manner with an estimated EC50 of 1-3 microM. The contractile effect of 100 microM carbachol was antagonized by pretreatment of atropine (1 microM) and 4DAMP (10 nM, antagonist selective for the M1 and M3 receptors) but not by pirenzepine (10 microM, antagonist selective for the M1 receptor), suggesting the involvement of the M3 but not the M1 muscarinic receptor. M3 receptor is also essential for the carbachol-induced PLC activation in the ciliary muscle cells, as indicated by the activity profiles of receptor subtype selective antagonists. For example, the stimulative effect of carbachol (EC50 = 20 microM) was antagonized by pirenzepine (pKi = 6.8), HHSiD (pKi = 7.6), 4DAMP (pKi = 9.5) and methoctramine (pKi < 6). Thus, these results indicate that an M3-like receptor subtype is essential in mediating the muscarinic agonists-induced functional changes, such as PLC activation or muscle contraction, in the ciliary muscle.
TL;DR: Data indicate that PCF can reduce the toxicity of D and may be a useful implant for treatment of PVR and a dose-proportional increase in D release.
Abstract: Intravitreal daunomycin (D) effectively suppresses cellular proliferation in experimental proliferative vitreoretinopathy (PVR) but has a narrow therapeutic safety range. Studies were undertaken to reduce toxicity of D by preparing a slow-release implant using polysulfone capillary fiber (PCF). Fabrication of the implant involved loading PCF with 1% D in tristearin (w/w), an excipient with diffusion-retardant properties. Two dose levels of the PCF-D device (15 μg and 30 μg/device) were prepared and sterilized prior to use. To examine the kinetics and efficacy of the device, rabbits were randomized and eyes were implanted as follows: 1) control group (PCF vehicle); 2) PCF-D (15 μg/device); 3) PCF-D (30 μg/device). Immediately after implantation, all eyes received an intravitreal injection of 2.5 × 105 retinal pigmented epithelial (RPE) cells. Thereafter, fractional retinal detachments (TRD) were graded by ophthalmoscopic examination. Also, fluorophotometry scanning from the retina to the anterior ...
TL;DR: 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: 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)