Showing papers in "Journal of Ocular Pharmacology and Therapeutics in 1986"
TL;DR: The focus of this review is on recent developments in topical ocular drug delivery systems relative to their success in overcoming the constraints imposed by the eye and to the improvements that have yet to be made.
Abstract: Existing ocular drug delivery systems are fairly primitive and inefficient, but the stage is set for the rational design of newer and significantly improved systems The focus of this review is on recent developments in topical ocular drug delivery systems relative to their success in overcoming the constraints imposed by the eye and to the improvements that have yet to be made In addition, this review attempts to place in perspective the importance of pharmacokinetic modeling, ocular drug pharmacokinetic and bioavailability studies, and choice of animal models in the design and evaluation of these delivery systems Five future challenges are perceived to confront the field These are: (a) The extent to which the protective mechanisms of the eye can be safely altered to facilitate drug absorption, (b) Delivery of drugs to the posterior portion of the eye from topical dosing, (c) Topical delivery of macromolecular drugs including those derived from biotechnology, (d) Improved technology which wil
485 citations
TL;DR: The results indicate that xylazine lowers IOP, in part, by suppressing sympathetic neuronal function which causes a reduction in aqueous flow which suggests a rational basis for combining a prejunctionally active agent with a postjunctionsally active one.
Abstract: Xylazine is an agent frequently used in combination with ketamine to anesthetize rabbits. Xylazine is also related pharmacologically to clonidine, a relatively selective α2-agonist. In the present studies, xylazine was examined for its effects on intraocular pressure (IOP) and pupil diameter (PD) in rabbits, cats and monkeys and on noradrenergic function in the cat nictitating membrane (CNM) preparation. Topical and unilateral administration of xylazine (1.0 mg) lowered IOP bilaterally in normal, unanesthetized rabbits, cats and monkeys and caused unilateral miosis in rabbits and cats. These ocular effects of xylazine were attenuated in superior cervical ganglionectomized (SX) cats and rabbits. In addition, intra-arterially administered xylazine (10, 33 and 100 μg) produced dose-related inhibition of contractions of the CNM elicited by electrically stimulating the pre- and postganglionic sympathetic trunks without altering the response to i.a. norepinephrine (10 μg). These data suggest that ocula...
43 citations
TL;DR: Various drug entry and exit pathways in the eye are presented and the role of some intraocular structures in the toxicity development is examined, including melanin binding, genetic heterogeneity, photosensitivity and environmental pollution.
Abstract: There have been many drugs reported to cause oculotoxic responses after their systemic administration. The severity of these toxicities range from minor ocular inconvenience to permanent loss of vision. This paper reviews the current literature and attempts to suggest some probable factors involved in the development of oculotoxicities by systemic drugs. Various drug entry and exit pathways in the eye are presented and the role of some intraocular structures in the toxicity development is examined. The issues of melanin binding, genetic heterogeneity, photosensitivity and environmental pollution are discussed.
38 citations
TL;DR: Eyelid closure and nasolacrimal occlusion may decrease the systemic absorption of topically applied drugs and in some subjects the initial absorption was also enhanced by this procedure.
Abstract: Eyelid closure and nasolacrimal occlusion may decrease the systemic absorption of topically applied drugs. We studied the absorption kinetics of 20 microliter 0.5% timolol eyedrops in eight healthy volunteers. Each subject was supine for 30 minutes after the drug application. In randomized order, the volunteers kept their eyelids closed (ELC), or applied nasolacrimal occlusion (NLO) or blinked normally. Blood samples were drawn up to 90 minutes and analyzed for timolol with a radioreceptor assay. There was great interindividual variation in the timolol absorption. NLO reduced the total timolol absorption, but in some subjects the initial absorption was also enhanced by this procedure.
37 citations
TL;DR: Results obtained with [D-ala2]-met-enkephalinamide suggest that a more practical strategy to circumvent a metabolic barrier to the ocular absorption of topically applied peptides is to administer metabolically stable peptide analogs.
Abstract: The objective of this study was to test the hypothesis that there existed substantial metabolic and permeation barriers to the ocular absorption of topically applied peptides in the albino...
33 citations
TL;DR: The visual fields of the pindolol group showed on the average a slight tendency towards improvement and in the timolol treated group a very slight tendency for deterioration, and the difference between these two trends was statistically significant.
Abstract: In a prospective, multicenter, randomized, double-masked study of glaucoma patients, visual fields, intraocular pressures, blood pressures, and pulse rates were measured after a 4-week was...
28 citations
27 citations
TL;DR: The factors that contribute to the observed high ocular hypotensive potency of L-645,151 include: high lipidsolubility of the prodrug; reduced lipid solubilityOf the drug L-643,799, and accumulation in the cornea; high inhibitory activity against carbonic anhydrase.
Abstract: The effects of the locally active carbonic anhydrase inhibitor L-645,151 on intraocular pressure (IOP), and aqueous humor flow were studied in normotensive albino rabbits, and correlated w...
26 citations
TL;DR: The penetration of topical amphotericin B was studied in Dutch-belted rabbits using bioassay and radioassay techniques and a pass-through effect was noted with higher levels initially but rapid fall-off subsequently.
Abstract: The penetration of topical amphotericin B was studied in Dutch-belted rabbits using bioassay and radioassay techniques. Seven percent of total amphotericin B in the corneas, as measured by recovered 14-C, and 5% in the aqueous was in a bioactive form. Drug was not detectable by bioassay after single drop administration but after a loading dose approach, drug was present in therapeutic amounts. In inflamed corneas, a pass-through effect was noted with higher levels initially but rapid fall-off subsequently.
21 citations
TL;DR: The effects of ketamine anesthesia in ocular pharmacological studies were investigated in albino rabbits and the measured ocular hypotensive response to ethoxzolamide was greatly reduced by ketamine treatment, demonstrating that great care should be taken in interpretation and comparison of ocular pharmacy data obtained in ketamine-anesthetized rabbits.
Abstract: The effects of ketamine anesthesia in ocular pharmacological studies were investigated in albino rabbits over a period of 6 hr. Ketamine injection (30 or 90 mg/kg, i.m.) was accompanied by...
21 citations
TL;DR: Intravenously administered flunixin meglumine before intraocular surgery should be considered as an adjunct therapy to reduce intraoperative and postoperative uveitis, confirming that prostaglandins are involved in the stability of the blood-aqueous barrier by paracentesis in the canine eye.
Abstract: The protein and PGE2 metabolite content of the aqueous humor from untreated and flunixin meglumine pretreated dogs was determined prior to and after anterior chamber paracentesis. In the untreated dogs the concentrations of protein and PGE2 metabolite in aqueous humor were greatly elevated secondary to paracentesis. Intravenously administered flunixin meglumine (1.1 mg/kg or 2.2 mg/kg) significantly reduced these inflammatory parameters, confirming that prostaglandins are involved in the stability of the blood-aqueous barrier by paracentesis in the canine eye. The clinical implication of these results is that intravenous adminstration of flunixin meglumine before intraocular surgery should be considered as an adjunct therapy to reduce intraoperative and postoperative uveitis.
TL;DR: Results suggest that domperidone could be used to treat glaucoma without producing cardiovascular disturbances and/or asthmatic attacks.
Abstract: Domperidone, a dopamine antagonist was found to delay the intraocular pressure (IOP) recovery in rabbit eyes after infusion with hypertonic saline and to lower the IOP of normal cat eyes, ...
TL;DR: In this article, the effect of entrapment of inulin, a model medium molecular weight compound, in positively charged, multilamellar liposomes on ocular inulin absorption following instillation of single an...
Abstract: The effect of entrapment of inulin, a model medium molecular weight compound, in positively charged, multilamellar liposomes on ocular inulin absorption following instillation of single an...
TL;DR: The hypothesis that bovine ciliary body has high NADPH regenerating capacity by the hexose monophosphate shunt is supported.
Abstract: The effect of t-butyl hydroperoxide (TBHP) on the oxidation of C1-radiolabeled glucose and C6-radiolabeled glucose by bovine ciliary body was investigated in the presence and absence of the glutathione reductase inhibitors nitrofurantoin (NF) and 1,3-bis(2-chloroethyl)-1-nitrosourea [BCNU]. 14CO2 production from 1-14C-glucose was markedly stimulated by TBHP and inhibited by BCNU. Using tissue extracts, BCNU was shown to inhibit both glutathione reductase and glucose-6-phosphate dehydrogenase. These results support the hypothesis that bovine ciliary body has high NADPH regenerating capacity by the hexose monophosphate shunt.
TL;DR: The daily pattern of corneal mitotic activity and the diurnal curve for plasma melatonin showed remarkable similarities, suggesting the possibility of a causal relationship between the two phenomena.
Abstract: Domestic chicks (Gallus domesticus) reared under continuous light, and thus developing light-induced avian glaucoma (LIAG), were tested at 4-hourly intervals around the clock, for evidence...
TL;DR: The results suggest that the ability to maintain the deepness of the anterior chamber depends on the elasticity of the viscous agent rather than its viscosity.
Abstract: Maintenance of the deepness of the anterior chamber is necessary to prevent the direct contact of surgical instruments with the corneal endothelium. Therefore, in this study, we measured t...
TL;DR: Four groups of latently infected rabbits were induced to shed HSV-1 into the tear film by a one-time ocular iontophoresis of 6-hydroxydopamine (6-HD) followed 3 days later by five consecutive days of twice daily topical Epi (Epi).
Abstract: Four groups of latently infected rabbits were induced to shed HSV-1 into the tear film by a one-time ocular iontophoresis of 6-hydroxydopamine (6-HD) followed 3 days later by five consecutive days of twice daily topical epinephrine (Epi). Groups 1 and 4 had both eyes inoculated and Groups 2 and 3 had only one eye inoculated. Groups 1 and 2 had eyes swabbed to detect HSV-1, and Groups 3 and 4 had eyes washed. Group 1 was iontophoresed with 1.0% 6-HD at 0.5 mAmp for 5 min, and Groups 2, 3 and 4 were iontophoresed with 0.1% 6-HD at 0.75 mAmp for 5 min. Group 1 received topical 2.0% Epi, and Groups 2, 3, and 4 received topical 1.0% Epi. Inoculated eyes in all groups shed HSV-1 during the induction period. The peak of HSV-1 shedding occurred on the last day of Epi application for Groups 1 and 2, and on the day after the last Epi application for Groups 3 and 4. The ratio of total positive tear film samples to total samples for inoculated eyes that received 6-HD and Epi were 53/119 (45%), 38/87 (44%), 24/66 (36%), and 14/33 (42%) for Groups 1, 2, 3, and 4, respectively. Therefore, even reduced concentrations of 6-HD and Epi, as well as beginning Epi 3 days after 6-HD, induced HSV-1 ocular shedding.
TL;DR: Pharmacologic data from human use suggests that ocular side effects of topically administered haloperidol may be less than those of pilocarpine, while systemic side effects may be more than that of timolol, and haloperIDol may become a cost-effective, once daily ocular hypotensive agent.
Abstract: This is a double masked, randomized, crossover design trial of orally administered haloperidol in human volunteers. There was a statistically significant drop of the intraocular pressure in non-glaucomatous volunteers at 3 and 4 hours following haloperidol administration. Glaucomatous patients on topical medications did not show a statistically significant drug effect. Non-glaucomatous volunteers showed a statistically significant decrease in pupillary diameter 3 hours following haloperidol administration while glaucomatous subjects showed no significant change in pupillary diameter. There were no significant changes in the near point of accomodation. Dopamine antagonists like haloperidol may act by blocking post-synaptic dopamine receptors in the ciliary body, resulting in vasoconstriction and subsequently decreased aqueous humor production. Pharmacologic data from human use suggests that ocular side effects of topically administered haloperidol may be less than those of pilocarpine, while systemic side effects may be less than those of timolol. Haloperidol may become a cost-effective, once daily ocular hypotensive agent. Problems with preparation of a viable topical vehicle, as well as potential long-term side effects will require a great deal of further investigation.
TL;DR: Ibuterol suppressed ocular hypertension induced by water loading and delayed the IOP recovery rate although its onset of action was delayed, and aqueous flow was increased significantly at 1 hr after ibuterol in fluorophotometric studies in normal rabbits.
Abstract: Ibuterol, a prodrug of terbutaline, was approximately 100 times more potent than terbutaline in producing ocular hypotension in the treated eye of normal and sympathectomized (SX) rabbits. In normal rabbits, ibuterol produced no change in IOP of the contralateral eye whereas in unilaterally SX rabbits a rise in IOP occurred in the SX (contralateral) eye when the normal eye was treated with ibuterol. Ibuterol also suppressed ocular hypertension induced by water loading and delayed the IOP recovery rate although its onset of action was delayed. Aqueous flow was increased significantly at 1 hr after ibuterol in fluorophotometric studies in normal rabbits. Pretreatment with forskolin antagonized rather than enhanced ibuterol-induced ocular hypotension. Pretreatment with diclofenac failed to suppress the development of tachyphylaxis to the ocular hypotensive effect of ibuterol. Although ibuterol is an effective ocular hypotensive agent in rabbits, the effects of this agent on aqueous flow are complex and tachyphylaxis to the ocular hypotensive effect develops fairly rapidly.
TL;DR: Sources for the high levels of uric acid reported in the aqueous humor from human glaucoma eyes were studied in the rabbit model and topical medication appears to be the source of ocular hyperuricosis.
Abstract: Sources for the high levels of uric acid reported in the aqueous humor from human glaucoma eyes were studied in the rabbit model. A hyperuricemia was produced by oxonic acid blockade of uricase prior to a systemic administration of uric acid. These animals showed no increase in aqueous humor uric acid. Topical medication of eyes with 1% epinephrine produced a statistically significant (P less than 0.001) rise in the level of uric acid in aqueous humor of treated eyes. Mean urate levels increased from 0.44 mg/dl to 0.82 mg/dl. Topical glaucoma medication appears to be the source of ocular hyperuricosis.
TL;DR: That this potent inhibitor of prostaglandin synthesis can reduce important signs of ocular inflammation is well supported in this model of paracentesis and administration of a leukotactic factor.
Abstract: A useful model that combines paracentesis with administration of a leukotactic factor was developed in order to study the effects of topical diclofenac sodium on various aspects of ocular inflammation. The increases in intraocular pressure (IOP) and secondary aqueous humor protein concentration induced in rabbits by anterior chamber paracentesis, as well as leukocyte accumulation in the anterior chamber induced by formyl-methionyl-leucyl-phenylalanine, were significantly reduced by topical application of diclofenac sodium at concentrations of 2 mM (0.064%, w/v) and higher. Lower doses consistently affected only IOP and secondary protein concentrations. A slight paracentesis-induced miosis was refractory to diclofenac sodium. That this potent inhibitor of prostaglandin synthesis can reduce important signs of ocular inflammation is well supported in this model.
TL;DR: Bendazac at a dosage ten-fold lower than that used in the clinics is anticataract drug when orally administered to "BLOA test selected" patients, at least for short term treatment of young, otherwise healthy humans with cortical cataract.
Abstract: It was found that two chemically very close Non-Steroid Antiinflammatory Drugs (NSAID), bendazac and benzydamine, were able to reduce the Biological Liquid Oxidant Activity (BLOA) in vitro (bendezac) and in vivo (bendazac and benzydamine). Four hundred and seven patients were treated with bendazac and 599 with benzydamine. After a single dose oral administration they effected a BLOA Reducing Activity (BRA) ranging from 5% to over 20% in about 40% of cataractous patients. When these drugs were able to reduce the BLOA, they showed anticataract activity in about 50% and about 90% of patients according to the extent of BRA, i.e., less than 20% and greater than or equal to 20% of the basal value. This fact suggests that the anticataract agent is not the original NSAID (prodrug) but a NSAID metabolite or an elicited endogenous compound which produced the BLOA reduction. Individual BLOA could be reduced in vivo by benzydamine or bendazac, by both or by neither of them. This finding may be accounted for by selective biotransformation of each patient's original NSAID into the antioxidant anticataract compound. However, other possible mechanisms of the anticataract activity beside antioxidant activity might take place, such as protein and membrane stabilization, together with a not yet defined activation of enzymes within the lens effecting the reversal of cataractous opacity. Several side effects were apparent in short and long term treatments. The final conclusion of our study is that bendazac at a dosage ten-fold lower than that used in the clinics is anticataract drug when orally administered to "BLOA test selected" patients, at least for short term treatment of young, otherwise healthy humans with cortical cataract.
TL;DR: Mitotic rate in the corneal epithelium, and adrenal and testis weight, were more sensitive indicators, showing that both the hormone and its antagonist induced changes in these experimental subjects.
Abstract: Domestic chicks reared under continuous dim light developed the eye enlargement and suppressed corneal growth characteristic of light-induced avian glaucoma (LIAG) and dim light buphthalmos (DLB). Administered corticosterone moderated these effects on both the globe of the eye and the cornea. The anti-adrenal agent Metyrapone had no discernable effects on the globe parameters of the eye, although the cornea was somewhat enlarged and the anterior chamber deeper than in controls. Mitotic rate in the corneal epithelium, and adrenal and testis weight, were more sensitive indicators, showing that both the hormone and its antagonist induced changes in these experimental subjects.
TL;DR: Proton NMR spectroscopy showed that the epithelial cells of the rabbit eye remained stable in both lactate production and HMPS activity for at least 8 hours, and although tBHP (1mM) resulted in an increase of glucose flow through the HMPS, the rate of lactateProduction was not affected.
Abstract: Proton NMR spectroscopy was performed on media collected from cultured lens epithelial cells of the rabbit eye incubated with Krebs-Ringer's solution containing 5.5mM C-glucose (labeled at the C-1 position). Comparing proton resonance intensities of the lactate-methyl group of the C-3 carbon (both 12C and 13C) enabled us to quantify the hexose monophosphate shunt (HMPS) activity. Our results showed that the epithelial cells remained stable in both lactate production and HMPS activity for at least 8 hours. In addition, although tBHP (1mM) resulted in an increase of glucose flow through the HMPS, the rate of lactate production was not affected. In contrast, KCN (2mM) caused a 72% increase of lactate production and a slight (6%) decrease of glucose consumption through the HMPS.
TL;DR: Findings will show the basic conditions for this eye drop solution to be an artificial tear fluid.
Abstract: Transcorneal permeability of M79175, aldose reductase inhibitor (Eisai), and various factors influencing it were examined using excised rabbit cornea mounted on the methacrylate apparatus....
TL;DR: It appears that combined H1- and H2-antagonist therapy is required for effective blockade of ocular responses to histamine that involve both receptor subtypes.
Abstract: Histamine-induced ocular surface redness was virtually abolished by a combination of cimetidine (H2-receptor antagonist) and pyrilamine (H1-receptor antagonist), whereas either antagonist administered alone produced no significant reduction. It appears that combined H1- and H2-antagonist therapy is required for effective blockade of ocular responses to histamine that involve both receptor subtypes.
TL;DR: Physiological doses of hCG from this major peak injected intravitreally in rabbit eyes resulted in significant decreases in IOP without associated irritation when compared with contralateral control eyes.
Abstract: Human chorionic gonadotropin (hCG) is a glycoprotein hormone composed of two dissimilar subunits α and β held together by noncovalent forces. Each subunit contains about 30% carbohydrate and is extensively crosslinked by disulfide bonds. Previous work from our laboratory with commercial preparations of hCG indicated that intravitreal injection of hCG lowered intraocular pressure (IOP). Our work has been extended by using purified hCG obtained by reverse phase high performance liquid chromatography of a commercial preparation. With a wide pore octyl silica column and a step gradient composed of dilute aqueous trifluoroacetic acid and methanol, several peaks were obtained. The major peak was shown by sodium dodecylsulfate-polyacrylamide gel electrophoresis and amino acid analysis to contain both α and β subunits. That this major peak contained intact hormone rather than a mixture of subunits was revealed by its ability to enhance the fluorescence of 8-anilino-1-naphthalene sulfonate and stimulate t...
TL;DR: High levels of M79175 accumulated to the lens as was expected from the results of corneal permeability, and lowering the pH of the solution demonstrated the tendency to decrease the concentration at 20 min.
Abstract: Transcorneal permeability of M79175 was estimated in vivo and the effects of pH and thickening agent on it were examined. The aqueous humor concentration of M79175 versus time profile showed the peak concentration of 850 ng/ml at 20 min after instillation of pH 7.0 eye drop solution. The permeability constant of M79175 was estimated by applying a physiologically based pharmacokinetic model to this profile. As was expected from the results in vitro, high permeability constant was observed in vivo. Lowering the pH of the solution demonstrated the tendency to decrease the concentration at 20 min. Thickening agent, Hydroyethylcellulose, did not change the aqueous humor concentration versus time profile. Ocular tissue distribution was examined using 14C-M79175. As was expected from the results of corneal permeability, high levels of M79175 accumulated to the lens.
TL;DR: The autologous model of EAU in pigmented guinea-pigs seems to be very appropriate for testing immunosuppressive drugs in conditions close to clinical practice, confirming earlier experiments in S-antigen induced experimental autoimmune uveoretinitis in rats.
Abstract: Pigmented guinea-pigs were immunized by a single bilateral footpad injection of their own retina from one enucleated eye, mixed with complete Freund's adjuvant. Ocular inflammation started on the third week, and was still detectable in the fourth month. Daily subcutaneous injections of Cyclosporine (CsA) (20 mg/kg) from the day of immunization totally prevented the ocular disease, clinically and histologically, confirming earlier experiments in S-antigen induced experimental autoimmune uveoretinitis in rats. When CsA injections (20 mg or 10 mg/kg) were started at the onset time of EAU, a rapid regression of the inflammation occurred. This curative therapy was given during two months. No relapse was observed after having stopped the treatment. On the fourth month, only mild lesions of photoreceptors were found histologically, compared to extensive retinal destruction in controls. Most control guinea-pigs developed antibodies to antigens contained in guinea-pig retinal extract as tested by ELISA. T...
TL;DR: NAP-HEX-Q is designed as a drug to prevent or reverse diabetic cataract formation by selective photoaffinity inhibition of RLAR with no significant effect on aldose reductase in other tissues.
Abstract: A reversible affinity inhibitor of rat lens aldose reductase (RLAR), that can be transformed into an irreversible inhibitor by low doses of X-rays or by exposure to light, has been synthes...