Journal of ocular pharmacology最新文献

We evaluated the pharmacodynamic and pharmacokinetic profile of Mipragoside, a monosialoganglioside isopropyl-ester (as 0.5% w/w ophthalmic gel), on allergic inflammation of the eye induced by reverse passive Arthus reaction, on a non-immune mast cell degranulation elicited by compound 48/80 and on ocular inflammation produced by horse serum. Conjunctiva was sensitized by injection of rabbit antisera to bovine proteins and the allergic conjunctivitis was triggered by intravenous administration of bovine gamma globulin. The permeability of the blood-conjunctival barrier was evaluated by a fluorometric method. Compound 48/80 was topically administered at concentration of 50mg/ml and histological analysis of conjunctiva was performed. Horse serum was administered by intravenous injection at different days. The pharmacokinetic profile of topical 3H-Mipragoside on 48/80 model was investigated and compared with untreated animals. Mipragoside treatment significantly reduced (p < 0.05 vs placebo) the conjunctival vasopermeability induced by reverse passive Arthus reaction as well as successfully reduced the eosinophil levels in the conjunctival epithelium (p < 0.01 vs placebo) elicited by compound 48/80. Further, Mipragoside successfully reduced the primary signs of ocular inflammation produced by horse serum administration. A radiotracer technique was used to evaluate the disposition of 3H-Mipragoside in the rabbit ocular tissues. Disposition of the drug was monitored at 30, 60, 120 and 240 min. 3H-Mipragoside levels in the inflamed conjunctiva were significantly higher (p < 0.01) than in the control eye.

Silicone oils, used as long-term retinal tamponades, cause retinal toxicity that may be related to certain ingredients. Specific additives, proven to increase corneal endothelial permeability, were added to a purified oil, and placed into the vitreous of rabbits to assess their effects on the retina. Oils were exchanged for vitreous at constant intraocular pressure to 1 ml oil volume. Blood-ocular barrier permeability was measured with fluorophotometry after intravenous dye, and retinal function was measured using dark-adapted electroretinography (ERG). Each parameter was determined at eight week intervals: this periodicity was chosen to allow any toxicity to develop based upon prior data in the literature. The fluorescein concentration in different ocular compartments indicated an increased aqueous humor fluorescein concentration after pure oil (a non-statistically significant 50% increase) or oil plus long chain additive (a significant 240% increase). After oil plus a linear series of compounds both aqueous humor (2000%) and anterior vitreous fluorescence (8000%) was statistically significantly increased, indicating a breakdown of the blood-aqueous barrier. The height of the b-wave of the ERG was unaffected by any oil in the presence or absence of additive. Overt changes were minimal with oil alone, increased with oil containing linear chain additive, and were extensive with oil with long chain additive.

Eyedrops of 0.25% insulin plus 0.5% BL-9 or Brij-78 were instilled into rabbit eyes twice a day for 3 months. It was found that the efficacy of insulin to lower the blood glucose concentration and the uptake of insulin into the systemic circulation remained the same throughout the experimental period. No allergic responses or local side effects could be detected, indicating that both insulin and permeation enhancers (BL-9 and Brij-78) are safe for instillation into the eyes for long periods of time. It is concluded that chronic administration of insulin and absorption enhancers into the eyes is a feasible method to replace injections for diabetes treatment.

The object of this study was to test whether flat, circular ophthalmic inserts releasing drug only from one side, would show improved activity parameters and reduced systemic absorption. To this purpose, uncoated and one-side coated hydroxypropylcellulose inserts containing timolol were prepared and evaluated. An acrylic copolymer (Eudragit RS) was used as coating material. Timolol release from inserts was studied both in vitro and in vivo. Timolol release in vitro from the coated inserts was much slower than from the uncoated ones, due to the smaller releasing surface area. Compared with timolol eyedrops (0.5%, 50 microliters), administration of 250 micrograms of timolol in uncoated or coated inserts produced a significantly greater hypotensive effect at 6 and 8 hr post instillation in rabbits with artificially increased intraocular pressure. The coated inserts containing 62.5 micrograms of timolol antagonised isoproterenol-induced ocular hypotension significantly more than timolol eyedrops (0.5%, 12.5 microliters) and uncoated inserts containing 62.5 micrograms of timolol. Both uncoated and coated inserts provided a significant sustaining of timolol release in tear fluid and decreased systemic peak concentrations of timolol with respect to the eyedrop control. However, one-side coated inserts failed to show significant improvements with respect to the uncoated samples.

The continuing development of ophthalmic steroids has resulted in compounds that have a low tendency to raise intraocular pressure (IOP). Preliminary clinical data have suggested that loteprednol etabonate (LE) 0.5% suspension may not elevate IOP while having promise as a potent topical ophthalmic steroid. This study was designed to evaluate the comparative potential of topical LE and prednisolone acetate (PA) to raise IOP in a population of individuals known to be steroid responders. The study used a double-masked, randomized, single eye, crossover design comparing LE 0.5% and PA 1.0%. Subjects instilled 1 drop of the assigned medication 4 times daily while awake, and follow-up examinations occurred on days 14, 28, and 42. Following a washout period of at least 14 days, subjects entered the second phase of the study, which was identical to the first phase, except that subjects received the alternate study medication. The mean IOP in the LE group increased from 17.4mm Hg at baseline to 21.5mm Hg at day 42 (p > 0.05), while in the PA group the mean IOP increased from 18.1mm Hg at baseline to 27.1mm Hg at day 42 (p < 0.05). There were no serious, severe, or clinically significant events in either group, and LE's effect on IOP was differentiable from that of PA. LE has less effect on IOP when compared to the IOP response induced by PA. LE may become a clinically useful ocular steroid with a favorable IOP-safety profile.

Vancomycin is an antibiotic which is especially active against Gram positive bacteria. At present, numerous infections of the anterior segment of the eye are caused by the Staphilococcus aureus and epidermis. Strains which are resistant to methicilin are more and more frequent and for this reason Vancomycin is becoming the antibiotic of choice to combat these infections since no resistance of the Staphilococcus to it has been demonstrated. The authors evaluated the levels of Vancomycin in aqueous humor after the administration of topical eye-drops. For the first two hours after the last administration, levels of 0.52 micrograms/ml were detected. These inhibit the growth of the majority of bacteria sensitive to Vancomycin. Between two and four hours, the levels decreased to 0.15 micrograms/ml; these are therapeutic levels for a large number of Gram positive bacteria. From four hours after the last administration, these levels are undetectable. Due to the success of its penetration, topical administration of Vancomycin should be considered as a therapeutic modality against infections by gram positive bacteria of the anterior segment. The ideal guideline for administration would be one drop every two hours, especially if the infection is severe. In this way, subconjunctival injection could be avoided.

A series of thiadiazole derivatives of carbonic anhydrase inhibitors were prepared and their physicochemical properties and pharmacological activities such as corneal permeabilities, inhibition of carbonic anhydrase activities were evaluated. The solubilities and pKa values were determined in varied pH of phosphate buffers at 35 degrees C after equilibrium. Intrinsic solubility and pKa value were calculated from the plot of solubility versus the reciprocal of hydrogen ion concentration. The distribution coefficient was determined in the system of octanol/pH 7.65 phosphate buffer. As a result, the sigma (Hammett constant) and pi (hydrophobic substituent constant) values of substituents were found to be correlated to the logarithm of Ka and partition coefficient. Corneal permeabilities of the analogue were determined in a specially designed diffusion cell using excised rabbit cornea, which ranged from 1.32 x 10(-5) (compound II) to 3.48 x 10(-7) cm/sec (compound VI). Compound with high permeability might be expected to be absorbed well after topical administration into the eye. The methodology of pH-stat was used to determine the inhibition of the carbonic anhydrase activity of the analogue. The IC50 values of the analogue around 10(-8) M as determined were less than that of acetazolamide. The results suggest that the analogue had good pharmacological activity. Finally, an equation for quantitative structure-activity relationship was established for the analogue, which is as follows: [formula: see text]

Experimental uveitis was successfully induced in rabbits by bovine serum albumin (BSA). Tetrandrine (Tet), 50 mg/kg/d i.p., and dexamethasone (Dex), 5 mg/kg/d i.p., for 8 d showed marked inhibition of uveitis in rabbits. Eight d after drug administration, ocular inflammation was markedly inhibited. The maximum inhibitory rate of Tet and Dex was 48.9% and 56.0%, respectively. The protein content of the aqueous humor (PAH) was reduced significantly; phytohemagglutinin (PHA)-induced peripheral T lymphocyte transformation of 3H-thymidine (3H TdR) incorporation was suppressed markedly; and serum circulating immune complexes (CIC) also were reduced. Four d after Dex withdrawal, ocular inflammation, PHA and CIC rose again, but these parameters were not changed after Tet withdrawal. These results suggest that Tet is an effective inhibitory agent on BSA-induced uveitis in rabbits. The inhibiting action may be related to the suppression of cellular and humoral immune function and, unlike Dex, Tet did not produce withdrawal rebound.

Antiglaucoma drugs were studied systematically on the ocular blood flow in ocular hypertensive rabbits. As expected, pilocarpine, clonidine and acetazolamide were all found to increase the ocular blood flow in the retina and choroid. However, their use in the clinics was much less than the beta-blockers, such as L-timolol, levobunolol, betaxolol and metipranolol. It was surprising to find that all non-specific and beta 1-specific adrenergic blockers decreased the ocular blood flow in ocular hypertensive rabbits. If this finding holds true in human patients, the use of beta-blockers for glaucoma treatment should be reconsidered. Dopamine antagonists, such as droperidol, metoclopramide and loxapine, were found to increase the ocular blood flow. Therefore, they might be able to replace beta-blockers for glaucoma treatment.

Alpha-2 and DA2 adrenoceptor agonists produce ocular hypotension in cats, rabbits, monkeys and humans. In this study, the effects of topical, unilateral administration of medetomidine (MED), an alpha-2 agonist, and Ha-118 (HA), a DA2 agonist, were compared on intraocular pressure (IOP) in normal, unilaterally sympathectomized (SX), and ocular hypertensive (oral water loaded) Dutch Belted (DB) and New Zealand White (NZW) rabbits. MED (75 micrograms) produced bilateral ocular hypotensive effects in both DB and NZW normal rabbits; however, HA (250 micrograms) lowered IOP unilaterally in NZW rabbits only. MED (25 micrograms) inhibited the rise in IOP caused by oral water loading in both DB and NZW rabbits; HA, on the other hand, was effective only in NZW rabbits. Topical bilateral pretreatment with metoclopramide, a DA2 antagonist, inhibited the ocular antihypertensive effect of HA in NZW rabbits. The IOP lowering effects of MED were absent in the SX eyes of DB and NZW rabbits, but hypotensive responses to MED were present in normal (contralateral) eyes of both strains. In contrast, HA was effective only in the treated, normal eyes of SX NZW rabbits. These data support pharmacodynamic roles for alpha-2 and DA2 receptors in modulating IOP. The lack of activity by HA in DB rabbit eyes suggests a possible absence of DA2 receptors or excessive binding of HA to pigment in the anterior segment of DB rabbit eyes.