Alginic acid effect on carteolol ocular pharmacokinetics in the pigmented rabbit.

The effect of alginic acid addition to 1% or 2% carteolol solutions on the ocular penetration of the drug has been evaluated in the pigmented rabbit. During single dose studies, an increase in bioavailability ranging from 40% to 60% was observed in the aqueous humor and in the iris-ciliary body. During repeated dose studies, this increased ocular bioavailability of carteolol in the presence of alginic acid led to an equivalent concentration in the target tissue, although the dosage was only once a day compared with twice a day for the usual carteolol eyedrops. 14C-carteolol distribution studies demonstrated the binding of carteolol in pigmented ocular tissues. Thus, the presence of alginic acid as a new excipient supports a possible decrease in dosage regimen, while retaining sufficient ocular bioavailability to lower intraocular pressure.

A new long acting ophthalmic formulation of carteolol containing alginic acid.

Alginic acid was evaluated as a potential vehicle in ophthalmic solutions for prolonging the therapeutic effect of carteolol. This anionic vehicle was expected to slow down drug elimination by the lacrimal flow, both by undergoing in-situ gel formation and by interacting with the mucus. In vitro studies indicated that carteolol is released slowly from alginic acid formulations, suggesting an ionic interaction. The adhesive behavior of alginic acid solution was better than that of another polymer, hydroxyethylcellulose (HEC). Intraocular pressure (IOP) measurements of rabbit eyes treated with a 1% carteolol formulation with or without alginic acid showed that this polymer significantly extended the duration of the pressure-reducing effect of carteolol to 8 h. The increased ocular bioavailability of 1% carteolol in the presence of alginic acid led to an equivalent concentration in the target tissue although administration was only once a day compared with twice a day for 1% carteolol alone. The overall results of this study indicate that the alginic-acid vehicle is an excellent drug carrier, well tolerated, and could be used for the development of a long-acting ophthalmic formulation of carteolol.

Antioxidant activity of plasma from subjects with and without senile cataract.

The relationship between overall plasma antioxidant activity and senile cataract was examined in 148 subjects aged 37-90 years. Antioxidant activity of plasma from 52 control and 96 patients with senile cataract was determined by a method which measures the capacity of plasma to inhibit auto-oxidation of bovine brain homogenate. In contrast to previous studies which demonstrated a relationship between decreased levels of antioxidant components in blood and the occurrence of lens opacities, the present study does not show any significant difference between subjects with and without senile cataract.

Oxygen free radicals adversely affect the regulation of vascular tone by nitric oxide in the rabbit retina under high intraocular pressure.

Flash electroretinograms (ERG) were recorded in the rabbit eye submitted to high intraocular pressure (HIOP) induced by the suction-cup method. When intraocular pressure rose to 100 mmHg, ERG was suppressed but rapidly recovered even under HIOP when animals were pre-treated either intravitreously with a nitric oxide donor, sodium nitroprusside, or intravenously with free radical scavengers, superoxide dismutase (SOD)+catalase. In contrast, injection of a nitric oxide synthesis inhibitor, nitro-L-arginine, into the vitreous cavity inhibited the protective effect of SOD+catalase during HIOP-induced ERG extinction. These results suggest that nitric oxide could play a role in the regulation of ocular vessel tone and that severe ischemia can impede this effect through oxygen-derived free radical generation.

Alterations of energetic metabolite levels by free radicals during optic nerve ischemia.

An experimental model of optic nerve ischemia was designed in the rabbit to determine early biochemical alterations, i.e.--changes of high energy phosphate metabolites (ATP and phosphocreatine)--in occlusive and peri-occlusive areas. Vascular occlusion provoked a rapid fall of ATP and phosphocreatine in the optic nerve. Free radicals scavengers, superoxide dismutase plus catalase or dimethylthiourea were able to counteract the drop of phosphate metabolites in the peri-occlusive area. These results show that hypoxia leads to oxygen-derived free radical generation which can be responsible for cell damage and emphasize the role of free radicals in the pathogenesis of ocular diseases related to vascular dysfunction.

2-(2-hydroxy-4-methylphenyl)aminothiazole hydrochloride as a dual inhibitor of cyclooxygenase/lipoxygenase and a free radical scavenger. 1st communication: in vitro studies.

2-(2-Hydroxy-4-methylphenyl)aminothiazole hydrochloride (CBS-113 A) inhibits cyclooxygenase in platelets and 5-lipoxygenase in leukocytes at micromolar concentrations. On the other hand the drug is a potent scavenger of oxygen-derived free radicals. Moreover and possibly consequently, CBS-113 A inhibits the oxygen burst of stimulated leukocytes and the release of an interleukin 1-like compound from vascular endothelial cells in culture. These properties could lead to another activity of therapeutic interest in comparison with anti-inflammatory drugs already available.

Oxidative stress and lens opacity: an overall approach to screening anticataractous drugs.

Since oxidative stress is a well substantiated hypothesis of cataract pathogenesis, screening was performed in acellular systems in order to select scavengers of reactive oxygen species; the selected compounds are at present being tested in lens culture and in animal models.

Structural determination of 'cord factor' from a Corynebacterium diphtheriae strain by a combination of mass spectral ionization methods: field desorption cesium cationization and electron impact mass spectrometry studies.

The composition and structure of a preparation of 'cord factor' (di-beta-hydroxy acyl trehaloses) from Corynebacterium diphtheriae have been determined by a combination mass spectral ionization methods. The methods were tested by means of synthetic 6,6'-dicorynomycolate of alpha-D-trehalose prior to their use on natural products. The determination of the molecular weight of the components and the estimation of their relative abundance in the natural mixture were made by field desorption mass spectrometry and cationization by means of cesium iodide. At least 22 molecular species differing from the chain length and the unsaturation degree were detected (carbon numbers C76 to C66). The position of acylation and the nature of the acyl chains were obtained from the electron impact mass spectra of the trimethylsilyl derivatives. The trehalose molecular was found to be esterified by a complex mixture of corynomycolic acids (3-hydroxy 2-alkyl fatty acids) which were present as saturated, mono-unsaturated and di-unsaturated homologues (carbon numbers C32 to C24). The 6 and 6' sites of acylation were the only detectable ones.