Uptake and release phenomena in contact lens care by silicone hydrogel lenses.

Contact lens solutions are highly complex mixtures of biocides (preservatives), surfactants, and other agents designed to disinfect, clean, and wet contact lenses. The commercialization of silicone hydrogel (SiHy) lenses has resulted in unique challenges to the manufacturers of contact lens solutions, because the properties of these materials differ markedly from those seen previously with poly-hydroxyethyl methacrylate-based hydrogels. Historically, hydrogel lens uptake and release of low-molecular weight preservatives such as chlorhexidine and thimerosal were known to result in allergic reactions, resulting in corneal irritation, stinging, conjunctival hyperemia, development of corneal infiltrates, palpebral lid changes, and corneal staining. However, little is known about the interaction of modern care systems with modern soft lens materials. Factors to be considered when evaluating the uptake and release of care components include the water content, charge, relative hydrophobicity, surface treatment, and porosity of the lens material, in conjunction with the concentration, charge/molecule, ionicity in the product matrix, molecular weight, and hydrophobicity of the care component in question. These factors control the sorption of the solution components by lenses, resulting in a variety of differences in the amount of the component taken up into the lens material and the amount and rate of subsequent release onto the ocular surface. Because both natural (ocular) and environmental biota become part of the solution-lens system during regimen use of any lens care product, these extraneously introduced substances should also be considered regarding their potential for uptake and either subsequent release onto the ocular surface or functioning as a scaffold for the adhesion of microbes. This article will review current knowledge concerning these interactions and investigate what clinically observable complications may arise from these interactions. It also reviews whether current methods to determine these interactions could be improved on.

Pharmacokinetics and Safety of Travoprost 0.004% Ophthalmic Solution Preserved with Polyquad in Pediatric Patients with Glaucoma.

PURPOSE: To evaluate the systemic pharmacokinetics (PKs) of travoprost 0.004% preserved with Polyquad® (TRAVATAN®) in pediatric patients with glaucoma or ocular hypertension. METHODS: This was a phase 1, open-label, multicenter clinical study of patients aged ≥2 months to <18 years. Patients received daily administration of travoprost 0.004% preserved with Polyquad in both eyes for 7 days. Plasma samples were collected 30 min before the final dose and at 10, 20, 40, and 80 min postdose. The main outcome measure was maximum concentration of travoprost free acid in plasma (Cmax). RESULTS: Included in the PK analysis were 24 patients (average age 9.6 ± 4.9 years). At least 1 sample with quantifiable levels of travoprost free acid was collected for 11 patients. The mean Cmax was 0.0471 ± 0.0105 ng/mL for patients aged 2 months to <3 years; 0.0258 ± 0.0128 ng/mL for ages 3 to <12 years; and 0.0109 ± 0.0005 ng/mL for ages 12 to <18 years. Travoprost was undetectable in samples collected predose from pediatric patients. Treatment-related adverse events (AEs) included hyperemia, eye pain, and eye pruritus (n = 1 each). There were no discontinuations or drug-related serious AEs. CONCLUSIONS: Travoprost free acid concentration in plasma was low in pediatric patients, detectable in only 11 of 24 patients. There was no accumulation of travoprost over the course of treatment. No clear relationship was observed between age/body surface area and Cmax. No increased risk was identified for the use of travoprost 0.004% preserved with Polyquad in patients <18 years of age.

The safety and intraocular pressure-lowering efficacy of brimonidine tartrate 0.15% preserved with polyquaternium-1.

PURPOSE: The safety and intraocular pressure (IOP)-lowering efficacy of brimonidine tartrate 0.15% preserved with polyquaternium-1 were evaluated and compared with brimonidine tartrate 0.15% preserved with chlorine dioxide in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). DESIGN: Randomized, double-masked, parallel group, multicenter equivalence study. PARTICIPANTS: Eight hundred forty-two patients randomized to the study treatments. METHODS: Patients with OAG or OHT and with qualifying IOP (22-36 mmHg at 8 am on 2 eligibility visits after an appropriate washout period from previous treatment) were assigned randomly to either brimonidine tartrate 0.15% preserved with polyquaternium-1 (brimonidine PQ) or brimonidine tartrate 0.15% preserved with chlorine dioxide (brimonidine P) dosed 3 times daily and were followed up for 6 months. Approximately one half of the study sites continued to follow up their patients for an additional 6 months to obtain longer-term safety data. RESULTS: Brimonidine PQ produced statistically significant and clinically relevant reductions from baseline ranging from 4.3 to 6.5 mmHg, which were statistically and clinically equivalent to brimonidine P at all 18 visit days and times. No safety concerns were identified based on an assessment of ocular and cardiovascular parameters. Patient discontinuations resulting from adverse events were similar for both groups and most of these were a result of signs or symptoms of ocular allergic reaction. CONCLUSIONS: Brimonidine PQ is equivalent in IOP-lowering efficacy and safety to brimonidine P.

[Significance of biological indicators of mercury exposure]. / Significato degli indicatori biologici di esposizione a mercurio.

BACKGROUND: It was considered appropriate to update of the significance and use of the different mercury exposure indicators. OBJECTIVE: The aim of the this paper was to correctly select biological media and sampling time and to understand the toxic kinetics of mercury for assessment of accurate biological monitoring. RESULTS: It was confirmed that mercury in blood (B-Hg) is a good indicator of recent exposure, while urinary mercury (U-Hg) indicates current exposure when mercury reaches the renal steady state. B-Hg values are greatly influenced by fish consumption, while the variables influencing U-Hg values are amalgam fillings, commercial gamma-globulin preparations, vaccines, topical remedies, environmental pollution and hobbies, occupational exposure and, partly, fish consumption. The speciation of mercury (Hg0, Hg++, methylmercury and ethylmercury) in biological media, should provide additional and important information in evaluating mercury toxicity. CONCLUSION: It was stressed that the appropriate choice of exposure indicators has to take account of the different variability factors and the characteristics of the toxic kinetics of mercury. The results of biological monitoring must be compared with references values, which are generally in the order of several micrograms/g creatinine, and limit values such as ACGIH BEI (U-Hg 35 micrograms/g creatinine and B-Hg 15 micrograms/l) or the DFG BAT (U-Hg 100 micrograms/l and B-Hg 25 micrograms/l).

Dermal absorption and hydrolysis of methylparaben in different vehicles through intact and damaged skin: using a pig-ear model in vitro.

Currently, there is a trend to reduce of parabens use due to concern about the safety of their unmetabolised forms. This paper focused on dermal absorption rate and effectiveness of first-pass biotransformation of methylparaben (MP) under in-use conditions of skincare products. 24-h exposure of previously frozen intact and tapestripped (20 strips) pig-ear skin to nine vehicles containing 0.1% MP (AD, applied dose of 10 µg/cm²), resulted in 2.0-5.8%AD and 2.9-7.6%AD of unmetabolised MP, and 37.0-73.0%AD and 56.0-95.0%AD of p-hydroxybenzoic acid, respectively, in the receptor fluid. The absorption rate of MP was higher from emulsions than from hydrogels, from enhancer-containing vehicles than from enhancer-free vehicles, and when skin was damaged. Experiments confirmed that the freezing of pig-ear skin slightly reduces hydrolysis of MP. After 4-h exposure of intact freshly excised and intact frozen stored skin, amount of

Perfusion cells for studying regional variation in oral-mucosal permeability in humans. I: Kinetic aspects in oral-mucosal absorption of alkylparabens.

PURPOSE: To evaluate regional differences in permeability of human oral mucosa. METHODS: Newly designed perfusion cells were used for the investigation. The cells were applied to 5 different sites, i.e., dorsum of tongue, ventral surface of tongue, labial mucosa, floor of mouth and buccal mucosa of human volunteers. Model drugs used were methyl-, ethyl-, propyl- and butylparaben, which are passively absorbed from oral mucosa and have different lipophilicities. Biexponential disappearance profiles of the alkylparabens were analyzed kinetically using a two-compartment linear open model. RESULTS: Both the partitioning parameters to the oral mucosa and the absorption rate constants to the blood circulation correlated to the lipophilicities of the compounds in all mucosa. As to the former parameter, no significant difference was recognized in all mucosa. While, the latter parameter exhibited the regional difference; the absorption rate constants in buccal mucosa were approximately one-half of those estimated in other oral mucosa. A positive relation was recognized between the retention in oral-mucosal compartment and the drug lipophilicity. CONCLUSIONS: The newly designed perfusion cells used in this study were useful to examine the regional variations of drug absorption from oral mucosa in humans. The absorption rate constant, the partition to oral mucosa and the residence time in oral mucosa increased with lipophilicity of the compound. The regional difference in the drug absorption process was demonstrated; the slow absorption and the prolonged retention were demonstrated in buccal mucosa.

Sorption of parabens by flexible tubings.

Flexible tubings are extensively used in pharmaceuticals, food industry, and in hospitals. This study was undertaken to compare various flexible tubings to determine their sorption characteristics, using methyl and propyl parabens. After 24 h, some tubings showed 100% sorption of propylparaben and over 40% for methylparaben. Significant losses were observed within a few hours using several tubings. For methylparaben, the losses were in the following decreasing order of sorption: Tygon, Clearflo, silicone, Nylotube, and Newtex. For propylparaben, the losses were in the following order: Tygon, Clearflo, silicone, Newtex, and Nylotube. Teflon, Zelite, and Vitube showed little to no losses of methyl and propylparaben over 120 h of study. The silicone tubing, refilled after 120 h with fresh methylparaben or propylparaben solutions, again showed significant losses within a few hours. The tubings show slow desorption when filled with the buffer vehicle. For Silastic tubing, increase in temperature from 25 to 40 degrees C, increase in pH from 3.5 to 6.5, tubing lot to lot variation, or curing with peroxide or platinum had little or no effect on paraben sorption. As expected, the sorption of parabens increased with increasing surface area of Silastic tubing. Results provided can be used to select the best tubings and to minimize paraben losses during production and filling of liquid pharmaceuticals andfood products containing these antimicrobial preservatives.

Skin permeation of parabens in excised guinea pig dorsal skin, its modification by penetration enhancers and their relationship with n-octanol/water partition coefficients.

Skin penetration of methyl, ethyl, propyl and butyl parabens through excised guinea pig dorsal skin was examined, and effects of the penetration enhancers, l-menthol plus ethanol itself and N-dodecyl-2-pyrrolidone, were observed. Permeability of coefficients of the parabens correlated with n-octanol/water partition coefficients. Addition of 1% l-menthol in 15% ethanol about sixteen times increased the permeability coefficient of methyl paraben, whereas this enhancer decreased that of butyl paraben to about one fifth of the control value. A similar, though weaker, tendency was observed for the effects of 15% ethanol itself. 0.025% suspension of N-dodecyl-2-pyrrolidone increased the permeability coefficient of methyl paraben about seven times, whereas it did not change that of butyl paraben significantly. Therefore, dependency of the permeability coefficients of the parabens on n-octanol/water partition coefficients almost disappeared in the presence of this compound. A spin label study with stratum corneum lipid liposomes revealed that increase of fluidity of the lipid bilayer by these penetration enhancers corresponded with their enhancement effects on skin penetration of methyl paraben. Perturbation of stratum corneum lipid lamella thus seems to be related with their enhancement of the absorption of hydrophilic paraben.