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      Acute Corneal Epithelial Change after Instillation of Benzalkonium Chloride Evaluated Using a Newly Developed in vivo Corneal Transepithelial Electric Resistance Measurement Method

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          Abstract

          Objective: Acute corneal permeability change after instillation of benzalkonium chloride (BAC) was evaluated using a newly developed in vivo corneal transepithelial electric resistance (TER) measurement method. Method: Corneal TER was measured by Ag/AgCl electrodes placed in the anterior aqueous chamber and on the cornea of live rabbit eyes. TER was measured and TER change after instillation of 0.05% BAC solution was monitored. After TER measurement, cornea was excised and fixed for transmission and scanning electron microscopy. For the control study, physiologic saline was used instead of BAC. Results: The TER of normal rabbit cornea was 602.3 ± 195.0 Ωcm<sup>2</sup>. TER decreased instantly after instillation of 0.05% BAC. In 5 s, TER decreased to 58.3 ± 5.2%. In 60 s, TER decreased to 18.5 ± 3.2%. At all time points, TER after instillation of 0.05% BAC was significantly lower than that of the control (p < 0.0001). Dissociation of tight junctions and the destruction of superficial cell membranes were observed under electron microscopy. Conclusion: Corneal epithelial change with increased permeability is rapid and intense after the instillation of highly concentrated BAC solution, accompanied by disorder of tight junctions and cell membranes of superficial cells. The newly developed in vivo corneal TER measurement method is suitable for assessing acute corneal change after drug instillation.

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          Most cited references15

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          Permeability of cornea, sclera, and conjunctiva: a literature analysis for drug delivery to the eye.

          The objective of this study was to collect a comprehensive database of ocular tissue permeability measurements found in a review of the literature to guide models for drug transport in the eye. Well over 300 permeability measurements of cornea, sclera, and conjunctiva, as well as corneal epithelium, stroma, and endothelium, were obtained for almost 150 different compounds from more than 40 different studies. In agreement with previous work, the corneal epithelium was shown generally to control transcorneal transport, where corneal stroma and endothelium contribute significantly only to the barrier for small, lipophilic compounds. In addition, other quantitative comparisons between ocular tissues are presented. This study provides an extensive database of ocular tissue permeabilities, which should be useful for future development and validation of models to predict rates of drug delivery to the eye.
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            Increased corneal hydration induced by potential ocular penetration enhancers: assessment by differential scanning calorimetry (DSC) and by desiccation.

            The corneal toxicity of some surfactants of possible use as ocular penetration enhancers was investigated by measuring their effect on hydration of rabbit corneas 'in vitro'. The tested substances were benzalkonium chloride (BAC), cetylpyridinium chloride (CPC), ethylenediaminetetraacetic acid disodium salt (EDTA), polyoxyethylene-20-stearyl ether (Brij 78, PSE), polyethoxylated castor oil (Cremophor EL, PCO) and sodium deoxycholate (DC). Freshly excised corneas, mounted in perfusion cells, were kept in contact for 1 h with solutions of these agents; corneal hydration was then evaluated by measuring: (a) their total (free+bound) water content by desiccation (gravimetric analysis); and (b) their free water content by differential scanning calorimetry (DSC). The DSC measurements also provided a rough quantitative estimate of corneal solutes. All tested agents significantly influenced corneal hydration, evidently as a consequence of alteration of the corneal epithelium. Although a brief contact with the precorneal tissues 'in vivo' may not prove harmful, the use of these compounds as potential ocular permeation enhancers or otherwise as ingredients of topical ocular formulations for long-term use should be considered with caution.
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              Application of in vivo confocal microscopy to the objective evaluation of ocular irritation induced by surfactants.

              An ocular irritation test using confocal laser scanning ophthalmoscopy has been developed in which corneal lesions subsequent to instillation of surfactants are specifically marked by fluorescein and assessed by digital image processing. The sum of the observed fluorescent corneal areas is taken into account as an endpoint of ocular irritation. Eight currently used nonionic, cationic and anionic surfactants were applied onto the cornea of rabbits and mice, four times per day during 3 days at various concentrations. Benzalkonium chloride, a cationic surfactant, at a concentration range of 0.01-0.5%, was tested in the same manner. The cornea was evaluated in vivo for ocular tolerance by confocal microscopy. In both rabbits and mice, the test revealed following irritation rankings: cationic>anionic>nonionic surfactants. Furthermore, in both animal models, the ocular damage increased with the concentration of benzalkonium. The test was sensitive enough to detect ocular microlesions at concentrations of surfactants as low as 0.01% for benzalkonium. These findings demonstrate the usefulness of confocal microscopy for the non-invasive, in situ evaluation of ocular tolerance.
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                Author and article information

                Journal
                ORE
                Ophthalmic Res
                10.1159/issn.0030-3747
                Ophthalmic Research
                S. Karger AG
                0030-3747
                1423-0259
                2007
                November 2007
                22 October 2007
                : 39
                : 6
                : 308-314
                Affiliations
                aDepartment of Ophthalmology and Visual Sciences and bDivision of Neurobiology and Behavior, Department of Translational Medical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, and cDepartment of Hospital Pharmacy, Nagasaki University Hospital of Medicine and Dentistry, Nagasaki, Japan
                Article
                109986 Ophthalmic Res 2007;39:308–314
                10.1159/000109986
                17957130
                59d91dca-fb6a-44e6-90c2-0dd417a98d6e
                © 2007 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 29 January 2007
                Page count
                Figures: 9, References: 33, Pages: 7
                Categories
                Original Paper

                Vision sciences,Ophthalmology & Optometry,Pathology
                Eye drops,Ophthalmic solution,Corneal epithelium,Benzalkonium chloride,Tight junction

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