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H. Liang, F. Brignole-Baudouin, L. Rabinovich-Guilatt, Z. Mao, L. Riancho, M.-O. Faure, J.-M. Warnet, G. Lambert, C. Baudouin; Reduction of Quaternary Ammonium-Induced Ocular Surface Toxicity by Emulsions: An in vivo Study in Rabbits. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2357. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate and compare the toxicological profiles of two quaternary ammonium compounds (QAC), benzalkonium chloride (BAK) and cetalkonium chloride (CKC) in standard solutions or in cationic emulsion formulations in rabbit eyes using newly developed in vivo and ex vivo experimental approaches.
Seventy (70) eyes of 35 adult male New Zealand albino rabbits were used. They were randomly divided into five groups receiving 15 times at 5-min intervals 50 µL of 1/ phosphate-buffered saline (PBS), 2/ PBS containing 0.02% BAK (BAK Sol) or 3/ 0.002% CKC (CKC Sol), 4/ emulsion containing 0.02% BAK (BAK Em) or 5/ 0.002% CKC (CKC Em). The ocular surface changes were investigated using slit-lamp examination, conjunctival impression cytology (IC), flow cytometry (FCM) and corneal in vivo confocal microscopy (IVCM). Standard immunohistology in cryosections was also processed for detecting CD45+ infiltrating and TUNEL+ apoptotic cells.
Clinical observations and IVCM showed the highest toxicity was induced by BAK Sol, characterized by damaged corneal epithelium and a high level of inflammatory infiltration. BAK Em and CKC Sol presented moderate effects, and CKC Em showed the lowest toxicity, with results similar to those of PBS. Conjunctival imprints analyzed by FCM showed higher expression of RLA-DR and TNFR1 markers in BAK Sol-instilled eyes than in all other groups, especially at 4h. Immunohistology was correlated with in vivo and ex vivo findings and confirmed this toxicity profile. A high level of infiltration of CD45+ inflammatory cells and TUNEL+ apoptotic cells was observed in limbus and conjunctiva, especially in QAC solution-receiving eyes compared to QAC emulsion-instilled eyes.
The acute administration of 15 instillations at 5-min intervals constitutes a rapid and efficient model to assess quaternary ammonium toxicity profiles. This model confirmed the highest toxicity for the BAK solution, and the lowest level of toxicity for the CKC emulsion. These in vivo and ex vivo experimental approaches demonstrated that ocular surface toxicity was reduced by using an emulsion compared to a traditional solution and that a CKC emulsion was safe for future ocular administration.
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