May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Reduction of Quaternary Ammonium-Induced Ocular Surface Toxicity by Emulsions: An in vivo Study in Rabbits
Author Affiliations & Notes
  • H. Liang
    Ophthalmology-Hosp Paris, CHNO des Quinze-Vights, Paris, France
    Department of Toxicology, Faculty of Biological and Pharmacological Sciences and INSERM UMR S872, Les Cordeliers, University Paris Descartes, Paris, France
  • F. Brignole-Baudouin
    Department of Toxicology, Faculty of Biological and Pharmacological Sciences and INSERM UMR S872, Les Cordeliers, University Paris Descartes, Paris, France
  • L. Rabinovich-Guilatt
    Novagali Pharma SA, Evry, France
  • Z. Mao
    Department of Toxicology, Faculty of Biological and Pharmacological Sciences and INSERM UMR S872, Les Cordeliers, University Paris Descartes, Paris, France
  • L. Riancho
    Department of Toxicology, Faculty of Biological and Pharmacological Sciences and INSERM UMR S872, Les Cordeliers, University Paris Descartes, Paris, France
  • M.-O. Faure
    Novagali Pharma SA, Evry, France
  • J.-M. Warnet
    Department of Toxicology, Faculty of Biological and Pharmacological Sciences and INSERM UMR S872, Les Cordeliers, University Paris Descartes, Paris, France
  • G. Lambert
    Novagali Pharma SA, Evry, France
  • C. Baudouin
    Ophthalmology-Hosp Paris, CHNO des Quinze-Vights, Paris, France
    Department of Toxicology, Faculty of Biological and Pharmacological Sciences and INSERM UMR S872, Les Cordeliers, University Paris Descartes, Paris, France
  • Footnotes
    Commercial Relationships  H. Liang, Grant CIFRE by Novagali, F; F. Brignole-Baudouin, None; L. Rabinovich-Guilatt, Novagali, E, F; Z. Mao, None; L. Riancho, None; M. Faure, Novagali, E, F; J. Warnet, None; G. Lambert, Novagali, E, F; C. Baudouin, Consultant, C.
  • Footnotes
    Support  Unrestricted grants from Quinze-Vingts National Ophthalmology Hospital, INSERM UMR S 872, and Novagali Pharma SA
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 2357. doi:
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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.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : 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.

Methods: : 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.

Results: : 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.

Conclusions: : 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.

Keywords: ocular irritancy/toxicity testing • inflammation • microscopy: confocal/tunneling 
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