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W. Collette, S. Khoh–Reiter, K. Rittenhouse, M. Shawer, H. Younis; Concordance of in vitro and in vivo Models to Screen Novel Compounds for Ocular Irritation . Invest. Ophthalmol. Vis. Sci. 2005;46(13):2651.
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Purpose: Ocular irritation testing is crucial in the early stages of drug discovery for compounds intended for ocular administration. These studies were conducted to determine if an in vitro cell model might be predictive of traditional topical ocular irritation screening in rabbits. Methods: Selected compounds (designated compound A–E) were screened in the SkinEthic human corneal cell system for up to 1 hour and cell cytotoxicity was determined using a MTT assay. For the in vivo screen, female Dutch–Belted rabbits were topically administered 50µL of compound in one eye twice daily for three days. Ocular irritation is scored through Day 5 according to an eye irritation scale (Organization for Economic Cooperation and Development, 1987). Results: In vivo Compounds A and B, that are in the same chemical class, produced a transient mild conjunctival redness. In vitro, these compounds had 93–96% cell viability. Compounds in another chemical class (C, D, and E) produced eye closure immediately after dosing (< 1 minute in duration) that resulted in grooming of the dosed eye immediately after dosing and subsequent mild conjunctival redness. These observations continued with dosing but resolved during the wash–out period. The effects of eye closure are dependent on the dose and type of formulation (solution, oil, emulsion) administered. In the in vitro assay, compounds C, D, and E were found to have a cell viability ranging from 88–100%. Conclusions: Results from this work demonstrate that effects related to pain response or those independent of cell damage will likely not be identified in an in vitro cell system. Also, the mild irritation and redness observed in vivo with some compounds was likely not sufficient to produce overt cytoxicity in the in vitro cell system. Additional work is ongoing to assess if an in vitro screening system can be used to identify the ocular irritation safety potential of small molecules prior to in vivo testing.
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