Abstract
BackgroundBenzalkonium chloride (BAC) is a common preservative used in ophthalmic solutions. The aim of this study was to compare the cytotoxic effects of BAC-containing ophthalmic solutions with a BAC-free ophthalmic solution using an organotypic 3-dimensional (3-D) corneal epithelial model and to determine the effects of latanoprost ophthalmic solution and its BAC-containing vehicle on corneal thickness in a monkey model.MethodsThe cytotoxicity of commercially available BAC-containing ophthalmic formulations of latanoprost (0.02% BAC) and olopatadine (0.01% BAC) was compared to that of BAC-free travoprost and saline in a corneal organotypic 3-D model using incubation times of 10 and 25 minutes. To compare the extent of differentiation of 3-D corneal cultures to monolayer transformed human corneal epithelial (HCE-T) cell cultures, expression levels (mRNA and protein) of the corneal markers epidermal growth factor receptor, transglutaminase 1 and involucrin were quantified. Finally, latanoprost ophthalmic solution or its vehicle was administered at suprapharmacologic doses (two 30 μL drops twice daily in 1 eye for 1 year) in monkey eyes, and corneal pachymetry was performed at baseline and at weeks 4, 13, 26 and 52.ResultsIn the 3-D corneal epithelial culture assays, there were no significant differences in cytotoxicity between the BAC-containing latanoprost and olopatadine ophthalmic solutions and BAC-free travoprost ophthalmic solution at either the 10- or 25-minute time points. The 3-D cultures expressed higher levels of corneal epithelial markers than the HCE-T monolayers, indicating a greater degree of differentiation. There were no significant differences between the corneal thickness of monkey eyes treated with latanoprost ophthalmic solution or its vehicle (both containing 0.02% BAC) and untreated eyes.ConclusionThe lack of cytotoxicity demonstrated in 3-D corneal cultures and in monkey studies suggests that the levels of BAC contained in ophthalmic solutions are not likely to cause significant direct toxicity to epithelium of otherwise normal corneas.
Highlights
Benzalkonium chloride (BAC) is a common preservative used in ophthalmic solutions
Because of its established efficacy compared to other agents, the most common preservative used in topical ocular solutions is benzalkonium chloride (BAC) [3]
Ocular hypotensive agents containing BAC have been reported to have greater toxicity than BAC-free solutions when evaluated in a transformed human corneal epithelial (HCE-T) monolayer cell culture model [6]
Summary
Benzalkonium chloride (BAC) is a common preservative used in ophthalmic solutions. Because of its established efficacy compared to other agents, the most common preservative used in topical ocular solutions is benzalkonium chloride (BAC) [3]. Ocular hypotensive agents containing BAC have been reported to have greater toxicity than BAC-free solutions when evaluated in a transformed human corneal epithelial (HCE-T) monolayer cell culture model [6]. This system does not adequately duplicate the stratified nature of corneal epithelium, which is better reflected in organotypic 3-dimensional (3-D) culturing conditions. The increased sensitivity may be due in part to rabbits having an extremely low blink rate [12] and thinner corneas [10] compared to humans
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