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M. Cormier, H. I. Cheong, J. Johnson, K. Hosseini; Cytotoxicity of β-Blockers in Human Corneal Epithelial and Pigment Retinal Epithelial Cell Lines: Comparison With Keratinocytes and Fibroblasts. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3613.
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β-blockers have been used extensively in topical preparations for the treatment of glaucoma and they are being considered for the treatment of a number of other ocular diseases. Local tolerability is essential for the successful topical treatment of ocular-related diseases. Cytotoxic action in cell culture models was used in this study as an indicator of irritation potential. The purpose of this work was to investigate differences in cytotoxicity between different cell types and to rank the cytotoxicity of the β-blocking agents in order to help identify the least irritating and most potent drug.
The MTT assay was used to compare the in vitro cytotoxicity of eight clinically available β-blockers (propranolol, alprenolol, atenolol, labetalol, metoprolol, pindolol, timolol, and bisoprolol) on primary and immortalized human corneal epithelial and retinal pigment epithelial cell lines, and primary human skin keratinocytes and fibroblasts. Different drug concentrations (covering two to three orders of magnitude) and different incubation times (from 30 min to 16 h) were studied. Results are expressed as percent of viability and as the drug concentration that decreases cell viability to 50% of control values (IC50). β-blocking constants were obtained from the literature (BJP 135 451 2002).
Large differences in cytotoxicity (about 60-fold) were observed between the different β-blockers on the same cell line. Conversely, for the same β-blocker, only relatively small differences in cytotoxicity were observed between the different cell lines. After 16 h incubation, the most cytotoxic β-blocker was propranolol, with an average IC50 of approximately 0.4 mM; the least cytotoxic was atenolol, with an average IC50 of about 23 mM. Timolol, a compound widely used for glaucoma, had an average IC50 of about 7 mM.Timolol and pindolol presented the highest ratio between their cytotoxicity and their β-blocking constant.
The large difference in cytotoxicity between the different β-blockers is surprising, considering that these drugs are structurally closely related, and was not anticipated from the literature.The similar cytotoxicity for any particular β-blocker in all cell types indicates that the origin of the tissue does not play a major role in susceptibility to the cytotoxic action of these drugs.Cytotoxicity results combined with potency data indicate that timolol and pindolol are the most biocompatible compounds and the most likely product candidates for the topical treatment of ocular-related diseases.
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