Abstract
Timolol maleate, ophthalmic solution, is frequently prescribed for glaucoma, although the use of this drop is likely to interfere with wound healing in the immediate corneal surgeries. The purpose of this study is to evaluate the toxicity of commercially prepared topical timolol maleate 0.005 and 0.05% and its preservative benzalkonium chloride (BAC) 0.0004 and 0.001%. And have also shown its preservative free effect on the corneal epithelia and changes in protein pattern. Rabbit (albino) corneal epithelial organ cultures were prepared as migrating (wounded) and non-migrating (unwounded) corneal epithelia. Corneas (n = 95) were removed and 7 mm epithelia were abraded mechanically. The abraded corneal epithelia (migrating) and non-abraded corneal epithelia (non-migrating) were incubated in modified supplemental hormonal epithelial media (SHEM) containing a) timolol maleate drop 0.005% concentration and 0.05% concentration supplied with BAC+ (0.001%) and b) BAC- (preservative free) timolol maleate (purified form) 0.005 and 0.05% and c) along with BAC+ 0.001 and 0.0004% concentration, d) only BAC with 0.001 and 0.0004% concentration. The media containing timolol maleate and BAC was replaced every 24 h. Phase contrast light microscopy of the ocular surface was carried out after haematoxilin-eosin staining and photographic documentation was performed at different time points 0, 24, 48, 72, and 96 h. 2-DE analysis demonstrated the changes in the proteins of migrating, non-migrating and treated corneal epithelia. Morphological studies confirmed the deleterious effect of timolol maleate 0.05% with BAC 0.001% and revealed enhanced corneal toxicity when compared to timolol 0.005% with the same concentration of BAC. Preservative BAC at 0.0004% showed no significant difference at protein level and morphological changes were also not observed on corneal epithelia. Both concentrations of timolol maleate with BAC 0.001% show down regulation of protein expressions. Corneal organ culture model has confirmed that topically applied timolol maleate 0.005 and 0.05% and its preservative BAC 0.001% showed deficiency in term of protein expressions, although the appropriate randomized clinical assessment are essential to certify these reports. Key words: Timolol maleate, BAC, toxicity.
Highlights
In ophthalmic solutions, preservative is used to prevent contamination during the treatment period
The corneas were demarcated with a 7 mm trephine, and burning and corneal anesthesia has been reported during the use of timolol maleate benzalkonium chloride (BAC)+ (Herreras, 1992; Costagliola, 2002; Ohtsuki, 2001, Thygesen, 2000)
Timolol maleate (D) (0.005%) treated corneal epithelium showed a significant thinning of the corneal epithelium (Figure 1g) where desquamations were seen in same concentration (P) with BAC 0.001% (Figure 1h)
Summary
Preservative is used to prevent contamination during the treatment period. Timolol maleate and its preservative BAC is used successfully worldwide as topical intraocular pressure lowering drug. Rabbits with intact corneas were decapitated and their eyes processed immediately on ice. For migrating corneal epithelia, the corneas were demarcated with a 7 mm trephine, and burning and corneal anesthesia has been reported during the use of timolol maleate BAC+ (Herreras, 1992; Costagliola, 2002; Ohtsuki, 2001, Thygesen, 2000). One of the most common preservative BAC for eye drops, has antibacterial effects (Friedlaender et al, 2006; Kowalski, 2006) and induces cytotoxic damage in conjunctival cells (de Saint Jean, 2000), with the thinning of cornea as well as stromal damage (Pisella, 2000). One clinical investigation has shown that the administration of timolol eye drops with its preservative BAC induces greater disruption of blood–aqueous barrier than the BAC alone (Miyake, 2001). It is suggested that the addition of BAC to the eye drops or in beta blockers contributes to these adverse affect
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