摘要：To evaluate the pharmacological characteristics of SA12590, a new oxime-derivative of the ethacrynic acid (ECA) derivative SA9000, we examined both its ocular hypotensive effects (in ocular normotensive cats and cynomolgus monkeys) and its potential corneal toxicity (in rats). A 50 μl topical administration of 3% SA12590 significantly reduced intraocular pressure (IOP) (by 3.5 mmHg) in anesthetized cats ( p <0.05). Twenty-four hours after 3 drops (5-min intervals) of 20 μl 3% SA12590, IOP was reduced by 8 mmHg ( p <0.05, n =4) in conscious monkeys without evidence of corneal toxicity. Three days' daily single 20 μl dosing with 3% SA12590 reduced IOP by 4 mmHg ( p <0.01, n =3) at 72 h after the first administration in conscious monkeys. The toxicity of topically administered 20 μl 3% SA9000 or SA12590 (3 drops with 5-min intervals) on rat corneal epithelium was assessed using a photo-slit lamp. In this study, 3% SA12590, unlike 3% SA9000, exhibited no corneal toxicity. In a glutathione assay for sulfhydryl (SH) reactivity, SA12590, unlike SA9000, displayed no in vitro SH reactivity. Thus, oxime-modification may both improve efficacy towards IOP upon topical administration and improve the safety profile, probably by enhancing corneal penetration and minimizing SH reactivity-related toxicity. These findings indicate that SA12590 has potential as a new ocular hypotensive drug.
