Effects of the new ethacrynic acid oxime derivative SA12590 on intraocular pressure in cats and monkeys.
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 microl 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 microl 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 microl 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 microl 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.
Shimazaki
Atsushi
A
Research and Development Center, Santen Pharmaceutical Co. Ltd., 8916-16 Takayama, Ikoma 630-0101, Japan. atsushi.shimazaki@santen.co.jp
Kirihara
Tomoko
T
Rao
Ponugoti Vasantha
PV
Tajima
Hisashi
H
Matsugi
Takeshi
T
Epstein
David Lee
DL
D000287:Administration, Topical; D000818:Animals; D002415:Cats; D002934:Cinnamates / Q000008:administration & dosage / Q000494:pharmacology; D003316:Corneal Diseases / Q000139:chemically induced / Q000473:pathology; D004232:Diuretics / Q000494:pharmacology*; D019573:Epithelium, Corneal / Q000187:drug effects / Q000473:pathology; D004976:Ethacrynic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007429:Intraocular Pressure / Q000187:drug effects*; D008252:Macaca fascicularis; D010091:Oximes / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D002934:Cinnamates; D004232:Diuretics; D010091:Oximes; C522782:SA12590; C496163:SA9000; D004976:Ethacrynic Acid