Effects of topical ethacrynic acid adducts on intraocular pressure in rabbits and monkeys
D. P. Tingey, A. Schroeder, M. P. Epstein and D. L. Epstein
Howe Laboratory of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston.
We evaluated the effect of topical ethacrynic acid on rabbit and monkey
intraocular pressure. In a preliminary experiment, 100-mmol/L ethacrynic
acid applied topically to Dutch-Belted rabbit eyes was associated with an
8-mm Hg lowering of intraocular pressure. However, corneal edema was
severe, and the corneal epithelium sloughed off. To try to maintain the
pressure-lowering effect but reduce the corneal side effects, we attempted
to create an adduct of ethacrynic acid by utilizing ethacrynic acid's
sulfhydryl reactivity. Ethacrynic acid was mixed with equimolar cysteine to
bind the sulfhydryl-reactive sites on ethacrynic acid. The goal was to
expose the cornea to adducted ethacrynic acid, which might then dissociate
in the anterior chamber via a retro-Michael reaction. Intraocular pressure
decreased 8.9 mm Hg (n = 40) with this treatment, and corneal edema was
lessened (32 of 40 eyes had mild to no edema). However, we observed that
when the eye was treated before ethacrynic acid-cysteine administration
with topical acetylcysteine, the corneal side effects were reduced further
and the intraocular pressure effect remained. In living cynomolgus monkeys
receiving a single pretreatment drop of 75-mmol/L acetylcysteine followed
by two drops of 130-mmol/L ethacrynic acid and 130-mmol/L cysteine, an
intraocular pressure lowering of 9.9 mm Hg was observed (n = 7). However,
in three of seven eyes corneal edema developed. Pretreatment with two drops
of acetylcysteine eliminated the pressure-lowering effect but did not
confer any added corneal protection. Our results indicate that topical
ethacrynic acid-cysteine is effective in lowering the intraocular pressure
of rabbits and cynomolgus monkeys and, when combined with acetylcysteine
pretreatment, may offer the potential for a new topical therapeutic regimen
for use in glaucoma.
