Our long-term objectives are to prevent visual loss and blindness in glaucoma parents by: 1) identifying biochemical mediators of the reduction of intraocular pressure (IOP) produced by various modalities of glaucoma therapy; 2) developing new medications which optimize delivery of these biochemical mediators.
The specific aims are to evaluate the efficacy and safety of exogenous topical administration of various prostaglandin (PG) derivatives for glaucoma therapy, and to determine the role of endogenously-produced PGs in mediating the ocular hypotensive effect of various medications and laser procedures. Based on results from single dose-response curves of IOP using new, potent, lipophilic derivatives of PGs, multiple dose studies will be performed by applying the agents twice daily in glaucomatous monkey eyes. Based on the safety and efficacy in the glaucomatous monkey eyes, the most appropriate PG derivative will be tested in a multiple-dose fashion by applying it twice a day for one week in glaucoma patients with careful monitoring of: local and systemic symptoms; visual acuity; conjunctival hyperemia; accommodative amplitude; pupillary diameter; aqueous flare; anterior chamber cellular response; IOP; pulse; blood pressure; Shirmer testing; and tonography. The effects of cyclo- oxygenase inhibitors (COIs) on the IOP response after epinephrine, timolol, pilocarpine phospholine iodide, arachidonic acid, PGF2 alpha, forskolin, vanadate, corynanthine, pergolide, salbutamol, and 6-fluoro-norepinephrine will be studied in rabbit, normal monkey, and/or glaucomatous monkey eyes. PG levels in the aqueous humor will be measured to determine whether these agents stimulate PG production, and whether the synthesis could be blocked by COIs. Based on the results from the animal studies, the effect of COIs on the IOP response of the clinically-used ocular hypotensive agents expected to act through PGs will be evaluated in glaucoma patients in a prospective, randomized, double-masked, placebo-controlled study. The effect of COIs on the IOP response after argon laser trabeculoplasty (LTP) will be evaluated in cats. PG levels after LTP will be measured. Argon laser treatment to the peripheral iris and Nd:YAG laser treatment to the trabecular mesh-work will be performed in cats to determine whether they also result in reduction of IOP mediated by PGs.
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