Abstract
Purpose: :
Poor compliance to topical therapy is a leading cause of glaucoma progression and visual loss. Dorzolamide, timolol, diltiazem, captopril and brimonidine were formulated in episcleral drug delivery devices (ESDDD) and tested in normotensive rabbits to examine the effect of these drugs in the intraocular pressure (IOP).
Methods: :
Animals (White New Zealand rabbits, n=4 per group) were implanted in the right eye at day 1. Left eyes were used as control. The IOP was assessed using a pneumatonometer in the first hours following implantation and twice a day at specific time points thereafter: days 2, 3, 5, 8, 15 and 22. In vitro elution studies were carried out to characterize the drug elution from the formulations. Pharmacokinetics studies were conducted in additional animals (n=3 per group), on which animals had repeated aqueous humor sampling for LC-MS quantification of the drug. The main outcome was the area under the IOP-time curve (AUC) for each animal from day 2 up to day 22. Mean AUC was compared statistically between tested and control eyes (p < 0.05).
Results: :
The IOP transiently increased in the implanted eyes immediately after surgery for the first 4 to 6 hours and decreased thereafter. In comparing the IOP-lowering effect over time (Days 2 to 22) as represented by the AUC, implanted vs. fellow eyes, eyes exposed to dorzolamide (p=0.03) and diltiazem (p=0.0073) demonstrated significantly lower IOP than control eyes. Though not statiscally significant, the IOP of eyes exposed to captopril (p=0.07) and timolol (p=0.08) were substantially below controls. Brimonidine showed the mildest effect after transscleral delivery. The maximum IOP lowering effects for the studied drugs were: 4.8 mmHg (dorzolamide, day 22); 4.5 (timolol, day 22); 6.9 (diltiazem, day 8); 7.0 (captopril, day 3); and 4.5 (brimonidine, day 15). The drug concentrations of these agents in the aqueous humor were below therapeutic concentrations demonstrated for the corresponding topical route and did not correlate with the in vitro release kinetics.
Conclusions: :
Transscleral drug delivery is a suitable route to provide direct drug delivery to the ciliary body and ocular tissues involved in glaucoma and aqueous humor dynamics. The effect of these drugs in lowering the IOP is independent from drug availability in the aqueous humor and likely due to direct and localized drug delivery to the uveal tissue.
Keywords: drug toxicity/drug effects • ciliary processes • intraocular pressure