Latrunculins’ effects on intraocular pressure, aqueous humor flow

PURPOSE. To determine the effects of latrunculin (LAT)-A or -B on intraocular pressure (IOP), aqueous humor flow (AHF), anterior chamber (AC) protein concentration ([protein] AC ), corneal endothelial permeability and morphology, and corneal thickness in living cynomolgus monkeys. METHODS. Topical LAT-A or LAT-B was administered to one eye, and vehicle to the other. IOP was measured by Goldmann tonometry, AHF and corneal endothelium transfer coefficient (k a ) by fluorophotometry, [protein] AC by Lowry assay, corneal endothelial cell morphology by specular microphotography, and corneal thickness by ultrasound pachymetry. RESULTS. LAT-A began to lower IOP at 6 hours and maximally reduced IOP by 4.6 mm Hg at 9 hours. LAT-B lowered IOP within 1 hour and maximally reduced IOP by 3.1 mm Hg at 6 hours. LAT-A increased AHF by 87% for 3 hours and increased k a by 94% over 6 hours; LAT-B increased k a by 39% over 6 hours without affecting AHF. LAT-A increased IV fluorescein entry into the cornea approximately 10 fold, but did not affect IV fluorescein entry into the AC. LAT-A increased [protein] AC by 25% at 2 hours but not 5.5 hours. LAT-B variably and insignificantly increased [protein] AC at 1 hour but not at 6.5 hours. LAT-A induced extensive corneal endothelial pseudoguttata within 1 hour, with normal cell counts by 7 days. LAT-B increased central corneal thickness maximally by 47 m at 3.5 hours. CONCLUSIONS. LAT-A and -B significantly reduced IOP and were consistent in their facility-increasing effect, indicating that pharmacologic disorganization of the actin cytoskeleton in the trabecular meshwork by latrunculins may be a useful antiglaucoma strategy. However, effects on corneal endothelium or ciliary epithelium are a potential safety issue. (Invest Ophthalmol Vis Sci. 2000;41: 1749 -1758 L atrunculins, macrolides isolated from the marine sponge Latrunculia magnifica, are specific, and potent actindisrupting agents that sequester monomeric G-actin, leading to the disassembly of actin filaments