Latrunculins' effects on intraocular pressure, aqueous humor flow, and corneal endothelium.
OBJECTIVE
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 (ka) 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 ka by 94% over 6 hours; LAT-B increased ka 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 microm 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.
Peterson
J A
JA
Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, USA.
Tian
B
B
McLaren
J W
JW
Hubbard
W C
WC
Geiger
B
B
Kaufman
P L
PL
D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism*; D018916:Blood-Aqueous Barrier / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology*; D002452:Cell Count; D003315:Cornea / Q000000981:diagnostic imaging; D004728:Endothelium, Corneal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005136:Eye Proteins / Q000378:metabolism; D005260:Female; D019793:Fluorescein / Q000378:metabolism; D015590:Fluorophotometry; D007429:Intraocular Pressure / Q000187:drug effects*; D008252:Macaca fascicularis; D008297:Male; D008387:Marine Toxins / Q000008:administration & dosage / Q000494:pharmacology*; D009883:Ophthalmic Solutions / Q000008:administration & dosage / Q000494:pharmacology; D010539:Permeability; D011161:Porifera; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D053778:Thiazolidines; D014463:Ultrasonography
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005136:Eye Proteins; D008387:Marine Toxins; D009883:Ophthalmic Solutions; D013844:Thiazoles; D053778:Thiazolidines; C037068:latrunculin B; C037067:latrunculin A; D019793:Fluorescein