Intraocular properties of a repository urokinase receptor antagonist a36 Peptide in rabbits.
OBJECTIVE
To evaluate the intraocular properties of A36, a peptide that directly antagonizes the cell surface urokinase receptor and so prevents pericellular urokinase plasminogen activator activity.


METHODS
A total of 41 rabbits were used. The toxicity study tested three doses of A36: 1 mg/ eye, 0.3 mg/eye, and 0.1 mg/eye. At 2 and 12 weeks, eyes were evaluated by ERG and histology. Pharmacokinetics were studied in rabbit eyes with the dose of 1 mg/eye in two different formulations: a micronized preparation and a non-micronized formulation. Eyes were enucleated at months 1, 2, 3, 4, and 5. Vitreous, retina, and choroid were collected separately for active A36 analysis.


RESULTS
We did not find ocular toxicity with low and medium doses. At the highest dose, there was a transient toxicity at 2 weeks but was not notable at 3 months. The target choroid concentration of A36 was chosen as > or =100 nM. The micronized formulation at months 1, 2, and 3 combined, showed variable levels in the choroid giving 5/10 (50%) of the therapeutic level; the non-micronized formulation at months 4 and 5 combined, gave 6/7 (86%) of the therapeutic level, although this difference was not statistically significant.


CONCLUSIONS
A36 appears to be long lasting; the non-micronized formulation of A36 gave concentrations above therapeutic level in the choroid at months 4 and 5. Optimization of the formulation of A36, particularly the particle size, may result in a promising new compound for exudative age-related macular degeneration treatment.
Falkenstein
Iryna A
IA
Joan and Irwin Jacobs Retina Center, Department of Ophthalmology, Shiley Eye Center, University of California, La Jolla, California, USA.
Cheng
Lingyun
L
Jones
Terence R
TR
Freeman
William R
WR
Babson
Bruce
B
Kozak
Igor
I
Tammewar
Ajay M
AM
Barron
Erin C
EC
D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D002829:Choroid / Q000187:drug effects* / Q000378:metabolism; D020256:Choroidal Neovascularization / Q000517:prevention & control*; D016503:Drug Delivery Systems; D004596:Electroretinography / Q000187:drug effects; D007267:Injections; D007429:Intraocular Pressure / Q000187:drug effects; D010456:Peptides, Cyclic / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D055293:Receptors, Urokinase Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012160:Retina / Q000187:drug effects* / Q000378:metabolism; D014822:Vitreous Body
D020533:Angiogenesis Inhibitors; D010456:Peptides, Cyclic; D055293:Receptors, Urokinase Plasminogen Activator