Intraocular properties of urokinase-derived antiangiogenic A6 peptide in rabbits.
To investigate the intraocular properties of an antiangiogenic peptide, A6, a total of 70 New Zealand rabbit eyes were used. For the toxicity study, 0.05 mL of 0.459 M or 0.148 M A6 was injected intravitreally; right eyes received A6, and left eyes received a vehicle. Serial intraocular pressure measurement, slit lamp, and indirect ophthalmoscopy were performed. The rabbit eyes were evaluated by fluorescein angiography, electroretinography, and histology after the scheduled sacrifice. The pharmacokinetics of an intravitreal A6 (0.05 mL of 0.488 M) and a subtenon A6 (0.5 mL of 0.305 M) injection was studied. There was no toxicity observed following the 0.148 M A6 intravitreal injections. In 2 eyes with a 0.459 M A6 intravitreal injection, focal retinal pigmentary change was observed at the injection site, which was contacted by the hyperosmolar drug bolus. Choroidal A6, following the intravitreal injection, remained therapeutic (>or=10 microM) for 72 hours. The vitreous half-life was 19.4 hours. Choroidal concentrations following the subtenon injection were minimal. The low choroidal concentrations observed may relate to the polar nature of A6. More hydrophobic analogs of A6 are likely to cross the retina more efficiently. However, in diseased eyes, in the area of choroidal neovascularization (CNV), the fluid-filled, damaged, edematous retina may permit the drug to enter the choroid in higher concentrations.
Koh
Hyoung J
HJ
Joan and Irwin Jacobs Retina Center, Department of Ophthalmology, Shiley Eye Center, University of California-San Diego, La Jolla, CA 92093-0941, USA.
Cheng
Lingyun
L
Bessho
Kenichiro
K
Jones
Terence R
TR
Davidson
Marie C
MC
Freeman
William R
WR
D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics* / Q000633:toxicity*; D000818:Animals; D002829:Choroid / Q000187:drug effects / Q000378:metabolism; D004596:Electroretinography; D005123:Eye / Q000187:drug effects* / Q000378:metabolism; D005451:Fluorescein Angiography; D006207:Half-Life; D007267:Injections; D007429:Intraocular Pressure / Q000187:drug effects; D010446:Peptide Fragments / Q000493:pharmacokinetics* / Q000633:toxicity*; D011817:Rabbits; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000493:pharmacokinetics* / Q000633:toxicity*; D014822:Vitreous Body / Q000187:drug effects / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D010446:Peptide Fragments; D014568:Urokinase-Type Plasminogen Activator; C489333:acetyl-lysyl-prolyl-seryl-seryl-prolyl-prolyl-glutamyl-glutamic acid amide