title: Topical pazopanib blocks VEGF-induced vascular leakage and neovascularization in the mouse retina but is ineffective in the rabbit.
abstract: OBJECTIVE
  To test the effect of pazopanib, a tyrosine kinase inhibitor that blocks VEGF and platelet-derived growth factor (PDGF) receptors and c-Kit, on vascular leakage and neovascularization (NV) in the retina.
  
  
  METHODS
  Pazopanib was tested to determine its effect on VEGF-induced vascular permeability via measurement of [(3)H]mannitol retina to lung (RLLR) and retina to renal leakage ratios (RRLR) and in rho/VEGF mice with subretinal NV. In rabbits, the effect of intravitreal, topical, and systemic pazopanib on VEGF-induced leakage was tested by vitreous fluorophotometry.
  
  
  RESULTS
  In mice, oral pazopanib (40 mg/kg twice a day [bid]) reduced RLLR (0.84 to 0.58, P = 0.0014) and RRLR (0.55 to 0.30, P = 0.0018) in VEGF-injected eyes. After intraocular injection of VEGF into both eyes, topical pazopanib (10 mg/mL three times a day [tid] for 14 days) reduced RLLR (0.85 vs. 0.56, P = 0.001), RRLR (0.44 vs. 0.28, P = 0.0075), and immunoreactive albumin in the retina compared to values in fellow eye controls. Treatment of one eye of rho/VEGF mice with 10 mg/mL, but not 5 mg/mL, pazopanib tid reduced the mean area of subretinal NV compared to that in fellow eyes (0.0055 vs. 0.0025 mm(2), P = 0.020). In rabbits, intravitreal pazopanib suppressed VEGF-induced fluorescein leakage, but topical (10 mg/mL four times a day [qid] or 12 mg/mL bid) had no significant effect. Systemic administration of pazopanib by osmotic pump with or without 10 mg/mL drops tid also failed to suppress VEGF-induced leakage.
  
  
  CONCLUSIONS
  Administration of pazopanib topically or systemically suppressed retinal vascular leakage in mice, but not rabbits. These data suggest differences in the blood-retinal barrier (BRB) of mice and rabbits and indicate that penetration through the outer BRB may be needed for topically administered drugs to exert effects in the retina.
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwase
authors.forename: Brian C
authors.initials: BC
authors.lastname: Oveson
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Hashida
authors.forename: Raquel
authors.initials: R
authors.lastname: Lima e Silva
authors.forename: Jikui
authors.initials: J
authors.lastname: Shen
authors.forename: Achim H
authors.initials: AH
authors.lastname: Krauss
authors.forename: David C
authors.initials: DC
authors.lastname: Gale
authors.forename: Peter
authors.initials: P
authors.lastname: Adamson
authors.forename: Peter A
authors.initials: PA
authors.lastname: Campochiaro
mesh_terms: D000284:Administration, Oral; D000287:Administration, Topical; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001813:Blood-Retinal Barrier / Q000187:drug effects*; D002199:Capillary Permeability / Q000187:drug effects*; D005260:Female; D015590:Fluorophotometry; D007191:Indazoles; D058449:Intravitreal Injections; D007668:Kidney / Q000378:metabolism; D008168:Lung; D008353:Mannitol / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D011817:Rabbits; D015861:Retinal Neovascularization / Q000517:prevention & control*; D013045:Species Specificity; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000633:toxicity
chemical_list: D020533:Angiogenesis Inhibitors; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D008353:Mannitol; C516667:pazopanib