title: Corneal neovascularization and ocular irritancy responses in dogs following topical ocular administration of an EP4-prostaglandin E2 agonist.
abstract: Prostaglandin receptor agonists have intraocular pressure-lowering effects in humans and are of interest in the treatment of glaucoma. The prostanoid receptor agonist PF-04475270 is a potent and selective agonist of the prostaglandin E(2) receptor EP4. This paper characterizes the toxicity associated with topical ocular administration of PF-04475270 in beagles. Dogs were given PF-04475270 topically to the eye on a consecutive daily dosing schedule for one or four weeks followed by a one-or four-week reversal period, respectively. Clinical observations, ophthalmic, and laboratory parameters were recorded. Necropsies were conducted at the end of the dosing and recovery phases, and histologic examinations performed. Corneal neovascularization that was considered adverse was observed at doses of >or=1.0 microg/eye and was not reversed by the end of the recovery phase. Dogs dosed with >or=0.25 microg/eye developed a dose-related conjunctival hyperemia that persisted throughout the reversal period. Corneal neovascular cells stained positive with EP4 and the endothelial biomarker Factor VIII-vWF. Other histopathology findings observed at doses of >or=1.0 microg included single-cell necrosis and neutrophils in the cornea, inflammatory cell infiltrates in the iris/ciliary body, and iridal endothelial cell hypertrophy. A resolving acute to subacute inflammation in the iris/ciliary body was observed after the four-week recovery period.
authors.affiliation: Drug Safety Research and Development, Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA. shirley.aguirre@pfizer.com
authors.forename: Shirley A
authors.initials: SA
authors.lastname: Aguirre
authors.forename: Wenhu
authors.initials: W
authors.lastname: Huang
authors.forename: Ganesh
authors.initials: G
authors.lastname: Prasanna
authors.forename: Bart
authors.initials: B
authors.lastname: Jessen
mesh_terms: D000287:Administration, Topical; D000818:Animals; D003315:Cornea / Q000187:drug effects / Q000473:pathology; D016510:Corneal Neovascularization / Q000139:chemically induced*; D004285:Dogs; D004338:Drug Combinations; D005123:Eye / Q000187:drug effects* / Q000473:pathology; D005169:Factor VIII / Q000032:analysis; D007429:Intraocular Pressure / Q000187:drug effects; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000633:toxicity*; D018078:Receptors, Prostaglandin E / Q000819:agonists*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013876:Thiophenes / Q000008:administration & dosage / Q000633:toxicity*; D018675:Toxicity Tests; D014841:von Willebrand Factor / Q000032:analysis
chemical_list: C545122:5-(3-(2-(3-hydroxy-4-(3-(trifluoromethyl)phenyl)butyl)-5-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate; D004338:Drug Combinations; C545650:PTGER4 protein, human; D011760:Pyrrolidinones; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013876:Thiophenes; C509423:factor VIII, von Willebrand factor drug combination; D014841:von Willebrand Factor; D005169:Factor VIII