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Abstract #25324 Published in IGR 12-1
Corneal neovascularization and ocular irritancy responses in dogs following topical ocular administration of an EP4-prostaglandin E(2) agonist
Aguirre S A; Wenhu Huang Prasanna G; Jessen BToxicologic Pathology 2009; 37: 911-920
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 (greater-than or equal to)1.0 (mu)g/eye and was not reversed by the end of the recovery phase. Dogs dosed with (greater-than or equal to)0.25 (mu)g/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 (greater-than or equal to)1.0 (mu)g 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.
S. A. Aguirre. Drug Safety Research and Development, Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA 92121, United States. shirley.aguirre@pfizer.com
Classification:
11.4 Prostaglandins (Part of: 11 Medical treatment)
2.2 Cornea (Part of: 2 Anatomical structures in glaucoma)
