title: The experimental antipsychotic agent 1192U90 targets tapetum lucidum in canine eyes.
abstract: To assess the potential adverse effects in people of the antipsychotic agent 1192U90, we dosed mice, rats, beagles, and cynomolgus monkeys for up to 3 mo. In dogs, but not the other species, 1192U90 caused ocular changes detectable ophthalmoscopically as loss of tapetal reflectivity, altered tapetal color, and the appearance of black pigmentation on the tapetal fundus. Eyes from affected dogs had atrophic tapeta lucidum due to cell loss. Rodlets in remaining tapetal cells were separated by electron-lucent spaces or finely granular material, varied in size and shape, and often contained irregularly shaped electron-dense inclusions. Nontapetal ocular structures were unaffected. Because 1192U90 caused no ocular changes in nontapetal species, we hypothesized that it targeted only tapetum lucidum and spared other ocular structures. We tried to test this hypothesis by dosing congenitally atapetal dogs; however, although these dogs were ophthalmoscopically "atapetal," they had scattered tapetal cells visible by electron microscopy, and these tapetal cells had ultrastructural changes indistinguishable from those that occurred in treated normal-eyed dogs. Tapetal degeneration caused by 1192U90 resembled that described in hereditary tapetal degeneration in beagles. That 1192U90 caused no ocular changes in nontapetal species suggests that the ocular changes in dogs do not imply a risk for humans, whose eyes also lack a tapetum lucidum.
authors.affiliation: Medicines Safety Evaluation Division, Glaxo Wellcome Inc., Research Triangle Park, North Carolina 27709-2700, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Dillberger
authors.forename: R L
authors.initials: RL
authors.lastname: Peiffer
authors.forename: M J
authors.initials: MJ
authors.lastname: Dykstra
authors.forename: M
authors.initials: M
authors.lastname: O'Mara
authors.forename: D K
authors.initials: DK
authors.lastname: Patel
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000633:toxicity; D002829:Choroid / Q000187:drug effects* / Q000473:pathology; D004285:Dogs; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D009928:Organ Specificity; D010857:Pigment Epithelium of Eye / Q000187:drug effects* / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D013844:Thiazoles / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; D013844:Thiazoles; C098658:1192U90