Dillberger J E, Peiffer R L, Dykstra M J, O'Mara M, Patel D K
Medicines Safety Evaluation Division, Glaxo Wellcome Inc., Research Triangle Park, North Carolina 27709-2700, USA.
Toxicol Pathol. 1996 Sep-Oct;24(5):595-601. doi: 10.1177/019262339602400509.
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.
为评估抗精神病药物1192U90对人类的潜在不良反应，我们对小鼠、大鼠、比格犬和食蟹猴给药长达3个月。在犬类中，而非其他物种，1192U90引起了可通过检眼镜检测到的眼部变化，表现为脉络膜反光消失、脉络膜颜色改变以及脉络膜眼底出现黑色色素沉着。受影响犬类的眼睛因细胞丢失而出现脉络膜萎缩。剩余脉络膜细胞中的视杆小体被电子透明间隙或细颗粒物质分隔开，大小和形状各异，且常常含有形状不规则的电子致密内含物。非脉络膜眼部结构未受影响。由于1192U90在无脉络膜的物种中未引起眼部变化，我们推测它仅靶向脉络膜，而不影响其他眼部结构。我们试图通过给先天性无脉络膜的犬类给药来验证这一假设；然而，尽管这些犬类通过检眼镜检查显示“无脉络膜”，但通过电子显微镜观察发现它们有散在的脉络膜细胞，且这些脉络膜细胞的超微结构变化与正常眼睛的犬类经治疗后出现的变化并无差异。1192U90引起的脉络膜变性与比格犬遗传性脉络膜变性中描述的情况相似。1192U90在无脉络膜的物种中未引起眼部变化，这表明犬类中的眼部变化对人类并不意味着有风险，因为人类的眼睛也没有脉络膜。
