Fortner J H, Milisen W B, Lundeen G R, Jakowski A B, Marsh P M
Drug Safety Evaluation, Pfizer Inc., Groton, Connecticut 06340.
Fundam Appl Toxicol. 1993 Aug;21(2):164-73. doi: 10.1006/faat.1993.1086.
An azalide antibiotic (CP-62,993) was administered at 100 mg/kg by oral gavage once daily for 35 consecutive days to 3 normal Beagle dogs (tapetal) and 3 Beagle dogs lacking a clinically apparent ocular tapetum (atapetal). The total dose delivered was approximately 100-fold the recommended clinical dose. Bilateral ophthalmoscopic changes were observed in the treated tapetal dogs on Day 36, consisting of mild to moderate tapetal decoloration with loss of the normal color change at the junction with the nontapetal fundus and muting of reflectivity of the normally highly reflective tapetum; treated atapetal and all control tapetal and atapetal dogs had no ophthalmoscopic changes. Microscopic examination of ocular tissue revealed rudimentary tapetal cell layers in the correct location in untreated, clinically atapetal eyes. Tapetal cells from treated tapetal and atapetal dogs were swollen and vacuolated, and contained intracytoplasmic, electron-dense debris but no recognizable tapetal rodlets. Lysosomal lamellar bodies were observed in the retinal ganglion cells of both treated groups and were neither enhanced nor reduced by the presence of a functional tapetum. Necrosis and inflammation were not observed in any ocular tissue. The altered ophthalmoscopic appearance of treated tapetal dogs was not influenced by the retinal changes because any effect on retinal transparency would have been seen in treated atapetal dogs. The decoloration and muting of reflectivity observed clinically in the tapetal fundus of dogs following prolonged exposure to high levels of CP-62,993 result from unique changes within the ocular tapetum itself and cannot be interpreted to be of consequence to nontapetal species including humans.
将一种氮杂内酯类抗生素（CP - 62,993）以100毫克/千克的剂量连续35天每天经口灌胃给予3只正常的比格犬（有脉络膜毯）和3只无明显临床可见脉络膜毯的比格犬（无脉络膜毯）。给药的总剂量约为推荐临床剂量的100倍。在第36天，观察到接受治疗的有脉络膜毯犬出现双侧眼底镜检查变化，包括轻度至中度脉络膜毯脱色，与无脉络膜毯眼底交界处正常颜色变化消失，以及正常高反射性脉络膜毯反射率减弱；接受治疗的无脉络膜毯犬以及所有对照有脉络膜毯和无脉络膜毯犬均无眼底镜检查变化。对眼组织的显微镜检查显示，未经治疗、临床上无脉络膜毯的眼睛在正确位置有发育不全的脉络膜毯细胞层。接受治疗的有脉络膜毯和无脉络膜毯犬的脉络膜毯细胞肿胀且有空泡，含有胞浆内电子致密碎片，但未观察到可识别的脉络膜毯小体。在两个治疗组的视网膜神经节细胞中均观察到溶酶体层状小体，其数量不受功能性脉络膜毯存在与否的影响。在任何眼组织中均未观察到坏死和炎症。接受治疗的有脉络膜毯犬眼底镜外观改变不受视网膜变化影响，因为若对视网膜透明度有任何影响，在接受治疗的无脉络膜毯犬中也会观察到。犬长时间暴露于高水平CP - 62,993后，临床上在有脉络膜毯眼底观察到的脱色和反射率减弱是由于眼脉络膜毯本身的独特变化所致，不能认为对包括人类在内的无脉络膜毯物种有影响。
