Schiavo D M, Green J D, Traina V M, Spaet R, Zaidi I
Research Department, Ciba-Geigy Corporation, Summit, New Jersey 07901.
Fundam Appl Toxicol. 1988 Feb;10(2):329-34. doi: 10.1016/0272-0590(88)90318-1.
CGS 14796C, cis-1-[(4-[(1-imidazolyl)methyl]-cyclohexyl)methyl)imidazole succinate, has been evaluated as a potential aromatase inhibitor. As part of the safety evaluation program, a 3-month oral toxicity study was performed in which beagle dogs were administered CGS 14796C by gavage at 5, 15, or 50 mg/kg/day. Ophthalmoscopically, changes in the tapetum lucidum affecting dogs from the 15 and 50 mg/kg dose levels were diffuse areas of pigmentation varying in appearance from a brownish peppered or mottled to a more uniform brown similar to that of the nontapetal area of the fundus. Tapetal reflectivity was absent or markedly reduced. Within the pigmented area, multiple islets (yellow, green, or orange) of tapetal cells were visible, suggestive of destruction of the tapetum. In no instance was retinal destruction, edema, vascular changes, or detachment observed. Ophthalmoscopic examinations performed during recovery revealed changes of slight increase in tapetal islets, suggestive of a slight progression and organization within the tapetum followed by an arrest of the toxic insult within the tapetal tissue. At light and electron microscopic examination of the ocular tissues, the lesions were tapetal cell degeneration/atrophy. These results demonstrated that the taptetum lucidum was a target tissue of toxicity for CGS 14796C, and indicated that the findings are without toxicological significance in atapetal species, including man, whose globes do not have this structure.
CGS 14796C，即顺式-1-[(4-[(1-咪唑基)甲基]环己基)甲基]咪唑琥珀酸盐，已被评估为一种潜在的芳香化酶抑制剂。作为安全性评估计划的一部分，进行了一项为期3个月的口服毒性研究，其中比格犬通过灌胃给予CGS 14796C，剂量为5、15或50mg/kg/天。在眼底镜检查中，15mg/kg和50mg/kg剂量组的犬出现的绒毡层变化为色素沉着的弥漫区域，外观从棕色点状或斑驳状到与眼底非绒毡层区域相似的更均匀的棕色不等。绒毡层反射消失或明显降低。在色素沉着区域内，可见多个绒毡层细胞岛（黄色、绿色或橙色），提示绒毡层遭到破坏。在任何情况下均未观察到视网膜破坏、水肿、血管变化或脱离。恢复期进行的眼底镜检查显示绒毡层小岛略有增加，提示绒毡层内有轻微进展和组织化，随后绒毡层组织内的毒性损伤停止。对眼组织进行光镜和电镜检查时，病变为绒毡层细胞变性/萎缩。这些结果表明绒毡层是CGS 14796C的毒性靶组织，并表明这些发现对包括人类在内的无绒毡层物种无毒理学意义，因为这些物种的眼球没有这种结构。
