Ellis W G, Bencken E, LeCouteur R A, Barbano J R, Wolfe B M, Jennings M B
Department of Pathology, School of Medicine, University of California, Davis 95616.
Toxicol Pathol. 1988;16(1):1-9. doi: 10.1177/019262338801600101.
Clinical and neuropathologic effects of chronically administered intravenous (iv) amphotericin B methyl ester (AME) were observed in 3 male dogs (2 German shorthaired pointers and 1 pit bull). Each dog received 6.2-7.3 g of AME (299-327 mg/kg body weight) over a period of 11-12 weeks. One dog developed neurologic signs of severe diffuse brain dysfunction and at necropsy all 3 dogs had a marked leukoencephalopathy, most severe in centrum ovale and subcortical white matter of frontal lobes. Brain histopathology included diffuse myelin loss, oligodendrocyte depletion, accumulation of macrophages filled with sudanophilic lipid, fibrillary astrogliosis, and swelling or fragmentation of many axons. Two control dogs administered iv glucose showed no neuropathologic abnormalities. These findings closely resemble the clinical and neuropathologic abnormalities that developed in patients during the first human trial of AME for treatment of fungal infections, but differ from those of animal studies that did not closely simulate the long-term drug administration required for antifungal therapy in humans. It was concluded that before human clinical trial is authorized, experimental protocols for animal studies of drug toxicity should reflect the anticipated human use of the drug, both in dose and duration.
在3只雄性犬（2只德国短毛指示犬和1只斗牛犬）中观察了长期静脉注射两性霉素B甲酯（AME）的临床和神经病理学效应。每只犬在11至12周的时间内接受了6.2 - 7.3克AME（299 - 327毫克/千克体重）。一只犬出现了严重弥漫性脑功能障碍的神经学体征，尸检时所有3只犬均有明显的白质脑病，在卵圆中心和额叶皮质下白质最为严重。脑组织病理学表现包括弥漫性髓鞘丢失、少突胶质细胞减少、充满嗜苏丹脂质的巨噬细胞积聚、纤维性星形胶质细胞增生以及许多轴突肿胀或断裂。2只静脉注射葡萄糖的对照犬未出现神经病理学异常。这些发现与在AME治疗真菌感染的首次人体试验中患者出现的临床和神经病理学异常非常相似，但与那些未紧密模拟人类抗真菌治疗所需长期给药的动物研究结果不同。得出的结论是，在批准人体临床试验之前，药物毒性动物研究的实验方案应在剂量和持续时间方面反映预期的人体用药情况。
