Morino T, Sano K, Hara H, Motoyama K, Iizuka K, Hara T, Matsumoto K, Yamamoto H
Jpn J Antibiot. 1986 Dec;39(12):3164-78.
Acute toxicity of isepamicin (HAPA-B), a new aminoglycoside antibiotic, in mice, rats and dogs was examined in comparison with amikacin (AMK) and gentamicin (GM). Intravenous LD50 values of HAPA-B were 234 mg/kg in male and 236 mg/kg in female for mice, 489 mg/kg in male and 476 mg/kg in female for rats and 720-864 mg/kg for dogs. Those of AMK were 183 mg/kg in male and 181 mg/kg in female for mice, 420 mg/kg in male and 417 mg/kg in female for rats. Those of GM were 50 mg/kg in male and 47 mg/kg in female for mice, 119 mg/kg in male and 124 mg/kg in female for rats. Intraperitoneal LD50 values of HAPA-B were 2,244 mg/kg in male and 2,272 mg/kg in female for mice, 1,664 mg/kg in male and 1,591 mg/kg in female for rats. Intramuscular LD50 values of HAPA-B were 2,508 mg/kg in male and 2,632 mg/kg in female for mice, 2,088 mg/kg in male and 2,111 mg/kg in female for rats and greater than 1,800 mg/kg for dogs. Those of AMK were 1,247 mg/kg in male and 1,334 mg/kg in female for mice, 2,324 mg/kg in male and 2,244 mg/kg in female for rats. Those of GM were 359 mg/kg in male and 360 mg/kg in female for mice, 559 mg/kg in male and 557 mg/kg in female for rats. Subcutaneous LD50 values of HAPA-B were 3,321 mg/kg in male and 3,320 mg/kg in female for mice, 3,451 mg/kg in male and 3,392 mg/kg in female for rats. Oral LD50 values of HAPA-B were more than 5,000 mg/kg in mice and rats. Ataxia, acratia, dyspnea and convulsions were observed following administration by all routes, except for oral route, of all drugs in mice, rats and dogs. The cause of early death was due to respiratory paralysis which is the typical acute toxic sign of aminoglycoside antibiotics, and that of late death was due to renal injuries. BUN and creatinine values of surviving dogs after day 14 increased after administration by either intravenous or intramuscular routes. Disintegration, necrosis and calcification of epithelial cells of the proximal convoluted tubuli were observed in rats which died during the course of the study, and atrophy, dilatation and eosinophilic degeneration in epithelial cells of the proximal convoluted tubuli and thickening of Bowman's capsule were observed in surviving dogs.
将新氨基糖苷类抗生素异帕米星（HAPA - B）与阿米卡星（AMK）和庆大霉素（GM）相比较，检测其对小鼠、大鼠和犬的急性毒性。异帕米星的静脉注射半数致死量（LD50）在小鼠中，雄性为234mg/kg，雌性为236mg/kg；在大鼠中，雄性为489mg/kg，雌性为476mg/kg；在犬中为720 - 864mg/kg。阿米卡星的静脉注射LD50在小鼠中，雄性为183mg/kg，雌性为181mg/kg；在大鼠中，雄性为420mg/kg，雌性为417mg/kg。庆大霉素的静脉注射LD50在小鼠中，雄性为50mg/kg，雌性为47mg/kg；在大鼠中，雄性为119mg/kg，雌性为124mg/kg。异帕米星的腹腔注射LD50在小鼠中，雄性为2244mg/kg，雌性为2272mg/kg；在大鼠中，雄性为1664mg/kg，雌性为1591mg/kg。异帕米星的肌肉注射LD50在小鼠中，雄性为2508mg/kg，雌性为2632mg/kg；在大鼠中，雄性为2088mg/kg，雌性为2111mg/kg；在犬中大于1800mg/kg。阿米卡星的肌肉注射LD50在小鼠中，雄性为1247mg/kg，雌性为1334mg/kg；在大鼠中，雄性为2324mg/kg，雌性为2244mg/kg。庆大霉素的肌肉注射LD50在小鼠中，雄性为359mg/kg，雌性为360mg/kg；在大鼠中，雄性为559mg/kg，雌性为557mg/kg。异帕米星的皮下注射LD50在小鼠中，雄性为3321mg/kg，雌性为3320mg/kg；在大鼠中，雄性为3451mg/kg，雌性为3392mg/kg。异帕米星的口服LD50在小鼠和大鼠中均超过5000mg/kg。在小鼠、大鼠和犬中，除口服给药外，所有药物经其他途径给药后均观察到共济失调、运动不能、呼吸困难和惊厥。早期死亡原因是呼吸麻痹，这是氨基糖苷类抗生素典型的急性毒性体征，晚期死亡原因是肾损伤。给药14天后存活犬的血尿素氮（BUN）和肌酐值在静脉或肌肉注射给药后升高。在研究过程中死亡的大鼠中观察到近端曲管上皮细胞的崩解、坏死和钙化，在存活犬中观察到近端曲管上皮细胞的萎缩、扩张和嗜酸性变性以及鲍曼囊增厚。
