[Toxicological studies on isepamicin (HAPA-B). I. Acute toxicity test in the mouse, rat and dog].

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.