[Toxicological studies on isepamicin (HAPA-B). II. Intramuscular subacute toxicity test in the rat]

Subacute toxicity in the rat of isepamicin (HAPA-B), a new aminoglycoside antibiotic, was examined in comparison with amikacin (AMK). Daily doses of 12.5, 25, 100 and 300 mg/kg of HAPA-B or 25 and 100 mg/kg of AMK were injected intramuscularly for 28 days. No animal died and there were no changes in general symptoms except for hemorrhage at injection sites of both drugs. Decreases in body weight gain and food consumption were observed in males and females in the HAPA-B 300 mg/kg dose group. Water consumption was increased in males in the HAPA-B 300 mg/kg and AMK 100 mg/kg dose groups. Elevations of serum creatinine and/or BUN in males and females were occasionally observed in the HAPA-B 300 mg/kg and AMK 100 mg/kg dose groups, and elevation of GOT, which seemed to be due to muscle injuries, was occasionally observed in a no dose-dependent manner with either drug. Increases in kidney and caecum weights of males and females in the HAPA-B 100, 300 mg/kg and AMK 25, 100 mg/kg dose groups and increases in adrenal relative-weights in males and females in the HAPA-B 300 mg/kg dose group were observed. At necropsy, discoloration and enlargement of the kidney were observed in a dose-dependent manner at or above 100 mg/kg with either drug. Histopathological findings indicated degeneration and necrosis in epithelial cells of the proximal convolute tubuli and thickening of basement membrane. Electron microscopic findings indicated an increase in number of large lysosomes containing myeloid bodies in the epithelial cells of the proximal convolute tubuli with both drugs. The above results suggest that HAPA-B has renal toxicity like other aminoglycoside antibiotics but its toxicity was lower than AMK. The non-toxic dose of HAPA-B in this test was 12.5 mg/kg.