[Toxicological studies on isepamicin (HAPA-B). VII. Chronic intramuscular test in the rat]

Chronic toxicity in the rat of isepamicin (HAPA-B), a new aminoglycoside antibiotic, was examined in comparison with amikacin (AMK). Daily doses of 3.125, 6.25, 25 and 100 mg/kg of HAPA-B or 25 and 100 mg/kg of AMK were injected intramuscularly for 6 months, and recovery test was carried out for 2 months after discontinuing the drug. No animal died and there were no changes in general symptoms except for hemorrhage of injection sites of both drugs. Decreases in body weight gain and food consumption were observed in 100 mg/kg dose group of either drug. Water consumption was markedly increased in males of the AMK 100 mg/kg dose group during administration and recovery periods. Decreases in erythrocytes, hematocrit and hemoglobin were observed in 100 mg/kg dose group of either drug. These decreases seemed to be due to renal injury. An increase in the number of platelets was also observed. This was likely caused by the hemorrhage at injection sites. These changes persisted into the recovery period. Elevation of BUN was observed in the 100 mg/kg dose group of either drug. Its value in the AMK 100 mg/kg dose group was markedly higher than that in the HAPA-B 100 mg/kg dose group and did not decrease back to the normal values even during the recovery period. An increase of urine volume and a decrease of urine specific gravity were observed in males in the 100 mg/kg group of either drug. Furthermore, NAG was elevated in a dose-dependent manner from 25 mg/kg with both drugs. The weight of kidney increased dose-relatedly and significantly in groups administered with 25 mg/kg or more of either drug and weight of caecum increased dose-relatedly and significantly in groups administered with 6.25 mg/kg or more of HAPA-B or 25 mg/kg or more of AMK. Discoloration and enlargement of the kidney occurred in a dose-dependent manner as observed by necropsy. Eosinophilic granular degeneration, swelling, fatty degeneration, necrosis, calcification in the epithelial cells of the proximal convoluted tubuli, and thickenings of Bowman'S capsule and tubular basement membrane were observed at 25 and 100 mg/kg dose groups of either drug. In recovery periods, after the necrosis disappeared, calcification and regeneration were observed in epithelial cells. Electron microscopic findings showed an increase in the number of large lysosomes containing myeloid bodies in the epithelial cells of the proximal convolute tubuli with either drug.(ABSTRACT TRUNCATED AT 400 WORDS)