isepamicin and Body-Weight

The temporal variation in the nephrotoxicity of low doses of isepamicin was studied in male Sprague-Dawley rats treated with a single daily intraperitoneal injection of saline (NaCl, 0.9%) or isepamicin (80 mg/kg of body weight) at either 0800, 1400, 2000, or 0200 h for 4 and 10 days. On day 10, the cellular regeneration (incorporation of [3H] thymidine into DNA of renal cortex) and cortical accumulation of isepamicin were significantly higher in animals treated at 1400 h than at 0200 h (P < 0.01). Immunogold labeling studies showed that isepamicin was essentially localized in the lysosomes of proximal tubular cells in all treated groups, but the density of the gold particles over the lysosomes was higher in animals treated at 1400 than at 0200 h. The results of the present study show that the renal toxicity of isepamicin was maximal at 1400 h (midlight period) and minimal at 0200 h (middark period).

Topics: Animals; Anti-Bacterial Agents; Body Weight; Circadian Rhythm; Gentamicins; Immunohistochemistry; Injections, Intraperitoneal; Kidney Cortex; Kidney Diseases; Kidney Tubules, Proximal; Male; Microscopy, Electron; Rats; Rats, Sprague-Dawley; Regeneration; Thymidine; Time Factors

Groups of adult guinea pigs were treated intramuscularly with isepamicin at doses of 100, 150 and 225 mg/kg/day for 21 days. For comparison, two other groups were administered either saline or amikacin 225 mg/kg/day. Auditory function, as measured by the Preyer pinna reflex and the brain stem evoked response, was impaired in both the isepamicin and amikacin groups treated with 225 mg/kg/day, and to a lesser extent in the group receiving isepamicin 150 mg/kg/day. Morphological evaluation of the organ in Corti, performed either by scanning electron microscopy or by light microscopy, showed the typical pattern of damage associated with the aminoglycosides. The greatest damage was observed at 225 mg/kg/day, with no difference between isepamicin and amikacin. Isepamicin 100 mg/kg/day produced no impairment in auditory function and very little change in the morphology of the organ of Corti.

Topics: Amikacin; Animals; Anti-Bacterial Agents; Auditory Threshold; Body Weight; Brain; Cochlear Duct; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Evoked Potentials, Auditory, Brain Stem; Gentamicins; Guinea Pigs; Hair Cells, Auditory; Hearing Disorders; Male; Microscopy, Electron, Scanning

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.

Topics: Amikacin; Animals; Body Weight; Dose-Response Relationship, Drug; Female; Gentamicins; Injections, Intramuscular; Kidney; Male; Rats

Effect of isepamicin (HAPA-B), a new aminoglycoside antibiotic, on fertility and reproductive performance in Wistar rats was studied. The drug was injected intramuscularly to rats at a daily dose of 25, 100 or 200 mg/kg. Male rats were treated for 63 days before mating and during the mating period, and female rats were treated for 2 weeks and through the mating period to the 7th day after mating. In male rats, an inhibition of body weight gain and a development of a pale color and hypertrophy of the kidney were observed in 100 and 200 mg/kg dose-groups. In female rats, inhibition of body weight gain was observed in 100 and 200 mg/kg dose-groups and a pale color of the kidney was seen in the 200 mg/kg group. No significant differences were observed in mating and fertility performance of male and female rats between the control and treated groups. Numbers of corpora lutea, implantation sites and living fetuses in the 200 mg/kg group decreased significantly. No external, visceral and skeletal anomalies due to the treatment of HAPA-B were observed in the live fetuses. No effect dose levels of HAPA-B found in this study were 25 mg/kg on parent rats and 100 mg/kg on reproduction ability and their fetuses.

Topics: Animals; Body Weight; Female; Fertility; Gentamicins; Injections, Intramuscular; Male; Pregnancy; Pregnancy, Animal; Rats

Peri- and post-natal effect of HAPA-B, a new aminoglycoside antibiotic, was studied in Jcl: Wistar rats. The antibiotic was given intramuscularly to dams at doses of 25, 100 and 200 mg/kg from day 17 of gestation to 21 days after delivery and throughout lactation. Influences of the drug on dams and their offspring were studied. A decrease in food intake and an increase in water intake were observed in the 200 mg/kg treated group. At autopsy of dams after weaning, pale discoloration and hypertrophy of the kidney were observed in 100 and 200 mg/kg groups. All other observations including delivery and nursing performance of dams, postnatal development of offspring, behavior and reproduction performance of the offspring were normal. The no effect dose level of HAPA-B found in this study was 25 mg/kg on rat dams and 100 mg/kg on the offspring.

Topics: Animals; Animals, Newborn; Behavior, Animal; Body Weight; Feeding Behavior; Female; Gentamicins; Injections, Intramuscular; Male; Pregnancy; Pregnancy, Animal; Rats