netilmicin and Abnormalities--Drug-Induced

The data on the toxicity of netilmicin in laboratory animals as well as preliminary data in man are reviewed. Netilmicin is less toxic to the VIIIth nerve than is gentamicin in all species tested. The data suggest that it probably is less ototoxic than tobramycin, although confirmatory studies should be performed. Netilmicin is also nephrotoxic than gentamicin in all species tested. It is less nephrotoxic than tobramycin in the rat and dog. Comparisons in the rat suggest that netilmicin has a flat dose--response curve that resembles the curve produced by streptomycin. In animals, netilmicin produces more neuromuscular blockade than gentamicin; however, neuromuscular blockade with aminoglycosides in man is rare and thus far no episodes have been associated with netilmicin during clinical investigation. Initial clinical studies in man indicate that netilmicin is efficacious and well tolerated. Presently available data suggest that netilmicin offers distinct advantages over older aminoglycosides. Final conclusions must await prospective randomized double-blind trials in man.

Topics: Abnormalities, Drug-Induced; Amikacin; Animals; Anti-Bacterial Agents; Bacterial Infections; Cochlea; Gentamicins; Glomerular Filtration Rate; Hair Cells, Auditory; Hearing; Humans; Kidney; Netilmicin; Reproduction

Teratological study on netilmicin (NTL), a new aminoglycoside antibiotic, was carried out in Sprague-Dawley rats (Slc : SD). NTL was administered intramuscularly to female rats from day 7 to day 17 of gestation at the dosages of 12.5, 25, 50 and 100 mg/kg. The decrease of food intake at the dosage of 50 mg/kg and more, and the resultant depression of maternal body weight gain at the dosage of 100 mg/kg were observed in dams receiving NTL. The depression of fetal growth, such as body weight and ossification of the sternebrae and caudal vertebrae, were detected in animals treated with 50 and 100 mg/kg of NTL. However, NTL failed to induce the external, visceral and skeletal anomalies in fetuses. Also, NTL did not cause any significant changes in birth rate, suckling rate, weaning rate, body weight, postnatal development, behavior and reproductive performance in F1. These results suggest that NTL has no adverse effect on rat fetuses and F1 generation at the dosage of 25 mg/kg or less.

Topics: Abnormalities, Drug-Induced; Animals; Animals, Newborn; Behavior, Animal; Body Weight; Drinking; Eating; Embryo Implantation; Female; Fertility; Fetus; Gentamicins; Injections, Intramuscular; Male; Maternal-Fetal Exchange; Netilmicin; Organ Size; Pregnancy; Rats; Rats, Inbred Strains

Fertility study on netilmicin (NTL), a new aminoglycoside antibiotic, was carried out in Sprague-Dawley rats (Slc : SD). NTL was administered intramuscularly to male rats at the daily dose of 12.5, 25, 50 and 100 mg/kg from 6 to 15 weeks of age for 9 weeks before mating and during the mating period, and to 10 weeks old female rats at the daily dose levels from day 14 before mating through day 7 after gestation. The increase of kidney weight at the dose of 12.5 mg/kg and more, the decreases of food intake and body weight were observed in treated male rats. The decreases of food intake and body weight were observed in female rats treated with the dose of 50 and 100 mg/kg. No dose-related changes were observed in mating and fertility ratios of parent animals, numbers of corpora lutea and implantations, fetal mortality, external, visceral and skeletal anomalies, body weight, body length and tail length of fetuses. Therefore, it can be concluded that maximum non-toxic dose level of NTL on rat fertility is 100 mg/kg.

Topics: Abnormalities, Drug-Induced; Animals; Drinking; Eating; Female; Fertility; Fetus; Gentamicins; Injections, Intramuscular; Kidney; Male; Maternal-Fetal Exchange; Netilmicin; Organ Size; Pregnancy; Rats; Rats, Inbred Strains; Sexual Behavior, Animal

Perinatal and postnatal study on netilmicin (NTL), a new aminoglycoside antibiotic, was carried out in Sprague-Dawley rats (Slc : SD). NTL was administered intramuscularly from day 17 of gestation throughout day 20 after delivery at the daily dose of 12.5, 25, 50 and 100 mg/kg. Water intake of pregnant and nursing dams was increased in the animals treated with 50 mg/kg or more of NTL. The increase of cecum weight was observed in F1 animals in all treated groups at 3 weeks of age. However, birth rate, suckling rate, weanling rate, body weight, postnatal development, behavior and reproductive function remained within normal ranges in all treated groups.

Topics: Abnormalities, Drug-Induced; Animals; Animals, Newborn; Body Weight; Female; Fertility; Fetus; Gentamicins; Injections, Intramuscular; Kidney; Lactation; Male; Maternal-Fetal Exchange; Netilmicin; Organ Size; Pregnancy; Rats; Rats, Inbred Strains; Sexual Behavior, Animal

Teratological study on netilmicin (NTL), a new aminoglycoside antibiotic, was carried out in New Zealand White rabbits. NTL was administered intramuscularly from day 60 to day 18 of gestation at the dose levels of 12.5, 35 and 100 mg/kg. The decrease of food intake, water intake and depression of body weight were observed in the pregnant animals treated with 100 mg/kg of NTL. Body weight and tail length of fetuses were significantly decreased in the animals treated with 35 and 100 mg/kg compared with those in saline control or vehicle control groups. However, no dose-related changes or anomalies were detected in mortality, external, visceral and skeletal examinations of fetuses. Thus, it can be concluded that NTL has no adverse effect on rabbit fetuses.

Topics: Abnormalities, Drug-Induced; Animals; Bone and Bones; Drinking; Eating; Female; Fetus; Gentamicins; Injections, Intramuscular; Male; Maternal-Fetal Exchange; Netilmicin; Organ Size; Pregnancy; Rabbits

1-N-Ethylsisomicin (netilmicin), a semisynthetic aminoglycoside antibiotic, was given parenterally to mice, rats, guinea pigs, rabbits, and dogs for toxicological evaluation. Acute signs of toxicity were consistent with neuromuscular blockade. Results of teratological studies in rats and rabbits were negative; the only effect observed was wavy ribs, a minor developmental variation, in rats. No effects were found on fertility, reproduction, or development of offspring. Single daily doses of 60 mg/kg s.c. for 10 weeks in young rats and 30 days in young dogs were non-toxic. No indication of toxicity was found in rats and dogs given single daily doses of 7.5 mg/kg i.v. for 2 weeks. Daily i.m. doses caused signs of neuromuscular blockade in rats after 2 weeks at 100 mg/kg and after 1 month at 50 mg/kg, and in dogs after 2 months at 75 mg/kg; dose levels of 150 mg/kg did not cause renal failure. No ocular changes or impairment of vestibular or auditory function were evident at any dose studied. Comparison with tobramycin, gentamicin, and kanamycin at s.c. doses of 50 or 150 mg/kg per day for 4 weeks showed netilmicin to be less nephrotoxic in rats than tobramycin or gentamicin and only slightly more nephrotoxic than kanamycin. Only mild changes were seen microscopically in kidneys of dogs given netilmicin at daily doses of 75 mg/kg i.m. for 3 months. The renal effects of netilmicin given at high multiples of the human therapeutic dose were one-half to one-third less that those of gentamicin and were not severe at any dosage.

Topics: Abnormalities, Drug-Induced; Animals; Animals, Newborn; Dogs; Dose-Response Relationship, Drug; Female; Gentamicins; Guinea Pigs; Kidney; Kidney Tubular Necrosis, Acute; Male; Mice; Netilmicin; Neuromuscular Junction; Pregnancy; Rabbits; Rats; Reproduction; Seizures