Subacute and chronic toxicity studies of triethylenetetramine dihydrochloride (TJA-250) by oral administration to F-344 rats.

Triethylenetetramine dihydrochloride (trientine-2HCl, TJA-250), a copper chelating agent used to treat Wilson's disease, was administered orally to male and female F-344 rats for 4 or 8 weeks at dosages of 0, 100, 350 or 1200 mg/kg/day or for 26 weeks at dosages of 50, 175 or 600 mg/kg/day. 4 or 8-week study. Two males receiving 1200 mg/kg/day died during week 8 of treatment. In males receiving 1200 mg/kg/day during weeks 5 to 8 of treatment, body weight gain and food consumption were decreased and hunched posture and thin build were observed. During week 4 or 8 of treatment urinalysis revealed, for males receiving 100 mg/kg/day or animals receiving 350 mg/kg/day or more, increased electrolyte outputs possibly due to the hydrochloride nature of trientine-2HCl, with low plasma alkaline phosphatase activities evident in animals receiving 350 or 1200 mg/kg/day. After 4 and 8 weeks, and during 8 weeks of treatment, high lung weights and bronchiolar epithelium hypertrophy and broncho-alveolar pneumonia were recorded for animals receiving 1200 mg/kg/day, and submucosal acute inflammation within the glandular region of the stomach was recorded for males receiving 350 or 1200 mg/kg/day and in all treated female groups. 26-week study. One male receiving 175 mg/kg/day and three males receiving 600 mg/kg/day died, showing lung changes. The body weight gain of animals receiving 600 mg/kg/day was slightly decreased. Blood chemistry and urinalysis examinations showed changes similar to those indicated in the 4- or 8-week study. The low plasma copper concentrations seen in males receiving 600 mg/kg/day, the slightly low liver copper concentrations found in animals receiving 600 or 175 mg/kg/day and the high urinary copper concentrations found in all treated groups, are attributed to the pharmacological action of trientine-2HCl. Histopathology revealed a dosage-related incidence and severity of focal chronic interstitial pneumonitis accompanied by fibrosis of the alveolar walls in females receiving 175 mg/kg/day or more and all treated male groups, but no significant pathological changes in the stomach. Apart from the histological changes found in the lung, all the above changes were reversible. In conclusion, the NOAEL of trientine-2HCl in this 26-week study was considered to be 50 mg/kg/day for females and less than 50 mg/kg/day for males.

Glucagon produced by recombinant DNA technology: repeated dose toxicity studies, intravenous administration to CD rats and beagle dogs for four weeks.

The toxicity of glucagon produced by recombinant DNA technology (Glucagon (ge)) was studied by daily intravenous administration to rats and dogs for 4 weeks. Pancreatic glucagon of bovine or porcine origin (Glucagon Novo) was used as a reference control in the dogs. Glucagon (ge) has the same sequence of the 29 amino acids as pancreatic glucagon of humans, cows, pigs, rats and dogs. The dosages were 0 (control), 0.2, 1.0 and 5.0 mg Glucagon (ge)/kg/day in the rats, and 0 (control), 1.0 and 5.0 mg Glucagon (ge) and 5.0 mg Glucagon (Novo)/kg/day in the dogs. The studies complied with current EEC, US and Japanese guidelines for 4 week toxicity studies of drugs. All dose levels were well tolerated. The plasma glucose and cardiovascular responses to dosing were monitored in the dogs and found to be in agreement with well-known effects of pancreatic glucagon. The most consistent finding in both species was an increase in liver weight. This change was without concomitant pathological deviations in the other parameters examined. There were no differences in the reaction of dogs following treatment with Glucagon (ge) or Glucagon (Novo). A dose of 1 mg Glucagon (ge)/kg/day was regarded as a clear no-toxic-effect-level in both species.

Four-week sub-acute toxicity study of S-(-)-9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl)-7-oxo-7H-pyrido-[1,2,3,-de] [1,4]benzoxazine-6- carboxylic acid hemihydrate (DR-3355) in CD rats and cynomolgus monkeys.

S-(-)-9-Fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H -pyrido-[1,2,3,-de] [1,4]benzoxazine-6-carboxylic acid hemihydrate, DR-3355, a new quinolone antimicrobial agent, was administered by oral gavage to groups of ten male and ten female CD rats at dosages of 50, 200 or 800 mg/kg/day and to groups of three male and three female cynomolgus monkeys at dosages of 10, 30, or 100 mg/kg/day. Both species were treated for four weeks. The vehicle (0.5% sodium carboxymethyl cellulose)-treated group served as control. Rats at the high dose showed salivation, slight increases in total leucocyte and lymphocyte counts, slight changes in the plasma electrolyte balance, and minor reductions in urea concentration. The articular surfaces of the humerus and femur of rats at the high dose showed minor degenerative changes. Increased caecal weight occurred in rats at all the treatment groups. Monkeys at the high dose showed salivation, diarrhoea and lost weight. There was no microscopic change in the tissues examined. No effect levels under these conditions were established at 200 mg/kg/day in the rat, and 30 mg/kg/day in the monkey.