Abstract
The chronic toxicity of potassium clavulanate (CVA-K) and BRL28500 were evaluated using dogs in 26-week intravenous administration studies followed by a 5-week off-dose period. The doses for CVA-K and BRL28500 were 10, 20, 50 and 100mg/kg (p. f. a.), and 80, 160, 320 and 800mg/kg (p. f. a.) respectively.
There were no deaths in either of the groups.
For general condition, dogs dosed with CVA-K at 100mg/kg showed reddening of the skin and mucous membranes, shaking of the head, facial oedema, a decrease in food intake and a reduction in body weight. Also some dogs of the same group showed decreased spontaneous activity, emaciation and signs of dehydration. In the BRL28500 treatment groups, there was reddening of the skin and mucous membranes, vomiting and salivation at 800mg/kg.
Urinalysis of dogs dosed with CVA-K showed occasional dark yellow coloration of the urine. There was also a very weak and equivocal response or positive reaction for protein, occult blood, and urine sugar in some animals at 100mg/kg. Some dogs dosed with BRL28500 also showed either a very weak and equivocal response or slight positive reaction for occult blood at 320 mg/kg and above, and dark yellow coloration of the urine at 800mg/kg. Haematological examination of the CVA-K groups showed increases in leukocyte count and platelet count at the highest dose of 100mg/kg. No haematological abnormalities were noted in any of the BRL28500 groups. Serum biochemical studies of dogs dosed with CVA-K revealed a decrease in total protein at 50mg/kg and above, and increases in Al-P, total bilirubin, GPT, BUN and creatinine at 100mg/kg. In the BRL28500 treatment groups, there were increases in total cholesterol and triglyceride at 160mg/kg and above.
In dogs dosed with CVA-K there was an increase in liver weight at 100mg/kg. Histopathological examination showed a ground glass-like appearance of the hepatocyte cytoplasm and also altered distribution of PAS positive material at 50mg/kg and above. In the BRL28500 groups, there was an increase in liver weight at 320mg/kg and above. There were the same ground glass-like appearance in hepatocytes and altered distribution of PAS positive material at 800mg/kg.
In view of the above results, the maximum non-effect dose levels in the present studies were considered to be 20mg/kg for CVA-K and 80mg/kg for BRL28500.
All the above findings and changes were slight and were reversible either at the end of the dosing period or at the end of the off-dose period.
