CHRONIC TOXICITY STUDY ON 4-ETHOXY-2-METHYL-5-MORPHOLINO-3(2H)-PYRIDAZINONE(M73101)IN RATS

Chronic toxicity and recovery tests of M73101, a new analgesic and antiinflammatory agent, were carried out using male and female JCL:SD rats. The drug was orally administered in doses of 0, 10, 30, 100, 300 and 1000mg/kg body weight/day for six months. A decrease of spontaneous activity in the group given 1000mg/kg and salivation in the groups given higher doses than 100mg/kg were observed during the administration period. In the 1000mg/kg group, inhibitions of body weight gain and of food efficiency were induced. An increased intake of water and a slight increase in urine volume and in urinary outputs of sodium, potassium and chloride were also observed in the highest dose group. No abnormality was observed in hematological findings in all groups tested. As to the biochemical findings of serum, the high dose groups showed an increase in total cholesterol, free cholesterol and triglyceride in females. Histopathological examination revealed a dose-dependent increase in liver weight and a hypertrophy of hepatocytes due to proliferation of smooth endplasmic reticulum. These changes were more intense in females than in males, suggesting the presence of a sex difference in the effect of M73101. A slight increase in kidney weight was also noted in the male groups given higher doses than 100mg/kg. A swelling and vacuolation of proximal tubular epithelial cells were observed in both sexes, and a single cell degeneration or necrosis was found electron-microscopically in the high dose groups. A change occuring in the gastro-intestinal tracts was ulcer formation due to swelling and subsequent desquemation of mucous epithelial cells. However the ulcer did not develop beyond lamina muscularis mucosae (grade I ulcer or erosion). In the recovery test, the symptoms and pathological changes mentioned above almost disappeared 4 to 8 weeks after the cessation of drug administration, except that a hypertrophy of hepatocytes still remained histologically to some extent in the highest dose groups. It was concluded that the target organs of M73101 were regarded virtually to be the liver, kidneys and gastro-intestinal tracts. The largest non-toxic dose of M73101 was considered to be about 30mg/kg body weight/day in male and female rats. Futhermore, it was suggested that the greatest safety dose was 100mg/kg body weight/day in male and female rats.