Buflomedil: One-Year Oral Safety Evaluation in Rats

ABSTRACT

Buflomedil was given as a dietary mix to Sprague-Dawley Rats for one year at dosages of 0, 25, 75, and 400 mg/kg/day. Each group contained thirty rats of each sex, of which 10/sex/group were preassigned to a withdrawal period of 3 months following the 1 -year drug administration period. There were no treatment-related deaths or clinical signs. Dosage-related decreases in body weight gain occurred during the 1-year treatment period. Food consumption was comparable to controls, except for a 10% decrease in high-dosage males during the first week of treatment. During the withdrawal period, body weight gain was higher than controls in all drug-treated groups. Hematocrit (PCV) and hemoglobin were slightly decreased during week 52 in high-dosage males; hematology values were comparable to controls during weeks 13 and 26 and at the end of the withdrawal period. There were no treatment-related changes in blood biochemistry. Urine pH was decreased in females at 75 mg/kg/day and in both sexes at 400 mg/kg/day. Discolored urine was observed in males at 75 mg/kg/day and in both sexes at 400 mg/kg/day. Urine pH and color were comparable to controls after the 3-month withdrawal period. There were slight decreases compared to controls in urine volume at all dosages in females during week 52; these changes were still evident in the mid- and high-dosage groups at the end of the withdrawal period. The only possibly treatment-related observation at necropsy was dirty tails at the end of the treatment period in the high-dosage group which may have been related to the discolored urine. Liver and kidney weights were slightly increased in males at 400 mg/kg/day at the end of the 1-year treatment period; these changes were not evident after the 3-month withdrawal period. There were no treatment-related histopathological changes. The changes observed were thought to result from either pharmacologic activity or physiological adaptation to compound administration or were marginal in severity. None were considered toxicologically significant. Therefore, the no-toxic-effect dosage was 400 mg/kg/day which is 40 times the maximum clinical dosage.