BUFLOMEDIL - ONE-YEAR ORAL SAFETY EVALUATION IN RATS

Buflomedil was given as a dietary mix to Sprague-Dawley Rats for one y ear at dosages of 0, 25, 75, and 400 mg/kg/day. Each group contained t hirty rats of each sex, of which 10/sex/group were preassigned to a wi thdrawal period of 3 months following the 1 -year drug administration period. There were no treatment-related deaths or clinical signs. Dosa ge-related decreases in body weight gain occurred during the 1-year tr eatment period. Food consumption was comparable to controls, except fo r a 10% decrease in high-dosage males during the first week of treatme nt, During the withdrawal period, body weight gain was higher than con trols in all drug-treated groups. Hematocrit (PCV) and hemoglobin were slightly decreased during week 52 in high-dosage males; hematology va lues 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 al 400 mg/kg/day. Discolored urine was observed in m ales at 75 mg/kg/day and in both sexes at 400 mg/kg/day. Urine pH and color were comparable lo controls after the 3-month withdrawal period. There were slight decreases compared to controls in urine volume at a ll dosages in females during week 52; these changes were still evident in the mid- and high-dosage groups al the end of the withdrawal perio d. The only possibly treatment-related observation at necropsy was dir ty tails at the end of the treatment period in the high-dosage group w hich may have been related to the discolored urine. Liver and kidney w eights 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 histopatho logical changes. The changes observed were thought to result from eith er pharmacologic activity or physiological adaptation to compound admi nistration or were marginal in severity. None were considered toxicolo gically significant. Therefore, the no-toxic-effect dosage was 400 mg/ kg/day which is 40 times the maximum clinical dosage.