Preclinical safety studies with Temofel, a new choleretic compound

Temofel (2,5-dimethyl-alpha-ethyl-benzhydrol) is a choleretic compound. Safety studies required for Phase I and II clinical trials were performed. No oestrogenic, antioestrogenic, androgenic or antiandrogenic effect was induced in infantile rats treated with 100 and 200 mg/kg. No CNS effects were induced by 50 mg/kg in mice. No haemodynamic or respiratory changes were induced in dogs by 300 mg/kg. In a 28-day oral toxicity study with 40, 80, 160, 320, 640 and 1280 mg/kg doses on Lati: CFY (SD) rats died at the 2 highest doses (640 and 1280 mg/kg). Large necrotic foci in the liver were found at the highest dose 1280 mg/kg. In rats treated with 320 mg/kg and higher doses, hepatic hyperplasia, renal tubular hyperplasia and protein retention in the renal cortex were observed. Testicular atrophy, damaged spermiogenesis, spermiohistogenesis and regulative Leydig-cell hyperplasia were induced by 640 and 1280 mg/kg. In a 28-day study on Velz: BEAGLE dogs with daily doses of 40, 120 and 360 mg/kg sporadically increased SAP activity occurred at the high dose. In a 6-month study rats were fed 400, 2000 and 10000 ppm Temofel. Growth was retarded in the medium and high dose group, no sperm could be seen in the urinary sediment of the high dose group. Testicular atrophy, complete lack of spermiogenesis, spermiohistogenesis occurred in this group. In contrast to the administration of 1280 mg/kg for 28 days by gavage, no hepatic or renal changes were induced by 10000 ppm consumed for 6 months. A 6-month canine study with 40, 120 and 360 mg/kg doses revealed sporadic SAP increase at the high dose.(ABSTRACT TRUNCATED AT 250 WORDS)