28-day oral toxicity study with soft corticosteroid BNP-166 in rats and dogs, followed by a 14-day recovery period.

The aim of the present study was to evaluate the soft corticosteroid BNP-166 in rats and dogs treated orally with 0.2, 2.0, and 20.0 mg/kg for 28 days and the reversibility of any abnormalities during a 14-day post-dosing period. The test substance, BNP-166, was well tolerated during the 28-day treatment period. The observed changes were all characteristic for the pharmacological actions of a glucocorticoid. Treatment related changes occurred in the adrenals and thymus, and, to a lesser extent, in the lymph nodes, spleen and liver. There were no statistically significant reductions in the cortisol levels of all groups in the 0.2 and 2 mg/kg treatments. Significant reductions were observed in the high-dose group (20 mg/kg), but levels returned to normal by the end of the 14-day recovery period. Based on the results, the No Observable Adverse Effect Level (NOAEL) of BNP-166 soft corticosteroid in rat and dog after 28-day oral administration is 2 mg/kg. This value is approximately 40 times higher than that of budesonide. Pharmacodynamic and receptor binding studies have shown BNP-166 to have a similar potency to budesonide; therefore, BNP-166 can be considered safer when administered orally than other corticosteroids such as prednisolone or budesonide.

Experimental teratogenicity of structurally similar compounds with or without piperazine-ring: a preliminary report.

For studying if piperazine-ring plays a role in teratogenicity pairs of compounds of similar structure and action (perphenazine-chloropromazine, chlorcyclizine--thenalidine, haloanisone--haloperiodol) had been selected, where only one of them contained piperazine-ring. The applied single doses were 3.7 X 10(-4) M/kg. Experiments were carried out on Wistar/H-Riop pregnant rats; equimolar doses of three drug-pairs were given orally on the 13th, 14th, or 15th gestational days, respectively. Perphenazine and chlorcyclizine, as alkyl-piperazine derivatives induced cleft palate and micromelia, while chlorpromazine and thenalidine did not. After the methoxyphenyl-piperazine containing substance--haloanisone--micromelia was higher as compared to that containing no piperazine moiety (haloperidol). These results indicate that the piperazine-ring may play an important role in the teratogenicity of drugs in rats.

Clofibrate and the development of rats.

The peri- and postnatal effects of Clofibrate (CPIB) were studied in Wistar-H-Riop rats. 150 mg/kg/day of CPIB given to mothers from 16th gestational day to the 22nd day post partum decreased the birth-weight and increased the liver-weight of the young rats the and perinatal mortality. This effect was studied in the offspring of dams treated during the last week of pregnancy or in different periods of lactation. Increased liver weight was found in the newborn at the end of treatment period however, it disappeared after 1 week without treatment.