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.

The effect of perphenazine treatment during the organogenesis in rats.

The teratogenic effect of perphenazine was studied in closed-bred Wistar rats. Rats were given the substance orally continuously on days 7 to 14 of pregnancy, or as a single dose on one of days 9-15. The doses were considerably higher than the specific neuroleptic doses of perphenazine (20-150 mg/kg). The fetal mortality and malformation rates were significantly higher in the perphenazine-treated groups than in the controls. The results were compared with the earlier results of methophenazine treatment. Perphenazine was found to be more toxic for rat embryos than methophenazine.

Action of the phenothiazine derivative methophenazine on prenatal development in rats.

Single doses of 100-400 mg/kg or multiple doses of 10 or 50 mg/kg of the phenothiazine derivative methophenzaine were given per osto Wistar rats at various times on the 7th-14th days fo gestation and the fetuses examined near term. Results indicated that methophenazine was mainly embryolethal when administered on the 8th-11th days, and was teratogenic at later times, producing types of malformations that depended on the day of treatment, the most susceptible period being the 13th and 14th days of gestation. Teratogenicity occurred only when the dosages were highly toxic to the pregnant rats. Ribovlavin given ip on the 14th day significantly reduced the embryolethal but not the teratogenic action of methophenazine.

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.

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.

Terminology of developmental abnormalities in common laboratory mammals (version 1).

This paper presents the first version of an internationally-developed glossary of terms for structural developmental abnormalities in common laboratory animals. The glossary is put forward by the International Federation of Teratology Societies (IFTS) Committee on International Harmonization of Nomenclature in Developmental Toxicology, and represents considerable progress toward harmonization of terminology in this area. The purpose of this effort is to provide a common vocabulary that will reduce confusion and ambiguity in the description of developmental effects, particularly in submissions to regulatory agencies worldwide. The glossary contains a primary term or phrase, a definition of the abnormality, and notes, where appropriate. Selected synonyms or related terms, which reflect a similar or closely related concept, are noted. Nonpreferred terms are indicated where their usage may be incorrect. Modifying terms used repeatedly in the glossary (e.g., absent, branched) are listed and defined separately, instead of repeating their definitions for each observation. Syndrome names are generally excluded from the glossary, but are listed separately in an appendix. The glossary is organized into broad sections for external, visceral, and skeletal observations, then subdivided into regions, structures, or organs in a general overall head to tail sequence. Numbering is sequential, and not in any regional or hierarchical order. Uses and misuses of the glossary are discussed. Comments, questions, suggestions, and additions from practitioners in the field of developmental toxicology are welcomed on the organization of the glossary as well as on the specific terms and definitions. Updates of the glossary are planned based on the comments received.