ABSTRACT
OBJECTIVE: Mifepristone (RU486) is an oral first-line contraceptive used by hundreds of millions of women, and recently it was tested for anticancer activity in both genders worldwide. We are developing metapristone (the N-monodemethyl RU486) as a potential metastasis chemopreventive. The present acute and 30-d subacute toxicity study aimed at examining and compared in parallel the potential toxicity of the two drugs. METHODS: The single-dose acute toxicity and 30-d subacute toxicity studies were conducted in mice and rats, respectively, by gavaging metapristone or mifepristone at various doses. Blood samples and organs were collected for blood chemistry, hematology and histology analyses. RESULTS: Oral mifepristone (3000 mg/kg) caused 30% and 40% death in female and male mice, respectively, within 15 h post-dosing. In comparison, the same dose of metapristone produced 30% acute death in males only. Thirty-day oral administration of the two drugs to rats (12.5, 50 and 200 mg/kg/day) caused reversible hepatotoxicity that only occurred at 200 mg/kg/day group, evidenced by the elevated liver enzyme activity and liver organ weight. CONCLUSION: The present study, for the first time, reveals reversible hepatotoxicity in rats caused by the 30-d consecutive administration at the high dose, and warns the potential hepatotoxicity caused by long-term administrations of high doses of mifepristone or metapristone in clinical trials but not by the acute single abortion doses.
Subject(s)
Abortifacient Agents, Steroidal/toxicity , Chemical and Drug Induced Liver Injury/pathology , Mifepristone/analogs & derivatives , Mifepristone/toxicity , Abortifacient Agents, Steroidal/administration & dosage , Animals , Female , Male , Mifepristone/administration & dosage , RatsABSTRACT
Our aim was to characterize an ovine model of preterm birth that allows analysis of the developmental effects of preterm birth in the absence of postnatal confounding factors. Preterm birth was induced at 131 days of gestation in 82 lambs; controls (n = 31) were born at term (145 days). Overall survival of preterm lambs was 60%; males had significantly lower survival than females (44% vs 76%); 94% of term lambs survived. Although the birth weight of preterm lambs was approximately 0.9 kg lower than in term lambs, the crown-to-rump and forelimb lengths were similar. At 9 weeks after term-equivalent age, there were no differences in body weight or dimensions between preterm and term lambs; when adjusted for body weight, the heart was 21% heavier in preterm than term lambs. We conclude that moderately preterm birth in sheep is characterized by a greater survival of female lambs than males and has significant effects on organ development.
Subject(s)
Disease Models, Animal , Labor, Induced , Premature Birth , Sheep, Domestic/growth & development , Abortifacient Agents, Steroidal/toxicity , Androstenols/toxicity , Animals , Betamethasone/administration & dosage , Betamethasone/therapeutic use , Female , Labor, Induced/methods , Male , Pregnancy , Premature Birth/chemically induced , Premature Birth/mortality , Protective Agents/administration & dosage , Protective Agents/therapeutic useABSTRACT
Glucocorticoids have been implicated in some of the immunosuppressive effects associated with acute ethanol (EtOH) intoxication, but other neuroendocrine mediators that are induced by EtOH can also be immunosuppressive. The possibility that glucocorticoids may act additively or synergistically with other mediators to produce immunosuppression has not been fully investigated. In the present study, complementary methods were used to address this issue. EtOH dose-responsively decreased the following parameters in the spleen in B6C3F1 mice: total cell number, mature B cell (IgM+IgD+) number, and expression of MHC class II molecules on B cells. These effects were most pronounced 12 hr after administration of EtOH. The glucocorticoid antagonist, RU 486, completely or partially blocked these effects. Thus, glucocorticoids seem necessary for full expression of these immunological changes in EtOH-treated mice. To determine if glucocorticoids are also sufficient to cause these effects, corticosterone was administered to achieve serum levels and kinetics comparable to those in EtOH-treated mice. This decreased the expression of MHC class II molecules on B cells to the same extent as treatment with EtOH. However, the other parameters were not affected by administration of corticosterone. Thus, corticosterone is necessary and sufficient to decrease expression of MHC class II molecules on splenic B cells, but other mediators in addition to corticosterone are required to decrease total spleen cell number and the number of mature B cells in the spleen.
Subject(s)
B-Lymphocytes/drug effects , Central Nervous System Depressants/toxicity , Ethanol/toxicity , Glucocorticoids/physiology , Histocompatibility Antigens Class II/biosynthesis , Immunosuppressive Agents/toxicity , Abortifacient Agents, Steroidal/toxicity , Analysis of Variance , Animals , Anti-Inflammatory Agents/toxicity , B-Lymphocytes/cytology , B-Lymphocytes/immunology , Cell Count/drug effects , Corticosterone/blood , Corticosterone/toxicity , Dose-Response Relationship, Drug , Female , Flow Cytometry , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Glucocorticoids/antagonists & inhibitors , Male , Mice , Mice, Inbred C57BL , Mifepristone/toxicity , Specific Pathogen-Free Organisms , Spleen/cytology , Spleen/drug effects , Spleen/immunologyABSTRACT
Evolution of pregnancy in rabbits depends upon ovarian progesterone. A deficiency in ovarian hormones was observed a long time ago to result either in abortion or in "partial pregnancy" or even in fetal anomalies. Administration to pregnant rabbits, from day 11 on, of a hormonal antagonist known for its anti-progesterone activity, RU486, at a sub-abortive dosage, reproduces the effects of ovarian hormone deficiencies.
