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PubMed2004

Effects of mifepristone on vascular endothelial growth factor and thrombospondin-1 mRNA in Ishikawa cells: implication for the endometrial effects of mifepristone.

Mifepristone has been used for both medical termination of pregnancy and emergency contraception. Mifepristone may have both an antiovulatory activity and an antiproliferative effect on the endometrium. We have evaluated the effect of mifepristone on vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1) using Ishikawa cells in vitro. Mifepristone, progesterone and 17beta-estradiol at concentrations of 1.0, 0.1 and 0.01 microM, were added to confluent cells and further cultured for additional 24 h. Total RNA was extracted from control and treated cells. After reverse transcription, VEGF, TSP-1 and beta-actin cDNAs were amplified with polymerase chain reaction spiked with 33p-dCTP. The relative abundance of VEGF 121 and 165 isoforms and TSP-1 mRNA were measured by scintillation spectroscopy. Mifepristone and progesterone did not stimulate VEGF mRNA 121 and 165 isoforms, while 17beta-estradiol increased both VEGF isoforms. Mifepristone did not stimulate TSP-1 mRNA at any concentration, but progesterone increased TSP-1 mRNA, and this effect was inhibited with mifepristone. 17beta-Estradiol did not increase TSP-1 expression. We hypothesized, based on these data, that the clinical finding of endometrial antiproliferative effect and low vaginal bleeding rate observed in women using mifepristone may be related to lack of stimulation of these angiogenic factors.

Adenocarcinoma↗
PubMed1994

Termination of early pregnancy by two regimens of mifepristone with misoprostol and mifepristone with PG05--a multicentre randomized clinical trial in China.

A multicentre randomized open clinical trial was conducted to compare the efficacy and side effects of two regimens of mifepristone with misoprostol, and mifepristone with PG05 for termination of early pregnancy (amenorrhoea < = 49 days). Six-hundred women in early pregnancy, who requested medical abortion were randomly allocated into 3 groups. In group 1 (n = 301), an initial dose of mifepristone 50 mg was given, followed by 25 mg every 12 hours up to a total dose of 150 mg mifepristone, plus a single oral dose of misoprostol 600 micrograms in the morning of the third day. In group 2 (n = 150), the same regimen of mifepristone was given, but dl-15-methyl PGF2 alpha (PG05) 1 mg vaginal suppository was inserted on the third day. In group 3 (n = 149), a single dose of mifepristone 200 mg was given and misoprostol 600 micrograms was used as in group 1. The complete abortion rate were 94.4%, 97.3%, and 94.6% for group 1, 2 and 3, respectively. 3.0, 2.0 and 2.7% of women had incomplete abortion, and 1.7, 0.7 and 2.0% of women in the 3 groups were treatment failures; in the remaining 1% in group 1 and 0.7% in group 3, treatment outcome could not be determined. There were no significant differences among the 3 groups. Lower abdominal pain was the main complaint which was reported by 82% of the subjects after PGs administration. The incidence of diarrhoea in PG05 group (38.7%) was significantly higher than that in the other two groups (21.6 and 20.1%) (P < 0.001), and so was vomiting. It was concluded that misoprostol, as an orally effective prostaglandin, in combination with mifepristone for induced abortion of early pregnancy was as effective as PG05 vaginal suppository. Besides, it has advantages of convenience of use, less side effects, easy storage and transfer, and low cost.

Abdominal Pain↗
PubMed1999

In vitro metabolism of mifepristone (RU-486) in rat, monkey and human hepatic S9 fractions: identification of three new mifepristone metabolites.

1. In vitro metabolism of the antiprogestin drug mifepristone (RU-486) was studied after incubation with rat, monkey and human hepatic S9 fractions in the presence of an NADPH-generating system. 2. Unchanged mifepristone (approximately 45% of the sample(s) in rat; approximately 70% in monkey; approximately 65% in human) plus six metabolites, three known and three new, were profiled, quantified and tentatively identified on the basis of MS and MS/MS data. 3. The proposed metabolic pathways for mifepristone are proposed, and the two metabolic steps are (A) N-demethylation and (B) methyl oxidation. 4. Step A formed N-desmethyl mifepristone (M1) in major amounts (approximately 35% s in rat, 16% in monkey and human) and N,N-didesmethyl mifepristone (M2) in minor amounts (< 5% s in all species). Step B, or in conjunction with step A, produced four minor/trace metabolites, namely hydroxymethyl mifepristone (M3), hydroxymethyl M1 (M4), hydroxymethyl M2 (M5) and formyl mifepristone (M6).

Acetates↗
PubMed1991

Pregnancy termination with mifepristone and gemeprost: a multicenter comparison between repeated doses and a single dose of mifepristone. World Health Organization.

OBJECTIVE: To compare two regimens of mifepristone plus gemeprost for early pregnancy termination. DESIGN: A prospective, randomized, multicenter trial. SETTING: Ten gynecological services, mostly in academic hospitals. PARTICIPANTS: Three hundred eighty-five healthy women up to 35 years of age with amenorrhea less than or equal to 49 days requesting pregnancy termination. TREATMENT: Mifepristone, 25 mg five times at 12-hour intervals (n = 192) or 600 mg as a single dose (n = 193) followed by 1 mg gemeprost 60 hours after the start of mifepristone. MAIN OUTCOME MEASURES: Pregnancy outcome, time of onset and duration of vaginal bleeding, subjective complaints, and hormone changes during treatment and 6-week follow-up. RESULTS: Treatment outcome was identical in both groups with an overall complete abortion rate of 92.7% among the 385 women included in the analysis. The frequency of complaints, bleeding patterns, and changes in hemoglobin, beta-human chorionic gonadotropin, estradiol, and progesterone were also similar in both groups. Cortisol (at 12 and 36 hours after mifepristone) and prolactin (at 12 hours) were significantly higher in the single 600-mg dose group. CONCLUSION: When used for early pregnancy termination with prostaglandin, a lower dose of mifepristone than the currently recommended single 600-mg dose may suffice.

Abortion, Induced↗
PubMed1993

The effect of dose of mifepristone and gestation on the efficacy of medical abortion with mifepristone and misoprostol.

Although it has been demonstrated that a combination of mifepristone and a prostaglandin is an effective method of inducing abortion in early pregnancy, the optimum dose of the antigestogen is unknown. Women (n = 220) requesting abortion in early pregnancy (< or = 63 days amenorrhoea) were randomized to receive a single dose of either 600 or 200 mg mifepristone followed 48 h later by a single dose of 600 micrograms misoprostol by mouth. The percentage of women who had a complete abortion (93.6% confidence interval 90.4-95.5%) was identical in the two groups. There was no significant difference in the number of women who passed the fetus within 4 h of receiving the prostaglandin (64 versus 74%), the days of bleeding (14.6 +/- 1.1 versus 15.3 +/- 0.9) nor in the onset of the next period (39.7 +/- 1.3 versus 36.7 +/- 1.3) respectively between the groups receiving 200 or 600 mg mifepristone. However, the complete abortion rate was significantly higher in women < or = 49 days compared to women 50-63 days amenorrhoea (97.5 versus 89.1% respectively; P < 0.02). There was no difference in any of the other parameters at different weeks of gestation. We conclude: (i) that the recommended dose of mifepristone could be reduced from 600 to 200 mg without loss of clinical efficacy, (ii) that the combination of mifepristone and 600 micrograms misoprostol is a highly effective alternative to vacuum aspiration for inducing abortion in women < 50 days amenorrhoea and (iii) at gestation > 56 days, this combination may result in too many incomplete abortions to be clinically acceptable.

Abortion, Induced↗
PubMedDate not supplied

Acceptability and feasibility of early pregnancy termination by mifepristone-misoprostol. Results of a large multicenter trial in the United States. Mifepristone Clinical Trials Group.

OBJECTIVES: To evaluate whether the regimen of oral mifepristone and misoprostol for medical abortion is acceptable to women and providers, in the United States, including physicians, nurses, and counselors, and whether proposed modifications of this regimen appear feasible for clinical practice. DESIGN: A prospective study. SETTING: Seventeen clinics in 15 states. PARTICIPANTS: A total of 2121 women with pregnancies of 63 days or less in duration. INTERVENTIONS: The administration of mifepristone, 600 mg, orally, followed after 2 days by the administration of misoprostol, 400 micrograms, orally. Clinical observation for 4 hours followed misoprostol administration. Two weeks later, at a checkup, women were questioned about the abortion experience. Providers also answered questions about acceptability and feasibility. MAIN OUTCOME MEASURES: Patient reports of overall satisfaction with the abortion, the number of women who would choose medical abortion again if needed or recommend the method to others, the best and worst features of the method, and provider and patient assessments of home use. RESULTS: The regimen was highly acceptable. Nearly all women (95.7%) would recommend it to others, 91.2% would choose it again, and 87.6% found it very or moderately satisfactory. Even among women for whom the method failed, 69.6% would try it again, 84.9% would recommend it to others, and 51.9% found it very or moderately satisfactory. The chance to avoid a surgical procedure was reported as the method's best feature. The most commonly cited worst features were the uncertainty and fear of side effects. Providers and women considered home use feasible and safe. CONCLUSIONS: American women found abortion with the use of mifepristone and misoprostol acceptable. Even most with unsuccessful outcomes would select the regimen again and recommend it to others. Most providers and women thought that home use of misoprostol should be available for women who prefer it.

Abortifacient Agents, Steroidal↗
PubMed1995

Inhibition of some aspects of acute inflammation of guinea-pig lung by intraperitoneal dexamethasone and mifepristone: demonstration of agonist activity of mifepristone in the guinea-pig.

We have determined the inhibitory activity of dexamethasone as an inhibitor of histamine-induced plasma protein extravasation (PPE) in guinea-pig lung and skin, and of lipopolysaccharide (LPS)-induced neutrophilia and platelet activating factor (PAF)-induced eosinophilia in guinea-pig lungs. Dexamethasone inhibited PAF-induced eosinophilia in guinea-pig lung (ED50 1.4 mg/kg i.p.). Higher doses of dexamethasone were required to inhibit LPS-induced neutrophilia (ED50 10.8 mg/kg i.p.). However, at doses up to 150 mg/kg i.p. dexamethasone did not inhibit histamine-induced plasma protein extravasation (PPE) in guinea-pig lung, but did inhibit PPE in guinea-pig skin. These preparations have previously been shown to be equally sensitive to inhibition by the beta 2-adrenoceptor agonist salmeterol. Dexamethasone inhibited PAF-induced eosinophilia (5 mg/kg) or LPS-induced neutrophilia (50 mg/kg) when given 3 h or 1 h prior to challenge. Inhibitory activity was lost when dexamethasone was administered 23 h prior to LPS or 1 h after PAF. The glucocorticoid antagonist mifepristone (1-100 mg/kg i.p.) caused dose-related inhibition of PAF-induced eosinophilia but not of LPS-induced neutrophilia. The highest dose of mifepristone used (100 mg/kg) did not reverse the inhibitory actions of dexamethasone (50 mg/kg) on LPS-induced neutrophilia. We suggest that the different inhibitory activity of dexamethasone in the preparations studied indicates differences in the sensitivity of the target cells involved to inhibition by dexamethasone. We also suggest that inhibition of PAF-induced eosinophilia by mifepristone reflects the partial agonist activity of this agent, demonstrated by others in different experimental systems.

Acute Disease↗
PubMed2004

[Effects of mifepristone on the proliferation, apoptosis, and cis-platinum (DDP) sensitivity of chemo-resistant human ovarian cancer cells].

BACKGROUND & OBJECTIVE: Mifepristone is an effective progesterone receptor antagonist. It was reported that mifepristone can inhibit the growth of ovarian carcinoma cells either in vitro or in vivo, but the exact mechanism is unknown. The effect of mifepristone on the growth, apoptosis and cis-platinum (DDP)-sensitivity of chemo-resistant ovarian carcinoma cell lines have scarcely been reported. The purpose of this study was to investigate the effect and its mechanism of mifepristone on the proliferation, apoptosis and DDP sensitivity of DDP-resistant human ovarian carcinoma cells, and to give experimental basis for treating refractory ovarian carcinoma with mifepristone. METHODS: DDP-resistant human ovarian carcinoma cell line SK-OV-3 cells were cultured in vitro, and the MTT assay was used to examine the antiproliferative effect of mifepristone with or without DDP on SK-OV-3 cells. The cooperative effects between mifepristone and DDP in inhibiting the growth of SK-OV-3 cells were analyzed. TdT mediated dUTP nick end labeling (TUNEL) and flow cytometry (FCM) were used to examine the effects of mifepristone with or without DDP on the apoptosis and cell cycle of SK-OV-3 cells. RESULTS: Mifepristone produced concentration-dependent antiproliferative effect on SK-OV-3 cells at all experimental concentrations.Enhanced antiproliferative effects were found when SK-OV-3 cells were cultured with mifepristone at 0.625, 1.25, 2.5, 5, 10, and 20 microg/ml combined with 1.25 microg/ml or 2.5 microg/ml DDP (q >1.15). Only additive effects were found when the cells were cultured with mifepristone and 0.625 microg/ml or 5.0 microg/ml DDP (0.85< q< 1.15). Mifepristone induced concentration-dependent apoptosis in SK-OV-3 cells and arrested cells in the G(0)/G(1)-phase of cell cycle. The apoptosis rate were 14.52%, 36.14%, and 53.22%,respectively,when the cells were cultured with mifepristone at 1.25, 2.50, and 5.00 microg/ml. The percentage of G(0)/G(1)-phase cells was increased with the concentration of mifepristone. Synergic effect between mifepristone (at 1.25, 2.5, and 5 microg/ml) and 2.5 microg/ml DDP was found in inducing SK-OV-3 cells apoptosis (q >1.15) and G0/G1-phase stasis. CONCLUSION: Mifepristone can inhibit the growth of chemo-resistant human ovarian carcinoma cells,and enhance its DDP sensitivity. This may be associated with the synergic effect between mifepristone and DDP in inducing apoptosis and G(0)/G(1)-phase stasis.

Apoptosis↗
PubMed1997

Clinical pharmacokinetics of mifepristone.

Mifepristone is a steroidal antiprogestin and antiglucocorticoid acting at the receptor level. The aromatic dimethylaminophenyl side chain in position 11 of the steroid structure is essential for the antagonistic properties of mifepristone. The pharmacokinetics of mifepristone are characterised by rapid absorption, a long half-life of 25 to 30 hours and micromolar serum concentrations following ingestion of doses currently in clinical use. The serum transport protein alpha 1-acid glycoprotein (AAG) regulates the serum kinetics of mifepristone. Binding to AAG limits the tissue availability of mifepristone, explaining the low metabolic clearance rate of 0.55 L/kg/day and the low volume of distribution of mifepristone. Also, similar serum concentrations of mifepristone following ingestion of single doses exceeding 100mg can be explained by saturation of the binding capacity of serum AAG. Following oral intake, mifepristone is extensively metabolised by demethylation and hydroxylation, the initial metabolic steps are catalysed by the cytochrome P450 (CYP) enzyme CYP3A4. The 3 most proximal metabolites, namely the monodemethylated, didemethylated and hydroxylated metabolites of mifepristone, all retain considerable affinity toward the human progesterone and glucocorticoid receptors; in addition, the serum concentrations of these 3 metabolites are in a similar range as those of the parent drug. Thus, the combined pool of mifepristone, as well as that of the metabolites, seems responsible for the biological actions of mifepristone. Combination therapy with mifepristone and low dose prostaglandin is currently in clinical use for termination of early pregnancy in China, France, Sweden and the UK. The combined regimen is well tolerated and highly efficacious with a 95% rate of complete pregnancy terminations. Recent clinical studies on pregnancy termination have focused on dose optimisation of mifepristone and evaluation of the orally active prostaglandin derivative misoprostol. In addition, several other indications for the clinical use of mifepristone, such as induction of labour, contraception, as well as treatment of various hormone dependent disorders, are emerging. The major obstacles currently inhibiting further evaluation and distribution of mifepristone are political rather than clinical. However, it is hoped that the eventual introduction of new antiprogesterone molecules by several manufacturers will enhance the availability of this important class of new drugs.

Abortifacient Agents, Steroidal↗
PubMed2000

Mifepristone for induction of labour.

BACKGROUND: The steroid hormone, progesterone, inhibits contractions of the uterus. Antiprogestins (including mifepristone) have been developed to antagonise the action of progesterone, and these have a recognised role in medical termination of early or mid-pregnancy. Animal studies have suggested that mifepristone may also have a role in inducing labour in late pregnancy. OBJECTIVES: To determine the effects of mifepristone for third trimester cervical ripening or induction of labour. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register, the Cochrane Controlled Trials Register, and reference lists of relevant papers. SELECTION CRITERIA: Selection criteria included: (1) clinical trials comparing mifepristone used for third trimester cervical ripening or labour induction with placebo/no treatment or other labour induction methods; (2) random allocation to the treatment or control group; (3) adequate allocation concealment; (4) violations of allocated management not sufficient to materially affect conclusions; (5) clinically meaningful outcome measures reported; (6) data available for analysis according to the random allocation; (7) missing data insufficient to materially affect the conclusions. DATA COLLECTION AND ANALYSIS: This is one of a series of reviews of methods of cervical ripening and labour induction using standardised methodology. Data were extracted by the reviewer and, independently, by a colleague. MAIN RESULTS: Seven trials, that recruited 594 women, are included. All trials compared mifepristone with placebo, except for one that compared mifepristone with no treatment. Compared to placebo, mifepristone treated women were less likely to have an unfavourable cervix at 48 hours (relative risk [RR] 0.36, 95% confidence intervals [CI] 0.2-0.63) or 96 hours (RR 0.39, 95% CI 0.23-0.66). Mifepristone treated women were more likely to have delivered within 48 and 96 hours of treatment than were placebo treated/no treatment women - 48 hours: RR 2.82, 95% CI 1.82-4.36; 96 hours: RR 3.40, 95% CI 1.96-5.92. Mifepristone treated women were less likely to undergo caesarean section (RR 0.71, 95% CI 0.53-0.95). There is little information about fetal outcome, although there was no evidence that neonatal hypoglycaemia might be more common after exposure to mifepristone. Similarly, there is little information about maternal side-effects although some nausea and vomiting was reported in one trial. REVIEWER'S CONCLUSIONS: There is insufficient information available from clinical trials to support the use of mifepristone to induce labour. However, available data do show that mifepristone is better than placebo at ripening the cervix, and inducing labour. There is evidence of a possible reduction in the incidence of caesarean section following mifepristone treatment (compared to placebo) that would justify further trials. We found no trials that compared mifepristone with alternative methods of inducing labour e.g. prostaglandins.

Clinical Trials as Topic↗
PubMed2003

The pharmacokinetics of mifepristone in humans reveal insights into differential mechanisms of antiprogestin action.

The pharmacokinetics of mifepristone is characterized by rapid absorption, a long half-life of 25-30 h, and high micromolar serum concentrations following ingestion of doses of >/=100 mg of the drug. The serum transport protein-alpha 1-acid glycoprotein (AAG)-regulates the serum kinetics of mifepristone in man. Binding to AAG limits the tissue availability of mifepristone, explaining its low volume of distribution and low metabolic clearance rate of 0.55 L/kg per day. In addition, the similar serum levels of mifepristone following ingestion of single doses exceeding 100 mg can be explained by saturation of the binding capacity of serum AAG. Mifepristone is extensively metabolized by demethylation and hydroxylation, the initial metabolic steps being catalyzed by the cytochrome P-450 enzyme CYP3A4. The three most proximal metabolites, namely, monodemethylated, didemethylated and hydroxylated metabolites of mifepristone, all retain considerable affinity toward human progesterone and glucocorticoid receptors. Also, the serum levels of these three metabolites are in ranges similar to those of the parent mifepristone. Thus, the combined pool of mifepristone-plus its metabolites-seems to be responsible for the biological actions of mifepristone. Recent clinical studies on pregnancy termination and emergency contraception have focused on optimization of the dose of mifepristone. In these studies it has become apparent that the doses efficient for pregnancy termination differ from those needed in emergency contraception-mifepristone is effective in emergency contraception at a dose of 10 mg, which results in linear pharmacokinetics. However, the >/=200 mg doses of mifepristone needed for optimal abortifacient effects of mifepristone result in saturation of serum AAG and thus nonlinear pharmacokinetics. In view of the pharmacokinetic data, it may be speculated that dosing of mifepristone for pregnancy termination and for emergency contraception could be reduced to approximately 100 mg and 2-5 mg, respectively. It remains to be seen whether the newly synthesized, more selective antiprogestins will prove more efficacious in the clinical arena.

Contraceptives, Postcoital, Synthetic↗
PubMed2004

Mifepristone is an effective oral alternative for the prevention of premature luteinizing hormone surges and/or premature luteinization in women undergoing controlled ovarian hyperstimulation for in vitro fertilization.

The present clinical study was conducted to investigate the effectiveness of a daily dose of 40 mg mifepristone in preventing premature LH surges in women undergoing controlled ovarian hyperstimulation (COH) for in vitro fertilization and to study the effect of this antiprogestin cotreatment on endometrial receptivity. This was a prospective, open-label, randomized, exploratory study in 15 healthy volunteer oocyte donors who were randomly allocated to the experimental COH group, including mifepristone (group 1), or the control group, using a long protocol with GnRH agonists (group 2), in a ratio of 2:1, i.e. 10 and five subjects, respectively. In group 1, human chorionic gonadotropin (hCG) was randomly administered (group 1A) or was withheld (group 1B) at the end of stimulation, so that two subgroups of five subjects each were formed, differing in the final oocyte maturation trigger. In all patients receiving mifepristone, 50 mg progesterone were administered im at the time of hCG administration to counteract residual antiprogestogenic activity of mifepristone. Serum estradiol, progesterone (P), LH, and FSH levels were monitored in each patient on d 3 and 6 and every 48 h thereafter. Endometrial biopsies were taken 2 and 7 d after hCG or P administration. Endometrial tissue was processed and evaluated in a blinded fashion for endometrial dating and quantitative PCR of at least four genes known to be up-regulated in receptive endometrium. The total FSH dose and duration of treatment in the two arms of the study were similar. The mean LH levels on d 6 of stimulation and the day of hCG/P treatment in the mifepristone group were 0.8 +/- 0.7 and 0.5 +/- 0.6 mIU/ml, and those in control subjects were 2.4 +/- 3.8 and 2.0 +/- 1.7 mIU/ml, respectively. No LH surges were observed in any subject treated with mifepristone. Serum P levels on the day of hCG/P were below the cut-off level (1.2 ng/ml) in all subjects of the mifepristone group (range, <0.5 to 1.05 ng/ml). The mean numbers of cumulus-oocyte complexes retrieved were 11.6 +/- 6.6 and 19.6 +/- 11.8 in the subgroup treated with mifepristone and hCG and in the control group, respectively. The mean percentages of metaphase II, metaphase I, and germinal vesicle stage oocytes were 86.2, 6.9, and 3.4% in the mifepristone group and 68.4, 6.1, and 11.2% in the control group. In the mifepristone group that did not receive hCG and received P only at the end of stimulation, an endogenous LH surge was not observed nor were oocytes obtained. Histological evaluation of endometrial samples in patients treated with mifepristone and hCG (group 1A) confirmed normal development, whereas in patients treated with mifepristone only (group 1B), there was a complete arrest of the endometrial maturation. The expression patterns of glycodelin, IGF-binding protein-7, glutathione peroxidase-3, and solute carrier family 1 member 1 show a striking absence of up-regulation in patients treated with mifepristone (groups 1A and 1B) compared with controls (group 2). The results of this exploratory study provide evidence that mifepristone is effective for the prevention of premature LH surges and/or premature luteinization in women undergoing COH for in vitro fertilization. However, endometrial receptivity status requires additional evaluation after decreasing RU-486 doses before this strategy can be considered as a new alternative to GnRH agonist/antagonist treatment.

Administration, Oral↗
PubMed1998

Mifepristone. Auxiliary therapeutic use in cancer and related disorders.

OBJECTIVE: To evaluate the efficacy of mifepristone, a potent antagonist of progesterone and glucorticoids, in the management of cancer and disorders related to reproduction. STUDY DESIGN: Reports describing clinical trials of mifepristone treatment of leiomyoma, breast cancer, endometriosis and meningioma were reviewed. Mifepristone is a potent antagonist of progesterone and glucocorticoids. It is an effective contraceptive and abortifacient and in addition has been used in the management of diseases associated with pregnancy and adrenal cortical function. Results of the clinical trials show that it has beneficial and palliative value in some cases. Mifepristone may be used as an adjuvant therapeutic agent in cases of unresectable meningioma and leiomyoma that are refractory to chemotherapy, endocrine treatment or irradiation. In extensive endometriosis, mifepristone is indicated for intractable pain, although its effect on the lesions will be minimal. In the management of unresectable and metastatic breast cancer, mifepristone may be considered after a course of chemotherapy and/or irradiation and only in combination with another agent. In Cushing's syndrome mifepristone may be used to treat the undesirable sequelae of excessive cortisol production-e.g., psychosis. It will have minimal or no effect on the lesions of the adrenal or pituitary. The adverse effects of the long-term use of mifepristone are slight to moderate and reflect antiglucocorticoid effects. During treatment with mifepristone one should be aware of the possibility that the patient will develop Addisonian-like syndrome in the face of elevated blood ACTH and cortisol levels. RESULTS: Leiomyoma treated with 25 or 50 mg/d of mifepristone underwent a 25-49% reduction in tumor size. Treatment of endometriosis with a daily dose of 50 or 100 mg of mifepristone alleviated pelvic pain and uterine cramps and induced about 55% regression of the lesions. Treatment of metastatic breast cancer with 200 or 400 mg/d of mifepristone resulted in a partial response. Unresectable meningioma treated with 200 or 400 mg/d of mifepristone produced objective improvement in about 25% of subjects. CONCLUSION: Mifepristone is beneficial as adjuvant treatment in the management of unresectable, hormone-dependent tumors and disorders of the female reproductive system that are refractory to chemotherapy and irradiation.

Adult↗
PubMed1994

Hepatic metabolism and distribution of mifepristone and its metabolites in rats.

The hepatic metabolism of mifepristone was studied in female Wistar rats following oral administration of 10 mg/kg. The extraction of mifepristone by the rat liver was effective, eliminating 80% of the mifepristone. During the absorption phase, the portal serum concentrations of mifepristone were over 10-fold higher than those measured in systemic serum. The serum concentrations of the monodemethylated, didemethylated and hydroxylated metabolites of mifepristone were lower in systemic serum, indicating that the metabolites were also effectively excreted by the rat liver. The distribution of mifepristone and its demethylated metabolites between serum, brain, muscle and adipose tissue was studied in lean and obese Zucker rats following repeated oral administration of 10 mg/kg. The individual serum concentrations of mifepristone varied considerably, from 24-482 ng/ml; the mean (+/- SE) serum concentrations for lean and obese rats were 167 (+/- 86) and 211 (+/- 62) ng/ml respectively. Mifepristone could be measured in brain in each animal, its concentrations being 28% of those measured in serum. Muscle tissue and serum contained approximately similar concentrations of mifepristone. Adipose tissue effectively concentrated mifepristone, and its concentrations were 40-fold higher in fat than in serum. The difference in the concentrations of mifepristone between the lean and obese animals was statistically significant only in brain tissue (P < 0.05). The serum concentrations and brain, muscle and adipose tissue concentrations of mifepristone were significantly correlated (P < 0.05). The distribution of the demethylated metabolites was roughly similar to that of mifepristone. However, their concentrations were significantly higher (P < 0.02) in the obese animals in each tissue type investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed2000

Mifepristone for preinduction cervical ripening beyond 41 weeks' gestation: a randomized controlled trial.

OBJECTIVE: To compare the effect of mifepristone with placebo on cervical ripening before labor induction in prolonged pregnancies. METHODS: One hundred eighty women with pregnancies beyond 41 weeks and undilated, uneffaced cervices were assigned randomly to receive mifepristone 200 mg or placebo and observed for 24 hours. We then gave intravaginal misoprostol 25 microg every 4 hours or intravenous oxytocin. We expected 60% of placebo-treated and 80% of mifepristone-treated women to deliver vaginally within 48 hours. RESULTS: Among 180 subjects, 97 received mifepristone and 83 received placebo. The mean interval (+/- standard deviation [SD]) from start of induction to delivery was 2209 +/- 698 minutes for mifepristone-treated subjects and 2671 +/- 884 minutes for placebo-treated subjects (P <.001, log-transformed data). Twelve (13. 6%) mifepristone-treated women and seven (10.8%) placebo-treated women delivered vaginally on day 1 (P =.60). After 24 hours, the median Bishop score for both groups was 3 (0-11) (P =.51). One hundred thirty-one subjects required misoprostol, 65 (67.0%) were mifepristone-treated women, and 66 (79.5%) placebo-treated women (P =.06). The median (range) oxytocin dose was 871.5 (0-22,174) mU for mifepristone-treated women and 2021.0 (0-24,750) mU for placebo-treated women (P =.02). Seventy-seven (87.5%) mifepristone-treated women and 46 (70.8%) placebo-treated women delivered vaginally 48 hours after the start of treatment (P =.01). There were nine cesareans in the mifepristone group and 18 in the placebo group (P =.02). More nonreassuring fetal heart rate patterns and uterine contractile abnormalities occurred in mifepristone-treated subjects. There were no statistically significant differences in neonatal outcomes between groups. CONCLUSION: Mifepristone had a modest effect on cervical ripening when given 24 hours before labor induction, appearing to reduce the need for misoprostol and oxytocin compared with placebo.

Adult↗
PubMed2003

Antiandrogen effects of mifepristone on coactivator and corepressor interactions with the androgen receptor.

Mifepristone is a potent antagonist of steroid hormone receptors such as glucocorticoid and progesterone receptors. We investigated the potential for mifepristone to act as an antiandrogen and compared it with partial androgen receptor (AR) agonists and antagonists, in particular bicalutamide. Mifepristone was an effective antiandrogen in vitro that inhibited transcription from three androgen-responsive promoters and blocked the agonist R1881 in a dose-dependent manner. Like bicalutamide, mifepristone also antagonized the action of androgen receptor with a (T877A) mutation. Mifepristone competed effectively with R1881 with a relative binding affinity comparable to that of cyproterone acetate, and much higher than that of hydroxyflutamide and bicalutamide in a binding assay. Mifepristone could effectively induce the binding of the herpes simplex viral protein 16/AR fusion protein to the hormone response elements in the murine mammary tumor virus-luciferase reporter. With either wild-type or T877A mutant AR, mifepristone alone was unable to induce any detectable interaction with coactivators transcriptional intermediary factor-2 or beta-catenin but could inhibit the R1881-induced binding of AR to transcriptional intermediary factor-2 and beta-catenin. Similarly, mifepristone could inhibit the R1881-induced N/C-terminal interaction in a dose-dependent manner even though mifepristone alone has no effect on the N/C-terminal interaction of AR. We found that mifepristone could induce a strong interaction between AR and corepressors nuclear receptor corepressor and silencing mediator for retinoid and thyroid hormone receptors in both transactivation and two-hybrid assays to a greater degree than hydroxyflutamide, cyproterone acetate, and bicalutamide. The AR-corepressor interaction was also seen in coimmunoprecipitation assays. Finally, mifepristone at high concentrations induced a low level of prostate-specific antigen expression in LNCaP and antagonized prostate-specific antigen expression induced by R1881. Mifepristone also antagonized R1881 action on the growth of LNCaP prostate cancer cells.

Androgen Antagonists↗
PubMed2005

Late follicular phase administration of mifepristone suppresses circulating leptin and FSH - mechanism(s) of action in emergency contraception?

OBJECTIVE: Low dose mifepristone (RU486) is highly effective in emergency post-coital contraception (EC), although the mechanism(s) of action remains unclear. We studied the endocrine actions of 10 mg mifepristone administered orally as a single dose to eight healthy volunteers (aged 20-45 years) during the late follicular phase. METHODS: Serum levels of LH, FSH, oestradiol, progesterone, leptin, mifepristone, cortisol, and gluco-corticoid bioactivity (GBA) were measured before and 1, 2, 4 and 8 h after ingestion of mifepristone on cycle day 10 or 11 (study day 1), and follow-up was continued for 10 days. Ovarian ultrasonography was performed on study days 1 and 7. Similar measurements were carried out during a control cycle. RESULTS: Mifepristone postponed ovulation, as evidenced by a 3.4+/-1.1 day (means+/-s.d.) delay (P < 0.005) in the LH surge and 3.6+/-4.0 day prolongation of the treatment cycle (P = 0.08). During the mifepristone cycle, an LH surge was displayed by five subjects when serum mifepristone levels had declined to 9.5+/-7.1 nmol/l. During the day of mifepristone administration, circulating GBA (P < 0.001) and leptin (P < 0.001) levels declined. On the day after mifepristone administration, mean serum FSH and leptin levels were lower than pretreatment values (3.8+/-1.8 IU/l vs 5.2+/-1.1 IU/l, n = 7, P < 0.05; 28.9+/-6.7 microg/l vs 33.2+/-9.0 microg/l, n = 7, P < 0.05 respectively), and the corresponding difference in the mean serum oestradiol concentration was borderline (452+/-252 pmol/l vs 647+/-406 pmol/l, n = 7, P = 0.056). In contrast to the control cycle, individual leptin levels declined during the follow-up after ingestion of mifepristone (n = 8, P < 0.01). CONCLUSIONS: These data showed that the commonly employed dose of mifepristone for EC delays ovulation and prolongs the menstrual cycle, when given during the late follicular phase. The mechanism of action of mifepristone may include a reduction of FSH secretion via a decrease in circulating leptin.

Adult↗
PubMed2003

[Study of effect of mifepristone on apoptosis of human ovarian cancer cell line 3AO].

OBJECTIVE: To investigate the effect of mifepristone on the activity of proliferation and the apoptosis, the expression of estrogen receptor (ER), progesterone receptor (PR) protein and morphology changes of human ovarian carcinoma cell line 3AO and SKOV3 in vitro. METHODS: The proliferative activity of 3AO and SKOV3, which were cultured in vitro, was measured by tetrazolium-based colorimetric assay (MTT assay). Flow cytormetry (FCM) was used to measure the expressive rate of ER, PR, p53 protein, bcl-2 protein, cell apoptotic rate and cell proliferative cycle of 3AO cells, which were cultured with different concentration and duration of mifepristone. The morphologic and ultrastructure changes of apoptotic 3AO cells was observed by the light and electron microscopy. RESULTS: Mifepristone inhibited significantly the proliferation of 3AO cells in dose-time dependent manner in vitro. The inhibitory rate of 3AO cells growth, which were cultured with different concentration of mifepristone (5, 10, 20, 40, 80 micro mol/L) and duration (24, 48, 72 h) was from 1.7% to 75.0% (P < 0.01), but the proliferation activity of SKOV3 cells in vitro had not significant changes (P > 0.05). 3AO cells apoptosis activity appeared the positive correlation with the dose of mifepristone and cultured duration (P < 0.01). Mifepristone blocked 3AO cells proliferative cycle at the G(0)-G(1) stage, decreased the cell radio of S stage. Mifepristone induced the apoptosis of 3AO cells in vitro. The light and electron microscopy demonstrated that 3AO cells cultured with mifepristone appeared typical morphological characteristics of apoptosis including the compaction and margination of the chromosomes, nuclear fragments and formation of apoptotic bodies. Mifepristone up-regulated significantly the expression of p53 protein, but down-regulated the expression of bcl-2 protein (P < 0.01). The expressive rates of p53 and bcl-2 proteins were (54.8 +/- 4.0)% and (10.1 +/- 1.2)%, respectively, when 3AO cells was cultured with mifepristone of 10 micro mol/L for 24 h. Compared with the expression rates of control group (27.1 +/- 3.3)% and (17.6 +/- 1.0)%, the difference was significant (P < 0.01). The expressive rate of PR protein of 3AO cells cultured with mifepristone of 10 micro mol/L for 48 h was (12.7 +/- 1.4)%, which was decreased compared with the expressive rate of control group (44.9 +/- 1.4)% (P < 0.01). CONCLUSIONS: Mifepristone inhibited significantly the proliferation and induced the cell apoptosis of cell line 3AO in dose-time dependent manner in vitro. The anti-tumor effect was related to down-regulation the expression of PR protein and bcl-2 protein, and to up-regulation the expression of p53 protein of 3AO cells.

Apoptosis↗