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Current Opinion in Obstetrics &... Jun 2002Mifepristone is an orally active progesterone antagonist. It can be used for both contraceptive and non-contraceptive clinical indications. It is a very effective drug... (Review)
Review
Mifepristone is an orally active progesterone antagonist. It can be used for both contraceptive and non-contraceptive clinical indications. It is a very effective drug for emergency contraception with a low incidence of side effects. There is a potential for mifepristone to be used as a once-a-month pill. There is a need, however, for a simple, inexpensive and accurate method to identify the luteinizing hormone surge before this method can be used in clinical practice. The daily administration of mifepristone offers promise as an effective method of contraception but more studies need to be done. The combination of mifepristone with a prostaglandin analogue is a well-established method for termination of pregnancy of up to 9 weeks. Recent data suggest that this combination may also be used up to 9-13 weeks of pregnancy. Although mifepristone is effective in dilating the cervix before vacuum aspiration, misoprostol is probably the drug of choice in most situations. In the second trimester, mifepristone is effective in shortening the abortion process induced by prostaglandin analogues. The combination of mifepristone and prostaglandin also offers a medical method for management of miscarriages. Mifepristone has been used for a number of other indications, but further studies are needed before such treatment can be recommended.
Topics: Abortifacient Agents, Steroidal; Contraceptives, Oral, Synthetic; Contraceptives, Postcoital, Synthetic; Female; Humans; Mifepristone; Pregnancy
PubMed: 12032390
DOI: 10.1097/00001703-200206000-00013 -
European Journal of Obstetrics,... Mar 2002The potentiality of mifepristone as an abortifacient and contraceptive drug along with its pharmacokinetic parameters is reviewed. Mifepristone or RU486 acts as... (Review)
Review
The potentiality of mifepristone as an abortifacient and contraceptive drug along with its pharmacokinetic parameters is reviewed. Mifepristone or RU486 acts as antagonist to progestational and glucocorticoid functions. It is an orally active compound with nearly 70% absorption rate but its bioavailability is reduced to around 40% because of the first-pass effect. Peak plasma concentrations of 1.9 +/- 0.8, 3.8 +/- 0.9 and 5.3 +/- 1.3 micromol/l are reached within 1-2 h after oral administration of 50, 200 and 600 mg mifepristone in women, respectively, and are maintained at relatively high level up to 48 or 72 h depending on the ingested dose. The plasma kinetics of mifepristone followed two-compartment open model with a mean alpha-half-life of 1.4h, volume of distribution 1.47 l/kg and beta-half-life of 20-30 h in most of the subjects studied. Clearance from the body was mainly through feces (83%). Biologically active mono-demethylated, di-demethylated and hydroxylated metabolites were found in plasma soon after oral administration of mifepristone. RU486 and its mono-demethylated metabolite bind to progesterone receptors with high affinity. Mifepristone-bound receptor dimers suppress transcription activation and thus, bring about anti-progestational activity that makes mifepristone a potential abortifacient and contraceptive agent. Clinical trials for termination of early pregnancy with 50-600 mg mifepristone plus a prostaglandin analogue achieved a success rate of 82-97%. However, abdominal pain, cramping, nausea, vomiting, bleeding and delay in onset of the next menstrual cycle were the side effects. Administration of 25 mg mifepristone twice 12h apart, as a post-coital contraceptive showed 100% contraceptive efficacy. A low dose of mifepristone which does not inhibit ovulation reduced fertility significantly by affecting endometrial milieu. These findings suggest that reduced dose(s) of mifepristone, 200 mg or less, may be used as a post-coital contraceptive and in combination with vaginal misoprostol for termination of early pregnancy with high efficacy and minimal or no side effects.
Topics: Abortifacient Agents, Steroidal; Biological Availability; Contraceptives, Postcoital, Synthetic; Female; Half-Life; Humans; Metabolic Clearance Rate; Mifepristone
PubMed: 11858883
DOI: 10.1016/s0301-2115(01)00522-x -
Pharmacotherapy Mar 2013Cushing's syndrome is a debilitating endocrine disorder caused by elevated circulating glucocorticoid levels. Although uncommon, Cushing's syndrome is associated with... (Review)
Review
Cushing's syndrome is a debilitating endocrine disorder caused by elevated circulating glucocorticoid levels. Although uncommon, Cushing's syndrome is associated with significant morbidity necessitating rapid reversal of hypercortisolemia. Primary therapy for most patients with Cushing's syndrome is surgical, but many patients will require additional treatments with radiation or drugs. Although several options for drug therapy exist, few are readily available and all have dose-limiting adverse effects. Mifepristone (RU 486), a first-in-class glucocorticoid receptor antagonist, was approved by the United States Food and Drug Administration in 2012 for use in Cushing's syndrome to control hyperglycemia in patients who are not surgical candidates or have not achieved remission from surgery. The drug is approved for oral once-daily administration. In its pivotal trial, 60% of patients responded to mifepristone with significant improvements in glycemic control and 38% had a reduction in diastolic blood pressure. The most common adverse events were nausea, fatigue, headache, endometrial hyperplasia, and hypokalemia. Adrenal insufficiency occurred in fewer than 5% of patients. The recommended starting dosage of mifepristone is 300 mg/day. The dosage may be increased every 2-4 weeks up to a maximum of 1200 mg/day, although it should not exceed 20 mg/kg/day. Significant drug-drug interactions exist due to mifepristone's effects on a number of cytochrome P450 enzymes. Despite its limitations, mifepristone is a welcome addition and an appropriate alternative to the available drug therapy for Cushing's syndrome.
Topics: Cushing Syndrome; Dose-Response Relationship, Drug; Drug Interactions; Hormone Antagonists; Humans; Mifepristone; Receptors, Glucocorticoid
PubMed: 23436494
DOI: 10.1002/phar.1202 -
Addiction Biology Jul 2023Preclinical and clinical work suggests that mifepristone may be a viable treatment for alcohol use disorder (AUD). This was a Phase 1/2, outpatient, cross-over,... (Randomized Controlled Trial)
Randomized Controlled Trial
Preclinical and clinical work suggests that mifepristone may be a viable treatment for alcohol use disorder (AUD). This was a Phase 1/2, outpatient, cross-over, randomized, double-blind, placebo-controlled trial with non-treatment-seeking individuals with AUD (N = 32). We assessed safety, alcohol craving and consumption, after 1-week mifepristone 600 mg/day administration, in a human laboratory study comprised of a single oral yohimbine administration (32.4 mg), a cue-reactivity procedure and alcohol self-administration. Safety was monitored by adverse events and hemodynamic parameters, alcohol craving by alcohol craving questionnaire and cue-induced saliva output. During the alcohol self-administration, we assessed alcohol pharmacokinetics, subjective effects and consumption. Outcomes were assessed using Generalized Estimating Equations and mediation analysis. Mild-moderate adverse events were reported in both conditions. There was no statistically significant difference between mifepristone and placebo in alcohol pharmacokinetics and subjective effects. Furthermore, blood pressure increased only in the placebo condition after the stress-induced laboratory procedures. Mifepristone, compared to placebo, significantly reduced alcohol craving and increased cortisol levels. Mifepristone-induced cortisol increase was not a mediator of alcohol craving. Mifepristone, compared to placebo, did not reduce alcohol consumption in the laboratory or in a naturalistic setting. This study successfully translated a developed preclinical procedure to a human laboratory study, confirming the safety of mifepristone in people with AUD and providing evidence to its role in reducing alcohol craving under stress procedures. The lack of effects on alcohol drinking may be related to the selection of non-treatment seekers and suggests future treatment-oriented trials should investigate mifepristone in people with AUD.
Topics: Humans; Craving; Mifepristone; Hydrocortisone; Alcoholism; Alcohol Drinking; Ethanol; Double-Blind Method
PubMed: 37369125
DOI: 10.1111/adb.13288 -
European Journal of Endocrinology Nov 2007Mifepristone (RU 486) blocks the action of cortisol by binding to the glucocorticoid receptor and, therefore, is of potential therapeutic value in Cushing's syndrome.... (Review)
Review
CONTEXT
Mifepristone (RU 486) blocks the action of cortisol by binding to the glucocorticoid receptor and, therefore, is of potential therapeutic value in Cushing's syndrome. However, research in endogenous hypercortisolism has been hampered by the controversy related to the use of mifepristone for inducing abortion. Currently, new studies are planned to better define the role of RU 486 in Cushing's syndrome. This paper reviews the available evidence concerning the therapeutic effects and adverse events of RU 486 in Cushing's syndrome.
EVIDENCE ACQUISITION
Original articles and reviews were identified using a PubMed search strategy covering the time period until February 2007.
EVIDENCE SYNTHESIS
Treatment of Cushing's syndrome with mifepristone has been reported in a total of 18 patients, with daily doses ranging from 5 to 30 mg/kg. Case reports indicate that the mifepristone-induced receptor blockade may lead to significant clinical improvement in patients with Cushing's syndrome in whom surgery and inhibitors of adrenal steroidogenesis fail to control hypercortisolism. Due to its rapid onset of action, mifepristone may be particularly useful in acute crises, e.g. in cortisol-induced psychosis. Side effects include adrenal insufficiency and, as a result of its antiprogestin action, endometrial hyperplasia in long-term treatment. Adrenal insufficiency can be assessed only by careful clinical evaluation, as the hormonal parameters are not reliable during receptor blockade, and is rapidly reversed by exogenous dexamethasone. Well-designed larger clinical trials are needed to better assess the value of this interesting drug in the treatment of Cushing's syndrome.
Topics: Animals; Cushing Syndrome; Humans; Mifepristone
PubMed: 17984235
DOI: 10.1530/EJE-07-0458 -
Drugs Mar 1993Mifepristone is a potent oral antiprogestogen which acts at the level of the receptor, having a high affinity for the progesterone receptor. Most of the clinical trials... (Review)
Review
Mifepristone is a potent oral antiprogestogen which acts at the level of the receptor, having a high affinity for the progesterone receptor. Most of the clinical trials have studied its efficacy in the termination of early pregnancy when used in conjunction with a low dosage of a prostaglandin analogue. In these studies, mifepristone 100 to 600mg administered as a single dose or over 3 or 4 days, 36 to 48 hours before a prostaglandin analogue given vaginally, intramuscularly or orally, induced complete abortion in about 95% of women. Used alone, mifepristone is an effective cervical priming agent prior to termination of first trimester pregnancy by vacuum aspiration, and facilitates termination of second trimester pregnancy by prostaglandin by reducing the interval between the start of prostaglandin treatment and termination, the cumulative prostaglandin dosage, and the adverse effects associated with these drugs. Mifepristone can also be used to induce labour in cases of intrauterine fetal death. Mifepristone has been shown to be an effective postcoital contraceptive with a likely emergency role, since its repeated use modifies the menstrual cycle. Pilot studies have been performed in unresectable meningioma and metastatic breast cancer, and in Cushing's syndrome. Mifepristone is generally well tolerated, and thus is an effective, appropriate, medical alternative to surgical termination of early pregnancy. It has as yet unexplored potential as a postcoital contraceptive and in oncology.
Topics: Contraceptives, Postcoital; Female; Humans; Mifepristone; Pregnancy
PubMed: 7682909
DOI: 10.2165/00003495-199345030-00007 -
Issues in Law & Medicine 2017
Review
Topics: Abortifacient Agents, Steroidal; Embryonic Development; Hormone Antagonists; Humans; Mifepristone
PubMed: 29108160
DOI: No ID Found -
Clinical Obstetrics and Gynecology Jun 1996Use of standard estrogen-progestin contraception remains problematic in several subgroups of patients (e.g., those in whom exogenous estrogens are contraindicated, such... (Review)
Review
Use of standard estrogen-progestin contraception remains problematic in several subgroups of patients (e.g., those in whom exogenous estrogens are contraindicated, such as survivors of hormone-dependent cancer, or patients with endometriosis or uterine fibroids). In addition, the postcoital contraception, even if already available, remains at least underused. Additionally, continuous intake of contraceptive steroids is under increasing scrutiny. Would antiprogestins, and specifically the applications of mifepristone such as the ones reviewed in this article offer significant improvements at such problematic occasions? The most attractive novel contraceptive application of mifepristone is that of emergency postcoital contraception after unprotected intercourse. In addition, various options in the endometrial category, specifically those requiring drug administration only during a limited time, might be used in the future. Mifepristone might offer contraceptive and therapeutic relief to patients suffering from endometriosis or uterine fibroids, both conditions that have been shown to benefit from mifepristone therapy. However, the use of mifepristone in contraceptive preparations that are widely available would pose an additional problem of possible misuse of the compound, the reason for currently limiting access to mifepristone. However, such risk should be easily avoidable in the case of postcoital contraception in which only one dose of mifepristone is needed. Regarding the future of mifepristone, and more broadly that of antiprogestins in contraception, the authors believe that they will have a place in the future contraceptive armament. As already emphasized, the strongest clinical areas are those of immediate postcoital and endometrial contraception. Additional studies evaluating parenteral modes of administration, the long-term endometrial effects, and safety and metabolic effects of prolonged antiprogestin administration are needed before mifepristone can be considered a part of the contraceptive arena.
Topics: Contraceptive Agents; Contraceptives, Postcoital; Endometrium; Female; Humans; Menstruation-Inducing Agents; Mifepristone; Ovulation
PubMed: 8734010
DOI: 10.1097/00003081-199606000-00019 -
Steroids Nov 2003When the first synthetic progesterone antagonist (mifepristone) was synthesized over 20 years ago, it was clear that it had a potential as an antifertility agent.... (Review)
Review
When the first synthetic progesterone antagonist (mifepristone) was synthesized over 20 years ago, it was clear that it had a potential as an antifertility agent. Research into the use of antiprogestogens for contraception have concentrated on three general approaches: (1) inhibition of ovulation, (2) inhibition of implantation and (3) disruption of implantation or "menstrual induction". The effect of mifepristone on the ovarian and endometrial cycle depends on dose, timing and frequency of administration. Doses of 10 mg per day or more suppress follicular development and estradiol levels. Ovulatory cycles are maintained in the dose of less than 2 mg although there is increased variability in cycle length. The endometrium shows some minor asynchronous changes, although these are not sufficient to prevent pregnancy. We have chosen to investigate daily doses between 2 and 5 mg which inhibit ovulation and menstruation in over 90% of cycles while still maintaining follicular development and levels of estradiol within the range found during the follicular phase. The endometrium shows proliferative or cystic changes lined by a layer of inactive glandular epithelium set in densely packed stroma. There is, however, an absence of proliferative activity as reflected by a reduced mitotic index and Ki67 staining. These unusual histological appearances are associated with downregulation of PR but a massive upregulation of AR in particularly glandular epithelium. The antiproliferative effect of mifepristone is reassuring suggesting that the risk of atypical hyperplasia due to the effect of prolonged exposure to estrogen unopposed by progesterone is low. In a pilot study, there were no pregnancies in 200 months of exposure in 50 women who used this method as their sole method of contraception. Daily mifepristone could provide a novel contraceptive method which should be devoid of the risks associated with estrogen containing combined oral contraceptive (COC), e.g. venous thromboembolism. The health benefits of avoiding the morbidity associated with menstruation are considerable. Recent surveys suggest that amenorrhoea would be popular with many women.
Topics: Cell Division; Contraceptives, Oral; Endometrium; Estrogens; Female; Humans; Mifepristone; Ovary; Progestins; Time Factors
PubMed: 14668004
DOI: 10.1016/j.steroids.2003.07.002 -
Steroids Jul 2020Mifepristone is one of potent anti-progesterone agents, which binds to progesterone receptors and glucocorticoid receptors. Until now, there are a lot of research...
Mifepristone is one of potent anti-progesterone agents, which binds to progesterone receptors and glucocorticoid receptors. Until now, there are a lot of research focusing on enhancing the solubility and oral bioavailability of Mifepristone. However, poor solubility and oral bioavailability has some undesirable consequences. In this work, Mifepristone in form D was discovered for the first time and characterized by PXRD, TGA, DSC, FT-IR, SEM and SS NMR. Form D was a metastable crystal type which manifested favorable stability under ambient conditions. Form D had better dissolution characteristic compared with commercial Mifepristone in 0.5% SDS solution. In addition, Mifepristone in form D exhibited a 1.43-fold higher peak plasma concentration (C) and 1.46-fold higher area under the curve (AUC) in rats. The work in this paper is a complement to the present understanding of drug polymorphism on the in vitro and in vivo behavior, and establishes the ground work for future development of Mifepristone in form D as a promising drug for the market.
Topics: Administration, Oral; Animals; Biological Availability; Female; Hormone Antagonists; Mifepristone; Molecular Conformation; Rats; Rats, Sprague-Dawley; Solubility
PubMed: 32389717
DOI: 10.1016/j.steroids.2020.108649