MIFEPRISTON IN OBSTETRICS - WHY NOT?

Cervical ripening is a critical component of normal parturition. There are substantial variations in labour induction (IOL) techniques around the world. Mifepristone causes the termination of unwanted pregnancies, but there is a lack of consensus on its use for labour induction. The purpose of our study was to compare the combination of Mifepristone and Misoprostol with the combination of a Foley balloon and Misoprostol for labour induction. The study included 175 pregnant women, with gestational age 37-42 weeks. In the study group - 88 pregnant aged 21-35 (28.56±3.23), a combination of Mifepristone-Misoprostol was used. A combination of Foley catheter and Misoprostol was used in the control group - 87 pregnant aged 21-35 (29.48±3.03). The outcomes were assessed. In the study group the rate of vaginal delivery was higher and the frequency of cesarean section was lower compared to the control group (75 vs. 72, and 13 vs. 15, respectively); The total duration of labour was shorter in the study group (p<0,05); There was no difference between groups in the incidences of neonatal morbidity on the first and the fifth minute of life (p>0,05); The pain level was significantly low in the study group compared to the control group (5±0,75 vs. 8±0,96) and no cervical laceration was revealed in the study group. The Mifepristone - Misoprostol combination has advantages over the Foley balloon - Misoprostol combination for induction of labour regarding reduction in pain intensity, duration of labour, and cervical laceration.

The FDA in the Crosshairs-Science, Politics, and Abortion.

In this Viewpoint, the Supreme Court case FDA v AHM is used to illustrate the tension the FDA faces between science and politics, and state authority over abortion vs federal authority over which drugs may be marketed nationwide.

Mifepristone decreases nicotine intake in dependent and non-dependent adult rats.

BACKGROUND: Addiction to tobacco and nicotine products has adverse health effects and afflicts more than a billion people worldwide. Therefore, there is an urgent need for new treatments to reduce tobacco and nicotine use. Glucocorticoid receptor blockade shows promise as a novel treatment for drug abuse and stress-related disorders. AIM: These studies aim to investigate whether glucocorticoid receptor blockade with mifepristone diminishes the reinforcing properties of nicotine in rats with intermittent or daily long access to nicotine. METHODS: The rats self-administered 0.06 mg/kg/inf of nicotine for 6 h per day, with either intermittent or daily access for 4 weeks before treatment with mifepristone. Daily nicotine self-administration models regular smoking, while intermittent nicotine self-administration models occasional smoking. To determine whether the rats were dependent, they were treated with the nicotinic acetylcholine receptor antagonist mecamylamine, and somatic signs were recorded. RESULTS: The rats with intermittent access to nicotine had a higher level of nicotine intake per session than those with daily access but only the rats with daily access to nicotine showed signs of physical dependence. Furthermore, mecamylamine increased nicotine intake during the first hour of access in rats with daily access but not in those with intermittent access. Mifepristone decreased total nicotine intake in rats with intermittent and daily access to nicotine. Moreover, mifepristone decreased the distance traveled and rearing in the open field test and operant responding for food pellets. CONCLUSION: These findings indicate that mifepristone decreases nicotine intake but this effect may be partially attributed to the sedative effects of mifepristone.

A Comparison of the Efficacy and Safety of Mifepristone and Misoprostol Versus Misoprostol alone for Induction of Labour in Nigerian Women with Intrauterine Fetal Death: A Triple Blind Randomized Controlled Trial.

BACKGROUND: Intrauterine foetal death (IUFD) is an unpleasant pregnancy outcome and prompt delivery of the dead foetus is usually desired by mothers. Unfortunately, spontaneous labour and delivery may not occur early and prolonged retention of the dead foetus in utero is life-threatening. Many of the agents currently used for the induction of labour may result in a prolonged delivery process. OBJECTIVES: To compare the efficacy and safety of mifepristone and misoprostol versus misoprostol alone for induction of labour in women with intrauterine foetal death. MATERIALS AND METHODS: This was a triple-blind randomized controlled trial. Eighty women were randomized into two groups. The intervention group received a single oral dose of 200 mg mifepristone, followed by 6-hourly 50 µg misoprostol vaginal insertion, after 24-hour intervals. The control group received a placebo, followed by 6-hourly 50 µg misoprostol vaginal insertion, after 24-hour intervals. The primary outcome measure was the induction to delivery interval. RESULTS: Maternal age, gestational age, parity and pre-induction bishop's score were comparable between the two groups. The mean induction to the delivery interval in the intervention group was significantly less in the intervention group than the control group (18.78 ± 6.51 hours versus 37.10 ± 10.10; P < 0.001). The total dose of misoprostol required for induction of labour; the need for oxytocin augmentation of labour; and the observed side effects of misoprostol were all significantly less in intervention group than control group (P < 0.001; P < 0.01; and P = 0.03, respectively). CONCLUSION: The combination of mifepristone and misoprostol has greater efficacy and better safety profile than the use of misoprostol alone for induction of labour. This combination should be considered when induction of labour is indicated for IUFD.

Significant Palliative Benefits Following Therapy With Mifepristone for Advanced Treatment Resistant Small Cell Lung Cancer.

BACKGROUND/AIM: Progesterone receptor antagonists have been found to provide significant extension of life and considerable palliative benefits in a large variety of very advanced cancers. Most of these treated cancers lack the classical nuclear progesterone receptor (nPR). The hypothesized targets are membrane (m) PRs to inhibit progesterone induced blocking factor (PIBF). To date, there have been no case reports documenting the efficacy of PR antagonists for small cell lung cancer (SCLC) confirmed by pathological analysis. The case reported here demonstrates the efficacy of the single oral agent mifepristone in treating resistant SCLC. CASE REPORT: A 58-year-old man, presenting with a persistent cough, dyspnea on exertion, and marked weakness, was diagnosed with stage IV non-SCLC (NSCLC) that tested positive for the EGFR mutation. He was treated with the single agent osimertinib. When symptoms returned eight months later, along with radiographic evidence of marked cancer progression, a lung biopsy showed SCLC. He failed to respond to pembrolizumab and subsequently to atezolizumab. He was then treated with the single agent mifepristone 200 mg per day orally. He showed marked clinical improvement associated with marked radiographic improvement. Though clinically doing very well, after one year, his dominant lesion increased in size. His oncologist elected to stop mifepristone and treat with camrelizumab with anlototinib. His clinical condition deteriorated on these drugs, and he died five months later. CONCLUSION: SCLC can be added to the long list of very advanced cancers that are treatment resistant to standard therapy, but respond well to PR antagonists.

Geographic Access to Early Pregnancy Loss Management.

Early pregnancy loss (EPL) is common, but patients face barriers to the most effective medication (mifepristone followed by misoprostol) and procedural (uterine aspiration) management options. This cross-sectional geospatial analysis evaluated access in New Mexico to mifepristone and misoprostol and uterine aspiration in emergency departments (comprehensive) and to uterine aspiration anywhere in a hospital (aspiration) for EPL. Access was defined as a 60-minute car commute. We collected data from hospital key informants and public databases and performed logistical regression to evaluate associations between access and rurality, area deprivation, race, and ethnicity. Thirty-five of 42 (83.3%) hospitals responded between October 2020 and August 2021. Two hospitals (5.7%) provided comprehensive management; 24 (68.6%) provided aspiration. Rural and higher deprivation areas had statistically significantly lower adjusted odds ratios for comprehensive management (0.03-0.07 and 0.3-0.4, respectively) and aspiration (0.03-0.06 and 0.1-0.3, respectively) access. Mifepristone and uterine aspiration implementation would address disparate access to EPL treatment.

Mifepristone implementation in primary care: Clinician and staff insights from a pilot learning collaborative.

OBJECTIVES: The ExPAND Mifepristone (ExPAND) learning collaborative aims to support primary care providers in overcoming logistical barriers to mifepristone provision. This qualitative study describes clinician and staff perspectives on the impact of ExPAND in two federally qualified health center networks (FQHCs). STUDY DESIGN: Researchers conducted semi-structured qualitative interview with a purposive sample of clinicians, staff, and leadership from two Illinois FQHCs. We analyzed transcripts in batches using modified grounded theory to identify themes regarding the reception of ExPAND and barriers to and facilitators of mifepristone implementation. RESULTS: Participants (n = 13) expressed strong support for providing mifepristone for miscarriage management at their clinics. Most also personally supported mifepristone for abortion care. Many participants felt that ExPAND reflected their clinics' values, as it strengthens the primary care relationship, emphasizes patient-centered care, and addresses disparities in access. Barriers to implementation included fear that providing abortion care would jeopardize FQHC funding and logistical hurdles due to the coronavirus disease pandemic. CONCLUSIONS: Participants felt that mifepristone provision in primary care was an important service, and that ExPAND helped achieve that goal. Future clinics participating in ExPAND would benefit from education about how FQHCs can provide mifepristone for abortion care while complying with federal funding restrictions. IMPLICATIONS: Learning collaboratives like ExPAND can prepare primary care clinics to provide mifepristone. Participants describe a clear benefit of mifepristone integration to their patients, and they report mifepristone integration aligns with clinic values.

Experiences with misoprostol-only used for self-managed abortion and acquired from an online or retail pharmacy in the United States.

OBJECTIVES: This study aimed to understand individual experiences with medication abortion using misoprostol-only among people living in the United States. STUDY DESIGN: We conducted 31 semistructured anonymous in-depth interviews with individuals who used misoprostol-only for self-managed medication abortion. Participants were recruited from Aid Access, an online telemedicine organization that provided prescriptions for misoprostol to eligible people in all 50 states in May and June 2020 when a combined mifepristone and misoprostol regimen was unavailable. We coded transcripts with a flexible coding approach and focused on perceptions and experiences with use. RESULTS: Participants were knowledgeable about misoprostol. Previous abortion experiences shaped perceptions of misoprostol-only by allowing comparison to the mifepristone and misoprostol regimen. Most participants expressed an unwavering desire for an effective abortion method, regardless of the medications or regimen. Individual physical experiences with misoprostol, including bleeding, cramping, nausea, and diarrhea, varied in intensity and duration. Participants proactively managed symptoms with self-care strategies and drew extensively from their prior experiences with menstruation, miscarriage, abortion, and childbirth. Clear instructions and information on potential complications and what to expect throughout the abortion fostered a sense of preparedness, and personalized interactions with an online help desk brought comfort. CONCLUSIONS: Misoprostol offered an essential abortion method for study participants. This regimen was physically challenging for some, and there is potentially a greater need for communication and support for individuals using misoprostol-only regimens. Prior reproductive experiences informed participant's knowledge, preparedness, pain management, and ability to both recognize and manage potential complications. IMPLICATIONS: As restrictions on mifepristone continue, more people may use misoprostol-only regimens. All regimens can be supported with detailed instructions, clear expectations, information on signs of potential complications, and personalized support. To achieve reproductive autonomy, people must have access to a range of abortion care options that meet their needs.

Reversal of medication abortion with progesterone: a systematic review.

BACKGROUND: We sought to determine whether there is evidence to recommend progesterone for individuals not wishing to complete a medication abortion after taking mifepristone. METHODS: We undertook an updated systematic review including a primary search for studies in which individuals received progesterone to reverse the effects of mifepristone, and a secondary search for studies in which individuals received mifepristone alone. We searched PubMed, Embase, Cochrane, CINAHL and grey literature up to December 2022. We used the Joanna Briggs Institute critical appraisal tools for risk of bias assessment. We compared ongoing pregnancy rates among individuals treated with progesterone to those managed expectantly. RESULTS: We did not find new studies in our secondary search. For the main search, we included three case series and one randomised controlled trial. Data were available for 561 individuals who received progesterone after mifepristone, of whom 271 (48%) had ongoing pregnancies. The quality of the evidence in the case series was low due to methodological and ethical issues. Enrollment in the randomised trial stopped early due to bleeding events in both arms. The ongoing pregnancy rate for individuals ≤7 weeks who received progesterone was 42% (95% CI 37-48) compared with 22% (95% CI 11-39) for mifepristone alone. At 7-8 weeks, the ongoing pregnancy rate was 62% (95% CI 52-71) in the progesterone group and 50% (95% CI 15- 85) in the mifepristone alone group. CONCLUSION: Based mostly on poor-quality data, it appears the ongoing pregnancy rate in individuals treated with progesterone after mifepristone is not significantly higher compared to that of individuals receiving mifepristone alone.

Mifepristone Use Among Obstetrician-Gynecologists in Massachusetts: Prevalence and Predictors of Use.

OBJECTIVES: We estimated the prevalence of mifepristone use for evidence-based indications among obstetrician-gynecologists in independent practice in Massachusetts and explored the demographic and practice-related factors associated with use. METHODS: We used data from a cross-sectional survey administered to Massachusetts obstetrician-gynecologists identified from the American Medical Association Physician Masterfile. We measured the prevalence of mifepristone use for four clinical scenarios: early pregnancy loss, medication abortion, cervical preparation before dilation and evacuation procedures, and cervical preparation before induction of labor. Multivariate regression was used to calculate the odds of mifepristone use for these scenarios based on practice type, years in practice, physician sex, and history of medication abortion training. RESULTS: A total of 198 obstetrician-gynecologists responded to the survey (response rate = 29.0%); this analysis was limited to 158 respondents who were not in residency or fellowship. Overall, 46.0% used mifepristone for early pregnancy loss and 38.6% for medication abortion. Fewer used mifepristone for cervical preparation before dilation and evacuation (26.0%) or before induction of labor (26.4%). Respondents in academic practice settings, with more years in practice, of female sex, and with sufficient medication abortion training were significantly more likely to use mifepristone for one or more evidence-based clinical indications. CONCLUSIONS: Sufficient medication abortion training during residency significantly predicts whether obstetrician-gynecologists use mifepristone in practice. The U.S. Supreme Court's overturning of Roe v. Wade will allow state-level abortion bans and restrictions to be in effect, which will reduce exposure to abortion training during residency. Increasing training in and utilization of mifepristone are critical for equitable access to reproductive health services. Further interventions may need to be developed to increase mifepristone use in nonacademic practice settings.

Steroid profile in patients with breast cancer and in mice treated with mifepristone.

Progesterone receptors (PRs) are biomarkers used as prognostic and predictive factors in breast cancer, but they are still not used as therapeutic targets. We have proposed that the ratio between PR isoforms A and B (PRA and PRB) predicts antiprogestin responsiveness. The MIPRA trial confirmed the benefit of 200 mg mifepristone, administered to patients with tumors with a high PRA/PRB ratio, but dose-ranging has not been conducted. The aim of this study was to establish the plasma mifepristone levels of patients from the MIPRA trial, along with the resultant steroid profiles, and compare these with those observed in mifepristone-treated mice using therapeutic schemes able to induce the regression of experimental mammary carcinomas with high PRA/PRB ratios: 6 mg pellets implanted subcutaneously, or daily doses of 12 mg/kg body weight. The plasma levels of mifepristone and other 19 plasma steroids were measured by liquid chromatography-tandem mass spectometry. In mifepristone-treated mice, plasma levels were lower than those registered in mifepristone-treated patients (i.e. day 7 after treatment initiation, pellet-treated mice: 8.4 ± 3.9 ng/mL; mifepristone-treated patients: 300.3 ± 31.7 ng/mL (mean ± s.d.; P < 0.001)). The increase in corticoid related steroids observed in patients was not observed in mifepristone-treated mice. The increase in progesterone levels was the most significant side effect detected in mifepristone-treated mice after 14 or 21 days of treatment, probably due to an ovarian compensatory effect not observed in postmenopausal patients. We conclude that in future clinical trials using mifepristone, the possibility of lowering the standard daily dose of 200 mg should be considered.

Changes in Induced Medical and Procedural Abortion Rates in a Commercially Insured Population, 2018 to 2022 : An Interrupted Time-Series Analysis.

BACKGROUND: During the COVID-19 pandemic, access to in-person care was limited, and regulations requiring in-person dispensing of mifepristone for medical abortions were relaxed. The effect of the pandemic and accompanying regulatory changes on abortion use is unknown. OBJECTIVE: To estimate changes in the incidence rate of induced medical and procedural abortions. DESIGN: Serial cross-sectional study with interrupted time-series analyses. SETTING: Commercially insured persons in the United States. PARTICIPANTS: Reproductive-aged women. INTERVENTION: Onset of the COVID-19 pandemic in March 2020 and subsequent regulatory changes affecting the in-person dispensing requirement for mifepristone. MEASUREMENTS: Monthly age-adjusted incidence rates of medical and procedural abortions were measured among women aged 15 to 44 years from January 2018 to June 2022. Medical abortions were classified as in-person or telehealth. Linear segmented time-series regression was used to calculate changes in abortion rates after March 2020. RESULTS: In January 2018, the estimated age-adjusted monthly incidence rate of abortions was 151 per million women (95% CI, 142 to 161 per million women), with equal rates of medical and procedural abortions. After March 2020, there was an immediate 14% decrease in the monthly incidence rate of abortions (21 per million women [CI, 7 to 35 per million women]; P = 0.004), driven by a 31% decline in procedural abortions (22 per million women [CI, 16 to 28 per million women]; P < 0.001). Fewer than 4% of medical abortions each month were administered via telehealth. LIMITATION: Only abortions reimbursed by commercial insurance were measured. CONCLUSION: The incidence rate of procedural abortions declined during the COVID-19 pandemic, and this lower rate persisted after other elective procedures rebounded to prepandemic rates. Despite removal of the in-person dispensing requirement for mifepristone, the use of telehealth for insurance-covered medical abortions remained rare. Amid increasing state restrictions, commercial insurers have the opportunity to increase access to abortion care, particularly via telehealth. PRIMARY FUNDING SOURCE: Health Resources and Services Administration.

Explaining the Fifth Circuit Court of Appeals Ruling on Mifepristone Access.

This Viewpoint summarizes the Fifth Circuit Court of Appeals ruling on access to mifepristone, the first of 2 pills used in medication abortion.

Fertility preservation in pregnant cancer patients after first-trimester abortion: a new challenge with possible solutions.

Fertility preservation in pregnant women recently diagnosed with cancer can be a challenge. Raised levels of human chorionic gonadotropin (Beta-hCG) and progesterone in this population of patients may pose a problem for the prompt initiation of controlled ovarian stimulation (COS) due to a potential negative feedback of these hormones on folliculogenesis; however, it is not feasible to wait for negativization of serum beta-hCG levels before starting controlled ovarian stimulation. In literature, very few cases have been reported regarding the preservation of fertility in pregnant women recently diagnosed with cancer. We performed an extended revision of the literature to evaluate the current knowledge of the management of fertility preservation in women with cancer and we examined two cases closely. The first case study involved a cancer patient who underwent surgical abortion at 6.5 weeks of gestation followed by administration of mifepristone to detach any minimal residual trophoblast and consequently to decrease serum beta-hCG and progesterone levels before starting COS. In the second case study, the cancer patient underwent surgical abortion at 7.1 weeks of gestation and simultaneous unilateral oophorectomy for ovarian tissue cryopreservation due to a limited time for COS. By analyzing the results of these studies, it could be hypothesized that mifepristone administration may favor the decrease of serum beta-hCG and progesterone levels in order to permit rapid initiation of COS. In cases where COS is not feasible, ovarian tissue cryopreservation should be considered as an alternative fertility preservation technique.

Uso de mifepristona en embarazo ectópico intersticial: un reporte de caso / Use of mifepristone in an interstitial ectopic pregnancy: a case report

Introducción: El embarazo ectópico intersticial es una forma de presentación poco frecuente, con una incidencia del 2-4% de los embarazos ectópicos; sin embargo, a pesar de su baja incidencia la mortalidad es cinco veces mayor, impactando en las cifras de mortalidad materna y representando en torno al 10-15% de los casos. Objetivo: Presentar un caso de embarazo ectópico intersticial, cuya ocurrencia es poco frecuente, así como el abordaje satisfactorio del manejo médico con mifepristona y metotrexato. Caso clínico: Mujer de 28 años con antecedente de resección tubárica por quiste paraovárico derecho, quien acudió a urgencias por hallazgo en ecografía obstétrica de sospecha de embarazo intersticial izquierdo y se le administró manejo farmacológico con dosis de metotrexato y mifepristona, con éxito. Conclusiones: El manejo médico con metotrexato y mifepristona para el embarazo ectópico intersticial parece ser una elección eficaz en los casos con estabilidad hemodinámica y deseo de conservación de la fertilidad.

Background: Interstitial ectopic pregnancy represents a rare form of presentation, with an incidence of 2-4% of all ectopic pregnancies. However, despite its low incidence, it is associated with a five-fold increase in mortality, significantly impacting maternal mortality rates, accounting for approximately 10-15% of cases. Objective: To present a case of interstitial ectopic pregnancy, which is a rare occurrence, as well as the successful medical management approach with mifepristone and methotrexate. Case report: A 28-year-old women with a history of right paraovarian cyst tubal resection presented to the emergency department due to suspected left interstitial pregnancy identified on obstetric ultrasound. The patient was successfully managed with pharmacological treatment using doses of methotrexate and mifepristone. Conclusions: Medical management with methotrexate and mifepristone for interstitial ectopic pregnancy appears to be an effective choice in cases with hemodynamic stability and a desire for fertility preservation.

Efficacy and safety of different subsequent therapies after fertility preserving surgery for endometriosis: A systematic review and network meta-analysis.

BACKGROUND: Endometriosis (EMT) is a benign and common estrogen-dependent disease. Hormonal therapy improves pain symptoms in most women with EMT. However, in many cases, laparoscopic fertility preservation surgery is considered a common treatment for EMT. The present study aimed to evaluate the efficacy and safety of dienogest, leuprolide, danazol, gestrinone, mifepristone and levonorgestrel intrauterine system (LNG-IUS) in relieving symptoms and delaying the recurrence of EMT cysts after fertility protection surgery. METHODS: We searched PubMed, the Cochrane Library, Web of Science, EMBase, China National Knowledge Infrastructure, VIP Database, China Biology Medicine disc, WanFang Data databases to collect randomized controlled trials (RCT) related to dienogest, leuprolide, danazol, gestrinone, mifepristone and LNG-IUS as a follow-up treatment after fertility preserving surgery for EMT. After literature screening, data extraction and quality evaluation, effective rate, recurrence rate, pregnancy rate and adverse reaction rate were used as outcome indicators to evaluate the efficacy and safety of drugs. Evidence networks included in the study were drawn and publication bias was assessed. The drugs most likely to be the best postoperative treatment were explored through mixed comparison of different drugs and efficacy ranking. RESULT: Effective rate: dienogest, leprerelin, gestrinone and LNG-IUS were better than placebo after EMT fertility preservation surgery; dienogest was superior to mifepristone and danazol. LNG-IUS is superior to danazol. LNG-IUS has the highest potential for improving the effectiveness of EMT symptoms. Recurrence rate: the application of dienogest, leuprolide, gestrinone, mifepristone and LNG-IUS after EMT fertility preservation surgery was lower than that of placebo; dienogest and LNG-IUS were lower than danazol. The recurrence rate of dinorgestrel was the last place with the highest performance. Pregnancy rate: in the cases with fertility requirements, dienogest and,leuprolide were better than placebo after EMT fertility preservation surgery; dienogest was superior to danazol, gestrinone and mifepristone. Leuprolide is superior to danazol and gestrinone. The first rank of dienogest pregnancy rate was the highest. Adverse reaction rate: the application of dienogest, leuprolide, danazol, gestrinone, mifepristone and LNG-IUS after EMT fertility preservation surgery was higher than that of placebo. After placebo, LNG-IUS had the highest adverse reaction rate. CONCLUSION: For patients after fertility preserving surgery for EMT, the recurrence rate of dienogest was the last place with highest preference. The first rank of dienogest pregnancy was the highest.

Glucocorticoid receptor modulator CORT125385 alleviates diet-induced hepatosteatosis in male and female mice.

Non-alcoholic fatty liver disease (NAFLD) is a common condition that can progress to the more severe conditions like non-alcoholic steatohepatitis (NASH) for which limited effective therapeutic options are available. In this study, we set out to evaluate the novel glucocorticoid receptor modulator CORT125385, an analogue of the previously studied miricorilant but without mineralocorticoid receptor binding activity. Male and female mice that received high-fat diet and fructose water were treated with either vehicle, CORT125385 or mifepristone. We found that CORT125385 significantly lowered hepatic triglyceride levels in male mice, and hepatic triglyceride and cholesterol levels in female mice. Mifepristone treatment had no effect in male mice, but significantly lowered hepatic triglyceride and cholesterol levels in female mice. In reporter assays in vitro, CORT125385 showed weak partial agonism on the progesterone receptor (PR) at high doses, as well as PR antagonism at a potency 1000-fold lower than mifepristone. In vivo, CORT125385 treatment did not influence PR-responsive gene expression in the oviduct, while mifepristone treatment strongly influenced these genes in the oviduct, thus excluding in vivo PR cross-reactivity of CORT125385 at a therapeutically active dose. We conclude that CORT125385 is a promising glucocorticoid receptor modulator that effectively reduces liver steatosis in male and female mice without affecting other steroid receptors at doses that lower hepatic lipid content.

Arrest of mouse preterm labor until term delivery by combination therapy with atosiban and mundulone, a natural product with tocolytic efficacy.

There is a lack of FDA-approved tocolytics for the management of preterm labor (PL). In prior drug discovery efforts, we identified mundulone and mundulone acetate (MA) as inhibitors of in vitro intracellular Ca2+-regulated myometrial contractility. In this study, we probed the tocolytic potential of these compounds using human myometrial samples and a mouse model of preterm birth. In a phenotypic assay, mundulone displayed greater efficacy, while MA showed greater potency and uterine-selectivity in the inhibition of intracellular-Ca2+ mobilization. Cell viability assays revealed that MA was significantly less cytotoxic. Organ bath and vessel myography studies showed that only mundulone exerted inhibition of myometrial contractions and that neither compounds affected vasoreactivity of ductus arteriosus. A high-throughput combination screen identified that mundulone exhibits synergism with two clinical-tocolytics (atosiban and nifedipine), and MA displayed synergistic efficacy with nifedipine. Of these combinations, mundulone+atosiban demonstrated a significant improvement in the in vitro therapeutic index compared to mundulone alone. The ex vivo and in vivo synergism of mundulone+atosiban was substantiated, yielding greater tocolytic efficacy and potency on myometrial tissue and reduced preterm birth rates in a mouse model of PL compared to each single agent. Treatment with mundulone after mifepristone administration dose-dependently delayed the timing of delivery. Importantly, mundulone+atosiban permitted long-term management of PL, allowing 71% dams to deliver viable pups at term (>day 19, 4-5 days post-mifepristone exposure) without visible maternal and fetal consequences. Collectively, these studies provide a strong foundation for the development of mundulone as a single or combination tocolytic for management of PL.