Mifepristone Research Articles

Factors behind failure of unsupervised self induced medical abortion : A Study from North India

Introduction : Unsafe abortions contribute to 8% of maternal mortality. Easy availability and rampant use of medical methods of abortion lead to upsurge in self induced abortion related complications. Present study was conducted to assess the profile, knowledge, attitude and reasons of preference of self induced abortion in women visiting our centre after complication or failure of medical abortion. We also tried to evaluate the burden of different complications and factors behind failure of self induced medical abortion. Material and Methods: It was a prospective mixed methods study performed in the department of obstetrics and gynaecology at a tertiary care centre. These women were interviewed by two doctors with the help of pre structured questionainare and their diagnosis, course of management and duration of stay in the hospital was noted down from hospital records. Results: We recruited 216 women visiting our facility after some complication of self induced medical abortion. 92 women used Mifepristone and misoprostol regimen and rest used misoprostol. 165 women have purchased drugs over the counter from pharmacists. Major source of information is husband or friends. Most of the patients [n= 87.9%] consider it low risk.97% patients follow incorrect drug schedule and misoprostol was taken by oral route only. Ruptured ectopic pregnancy, anaemia, Sepsis, Incomplete abortion, Missed abortion and continuation of pregnancy was observed in 1.8%, 69.44%, 8.3%, 68.5 %, 9.7% and 23.14%. Conclusion: Neglect of eligibility criteria and faulty drug regimens are the most common reasons for failure on self induced medical abortions. Low perceived risk and reluctance to hospital visit and interventions are most common reasons of preference of self induced abortions.

Clinical effect of Chinese herbal medicine decoction combined with mifepristone in the treatment of uterine fibroids and its influence on sex hormone levels

Objective To observe the curative effect of Chinese herbal medicine decoction combined with mifepristone in the treatment of uterine fibroids and the effects on hormone levels. Methods 100 patients with uterine fibroids were divided into the treatment group and control group according to random number table, 50 cases in each group. The treatment group was given the liquid form joint mifepristone, the control group was given mifepristone. The two groups were treated for a course of 3 months. The sex hormone levels before and after treatment, the symptoms and signs integral related indicators were compared. The clinical efficacy was evaluated. Results The total effective rate of the treatment group was 84%, which was obviously higher than 66% of the control group (χ2=9.88, P<0.05). Compared with before treatment[the control group, LH: (57.2±9.6)U/L, E2: (17.9±6.9)pmol/L, FSF: (32.7±8.5)g/L, P: (17.5±5.2)nmol/L; the treatment group, LH: (56.7±10.2)U/L, E2: (17.3±7.9)pmol/L, FSF: (33.5±7.9)g/L, P: (18.4±3.2)nmol/L], after treatment the levels of sex hormones in the two groups significantly reduced[the control group, LH: (47.5±8.3)U/L, E2: (12.5±3.8)pmol/L, FSF: (18.3±6.9)g/L, P: (14.8±3.2)nmol/L; the treatment group, LH: (38.7±8.1)U/L, E2: (7.5±4.3)pmol/L, FSF: (10.2±5.2)g/L, P: (10.5±4.8)nmol/L], the differences were statistically significant(all P<0.05). Conclusion Chinese herbal medicine decoction combined with mifepristone in the treatment of uterine fibroids has good clinical curative effect, by increasing the body's immunity, lowering levels of sex hormones in the body, inhibition of smooth muscle tissue, thus to narrow the myoma, improve clinical symptoms, it is worthy of promoting. Key words: Leiomyoma; Mifepristone; T lymphocyte

Analysis of the treatment of 34 cases with cesarean scar pregnancy

Objective To explore the diagnosis and treatment for the incision cesarean section scar pregnancy(CSP). Methods The clinical data of 34 patients with CSP admitted were retrospectively analyzed, and analyzed the methods of diagnosis and treatment of CSP. Results Our results showed that 9 cases after treatment with mifepristone combined with suction palace obtained success, 2 cases of bleeding assisted with balloon compression; 8 cases after mifepristone combined hysteroscopy under suction palace treatment obtained success, 1 case was failed and transfer to laparotomy. Mifepristone combined with transvaginal lesion resection of scar pregnancy was succeed in 9 cases, 2 cases were failed, of which 1 case was bleeding more and transfer to laparotomy, 1 case was confirmed remaining during a review after half a month open.7 cases were succeed in the transabdominal lesion resection of pregnancy (3 cases of transit); without hysterectomy; 3 cases were turn to the superior hospital for treatment of intervention.The statistical results showed that no statistical significant difference was obtained among the scores of different age, length of hospital stay, hospital expenses and rescue of shock in different teams of surgery.For the haemorrhage amount, the bleeding was at least in hysteroscopy group, and was at most in abdominal resection of lesions group (rescue of shock was on the high side). Conclusion Uterine scar pregnancy is a relatively rare and dangerous clinical special type of ectopic pregnancy, early diagnosis and appropriate therapeutic strategy are important. The mifepristone combined with suction palace and resection of the pregnancy lesions are safe and effective method for treatment. Key words: Cesarean section; Pregnancy; Cicatrix

Clinical observation of small dose mifepristone combined with traditional Chinese medicine in the treatment of uterine gland disease

Objective To observe the clinical effect of small dose mifepristone combined with traditional Chinese medicine in the treatment of uterine gland disease. Methods 76 patients with uterine gland disease were selected, they were divided into the observation group(n=38) and control group(n=38) by using random number table method.The control group was treated with small dose of mifepristone, while the observation group was treated with small dose of mifepristone combined with traditional Chinese medicine.The clinical curative effects of the two groups were compared. Results After treatment, in the observation group, the pain degree of patients[(21.30±6.70)points], influence activity level[(17.30±12.00)points], activity loss[(1.80±0.70)spots] and grades of dysmenorrheal[(0.60±0.20)stages] were lower than those in the control group, the differences were statistically significant(t=5.645, 7.023, 4.932, 3.994, all P<0.05). After treatment, in the observation group, the uterine volume[(56.20±2.00)mm3], CA125 level [(32.10±2.10)U/mL] were lower than those of the control group (t=4.024, 4.413, all P<0.05). The incidence rate of adverse reaction of the observation group was 7.89%, which was significantly lower than that of the control group, the difference was statistically significant(χ2=14.757, P<0.05). The patients were followed up for 8 months, the recurrence rate of the observation group was 5.26%, which was lower than 26.32% of the control group, the difference was statistically significant (χ2=16.678, P=0.000). The menstrual recovery ratio less than or equal to three months of the control group was 81.58%, which was significantly higher than 63.16% of the control group, the difference was statistically significant (χ2=8.484, P=0.003). Conclusion In the treatment process of adenomyosis, the small dose of mifepristone combined with traditional Chinese medicine can alleviate the clinical symptoms, reduce the pain and reduce the volume of uterus, and it has less adverse reaction, safe and reliable, it is worth of clinical application. Key words: Uterine gland disease; Mifepristone; Traditional Chinese medicine; Curative effect

Induced termination of second trimester pregnancy in women with scarred uterus

Objective To investigate the suitable mode of induced termination of pregnancy at second trimester for women with scarred uterus. Methods A retrospective study was performed in 120 cases of second trimester pregnant women with scarred uterus, who requested termination of pregnancy in Department of Obstetrics, Ruijin Hospital of Shanghai Jiaotong University from January 2010 to July 2016. The indications of termination of pregnancy were fetal anomaly, serious pregnant complication, intrauterine fetal deaths and personal factors. The interval time of previous operation to this pregnancy were recorded. It was <2 years in 35 cases and ≥2 years in 85 cases. The patients with normal hepatic function began to take mifepristone combined with ethacridine lactate (group A, 62 cases). The method of mifepristone combined with misoprostol was used in the patients who failed to amniotomy to inject ethacridine lactatebecause of oligohydramnios or small gestational age (group B, 58 cases). The detail information of every patient was recorded, including age, gestational weeks, gravidity, parity, the mode of previous operation, previous operation time and indication, the mode of induced labor inthis pregnancy, the interval time from administration to uterine contraction, delivery or not and the interval time from induction to delivery, postpartum hemorrhage, the successful rate of induce labor, and placental retention ratio. Results ⑴ It had no significant differe-nce between groups A and B in age, gravidity, parity and the interval time of previous operation to this pregnancy (P>0.05). There was significant difference between two groups in gestational weeks of induction (P 0.05), but the time from induction to regular uterine contractionand delivery in group B was significant shorter than that of group A (P 0.05). Conclusions Both of methods of mifepristone combined with misoprostol and the mifepristone combined with ethacridine lactate are feasible to induce second trimester termination of pregnancy for women with scarred uterus. Key words: Uterus/PA; Cicatrix; Labor, induced; Pregnancy trimester, second

Progesterone Receptor Isoform Ratio: A Breast Cancer Prognostic and Predictive Factor for Antiprogestin Responsiveness

Compelling evidence shows that progestins regulate breast cancer growth. Using preclinical models, we demonstrated that antiprogestins are inhibitory when the level of progesterone receptor isoform A (PR-A) is higher than that of isoform B (PR-B) and that they might stimulate growth when PR-B is predominant. The aims of this study were to investigate ex vivo responses to mifepristone (MFP) in breast carcinomas with different PR isoform ratios and to examine their clinical and molecular characteristics. We performed human breast cancer tissue culture assays (n = 36) to evaluate the effect of MFP on cell proliferation. PR isoform expression was determined by immunoblotting (n = 282). Tumors were categorized as PRA-H (PR-A/PR-B ≥ 1.2) or PRB-H (PR-A/PR-B ≤ 0.83). RNA was extracted forRibo-Zero-Seq sequencing to evaluate differentially expressed genes.Subtypes and risk scores were predicted using the PAM50 gene set, the data analyzed using The Cancer Genome Atlas RNA-seq gene analysis and other publicly available gene expression data. Tissue microarrays were performed using paraffin-embedded tissues (PRA-H n = 53, PRB-H n = 24), and protein expression analyzed by immunohistochemistry.All statistical tests were two-sided. One hundred sixteen out of 222 (52.3%) PR+ tumors were PRA-H, and 64(28.8%) PRB-H. Cell proliferation was inhibited by MFP in 19 of 19 tissue cultures from PRA-H tumors. A total of 139 transcripts related to proliferative pathways were differentially expressed in nine PRA-H and seven PRB-H tumors. PRB-H and PRA-H tumors were either luminal B or A phenotypes, respectively ( P = .03). PRB-H cases were associated with shorter relapse-free survival (hazard ratio [HR] = 2.70, 95% confidence interval [CI] = 1.71 to 6.20, P = .02) and distant metastasis-free survival (HR = 4.17, 95% CI = 2.18 to 7.97, P < .001). PRB-H tumors showed increased tumor size ( P < .001), Ki-67 levels ( P < .001), human epidermal growth factor receptor 2 expression ( P = .04), high grades ( P = .03), and decreased total PR ( P = .004) compared with PRA-H tumors. MUC-2 ( P < .001) and KRT6A ( P = .02) were also overexpressed in PRB-H tumors. The PRA/PRB ratio is a prognostic and predictive factor for antiprogestin responsiveness in breast cancer.

Non-reproductive system effects of progesterone and its non-selective antagonists mifepristone

В статье представлен анализ данных литературы о влиянии прогестерона на функционирование сердечно-сосудистой, костно-мышечной, нервной системы. Обсуждаются возможные эффекты ингибирования активности прогестерона. Показано, что в физиологических концентрациях прогестерон обладает кардиопротекторным эффектом, замедляет апоптоз кардиомиоцитов, может значительно влиять на процессы реполяризации в миокарде, обмен липидов, синтез оксида азота. Продемонстрировано, что прогестерон может способствовать укорочению интервала QT, тогда как удлинение данного интервалаассоциировано с риском развития аритмий. Кроме того, приведены данные о влиянии прогестерона на центральную нервную систему, обсуждается способность гормона регулировать поведениечеловека, а также его влияние на риск развития депрессии и когнитивных нарушений. Обсуждаются протекторные эффекты прогестерона при мозговоминсульте. Приведены данные о влиянии неселективного блокатора рецепторов к прогестерону – мифепристона. Анализ данных лабораторных и клиническихисследований позволяет утверждать, что препарат взаимодействует с рецепторами как к прогестерону, так и к глюкокортикоидам и в меньшей степени ктестостерону. Представленные данные показали недостаточно изученную безопасность при длительном применении мифепристона, продолжительностьбольшинства клинических исследований не превышает 6-ти месяцев и чаще представлена в дозе 5–10 мг в сутки. Представлены два клинических случаяразвития аритмии у женщин, получавших длительную терапию мифепристоном в дозе 50 мг в связи с лейомиомой матки. В обоих случаях развитие аритмиипациентки связывают с началом терапии мифепристоном. Безусловно, статья имеет ряд ограничений. В теоретической части приведены данные, касающиеся только эндогенного или природного прогестерона. Приэтом синтетические аналоги могут оказывать совершенно иное воздействие на сердечно-сосудистую систему и обмен холестерина. Имеющиеся в литературесведения о безопасности длительного применения мифепристона требуют проведения дополнительных клинических исследований с оценкой влиянияпрепарата на сердечно-сосудистую, костно-мышечную и нервную систему.

Abstract P6-12-15: Efficacy results of a phase 1/2 study of glucocorticoid receptor (GR) antagonist mifepristone (MIFE) in combination with eribulin in GR-positive triple-negative breast cancer (TNBC)

Abstract Background: GR is variably expressed in TNBC and high expression is associated with poor prognosis in estrogen receptor-negative (ER-) early stage breast cancer. Treatment with mifepristone (MIFE) potentiates the effectiveness of chemotherapy in GR+ TNBC xenografts. Enrollment is complete in this study of patients with GR+ TNBC treated at the recommended Phase 2 dose (RP2D) of MIFE in combination with eribulin. Objectives: To determine the safety, tolerability, pharmacokinetics (PK) and clinical activity of the MIFE plus eribulin combination in pts with GR+ TNBC at the RP2D. Methods: Eligibility: In Part 1 (dose finding), pts with solid tumors; in Part 2 (expansion phase), pts with TNBC (GR result required at time of screening in Part 1, but could be pending at time of screening in Part 2). Up to 5 prior chemotherapy regimens for advanced disease; ECOG PS 0-1; adequate end-organ function. Design: 3 + 3 dose escalation scheme. After a 7-day lead-in of oral daily MIFE alone, MIFE was continued daily and eribulin was given on days 1 and 8 of a 21-day cycle. GR+ was defined as &amp;gt;10% of tumor cells with any intensity of GR staining. Results: 16 pts with metastatic breast cancer were treated in Part 1, and 21 pts with TNBC were treated in Part 2. Median age was 54 (range 30-81). MTD/RP2D was MIFE 300 mg/day + eribulin 1.1 mg/m2. Safety: DLT in Part 1 was neutropenia. Neutropenia occurred in 23/36 total patients (2 Grade [G] 1, 10 G3, 11 G4); 2 instances included neutropenic fever. Recovery of WBC was brisk with growth factor support. Neuropathy was observed in 8 pts (5 G1, 1 G2, 2 G3). Other most common AEs (fatigue, hypokalemia, nausea, alopecia) were mainly G1 or G2; among these, G3/G4 events were limited to fatigue (4 G3), hypokalemia (3 G3 and 1 G4) and nausea (1 G3). There were 2 instances of G1 vaginal bleeding. There was no impact of MIFE on eribulin PK. Efficacy: There were 23 evaluable pts with TNBC across Parts 1 and 2 treated at the RP2D: 21 GR+, 2 GR status unknown; median of 3 prior chemotherapy regimens; 1 patient had received prior eribulin. Responses were: 3 PR, 8 SD, 11 PD and one too early to assess. Median PFS was 9 weeks. Conclusions: MIFE plus eribulin was well tolerated and appears to be an active treatment regimen. Five TNBC patients had a PFS longer than the upper 95% CI for PFS (i.e., &amp;gt;15 wks) reported by Aogi et al. for TNBC treated with eribulin (Annals of Oncology 2012?23:144148). Clinical trial information: NCT02014337. Citation Format: Han HS, Wilks S, Paplomata E, Modiano MR, Becerra C, Braiteh FS, Spira AI, Pluard TJ, Richards DA, Conzen SD, Baker G, Fishman RS, Marcantonio A, O'Shaughnessy J, Nanda R. Efficacy results of a phase 1/2 study of glucocorticoid receptor (GR) antagonist mifepristone (MIFE) in combination with eribulin in GR-positive triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-12-15.

Clinical effect of three doses of mifepristone on patients with dysfunctional uterine bleeding

Objective To explore the clinical effect of three doses of mifepristone on patients with dysfunctional uterine bleeding. Methods 150 patients with dysfunctional uterine bleeding were chosen, and they were randomly divided into 3 groups, including low dose group (50 patients), middle dose group (50 patients) and high dose group (50 patients). All patients adopted routine treatment.On the basis of this, the low dose group received 6.25mg/d mifepristone, the middle dose group received 12.5mg/d mifepristone, the high dose group received 18.25mg/d mifepristone, continued 6 months.The influence of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E), progesterone (P), volume of uterine and endometrail thickness of patients were observed. Results After treatment, the FSH, LH, E and P levels in the three groups were significantly decreased compared with before treatment (FSH: t=4.406, 5.329, 3.610, LH: t=4.563, 6.134, 4.455, P=0.000, 0.000, 0.000; P=0.000, 0.000, 0.000; E: t=7.173, 6.815, 7.018, P=0.000, 0.000, 0.000; E: t=2.367, 6.315, 4.351, P=0.020, 0.000, 0.000), and the difference were statistically significant (all P 0.05). Compared with the low dose group, E levels in the middle dose group and high dose group significantly decreased(t=3.850, 2.085, P=0.000, 0.004). Before and after treatment, the uterine volume among the three groups had no significant difference (P>0.05). After treatment, the functional uterine bleeding symptoms were significantly relieved in the three groups, the effective rate was 100%.The recurrence rate of the low dose group was 32%, which was significantly higher than 8% and 10% of the middle dose group and high dose group.The amenorrhea rate of the middle dose group and high dose group(6% and 2%) was significantly lower than that of the low dose group (46%). Conclusion The treatment of 12.5mg/d mifepristone is effectively adapted to patients with dysfunctional uterine bleeding. Key words: Mifepristone; Uterine bleeding; Dose-respone relationship, drug

Mifepristone combined with Gongliuxiao capsule for patients with hysteromyoma

Objective To explore the effect of mifepristone combined with Gongliuxiao for patients with hysteromyoma.Methods 90 patients with hysteromyoma treated at our department from July,2014 to June,2015 were selected and divided into a control group (45 cases) and an observation group (45 cases) using random number table method.The control group were treated with mifepristone and the observation group with mifepristone and Gongliuxiao capsule.The short-term treatment effect was evaluated in both groups.Before and after the treatment,the maximum myoma volume,uterine volume,cell factors and sex hormone levels were compared between these two groups.Results The total effective rate was 93.33％ in the observation group and 77.78％ in the control group (P ＜ 0.05).The maximum myoma volume and uterine volume were (105.62±23.17) cm3 and (34.63±13.56) cm3 in the observation group and were (118.29±25.46) cm3 and (48.72±15.68) cm3 in the control group (P ＜ 0.05).The serum levels of TNF2 alpha and IL-22 were (21.29±10.43) ng/L and (20.36±8.56) ng/L in the observation group and were (16.69±3.17) ng/L and (33.25±13.05) ng/L in the control group,with statistical differences (P ＜ 0.05).The levels of E2 and P were (160.37±44.93) pmmol/L and (9.03±2.85) μg/L in the observation group and were (227.66±54.63) pmmol/L and (15.92±2.66) μg/L in the control group (P ＜ 0.05).There was no statistical difference in the incidence of clinical adverse reactions during the treatment period between these two groups (P ＞ 0.05).Conclusions Mifepristone combined with Gongliuxiao for patients with hysteromyoma is obviously effective and can improve the patients' endocrine function and prognosis.

Effects of Jiawei Shaoyao-Gancao Decoction and Its Drug-Containing Serum on Proliferation, Apoptosis, and Ultrastructure of Human Adenomyosis Foci Cells.

Objective The present study aimed to investigate the effects of Jiawei Shaoyao-Gancao Decoction (JSGD) and its drug-containing serum (CDS) on the proliferation, apoptosis, and ultrastructure of human adenomyosis foci cells. Methods Primary cultures of human adenomyosis foci cells were prepared from hard uterine lesions of adenomyosis patients. The cells were treated with JSGD (10 and 20 mg/ml), CDS, and mifepristone (MIF) for 24 or 48 h. Cell proliferation was detected using CCK-8 assay, cell apoptosis was measured by flow cytometry, and the cell ultrastructure was observed by transmission electron microscopy (TEM). Results JSGD and CDS significantly induced cell apoptosis and inhibited cell proliferation for 24 h or 48 h, in which the effects of JSGD were in a dose-dependent manner. The effect of CDS for 24 h was higher than that of CDS for 48 h. Moreover, JSGD and CDS treatments induced marked apoptosis in adenomyosis foci cells, characterized by nucleus chromatin, condensation, fragmentation, mitochondria and endoplasmic swelling, and autophagy-lysosome. Conclusions JSGD and CDS can suppress proliferation and induce apoptosis in adenomyosis foci cells, through altering their ultrastructure. The results provided support for JSGD and CDS in the treatment of adenomyosis and gained further insight into the effect of this prescription.

Chitosan-based nanoparticles for improved anticancer efficacy and bioavailability of mifepristone.

In addition to its well-known abortifacient effect, mifepristone (MIF) has been used as an anticancer drug for various cancers in many studies with an in-depth understanding of the mechanism of action. However, application of MIF is limited by its poor water solubility and low oral bioavailability. In this work, we developed a drug delivery system based on chitosan nanoparticles (CNs) to improve its bioavailability and anticancer activity. The MIF-loaded chitosan nanoparticles (MCNs) were prepared by convenient ionic gelation techniques between chitosan (Cs) and tripolyphosphate (TPP). The preparation conditions, including Cs concentration, TPP concentration, Cs/MIF mass ratio, and pH value of the TPP solution, were optimized to gain better encapsulation efficiency (EE) and drug loading capacity (DL). MCNs prepared with the optimum conditions resulted in spherical particles with an average size of 200 nm. FTIR and XRD spectra verified that MIF was successfully encapsulated in CNs. The EE and DL of MCNs determined by HPLC were 86.6% and 43.3%, respectively. The in vitro release kinetics demonstrated that MIF was released from CNs in a sustained-release manner. Compared with free MIF, MCNs demonstrated increased anticancer activity in several cancer cell lines. Pharmacokinetic studies in male rats that were orally administered MCNs showed a 3.2-fold increase in the area under the curve from 0 to 24 h compared with free MIF. These results demonstrated that MCNs could be developed as a potential delivery system for MIF to improve its anticancer activity and bioavailability.

Clinical effect of mifepristone combined with misoprostol for termination of pregnancy in high risk pregnant women

Objective To explore the clinical effect of mifepristone combined with misoprostol for termination of pregnancy in high risk pregnant women and provide reference for clinical treatment. Methods 182 cases of high-risk maternal were divided into observation group and control group by the random number table method, each group 91 cases.The control group was treated with conventional abortion termination of pregnancy, the observation group was treated with the artificial abortion before oral administration of mifepristone tablets and misoprostol tablets.The operation time, the amount of blood loss, the degree of pain, the degree of cervical softening and the occurrence of complications of induced abortion were compared between the two groups. Results The operation time of the observation group was (2.21±1.41)min, intraoperative bleeding was (15.29 ±4.06)mL, which were significantly less than those of the control group (t=7.122, 8.256, all P<0.05); The pain degree grade I in the observation group was 58.24%, which was significantly higher than that in the control group, grade III accounted for 5.49%, which was significantly lower than the that in the control group (χ2=44.887, 44.121, all P<0.05), the observation group of cervical softening full was 59 cases, full softening rate was 64.84% and the control group in the cervical softening full was 41 cases, softening full rate was 45.05%.Fully softening rate in the observation group was significantly higher than that in the control group (χ2=7.191, 8.411, P<0.05), the control group, the incidence of uterine perforation in 2 cases, the occurrence of artificial abortion syndrome 7 cases, the incidence of complications for 9.89%, the observation group had no uterine perforation occurred, 1 case of artificial abortion syndrome and complications occurred rate was 1.10%.The incidence of complications in the observation group was significantly lower than that in the control group (χ2=6.772, P<0.05). Conclusion Mifepristone combined with misoprostol for high-risk maternal termination of pregnancy could significantly shorten the artificial abortion operation time, reduce intraoperative blood loss, reduce the patient pain, reduce the incidence of complications. Key words: High risk maternal; Termination of pregnancy; Mifepristone; Misoprostol

The use of mifepristone as emergency contraceptions method

The use of mifepristone as emergency contraceptions method

Endogenous opioids regulate glucocorticoid-dependent stress-coping strategies in mice

Coping skills are essential in determining the outcomes of aversive life events. Our research was aimed to elucidate the molecular underpinnings of different coping styles in two inbred mouse strains, C57BL/6J and SWR/J. We compared the influence of a preceding stressor (0.5h of restraint) on behavioral and gene expression profiles between these two strains. The C57BL/6J strain exhibited increased conditioned fear and high immobility (passive coping). Oppositely, the SWR/J mice demonstrated low freezing and immobility, low post-restraint anxiety and considerable struggling during the forced swim test (active coping). Gene profiling in the amygdala revealed transcriptional patterns that were related to the differential stress reactivity, such as the activation of glucocorticoid-dependent genes specifically in the C57BL/6J mice. Post-restraint blood sampling for corticosterone levels confirmed the association of hypothalamic–pituitary–adrenal (HPA) activation with a passive coping style. Pharmacological tools were used to modulate the stress-coping strategies. The blockade of opioid receptors (ORs) before the aversive event caused transcriptional and neuroendocrine changes in the SWR/J mice that were characteristic of the passive coping strategy. We found that treatment with a glucocorticoid receptor (GR) agonist (dexamethasone (DEX), 4mg/kg) impaired the consolidation of fear memory in the C57BL/6J mice and that this effect was reversed by OR blockade (naltrexone (NTX), 2mg/kg). In parallel, a glucocorticoid receptor antagonist (mifepristone (MIF), 20mg/kg) reversed the effect of morphine (20mg/kg) on conditioned fear in the C57BL/6J mice. Our results suggest that in mice, stress-coping strategies are determined by opioid-dependent mechanisms that modulate activity of the HPA axis.

Phase 1/2 study of glucocorticoid receptor (GR) antagonist mifepristone (MIFE) in combination with eribulin (E) in advanced solid tumors, with dose expansion in patients with GR-positive (GR+) triple-negative breast cancer (TNBC).

e12550Background: GR is highly expressed in TNBC and is associated with a poor prognosis in estrogen receptor-negative (ER-) early stage breast cancer. Treatment with MIFE potentiates the effects of chemotherapy (ctx) in TNBC xenografts. Here we describe the results of an ongoing trial including outcomes to date in all patients with GR+ TNBC treated at the recommended Phase 2 dose (RP2D). Objectives: To determine the safety, tolerability, pharmacokinetics (PK) and clinical activity of the MIFE+E combination in pts with GR+ TNBC at the RP2D. Methods: Eligibility: Phase 1, pts with solid tumors; Phase 2, pts with GR+ TNBC; up to 5 prior ctx regimens for advanced disease; ECOG PS 0-1; adequate end-organ function. Design: 3 + 3 dose escalation scheme. After a 7-day lead-in of oral daily MIFE alone, MIFE was continued daily and E was given on days 1 and 8 of a 21-day cycle. Results: 16 pts with metastatic breast cancer were enrolled in Phase 1 (3 with GR+ TNBC). MTD/RP2D was MIFE 300 mg/day + E 1.1 mg/m2. To d...

546. Development of MFP-Inducible System for AAV5 Gene Therapy of Chronic Diseases in the Liver

Introduction: Gene therapy offers long term solutions for chronic diseases, whereby the transgene is continuously expressed upon single vector administration. However in some cases it would be desirable to tightly regulate or switch off transgene expression. Methods: We are investigating regulated gene expression based on the mifepristone (MFP)-inducible GeneSwitch system. The GeneSwitch protein comprises yeast Gal4 DNA-binding domain, a human p65 activation domain and a MFP controlled domain derived from the human progesterone receptor. The classical GeneSwitch system consists of two expression cassettes on two separate vectors; one containing the GeneSwitch sequence and one containing the transgene. We compared this two-vector system to a single-vector system, where the two cassettes were put into one vector for efficacy in vitro and in vivo. Results: We show inducible expression of EPO, IGF and GNDF obtained in vitro upon addition of MFP to cells transfected with plasmids containing GeneSwitch and the gene expression cassette. The kinetics of EPO mRNA and protein expression followed a dose dependent fashion in the range of 0.1 to 10 nM MFP and reached a plateau at higher MFP concentrations. Surprisingly, the GeneSwitch protein expression decreased 48h after MFP induction. The indicibility of the single versus the two-vector system of GeneSwitch-EPO was compared. Both systems were equally inducible based on total amount of EPO produced in the presence of MFP and related to background expression in the absence of MFP. In vivo proof of concept was obtained for EPO in the liver. EPO is characterized by clear expression kinetics in plasma and raises blood hematocrit, hence provides a reliable in-life read-out for gene inducibility. Mice were injected with different doses of AAV5-AAT-GeneSwitch-EPO and gene expression was induced in two separate rounds at 4 and 8 weeks p.i. EPO plasma levels increased approximately 2-logs in the single or two-vector system-injected mice, compared to un-induced groups. Moreover in the absence of MFP background expression of EPO was lower in the single-vector system and hematocrit levels were unaffected. Measurements of MFP in tissue matrices and in plasma by mass spectrometry show the presence of MFP in plasma and liver, validating applicability of the GeneSwitch system in the liver. Conclusion: Overall, our data indicate that transgene expression can be repeatedly regulated in the liver using the GeneSwitch system and provides us with a novel AAV5 vector for further development.

FDA's Action on “Abortion Pill”

More than 1 million U.S. women seek abortion services each year. When mifepristone (initially known as RU-486) was introduced in September 2000, many expected it to improve access to abortion services. However, hundreds of targeted restrictions on abortion provision have continued to shrink access — and 89% of U.S. counties currently have no abortion providers. To reflect …

The Architecture and Function of Monoclonal Antibody-Functionalized Mesoporous Silica Nanoparticles Loaded with Mifepristone: Repurposing Abortifacient for Cancer Metastatic Chemoprevention.

The circulating tumor cells (CTCs) existing in cancer survivors are considered the root cause of cancer metastasis. To prevent the devastating metastasis cascade from initiation, we hypothesize that a biodegradable nanomaterial loaded with the abortifacient mifepristone (MIF) and conjugated with the epithelial cell adhesion molecule antibody (aEpCAM) may serve as a safe and effective cancer metastatic preventive agent by targeting CTCs and preventing their adhesion-invasion to vascular intima. It is demonstrated that MIF-loaded mesoporous silica nanoparticles (MSN) coated with aEpCAM (aE-MSN-M) can specifically target and bind colorectal cancer cells in either cell medium or blood through EpCAM recognition proven by quantitative flow cytometric detection and free aEpCAM competitive assay. The specific binding results in downregulation of the captured cells and drives them into G0/G1 phase primarily attributed to the effect of aEpCAM. The functional nanoparticles significantly inhibit the heteroadhesion between cancer cells and endothelial cells, suggesting the combined inhibition effects of aEpCAM and MIF on E-selectin and ICAM-1 expression. The functionalized nanoparticles circulate in mouse blood long enough to deliver MIF and inhibit lung metastasis. The present proof-of-concept study shows that the aE-MSN-M can prevent cancer metastasis by restraining CTC activity and their adhesion-invasion to vascular intima.

Contrast of retinal structure and function developing of premature rats versus full-term newborn rats

Background Premature birth is a high risk factor of abnormal development in the morphology and function of vision system.To observe the effect of premature birth on the structural and functional development of neonatal retina is of great importance. Objective This study aimed to compare the differences of retinal structure and function between premature rats and normal rats. Methods Twenty-eight gestational SD rats were randomized to bacterial lipopolysaccharide (LPS)-induced preterm (LP) group, mifepristone-induced preterm (RP) group, cesarean section-induced preterm (CP) group and normal control group, with 10-12 rats from each nest.LPS (20 μg/kg) or mifepristone (10 mg/kg) was injected on the 18 th day of gestation in the LP group and RP group, respectively, to establish premature birth rat models, and cesarean delivery was performed on the 19 th day of gestation in the CP group.Full-term newborn rats born in 22 days after gestation in the normal group.Systemic circulatory perfusion was carried out in the neonatal rats using normal saline solution and 4% triformal on postnetal 4, 7, 10 and 14 days and then the retinal sections of the left eyes were prepared for the hematoxylin and eosin staining to examin the retinal layers and cells counting.Electroretinogram (ERG) based on international standardization was recorded in the rats on postnetal 14, 21 and 28 days to evaluate the retinal function.All the results were compared between the premature rats and the normal rats.The use and care of the animals complied with the Regulations for the Administraion of Affair Concerning Experimental animals by State Science and Technology Commission. Results The number of neuroblast layers was more on postnetal 4-day and 7-day rats in the LP group, CP group and the RP group than those in the normal control group (LP: t=-7.07, -4.97, both at P 0.05). Compared with the normal group, the amplitudes of Rod-b wave, Max-a and b waves, oscillatory potentials (OPs), Cone-b wave and flicker ERG were not significantly changed on postnetal 14-day, 21-day and 28-day rats among the LP group, CP group and RP group (all at P>0.05). However, the latencies of Max-a and b waves were significantly extended on postnetal 14-day rats in the LP group (t =-3.94, -3.31, all at P<0.01), and the latencies of Rod-b wave, Max-b wave and Cone-b wave were prolonged in the CP group in comparison with the normal group (t=-2.42, -2.61, -2.16, all at P =0.02). Also, the latency of Max-b wave was extended in the RP group in comparison with the normal group (t=-3.67, P<0.01). In addition, the latencies of Max-a and b waves in 21-day rats and Max-b latency in 28-day rats in the LP group were significantly longer than those in the normal group (t =-3.18, -3.45, -3.61, all at P<0.01). Conclusions The developing lags of retinal structure and function propably are the anatomical basis of preterm children prone to retinal diseases. Key words: Premature/chemically and surgery induced; Gestational age; Animals, newborn; Development; Retina; Electroretinogram; Structure; Rats, Sprague Dawley