STUDY TO EVALUATE EFFECTS OF MIFEPRISTONE 25mg IN MANAGEMENT OF UTERINE FIBROIDS

Background: In India, the uterine broid is a common indication of hysterectomy. An effective option for medical treatment may decrease the morbidity associated with hysterectomy. Objectives: We aimed to evaluate the effect of mifepristone (25 mg), progesterone antagonist, on uterine broids in perimenopausal women. Material And Methods: Fifty perimenopausal women having symptomatic uterine broids were selected from Gynaecology OPD and given 25 mg mifepristone once daily continuously for 2–4 cycles of 3 months each. Variables such as baseline broid size, position, and haemoglobin were measured and followed at 3, 6, 9, and 12 months. The data were entered in MS EXCELspreadsheet and analysis was done using Statistical Package for Social Sciences (SPSS) version 21.0. APvalue of <0.05 was considered as statistically signicant. Results: Majority were intramural broids (70%) followed by submucosal in 18%. Size of broids ranged from 7 cm; the majority of broids were in 5–7 cm size. No signicant association of location with the size of broid was found. Out of 50 cases included in the study, change in size in uterine broids was observed in 95.14% cases. There was an increase in haemoglobin, from 8.6 g% at baseline to 9.5 g% at 12 months. Conclusion: Mifepristone resulted in a reduction in uterine broids size and an increase in haemoglobin at the end of 12 months. It may be an option for uterine leiomyoma treatment, as it is given orally, cost-effective and has minimal side effects.

Basket study of the oral progesterone antagonist onapristone ER in women with progesterone receptor positive (PR+) recurrent granulosa cell tumor (GCT), low-grade serous ovarian cancer (LGSOC), or endometrioid endometrial cancer (EEC).

TPS6098 Background: Onapristone extended release (ER) is a type I full progesterone antagonist that inhibits progesterone mediated PR activation and stabilizes PR association with corepressors. Onapristone has shown activity across multiple preclinical models of hormonally driven cancer. A phase I dose escalation study of onapristone ER in PR+ breast, endometrial and ovarian cancer patients found all doses tested to be well tolerated, with 50mg PO BID determined to be the recommended phase 2 dose (RP2D). GCT (98% of cases PR+), LGSOC (58% of cases PR+) and EEC (67% of cases PR+) are hormonally driven cancers which generally have poor responses to chemotherapy and limited treatment options in the recurrent setting. Methods: This is an open-label, investigator-initiated basket study of onapristone ER in patients with PR+ recurrent GCT, LGSOC, or EEC currently enrolling patients at Memorial Sloan Kettering Cancer Center in NY, USA (NCT03909152). The primary objective is to evaluate the efficacy, in terms of response rate by RECIST 1.1 criteria, within 36 weeks of treatment. Eligible patients must have received at least 1 prior line of chemotherapy, have measurable disease by RECIST 1.1 criteria, and have tumor tissue collected within 3 years prior to enrollment with PR expression ≥ 1% by IHC. Patients are allowed to have unlimited additional prior lines of chemotherapy, biologic therapy, immunotherapy or hormonal therapy. Enrolled patients are treated with onapristone ER 50mg PO BID until time of progression or intolerable toxicity. The 3 disease cohorts are currently enrolling to Stage I in parallel with expansion from stage I to stage II planned when the prespecified response criteria are met for each cohort as described in the table below. Clinical trial information: NCT03909152. [Table: see text]

Functional Hierarchy of Uterotonics Required for Successful Parturition in Mice

Parturition is an essential process in placental mammals for giving birth to offspring. However, the molecular machineries of parturition are not fully understood. We investigated whether oxytocin plays a crucial role in the progress of parturition in cooperation with the prostaglandin F2α (PGF2α) receptor. We first examined alterations in the expression of uterine contraction-associated genes in uteri of oxytocin receptor–deficient mice (Oxtr−/−) during parturition. We found that induction of cyclooxygenase (COX)-2 and connexin 43 expression was impaired in Oxtr−/−, whereas that of PGF2α receptor expression was not. We next generated mice with double knockout of genes for the oxytocin receptor/oxytocin and PGF2α receptor (Oxtr−/−;Ptgfr−/− and Oxt−/−;Ptgfr−/−) and evaluated their parturition with Oxtr−/−, Oxt−/−, Ptgfr−/−, and wild-type mice. In Oxtr−/−;Ptgfr−/− and Oxt−/−;Ptgfr−/−, pregnancy rates were similar to those of other genotypes. However, normal parturition was not observed in Oxtr−/−;Ptgfr−/− or Oxt−/−;Ptgfr−/− because of persistent progesterone from the corpus luteum, as observed in Ptgfr−/−. We administered RU486, a progesterone antagonist, to Ptgfr−/−, Oxtr−/−;Ptgfr−/−, and Oxt−/−;Ptgfr−/− on gestation day 19. These mice were able to deliver a living first pup and the parturition onset was similar to that in Ptgfr−/−. Meanwhile, unlike Ptgfr−/−, ∼75% of Oxtr−/−;Ptgfr−/− and Oxt−/−;Ptgfr−/− administered RU486 remained in labor at 24 hours after the onset of parturition. All of the pups that experienced prolonged labor died. We thus revealed that the oxytocin receptor is an upstream regulator of COX-2 and connexin 43 in the uterus during parturition and that both oxytocin/oxytocin receptor and PGF2α receptor are major components for successful parturition.

Efficacy of Mefipristone for induction of labour in late term pregnancy

Background: Late-term pregnancy defined as one that has reached between 41 0/7 weeks and 41 6/7 weeks of gestation is associated with an increased maternal morbidity as well as an increased risk of fetal and neonatal mortality and morbidity. Mifepristone, an anti-glucocorticoid and antiprogesterone, though not an oxytocic increases uterine activity and causes cervical effacement and dilatation and improves the Bishop score without over/hyper stimulation of uterus. Increased maternal and fetal mortality from late term pregnancy could be prevented by induction of labour. The objective of this study was to know the efficacy of single dose of oral mifepristone in induction of labour in late term pregnancy and to assess the induction delivery interval in the study population.Methods: This was a prospective interventional study conducted in Department of Obstetrics and Gynaecology at BGS Global Institute of Medical Sciences, Bengaluru. 100 Women with late term pregnancy who fulfilled the inclusion and exclusion criteria were considered for the study after an informed written consent.Results: 73.5% (n=36) of multigravida and 80.4% (n=41) of prim gravida showed improvement in the Bishop score post induction with mifepristone and majority (89.79 % primigravida and 84.31% multigravida) of the study population had vaginal delivery. Multigravida (73.5%) had less induction delivery interval (less than 48hours) compared to primigravida (19.6%).Conclusions: Mifepristone, a progesterone antagonist causes a significant improvement in the Bishop’s score and is associated with an increased rate of vaginal deliveries.

Intrauterine foetal demise in pre-eclampsia - role of mifepristone: a case series

Mifepristone is a steroid, which is a progesterone antagonist and is widely used for termination of pregnancies in all the trimester. It increases the sensitivity of the uterus to prostaglandins and ripens the cervix. Its role in inducing women with intra uterine demise is on the rise with varying dose regimen either alone or in combination with misoprostol. Among the various causes of intrauterine demise, one of the most important is hypertensive disorders of pregnancy complicating around 10% of pregnancies worldwide, Serum uric acid, a marker of oxidative stress is an important parameter in defining poor fetal outcome in women with pre-eclampsia. Induction of labour in women diagnosed with intrauterine demise is again a challenge in such women and mifepristone helps to a larger extent. In present case series, authors present six women presenting with pre-eclampsia with intrauterine demise, their clinical and biochemistry profile and responding to single dose of mifepristone of 200 mg with mean induction to delivery interval being 40 hours. Henceforth, authors conclude that even single dose of mifepristone can work wonders taking into consideration the cost of the drug and thus can be definitely employed in daily clinical practice.