Investigating the Effects of Mifepristone (RU486) in the Behavioral, Hormonal and Central Responses to Acute Stress

Depression is associated with glucocorticoid hypersecretion, due to dysfunction of the hypothalamo-pituitary-adrenocorticol axis (HPA-axis). Because excess glucocorticoids are associated with depressive-like features in humans, glucocorticoid receptor antagonists are currently being tested for antidepressant efficacy in clinical trials. In the current study the hypothesis that mifepristone (RU486), a glucocorticoid receptor antagonist, would decrease the neuroendocrine and central HPA-axis responses to an acute stressor and attentuate depressive like behavior in an animal model of behavioral helplessness (forced swim test) was tested. Adult male rats were treated with 10 mglkg RU486 (subcutaneous) for five days and then exposed to a IO-minute forced swim test (FST), conducted in Plexiglas cylinders. FST sessions were videotaped for later analysis of behavioral immobility. Plasma ACTH and corticosterone CORT were measured at 15min and 90min after FST cessation. Animals were perfused and brains were collected for immunocytochemical assessment of c-Fos expression in the medial prefrontal cortex (mPFC), a brain region implicated in both depression and central control of the HPA axis. RU486 significantly decreased peak ACTH and CORT concentrations following FST exposure. In addition, glucocorticoid negative feedback was at1enuated in RU486-treated animals exposed to the FST. Exposure to FST alone induced c-FOS expression in the mPFC, as measured by the number of c-Fos positive neurons. Treatment with RU486 significantly increased the number of rnPFC c-Fos positive cell following FST exposure. The behavioral data obtained from FST paradigm, demonstrated that RU486 decreased immobility in the FST illustrating the potential efficacy of this drug as an antidepressant. Collectively these data suggest that RU486 dampens HPA-axis responses to stress, possibly by enhancing the excitability of stress-inhibitory neurons in the mPFC. This is particularly exciting, given the fact that this neural region is associated with decreased neural activity during depression in humans.

Effects of the glucocorticoid antagonist, mifepristone, on the consequences of withdrawal from long term alcohol consumption

BACKGROUND: Studies were carried out to test the hypothesis that administration of a glucocorticoid Type II receptor antagonist, mifepristone (RU38486), just prior to withdrawal from chronic alcohol treatment, would prevent the consequences of the alcohol consumption and withdrawal in mice. MATERIALS AND METHODS: The effects of administration of a single intraperitoneal dose of mifepristone were examined on alcohol withdrawal hyperexcitability. Memory deficits during the abstinence phase were measured using repeat exposure to the elevated plus maze, the object recognition test, and the odor habituation/discrimination test. Neurotoxicity in the hippocampus and prefrontal cortex was examined using NeuN staining. RESULTS: Mifepristone reduced, though did not prevent, the behavioral hyperexcitability seen in TO strain mice during the acute phase of alcohol withdrawal (4 hours to 8 hours after cessation of alcohol consumption) following chronic alcohol treatment via liquid diet. There were no alterations in anxiety-related behavior in these mice at 1 week into withdrawal, as measured using the elevated plus maze. However, changes in behavior during a second exposure to the elevated plus maze 1 week later were significantly reduced by the administration of mifepristone prior to withdrawal, indicating a reduction in the memory deficits caused by the chronic alcohol treatment and withdrawal. The object recognition test and the odor habituation and discrimination test were then used to measure memory deficits in more detail, at between 1 and 2 weeks after alcohol withdrawal in C57/BL10 strain mice given alcohol chronically via the drinking fluid. A single dose of mifepristone given at the time of alcohol withdrawal significantly reduced the memory deficits in both tests. NeuN staining showed no evidence of neuronal loss in either prefrontal cortex or hippocampus after withdrawal from chronic alcohol treatment. CONCLUSIONS: The results suggest mifepristone may be of value in the treatment of alcoholics to reduce their cognitive deficits.

First-trimester medical abortion with mifepristone 200 mg and misoprostol: a systematic review

http://download.journals.elsevierhealth.com/pdfs/journals/0010-7824/PIIS0010782412006439.pdf

Two Distinct Oral Routes of Misoprostol in Mifepristone Medical Abortion. A Randomized Controlled Trial

http://pdfs.journals.lww.com/greenjournal/2008/12000/Two_Distinct_Oral_Routes_of_Misoprostol_in.18.pdf?token=method|ExpireAbsolute;source|Journals;ttl|1369920806057;payload|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;hash|BM4+yd44xH/IRKdsrM1Wzg==

Effectiveness of medical abortion with mifepristone and buccal misoprostol through 59 gestational days

BACKGROUND: From 2001 to March 2006, Planned Parenthood Federation of America (Planned Parenthood) health centers throughout the United States provided medical abortions principally by a regimen of oral mifepristone, followed 24-48 h later by vaginal misoprostol. In late March 2006, analyses of serious uterine infections following medical abortions led Planned Parenthood to change the route of misoprostol administration and to employ additional measures to minimize subsequent serious uterine infections. In August 2006, we conducted an extensive audit of medical abortions with the new buccal misoprostol regimen so that patients could be given accurate information about the success rate of the new regimen. OBJECTIVES: We sought to evaluate the effectiveness of the buccal medical abortion regimen and to examine correlates of its success during routine service delivery. METHODS: In 2006, audits were conducted in 10 large urban service points to estimate the success rates of the buccal regimen. Success was defined as medical abortion without vacuum aspiration. These audits also permitted estimates of success rates with oral misoprostol following mifepristone in a subset in which 98% of the subjects stemmed from two sites. RESULTS: The effectiveness of the buccal misoprostol-mifepristone regimen was 98.3% for women with gestational ages below 60 days. The oral misoprostol-mifepristone regimen, used by 278 women with a gestational age below 50 days, had a success rate of 96.8%. CONCLUSION: In conjunction with 200 mg of mifepristone, use of 800 mcg of buccal misoprostol up to 59 days of gestation is as effective as the use of 800 mcg of vaginal misoprostol up to 63 days of gestation.

Chronic potassium depletion increases adrenal progesterone production that is necessary for efficient renal retention of potassium.

Modern dietary habits are characterized by high-sodium and low-potassium intakes, each of which was correlated with a higher risk for hypertension. In this study, we examined whether long-term variations in the intake of sodium and potassium induce lasting changes in the plasma concentration of circulating steroids by developing a mathematical model of steroidogenesis in mice. One finding of this model was that mice increase their plasma progesterone levels specifically in response to potassium depletion. This prediction was confirmed by measurements in both male mice and men. Further investigation showed that progesterone regulates renal potassium handling both in males and females under potassium restriction, independent of its role in reproduction. The increase in progesterone production by male mice was time dependent and correlated with decreased urinary potassium content. The progesterone-dependent ability to efficiently retain potassium was because of an RU486 (a progesterone receptor antagonist)-sensitive stimulation of the colonic hydrogen, potassium-ATPase (known as the non-gastric or hydrogen, potassium-ATPase type 2) in the kidney. Thus, in males, a specific progesterone concentration profile induced by chronic potassium restriction regulates potassium balance.

Dexamethasone induces posttranslational degradation of GLUT2 and inhibition of insulin secretion in isolated pancreatic beta cells. Comparison with the effects of fatty acids.

GLUT2 expression is strongly decreased in glucose-unresponsive pancreatic beta cells of diabetic rodents. This decreased expression is due to circulating factors distinct from insulin or glucose. Here we evaluated the effect of palmitic acid and the synthetic glucocorticoid dexamethasone on GLUT2 expression by in vitro cultured rat pancreatic islets. Palmitic acid induced a 40% decrease in GLUT2 mRNA levels with, however, no consistent effect on protein expression. Dexamethasone, in contrast, had no effect on GLUT2 mRNA, but decreased GLUT2 protein by about 65%. The effect of dexamethasone was more pronounced at high glucose concentrations and was inhibited by the glucocorticoid antagonist RU-486. Biosynthetic labeling experiments revealed that GLUT2 translation rate was only minimally affected by dexamethasone, but that its half-life was decreased by 50%, indicating that glucocorticoids activated a posttranslational degradation mechanism. This degradation mechanism was not affecting all membrane proteins, since the alpha subunit of the Na+/K+-ATPase was unaffected. Glucose-induced insulin secretion was strongly decreased by treatment with palmitic acid and/or dexamethasone. The insulin content was decreased ( approximately 55 percent) in the presence of palmitic acid, but increased ( approximately 180%) in the presence of dexamethasone. We conclude that a combination of elevated fatty acids and glucocorticoids can induce two common features observed in diabetic beta cells, decreased GLUT2 expression, and loss of glucose-induced insulin secretion.

Termination of pregnancy among teenagers - why more surgical terminations?

Introduction: In 2012, a study by K. Chatziioannidou and S-C. Renteria showed that teenagers chose to undergo a surgical termination of pregnancy (TOP) more often than a medical TOP (mifepristone followed by misoprostol) when they decided to terminate a pregnancy. It also showed that the teenagers' choice for a medical versus surgical method is inversely proportional to the adults' choice although the efficiency of the medical method showed even better results for teenagers than for adults. According to the hypothesis made, the reasons for this choice might be influenced by the following facts: (i) the belated call to make an appointment, the medical procedure not being available after 9 weeks of gestation; (ii) the imperative request for confidentiality; (iii) the beliefs and subjective appreciation of the medical staff. Objectives: The aim of this retrospective and qualitative study is to analyse the reasons why, in case of a TOP, teenagers chose the surgical method more often than their adult counterparts. Material: (i) All teenagers who were admitted for an abortive procedure during 2011 in the in- or outpatient ward. (ii) The professional team (midwives and sexual and reproductive counsellors) in charge in the case of a TOP request. Methods: The information about the patient's history and the biopsycho- social data was retrieved from the patient files filled out by midwives and sexual and reproductive health counsellors during the first appointment for a TOP request or during its process. The professionals' appreciation was evaluated by means of a semi-structured questionnaire. Results: Concerning the choice of the method for a pregnancy termination, the results of our research show that: (i) Out of 47 teenagers, 27 chose the surgical method and 17 the medical method. (ii) Three had a second trimester abortion (which includes use of the medical method). (iii) Fifteen teenagers out of the 27 who chose a surgical method consulted between the 9th and 14th weeks of amenorrhoea and therefore did not have any other choice. The reasons for their 'late arrival' will be explained in detail. The 12 teenagers who arrived before the 8th week of amenorrhoea and chose to undertake abortion by suction & curettage under general anaesthesia did it for the following reasons: (i) Four were afraid of bleeding and pain. (ii) Five thought that the organisation of the surgical procedure was easier. (iii) Two did not trust the abortion pill. (iv) One was taken to her mother's gynaecologist where she had a D&C. Confidentiality was requested nine times out of 27 when choosing the surgical method, and six times out of 17 when choosing the medical method. Therefore, although confidentiality concerns a third of the teenagers' pregnancy termination requests, it does not seem to be a significant element for the choice of the method. As for the subjective appreciation of the professionals, the first results of the discussions seem to show that teenagers were reluctant or resistant towards the medical method. Conclusion: This study shows that the reasons why teenagers still prefer the use of the surgical over the medical method compared to adults, seem to include the late request for an appointment, fear of pain and bleeding and organisational issues. Confidentiality does not seem to greatly influence the teenagers' choice. Nonetheless, medical professionals seem to favour the suction curettage procedure performed under anesthesia because they associate young age with vulnerability and psychological frailty and consequently diminished ability to cope with pain and emotional distress during the medical procedures.

Longitud cervical como predictor de exito en induccion de trabajo de parto en nuliparas

La inducción del trabajo de parto ha demostrado aumentar simultáneamente las tasas de cesárea, especialmente en nulíparas con cérvix clínicamente desfavorables. Ya que la valoración clínica del cérvix es un método subjetivo, aunque ampliamente utilizado, el objetivo del presente estudio fue determinar la utilidad de la medición ecográfica de la longitud cervical comparándola con el puntaje de Bishop, en la predicción del éxito de la inducción del parto en las pacientes nulíparas en el servicio de Obstetricia del Hospital Universitario Clínica San Rafael, Bogotá. Materiales y métodos: Se realizó un estudio observacional, evaluando una cohorte prospectiva de 80 gestantes a quienes se les realizó valoración ultrasonográfica y clínica del cérvix antes de iniciar la inducción del trabajo de parto. Resultados: El análisis bivariado demostró que las pacientes con longitud cervical >20mm tienen 1.57 veces la probabilidad de tener parto por cesárea (RR 1.57 IC95% 1.03-2.39 p <0.05). De manera similar las pacientes con puntaje de Bishop 0 a 3 tienen 2.33 veces la probabilidad de tener parto por cesárea (RR 2.33 IC95% 1.28-4.23 p <0.05). La regresión logística binaria demostró que la edad materna y la longitud cervical fueron los únicos parámetros independientes con significancia estadística para predecir el éxito de la inducción. Conclusiones: La medición ecográfica de la longitud cervical tiene mayor utilidad que la valoración clínica del cérvix en la predicción del éxito de la inducción del parto en nulíparas.

Women's acceptability of misoprostol treatment for incomplete abortion by midwives and physicians : secondary outcome analysis from a randomized controlled equivalence trial at district level in Uganda

OBJECTIVE: This study aimed to assess women´s acceptability of diagnosis and treatment of incomplete abortion with misoprostol by midwives, compared with physicians. METHODS: This was an analysis of secondary outcomes from a multi-centre randomized controlled equivalence trial at district level in Uganda. Women with first trimester incomplete abortion were randomly allocated to clinical assessment and treatment with misoprostol by a physician or a midwife. The randomisation (1:1) was done in blocks of 12 and stratified for health care facility. Acceptability was measured in expectations and satisfaction at a follow up visit 14-28 days following treatment. Analysis of women's overall acceptability was done using a generalized linear mixed-effects model with an equivalence range of -4% to 4%. The study was not masked. The trial is registered at ClinicalTrials.org, NCT 01844024. RESULTS: From April 2013 to June 2014, 1108 women were assessed for eligibility of which 1010 were randomized (506 to midwife and 504 to physician). 953 women were successfully followed up and included in the acceptability analysis. 95% (904) of the participants found the treatment satisfactory and overall acceptability was found to be equivalent between the two study groups. Treatment failure, not feeling calm and safe following treatment, experiencing severe abdominal pain or heavy bleeding following treatment, were significantly associated with non-satisfaction. No serious adverse events were recorded. CONCLUSIONS: Treatment of incomplete abortion with misoprostol by midwives and physician was highly, and equally, acceptable to women. TRIAL REGISTRATION: ClinicalTrials.gov NCT01844024.