Friday, June 26, 2015

Mifepristone. Mifeprex, Corlux, Korlym, progesterone inhibitors

Mifepristone: An Overview

Mifepristone (RU-486) was the first antiprogesterine to be developed for clinical use




 Here are two of the most recent reports I found
Efficacy of the Progesterone Receptor Antagonist Mifepristone for Palliative Therapy of Patients with a Variety of Advanced Cancer Types
JEROME H. CHECK, EBONY DIX, RACHAEL COHEN, DIANE CHECK and CARRIE WILSON
+ Author Affiliations
The University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School at Camden, Cooper Hospital/University Medical Center, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Camden, New Jersey, U.S.A.
Correspondence to: Jerome H. Check, MD, Ph.D., 7447 Old York Road, Melrose Park, PA 19027, U.S.A. Tel: +1 2156354156, Fax: +1 2156352304, e-mail: laurie@ccivf.com 

Abstract Background: Mifepristone has been demonstrated to improve longevity and quality of life in mice with spontaneous murine cancer without progesterone receptors and in human colon cancer. The present study evaluated the palliative effect of mifepristone in a variety of different types of human cancer.
Patients and Methods: Mifepristone was given at 200 mg daily orally with permission from the Food and Drug Administration to people with widely metastatic human cancer no longer responsive to other chemotherapy regimens.
Results: Improvement in pain and energy and/or length of life was found in thymic epithelial cell carcinoma, transitional cell carcinoma of the renal pelvis, leiomyosarcoma, pancreatic carcinoma, malignant fibrous histiocytoma and another case of adenocarcinoma of the colon.
Conclusion: Our data demonstrate a palliative role for the use of mifepristone in cancer therapy. Progesterone receptor antagonists(inhibitors) should be given a therapeutic trial in larger controlled studies of various malignancies in humans.

Key words: Metastatic human cancer palliation progesterone receptor antagonist tumor microenvironment mifepristone
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Antiprogestin mifepristone inhibits the growth of cancer cells of reproductive and non-reproductive origin regardless of progesterone receptor expression
Chelsea R Tieszen , Alicia A Goyeneche , BreeAnn N Brandhagen , Casey T Ortbahn  and Carlos M Telleria
Division of Basic Biomedical Sciences, Sanford School of Medicine of The University of South Dakota, 414 East Clark Street, Vermillion, SD, USA
 author email corresponding author email
BMC Cancer 2011, 11:207doi:10.1186/1471-2407-11-207
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2407/11/207
  
. It is not only a progesterone inhibitor, but also acts as a glucocorticoid inhibitor The fundamental importance of progesterone for human conception and throughout pregnancy has meant that mifepristone has been used for emergency contraception :\"the morning after"  and as part of a safe medical abortion in the first and second trimester of pregnancy.
It has also been used as part of the therapy to manage fetal death in utero in the third trimester of pregnancy. There are many other uses based on its mechanism of action blocking cortisol and reducing the bleeding associated with uterine fibroids and shrinking them.

According to medical pathologists meningioma cells look the same under a medical microscope as uterine fibroid cells, in a subset of meningioma patients in NCI SWOG Phase 1 and Phase 2 it worked the same way on uterine fibroids with no serious risks of neurological injury from brain surgery and/or brain radiation. It had previously been tested on aggressive recurrent and multiple meningiomas after patients had exhausted both standard treatments and other experimental chemo drug therapies that may cause serious complications, late effects of radiation and death.

Key words: Cushing's syndrome, meningioma, pregnancy, progesterone, progestogen, RU486, therapeutic abortion

Introduction
Most health professionals will be familiar with the antioestrogens, clomiphene citrate and tamoxifen for breast cancer. These drugs have been used for years for conditions as diverse as infertility and breast cancer respectively. It was not until 1983 that a drug with antiprogestogenic activity was developed. Mifepristone was the first drug to compete and inhibit progesterone at its receptor, just like Tamoxifin the designer darling breast cancer drug competes with the estrogen .

Pharmacology
The progesterone receptor is one of several proteins synthesised by the action of oestradiol on the endometrium. This receptor is a dimer of two distinct proteins and binds progesterone which is a planar steroid. By contrast, mifepristone is a non-planar molecule. This bent, rigid, molecular structure seems important for anti steroid compounds.

Mifepristone binds to the progesterone receptor five times more avidly than progesterone. It also binds with the glucocorticoid receptor three times more strongly than dexamethasone. By contrast, mifepristone binds to the androgen receptor with only one quarter of the affinity of testosterone and has essentially no binding to the mineralocorticoid receptor or oestradiol receptors.
Approximately 85% of mifepristone is absorbed after oral administration. It has a long elimination half-life.
As mifepristone has antiprogestogenic activity, it has been studied in situations where its action may alter the course of conditions related to excess cortisol like stress related depression.

Meningioma
Meningioma is a generally benign tumor of the central nervous system. 80% of these benign tumors contain progesterone receptors. Unlike most breast cancer, meningiomas are commonly strongly progesterone receptor positive, only the more aggressive malignant ones 10% are oestrogen receptor positive. Mifepristone inhibits growth of meningioma cells in culture and reduces the size of human meningioma implanted into nude mice.
Patients with unresectable meningioma have been treated with oral mifepristone 200 mg daily for a median duration of therapy of 35 months (range 2–157 months). Several meningioma patients including myself and Doris Laird who testified in US Congress that it saved her life have safely and successfully taken it for more than 10 years.  In one series there were 19 women and 9 men with persistent or recurrent unresectable meningioma who already had serious side effects from multiple surgeries and radiation.  Eight patients responded to the therapy, as shown by reduced tumour size on computerized tomography or magnetic resonance imaging and improvement in visual field examination.  Endometrial hyperplasia (or benign endometrial changes as documented in Rochester study of fibroid therapy 2007) did occur in three premenopausal women, but did not prove dose limiting especially in view of its long-term safety used for patients with Cushing's syndrome.

Uterine fibroids
Uterine fibroids, or leiomyomata, are the most common tumours in women. The fibroids and their nourishing blood vessels are rich in progesterone receptors. Several trials have shown that mifepristone can reduce the size of uterine fibroids by 50% and effectively reduce menstrual blood loss. A recent randomised double-blind clinical trial of 10 mg mifepristone or placebo found that mifepristone reduced uterine and fibroid size and reduced menstrual blood loss. It also increased haemoglobin concentration so the female patients were no longer anemic and many did not need a hysterectomy as long as they took the drug.

Intrauterine fetal death
Progesterone is critical for establishing and maintaining pregnancy. The first WHO study in Australia used mifepristone to manage fetal death in late pregnancy. In these cases, the baby has died, but the placenta has not and it continues to synthesise progesterone for some weeks. This prevents labour and continues the pregnancy in very difficult emotional circumstances for any woman carrying a dead baby. For women with an unexplained fetal death in utero, and who have an unripe cervix, mifepristone typically induces delivery within 72 hours which can also eliminate the medical neccessity of a c section. I think most women would prefer not to be cut open.

Contraception
Mifepristone has been used as an emergency contraceptive. In randomised controlled studies, it is as effective as other regimens, such as those using levonorgestrel and saver than some of the new added hormone bith control pills. In WHO studies of emergency contraception within seven days of unprotected intercourse, mifepristone was effective at doses of 600 mg, 50 mg and even does as low as 10 mg.  This is important in low income countries with limited health care, few pharmaceutical resources and frequent early childhood death from malnutrition or human diseases like malaria.

Cushing's syndrome
As mifepristone is a glucocorticoid receptor antagonist, it has been studied in Cushing's syndrome. The first patient to be treated received mifepristone doses of up to 1500 mg daily for nine weeks. No adverse effects were observed. Some patients with Cushing's syndrome have been successfully treated with mifepristone for up to 10 years.

Recently, (SPRMs) selective progesterone receptor modulators have been developed. These drugs are the 'bio chemical successors' to mifepristone. They show partial agonist and partial antagonist effects on various progesterone target tissues. For example, Asoprisnil has antiproliferative effects on the endometrium and can decrease the size and growth of uterine fibroids by reducing uterine artery blood flow. Corlux is another brand name of Mifepristone that is being used to treat major depression.  It could help brain tumor survivors in two ways, those suffering from clinical depression post op which is quite common after the medical crisis is over and those at risk of gradual progression of residual tumor if every single bad cell was not surgically removed before they have to take the risks of completely zapping it with radiation.. 

Conclusion
In the 25 years since its safe effective use was first reported, mifepristone has been registered and widely used for safe medical abortion in many countries. These include the United Kingdom (since 1991), Sweden (1992), USA (2000) New Zealand (2001) and Australia (2006) Many other documented evidence based lifesaving uses are still off label uses. There has been so much political furor over its abortion and morning after pill use in the US that it is not easily available to other types of qualified medical specialists in this country, like endocrinologists, gynocologists and oncology doctors. They do not use it for medically beneficial uses in women's health care like meningiomas or fibroids simply because it is extra FDA paperwork hassle and the cost is not covered by insurance.  The American health insurance accountants and hospital lobbyists that follow the bucks are missing the boat here, In fact for private health insurers, Medicare and Medicaid it would be much cheaper to provide this drug than approximately 20 thousand brain surgeries a year and millions of hysterectomies 1/3 of all women eventually need to have for uterine fibroids. It could reduce US hospital costs immensely for all of us. 
 
I used a 2009 Australian medical report on Mifepristone as a template for some additional text in my own words I added above.   According to recent 2010-2011 research I think it blocks further tumor growth and shrink thousands of low grade pituitary adenomas, acoustic neuromas and vestibular shwannomas and some subset of ovarian cancers. Some cancer patients, male and female would certainly benefit from this old generic drug in terms of improving their overall quality of life and longterm survival rate as Doris Laird,  I and 40 others have done thanks to the Feminist Majority Foundation and the FDA . To fight rising cancer rates on a global scale, it could be produced cost effectively and FDA approved sooner than any other new drugs.

Again here are two of the most recent reports I found, there are many in PUB MED and I list them in other posts
Efficacy of the Progesterone Receptor Antagonist Mifepristone for Palliative Therapy of Patients with a Variety of Advanced Cancer Types
JEROME H. CHECK, EBONY DIX, RACHAEL COHEN, DIANE CHECK and CARRIE WILSON
+ Author Affiliations
The University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School at Camden, Cooper Hospital/University Medical Center, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Camden, New Jersey, U.S.A.
Correspondence to: Jerome H. Check, MD, Ph.D., 7447 Old York Road, Melrose Park, PA 19027, U.S.A. Tel: +1 2156354156, Fax: +1 2156352304, e-mail: laurie@ccivf.com

Abstract Background: Mifepristone has been demonstrated to improve longevity and quality of life in mice with spontaneous murine cancer without progesterone receptors and in human colon cancer. The present study evaluated the palliative effect of mifepristone in a variety of different types of human cancer.
Patients and Methods: Mifepristone was given at 200 mg daily orally with permission from the Food and Drug Administration to people with widely metastatic human cancer no longer responsive to other chemotherapy regimens.
Results: Improvement in pain and energy and/or length of life was found in thymic epithelial cell carcinoma, transitional cell carcinoma of the renal pelvis, leiomyosarcoma, pancreatic carcinoma, malignant fibrous histiocytoma and another case of adenocarcinoma of the colon.
Conclusion: Our data demonstrate a palliative role for the use of mifepristone in cancer therapy. Progesterone receptor antagonists(inhibitors) should be given a therapeutic trial in larger controlled studies of various malignancies in humans.

Key words: Metastatic human cancer palliation progesterone receptor antagonist tumor microenvironment mifepristone
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Antiprogestin mifepristone inhibits the growth of cancer cells of reproductive and non-reproductive origin regardless of progesterone receptor expression
Chelsea R Tieszen , Alicia A Goyeneche , BreeAnn N Brandhagen , Casey T Ortbahn  and Carlos M Telleria
Division of Basic Biomedical Sciences, Sanford School of Medicine of The University of South Dakota, 414 East Clark Street, Vermillion, SD, USA
 author email corresponding author email
BMC Cancer 2011, 11:207doi:10.1186/1471-2407-11-207
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2407/11/207
 
 
 GBYAY Anne McGinnis Breen
See my ponytail bouncing and my smiley face winking at you? &;>)

2014-2015 Facts about Meningioma Survival

Meningioma

  • Meningiomas have the highest number of estimated new cases of all primary brain tumors in the US, with 24,980 cases in 2014 and 25,190 in 2015. I think California has 6 or 7,000 per yr and Arizona has about 900 per yr.
  • Meningiomas are the most frequently reported tumors in the  US, accounting for 36.1% of brain tumors overall (Figure 8a).
  • Non-malignant meningiomas with behavior codes /0 (benign) or /1 (uncertain) account for 98.5% of meningiomas reported to CBTRUS (Table 9).
  • Meningiomas are most common in older adults and least common in children (Table 10).
  • Incidence of meningiomas increases with age, with a dramatic increase after age 65. Even among the population aged 85 years and older, these rates continue to be high (Table 10).
  • Non-malignant meningiomas are 2.3 times more common in females as compared to males (Figure 12).
  • Incidence of meningioma is significantly higher in blacks than in whites (Figure 13).
  • Ten-year relative survival for malignant meningioma is 57.2% (Table 22).
  • Age had a large effect on relative survival after diagnosis with malignant meningioma: 10-year survival was 84.4% for ages 24–44, and 33.5% for 75+ (Table 23).
  • Incidence of meningioma varies significantly among regions of the United States (Figure 21). The highest incidence is found in the Middle Atlantic, while the lowest is in the West North Central region (I think California has 6 or 7,000 per yr and Arizona has about 950 per yr).
  • NY and NJ have the most m cases on the east coast. There is a CBTRUS Table for each state

  •  My notes AMB 
  • They have not yet published any actual 3, 5 or 10 year survival rates for low grade meningioma.  It was about 67% survival at 5 yr which is worse than the survival rate for breast cancer.  And a meningioma diagnosis is linked to an increased risk for breast cancer. 

CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007–2011


From Table 18.
Estimated Number of Casesa,b of Brain and Central Nervous System Tumors Overall and by Behavior by Major Histology Groupings and Histology, 2014, 2015  
 
 
  GBYAY Anne McGinnis Breen
1st bt surgery 1986, recurrence 1992, 2nd bt surgery2001,
NCI 1992 SWOG 9005 Phase 3 clinical trial FDA approved safe for longterm use
Mifeprex for meningioma 1996 to 1999 and again Feb 2005 to present day
Squamous cell carcinoma, half of upper left lung removed, Sept 2014
 
 See my ponytail bouncing and my smiley face winking at you? &;>)
 
Please scroll all the way down for my list of 28 questions (more like 150 items) to ask your medical team about brain tumor treatments plus facts about my successful individual NCI clinical trial experience with an alternative drug therapy RU486 Mifepristone generic (Brand names:  MIFEPREX,  CORLUX, KORLYM) Progesterone inhibitor for recurrent meningioma, my thoughts about depression and recurrence and my blog arguments about obsolete REFERENCE MAN 1990s EPA radiation risk calculations for women and children found at  http://gbyay.blogspot.com 
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Keep your faith, cherish your reason, treasure your mind and hold to your own good purpose...be not afraid!