Mifepristone

For the song RU486 by Stone Sour, see House of Gold & Bones – Part 1.
Mifepristone
Systematic (IUPAC) name
11β-[p-(Dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one
Clinical data
Trade names Mifeprex
AHFS/Drugs.com monograph
MedlinePlus a600042
Pregnancy
category
  • US: X (Contraindicated)
Legal status
Routes of
administration		 By mouth
Pharmacokinetic data
Bioavailability 69%
Protein binding 98%
Metabolism Liver
Biological half-life 18 hours
Excretion Fecal: 83%; Kidney: 9%
Identifiers
CAS Number 84371-65-3 YesY
ATC code G03XB01
PubChem CID 55245
IUPHAR/BPS 2805
DrugBank DB00834 YesY
ChemSpider 49889 YesY
UNII 320T6RNW1F YesY
KEGG D00585 YesY
ChEBI CHEBI:50692 YesY
ChEMBL CHEMBL157 YesY
Chemical data
Formula C29H35NO2
Molar mass 429.60 g/mol
Physical data
Density 1.189 g/cm3
Melting point 194 °C (381 °F)
Boiling point 629 °C (1,164 °F)
  (verify)

Mifepristone, also known as RU-486, is a medication typically used with misoprostol to bring about an abortion.[1] This combination is more than 95% effective during the first 50 days of pregnancy. It is also effective in the second trimester of pregnancy.[2][3] Two weeks after use effectiveness should be verified. It is taken by mouth.[1]

Common side effects include abdominal pain, feeling tired, and vaginal bleeding. Serious side effects may include heavy vaginal bleeding, bacterial infection, a malformed baby if the pregnancy does not end. If used appropriate follow up care needs to be available. It works by blocking the effects of progesterone. and causing contractions of the uterus.[1]

Mifepristone was developed in 1980 and come into use in France in 1987.[4] It became available in the United States in 2000.[2] It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[5] As of 2014 it is not easily available in either Canada or Australia.[6] Cost and availability limits access in many parts of the developing world.[7][8] In the United States it costs more than US$200 ($200 in 2016) a dose.[9]

Medical uses

Abortion

There is good evidence supporting the effectiveness of mifepristone and misoprostol for abortions up to 63 days of pregnancy.[10]

In the U.S. it is Food and Drug Administration-approved to terminate intrauterine pregnancies of up to 49 days gestation. Under the FDA-approved regimen, a dose is administered by a clinician following a counseling session. Two days later, a clinician administers misoprostol, to induce contractions. In European studies, this method terminated 96 to 99% of pregnancies of up to 49 days gestation, but in one large multicenter trial in the United States conducted from September 1994 to September 1995, the efficacy was lower (92%), which the authors of the study suggested may have been due to lack of experience with this method in the United States and/or the design of their study.[11]

According to the current RCOG abortion guideline:[12]

In France it is approved for:

  1. medical termination of intrauterine pregnancies of up to 49 days gestation (up to 63 days gestation in Britain and Sweden)
  2. softening and dilatation of the cervix prior to mechanical cervical dilatation for pregnancy termination
  3. use in combination with gemeprost for termination of pregnancies between 13 and 24 weeks gestation
  4. labor induction in fetal death in utero[13]

Emergency birth control

Mifepristone can also be used in smaller doses as an emergency birth control; if taken after sex but before ovulation, it can prevent ovulation and so prevent pregnancy. In this role, a small dose is not as effective as a large dose, but has fewer side effects.[14] Mifeprex and Mifegyne are only available in 200-mg tablets.[15]

A review of studies in humans found that the contraceptive effects of the small dose were probably due mainly to its effects on ovulation, and not inhibition of implantation, but "the knowledge of the mechanism of action remains incomplete". Treatment with 200 mg of mifepristone changes steroid receptor expression in the Fallopian tube, inhibits endometrial development, and effectively prevents implantation.[16]

Other uses

Mifepristone is approved for use in the United States and the EU for the treatment of Cushing's syndrome.[17][18]

Mifepristone showed no detectable anti-HIV activity in clinical trials.[19][20][21][22]

Mifepristone showed initial promise in psychotic major depression, a difficult to treat form of depression,[23] but a phase-III clinical trial was terminated early due to lack of efficacy.[24]

Use as a cervical ripening agent has also been described.[25]

Side effects

Nearly all women using the mifepristone/misoprostol regimen experienced abdominal pain, uterine cramping, and vaginal bleeding or spotting for an average of 9–16 days. Up to 8% of women experienced some type of bleeding for 30 days or more. Other less common side effects included nausea, vomiting, diarrhea, dizziness, fatigue, and fever.[26] Pelvic inflammatory disease is a very rare but serious complication.[27] Excessive bleeding and incomplete termination of a pregnancy require further intervention by a doctor (such as vacuum aspiration). Between 4.5 and 7.9% of women required surgical intervention in clinical trials.[26] Mifepristone is contraindicated in the presence of an intrauterine device, as well as with ectopic pregnancy, adrenal failure, hemorrhagic disorders, inherited porphyria, and anticoagulant or long-term corticosteroid therapy.[26]

The FDA prescribing information states no data are available on the safety and efficacy of mifepristone in women with chronic medical conditions, and "women who are more than 35 years of age and who also smoke 10 or more cigarettes per day should be treated with caution because such patients were generally excluded from clinical trials of mifepristone."[26]

A postmarketing summary found, of about 1.52 million women who had received mifepristone until April 2011 in the United States, 14 were reported to have died after application. Eight of these cases were associated with sepsis; the other six had various causes such as drug abuse and suspected murder. Other incidents reported to the FDA included 612 nonlethal hospitalizations, 339 blood transfusions, 48 severe infections, and 2,207 (0.15%) adverse events altogether.[28]

Cancer

No long-term studies to evaluate the carcinogenic potential of mifepristone have been performed. This is in accord with ICH guidelines, which do not require carcinogencity testing in nongenotoxic drugs intended for administration for fewer than six months.[29]

Pregnancy

It is unclear if anything can be done to stop an abortion with mifepristone if a women changes her mind after taking the medication.[30]

Neonatal exposure to a single large dose of mifepristone in rats was not associated with any reproductive problems, although chronic low-dose exposure of newborn rats to mifepristone was associated with structural and functional reproductive abnormalities.[26]

Teratology studies in mice, rats, and rabbits revealed teratogenicity for rabbits, but not rats or mice.[26] The rate of birth defects in human infants exposed in utero to mifepristone and misoprostol is very low,[31] and may be due to misoprostol alone.[32]

Pharmacology

It is a synthetic, steroidal antiprogestogen and antiglucocorticoid. It is a 19-norsteroid with substitutions at positions C11 and C17 (17β-hydroxy-11β-(4-(dimethylamino)phenyl)-17α-(1-propynyl)estra-4,9-dien-3-one), which antagonizes cortisol action competitively at the receptor level.[33] Mifepristone is a low-efficacy partial agonist of the progesterone receptor. It is also a glucocorticoid receptor antagonist to a lesser extent.

In the presence of progesterone, mifepristone acts as a competitive progesterone receptor antagonist (in the absence of progesterone, mifepristone acts as a partial agonist). Mifepristone is a 19-nor steroid with a bulky p-(dimethylamino)phenyl substituent above the plane of the molecule at the 11β-position responsible for inducing or stabilizing an inactive receptor conformation and a hydrophobic 1-propynyl substituent below the plane of the molecule at the 17α-position that increases its progesterone receptor binding affinity.[34][20][35]

In addition to being an antiprogestogen, mifepristone is also an antiglucocorticoid and a weak antiandrogen. Mifepristone's relative binding affinity at the progesterone receptor is more than twice that of progesterone, its relative binding affinity at the glucocorticoid receptor is more than three times that of dexamethasone and more than 10 times that of cortisol; its relative binding affinity at the androgen receptor is less than one-third that of testosterone. It does not bind to the estrogen receptor or the mineralocorticoid receptor.[36]

Mifepristone as a regular contraceptive at 2 mg daily prevents ovulation (1 mg daily does not). A single preovulatory 10-mg dose of mifepristone delays ovulation by three to four days and is as effective an emergency contraceptive as a single 1.5-mg dose of the progestin levonorgestrel.[21]

In women, mifepristone at doses greater or equal to 1 mg/kg antagonizes the endometrial and myometrial effects of progesterone. In humans, an antiglucocorticoid effect of mifepristone is manifested at doses greater or equal to 4.5 mg/kg by a compensatory increase in ACTH and cortisol. In animals, a weak antiandrogenic effect is seen with prolonged administration of very high doses of 10 to 100 mg/kg.[13][37]

In medical abortion regimens, mifepristone blockade of progesterone receptors directly causes endometrial decidual degeneration, cervical softening and dilatation, release of endogenous prostaglandins, and an increase in the sensitivity of the myometrium to the contractile effects of prostaglandins. Mifepristone-induced decidual breakdown indirectly leads to trophoblast detachment, resulting in decreased syncytiotrophoblast production of hCG, which in turn causes decreased production of progesterone by the corpus luteum (pregnancy is dependent on progesterone production by the corpus luteum through the first nine weeks of gestation—until placental progesterone production has increased enough to take the place of corpus luteum progesterone production). When followed sequentially by a prostaglandin, mifepristone 200 mg is (100 mg may be, but 50 mg is not) as effective as 600 mg in producing a medical abortion.[34][35]

'Contragestion' is a term promoted by Étienne-Émile Baulieu in the context of his advocacy of mifepristone, defining it as inclusive of some hypothesized mechanisms of action of some contraceptives and those of mifepristone to induce abortion.[38] Baulieu's definition of a 'contragestive' included any birth control method that could possibly act after fertilization and before nine-weeks gestational age.[38]

History

In April 1980, as part of a formal research project at Roussel-Uclaf for the development of glucocorticoid receptor antagonists, chemist Georges Teutsch synthesized mifepristone (RU-38486, the 38,486th compound synthesized by Roussel-Uclaf from 1949 to 1980; shortened to RU-486), which was discovered to also be a progesterone receptor antagonist.[39][40] In October 1981, endocrinologist Étienne-Émile Baulieu, a consultant to Roussel-Uclaf, arranged tests of its use for medical abortion in 11 women in Switzerland by gynecologist Walter Herrmann at the University of Geneva's Cantonal Hospital, with successful results announced on April 19, 1982.[39][41] On October 9, 1987, following worldwide clinical trials in 20,000 women of mifepristone with a prostaglandin analogue (initially sulprostone or gemeprost, later misoprostol) for medical abortion, Roussel-Uclaf sought approval in France for their use for medical abortion, with approval announced on September 23, 1988.[39][42]

On October 21, 1988, in response to antiabortion protests and concerns of majority (54.5%) owner Hoechst AG of Germany, Roussel-Uclaf’s executives and board of directors voted 16 to 4 to stop distribution of mifepristone, which they announced on October 26, 1988.[39][43] Two days later, the French government ordered Roussel-Uclaf to distribute mifepristone in the interests of public health.[39][44] French Health Minister Claude Évin explained: "I could not permit the abortion debate to deprive women of a product that represents medical progress. From the moment Government approval for the drug was granted, RU-486 became the moral property of women, not just the property of a drug company."[39] Following use by 34,000 women in France from April 1988 to February 1990 of mifepristone distributed free of charge, Roussel-Uclaf began selling Mifegyne (mifepristone) to hospitals in France in February 1990 at a price (negotiated with the French government) of US$48 ($86.94 in 2016) per 600-mg dose.[39]

Mifegyne was subsequently approved in Great Britain on July 1, 1991,[45] and in Sweden in September 1992,[46] but until his retirement in late April 1994, Hoechst AG chairman Wolfgang Hilger, a devout Roman Catholic, blocked any further expansion in availability.[39][47] On May 16, 1994, Roussel-Uclaf announced it was donating without remuneration all rights for medical uses of mifepristone in the United States to the Population Council,[48] which subsequently licensed mifepristone to Danco Laboratories, a new single-product company immune to antiabortion boycotts, which won FDA approval as Mifeprex on September 28, 2000.[49]

On April 8, 1997, after buying the remaining 43.5% of Roussel-Uclaf stock in early 1997,[50] Hoechst AG (US$30 ($45.26 in 2016) billion annual revenue) announced the end of its manufacture and sale of Mifegyne (US$3.44 ($5.19 in 2016) million annual revenue) and the transfer of all rights for medical uses of mifepristone outside of the United States to Exelgyn S.A., a new single-product company immune to antiabortion boycotts, whose CEO was former Roussel-Uclaf CEO Édouard Sakiz.[51] In 1999, Exelgyn won approval of Mifegyne in 11 additional countries, and in 28 more countries over the following decade.[52]

Society and culture

Mifepristone is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[5] It is on the complementary list and is included with a special note "where permitted under national law and where culturally acceptable".[5]

Legal status

United States

Roussel Uclaf did not seek U.S. approval, so in the United States legal availability was not initially possible.[53] The United States banned importation of mifepristone for personal use in 1989, a decision supported by Roussel Uclaf. In 1994, Roussel Uclaf gave the U.S. drug rights to the Population Council in exchange for immunity from any product liability claims.[48][54] The Population Council sponsored clinical trials in the United States.[55] The drug went on approvable status from 1996. Production was intended to begin through the Danco Group in 1996, but they withdrew briefly in 1997 due to a corrupt business partner, delaying availability again.[56][57] Mifepristone was approved for abortion in the United States by the FDA in September 2000.[58] It is legal and available in all 50 states, Washington, D.C., Guam, and Puerto Rico.[59] It is a prescription drug, but it is not available to the public through pharmacies; its distribution is restricted to specially qualified licensed physicians, sold by Danco Laboratories under the trade name Mifeprex.

Medical abortions voluntarily reported by 33 U.S. states[60] to the CDC have increased as a percentage of total abortions every year since the approval of mifepristone: 1.0% in 2000, 2.9% in 2001, 5.2% in 2002, 7.9% in 2003, 9.3% in 2004, 9.9% in 2005, 10.6% in 2006, and 13.1% in 2007 (20.3% of those at less than 9 weeks gestation).[61] A Guttmacher Institute survey of abortion providers estimated that medical abortions accounted for 17% of all abortions and slightly over 25% of abortions before 9 weeks gestation in the United States in 2008 (94% of nonhospital medical abortions used mifepristone and misoprostol, 6% used methotrexate and misoprostol).[62] Medical abortions accounted for 32% of first trimester abortions at Planned Parenthood clinics in the United States in 2008.[63]

Subsection H

Some drugs are approved by the FDA under subsection H, which has two subparts. The first sets forth ways to rush experimental drugs, such as aggressive HIV and cancer treatments, to market when speedy approval is deemed vital to the health of potential patients. The second part of subsection H applies to drugs that not only must meet restrictions for use due to safety requirements, but also are required to meet postmarketing surveillance to establish that the safety results shown in clinical trials are seconded by use in a much wider population. Mifepristone was approved under the second part of subsection H. The result is that women cannot pick the drug up at a pharmacy, but must now receive it directly from a doctor. Due to the possibility of adverse reactions such as excessive bleeding, which may require a blood transfusion, and incomplete abortion, which may require surgical intervention, the drug is only considered safe if a physician who is capable of administering a blood transfusion or a surgical abortion is available to the patient in the event of such emergencies.[64] The approval of mifepristone under subsection H included a black box warning.

Europe

Outside the United States, it is marketed and distributed by Exelgyn Laboratories under the tradename Mifegyne. Mifepristone was approved for use in France in 1988 (initial marketing in 1989), the United Kingdom in 1991, Sweden in 1992, then Austria, Belgium, Denmark, Finland, Germany, Greece, Luxembourg, the Netherlands, Spain, and Switzerland in 1999.[65] In 2000, it was approved in Norway, Russia and Ukraine. Serbia and Montenegro approved it in 2001,[66] Belarus and Latvia in 2002, Estonia in 2003, Moldova in 2004, Albania and Hungary in 2005, Portugal in 2007, and Romania in 2008.[52] In Italy, clinical trials have been constrained by protocols requiring women be hospitalized for three days, but the drug was finally approved on July 30, 2009 (officialized later in the year), despite strong opposition from the Vatican. In Italy, the pill must be prescribed and used in a clinical structure and is not sold at chemists.[67] It was approved in Hungary in 2005, but as of 2005 had not been released on the market yet, and was the target of protests.[68] Mifepristone is not approved in Ireland, where abortion is illegal, or Poland, where abortion is highly restricted.[69]

In France, the percentage of medical abortions of all abortions continues to increase: 38% in 2003, 42% in 2004, 44% in 2005, 46% in 2006, 49% in 2007 (vs. 18% in 1996).[70] In England and Wales, 52% of early abortions (less than 9 weeks gestation) in 2009 were medical; the percentage of all abortions that are medical has increased every year for the past 14 years (from 5% in 1995 to 40% in 2009) and has more than doubled in the last five years.[71] In Scotland, 81.2% of early abortions in 2009 were medical (up from 55.8% in 1992 when medical abortion was introduced); the percentage of all abortions that are medical has increased every year for the past 17 years (from 16.4% in 1992 to 69.9% in 2009).[72] In Sweden, 85.6% of early abortions and 73.2% of abortions before the end of the 12th week of gestation in 2009 were medical; 68.2% of all abortions in 2009 were medical.[73] In Great Britain and Sweden, mifepristone is licensed for use with vaginal gemeprost or oral misoprostol. As of 2000, more than 620,000 women in Europe had had medical abortions using a mifepristone regimen.[74] In Denmark, mifepristone was used in between 3,000 and 4,000 of just over 15,000 abortions in 2005.[75]

Other countries

Mifepristone was banned in Australia in 1996. In late 2005, a private member's bill was introduced to the Australian Senate to lift the ban and transfer the power of approval to the Therapeutic Goods Administration. The move caused much debate in the Australian media and amongst politicians. The bill passed the Senate on 10 February 2006, and mifepristone is now legal in Australia. It is provided regularly at several specialized abortion clinics per state.[76][77]

In New Zealand, pro-choice doctors established an import company, Istar, and submitted a request for approval to MedSafe, the New Zealand pharmaceutical regulatory agency. After a court case brought by Right to Life New Zealand failed, use of mifepristone was permitted.[78]

The drug was approved in Israel in 1999.[79]

Clinical trials of mifepristone in China began in 1985. In October 1988, China became the first country in the world to approve mifepristone. Chinese organizations tried to purchase mifepristone from Roussel Uclaf, which refused to sell it to them, so in 1992 China began its own domestic production of mifepristone. In 2000, the cost of medical abortion with mifepristone was higher than surgical abortion and the percentage of medical abortions varied greatly, ranging from 30% to 70% in cities to being almost nonexistent in rural areas.[80][81] A report from the United States Embassy in Beijing in 2000 said mifepristone had been widely used in Chinese cities for about two years, and that according to press reports, a black market had developed with many women starting to buy it illegally (without a prescription) from private clinics and drugstores for about US$15 ($20.61 in 2016), causing Chinese authorities to worry about medical complications from use without physician supervision.[82]

In 2001, mifepristone was approved in Taiwan.[83] Vietnam included mifepristone in the National Reproductive Health program in 2002.[84]

It is approved in only one sub-Saharan African country—South Africa, where it was approved in 2001.[85] It is also approved in one north African country—Tunisia, also in 2001.[86]

Mifepristone was approved for use in India in 2002, where medical abortion is referred to as "medical termination of pregnancy". It is only available under medical supervision, not by prescription, due to adverse reactions such as excessive bleeding, and criminal penalties are given for buying or selling it on the black market or over-the-counter at pharmacies.[87]

Medical abortion used to be available in Canada but on a limited basis using methotrexate and misoprostol. Clinical trials were done in 2000 in various Canadian cities comparing methotrexate to mifepristone, after approbation by the federal government. While both drugs had overall similar results, mifepristone was found to act faster.[88] Health Canada gave approval to mifepristone in July 2015.[89]

Mifepristone was registered for use in Azerbaijan, Georgia, and Uzbekistan in 2002, in Guyana and Moldova in 2004, in Mongolia in 2005, and in Armenia in 2007.[52][90]

Controversy

Main article: Abortion controversy

Many pro-life groups in the United States actively campaigned against the approval of mifepristone[91][92][93] and continue to actively campaign for its withdrawal.[94] They cite either ethical issues with abortion or safety concerns regarding the drug and the adverse reactions associated with it.[95] Religious and pro-life groups outside the United States have also protested mifepristone, especially in Germany[96] and Australia.[97][98]

Research

The original target for the research group was the discovery and development of compounds with antiglucocorticoid properties.[99] These antiglucocorticoid properties are of great interest in the treatment of severe mood disorders and psychosis, although a review of published articles was inconclusive on their efficacy, and considered the use of these drugs in mood disorders at 'proof of concept' stage.[100]

References

  1. 1 2 3 "Mifepristone". The American Society of Health-System Pharmacists. Retrieved December 19, 2015.
  2. 1 2 Rexrode, edited by Marlene Goldman, Rebecca Troisi, Kathryn (2012). Women and health (2nd ed.). Oxford: Academic. p. 236. ISBN 9780123849793.
  3. ↑ Wildschut, H; Both, MI; Medema, S; Thomee, E; Wildhagen, MF; Kapp, N (19 January 2011). "Medical methods for mid-trimester termination of pregnancy.". The Cochrane database of systematic reviews (1): CD005216. doi:10.1002/14651858.CD005216.pub2. PMID 21249669.
  4. ↑ Corey, E.J. (2012). "Mifepristone". Molecules and Medicine. John Wiley & Sons. ISBN 9781118361733.
  5. 1 2 3 "19th WHO Model List of Essential Medicines (April 2015)" (PDF). WHO. April 2015. Retrieved May 10, 2015.
  6. ↑ Nelson, Erin (2014). "Access to Abortion Services". Law, Policy and Reproductive Autonomy. A&C Black. ISBN 9781782251569.
  7. ↑ Hussein, edited by Julia; McCaw-Binns,, Affette; Webber, Roger (2012). Maternal and perinatal health in developing countries. Wallingford, Oxfordshire: CABI. p. 104. ISBN 9781845937461.
  8. ↑ Winikoff, B; Sheldon, W (September 2012). "Use of medicines changing the face of abortion.". International perspectives on sexual and reproductive health 38 (3): 164–6. doi:10.1363/3816412. PMID 23018138.
  9. ↑ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 368. ISBN 9781284057560.
  10. ↑ Chen, MJ; Creinin, MD (July 2015). "Mifepristone With Buccal Misoprostol for Medical Abortion: A Systematic Review.". Obstetrics and gynecology 126 (1): 12–21. doi:10.1097/aog.0000000000000897. PMID 26241251.
  11. ↑ Spitz IM, Bardin CW, Benton L, Robbins A (April 1998). "Early pregnancy termination with mifepristone and misoprostol in the United States". N. Engl. J. Med. 338 (18): 1241–7. doi:10.1056/NEJM199804303381801. PMID 9562577.
  12. ↑ RCOG (2004). The Care of Women Requesting Induced Abortion: Evidence-based clinical guideline number 7 (PDF). London: RCOG Press. ISBN 1-904752-06-3. Archived from the original (PDF) on February 27, 2008.
  13. 1 2 Exelgyn Laboratories (February 2006). "Mifegyne UK Summary of Product Characteristics (SPC)". Retrieved 2007-03-09.
  14. ↑ Piaggio G, von Hertzen H, Heng Z, Bilian X, Cheng L (December 2003). "Meta-analyses of randomized trials comparing different doses of mifepristone in emergency contraception". Contraception 68 (6): 447–52. doi:10.1016/S0010-7824(03)00142-2. PMID 14698075.
  15. ↑ Wertheimer RE (November 2000). "Emergency postcoital contraception". Am Fam Physician 62 (10): 2287–92. PMID 11126855.
  16. ↑ Gemzell-Danielsson K, Marions L (2004). "Mechanisms of action of mifepristone and levonorgestrel when used for emergency contraception". Hum. Reprod. Update 10 (4): 341–8. doi:10.1093/humupd/dmh027. PMID 15192056.
  17. ↑ Healy D (2009). "Mifepristone: an overview for Australian practice". Australian Prescriber 32 (6): 152–154.
  18. ↑ FDA approves Korlym for patients with endogenous Cushing’s syndrome, Food & Drug Administration, February 17, 2012, Retrieved 2014-01-18
  19. ↑ Flexner C (December 2007). "HIV drug development: the next 25 years". Nat Rev Drug Discov 6 (12): 959–66. doi:10.1038/nrd2336. PMID 17932493.
  20. 1 2 Schimmer, Bernard P.; Parker, Keith L. (2006). "Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs; Inhibitors of the Synthesis and Actions of Adrenocortical Hormones". In in Brunton, Laurence L.; Lazo, John S.; Parker, Keith L. (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill. pp. 1587–1612. ISBN 0-07-142280-3.
  21. 1 2 Chabbert-Buffet N, Meduri G, Bouchard P, Spitz IM (2005). "Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications". Hum Reprod Update 11 (3): 293–307. doi:10.1093/humupd/dmi002. PMID 15790602.
  22. ↑ Tang OS, Ho PC (2006). "Clinical applications of mifepristone". Gynecol Endocrinol 22 (12): 655–9. doi:10.1080/09513590601005946. PMID 17162706.
  23. ↑ Belanoff JK, Flores BH, Kalezhan M, Sund B, Schatzberg AF (October 2001). "Rapid reversal of psychotic depression using mifepristone". J Clin Psychopharmacol 21 (5): 516–21. doi:10.1097/00004714-200110000-00009. PMID 11593077.
  24. ↑ Damian Gard for Fierce Biotech. May 7, 2014. Corcept tanks as depression drug comes up short in Phase III
  25. ↑ Clark K, Ji H, Feltovich H, Janowski J, Carroll C, Chien EK (May 2006). "Mifepristone-induced cervical ripening: structural, biomechanical, and molecular events". Am. J. Obstet. Gynecol. 194 (5): 1391–8. doi:10.1016/j.ajog.2005.11.026. PMID 16647925.
  26. 1 2 3 4 5 6 "Mifeprex label" (PDF). FDA. 2005-07-19. Archived from the original (PDF) on 2006-06-28. Retrieved 2006-08-22.
  27. ↑ Lawton BA, Rose SB, Shepherd J (April 2006). "Atypical presentation of serious pelvic inflammatory disease following mifepristone-induced medical abortion". Contraception 73 (4): 431–2. doi:10.1016/j.contraception.2005.09.003. PMID 16531180.
  28. ↑ "Mifepristone U.S. Postmarketing Adverse Events Summary through 04/30/2011" (PDF). Retrieved 2011-11-14.
  29. ↑ "www.ich.org" (PDF).
  30. ↑ Grossman, D; White, K; Harris, L; Reeves, M; Blumenthal, PD; Winikoff, B; Grimes, DA (September 2015). "Continuing pregnancy after mifepristone and "reversal" of first-trimester medical abortion: a systematic review.". Contraception 92 (3): 206–11. doi:10.1016/j.contraception.2015.06.001. PMID 26057457.
  31. ↑ Gary MM, Harrison DJ (February 2006). "Analysis of severe adverse events related to the use of mifepristone as an abortifacient". Ann Pharmacother 40 (2): 191–7. doi:10.1345/aph.1G481. PMID 16380436.
  32. ↑ Orioli IM, Castilla EE (April 2000). "Epidemiological assessment of misoprostol teratogenicity". BJOG 107 (4): 519–23. doi:10.1111/j.1471-0528.2000.tb13272.x. PMID 10759272.
  33. ↑ Gallagher P, Young AH (March 2006). "Mifepristone (RU-486) treatment for depression and psychosis: a review of the therapeutic implications". Neuropsychiatr Dis Treat 2 (1): 33–42. PMC 2671735. PMID 19412444.
  34. 1 2 Loose, Davis S.; Stancel, George M. (2006). "Estrogens and Progestins". In in Brunton, Laurence L.; Lazo, John S.; Parker, Keith L. (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill. pp. 1541–1571. ISBN 0-07-142280-3.
  35. 1 2 Fiala C, Gemzel-Danielsson K (July 2006). "Review of medical abortion using mifepristone in combination with a prostaglandin analogue". Contraception 74 (1): 66–86. doi:10.1016/j.contraception.2006.03.018. PMID 16781264.
  36. ↑ Heikinheimo O, Kekkonen R, Lahteenmaki P (2003). "The pharmacokinetics of mifepristone in humans reveal insights into differential mechanisms of antiprogestin action". Contraception 68 (6): 421–6. doi:10.1016/S0010-7824(03)00077-5. PMID 14698071.
  37. ↑ Danco Laboratories (July 19, 2005). "Mifeprex U.S. prescribing information" (PDF). Archived from the original (PDF) on 2007-01-07. Retrieved 2007-03-09.
  38. 1 2 Baulieu, Étienne-Émile (1985). "RU 486: An antiprogestin steroid with contragestive activity in women". In Baulieu, Étienne-Émile; Segal, Sheldon J. The antiprogesin steroid RU 486 and human fertility control (Proceedings of a conference on the antiprogestational compound RU 486, held October 23–25, 1984, in Bellagio, Italy). New York: Plenum Press. pp. 1–25. ISBN 0-306-42103-8.
    Baulieu, Étienne-Émile (1985). "Contragestion by antiprogestin: a new approach to human fertility control". Abortion: medical progress and social implications (Symposium held at the Ciba Foundation, London, 27–29 November 1984). Ciba Foundation Symposium 115. London: Pitman. pp. 192–210. ISBN 0-272-79815-0. PMID 3849413.
    Baulieu, Étienne-Émile (1989). "Contragestion with RU 486: a new approach to postovulatory fertility control (from Meet the experts — Antiprogestins, edited by Baulieu, É-É; Proceedings of a meeting held in Rio de Janeiro, Brazil, 27 October 1988)". Acta Obstetricia et Gynecologica Scandinavica. Supplement 149: 5–8. ISSN 0300-8835. PMID 2694738.
    Greenhouse, Steven (February 12, 1989). "A new pill, a fierce battle". The New York Times Magazine. p. SM22.
    Palca J (September 1989). "The pill of choice?". Science 245 (4924): 1319–23. doi:10.1126/science.2781280. JSTOR 1704254. PMID 2781280.
    Baulieu EE (September 1989). "Contragestion and other clinical applications of RU 486, an antiprogesterone at the receptor". Science 245 (4924): 1351–7. doi:10.1126/science.2781282. JSTOR 1704267. PMID 2781282.
    Baulieu EE (October 1989). "The Albert Lasker Medical Awards. RU-486 as an antiprogesterone steroid. From receptor to contragestion and beyond". JAMA 262 (13): 1808–1814. doi:10.1001/jama.262.13.1808. PMID 2674487.
    Bonner, Staci (July 1991). "Drug of choice". SPIN 7 (4): 55–56, 88. ISSN 0886-3032.
    Baulieu, Étienne-Émile; Rosenblum, Mort (November 15, 1991). The "abortion pill": RU-486: a woman's choice (translation of: 'Génération pilule). New York: Simon & Schuster. pp. 18, 26–28. ISBN 0-671-73816-X.
    Beck, Joan (January 2, 1992). "RU-486 pill adds a new dimension to the abortion debate". Chicago Tribune. p. 25.
    Chesler, Ellen (July 31, 1992). "RU-486: we need prudence, not politics". The New York Times. p. A27.
    Baulieu, Étienne-Émile (April 13, 1993). "1993: RU 486—a decade on today and tomorrow". In Donaldson, Molla S.; Dorflinger, Laneta; Brown, Sarah S.; Benet, Leslie Z. Clinical applications of mifepristone (RU 486) and other antiprogestins; assessing the science and recommending a research agenda; (Committee on Anti-progestins: Assessing the Science; Division of Health Promotion and Disease Prevention; Institute of Medicine). Washington, D.C.: National Academy Press. pp. 71–119. ISBN 0-309-04949-0.
    Baulieu EE (June 1994). "RU486: a compound that gets itself talked about". Hum. Reprod. 9 Suppl 1: 1–6. doi:10.1093/humrep/9.suppl_1.1. PMID 7962455.
    Baulieu, Étienne-Émile (1997). "Innovative procedures in family planning". In Johannisson, Elisabeth; Kovács, László; Resch, Bela A; Bruyniks, Nico P. Assessment of research and service needs in reproductive health in Eastern Europe — concerns and commitments. Proceedings of a workshop organized by the ICRR and the WHO Collaborating Centre on Research in Human Reproduction in Szeged, Hungary, 25–27 October 1993. New York: Parthenon Publishing. pp. 51–60. ISBN 1-85070-696-4.
    . (2008). "contragestive". The American Heritage medical dictionary. Boston: Houghton Mifflin. p. 124. ISBN 978-0-618-94725-6.
    adj. Capable of preventing gestation, either by preventing implantation or by causing the uterine lining to shed after implantation. —n. A contragestive drug or agent.
    Ammer, Christine (2009). "contragestive". The encyclopedia of women's health (6th ed.). New York: Facts On File. pp. 124–125. ISBN 978-0-8160-7407-5.
    Also contragestant, abortion pill. A substance called mifepristone, or RU-486, which was developed by Dr. Etienne Baulieu and the Roussel-Uclaf company. The contragestive blocks progesterone receptors in the endometrium (uterine lining), preventing its buildup by progesterone; hence the uterus cannot sustain a pregnancy. It does not prevent fertilization or implantation, so technically it is an ABORTIFACIENT rather than a contraceptive.
  39. 1 2 3 4 5 6 7 8 Baulieu, Étienne-Émile; Rosenblum, Mort (1991). The "abortion pill": RU-486, a woman's choice. New York: Simon & Schuster. ISBN 0-671-73816-X.
    Lader, Lawrence (1991). RU 486: the pill that could end the abortion wars and why American women don't have it. Reading: Addison-Wesley. ISBN 0-201-57069-6.
    Villaran, Gilda (1998). "RU 486". In Schlegelmilch, Bodo B. (ed.). Marketing ethics: an international perspective. London: Thomson Learning. pp. 155–190. ISBN 1-86152-191-X.
    Ulmann, André (2000). "The development of mifepristone: a pharmaceutical drama in three acts". J Am Med Womens Assoc 55 (3 Suppl): 117–20. PMID 10846319.
  40. ↑ Teutsch, Georges (November 24, 1989). "RU 486 development". Science 246 (4933): 985. doi:10.1126/science.2587990. PMID 2587990.
    Cherfas, J (November 24, 1989). "Dispute surfaces over paternity of RU 486". Science 246 (4933): 994. doi:10.1126/science.2587988. PMID 2587988.
    Philibert, D; Teutsch, G (February 9, 1990). "RU 486 development". Science 246 (4943): 622. doi:10.1126/science.2300819. PMID 2300819.
    Ulmann, A; Teutsch, G; Philibert, D (June 1990). "RU 486". Scientific American. Vol. 262 no. 6. pp. 42–8. doi:10.1038/scientificamerican0690-42. PMID 2343294.
    Teutsch, G.; Deraedt, R.; Philibert, D. (1993). "Mifepristone". In Lednicer, Daniel (ed.). Chronicles of drug discovery, Vol. 3. Washington, DC: American Chemical Society. pp. 1–43. ISBN 0-8412-2523-0.
    Teutsch, G; Philibert, D (June 1994). "History and perspectives of antiprogestins from the chemist's point of view". Human Reprod 9 (Suppl 1): 12–31. doi:10.1093/humrep/9.suppl_1.12. PMID 7962457.
    Sittig, Marshall (ed.), ed. (2007). "Mifepristone". Pharmaceutical manufacturing encyclopedia (3rd ed.). Norwich, NY: William Andrew Publishing. pp. 2307–2310. ISBN 1-60119-339-4.
    US patent 4,386,085, Teutsch, Jean G.; Costerousse, Germain; Philibert, Daniel; Deraedt, Roger, "Novel steroids", issued 1983-05-31 assigned to Roussel Uclaf
  41. ↑ Eder, Richard (April 20, 1982). "Birth control: 4-day pill is promising in early test". The New York Times. p. C1.
    Herrmann, Walter; Wyss, Rolf; Riondel, Anne; Philibert, Daniel; Teutsch, Georges; Sakiz, Edouard; Baulieu, Étienne-Émile (May 17, 1982). "The effects of an antiprogesterone steroid in women: interruption of the menstrual cycle and of early pregnancy". C R Seances Acad Sci III 294 (18): 933–8. PMID 6814714.
  42. ↑ Kolata, Gina (September 24, 1988). "France and China allow sale of a drug for early abortion". The New York Times. p. A1.
  43. ↑ Greenhouse, Steven (October 27, 1988). "Drug maker stops all distribution of abortion pill". The New York Times. p. A1.
  44. ↑ Greenhouse, Steven (October 29, 1988). "France ordering company to sell its abortion drug". The New York Times. p. A1.
  45. ↑ Smith, W. (September 1991). "Great Britain second country to allow use of RU-486". Plan Parent Eur 20 (2): 20. PMID 12284548.
  46. ↑ . (December 1992). "RU 486 licensed in Sweden". IPPF Med Bull 26 (6): 6. PMID 12346922.
  47. ↑ Newman, Barry (February 22, 1993). "Drug dilemma: among those wary of abortion pill is maker's parent firm; Germany's Hoechst is facing pressure from Clinton to sell RU-486 in U.S.". The Wall Street Journal. p. A1.
    "F.D.A. says company delays abortion pill". The New York Times. Associated Press. April 16, 1993. p. A14.
    Jouzaitis, Carol (October 17, 1994). "Abortion pill battle surprises French firm". Chicago Tribune. p. 1 (Business).
  48. 1 2 Seelye, Katharine Q. (May 17, 1994). "Accord opens way for abortion pill in U.S. in 2 years". The New York Times. p. A1.
  49. ↑ Kolata, Gina (September 29, 2000). "U.S. approves abortion pill; drug offers more privacy and could reshape debate". The New York Times. p. A1.
  50. ↑ Moore, Stephen D.; Kamm, Thomas; Fleming, Charles (December 11, 1996). "Hoechst to seek rest of Roussel-Uclaf; expected $3.04 billion offer would add to the wave of drug-sector linkups". The Wall Street Journal. p. A3.
    Marshall, Matt (December 11, 1996). "Hoechst offers to pay $3.6 billion for rest of Roussel". The Wall Street Journal. p. A8.
    Bloomberg Business News (December 11, 1996). "Hoechst to buy rest of Roussel". The New York Times. p. D4.
  51. ↑ Bloomberg News (April 9, 1997). "Pill for abortion ends production". The New York Times. p. D2.
    Jouzaitis, Carol (April 9, 1997). "Abortion pill maker bows to boycott heat; German firm gives up RU-486 patent; little impact likely in U.S.". Chicago Tribune. p. 4.
    Lavin, Douglas (April 9, 1997). "Hoechst will stop making abortion pill". The Wall Street Journal. p. A3.
    . (April 18, 1997). "Roussel-Uclaf to transfer RU 486 rights". Reprod Freedom News 6 (7): 8. PMID 12292550.
    Dorozynski, Alexander (April 19, 1997). "Boycott threat forces French company to abandon RU486". BMJ 314 (7088): 1150. doi:10.1136/bmj.314.7088.1145m. PMC 2126515. PMID 9146386.
  52. 1 2 3 . (November 4, 2009). "List of mifepristone approval" (PDF). New York: Gynuity Health Projects.
    . (November 4, 2009). "Map of mifepristone approval" (PDF). New York: Gynuity Health Projects. Retrieved 2010-06-11.
  53. ↑ Klitsch M (November–December 1991). "Antiprogestins and the abortion controversy: a progress report". Fam Plann Perspect 23 (6): 275–82. doi:10.2307/2135779. JSTOR 2135779. PMID 1786809.
  54. ↑ Nancy Gibbs (October 2, 2000). "The Pill Arrives". Cnn.com. Retrieved 2006-09-20.
  55. ↑ Tamar Lewin (January 30, 1995). "Clinical Trials Giving Glimpse of Abortion Pill". The New York Times. Retrieved 2006-09-20.
  56. ↑ Tamar Lewin (November 13, 1997). "Lawsuits' Settlement Brings New Hope for Abortion Pill". The New York Times. Retrieved 2006-09-16.
  57. ↑ Sharon Lerner (August 2000). "RU Pissed Off Yet?". The Village Voice. Retrieved 2006-09-16.
  58. ↑ "FDA approval letter for Mifepristone". FDA. September 28, 2000. Archived from the original on 2006-08-29. Retrieved 2006-09-16.
  59. ↑ "Medication Abortion in the United States: Mifepristone Fact Sheet" (PDF). Gynuity Health Projects. 2005. Archived from the original (PDF) on September 24, 2007.
  60. ↑ excluding Alabama, California, Connecticut, Washington, D.C., Florida, Georgia, Hawaii, Illinois, Kentucky, Louisiana, Massachusetts, Maryland, Nebraska, Nevada, New Hampshire, Rhode Island, Tennessee, and Wisconsin
  61. ↑ Pazol, Karen; Zane, Suzanne B.; Parker, Wilda, Y.; Hall, Laura R.; Gamble, Sonya B.; Hamdan, Saeed; Berg, Cynthia; Cook, Douglas A.; Division of Reproductive Health (February 25, 2011). "Abortion surveillance — United States, 2007" (PDF). MMWR Surveill Summ. 60 (1): 1–44. PMID 21346710.
  62. ↑ Jones, Rachel K.; Kooistra, Kathryn (March 2011). "Abortion incidence and access to services in the United States, 2008" (PDF). Perspect Sex Reprod Health. 43 (1): 41–50. doi:10.1363/4304111. PMID 21388504.
    Stein, Rob (January 11, 2011). "Decline in U.S. abortion rate stalls". The Washington Post. p. A3.
  63. ↑ Fjerstad, Mary; Trussell, James; Sivin, Irving; Lichtenberg, E. Steve; Cullins, Vanessa (July 9, 2009). "Rates of serious infection after changes in regimens for medical abortion" (PDF). New England Journal of Medicine 361 (2): 145–151. doi:10.1056/NEJMoa0809146. PMC 3568698. PMID 19587339.
    Allday, Erin (July 9, 2009). "Change cuts infections linked to abortion pill". San Francisco Chronicle. p. A1.
  64. ↑ Woodcock, Janet (2006-05-12). "Testimony on RU-486". Committee on Government Reform, House of Representatives. FDA. Archived from the original on 2006-09-27. Retrieved 2006-08-19.
  65. ↑ Christin-Maitre, S., Bouchard, P., Spitz, I. M. (2000). "Medical termination of pregnancy". New England Journal of Medicine 342 (13): 946–56. doi:10.1056/NEJM200003303421307. PMID 10738054.
  66. ↑ Stojnic J, et al. (2006). "Medicamentous abortion with mifepristone and misoprostol in Serbia and Montenegro". Vojnosanitetski pregled. Military-medical and pharmaceutical review 63 (6): 558–63. doi:10.2298/VSP0606558S. PMID 16796021.
  67. ↑ "Abortion pill approved in Italy". BBC News. July 31, 2009. Retrieved 2009-07-31.
  68. ↑ "Abortion pill sparks bitter protest". The Budapest Times. September 19, 2005. Retrieved 2006-09-16.
  69. ↑ Peter S. Green (June 24, 2003). "A Rocky Landfall for a Dutch Abortion Boat". The New York Times. Retrieved 2006-09-16.
  70. ↑ Vilain, Annick (December 2009). "Voluntary terminations of pregnancies in 2007" (PDF). DREES, Ministry of Health. Archived from the original (PDF) on March 31, 2010. Retrieved 2010-06-09.
  71. ↑ Department of Health (May 25, 2010). "Abortion statistics, England and Wales: 2009". Department of Health (United Kingdom). Retrieved 2010-06-09.
  72. ↑ ISD Scotland (May 25, 2010). "Abortion Statistics, year ending December 2009". Information Services Division (ISD), NHS National Services Scotland. Retrieved 2010-06-09.
  73. ↑ National Board of Health and Welfare, Sweden (May 12, 2010). "Induced Abortions 2010" (PDF). National Board of Health and Welfare, Sweden. Retrieved 2010-06-09.
  74. ↑ "FDA Approves Mifepristone for the Termination of Early Pregnancy". FDA press release/U.S. Gov. 2000. Archived from the original on 2006-09-10. Retrieved 2009-04-27.
  75. ↑ "The abortion pill Mifegyne tested for adverse reactions". Danish Medicines Agency. July 27, 2005. Retrieved 2006-09-20.
  76. ↑ "Marie Stopes International Australia – Medical Abortion". 2010. Archived from the original on November 22, 2010. Retrieved 2010-12-15.
  77. ↑ "Abortion pill – RU486 (mifepristone)". Better Health Channel Victoria. July 2010. Archived from the original on August 14, 2010. Retrieved 2010-12-15.
  78. ↑ Sparrow MJ (2004). "A woman's choice". Aust NZ J Obstet Gynaecol 44 (2): 88–92. doi:10.1111/j.1479-828X.2004.00190.x. PMID 15089829.
  79. ↑ Etienne-Emile Baulieu, Daniel S. Seidman, Selma Hajri (October 2001). "Mifepristone(RU-486) and voluntary termination of pregnancy: enigmatic variations or anecdotal religion-based attitudes?". Human Reproduction. Retrieved 2006-09-16.
  80. ↑ Ulmann A (2000). "The development of mifepristone: a pharmaceutical drama in three acts". J Am Med Women's Assoc 55 (3 Suppl): 117–20. PMID 10846319.
  81. ↑ Wu S (2000). "Medical abortion in China". J Am Med Women's Assoc 55 (3 Suppl): 197–9, 204. PMID 10846339.
  82. ↑ "Family planning in China: RU-486, abortion, and population trends". U.S. Embassy Beijing. 2000. Retrieved 2006-09-14.
  83. ↑ Tsai EM, Yang CH, Lee JN (2002). "Medical abortion with mifepristone and misoprostol: a clinical trial in Taiwanese women". J Formos Med Assoc 101 (4): 277–82. PMID 12101864.
  84. ↑ Ganatra B, Bygdeman M, Nguyen DV, Vu ML, Phan BT (2004). "From research to reality: the challenges of introducing medical abortion into service delivery in Vietnam". Reprod Health Matters 12 (24): 105–13. doi:10.1016/S0968-8080(04)24022-8. PMID 15938163.
  85. ↑ "Medical Abortion-Implications for Africa" (PDF). Ipas. 2003. Retrieved 2006-09-16.
  86. ↑ Hajri S (2004). "Medication abortion: the Tunisian experience". Afr J Reprod Health 8 (1): 63–9. doi:10.2307/3583307. JSTOR 3583307. PMID 15487615.
  87. ↑ "Mifepristone can be sold only to approved MTP Centres: Rajasthan State HRC". Indian Express Health Care Management. 2000.
  88. ↑ ."Results of the Canadian trials of RU486, the 'Abortion Pill'." (n.d.). Retrieved 2006-12-08.
  89. ↑ "RU-486 abortion pill approved by Health Canada". Retrieved 2015-07-30.
  90. ↑ "Medication Abortion". Ibis. 2002. Retrieved 2006-09-19.
  91. ↑ Paige Comstock Cunningham, Leanne McCoy, Clarke D. Ferguson (February 28, 1995). "Citizen Petition to the U.S. Food and Drug Administration". Americans United for Life. Retrieved 2006-09-20.
  92. ↑ Margaret Talbot (July 11, 1999). "The Little White Bombshell". The New York Times. Retrieved 2006-09-20.
  93. ↑ "Abortion Foes To Boycott Drugs (Altace) Made By RU-486 Manufacturer". The Virginia Pilot. July 8, 1994. Retrieved 2006-09-15.
  94. ↑ Stan Guthrie (June 11, 2001). "Counteroffensive Launched on RU-486". Christianity Today. Retrieved 2006-09-20.
  95. ↑ Gina Kolata (September 24, 2003). "Death at 18 Spurs Debate Over a Pill For Abortion". The New York Times. Retrieved 2006-09-20.
  96. ↑ John L. Allen (February 12, 1999). "Abortion debates rock Germany: introduction of abortion pill exacerbates controversy". National Catholic Reporter. Retrieved 2006-09-14.
  97. ↑ "Catholic and Evangelical students join Muslims in RU-486 fight". Catholic News. February 9, 2006. Archived from the original on October 27, 2006. Retrieved 2006-09-18.
  98. ↑ "Death Toll Rises to 11 Women". Australians Against RU-486. 2006. Retrieved 2006-09-20.
  99. ↑ Hazra BG, Pore VS (2001). "Mifepristone (RU-486), the recently developed antiprogesterone drug and its analogues.". J Indian Inst Sci. 81: 287–98.
  100. ↑ Peter Gallagher, Navdeep Malik, James Newham, Allan H Young, Nicol Ferrier, Paul Mackin (2008). "Antiglucocorticoid treatments for mood disorders.". Cochrane Database Syst. Review: CD005168. doi:10.1002/14651858.CD005168.pub2. PMID 18254070.

External links

This article is issued from Wikipedia - version of the Sunday, February 07, 2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.