Mifepristone , also known as RU-486 , is a drug normally used in combination with misoprostol, to have an abortion. This combination is more than 95% effective during the first 50 days of pregnancy. It is also effective in the second trimester of pregnancy. The effectiveness should be verified two weeks after use. It was taken by mouth.
Common side effects include abdominal pain, fatigue, and vaginal bleeding. Serious side effects may include severe vaginal bleeding, bacterial infections, and deformed infants if the pregnancy does not end. If appropriate, appropriate follow-up care should be available. Mifepristone is an antiprogestogen and works by blocking the effects of progesterone and causing uterine contractions.
Mifepristone was developed in 1980 and began to be used in France in 1987. Mifepristone became available in the United States in 2000. It is on the World Health Organization's Essential Medicines List, the most effective and safe medication needed in the health system. Mifepristone is approved by Health Canada in 2015 and is available in Canada in January 2017. Cost and availability limit access in many parts of the developing world. In the United States it costs more than US $ 200 (equivalent to $ 206.49 in 2017) dose.
Video Mifepristone
Medical use
Abortion
Mifepristone followed by an analogue prostaglandin (misoprostol or gemeprost) is used for medical abortion. Medical organizations have found this combination safe and effective. A guide from the Royal College of Obstetricians and Gynecologists explains medical abortion using mifepristone and misoprostol as effective and appropriate at gestational age. World Health Organization and Congress The American Obstetrician and Gynecologist recommends mifepristone followed by misoprostol for first and second medical abortions. Mifepristone alone is less effective, resulting in abortion within 1-2 weeks at 8% to 46% of pregnancies.
Cushing's Syndrome
Mifepristone is used for medical treatment of high blood sugar (hyperglycemia) caused by high levels of cortisol in the blood (hypercortisolism) in adults with endogenous Cushing syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or can not undergo surgery.
Emergency contraception
Mifepristone is used for emergency contraception.
Maps Mifepristone
Side effects
Almost all women using a mifepristone/misoprostol regimen experience abdominal pain, uterine cramps, and vaginal bleeding or spotting an average of 9-16 days. Up to 8% of women experience some type of bleeding for 30 days or more. Other less common side effects include nausea, vomiting, diarrhea, dizziness, fatigue, and fever. Pelvic inflammatory disease is a very rare but serious complication. Excessive bleeding and incomplete termination of pregnancy require further intervention by the doctor (such as vacuum aspiration). Between 4.5 and 7.9% of women require surgical intervention in clinical trials. Mifepristone is contraindicated in the presence of intrauterine devices, as well as with ectopic pregnancy, adrenal failure, hemorrhagic disorders, inherited porphyria, and anticoagulant or long-term corticosteroid therapy.
The FDA prescribed information saying no data was available about the safety and efficacy of mifepristone in women with chronic medical conditions, and "women over 35 years old and who also smoked 10 cigarettes or more per day should be treated with caution because such patients are generally removed from clinical trials of mifepristone. "
A postmarketing summary was found, about 1.52 million women who had received mifepristone until April 2011 in the United States, 14 were reported to have died after the application. Eight of these cases were associated with sepsis; six others have various causes such as drug abuse and murder allegations. Other reported incidents to the FDA include 612 non-lethal hospitalizations, 339 blood transfusions, 48 ​​serious infections, and 2,207 (0.15%) adverse events altogether.
Cancer
There is no long-term study to evaluate the carcinogenic potential of mifepristone that has been done. This is in accordance with ICH guidelines, which do not require a carcinogenicity test of nongenotoxic drugs intended for administration of less than six months.
Pregnancy
Mifepristone alone produces abortion within 1-2 weeks in 8% to 46% of pregnancies. There is no evidence that the effects of mifepristone can be reversed, although some pro-life groups claim otherwise.
In those who continue the pregnancy after using mifepristone along with misoprostol for termination, birth defects can occur. Large single-dose mifepristone exposure in newborn mice was not associated with reproductive problems, although chronic low-dose exposure of mice to mifepristone was associated with structural and functional reproductive disorders. Studies in rats, mice, and rabbits revealed teratogenicity for rabbits, but not rats or mice.
Pharmacology
Pharmacodynamics
Mifepristone is a steroidal antiprogestogen (IC 50 = 0.025 nM for PR), and antiglucocorticoid (IC 50 = 2.2 nM for GR) and antiandrogen (IC 50 = 10 nM for AR) to a much lower level. It antagonizes the action of cortisol competitively at the receptor level.
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- or steroid with a large phenyl substituent p - (dimethylamino) above the molecular plane at 11? -position responsible for inducing or stabilizing the conformation of inactive and hydrophobic receptors 1- substituents propynyl below the molecular plane at 17? -position that increases affinity binds to its progesterone receptor.
In addition to being an antiprogestogen, mifepristone is also a weak antigilinocorticoid and antiandrogen. The relative affinity of Mifepristone at progesterone receptor is more than twice that of progesterone, its relative binding affinity in glucocorticoid receptors more than triples from dexamethasone and more than ten times that of cortisol; the relative affinity of the androgen receptor is less than one-third of testosterone. It does not bind to estrogen receptors or mineralocorticoid receptors.
Mifepristone as a regular contraceptive at 2 mg a day prevents ovulation (1 mg a day is not). Ten prescribed single mifepristone pre-ovulation delays ovulation for up to three to four days and is effective as emergency contraception as a single dose of 1.5 mg levonorgestrel progestin.
In women, mifepristone at doses greater than or equal to 1 mg/kg antagonizes the effects of endometrium and myometrium progesterone. In humans, the antifungal effects of mifepristone are manifested at doses greater than or equal to 4.5 mg/kg by increased ACTH and cortisol compensation. In animals, a weak antiandrogenic effect is seen with a very long dose of 10 to 100 mg/kg.
In the medical abortion regimen, the mifepristone blockade of progesterone receptors directly leads to desidual decidual endometrium, softening and cervical dilatation, endogenous prostaglandin release, and increased myometrial sensitivity to contractile prostaglandin effects. Mifepristone-induced decidual discontinuation indirectly leads to the release of trophoblasts, resulting in a decrease in the production of hCG syncytiotrophoblasts, which in turn leads to a decrease in progesterone production by the corpus luteum (pregnancy depends on progesterone production by the corpus luteum through the first nine weeks of pregnancy-for placental progesterone production has increased considerably to take the production of progesterone corpus luteum). When followed sequentially by prostaglandins, mifepristone 200 mg (100 mg is possible, but 50 mg is not) is as effective as 600 mg in producing medical abortions.
'Contragestion' is a term promoted by ÃÆ'â € ° tienne-ÃÆ'â € ° mile Baulieu in the context of its defense of mifepristone, defining it as inclusive of several mechanisms of action of some contraceptive and hypothetical mifepristone to induce abortion. Baulieu's definition of 'contragestive' includes any birth control methods that may act after conception and before nine weeks of gestation.
Pharmacokinetics
The elimination half-life is very complex; according to the label: "After the distribution phase, the elimination is initially slow, the concentration decreases by half between about 12 and 72 hours, and then faster, gives the elimination half-life of 18 hours.By radio signal receptor testing techniques, the terminal half-life of up to 90 hours, all the mifepristone metabolites that can bind to the progesterone receptor. "
Chemistry
Mifepristone, also known as 11? - (4- (dimethylamino) phenyl) -17? - (1-propynyl) estra-4,9-dien-17? -ol-3-one, is a synthetic estrus steroid and a steroid hormone derivative such as progesterone, cortisol, and testosterone. It has substitution in C11? and C17? position and double bond at position C4 (5) and C9 (10).
History
In April 1980, as part of a formal research project at the French pharmaceutical company Roussel-Uclaf for the development of glucocorticoid receptor antagonists, chemist Georges Teutsch synthesized mifepristone (RU-38486, 38486 compound synthesized by Roussel-Uclaf from 1949 to 1980). ; Shortened to RU-486), which is also found to be a progesterone receptor antagonist. In October 1981, the endocrinologist ÃÆ'â € ° tienne-ÃÆ'â € ° mile Baulieu, consultant to Roussel-Uclaf, arranged a test of its use for medical abortion in 11 women in Switzerland by gynecologist Walter Herrmann at the University of Geneva Canton Hospital, with successful results was announced on April 19, 1982. On 9 October 1987, after worldwide clinical trials of 20,000 mifepristone women with prostaglandin analogues (originally sulprostone or gemeprost, then misoprostol) for medical abortion, Roussel-Uclaf requested approval in France for its use for medical. abortion, with approval announced on September 23, 1988.
On October 21, 1988, in response to anti-abortion protests and majority concerns (54.5%) of Hoechst AG's owners from Germany, Roussel-Uclaf's executives and board of directors voted 16 to 4 to stop the distribution of mifepristone, which they announced on 26 October 1988. Two days later, the French government ordered Roussel-Uclaf to distribute mifepristone for the sake of public health. French Health Minister Claude ÃÆ' â € ° vin explains: "I can not allow abortion debate to rob women of products representing medical progress." From the moment the Government's approval for the drug was given, RU-486 belongs to a woman's morality, not just the drug company. "After being used by 34,000 women in France from April 1988 to February 1990 from the freely distributed mifepristone, Roussel-Uclaf began selling Mifegyne (mifepristone) to a French hospital in February 1990 at a price (negotiated with the French government) span> US $ 48 (equivalent to $ 89.91 in 2017) per dose of 600 mg.
Mifegyne was then approved in Great Britain on July 1, 1991, and in Sweden in September 1992, but until his retirement in late April 1994, the chairman of Hoechst AG Wolfgang Hilger, a devout Roman Catholic, hindered further expansions in availability. On May 16, 1994, Roussel-Uclaf announced that they donated in exchange for all rights to the medical use of mifepristone in the United States to the Population Council, which subsequently licensed mifepristone to Danco Laboratories, a new single product company resistant to the anti-abortion boycott, which won FDA approval as Mifeprex on September 28, 2000.
On April 8, 1997, after buying the remaining 43.5% of Roussel-Uclaf's shares in early 1997, Hoechst AG (<$ 30) per year and sales of Mifegyne ($ 5.37 million in annual revenue per year) and transfer of all rights to medical use of mifepristone outside the United States to Exelgyn SA, the company's new single product immune to the anti-abortion boycott, whose CEO is former CEO Roussel-Uclaf â € ° douard Sakiz. In 1999, Exelgyn won Mifegyne approval in 11 additional countries, and in 28 other countries over the next decade.
Society and culture
Mifepristone is on the WHO Essential Medicines List of the most important drugs needed in basic healthcare systems. It is on the complementary list and included with special notes "if permitted under national law and where culturally acceptable".
Usage
United States
Voluntary medical abortions reported by 33 US states to CDC have increased as a percentage of total abortions each 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 less than 9 weeks pregnancy).
The Guttmacher Institute survey of abortion providers estimated that medical abortion accounted for 17% of all abortions and slightly more than 25% of abortions before 9 weeks of pregnancy in the United States in 2008 (94% of non-hospital medical abortions used mifepristone and misoprostol, 6% were used methotrexate and misoprostol). Medical abortions accounted for 32% of first trimester abortions at the Planned Parenthood clinic in the United States in 2008.
By 2014, about 272,400 drug abortions were provided at non-hospital facilities, representing a 14% increase since 2011. Medical abortions accounted for 31% of all non-hospital abortions, compared to 24% in 2011. Half or more of all abortions (50 -68%) provided by facilities with an annual case burden of less than 400 procedures is an early treatment abortion.
Europe
In France, the percentage of medical abortions of all abortions continued to increase: 38% in 2003, 42% in 2004, 44% in 2005, 46% in 2006, 49% in 2007 (vs. 18% in 1996). In England and Wales, 52% of early abortions (less than 9 weeks of gestation) in 2009 were medical; the percentage of all medical abortions has increased annually over the last 14 years (from 5% in 1995 to 40% in 2009) and has more than doubled in the last five years. 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 medical abortions has increased annually over the past 17 years (from 16.4% in 1992 to 69.9% in 2009). In Sweden, 85.6% of early abortions and 73.2% of abortions before the end of the 12th week of pregnancy in 2009 were medical; 68.2% of all abortions in 2009 were medical. In the UK and Sweden, mifepristone is licensed for use with vaginal pyrolysis or oral misoprostol. In 2000, more than 620,000 women in Europe have had medical abortions using a mifepristone regimen. In Denmark, mifepristone was used between 3,000 and 4,000 for just over 15,000 abortions in 2005.
Legal status
United States
Mifepristone was approved for abortion in the United States by the FDA in September 2000. Mifepristone is legal and is available in all 50 states, Washington, D.C., Guam, and Puerto Rico. This is a prescription drug, but not available to the public through pharmacies; the distribution is limited to qualified licensed specialized doctors, sold by Danco Laboratories under the trade name Mifeprex.
Roussel Uclaf did not ask for U.S. approval, so the availability of US law was initially impossible. The United States banned the import of mifepristone for personal use in 1989, a decision endorsed by Roussel Uclaf. In 1994, Roussel Uclaf granted the US drug right to the Population Council in return for immunity from any product liability claim. The Population Council sponsors clinical trials in the United States. The drug came into force from 1996. Production was intended to start through Danco Group in 1996, but they withdrew briefly in 1997 because of a corrupt business partner, delaying availability again.
In 2016, the US Food and Drug Administration approves mifepristone, to end the pregnancy through 70 days of pregnancy (70 days or less since the woman's first day of menstruation). The approved dose regimen is 200 mg of mifepristone taken. (swallowed). 24 to 48 hours after taking mifepristone, 800 mcg (microgram) misoprostol is taken buccally (in the bladder), at the appropriate location for the patient.
Mifepristone 300 mg tablet (Korlym) has marketing authorization in the United States of the FDA for medical treatment of high blood sugar (hyperglycemia) caused by high blood cortisol levels (hypercortisolism) in adults with Cushing endogenous syndrome who have type 2 diabetes mellitus or glucose intolerance and has failed surgery or can not be operated on.
Subsection H
Some drugs are approved by the FDA based on subsection H, which has two subparts. The first establishes a way to speed up experimental drugs, such as aggressive HIV and cancer care, into the market when quick approval is considered essential for potential patient health. The second part of subsection H applies to drugs that must not only meet the restrictions to be used due to safety requirements but are also required to meet post-marketing surveillance to establish that safety results demonstrated in clinical trials are supported by use in a much broader population. Mifepristone is approved under the second part of subsection H. The result is that women can not take drugs at pharmacies, but now must receive them directly from the doctor. Because of the possibility of adverse reactions such as excessive bleeding, which may require blood transfusions, and incomplete abortions, which may require surgical intervention, this medication is only considered safe if the doctor is able to perform blood transfusion or surgical abortion. available to patients in the event of an emergency like that. Mifepristone Approval under H section includes black box warning.
Europe
Outside the United States, it is marketed and distributed by Exelgyn Laboratories under the trade name Mifegyne. Mifepristone was approved for use in France in 1988 (initial marketing in 1989), United Kingdom in 1991, Sweden in 1992, then Austria, Belgium, Denmark, Finland, Germany, Greece, Luxembourg, Netherlands, Spain, and Switzerland 1999 In 2000, approved in Norway, Russia and Ukraine. Serbia and Montenegro agreed in 2001, Belarus and Latvia in 2002, Estonia in 2003, Moldova in 2004, Albania and Hungary in 2005, Portugal in 2007, Romania in 2008, Bulgaria, Czech Republic and Slovenia in 2013. In Italy, clinical trials was restricted by a protocol requiring women to be hospitalized for three days, but the drug was finally approved on July 30, 2009 (endorsed at the end of the year), despite strong opposition from the Vatican. In Italy, pills should be prescribed and used in clinical structures and not sold to chemists. It was approved in Hungary in 2005, but in 2005 has not been released in the market, and became the target of protests. Mifepristone is not approved in Ireland, where abortion is illegal, or Polish, where abortion is severely restricted.
Mifepristone 200 mg tablet (Mifegyne, Mifepristone Linepharma, Medabon) has marketing authorization in the European Economic Area of ​​the European Medicines Agency (EMA) for:
- First initial trimester medical abortion when followed by prostaglandin analogue (misoprostol or gemeprost) up to 63 days gestational age
- Second trimester medical abortion when followed by prostaglandin analog
- Softening and widening of the cervix before first trimester surgical abortion
- Induction of labor after fetal death in utero when prostaglandin and oxytocin analogs are contraindicated
Other countries
Mifepristone was banned in Australia in 1996. At the end of 2005, private member bills were introduced to the Australian Senate to lift the ban and transfer the power of approval to the Therapeutic Goods Administration. This move has caused much debate in the Australian media and among politicians. The bill was passed by the Senate on 10 February 2006, and mifepristone is now legal in Australia. This is provided regularly at some state-specific abortion clinics. Mifepristone 200 mg tablet has marketing authorization in Australia from the Therapeutic Goods Administration (TPA) for first trimester early medical abortion when followed by misoprostol analog prostaglandin through 63 days of gestation and second trimester medical abortion when followed by prostaglandin analogue.
In New Zealand, pro-choice doctors set up an import company, Istar, and apply for approval to MedSafe, the New Zealand pharmaceutical watchdog. After a court case brought by the Right to Live New Zealand failed, the use of mifepristone was permitted.
The drug was approved in Israel in 1999.
Clinical trials of mifepristone in China began in 1985. In October 1988, China became the first country in the world to approve mifepristone. The Chinese organizations tried to buy mifepristone from Roussel Uclaf, who refused to sell it to them, so in 1992 China started its own domestic production of mifepristone. In 2000, the cost of medical abortion with mifepristone was higher than for surgical abortion and the percentage of medical abortion varied considerably, ranging from 30% to 70% in cities to virtually nonexistent in rural areas. 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 according to press reports, the black market has grown with many women beginning to buy illegally (without a prescription) from the clinic private and drugstore for about US $ 15 (equivalent to $ 21.32 in 2017), causing Chinese authorities to worry about medical complications from unattended use of doctors.
In 2001, mifepristone was approved in Taiwan. Vietnam included mifepristone in the National Reproductive Health program in 2002.
It was approved only in one sub-Saharan African country - South Africa, where it was approved in 2001. It is also approved in one north African country - Tunisia, also in 2001.
Mifepristone was approved for use in India in 2002, where medical abortion was termed "pregnancy termination". These are only available under medical supervision, not by prescription, because of adverse reactions such as excessive bleeding, and criminal penalties are granted to buy or sell them on the black market or over-the-counter at pharmacies.
Medical abortions are usually available in Canada but are limited using methotrexate and misoprostol. Clinical trials were conducted in 2000 in various Canadian cities comparing methotrexate with mifepristone, after being approved by the federal government. While both drugs have the same overall outcome, mifepristone is found to act faster. Health Canada approved mifepristone in July 2015. Initially, its use was limited to seven weeks after pregnancy, but this was changed to nine weeks by 2017. The prior written consent requirement of the woman also ended at the same time. These can be distributed directly to the patient by a pharmacist or health care professional who prescribes it. Women are required to have ultrasound to ensure non-ectopic pregnancy.
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.
Low-dose mifepristone tablets (Bi Yun, Fu Nai Er, Hou Ding Nuo, Dian Hua, Si Mi An) for emergency contraception are available directly from pharmacists without prescription and prescription in China.
Low-dose mifepristone tablets for emergency contraception are available by prescription in Armenia (Gynepriston), Russia (Agesta, Gynepriston, Mifepristone 72, Negele), Ukraine (Gynepriston), and Vietnam (Mifestad 10, Ciel EC).
Controversy
Many pro-life groups in the United States are actively campaigning against mifepristone approval and are actively campaigning for the withdrawal. They cite one of the ethical issues with abortion or drug-related safety issues and the negative reactions associated with it. Religious and pro-life groups outside the United States are also protesting against mifepristone, especially in Germany and Australia.
Research
The original target for the study group was the discovery and development of compounds with antigilitocorticoid properties. These anticocorticoid properties are particularly attractive in the treatment of severe mood disorders and psychosis, although review of published articles is inconclusive on their efficacy, and considers the use of these drugs in mood disorders at the 'proof of concept' stage. Mifepristone shows early promise in major psychotic depression, a form of depression that is difficult to treat, but phase III clinical trials are terminated earlier due to lack of efficacy.
The use of mifepristone as a cervical cooking agent has been described. Drugs have been studied as an antiandrogen in the treatment of prostate cancer. Mifepristone showed no anti-HIV activity was detected in clinical trials.
References
Source of the article : Wikipedia
0 Comments