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Misoprostol is a drug that is used for the prevention of non steroidal anti inflammatory drug (NSAID) induced gastric ulcers, for early abortion, to treat missed miscarriage, and to induce labor. The latter use is controversial in the United States. Misoprostol was invented and marketed by G.D. Searle & Company (now Pfizer) under the trade name Cytotec (often misspelled Cyotec), but other brand-name and generic formulations are now available as well.

Pharmacologically, misoprostol is a synthetic prostaglandin E₁ (PGE₁) analogue.

1 Ulcer prevention
2 Labor induction
- 2.1 Controversy
3 Induced abortion
- 3.1 Earlier pregnancy
- 3.2 Later pregnancy
4 Missed miscarriage
5 Post-partum hemorrhage
6 Other gynecological uses
7 Erectile dysfunction
8 Pharmacology
9 Side effects and contraindications
10 References
11 External links and further reading

Ulcer prevention

Misoprostol is approved for use in the prevention of NSAID induced gastric ulcers. It acts upon gastric parietal cells, inhibiting the secretion of gastric acid via G-protein coupled receptor mediated inhibition of adenylate cyclase, which leads to decreased intracellular cyclic AMP levels and decreased proton pump activity at the apical surface of the parietal cell. Because other classes of drugs, especially H2-receptor antagonists and proton pump inhibitors, are more effective for the treatment of acute peptic ulcers, Misoprostol is only indicated for use by people who are both taking NSAIDs and are at high risk for NSAID induced ulcers, including the elderly and people with ulcer complications. Misoprostol is sometimes coprescribed with NSAIDs to prevent their common adverse effect of gastric ulceration (e.g. with Diclofenac in Arthrotec).

Misoprostol has other protective actions, but is only clinically effective at doses high enough to reduce gastric acid secretion. For instance, at lower doses misoprostol may stimulate increased secretion of the protective mucus that lines the gastrointestinal tract and increase mucosal blood flow, thereby increasing mucosal integrity. However, these effects are not pronounced enough to warrant prescription of misoprostol at doses lower than those needed to achieve gastric acid suppression.

However, even in the treatment of NSAIDs induced ulcers, omeprazole proved to be at least as effective as misoprostol^{[citation needed]}, but significantly better tolerated, and therefore misoprostol should not be considered a first choice treatment. Misoprostol induced diarrhea and the need of multiple daily doses (typically four) are the main issues impairing compliance with therapy.

Labor induction

Misoprostol is commonly used for labor induction. It causes uterine contractions and the ripening (effacement or thinning) of the cervix.^[1] Misoprostol is more effective in starting labor than other drugs used for labor induction.^[2]^:87 It is also significantly less expensive than the other commonly used ripening agent, dinoprostone (trade names Cervidil and Prepidil).^[3]

Oxytocin (trade names Pitocin and Syntocinon) has long been used as the standard agent for labor induction, but doesn't work well when the cervix is not yet ripe. In addition to being used alone to induce labor, misoprostol may be used in conjunction with oxytocin.^[3]

Protocols for inducing labor with misoprostol typically call for 25 μg to be administered vaginally.^[4] In countries where the only approved use of misoprostol is ulcer prevention, misoprostol is not sold in tablets smaller than 100 μg. When used for induction, the 100 μg tablet is commonly split into two or four pieces.^[5]

Controversy

When Cytotec first came on the market, the label listed a contraindication that it not be used on pregnant women. In August 2000, due to increase of "off label" usage, Searle (the manufacturer of Cytotec) distributed a letter warning against the use of misoprostol in pregnant women. In addition to citing the abortifacient nature of the drug, the letter cited reports of uterine rupture and death associated with using misoprostol to induce labor. All cervical ripening and induction agents can cause uterine hyperstimulation, which can negatively affect the blood supply to the fetus and increases the risk of complications such as uterine rupture.^[5] Concern has been raised that uterine hyperstimulation that occurs during a misoprostol induced labor is more difficult to treat than hyperstimulation during labors induced by other drugs.^[6] Other rare complications include amniotic fluid embolism; a 2006 study showed that the use of drugs to induce labor nearly doubled the risk.^[7] Because the complications are rare, it is difficult to determine if misoprostol causes a higher risk than do other cervical ripening agents. One estimate is that it would require approximately 61,000 patients enrolled in randomized controlled trials to detect a clinically significant difference in serious fetal complications and approximately 155,000 patients to detect a clinically significant difference in serious maternal complications.^[8]

This letter generated much controversy over the use of misoprostol in labor inductions.^[4] The American College of Obstetricians and Gynecologists holds that substantial evidence supports the use of misoprostol for induction of labor, a position it reaffirmed in 2000 in response to the Searle letter.^[9] Misoprostol is also on the WHO essential drug list for labor induction.^[10]

Induced abortion

Earlier pregnancy

Misoprostol is one of the drugs used for medical abortions in lieu of surgical evacuation. The advantages of medical abortion over surgical abortion include reduced invasiveness of the procedure, lack of risks from general anesthesia (which is sometimes used for surgical abortions), and lack of risk of secondary infertility due to scarring and intrauterine adhesions (Asherman's Syndrome).^{[citation needed]} Furthermore, it is less complicated to administer and less expensive.

In many countries,^[which?] including China, it is used in conjunction with mifepristone (RU-486). After mifepristone is taken orally, misoprostol is taken 24–72 hours later, causing the expulsion of the embryo and associated matter in approximately 92% of the cases. No large studies have established a protocol for the use of misoprostol alone,^[11] and the range of efficacy is 65%–93% depending on sample size, gestational age, and other test variables;^[12] Misoprostol alone may be more effective in earlier gestation.^[13] The side effects associated with the misoprostol only regimen are generally much more severe than those associated with the combined regimens.^{[citation needed]} Misoprostol is used for self-induced abortions in Brazil, where black market prices exceed US $100 per dose. Illegal medically unsupervised misoprostol abortions in Brazil are associated with a lower complication rate than other forms of illegal self-induced abortion, but are still associated with a higher complication rate than legal, medically supervised surgical and chemical abortions. Failed misoprostol abortions are associated with birth defects in some cases.^[14]^[15]^[16]^[17]^[18] Poor immigrant populations in New York have also been observed to use self administered misoprostol to induce abortions, as this method is much cheaper than a surgical abortion (about $2 per dose).^[19]

Later pregnancy

Misoprostol can also be used to dilate the cervix in preparation for a surgical abortion, particularly in the second trimester (either alone or in combination with laminaria stents).

Missed miscarriage

Misoprostol is sometimes used to treat early fetal death in the absence of spontaneous miscarriage, but further research is needed to establish a safe, effective protocol.^[20]

Post-partum hemorrhage

Misoprostol is also used to prevent and treat post-partum hemorrhage, but it has more side effects and is less effective than oxytocin for this purpose.^[21] However, it is inexpensive and thermostable (thus does not require refrigeration like oxytocin) making it a cost effective and valuable drug to use in the developing world.^[22]

Other gynecological uses

Although the practice remains uncommon, some gynecologists are now using low doses of misoprostol to soften the cervix prior to the insertion of intrauterine devices (especially in nulliparous women where insertion may be challenging).

Erectile dysfunction

A 1998 study found misoprostol to be helpful as a supplement to a vacuum pump (VED) in the treatment of erectile dysfunction, but not effective by itself.^[23] The paper concluded "The intraurethral application of misoprostol significantly improves the quality of VED-induced erections. This agent seems to be a cheap intraurethral adjunct to VED with mild to moderate local side-effects".

Pharmacology

Misoprostol, a prostaglandin, binds to myometrial cells to cause strong myometrial contractions leading to expulsion of tissue. This agent also causes cervical ripening with softening and dilation of the cervix.

Side effects and contraindications

The most commonly reported adverse effect of taking a misoprostol 200 µg tablet by mouth four times a day to reduce the risk of NSAID induced gastric ulcers is diarrhea. In clinical trials, an average 13% of patients reported diarrhea, which was dose-related and usually developed early in the course of therapy (after 13 days) and was usually self-limiting (often resolving within 8 days), but sometimes (in 2% of patients) required discontinuation of misoprostol.^[24]

The next most commonly reported adverse effects of taking a misoprostol 200 µg tablet by mouth four times a day to reduce the risk of NSAID induced gastric ulcers are: abdominal pain, nausea, flatulence, headache, dyspepsia, vomiting, and constipation, but none of these adverse effects occurred significantly more often than when taking placebos.^[24]

Misoprostol should not be taken by pregnant women to reduce the risk of NSAID induced gastric ulcers because it increases uterine tone and contractions in pregnancy which may cause partial or complete abortions, and because its use in pregnancy has been associated with birth defects.^[24]^[25]

One study suggests that misoprostol, if given vaginally rather than orally along with mifepristone to terminate a pregnancy, can increase the risk of serious infection with Clostridium sordellii.^[26]

References

^ Goldberg AB, Greenberg MB, Darney PD (January 2001). "Misoprostol and pregnancy". N. Engl. J. Med. 344 (1): 38–47. doi:10.1056/NEJM200101043440107. PMID 11136959.
^ Wagner, Marsden (2006). Born in the USA: how a broken maternity system must be fixed to put mothers and infants first. Berkeley: University of California Press. ISBN 0-520-24596-2.
^ ^a ^b Summers L (1997). "Methods of cervical ripening and labor induction". J Nurse Midwifery 42 (2): 71–85. doi:10.1016/S0091-2182(96)00138-3. PMID 9107114.
^ ^a ^b Goldberg AB, Wing DA (2003). "Induction of labor: the misoprostol controversy". J Midwifery Womens Health 48 (4): 244–8. doi:10.1016/S1526-9523(03)00087-4. PMID 12867908. http://www.medscape.com/viewarticle/458959. Retrieved 2009-08-03.
^ ^a ^b Briggs GG, Wan SR (June 2006). "Drug therapy during labor and delivery, part 2". Am J Health Syst Pharm 63 (12): 1131–9. doi:10.2146/ajhp050265.p2. PMID 16754739. http://www.medscape.com/viewarticle/535774. Retrieved 2009-08-03.
^ Wagner (2006), which cites:

Wing DA, Paul RH (July 1996). "A comparison of differing dosing regimens of vaginally administered misoprostol for preinduction cervical ripening and labor induction". Am. J. Obstet. Gynecol. 175 (1): 158–64. doi:10.1016/S0002-9378(96)70267-3. PMID 8694043.

Wing DA, Rahall A, Jones MM, Goodwin TM, Paul RH (June 1995). "Misoprostol: an effective agent for cervical ripening and labor induction". Am. J. Obstet. Gynecol. 172 (6): 1811–6. doi:10.1016/0002-9378(95)91416-1. PMID 7778637.
^ Kramer, M.S.; Rouleau, Jocelyn; Baskett, Thomas F; Joseph, KS (2006). "Amniotic-fluid embolism and medical induction of labour: a retrospective, population-based cohort study". The Lancet 368 (9545): 1444–1448. doi:10.1016/S0140-6736(06)69607-4. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(06)69607-4/abstract.
^ Goldberg (2003), which cites:

Weeks A, Alfirevic Z (September 2006). "Oral misoprostol administration for labor induction". Clin Obstet Gynecol 49 (3): 658–71. doi:10.1097/00003081-200609000-00023. PMID 16885670.
^ Goldberg (2003), which cites:

American College of Obstetricians and Gynecologists (November 1999). "Induction of labor with misoprostol". ACOG committee opinion no. 228 (Washington, DC).

American College of Obstetricians and Gynecologists (November 1999). "Response to Searle's drug warning on misoprostol". ACOG committee opinion no. 248 (Washington, DC).
^ WHO. "WHO Essential drug list 2005 section 22.1 website" (PDF). http://whqlibdoc.who.int/hq/2005/a87017_eng.pdf. Retrieved 2006-12-06.
^ "Annotated Bibliography on Misoprostol Alone for Early Abortion" (PDF). Gynuity Health Projects. http://www.rhtp.org/news/publications/documents/Miso%20for%20Pregnancy%20Termination.Bibliography.pdf. Retrieved 2006-08-22.
^ "Medication Abortion: Misoprostol Alone". Ibis. http://www.medicationabortion.com/misoprostol/index.html. Retrieved 2006-09-08.
^ "Instructions for Use: Abortion Induction with Misoprostol in Pregnancies up to 9 Weeks LMP" (PDF). Gynuity Health Projects. 2003. http://www.rhtp.org/news/publications/documents/Miso%20for%20Pregnancy%20Termination.IFU.English.pdf#search=%22%20site%3Awww.rhtp.org%20misoprostol%20abortion%20success%20rate%22. Retrieved 2006-08-24.
^ Corta, SH et al. (1993). "Misoprostol and illegal abortion in Rio de Janeiro, Brazil". Lancet 15 (341): 1258–61. doi:10.1016/0140-6736(93)91156-G. PMID 8098402.
^ Coelho, HL et al. (1994). "Misoprostol: the experience of women in Fortaleza, Brazil". Contraception 49 (2): 101–10. doi:10.1016/0010-7824(94)90084-1. PMID 8143449.
^ Barbosa, RM; Arilha, M (1993). "The Brazilian Experience with Cytotec". Stud Fam Plann 24 (4): 236–40. doi:10.2307/2939191. JSTOR 2939191. PMID 8212093.
^ Rocha, J et al. (1994). "Brazil investigates drug's possible link with birth defects". BMJ 309 (6957): 757–8. PMID 7950553.
^ Gonzalez, CH et al. (1993). "Limb deficiency with or without Mobius sequence in seven Brazilian children associated with misoprostol use in the first trimester of pregnancy". Am J Med Genet 47 (1): 59–64. doi:10.1002/ajmg.1320470113. PMID 8368254.
^ John Leland: "Abortion Might Outgrow Its Need for Roe v. Wade", The New York Times, October 2, 2005
^ Neilson JP et al. (2006). Neilson, James P. ed. "Medical treatment for early fetal death (less than 24 weeks)". Cochrane Database Syst Rev 19 (3): CD002253. doi:10.1002/14651858.CD002253.pub3. PMID 16855990.
^ J Villar MD et al. (2002). "Systematic Review of Randomized Controlled Trials of Misoprostol to Prevent Postpartum Hemorrhage". Obstetrics & Gynecology. http://www.greenjournal.org/cgi/content/abstract/100/6/1301. Retrieved 2006-09-21.
^ Bradley SEK, Prata N, Young-Lin N, Bishai DM (2007). "Cost-effectiveness of misoprostol to control postpartum hemorrhage in low-resource settings." International Journal of Gynecology and Obstetrics, 97: 52–56.
^ Ekmekçioğlu, Demirci, Yilmaz & Tatli (1998). "Intraurethral misoprostol: a different agent in the treatment of erectile dysfunction". Sexual Dysfunction 1 (3): 161. doi:10.1046/j.1460-2679.1998.00030.x. http://www.blackwell-synergy.com/doi/full/10.1046/j.1460-2679.1998.00030.x.
^ ^a ^b ^c Pfizer (September 2006). "Cytotec US Prescribing Information" (PDF). http://www.pfizer.com/pfizer/download/uspi_cytotec.pdf. Retrieved 2007-03-15.
^ Pharmacia (July 2004). "Cytotec UK SPC (Summary of Product Characteristics)". http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=9352. Retrieved 2007-03-15.
^ KAronoff DM, Hao Y, Chung J, Coleman N, Lewis C, Peres CM, Serezani CH, Chen GH, Flamand N, Brock TG, Peters-Golden M (June 15, 2008). "Misoprostol Impairs Female Reproductive Tract Innate Immunity against Clostridium sordellii". J Immunol. 180 (12): 8222–30.. . PMID 18523288. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2667109.

External links and further reading

Misoprostol.org an independent website containing dosage guidelines and advice on misoprostol use.
www.yorku.ca A York University study outlining potential links toward autism.

[1] The Mechanism of Action and Pharmacology of Mifepristone, Misoprostol, and Methotrexate

UpToDate Contents

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1. 人工妊娠中絶に対するミソプロストール単独投与 misoprostol as a single agent for medical termination of pregnancy
2. 陣痛誘発前に未成熟な頸管を熟化させる手技 techniques for ripening the unfavorable cervix prior to induction
3. 妊娠初期における薬物による中絶 first trimester medication abortion termination of pregnancy
4. 非ステロイド性抗炎症剤（NSAIDs）（アスピリンを含む）：胃十二指腸障害の一次予防 nsaids including aspirin primary prevention of gastroduodenal toxicity
5. 妊娠中期の中絶：陣痛誘発（薬剤）による中絶 second trimester pregnancy termination induction medication termination

English Journal

Unsafe abortion and postabortion care - an overview.

Rasch V.SourceDepartment of Obstetrics and Gynecology, Odense University Hospital, Odense, Denmark.
Acta obstetricia et gynecologica Scandinavica." abstractLink="yes" alsec="jour" alterm="Acta Obstet Gynecol Scand.2011 Jul;90(7):692-700. doi: 10.1111/j.1600-0412.2011.01165.x. Epub 2011 May 25.
Forty per cent of the world's women are living in countries with restrictive abortion laws, which prohibit abortion or only allow abortion to protect a woman's life or her physical or mental health. In countries where abortion is restricted, women have to resort to clandestine interventions to have
PMID 21542813

Administration of misoprostol by trained traditional birth attendants to prevent postpartum haemorrhage in home births in Pakistan: randomised placebo-controlled trial.

Durocher J, Blum J, Walraven G, Zuberi N, Mobeen N.SourceGynuity Health Projects, New York, NY, USA Delegation of the Aga Khan Development Network Foundation, Aiglemont, Gouvieux, France Department of Obstetrics and Gynaecology, Aga Khan University, Karachi, Pakistan Department of Community Health Sciences, Aga Khan University, Karachi, Pakistan.
BJOG : an international journal of obstetrics and gynaecology." abstractLink="yes" alsec="jour" alterm="BJOG.2011 Jul;118(8):1018-9. doi: 10.1111/j.1471-0528.2011.03016.x.
PMID 21658198

Japanese Journal

NSAIDs潰瘍の予防・治療における抗潰瘍薬の位置づけプロスタグランジン製剤・防御因子増強薬 (特集 NSAIDs潰瘍--最新の予防・治療) -- (NSAIDs潰瘍の予防・治療戦略)

藤川佳子,渡辺俊雄,富永和作 [他]
日本臨床 69(6), 1039-1043, 2011-06
NAID 40018850023

NSAIDs潰瘍の予防・治療における抗潰瘍薬の位置づけプロトンポンプ阻害薬・H2受容体拮抗薬 (特集 NSAIDs潰瘍--最新の予防・治療) -- (NSAIDs潰瘍の予防・治療戦略)

塩谷昭子,鎌田智有,楠裕明 [他]
日本臨床 69(6), 1032-1038, 2011-06
NAID 40018850022

IS-54 Titrated Oral Misoprostol Solution Compared With Intravenous Oxytocin for Labor Augmentation(Group7 Perinatology1,International Session)

Ho Ming,Cheng Shi-Yann,Li Tsai-Chung
日本産科婦人科學會雜誌 63(2), 931, 2011-02-01
NAID 110008510207

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リンク元	「プロスタグランジン製剤」「ミソプロストール」

「プロスタグランジン製剤」

Misoprostol
Systematic (IUPAC) name
	Methyl 7-((1R,2R,3R)-3-hydroxy-2-((S,E)-4-hydroxy-4-methyloct-1-enyl)-5-oxocyclopentyl)heptanoate
Clinical data
Trade names	Cytotec
AHFS/Drugs.com	monograph
MedlinePlus	a689009
Pregnancy cat.	X
Legal status	℞ Prescription only
Routes	Oral, Vaginal, Sublingual
Pharmacokinetic data
Bioavailability	extensively absorbed
Protein binding	85%
Metabolism	de-esterified to misoprostol acid, then to prostaglandin F analogs
Half-life	20–40 minutes
Excretion	Renal:80%; Fecal:15%
Identifiers
CAS number	59122-46-2
ATC code	A02BB01
PubChem	CID 5282381
IUPHAR ligand	1936
DrugBank	DB00929
ChemSpider	4445541
UNII	0E43V0BB57
KEGG	D00419
ChEMBL	CHEMBL606
Chemical data
Formula	C22H38O5
Mol. mass	382.534 g/mol
SMILES	eMolecules & PubChem
	InChI InChI=1S/C22H38O5/c1-4-5-14-22(2,26)15-10-12-18-17(19(23)16-20(18)24)11-8-6-7-9-13-21(25)27-3/h10,12,17-18,20,24,26H,4-9,11,13-16H2,1-3H3/b12-10+/t17-,18-,20-,22?/m1/s1 ; Key:OJLOPKGSLYJEMD-URPKTTJQSA-N ;
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