同: equine conjugated estrogens

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/05/21 16:52:12」(JST)

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Premarin is the commercial name for a medication consisting primarily of conjugated estrogens. Isolated from mares' urine (pregnant mares' urine), it is manufactured by Wyeth Pharmaceuticals (part of Pfizer since January 2009) and has been marketed since 1942. It is available in oral (0.3/0.45/0.625/0.9/1.25 mg), IV, and topical (vaginal) form.^[1]

Medical uses

Premarin is a form of hormone replacement therapy.^[2] Premarin pills are used most commonly in post menopausal women who have had a hysterectomy to treat hot flashes, and burning, itching, and dryness of the vagina and surrounding areas.^[3] It can also be used in conjunction with a progestin pill in women who have not had a hysterectomy. For women already taking the drug it can be used to treat osteoporosis, although it is not recommended solely for this use.^[4] Some lesser known uses are the treatment of symptoms associated with metastatic breast cancer in men and women and prostate cancer in men.^[5]^[6]

Side effects

The most common side effects associated with Premarin use are vaginal yeast infections, vaginal spotting or bleeding, painful menses, and cramping of the legs.While there are some contradictory data, estrogen alone does not appear to increase the risk of coronary heart disease or breast cancer, like estrogen with progestin does. ^[7]

Pharmacology

The major forms of estrogen in Premarin are estrone (>50%), equilin (15-25%) and equilenin. The estrogens in Premarin are often called "conjugated equine estrogens" (CEE) because the estrogen molecules are generally present with hydrophilic side-groups attached such as sulfate.^[8] Thus, estrone sulfate is actually the major active constituent in Premarin. Estrone sulfate is easily absorbed into the blood after the tablets are taken by women.^[9]

Estrone sulfate

Society and culture

History

Premarin was first introduced in 1942 by Wyeth Ayerst as a treatment for hot flashes and other symptoms of menopause; at that time, Wyeth Ayerst only had to prove its safety, and not its efficacy.^[10] In response to the 1962 Kefauver Harris Amendment the FDA had its efficacy reviewed, and in 1972 found it effective for menopausal symptoms and probably effective for osteoporosis.^[11] The review also determined that two estrogens—estrone sulfate and equilin sulfate—were primarily responsible for Premarin’s activity, and it laid the groundwork for Abbreviated New Drug Application (ANDA) submissions of generic versions.^[10] In 1984 an NIH consensus panel found that estogens were effective for preventing osteoporosis^[12] and 1986 thr FDA announced in the Federal Register that Premarin was effective for preventing osteoporosis.^[13] This announcement led to a rapid growth in sales, and interest from generic manufacturers to introduce generic versions.^[10]

Health effects

Research starting in 1975 showed substantially increased risk of endometrial cancer.^[14]^[15] Since 1976 the drug has carried a label warning about the risk.^[16] As part of the Women's Health Initiative sponsored by the National Institutes of Health, a large-scale clinical trial for Hormone Replacement Therapy showed that long-term use of progestin and estrogen may increase the risk of strokes, heart attacks, blood clots, and breast cancer.^[17] Following these results, Wyeth experienced a significant decline in its sales of Premarin, Prempro (conjugated equine estrogens) and related hormones, from over $2 billion in 2002 to just over $1 billion in 2006.^[18]

Litigation

This drug has been the subject of litigation; more than 13,000 people have sued Wyeth between 2002 and 2009. Wyeth and Pharmacia & Upjohn prevailed in the vast majority of hormone therapy cases previously set for trial through a combination of rulings by judges, verdicts by juries, and dismissals by plaintiffs themselves.^[19] Of the company’s losses, two of the jury verdicts were reversed post-trial and others are being challenged on appeal. Wyeth also won five summary judgments on Prempro cases and had 15 cases voluntarily dismissed by plaintiffs. The company won dismissals in another 3,000 cases.^[20] In 2006, Mary Daniel, in a trial in Philadelphia, was awarded $1.5 million in compensatory damages as well as undisclosed punitive damages. As of 2010, Wyeth had won the last four of five cases, most recently in Virginia, finding that they were not responsible for the breast cancer of plaintiff Georgia Torkie-Tork.^[21] Wyeth has been quoted as saying "many risk factors associated with breast cancer have been identified, but science cannot establish what role any particular risk factor or combination play in any individual woman's breast cancer." ^[22] Wyeth's counsel in the case also noted that in the WHI trial, 99.62 percent of women took the drug and "did not get breast cancer."^[20]

References

^ Premarin (conjugated estrogens) Vaginal cream - detailed view: safety labeling changes approved by FDA Center for Drug Evaluation and Research (CDER) November 2008
^ Greer, Iain A.; Ginsberg, Jeff; Forbes, Charles (29 December 2006). Women's vascular health (in English). CRC Press. ISBN 9780340809976.
^ Nezhat, Camran; Nezhat, Farr; Nezhat, Ceana (7 July 2008). Nezhat's Operative gynecologic laparoscopy and hysteroscopy (in English). Cambridge University Press. ISBN 9781139472005. Retrieved 7 May 2015.
^ Maeda, Sergio Setsuo; Lazaretti-Castro, Marise; Maeda, Sergio Setsuo; Lazaretti-Castro, Marise (2014). "An overview on the treatment of postmenopausal osteoporosis". Arquivos Brasileiros de Endocrinologia & Metabologia 58 (2): 162–171. doi:10.1590/0004-2730000003039. ISSN 0004-2730. Retrieved 2015-05-07.
^ "Breast cancer: major risk factors and recent developments in treatment". Asian Pac J Cancer Prev 15 (8): 3353–8. 2014. PMID 24870721.
^ Learning, Jones & Bartlett (2015-01-14). 2015 Nurse's Drug Handbook (in English). Jones & Bartlett Publishers. ISBN 9781284091373. Retrieved 2015-05-07.
^ http://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety-RelatedDrugLabelingChanges/ucm121062.htm
^ Bernstein, S.; Solomon, S. (2012-12-06). Chemical and Biological Aspects of Steroid Conjugation (in English). Springer Science & Business Media. ISBN 9783642951770. Retrieved 2015-05-07.
^ Troy, David B.; Beringer, Paul (2006). Remington: The Science and Practice of Pharmacy (in English). Lippincott Williams & Wilkins. ISBN 9780781746731. Retrieved 2015-05-12.
^ ^a ^b ^c Jim Kling October 2000 The Strange Case of Premarin Modern Drug Discovery (3):8 46–52
^ Federal Register 37, July 25, 1972 pp 14826-28
^ National Institutes of Health Consensus Development Conference Statement. April 2-4, 1984 Osteoporosis
^ Food and Drug Administration. May 5, 1997 Conjugated Estrogens - Letter from Dr. Janet Woodcock: Approvability of a Synthetic Generic Version of Premarin
^ Ziel HK, Finkle WD (4 December 1975). "Increased risk of endometrial carcinoma among users of conjugated estrogens". New England Journal of Medicine 293: 1167–1170. doi:10.1056/NEJM197512042932303. PMID 171569.
^ McDonald TW et al. (15 March 1977). "Exogenous estrogen and endometrial carcinoma: case-control and incidence study". American J Obstet Gynecol 127: 572–580. PMID 190887.
^ Natasha Singer and Duff Wilson (12 December 2009). "Menopause, as Brought to You by Big Pharma". New York Times.
^ Brunner RL et al; Womens Health Initiative Investigators (26 September 2005). "Effects of conjugated equine estrogen on health-related quality of life in postmenopausal women with hysterectomy: results from the Women's Health Initiative randomized clinical trial". Archives of Internal Medicine 165 (17): 1976–1986. doi:10.1001/archinte.165.17.1976. PMID 16186467.
^ "Earnings Results for the 2006 Fourth Quarter and Full Year" (PDF) (Press release). Wyeth.
^ "Pfizer Statement on Prempro". Indy News Channel. ^{[dead link]}
^ ^a ^b Jef Feeley (February 24, 2010). "Pfizer wins trial over claim Prempro caused cancer". Bloomberg.
^ "Pfizer properly warned about Prempro risks, jury finds". 3 December 2010.
^ "Legal Intelligencer: Philadelphia jury returns defense verdict in HRT case, Amaris Elliott Engel".

External links

Information page of the manufacturer
Premarin information at the Food and Drug Administration (FDA) website
WHI Follow-up Study Confirms Health Risks of Long-Term Combination Hormone Therapy Outweigh Benefits for Postmenopausal Women NIH press release, March 4, 2008
National Health Lung and Blood Institute's WHI website

UpToDate Contents

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1. 膣萎縮症の治療 treatment of vaginal atrophy
2. 更年期のほてり menopausal hot flashes
3. 重度または持続性子宮出血のマネージメント managing an episode of severe or prolonged uterine bleeding
4. ホルモン療法を用いた閉経期症状の治療 treatment of menopausal symptoms with hormone therapy
5. 骨粗鬆症の予防および治療のための選択的エストロゲン受容体調節剤 selective estrogen receptor modulators for prevention and treatment of osteoporosis

English Journal

Association of testosterone with estrogen abolishes the beneficial effects of estrogen treatment by increasing ROS generation in aorta endothelial cells.

Costa TJ1, Ceravolo GS2, dos Santos RA1, de Oliveira MA1, Araújo PX1, Giaquinto LR1, Tostes RC3, Akamine EH1, Fortes ZB1, Dantas AP4, Carvalho MH5.
American journal of physiology. Heart and circulatory physiology.Am J Physiol Heart Circ Physiol.2015 Apr 1;308(7):H723-32. doi: 10.1152/ajpheart.00681.2014. Epub 2015 Jan 30.
Testosterone has been added to hormone replacement therapy to treat sexual dysfunction in postmenopausal women. Whereas estrogen has been associated with vascular protection, the vascular effects of testosterone are contradictory and the effects of its association with estrogen are largely unknown.
PMID 25637546

Recent advances in the pharmacologic treatment of spinal cord injury.

Cox A1, Varma A, Banik N.
Metabolic brain disease.Metab Brain Dis.2015 Apr;30(2):473-82. doi: 10.1007/s11011-014-9547-y. Epub 2014 May 16.
A need exists for the effective treatment of individuals suffering from spinal cord injury (SCI). Recent advances in the understanding of the pathophysiological mechanisms occurring in SCI have resulted in an expansion of new therapeutic targets. This review summarizes both preclinical and clinical
PMID 24833553

New drugs 2015, part 1.

Hussar DA1.
Nursing.Nursing.2015 Apr;45(4):40-8; quiz 48-9. doi: 10.1097/01.NURSE.0000461853.25938.20.
PMID 25719949

Japanese Journal

IS-75 Premarin therapy in experimental spinal cord injury : an animal model study(Group10 Women's Health1,International Session)

Chang F. -M.,Kang L.,Ko H. -C.,Chen S. -H.,Lin M. -T.
日本産科婦人科學會雜誌 62(2), 798, 2010-02-01
NAID 110007686817

エストラジオール測定系におけるエストロゲン補充製剤の影響

狩野賢二,柴田宏,益田順一
臨床病理 48(11), 1059-1063, 2000-11-25
NAID 10005867284

Equilin, a principal component of the estrogen replacement therapy premarin, increases the growth of cortical neurons via an NMDA receptor-dependent mechanism

BRINTON RD
Exp Neurol 147(2), 211-220, 1997
NAID 30020347698

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★リンクテーブル★

関連記事	「Premarin」「PREMARIN」

「Premarin」

Premarin
Combination of
Estrone sulfate	Estrogen
Equilin	Estrogen
Equilenin	Estrogen
Clinical data
AHFS/Drugs.com	Consumer Drug Information
Pregnancy; category	X;
Legal status	℞ (Prescription only);
Routes of; administration	Oral, topical, IV
Identifiers
CAS Registry Number	12126-59-9
ATC code	G03CA57
PubChem	CID 656613
ChemSpider	570974
UNII	IU5QR144QX
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　　[★] プレマリン、結合型エストロゲン

「PREMARIN」

　　[★]

関: conjugated equine estrogen

[1] Premarin (conjugated estrogens) Vaginal cream - detailed view: safety labeling changes approved by FDA Center for Drug Evaluation and Research (CDER) November 2008

[2] Greer, Iain A.; Ginsberg, Jeff; Forbes, Charles (29 December 2006). Women's vascular health (in English). CRC Press. ISBN 9780340809976.

[3] Nezhat, Camran; Nezhat, Farr; Nezhat, Ceana (7 July 2008). Nezhat's Operative gynecologic laparoscopy and hysteroscopy (in English). Cambridge University Press. ISBN 9781139472005. Retrieved 7 May 2015.

[4] Maeda, Sergio Setsuo; Lazaretti-Castro, Marise; Maeda, Sergio Setsuo; Lazaretti-Castro, Marise (2014). "An overview on the treatment of postmenopausal osteoporosis". Arquivos Brasileiros de Endocrinologia & Metabologia 58 (2): 162–171. doi:10.1590/0004-2730000003039. ISSN 0004-2730. Retrieved 2015-05-07.

[5] "Breast cancer: major risk factors and recent developments in treatment". Asian Pac J Cancer Prev 15 (8): 3353–8. 2014. PMID 24870721.

[6] Learning, Jones & Bartlett (2015-01-14). 2015 Nurse's Drug Handbook (in English). Jones & Bartlett Publishers. ISBN 9781284091373. Retrieved 2015-05-07.

[7] ttp://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety-RelatedDrugLabelingChanges/ucm121062.htm

[8] Bernstein, S.; Solomon, S. (2012-12-06). Chemical and Biological Aspects of Steroid Conjugation (in English). Springer Science & Business Media. ISBN 9783642951770. Retrieved 2015-05-07.

[9] Troy, David B.; Beringer, Paul (2006). Remington: The Science and Practice of Pharmacy (in English). Lippincott Williams & Wilkins. ISBN 9780781746731. Retrieved 2015-05-12.

[MDD-10] Jim Kling October 2000 The Strange Case of Premarin Modern Drug Discovery (3):8 46–52

[11] Federal Register 37, July 25, 1972 pp 14826-28

[12] National Institutes of Health Consensus Development Conference Statement. April 2-4, 1984 Osteoporosis

[Woodcock1997-13] Food and Drug Administration. May 5, 1997 Conjugated Estrogens - Letter from Dr. Janet Woodcock: Approvability of a Synthetic Generic Version of Premarin

[14] Ziel HK, Finkle WD (4 December 1975). "Increased risk of endometrial carcinoma among users of conjugated estrogens". New England Journal of Medicine 293: 1167–1170. doi:10.1056/NEJM197512042932303. PMID 171569.

[15] McDonald TW et al. (15 March 1977). "Exogenous estrogen and endometrial carcinoma: case-control and incidence study". American J Obstet Gynecol 127: 572–580. PMID 190887.

[Singer-16] Natasha Singer and Duff Wilson (12 December 2009). "Menopause, as Brought to You by Big Pharma". New York Times.

[Brunner-17] Brunner RL et al; Womens Health Initiative Investigators (26 September 2005). "Effects of conjugated equine estrogen on health-related quality of life in postmenopausal women with hysterectomy: results from the Women's Health Initiative randomized clinical trial". Archives of Internal Medicine 165 (17): 1976–1986. doi:10.1001/archinte.165.17.1976. PMID 16186467.

[18] "Earnings Results for the 2006 Fourth Quarter and Full Year" (PDF) (Press release). Wyeth.

[19] "Pfizer Statement on Prempro". Indy News Channel. ^{[dead link]}

[Bloomberg_2010-20] Jef Feeley (February 24, 2010). "Pfizer wins trial over claim Prempro caused cancer". Bloomberg.

[21] "Pfizer properly warned about Prempro risks, jury finds". 3 December 2010.

[22] "Legal Intelligencer: Philadelphia jury returns defense verdict in HRT case, Amaris Elliott Engel".

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