関: letrozole

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/11/05 01:02:47」(JST)

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Letrozole (INN, trade name Femara) is an oral non-steroidal aromatase inhibitor for the treatment of hormonally-responsive breast cancer after surgery.

Uses

FDA-approved use

Femara 2.5 mg oral tablet

Letrozole is approved by the United States Food and Drug Administration (FDA) for the treatment of local or metastatic breast cancer that is hormone receptor positive or has an unknown receptor status in postmenopausal women.^[2]

Off-label uses

Letrozole has been used for ovarian stimulation by fertility doctors since 2001 because it has fewer side-effects than clomiphene (Clomid) and less chance of multiple gestation. A Canadian study presented at the American Society of Reproductive Medicine 2005 Conference suggested that letrozole may increase the risk of birth defects.^{[citation needed]} A more detailed ovulation induction follow-up study found that letrozole, compared with a control group of clomiphene, had significantly lower congenital malformations and chromosomal abnormalities at an overall rate of 2.4% (1.2% major malformations) compared with clomiphene 4.8% (3.0% major malformations).^[3] Despite this, India banned the usage of letrozole in 2011, citing potential risks to infants.^[4] In 2012, an Indian parliamentary committee said that the drug controller office colluded with letrozole's makers to approve the drug for infertility in India and also stated that letrozole's use for infertility was illegal worldwide;^[5] however, such off-label uses are legal in many countries such as the US and UK.^[6]^[7]

The anti-estrogen action of letrozole has been shown to be useful in pretreatment for termination of pregnancy, in combination with misoprostol. It can be used in place of mifepristone, which is expensive and unavailable in many countries.^[8]

Letrozole is sometimes used as a treatment for gynecomastia, although it is probably most effective at this if caught in an early stage (such as in users of anabolic steroids).^[9]^[10]^{[unreliable source?]}

Some studies have shown that letrozole can be used to promote spermatogenesis in male patients suffering from nonobstructive azoospermia.^[11]

Letrozole has also been shown to delay the fusing of the growth plates in mice.^[12] When used in combination with growth hormone, letrozole has been shown effective in one adolescent boy with a short stature.^[13]

Letrozole has also been used to treat endometriosis.^[14]

Mechanism of action

Estrogens are produced by the conversion of androgens through the activity of the aromatase enzyme. Estrogens then bind to an estrogen receptor, which causes cells to divide.

Letrozole prevents the aromatase from producing estrogens by competitive, reversible binding to the heme of its cytochrome P450 unit. The action is specific, and letrozole does not reduce production of mineralo- or corticosteroids.

Contraindications

Letrozole is contraindicated in women having a pre-menopausal hormonal status, during pregnancy and lactation.^[15]

Adverse effects

The most common side effects are sweating, hot flashes, arthralgia (joint pain), and fatigue.^[15]

Generally, side effects include signs and symptoms of hypoestrogenism. There is concern that long term use may lead to osteoporosis,^[2] which is in certain patient populations such as post-menopausal women or osteoporotics, bisphosphonates may also be prescribed.^{[citation needed]}

Interactions

Letrozole inhibits the liver enzyme CYP2A6, and to a lesser extent CYP2C19, in vitro, but no relevant interactions with drugs like cimetidine and warfarin have been observed.^[15]

Comparison with tamoxifen

Tamoxifen is also used to treat hormonally-responsive breast cancer, but it does so by interfering with the estrogen receptor. However, letrozole is effective only in post-menopausal women, in whom estrogen is produced predominantly in peripheral tissues (i.e. in adipose tissue, like that of the breast) and a number of sites in the brain.^[16] In pre-menopausal women, the main source of estrogen is from the ovaries not the peripheral tissues, and letrozole is ineffective.

In the BIG 1–98 Study, of post-menopausal women with hormonally-responsive breast cancer, letrozole reduced the recurrence of cancer, but did not change survival rate, compared to tamoxifen.^[17]^[18]

Synthesis

Letrozole can by synthesized from 4-cyanobenzyl bromide, triazole, and 4-fluorobenzonitrile:^[19]

Letrolzole synthesis

See also: (according to art of drug synthesis book)

Bhatnagar, A. S. (1990). J. Steroid Biochem. Mol. Biol., 37: 1021–1027.
Bowman, R. M., Steele, R. E., and Browne, L. J. (1990). US 497872 (to Ciba-Gigy).
Demers, L. M. (1994). J. Steroid Biochem. Mol. Biol., 44: 520.
Haynes, B. P., Dowsett, M., Miller, W. R., Dixon, J. M., and Bhatnagar, A. S. (2003). J. Steroid Biochem. Mol. Biol., 87: 35–45.
Lamb, H. M. and Adkins, J. C. (1998). Drugs, 56: 1125–1140.
Prous, J., Graul, A., and Castan˜er, J. (1994). Drugs Fut., 19: 335–337.
Sioufi, A., Gauducheau, N., Pineau, V., Marfil, F., Jaouen, A., Cardot, J. M., Godbillon, J., Czendlik, C., Howald, H., Pfister, Ch., and Vreeland, F. (1997). Biopharm. Drug Dispos., 18: 779–789.

References

^ ^a ^b ^c 003330 Letrozole
^ ^a ^b Drugs.com: monograph for letrozole. It is also used for ovarian cancer patients after they have completed chemotherapy.
^ Tulandi T, Martin J, Al-Fadhli R, et al. (June 2006). "Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate". Fertility and Sterility 85 (6): 1761–5. doi:10.1016/j.fertnstert.2006.03.014. PMID 16650422.
^ Sinha, Kounteya (18 October 2011). "Finally, expert panel bans fertility drug Letrozole". The Times of India. Retrieved 14 November 2011.
^ "House panel to govt: Punish those guilty of approving Letrozole". The Times of India. 10 April 2007. Retrieved 9 May 2012.
^ Chen DT, Wynia MK, Moloney RM, Alexander GC (2009). "Physician knowledge of the FDA-approved indications of commonly prescribed drugs: results of a national survey". Pharmacoepidemiology and Drug Safety 18 (11): 1–7. doi:10.1002/pds.1825. PMID 19697444.
^ "GMC | Good practice in prescribing medicines – guidance for doctors". Gmc-uk.org. 16 February 2007. Retrieved 21 November 2011.
^ Vivian Chi Yan Lee, Ernest Hung Yu Ng, William Shu Biu Yeung, Pak Chung Ho (2011). "Misoprostol With or Without Letrozole Pretreatment for Termination of Pregnancy". Ob Gyn. 117 (2, Part 1): 317–323. doi:10.1097/AOG.0b013e3182073fbf.
^ Santen, R. J.; Brodie, H.; Simpson, E. R.; Siiteri, P. K.; Brodie, A. (2009). "History of Aromatase: Saga of an Important Biological Mediator and Therapeutic Target". Endocrine Reviews 30 (4): 343–375. doi:10.1210/er.2008-0016. PMID 19389994. edit
^ "Gynecomastia and Letrozole". GYNECOMASTIA-GYNO.COM: ...a resource for gynecomastia sufferers... 16 December 2008. Archived from the original on 26 June 2010. Retrieved 26 April 2012.
^ Geneviève Patry, Keith Jarvi, Ethan D. Grober, Kirk C. Lo (August 2009). "Use of the aromatase inhibitor letrozole to treat male infertility". Fertility and Sterility 92 (2): 829.e1–829.e2. doi:10.1016/j.fertnstert.2009.05.014.
^ R Eshet, G Maor, T Ben Ari, M Ben Eliezer, G Gat-Yablonski, M Phillip (2004). "The aromatase inhibitor letrozole increases epiphyseal growth plate height and tibial length in peripubertal male mice". Journal of Endocrinology 182 (1): 165–172. doi:10.1677/joe.0.1820165. PMID 15225141.
^ Ping Zhou MD, Bina Shah MD, Kris Prasad PhD, Raphael David MD (2005). "Letrozole Significantly Improves Growth Potential in a Pubertal Boy With Growth Hormone Deficiency". Journal of the American Academy of Pediatrics 115 (2): 245–248. doi:10.1542/peds.2004-1536. PMID 15653791.
^ Endometriosis ESHRE abstract
^ ^a ^b ^c Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X.
^ Simpson ER (2003). "Sources of estrogen and their importance". The Journal of Steroid Biochemistry and Molecular Biology 86 (3–5): 225–30. doi:10.1016/S0960-0760(03)00360-1. PMID 14623515.
^ Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer, the BIG 1–98 Collaborative Group, N Engl J Med, 361:766, 2009 Aug 20
^ 32nd Annual San Antonio Breast Cancer Symposium
^ Lang, M; Batzl, C; Furet, P; Bowman, R; Hausler, A; Bhatnagar, A (1993). "Structure-activity relationships and binding model of novel aromatase inhibitors". The Journal of Steroid Biochemistry and Molecular Biology 44 (4–6): 421–8. doi:10.1016/0960-0760(93)90245-R. PMID 8476755.

External links

Femara website

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. レトロゾールによる排卵誘発 ovulation induction with letrozole
2. HER2陰性ホルモン受容体陽性転移性乳癌への治療法：内分泌療法および分子標的薬 treatment approach to metastatic hormone receptor positive her2 negative breast cancer endocrine therapy and targeted agents
3. 排卵誘発の概要 overview of ovulation induction
4. 非転移性ホルモン受容体陽性乳癌に対する補助内分泌療法 adjuvant endocrine therapy for non metastatic hormone receptor positive breast cancer
5. アロマターゼ阻害剤による骨量減少の評価およびマネージメント evaluation and management of aromatase inhibitor induced bone loss

English Journal

Development and validation of a rapid LC-MS/MS method to quantify letrozole in human plasma and its application to therapeutic drug monitoring.

Shao R1, Yu LY1, Lou HG1, Ruan ZR1, Jiang B1, Chen JL1.
Biomedical chromatography : BMC.Biomed Chromatogr.2016 Apr;30(4):632-7. doi: 10.1002/bmc.3607. Epub 2015 Oct 20.
A selective, rapid, and sensitive liquid chromatography-tandem mass spectrometry(LC-MS/MS) method was developed and validated for the determination of letrozole (LTZ) in human plasma, using anastrozole as internal standard (IS). Sample preparation was performed by one-step protein precipitation with
PMID 26317321

Phase I Study of Panobinostat (LBH589) and Letrozole in Postmenopausal Metastatic Breast Cancer Patients.

Tan WW1, Allred JB2, Moreno-Aspitia A3, Northfelt DW4, Ingle JN5, Goetz MP5, Perez EA3.
Clinical breast cancer.Clin Breast Cancer.2016 Apr;16(2):82-6. doi: 10.1016/j.clbc.2015.11.003. Epub 2015 Nov 17.
INTRODUCTION: Histone deacetylase inhibitors have been found to restore sensitivity to the estrogen receptor in endocrine-resistant and triple-negative breast cancer cell lines. We decided to test panobinostat, a pan-histone deacetylase inhibitor, because of preclinical data, combined with letrozole
PMID 26774555

Identifying treatment effect heterogeneity in clinical trials using subpopulations of events: STEPP.

Lazar AA1, Bonetti M2, Cole BF3, Yip WK4, Gelber RD4.
Clinical trials (London, England).Clin Trials.2016 Apr;13(2):169-79. doi: 10.1177/1740774515609106. Epub 2015 Oct 22.
BACKGROUND: Investigators conducting randomized clinical trials often explore treatment effect heterogeneity to assess whether treatment efficacy varies according to patient characteristics. Identifying heterogeneity is central to making informed personalized healthcare decisions. Treatment effect h
PMID 26493094

Japanese Journal

フェマーラ(新薬のプロフィル)

木村淳子
ファルマシア 42(7), 738-739, 2006-07-01
NAID 110006264407

Influence of letrozole (Femara) and anastrozole (Arimidex) on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over-designed study

GEISLER J
J Clin Oncol. 20, 751-757, 2002
NAID 30022788235

Related Pictures

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★リンクテーブル★

リンク元

「レトロゾール」

Letrozole
Systematic (IUPAC) name
	4,4'-((1H-1,2,4-triazol-1-yl)methylene)dibenzonitrile
Clinical data
Trade names	Femara
AHFS/Drugs.com	monograph
MedlinePlus	a698004
Licence data	US FDA:link
Pregnancy cat.	US: D;
Legal status	CA: Schedule VII; UK: POM; US: ℞-only;
Routes	Oral
Pharmacokinetic data
Bioavailability	99.9%
Protein binding	60%, mainly to albumin
Metabolism	pharmacologically-inactive carbinol metabolite (4,4΄-methanol-bisbenzonitrile)
Half-life	2 days
Excretion	Kidneys
Identifiers
CAS number	112809-51-5
ATC code	L02BG04
PubChem	CID 3902
DrugBank	DB01006
ChemSpider	3765
UNII	7LKK855W8I
KEGG	D00964
ChEBI	CHEBI:6413
ChEMBL	CHEMBL1444
Chemical data
Formula	C17H11N5
Mol. mass	285.303 g/mol
	SMILES N#Cc1ccc(cc1)C(c2ccc(C#N)cc2)n3ncnc3;
	InChI InChI=1S/C17H11N5/c18-9-13-1-5-15(6-2-13)17(22-12-20-11-21-22)16-7-3-14(10-19)4-8-16/h1-8,11-12,17H ; Key:HPJKCIUCZWXJDR-UHFFFAOYSA-N ;
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英: letrozole
関: フェマーラ Femara

[Letrozole-1] 003330 Letrozole

[FDA-2] Drugs.com: monograph for letrozole. It is also used for ovarian cancer patients after they have completed chemotherapy.

[3] Tulandi T, Martin J, Al-Fadhli R, et al. (June 2006). "Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate". Fertility and Sterility 85 (6): 1761–5. doi:10.1016/j.fertnstert.2006.03.014. PMID 16650422.

[4] Sinha, Kounteya (18 October 2011). "Finally, expert panel bans fertility drug Letrozole". The Times of India. Retrieved 14 November 2011.

[5] "House panel to govt: Punish those guilty of approving Letrozole". The Times of India. 10 April 2007. Retrieved 9 May 2012.

[6] Chen DT, Wynia MK, Moloney RM, Alexander GC (2009). "Physician knowledge of the FDA-approved indications of commonly prescribed drugs: results of a national survey". Pharmacoepidemiology and Drug Safety 18 (11): 1–7. doi:10.1002/pds.1825. PMID 19697444.

[7] "GMC | Good practice in prescribing medicines – guidance for doctors". Gmc-uk.org. 16 February 2007. Retrieved 21 November 2011.

[8] Vivian Chi Yan Lee, Ernest Hung Yu Ng, William Shu Biu Yeung, Pak Chung Ho (2011). "Misoprostol With or Without Letrozole Pretreatment for Termination of Pregnancy". Ob Gyn. 117 (2, Part 1): 317–323. doi:10.1097/AOG.0b013e3182073fbf.

[9] Santen, R. J.; Brodie, H.; Simpson, E. R.; Siiteri, P. K.; Brodie, A. (2009). "History of Aromatase: Saga of an Important Biological Mediator and Therapeutic Target". Endocrine Reviews 30 (4): 343–375. doi:10.1210/er.2008-0016. PMID 19389994. edit

[10] "Gynecomastia and Letrozole". GYNECOMASTIA-GYNO.COM: ...a resource for gynecomastia sufferers... 16 December 2008. Archived from the original on 26 June 2010. Retrieved 26 April 2012.

[11] Geneviève Patry, Keith Jarvi, Ethan D. Grober, Kirk C. Lo (August 2009). "Use of the aromatase inhibitor letrozole to treat male infertility". Fertility and Sterility 92 (2): 829.e1–829.e2. doi:10.1016/j.fertnstert.2009.05.014.

[12] R Eshet, G Maor, T Ben Ari, M Ben Eliezer, G Gat-Yablonski, M Phillip (2004). "The aromatase inhibitor letrozole increases epiphyseal growth plate height and tibial length in peripubertal male mice". Journal of Endocrinology 182 (1): 165–172. doi:10.1677/joe.0.1820165. PMID 15225141.

[13] Ping Zhou MD, Bina Shah MD, Kris Prasad PhD, Raphael David MD (2005). "Letrozole Significantly Improves Growth Potential in a Pubertal Boy With Growth Hormone Deficiency". Journal of the American Academy of Pediatrics 115 (2): 245–248. doi:10.1542/peds.2004-1536. PMID 15653791.

[14] Endometriosis ESHRE abstract

[AustriaCodex-15] Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X.

[16] Simpson ER (2003). "Sources of estrogen and their importance". The Journal of Steroid Biochemistry and Molecular Biology 86 (3–5): 225–30. doi:10.1016/S0960-0760(03)00360-1. PMID 14623515.

[17] Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer, the BIG 1–98 Collaborative Group, N Engl J Med, 361:766, 2009 Aug 20

[18] 32nd Annual San Antonio Breast Cancer Symposium

[19] Lang, M; Batzl, C; Furet, P; Bowman, R; Hausler, A; Bhatnagar, A (1993). "Structure-activity relationships and binding model of novel aromatase inhibitors". The Journal of Steroid Biochemistry and Molecular Biology 44 (4–6): 421–8. doi:10.1016/0960-0760(93)90245-R. PMID 8476755.

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Femara