| 词条 | Toremifene |
| 释义 |
| verifiedrevid = 470611877 | IUPAC_name = 2-[4-[(1Z)-4-chloro-1,2-diphenyl-but-1-en-1-yl]phenoxy]-N,N-dimethylethanamine | image = Toremifene.svg | width = 250px | pronounce = {{IPAc-en|ˈ|t|ɔːr|ə|m|ɪ|f|iː|n}} | tradename = Fareston, others | Drugs.com = {{drugs.com|monograph|fareston}} | MedlinePlus = a608003 | pregnancy_AU = | pregnancy_US = | pregnancy_category = | licence_EU = yes | legal_AU = | legal_UK = | legal_US = | legal_status = | routes_of_administration = By mouth | class = Selective estrogen receptor modulator | bioavailability = Good[1] | protein_bound = >99%[1] | metabolism = Liver (CYP3A4)[3][1] | metabolites = N-Desmethyltoremifene; 4-Hydroxytoremifene; Ospemifene[5][6] | elimination_half-life = Toremifene: 5–6 days[5][1] Metabolites: 4–21 days[1][6] | excretion = Feces: 70% (as metabolites)[1] | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 89778-26-7 | CAS_supplemental = 89778-27-8 (citrate) | ATC_prefix = L02 | ATC_suffix = BA02 | ATC_supplemental = | PubChem = 3005573 | IUPHAR_ligand = 4325 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00539 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 2275722 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 7NFE54O27T | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D08620 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 9635 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 1655 | PDB_ligand = T0R | synonyms = (Z)-Toremifene; 4-Chlorotamoxifen; Acapodene; CCRIS-8745; FC-1157; FC-1157a; GTx-006; NK-622; NSC-613680 | C=26 | H=28 | Cl=1 | N=1 | O=1 | molecular_weight = 405.959 g/mol | SMILES = ClCCC(/c1ccccc1)=C(/c2ccc(OCCN(C)C)cc2)c3ccccc3 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C26H28ClNO/c1-28(2)19-20-29-24-15-13-23(14-16-24)26(22-11-7-4-8-12-22)25(17-18-27)21-9-5-3-6-10-21/h3-16H,17-20H2,1-2H3/b26-25- | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = XFCLJVABOIYOMF-QPLCGJKRSA-N }}Toremifene, sold under the brand name Fareston among others, is a medication which is used in the treatment of advanced breast cancer in postmenopausal women.[2][3][4] It is taken by mouth.[2]Side effects of toremifene include hot flashes, sweating, nausea, vomiting, dizziness, vaginal discharge, and vaginal bleeding.[3][17] It can also cause blood clots, irregular heartbeat, cataracts, visual disturbances, elevated liver enzymes, endometrial hyperplasia, and endometrial cancer.[3] High blood calcium levels can occur in women with bone metastases.[3] The drug is a selective estrogen receptor modulator (SERM) and hence is a mixed agonist–antagonist of the estrogen receptor (ER), the biological target of estrogens like estradiol.[3][17] It has estrogenic effects in bone, the liver, and the uterus and antiestrogenic effects in the breasts.[3][23][24][3] It is a triphenylethylene derivative and is closely related to tamoxifen.[26] Toremifene was introduced for medical use in 1997.[27][28] It was the first antiestrogen to be introduced since tamoxifen in 1978.[29] It is not available as a generic medication in the United States.[5] Medical usesToremifene is approved for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor-positive or unknown-status tumors.[2][3] This is its only approved use in the United States.[6] It shows equivalent effectiveness to tamoxifen for this indication.[3] Toremifene has been found to be effective in the treatment of breast pain and may be a better drug than tamoxifen for this indication.[6] Toremifene has been reported to significantly improve symptoms of gynecomastia in men.[7] Side effectsThe side effects of toremifene are similar to those of tamoxifen.[3] The most common side effect is hot flashes.[3] Other side effects include sweating, nausea, vomiting, dizziness, vaginal discharge, and vaginal bleeding.[3][8] In women with bone metastases, hypercalcemia may occur.[3] Toremifene has a small risk of thromboembolic events.[3] Cataracts, vision changes, and elevation of liver enzymes have been reported.[3][8] The drug prolongs the QT interval and hence has a risk of potentially fatal dysrhythmias.[3] The risk of dysrhythmias can be reduced by avoiding use in patients with hypokalemia, hypomagnesemia, pre-existing QT prolongation, and in those taking other QT-prolonging drugs.[3] Because toremifene has estrogenic actions in the uterus, it can increase the risk of endometrial hyperplasia and endometrial cancer.[3] InteractionsToremifene is a substrate of CYP3A4, a cytochrome P450 enzyme, and hence drugs that induce or inhibit this enzyme can respectively decrease or increase levels of toremifene in the body.[3] PharmacologyPharmacodynamicsToremifene is a competitive ligand of the estrogen receptor and has mixed agonistic and antagonistic actions in a tissue-selective manner.[3][8] It has estrogenic activity in bone, partial estrogenic activity in the uterus and liver, and pure antiestrogenic activity in the breasts.[3][9][10][11] The drug is very similar to tamoxifen and shares most of its properties.[3][9][10][11] There are some indications that it may be safer than tamoxifen as it is not a hepatocarcinogen in animals and may have less potential for genotoxicity.[3][4] However, clinical studies have found no significant differences between toremifene and tamoxifen, including in terms of effectiveness, tolerability, and safety, and hence the clinical use of toremifene has been somewhat limited.[3][4] Toremifene has been found to have antigonadotropic effects in postmenopausal women,[12] progonadotropic effects in men,[13] to increase sex hormone-binding globulin levels,[12] and to decrease insulin-like growth factor 1 levels by about 20% in postmenopausal women and men.[14] Toremifene has about one-third of the potency of tamoxifen; i.e., 60 mg toremifene is roughly equivalent to 20 mg tamoxifen in the treatment of breast cancer.[15] {{Tissue-specific estrogenic and antiestrogenic activity of SERMs}}PharmacokineticsThe bioavailability of toremifene has not been precisely determined but is known to be good.[1] The drug is more than 99% bound to plasma proteins.[1] It is metabolized in the liver primarily by CYP3A4 and then undergoes secondary hydroxylation.[1] The metabolites of toremifene include N-desmethyltoremifene and 4-hydroxytoremifene and are less active than toremifene itself.[1][16] Ospemifene (deaminohydroxytoremifene) is also a major metabolite of toremifene.[17] Toremifene and 4-hydroxytoremifene have a very long elimination half-life of 5 to 6 days, while N-desmethyltoremifene has an even longer elimination half-life of 6 to 21 days and ospemifene has an elimination half-life of 4 days.[1][17] The long elimination half-lives of toremifene and its metabolites can be attributed to enterohepatic recirculation.[11] Toremifene is eliminated 70% in the feces, as metabolites.[1] Unlike tamoxifen, toremifene is not a prodrug and does not depend on metabolism by CYP2D6 for bioactivation; hence, it may be preferable to tamoxifen in CYP2D6 poor metabolizers or in patients who are taking a drug that inhibits CYP2D6.[18] Chemistry{{See also|List of selective estrogen receptor modulators|Triphenylethylene}}Toremifene, also known as 4-chlorotamoxifen, is a derivative of triphenylethylene and a close analogue of tamoxifen.[19] It is also closely related to afimoxifene (4-hydroxytamoxifen) and ospemifene (deaminohydroxytoremifene).[18][20] HistoryToremifene was introduced in the United States in 1997.[21][22] It was the first antiestrogen to be introduced in this country since tamoxifen in 1978.[23] Society and cultureGeneric namesToremifene is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}} and {{abbrlink|BAN|British Approved Name}}, while toremifene citrate is its {{abbrlink|USAN|United States Adopted Name}} and {{abbrlink|JAN|Japanese Accepted Name}} and torémifène is its {{abbrlink|DCF|Dénomination Commune Française}}.[24][25][26][27]Brand namesToremifene is marketed almost exclusively under the brand name Fareston.[25][27] AvailabilityToremifene is marketed widely throughout the world and is available in the United States, the United Kingdom, Ireland, many other European countries, South Africa, Australia, New Zealand, and elsewhere throughout the world.[25][27] Research{{Update section|date=April 2017|reason=}}Toremifene was also evaluated for prevention of prostate cancer and had the tentative brand name Acapodene.[28] In 2007 the pharmaceutical company GTx, Inc was conducting two different phase 3 clinical trials; First, a pivotal Phase clinical trial for the treatment of serious side effects of androgen deprivation therapy (ADT) (especially vertebral/spine fractures and hot flashes, lipid profile, and gynecomastia) for advanced prostate cancer, and second, a pivotal Phase III clinical trial for the prevention of prostate cancer in high risk men with high grade prostatic intraepithelial neoplasia, or PIN. Results of these trials are expected by first quarter of 2008[29] An NDA for the first application (relief of prostate cancer ADT side effects) was submitted in Feb 2009,[30] and in Oct 2009 the FDA said they would need more clinical data, e.g. another phase III trial.[31] Ultimately, development was discontinued and toremifene was never marketed for complications associated with ADT or the treatment or prevention of prostate cancer.[32] References1. ^1 2 3 4 5 6 7 8 9 10 11 {{cite book|author1=Vincent T. DeVita Jr.|author2=Theodore S. Lawrence|author3=Steven A. Rosenberg|title=DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology|url=https://books.google.com/books?id=HEAYBgAAQBAJ&pg=PT1126|date=7 January 2015|publisher=Wolters Kluwer Health|isbn=978-1-4698-9455-3|pages=1126–}} 2. ^1 2 https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020497s006lbl.pdf 3. ^1 2 3 4 5 6 7 {{cite book|author1=William R. Miller|author2=James N. Ingle|title=Endocrine Therapy in Breast Cancer|url=https://books.google.com/books?id=00_LBQAAQBAJ&pg=PA55|date=8 March 2002|publisher=CRC Press|isbn=978-0-203-90983-6|pages=55–57}} 4. ^1 2 3 4 {{cite book|author1=Bruce A. Chabner|author2=Dan L. Longo|title=Cancer Chemotherapy and Biotherapy: Principles and Practice|url=https://books.google.com/books?id=0U4aj4GZWCIC&pg=PA659|date=7 December 2011|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-4820-6|pages=659–}} 5. ^{{Cite news|url=https://www.drugs.com/availability/generic-fareston.html|title=Generic Fareston Availability - Drugs.com|work=Drugs.com|access-date=2018-02-08|language=en-US}} 6. ^{{cite book|author1=Kirby I. Bland|author2=Edward M. Copeland|author3=V. Suzanne Klimberg|author4=William J Gradishar|title=The Breast E-Book: Comprehensive Management of Benign and Malignant Diseases|url=https://books.google.com/books?id=hJwqDwAAQBAJ&pg=PA86|date=29 June 2017|publisher=Elsevier Health Sciences|isbn=978-0-323-51187-2|pages=86–}} 7. ^{{cite journal|last1=Tabbal|first1=Mahmoud|last2=Fuleihan|first2=Ghada El-Hajj|title=Future Therapies|year=2010|pages=713–732|doi=10.1016/B978-0-12-374602-3.00057-2}} 8. ^1 2 3 4 {{cite book|author1=David Schiff|author2=Isabel Arrillaga|author3=Patrick Y. 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Scott McMeekin, David G Mutch|title=Clinical Gynecologic Oncology E-Book|url=https://books.google.com/books?id=MkoQDgAAQBAJ&pg=PA124|date=4 February 2017|publisher=Elsevier Health Sciences|isbn=978-0-323-44316-6|pages=124–}} 24. ^{{cite book|author=J. Elks|title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA1222|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=1222–}} 25. ^1 2 {{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA1048|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=1048–}} 26. ^{{cite book|author1=I.K. Morton|author2=Judith M. 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Clin Prostate Cancer 2005;3:211-4. {{PMID|15882476}} 29. ^{{cite press release| title = GTx's Phase III Clinical Development of ACAPODENE on Course Following Planned Safety Review | publisher = GTx Inc. | date = 2007-07-12| url = http://phx.corporate-ir.net/phoenix.zhtml?c=148196&p=irol-newsArticle&ID=1025420&highlight= | accessdate = 2006-07-14 }} 30. ^{{cite press release| title = GTx Announces Toremifene 80 mg NDA Accepted for Review by FDA | url = http://phx.corporate-ir.net/phoenix.zhtml?c=148196&p=irol-newsArticle&ID=1257471&highlight= }} 31. ^{{cite web |url=http://www.genengnews.com/gen-news-highlights/gtx-and-ipsen-end-prostate-cancer-collaboration-due-to-costs-of-fda-requested-phase-iii-study/81244761/ |title=GTx and Ipsen End Prostate Cancer Collaboration due to Costs of FDA-Requested Phase III Study |date=2 Mar 2011 }} 32. ^{{Cite web|url=http://adisinsight.springer.com/drugs/800004087|title=Toremifene - AdisInsight|website=adisinsight.springer.com|language=en|access-date=2018-02-08}} Further reading
External links
9 : Amines|Hepatotoxins|Hormonal antineoplastic drugs|Organochlorides|Phenol ethers|Progonadotropins|Selective estrogen receptor modulators|Triphenylethylenes|World Anti-Doping Agency prohibited substances |
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