fbpx
Wikipedia

Tamoxifen

February 15, 2024

Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men.[13] It is also being studied for other types of cancer.[13] It has been used for Albright syndrome.[14] Tamoxifen is typically taken daily by mouth for five years for breast cancer.[14]

Tamoxifen
Clinical data
Trade namesNolvadex, Genox, Tamifen, others[1]
Other namesTMX; ICI-46474
AHFS/Drugs.comMonograph
MedlinePlusa682414
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classSelective estrogen receptor modulator
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability~100%[5][6]
Protein binding>99% (albumin)[5][7]
MetabolismLiver (CYP3A4, CYP2C9, CYP2D6)[5][12][8]
Metabolites• N-Desmethyltamoxifen[8][9]
• Endoxifen (4-hydroxy-N-desmethyltamoxifen)[8][9]
• Afimoxifene (4-hydroxytamoxifen)[8][9]
• N,N-Didesmethyltamoxifen[8]
• Norendoxifen (4-hydroxy-N,N-didesmethyltamoxifen)[8]
• Others, conjugates[8][10][11]
Elimination half-life5–7 days[5][8]
ExcretionFeces: 65%
Urine: 9%
Identifiers
  • (Z)-2-[4-(1,2-Diphenylbut-1-enyl)phenoxy]-N,N-dimethylethanamine
CAS Number
  • 10540-29-1 Y
  • citrate: 54965-24-1
PubChem CID
  • 2733526
  • citrate: 2733525
IUPHAR/BPS
  • 1016
DrugBank
  • DB00675 Y
  • citrate: DBSALT000168
ChemSpider
  • 2015313 Y
  • citrate: 2015312
UNII
  • 094ZI81Y45
  • citrate: 7FRV7310N6
KEGG
  • D08559 Y
  • citrate: D00966
ChEBI
  • CHEBI:41774 Y
  • citrate: CHEBI:9397
ChEMBL
  • ChEMBL83 Y
  • citrate: ChEMBL786
PDB ligand
  • CTX (PDBe, RCSB PDB)
CompTox Dashboard (EPA)
  • DTXSID1034187
ECHA InfoCard100.031.004
Chemical and physical data
FormulaC26H29NO
Molar mass371.524 g·mol−1
3D model (JSmol)
  • Interactive image
  • CN(C)CCOc1ccc(cc1)/C(c2ccccc2)=C(/CC)c3ccccc3
  • InChI=1S/C26H29NO/c1-4-25(21-11-7-5-8-12-21)26(22-13-9-6-10-14-22)23-15-17-24(18-16-23)28-20-19-27(2)3/h5-18H,4,19-20H2,1-3H3/b26-25- Y
  • Key:NKANXQFJJICGDU-QPLCGJKRSA-N Y
  (verify)

Serious side effects include a small increased risk of uterine cancer, stroke, vision problems, and pulmonary embolism.[14] Common side effects include irregular periods, weight loss, and hot flashes.[14] It may cause harm to the baby if taken during pregnancy or breastfeeding.[14] It is a selective estrogen-receptor modulator (SERM) and works by decreasing the growth of breast cancer cells.[14][15] It is a member of the triphenylethylene group of compounds.[16]

Tamoxifen was initially made in 1962, by chemist Dora Richardson.[17][18] It is on the World Health Organization's List of Essential Medicines.[19] Tamoxifen is available as a generic medication.[14] In 2020, it was the 317th most commonly prescribed medication in the United States, with more than 900 thousand prescriptions.[20][21]

Medical uses edit

Dysmenorrhea edit

Tamoxifen has been used effectively to improve blood flow, reduce uterine contractility and pain in dysmenorrhea patients.[22]

Breast cancer edit

Tamoxifen is used for the treatment of both early and advanced estrogen receptor-positive (ER-positive or ER+) breast cancer in pre- and postmenopausal women.[23] Tamoxifen increases the risk of postmenopausal bleeding, endometrial polyps, hyperplasia, and endometrial cancer; using tamoxifen with an intrauterine system releasing levonorgestrel might increase vaginal bleeding after 1 to 2 years, but reduces somewhat endometrial polyps and hyperplasia, but not necessarily endometrial cancer.[24] Additionally, it is the most common hormone treatment for male breast cancer.[25] It is also approved by the FDA for the prevention of breast cancer in women at high risk of developing the disease.[26] It has been further approved for the reduction of contralateral (in the opposite breast) cancer. The use of tamoxifen is recommended for 10 years.[27]

In 2006, the large STAR clinical study concluded that raloxifene is also effective in reducing the incidence of breast cancer. Updated results after an average of 6.75 years of follow up found that raloxifene retains 76% of tamoxifen's effectiveness in preventing invasive breast cancer, with 45% fewer uterine cancers and 25% fewer blood clots in women taking raloxifene than in women taking tamoxifen.[28][29][30]

Infertility edit

Tamoxifen is used for ovulation induction to treat infertility in women with anovulatory disorders. It is given at days three to seven of a woman's cycle.[31]

Tamoxifen improves fertility in males with infertility by disinhibiting the hypothalamic–pituitary–gonadal axis (HPG axis) via ER antagonism and thereby increasing the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and increasing testicular testosterone production.[32]

Gynecomastia edit

Tamoxifen is used to prevent and treat gynecomastia.[33][34] It is taken as a preventative measure in small doses, or used at the onset of any symptoms such as nipple soreness or sensitivity. Other medications are taken for similar purposes such as clomifene and the anti-aromatase drugs which are used in order to try to avoid the hormone-related adverse effects.

Tamoxifen doses and rates of bicalutamide-induced breast symptoms in men
Follow-up
timepoint		 Tamoxifen dosage
Placebo 1 mg/day 2.5 mg/day 5 mg/day 10 mg/day 20 mg/day
0 months
–
6 months 98% 90% 80% 54% 22% 10%
12 months 99% 95% 84% 56% 38% 19%
Notes: Prevention of breast symptoms—specifically gynecomastia and breast pain—induced by 150 mg/day bicalutamide monotherapy with tamoxifen in 282 men with prostate cancer. Bicalutamide and tamoxifen were initiated at the same time (0 months). Estradiol levels were in the range of about 22 to 47 pg/mL in the treated group.[35] Sources: [36][35]

Early puberty edit

Tamoxifen is useful in the treatment of peripheral precocious puberty, for instance due to McCune–Albright syndrome, in both girls and boys.[37][38][39] It has been found to decrease growth velocity and the rate of bone maturation in girls with precocious puberty, and hence to improve final height in these individuals.[37][38]

Available forms edit

 
Nolvadex (tamoxifen) 20 mg tablets.

Tamoxifen is available as a tablet or oral solution.[40][41]

Contraindications edit

Tamoxifen has a number of contraindications, including known hypersensitivity to tamoxifen or other ingredients, individuals taking concomitant coumarin-type anticoagulant therapy, and women with a history of venous thromboembolism (deep vein thrombosis or pulmonary embolism).[12]

Side effects edit

A report in September 2009 from Health and Human Services' Agency for Healthcare Research and Quality suggests that tamoxifen, raloxifene, and tibolone used to treat breast cancer significantly reduce invasive breast cancer in midlife and older women, but also increase the risk of adverse side effects.[42]

Endometrial cancer edit

Tamoxifen is a selective estrogen receptor modulator (SERM).[43] Even though it is an antagonist in breast tissue it acts as partial agonist on the endometrium and has been linked to endometrial cancer in some women. Therefore, endometrial changes, including cancer, are among tamoxifen's side effects.[44] With time, risk of endometrial cancer may be doubled to quadrupled, which is a reason tamoxifen is typically only used for five years.[45]

The American Cancer Society lists tamoxifen as a known carcinogen, stating that it increases the risk of some types of uterine cancer while lowering the risk of breast cancer recurrence.[46]

Cardiovascular and metabolic edit

Tamoxifen treatment of postmenopausal women is associated with beneficial effects on serum lipid profiles. However, long-term data from clinical trials have failed to demonstrate a cardioprotective effect.[47] For some women, tamoxifen can cause a rapid increase in triglyceride concentration in the blood. In addition, there is an increased risk of thromboembolism especially during and immediately after major surgery or periods of immobility.[48] Use of tamoxifen has been shown to slightly increase risk of deep vein thrombosis, pulmonary embolism, and stroke.[49]

Liver toxicity edit

Tamoxifen has been associated with a number of cases of hepatotoxicity.[50] Several different varieties of hepatotoxicity have been reported.[50] Tamoxifen can also precipitate non-alcoholic fatty liver disease in obese and overweight women (not in normal weight women) at an average rate of 40% after a year use with 20 mg/day.[51]

Overdose edit

Acute overdose of tamoxifen has not been reported in humans.[12] In dose-ranging studies, tamoxifen was administered at very high doses in women (e.g., 300 mg/m2) and was found to produce acute neurotoxicity including tremor, hyperreflexia, unsteady gait, and dizziness.[12] These symptoms occurred within three to five days of therapy and disappeared within two to five days of discontinuation of therapy.[12] No indications of permanent neurotoxicity were observed.[12] QT prolongation was also observed with very high doses of tamoxifen.[12] There is no specific antidote for overdose of tamoxifen.[12] Instead, treatment should be based on symptoms.[12]

Interactions edit

Patients with variant forms of the gene CYP2D6 may not receive full benefit from tamoxifen because of too slow metabolism of the tamoxifen prodrug into its active metabolites.[52][53] On 18 October 2006, the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifen to include information about this gene in the package insert.[54] Certain CYP2D6 variations in breast cancer patients lead to a worse clinical outcome for tamoxifen treatment.[55] Genotyping therefore has the potential for identification of women who have these CYP2D6 phenotypes and for whom the use of tamoxifen is associated with poor outcomes. Recent research has shown that 7–10% of women with breast cancer may not receive the full medical benefit from taking tamoxifen due to their genetic make-up. DNA Drug Safety Testing can examine DNA variations in the CYP2D6 and other important drug processing pathways. More than 20% of all clinically used medications are metabolized by CYP2D6 and knowing the CYP2D6 status of a person can help the doctor with the future selection of medications.[56] Other molecular biomarkers may also be used to select appropriate patients likely to benefit from tamoxifen.[57]

Recent studies suggest that taking the selective serotonin reuptake inhibitors (SSRIs) antidepressants paroxetine (Paxil), fluoxetine (Prozac), and sertraline (Zoloft) can decrease the effectiveness of tamoxifen, as these drugs compete for the CYP2D6 enzyme which is needed to metabolize tamoxifen into its active forms.[58] A U.S. study presented at the American Society of Clinical Oncology's annual meeting in 2009 found that after two years, 7.5% of women who took only tamoxifen had a recurrence, compared with 16% who took either paroxetine, fluoxetine or sertraline, drugs considered to be the most potent CYP2D6 inhibitors. That difference translates to a 120% increase in the risk of breast cancer recurrence. Patients taking the SSRIs Celexa (citalopram), Lexapro (escitalopram), and Luvox (fluvoxamine) did not have an increased risk of recurrence, due to their lack of competitive metabolism for the CYP2D6 enzyme.[59] A newer study demonstrated a clearer and stronger effect from paroxetine in causing the worst outcomes. Patients treated with both paroxetine and tamoxifen have a 67% increased risk of death from breast cancer, from 24% to 91%, depending on the duration of coadministration.[60]

Tamoxifen interacts with certain other antiestrogens.[5] The aromatase inhibitor aminoglutethimide induces the metabolism of tamoxifen.[5] Conversely, the aromatase inhibitor letrozole does not affect the metabolism of tamoxifen.[5] However, tamoxifen induces the metabolism of letrozole and significantly reduces its concentrations.[5]

Pharmacology edit

Pharmacodynamics edit

Selective estrogen receptor modulator activity edit

 
Crystallographic structure of afimoxifene (carbon = white, oxygen = red, nitrogen = blue) complexed with ligand binding domain of estrogen receptor alpha (ERα) (cyan ribbon).[61]

Tamoxifen acts as a selective estrogen receptor modulator (SERM), or as a partial agonist of the estrogen receptors (ERs). It has mixed estrogenic and antiestrogenic activity, with its profile of effects differing by tissue. For instance, tamoxifen has predominantly antiestrogenic effects in the breasts but predominantly estrogenic effects in the uterus and liver. In breast tissue, tamoxifen acts as an ER antagonist so that transcription of estrogen-responsive genes is inhibited.[62] A beneficial side effect of tamoxifen is that it prevents bone loss by acting as an ER agonist (i.e., mimicking the effects of estrogen) in this cell type. Therefore, by inhibiting osteoclasts, it prevents osteoporosis.[63][64] When tamoxifen was launched as a drug, it was thought that tamoxifen would act as an ER antagonist in all tissues, including bone, and therefore it was feared that it would contribute to osteoporosis. It was therefore very surprising that the opposite effect was observed clinically. Hence tamoxifen's tissue selective action directly led to the formulation of the concept of SERMs.[65]

Tissue-specific estrogenic and antiestrogenic activity of SERMs
Medication Breast Bone Liver Uterus Vagina Brain
Lipids Coagulation SHBGTooltip Sex hormone-binding globulin IGF-1Tooltip Insulin-like growth factor 1 Hot flashes Gonadotropins
Estradiol + + + + + + + + + +
"Ideal SERM" – + + ± ± ± – + + ±
Bazedoxifene – + + + + ? – ± – ?
Clomifene – + + ? + + – ? – ±
Lasofoxifene – + + + ? ? ± ± – ?
Ospemifene – + + + + + ± ± – ±
Raloxifene – + + + + + ± – – ±
Tamoxifen – + + + + + + – – ±
Toremifene – + + + + + + – – ±
Effect: + = Estrogenic / agonistic. ± = Mixed or neutral. – = Antiestrogenic / antagonistic. Note: SERMs generally increase gonadotropin levels in hypogonadal and eugonadal men as well as premenopausal women (antiestrogenic) but decrease gonadotropin levels in postmenopausal women (estrogenic). Sources: See template.

Tamoxifen is a long-acting SERM, with a nuclear retention of the ER–tamoxifen (or metabolite) complex of greater than 48 hours.[66][67] It has relatively little affinity for the ERs itself and instead acts as a prodrug of active metabolites such as endoxifen (4-hydroxy-N-desmethyltamoxifen) and afimoxifene (4-hydroxytamoxifen; 4-OHT).[9] These metabolites have approximately 30 to 100 times greater affinity for the ERs than tamoxifen itself.[8][68] Per one study, tamoxifen had 7% and 6% of the affinity of estradiol for the ERα and ERβ, respectively, whereas afimoxifene had 178% and 338% of the affinity of estradiol for the ERα and ERβ, respectively.[69] Hence, afimoxifene showed 25-fold higher affinity for the ERα and 56-fold higher affinity for the ERβ than tamoxifen.[70] The antiestrogenic potencies of endoxifen and afimoxifene are very similar.[9] However, endoxifen occurs in much higher concentrations than afimoxifene and is now thought to be the major active form of tamoxifen in the body.[8][9][71]

Tamoxifen binds to ER competitively (with respect to the endogenous agonist estrogen) in tumor cells and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. It is a nonsteroidal agent with potent antiestrogenic properties which compete with estrogen for binding sites in breast and other tissues. Tamoxifen causes cells to remain in the G0 and G1 phases of the cell cycle. Because it prevents (pre)cancerous cells from dividing but does not cause cell death, tamoxifen is cytostatic rather than cytocidal. Tamoxifen binds to ER, the ER/tamoxifen complex recruits other proteins known as co-repressors, and the complex then binds to DNA to modulate gene expression. Some of these proteins include NCoR and SMRT.[72] Tamoxifen function can be regulated by a number of different variables including growth factors.[73] Tamoxifen needs to block growth factor proteins such as ErbB2/HER2[74] because high levels of ErbB2 have been shown to occur in tamoxifen resistant cancers.[75] Tamoxifen seems to require a protein PAX2 for its full anticancer effect.[74][76] In the presence of high PAX2 expression, the tamoxifen/ER complex is able to suppress the expression of the pro-proliferative ERBB2 protein. In contrast, when AIB-1 expression is higher than PAX2, tamoxifen/ER complex upregulates the expression of ERBB2 resulting in stimulation of breast cancer growth.[74][77]

Tamoxifen is antigonadotropic in postmenopausal women and partially suppresses levels of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in such women.[78] However, it has progonadotropic effects in premenopausal women and increases estrogen levels by 6-fold in them.[78] Due to the nature of tamoxifen as a competitive ER ligand, this increase in estrogen levels is liable to interfere with the antiestrogenic efficacy of tamoxifen.[78] The effects of tamoxifen on breast cancer Ki-67 expression, sex hormone-binding globulin (SHBG) levels, and IGF-1 levels are dose-dependent across a dosage range of 1 to 20 mg/day in women with breast cancer.[79] Tamoxifen has been found to decrease insulin-like growth factor 1 (IGF-1) levels by 17 to 38% in women and men.[80] Suppression of IGF-1 production in the liver is a well-known action of estrogens and SERMs.[80] A 10 mg/day dosage of tamoxifen is nearly as effective as a 20 mg/day dosage in suppressing IGF-1 levels.[5]

Other activities edit

Afimoxifene is an agonist of the G protein-coupled estrogen receptor (GPER) with relatively low affinity.[81] Its affinity for the receptor is in the range of 100 to 1,000 nM, relative to 3 to 6 nM for estradiol.[81]

In addition to its activity as a SERM, afimoxifene binds to both the estrogen-related receptor β and estrogen-related receptor γ and is an antagonist of the estrogen-related receptor γ (ERRγ).[82]

Norendoxifen (4-hydroxy-N,N-didesmethyltamoxifen), another active metabolite of tamoxifen, has been found to act as a potent competitive aromatase inhibitor (IC50 = 90 nM), and may also be involved in the antiestrogenic activity of tamoxifen.[83]

In addition to its activity as a SERM, tamoxifen is a potent and selective protein kinase C inhibitor, and is active in this regard at therapeutic concentrations.[84] This action is thought to underlie the efficacy of tamoxifen in the treatment of bipolar disorder.[84]

Tamoxifen is an inhibitor of P-glycoprotein.[12]

Pharmacokinetics edit

Absorption edit

Tamoxifen is rapidly and extensively absorbed from the intestines with oral administration.[5][6] The oral bioavailability of tamoxifen is approximately 100%, which is suggestive of minimal first-pass metabolism in the intestines and liver.[5] Following intake, peak levels of tamoxifen occur after three to seven hours.[85][5] Steady state levels of tamoxifen are reached typically after 3 to 4 weeks but possibly up to 16 weeks of daily administration.[5][11] Steady state levels of afimoxifene are achieved after 8 weeks of daily tamoxifen administration.[11][7] Peak levels of tamoxifen after a single 40 mg oral dose were 65 ng/mL and steady state levels at 20 mg/day were 310 ng/mL.[5] Levels of tamoxifen show clear dose dependency across a dosage range of 1 to 20 mg/day.[5][86] Endoxifen levels are approximately 5 to 10 times higher than afimoxifene levels, with large interindividual variability.[8][9] Endoxifen levels have been reported as 10.8 to 15.9 ng/mL at steady state in CYP2D6 normal metabolizers during therapy with 20 mg/day tamoxifen.[8] The most abundant metabolites of tamoxifen in terms of circulating concentrations are N-desmethyltamoxifen, N,N-didesmethyltamoxifen, (Z)-endoxifen, and tamoxifen N-oxide.[10][87]

Distribution edit

The volume of distribution of tamoxifen is 50 to 60 L/kg and its clearance has been estimated as 1.2 to 5.1 L/hour.[5][85] High concentrations of tamoxifen have been found in breast, uterus, liver, kidney, lung, pancreas, and ovary tissue in animals and humans.[5] Levels of tamoxifen in the uterus have been found to be 2- to 3-fold higher than in the circulation[5] and in the breasts 10-fold higher than in the circulation.[86] The plasma protein binding of tamoxifen and afimoxifene is greater than 99%.[7] A majority of tamoxifen is bound to albumin.[5] Albumin alone binds 98.8% of tamoxifen while other plasma proteins are not greatly involved.[88]

Metabolism edit

Tamoxifen and its metabolites in humans[89]
Compound Mean plasma
concentrations 		Effect on ER / affinity for ERa
Tamoxifen 190–420 nmol/L Weak antagonist / 2%
N-Desmethyltamoxifen 280–800 nmol/L Weak antagonist / 1%
N,N-Desmethyltamoxifen 90–120 nmol/L Weak antagonist
Endoxifen 14–130 nmol/L Strong antagonist / equal to afimoxifene
Afimoxifene 3–17 nmol/Lb Strong antagonist / 188%
α-Hydroxytamoxifen 1 nmol/L None
3,4-Dihydroxytamoxifen ? Weak antagonist / high affinity
Tamoxifen N-oxide 15–24 nmol/L Weak antagonistc
Footnotes: a = Estradiol is 100%. b = One study reported a much higher concentration (67 nmol/L). c = Might be due to reduction to tamoxifen.

Tamoxifen is a prodrug and is metabolized in the liver by the cytochrome P450 isoforms CYP3A4, CYP2C9, and CYP2D6 into active metabolites such as endoxifen (4-hydroxy-N-desmethyltamoxifen) and afimoxifene (4-hydroxytamoxifen).[5][12][8] Conversion of tamoxifen by N-demethylation into N-desmethyltamoxifen, which is catalyzed primarily by CYP3A4 and CYP3A5, is responsible for approximately 92% of tamoxifen metabolism.[9] Conversely, 4-hydroxylation of tamoxifen into afimoxifene is responsible for only about 7% of tamoxifen metabolism.[9] Following its formation, N-desmethyltamoxifen is oxidized into several other metabolites, the most notable of which is endoxifen.[9] Another active metabolite, norendoxifen (4-hydroxy-N,N-didesmethyltamoxifen), is formed via N-demethylation of endoxifen or 4-hydroxylation of N,N-didesmethyltamoxifen.[8] Tamoxifen and its metabolites undergo conjugation, including glucuronidation and sulfation.[11] Tamoxifen may inhibit its own metabolism.[5]

Elimination edit

Tamoxifen has a long elimination half-life of typically 5 to 7 days, with a range of 4 to 11 days.[5][8][85] Similarly, the half-life of afimoxifene is 14 days.[7] Conversely, the half-life of endoxifen is 50 to 70 hours (2–3 days).[8] The long half-lives of tamoxifen and afimoxifene are attributed to their high plasma protein binding as well as to enterohepatic recirculation.[7] Upon discontinuation of treatment, levels of tamoxifen and its metabolites persist in the circulation for at least 6 weeks.[7] Tamoxifen is excreted in bile and is eliminated in feces, while small amounts are eliminated in urine.[5]

Chemistry edit

Tamoxifen is a nonsteroidal SERM of the triphenylethylene family and was structurally derived from diethylstilbestrol-like estrogens and antiestrogens such as chlorotrianisene and ethamoxytriphetol.[90][91][92][93] Initially, clomifene was synthesized, and tamoxifen was developed subsequently.[90][92][93] Tamoxifen is closely related structurally to other triphenylethylenes, such as clomifene, nafoxidine, ospemifene, toremifene, and numerous others.[94][95] Other SERMs, like raloxifene, are structurally distinct from tamoxifen and other triphenylethylenes.[95]

History edit

In the late 1950s, pharmaceutical companies were actively researching a newly discovered class of anti-estrogen compounds in the hope of developing a morning-after contraceptive pill. Arthur L Walpole was a reproductive endocrinologist who led such a team at the Alderley Park research laboratories of ICI Pharmaceuticals.[18] It was there in 1962 that chemist Dora Richardson first synthesized tamoxifen, back then known as ICI-46,474, when she was looking to create triphenylethylene derivatives for the contraceptive pill project that her team was researching.[96]

This compound was originally created to work as an estrogen inhibitor, but instead was found to stimulate ovulation in participants of the drug testing trial.[17] Walpole and his colleagues filed a UK patent covering this compound in 1962, but patent protection on this compound was repeatedly denied in the US until the 1980s.[97] Tamoxifen did eventually receive marketing approval as a fertility treatment, but the class of compounds never proved useful in human contraception. A link between estrogen and breast cancer had been known for many years, but cancer treatments were not a corporate priority at the time, and Walpole's personal interests were important in keeping support for the compound alive in the face of this and the lack of patent protection.[18] It was only when Walpole threatened to leave his position that corporate decided to allow trials and testing for tamoxifen as a drug that could be used to treat breast cancer. Without Walpole's effort towards defending the work that his team had done in discovering a possibly revolutionary source for breast cancer treatment, tamoxifen could have become a discarded or under-researched idea. Walpole's team consisted of Dora Richardson and G. A. Snow, who worked on the chemistry portion of the project, along with G. E. Paget and J. K. Walley, who focused primarily on the biological side.[17]

Tamoxifen is one of three drugs in an anti-angiogenetic protocol developed by Dr. Judah Folkman, a researcher at Children's Hospital at Harvard Medical School in Boston. Folkman discovered in the 1970s that angiogenesis – the growth of new blood vessels – plays a significant role in the development of cancer. Since his discovery, an entirely new field of cancer research has developed. Clinical trials on angiogenesis inhibitors have been underway since 1992 using many different drugs. The Harvard researchers developed a specific protocol for a golden retriever named Navy who was cancer-free after receiving the prescribed cocktail of celecoxib, doxycycline, and tamoxifen – the treatment subsequently became known as the Navy Protocol.[98] Furthermore, tamoxifen treatment alone has been shown to have anti-angiogenetic effects in animal models of cancer which appear to be, at least in part, independent of tamoxifen's ER antagonist properties.[99]

Other antiestrogens, such as ethamoxytriphetol (MER-25) and clomifene (MRL-41), were assessed for treatment of breast cancer and found to be effective before tamoxifen, but were plagued with toxicity issues.[100][101] The first clinical study of tamoxifen took place at the Christie Hospital in 1971, and showed a convincing effect in advanced breast cancer, but nevertheless ICI's development programme came close to termination when it was reviewed in 1972.[102] In an unpublished article from the early days of the trial, Dora Richardson documented her team's excitement about tamoxifen's effects in counteracting infertility problems and the early positive effects found in breast cancer patients. Unfortunately, this work was not well received by everyone, as the team was supposed to be looking for a contraceptive pill.[17] Tamoxifen's further development may have been bolstered by a second clinical study by Harold W.C. Ward [103] at the Queen Elizabeth Hospital, Birmingham. Ward's study showed a more definitive response to the drug at a higher dosage. Walpole also may have helped to convince the company to market tamoxifen for late stage breast cancer in 1973.[97] He was also instrumental in funding V. Craig Jordan to work on tamoxifen. In 1972, ICI Pharmaceuticals Division abandoned development of tamoxifen for financial reasons. The drug was subsequently reinvented from a failed contraceptive, to become tamoxifen, the gold standard for the adjuvant treatment of breast cancer and the pioneering medicine for chemprevention for high-risk women.[104][105] Two books, Estrogen Action, Selective Estrogen Receptor Modulators and Women's Health (Imperial College Press 2013) and Tamoxifen: Pioneering Medicine in Breast Cancer (Springer 2013) tell this story.

Comparison of early clinical experience with antiestrogens for advanced breast cancer
Antiestrogen Dosage Year(s) Response rate Adverse effects
Ethamoxytriphetol 500–4,500 mg/day 1960 25% Acute psychotic episodes
Clomifene 100–300 mg/day 1964–1974 34% Risks of cataracts
Nafoxidine 180–240 mg/day 1976 31% Cataracts, ichthyosis, photophobia
Tamoxifen 20–40 mg/day 1971–1973 31% Transient thrombocytopeniaa
Footnotes: a = "The particular advantage of this drug is the low incidence of troublesome side effects (25)." "Side effects were usually trivial (26)." Sources: [100][106]

1980 saw the publication of the first trial to show that tamoxifen given in addition to chemotherapy improved survival for patients with early breast cancer.[107] In advanced disease, tamoxifen is now only recognized as effective in ER+ patients, but the early trials did not select ER+ patients, and by the mid-1980s the clinical trial picture was not showing a major advantage for tamoxifen.[108] Nevertheless, tamoxifen had a relatively mild side-effect profile, and a number of large trials continued.

The pharmacology of SERMs was discovered, defined, and deciphered during the 1980s.[109] A clinical strategy was described[110] that led to the creation of SERMs as a group of multifunctional medicines aimed at the treatment or prevention of many conditions in postmenopausal women, e.g. osteoporosis and breast cancer. This story is told in: V. Craig Jordan, ed. 2013. "Estrogen Action, Selective Estrogen Receptor Modulators and Women's Health" Imperial College Press, Singapore.

The early sales of tamoxifen in both the UK and in the U.S. far exceeded ICI's original estimate, but despite this, at the annual portfolio review ICI's board members still asserted that "there was no market for cancer", leaving the drug's marketing success to rely on its clinical results and clinicians' and scientists' interests in it. Shortly after, Dora Richardson published a history of tamoxifen that, unusually for that type of paper, included personal accounts and letters from patients who attributed their healing to the drug. It is by giving voice to cancer patients using tamoxifen, and so helping to push it forward, by justifying it both morally and scientifically to corporations.[17]

It was not until 1998 that the meta-analysis of the Oxford-based Early Breast Cancer Trialists' Collaborative Group showed definitively that tamoxifen was effective for early breast cancer.[111]

Society and culture edit

Brand names edit

Tamoxifen is marketed under the brand names Nolvadex and Soltamox, and a variety of other brand names throughout the world.[1][112]

Economics edit

Global sales of tamoxifen in 2001 were approximately $1.02 billion.[113] Since the expiration of the patent in 2002, it is widely available as a generic drug around the world. As of 2004, tamoxifen was the world's largest selling hormonal drug for the treatment of breast cancer.[114]

Research edit

In McCune-Albright syndrome (MAS) tamoxifen has been used to treat premature puberty and the consequences of premature puberty. Tamoxifen has been seen to decrease rapid bone maturation which is the result of excessive estrogen and alter predicted adult height (PAH).[115][116] The same effects have also been seen in short pubertal boys.[117] However, one in vitro study in 2007 and later an in vivo study in 2008 have shown that tamoxifen induces apoptosis in growth plate chondrocytes, reduces serum insulin-like growth factor 1 (IGF-1) levels and causes persistent retardation of longitudinal and cortical radial bone growth in young male rats, leading the researchers to express concern giving tamoxifen to growing individuals.[118][119]

Tamoxifen has been studied in the treatment of the rare conditions of retroperitoneal fibrosis[120] and idiopathic sclerosing mesenteritis.[121] It has also been proposed as part of a treatment plan for Riedel's thyroiditis.[122]

Tamoxifen is used as a research tool to trigger tissue-specific gene expression in many conditional expression constructs in genetically modified animals including a version of the Cre-Lox recombination technique.[123] While widely used in transgenic research, the strong anabolic effect of tamoxifen on bone might confound this approach, especially as it relates to bone-targeted constructs.

Tamoxifen may be effective in the treatment of mania in people with bipolar disorder.[124] This is thought to be due to blockade of protein kinase C (PKC), an enzyme that regulates neuron activity in the brain.[124][125] Researchers believe PKC is overactive during the mania in bipolar patients.[124][125] As of September 2019, endoxifen, a major active metabolite of tamoxifen with a 4-fold more potent PKC inhibition, was in phase III clinical trials for bipolar disorder.[126][127]

References edit

  1. ^ a b "NCI Drug Dictionary". 2 February 2011. from the original on 8 December 2015. Retrieved 12 September 2021.
  2. ^ "Tamoxifen Use During Pregnancy". Drugs.com. 25 July 2019. Retrieved 27 January 2020.
  3. ^ "Tamoxifen citrate tablet, film coated". DailyMed. Retrieved 12 September 2021.
  4. ^ "Soltamox- tamoxifen citrate liquid". DailyMed. Retrieved 12 September 2021.
  5. ^ a b c d e f g h i j k l m n o p q r s t u v w Morello KC, Wurz GT, DeGregorio MW (2003). "Pharmacokinetics of selective estrogen receptor modulators". Clinical Pharmacokinetics. 42 (4): 361–372. doi:10.2165/00003088-200342040-00004. PMID 12648026. S2CID 13003168.
  6. ^ a b Brenner GM, Stevens C (28 September 2017). Brenner and Stevens' Pharmacology E-Book. Elsevier Health Sciences. pp. 394–. ISBN 978-0-323-39172-6.
  7. ^ a b c d e f Chabner BA, Longo DL (7 December 2011). Cancer Chemotherapy and Biotherapy: Principles and Practice. Lippincott Williams & Wilkins. pp. 655–. ISBN 978-1-4511-4820-6.
  8. ^ a b c d e f g h i j k l m n o p Sanchez-Spitman AB, Swen JJ, Dezentje VO, Moes DJ, Gelderblom H, Guchelaar HJ (June 2019). "Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen". Expert Review of Clinical Pharmacology. 12 (6): 523–536. doi:10.1080/17512433.2019.1610390. PMID 31008668.
  9. ^ a b c d e f g h i j Klein DJ, Thorn CF, Desta Z, Flockhart DA, Altman RB, Klein TE (November 2013). "PharmGKB summary: tamoxifen pathway, pharmacokinetics". Pharmacogenetics and Genomics. 23 (11): 643–647. doi:10.1097/FPC.0b013e3283656bc1. PMC 4084801. PMID 23962908.
  10. ^ a b Mürdter TE, Schroth W, Bacchus-Gerybadze L, Winter S, Heinkele G, Simon W, et al. (May 2011). "Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma". Clinical Pharmacology and Therapeutics. 89 (5): 708–717. doi:10.1038/clpt.2011.27. PMID 21451508. S2CID 20082053.
  11. ^ a b c d Nagar S (2010). "Pharmacokinetics of Anti-Cancer Drugs Used in Breast Cancer Chemotherapy". Chemo Fog. Advances in Experimental Medicine and Biology. Vol. 678. pp. 124–132. doi:10.1007/978-1-4419-6306-2_16. ISBN 978-1-4419-6305-5. PMID 20738014. S2CID 12537667.
  12. ^ a b c d e f g h i j k "Nolvadex (Tamoxifen Citrate) tablets". DailyMed. 3 November 2016. Retrieved 12 September 2021.
  13. ^ a b "Tamoxifen Citrate". NCI. 26 August 2015. from the original on 4 January 2016. Retrieved 28 November 2015.
  14. ^ a b c d e f g "Tamoxifen Citrate". The American Society of Health-System Pharmacists. from the original on 4 January 2014. Retrieved 27 November 2015.
  15. ^ "Selective estrogen receptor modulators". from the original on 9 December 2013. Retrieved 28 November 2015.
  16. ^ Cano A, Calaf i Alsina J, Duenas-Diez JL, eds. (2006). Selective Estrogen Receptor Modulators a New Brand of Multitarget Drugs. Berlin, Heidelberg: Springer-Verlag Berlin Heidelberg. p. 52. ISBN 9783540347422.
  17. ^ a b c d e Quirke VM (12 September 2017). "Tamoxifen from Failed Contraceptive Pill to Best-Selling Breast Cancer Medicine: A Case-Study in Pharmaceutical Innovation". Frontiers in Pharmacology. 8: 620. doi:10.3389/fphar.2017.00620. PMC 5600945. PMID 28955226.
  18. ^ a b c Jordan VC (January 2006). "Tamoxifen (ICI46,474) as a targeted therapy to treat and prevent breast cancer". British Journal of Pharmacology. 147 (Suppl 1): S269–S276. doi:10.1038/sj.bjp.0706399. PMC 1760730. PMID 16402113.
  19. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  20. ^ "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  21. ^ . ClinCalc. Archived from the original on 22 September 2020. Retrieved 7 October 2022.
  22. ^ Thomas B, Magos A (2009). "Modern management of dysmenorrhoea". Trends in Urology, Gynaecology & Sexual Health. 14 (5): 25–29. doi:10.1002/tre.120.
  23. ^ Jordan VC (October 1993). "Fourteenth Gaddum Memorial Lecture. A current view of tamoxifen for the treatment and prevention of breast cancer". British Journal of Pharmacology. 110 (2): 507–517. doi:10.1111/j.1476-5381.1993.tb13840.x. PMC 2175926. PMID 8242225.
  24. ^ Romero SA, Young K, Hickey M, Su HI (December 2020). "Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen". The Cochrane Database of Systematic Reviews. 12 (2): CD007245. doi:10.1002/14651858.CD007245.pub4. PMC 8092675. PMID 33348436.
  25. ^ . CancerHelp UK. Cancer Research UK. 28 September 2007. Archived from the original on 1 December 2008. Retrieved 22 March 2009.
  26. ^ Center for Drug Evaluation and Research (7 July 2005). . U.S. Food and Drug Administration. Archived from the original on 19 June 2007. Retrieved 3 July 2007.
  27. ^ Burstein HJ, Temin S, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, et al. (July 2014). "Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update". Journal of Clinical Oncology. 32 (21): 2255–2269. doi:10.1200/JCO.2013.54.2258. PMC 4876310. PMID 24868023.
  28. ^ National Cancer Institute (26 April 2006). . U.S. National Institutes of Health. Archived from the original on 4 July 2007. Retrieved 3 July 2007.
  29. ^ University of Pittsburgh. . Archived from the original on 11 June 2007. Retrieved 3 July 2007.
  30. ^ Love S (22 April 2006). . Archived from the original on 2 August 2009. Retrieved 19 March 2009.
  31. ^ Steiner AZ, Terplan M, Paulson RJ (June 2005). "Comparison of tamoxifen and clomiphene citrate for ovulation induction: a meta-analysis". Human Reproduction. 20 (6): 1511–1515. doi:10.1093/humrep/deh840. PMID 15845599.
  32. ^ Chua ME, Escusa KG, Luna S, Tapia LC, Dofitas B, Morales M (September 2013). "Revisiting oestrogen antagonists (clomiphene or tamoxifen) as medical empiric therapy for idiopathic male infertility: a meta-analysis". Andrology. 1 (5): 749–757. doi:10.1111/j.2047-2927.2013.00107.x. PMID 23970453. S2CID 38345293.
  33. ^ Lapid O, van Wingerden JJ, Perlemuter L (2013). "Tamoxifen therapy for the management of pubertal gynecomastia: a systematic review". Journal of Pediatric Endocrinology & Metabolism. 26 (9–10): 803–807. doi:10.1515/jpem-2013-0052. PMID 23729603. S2CID 2101602.
  34. ^ Viani GA, Bernardes da Silva LG, Stefano EJ (July 2012). "Prevention of gynecomastia and breast pain caused by androgen deprivation therapy in prostate cancer: tamoxifen or radiotherapy?". International Journal of Radiation Oncology, Biology, Physics. 83 (4): e519–e524. doi:10.1016/j.ijrobp.2012.01.036. PMID 22704706.
  35. ^ a b Fradet Y, Egerdie B, Andersen M, Tammela TL, Nachabe M, Armstrong J, Morris T, Navani S (July 2007). "Tamoxifen as prophylaxis for prevention of gynaecomastia and breast pain associated with bicalutamide 150 mg monotherapy in patients with prostate cancer: a randomised, placebo-controlled, dose-response study". Eur. Urol. 52 (1): 106–14. doi:10.1016/j.eururo.2007.01.031. PMID 17270340.
  36. ^ Fentiman IS (January 2018). "Managing Male Mammary Maladies". Eur J Breast Health. 14 (1): 5–9. doi:10.5152/ejbh.2017.3841. PMC 5758064. PMID 29322112.
  37. ^ a b Neyman A, Eugster EA (December 2017). "Treatment of Girls and Boys with McCune-Albright Syndrome with Precocious Puberty - Update 2017". Pediatric Endocrinology Reviews. 15 (2): 136–141. doi:10.17458/per.vol15.2017.nau.treatmentgirlsboys. PMC 5808444. PMID 29292624.
  38. ^ a b Haddad NG, Eugster EA (June 2019). "Peripheral precocious puberty including congenital adrenal hyperplasia: causes, consequences, management and outcomes". Best Practice & Research. Clinical Endocrinology & Metabolism. 33 (3): 101273. doi:10.1016/j.beem.2019.04.007. hdl:1805/19111. PMID 31027974. S2CID 135410503.
  39. ^ Zacharin M (May 2019). "Disorders of Puberty: Pharmacotherapeutic Strategies for Management". Pediatric Pharmacotherapy. Handbook of Experimental Pharmacology. Vol. 261. pp. 507–538. doi:10.1007/164_2019_208. ISBN 978-3-030-50493-9. PMID 31144045. S2CID 169040406.
  40. ^ Product Information: tamoxifen citrate oral tablets, tamoxifen citrate oral tablets. Watson Laboratories (per manufacturer), Corona, CA, 2011.
  41. ^ Product Information: SOLTAMOX(R) oral solution, tamoxifen citrate oral solution. Midatech Pharma US Inc (per FDA), Raleigh, NC, 2018.
  42. ^ OncoGenetics.Org (September 2009). . OncoGenetics.Org. Archived from the original on 24 September 2009. Retrieved 14 September 2009.
  43. ^ Gallo MA, Kaufman D (February 1997). "Antagonistic and agonistic effects of tamoxifen: significance in human cancer". Seminars in Oncology. 24 (1 Suppl 1): S1-71-S1-80. PMID 9045319.
  44. ^ Grilli S (2006). (PDF). Annali dell'Istituto Superiore di Sanità. 42 (2): 170–173. PMID 17033137. Archived from the original (PDF) on 10 August 2007. Retrieved 3 July 2007.
  45. ^ "Tamoxifen for Breast Cancer & Side Effects". Health and Life. 11 December 2009. from the original on 16 February 2010.
  46. ^ "Known and Probable Carcinogens". American Cancer Society. 3 February 2006. from the original on 17 March 2008. Retrieved 21 March 2008.
  47. ^ Esteva FJ, Hortobagyi GN (June 2006). "Comparative assessment of lipid effects of endocrine therapy for breast cancer: implications for cardiovascular disease prevention in postmenopausal women". Breast. 15 (3): 301–312. doi:10.1016/j.breast.2005.08.033. PMID 16230014.
  48. ^ Decensi A, Maisonneuve P, Rotmensz N, Bettega D, Costa A, Sacchini V, et al. (February 2005). "Effect of tamoxifen on venous thromboembolic events in a breast cancer prevention trial". Circulation. 111 (5): 650–656. doi:10.1161/01.CIR.0000154545.84124.AC. PMID 15699284.
  49. ^ Harvey HA, Kimura M, Hajba A (April 2006). "Toremifene: an evaluation of its safety profile". Breast. 15 (2): 142–157. doi:10.1016/j.breast.2005.09.007. PMID 16289904.
  50. ^ a b Cameron R, Feuer G, de la Iglesia F (6 December 2012). Drug-Induced Hepatotoxicity. Springer Science & Business Media. pp. 565–. ISBN 978-3-642-61013-4.
  51. ^ Osman KA, Osman MM, Ahmed MH (January 2007). "Tamoxifen-induced non-alcoholic steatohepatitis: where are we now and where are we going?". Expert Opinion on Drug Safety. 6 (1): 1–4. doi:10.1517/14740338.6.1.1. PMID 17181445. S2CID 33505288.
  52. ^ Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, et al. (December 2005). "Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes". Journal of Clinical Oncology. 23 (36): 9312–9318. doi:10.1200/JCO.2005.03.3266. PMID 16361630.
  53. ^ Beverage JN, Sissung TM, Sion AM, Danesi R, Figg WD (September 2007). "CYP2D6 polymorphisms and the impact on tamoxifen therapy". Journal of Pharmaceutical Sciences. 96 (9): 2224–2231. doi:10.1002/jps.20892. PMID 17518364.
  54. ^ Information about CYP2D6 and tamoxifen from DNADirect's website 11 March 2007 at the Wayback Machine
  55. ^ Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S, et al. (October 2009). "Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen". JAMA. 302 (13): 1429–1436. doi:10.1001/jama.2009.1420. PMC 3909953. PMID 19809024.
  56. ^ Information about Tamoxitest and how DNA testing can help in the selection of the best treatment methodology from Genelex's website 27 May 2010 at the Wayback Machine
  57. ^ Criscitiello C, Fumagalli D, Saini KS, Loi S (December 2010). "Tamoxifen in early-stage estrogen receptor-positive breast cancer: overview of clinical use and molecular biomarkers for patient selection". OncoTargets and Therapy. 4: 1–11. doi:10.2147/OTT.S10155. PMC 3084302. PMID 21552410.
  58. ^ Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, et al. (January 2005). "CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment". Journal of the National Cancer Institute. 97 (1): 30–39. doi:10.1093/jnci/dji005. PMID 15632378.
  59. ^ Staff Reports (Summer 2009). "ASCO Updates: Antidepressants Reduce the Effectiveness of Tamoxifen". CURE (Cancer Updates, Research and Education). from the original on 22 June 2009.
  60. ^ Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, Pritchard KI, Austin PC, Paszat LF (February 2010). "Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study". BMJ. 340: c693. doi:10.1136/bmj.c693. PMC 2817754. PMID 20142325.
  61. ^ PDB: 3ERT​; Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL (December 1998). "The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen". Cell. 95 (7): 927–937. doi:10.1016/S0092-8674(00)81717-1. PMID 9875847. S2CID 10265320.
  62. ^ Wang DY, Fulthorpe R, Liss SN, Edwards EA (February 2004). "Identification of estrogen-responsive genes by complementary deoxyribonucleic acid microarray and characterization of a novel early estrogen-induced gene: EEIG1". Molecular Endocrinology. 18 (2): 402–411. doi:10.1210/me.2003-0202. PMID 14605097.
  63. ^ Nakamura T, Imai Y, Matsumoto T, Sato S, Takeuchi K, Igarashi K, et al. (September 2007). "Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts". Cell. 130 (5): 811–823. doi:10.1016/j.cell.2007.07.025. PMID 17803905. S2CID 17177462.
  64. ^ Krum SA, Miranda-Carboni GA, Hauschka PV, Carroll JS, Lane TF, Freedman LP, Brown M (February 2008). "Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival". The EMBO Journal. 27 (3): 535–545. doi:10.1038/sj.emboj.7601984. PMC 2241656. PMID 18219273.
  65. ^ Mincey BA, Moraghan TJ, Perez EA (August 2000). "Prevention and treatment of osteoporosis in women with breast cancer". Mayo Clinic Proceedings. 75 (8): 821–829. doi:10.4065/75.8.821. PMID 10943237.
  66. ^ Runnebaum B, Rabe T (17 April 2013). Gynäkologische Endokrinologie und Fortpflanzungsmedizin: Band 1: Gynäkologische Endokrinologie. Springer-Verlag. pp. 88–. ISBN 978-3-662-07635-4.
  67. ^ Hammond CB, Maxson WS (January 1982). "Current status of estrogen therapy for the menopause". Fertility and Sterility. 37 (1): 5–25. doi:10.1016/S0015-0282(16)45970-4. PMID 6277697.
  68. ^ Ahmad A, Shahabuddin S, Sheikh S, Kale P, Krishnappa M, Rane RC, Ahmad I (December 2010). "Endoxifen, a new cornerstone of breast cancer therapy: demonstration of safety, tolerability, and systemic bioavailability in healthy human subjects". Clinical Pharmacology and Therapeutics. 88 (6): 814–817. doi:10.1038/clpt.2010.196. PMID 20981001. S2CID 24590365.
  69. ^ Kuhl H (August 2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 (Suppl 1): 3–63. doi:10.1080/13697130500148875. PMID 16112947. S2CID 24616324.
  70. ^ Potts RO, Lobo RA (May 2005). "Transdermal drug delivery: clinical considerations for the obstetrician-gynecologist". Obstetrics and Gynecology. 105 (5 Pt 1): 953–961. doi:10.1097/01.AOG.0000161958.70059.db. PMID 15863530. S2CID 23411589.
  71. ^ Binkhorst L, Mathijssen RH, Jager A, van Gelder T (March 2015). "Individualization of tamoxifen therapy: much more than just CYP2D6 genotyping". Cancer Treatment Reviews. 41 (3): 289–299. doi:10.1016/j.ctrv.2015.01.002. PMID 25618289.
  72. ^ Shang Y, Hu X, DiRenzo J, Lazar MA, Brown M (December 2000). "Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription". Cell. 103 (6): 843–852. doi:10.1016/S0092-8674(00)00188-4. PMID 11136970. S2CID 6659079.
  73. ^ Massarweh S, Osborne CK, Creighton CJ, Qin L, Tsimelzon A, Huang S, et al. (February 2008). "Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function". Cancer Research. 68 (3): 826–833. doi:10.1158/0008-5472.CAN-07-2707. PMID 18245484.
  74. ^ a b c Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, et al. (December 2008). "Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen". Nature. 456 (7222): 663–666. Bibcode:2008Natur.456..663H. doi:10.1038/nature07483. PMC 2920208. PMID 19005469.
  75. ^ Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, Fuqua SA, et al. (March 2003). "Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer". Journal of the National Cancer Institute. 95 (5): 353–361. doi:10.1093/jnci/95.5.353. PMID 12618500.
  76. ^ "New Mechanism Predicts Tamoxifen Response: PAX2 gene implicated in tamoxifen-induced inhibition of ERBB2/HER2-mediated tumor growth". www.modernmedicine.com. 13 November 2008. from the original on 14 July 2011. Retrieved 14 November 2008.
  77. ^ "Study sheds new light on tamoxifen resistance". News. CORDIS News. from the original on 20 February 2009. Retrieved 14 November 2008.
  78. ^ a b c Li J, Ma Z, Jiang RW, Wu B (September 2013). "Hormone-related pharmacokinetic variations associated with anti-breast cancer drugs". Expert Opinion on Drug Metabolism & Toxicology. 9 (9): 1085–1095. doi:10.1517/17425255.2013.802771. PMID 23687971. S2CID 26846314.
  79. ^ Fabian CJ, Kimler BF (March 2005). "Selective estrogen-receptor modulators for primary prevention of breast cancer". Journal of Clinical Oncology. 23 (8): 1644–1655. doi:10.1200/JCO.2005.11.005. PMID 15755972.
  80. ^ a b Duarte FH, Jallad RS, Bronstein MD (November 2016). "Estrogens and selective estrogen receptor modulators in acromegaly". Endocrine. 54 (2): 306–314. doi:10.1007/s12020-016-1118-z. PMID 27704479. S2CID 10136018.
  81. ^ a b Prossnitz ER, Arterburn JB (July 2015). "International Union of Basic and Clinical Pharmacology. XCVII. G Protein-Coupled Estrogen Receptor and Its Pharmacologic Modulators". Pharmacological Reviews. 67 (3): 505–540. doi:10.1124/pr.114.009712. PMC 4485017. PMID 26023144.
  82. ^ Ariazi EA, Jordan VC (2006). "Estrogen-related receptors as emerging targets in cancer and metabolic disorders". Current Topics in Medicinal Chemistry. 6 (3): 203–215. doi:10.2174/1568026610606030203. PMID 16515477.
  83. ^ Liu J, Flockhart PJ, Lu D, Lv W, Lu WJ, Han X, et al. (September 2013). "Inhibition of cytochrome p450 enzymes by the e- and z-isomers of norendoxifen". Drug Metabolism and Disposition. 41 (9): 1715–1720. doi:10.1124/dmd.113.052506. PMC 3876808. PMID 23824607.
  84. ^ a b Zarate CA, Manji HK (2009). "Protein kinase C inhibitors: rationale for use and potential in the treatment of bipolar disorder". CNS Drugs. 23 (7): 569–582. doi:10.2165/00023210-200923070-00003. PMC 2802274. PMID 19552485.
  85. ^ a b c DeVita VT, Lawrence TS, Rosenberg SA (18 March 2016). Prostate and Other Genitourinary Cancers: From Cancer: Principles & Practice of Oncology, 10th edition. Wolters Kluwer Health. pp. 990–. ISBN 978-1-4963-5421-1.
  86. ^ a b Kisanga ER, Gjerde J, Guerrieri-Gonzaga A, Pigatto F, Pesci-Feltri A, Robertson C, et al. (April 2004). "Tamoxifen and metabolite concentrations in serum and breast cancer tissue during three dose regimens in a randomized preoperative trial". Clinical Cancer Research. 10 (7): 2336–2343. doi:10.1158/1078-0432.ccr-03-0538. PMID 15073109.
  87. ^ Jordan VC (1982). "Metabolites of tamoxifen in animals and man: identification, pharmacology, and significance". Breast Cancer Research and Treatment. 2 (2): 123–138. doi:10.1007/BF01806449. PMID 6184101. S2CID 25119313.
  88. ^ Lien EA, Solheim E, Lea OA, Lundgren S, Kvinnsland S, Ueland PM (April 1989). "Distribution of 4-hydroxy-N-desmethyltamoxifen and other tamoxifen metabolites in human biological fluids during tamoxifen treatment". Cancer Research. 49 (8): 2175–2183. PMID 2702659.
  89. ^ Brauch H, Mürdter TE, Eichelbaum M, Schwab M (October 2009). "Pharmacogenomics of tamoxifen therapy". Clinical Chemistry. 55 (10): 1770–1782. doi:10.1373/clinchem.2008.121756. PMID 19574470.
  90. ^ a b Jordan VC (1986). Estrogen/antiestrogen Action and Breast Cancer Therapy. Univ of Wisconsin Press. pp. 28, 154. ISBN 978-0-299-10480-1.
  91. ^ Pratt WB (1994). The Anticancer Drugs. Oxford University Press. pp. 21–. ISBN 978-0-19-506739-2.
  92. ^ a b Maximov PY, McDaniel RE, Jordan VC (23 July 2013). Tamoxifen: Pioneering Medicine in Breast Cancer. Springer Science & Business Media. pp. 7–. ISBN 978-3-0348-0664-0.
  93. ^ a b Ravina E (11 January 2011). The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. pp. 177–178. ISBN 978-3-527-32669-3.
  94. ^ Cano A, Calaf i Alsina J, Duenas-Diez JL (22 September 2006). Selective Estrogen Receptor Modulators: A New Brand of Multitarget Drugs. Springer Science & Business Media. pp. 52–. ISBN 978-3-540-34742-2.
  95. ^ a b Orwoll ES, Bilezikian JP, Vanderschueren D (30 November 2009). Osteoporosis in Men: The Effects of Gender on Skeletal Health. Academic Press. pp. 717–. ISBN 978-0-08-092346-8.
  96. ^ Sneader W (2005). Drug Discovery: A History. New York: Wiley. p. 472 pages. ISBN 978-0-471-89979-2.
  97. ^ a b Jordan VC (March 2003). "Tamoxifen: a most unlikely pioneering medicine". Nature Reviews. Drug Discovery. 2 (3): 205–213. doi:10.1038/nrd1031. PMID 12612646. S2CID 31333174.
  98. ^ Kirk E (24 July 2002). "Dog's tale of survival opens door in cancer research". Health and Behavior. USA Today. from the original on 28 June 2008. Retrieved 24 June 2008.
  99. ^ Blackwell KL, Haroon ZA, Shan S, Saito W, Broadwater G, Greenberg CS, Dewhirst MW (November 2000). "Tamoxifen inhibits angiogenesis in estrogen receptor-negative animal models". Clinical Cancer Research. 6 (11): 4359–4364. PMID 11106254. from the original on 6 September 2008.
  100. ^ a b Jensen EV, Jordan VC (June 2003). "The estrogen receptor: a model for molecular medicine". Clin. Cancer Res. 9 (6): 1980–9. PMID 12796359.
  101. ^ Howell A, Jordan VC (2013). "Adjuvant Antihormone Therapy". In Jordon VC (ed.). Estrogen Action, Selective Estrogen Receptor Modulators And Women's Health: Progress And Promise. World Scientific. pp. 229–254. doi:10.1142/9781848169586_0010. ISBN 978-1-84816-959-3.
  102. ^ Cole MP, Jones CT, Todd ID (June 1971). "A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI46474". British Journal of Cancer. 25 (2): 270–275. doi:10.1038/bjc.1971.33. PMC 2008453. PMID 5115829.
  103. ^ Ward HW (January 1973). "Anti-oestrogen therapy for breast cancer: a trial of tamoxifen at two dose levels". British Medical Journal. 1 (5844): 13–14. doi:10.1136/bmj.1.5844.13. PMC 1588574. PMID 4567104.
  104. ^ "Maverick and pioneer whose work is improving odds in breast cancer fight". from the original on 28 June 2013. Retrieved 5 November 2013.
  105. ^ "Maverick and pioneer whose work is improving odds in breast cancer fight". The Yorkshire Post. 27 June 2013. from the original on 9 March 2016. Retrieved 7 April 2017.
  106. ^ Howell A, Jordan VC (2013). "Adjuvant Antihormone Therapy". In Craig JV (ed.). Estrogen Action, Selective Estrogen Receptor Modulators And Women's Health: Progress And Promise. World Scientific. pp. 229–254. doi:10.1142/9781848169586_0010. ISBN 978-1-84816-959-3.
  107. ^ Baum M, Brinkley DM, Dossett JA, McPherson K, Patterson JS, Rubens RD, et al. (August 1983). "Improved survival among patients treated with adjuvant tamoxifen after mastectomy for early breast cancer". Lancet. 2 (8347): 450. doi:10.1016/S0140-6736(83)90406-3. PMID 6135926. S2CID 54230182.
  108. ^ Furr BJ, Jordan VC (1984). "The pharmacology and clinical uses of tamoxifen". Pharmacology & Therapeutics. 25 (2): 127–205. doi:10.1016/0163-7258(84)90043-3. PMID 6438654.
  109. ^ Jordan VC (August 2001). "Selective estrogen receptor modulation: a personal perspective". Cancer Research. 61 (15): 5683–5687. PMID 11479197.
  110. ^ Lerner LJ, Jordan VC (July 1990). "Development of antiestrogens and their use in breast cancer: eighth Cain memorial award lecture". Cancer Research. 50 (14): 4177–4189. PMID 2194650.
  111. ^ Early Breast Cancer Trialists' Collaborative Group (May 1998). "Tamoxifen for early breast cancer: an overview of the randomised trials". Lancet. 351 (9114): 1451–1467. doi:10.1016/S0140-6736(97)11423-4. PMID 9605801. S2CID 46287542.
  112. ^ "Tamoxifen".
  113. ^ . BioPortfolio Limited. Archived from the original on 16 May 2008. Retrieved 14 November 2008.
  114. ^ Vose B. "AstraZenecain Cancer: Slide #15" (PDF). AstraZeneca Annual Business Review. www.astrazeneca.com. (PDF) from the original on 31 January 2010. Retrieved 28 March 2009. 2004 tamoxifen market share: 70% Source: IMS HEALTH, IMS MIDAS Monthly. July 2004. Aromatase Inhibitors + Tamoxifen
  115. ^ Eugster EA, Shankar R, Feezle LK, Pescovitz OH (1999). "Tamoxifen treatment of progressive precocious puberty in a patient with McCune-Albright syndrome". Journal of Pediatric Endocrinology & Metabolism. 12 (5): 681–686. doi:10.1515/jpem.1999.12.5.681. PMID 10703542. S2CID 71034635.
  116. ^ Eugster EA, Rubin SD, Reiter EO, Plourde P, Jou HC, Pescovitz OH (July 2003). "Tamoxifen treatment for precocious puberty in McCune-Albright syndrome: a multicenter trial". The Journal of Pediatrics. 143 (1): 60–66. doi:10.1016/S0022-3476(03)00128-8. PMID 12915825.
  117. ^ Kreher NC, Eugster EA, Shankar RR (December 2005). "The use of tamoxifen to improve height potential in short pubertal boys". Pediatrics. 116 (6): 1513–1515. doi:10.1542/peds.2005-0577. PMID 16322179. S2CID 45133251.
  118. ^ Karimian E, Chagin AS, Gjerde J, Heino T, Lien EA, Ohlsson C, Sävendahl L (August 2008). "Tamoxifen impairs both longitudinal and cortical bone growth in young male rats". Journal of Bone and Mineral Research. 23 (8): 1267–1277. doi:10.1359/jbmr.080319. PMID 18348701. S2CID 35813153.
  119. ^ Chagin AS, Karimian E, Zaman F, Takigawa M, Chrysis D, Sävendahl L (May 2007). "Tamoxifen induces permanent growth arrest through selective induction of apoptosis in growth plate chondrocytes in cultured rat metatarsal bones". Bone. 40 (5): 1415–1424. doi:10.1016/j.bone.2006.12.066. PMID 17293177.
  120. ^ van Bommel EF, Hendriksz TR, Huiskes AW, Zeegers AG (January 2006). "Brief communication: tamoxifen therapy for nonmalignant retroperitoneal fibrosis". Annals of Internal Medicine. 144 (2): 101–106. doi:10.7326/0003-4819-144-2-200601170-00007. PMID 16418409. S2CID 25699557.
  121. ^ Akram S, Pardi DS, Schaffner JA, Smyrk TC (May 2007). "Sclerosing mesenteritis: clinical features, treatment, and outcome in ninety-two patients". Clinical Gastroenterology and Hepatology. 5 (5): 589–96, quiz 523–4. doi:10.1016/j.cgh.2007.02.032. PMID 17478346.
  122. ^ Dabelic N, Jukic T, Labar Z, Novosel SA, Matesa N, Kusic Z (April 2003). "Riedel's thyroiditis treated with tamoxifen" (PDF). Croatian Medical Journal. 44 (2): 239–241. PMID 12698518. (PDF) from the original on 10 September 2008.
  123. ^ Feil R, Brocard J, Mascrez B, LeMeur M, Metzger D, Chambon P (October 1996). "Ligand-activated site-specific recombination in mice". Proceedings of the National Academy of Sciences of the United States of America. 93 (20): 10887–10890. Bibcode:1996PNAS...9310887F. doi:10.1073/pnas.93.20.10887. PMC 38252. PMID 8855277.
  124. ^ a b c Talaei A, Pourgholami M, Khatibi-Moghadam H, Faridhosseini F, Farhoudi F, Askari-Noghani A, Sadeghi R (June 2016). "Tamoxifen: A Protein Kinase C Inhibitor to Treat Mania: A Systematic Review and Meta-Analysis of Randomized, Placebo-Controlled Trials". Journal of Clinical Psychopharmacology. 36 (3): 272–275. doi:10.1097/JCP.0000000000000492. PMID 27088436. S2CID 39792641.
  125. ^ a b Saxena A, Scaini G, Bavaresco DV, Leite C, Valvassori SS, Carvalho AF, Quevedo J (November 2017). "Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature". Molecular Neuropsychiatry. 3 (2): 108–124. doi:10.1159/000480349. PMC 5701269. PMID 29230399.
  126. ^ "Endoxifen - Intas Pharmaceuticals/Jina pharmaceuticals". AdisInsight. Springer Nature Switzerland AG.
  127. ^ Ahmad I (January 2018). "Tamoxifen a pioneering drug: An update on the therapeutic potential of tamoxifen derivatives". European Journal of Medicinal Chemistry. 143: 515–531. doi:10.1016/j.ejmech.2017.11.056. PMID 29207335.

Further reading edit

External links edit

  • "Tamoxifen". Drug Information Portal. U.S. National Library of Medicine.
  • "Tamoxifen citrate". Drug Information Portal. U.S. National Library of Medicine.
  • "Tamoxifen citrate". National Cancer Institute. 5 October 2006.

February 15, 2024
tamoxifen, sold, under, brand, name, nolvadex, among, others, selective, estrogen, receptor, modulator, used, prevent, breast, cancer, women, also, being, studied, other, types, cancer, been, used, albright, syndrome, typically, taken, daily, mouth, five, year. Tamoxifen sold under the brand name Nolvadex among others is a selective estrogen receptor modulator used to prevent breast cancer in women and men 13 It is also being studied for other types of cancer 13 It has been used for Albright syndrome 14 Tamoxifen is typically taken daily by mouth for five years for breast cancer 14 TamoxifenClinical dataTrade namesNolvadex Genox Tamifen others 1 Other namesTMX ICI 46474AHFS Drugs comMonographMedlinePlusa682414License dataUS DailyMed TamoxifenPregnancycategoryAU B3 2 Routes ofadministrationBy mouthDrug classSelective estrogen receptor modulatorATC codeL02BA01 WHO Legal statusLegal statusAU S4 Prescription only CA only UK POM Prescription only US only 3 4 Pharmacokinetic dataBioavailability 100 5 6 Protein binding gt 99 albumin 5 7 MetabolismLiver CYP3A4 CYP2C9 CYP2D6 5 12 8 Metabolites N Desmethyltamoxifen 8 9 Endoxifen 4 hydroxy N desmethyltamoxifen 8 9 Afimoxifene 4 hydroxytamoxifen 8 9 N N Didesmethyltamoxifen 8 Norendoxifen 4 hydroxy N N didesmethyltamoxifen 8 Others conjugates 8 10 11 Elimination half life5 7 days 5 8 ExcretionFeces 65 Urine 9 IdentifiersIUPAC name Z 2 4 1 2 Diphenylbut 1 enyl phenoxy N N dimethylethanamineCAS Number10540 29 1 Ycitrate 54965 24 1PubChem CID2733526citrate 2733525IUPHAR BPS1016DrugBankDB00675 Ycitrate DBSALT000168ChemSpider2015313 Ycitrate 2015312UNII094ZI81Y45citrate 7FRV7310N6KEGGD08559 Ycitrate D00966ChEBICHEBI 41774 Ycitrate CHEBI 9397ChEMBLChEMBL83 Ycitrate ChEMBL786PDB ligandCTX PDBe RCSB PDB CompTox Dashboard EPA DTXSID1034187ECHA InfoCard100 031 004Chemical and physical dataFormulaC 26H 29N OMolar mass371 524 g mol 13D model JSmol Interactive imageSMILES CN C CCOc1ccc cc1 C c2ccccc2 C CC c3ccccc3InChI InChI 1S C26H29NO c1 4 25 21 11 7 5 8 12 21 26 22 13 9 6 10 14 22 23 15 17 24 18 16 23 28 20 19 27 2 3 h5 18H 4 19 20H2 1 3H3 b26 25 YKey NKANXQFJJICGDU QPLCGJKRSA N Y verify Serious side effects include a small increased risk of uterine cancer stroke vision problems and pulmonary embolism 14 Common side effects include irregular periods weight loss and hot flashes 14 It may cause harm to the baby if taken during pregnancy or breastfeeding 14 It is a selective estrogen receptor modulator SERM and works by decreasing the growth of breast cancer cells 14 15 It is a member of the triphenylethylene group of compounds 16 Tamoxifen was initially made in 1962 by chemist Dora Richardson 17 18 It is on the World Health Organization s List of Essential Medicines 19 Tamoxifen is available as a generic medication 14 In 2020 it was the 317th most commonly prescribed medication in the United States with more than 900 thousand prescriptions 20 21 Contents 1 Medical uses 1 1 Dysmenorrhea 1 2 Breast cancer 1 3 Infertility 1 4 Gynecomastia 1 5 Early puberty 1 6 Available forms 2 Contraindications 3 Side effects 3 1 Endometrial cancer 3 2 Cardiovascular and metabolic 3 3 Liver toxicity 4 Overdose 5 Interactions 6 Pharmacology 6 1 Pharmacodynamics 6 1 1 Selective estrogen receptor modulator activity 6 1 2 Other activities 6 2 Pharmacokinetics 6 2 1 Absorption 6 2 2 Distribution 6 2 3 Metabolism 6 2 4 Elimination 7 Chemistry 8 History 9 Society and culture 9 1 Brand names 9 2 Economics 10 Research 11 References 12 Further reading 13 External linksMedical uses editDysmenorrhea edit Tamoxifen has been used effectively to improve blood flow reduce uterine contractility and pain in dysmenorrhea patients 22 Breast cancer edit Tamoxifen is used for the treatment of both early and advanced estrogen receptor positive ER positive or ER breast cancer in pre and postmenopausal women 23 Tamoxifen increases the risk of postmenopausal bleeding endometrial polyps hyperplasia and endometrial cancer using tamoxifen with an intrauterine system releasing levonorgestrel might increase vaginal bleeding after 1 to 2 years but reduces somewhat endometrial polyps and hyperplasia but not necessarily endometrial cancer 24 Additionally it is the most common hormone treatment for male breast cancer 25 It is also approved by the FDA for the prevention of breast cancer in women at high risk of developing the disease 26 It has been further approved for the reduction of contralateral in the opposite breast cancer The use of tamoxifen is recommended for 10 years 27 In 2006 the large STAR clinical study concluded that raloxifene is also effective in reducing the incidence of breast cancer Updated results after an average of 6 75 years of follow up found that raloxifene retains 76 of tamoxifen s effectiveness in preventing invasive breast cancer with 45 fewer uterine cancers and 25 fewer blood clots in women taking raloxifene than in women taking tamoxifen 28 29 30 Infertility edit Tamoxifen is used for ovulation induction to treat infertility in women with anovulatory disorders It is given at days three to seven of a woman s cycle 31 Tamoxifen improves fertility in males with infertility by disinhibiting the hypothalamic pituitary gonadal axis HPG axis via ER antagonism and thereby increasing the secretion of luteinizing hormone LH and follicle stimulating hormone FSH and increasing testicular testosterone production 32 Gynecomastia edit Tamoxifen is used to prevent and treat gynecomastia 33 34 It is taken as a preventative measure in small doses or used at the onset of any symptoms such as nipple soreness or sensitivity Other medications are taken for similar purposes such as clomifene and the anti aromatase drugs which are used in order to try to avoid the hormone related adverse effects vte Tamoxifen doses and rates of bicalutamide induced breast symptoms in men Follow uptimepoint Tamoxifen dosagePlacebo 1 mg day 2 5 mg day 5 mg day 10 mg day 20 mg day0 months 6 months 98 90 80 54 22 10 12 months 99 95 84 56 38 19 Notes Prevention of breast symptoms specifically gynecomastia and breast pain induced by 150 mg day bicalutamide monotherapy with tamoxifen in 282 men with prostate cancer Bicalutamide and tamoxifen were initiated at the same time 0 months Estradiol levels were in the range of about 22 to 47 pg mL in the treated group 35 Sources 36 35 Early puberty edit Tamoxifen is useful in the treatment of peripheral precocious puberty for instance due to McCune Albright syndrome in both girls and boys 37 38 39 It has been found to decrease growth velocity and the rate of bone maturation in girls with precocious puberty and hence to improve final height in these individuals 37 38 Available forms edit nbsp Nolvadex tamoxifen 20 mg tablets Tamoxifen is available as a tablet or oral solution 40 41 Contraindications editTamoxifen has a number of contraindications including known hypersensitivity to tamoxifen or other ingredients individuals taking concomitant coumarin type anticoagulant therapy and women with a history of venous thromboembolism deep vein thrombosis or pulmonary embolism 12 Side effects editA report in September 2009 from Health and Human Services Agency for Healthcare Research and Quality suggests that tamoxifen raloxifene and tibolone used to treat breast cancer significantly reduce invasive breast cancer in midlife and older women but also increase the risk of adverse side effects 42 Endometrial cancer edit Tamoxifen is a selective estrogen receptor modulator SERM 43 Even though it is an antagonist in breast tissue it acts as partial agonist on the endometrium and has been linked to endometrial cancer in some women Therefore endometrial changes including cancer are among tamoxifen s side effects 44 With time risk of endometrial cancer may be doubled to quadrupled which is a reason tamoxifen is typically only used for five years 45 The American Cancer Society lists tamoxifen as a known carcinogen stating that it increases the risk of some types of uterine cancer while lowering the risk of breast cancer recurrence 46 Cardiovascular and metabolic edit Tamoxifen treatment of postmenopausal women is associated with beneficial effects on serum lipid profiles However long term data from clinical trials have failed to demonstrate a cardioprotective effect 47 For some women tamoxifen can cause a rapid increase in triglyceride concentration in the blood In addition there is an increased risk of thromboembolism especially during and immediately after major surgery or periods of immobility 48 Use of tamoxifen has been shown to slightly increase risk of deep vein thrombosis pulmonary embolism and stroke 49 Liver toxicity edit Tamoxifen has been associated with a number of cases of hepatotoxicity 50 Several different varieties of hepatotoxicity have been reported 50 Tamoxifen can also precipitate non alcoholic fatty liver disease in obese and overweight women not in normal weight women at an average rate of 40 after a year use with 20 mg day 51 Overdose editAcute overdose of tamoxifen has not been reported in humans 12 In dose ranging studies tamoxifen was administered at very high doses in women e g 300 mg m2 and was found to produce acute neurotoxicity including tremor hyperreflexia unsteady gait and dizziness 12 These symptoms occurred within three to five days of therapy and disappeared within two to five days of discontinuation of therapy 12 No indications of permanent neurotoxicity were observed 12 QT prolongation was also observed with very high doses of tamoxifen 12 There is no specific antidote for overdose of tamoxifen 12 Instead treatment should be based on symptoms 12 Interactions editPatients with variant forms of the gene CYP2D6 may not receive full benefit from tamoxifen because of too slow metabolism of the tamoxifen prodrug into its active metabolites 52 53 On 18 October 2006 the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifen to include information about this gene in the package insert 54 Certain CYP2D6 variations in breast cancer patients lead to a worse clinical outcome for tamoxifen treatment 55 Genotyping therefore has the potential for identification of women who have these CYP2D6 phenotypes and for whom the use of tamoxifen is associated with poor outcomes Recent research has shown that 7 10 of women with breast cancer may not receive the full medical benefit from taking tamoxifen due to their genetic make up DNA Drug Safety Testing can examine DNA variations in the CYP2D6 and other important drug processing pathways More than 20 of all clinically used medications are metabolized by CYP2D6 and knowing the CYP2D6 status of a person can help the doctor with the future selection of medications 56 Other molecular biomarkers may also be used to select appropriate patients likely to benefit from tamoxifen 57 Recent studies suggest that taking the selective serotonin reuptake inhibitors SSRIs antidepressants paroxetine Paxil fluoxetine Prozac and sertraline Zoloft can decrease the effectiveness of tamoxifen as these drugs compete for the CYP2D6 enzyme which is needed to metabolize tamoxifen into its active forms 58 A U S study presented at the American Society of Clinical Oncology s annual meeting in 2009 found that after two years 7 5 of women who took only tamoxifen had a recurrence compared with 16 who took either paroxetine fluoxetine or sertraline drugs considered to be the most potent CYP2D6 inhibitors That difference translates to a 120 increase in the risk of breast cancer recurrence Patients taking the SSRIs Celexa citalopram Lexapro escitalopram and Luvox fluvoxamine did not have an increased risk of recurrence due to their lack of competitive metabolism for the CYP2D6 enzyme 59 A newer study demonstrated a clearer and stronger effect from paroxetine in causing the worst outcomes Patients treated with both paroxetine and tamoxifen have a 67 increased risk of death from breast cancer from 24 to 91 depending on the duration of coadministration 60 Tamoxifen interacts with certain other antiestrogens 5 The aromatase inhibitor aminoglutethimide induces the metabolism of tamoxifen 5 Conversely the aromatase inhibitor letrozole does not affect the metabolism of tamoxifen 5 However tamoxifen induces the metabolism of letrozole and significantly reduces its concentrations 5 Pharmacology editPharmacodynamics edit Selective estrogen receptor modulator activity edit nbsp Crystallographic structure of afimoxifene carbon white oxygen red nitrogen blue complexed with ligand binding domain of estrogen receptor alpha ERa cyan ribbon 61 Tamoxifen acts as a selective estrogen receptor modulator SERM or as a partial agonist of the estrogen receptors ERs It has mixed estrogenic and antiestrogenic activity with its profile of effects differing by tissue For instance tamoxifen has predominantly antiestrogenic effects in the breasts but predominantly estrogenic effects in the uterus and liver In breast tissue tamoxifen acts as an ER antagonist so that transcription of estrogen responsive genes is inhibited 62 A beneficial side effect of tamoxifen is that it prevents bone loss by acting as an ER agonist i e mimicking the effects of estrogen in this cell type Therefore by inhibiting osteoclasts it prevents osteoporosis 63 64 When tamoxifen was launched as a drug it was thought that tamoxifen would act as an ER antagonist in all tissues including bone and therefore it was feared that it would contribute to osteoporosis It was therefore very surprising that the opposite effect was observed clinically Hence tamoxifen s tissue selective action directly led to the formulation of the concept of SERMs 65 vte Tissue specific estrogenic and antiestrogenic activity of SERMs Medication Breast Bone Liver Uterus Vagina BrainLipids Coagulation SHBGTooltip Sex hormone binding globulin IGF 1Tooltip Insulin like growth factor 1 Hot flashes GonadotropinsEstradiol Ideal SERM Bazedoxifene Clomifene Lasofoxifene Ospemifene Raloxifene Tamoxifen Toremifene Effect Estrogenic agonistic Mixed or neutral Antiestrogenic antagonistic Note SERMs generally increase gonadotropin levels in hypogonadal and eugonadal men as well as premenopausal women antiestrogenic but decrease gonadotropin levels in postmenopausal women estrogenic Sources See template Tamoxifen is a long acting SERM with a nuclear retention of the ER tamoxifen or metabolite complex of greater than 48 hours 66 67 It has relatively little affinity for the ERs itself and instead acts as a prodrug of active metabolites such as endoxifen 4 hydroxy N desmethyltamoxifen and afimoxifene 4 hydroxytamoxifen 4 OHT 9 These metabolites have approximately 30 to 100 times greater affinity for the ERs than tamoxifen itself 8 68 Per one study tamoxifen had 7 and 6 of the affinity of estradiol for the ERa and ERb respectively whereas afimoxifene had 178 and 338 of the affinity of estradiol for the ERa and ERb respectively 69 Hence afimoxifene showed 25 fold higher affinity for the ERa and 56 fold higher affinity for the ERb than tamoxifen 70 The antiestrogenic potencies of endoxifen and afimoxifene are very similar 9 However endoxifen occurs in much higher concentrations than afimoxifene and is now thought to be the major active form of tamoxifen in the body 8 9 71 Tamoxifen binds to ER competitively with respect to the endogenous agonist estrogen in tumor cells and other tissue targets producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects It is a nonsteroidal agent with potent antiestrogenic properties which compete with estrogen for binding sites in breast and other tissues Tamoxifen causes cells to remain in the G0 and G1 phases of the cell cycle Because it prevents pre cancerous cells from dividing but does not cause cell death tamoxifen is cytostatic rather than cytocidal Tamoxifen binds to ER the ER tamoxifen complex recruits other proteins known as co repressors and the complex then binds to DNA to modulate gene expression Some of these proteins include NCoR and SMRT 72 Tamoxifen function can be regulated by a number of different variables including growth factors 73 Tamoxifen needs to block growth factor proteins such as ErbB2 HER2 74 because high levels of ErbB2 have been shown to occur in tamoxifen resistant cancers 75 Tamoxifen seems to require a protein PAX2 for its full anticancer effect 74 76 In the presence of high PAX2 expression the tamoxifen ER complex is able to suppress the expression of the pro proliferative ERBB2 protein In contrast when AIB 1 expression is higher than PAX2 tamoxifen ER complex upregulates the expression of ERBB2 resulting in stimulation of breast cancer growth 74 77 Tamoxifen is antigonadotropic in postmenopausal women and partially suppresses levels of the gonadotropins luteinizing hormone LH and follicle stimulating hormone FSH in such women 78 However it has progonadotropic effects in premenopausal women and increases estrogen levels by 6 fold in them 78 Due to the nature of tamoxifen as a competitive ER ligand this increase in estrogen levels is liable to interfere with the antiestrogenic efficacy of tamoxifen 78 The effects of tamoxifen on breast cancer Ki 67 expression sex hormone binding globulin SHBG levels and IGF 1 levels are dose dependent across a dosage range of 1 to 20 mg day in women with breast cancer 79 Tamoxifen has been found to decrease insulin like growth factor 1 IGF 1 levels by 17 to 38 in women and men 80 Suppression of IGF 1 production in the liver is a well known action of estrogens and SERMs 80 A 10 mg day dosage of tamoxifen is nearly as effective as a 20 mg day dosage in suppressing IGF 1 levels 5 Other activities edit Afimoxifene is an agonist of the G protein coupled estrogen receptor GPER with relatively low affinity 81 Its affinity for the receptor is in the range of 100 to 1 000 nM relative to 3 to 6 nM for estradiol 81 In addition to its activity as a SERM afimoxifene binds to both the estrogen related receptor b and estrogen related receptor g and is an antagonist of the estrogen related receptor g ERRg 82 Norendoxifen 4 hydroxy N N didesmethyltamoxifen another active metabolite of tamoxifen has been found to act as a potent competitive aromatase inhibitor IC50 90 nM and may also be involved in the antiestrogenic activity of tamoxifen 83 In addition to its activity as a SERM tamoxifen is a potent and selective protein kinase C inhibitor and is active in this regard at therapeutic concentrations 84 This action is thought to underlie the efficacy of tamoxifen in the treatment of bipolar disorder 84 Tamoxifen is an inhibitor of P glycoprotein 12 Pharmacokinetics edit Absorption edit Tamoxifen is rapidly and extensively absorbed from the intestines with oral administration 5 6 The oral bioavailability of tamoxifen is approximately 100 which is suggestive of minimal first pass metabolism in the intestines and liver 5 Following intake peak levels of tamoxifen occur after three to seven hours 85 5 Steady state levels of tamoxifen are reached typically after 3 to 4 weeks but possibly up to 16 weeks of daily administration 5 11 Steady state levels of afimoxifene are achieved after 8 weeks of daily tamoxifen administration 11 7 Peak levels of tamoxifen after a single 40 mg oral dose were 65 ng mL and steady state levels at 20 mg day were 310 ng mL 5 Levels of tamoxifen show clear dose dependency across a dosage range of 1 to 20 mg day 5 86 Endoxifen levels are approximately 5 to 10 times higher than afimoxifene levels with large interindividual variability 8 9 Endoxifen levels have been reported as 10 8 to 15 9 ng mL at steady state in CYP2D6 normal metabolizers during therapy with 20 mg day tamoxifen 8 The most abundant metabolites of tamoxifen in terms of circulating concentrations are N desmethyltamoxifen N N didesmethyltamoxifen Z endoxifen and tamoxifen N oxide 10 87 Distribution edit The volume of distribution of tamoxifen is 50 to 60 L kg and its clearance has been estimated as 1 2 to 5 1 L hour 5 85 High concentrations of tamoxifen have been found in breast uterus liver kidney lung pancreas and ovary tissue in animals and humans 5 Levels of tamoxifen in the uterus have been found to be 2 to 3 fold higher than in the circulation 5 and in the breasts 10 fold higher than in the circulation 86 The plasma protein binding of tamoxifen and afimoxifene is greater than 99 7 A majority of tamoxifen is bound to albumin 5 Albumin alone binds 98 8 of tamoxifen while other plasma proteins are not greatly involved 88 Metabolism edit Tamoxifen and its metabolites in humans 89 Compound Mean plasmaconcentrations Effect on ER affinity for ERaTamoxifen 190 420 nmol L Weak antagonist 2 N Desmethyltamoxifen 280 800 nmol L Weak antagonist 1 N N Desmethyltamoxifen 90 120 nmol L Weak antagonistEndoxifen 14 130 nmol L Strong antagonist equal to afimoxifeneAfimoxifene 3 17 nmol Lb Strong antagonist 188 a Hydroxytamoxifen 1 nmol L None3 4 Dihydroxytamoxifen Weak antagonist high affinityTamoxifen N oxide 15 24 nmol L Weak antagonistcFootnotes a Estradiol is 100 b One study reported a much higher concentration 67 nmol L c Might be due to reduction to tamoxifen Tamoxifen is a prodrug and is metabolized in the liver by the cytochrome P450 isoforms CYP3A4 CYP2C9 and CYP2D6 into active metabolites such as endoxifen 4 hydroxy N desmethyltamoxifen and afimoxifene 4 hydroxytamoxifen 5 12 8 Conversion of tamoxifen by N demethylation into N desmethyltamoxifen which is catalyzed primarily by CYP3A4 and CYP3A5 is responsible for approximately 92 of tamoxifen metabolism 9 Conversely 4 hydroxylation of tamoxifen into afimoxifene is responsible for only about 7 of tamoxifen metabolism 9 Following its formation N desmethyltamoxifen is oxidized into several other metabolites the most notable of which is endoxifen 9 Another active metabolite norendoxifen 4 hydroxy N N didesmethyltamoxifen is formed via N demethylation of endoxifen or 4 hydroxylation of N N didesmethyltamoxifen 8 Tamoxifen and its metabolites undergo conjugation including glucuronidation and sulfation 11 Tamoxifen may inhibit its own metabolism 5 Elimination edit Tamoxifen has a long elimination half life of typically 5 to 7 days with a range of 4 to 11 days 5 8 85 Similarly the half life of afimoxifene is 14 days 7 Conversely the half life of endoxifen is 50 to 70 hours 2 3 days 8 The long half lives of tamoxifen and afimoxifene are attributed to their high plasma protein binding as well as to enterohepatic recirculation 7 Upon discontinuation of treatment levels of tamoxifen and its metabolites persist in the circulation for at least 6 weeks 7 Tamoxifen is excreted in bile and is eliminated in feces while small amounts are eliminated in urine 5 Chemistry editTamoxifen is a nonsteroidal SERM of the triphenylethylene family and was structurally derived from diethylstilbestrol like estrogens and antiestrogens such as chlorotrianisene and ethamoxytriphetol 90 91 92 93 Initially clomifene was synthesized and tamoxifen was developed subsequently 90 92 93 Tamoxifen is closely related structurally to other triphenylethylenes such as clomifene nafoxidine ospemifene toremifene and numerous others 94 95 Other SERMs like raloxifene are structurally distinct from tamoxifen and other triphenylethylenes 95 History editIn the late 1950s pharmaceutical companies were actively researching a newly discovered class of anti estrogen compounds in the hope of developing a morning after contraceptive pill Arthur L Walpole was a reproductive endocrinologist who led such a team at the Alderley Park research laboratories of ICI Pharmaceuticals 18 It was there in 1962 that chemist Dora Richardson first synthesized tamoxifen back then known as ICI 46 474 when she was looking to create triphenylethylene derivatives for the contraceptive pill project that her team was researching 96 This compound was originally created to work as an estrogen inhibitor but instead was found to stimulate ovulation in participants of the drug testing trial 17 Walpole and his colleagues filed a UK patent covering this compound in 1962 but patent protection on this compound was repeatedly denied in the US until the 1980s 97 Tamoxifen did eventually receive marketing approval as a fertility treatment but the class of compounds never proved useful in human contraception A link between estrogen and breast cancer had been known for many years but cancer treatments were not a corporate priority at the time and Walpole s personal interests were important in keeping support for the compound alive in the face of this and the lack of patent protection 18 It was only when Walpole threatened to leave his position that corporate decided to allow trials and testing for tamoxifen as a drug that could be used to treat breast cancer Without Walpole s effort towards defending the work that his team had done in discovering a possibly revolutionary source for breast cancer treatment tamoxifen could have become a discarded or under researched idea Walpole s team consisted of Dora Richardson and G A Snow who worked on the chemistry portion of the project along with G E Paget and J K Walley who focused primarily on the biological side 17 Tamoxifen is one of three drugs in an anti angiogenetic protocol developed by Dr Judah Folkman a researcher at Children s Hospital at Harvard Medical School in Boston Folkman discovered in the 1970s that angiogenesis the growth of new blood vessels plays a significant role in the development of cancer Since his discovery an entirely new field of cancer research has developed Clinical trials on angiogenesis inhibitors have been underway since 1992 using many different drugs The Harvard researchers developed a specific protocol for a golden retriever named Navy who was cancer free after receiving the prescribed cocktail of celecoxib doxycycline and tamoxifen the treatment subsequently became known as the Navy Protocol 98 Furthermore tamoxifen treatment alone has been shown to have anti angiogenetic effects in animal models of cancer which appear to be at least in part independent of tamoxifen s ER antagonist properties 99 Other antiestrogens such as ethamoxytriphetol MER 25 and clomifene MRL 41 were assessed for treatment of breast cancer and found to be effective before tamoxifen but were plagued with toxicity issues 100 101 The first clinical study of tamoxifen took place at the Christie Hospital in 1971 and showed a convincing effect in advanced breast cancer but nevertheless ICI s development programme came close to termination when it was reviewed in 1972 102 In an unpublished article from the early days of the trial Dora Richardson documented her team s excitement about tamoxifen s effects in counteracting infertility problems and the early positive effects found in breast cancer patients Unfortunately this work was not well received by everyone as the team was supposed to be looking for a contraceptive pill 17 Tamoxifen s further development may have been bolstered by a second clinical study by Harold W C Ward 103 at the Queen Elizabeth Hospital Birmingham Ward s study showed a more definitive response to the drug at a higher dosage Walpole also may have helped to convince the company to market tamoxifen for late stage breast cancer in 1973 97 He was also instrumental in funding V Craig Jordan to work on tamoxifen In 1972 ICI Pharmaceuticals Division abandoned development of tamoxifen for financial reasons The drug was subsequently reinvented from a failed contraceptive to become tamoxifen the gold standard for the adjuvant treatment of breast cancer and the pioneering medicine for chemprevention for high risk women 104 105 Two books Estrogen Action Selective Estrogen Receptor Modulators and Women s Health Imperial College Press 2013 and Tamoxifen Pioneering Medicine in Breast Cancer Springer 2013 tell this story vte Comparison of early clinical experience with antiestrogens for advanced breast cancer Antiestrogen Dosage Year s Response rate Adverse effectsEthamoxytriphetol 500 4 500 mg day 1960 25 Acute psychotic episodesClomifene 100 300 mg day 1964 1974 34 Risks of cataractsNafoxidine 180 240 mg day 1976 31 Cataracts ichthyosis photophobiaTamoxifen 20 40 mg day 1971 1973 31 Transient thrombocytopeniaaFootnotes a The particular advantage of this drug is the low incidence of troublesome side effects 25 Side effects were usually trivial 26 Sources 100 106 1980 saw the publication of the first trial to show that tamoxifen given in addition to chemotherapy improved survival for patients with early breast cancer 107 In advanced disease tamoxifen is now only recognized as effective in ER patients but the early trials did not select ER patients and by the mid 1980s the clinical trial picture was not showing a major advantage for tamoxifen 108 Nevertheless tamoxifen had a relatively mild side effect profile and a number of large trials continued The pharmacology of SERMs was discovered defined and deciphered during the 1980s 109 A clinical strategy was described 110 that led to the creation of SERMs as a group of multifunctional medicines aimed at the treatment or prevention of many conditions in postmenopausal women e g osteoporosis and breast cancer This story is told in V Craig Jordan ed 2013 Estrogen Action Selective Estrogen Receptor Modulators and Women s Health Imperial College Press Singapore The early sales of tamoxifen in both the UK and in the U S far exceeded ICI s original estimate but despite this at the annual portfolio review ICI s board members still asserted that there was no market for cancer leaving the drug s marketing success to rely on its clinical results and clinicians and scientists interests in it Shortly after Dora Richardson published a history of tamoxifen that unusually for that type of paper included personal accounts and letters from patients who attributed their healing to the drug It is by giving voice to cancer patients using tamoxifen and so helping to push it forward by justifying it both morally and scientifically to corporations 17 It was not until 1998 that the meta analysis of the Oxford based Early Breast Cancer Trialists Collaborative Group showed definitively that tamoxifen was effective for early breast cancer 111 Society and culture editBrand names edit Tamoxifen is marketed under the brand names Nolvadex and Soltamox and a variety of other brand names throughout the world 1 112 Economics edit Global sales of tamoxifen in 2001 were approximately 1 02 billion 113 Since the expiration of the patent in 2002 it is widely available as a generic drug around the world As of 2004 update tamoxifen was the world s largest selling hormonal drug for the treatment of breast cancer 114 Research editIn McCune Albright syndrome MAS tamoxifen has been used to treat premature puberty and the consequences of premature puberty Tamoxifen has been seen to decrease rapid bone maturation which is the result of excessive estrogen and alter predicted adult height PAH 115 116 The same effects have also been seen in short pubertal boys 117 However one in vitro study in 2007 and later an in vivo study in 2008 have shown that tamoxifen induces apoptosis in growth plate chondrocytes reduces serum insulin like growth factor 1 IGF 1 levels and causes persistent retardation of longitudinal and cortical radial bone growth in young male rats leading the researchers to express concern giving tamoxifen to growing individuals 118 119 Tamoxifen has been studied in the treatment of the rare conditions of retroperitoneal fibrosis 120 and idiopathic sclerosing mesenteritis 121 It has also been proposed as part of a treatment plan for Riedel s thyroiditis 122 Tamoxifen is used as a research tool to trigger tissue specific gene expression in many conditional expression constructs in genetically modified animals including a version of the Cre Lox recombination technique 123 While widely used in transgenic research the strong anabolic effect of tamoxifen on bone might confound this approach especially as it relates to bone targeted constructs Tamoxifen may be effective in the treatment of mania in people with bipolar disorder 124 This is thought to be due to blockade of protein kinase C PKC an enzyme that regulates neuron activity in the brain 124 125 Researchers believe PKC is overactive during the mania in bipolar patients 124 125 As of September 2019 update endoxifen a major active metabolite of tamoxifen with a 4 fold more potent PKC inhibition was in phase III clinical trials for bipolar disorder 126 127 References edit a b NCI Drug Dictionary 2 February 2011 Archived from the original on 8 December 2015 Retrieved 12 September 2021 Tamoxifen Use During Pregnancy Drugs com 25 July 2019 Retrieved 27 January 2020 Tamoxifen citrate tablet film coated DailyMed Retrieved 12 September 2021 Soltamox tamoxifen citrate liquid DailyMed Retrieved 12 September 2021 a b c d e f g h i j k l m n o p q r s t u v w Morello KC Wurz GT DeGregorio MW 2003 Pharmacokinetics of selective estrogen receptor modulators Clinical Pharmacokinetics 42 4 361 372 doi 10 2165 00003088 200342040 00004 PMID 12648026 S2CID 13003168 a b Brenner GM Stevens C 28 September 2017 Brenner and Stevens Pharmacology E Book Elsevier Health Sciences pp 394 ISBN 978 0 323 39172 6 a b c d e f Chabner BA Longo DL 7 December 2011 Cancer Chemotherapy and Biotherapy Principles and Practice Lippincott Williams amp Wilkins pp 655 ISBN 978 1 4511 4820 6 a b c d e f g h i j k l m n o p Sanchez Spitman AB Swen JJ Dezentje VO Moes DJ Gelderblom H Guchelaar HJ June 2019 Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen Expert Review of Clinical Pharmacology 12 6 523 536 doi 10 1080 17512433 2019 1610390 PMID 31008668 a b c d e f g h i j Klein DJ Thorn CF Desta Z Flockhart DA Altman RB Klein TE November 2013 PharmGKB summary tamoxifen pathway pharmacokinetics Pharmacogenetics and Genomics 23 11 643 647 doi 10 1097 FPC 0b013e3283656bc1 PMC 4084801 PMID 23962908 a b Murdter TE Schroth W Bacchus Gerybadze L Winter S Heinkele G Simon W et al May 2011 Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma Clinical Pharmacology and Therapeutics 89 5 708 717 doi 10 1038 clpt 2011 27 PMID 21451508 S2CID 20082053 a b c d Nagar S 2010 Pharmacokinetics of Anti Cancer Drugs Used in Breast Cancer Chemotherapy Chemo Fog Advances in Experimental Medicine and Biology Vol 678 pp 124 132 doi 10 1007 978 1 4419 6306 2 16 ISBN 978 1 4419 6305 5 PMID 20738014 S2CID 12537667 a b c d e f g h i j k Nolvadex Tamoxifen Citrate tablets DailyMed 3 November 2016 Retrieved 12 September 2021 a b Tamoxifen Citrate NCI 26 August 2015 Archived from the original on 4 January 2016 Retrieved 28 November 2015 a b c d e f g Tamoxifen Citrate The American Society of Health System Pharmacists Archived from the original on 4 January 2014 Retrieved 27 November 2015 Selective estrogen receptor modulators Archived from the original on 9 December 2013 Retrieved 28 November 2015 Cano A Calaf i Alsina J Duenas Diez JL eds 2006 Selective Estrogen Receptor Modulators a New Brand of Multitarget Drugs Berlin Heidelberg Springer Verlag Berlin Heidelberg p 52 ISBN 9783540347422 a b c d e Quirke VM 12 September 2017 Tamoxifen from Failed Contraceptive Pill to Best Selling Breast Cancer Medicine A Case Study in Pharmaceutical Innovation Frontiers in Pharmacology 8 620 doi 10 3389 fphar 2017 00620 PMC 5600945 PMID 28955226 a b c Jordan VC January 2006 Tamoxifen ICI46 474 as a targeted therapy to treat and prevent breast cancer British Journal of Pharmacology 147 Suppl 1 S269 S276 doi 10 1038 sj bjp 0706399 PMC 1760730 PMID 16402113 World Health Organization 2019 World Health Organization model list of essential medicines 21st list 2019 Geneva World Health Organization hdl 10665 325771 WHO MVP EMP IAU 2019 06 License CC BY NC SA 3 0 IGO The Top 300 of 2020 ClinCalc Retrieved 7 October 2022 Tamoxifen Citrate Drug Usage Statistics ClinCalc Archived from the original on 22 September 2020 Retrieved 7 October 2022 Thomas B Magos A 2009 Modern management of dysmenorrhoea Trends in Urology Gynaecology amp Sexual Health 14 5 25 29 doi 10 1002 tre 120 Jordan VC October 1993 Fourteenth Gaddum Memorial Lecture A current view of tamoxifen for the treatment and prevention of breast cancer British Journal of Pharmacology 110 2 507 517 doi 10 1111 j 1476 5381 1993 tb13840 x PMC 2175926 PMID 8242225 Romero SA Young K Hickey M Su HI December 2020 Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen The Cochrane Database of Systematic Reviews 12 2 CD007245 doi 10 1002 14651858 CD007245 pub4 PMC 8092675 PMID 33348436 Breast cancer in men CancerHelp UK Cancer Research UK 28 September 2007 Archived from the original on 1 December 2008 Retrieved 22 March 2009 Center for Drug Evaluation and Research 7 July 2005 Tamoxifen Information reducing the incidence of breast cancer in women at high risk U S Food and Drug Administration Archived from the original on 19 June 2007 Retrieved 3 July 2007 Burstein HJ Temin S Anderson H Buchholz TA Davidson NE Gelmon KE et al July 2014 Adjuvant endocrine therapy for women with hormone receptor positive breast cancer american society of clinical oncology clinical practice guideline focused update Journal of Clinical Oncology 32 21 2255 2269 doi 10 1200 JCO 2013 54 2258 PMC 4876310 PMID 24868023 National Cancer Institute 26 April 2006 Study of Tamoxifen and Raloxifene STAR Trial U S National Institutes of Health Archived from the original on 4 July 2007 Retrieved 3 July 2007 University of Pittsburgh STAR Study of Tamoxifen and Raloxifen Archived from the original on 11 June 2007 Retrieved 3 July 2007 Love S 22 April 2006 Study Finds New Use for Raloxifene Reducing Breast Cancer in High Risk Postmenopausal Women Archived from the original on 2 August 2009 Retrieved 19 March 2009 Steiner AZ Terplan M Paulson RJ June 2005 Comparison of tamoxifen and clomiphene citrate for ovulation induction a meta analysis Human Reproduction 20 6 1511 1515 doi 10 1093 humrep deh840 PMID 15845599 Chua ME Escusa KG Luna S Tapia LC Dofitas B Morales M September 2013 Revisiting oestrogen antagonists clomiphene or tamoxifen as medical empiric therapy for idiopathic male infertility a meta analysis Andrology 1 5 749 757 doi 10 1111 j 2047 2927 2013 00107 x PMID 23970453 S2CID 38345293 Lapid O van Wingerden JJ Perlemuter L 2013 Tamoxifen therapy for the management of pubertal gynecomastia a systematic review Journal of Pediatric Endocrinology amp Metabolism 26 9 10 803 807 doi 10 1515 jpem 2013 0052 PMID 23729603 S2CID 2101602 Viani GA Bernardes da Silva LG Stefano EJ July 2012 Prevention of gynecomastia and breast pain caused by androgen deprivation therapy in prostate cancer tamoxifen or radiotherapy International Journal of Radiation Oncology Biology Physics 83 4 e519 e524 doi 10 1016 j ijrobp 2012 01 036 PMID 22704706 a b Fradet Y Egerdie B Andersen M Tammela TL Nachabe M Armstrong J Morris T Navani S July 2007 Tamoxifen as prophylaxis for prevention of gynaecomastia and breast pain associated with bicalutamide 150 mg monotherapy in patients with prostate cancer a randomised placebo controlled dose response study Eur Urol 52 1 106 14 doi 10 1016 j eururo 2007 01 031 PMID 17270340 Fentiman IS January 2018 Managing Male Mammary Maladies Eur J Breast Health 14 1 5 9 doi 10 5152 ejbh 2017 3841 PMC 5758064 PMID 29322112 a b Neyman A Eugster EA December 2017 Treatment of Girls and Boys with McCune Albright Syndrome with Precocious Puberty Update 2017 Pediatric Endocrinology Reviews 15 2 136 141 doi 10 17458 per vol15 2017 nau treatmentgirlsboys PMC 5808444 PMID 29292624 a b Haddad NG Eugster EA June 2019 Peripheral precocious puberty including congenital adrenal hyperplasia causes consequences management and outcomes Best Practice amp Research Clinical Endocrinology amp Metabolism 33 3 101273 doi 10 1016 j beem 2019 04 007 hdl 1805 19111 PMID 31027974 S2CID 135410503 Zacharin M May 2019 Disorders of Puberty Pharmacotherapeutic Strategies for Management Pediatric Pharmacotherapy Handbook of Experimental Pharmacology Vol 261 pp 507 538 doi 10 1007 164 2019 208 ISBN 978 3 030 50493 9 PMID 31144045 S2CID 169040406 Product Information tamoxifen citrate oral tablets tamoxifen citrate oral tablets Watson Laboratories per manufacturer Corona CA 2011 Product Information SOLTAMOX R oral solution tamoxifen citrate oral solution Midatech Pharma US Inc per FDA Raleigh NC 2018 OncoGenetics Org September 2009 Medications Effective in Reducing Risk of Breast Cancer But Increase Risk of Adverse Effects OncoGenetics Org Archived from the original on 24 September 2009 Retrieved 14 September 2009 Gallo MA Kaufman D February 1997 Antagonistic and agonistic effects of tamoxifen significance in human cancer Seminars in Oncology 24 1 Suppl 1 S1 71 S1 80 PMID 9045319 Grilli S 2006 Tamoxifen TAM the dispute goes on PDF Annali dell Istituto Superiore di Sanita 42 2 170 173 PMID 17033137 Archived from the original PDF on 10 August 2007 Retrieved 3 July 2007 Tamoxifen for Breast Cancer amp Side Effects Health and Life 11 December 2009 Archived from the original on 16 February 2010 Known and Probable Carcinogens American Cancer Society 3 February 2006 Archived from the original on 17 March 2008 Retrieved 21 March 2008 Esteva FJ Hortobagyi GN June 2006 Comparative assessment of lipid effects of endocrine therapy for breast cancer implications for cardiovascular disease prevention in postmenopausal women Breast 15 3 301 312 doi 10 1016 j breast 2005 08 033 PMID 16230014 Decensi A Maisonneuve P Rotmensz N Bettega D Costa A Sacchini V et al February 2005 Effect of tamoxifen on venous thromboembolic events in a breast cancer prevention trial Circulation 111 5 650 656 doi 10 1161 01 CIR 0000154545 84124 AC PMID 15699284 Harvey HA Kimura M Hajba A April 2006 Toremifene an evaluation of its safety profile Breast 15 2 142 157 doi 10 1016 j breast 2005 09 007 PMID 16289904 a b Cameron R Feuer G de la Iglesia F 6 December 2012 Drug Induced Hepatotoxicity Springer Science amp Business Media pp 565 ISBN 978 3 642 61013 4 Osman KA Osman MM Ahmed MH January 2007 Tamoxifen induced non alcoholic steatohepatitis where are we now and where are we going Expert Opinion on Drug Safety 6 1 1 4 doi 10 1517 14740338 6 1 1 PMID 17181445 S2CID 33505288 Goetz MP Rae JM Suman VJ Safgren SL Ames MM Visscher DW et al December 2005 Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes Journal of Clinical Oncology 23 36 9312 9318 doi 10 1200 JCO 2005 03 3266 PMID 16361630 Beverage JN Sissung TM Sion AM Danesi R Figg WD September 2007 CYP2D6 polymorphisms and the impact on tamoxifen therapy Journal of Pharmaceutical Sciences 96 9 2224 2231 doi 10 1002 jps 20892 PMID 17518364 Information about CYP2D6 and tamoxifen from DNADirect s website Archived 11 March 2007 at the Wayback Machine Schroth W Goetz MP Hamann U Fasching PA Schmidt M Winter S et al October 2009 Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen JAMA 302 13 1429 1436 doi 10 1001 jama 2009 1420 PMC 3909953 PMID 19809024 Information about Tamoxitest and how DNA testing can help in the selection of the best treatment methodology from Genelex s website Archived 27 May 2010 at the Wayback Machine Criscitiello C Fumagalli D Saini KS Loi S December 2010 Tamoxifen in early stage estrogen receptor positive breast cancer overview of clinical use and molecular biomarkers for patient selection OncoTargets and Therapy 4 1 11 doi 10 2147 OTT S10155 PMC 3084302 PMID 21552410 Jin Y Desta Z Stearns V Ward B Ho H Lee KH et al January 2005 CYP2D6 genotype antidepressant use and tamoxifen metabolism during adjuvant breast cancer treatment Journal of the National Cancer Institute 97 1 30 39 doi 10 1093 jnci dji005 PMID 15632378 Staff Reports Summer 2009 ASCO Updates Antidepressants Reduce the Effectiveness of Tamoxifen CURE Cancer Updates Research and Education Archived from the original on 22 June 2009 Kelly CM Juurlink DN Gomes T Duong Hua M Pritchard KI Austin PC Paszat LF February 2010 Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen a population based cohort study BMJ 340 c693 doi 10 1136 bmj c693 PMC 2817754 PMID 20142325 PDB 3ERT Shiau AK Barstad D Loria PM Cheng L Kushner PJ Agard DA Greene GL December 1998 The structural basis of estrogen receptor coactivator recognition and the antagonism of this interaction by tamoxifen Cell 95 7 927 937 doi 10 1016 S0092 8674 00 81717 1 PMID 9875847 S2CID 10265320 Wang DY Fulthorpe R Liss SN Edwards EA February 2004 Identification of estrogen responsive genes by complementary deoxyribonucleic acid microarray and characterization of a novel early estrogen induced gene EEIG1 Molecular Endocrinology 18 2 402 411 doi 10 1210 me 2003 0202 PMID 14605097 Nakamura T Imai Y Matsumoto T Sato S Takeuchi K Igarashi K et al September 2007 Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts Cell 130 5 811 823 doi 10 1016 j cell 2007 07 025 PMID 17803905 S2CID 17177462 Krum SA Miranda Carboni GA Hauschka PV Carroll JS Lane TF Freedman LP Brown M February 2008 Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival The EMBO Journal 27 3 535 545 doi 10 1038 sj emboj 7601984 PMC 2241656 PMID 18219273 Mincey BA Moraghan TJ Perez EA August 2000 Prevention and treatment of osteoporosis in women with breast cancer Mayo Clinic Proceedings 75 8 821 829 doi 10 4065 75 8 821 PMID 10943237 Runnebaum B Rabe T 17 April 2013 Gynakologische Endokrinologie und Fortpflanzungsmedizin Band 1 Gynakologische Endokrinologie Springer Verlag pp 88 ISBN 978 3 662 07635 4 Hammond CB Maxson WS January 1982 Current status of estrogen therapy for the menopause Fertility and Sterility 37 1 5 25 doi 10 1016 S0015 0282 16 45970 4 PMID 6277697 Ahmad A Shahabuddin S Sheikh S Kale P Krishnappa M Rane RC Ahmad I December 2010 Endoxifen a new cornerstone of breast cancer therapy demonstration of safety tolerability and systemic bioavailability in healthy human subjects Clinical Pharmacology and Therapeutics 88 6 814 817 doi 10 1038 clpt 2010 196 PMID 20981001 S2CID 24590365 Kuhl H August 2005 Pharmacology of estrogens and progestogens influence of different routes of administration Climacteric 8 Suppl 1 3 63 doi 10 1080 13697130500148875 PMID 16112947 S2CID 24616324 Potts RO Lobo RA May 2005 Transdermal drug delivery clinical considerations for the obstetrician gynecologist Obstetrics and Gynecology 105 5 Pt 1 953 961 doi 10 1097 01 AOG 0000161958 70059 db PMID 15863530 S2CID 23411589 Binkhorst L Mathijssen RH Jager A van Gelder T March 2015 Individualization of tamoxifen therapy much more than just CYP2D6 genotyping Cancer Treatment Reviews 41 3 289 299 doi 10 1016 j ctrv 2015 01 002 PMID 25618289 Shang Y Hu X DiRenzo J Lazar MA Brown M December 2000 Cofactor dynamics and sufficiency in estrogen receptor regulated transcription Cell 103 6 843 852 doi 10 1016 S0092 8674 00 00188 4 PMID 11136970 S2CID 6659079 Massarweh S Osborne CK Creighton CJ Qin L Tsimelzon A Huang S et al February 2008 Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function Cancer Research 68 3 826 833 doi 10 1158 0008 5472 CAN 07 2707 PMID 18245484 a b c Hurtado A Holmes KA Geistlinger TR Hutcheson IR Nicholson RI Brown M et al December 2008 Regulation of ERBB2 by oestrogen receptor PAX2 determines response to tamoxifen Nature 456 7222 663 666 Bibcode 2008Natur 456 663H doi 10 1038 nature07483 PMC 2920208 PMID 19005469 Osborne CK Bardou V Hopp TA Chamness GC Hilsenbeck SG Fuqua SA et al March 2003 Role of the estrogen receptor coactivator AIB1 SRC 3 and HER 2 neu in tamoxifen resistance in breast cancer Journal of the National Cancer Institute 95 5 353 361 doi 10 1093 jnci 95 5 353 PMID 12618500 New Mechanism Predicts Tamoxifen Response PAX2 gene implicated in tamoxifen induced inhibition of ERBB2 HER2 mediated tumor growth www modernmedicine com 13 November 2008 Archived from the original on 14 July 2011 Retrieved 14 November 2008 Study sheds new light on tamoxifen resistance News CORDIS News Archived from the original on 20 February 2009 Retrieved 14 November 2008 a b c Li J Ma Z Jiang RW Wu B September 2013 Hormone related pharmacokinetic variations associated with anti breast cancer drugs Expert Opinion on Drug Metabolism amp Toxicology 9 9 1085 1095 doi 10 1517 17425255 2013 802771 PMID 23687971 S2CID 26846314 Fabian CJ Kimler BF March 2005 Selective estrogen receptor modulators for primary prevention of breast cancer Journal of Clinical Oncology 23 8 1644 1655 doi 10 1200 JCO 2005 11 005 PMID 15755972 a b Duarte FH Jallad RS Bronstein MD November 2016 Estrogens and selective estrogen receptor modulators in acromegaly Endocrine 54 2 306 314 doi 10 1007 s12020 016 1118 z PMID 27704479 S2CID 10136018 a b Prossnitz ER Arterburn JB July 2015 International Union of Basic and Clinical Pharmacology XCVII G Protein Coupled Estrogen Receptor and Its Pharmacologic Modulators Pharmacological Reviews 67 3 505 540 doi 10 1124 pr 114 009712 PMC 4485017 PMID 26023144 Ariazi EA Jordan VC 2006 Estrogen related receptors as emerging targets in cancer and metabolic disorders Current Topics in Medicinal Chemistry 6 3 203 215 doi 10 2174 1568026610606030203 PMID 16515477 Liu J Flockhart PJ Lu D Lv W Lu WJ Han X et al September 2013 Inhibition of cytochrome p450 enzymes by the e and z isomers of norendoxifen Drug Metabolism and Disposition 41 9 1715 1720 doi 10 1124 dmd 113 052506 PMC 3876808 PMID 23824607 a b Zarate CA Manji HK 2009 Protein kinase C inhibitors rationale for use and potential in the treatment of bipolar disorder CNS Drugs 23 7 569 582 doi 10 2165 00023210 200923070 00003 PMC 2802274 PMID 19552485 a b c DeVita VT Lawrence TS Rosenberg SA 18 March 2016 Prostate and Other Genitourinary Cancers From Cancer Principles amp Practice of Oncology 10th edition Wolters Kluwer Health pp 990 ISBN 978 1 4963 5421 1 a b Kisanga ER Gjerde J Guerrieri Gonzaga A Pigatto F Pesci Feltri A Robertson C et al April 2004 Tamoxifen and metabolite concentrations in serum and breast cancer tissue during three dose regimens in a randomized preoperative trial Clinical Cancer Research 10 7 2336 2343 doi 10 1158 1078 0432 ccr 03 0538 PMID 15073109 Jordan VC 1982 Metabolites of tamoxifen in animals and man identification pharmacology and significance Breast Cancer Research and Treatment 2 2 123 138 doi 10 1007 BF01806449 PMID 6184101 S2CID 25119313 Lien EA Solheim E Lea OA Lundgren S Kvinnsland S Ueland PM April 1989 Distribution of 4 hydroxy N desmethyltamoxifen and other tamoxifen metabolites in human biological fluids during tamoxifen treatment Cancer Research 49 8 2175 2183 PMID 2702659 Brauch H Murdter TE Eichelbaum M Schwab M October 2009 Pharmacogenomics of tamoxifen therapy Clinical Chemistry 55 10 1770 1782 doi 10 1373 clinchem 2008 121756 PMID 19574470 a b Jordan VC 1986 Estrogen antiestrogen Action and Breast Cancer Therapy Univ of Wisconsin Press pp 28 154 ISBN 978 0 299 10480 1 Pratt WB 1994 The Anticancer Drugs Oxford University Press pp 21 ISBN 978 0 19 506739 2 a b Maximov PY McDaniel RE Jordan VC 23 July 2013 Tamoxifen Pioneering Medicine in Breast Cancer Springer Science amp Business Media pp 7 ISBN 978 3 0348 0664 0 a b Ravina E 11 January 2011 The Evolution of Drug Discovery From Traditional Medicines to Modern Drugs John Wiley amp Sons pp 177 178 ISBN 978 3 527 32669 3 Cano A Calaf i Alsina J Duenas Diez JL 22 September 2006 Selective Estrogen Receptor Modulators A New Brand of Multitarget Drugs Springer Science amp Business Media pp 52 ISBN 978 3 540 34742 2 a b Orwoll ES Bilezikian JP Vanderschueren D 30 November 2009 Osteoporosis in Men The Effects of Gender on Skeletal Health Academic Press pp 717 ISBN 978 0 08 092346 8 Sneader W 2005 Drug Discovery A History New York Wiley p 472 pages ISBN 978 0 471 89979 2 a b Jordan VC March 2003 Tamoxifen a most unlikely pioneering medicine Nature Reviews Drug Discovery 2 3 205 213 doi 10 1038 nrd1031 PMID 12612646 S2CID 31333174 Kirk E 24 July 2002 Dog s tale of survival opens door in cancer research Health and Behavior USA Today Archived from the original on 28 June 2008 Retrieved 24 June 2008 Blackwell KL Haroon ZA Shan S Saito W Broadwater G Greenberg CS Dewhirst MW November 2000 Tamoxifen inhibits angiogenesis in estrogen receptor negative animal models Clinical Cancer Research 6 11 4359 4364 PMID 11106254 Archived from the original on 6 September 2008 a b Jensen EV Jordan VC June 2003 The estrogen receptor a model for molecular medicine Clin Cancer Res 9 6 1980 9 PMID 12796359 Howell A Jordan VC 2013 Adjuvant Antihormone Therapy In Jordon VC ed Estrogen Action Selective Estrogen Receptor Modulators And Women s Health Progress And Promise World Scientific pp 229 254 doi 10 1142 9781848169586 0010 ISBN 978 1 84816 959 3 Cole MP Jones CT Todd ID June 1971 A new anti oestrogenic agent in late breast cancer An early clinical appraisal of ICI46474 British Journal of Cancer 25 2 270 275 doi 10 1038 bjc 1971 33 PMC 2008453 PMID 5115829 Ward HW January 1973 Anti oestrogen therapy for breast cancer a trial of tamoxifen at two dose levels British Medical Journal 1 5844 13 14 doi 10 1136 bmj 1 5844 13 PMC 1588574 PMID 4567104 Maverick and pioneer whose work is improving odds in breast cancer fight Archived from the original on 28 June 2013 Retrieved 5 November 2013 Maverick and pioneer whose work is improving odds in breast cancer fight The Yorkshire Post 27 June 2013 Archived from the original on 9 March 2016 Retrieved 7 April 2017 Howell A Jordan VC 2013 Adjuvant Antihormone Therapy In Craig JV ed Estrogen Action Selective Estrogen Receptor Modulators And Women s Health Progress And Promise World Scientific pp 229 254 doi 10 1142 9781848169586 0010 ISBN 978 1 84816 959 3 Baum M Brinkley DM Dossett JA McPherson K Patterson JS Rubens RD et al August 1983 Improved survival among patients treated with adjuvant tamoxifen after mastectomy for early breast cancer Lancet 2 8347 450 doi 10 1016 S0140 6736 83 90406 3 PMID 6135926 S2CID 54230182 Furr BJ Jordan VC 1984 The pharmacology and clinical uses of tamoxifen Pharmacology amp Therapeutics 25 2 127 205 doi 10 1016 0163 7258 84 90043 3 PMID 6438654 Jordan VC August 2001 Selective estrogen receptor modulation a personal perspective Cancer Research 61 15 5683 5687 PMID 11479197 Lerner LJ Jordan VC July 1990 Development of antiestrogens and their use in breast cancer eighth Cain memorial award lecture Cancer Research 50 14 4177 4189 PMID 2194650 Early Breast Cancer Trialists Collaborative Group May 1998 Tamoxifen for early breast cancer an overview of the randomised trials Lancet 351 9114 1451 1467 doi 10 1016 S0140 6736 97 11423 4 PMID 9605801 S2CID 46287542 Tamoxifen Cancer the generic impact BioPortfolio Limited Archived from the original on 16 May 2008 Retrieved 14 November 2008 Vose B AstraZenecain Cancer Slide 15 PDF AstraZeneca Annual Business Review www astrazeneca com Archived PDF from the original on 31 January 2010 Retrieved 28 March 2009 2004 tamoxifen market share 70 Source IMS HEALTH IMS MIDAS Monthly July 2004 Aromatase Inhibitors Tamoxifen Eugster EA Shankar R Feezle LK Pescovitz OH 1999 Tamoxifen treatment of progressive precocious puberty in a patient with McCune Albright syndrome Journal of Pediatric Endocrinology amp Metabolism 12 5 681 686 doi 10 1515 jpem 1999 12 5 681 PMID 10703542 S2CID 71034635 Eugster EA Rubin SD Reiter EO Plourde P Jou HC Pescovitz OH July 2003 Tamoxifen treatment for precocious puberty in McCune Albright syndrome a multicenter trial The Journal of Pediatrics 143 1 60 66 doi 10 1016 S0022 3476 03 00128 8 PMID 12915825 Kreher NC Eugster EA Shankar RR December 2005 The use of tamoxifen to improve height potential in short pubertal boys Pediatrics 116 6 1513 1515 doi 10 1542 peds 2005 0577 PMID 16322179 S2CID 45133251 Karimian E Chagin AS Gjerde J Heino T Lien EA Ohlsson C Savendahl L August 2008 Tamoxifen impairs both longitudinal and cortical bone growth in young male rats Journal of Bone and Mineral Research 23 8 1267 1277 doi 10 1359 jbmr 080319 PMID 18348701 S2CID 35813153 Chagin AS Karimian E Zaman F Takigawa M Chrysis D Savendahl L May 2007 Tamoxifen induces permanent growth arrest through selective induction of apoptosis in growth plate chondrocytes in cultured rat metatarsal bones Bone 40 5 1415 1424 doi 10 1016 j bone 2006 12 066 PMID 17293177 van Bommel EF Hendriksz TR Huiskes AW Zeegers AG January 2006 Brief communication tamoxifen therapy for nonmalignant retroperitoneal fibrosis Annals of Internal Medicine 144 2 101 106 doi 10 7326 0003 4819 144 2 200601170 00007 PMID 16418409 S2CID 25699557 Akram S Pardi DS Schaffner JA Smyrk TC May 2007 Sclerosing mesenteritis clinical features treatment and outcome in ninety two patients Clinical Gastroenterology and Hepatology 5 5 589 96 quiz 523 4 doi 10 1016 j cgh 2007 02 032 PMID 17478346 Dabelic N Jukic T Labar Z Novosel SA Matesa N Kusic Z April 2003 Riedel s thyroiditis treated with tamoxifen PDF Croatian Medical Journal 44 2 239 241 PMID 12698518 Archived PDF from the original on 10 September 2008 Feil R Brocard J Mascrez B LeMeur M Metzger D Chambon P October 1996 Ligand activated site specific recombination in mice Proceedings of the National Academy of Sciences of the United States of America 93 20 10887 10890 Bibcode 1996PNAS 9310887F doi 10 1073 pnas 93 20 10887 PMC 38252 PMID 8855277 a b c Talaei A Pourgholami M Khatibi Moghadam H Faridhosseini F Farhoudi F Askari Noghani A Sadeghi R June 2016 Tamoxifen A Protein Kinase C Inhibitor to Treat Mania A Systematic Review and Meta Analysis of Randomized Placebo Controlled Trials Journal of Clinical Psychopharmacology 36 3 272 275 doi 10 1097 JCP 0000000000000492 PMID 27088436 S2CID 39792641 a b Saxena A Scaini G Bavaresco DV Leite C Valvassori SS Carvalho AF Quevedo J November 2017 Role of Protein Kinase C in Bipolar Disorder A Review of the Current Literature Molecular Neuropsychiatry 3 2 108 124 doi 10 1159 000480349 PMC 5701269 PMID 29230399 Endoxifen Intas Pharmaceuticals Jina pharmaceuticals AdisInsight Springer Nature Switzerland AG Ahmad I January 2018 Tamoxifen a pioneering drug An update on the therapeutic potential of tamoxifen derivatives European Journal of Medicinal Chemistry 143 515 531 doi 10 1016 j ejmech 2017 11 056 PMID 29207335 Further reading editDean L 2014 Tamoxifen Therapy and CYP2D6 Genotype In Pratt VM McLeod HL Rubinstein WS et al eds Medical Genetics Summaries National Center for Biotechnology Information NCBI PMID 28520357 Bookshelf ID NBK247013 External links edit Tamoxifen Drug Information Portal U S National Library of Medicine Tamoxifen citrate Drug Information Portal U S National Library of Medicine Tamoxifen citrate National Cancer Institute 5 October 2006 Portal nbsp Medicine Retrieved from https en wikipedia org w index php title Tamoxifen amp oldid 1195788844, wikipedia, wiki, book, books, library,

article

, read, download, free, free download, mp3, video, mp4, 3gp, jpg, jpeg, gif, png, picture, music, song, movie, book, game, games.