|Company Name:||LGM Pharma |
|Tamoxifen Chemical Properties|
|Tamoxifen Usage And Synthesis|
|Antiestrogen drug||Tamoxifen is non-steroidal anti-estrogen drugs. Its structure is similar to estrogen, existing Z type and O type isomers. The physical and chemical properties are different from each other, and physiological activity is different. E type has weak estrogenic activity, Z type having the effect of anti-estrogen. If the estrogen receptor (ER) is present in breast cancer cells, estrogen enters into tumor cells and binds with ER, promoting mRNA and DNA synthesis of tumor cells, stimulating tumor cell growth. However, Tamoxifen Z isomer enters into the cell, competitively binding with ER to form receptor complexes, inhibiting that estrogen plays an role, and inhibiting proliferation of breast cancer cells. Clinically it is mainly used for high levels of estrogen in breast cancer patients, which combines with androgen and other anticancer drugs (such as doxorubicin, etc., enhancing the effectiveness and showing good effect in postmenopausal patients with advanced breast cancer. Oral: once 10 ~ 20mg, 2 times 1 day. Common side effects are flushing, genital itching, occasional vaginal bleeding, a few may have a headache, fluid retention, for a long time may have retinal disease, vision loss, the other can have bone marrow suppression and gastrointestinal reactions.|
Tamoxifen is used to treat breast cancer, and can reduce mortality and recurrence rate of estrogen-dependent breast cancer patients, so it has a good prospect. Another endocrine therapy aromatase inhibitor, it can inhibit effect of aromatase, preventing that the and rostenedione secreted by adrenal gland is transformed into estrogen in peripheral tissues (fat, skin, muscle), further reducing estrogen levels in postmenopausal women. It is currently one of the important means to treat postmenopausal patients with estrogen and progesterone receptor-positive breast cancer.
Figure 1 Mechanism of action of Tamoxifen and aromatase inhibitors
|Origin of the study||In the 1960s, as for initial research of estrogen drug, scientists found that anti-estrogen drugs can prevent endometrial hyperplasia and embryo implantation in rats, and has the role of contraception, hoping that it can be used as contraceptives for use in humans. In1966 UK reproductive endocrinologist Walpole firstly reported study of Tamoxifen. When investigating an anti-estrogen substance -tristyrylphenol, they found that its two derivatives had different physiological effects. They used vaginal epithelium keratosis index and uterine weight growth index as the evaluation index. Results showed that homeopathic structure (ICI47,699) has estrogen-like effects on uterus and vaginal epithelial cells in rat and mice; trans structure (ICI46,747) has very weak estrogenic effect on vaginal epithelial cells in rat, has an anti-estrogenic effect on the uterus, which can terminate early pregnancy and inhibit ovulation, but it also has anti-estrogenic effect on uterus and vaginal epithelial cells in mouse. Trans structure ICI46,747 which is now Tamoxifen, scientists expect that ICI46,747 can be used as a new contraceptives in humans. However, during the clinical trial, they found that the drug did not show the same effect in rats, but the drug can stimulate endometrial hyperplasia, and promote ovulation. Thus, clinically Tamoxifen was firstly used as ovulation drugs in anovulatory infertility patients, and still in use. For the current field of assisted reproductive technology treatment of ovarian hyperstimulation program, it also has a good effect on ovulation. Thus, Tamoxifen had both estrogen-like and anti-estrogenic effects, and showed different effects on different species and tissues.|
Figure 2 The structural formula of Tamoxifen.
The above information is edited by the Chemicalbook of Liu Yujie.
|Uses||1. Treatment for Women with metastatic breast cancer recurrence. |
2. Used as adjuvant therapy after surgery for breast cancer metastasis, and relapse prevention.
3. For the treatment of ovarian cancer, endometrial cancer and endometriosis.
|Pharmacokinetics||This product is easily absorbed orally, generally three hours after taking the drug concentration in the blood is up to the peak; because of enterohepatic circulation, the concentration of product is a more lasting in vivo; in the liver metabolism this product mainly excreted in the feces by biliary (58% to 100% ) rarely excreted in urine (only 2% to 21%); after the anima taking isotopically labeled this product, it is found that radioactivity is the highest in animal ovaries.After it is used for post-menopausal women, the concentration in endometrium is 2 times in plasma .|
|Adverse reactions||1. Early treatment of bone cancer pain and may be a transient increase, continued treatment can be gradually reduced. |
2. gastrointestinal reactions: loss of appetite, nausea, vomiting, diarrhea.
3. Reproductive system: menstrual disorders, amenorrhea, vaginal bleeding, genital itching, endometrial hyperplasia, endometrial polyps and endometrial cancer.
4. Skin: facial flushing, rash, hair loss.
5. Bone marrow: occasionally neutropenia and thrombocytopenia.
6. Liver function: occasionally abnormalities.
7. Eyes: using for long time (17 months or more) and large number (240 ~ 320mg per day), may appear retinal lesions or corneal opacity .
8. The rare and needed attention of side effects: insanity, pulmonary embolism (showing shortness of breath), thrombosis, weakness, drowsiness.
|Contraindications||1. It is contraindicated in patients who are allergic to this product. |
2. It is contraindicated in patients with fundus diseases.
3. It is contraindicated in patients who have history of deep vein thrombosis and pulmonary embolism or are receiving anticoagulant therapy.
4. It is contraindicated in pregnant woman and nursing mothers.
|Precautions||1. Abnormal liver function should be used with caution. If bone metastasis, patients are needed to regularly check blood calcium in the early treatment. |
2.Pregnancy safety of this drug is classified as D class by FDA.
|Drug interactions||1. The drug combines with fluorouracil, cyclophosphamide, methotrexate, vincristine and doxorubicin, etc. and can improve the effects. |
2. The drug can increase the dopaminergic effect of bromocriptine mesylate.
3. The data show that the drug can prolong neuromuscular blockade of atracurium.
4. The drug can enhance the effect of anticoagulants, not combining with anticoagulants (such as warfarin, two coumarin anticoagulants).
5. Antacids and cimetidine, famotidine, ranitidine can change the pH of the stomach, making the drug enteric-coated tablets decomposed and showing a stimulating effect on the stomach, so when l in combination , these drugs should be interval of 1 to 2 hours.
6. Estrogen can affect the therapeutic effect of the drug, should not be combined.
7. The in vitro test results show that the drug may inhibit the metabolism of tacrolimus.
8.When in combination with mitomycin, the risk of hemolytic syndrome and hematuria increased.
9. The drug combines with triptolide which can lead to accelerate tumor growth in mice, so the combination should be cautious.
10. with allopurinol, the drug may increase liver toxicity.
11. The drug combines with other cytotoxic drugs, increasing the risk of thromboembolism.
|Chemical Properties||White Crystalline Solid|
|Usage||A nonsteroidal estrogen antagonist of interest in the treatment of some forms of breast cancer. Tamoxifen is a Protein Kinase C inhibitor, and induces apoptosis in human malignant glioma cell lines|
|Usage||Tamoxifen is a selective estrogen response modifier (SERM), protein kinase C inhibitor and anti-angiogenetic factor. Tamoxifen is a prodrug that is metabolized to active metabolites 4-hydroxytamoxifen
(4-OHT) and endoxifen by cytochrome P450 isoforms CYP2D6 and CYP3A4. In breast cancer, the gene repressor activity of tamoxifen against ERBB2 is dependent upon PAX2. Blocks estradiol-stimulated VEGF
production in breast tumor cells.
Protein kinase C inhibitor. Induces apoptosis in human malignant glioma cell lines. Tamoxifen and its metabolite 4-hydroxytamoxifen are selective estrogen response mo
difiers (SERMs) that act as estrogen antagonists in mammary gland. Blocks estradiol-stimulated VEGF production in breast tumor cells.|
|Tamoxifen Preparation Products And Raw materials|