What Is an Antiestrogen?

Tamoxifen is used to treat advanced breast and ovarian cancer. In the treatment of breast cancer, the effective rate is generally 30%. The effect of estrogen receptor positive patients is better (49%), and the effect of negative patients is poor (7%). Both premenopausal and postmenopausal patients can be used, and people who are postmenopausal and over 60 years of age are more effective than premenopausal and young patients. From the site of the lesion, the skin, lymph nodes, and soft tissues have a good effect, and the bone and visceral metastasis have a poor effect.
Tamoxifen

On October 27, 2017, the list of carcinogens published by the International Agency for Research on Cancer of the World Health Organization initially compiled and referenced tamoxifen in the list of carcinogens of the first class. ^[1]

Drug type: Essential medicines
Drug name: Tamoxifen
English name: Tamoxifen
Chinese alias: Tamoxifen; tamoxifen; tamoxifen

English alias: Tam; Nolvadex; Ledertam
CAS: 10540-29-1
Molecular formula: C26H29NO
Molecular weight: 371.51500

Tamoxifen Basic Information

Chinese name: Tamoxifen

Chinese alias: (Z) -2- [4- (1,2-diphenyl-1-butene) phenoxy] -N, N-dimethylethylamine; nitrogen N-demethyl tamoxifen hydrochloride Tamoxifen

English name: tamoxifen

English alias: Oncomox; [3H] -Tamoxifen; Soltamox; Crisafeno; trans-2- [4- (1,2-diphenyl-1-butenyl) phenoxy] -N, N-dimethylethylamine;

CAS number: 10540-29-1

Molecular formula: C ₂₆ H ₂₉ NO

Molecular weight: 371.51500

Exact mass: 371.22500

Chemical structure: as shown on the right

PSA: 12.4000

LogP: 5.99610 ^[2]

Tamoxifen physical and chemical properties

Appearance and properties: fine off-white crystalline powder

Density: 1.042 g / cm ³

Melting point: 97-98ºC

Flash point: 140ºC

Refractive index: 1.582

Storage conditions: 2-8ºC vapor pressure: 1.85E-09mmHg at 25 ° C

Tamoxifen Toxicology Data

I. Test method: oral

Intake dose: 5600 ug / kg / 1W-I

Test object: person-woman

Type of toxicity: acute

Toxic effects: skin and appendages-breast cancer

Intake dose: 200 g / kg / number

Test object: person-woman

Type of toxicity: acute

Toxic effects: 1. Nausea or vomiting

2. Leukopenia

3. Thrombocytopenia III. Test method: Not reported

Intake dose: 5600 ug / kg / 2W-I

Test object: person-woman

Type of toxicity: acute

Toxic effects: Anemia

Test method: oral intake dose: 4100 mg / kg

Test subject: rodent-rat

Type of toxicity: Acute toxicity: Detailed lethal dose values other than reported

Tamoxifen Ecological Data

This substance may be harmful to the environment. Special attention should be given to water bodies.

Tamoxifen molecular structure data

1. Molar refractive index: 118.89

2. Molar volume (m3 / mol): 356.2

3. Isotonic specific volume (90.2K): 898.14, Surface tension (dyne / cm): 40.4

5. Polarizability (10-24cm3): 47.13 calculated chemical data

1. Hydrophobic parameter calculation reference value (XlogP): 7.1

2.Number of hydrogen bond donors: 0

3.Number of hydrogen bond acceptors: 2

4.Number of rotatable chemical bonds: 8

5.Number of tautomers: none

6. Topological molecular polar surface area 12.5

7.Number of heavy atoms: 28

8.Surface charge: 0

9.Complexity: 463

10.Number of isotope atoms: 0

11. Determine the number of atomic stereocenters: 0

12. Uncertain number of atomic stereocenters: 0

13. Determine the number of chemical bond stereocenters: 1

14. Uncertain number of chemical bond stereocenters: 0

15.Number of covalent bond units: 1

Tamoxifen Properties and Stability

It will not decompose when used and stored in accordance with specifications. ^[3]

Tamoxifen related drug label information

Tamoxifen classification name

Primary classification: Endocrine system drugs Secondary classification: Gonad disease medication

Tamoxifen drug English name

Tamoxifen

Tamoxifen drug alias

Tamoxifen citrate, Tamoxifen citrate, Tamoxifen, Novartis, Tamoxifen citrate Xifen, Tamoxifen, Breast Cancer Suppressant, Nolvadex, Tam, TamoxifenCitrate

Tamoxifen drug dosage form

1. Tablet: 10mg; 2. Capsule: 10mg.

Tamoxifen pharmacological action

Is a synthetic anti-estrogen drug. The structure is similar to estrogen. It can compete with estrogen for the estrogen receptor, form a stable complex with the estrogen receptor, and transport into the nucleus, preventing the opening of chromosomal genes, thereby inhibiting the growth and development of cancer cells.

Tamoxifen pharmacokinetics

After oral administration of 20 mg of the drug, the peak drug concentration reached 0.14 g / ml in 4-7 hours. A second peak due to enterohepatic circulation occurs 4 days or more after administration. The half-life phase is more than 7 days, and the phase is 7 to 14 hours. 4 to 10 weeks after the administration, the objective signs improved, and if there were bone metastases, it was effective for several months. A single dose of anti-estrogen effect lasts for several weeks. This drug is metabolized in the liver. The main metabolites are N-desmethyl tamoxifen and 4-hydroxy tamoxifen. It also binds to estrogen receptors. The drug is mostly excreted in the form of conjugates, and a small amount is excreted from urine. The elimination half-life of the parent compound of this product is 5-7 days, and the metabolite nitrogen-desmethyl tamoxifen is 14 days. Indication

1. Adjuvant therapy for breast cancer after surgery, for estrogen receptor-positive patients, especially in patients over 60 years of age after menopause, the effect is better. 2. Advanced breast cancer, or those who relapse after treatment. Good effect on skin, lymph node and soft tissue metastasis. Endometrial cancer. Contraindications

1. Pregnant women and those with thromboembolic disease. 2. Those with deep venous thrombosis. 3. People with history of pulmonary embolism.

Tamoxifen precautions

1. Check for visual impairment and liver and kidney insufficiency before use. 2. For patients who have been taking this product for a long time and are at risk of thromboembolism, blood tests should be checked regularly during treatment. If there is bone metastasis, blood calcium should be checked regularly at the beginning of treatment. During long-term treatment with this product for more than 2 years, liver function should be tested regularly. 3. When abnormal vaginal bleeding occurs, you should see a doctor immediately and conduct a comprehensive examination. The drug should be discontinued when there is a large amount of vaginal bleeding. 4. Patients treated with this product have an increased risk of endometrial cancer, so careful gynecological examination should be performed. 5. The use of this product can appear sudden ovarian functional cysts and excessive menstruation and irregular uterine bleeding. Therefore, if you must use this medicine before menopause, you should also take anti-gonadotropin drugs.

Tamoxifen adverse reactions

1. Gastrointestinal reactions: loss of appetite, nausea, vomiting, diarrhea. 2. Secondary anti-estrogen effects: facial flushing, vulvar itching, menstrual disorders, amenorrhea, increased vaginal discharge, vaginal bleeding, etc. 3. Neuropsychiatric symptoms: headache, dizziness, depression, etc. 4. Long-term application of large doses can cause visual impairment, such as cataracts. 5. Myelosuppression: A few patients may have transient leukocytes and thrombocytopenia. 6. Others: rash, hair loss, weight gain, abnormal liver function, etc.

Tamoxifen dosage

1. Breast cancer: better effect on estrogen receptor positive breast cancer patients. Orally 10 to 20 mg twice daily. 2. Endometrial cancer: This product has the effect of promoting progesterone receptor levels. Those with low progesterone receptor levels can use this product to increase the receptor level before treatment with progestin, or both at the same time to improve the efficacy. The general dose is 10 to 20 mg orally twice a day.

Tamoxifen drug interactions

1. This product can be combined with antitumor drugs such as doxorubicin, vincristine, methotrexate, cyclophosphamide, fluorouracil, etc. to enhance the activity and efficacy, but the combined dose should be noted. 2. When combined with phenobarbital, it can reduce the steady-state blood concentration of this product. 3. Estrogen can affect the treatment effect of this product, and it should not be combined with estrogen drugs. 4. Antacids, cimetidine, famotidine, ranitidine, etc. can change gastric pH. Decomposing the casing of this product in advance can have a stimulating effect on the stomach. Therefore, the combination with the above drugs should be spaced 1 to 2 hours. 5. Combination with anti-vitamin K drugs can increase the effect of anticoagulants and increase the risk of bleeding, so it should not be combined. 6. Combined with Aminutamide will reduce the metabolism of this product and reduce its efficacy. 7. Combined with cyclophosphamide, fluorouracil, and methotrexate can increase the risk of thromboembolism. We must weigh the advantages and disadvantages when combined. 8. This product may increase the plasma concentration of cyclosporine. 9. Combined with etoposide can increase the toxicity of this product. 10. This product can reduce the plasma concentration of letrozole by inducing cytochrome P450 enzymes.

Tamoxifen drug evaluation

The effective rate of this product in the clinical treatment of breast cancer is generally about 30%. The effect is better in patients with positive estrogen receptors, and less effective in patients with negative results. Premenopausal and postmenopausal patients can be used, and postmenopausal medication is better than premenopausal and young patients. From the site of the lesion, the skin, lymph nodes, and soft tissues have a good effect, and the bone and visceral metastasis have a poor effect. The efficacy of this product for the treatment of ovarian cancer is better than other estrogen preparations, and the side effects are significantly lower. ^[4]

Tamoxifen Pharmacopeia Introduction

[Identification] (1) Take an appropriate amount of this product, add 5ml of acetic anhydride-pyridine (1: 5), shake well, heat on a water bath, and change the color of the solution from yellow to red. (2) Take this product, add absolute ethanol to dissolve and dilute it to make a solution containing about 10 g per ml. According to ultraviolet-visible spectrophotometry (Appendix IV A), it has maximum absorption at the wavelengths of 238nm and 278nm. (3) The infrared absorption spectrum of this product should be consistent with the control spectrum (spectrum set 265); if not, take this product and re-crystallize it with acetone for measurement. [Inspection] Take this product for drying weight loss and dry it at 105 ° C for 4 hours. The weight loss should not exceed 0.5% (Appendix L). Related substances are protected from light, and the new system is used temporarily. Take this product, weigh it accurately, add the mobile phase to dissolve and quantitatively dilute to make a solution containing about 1.5mg per lml as the test solution; take an appropriate amount, and use the mobile phase to quantitatively dilute to make 7.5 per lml. A g solution was used as a control solution; another E-isomer reference was weighed, and the mobile phase was dissolved and quantitatively diluted to make a solution containing about 7.5 g per 1 ml as a reference solution. According to the high performance liquid chromatography (Appendix VD) test, octadecylsilane bonded silica gel was used as the filler, and phosphate buffer solution (taken 0.9 g of sodium dihydrogen phosphate and N, N-dimethyloctylamine 4.8 g, add water to dissolve and dilute to 1000ml, adjust the pH value to 3.0 with phosphoric acid-acetonitrile (60:40) as the mobile phase, the detection wavelength is 240nm. Take 10 l of the mixed solution of the reference solution and the reference solution, and inject it into the liquid chromatograph to adjust the detection sensitivity so that the peak height of the tamoxifen citrate chromatographic peak is about 30% of the full scale. The number of theoretical plates is E- The calculated isomer peak is not less than 2000, and the resolution of the E-isomer peak and the main component peak (Z-isomer) should be greater than 3.0. Then, accurately measure 10 l each of the test solution, the reference solution and the reference solution, and inject them into the liquid chromatograph respectively, and record the chromatogram to twice the retention time of the main component peak. If there is a peak with the same retention time of the isomer peak in the chromatogram of the reference solution, the peak area must not be greater than the area of the main peak of the reference solution (0.5%); if there are other impurity peaks, a single impurity peak The area must not be greater than the area of the main peak of the control solution (0.5%), and the sum of the areas of other impurity peaks must not be greater than twice the area of the main peak of the control solution (1.0%). [Content determination] Take about 0.35g of this product, accurately weigh, add 50ml of glacial acetic acid, and dissolve at a slight temperature, then add 1 drop of crystal violet indicator solution, titrate with perchloric acid titration solution (0.1mol / L) until the solution shows It is blue-green, and the result of the titration is corrected by a blank test. Per 1ml of perchloric acid titration solution (0.1mol / L) is equivalent to 56.36mg of C 26H29NO · C6H807. [Category] Antitumor drug. [Storage] Shading, sealed, and stored in a dry place. ^[5]