Diethylstilbestrol is a synthetic non steroidal estrogen, chemical formula CeighteenHtwentyOtwo。It can produce all the same pharmacological and therapeutic effects as natural estradiol.It is mainly used for functional bleeding and amenorrhea caused by low estrogen and hormone imbalance. It can also be used before stillbirth induction to improve the sensitivity of uterine muscle layer to oxytocin.
On October 27, 2017, the list of carcinogens published by the International Agency for Research on Cancer of the World Health Organization (WHO) was preliminarily sorted out for reference, and diethylstilbestrol was included in the list of Class 1 carcinogens.[4]
On December 27, 2019, diethylstilbestrol was included in the list of drugs and other compounds prohibited from use in food animals.[1]
Solubility: soluble in ethanol, ether, chloroform, fatty oil and dilute alkali solution, almost insoluble in water[5]
Molecular structure data
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Molar refractive index: 86.16
Molar volume (cmthree/mol）：260.0
Isotonic specific volume (90.2K): 654.4
Surface tension (dyne/cm): 40.0
Polarization (10-24cmthree）：34.16[5]
Calculate chemical data
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Drainage parameter calculation reference value (XlogP): 0
Number of hydrogen bond donors: 2
Number of hydrogen bond receptors: 2
Number of rotatable chemical bonds: 4
Number of tautomers: 9
Topological molecular polar surface area: 40.5
Number of heavy atoms: 20
Surface charge: 0
Complexity: 286
Number of isotope atoms: 0
Determine the number of atomic structure centers: 0
Number of uncertain atomic structure centers: 0
Determine the number of chemical bond stereocenters: 1
Number of uncertain chemical bond structure centers: 0
Number of covalent bond units: 1[5]
Drug use
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indication
1. Diethylstilbestrol tablets are mainly used to supplement estrogen deficiency in the body, such as atrophic vaginitis, female gonadal dysplasia, menopausal syndrome, senile vulva dryness and vaginitis, primary ovarian absence after ovariectomy.
2. Breast cancer, postmenopausal and male advanced breast cancer, who cannot be operated.
3. Prostate cancer is an advanced patient that cannot be treated surgically.4. Prevent postpartum lactation, withdrawal (or return) of milk.[2]
Dosage and usage
1. Amenorrhea: A small oral dose can stimulate the anterior pituitary gland to secrete gonadotropin, which does not exceed 0.25 mg per day.
2. For artificial menstrual cycle: take 0.25mg every day for 20 days, and then treat with the same method after menstruation, a total of 3 cycles.
3. For prolonged menstrual cycle and uterine hypoplasia: take 0.1~0.2 mg daily for 6 months, and stop taking during menstruation.
4. Treatment of functional uterine bleeding: 0.5~1mg per night for 20 days.
5. For menopausal syndrome: take 0.25mg daily, and change it to 0.1mg daily after symptom control (as in the case of daily sublingual administration of 5-10mg methyltestosterone, the effect is better).
6. Demulsification: 5mg each time, 2-3 times a day, for 3 consecutive days;Or intramuscular injection of 4mg once a day for 3 to 5 days, at the same time, tighten the double breasts and feed less liquid.
7. Senile vaginitis: vaginal thiazide, 1-2 tablets (0.2mg each) every night for 7 days.
8. Cooperate with surgery for prostate cancer: 6~10mg, three times a day, for 2~3 months.
9. It is used for infertility caused by uterine dysplasia and thick cervical secretions: use small doses to make cervical mucus thin and sperm easy to penetrate. After menstruation, take 0.1mg daily for 15 days, with a course of treatment of 3-6 months.
10. It is used for missed abortion (stillbirth within 7 months of pregnancy, and still not delivered after 2 months or more): 5mg each time, three times a day, 5 to 7 days as a course of treatment, and 5 days after withdrawal. If it is invalid, one course of treatment can be repeated.
matters needing attention
1. There may be nausea, vomiting, anorexia, headache and other adverse reactions.Long term application may cause endometrial hyperplasia, which may lead to uterine bleeding and hypertrophy.
2. The medicine should be taken according to the specified method. Stopping the medicine halfway can cause uterine bleeding.
3. It is forbidden for patients with liver and kidney diseases and pregnant women.
4. Do not use it for cancer patients (except for prostate cancer patients).
5. A few patients have pain in the heart fossa.There is also increased sexual desire.
6. Breast disease, endometritis, bleeding tendency and menopausal follicular overuse should not be used.
7. Long term and massive application can induce malignant tumors of reproductive system;Drug use during pregnancy may lead to the risk of congenital defects of the fetus, and the risk of vaginal adenosis or cervical cancer (DES syndrome) of female infants increases after adulthood.
Adverse reactions
When pregnant women take this medicine, the incidence of cervical and vaginal adenosis and adenocarcinoma in their female offspring increases after puberty, and the incidence of reproductive tract abnormalities and sperm abnormalities in their male offspring also increases.See estrogen for others.There may be nausea, vomiting, loss of appetite, headache. Long term use can cause endometrial hyperplasia and uterine bleeding and hypertrophy.
taboo
1. Do not use estrogen during pregnancy. Systemic medication may lead to fetal malformation. Vaginal medication should also be noted.After medication, female fetuses may suffer from reproductive tract abnormalities, vaginal adenosis in adolescence, and rare cases of vaginal cancer or cervical cancer in the reproductive age;Feminization of male fetuses, testicular dysplasia.Estrogen can enter the milk through the breast and be discharged, and can inhibit lactation. It is forbidden for lactating women.
2. The following cases should be prohibited: ① Known or suspected to have breast cancer, except when it is used to treat advanced metastatic breast cancer; ②Known or suspected to have estrogen dependent tumors; ③Acute thrombophlebitis or thromboembolism; ④When estrogen was used in the past, there was a history of thrombophlebitis or thromboembolism, except when it was used to treat advanced breast cancer and prostate cancer; ⑤Have a history of cholestatic jaundice; ⑥Undiagnosed irregular vaginal bleeding.
3. Estrogen should be used with caution in the following diseases: ① asthma; ②Cardiac insufficiency; ③Epilepsy; ④Mental depression: ⑤ Migraine; ⑥With renal insufficiency, estrogen can aggravate water retention; ⑦Diabetes mellitus; ⑧Benign breast disease; ⑨Cerebrovascular diseases; ⑩Coronary artery disease; ⑩Endometriosis; ⑩Gallbladder disease or history, especially gallstones; ⑩Abnormal liver function; ⑩High blood calcium, accompanied by tumor or metabolic bone disease; ⑩Hypertension; ⑩Jaundice during pregnancy or history of jaundice, estrogen has the risk of promoting recurrence of liver damage; ⑩Acute, intermittent or complex liver purpura; ⑩Abnormal renal function; ⑩Thyroid disorders; ⑩fibroid.It is forbidden for patients with liver and kidney disease and pregnant women.[2]
Interaction
1. When used together with anticoagulants, estrogen can reduce the anticoagulant effect. When it must be used together, the dosage of anticoagulants should be adjusted.Equal use with carbamazepine, phenobarbital, phenytoin sodium, promidone and rifampicin can reduce the effect of estrogen, which is due to the induction of liver microsomal enzymes and the acceleration of estrogen metabolism.
2. When used together with tricyclic antidepressants, a large amount of estrogen can enhance the adverse reactions of antidepressants and reduce their due effects.When used together with antihypertensive drugs, the antihypertensive effect can be reduced.Reduce the therapeutic effect of tamoxifen.Increase the absorption of calcium agent.[3]
pharmacological action
It is a synthetic non steroidal estrogen, which can produce all pharmacological and therapeutic effects the same as natural estradiol.
① Promote the normal development of female organs and accessory sexual characteristics.
② Promote endometrial hyperplasia and vaginal epithelial keratinization.
③ Enhance uterine contraction and increase the sensitivity of uterus to oxytocin.
④ Small dose stimulation and large dose inhibition of anterior pituitary gonadotropin and prolactin secretion.
⑤ Anti androgen effect.
Pharmacokinetics
This product has good oral effect and is not easy to be damaged by liver. Its metabolic pathway is still unclear.[3]
Pharmacopoeia information
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essential information
This product is（E）-4,4 '- (1,2-diethyl-1,2-vinylene) bisphenol, calculated as dry product, containing CeighteenHtwentyOtwoIt should be 97.0% - 103.0%.
character
This product is colorless crystal or white crystalline powder, almost odorless.
This product is easily soluble in methanol, soluble in ethanol, ether or fatty oil, slightly soluble in chloroform, almost insoluble in water, and soluble in dilute sodium hydroxide solution.
melting point
The melting point of this product (general rule 0612) is 169~172 ℃.
identify
1. Take about 10mg of this product, add 1mL of sulfuric acid to dissolve it, and the solution will appear orange yellow (hexanestrol is light yellow). Dilute it with 10mL of water, and the orange color will disappear.
2. In the chromatogram recorded under the content determination item, the retention time of the two main peaks of the test solution should be consistent with the retention time of the corresponding two main peaks of the reference solution.
3. The infrared absorption spectrum of this product should be consistent with the control spectrum (spectrum set 28 figure).
inspect
PH
Take 0.10g of this product, add 5.0mL of 70% ethanol to dissolve it, and the solution should show neutral reaction when encountering litmus test paper.
Related substances
Determine according to the method of high performance liquid chromatography (general rule 0512).
Test solution: Take a proper amount of this product, add ethanol water (1:1) to dissolve it and dilute it to make a solution containing about 0.5mg per 1mL.
Control solution: precisely measure 1mL of the test solution, place it in a 50mL measuring flask, dilute it with ethanol water (1:1) to the scale, and shake it up.
System suitability solution: take about 10mg of diethylstilbestrol reference substance, add 50mL of chloroform to dissolve it, place it in the dark for at least 5 hours, measure 5.0mL, evaporate chloroform, and add 25mL of ethanol water (1:1) to dissolve the residue (cis and trans forms of diethylstilbestrol).
Chromatographic conditions: octadecyl silane bonded silica gel is used as filler, methanol water (80:20) is used as mobile phase, detection wavelength is 254nm, and injection volume is 10 µ L.
Requirements for system applicability: in the chromatogram of system applicability solution, the peak sequence is diethylstilbestrol trans body peak and diethylstilbestrol cis body peak, the number of theoretical plates calculated according to diethylstilbestrol trans body peak should not be less than 1000, and the resolution between diethylstilbestrol trans body peak and cis body peak should be greater than 5.0.
Determination method: Precisely measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram to twice the retention time of diethylstilbestrol cis peak.
Limit: if there are impurity peaks in the chromatogram of the test solution, there should be no more than 4, and the area of a single impurity peak should not be greater than 1.26 times the sum of the cis peak area of diethylstilbestrol and the trans peak area of diethylstilbestrol in the reference solution, 0.5 times (1.0%),The sum of the peak areas of each impurity shall not be greater than 1.26 times of the sum of the cis and trans peak areas of diethylstilbestrol in the reference solution.
Loss on drying
Take this product, dry it at 105 ℃ to constant weight, and the weight loss shall not exceed 0.5% (general rule 0831).
Ignition residue
Not more than 0.1% (general rule 0841).
Assay
Determine according to the method of high performance liquid chromatography (general rule 0512).
Test solution: Take an appropriate amount of this product, weigh it accurately, add ethanol water (1:1) to dissolve it and dilute it quantitatively to make a solution containing about 0.1mg per 1mL.
Reference solution: Take an appropriate amount of diethylstilbestrol reference solution, weigh it precisely, add ethanol water (1:1) to dissolve it and dilute it quantitatively to prepare a solution containing about 0.1mg per 1mL.
System suitability solution, chromatographic conditions and system suitability requirements: see relevant substances.
Determination method: Precisely measure the test solution and the reference solution, respectively inject them into the liquid chromatograph, and record the chromatogram.The external standard method is used to calculate the sum of the cis peak area of diethylstilbestrol and the trans peak area of diethylstilbestrol.
category
Estrogens.
Storage
Shading, sealed storage.
preparation
1. Diethylstilbestrol Tablets.
2. Diethylstilbestrol injection.[6]
security information
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Safety terminology
S36/37/39：Wear suitable protective clothing, gloves and eye/face protection.
Wear appropriate protective clothing, gloves and goggles or mask.
S45：In case of accident or if you feel unwell, seek medical advice immediately (show the label whenever possible.)
In case of accident or discomfort, seek medical advice immediately (show the label if possible).
S53：Avoid exposure - obtain special instructions before use.
Avoid contact and obtain special instructions before use.
S60：This material and its container must be disposed of as hazardous waste.
The substance and its container must be disposed of as hazardous waste.
S61：Avoid release to the environment. Refer to special instructions / safety data sheets.
Avoid release to the environment.Refer to Special Instructions/Safety Data Sheet.
Risk terminology
R36/37/38：Irritating to eyes, respiratory system and skin.
Irritating to eyes, respiratory system and skin.
R40：Limited evidence of a carcinogenic effect.
Few reports have cancer consequences.
R45：May cause cancer.
May cause cancer.
R51/53：Toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment.
It is toxic to aquatic organisms and may have long-term adverse effects on the water environment.
