CN109620832B - Application of glycocholic acid in preparation of anti-hyperplasia of mammary glands medicine - Google Patents
Application of glycocholic acid in preparation of anti-hyperplasia of mammary glands medicine Download PDFInfo
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- 108010007979 Glycocholic Acid Proteins 0.000 title claims abstract description 34
- RFDAIACWWDREDC-UHFFFAOYSA-N Na salt-Glycocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCC(O)=O)C)C1(C)C(O)C2 RFDAIACWWDREDC-UHFFFAOYSA-N 0.000 title claims abstract description 34
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 title claims abstract description 34
- 229940099347 glycocholic acid Drugs 0.000 title claims abstract description 34
- 206010020718 hyperplasia Diseases 0.000 title claims abstract description 31
- 239000003814 drug Substances 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 4
- 210000005075 mammary gland Anatomy 0.000 title claims description 33
- 239000004480 active ingredient Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 5
- 206010006256 Breast hyperplasia Diseases 0.000 abstract 1
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 241000700159 Rattus Species 0.000 description 14
- 230000000694 effects Effects 0.000 description 12
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical group C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 8
- 210000000481 breast Anatomy 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 229960001603 tamoxifen Drugs 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229940011871 estrogen Drugs 0.000 description 3
- 239000000262 estrogen Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 210000002445 nipple Anatomy 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 2
- UYIFTLBWAOGQBI-BZDYCCQFSA-N Benzhormovarine Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4O)C)CC2=CC=3OC(=O)C1=CC=CC=C1 UYIFTLBWAOGQBI-BZDYCCQFSA-N 0.000 description 2
- 239000004380 Cholic acid Substances 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 208000030270 breast disease Diseases 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 2
- 229960002471 cholic acid Drugs 0.000 description 2
- 235000019416 cholic acid Nutrition 0.000 description 2
- 230000005786 degenerative changes Effects 0.000 description 2
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 229950002007 estradiol benzoate Drugs 0.000 description 2
- 239000000186 progesterone Substances 0.000 description 2
- 229960003387 progesterone Drugs 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229940123407 Androgen receptor antagonist Drugs 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 206010006242 Breast enlargement Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010058314 Dysplasia Diseases 0.000 description 1
- 229940102550 Estrogen receptor antagonist Drugs 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 150000001841 cholesterols Chemical class 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 230000008473 connective tissue growth Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 230000036732 histological change Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229940126680 traditional chinese medicines Drugs 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
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- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Gynecology & Obstetrics (AREA)
- Epidemiology (AREA)
- Pregnancy & Childbirth (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
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Abstract
The invention relates to application of chemical drugs in the field of medicine, in particular to application of glycocholic acid in a breast hyperplasia resistant drug. The invention provides a new application field of glycocholic acid, glycocholic acid can be applied to preparation of anti-mammary-hyperplasia drugs, glycocholic acid is used as an effective active ingredient of the anti-mammary-hyperplasia drugs, and the invention is beneficial to development of novel anti-mammary-hyperplasia drugs.
Description
Technical Field
The invention relates to application of a chemical medicament in the field of medicine, namely application of glycocholic acid (3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestane-24-carboxylic acid-24-glycinamide or N- [ (3 alpha, 5 beta, 7 alpha, 12 alpha) -3,7, 12-trihydroxy-24-oxocholestane-24-yl ] glycine) in preparing a medicament for treating hyperplasia of mammary glands.
Background
Hyperplasia of mammary glands refers to hyperplasia of mammary epithelium and fibrous tissue, degenerative changes of mammary tissue ducts and mammary lobules in structure and growth of progressive connective tissue, and the pathogenesis of hyperplasia is mainly due to endocrine hormone imbalance. The hyperplasia of mammary glands is also called as mammary gland dysplasia, is the most common breast disease of women of childbearing age, can occur at any age after the beginning of puberty, particularly women of 20-45 years old mostly, the incidence rate of the hyperplasia of mammary glands accounts for 74.1 percent of all breast diseases, accounts for 40 percent of women of childbearing age, and has a tendency of rising year by year, and the disease is listed as a high risk factor of breast cancer at present. The disease is characterized in that hyperplasia of mammary gland components shows abnormality on structure, quantity and tissue form, resulting in physiological hyperplasia and involution insufficiency of normal mammary gland lobules, forming disorder of normal mammary gland structure, and is degenerative change and progressive connective tissue growth of mammary gland tissue ducts and mammary gland lobules on the structure.
The existing method for treating hyperplasia of mammary glands mainly adopts western medicine treatment, for example, potassium iodide is orally taken by patients with obvious symptoms and wide lesion range to relieve the symptoms, androgen and estrogen receptor antagonist are also adopted to inhibit estrogen effect, soften nodules and relieve the symptoms, the conventional application is not suitable due to large adverse reaction, the traditional Chinese medicine treatment has small side effect and can partially relieve the symptoms, but the traditional Chinese medicines used in the existing market have various types, different effects and unsatisfactory curative effect.
Glycocholic acid is a combined cholic acid, is generated by combining cholic acid, a metabolite of cholesterol in liver, and glycine, has the physiological effects of promoting fat digestion and absorption in intestinal tracts, has a strong inhibition effect on acute and chronic inflammation and has the effect of regulating the immune function of organisms, and can be clinically used as a pharmaceutical excipient and an absorption enhancer.
Disclosure of Invention
Aiming at the problems existing in the existing treatment of hyperplasia of mammary glands, the invention provides a new application of glycocholic acid, namely the effect of resisting hyperplasia of mammary glands, by fully utilizing the characteristic that glycocholic acid is an endogenous active ingredient of a human body.
The molecular structural formula of glycocholic acid is:
application of glycocholic acid as medicine for treating hyperplasia of mammary glands is provided.
The application amount of glycocholic acid is 7.5-30 mg/kg.
The invention verifies that glycocholic acid has the characteristic of inhibiting the activity of hyperplasia of mammary glands through rat hyperplasia of mammary glands model intervention experiments, has the function of obviously inhibiting the hyperplasia of mammary glands of rats, and screens out corresponding dosage in animal experiments, and the invention is favorable for continuously developing glycocholic acid into a good medicament for treating hyperplasia of mammary glands.
Drawings
FIG. 1 is a graph of glycocholic acid effect on mammary gland histological changes in mammary gland hyperplasia rats;
wherein: a is a normal control group, B is a model control group, C is a tamoxifen group, D is a glycocholic acid low-dose group, E is a glycocholic acid medium-dose group, and F is a glycocholic acid high-dose group.
Detailed description of the preferred embodiments
Example one
Glycocholic acid for inhibiting mammary gland hyperplasia of rat
1. Experimental animals: SD, CV grade female rat, weight 200 + -20 g, purchased from the experimental animal center of Dalian medical university, and the experimental animal produces license number SCXK (Liao) 2013-.
2. Reagent: glycocholic acid, alatin reagent, lot number: h1520042, the purity is more than or equal to 97 percent; estradiol benzoate injection, shanghai tong pharmaceutical industry gmbh, lot number: s171202; progesterone injection, tianjin jinyao pharmaceutical limited, lot number: 1704101.
3. the method comprises the following steps: and (3) establishing a rat mammary gland hyperplasia model. SD female non-pregnant rats were 60 and randomly divided into 6 groups: a normal control group, a model control group, a tamoxifen group, a glycocholic acid low-dose group, a glycocholic acid medium-dose group and a glycocholic acid high-dose group, wherein each group contains 10 animals. Normal control group animals were injected intramuscularly with 0.1 mL/mouse of physiological saline 1 time per day for 30 consecutive days, and other groups were injected intramuscularly with 0.5mg/kg of estradiol benzoate 1 time per day for 25 consecutive days, followed by intramuscular injection of progesterone 4mg/kg 1 time per day for 5 consecutive days.
4. As a result: the influence on the diameter of the mammary gland and the height of the nipple is shown in table 1, the breast of the model group animals is obviously enlarged after the injection of the estrogen, the diameter of the breast and the height of the nipple are obviously increased compared with the normal group, glycocholic acid can inhibit the breast enlargement caused by the estrogen, and the diameter of the breast and the height of the nipple are not obviously increased.
Example two
Effect of Glycocholic acid on mammary histopathological changes in mammary hyperplasia rat model
1. The method comprises the following steps: and taking rats in a normal control group, a model group, a tamoxifen group and glycocholic acid low, medium and high dose groups, taking down a second pair of complete mammary gland tissues after the last administration, embedding paraffin, slicing, HE staining, and observing the morphological change of the mammary gland tissues of the rats in each group under an optical microscope. The acini and ducts in the mammary lobules and lobules of the rats in each group were measured by stereometry and different fields of view were counted for each pathological section, as shown in table 2.
2, results: as shown in figure 1: no obvious hyperplasia of mammary tissue of rats in the normal control group is observed under a light microscope. In the mammary tissue of the rat in the model group, the lobules and acinar epithelia of the mammary gland are obviously proliferated, the duct of the mammary gland is dilated, and the secretion of the gland is increased. After the glycocholic acid is used for treating hyperplasia of mammary glands and duct dilation, the number of lobules and acini of mammary glands is reduced, the acini begins to shrink, the secretion in cavities is obviously reduced, and the hyperplasia condition is obviously improved.
Table 1: effect of Glycocholic acid on mammary diameter and mammary height in mammary hyperplasia rats
| Group of | n | Dosage (/ kg) | Diameter of breast (mm) | Breast height (mm) |
| Normal control group | 10 | 10mL | 0.989±0.043** | 0.985±0.098** |
| Model control group | 10 | 10mL | 1.837±0.294 | 2.254±0.312 |
| Tamoxifen group | 10 | 1.8mg | 1.650±0.303* | 1.822±0.302** |
| Glycocholic acid low dose group | 10 | 7.5mg | 1.724±0.236* | 1.814±0.383** |
| Glycocholic acid medium dose group | 10 | 15mg | 1.801±0.227 | 1.998±0.318** |
| Glycocholic acid high dose group | 10 | 30mg | 1.822±0.274 | 2.001±0.318** |
Note: compared with the model control group,*the expression P is less than 0.05,**represents P < 0.01
Table 2: effect of Glycocholic acid on pathological changes of mammary lobules and ducts of mammary gland hyperplasia rats
Note: compared with the model control group,*the expression P is less than 0.05,**represents P < 0.01
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