CN109620832A - Glycocholic acid is preparing the application in resisting hyperplasia of mammary glands drug - Google Patents
Glycocholic acid is preparing the application in resisting hyperplasia of mammary glands drug Download PDFInfo
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- CN109620832A CN109620832A CN201910030822.7A CN201910030822A CN109620832A CN 109620832 A CN109620832 A CN 109620832A CN 201910030822 A CN201910030822 A CN 201910030822A CN 109620832 A CN109620832 A CN 109620832A
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- glycocholic acid
- drug
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- 108010007979 Glycocholic Acid Proteins 0.000 title claims abstract description 42
- 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 42
- 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 42
- 229940099347 glycocholic acid Drugs 0.000 title claims abstract description 42
- 210000005075 mammary gland Anatomy 0.000 title claims abstract description 28
- 239000003814 drug Substances 0.000 title claims abstract description 19
- 206010020718 hyperplasia Diseases 0.000 title claims abstract description 17
- 229940079593 drug Drugs 0.000 title claims abstract description 12
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 229940124597 therapeutic agent Drugs 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 238000001727 in vivo Methods 0.000 claims 1
- 239000000829 suppository Substances 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 2
- 210000000481 breast Anatomy 0.000 description 17
- 241000700159 Rattus Species 0.000 description 14
- 210000001519 tissue Anatomy 0.000 description 10
- 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
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 230000035755 proliferation Effects 0.000 description 8
- 201000010099 disease Diseases 0.000 description 7
- 230000000694 effects Effects 0.000 description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 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
- 238000000034 method Methods 0.000 description 4
- 229960001603 tamoxifen Drugs 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 229940011871 estrogen Drugs 0.000 description 3
- 239000000262 estrogen Substances 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
- 208000024891 symptom Diseases 0.000 description 3
- 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
- 239000004471 Glycine Substances 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
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 230000036285 pathological change Effects 0.000 description 2
- 231100000915 pathological change Toxicity 0.000 description 2
- 239000000186 progesterone Substances 0.000 description 2
- 229960003387 progesterone Drugs 0.000 description 2
- OVBICQMTCPFEBS-SATRDZAXSA-N (2s)-1-[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-[bi Chemical compound CC(O)=O.CC(O)=O.C([C@@H](C(=O)N[C@H](CCCCN=C(NCC)NCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN=C(NCC)NCC)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 OVBICQMTCPFEBS-SATRDZAXSA-N 0.000 description 1
- 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 1
- XIIAYQZJNBULGD-UHFFFAOYSA-N (5alpha)-cholestane Natural products C1CC2CCCCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 XIIAYQZJNBULGD-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 102100032187 Androgen receptor Human genes 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- 102100038595 Estrogen receptor Human genes 0.000 description 1
- 208000000571 Fibrocystic breast disease Diseases 0.000 description 1
- 206010026730 Mammary duct ectasia Diseases 0.000 description 1
- 208000031816 Pathologic Dilatation Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 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
- 108010080146 androgen receptors Proteins 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 208000011803 breast fibrocystic disease Diseases 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 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 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 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 1
- 238000010586 diagram Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 108700032141 ganirelix Proteins 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 238000000879 optical micrograph Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Classifications
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- 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)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The application of the purposes that the present invention relates to chemicals in field of medicaments, specifically glycocholic acid in resisting hyperplasia of mammary glands drug.The present invention provides the new application field of glycocholic acid, glycocholic acid, which can be applicable to, to be prepared in resisting hyperplasia of mammary glands drug, effective active composition of the glycocholic acid as resisting hyperplasia of mammary glands drug, and the present invention helps to develop novel resisting hyperplasia of mammary glands drug.
Description
Technical field
The purposes that the present invention relates to chemicals in field of medicaments, i.e. glycocholic acid (3 α, 7 α, -5 β of 12 α-trihydroxy -
Cholestane -24- carboxylic acid -24- glycine amide or N- [(3 α, 5 β, 7 α, 12 α) -3,7,12- trihydroxy -24- oxo cholestane -24-
Base] glycine), the application in preparation treatment proliferation of mammary gland disease drug.
Background technique
Cyclomastopathy refers to breast epithelium and proliferation of fibrous tissue, breast tissue conduit and newborn leaflet moving back in structure
Row venereal disease becomes and the growth of progressive connective tissue, and pathogenic factor is mainly since endocrine hormone is lacked of proper care.Cyclomastopathy
Also known as mammary dysplasia is women of child-bearing age's one of the most common type breast disease, can be betided any after pubarche
Age, especially in the majority with 20~45 years old women, disease incidence accounts for the 74.1% of whole breast diseases, accounts for the 40% of the women of child-bearing age,
And have the tendency that rising year by year, the disease has been cited as the high risk factor of breast cancer at present.The feature of this disease is mammary gland constituent
Hyperplasia, show exception on structure, quantity and tissue morphology, cause normal breast leaflet physiological hyperplasia and return to the past not
Entirely, the disorder for forming mammary gland normal configuration, is the retrogression pathological changes and progress of breast tissue conduit and lobule of mammary gland in structure
The growth of property connective tissue.
The method for the treatment of cyclomastopathy is mainly with western medical treatment at present, as symptom is more apparent, extent of disease is wide
Sufferer, which takes orally potassium iodide, can be relieved symptom, also inhibit estrogen effect using androgen and estrogen receptor antagon, soften
Tubercle, mitigating symptom should not routinely apply since adverse reaction is larger, and Chinese medicine treatment side effect is smaller, can partially alleviate disease
Shape, but used Chinese medicine is many kinds of currently on the market, and effect is irregular, and curative effect is unequal to ideal.
Glycocholic acid is a kind of conjucated bile acids, is that metabolite cholic acid of the cholesterol in liver generates in conjunction with glycine
, physiological action be mainly promote in enteron aisle fat digestion and absorption, glycocholic acid have to acute and chronic inflammation compared with
Strong inhibiting effect and have the function of adjusting body's immunity, clinically glycocholic acid can be used as drug excipient and
Sorbefacient.
Summary of the invention
The problem of for the treatment of existing cyclomastopathy, making full use of glycocholic acid is human endogenous's active constituent
The characteristics of, the present invention provides the new application of glycocholic acid, i.e. resisting hyperplasia of mammary glands acts on.
The molecular structural formula of glycocholic acid are as follows:
Application of the glycocholic acid as cyclomastopathy therapeutic agent.
The usage amount of glycocholic acid is glycocholic acid 7.5-30mg/kg.
The present invention, which demonstrates glycocholic acid by rat mammary gland model of hyperplasia intervention experiment, has inhibition proliferation of mammary gland activity
The characteristics of, glycocholic acid significantly inhibits rat mammary gland hyperplasia, and filters out corresponding dosage in animal experiments, this
It is good treatment proliferation of mammary gland drug that one invention, which facilitates continual exploitation glycocholic acid,.
Detailed description of the invention
Fig. 1 is the influence comparative diagram that glycocholic acid changes proliferation of mammary gland rat breast tissue；
Wherein: A is Normal group, B is model control group, C is tamoxifen group, D is glycocholic acid low dose group, E
It is glycocholic acid high dose group for glycocholic acid middle dose group, F.
Specific embodiment
Embodiment one
Glycocholic acid inhibits rat mammary gland hyperplasia
1. experimental animal: SD, CV grades of female rats, 200 ± 20g of weight are purchased from Dalian Medical Univ's Experimental Animal Center,
Experimental animal production licence number SCXK (the Liao Dynasty) 2013-0003.
2. reagent: glycocholic acid, Aladdin Reagent Company, lot number: H1520042, purity >=97%；Oestradiol benzoate
Injection, Shanghai General Pharmaceutical Co., ltd., lot number: S171202；Progesterone injection, the Tianjin gold credit limited public affairs of medicine company
Department, lot number: 1704101.
3. method: the foundation of rat mammary gland model of hyperplasia.The non-pregnant rat of SD female 60 is taken, is randomly divided into 6 groups: is normal right
According to group, model control group, tamoxifen group, glycocholic acid low dose group, glycocholic acid middle dose group, glycocholic acid high dose
Group, every group 10.Normal group animal muscle injecting normal saline 0.1mL/, 1 time a day, continuous 30 days, other each groups
Intramuscular injection oestradiol benzoate 0.5mg/kg, 1 time a day, continuous 25 days, subsequent intramuscular injection progesterone 4mg/kg, daily 1
It is secondary, continuous 5 days.
4. result: cream after estrogen is injected in the influence to mammary gland diameter and height of nipples, as shown in table 1, model group animal
Room significantly increases, and shows as more normal group of breast diameter and height of nipples and dramatically increases, glycocholic acid can inhibit estrogen to draw
The breast risen increases, and breast diameter and height of nipples are without obviously increasing.
Embodiment two
The influence that glycocholic acid changes proliferation of mammary gland rat model breast tissue pathology
1. method: taking Normal group, model group, tamoxifen group and glycocholic acid low, middle and high dose groups rat, end
After secondary administration, second pair of complete breast tissue, paraffin embedding, slice, HE dyeing, optical microphotograph microscopic observation each group rat are removed
Breast tissue morphological change.To in the lobule of mammary gland and leaflet of each group rat acinus and conduit carry out three-dimensional meterological and survey
Fixed, every pathological section takes the different visuals field to be counted, as shown in table 2.
2 results: as shown in Fig. 1: being observed under light microscopic, the rat breast tissue of Normal group is existing without obvious hyperplasia
As.There is obvious hyperplasia, mammary duct ectasia, glandular secretion in lobule of mammary gland, acinar epithelia in the rat breast tissue of model group
Increase.After glycocholic acid is intervened, lobule of mammary gland and acinus number are reduced, and acinus starts atrophy, and luminal sectetion significantly reduces, and are increased
Raw situation be improved significantly, sufficiently prove that glycocholic acid can anti-hyperplasia of mammary glands and ductal ectasia.
Table 1: influence of the glycocholic acid to proliferation of mammary gland rat breast diameter and breast height
| Group | n | Dosage (/kg) | Breast diameter (mm) | Breast height (mm) |
| Normal 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 middle 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 model control group,*Indicate P < 0.05,**Indicate P < 0.01
Table 2: influence of the glycocholic acid to the pathological change of proliferation of mammary gland rat mammary gland leaflet and conduit
Note: compared with model control group,*Indicate P < 0.05,**Indicate P < 0.01.
Claims (4)
1. application of the glycocholic acid as cyclomastopathy therapeutic agent.
2. a kind of resisting hyperplasia of mammary glands drug for being converted into glycocholic acid in vivo containing glycocholic acid or as its derivative.
3. purposes as claimed in claim 1 or 2, which is characterized in that the drug includes the glycocholic acid of therapeutically effective amount
With the pharmaceutically acceptable carrier of surplus.
4. purposes according to claim 3, which is characterized in that the drug is oral preparation, suppository, injection or transdermal
Agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910030822.7A CN109620832B (en) | 2019-01-14 | 2019-01-14 | Application of glycocholic acid in preparation of anti-hyperplasia of mammary glands medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910030822.7A CN109620832B (en) | 2019-01-14 | 2019-01-14 | Application of glycocholic acid in preparation of anti-hyperplasia of mammary glands medicine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109620832A true CN109620832A (en) | 2019-04-16 |
| CN109620832B CN109620832B (en) | 2021-01-01 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910030822.7A Active CN109620832B (en) | 2019-01-14 | 2019-01-14 | Application of glycocholic acid in preparation of anti-hyperplasia of mammary glands medicine |
Country Status (1)
| Country | Link |
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| CN109620832B (en) | 2021-01-01 |
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