CN114533748A - Application of pulsatilla chinensis saponin B4 in preparation of medicine for treating or preventing uterine fibroid - Google Patents
Application of pulsatilla chinensis saponin B4 in preparation of medicine for treating or preventing uterine fibroid Download PDFInfo
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- 239000003814 drug Substances 0.000 title claims abstract description 24
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- 229930182490 saponin Natural products 0.000 title claims description 7
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- 208000010579 uterine corpus leiomyoma Diseases 0.000 title description 9
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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Abstract
The invention discloses application of pulsatilla saponin B4 as a unique active ingredient in preparing a medicament for treating or preventing uterine fibroids. The anemonin B4 has good therapeutic effect on hysteromyoma of rats molded by estrogen loading method.
Description
Technical Field
The invention relates to the technical field of medicines. More specifically, the invention relates to an application of pulsatilla saponin B4 in preparing a medicament for treating or preventing uterine fibroids.
Background
Hysteromyoma is one of the most common benign tumors in female reproductive organs, is one of the most common tumors in human bodies, is also called fibroid and uterine fibroid, and is mainly formed by hyperplasia of uterine smooth muscle cells. The etiology of uterine fibroids is still unclear to date and may involve more complex interactions between cell mutations, sex hormones and local growth factors in the normal muscle layer. Uterine fibroid belongs to benign tumor with very small malignant change probability, while uterine cancer (endometrial cancer) belongs to malignant tumor and is caused by infection of venereal disease, long-term cervical injury, broken skin, erosion, inflammation and other causes. The common symptoms of the two are also different. The symptoms of hysteromyoma are mostly manifested in the period of menstruation, mostly in submucosal and muscular wall myoma, mostly in excessive menstruation, prolonged or shortened menstruation period. Common symptoms of uterine cancer are: vaginal bleeding, irregular menstrual cycles and intermenstrual bleeding, and postmenopausal vaginal bleeding. The treatment method of the uterine fibroid is different from that of uterine cancer, and the treatment method of the uterine cancer mainly comprises operation treatment, radiotherapy, hormone, chemotherapy and the like; the diameter of the uterine fibroid is below 2-3 cm, generally, the observation is recommended, the treatment is not needed, the symptom caused by exceeding 5 cm or special positions needs uterine curettage, myoma removal or hormone treatment, and the current drug treatment mainly comprises western medicines such as gonadotropin releasing hormone agonist, mifepristone, danazol, tamoxifen (tamoxifen), androgen medicine and the like. Thus, unlike treatment methods, drugs and methods for treating uterine cancer are not applicable to uterine fibroids. The pulsatilla chinensis has the effects of clearing heat, removing toxicity, cooling blood and the like, and the pulsatilla chinensis saponin B4 has not been reported to prevent and treat hysteromyoma at present.
Disclosure of Invention
The invention aims to solve at least the problems and provides the application of the pulsatilla saponin B4 in preparing the medicine for treating or preventing the uterine fibroid, and the pulsatilla saponin B4 has a better treatment effect on the uterine fibroid of a rat molded by an estrogen loading method.
To achieve these objects and other advantages in accordance with the present invention, there is provided a use of pulsatillae radix saponin B4 as a sole active ingredient for the preparation of a medicament for treating or preventing uterine fibroids.
Preferably, the medicament contains effective amount of pulsatilla saponin B4 and pharmaceutically acceptable carrier.
Preferably, the medicament contains a therapeutically effective amount of hydrochloride, perchlorate, methanesulfonate, phosphate, citrate or sulfate of pulsatilla saponin B4 and a pharmaceutically acceptable carrier.
Preferably, the pharmaceutically acceptable carrier includes diluents, solubilizers, cosolvents, disintegrants, dispersants, lubricants, flavoring agents, antioxidants, binders, absorbents, wetting agents, buffering agents, and crosslinking agents.
Preferably, the medicament is formulated into a pharmaceutically acceptable dosage form.
Preferably, the dosage form comprises pills, tablets, powders, capsules, granules, powders, dripping pills, drops, sprays, injections, suspensions, ointments, gels and suppositories.
Preferably, the dosage of the pulsatilla saponin B4 is not less than 1 mg/kg-d.
The invention at least comprises the following beneficial effects:
in the invention, the pulsatilla saponin B4 is used as the only active ingredient for treating or preventing the uterine fibroid, for a rat molded by an estrogen loading method, the pulsatilla saponin B4 can improve the unhairing symptom and the temperament, improve the uterine cyst, nodule and swelling, improve the form of the uterine smooth muscle, improve the uterine coefficient, reduce the estradiol level, the estrogen receptor level and the progesterone level, and in addition, the absorption promoting effect of chitosan, 15-hydroxystearic acid polyethylene glycol ester and the combination of the chitosan and the 15-hydroxystearic acid polyethylene glycol ester on B4 is not obvious;
the lowest dose of the oral administration mode used in the experiment is 20mg/kg, the bioavailability is relatively low compared with the injection form, and the lowest dose is not lower than 1mg/kg when the injection administration mode is used.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
Drawings
FIG. 1 is a histopathological observation of the uterus of various groups of rats according to the present invention;
FIG. 2 is a graph of uterine coefficients of various groups of rats according to the present invention;
FIG. 3 is a graph showing the expression of estradiol in serum and tissue of rats in each group according to the present invention;
FIG. 4 is a graph of the expression of estrogen receptors in rat serum and tissue of various groups according to the present invention;
FIG. 5 is a graph of the serum and tissue progesterone expression profiles of various groups of rats according to the present invention.
Detailed Description
The present invention is further described in detail below with reference to the attached drawings so that those skilled in the art can implement the invention by referring to the description text.
It is to be noted that the experimental methods described in the following embodiments are all conventional methods unless otherwise specified, and the reagents and materials are commercially available unless otherwise specified.
1 Material
1.1 animals
CD (SD) rat, female, non-pregnant, weight 200-: SCXK (Zhe) 2019-: 20210624Aazz 0619000227. The animal raising room has natural light and shade period, room temperature, free temperature of animals and drinking water.
1.2 drugs and reagents
Estradiol benzoate injection, 2mg/mL, nibo second hormone plant, lot No.: (2016)110252511, respectively; progesterone injection, 10mg/mL, ningbo second hormone factory, lot No.: 110251670, respectively; pulsatillae saponin B4, prepared and provided by laboratory; chitosan, alatin limited, lot number: 9012-76-4; 15-hydroxystearic acid polyethylene glycol ester, fengli seiki limited, lot number: 73059868E 0; mifepristone, mclin ltd, lot No.: m830038.
Rat estradiol (E2) ELISA kit: jiangsu enzyme immunity industry Co., Ltd, batch number: the MM-0575R1 is used,
rat Estrogen Receptor (ER) ELISA kit: jiangsu enzyme immunity industry Co., Ltd, batch number: the MM-0567R1 is,
rat progestogen receptor (P) ELISA kit: jiangsu enzyme immunity industry Co., Ltd, batch number: MM-0551R 1.
2 method
2.1 grouping
The weight of the Chinese medicinal composition is randomly divided into 7 groups, 8 groups respectively of a blank control group, a model control group and a positive control group, 8 groups respectively of pulsatilla saponin B420 mg/kg group, pulsatilla saponin B420 mg/kg + chitosan 50mg/kg group, pulsatilla saponin B420 mg/kg + 15-hydroxystearic acid polyethylene glycol ester 50mg/kg group and pulsatilla saponin B420 mg/kg + (chitosan + 15-hydroxystearic acid polyethylene glycol ester) 50mg/kg group, and for convenience of brief description, the groups are respectively represented by control (control), mol, P, B4, B4+ K, B4+ J, B4+ K + J in the drawing.
2.2 model preparation
After 3 days of adaptive breeding, the rat is molded by adopting an estrogen loading method: except for the blank control group, six groups of rats were administered daily intramuscular injection of estradiol benzoate (0.5mg/kg), every other day each rat was given an additional injection of progesterone (1mg/kg), continuously injected for 9 weeks, weighed once a day, and the amount of the molding drug was adjusted according to body weight. The pathological display of rat uterus indicates that gland hyperplasia and muscle fiber obviously proliferate, which indicates that the molding is successful.
2.3 administration of drugs
Except for a blank control group, the rats in the other six groups are administrated after the molding is successful, the positive control group is injected with mifepristone 1.25mg/kg in the abdominal cavity every day, the four B4 administration groups are administrated by intragastric administration with B420 mg/kg and (or not) 50mg/kg absorption promoting agent, and the blank control group and the model control group are administrated with the same amount of physiological saline every day.
2.4 rat uterine pathology examination
After 4 weeks of administration, the rats were treated, the abdominal cavity was opened, the uterus and myoma morphology were observed, the uterus was cut along the uterine bladder junction, fat was stripped, a photograph was taken, weighed, and the uterine viscera coefficients were calculated. And fresh lesion tissues were fixed in paraformaldehyde and HE stained.
3 results of
3.1 modeling and general behavioral changes in the post-rat
Before molding, rats in each group have mild temperament, smooth and moist hair, and good drinking and eating. The hair color of each modeling module is yellow, the fur is messy, part of rats have the hair removal symptom, the hair removal area is increased along with the extension of the modeling time, and the rats are in an irritative state, are not easy to grab and are glary. The situation is improved after administration.
3.2 general morphological Observation of uterus
After the experiment was completed, the uteri of each group of rats were dissected: the blank control group had uniform uterine tissue, bright color, symmetrical uterine on both sides, and Y-shaped uterus, and no nodule or cyst was observed. The root of the uterus of the model control group is obviously thickened and dark in color, and lumps with different sizes of rice grains can be induced by touch. The positive control group and the four B4 administration groups had uniform uterus texture, light color, and no obvious cyst, nodule and swelling.
3.3 Observation of uterine histopathology
According to the HE staining result, the uterine smooth cells of the rats in the blank control group are regularly and closely arranged, the shape is normal, the color is uniform, inflammatory cell infiltration is not seen in a muscular layer, and hyperplasia is not occurred; the uterine smooth muscle of the rat in the model control group is thickened, the cell boundary is unclear, the cell nucleus is oblate, the arrangement of muscle fiber is disordered, and obvious inflammatory cell infiltration can be seen. The uterine smooth cells of the rats in the positive control group and the four B4 administration groups are arranged regularly, have normal shapes and uniform colors, and have reduced infiltration of muscle layer inflammatory cells, as shown in figure 1.
3.4 uterine coefficient
The ratio of the weight of the uterus to the body weight of the rat is relatively constant under normal conditions, and when the state of the uterus of the rat is damaged and changed, the uterus coefficient is changed. The uterus coefficient is 100% of the uterus weight, and when the uterus coefficient is increased, the uterus is shown to be hyperemic, edematous or hypertrophic.
The study found that the uterine coefficients of the model control group were significantly increased compared to the blank control group, while the uterine coefficients of the positive control group and the four B4-administered groups were significantly decreased compared to the model control group. This indicates that the drug has significant therapeutic effect on hysteromyoma, as shown in figure 2,###p<0.001，***p<0.001。
3.5 estradiol expression
Estradiol (E2) is a natural estrogen secreted by the mature follicular follicle of the ovary in vivo, and can promote endometrial hyperplasia and enhance contraction of the uterine smooth muscle. Clinically, elevation of E2 is often caused by ovarian disease. Therefore, the expression level of E2 can be detected as a diagnostic index of ovarian and uterine diseases.
In the experiment, the E2 levels in the serum and the uterine tissue of the rat are detected, compared with a blank control group, the E2 level of a model control group is obviously increased, and compared with the model control group, the E2 levels of a positive control group and four B4 administration groups are obviously reduced. This shows that the drug has significant therapeutic effect on hysteromyoma, as shown in fig. 3, serum is on the left side, tissue is on the right side,###p<0.001，*p<0.05，**p<0.01，***p<0.001。
3.6 Estrogen receptor expression
Estrogen Receptor (ER) is a protein molecule that specifically binds to hormones to form hormone-receptor complexes, allowing estrogen to exert its biological effects. Clinical researches show that the increase of ER is usually accompanied with the increase of hysteromyoma, and the inhibition or reduction of estrogen level can prevent the growth of the hysteromyoma, reduce the hysteromyoma and improve clinical symptoms.
The experiment shows that the ER level of the model control group is obviously increased compared with a blank control group, and the ER level of the positive control group and four B4 administration groups is obviously reduced compared with the model control group. This shows that the drug has significant therapeutic effect on hysteromyoma, as shown in fig. 4, serum is on the left side, tissue is on the right side,###p<0.001，*p<0.05，**p<0.01，***p<0.001。
3.7 Progesterone expression
Progesterone (P), a natural progestogen secreted by the ovarian corpus luteum. Progesterone has been reported as the first hormone responsible for the growth of uterine fibroids.
In the experiment, the P levels in the serum and the uterine tissue of the rat are detected, so that the P level of the model control group is obviously increased compared with that of the blank control group, and the P levels of the positive control group and the four B4 administration groups are obviously reduced compared with that of the model control group. This shows that the drug has significant therapeutic effect on hysteromyoma, as shown in fig. 5, serum is on the left side, tissue is on the right side,###p<0.001，*p<0.05，**p<0.01，***p<0.001。
4 conclusion
B4 has better therapeutic effect on rat uterine fibroids. However, the absorption promoting effect of chitosan, 15-hydroxystearic acid polyethylene glycol ester and the combination of the chitosan and the 15-hydroxystearic acid polyethylene glycol ester on B4 is not obvious.
The lowest dose of the oral administration mode used in the experiment is 20mg/kg, the bioavailability is relatively low compared with the injection form, and the lowest dose is not lower than 1mg/kg when the injection administration mode is used.
The number of apparatuses and the scale of the process described herein are intended to simplify the description of the present invention. Applications, modifications and variations of the present invention will be apparent to those skilled in the art.
While embodiments of the invention have been described above, it is not intended to be limited to the details shown, described and illustrated herein, but is to be accorded the widest scope consistent with the principles and novel features herein disclosed, and to such extent that such modifications are readily available to those skilled in the art, and it is not intended to be limited to the details shown and described herein without departing from the general concept as defined by the appended claims and their equivalents.
Claims (7)
1. Application of pulsatilla saponin B4 as the only active component in preparing the medicine for treating or preventing hysteromyoma.
2. The use of claim 1, wherein the medicament comprises a therapeutically effective amount of pasqueflower saponin B4 and a pharmaceutically acceptable carrier.
3. The use of claim 1, wherein the medicament comprises a therapeutically effective amount of the hydrochloride, perchlorate, methanesulfonate, phosphate, citrate or sulfate salt of pasqueflower saponin B4 and a pharmaceutically acceptable carrier.
4. Use according to claim 2 or 3, wherein the pharmaceutically acceptable carrier comprises diluents, solubilizers, cosolvents, disintegrants, dispersants, lubricants, flavoring agents, antioxidants, binders, absorbents, wetting agents, buffers, cross-linking agents.
5. The use of claim 4, wherein the medicament is formulated into a pharmaceutically acceptable dosage form.
6. The use of claim 5, wherein the dosage form comprises a pill, tablet, powder, capsule, granule, powder, drop, spray, injection, suspension, ointment, gel, suppository.
7. The use according to claim 1, wherein the pulsatillae radix saponin B4 is administered in an amount of not less than 1 mg/kg-d.
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| CN107137413A (en) * | 2017-06-21 | 2017-09-08 | 苏州大学 | Pulchinenoside B4Application in the medicine for preparing treatment pain |
| CN110090221A (en) * | 2018-01-31 | 2019-08-06 | 四川英路维特医药科技有限公司 | A kind of Radix Pulsatillae extract treats the purposes in viral and/or bacteriosis drug in preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107137413A (en) * | 2017-06-21 | 2017-09-08 | 苏州大学 | Pulchinenoside B4Application in the medicine for preparing treatment pain |
| CN110090221A (en) * | 2018-01-31 | 2019-08-06 | 四川英路维特医药科技有限公司 | A kind of Radix Pulsatillae extract treats the purposes in viral and/or bacteriosis drug in preparation |
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