Active ingredient for preparing medicament for treating hysteromyoma and application thereof
阅读说明：本技术 用于制备治疗子宫肌瘤药物的活性成分及其应用 (Active ingredient for preparing medicament for treating hysteromyoma and application thereof ) 是由 姚军 周梦宇 李勇 王磊 罗岩 袁洁 沈静 艾拉旦·麦麦提艾力 李洋 于 2020-05-26 设计创作，主要内容包括：本发明所提供的用于制备治疗子宫肌瘤药物的活性成分及其应用,使用本发明提供的活性成分进行大鼠子宫肌瘤模型治疗后,大鼠子宫各项指标均优于其它组,且与正常组相比无显著性差异；血清E2、P、IL-6和TNF-α含量与正常组相比无显著性差异；子宫肌瘤模型组织中ER-α水平显著降低；且对血液中肝功能指标ALT、ALP、AST的含量有不同程度的影响,对肾功能指标CRE、UREA的含量影响较小,本发明提供的活性成分能够显著改善子宫肌瘤模型症状,为棉酚类药物在疾病治疗方面起到减毒增效的积极作用,同时为子宫肌瘤新药的开发与研究提供了科学理论基础。(After the active ingredient provided by the invention is used for treating the uterine fibroid model of a rat, all indexes of the rat uterus are superior to those of other groups, and the active ingredient has no significant difference compared with a normal group; the contents of E2, P, IL-6 and TNF-alpha in the serum are not significantly different from those in a normal group; significant reduction in ER- α levels in uterine fibroid model tissues; the active ingredients provided by the invention can obviously improve the symptoms of the hysteromyoma model, play a positive role in reducing toxicity and improving efficacy for gossypol medicines in disease treatment, and provide a scientific theoretical basis for development and research of new medicines for the hysteromyoma.)
1. The active ingredient for preparing the medicament for treating the hysteromyoma is characterized by being (-) -gossypol acetate.
2. Active ingredient of claim 1, for the preparation of a medicament for the treatment of uterine fibroids, characterized in that (-) -gossypol acetate, which is complexed with vitamin B when used for the treatment of uterine fibroids1、B6And potassium chloride.
3. Use of an active ingredient according to any one of claims 1-2 for the preparation of a medicament for the treatment of uterine fibroids in the treatment of uterine fibroids.
4. Use of an active ingredient for the preparation of a medicament according to any one of claims 1-2 for the treatment of uterine fibroids in a medicament for the treatment of uterine fibroids.
5. Use of an active ingredient according to any one of claims 1-2 for the manufacture of a medicament for the treatment of uterine fibroids in the manufacture of a medicament for the treatment of disorders associated with estrogen abnormalities.
6. Use of an active ingredient as claimed in any of claims 1 to 2 for the preparation of a medicament for the treatment of uterine fibroids for the preparation of a medicament for the treatment of disorders associated with progestagen abnormalities.
Technical Field
The invention relates to the technical field of research and development of tumor drugs. In particular to the technical field of preparation of related medicaments for treating hysteromyoma.
Background
The hysteromyoma is widely considered as benign tumor with sex hormone dependence, and in the existing medicines for treating hysteromyoma diseases, the compound gossypol acetate tablet is a macromolecular non-hormone medicine with dialdehyde naphthalene, and the medicine molecules of the compound gossypol acetate tablet can act on female and progestational hormone receptors in endometrium, myoma and myoma in a short time to play a biological role of inhibiting hormone secretion, so that the function of the endometrium is recovered to be normal, and the adverse reaction is slight. The compound gossypol acetate tablet comprises gossypol acetate, potassium chloride, and vitamin B1Vitamin B6Wherein gossypol acetate is the raceme of gossypol, including L-gossypol [ (-) -gossypol]And dextro-gossypol [ (+) -gossypol]With the progress of research, it is found that the activity and toxicity of (-) -gossypol and (+) -gossypol are different. The current research shows that the toxicity and the activity of (-) -gossypol and (+) -gossypol are basically considered to be strong in (-) -gossypol activity and strong in toxicity, but some experiments consider that (+) -gossypol is prepared by using beta-cyclodextrinGossypol is highly toxic.
At present, more toxicity and activity of (-) -gossypol and (+) -gossypol are researched, but no report exists for the application of the (-) -gossypol and the (+) -gossypol in the treatment of uterine fibroids.
Disclosure of Invention
Aiming at the current situation that (-) -gossypol acetate is not used as an active ingredient to be applied to the technical scheme for preparing the uterine fibroid treatment medicament in the prior art, the invention aims to provide (-) -gossypol acetate to be applied to the preparation of the uterine fibroid treatment medicament as the active ingredient, obtain obvious medicinal effect by establishing a rat uterine fibroid model, have obvious treatment effect on uterine fibroid diseases, play a positive role in attenuation and synergy for the (-) -gossypol medicaments in the aspect of disease treatment, and provide a scientific theoretical basis for the development and research of novel (-) -gossypol medicaments.
The invention is realized by the following technical scheme:
the invention provides an active ingredient for preparing a medicament for treating hysteromyoma, wherein the active ingredient is (-) -gossypol acetate.
Furthermore, the active ingredient (-) -gossypol acetate is compounded with vitamin B when being used for preparing the medicine for treating hysteromyoma1、B6And potassium chloride.
The active ingredient (-) -gossypol acetate is used for preparing the active ingredient of the medicine for treating the uterine fibroid and is applied to the treatment of the uterine fibroid.
The active ingredient (-) -gossypol acetate is used for preparing the active ingredient of the medicine for treating the uterine fibroid and is applied to the medicine for treating the uterine fibroid.
The active ingredient (-) -gossypol acetate is used for preparing the active ingredient of the medicine for treating hysteromyoma and the application of the active ingredient of the medicine for treating estrogen abnormality related diseases.
The active ingredient (-) -gossypol acetate is used for preparing the active ingredient of the medicine for treating hysteromyoma and the application of the active ingredient of the medicine for treating the diseases related to the abnormal progestogen.
By implementing the specific invention content of the invention, the following beneficial effects can be achieved:
(1) the invention provides (-) -gossypol acetate as an active ingredient applied to the preparation of a medicine for treating uterine fibroids, which evaluates the drug effect of the (-) -gossypol acetate by establishing a rat uterine fibroid model, discusses the treatment effect of the (-) -gossypol acetate on uterine fibroids, plays the positive role of attenuation and synergy for the (-) -gossypol acetate medicines in the aspect of disease treatment, and provides a scientific theoretical basis for the development and research of new (-) -gossypol acetate medicines.
(2) After the active ingredient provided by the invention is used for treating the uterine fibroid model of a rat, all indexes of the rat uterus are superior to those of other groups, and the active ingredient has no significant difference compared with a normal group; serum E2P, IL-6 and TNF-alpha contents were not significantly different from those of the normal group; significant reduction in ER- α levels in uterine fibroid model tissues; the active ingredients provided by the invention can obviously improve the symptoms of the hysteromyoma model, play a positive role in reducing toxicity and improving efficacy for gossypol medicines in disease treatment, and provide a scientific theoretical basis for development and research of new medicines for the hysteromyoma.
Drawings
FIG. 1 is a graph showing the variation trend of body mass of rats in different treatment groups.
Shown in FIG. 1 are normal control group, modest as model control group, positive control group for positive drug, (+) -GA high (+) -gossypol acetate high dose group, (+) -GA medium dose group for (+) -gossypol acetate in (+) -GA, low (+) -GA low (+) -gossypol acetate low dose group, (-) -GA high (-) -gossypol acetate high dose group, (-) -GA high dose group for (-) -gossypol acetate in (-) -GA, and (-) -gossypol acetate low (-) -gossypol acetate high dose group for (-) -gossypol acetate
Figure 2 shows the uterine morphology of rats in the untreated group.
The model1 shown in FIG. 2 is
FIG. 3 is a graph of HE staining (magnification × 200) of uterus of rats in the untreated group.
In FIG. 3, a-b are shown as normal group, c-d are shown as model group, e is shown as positive control group, f-h is shown as (-) -gossypol acetate low, medium and high dose group, i-k is shown as (+) -gossypol acetate low, medium and high dose group.
FIG. 4 is an ER-alpha immunohistochemistry (200-fold) of uterine tissue of rats in the untreated group.
FIG. 5 is a graph of PR immunohistochemistry (200-fold) of uterine tissue of rats in the untreated group.
In FIGS. 4-5, a is shown as normal group, b is model group, c is positive control group, d-f is (-) -gossypol acetate low, medium and high dose group, g-i is (+) -gossypol acetate low, medium and high dose group.
Detailed Description
The present invention will be described below by way of examples, but the present invention is not limited to the following examples.
The reagent of the invention comprises: (-) -gossypol acetate, (+) -gossypol acetate (self-made in laboratories); physiological saline (batch number: 1803025, Xinjiang pharmaceutical Co., Ltd., national drug group); picric acid, analytically pure (batch: 20160531, Taishan city Yueqiao reagent plastics, Ltd.). Compound gossypol acetate tablet (batch number: 181003, Xian northern pharmaceutical Co., Ltd.), vitamin B1(batch No. 20180918, Xinjiang pharmaceutical Co., Ltd., national drug group), vitamin B6(batch No. 20181220, Xinjiang pharmaceutical Co., Ltd., national drug group), potassium chloride sustained-release tablet (batch No. 19043401, national drug group, hong Kong, Shanghai Haihong group practice group, Chaohu lake, pharmaceutical Co., Ltd.). Estradiol benzoate injection (batch No. 190116, Shanghai Quanyu Biotechnology animal medicine Co., Ltd.), progesterone injection (batch No. 20190116, Chuangxin pharmaceutical industry group Co., Ltd., Jiangxi province), physiological saline, chloral hydrate, 4% paraformaldehyde (batch No. 20190523, Biosharp Co., Ltd.), surgical instrument (Zhang Houng City, Japan)Jinfeng red light medical surgical instrument factory), nitric acid (guaranteed reagent), hydrogen peroxide (analytically pure), K standard stock solution (national center for standards substance), rat E2PROG, IL-6, TNF-alpha ELISA kit (batch No. 201908, Shanghai enzyme-linked Biotech Co., Ltd.), hematoxylin, eosin dye solution (Biosharp Co., Ltd.), rat estrogen receptor alpha antibody (batch No. BS-0253R, Beijing Boaosen Biotech Co., Ltd.), rat progesterone receptor antibody (batch No. BS-23376R, Beijing Boaosen Biotech Co., Ltd.), DAB color development kit (batch No. ZLI-9018, Beijing Zhongshan Jinqiao Biotech Co., Ltd.), serum block (batch No. SL034, Beijing Solebao Tech Co., Ltd.), immunohistochemical SP kit (batch No. SP-9001, Beijing Zhongshan Jinqiao Biotech Co., Ltd.), buffer solution, citric acid antigen repair solution (Biosharp Co., Ltd.)
The apparatus of the invention comprises: AF2004 electronic balance: shanghai Shunhui scientific instruments Ltd, multiskanMK3 full-automatic enzyme standard instrument: thermo scientific, Multifuge X3R model low temperature centrifuge: U.S. Thermo scientific, model BS-200, fully automated biochemical analyzer: south kyo prasei equipment gmbh, DMI4000B fluorescence inverted microscope: lycra, microwave oven, Leica embedding machine model EG 1150: beijing Hao Nuo Sci Ltd; CV5030 full-automatic sheet sealing machine: beijing Hao Nuo Sci Ltd; model RM2135 LEICA manual microtome; electric heating constant temperature water bath: guangming medical instruments, Inc., Beijing; type DFC390 trinocular microscope: laica corporation, ICV-450 model electric heating constant temperature incubator: japanese ASONE, CEM MARS6 high-throughput closed microwave digestion system, PinAACLE 900 flame atomic absorption spectrometer: perkin elmer corporation (shanghai) ltd, gavage needle; 1mL syringe: eagle pond Rong Jia group medical instrument industry Co., Ltd, lot number: 190301; a disposable culture dish; surgical instruments: south Chang Huayi medical devices, Inc.; analytical balance model DY 15K: shanghai Banqing instruments, Inc. The reagents and materials can be purchased through public channels, and the equipment and instruments adopted in the process are all common equipment in the field. All materials, reagents and equipment selected for use in the present invention are well known in the art, but do not limit the practice of the invention, and other reagents and equipment well known in the art may be suitable for use in the practice of the following embodiments of the invention.
The following examples further illustrate the present invention but are not to be construed as limiting the invention. Modifications or substitutions to methods, procedures, or conditions of the invention may be made without departing from the spirit and scope of the invention.
120 SD healthy rats, female, body mass (180. + -. 20) g, provided by the animal laboratory centre of Xinjiang medical university, license number: SCXK (New) 2018-. The animals are raised in the animal experiment center of Xinjiang medical university, and the animal laboratory is in SPF environment, the room temperature is 20 +/-2 ℃, and the relative humidity is 20-40%.
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