Chinese medicine composition for promoting bile secretion and relieving blood stasis, and preparation method and application thereof

Abstract

The present invention relates to the field of traditional Chinese medicine and network pharmacology, and in particular to a Chinese medicine composition for promoting gallbladder and relieving blood stasis, and a preparation method and application thereof. The Chinese medicine composition is prepared from the following raw materials: by mass, 15-30 parts of ginseng, 12-15 parts of atractylodes macrocephala, 6-12 parts of zedoaria, 12-15 parts of curcuma, 40-50 parts of smilax china, 10-15 parts of tribulus truncatum, 12-15 parts of fritillaria thunbergii, 10-15 parts of thorny thorn, 20-30 parts of fenugreek, 20-30 parts of lycopodii, and 20-30 parts of cat's claw. The present invention also provides a preparation method of the above-mentioned Chinese medicine composition for promoting gallbladder and relieving blood stasis. The above-mentioned Chinese medicine composition for promoting bile secretion and relieving blood stasis has the effects of promoting qi and resolving phlegm, reducing swelling and dispersing nodules, relieving blood stasis and relieving pain, and clearing the liver and gallbladder. It is combined with chemotherapy drugs to treat advanced bile duct cancer, especially for patients with symptoms of deficiency of vital energy, toxicity and blood stasis, it can improve the overall efficacy, enhance the effect of chemotherapy drugs, improve the toxic and side effects after chemotherapy, improve the quality of life of bile duct cancer patients, enhance the immunity of bile duct cancer patients, delay the recurrence and metastasis of tumors, and has a relatively good clinical treatment effect.

Description

Technical Field

[0001] The invention relates to the field of traditional Chinese medicine and network pharmacology, and in particular to a bile-promoting and blood-stasis-removing Chinese medicine composition and a preparation method and application thereof. Background Art

[0002] Cholangiocarcinoma is a malignant tumor originating from bile duct epithelial cells, and its incidence has shown a clear upward trend in recent years. Cholangiocarcinoma can be divided into intrahepatic, perihilar and distal cholangiocarcinoma. There is currently a lack of effective treatment for cholangiocarcinoma, and its only cure is radical surgical resection. However, there are no obvious symptoms in the early stages of the disease, and the disease progresses rapidly. Most patients are already in the late stages of the disease when diagnosed, and have lost the best time for surgical treatment. Even if surgical resection is possible, the 5-year survival rate after surgery is only 20% to 40%, and the postoperative recurrence rate is high.

[0003] Modern medical treatment mainly uses surgery, radiotherapy, chemotherapy, and targeted therapy. Chemotherapy is an important means of tumor treatment. Gemcitabine combined with platinum chemotherapy is the first-line chemotherapy for cholangiocarcinoma. However, chemotherapy can cause varying degrees of damage to normal tissues such as the body's immune system, hematopoietic system, and digestive system, causing a series of toxic side effects; and it is easy to develop drug resistance. Targeted treatments for cholangiocarcinoma are mostly small-sample clinical studies, and are prone to drug resistance; in immunotherapy, only PD-1 inhibitors have good effects in phase II clinical trials; clinical trial data for radiotherapy are limited. Therefore, there is an urgent need to find an effective treatment plan, so the medical community has turned its attention to Chinese herbal medicine, hoping to find new therapeutic targets.

[0004] Tang Guanhao found that the combination of Jiawei Wumei Pills and afatinib can improve the quality of life of patients, improve clinical symptoms, and reduce the toxic and side effects of targeted drugs in the treatment of biliary tract cancer. In addition, Xia Zhenwei observed the clinical efficacy of Yinchen Lidan Decoction combined with percutaneous transhepatic bile duct drainage (PTCD) in the treatment of cholangiocarcinoma with obstructive jaundice in 72 cases and concluded that Yinchen Lidan Decoction combined with PTCD can not only promote bile excretion and restore liver function in patients, but also improve patients' poor appetite and fatigue.

[0005] Although a large number of studies have shown that traditional Chinese medicine and Chinese medicine preparations have advantages that deserve recognition in delaying the metastasis of cholangiocarcinoma, there are relatively few reports in the prior art on the combined use of Chinese medicine compositions and chemotherapy regimens to reduce the side effects of chemotherapy and increase clinical efficacy and safety. Summary of the invention

[0006] The deficiency of vital energy in patients with advanced cholangiocarcinoma is obvious, which is easy to cause local recurrence and metastasis, and the cancer toxicity is rampant. The clinical manifestations are mostly jaundice, weight loss, pain in the liver area, and even pain in multiple parts of the body. In severe cases, bile duct obstruction and ascites may also occur. Based on this, the present invention summarizes a Chinese medicine composition for promoting bile and relieving blood stasis in long-term clinical practice, which can assist the cholangiocarcinoma chemotherapy in enhancing the effect and reducing the toxicity of the treatment of advanced cholangiocarcinoma, and has good clinical efficacy and safety.

[0007] Specifically, the first aspect of the present invention provides a Chinese medicine composition for promoting bile secretion and relieving blood stasis, comprising the following raw materials in parts by weight:

[0008] 15-30 parts of ginseng, 12-15 parts of atractylodes, 6-12 parts of zedoaria, 12-15 parts of curcuma, 40-50 parts of smilax china, 10-15 parts of trifoliate orange, 12-15 parts of fritillaria thunbergii, 10-15 parts of gleditsia spinosa, 20-30 parts of fenugreek, 20-30 parts of lithospermum officinale, and 20-30 parts of cat's claw.

[0009] Preferably, the Chinese medicine composition is in the form of pills, granules, tablets, oral liquid preparations, powders, pastes or capsules.

[0010] The second aspect of the present invention provides a method for preparing the above-mentioned Chinese medicine composition for promoting bile secretion and relieving blood stasis, comprising the following steps: weighing each raw material according to the above-mentioned weight portion, and making each raw material into corresponding concentrated granules; and uniformly mixing the concentrated granules of all raw materials.

[0011] A method for preparing the above-mentioned Chinese medicine composition for promoting bile secretion and relieving blood stasis comprises: first weighing each raw material according to the above-mentioned weight portion, adding 5-10 times the weight portion of water to soak for 30-120 minutes, heating and decocting the soaked raw materials together with the water, filtering, collecting the filtrate, adding 5-10 times the weight portion of water to the filter residue again, decocting, filtering, collecting the filtrate, combining the filtrates obtained by filtering after two decoctions, heating and concentrating, and obtaining a decoction of the Chinese medicine composition for promoting bile secretion and relieving blood stasis.

[0012] A preparation method of a Chinese medicine composition for promoting bile secretion and relieving blood stasis comprises: firstly weighing each raw material according to the above weight, crushing each raw material, sieving, and fully mixing to obtain mixed medicine powder; weighing millet which is 4-6% of the weight of the mixed medicine powder, adding 8-12 times of clear water to boil until there is no hard core, taking a small amount of the mixed medicine powder to a medicine plaque, putting the millet into the medicine plaque to shake the medicine plaque to make it fully mixed, spraying pure water, adding the mixed medicine powder, and then shaking the medicine plaque, repeating the above steps until the mixed medicine powder is added completely, and finally drying to obtain water pills of the Chinese medicine composition for promoting bile secretion and relieving blood stasis.

[0013] A method for preparing a bile-promoting and stasis-removing Chinese medicine composition comprises: firstly weighing each raw material according to the above weight, crushing and sieving each raw material, and fully mixing to obtain a bile-promoting and stasis-removing Chinese medicine composition powder.

[0014] The third aspect of the present invention provides a use of the above-mentioned Chinese medicine composition in the preparation of a drug for treating bile duct cancer in combination with a chemotherapy drug. The bile duct cancer is preferably advanced bile duct cancer. The chemotherapy drugs are preferably gemcitabine and cisplatin.

[0015] Preferably, the Chinese medicine composition is used in the preparation of a drug for treating bile duct cancer in combination with the chemotherapy drug in at least one of the following aspects:

[0016] 1) Reduce tumor marker levels;

[0017] 2) Improve clinical symptoms of TCM;

[0018] 3) Improve patients’ quality of life;

[0019] 4) Reduce the incidence of adverse reactions.

[0020] The fourth aspect of the present invention provides a pharmaceutical composition for treating advanced cholangiocarcinoma, wherein the effective ingredients thereof include gemcitabine, cisplatin and the above-mentioned bile-promoting and blood-stasis-removing Chinese medicine composition.

[0021] Ginseng is the dried root and rhizome of the Araliaceae plant Panax ginseng. It tastes sweet and slightly bitter, is slightly warm in nature, and enters the spleen, lung, heart, and kidney meridians. It nourishes the spleen and lungs, produces body fluids and nourishes blood. Leigong Paoyi Yaoxing Jie: "Life is based on qi, and the lungs are the master of qi... Ginseng can replenish qi, so it is suitable for the lungs." Ye Tianshi said that it "is slightly cold and clears the lungs. When the lungs are strong, the qi is sufficient and the mind is at peace." Ginsenosides can fight against many different types of human cancers through different biological effects. Ginsenoside Rg3 enhances the anti-proliferative effect of erlotinib on AsPC-1 and BxPC-3 pancreatic cancer cells and xenograft tumors, and induces cancer cell apoptosis. The protopanaxadiol type saponins break the sugar chain of the ligand after heating to form the product ginsenoside Rh2, which has excellent anti-tumor activity and can inhibit the proliferation of tumor cells. Therefore, Lidan Tongyu Decoction reuses ginseng as the main drug to enhance the anti-evil effect, that is, to regulate and enhance the immune system's ability to recognize and kill tumors.

[0022] Curcuma is the dried root of the plant Curcuma of the ginger family. It is pungent and bitter in taste and cold in nature. It enters the liver, gallbladder and heart meridians. It has the functions of promoting blood circulation and relieving pain, promoting qi and relieving depression, clearing the heart and cooling blood, and promoting bile and relieving jaundice. "Tang Materia Medica" states: "It can cure blood stasis, lower qi, promote tissue regeneration, stop bleeding, break bad blood, hematuria, hematuria and wounds". Curcuma is widely used in clinical tumor treatment. A variety of anti-tumor active ingredients have been isolated and identified from volatile oils, mainly including β-elemene, furadiene, germacron, curcumin and other active ingredients. It exerts anti-tumor effects by inducing cell apoptosis, inhibiting cell mitosis, reversing multidrug resistance, enhancing radiotherapy and chemotherapy sensitivity and enhancing body immunity.

[0023] Curcuma is the dried rhizome of the ginger family plant Curcuma zedoaria, Curcuma guangxiensis or Curcuma wenyujin. It tastes sweet, spicy and bitter, is warm in nature, and enters the liver and spleen meridians. It has the functions of breaking blood, promoting qi, eliminating accumulation and relieving pain. "Compendium of Materia Medica" records: "Curcuma zedoaria and stewed costus root can treat all cold and heart-wrenching pains, and those who want to die when they have heart and stomach pains for a long time." Curcuma is one of the commonly used anti-tumor Chinese medicines in clinical practice. The volatile oil of Curcuma has pharmacological effects such as protecting liver function, anti-inflammatory, antibacterial, antioxidant, and anti-thrombotic. Curcuma volatile oil can be extracted to obtain curcumol, and the pharmacological mechanism of this sesquiterpenoid compound in the treatment of various tumors has been gradually excavated. The anti-tumor effect of curcumol is mainly concentrated in inhibiting tumor cell proliferation, inhibiting angiogenesis, inhibiting tumor cell invasion and metastasis, and reversing tumor cell resistance.

[0024] Smilax china is the dried root of the lily family plant Smilax china. It tastes sweet, slightly bitter, astringent, and is neutral in nature. It enters the liver and kidney meridians and has the functions of removing dampness and turbidity, removing wind and removing numbness, and removing toxins and dispersing blood stasis. "Compendium of Materia Medica" records: "Smilax china is sweet, slightly bitter, and neutral in nature. Indications: replenishing deficiency and fatigue, strengthening qi and strength, quenching thirst, and promoting urination." Smilax china is a commonly used anti-tumor drug in clinical practice, and in vitro and in vivo anti-tumor studies have shown that the active substance tannin part in Smilax china can effectively inhibit the growth of tumor cells, block the tumor cell cycle at the GO / G1 phase, and induce apoptosis of advanced lung cancer cells. Smilax china sapogenin has a significant effect in inducing apoptosis of liver cancer HepG2 cells, and can inhibit the migration, growth and invasion of ovarian cancer cells CAOV3. Smilax china sapogenin derivatives can inhibit the proliferation of MCF-7 cells and induce cell apoptosis.

[0025] Cat's Claw is the dried root of Ranunculaceae, which is sweet and pungent, warm in nature, and enters the liver and lung meridians. It has the functions of detoxification, swelling, phlegm and stagnation. "Guangxi Chinese Materia Medica" states: "(Cat's Claw) tastes sour and sweet, is neutral in nature, and non-toxic. It enters the liver and lung meridians. It removes fire and resolves phlegm. It treats phlegm-fire scrofula." "Chinese Pharmacopoeia" states: "It is sweet, pungent, and warm. It enters the liver and lung meridians. It resolves phlegm and resolves stagnation, detoxification and swelling. It is used for scrofula, phlegm nodules, carbuncle swelling, snake and insect bites." The various biologically active ingredients contained in Cat's Claw, such as chloroform, saponins, fatty acids, n-butanol, polysaccharides, etc., have anti-tuberculosis and anti-tumor effects. The various chemical components such as polyphenols, coumarins, alkaloids, etc. have the functions of promoting immunity, anti-inflammatory, anti-oxidation, and protecting the liver. The ethyl acetate in cat's claw can help treat breast cancer by inducing apoptosis in human breast cancer MCF-7 cells, and it also has a certain inhibitory effect on the growth and reproduction of cancer cells in human T-cell lymphoma. The total saponins of cat's claw have a clear therapeutic effect on intrahepatic bile duct carcinoma.

[0026] Wangbuliuxing is the dried mature seeds of the plant of Caryophyllaceae, which is bitter and flat in nature. It belongs to the liver and stomach meridians. It has the functions of promoting blood circulation and menstruation, promoting lactation and reducing swelling, and promoting diuresis and relieving stranguria. "Benjing": "It is used to treat wounds, stop bleeding and relieve pain, remove thorns, and eliminate wind and internal cold." "Rihuazi Bencao": "It treats back hair, wandering wind, rubella, irregular menstruation and dystocia in women." Modern pharmacological studies have shown that Wangbuliuxing contains chemical components, and its main extracts include saponins, cyclic peptides, triterpenoid saponins, flavonoid glycosides and volatile oils. These main components have certain effects on anti-tumor and inhibiting angiogenesis. And because of its obvious effects in anti-oxidation, anti-inflammatory, antibacterial, and promoting milk secretion, it is widely recognized by doctors in clinical applications.

[0027] Fritillaria thunbergii is the dried bulb of Fritillaria thunbergii of the Liliaceae family. It tastes bitter and is cold in nature. It belongs to the lung and heart meridians. It can clear away heat, resolve phlegm, relieve cough, detoxify, disperse nodules and eliminate carbuncle. Huang Yuanyu said that it can "clear the lungs and relieve heat, relieve depression and break up coagulation". Fritillaria thunbergii is a commonly used anti-tumor Chinese medicine in clinical practice. The main chemical components of Fritillaria thunbergii, such as flavonoids and saponins, can relieve cough, anti-inflammatory and analgesia. It also has the effect of reversing the multidrug resistance of cancer cells such as liver cancer and breast cancer. Its effect of reversing drug resistance is mainly achieved by inhibiting the expression of P-glycoprotein (P-gp). The main chemical components of Fritillaria thunbergii, quercetin and kaempferol, have antioxidant effects and can inhibit the growth and reproduction of tumor cells. Fritillaria thunbergii acetone can achieve anti-tumor effects by inducing tumor cell apoptosis.

[0028] Gleditsia sinensis is the dried thorn of the leguminous plant Gleditsia sinensis, also known as Gleditsia sinensis needle. It is pungent in taste and warm in nature. It enters the liver and stomach meridians and has the functions of reducing swelling, detoxifying and discharging pus. Pharmacological studies have shown that Gleditsia sinensis has a significant inhibitory effect on some intestinal bacteria, and the inhibitory intensity is affected by the drug concentration. The chemical components of Gleditsia sinensis, such as saponins and alkaloids, are widely used in the field of skin diseases because of their antibacterial and anti-inflammatory effects. Gleditsia sinensis saponins also have the effect of enhancing human immunity. The combination of Fritillaria thunbergii and Gleditsia sinensis can reduce swelling, disperse nodules, detoxify and discharge pus, and has a good effect on tumors that are diagnosed as phlegm and blood stasis in traditional Chinese medicine.

[0029] Psoralea corylifolia is the dried pseudobulb of the orchid Dujuanlan, Dusuanlan or Yunnan Dusuanlan. It tastes sweet and slightly spicy, is cool in nature, and belongs to the liver and spleen meridians. It has the functions of clearing away heat and detoxifying, resolving phlegm and dispersing nodules. Modern pharmacological research has studied the anti-tumor effect of Psoralea corylifolia extract, but lacks research on specific effective ingredients. Psoralea corylifolia extract has a certain killing effect on tumor cells, has a regulating effect on the tumor microenvironment, can inhibit the growth, invasion and migration of tumor cells, and can play a synergistic role when used together with Western medicine anti-tumor treatment. Psoralea corylifolia extract inhibits the invasive ability of breast cancer cells by regulating the content of interleukin (IL)-2 and IL-10. Psoralea corylifolia polysaccharide can play an anti-tumor effect by promoting the proliferation of related immune cells.

[0030] Atractylodes macrocephala is a tuberous root of the Atractylodes macrocephala plant of the Asteraceae family. It tastes bitter and sweet, is warm in nature, and enters the spleen and stomach meridians. It has the functions of tonifying qi and strengthening the spleen, drying dampness and promoting diuresis, stopping sweating, and calming the fetus. Li Gao: "It removes dampness from all meridians and regulates the spleen and stomach." Wang Haogu: "It regulates the middle and benefits the spleen, tonifies the liver and wind deficiency, and treats strong tongue root, vomiting after eating, stomach pain, heaviness, acute pain under the heart, water under the heart, Chong meridian disease, reverse qi and urgency, umbilical and abdominal pain." Pharmacological studies have shown that it has anti-inflammatory, antioxidant, anti-cancer, liver protection, antibacterial and immunomodulatory functions. It is a commonly used drug for the treatment or adjuvant treatment of digestive system tumors such as liver cancer and gastric cancer. Lactones, polysaccharides and volatile oil components are often considered to be the main active ingredients of Atractylodes macrocephala. Atractylodes lactone I can inhibit the production of inflammatory factors through pathways such as Toll-like receptor 4 (TLR4) / MAPK / NF-κB, and reverse acetaminophen-induced oxidative stress liver injury. Hepatocellular damage and metabolic disorders caused by liver inflammation and oxidative stress are important antecedent factors for the development of cholangiocarcinoma. Therefore, therapeutic intervention in diseases such as hepatitis is expected to slow down the occurrence and development of cholangiocarcinoma in the early stages of the disease before malignant tumors are formed.

[0031] Lithospermum officinale is the dried aerial part of Salvia sinensis of the genus Salvia of the family Lamiaceae. It tastes bitter and pungent, is neutral (or cool) in nature, and enters the stomach, liver, and lung meridians. It has the functions of clearing away heat and detoxifying, promoting blood circulation and removing blood stasis, and softening and dispersing nodules. The main chemical components of Lithospermum officinale are terpenes and polysaccharides, which have antioxidant, anti-inflammatory, bactericidal and anti-tumor effects. Among them, polysaccharides have inhibitory effects on various tumor cells such as liver cancer and lung cancer, and play a significant therapeutic role in various infectious diseases. Pharmacological experiments have shown that the anti-tumor effects of polysaccharides are mainly concentrated in cytotoxicity, inhibition of tumor cell invasion and metastasis, regulation of vascular endothelial growth factor, regulation of interleukins, induction of cell apoptosis and mitochondrial damage, and inhibition of tumor cell invasion and metastasis. Lithospermum officinale water extract can inhibit the proliferation of various tumor cell lines.

[0032] The Chinese medicine composition for promoting gallbladder and relieving blood stasis provided by the present invention is composed of ginseng and atractylodes macrocephala as the main medicines, which has the effects of nourishing the five internal organs, replenishing qi and promoting body fluid, supporting the body's positive energy, and enhancing the effect of resisting evil; Curcuma and Curcuma are the ministerial medicines, and the late stage of bile duct cancer often enters the blood after a long illness. The two medicines are used together, which can not only comb the qi of the liver and gallbladder Shaoyang, but also enter the blood to lead all medicines to break the blood stasis, and play the effect of qi and blood coordination; Smilax glabra, Trillium, Fritillaria thunbergii, Gleditsia sinensis, Vaccaria segetalis, Lithospermum officinale, and Cat's Claw are the assistant medicines, and the seven medicines are used together, which not only has remarkable effects of resolving phlegm and dispersing stagnation, relieving blood stasis and detoxifying, but also can eliminate the primary lesion to a certain extent, and also has a certain effect on the removal and prevention of secondary metastatic lesions. The combination of all medicines can play the effects of promoting qi and resolving phlegm, reducing swelling and dispersing stagnation, relieving blood stasis and relieving pain, and clearing the liver and gallbladder, and clinically treats the disorder of qi mechanism and dispersing qi of bile duct cancer, the mutual binding of phlegm and blood stasis, and the stagnation of liver and gallbladder and the deficiency of positive energy.

[0033] Therefore, the bile-boosting and blood-stasis-removing Chinese medicine composition provided by the present invention is a clinical experience prescription created in accordance with the pathogenesis of bile duct cancer, and has the effects of promoting qi and resolving phlegm, reducing swelling and dispersing nodules, relieving blood stasis and relieving pain, and clearing the liver and gallbladder; it is combined with chemotherapy drugs to treat advanced bile duct cancer, especially for patients with symptoms of deficiency of vital energy, toxicity and blood stasis, it can improve the overall efficacy, enhance the effect of chemotherapy drugs, improve the toxic and side effects after chemotherapy, improve the quality of life of bile duct cancer patients, enhance the immunity of bile duct cancer patients, delay the recurrence and metastasis of tumors, and has a relatively good clinical treatment effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 A drug component-target network diagram of the traditional Chinese medicine composition provided by the present invention;

[0035] Figure 2 A Venn diagram of the Chinese medicine composition provided by the present invention and cholangiocarcinoma targets;

[0036] Figure 3 The Chinese medicine composition provided by the present invention and the PPI diagram of the target of cholangiocarcinoma;

[0037] Figure 4 GO enrichment analysis diagram of potential related targets of the Chinese medicine composition for treating cholangiocarcinoma provided by the present invention;

[0038] Figure 5 This is a KEGG pathway enrichment analysis diagram of potential related targets for the treatment of cholangiocarcinoma by the traditional Chinese medicine composition provided by the present invention. DETAILED DESCRIPTION

[0039] The technical solution of the present invention is further described in detail below through specific implementation methods.

[0040] The terms used in the present invention are all commonly used terms in the relevant field, so the raw materials, equipment, preparation processes, testing methods, etc. used without special explanation are all existing technologies in the relevant field.

[0041] The molecular mechanism of the bile-promoting and blood-stasis-removing Chinese medicine composition provided by the present invention in treating bile duct cancer was analyzed using network pharmacology.

[0042] (1) Screening of effective ingredients in Chinese medicine compositions for the treatment of cholangiocarcinoma

[0043] The chemical components of each drug were retrieved by using the drugs in the traditional Chinese medicine compound as keywords through the TCMSP database. The active components were initially screened according to the two ADME attribute values ​​of "oral bioavailability (OB) ≥ 30% and drug-likeness (DL) ≥ 0.18" to obtain the active compounds and their target proteins, and the compounds with inactive target components were eliminated. The names of the obtained chemical components were input into the Pubchem database for search, and the SMILES structural formula and 2D structure of the chemical components were obtained, and imported into the Swiss Target Prediction database for target prediction. The gene names of the obtained targets were corrected using the Uniprot database.

[0044] The effective ingredients of the Chinese medicine composition of the present invention were found to be 70 effective ingredients (including 17 ginseng, 3 curcuma, 11 smilax, 10 cat's claw, 4 vaccaria, 5 fritillaria, 10 licorice, 3 trifoliate mushrooms, 1 zedoaria, 4 atractylodes, 2 lithospermum) after screening by OB≥30% and DL≥0.18, see Table 1. The relationship network of the active ingredients of Lidantongyu Decoction and its targets was drawn and analyzed using Cytoscape 3.9.1, and a total of 325 nodes (including 225 targets and 70 active ingredients) and 1456 relationships were obtained, see Table 1. Figure 1 .

[0045] in, Figure 1 The square in the figure is the drug, the circle is the active ingredient of the drug, the octagon is the common active ingredient of the drug, the diamond is the target, and the area represents the degree value; YJ represents Curcuma, BQ represents Smilax china, MZC represents Cat's Claw, WBLX represents Vaccaria, ZBM represents Fritillaria thunbergii, ZJC represents Gleditsia sinensis, SCG represents Trichosanthes kirilowii, EZ represents Curcuma, BZ represents Atractylodes macrocephala, and SJC represents Ipomoea aquatica; A1 is shared by Cat's Claw, Ginseng, Trichosanthes kirilowii, Ipomoea aquatica, Curcuma, Gleditsia sinensis, Fritillaria thunbergii, and Smilax china; B1 is shared by Smilax china, Gleditsia sinensis, and Curcuma; C1 is shared by Ginseng, Trichosanthes kirilowii, Vaccaria, Gleditsia sinensis, and Cat's Claw; D1 is shared by Ginseng and Gleditsia sinensis; E1 is shared by Vaccaria, Gleditsia sinensis, and Gleditsia sinensis.

[0046] Table 1 Basic information of Chinese medicinal ingredients in the Chinese medicinal composition for promoting bile secretion and relieving blood stasis

[0047] Name of Chinese medicine Number of compounds Number of effective compounds Number of targets Turmeric 222 3 62 Smilax 39 11 66 Cat's Claw 79 10 48 Vaccaria 26 4 161 Fritillaria thunbergii 17 5 43 Gleditsia sinensis 30 10 188 Trillium 18 3 60 Curcuma 81 1 21 Atractylodes macrocephala 55 4 17 Ginseng 190 17 106 Ishimi 16 2 145

[0048] (2) Screening of drug targets for traditional Chinese medicine compositions and collection of targets related to lung cancer

[0049] Disease targets were retrieved through the OMIM database and the GeneCards database disease database with the keyword "Cholangiocarcinoma", and the obtained targets were screened with a correlation of ≥6.0. In the GeneCards database, the higher the score value, the closer the target is to the disease. According to experience, if there are too many targets, the target with a score greater than the median is set as a potential target for cholangiocarcinoma. After merging the targets of the two disease databases and deleting duplicate values, 1708 cholangiocarcinoma targets were obtained.

[0050] (3) Prediction of potential targets for Chinese medicine combination in the treatment of cholangiocarcinoma

[0051] The target of cholangiocarcinoma disease and the target of each active ingredient of the Chinese medicine composition provided by the present invention were introduced into the Venny2.1 online platform to make a Venn diagram, and 102 potential targets of Lidantongyu Decoction for preventing and treating cholangiocarcinoma were obtained by taking the intersection. Figure 2 The 102 intersection targets were imported into the String database for PPI network construction. The biological species was set to "Homosapiens" and the minimum required interaction score was set to the highest confidence (Highestconfidence) ≥ 0.4 for screening. The rest of the settings were default settings. At the same time, the disconnected nodes in the network were hidden. Finally, the PPI interaction network diagram was obtained, involving a total of 183 nodes and 3921 edges. It was imported into CytoScape3.9.1 for further analysis to obtain the PPI network diagram, see Figure 3 The top ten targets screened out according to the degree value are AKT1, TP53, IL6, TNF, BCL2, HIF1A, CASP3, MYC, ESR1, and EGFR. It is speculated that these targets play an important role in the treatment of cholangiocarcinoma with Lidantongyu Decoction, as shown in Table 2.

[0052] Table 2 Core targets of the Chinese medicine composition for promoting bile secretion and relieving blood stasis against cholangiocarcinoma

[0053]

[0054] (4) Topological analysis of the network pharmacology of traditional Chinese medicine combination in the treatment of cholangiocarcinoma

[0055] The results of network pharmacology showed that the Chinese medicine composition for promoting bile secretion and relieving stasis had 102 common targets with cholangiocarcinoma, indicating that these were potential targets for the Chinese medicine composition for promoting bile secretion and relieving stasis in the treatment of cholangiocarcinoma. By establishing a PPI network for topological analysis, 10 key targets were obtained, namely AKT1, TP53, IL6, TNF, BCL2, HIF1A, CASP3, MYC, ESR1, and EGFR. Among them, the AKT1 signaling pathway is related to cell carcinogenesis, regulating protein synthesis and cell survival, and the disorder of the AKT1 pathway may play an important role in the development of cholangiocarcinoma. TP53 is a tumor suppressor gene that plays an important role in multiple links such as cell cycle, homologous recombination repair of DNA double-strand damage, and cell apoptosis. TP53 mutations are common in multiple tumors such as lung cancer, breast cancer, and digestive tract tumors. Among them, the TP53 mutation rate in advanced cholangiocarcinoma is significantly higher than that in early cholangiocarcinoma. IL6, as an inflammation-related cytokine, participates in tumorigenesis and cancer progression. Studies have shown that IL6 promotes the growth and metastasis of cholangiocarcinoma cells. TNF is a cytokine with important biological activity. The interaction between the two TNF receptors present on cells has a cytotoxic effect on a variety of tumor cells. BCL2 is a significant apoptosis regulator and a key factor in the occurrence and development of a variety of cancers. In addition, some proteins in the Bcl-2 family are associated with the resistance of cholangiocarcinoma to conventional treatments. HIF1A can activate genes encoding proteins involved in hypoxia homeostasis response, and can also induce the expression of proteins that control glucose metabolism, cell proliferation and angiogenesis. When the metabolic demand of tumor growth exceeds the limit of vascular supply, HIF1A is activated, leading to metabolic reprogramming, thereby promoting the progression of cancer. CASP3 is a convergence point for the transmission of multiple apoptosis-stimulating signals. MYC provides essential metabolic support for the rapid proliferation of tumor cells by promoting the expression of tumor-related genes and enhancing RNA synthesis throughout the tumor cell transcriptome, thereby promoting cancer growth and survival. ESR1 is a ligand-activated transcription factor that is associated with the occurrence of a variety of tumors. EGFR signaling contributes to the development and progression of cholangiocarcinoma, and EGFR inhibitors reduce the expression of cyclooxygenase COX2 in cholangiocarcinoma cells.

[0056] Therefore, the above key points mainly play a role in inflammation, cell cycle, angiogenesis, etc., thereby affecting the biological processes such as proliferation, migration, drug resistance and angiogenesis of cholangiocarcinoma cells, and promoting the development of cholangiocarcinoma. Therefore, the Chinese medicine composition for promoting bile and stasis can treat cholangiocarcinoma by regulating inflammation, cell cycle, angiogenesis, etc.

[0057] (5) GO functional analysis and KEGG pathway enrichment analysis of potential related targets of Chinese medicine combination for the treatment of cholangiocarcinoma

[0058] The Metascape platform was used to perform GO function and KEGG pathway enrichment analysis on the 102 intersection targets obtained from the PPI network analysis. The qualified results were screened with a threshold of P < 0.01. The Microbiome Online Platform was used for visualization, and the top 20 items were plotted as GO biological function analysis bar charts and KEGG enrichment pathway analysis bubble charts.

[0059] The results of GO enrichment analysis are as follows Figure 4 As shown, a total of 1808 results were obtained, of which 1558 were biological processes (BP), which were mainly enriched in the positive regulation of cell migration, response to hormones, response to inorganic substances, response to xenobiotic stimulation, regulation of apoptosis signaling pathways and protein phosphorylation. There were 61 cell components (CC), which were mainly enriched in transcriptional regulatory complexes, membrane rafts, nuclear membranes, organelle outer membranes, spindles and centrosomes. There were 189 molecular functions (MF), which were mainly enriched in DNA binding transcription factors, kinases, protein kinases, kinase regulation and ubiquitin-like protein ligases. This shows that the biological process of the Chinese medicine composition for promoting gallbladder and relieving blood stasis in treating cholangiocarcinoma is mainly reflected in the positive regulation of cell migration, regulation of apoptosis signaling pathways and protein phosphorylation; the cell components are mainly reflected in membrane rafts, nuclear membranes and organelle outer membranes. The molecular functions are mainly reflected in DNA binding transcription factors, protein kinase activity and ubiquitin-like protein ligases.

[0060] KEGG pathway enrichment analysis results are as follows Figure 5As shown, a total of 189 pathways are involved. The horizontal axis of the KEGG pathway enrichment analysis is the ratio of the number of genes enriched in each pathway to the number of genes in all pathways, and the vertical axis is the name of the pathway. The results showed that the Chinese medicine composition for promoting bile duct and relieving blood stasis mainly acts on cancer signaling pathways (Pathways in cancer), PI3K-AKT signaling pathway (PI3K-Akt signaling pathway), JAK-STAT signaling pathway (JAK-STATsignaling pathway), NF-κB signaling pathway (NF-kappa B signaling pathway), Wnt signaling pathway (Wnt signaling pathway) and other signaling pathways. The results of KEGG pathway enrichment analysis suggest that the signaling pathways related to the treatment of bile duct cancer by the Chinese medicine composition are mainly reflected in the PI3K-AKT signaling pathway, JAK-STAT signaling pathway, NF-κB signaling pathway, Wnt signaling pathway and other signaling pathways. The activation of PI3K / AKT signaling pathway is abnormally expressed in cholangiocarcinoma tissues. The expression of PI3K pathway-related molecules p85α, mTOR, and GSK-3β all play an important role in the proliferation and invasion of cholangiocarcinoma. JAK / STAT pathway activation is directly involved in several cellular process characteristics of cancer cells, including cell growth, proliferation, and apoptosis. Abnormal JAK / STAT activation has been detected in 50% of cholangiocarcinoma patients, especially in the inflammatory microenvironment. The NF-κB signaling pathway promotes the proliferation and differentiation of tumor cells by upregulating cell growth factors through transcriptional regulation of multiple genes, inhibits tumor cell apoptosis by downregulating the expression of pro-apoptotic genes, and promotes tumor infiltration and metastasis. Blocking the NF-κB signaling pathway has a significant inhibitory effect on the growth of cholangiocarcinoma. Its mechanism is related to blocking NF-κB activation, thereby inhibiting the proliferation of cholangiocarcinoma cells and causing cell cycle arrest and increased apoptosis. The Wnt signaling pathway is involved in the regulation, invasion, and migration of cancer cells, making it a promising approach for drugs targeting β-catenin expression. In preclinical cholangiocarcinoma models, Wnt blockade resulted in increased apoptosis, cell cycle arrest, and chemoresistance.

[0061] In summary, the bile-boosting and blood-stasis-removing Chinese medicine composition affects biological processes such as proliferation and apoptosis of bile duct cancer cells by regulating key molecules such as AKT1, TP53 and IL6, thereby playing a role in treating bile duct cancer.

[0062] Based on the above analysis, the present invention provides a Chinese medicine composition for promoting bile secretion and relieving blood stasis, comprising the following raw materials in parts by weight: 15-30 parts of ginseng, 12-15 parts of atractylodes, 6-12 parts of zedoaria, 12-15 parts of curcuma, 40-50 parts of smilax china, 10-15 parts of trifoliate orange, 12-15 parts of fritillaria thunbergii, 10-15 parts of gleditsia thorn, 20-30 parts of fenugreek, 20-30 parts of lithospermum officinale, and 20-30 parts of cat's claw.

[0063] The second aspect of the present invention provides a method for preparing the above-mentioned Chinese medicine composition for promoting bile secretion and relieving blood stasis, comprising the steps of: weighing each raw material according to the above-mentioned weight portion, and making each raw material into corresponding concentrated granules; and uniformly mixing the concentrated granules of all raw materials.

[0064] A method for preparing the above-mentioned Chinese medicine composition for promoting bile secretion and relieving blood stasis comprises: first weighing each raw material according to the above-mentioned weight portion, adding 5-10 times the weight portion of water to soak for 30-120 minutes, heating and decocting the soaked raw materials together with the water, filtering, collecting the filtrate, adding 5-10 times the weight portion of water to the filter residue again, decocting, filtering, collecting the filtrate, combining the filtrates obtained by filtering after two decoctions, heating and concentrating, and obtaining a decoction of the Chinese medicine composition for promoting bile secretion and relieving blood stasis.

[0065] A preparation method of a Chinese medicine composition for promoting bile secretion and relieving blood stasis comprises: firstly weighing each raw material according to the above weight, crushing each raw material, sieving, and fully mixing to obtain mixed medicine powder; weighing millet which is 4-6% of the weight of the mixed medicine powder, adding 8-12 times of clear water to boil until there is no hard core, taking a small amount of the mixed medicine powder to a medicine plaque, putting the millet into the medicine plaque to shake the medicine plaque to make it fully mixed, spraying pure water, adding the mixed medicine powder, and then shaking the medicine plaque, repeating the above steps until the mixed medicine powder is added completely, and finally drying to obtain water pills of the Chinese medicine composition for promoting bile secretion and relieving blood stasis.

[0066] A method for preparing a bile-promoting and stasis-removing Chinese medicine composition comprises: firstly weighing each raw material according to the above weight, crushing and sieving each raw material, and fully mixing to obtain a bile-promoting and stasis-removing Chinese medicine composition powder.

[0067] The implementation process of the present invention is further explained in detail below in conjunction with embodiments.

[0068] Embodiment 1 The present invention provides a Chinese medicine compound granule for promoting gallbladder and relieving blood stasis, which is prepared from the following raw materials: 20g of ginseng, 15g of Atractylodes macrocephala, 10g of Curcuma zedoaria, 15g of Curcuma aromatica, 50g of Smilax glabra, 15g of Tripterygium wilfordii, 15g of Fritillaria thunbergii, 15g of Gleditsia sinensis, 30g of Vaccaria segetalis, 30g of Lithospermum officinale, and 30g of Cat's Claw. The preparation method of the Chinese medicine compound granule for promoting gallbladder and relieving blood stasis provided in this embodiment comprises: each of the above raw materials is respectively made into corresponding concentrated granules, and then the concentrated granules of all the raw materials are uniformly mixed.

[0069] Example 2

[0070] The embodiment of the present invention provides a Chinese medicine compound decoction for promoting gallbladder and relieving blood stasis, which is prepared from the following raw materials: 15g of ginseng, 10g of atractylodes, 8g of zedoaria, 14g of turmeric, 45g of smilax china, 13g of tribulus thunbergii, 13g of thunbergia thunbergii, 13g of thorny thorn, 25g of fenugreek, 25g of lycopodii, and 30g of cat's claw. The preparation method of the Chinese medicine decoction for promoting gallbladder and relieving blood stasis provided in the embodiment comprises: first weighing each raw material according to the above weight, adding 8 times the weight of water to soak for 60 minutes, heating and decocting the soaked raw materials together with water, filtering, collecting the filtrate, adding 7 times the weight of water to the filter residue again, decocting, filtering, collecting the filtrate, combining the filtrates obtained by filtering after two decoctions, heating and concentrating, and obtaining the decoction.

[0071] Example 3

[0072] The embodiment of the present invention provides a Chinese medicine compound pill for promoting gallbladder and relieving blood stasis, which is prepared from the following raw materials: 25g of ginseng, 18g of atractylodes, 12g of zedoaria, 13g of turmeric, 48g of smilax china, 14g of tribulus thunbergii, 14g of thunbergii, 14g of smilax china, 28g of cyperus rotundus, 28g of lycopodii, and 27g of cat's claw. The preparation method of the Chinese medicine decoction for promoting gallbladder and relieving blood stasis provided in this embodiment comprises: first weighing each raw material according to the above weight, crushing each raw material, sieving, and fully mixing, weighing millet with a weight of 5% of the powder, adding 10 times of water to boil without hard core, taking a small amount of powder to the medicine plaque, putting millet into the medicine plaque to make it fully mixed, spraying pure water, adding powder, and then shaking the medicine plaque, repeating the above steps until the powder is added, and finally drying to obtain water pills.

[0073] Example 4

[0074] The embodiment of the present invention provides a Chinese medicine compound powder for promoting gallbladder and relieving blood stasis, which is prepared from the following raw materials: 30g of ginseng, 20g of atractylodes, 6g of zedoaria, 12g of curcuma, 40g of smilax china, 10g of tribulus truncatum, 12g of fritillaria thunbergii, 10g of licorice, 20g of radix gleditsinae, 20g of fenugreek, and 20g of cat's claw. The preparation method of the Chinese medicine powder for promoting gallbladder and relieving blood stasis provided in this embodiment comprises: first weighing each raw material according to the above weight, crushing and sieving each raw material, and fully mixing.

[0075] Clinical study on the treatment of advanced cholangiocarcinoma with Chinese medicine combination combined with chemotherapy

[0076] The above-mentioned Chinese medicine compound preparation for promoting gallbladder and relieving blood stasis provided in Examples 1-4 of the present invention has ginseng, curcuma, and smilax china as the main medicines, thunbergia thunbergii, thorn of gleditsia, fenugreek, trillium, cat's claw, and atractylodes as the ministerial medicines, and zedoaria and lithospermum officinale as the adjuvant medicines. It has the effects of promoting qi and resolving phlegm, reducing swelling and dispersing nodules, relieving blood stasis and relieving pain, and clearing the liver and gallbladder. It is a clinical experience prescription created in accordance with the pathogenesis of bile duct cancer, and has a relatively good therapeutic effect in the adjuvant chemotherapy treatment of bile duct cancer.

[0077] The following specific clinical study on the treatment of advanced bile duct cancer with the Chinese medicine composition provided in Examples 1-4 combined with chemotherapy was conducted with patients whose symptoms after chemotherapy showed deficiency of vital energy, toxicity and blood stasis.

[0078] Study subjects : The Department of Integrated Traditional Chinese and Western Medicine of Henan Cancer Hospital and the Oncology Ward of the Third Affiliated Hospital of Henan University of Traditional Chinese Medicine selected 150 patients with advanced cholangiocarcinoma (iCCA) who met the inclusion criteria and had symptoms of deficiency of vital energy, toxicity and blood stasis. The study period was from June 2021 to December 2023.

[0079] Inclusion criteria All patients were diagnosed by cytological or histopathological examination and were evaluated as stable advanced cholangiocarcinoma patients according to the WHO solid tumor efficacy evaluation criteria for more than 1 month after the prescribed chemotherapy cycle, with a KPS score of ≥60 points, an expected survival period of more than 6 months, basically normal liver and kidney function and electrocardiogram, no brain metastasis, and informed consent was obtained.

[0080] Effect of Chinese medicine combination on treating advanced cholangiocarcinoma

[0081] A total of 150 patients with advanced cholangiocarcinoma (deficiency of vital energy, toxicity and stasis type) who met the inclusion criteria were selected from the Department of Integrated Traditional Chinese and Western Medicine of Henan Cancer Hospital and the Tumor Ward of the Third Affiliated Hospital of Henan University of Traditional Chinese Medicine. They were randomly divided into a treatment group of 30 cases and a control group of 30 cases. The specific groups are as follows:

[0082] Treatment groups 1-4: respectively adopt the Chinese medicine compound Chinese medicine preparation for promoting gallbladder and relieving blood stasis provided by Examples 1-4 of the present invention combined with chemotherapy, wherein the chemotherapy drugs are gemcitabine and cisplatin. Wherein, the method of taking the Chinese medicine compound preparation: granules: 1 dose per day, taken twice a day in the morning and evening; decoction: 1 dose per day, decocted in water twice a day in the morning and evening; pills: 3 times a day, 9g / time; powder: 3 times a day, 12g / time. One dose per day, chemotherapy twice a day, 21 days as a course of treatment, and observation for 2 courses of treatment.

[0083] Chemotherapy regimen: gemcitabine 1000 mg / m 2 , intravenous drip for 1 and 8 days; cisplatin 25 mg / m 2 , divided into 1, 8-day intravenous drip, 21 days as a cycle, combined with Chinese medicine for 2 consecutive cycles of treatment.

[0084] Control group: chemotherapy alone, with gemcitabine and cisplatin as chemotherapy drugs, gemcitabine 1000mg / m 2 , divided into 1 and 8 days of intravenous drip; cisplatin 25mg / m 2 , divided into 1 and 8 days of intravenous drip, 21 days as a cycle, and observe for 2 cycles.

[0085] All drugs in the traditional Chinese medicine preparations were purchased from China Resources Sanjiu Pharmaceutical Co., Ltd., and Chinese medicinal materials were purchased from the Third Affiliated Hospital of Henan University of Traditional Chinese Medicine; gemcitabine, Lilly France S.AS, national medicine approval number H20100030; cisplatin, Qilu Pharmaceutical Co., Ltd., national medicine approval number H37021358.

[0086] Experimental methods: The efficacy indicators such as TCM syndrome score, tumor size, KPS score, tumor markers CEA, CA199 level, and blood routine, liver and kidney function damage were evaluated in treatment groups 1-4 and the control group before and after treatment.

[0087] Experimental results:

[0088] As shown in Table 3, there was no statistical difference in the baseline data of patients in each group in terms of gender, age, stage, Child-Pugh grade, tumor classification, tumor size, TCM syndrome score, KPS score, serum tumor markers CEA, CA199, concomitant obstructive jaundice, and concomitant viral hepatitis (P>0.05), and the groups were comparable.

[0089] Table 3 Comparison of general data of patients with advanced iCCA with deficiency of vital energy, toxicity and stasis

[0090]

[0091]

[0092] (1) Comparison of solid tumor size

[0093] As shown in Tables 4-7, after two cycles of treatment, the tumor lesions of each subject were reduced compared with those before treatment, among which the tumor reduction in each treatment group (P=0.027<0.05) was statistically significant compared with that before treatment, and there was no statistical difference in tumor reduction in the control group (P=0.596>0.05); the reduction range of tumors in each group was compared with P>0.05, indicating that there was no statistical difference in tumor reduction among the treatment methods of each group; the objective effective rate of each treatment group was higher than that of the control group, and the disease control rate was also higher than that of the control group, among which the objective effective rate of treatment group 1 using the Chinese medicine compound granules provided in Example 1 was the highest, and the disease control rate was also the highest. After analysis, there was no statistically significant difference in the total effective rate and disease control rate among the four treatment methods (P>0.05).

[0094] Table 4 Comparison of indicators before treatment in each group of patients with advanced iCCA with deficiency of vital energy, toxicity and stasis

[0095]

[0096] Note: The indicators of each group of patients before treatment were tested by independent sample t test, P>0.05, the difference was not statistically significant, and the treatment groups were comparable to the control group.

[0097] Table 5 Comparison of tumor size in each group of patients before and after treatment

[0098] Group Number of cases Before treatment After treatment t-value P-value Control group 29 4.720±1.36 4.230±1.750 1.191 0.239 Treatment Group 1 29 4.650±1.50 3.460±2.060 2.866 0.006 Treatment Group 2 29 4.745±1.206 3.426±1.805 5.023 <0.0001 Treatment Group 3 29 4.802±1.306 3.501±1.765 4.954 <0.0001 Treatment Group 4 29 4.701±1.247 3.345±1.412 5.164 <0.0001

[0099] Table 6 Comparison of tumor size differences before and after treatment in each group of patients

[0100]

[0101] Note: Comparison of tumor size differences before and after treatment among the groups of patients, P>0.05, there was no statistical difference in the degree of tumor reduction.

[0102] Table 7 Comparison of objective efficacy and disease control rate of each treatment group

[0103] Group CR PR SD PD ORR% DCR% Control group 0 7 14 8 24.14 72.41 Treatment Group 1 0 10 15 4 34.48 86.21 Treatment Group 2 0 9 14 6 31.03 79.31 Treatment Group 3 0 9 15 5 31.03 82.76 Treatment Group 4 0 9 14 6 31.03 79.31 <![CDATA[χ 2 Value]]> -- -- -- -- 0.783 1.897 P-value -- -- -- -- 0.941 0.755

[0104] (2) TCM syndrome score

[0105] As shown in Tables 8-9, after treatment, the TCM syndrome scores of each treatment group and the control group were lower than those before treatment, and the difference was statistically significant (P < 0.05). The range of reduction in each treatment group was significantly greater than that in the control group, and the difference was statistically significant (P < 0.05). After treatment, the total effective rate of TCM syndrome improvement in the treatment group was higher than that in the control group, and the difference was statistically significant (P < 0.05). Among them, among the treatment groups, the total effective rate of TCM syndrome improvement in treatment group 1 using the Chinese medicine compound granules provided in Example 1 was the highest.

[0106] Table 8 Comparison of TCM syndrome scores in each group of patients

[0107]

[0108] Table 9 Total effective rate of improvement of TCM syndromes in each group of patients

[0109]

[0110] (3) KPS score

[0111] As shown in Tables 10-11, the KPS scores of each group after treatment were improved compared with those before treatment, and there were statistical differences within the group (P < 0.01). The improvement in each treatment group was greater than that in the control group (P < 0.01), and the difference was statistically significant. This shows that each treatment group is superior to the control group in improving the quality of life of patients with bile duct cancer. The total improvement rate of KPS scores of each group of patients after treatment was higher in the treatment group than in the control group, and the difference was statistically significant (P < 0.01). Among them, the KPS score and improvement rate of treatment group 1 using the Chinese medicine compound granules provided in Example 1 were the best.

[0112] Table 10 Comparison of KPS scores of patients in each group before and after treatment

[0113]

[0114] Table 11 Comparison of KPS score improvement rate in each group of patients Note: The improvement rate of KPS scores in each treatment group was better than that in the control group, P < 0.01, and the difference was statistically significant.

[0115] (4) Tumor markers

[0116] As shown in Tables 12-13, the serum tumor marker levels of each group after treatment were compared and it was found that the CEA and CA199 levels of the two groups after treatment were significantly lower than those before treatment, and the intra-group comparison was statistically significant (P<0.01); the difference in serum CEA and CA199 levels of the two groups of patients before and after treatment was compared, and the treatment group was greater than the control group (P<0.01), which was statistically significant, indicating that the treatment group had a significant advantage in reducing the tumor marker levels. Among them, the tumor marker levels of treatment group 1 using the Chinese medicine compound granules provided in Example 1 were reduced the most.

[0117] Table 12 Comparison of tumor marker levels in each group of patients

[0118]

[0119]

[0120] Table 13 Comparison of tumor marker differences among groups of patients

[0121]

[0122] (5) Toxic and side effects

[0123] As shown in Tables 14-15, the incidence of liver injury, leukocyte and digestive tract reaction reduction in each treatment group after chemotherapy was significantly lower than that in the control group, with statistically significant differences (P < 0.05); there was no significant statistical difference in red blood cell, platelet and renal function damage among the groups (P > 0.05). Among them, the treatment group 1 using the Chinese medicine compound granules provided in Example 1 had the lowest adverse reaction rate after chemotherapy.

[0124] Table 14 Comparison of adverse reaction rates in each group of patients after chemotherapy

[0125] Group Red blood cells leukocyte platelets Gastrointestinal reactions Liver damage Kidney damage Control group 19(65.5％) 22(75.9％) 8(27.6％) 25(86.2％) 11(37.9％) 10(35％) Treatment Group 1 18(62.1％) 11(37.9％) 7(24.1％) 15(51.7％) 4(13.8％) 8(27.6％) Treatment Group 2 17(58.6％) 12(41.4％) 6(20.7％) 16(55.2％) 3(10.3％) 8(27.6％) Treatment Group 3 17(58.6％) 13(44.8％) 7(24.1％) 16(55.2％) 4(13.8％) 7(24.1％) Treatment Group 4 18(62.1％) 12(41.4％) 7(24.1％) 17(58.6％) 4(13.8％) 8(27.6％) <![CDATA[X 2 Value]]> 0.407 11.32 0.377 9.717 10.03 0.816 P-value 0.982 0.023 0.984 0.046 0.04 0.936

[0126] Therefore, the bile-boosting and blood-stasis-removing Chinese medicine composition provided in the embodiment of the present invention combined with chemotherapy has obvious advantages in the treatment of advanced cholangiocarcinoma, and is better than chemotherapy alone in reducing the levels of tumor markers CEA and CA199, improving clinical symptoms in traditional Chinese medicine, improving the quality of life of patients with advanced cholangiocarcinoma, and reducing the incidence of adverse reactions. Moreover, the bile-boosting and blood-stasis-removing Chinese medicine composition provided in Example 1 of the present invention combined with chemotherapy has the best overall therapeutic effect in the treatment of advanced cholangiocarcinoma.

[0127] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, ordinary technicians in the field should understand that the specific implementation methods of the present invention can still be modified or some technical features can be replaced by equivalents without departing from the spirit of the technical solution of the present invention, which should be included in the scope of the technical solution for protection of the present invention.

Claims

1. A Chinese medicine composition for promoting bile secretion and relieving blood stasis, characterized in that: It includes the following raw materials in parts by weight: 15-30 parts of ginseng, 12-15 parts of atractylodes, 6-12 parts of zedoaria, 12-15 parts of curcuma, 40-50 parts of smilax china, 10-15 parts of trifoliate orange, 12-15 parts of fritillaria thunbergii, 10-15 parts of gleditsia spinosa, 20-30 parts of fenugreek, 20-30 parts of lithospermum officinale, and 20-30 parts of cat's claw.

2. The Chinese medicine composition for promoting bile secretion and relieving blood stasis according to claim 1, characterized in that: The Chinese medicine composition is in the form of pills, granules, tablets, oral liquid preparations, powders, pastes or capsules.

3. A method for preparing the Chinese medicine composition for promoting bile secretion and relieving blood stasis as claimed in claim 1, comprising the steps of: weighing each raw material according to the weight portion as claimed in claim 1, and making each raw material into corresponding concentrated granules; and uniformly mixing the concentrated granules of all raw materials.

4. A method for preparing the Chinese medicine composition for promoting bile secretion and relieving blood stasis according to claim 1, comprising: First, weigh each raw material according to the weight portion described in claim 1, add 5-10 times the weight portion of water and soak for 30-120 minutes, heat and decoct the soaked raw materials together with the water, filter, collect the filtrate, add 5-10 times the weight portion of water to the filter residue again, decoct, filter, collect the filtrate, combine the filtrates obtained after two decoctions, heat and concentrate, and obtain a Chinese medicine composition decoction for promoting bile and relieving blood stasis.

5. A method for preparing the Chinese medicine composition for promoting bile secretion and relieving blood stasis according to claim 1, comprising: First, weigh each raw material according to the weight of claim 1, crush each raw material, sieve, and fully mix to obtain a mixed powder; weigh 4-6% of the weight of the mixed powder, add 8-12 times of clean water to boil until there is no hard core, take a small amount of the mixed powder to a medicine plaque, put the millet into the medicine plaque to shake it to make it fully mixed, spray pure water, add the mixed powder, and then shake the medicine plaque, repeat the above steps until the mixed powder is added, and finally dry to obtain the Chinese medicine composition water pills for promoting bile and relieving blood stasis.

6. A method for preparing the Chinese medicine composition for promoting bile secretion and relieving blood stasis according to claim 1, comprising: Firstly, the raw materials are weighed according to the weight of claim 1, and the raw materials are crushed, sieved, and fully mixed to obtain the bile-promoting and blood-stasis-removing Chinese medicine composition powder.

7. Use of the Chinese medicine composition for promoting bile secretion and relieving blood stasis according to claim 1 or 2 in the preparation of a drug for treating bile duct cancer in combination with chemotherapy drugs.

8. The use according to claim 7, characterized in that The chemotherapy drugs are gemcitabine and cisplatin.

9. The use according to claim 7 or 8, characterized in that The use of the Chinese medicine composition for promoting bile secretion and relieving blood stasis in preparing a drug for treating bile duct cancer in combination with the chemotherapy drug in at least one of the following aspects: 1) Reduce tumor marker levels; 2) Improve clinical symptoms of TCM; 3) Improve patients’ quality of life; 4) Reduce the incidence of adverse reactions.

10. A pharmaceutical composition for treating advanced cholangiocarcinoma, characterized in that: The effective ingredients include gemcitabine, cisplatin and the bile-boosting and blood-stasis-removing Chinese medicine composition according to claim 1 or 2.

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