Traditional Chinese medicine composition capable of resisting multiple myeloma as well as preparation method and application of traditional Chinese medicine composition

Abstract

The invention belongs to the field of traditional Chinese medicine compounds, and particularly discloses a traditional Chinese medicine composition with multiple myeloma resistance and a preparation method and application thereof, and the traditional Chinese medicine composition comprises astragalus membranaceus, semen cuscutae, oldenlandia diffusa, scutellaria baicalensis, rhizoma smilacis glabrae, abelmoschus manihot flowers, curcuma zedoary and angelica sinensis. Research results show that after the traditional Chinese medicine composition provided by the invention is used for treatment, the blood stasis, deficiency, sleep and diet dimension integrals of a patient are obviously lower than those of a control group; body function and overall life quality scores are higher than those of a control group; the scores of fatigue, anorexia, constipation and adverse reaction treatment are obviously lower than those of a control group. Through multi-dimensional analysis of a human-derived multiple myeloma cell line, bone marrow mesenchymal stem cells, mouse-derived mononuclear-macrophages and an NOD / SCID mouse model, the traditional Chinese medicine composition can improve the bone marrow microenvironment and regulate and control the action mode and mechanism of bone metabolism, can remarkably reduce the adverse reaction of bortezomib, and is good in safety.

Description

Technical Field

[0001] The present invention relates to the field of Chinese medicine compound prescriptions, and in particular to a Chinese medicine composition with anti-multiple myeloma effect, and its preparation method and application. The present invention provides a target prescription-target drug system with satisfactory efficacy for the integrated Chinese and Western medicine treatment model of multiple myeloma under the guidance of the advanced Chinese medicine "cancer poison-state target" theory. Background Art

[0002] Multiple Myeloma (MM) is a malignant disease characterized by abnormal proliferation of clonal plasma cells, usually accompanied by the secretion of a large amount of monoclonal immunoglobulin. The incidence of MM accounts for about 10% of blood system tumors, and it is the second most common malignant tumor of the blood system. MM is more common in the elderly, with a median age of 69 years old. The main clinical features are bone pain, pathological fractures, anemia, proteinuria and renal insufficiency.

[0003] With the continuous emergence of new drugs and the improvement of detection methods, the diagnosis and treatment of MM have been continuously improved and perfected. For newly diagnosed MM patients with good overall physical status scores, autologous hematopoietic stem cell transplantation should be the first choice after effective induction therapy based on drugs such as proteasome inhibitors, immunomodulators, and monoclonal antibodies. However, elderly and frail MM patients have many underlying diseases and are not suitable for transplantation and chemotherapy. In addition, maintenance therapy after remission, maximizing deep remission, and reducing relapse have become the consensus of MM treatment. MM is extremely heterogeneous, and multiple mechanisms such as immune escape and clonal evolution cause most patients to develop drug resistance during treatment, leading to disease progression and relapse. Nuclear export protein inhibitors, dual antibodies, and chimeric antigen receptor T cell therapy are the main treatment options for relapsed patients, while patients with multiple lines of relapse have more complications, poor treatment tolerance, and short survival.

[0004] Traditional Chinese medicine has the advantages of improving clinical symptoms, reducing complications, improving quality of life, and increasing tolerance in the treatment of MM. Summary of the invention

[0005] Purpose of the invention: The disease name "multiple myeloma" is not clearly mentioned in traditional Chinese medicine books. According to its onset characteristics and clinical symptoms, it can be classified into the categories of "bone arthritis", "bone erosion", "deficiency", "low back pain", etc. Although there are more and more new drugs for the treatment of MM, the disease is still incurable, and coping with recurrence has always been the focus and difficulty of clinical practice.

[0006] The present invention interprets the pathogenesis of MM from the perspective of cancer-toxin theory through syndrome differentiation and treatment, and grasps the dynamic process of the struggle between the positive and the negative from the overall perspective. Specifically, cancer-toxin is easy to recur and consumes qi and blood. Therefore, it is essential to protect the positive energy, fight cancer and detoxify. If the positive energy is strong, the negative energy will be prevented from going out, the yin and yang will be balanced, and the disease will be cured; if the positive energy is weak, the restraint will be powerless, the yin and yang will be out of harmony, and all kinds of changes will occur; the prescription should be formulated with the complex method, and the deficiency and excess will be considered. According to the key pathogenesis of MM, targeted prevention and treatment methods are proposed: strengthening the positive energy to fight cancer, tonifying the kidney and detoxifying; removing blood stasis and removing phlegm, multiple methods are adopted simultaneously; staged treatment and full-process management.

[0007] The traditional cancer toxin theory points out that "cancer toxin" is a specific pathogenic factor of tumor occurrence, and the deficiency of vital energy is the premise of tumor occurrence. The internal and external factors are interrelated, and the deficiency and excess are mixed, and they are mutually causal. Phlegm, blood stasis, heat, and dampness are the pathological products of the deficiency of vital energy and cancer toxin. Mixed with them, they help cancer toxins to linger and be difficult to cure, or rob the essence of vital energy. The cancer toxin theory is an important academic thought in the field of tumors. However, it lacks the basis of modern scientific theories and cannot be more widely recognized internationally.

[0008] Implementation plan: With the deepening of MM research, new therapies and new drugs emerge in an endless stream, and basic research and clinical applications are constantly transforming each other. At the same time, the development and application of fields such as artificial intelligence and the cross-integration of multiple disciplines have made the traditional diagnosis and treatment model unable to meet the emerging new problems. The inventor team combined the cancer toxin theory with clinical practice, made full use of the progress of modern medical diagnosis and treatment methods and mechanism research, explored the targets that affect diseases, symptoms, and clinical indicators, and promoted the deep integration of precision diagnosis and treatment and syndrome differentiation and treatment in the context of the new drug era, achieving a higher level of disease-syndrome combination, fully tapping the powerful potential of Chinese and Western medicine synergy, and summarizing the Chinese and Western integrated treatment strategy that is more suitable for the MM new drug era. The scientific connotation of its application in MM has been further interpreted, including: deficiency of body cancer toxins and protein overload; deficiency of body cancer toxins and tumor immune microenvironment.

[0009] Technical solution, in order to achieve the above purpose, the technical solution adopted by the present invention is:

[0010] A Chinese medicinal composition with anti-tumor activity comprises astragalus, dodder seed, oldenlandia diffusa, scutellaria, smilax glabra, hibiscus flower, zedoaria and angelica.

[0011] As a preferred embodiment, the above-mentioned traditional Chinese medicine composition with anti-tumor activity is made of 30-90 parts of Astragalus, 15-45 parts of Cuscuta, 30-90 parts of Hedyotis diffusa, 15-45 parts of Smilax glabra, 15-45 parts of Hibiscus flower, 10-30 parts of Curcuma, 10-30 parts of Angelica sinensis, and 6-18 parts of Scutellaria baicalensis.

[0012] As a more preferred embodiment, the above-mentioned traditional Chinese medicine composition with anti-tumor activity is prepared from 30 parts of Astragalus, 15 parts of Cuscuta, 30 parts of Hedyotis diffusa, 15 parts of Smilax glabra, 15 parts of Hibiscus flower, 10 parts of Curcuma, 10 parts of Angelica sinensis, and 6 parts of Scutellaria baicalensis.

[0013] The preparation method of the anti-tumor Chinese medicine composition of the present invention comprises the following steps: putting various Chinese medicine raw materials into a container, adding water, soaking, then decocting or refluxing for extraction, combining the extracts, and concentrating to prepare an extract.

[0014] As a preferred embodiment, the preparation method of the above-mentioned anti-tumor Chinese medicine composition comprises the following steps: adding 5-20 times the weight of the total medicinal materials in water, soaking for 30-60 minutes, boiling over high heat and then decocting or reflux extraction 1-3 times, each time for 1-3 hours, combining the extracts, concentrating under reduced pressure at 50-80°C, and concentrating to prepare an extract.

[0015] As a preferred embodiment, the extract and a pharmaceutically acceptable carrier are prepared into pills, syrups, mixtures, decoctions, tablets, powders, pastes, capsules, oral liquids, granules or injections.

[0016] The present invention is aimed at the clinical symptoms of MM patients and is formulated according to the compatibility principle of "monarch, minister, assistant and envoy". Astragalus is used to replenish the qi of the spleen and lungs, so that qi is strong and blood flows; Cuscuta chinensis nourishes the liver and kidneys, replenishes essence and nourishes the marrow. The two medicines are used together as monarch medicines to strengthen the body and eliminate evil. Hedyotis diffusa and Scutellaria baicalensis are anti-cancer, detoxify and clear heat, while Smilax glabra and Hibiscus tiliaceus flowers are dampness-clearing and detoxifying. The four medicines are ministerial medicines to clear heat, poison, phlegm and dampness in the body. Curcuma zedoaria is pungent and warm, breaks up blood stasis, eliminates symptom accumulation, promotes qi and relieves pain; Angelica sinensis is sweet and warm, nourishes blood and activates blood circulation, dispels cold and relieves pain. The two medicines are adjuvants to generate new blood and resolve blood stasis. All the medicines are combined to attack from the inside and attack from the outside, and the qi of cancer, toxicity and evil blood stasis has no place to attach. The whole prescription attacks and replenishes in parallel, and plays the effects of tonifying the kidney, detoxifying, removing blood stasis and clearing heat.

[0017] Beneficial effects:

[0018] In the early stage of the present invention, the clinical data of real-world patients were retrospectively analyzed to explore the pathogenesis, symptoms and medication characteristics of MM, and combined with clinical practice, the Chinese medicine compound composition of the present invention (Xuanbi Xiaoliu Fang) for treating MM was created. Based on the core pathogenesis of MM with kidney deficiency as the basis and phlegm, blood stasis and toxin accumulation, the present invention combines the key syndromes of deficiency, toxins, phlegm, blood stasis and other key elements of patients, takes Xuanbi Xiaoliu Fang as the target prescription, conducts clinical observations on MM patients at different stages such as initial diagnosis, follow-up period, relapse and refractory treatment, verifies its clinical efficacy, and gradually builds a more complete prescription and medicine system. In addition, the target drugs are selected in combination with the different treatment stages, symptom burden and key mechanisms of the patients, and the target is accurately hit to give full play to the advantages of disease-target combination and regulate the overall steady state and local microenvironment. Its model diagram is as follows Figure 1As shown. Clinical experimental results show that the Chinese medicine compound composition (Xuanbi Xiaoliu Fang) of the present invention can significantly relieve the symptoms of fatigue, bone pain, anemia, limb numbness, dizziness and other symptoms of clinical MM patients, and deal with potential infections, peripheral neuropathy, hematological toxicity, gastrointestinal dysfunction and other complications. The mechanism of action of the present invention is to treat multiple myeloma by inhibiting the proliferation of myeloma cells, improving the bone marrow microenvironment, and regulating bone metabolism.

[0019] In addition, the preparation method provided by the present invention has a reasonable process design, can prepare drugs in different dosage forms according to actual needs, and has good safety through clinical observation. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 This is a diagram of the integrated treatment model for MM with the Xuanbi Xiaoliu prescription as the core.

[0021] Figure 2 This is a clinical observation on the treatment of MM patients with Xuanbi Xiaoliu recipe.

[0022] Figure 3 The Xuanbi Xiaoliu recipe inhibits MM cell proliferation and regulates bone metabolism at the cellular level. DETAILED DESCRIPTION

[0023] The present invention can be better understood according to the following examples. The following embodiments of the present invention are further described in detail in conjunction with the accompanying drawings and examples. The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention.

[0024] Example 1

[0025] 1. A Chinese medicinal composition with anti-tumor activity, which is prepared from 30 parts of astragalus, 15 parts of dodder seeds, 30 parts of oldenlandia diffusa, 15 parts of smilax glabra, 15 parts of hibiscus flowers, 10 parts of curcuma, 10 parts of angelica, and 6 parts of scutellaria.

[0026] 2. A method for preparing a Chinese medicine composition having anti-tumor activity, comprising the following steps:

[0027] Take 30 parts of astragalus, 15 parts of dodder seeds, 30 parts of oldenlandia diffusa, 15 parts of smilax glabra, 15 parts of hibiscus flowers, 10 parts of curcuma, 10 parts of angelica and 6 parts of scutellaria, add water 10 times the weight of the medicinal materials, soak for 30 minutes, boil over high heat and then simmer over low heat, extract twice, each time for 1 hour, combine the extracts, concentrate under reduced pressure at 50-80°C, and concentrate to prepare an extract containing 2.0 g / ml of the crude drug.

[0028] Example 2

[0029] 1. A Chinese medicinal composition with anti-tumor activity, which is prepared from 90 parts of astragalus, 45 parts of dodder seeds, 90 parts of oldenlandia diffusa, 45 parts of smilax glabra, 45 parts of hibiscus flowers, 30 parts of curcuma, 30 parts of angelica, and 18 parts of scutellaria.

[0030] 2. A method for preparing a Chinese medicine composition having anti-tumor activity, comprising the following steps:

[0031] Take 90 parts of astragalus, 45 parts of dodder seeds, 90 parts of oldenlandia diffusa, 45 parts of smilax glabra, 45 parts of hibiscus flowers, 30 parts of curcuma, 30 parts of angelica, and 18 parts of scutellaria, add water 12 times the weight of the medicinal materials, soak for 30 minutes, boil over high heat and then simmer over low heat, extract 3 times, each time for 1 hour, combine the extracts, concentrate under reduced pressure at 50-80°C, and concentrate to prepare an extract containing 2.0 g / ml of the crude drug.

[0032] Example 3

[0033] 1. A Chinese medicinal composition with anti-tumor activity, which is prepared from 60 parts of astragalus, 30 parts of dodder seeds, 60 parts of oldenlandia diffusa, 30 parts of smilax glabra, 30 parts of hibiscus flowers, 10 parts of curcuma, 10 parts of angelica, and 6 parts of scutellaria.

[0034] 2. A method for preparing a Chinese medicine composition having anti-tumor activity, comprising the following steps:

[0035] Take 60 parts of astragalus, 30 parts of dodder seeds, 60 parts of oldenlandia diffusa, 30 parts of smilax glabra, 30 parts of hibiscus flowers, 10 parts of curcuma, 10 parts of angelica, and 6 parts of scutellaria, add water 12 times the weight of the medicinal materials, soak for 30 minutes, boil over high heat and then simmer over low heat, extract 3 times, each time for 1 hour, combine the extracts, concentrate under reduced pressure at 50-80°C, and concentrate to prepare an extract containing 2.0 g / ml of the crude drug.

[0036] Example 4 Clinical Observation on Treatment of MM Patients with Chinese Medicine Composition (Xuanbi Xiaoliu Recipe)

[0037] The control group was treated with bortezomib-based therapy according to the National Comprehensive Cancer Network (NCCN) multiple myeloma guidelines. The initial induction was treated with VCD regimen for 1-2 courses followed by VRD regimen sequential treatment. The efficacy was evaluated after 4 courses. The observation group was treated with the extract of the Chinese medicine composition of Example 1 (Xuanbi Xiaoliu Fang) orally on the basis of the treatment regimen of the control group. The comparison of TCM syndrome scores of the two groups of patients in each dimension before treatment is as follows Figure 2As shown in A, there was no statistically significant difference (P>0.05). After treatment, the scores and total scores of the stasis, phlegm, deficiency, sleep, and diet dimensions of the two groups of patients were significantly reduced compared with those before treatment (P<0.05), and the score of the heat dimension of the observation group was significantly lower than that before treatment (P<0.05); and after treatment, the scores and total scores of the stasis, deficiency, sleep, and diet dimensions of the observation group were significantly lower than those of the control group (P<0.05). Comparison of the scores of each dimension of EORTC QLQ-C30 between the two groups before treatment is as follows Figure 2 As shown in B, there were no statistically significant differences (P>0.05). After treatment, the fatigue, pain, dyspnea, sleep disorder, and economic stress scores of the two groups of patients were significantly reduced compared with those before treatment (P<0.05); the physical function, role function, emotional function, cognitive function, social function, and overall quality of life scores were significantly increased compared with those before treatment (P<0.05). After treatment, the nausea and vomiting, loss of appetite, and constipation scores of the observation group were significantly reduced compared with those before treatment (P<0.05). After treatment, the physical function and overall quality of life scores of the observation group were significantly higher than those of the control group, and the fatigue, loss of appetite, and constipation scores were significantly lower than those of the control group, and the differences were statistically significant (P<0.05). Comparison of the scores of each dimension of QLQ-MY20 between the two groups of patients before treatment is as follows Figure 2 As shown in C, there was no statistically significant difference (P>0.05). After treatment, the disease symptoms and adverse reaction scores of the two groups of patients were significantly reduced compared with those before treatment, and the body image and future expectation scores were significantly increased, and the differences were statistically significant (P<0.05). The adverse reaction score of the observation group after treatment was significantly lower than that of the control group, and the difference was statistically significant (P<0.05). The distribution of clinical efficacy between the two groups was compared as shown in Figure 2 D, the difference was not statistically significant (P>0.05). Figure 2 As shown in Figure E, the control group had 7 cases of hematological toxicity, 16 cases of gastrointestinal reactions, 17 cases of peripheral neuropathy, 20 cases of pulmonary infection, 3 cases of herpes zoster, 3 cases of rash, and 1 case of liver function damage; the observation group had 10, 7, 12, 8, 1, 0, and 1 cases, respectively. The incidence of gastrointestinal reactions (2 = 6.04, P < 0.05) and pulmonary infection (2 = 9.76, P < 0.05) in the observation group were significantly lower than those in the control group, which also shows that the Chinese medicine composition of the present invention can alleviate the adverse reactions caused by bortezomib.

[0038] Example 5: The serum containing the Chinese medicine composition (Xuanbi Xiaoliu Fang) inhibits MM cell proliferation and regulates bone metabolism at the cellular level

[0039] In order to study the regulatory effect of the effective ingredients of Xuanbi Xiaoliu Fang on various cells after entering the blood, drug-containing serum was prepared from SPF-grade male SD rats. The drug-containing serum (abbreviated as XBXLF) of the extract of the Chinese medicine composition of Example 1 (Xuanbi Xiaoliu Fang) was diluted with 1640 complete culture medium to contain 0, 5, 10, 15, and 20% of culture medium for cell experiments, and blank serum was used as the control group (Ctrl). Figure 3 The results of A&B showed that the CCK8 kit analysis showed that more than 10% of XBXLF could significantly inhibit the proliferation of human MM cell lines KMS28PE cells and CAG cells. Then, RNA-seq sequencing analysis was performed on the above two pairs of MM cells. Figure 3 C Volcano plot shows the significant difference of transcripts between Ctrl group and XBXLF group. Figure 3 The results of GO enrichment analysis of DG sequencing results showed that XBXLF can significantly interfere with the cell metabolism, phosphorylation, and histone demethylation levels that are closely related to MM cell proliferation. In order to clarify the effect of XBXLF on osteoclast differentiation, mouse macrophages RAW264.7 were selected, and osteoclast differentiation was induced by cytokines RANKL and CSF for 7 to 10 days. After rapid fixation with citric acid fixative, tartrate-resistant acid phosphatase (TRAP) staining was used. Figure 3 The results showed that XBXLF could gradually inhibit the differentiation of RAW264.7 cells into osteoclasts. In order to clarify the effect of XBXLF on osteogenic differentiation, human bone marrow mesenchymal stem cells (BMSCs) were selected and culture medium was added with 5 μg / ml insulin, 0.1 μM dexamethasone, 0.2 mM vitamin C and 10 mM β-glycerophosphate. The medium was changed every 3 days for 15 consecutive days of differentiation. On the last day, the culture medium was discarded and the calcium nodules were stained with Alizarin red after fixation with 4% paraformaldehyde. Figure 3 The results showed that XBXLF can promote the differentiation of BMSCs into osteoblasts. The MM tibia model mice were gavaged daily at a dose of 14.6 g / kg for 4 consecutive weeks, and then blood was collected from the eye sockets. The serum was separated and the calcium concentration was detected by a kit. Figure 3 The results showed that the calcium content in the serum of mice in the XBXLF group was significantly lower than that in the Ctrl group.

Claims

1. A Chinese medicine composition with anti-tumor activity, characterized in that: It includes Astragalus, Cuscuta, Oldenlandia diffusa, Scutellaria, Smilax glabra, Hibiscus mallow flower, Curcuma and Angelica sinensis.

2. The Chinese medicine composition with anti-tumor activity according to claim 1, characterized in that: The invention is prepared from 30-90 parts of astragalus, 15-45 parts of dodder seeds, 30-90 parts of oldenlandia diffusa, 15-45 parts of smilax glabra, 15-45 parts of hibiscus flowers, 10-30 parts of zedoaria, 10-30 parts of angelica and 6-18 parts of scutellaria.

3. The Chinese medicine composition with anti-tumor activity according to claim 1, characterized in that: The medicine is prepared from 30 parts of astragalus, 15 parts of dodder seeds, 30 parts of oldenlandia diffusa, 15 parts of smilax glabra, 15 parts of hibiscus flowers, 10 parts of zedoaria, 10 parts of angelica and 6 parts of scutellaria.

4. The method for preparing the anti-tumor Chinese medicine composition according to any one of claims 1 to 3, characterized in that: The following steps are involved: Put each Chinese medicine raw material into a container, add water, soak, then decoct or reflux extract, combine the extracts, and concentrate to prepare an extract.

5. The method for preparing the anti-tumor Chinese medicine composition according to claim 4, characterized in that: The preparation method comprises the following steps: adding water in an amount 5-20 times of the total weight of the medicinal materials, soaking for 30-60 minutes, boiling over high heat and then decocting or refluxing for extraction 1-3 times, each time for 1-3 hours, combining the extracts, concentrating under reduced pressure at 50-80°C, and concentrating to prepare an extract.

6. The method for preparing the anti-tumor Chinese medicine composition according to claim 5, characterized in that: The extract and a pharmaceutically acceptable carrier are prepared into pills, syrups, mixtures, decoctions, tablets, powders, pastes, capsules, oral liquids, granules or injections.

7. Use of the anti-tumor Chinese medicinal composition according to any one of claims 1 to 3 in the preparation of a medicament for multiple myeloma.

8. Use of the anti-tumor Chinese medicine composition according to any one of claims 1 to 3 in alleviating the adverse reactions of bortezomib.

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