CN114588214B

CN114588214B - Composition and granules for improving bone marrow suppression after chemotherapy and preparation method

Info

Publication number: CN114588214B
Application number: CN202210255703.3A
Authority: CN
Inventors: 不公告发明人
Original assignee: Dongguan Tcm Hospital
Current assignee: Dongguan Tcm Hospital
Priority date: 2022-03-15
Filing date: 2022-03-15
Publication date: 2022-11-15
Anticipated expiration: 2042-03-15
Also published as: CN114588214A

Abstract

The invention provides a composition for improving bone marrow suppression after chemotherapy, granules and a preparation method thereof, and relates to the field of traditional Chinese medicines. The composition is simple in preparation method, effects of the medicines can be fully exerted through compounding of the seven medicines, the components interact with each other to realize synergistic interaction, osteogenic differentiation of mesenchymal stem cells can be effectively promoted, hematopoiesis is promoted, a hematopoietic microenvironment is improved, and therefore improvement of bone marrow suppression after chemotherapy is achieved.

Description

Composition and granules for improving bone marrow suppression after chemotherapy and preparation method

Technical Field

The invention relates to the field of traditional Chinese medicines, and in particular relates to a composition and granules for improving bone marrow suppression after chemotherapy and a preparation method thereof.

Background

The post-chemotherapy myelosuppression generally refers to the decrease of hematopoietic function of bone marrow, the decrease of activity of blood cell precursors in bone marrow, and the decrease of peripheral blood trilineage cells, especially the decrease of granulocytes in patients after chemotherapy. Myelosuppression delays the progress of chemotherapy and may lead to serious complications that endanger life, and studies on myelosuppression after chemotherapy are of great interest. Currently, rhG-CSF (short for short-acting leukogenic agent) or PEG-rhG-CSF (short for long-acting leukogenic agent) is mainly used for treating bone marrow suppression after chemotherapy in clinic. The short-acting whitening agent or the long-acting whitening agent has adverse reactions such as fever, muscle bone joint pain and the like after being used, wherein the short-acting whitening agent has short half-life period, needs repeated medication and large clinical dosage, the long-acting whitening needle has high price, and part of areas are not brought into medical treatment, and the use of the drugs is limited to a certain extent under the conditions. Therefore, finding more effective therapeutic drugs is currently the focus of relevant research.

The traditional Chinese medicine has a good effect of improving the bone marrow suppression after chemotherapy, and has a great potential. The He Shi marrow generation formula (abbreviated as marrow generation formula) created by professor of He Shi Dong of famous and old traditional Chinese medicine in Guangdong province has obvious curative effect on improving bone marrow suppression after chemotherapy and the like, and the formula consists of seven traditional Chinese medicines including semen cuscutae, herba epimedii, glossy privet fruit, barbary wolfberry fruit, astragalus, bighead atractylodes rhizome and caulis spatholobi, and has the effects of tonifying kidney, generating marrow, strengthening spleen, tonifying qi, enriching blood and promoting blood circulation. The clinical application has good feedback for patients, stable marrow generating effect and high safety. In order to protect the exclusive rights of the invention creation, respect the labor achievement, promote the development of science and technology and economy, and the invention creation popularization and application, the production and application of the He shi myelogenous prescription are filed.

The traditional Chinese medicine theory does not have a concrete concept of bone marrow suppression, but the clinical symptoms of patients with bone marrow suppression, such as inappetence, hypodynamia, shortness of breath, sweating, intolerance of cold and the like, are combined for judgment, and the patients with bone marrow suppression mostly belong to the categories of consumptive disease and blood deficiency in the traditional Chinese medicine. Furthermore, most chemotherapy drugs are strongly toxic and cold with severe fever, and they compete with healthy qi directly in the middle-jiao to disturb qi and blood in the middle-jiao, and may involve the spleen and kidney, damage essence and blood, and consume yin and blood in darkness. The classic theory of traditional Chinese medicine considers that the spleen governs transportation and transformation to be acquired root and distributes the essence of food, which are the source of qi and blood generation and transformation, and all bones of the five viscera are all supported by the spleen. Kidneys are the innate root, governing bone and producing marrow, and storing essence and producing blood. The spleen and stomach are weak, the functions of the spleen and the stomach are disabled, food essence cannot be normally distributed, and qi and blood are generated and generated without source; when kidney essence is deficient and marrow sea is empty, essence and blood are not generated. For example, the theory of "Lixueyuan" clearly summarizes that the treatment of deficiency is enough to cure deficiency with three causes, namely, lung, spleen and kidney are the same, namely, lung is the day of five internal organs, spleen is the mother of all bones, kidney is the root of life, and the treatment of lung, spleen and kidney is sufficient. The traditional Chinese medicine fully follows the treatment concept, and clinical treatment is mostly carried out by applying classic tonifying products such as four-ingredient decoction, four-monarch drug decoction, eight-ingredient decoction, zuogui pill, danggui pill and the like, and finally can obtain better clinical curative effect by taking methods of tonifying lung, tonifying spleen and tonifying kidney.

Aiming at the problem that the treatment price is high and no marrow suppression concrete concept exists in the traditional Chinese medicine theory in the prior art for improving the marrow suppression level after chemotherapy, the need of finding an improvement composition which is low in price and can realize the marrow suppression after chemotherapy is very necessary.

Disclosure of Invention

Aiming at the problems in the prior art, the invention provides a composition for improving bone marrow suppression after chemotherapy, granules and a preparation method thereof, the composition is simple in preparation method, the effects of the medicines can be fully exerted by compounding of seven medicines, the components interact with each other to realize synergistic interaction, osteogenic differentiation of mesenchymal stem cells can be effectively promoted, hematopoiesis is promoted, a hematopoietic microenvironment is improved, and thus the improvement of the bone marrow suppression after chemotherapy is realized.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

the invention provides a composition, which comprises dodder, epimedium, glossy privet fruit, medlar, astragalus root, largehead atractylodes rhizome and suberect spatholobus stem.

Further, the composition comprises the following components in parts by weight: 9-12 parts of semen cuscutae, 9-12 parts of herba epimedii, 9-12 parts of glossy privet fruit, 9-12 parts of medlar, 18-22 parts of astragalus, 8-12 parts of bighead atractylodes rhizome and 12-16 parts of caulis spatholobi.

Preferably, the composition comprises the following components in parts by weight: 10 parts of semen cuscutae, 10 parts of herba epimedii, 10 parts of glossy privet fruit, 10 parts of medlar, 20 parts of astragalus mongholicus, 10 parts of bighead atractylodes rhizome and 15 parts of caulis spatholobi.

Preferably, the weight ratio of the south dodder seed to the epimedium herb is 1.

Preferably, the weight ratio of the glossy privet fruit to the barbary wolfberry fruit is 1.

Preferably, the weight ratio of the astragalus to the bighead atractylodes rhizome is 2.

Further, the invention also provides a preparation method of the composition, which comprises the following steps: soaking semen Cuscutae, herba Epimedii, fructus Ligustri Lucidi, fructus Lycii, radix astragali, atractylodis rhizoma and caulis Spatholobi in water, decocting, mixing decoctions, filtering, concentrating, adding dextrin, oven drying, pulverizing, adding ethanol, granulating, drying, and grading.

Further, the soaking time is 30min.

Further, the decocting includes two times of decocting, i.e., a first time of decocting and a second time of decocting.

Furthermore, the time of the first decoction is 1.5-2h, preferably 2h, and the time of the second decoction is 0.5-1h, preferably 1h.

Further, the addition amount of the dextrin is 28-32g; preferably 30g.

Further, the amount of ethanol added is 3 to 6g, preferably 5g.

Furthermore, the composition provided by the invention can be applied to preparing a post-treatment myelosuppression medicament.

The technical effects obtained by the invention are as follows:

the prescription of the Hus Shengsui (abbreviated as Shengsui prescription) in the invention is composed of seven common traditional Chinese medicines of dodder, epimedium, glossy privet fruit, medlar, astragalus root, largehead atractylodes rhizome and suberect spatholobus stem. The dodder seed is pungent, sweet and mild in nature and has the effects of entering liver, kidney and spleen channels, tonifying liver and kidney, securing essence and reducing urination, preventing miscarriage, improving eyesight and stopping diarrhea; herba epimedii enters liver and kidney meridians, has the main effects of tonifying kidney yang, strengthening muscles and bones and dispelling wind-damp, and is recorded in compendium of materia medica: ' producing sperm and replenishing marrow, nourishing blood and tonifying yang, strengthening tendons and bones, treating all deficiency and impairment, deafness and dim eyesight, dizziness and dysentery; the glossy privet fruit is sweet, bitter and cool in nature and flavor, enters liver and kidney channels, and has the effects of nourishing liver and kidney, improving eyesight and blackening hair; the medlar is sweet and neutral in taste, enters liver and kidney channels, has the efficacies of nourishing liver and kidney, replenishing vital essence and improving eyesight, is a good medicine for nourishing liver and kidney, nourishing blood and replenishing vital essence and improving eyesight, and is recorded in the book of materia medica Jing Jizhu: medlar can tonify essence and qi and strengthen vagina; the astragalus root is sweet in nature and slightly warm in taste, enters spleen and lung channels, and has the effects of tonifying qi and invigorating yang, consolidating superficial resistance and arresting sweating, inducing diuresis and relieving swelling, promoting the production of body fluid and nourishing blood, activating stagnancy and removing obstruction in channels, expelling toxin and pus, and astringing sores and promoting granulation, and the astragalus root is recorded in the herbal essentials: "Shengxue, sheng Jie, pus discharge and interior support, sheng Yao for treating sores and abscess". The white atractylodes rhizome is sweet, bitter and warm in nature and taste, and enters spleen and stomach meridians, has the effects of strengthening spleen and replenishing qi, eliminating dampness and promoting diuresis, stopping sweating and preventing abortion, and is a key spleen-invigorating medicine for people who do not have pockmarks and yang deficiency and heat; spatholobus stem, bitter in flavor, sweet and warm in nature, enters liver and kidney channels, and has the effects of promoting blood circulation, enriching blood, regulating menstruation, relieving pain, relaxing tendons and activating collaterals. In the formula, dodder seed and epimedium herb are used for tonifying kidney yang as monarch, glossy privet fruit and barbary wolfberry fruit are used for nourishing kidney yin as minister, astragalus and largehead atractylodes rhizome are used for tonifying spleen and stomach and protecting postheaven as assistant, and rattan with blood and rattan as messenger. The whole formula has the effects of tonifying kidney and producing marrow, strengthening spleen and tonifying qi, and enriching blood and activating blood. The clinical application has good feedback for patients, stable marrow generating effect and high safety. In the previous research work, the marrow-producing prescription is researched by using a network pharmacology means, and the result shows that the dodder, the epimedium herb, the glossy privet fruit, the medlar, the astragalus root, the suberect spatholobus stem and the largehead atractylodes rhizome in the marrow-producing prescription can promote the bone marrow hyperplasia and have the positive promoting function of improving the hematopoiesis. Studies have found that the radix astragali injection prepared from radix astragali can increase the number of leukocytes, neutrophils, lymphocytes and monocytes of mice of the model of leukopenia. Caulis Spatholobi has the effect of improving hemopoiesis function, and can activate hemopoiesis system via multiple ways. The caulis Spatholobi can promote bone marrow granulocyte division, increase mouse leukocyte and bone marrow nucleated cell number, and has obvious stimulation effect on proliferation of myelomonocytic progenitor cells of anemic mice. Researches find that the bighead atractylodes rhizome has obvious positive promoting function on the leucocyte and function of an immunosuppressed mouse induced by cyclophosphamide and can also obviously improve the lymphocyte function of a normal mouse. Specifically, the quercetin contained in the medlar, the astragalus, the glossy privet fruit and the dodder seed can increase the proliferation activity of the mesenchymal stem cells and promote the osteogenic differentiation of the mesenchymal stem cells, and the mesenchymal stem cells not only have the mechanical support function for the hematopoietic stem cells in the bone marrow, but also can secrete various growth factors (such as IL-6, IL-11, LIF, M-CSF, SCF and the like) to support hematopoiesis. The quercetin can obviously improve the peripheral blood leukocyte count of mice with hypoimmunity caused by cyclophosphamide, can promote the proliferation of immune cells, regulate the immunosuppression and improve the immunity of organisms, the catechin contained in the caulis spatholobi, the quercetin neutralized by the medlar, the astragalus, the glossy privet fruit and the dodder, the kaempferol contained in the astragalus, the glossy privet fruit, the dodder and the epimedium, the luteolin contained in the caulis spatholobi, the glossy privet fruit and the epimedium and the like can directly or indirectly act on IL-6, IL-2, IL-10 and EGFR, the hematopoietic function in the organisms is activated, and the leukocyte count is increased. Luteolin has protective effect on natural aging of human erythrocyte, and can prolong service life of erythrocyte. Catechin can regulate expression of hemopoietic genes such as HBE, HBG, HBA, HBB and HBD, erythropoietin receptor EPOR and key transcription factors MYB and PU.1 influencing hematopoiesis, and promote proliferation and differentiation of hematopoiesis and erythroid progenitor cells. The astragalus polysaccharide contained in the astragalus can improve the immunoglobulin, immune cell subgroup and leukocyte level of a patient with postoperative adjuvant chemotherapy (oxaliplatin + tegafur SOX) for the gastric cancer, improve the immune state and promote later-period rehabilitation. Icaritin contained in epimedium has the effect of promoting thrombopoiesis on an ITP mouse by regulating T cell polarization. From the aspect of the passage: the PI3K-Akt pathway is a signal transduction pathway of corresponding extracellular survival and growth of cells and is a signal transduction pathway involved in the regulation of cell growth, proliferation and differentiation. The PI3K-Akt pathway is closely related to blood diseases. The astragalus polysaccharide can promote the proliferation and differentiation of bone marrow stem cells, up-regulate the expression of PI3K and AKT mRNA, improve the protein content of pPI3K and p-AKT, and prompt that the astragalus polysaccharide activates a PI3K/AKT signal transduction pathway, and the regulation and control effect of the astragalus polysaccharide on the bone marrow stem cells is probably closely related to the PI3K/AKT signal transduction pathway. The tumor suppressor gene lipoid phosphatase PTEN can convert PIP3 into PIP2 through dephosphorylation of messenger PIP3 generated by activating PI3K, so that the activity of the PTEN is lost, akt phosphorylation is blocked, a negative regulation effect on a PI3K/Akt signal channel is achieved, expression of PTEN mRNA can be down-regulated after astragalus polysaccharide stem, and inhibition of activation of the PI3K/AKT signal transduction channel is reduced, and thus proliferation of bone marrow stem cells is promoted. Catechin can activate JAK-STAT signal channel related to hematopoietic factor, promote hematopoiesis, and improve hematopoietic microenvironment. The formula disclosed by the invention can realize an excellent synergistic effect on improving bone marrow suppression after chemotherapy through reasonable compounding.

Detailed Description

The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.

Before the present embodiments are further described, it is to be understood that the scope of the invention is not limited to the particular embodiments described below; it is also to be understood that the terminology used in the examples is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention.

When numerical ranges are given in the examples, it is understood that both endpoints of each of the numerical ranges and any number between the two endpoints are optional unless otherwise specified in the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

It should be noted that the raw materials used in the present invention are all common commercial products, and the specifications and standards of the relevant raw materials are shown in table 1, and thus the sources thereof are not particularly limited.

TABLE 1 raw and auxiliary materials specification and quality standard

Example 1

A composition comprises semen Cuscutae 10 parts, herba Epimedii 10 parts, fructus Ligustri Lucidi 10 parts, fructus Lycii 10 parts, radix astragali 20 parts, atractylodis rhizoma 10 parts and caulis Spatholobi 15 parts. Soaking the seven medicines in water for 30 minutes, decocting twice, decocting for 2 hours for the first time, decocting for 1 hour for the second time, mixing decoctions, filtering, concentrating the filtrate, adding an appropriate amount of dextrin, mixing uniformly, drying, pulverizing, adding an appropriate amount of ethanol, preparing into wet granules, drying, finishing granules, and preparing into 1000g granules.

Comparative example 1

A composition comprises semen Cuscutae 10 parts, herba Epimedii 10 parts, fructus Ligustri Lucidi 10 parts, fructus Lycii 10 parts, hispid Fig 20 parts, atractylodis rhizoma 10 parts and caulis Spatholobi 15 parts. The preparation method was the same as in example 1 except that the kind of the drug was changed.

Comparative example 2

A composition comprises semen Cuscutae 10 parts, herba Epimedii 10 parts, fructus Ligustri Lucidi 10 parts, fructus Lycii 10 parts, radix astragali 20 parts, atractylodis rhizoma 10 parts, caulis Spatholobi 15 parts, radix Morindae officinalis 15 parts and radix rehmanniae Preparata 15 parts. The preparation method was the same as in example 1 except that the kinds of the drugs were added.

1. Effect of the composition of the invention on bone marrow suppression after chemotherapy in mice

The test method comprises the following steps: BALB/c mice were selected and randomly divided into 5 groups of 10 mice, one of which was a blank group, one of which was a model group, and the remaining groups were example groups, and the remaining mice were inoculated with mouse gastric cancer cells (MFC, density 1X 10, except the blank group) ⁷ mL ^-1 ) 0.2mL for each, when the volume of the axillary tumor is more than or equal to 200mm ³ And when no ulceration exists, the gastric cancer tumor-bearing mouse is successfully modeled, 100mg/kg of Cyclophosphamide (CTX) is injected into the abdominal cavity of the mouse, the injection is carried out once a day for three consecutive days, and a bone marrow suppression model after chemotherapy of the mouse is established.On the next day after the model is successfully made, each example group is intragastrically administrated with 0.2mL of the medicament in each example (the particles are dissolved and prepared into a solution of 3 g/mL), and the blank group and the model group are administrated with the same amount of normal saline once a day for seven days; after the last dose, mice were bled from their eyes, mixed with sodium citrate at a ratio of 9.

Table 2 influence of groups on the conventional index of mouse blood

(Note: Δ: P < 0.05; Δ: P < 0.01; P < 0.05; P < 0.01; see: blank).

As can be seen from the above table, WBC, RBC, hb, and PLT of the model group mice are significantly reduced compared to the blank group, and WBC, RBC, hb, and PLT of the example 1 group are significantly improved compared to the model group. When hispid fig is used instead of astragalus, or morinda officinalis and prepared rehmannia root are additionally added, as shown in comparative example 1 and comparative example 2, WBC of mice is significantly improved, RBC and PLT are significantly improved, and Hb is not significantly improved in comparative example 1 group compared to model group; compared with the model group, the WBC of the mice is greatly improved, the PLT is obviously improved, and the RBC and Hb are not obviously improved in the comparative example 2 group, so that the composition can effectively improve the bone marrow suppression condition of the mice after chemotherapy.

2. Demonstration of the effectiveness of the compositions of the invention to improve chemotherapy-related myelosuppression

Note:

1. the laboratory test results of each patient in the study design are divided into two stages, wherein the first stage takes the chemotherapy starting date as the starting point, the chemotherapy ending of two cycles (42 days) as the end point, the second stage takes the chemotherapy starting date of the third cycle as the starting point, the chemotherapy ending of four cycles (42 days) as the end point, the blood routine results of each stage of each patient are plotted on a line graph, and each line graph is plotted on a trend line.

2. Description of basic case conditions: a total of 11 cases were enrolled, 3 males and 6 females, with an average age of 57 years, with each case having the same number of first-stage and second-stage blood norms, 86 first-stage and 86 second-stage blood norms.

Each patient makes a line graph of each relevant index in the first and second stage blood routine, then makes a trend line of the line graph, and records the slope of each trend line. When the same index slope in the first and second stages is the same, the smaller the value is, the more stable the data change in the stage is; when the slope is positive and negative, the rising of the data is represented by the positive slope, the falling of the data is represented by the negative slope, and the more stable the entry is brought into the stage with the positive slope; the slope is negative, and it is considered that the more negative the value is, the more stable the data is, and the more stable the data is included in the phase.

The research refers to the index Standard of the acute and subacute toxic response of anticancer drugs in the world health organization for grading the conventional myelocyte count, the leukocyte count, the hemoglobin, the platelet count and other indexes of the blood after chemotherapy, and counts the occurrence of the bone marrow suppression of all levels in the first and second stages.

TABLE 3 Scale of acute and subacute toxicity response of anti-cancer drugs by world health organization

Experimental results of preliminary study

(1) The first stage and the second stage data trend line slope statistical result:

TABLE 4 two-phase data trend line slope statistics

TABLE 5 two-phase data trend line slope stability statistics

(2) Comparison of myelosuppression status in first and second stages

TABLE 6 comparison of the first and second stages of leukocyte inhibition

TABLE 7 comparison of first and second stages of neutrophil inhibition

TABLE 8 comparison of the first and second stages of platelet inhibition

TABLE 9 comparison of hemoglobin inhibition in the first and second stages

Analysis of clinical observations:

as can be seen from table 5, the slope stability of the second-stage white blood cell count, neutrophil count, red blood cell count, platelet count, and hemoglobin trend lines were all higher than that of the first-stage.

As can be seen from tables 6-8, white blood cell counts were observed at the second stage of clinical observation with 0-fold level III myelosuppression and 0-fold level IV myelosuppression, while 10-fold level III myelosuppression and 7-fold level IV myelosuppression occurred at the first stage. Neutrophil counts in the second phase of clinical observation, 1 in III degree myelosuppression and 0 in IV degree, while 7 in the first phase and 8 in IV degree myelosuppression. Platelet counts in the second phase of clinical observation, 3 and 0 degrees of III and 3 and 8 and 3 degrees of IV myelosuppression occurred in the first phase. Hemoglobin in the second phase of clinical observation, level III myelosuppression occurred 4 times, level IV myelosuppression 1 time, while level III myelosuppression in the first phase occurred 9 times, level IV myelosuppression occurred 5 times.

The preliminary results of this clinical observation show: for myelosuppression after chemotherapy, the change of myelosuppression is gradually stabilized along with the prolonging of the time of the oral myelogenesis formula, and the chance of developing the myelosuppression of III and IV degrees is reduced, so that the myelogenesis formula can stably promote and maintain the bone marrow hematopoiesis.

Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and do not limit the protection scope of the present invention, and those skilled in the art can make simple modifications or equivalent substitutions on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.

Claims

1. A composition for improving post-chemotherapy myelosuppression, characterized by: the traditional Chinese medicine composition is composed of, by weight, 10 parts of semen cuscutae, 10 parts of herba epimedii, 10 parts of glossy privet fruit, 10 parts of wolfberry fruit, 20 parts of astragalus membranaceus, 10 parts of bighead atractylodes rhizome and 15 parts of caulis spatholobi.

2. A method of preparing the composition of claim 1, wherein: the method comprises the following steps: soaking semen Cuscutae, herba Epimedii, fructus Ligustri Lucidi, fructus Lycii, radix astragali, atractylodis rhizoma and caulis Spatholobi in water, decocting, mixing decoctions, filtering, concentrating, adding dextrin, oven drying, pulverizing, adding ethanol, granulating, drying, and grading.

3. The production method according to claim 2, characterized in that: the decoction comprises two times of decoction, namely a first time of decoction and a second time of decoction.

4. The production method according to claim 3, characterized in that: the time of the first decoction is 1.5-2h, and the time of the second decoction is 0.5-1h.

5. The method of claim 2, wherein: the addition amount of the dextrin is 28-32g.

6. The production method according to claim 2, characterized in that: the adding amount of the ethanol is 3-6g.

7. Use of the composition of claim 1 for the preparation of a medicament for ameliorating post-chemotherapy myelosuppression.