A traditional Chinese medicine composition for treating tumor cachexia, and a preparation method and application thereof

Abstract

The application belongs to the field of traditional Chinese medicines, and particularly relates to a traditional Chinese medicine composition for treating tumor cachexia and a preparation method and application thereof. The traditional Chinese medicine composition is composed of the following raw materials in parts by weight: cassia twig 7-15 parts, white peony root 16-24 parts, raw ginger 13-21 parts, jujube 7-15 parts, and licorice 4-12 parts. The traditional Chinese medicine composition is a whole traditional Chinese medicine formula, has the advantages of easy availability of medicine source, remarkable medicine effect, few side effects, and simple preparation process, can effectively improve the weight loss, fat loss, and muscle atrophy process of tumor cachexia patients, improve the treatment effect and life quality, prolong the survival time of patients, and can be used for preparing a medicine for treating tumor cachexia.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine, and in particular to a traditional Chinese medicine composition for treating tumor cachexia and its application. Background Technology

[0002] Cancer cachexia is a multi-organ metabolic and nutritional disorder that cannot be completely reversed by routine nutritional support, leading to treatment-related complications, persistent functional decline, and cancer-related death. Cachexia occurs in 50%–80% of cancer patients and is the direct cause of death in 22% of cancer patients. Despite its extremely serious clinical impact, effective treatment interventions remain very limited. Current treatment strategies include nutritional support and appetite stimulation (such as medroxyprogesterone acetate and alamolin), which, while slowing weight loss by increasing appetite, fail to address the underlying metabolic disorder or reverse tissue wasting, especially skeletal muscle loss.

[0003] Tumor-derived inflammatory mediators TNF-α, IL-6, and extracellular vesicles are key drivers of cachexia pathogenesis. These factors induce anorexia by disrupting central nervous system homeostasis and simultaneously activate peripheral proteolytic and lipolytic pathways in skeletal muscle and adipose tissue. Recent research has revealed that the PI3K / AKT pathway can regulate protein synthesis and energy metabolism, possessing potential for targeted therapy. However, the multifactorial nature of this syndrome may limit the effectiveness of single-target therapies. Therefore, the complexity of these interaction mechanisms suggests that multi-target treatments may be more effective than single-pathway interventions in managing tumor cachexia, a systemic disease. Traditional Chinese medicine (TCM), with its unique "multi-component, multi-target" regulatory framework, has significant advantages in addressing multifactorial diseases; therefore, there is an urgent need to develop a highly effective TCM formula for treating tumor cachexia. Summary of the Invention

[0004] To address the aforementioned problems, this invention provides a traditional Chinese medicine composition for treating tumor cachexia, its preparation method, and its application. The traditional Chinese medicine composition provided by this invention can effectively improve the progression of weight loss, fat loss, and muscle atrophy in patients with tumor cachexia, thereby enhancing treatment efficacy and quality of life, and prolonging patient survival time.

[0005] To achieve the above objectives, the specific technical solution of the present invention is as follows: The first aspect of the present invention provides a traditional Chinese medicine composition for treating tumor cachexia, the traditional Chinese medicine composition being composed of the following raw materials in parts by weight: 7 to 15 parts of cinnamon twig, 16 to 24 parts of white peony root, 13 to 21 parts of ginger, 7 to 15 parts of jujube, and 4 to 12 parts of licorice root.

[0006] Furthermore, the traditional Chinese medicine composition is composed of the following raw materials in parts by weight: 9 parts cinnamon twig, 18 parts white peony root, 15 parts ginger, 9 parts jujube, and 6 parts licorice root.

[0007] Furthermore, the traditional Chinese medicine composition is used to improve symptoms of weight loss, fat loss, and / or muscle atrophy in patients with tumor cachexia.

[0008] Furthermore, the tumor is any one or more of colorectal cancer, gastric cancer, pancreatic cancer, esophageal cancer, lung cancer, and liver cancer. Tumor cachexia refers to a multi-organ syndrome characterized by anorexia, decreased physical strength, abnormal nutrient metabolism, muscle atrophy, and fat loss, which is a symptom of various malignant tumors such as colorectal cancer, gastric cancer, pancreatic cancer, esophageal cancer, lung cancer, and liver cancer.

[0009] Furthermore, the tumor is colorectal cancer.

[0010] The second aspect of the present invention provides a method for preparing the traditional Chinese medicine composition, wherein the raw materials of the traditional Chinese medicine composition are weighed according to the specified weight parts, then soaked in water, decocted once to three times, the dregs are filtered to obtain the decoction, and the preparation is completed.

[0011] Furthermore, the mass of the water is 4 to 6 times the total mass of the raw materials; the soaking time is 25 to 35 minutes.

[0012] Furthermore, the simmering process involves bringing the water to a boil over high heat, then reducing the heat to low and simmering for 30 to 50 minutes.

[0013] A third aspect of the present invention provides the application of the aforementioned traditional Chinese medicine composition in the preparation of a medicament for treating tumor cachexia.

[0014] Furthermore, the tumor is any one or more of colorectal cancer, gastric cancer, pancreatic cancer, esophageal cancer, lung cancer, and liver cancer.

[0015] Furthermore, the drug is used to improve symptoms of weight loss, fat loss, and / or muscle atrophy in patients with cancer cachexia.

[0016] A third aspect of the present invention provides a medicament for treating tumor cachexia, wherein the medicament uses the traditional Chinese medicine composition or an aqueous extract of the traditional Chinese medicine composition as the main active ingredient.

[0017] Furthermore, the drug is composed of the traditional Chinese medicine composition and pharmaceutically acceptable excipients.

[0018] Furthermore, the dosage form of the drug is tablets, capsules, granules, pills, or oral liquids.

[0019] Furthermore, the tumor is any one or more of colorectal cancer, gastric cancer, pancreatic cancer, esophageal cancer, lung cancer, and liver cancer.

[0020] Furthermore, the tumor is colorectal cancer.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention provides a traditional Chinese medicine composition for treating tumor cachexia, its preparation method, and its application. The composition comprises the following raw materials in parts by weight: 7-15 parts cinnamon twig, 16-24 parts white peony root, 13-21 parts fresh ginger, 7-15 parts jujube, and 4-12 parts licorice root. The preparation method includes: weighing each raw material according to the above parts by weight, soaking in water, decocting once and three times, combining the decoctions, and filtering out the dregs. This traditional Chinese medicine composition is a complete herbal formula with simple formulation, readily available medicinal materials, a simple preparation process, few side effects, and significant efficacy. It can effectively improve the progression of weight loss, fat loss, and muscle atrophy in patients with tumor cachexia, enhance treatment efficacy and quality of life, and prolong patient survival time. It can be used to prepare drugs for treating tumor cachexia.

[0022] The traditional Chinese medicine composition provided by this invention is derived from Xiao Jianzhong Tang but with ingenious innovation. Xiao Jianzhong Tang uses maltose as the chief ingredient to warm the middle and tonify deficiency. Cinnamon twig and peony root harmonize the Ying and Wei, ginger and jujube strengthen the spleen and stomach, and prepared licorice root harmonizes all the ingredients. "Three ingredients form a formula that governs all six meridians," possessing the functions of tonifying the middle, harmonizing Yin and Yang, and promoting the smooth flow of Qi and blood. This formula not only treats abdominal pain due to deficiency, but can also be adapted and applied to various diseases caused by imbalance of the middle Jiao. It is truly a model of "using simplicity to manage complexity" in classical formulas. Since the main function of maltose in Xiao Jian Zhong Tang is to "harmonize the stomach," this application, based on the Xiao Jian Zhong Tang formula, removes maltose, the chief herb in Xiao Jian Zhong Tang, and uses a large amount of white peony root as the chief herb to soothe the liver, nourish blood, relieve spasms, and alleviate pain, which aligns with modern research. Combined with cinnamon twig, it harmonizes the Ying and Wei, and promotes the flow of Yin and Yang. A large amount of ginger and jujube are added as adjuvants to specifically strengthen the spleen and harmonize the stomach, thus providing the source of Qi and blood production. Licorice root is used as the guiding herb to harmonize the other herbs and also to alleviate spasms. The entire formula is based on the principle of "harmony," combining tonification and purgation without being cloying or drying. Its aim is to restore the central function of the middle Jiao by harmonizing the liver and spleen and promoting the flow of Ying and Wei, thus practicing the theory of "the spleen governs the muscles." It is suitable for various symptoms of weakness and exhaustion caused by disharmony of the middle Jiao and liver and spleen, and is especially suitable for chronic wasting states such as tumor cachexia. Attached Figure Description

[0023] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0024] Figure 1This invention presents the overall therapeutic effect of the traditional Chinese medicine composition on mice with cancer cachexia. A: Body weight of the tumor-bearing mouse. B: Body weight of the mouse after tumor removal. C: Tumor weight. D: Curve showing changes in food intake of the mouse. E: Average food consumption during the experiment. Data are expressed as mean ± standard deviation (n=6), statistical significance: ### p <0.001 compared with the control group, * p <0.05,** p <0.01, *** p <0.001 compared with the CAC group.

[0025] Figure 2 The herbal composition of this invention alleviated muscle atrophy in cancer cachexia mice. A: Bar chart of mouse gripping force. B: Bar chart of gastrocnemius muscle weight. C: Bar chart of soleus muscle weight. D: Bar chart of quantitative analysis of muscle cross-sectional area as a percentage of control group. E: Representative image of hematoxylin-eosin (H&E) stained section of gastrocnemius muscle tissue, scale bar = 50 μm. Data are expressed as mean ± standard deviation (n = 6-10), statistical significance: # p <0.05 compared with the control group, * p <0.05 compared with the CAC group.

[0026] Figure 3 This invention relates to a traditional Chinese medicine composition that reduces adipose tissue atrophy in cancer cachexia mice. A: Bar chart of epididymal white adipose tissue (eWAT) weight. B: Bar chart of quantitative analysis of adipose tissue cross-sectional area. C: Representative image of a gastrocnemius muscle section stained with hematoxylin and eosin (H&E), scale bar = 50 μm. Data are expressed as mean ± standard deviation (n=6), statistical significance: ## p <0.01、### p <0.001 compared with the control group, * p <0.05、** p <0.01 compared with the CAC group.

[0027] Figure 4 This invention illustrates the effects of the traditional Chinese medicine composition on cachexia-promoting cytokines and factors in the serum of cachectic mice. A: Bar chart of serum IFN-γ content. B: Bar chart of serum TNF-α content. C: Bar chart of serum IL-6 content. D: Bar chart of serum exosome content. Data are expressed as mean ± standard deviation (n=3-6), statistical significance: ## p <0.01、### p <0.001 compared with the control group;* p <0.05、** p <0.01、*** p <0.001 compared with the CAC group. Detailed Implementation

[0028] The specific embodiments of the present invention are described in detail below, but it should be understood that the scope of protection of the present invention is not limited to the specific embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise specified, the experimental methods described in the embodiments of the present invention are conventional methods, and the materials and reagents used in the following embodiments are commercially available unless otherwise specified.

[0029] Example 1 A traditional Chinese medicine composition for treating tumor cachexia is prepared by the following steps.

[0030] Weigh out 9 parts cinnamon twigs, 20 parts white peony root, 16 parts ginger, 15 parts jujubes, and 6 parts licorice root. Add 5 times the weight of the ingredients in purified water and soak for 30 minutes. First, boil over high heat, then simmer over low heat for 40 minutes. Filter out the dregs to obtain the first decoction. Add warm water again, boil over high heat until boiling, then simmer over low heat for 40 minutes. Filter out the dregs to obtain the second decoction. Mix the two decoctions thoroughly to obtain the final product.

[0031] Example 2 A traditional Chinese medicine composition for treating tumor cachexia is prepared by the following steps.

[0032] Weigh out 7 parts cinnamon twigs, 16 parts white peony root, 13 parts ginger, 7 parts jujubes, and 4 parts licorice root. Add 4 times the weight of the ingredients in purified water and soak for 35 minutes. First, boil over high heat, then simmer over low heat for 35 minutes. Filter out the dregs and obtain the medicinal liquid.

[0033] Example 3 A traditional Chinese medicine composition for treating tumor cachexia is prepared by the following steps.

[0034] Weigh out 15 parts cinnamon twigs, 24 parts white peony root, 21 parts fresh ginger, 15 parts jujubes, and 12 parts licorice root. Add 6 times the weight of the ingredients in purified water and soak for 25 minutes. First, boil over high heat, then simmer over low heat for 30 minutes. Filter out the dregs to obtain the first decoction. Add warm water again, boil over high heat until boiling, then simmer over low heat for 30 minutes. Filter out the dregs to obtain the second decoction. Add warm water again, boil over high heat until boiling, then simmer over low heat for 30 minutes. Filter out the dregs to obtain the third decoction. Mix the three decoctions thoroughly to obtain the final product.

[0035] Comparative Example 1 A traditional Chinese medicine composition for treating tumor cachexia is prepared by the following steps.

[0036] Weigh out 30 parts maltose, 9 parts cinnamon twigs, 20 parts white peony root, 9 parts ginger, 15 parts jujubes, and 6 parts licorice root. Add 5 times the weight of the ingredients in purified water and soak for 30 minutes. First, boil over high heat, then simmer over low heat for 40 minutes. Filter out the dregs to obtain the first decoction. Add warm water again, boil over high heat until boiling, then simmer over low heat for 40 minutes. Filter out the dregs to obtain the second decoction. Mix the two decoctions thoroughly to obtain the final product.

[0037] Examples 1-3 have similar effects. For ease of subsequent discussion and reference, the experimental results of Example 1 will be used as an example. The following are the experimental results of Example 1.

[0038] This invention is based on the traditional Chinese medicine theory that "the spleen governs the muscles." It uses a traditional Chinese medicine composition that strengthens the spleen and stomach to treat tumor cachexia. The invention focuses on the effects of the traditional Chinese medicine composition on the food intake, body weight, gastrocnemius muscle weight, gastrocnemius muscle cross-sectional area, and inflammatory factors in the blood of cachexia mice. The invention explores the effect of the traditional Chinese medicine composition on improving tumor cachexia through animal experiments on mice, and provides a clinical drug formula for the prevention and treatment of tumor cachexia with traditional Chinese medicine.

[0039] I. Experimental Methods Thirty-six adult male C57BL / 6 mice (8 weeks old) were randomly divided into six groups: control group, cachexia model group (CAC), medroxyprogesterone acetate group (MA), treatment group of traditional Chinese medicine composition of Example 1 of the present invention (XJZD), and treatment groups of low-dose, medium-dose and high-dose traditional Chinese medicine composition of Comparative Example 1 of the present invention (L-XJZD, M-XJZD, H-XJZD).

[0040] Mice in the cachexia model group, medroxyprogesterone acetate group, Example 1, and Comparative Example 1 treatment group were subcutaneously injected with 1×10⁻⁶ mmol / L in the back of the right forelimb axilla. 7 A mouse cachexia model was induced by injecting CT26 colon cancer cells at a dose of / mL, while control mice were injected with an equal volume of physiological saline. After 7 days of acclimatization, the control and cachexia model groups were administered 0.5 mL of physiological saline by gavage; the medroxyprogesterone acetate group was administered 0.5 mL of medroxyprogesterone acetate by gavage (dose of 100 mg / kg); the L-XJZD, M-XJZD, H-XJZD, and F-XJZD groups were administered 0.5 mL of medroxyprogesterone acetate by gavage (concentrated using a rotary evaporator), at doses of 6.6 g / kg, 13.2 g / kg, 26.4 g / kg, and 13.2 g / kg, respectively (M-XJZD group was equivalent to the normal adult dose), once daily. From day 7, mouse body weight and food intake were measured every 2 days, and tumor size was measured every 2 days using calipers and calculated using the following formula: Tumor volume (mm) 3 = 0.52 × length × width 2At the end of the experiment, the gripping force of the mice was measured using a GSM grip dynamometer (Ugo Basile SRL, Italy) according to the instrument's instruction manual.

[0041] Animal sampling: Three weeks after drug intervention, mice were anesthetized using an air anesthesia machine, and blood was collected by enucleation. The blood was placed in a coagulation-promoting tube and allowed to stand for 15 minutes, then centrifuged at 3000 g for 15 minutes to obtain mouse serum. Mice were euthanized by cervical dislocation, and the gastrocnemius muscle and epididymal fat of the hind limbs were rapidly separated. The weights were accurately weighed and recorded on an analytical balance. The gastrocnemius muscle and half of the adipose tissue of the left hind limb were placed in a test tube containing 4% (w / v) paraformaldehyde solution for preservation and hematoxylin-eosin staining. The gastrocnemius muscle and the other half of the adipose tissue of the right hind limb were placed in a cryovial, rapidly cooled in liquid nitrogen, and then stored at 80°C.

[0042] HE staining and cross-sectional area detection of gastrocnemius muscle: Mouse gastrocnemius muscle and epididymal adipose tissue (eWAT) were fixed with 4% (w / v) paraformaldehyde, dehydrated with ethanol and xylene, and then embedded in paraffin. For tissue morphology observation, the paraffin-embedded tissue was cut into 5-micrometer thick sections and then stained with hematoxylin and eosin. Images of the stained tissue sections were acquired using an optical microscope (Olympus, Japan) and analyzed using ImageJ software (V1.8.0, Wayne Rasband, National Institutes of Health, USA).

[0043] Serum inflammatory factors, including interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), were measured using an ELISA kit (Shanghai Enzyme-Linked Biotechnology Co., Ltd.), following the manufacturer's instructions. The concentrations of each factor were calculated, and quantification was performed using a standard curve method. Furthermore, exosomes were isolated from mouse serum using an exosome preparation kit for subsequent analysis. The isolated exosome samples were analyzed using a nanoparticle tracking analyzer (Particle Metrix GmbH, Meerbusch, Germany), and the total protein concentration was determined using the BCA protein assay (Beyotime, Shanghai, China).

[0044] II. Experimental Results To evaluate the effect of XJZD on improving cachexia, mice with cachexia were treated with a combination of traditional Chinese medicine at doses of 6.6 g / kg (L-XJZD), 13.2 g / kg (M-XJZD), 26.4 g / kg (H-XJZD), and 13.2 g / kg (F-XJZD).

[0045] Physiological parameter data from animal experiments are summarized in Figure 1The CAC group showed a 6.5% weight loss on day 15, indicating cachexia (weight loss >5%). Compared to the CAC group, the XJZD group showed a slight decrease in mean tumor weight, but this difference was not statistically significant. At the end of the experiment, the tumor-free body weight of mice in the CAC group was significantly reduced, while the positive control group (MA) showed a significantly reduced cachexia-related weight loss compared to the control group. Furthermore, XJZD at doses of 6.6 g / kg and 13.2 g / kg significantly improved weight loss in the cancer cachexia model, while the high-dose group at 26.4 g / kg showed relatively weaker efficacy. Food intake in the CAC group was significantly lower than that in the control group on day 15. Figure 1 E in the figure shows the average daily food intake of mice in each group, and the CAC group was significantly lower than the control group ( p <0.05). Compared with the CAC group, the food intake of the L-XJZD, M-JZXD, and MA groups was significantly increased. However, there was no statistically significant difference in the average daily food intake between the H-XJZD and CAC groups. The F-XJZD group was more effective than the L-XJZD, M-XJZD, and H-XJZD groups in improving symptoms such as weight loss and anorexia in cachectic mice.

[0046] from Figure 2 It can be seen that the grip strength of the cachectic model mice was significantly lower than that of the control group, while the grip strength of the M-XJZD group was significantly higher than that of the CAC group. The gastrocnemius muscle mass of cachectic mice was significantly reduced, while the L-XJZD and M-XJZD groups showed significant improvement in muscle atrophy in tumor-bearing mice. The soleus muscle weight appeared to remain unchanged in both the CAC group and the treatment group. Furthermore, H&E staining of gastrocnemius muscle tissue showed that XJZD treatment at doses of 6.6 g / kg and 13.2 g / kg significantly reduced the reduction in muscle fiber cross-sectional area in CT26 tumor-bearing mice. The F-XJZD group was superior to the L-XJZD, M-XJZD, and H-XJZD groups in improving muscle atrophy in cachectic mice.

[0047] from Figure 3 It can be seen that cachexia is usually accompanied by adipose tissue loss. Compared with the control group, the CAC group significantly reduced epididymal fat (eWAT) weight and a decrease in the cross-sectional area (CSA) of adipocytes in the eWAT tissue was observed. Furthermore, all treatment groups except the H-XJZD group showed significant therapeutic effects in improving fat loss. However, the cross-sectional area of ​​eWAT adipocytes in the L-XJZD group appeared to remain unchanged. The F-XJZD group was superior to the L-XJZD, M-XJZD, and H-XJZD groups in improving fat loss in cachexia mice.

[0048] from Figure 4It can be seen that cachexia is usually accompanied by abnormal activation of inflammatory factors. Compared with the control group, the serum levels of IL-6, IFN-γ, and TNF-α were significantly increased in the CAC group, while the cytokine changes were significantly weakened in the M-XJZD group. Figure 4 In the L-XJZD and MA groups, the levels of IFN-γ and TNF-α were lower than those in the CAC group, but in the H-XJZD group, only the level of IFN-γ was lower (in the CAC group). Figure 4 In addition, serum exosomes, as one of the cachexia-promoting factors, were elevated in CT26 tumor mice. In the M-XJZD group, the level of exosomes isolated from the same volume of mouse serum was significantly lower than that in the CAC group (AC). Figure 4 (D in the text). The F-XJZD group was superior to the L-XJZD, M-XJZD and H-XJZD groups in improving inflammatory factors in cachectic mice.

[0049] In summary, the traditional Chinese medicine composition for treating tumor cachexia provided by this invention can not only increase the food intake and weight of cachexia patients, but also alleviate skeletal muscle and adipose tissue atrophy, improve the quality of life of patients and prolong their survival period.

[0050] It should be noted that when numerical ranges are involved in this invention, it should be understood that both endpoints of each numerical range and any value between the two endpoints can be selected. Since the steps and methods used are the same as in the embodiments, preferred embodiments are described here to avoid redundancy. Although preferred embodiments of the invention have been described, those skilled in the art, once they understand the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments as well as all changes and modifications falling within the scope of this invention.

[0051] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. The application of a traditional Chinese medicine composition in the preparation of a drug for treating tumor cachexia, characterized in that, The traditional Chinese medicine composition is made from the following raw materials in parts by weight: 7-15 parts cinnamon twig, 16-24 parts white peony root, 13-21 parts fresh ginger, 7-15 parts jujube, and 4-12 parts licorice root; the tumor is any one or more of colorectal cancer, gastric cancer, pancreatic cancer, esophageal cancer, lung cancer, and liver cancer.

2. The application of the traditional Chinese medicine composition according to claim 1 in the preparation of a drug for treating tumor cachexia, characterized in that, The traditional Chinese medicine composition is made from the following raw materials in parts by weight: 9 parts cinnamon twig, 18 parts white peony root, 15 parts fresh ginger, 9 parts jujube, and 6 parts licorice root.

3. The application of the traditional Chinese medicine composition according to claim 1 in the preparation of a drug for treating tumor cachexia, characterized in that, The preparation method of the traditional Chinese medicine composition is as follows: weigh the raw materials of the traditional Chinese medicine composition according to the specified weight parts, then soak them in water, decoct them 1 to 3 times, filter the residue, obtain the decoction, and complete the preparation.

4. The application of the traditional Chinese medicine composition according to claim 3 in the preparation of a drug for treating tumor cachexia, characterized in that, The mass of the water is 4 to 6 times the total mass of the raw drug; the soaking time is 25 to 35 minutes.

5. The application of the traditional Chinese medicine composition according to claim 3 in the preparation of a drug for treating tumor cachexia, characterized in that, The simmering process involves bringing the water to a boil over high heat, then reducing the heat to low and simmering for 30 to 50 minutes.

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