Application of Nutmeg and Schisandra Pills in the Preparation of Drugs to Reduce Cardiotoxicity Related to Anthracycline Chemotherapy Drugs and Tumor Molecularly Targeted Therapies

Abstract

This application provides anthracycline chemotherapy drug for tumor molecular targeting. Nutmeg Five Flavor Pill has a significant effect on improving doxorubicin / trastuzumab-related cardiotoxicity and can restore intestinal flora balance and improve intestinal metabolism.

Description

Technical Field

[0001] This application pertains to the pharmaceutical field, specifically, it provides the application of Nutmeg and Schisandra pills in the preparation of drugs that reduce the cardiotoxicity associated with anthracycline chemotherapy drugs targeting tumors. Background Technology

[0002] According to the latest data, nearly 2.3 million new cases of breast cancer were diagnosed globally in 2022, with approximately 670,000 deaths, ranking first in both incidence and mortality among female cancers. According to the latest statistics from the National Cancer Center of China in 2022, there were 357,200 new cases of breast cancer, second only to lung cancer among female cancers, accounting for 15.6%. Approximately 20-30% of breast cancer patients overexpress HER2, which is usually associated with poor prognosis. Anthracyclines are the cornerstone of adjuvant chemotherapy for breast cancer, significantly improving the survival of breast cancer patients. Trastuzumab is the first humanized monoclonal antibody targeting HER2 and is a first-line treatment for HER2-positive recurrent and metastatic breast cancer. Multiple studies have shown that adding trastuzumab to adjuvant chemotherapy can significantly improve disease-free survival and overall survival in breast cancer patients.

[0003] However, both anthracyclines and trastuzumab can cause serious cardiotoxicity. Multiple large-scale clinical studies have shown that the incidence of cardiovascular toxicity further increases, reaching as high as 25%, when the two drugs are used in combination or sequentially. Currently, cardiotoxicity related to antitumor drugs has become a significant challenge hindering safe clinical drug use. In terms of treatment, only dexrazoxane monotherapy is a cardioprotective agent approved by the U.S. Food and Drug Administration (FDA), but its clinical use is limited due to the occurrence of secondary malignancies and myelodysplastic syndromes. Therefore, finding more effective cardioprotective agents is of great significance for the safe use of antitumor drugs.

[0004] Nutmeg Five-Flavor Pill, originating from the *Collection of Mongolian Medical Prescriptions*, is included in the *Drug Standards of the Ministry of Health of the People's Republic of China: Mongolian Medicine*. It is composed of five medicinal herbs: nutmeg, costus root, sandalwood, jujube, and long pepper. Studies have shown that nutmeg has antiarrhythmic and antioxidant effects, while jujube has the effects of clearing heat from the heart, strengthening the heart, and calming the mind, showing good efficacy for heart diseases such as stabbing pain and palpitations. According to the 2020 edition of the *Pharmacopoeia of the People's Republic of China*, jujube promotes blood circulation, nourishes the heart, and calms the mind, and can be used to treat clinical symptoms of ischemic heart disease (IHD). Multiple studies have shown that Nutmeg Five-Flavor Pill plays an important role in the treatment of various heart diseases, such as its use in treating arrhythmias and its protective effect against myocardial infarction. However, there are currently no research reports on the efficacy of Nutmeg Five-Flavor Pill in treating cardiotoxicity associated with anthracycline chemotherapy drugs / tumor molecularly targeted drugs.

[0005] Therefore, the development of applications for Nutmeg Five Flavor Pills can not only increase its new indications and broaden its uses, but also help improve the quality of medical care and has broad market prospects. Summary of the Invention

[0006] On the one hand, this application provides the application of Nutmeg and Schisandra pills in the preparation of drugs that reduce the cardiotoxicity associated with anthracycline chemotherapy drugs targeting tumor molecules.

[0007] Furthermore, the anthracycline chemotherapy drug targeting tumor molecules is doxorubicin and trastuzumab.

[0008] Furthermore, the cardiotoxicity includes decreased left ventricular ejection fraction and left ventricular shortening fraction, increased left ventricular end-systolic volume and left ventricular end-systolic diameter, increased serum cTnI and BNP levels, and cardiac tissue pathological damage.

[0009] Furthermore, the drug has one or more of the following functions:

[0010] (1) Increases left ventricular ejection fraction and left ventricular shortening fraction;

[0011] (2) Decreases left ventricular end-systolic volume and increases left ventricular end-systolic diameter;

[0012] (4) Reduce serum levels of cTnI and BNP;

[0013] (3) Improves pathological damage to cardiac tissue.

[0014] On the one hand, this application provides the application of Nutmeg and Schisandra pills in the preparation of drugs that alleviate intestinal microbial dysbiosis caused by anthracycline chemotherapy drugs targeting tumors.

[0015] Furthermore, the anthracycline chemotherapy drug targeting tumor molecules is doxorubicin and trastuzumab.

[0016] Furthermore, the gut microbiota dysbiosis includes an increase in the abundance of Firmicutes and Actinobacteria; a decrease in the abundance of Lactobacillus, Trichophyton, Clostridia, and Prevotella; an increase in the abundance of Bifidobacteria and Clostridia; an increase in the abundance of Muribaculaceae, Bifidobacterium, Clostridium sensu stricto, and Faecalibacterium; and a decrease in the abundance of orank_f_norank_o_Clostridia, RF39, and Lachnospiraceae NK4A136_group.

[0017] Furthermore, the drug has one or more of the following functions:

[0018] (1) Reduce the abundance of Firmicutes and Actinobacteria;

[0019] (2) Increase the abundance of Lactobacillus, Trichophyton, norank_o_Clostridia_UCG-014, and Prevotella in rats;

[0020] (3) Reduce the abundance of Bifidobacteriaceae and Clostridiumceae;

[0021] (4) Reduce the abundance of norank_f_Muribaculaceae, Bifidobacterium, Clostridium sensu_stricto_1, and Faecalibacterium;

[0022] (5) Increase the abundance of norank_f_norank_o_Clostridia_UCG-014, norank_f_norank_o_RF39 and Lachnospiraceae_NK4A136_group.

[0023] On the one hand, this application provides the application of Nutmeg and Schisandra pills in the preparation of drugs that alleviate metabolic disorders caused by anthracycline chemotherapy drugs targeting tumor molecules.

[0024] Furthermore, the anthracycline chemotherapy drug targeting tumor molecules is doxorubicin and trastuzumab.

[0025] Furthermore, the drug regulates the levels of tryptophan metabolites.

[0026] Furthermore, the drug is taken orally.

[0027] Furthermore, the drug includes pharmaceutically acceptable excipients.

[0028] The nutmeg five-flavor pills described in this application are prepared from nutmeg, costus root, costus root, jujube, and long pepper. While complying with relevant Mongolian medicine knowledge and national standards, the proportions of ingredients and excipients may vary due to differences in manufacturers and understanding of the formula.

[0029] The technical solution of this application is preferably used for breast cancer patients, but it can also be used for other patients using anthracycline chemotherapy drugs and tumor molecular targeted drugs, such as doxorubicin and trastuzumab.

[0030] Nutmeg Five-Flavor Pill is a core medicine in Mongolian medicine for treating "Hei". It is used for heart "Hei" disease, heart pain, delirium, syncope, palpitations, etc. Studies have found that Nutmeg Five-Flavor Pill also has a good effect on improving doxorubicin / trastuzumab-related cardiotoxicity, and can restore the balance of intestinal flora and improve intestinal metabolism. It is especially effective for breast cancer patients with intestinal flora disorder after receiving sequential therapy of doxorubicin and trastuzumab.

[0031] The advantages of Nutmeg Five-Flavor Pill in improving doxorubicin / trastuzumab-related cardiotoxicity are as follows:

[0032] Nutmeg Five-Flavor Pills have a significant effect on improving cardiotoxicity associated with doxorubicin / trastuzumab, fully demonstrating the therapeutic advantages of effective components of traditional Chinese medicine, and providing an effective strategy for preventing and treating cardiotoxicity associated with sequential therapy of doxorubicin and trastuzumab.

[0033] The regulatory effect of Nutmeg Five Flavor Pill on intestinal flora: Sequential therapy with doxorubicin and trastuzumab disrupts the balance of intestinal flora, while Nutmeg Five Flavor Pill has a significant advantage in improving the composition of beneficial flora and restoring the balance of flora.

[0034] The regulatory effect of Nutmeg and Schisandra Pill on the body's metabolism: Sequential therapy with doxorubicin and trastuzumab can disrupt the body's metabolic balance, while Nutmeg and Schisandra Pill has a significant advantage in improving the body's metabolic balance. Attached Figure Description

[0035] Figure 1 This shows the changes in rat body weight during the drug administration period;

[0036] Figure 2A The cTnI content in the plasma of rats in each group;

[0037] Figure 2B The BNP content in the plasma of rats in each group;

[0038] Figure 3A Left ventricular ejection fraction (LVEF) of rats in each group;

[0039] Figure 3B The shortening rate of the left ventricular short axis in each group of rats;

[0040] Figure 3C The left ventricular end-systolic volume of rats in each group;

[0041] Figure 3D The left ventricular end-systolic diameter of rats in each group;

[0042] Figure 4A M-mode echocardiography of normal rats;

[0043] Figure 4B M-mode echocardiography of normal rats;

[0044] Figure 4C M-mode echocardiography of rats in the high-dose group of Nutmeg and Schisandra chinensis pills;

[0045] Figure 4D M-mode echocardiography of rats in the low-dose group of Nutmeg and Schisandra chinensis pills;

[0046] Figure 5A HE staining of the heart of a normal rat group;

[0047] Figure 5B HE staining results of the heart of rats in the model group;

[0048] Figure 5C HE staining results of the hearts of rats in the low-dose nutmeg and schisandra pill group;

[0049] Figure 6A PCA diagram in positive ion mode;

[0050] Figure 6B PCA diagram in negative ion mode;

[0051] Figure 7A OPLS-DA plots of the normal group and the model group under positive ion mode;

[0052] Figure 7B OPLS-DA plots of the model group and the Nutmeg and Schisandra pill group under positive ion mode;

[0053] Figure 8A Volcano plot of differentially metabolites between the model group and the normal group;

[0054] Figure 8B Volcano diagram of differential metabolites between the model group and the nutmeg and schisandra pill group;

[0055] Figure 9 Venn diagram showing the differences in metabolites among the normal group, model group, and nutmeg and schisandra pill group (left side: model group vs. normal group; right side: nutmeg and schisandra pill group vs. model group);

[0056] Figure 10 For KEGG pathway enrichment analysis;

[0057] Figure 11 For α-diversity analysis;

[0058] Figure 12A For A NMI)S analysis;

[0059] Figure 12B PCoA principal coordinate analysis;

[0060] Figure 13A The relative abundance of microorganisms in each group at the phylum level;

[0061] Figure 13B The relative abundance of microorganisms in each group at the scientific level;

[0062] Figure 13C The relative microbial abundance of each group at the genus level;

[0063] Figure 14A Analyze the evolutionary branching diagram for LEfSe;

[0064] Figure 14B Analyze the bar chart for LEfSe. Detailed Implementation

[0065] The following examples are for illustrative purposes only and are not intended to limit the scope of the invention. Where specific techniques or conditions are not specified in the examples, they should be performed according to the techniques or conditions described in the literature in this field, or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased from legitimate channels.

[0066] Experimental Example 1

[0067] In this embodiment, a pharmacodynamic experiment was conducted using Nutmeg Five-Flavor Pills to clarify their protective effect against doxorubicin / trastuzumab-induced cardiotoxicity. The Nutmeg Five-Flavor Pills used in the following experimental examples were purchased from Inner Mongolia Kulun Mongolian Medicine Co., Ltd., and their formula mainly contains traditional Chinese medicines such as nutmeg, costus root, jujube, and long pepper.

[0068] Drugs and dosages

[0069] The cumulative dose of doxorubicin in the model group was 15 mg / kg, and the cumulative dose of trastuzumab was 20 mg / kg. The low-dose administration of Nutmeg and Schisandra chinensis pills was 0.81 mg / kg; the high-dose administration was 1.62 mg / kg. The dosages for both doxorubicin and trastuzumab were based on the modeling doses in the literature. The low-dose group of Nutmeg and Schisandra chinensis pills was equivalent to the clinically equivalent dose, and the high-dose group was equivalent to twice the clinically equivalent dose. Doxorubicin was administered via tail vein injection, and trastuzumab was administered via intraperitoneal injection. Nutmeg and Schisandra chinensis pills were suspended in sodium carboxymethyl cellulose and administered by gavage.

[0070] animal

[0071] Eight-week-old female SD rats, weighing 200±20g.

[0072] Methods and Results

[0073] Animal grouping

[0074] After one week of acclimatization, the rats were recorded and randomly divided into four groups: control group, model group, low-dose nutmeg and schisandra pill group, and high-dose nutmeg and schisandra pill group, with 10 rats in each group.

[0075] Animal modeling and drug administration

[0076] After grouping, the experimental cycle was 36 days. From day 1 to day 11, doxorubicin was injected every other day for a total of 6 times, with a cumulative dose of 15 mg / kg, administered via tail vein injection. From day 19 to day 29, trastuzumab was injected every other day for a total of 6 times, with a cumulative dose of 20 mg / kg, administered via intraperitoneal injection. The treatment group received the corresponding dose of nutmeg and schisandra pills via gavage. The total treatment period was 36 days. The rats' condition was monitored and recorded throughout the treatment period, including changes in weight, activity level, and mortality.

[0077] Indicator Testing

[0078] After the last administration, rats in each group were fasted for 24 hours but allowed free access to water. After anesthetizing the rats, transthoracic two-dimensional M-mode echocardiography was used to detect the cardiac function of the rats. The main measured indicators were left ventricular end-diastolic diameter (LVIDd) and left ventricular end-systolic diameter (LVIDs), and the left ventricular ejection fraction (LVEF) and shortening fraction (%FS) parameters were calculated. Rat feces were collected and 16S rRNA high-throughput sequencing was performed. Rat serum was collected and myocardial injury markers such as cTnI and BNP were detected using kits, and extensive targeted metabolic detection was performed. The heart was dissected, pathologically stained, and the pathological changes of the heart in each group of rats were observed.

[0079] Experimental results

[0080] General condition observation of rats

[0081] During the administration period, the control group rats were in good condition, with normal water and food intake. The model group rats were in poor condition, with decreased appetite, reduced activity, and significant hair loss. The rats in the nutmeg and schisandra pill group showed improvement compared to the model group, without significant hair loss or ascites, and experienced slower weight loss. No rat deaths occurred during the administration period. The changes in body weight of rats in each group during the administration period are shown in the attached table. Figure 1 .

[0082] Nutmeg Five-Flavor Pills Reduce Doxorubicin / Trastuzumab-Related Cardiotoxicity

[0083] Changes in myocardial injury markers in the blood of rats in each group after treatment are shown in the figure. Figure 2A -B. Compared with the control group, cTnI in the model group was significantly increased (P < 0.01); compared with the model group, cTnI in both the high-dose and low-dose groups of Roukou Wuwei Wan was significantly decreased, with statistically significant differences (P < 0.05); compared with the control group, BNP in the model group was significantly increased (P < 0.01); compared with the model group, BNP in both the high-dose and low-dose groups of Roukou Wuwei Wan was significantly decreased, with statistically significant differences (P < 0.05).

[0084] Changes in cardiac function in each group of rats after treatment are shown in the figure. Figure 3A -D. Compared with the control group, the model group showed significantly increased LVIDs and LVESV (P < 0.01), and significantly decreased LVEF and FS (P < 0.01); compared with the model group, the low-dose nutmeg and schisandra pill group showed significantly decreased LVIDs and LVESV (P < 0.01), and significantly increased LVEF and FS (P < 0.01). M-mode echocardiography of rats in each group is shown below. Figure 4A -D.

[0085] The pathological changes of the heart in each group of rats are as follows: Figure 5A As shown in Figure C, the normal group showed uniformly arranged and normal-shaped cardiomyocytes with neatly arranged muscle fibers. The model group exhibited cardiomyocyte edema, inflammatory cell aggregation, disordered arrangement, and even breakage. Compared with the model group, the nutmeg and schisandra pill group showed more uniformly arranged cardiomyocytes, reduced edema, and less fiber disorder. These results indicate that the nutmeg and schisandra pill improved the morphological changes in the myocardium induced by doxorubicin / trastuzumab in mice and alleviated pathological damage to cardiomyocytes.

[0086] Experimental Example 2

[0087] In this embodiment, a low dose of nutmeg and schisandra pills was used to study the changes in biochemical markers in rat plasma after administration of nutmeg and schisandra pills.

[0088] method

[0089] The rat model was established in the same manner as in Example 1. After the drug administration period, rat plasma samples were collected. After thawing, the samples were vortexed for 10 seconds, and 50 μL of the sample was transferred to the corresponding numbered centrifuge tube. 300 μL of 20% acetonitrile-methanol internal standard extraction solution was added, vortexed for 3 min, and centrifuged at 12,000 rpm / min for 10 min at 4 °C. After centrifugation, the supernatant was transferred and allowed to stand at -20 °C for 30 min; then centrifuged again at 12,000 rpm / min for 3 min at 4 °C, and the supernatant was used for analysis.

[0090] result

[0091] PCA analysis

[0092] PCA score Figure 6A As shown in Figure B, the PCA results indicate that the normal group, model group, and nutmeg and schisandra pill administration group were well distinguishable under both positive and negative ion modes, suggesting that the metabolic profiles of the rats in each group were different. The model group was furthest from the normal group in the figure, indicating that the metabolic profile of the rats in the model group was significantly different from that of the normal group. The nutmeg and schisandra pill group was well distinguishable from the model group, indicating that nutmeg and schisandra pill significantly altered the metabolic profile of the model rats.

[0093] OPLS-DA Analysis

[0094] To further distinguish the differences in the physiological and metabolic environment of rats under different conditions, the supervised pattern recognition method OPLS-DA was used for analysis. Figure 7A As shown in Figure -B, under positive ion mode, the normal group and the model group, as well as the model group and the Nutmeg and Schisandra pill group, are clearly distinguishable, located on opposite sides of the ordinate, indicating significant differences between groups. A 200 permutation test was performed to validate the OPLS-DA model. The simulated values ​​are all lower than the rightmost original values, and the intercepts of the Q2 regression lines are all less than 0.05. These results indicate that the model has good fit and predictive ability, and there is no overfitting, making the results reliable.

[0095] Screening of differential metabolites

[0096] Based on the established OPLS-DA model, differentially expressed metabolites were screened using criteria such as VIP > 1, P < 0.05, or FC > 1.5. Figure 8A As shown in -B, compared with the normal group, there were 971 differentially expressed variables, of which 286 were upregulated and 685 were downregulated; compared with the nutmeg and schisandra pill group, there were 399 differentially expressed variables, of which 186 were upregulated and 213 were downregulated. Taking the intersection of the differentially expressed metabolites from both groups revealed 210 common differentially expressed metabolites, see [see...]. Figure 9 .

[0097] Enrichment pathway analysis

[0098] To further investigate the effects of Nutmeg and Schisandra chinensis pills on the metabolic function and pathways of doxorubicin / trastuzumab rats, the data of the aforementioned 269 differentially expressed metabolites were imported into MetaboAnalyst 6.0 for KEGG enrichment analysis. Figure 10 As shown, using P < 0.05 and Impact > 0.1 as screening criteria, tryptophan metabolism was identified as the key metabolic pathway, and the key metabolites identified were indole-3-acetaldehyde, 3-hydroxy-2-aminobenzoic acid, 4-(2-aminophenyl)-2,4-dioxobutyric acid, and 5-hydroxyindoleacetic acid.

[0099] Metabolites, as the basis of an organism's phenotype, serve as an important window into understanding various biological processes and mechanisms. Metabolomics has become a powerful tool for discovering cardiovascular biomarkers, conducting early predictions, and assessing risks. By exploring the relationship and mechanisms between cardiovascular disease and the metabolome, and mapping the cardiovascular metabolome, a basis can be provided for the early prevention and mechanistic research of cardiovascular disease. Tryptophan is an essential amino acid for the human body, a core component in the synthesis of many proteins, and a key substrate source for promoting the generation of a series of key molecules. Tryptophan can generate various derivatives through the tryptophan-kynurenine metabolic pathway, the tryptophan-indole metabolic pathway, and the tryptophan-5-hydroxytryptamine pathway, exerting biological effects. Broadly targeted metabolomics results indicate that Nutmeg Five-Flavor Pills may alleviate doxorubicin / trastuzumab-related cardiotoxicity by regulating tryptophan metabolism.

[0100] Experimental Example 3

[0101] In this embodiment, a low dose of nutmeg and schisandra pills was used to study the effect of nutmeg and schisandra pills on the intestinal flora of rats.

[0102] method

[0103] The rat model was established in the same manner as in Example 1. After the drug administration period, rat feces were collected, and DNA was extracted using the CTAB extraction method, strictly following the manufacturer's instructions. Subsequent procedures included amplification, library construction, sequencing, and data processing.

[0104] result

[0105] α biodiversity

[0106] Alpha diversity is primarily used to study community diversity within a specific habitat (or sample). Sobs, Chao, and Ace are indices used to assess community richness; higher indices indicate a richer community. Shannon is an index used to reflect community diversity; higher indices indicate a more complex sample diversity. For example... Figure 11 As shown, compared with the control group, the Sobs, Chao, Ace, and Shannon indices in the model group were significantly decreased (P < 0.01); compared with the model group, the Sobs, Chao, Ace, and Shannon indices in the Roukou Wuwei Wan (nutmeg and schisandra pill) administration group were significantly decreased (P < 0.01). These results indicate that doxorubicin / trastuzumab alters the composition of the gut microbiota in normal rats, reducing its diversity and richness, while Roukou Wuwei Wan can improve the diversity and richness of the rat gut microbiota.

[0107] β biodiversity

[0108] Beta diversity analysis compares the microbial community composition of different samples, including principal component analysis (PCA), principal coordinates analysis (PCoA), and non-metric multi-dimensional scaling (NMDS).

[0109] like Figure 12A As shown in Figure B, the control group, model group, and nutmeg and schisandra pill group were well separated in both analyses and were relatively close to the normal group. This result indicates that nutmeg and schisandra pill can change the intestinal flora structure of the model group rats and make it closer to the normal group.

[0110] Nutmeg and Schisandra pills altered the gut microbiota composition in doxorubicin / trastuzumab-induced cardiotoxic rats at a multi-species level.

[0111] To investigate specific changes in the bacterial community, cluster histograms were plotted to show variations in the gut microbiota at the phylum, genus, and subgroup levels within each sample. For example... Figure 13A As shown in -C, at the phylum level, Firmicutes, Bacteroidetes, and Actinobacteriota were the dominant phyla in all three groups. Compared to the normal group, the abundance of Firmicutes and Actinobacteriota in the model group showed an increasing trend, while the abundance of Firmicutes and Actinobacteriota in the Nutmeg Five-Flavor Pill group decreased.

[0112] At the family level, doxorubicin followed by trastuzumab reduced the abundance of Lactobacillaceae, Lachnospiraceae, norank_o_Clostridia_UCG-014, and Prevotellaceae in rats, while increasing the abundance of Bifidobacteriaceae and Clostridiaceae. Conversely, administration of Roukou Wuwei Wan (a traditional Chinese medicine) increased the abundance of Lachnospiraceae and norank_o_Clostridia_UCG-014 in rats, while decreasing the abundance of Bifidobacteriaceae and Clostridiaceae.

[0113] At the genus level, doxorubicin sequentially followed by trastuzumab increased the abundance of norank_f_Muribaculaceae, Bifidobacterium, Clostridium sensu_stricto_1, and Faecalibaculum in rats, while decreasing the abundance of norank_f_norank_o_Clostridia_UCG-014, norank_f_norank_o_RF39, and Lachnospiraceae_NK4A136_group; while administration of Nutmeg-Five Flavor Pills decreased the abundance of Bifidobacterium, Clostridium sensu_stricto_1, Faecalibaculum, and norank_f_Erysipelotrichaceae in rats.

[0114] LEfSe analysis

[0115] Linear discriminant analysis (LEfSe) can be used to identify the species characteristics that best explain the differences between two or more groups of samples, and the extent to which these characteristics influence the differences between groups. To determine which bacteria were altered by the treatment with Nutmeg-Schisandra pills, thereby alleviating doxorubicin / trastuzumab-induced cardiotoxicity, a high-dimensional comparison using linear discriminant analysis (LDA) effect size (LEfSe) was performed to identify significant differences in bacterial community dominance between the two groups.

[0116] In the model group, Actinobacteria and Bifidobacteria were relatively enriched; while the Nutmeg and Schisandra chinensis group showed increased abundance of Norank_f_Norank_o_Clostridia_UCG-014, Clostridia_UCG-014, and Norank_o_Clostridia_UCG-014. Figure 14A -B). The above results collectively highlight that doxorubicin / trastuzumab significantly alters the diversity and composition of the gut microbiota, and that nutmeg and five-flavor pills may mitigate cardiotoxicity by modulating these changes.

[0117] The above descriptions are merely embodiments of the present invention. Those skilled in the art, possessing prior knowledge of all common technical knowledge in the field prior to the application date or priority date, are capable of understanding all existing technologies in that field and have the ability to apply conventional experimental methods prior to that date. Therefore, those skilled in the art can, based on the guidance provided in this application, improve and implement this solution in conjunction with their own capabilities. It should be noted that those skilled in the art can make several modifications and improvements without departing from the structure of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications will not affect the effectiveness of the implementation of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

[0118] It should be noted that those skilled in the art can make various modifications and improvements without departing from the inventive concept, and these all fall within the scope of protection of this invention. Furthermore, it should be understood that after reading the above teachings, those skilled in the art can make various alterations or modifications to this invention, and the equivalent forms obtained also fall within the scope of protection of this application. It should also be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided by this invention through logical analysis, reasoning, or limited experimentation are all within the scope of protection of the appended claims. Therefore, the scope of protection of this patent should be determined by the content of the appended claims, and the specification and drawings can be used to interpret the content of the claims.

Claims

1. The application of Nutmeg and Schisandra Pill in the preparation of drugs to alleviate cardiotoxicity associated with doxorubicin and trastuzumab; the cardiotoxicity includes decreased left ventricular ejection fraction and left ventricular shortening fraction, increased left ventricular end-systolic volume and left ventricular end-systolic diameter, increased serum cTnI and BNP levels, and cardiac tissue pathological damage; the Nutmeg and Schisandra Pill is prepared from nutmeg, costus root, costus root, jujube, and long pepper.

2. The application according to claim 1, wherein, The drug has one or more of the following functions: (1) Increases left ventricular ejection fraction and left ventricular shortening fraction; (2) Decreases left ventricular end-systolic volume and increases left ventricular end-systolic diameter; (3) Reduce serum levels of cTnI and BNP; (4) Improves cardiac tissue pathological damage.

3. The application according to claim 1 or 2, wherein the drug is taken orally.

4. The application according to claim 3, wherein the medicament comprises pharmaceutically acceptable excipients.

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