A traditional Chinese medicine composition for preventing and treating adverse reactions related to new generation targeted and immunotherapy for tumors and a preparation method thereof

Abstract

The rapid development of tumor molecular targeted drugs and immunotherapy promotes the progress of tumor treatment field, but the treatment means of related adverse reactions is very single, the application discloses a kind of traditional Chinese medicine composition and preparation method for preventing and treating new generation of tumor targeted and immunotherapy related adverse reactions.The composition includes the following mass parts of traditional Chinese medicinal materials: 3-20 parts of radix astragali, 3-18 parts of radix rehmanniae, 3-15 parts of radix lithospermi, 3-20 parts of old snake tongue grass, 3-20 parts of white milk vetch, 3-18 parts of old heron grass, 3-12 parts of gallnut, 3-20 parts of fried elaterium, 3-10 parts of raw licorice.The traditional Chinese medicine composition has the effects of nourishing yin and benefiting qi, promoting blood circulation to expel wind, detoxifying and removing turbidity, and is good for preventing and treating skin rash, gastrointestinal inflammation and diarrhea, hypothyroidism, proteinuria, hypertension, pneumonia, myocarditis and the like.The preparation method is decoction, granules, pills and capsule preparations.The application is simple, economical and effective, has no toxic side effects, and is helpful to prolong the tolerance period of targeted and immunotherapy and improve the survival quality of patients.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine technology, and specifically relates to a traditional Chinese medicine composition and preparation method for preventing and treating adverse reactions related to next-generation targeted and immunotherapy for tumors.

[0002] Malignant tumors are a global problem that seriously threatens human life and health. According to statistics released by the National Cancer Center where the patent applicant is located, there were 4.8247 million new cancer cases and 2.5742 million cancer deaths in my country in 2022, with the incidence rate increasing by an average of 1.4% per year. With the rapid development of molecular biology and cytogenetics, tumor molecularly targeted drugs, such as epidermal growth factor receptor (EGFR) inhibitors, human epidermal growth factor receptor-2 (HER-2) inhibitors, anti-vascular endothelial growth factor antibodies, and antibody-drug conjugates (ADCs), and tumor immunotherapy, such as anti-programmed cell death receptor-1 (PD-1) / programmed cell death ligand-1 (PD-L1) monoclonal antibodies, anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies, and chimeric antigen receptor T-cell (CAR-T) immunotherapy, are rapidly expanding the field of tumor treatment and advancing the development of tumor treatment concepts and theories.

[0003] However, common adverse reactions associated with targeted and immunotherapy for tumors, such as rash, gastroenteritis and diarrhea, proteinuria, hypertension, hypothyroidism, pneumonia, and myocarditis, seriously affect the treatment effect and quality of life of patients. Overall, skin rash is the earliest and most common adverse reaction during targeted therapy and immunotherapy, with an incidence rate as high as 79%–88% for targeted therapy and 30%–60% for immunotherapy. Gastroenteritis, mainly manifested as diarrhea, is one of the major adverse reactions of many targeted drugs, with an incidence rate as high as 50%, while the incidence rate of immunotherapy-related gastroenteritis is 8%–27%, sometimes forcing discontinuation of the drug. In clinical trials using targeted drugs, the incidence of hypertension was observed to be approximately 30%, mostly grade 3 hypertension, and 6%–26% of patients also experienced varying degrees of hypertension during immunotherapy. Myocarditis is a rare immune-related adverse reaction; large-scale retrospective studies abroad showed an incidence rate of 1.14% for myocarditis, but a mortality rate as high as 39.7%–50%. Hypothyroidism is a manifestation of the endocrine system affected by targeted and immunotherapies; if patients experience unexplained fatigue, weight gain, hair loss, etc., during treatment, it may be a sign of adverse reactions. Chills, constipation, depression, and other symptoms may indicate hypothyroidism. Studies show that the incidence of hypothyroidism caused by targeted drugs is around 11%, while the incidence caused by immunotherapy is 5%-10%. Pneumonia mainly manifests as dyspnea, cough, chest pain, and fever. The incidence of immunotherapy-related pneumonia is 3%-5%, with 72% of patients experiencing grade 1-2 pneumonia, requiring further treatment with hormones or immunosuppressants. Reports of pneumonia caused by targeted therapy are also increasing. For example, interstitial pneumonia is the most serious adverse reaction to erlotinib, with an incidence of 0.4%-5.8%, of which approximately 0.6% are fatal. Studies show that targeted therapy combined with chemotherapy has a 5% higher probability of causing proteinuria than chemotherapy alone. Most patients experience grade 1 or 2 proteinuria, while grade 3 or severe nephrotic syndrome (grade 4) is very rare. The incidence of acute kidney injury during immunotherapy is 2.2%-5%, requiring permanent discontinuation of immune checkpoint inhibitors and monitoring of creatinine and urine protein every 24 hours.

[0004] The aforementioned adverse reactions not only occur in clinically used targeted and immunotherapeutic drugs, but also restrict the development of next-generation ADC targeted drugs and next-generation CAR-T immunotherapies.

[0005] ADCs (Adverse Drug-Induced Combinations) are a class of targeted biopharmaceuticals that link cytotoxic drugs to monoclonal antibodies via a linker. Adverse reactions are often caused by factors such as toxicity from binding to normal cells with low specificity, premature drug release due to inappropriate linker selection, decreased immunogenicity due to protein aggregation, and increasing drug resistance in tumor cells. Eight ADC drugs have been approved for clinical use globally. According to current expert consensus, the common adverse reactions described in this patent all occur during the clinical use of ADC drugs. For example, goxastuzumab has an emetic effect, with an incidence of nausea of ​​69%, vomiting of 49%, and diarrhea of ​​63%; trastuzumab emtansine has an incidence of non-infectious pneumonia and radiation-induced pneumonia of 0.8%–1.1% and 1.8%, respectively. CAR-T cell therapy uses genetic engineering to modify a patient's own T cells to specifically recognize and kill tumor cells, and has become an important treatment for refractory and relapsed lymphomas. However, it can also cause related adverse reactions due to off-target effects and the release of large amounts of cytokines by co-stimulatory molecules. Cytokine release syndrome is one of the most common acute adverse reactions in CAR-T cell therapy, leading to systemic inflammatory responses, including pneumonia, myocarditis, and gastrointestinal reactions. It usually occurs in the first week after treatment, and common symptoms include fever, chills, fatigue, headache, nausea, and vomiting. In addition, clinical studies have shown that the incidence of rash in CAR-T therapy for B-lymphocyte hematologic malignancies is 12%.

[0006] Therefore, the core pathogenesis of adverse reactions caused by new-generation targeted and immunotherapies lies in the fact that while these new methods enhance the activity of the immune system and attack tumor cells, they fail to increase the resistance of normal cells to immune-killing agents in line with the increased activity of the immune system. This disrupts the balance between autoimmunity and immune responses, leading to adverse reactions. Extensive clinical literature review shows that treatments guided by the traditional Chinese medicine approach of "strengthening the body's resistance and detoxifying" often yield good clinical results. "Cancer toxins" are the toxicity produced by tumor cells, while "drug toxins" are the damage caused by an overactive immune system relative to normal cells. On the one hand, when "cancer toxins" disrupt the body's balanced state, the body's sensitivity to drugs decreases, making it more susceptible to damage from "drug toxins." The combination of "cancer toxins" and "drug toxins" becomes a cause of adverse reactions. On the other hand, cancer patients often suffer from deficiency of both yin and yang, making them unable to resist "drug toxins," leading to the spread of toxins throughout the body and causing adverse reactions in the corresponding weak areas. Therefore, this patent, from the perspective of strengthening the body's resistance and detoxifying, selects clinically experienced medications to enhance the body's cellular adaptability to the new therapy, ensuring the smooth progress of treatment.

[0007] Although traditional Chinese medicine (TCM) has become an indispensable part of comprehensive cancer treatment in my country, and its efficacy in treating adverse events associated with targeted and immunotherapy has been fully validated in numerous clinical trials and evidence-based studies, the treatment of adverse reactions related to targeted and immunotherapy still mainly relies on glucocorticoids combined with routine symptomatic management. Because hormonal drugs should be used following a slow tapering principle, requiring 6-8 weeks or even longer to prevent relapse, the risk of fungal infections, osteoporosis, and gastrointestinal reactions is greatly increased. Summary of the Invention

[0008] To address the aforementioned issues, the applicant of this invention, based on multiple scientific research projects, clinical studies, and basic research, has invented a traditional Chinese medicine composition and preparation method for preventing and treating adverse reactions related to next-generation targeted and immunotherapy for tumors. This traditional Chinese medicine composition nourishes Yin and Qi, invigorates blood and dispels wind, detoxifies and eliminates turbidity. When used together, the various herbs can nourish Yin and assist Yang, regulate Qi and blood, address the internal organs, and remove blood stasis and toxins. It has good preventive and / or therapeutic effects on adverse reactions related to next-generation targeted and immunotherapy, with a high efficacy rate and no side effects on the human body.

[0009] This invention is achieved through the following technical solution: a traditional Chinese medicine composition and preparation method for preventing and treating adverse reactions related to next-generation targeted and immunotherapy for tumors. The traditional Chinese medicine composition is made from the following raw materials in the following weight / volume parts: Astragalus membranaceus 3-20 parts, Rehmannia glutinosa 3-18 parts, Lithospermum erythrorhizon 3-15 parts, Hedyotis diffusa 3-20 parts, Tribulus terrestris 3-20 parts, Geranium wilfordii 3-18 parts, Galla chinensis 3-12 parts, stir-fried Shenqu 3-20 parts, and raw Glycyrrhiza uralensis 3-10 parts.

[0010] Preferably, the composition comprises the following components in parts by weight: 5-15 parts Astragalus membranaceus, 5-12 parts Rehmannia glutinosa, 5-10 parts Lithospermum erythrorhizon, 5-15 parts Hedyotis diffusa, 5-15 parts Tribulus terrestris, 5-12 parts Geranium wilfordii, 3-12 parts Gallnut, 5-12 parts Fried Shenqu, and 3-8 parts Glycyrrhiza uralensis.

[0011] More preferably, the composition comprises the following components in parts by weight: 10 parts Astragalus membranaceus, 10 parts Rehmannia glutinosa, 10 parts Lithospermum erythrorhizon, 10 parts Hedyotis diffusa, 10 parts Tribulus terrestris, 10 parts Geranium wilfordii, 6 parts Gallnut, 10 parts stir-fried Shenqu (medicated leaven), and 5 parts raw Glycyrrhiza uralensis.

[0012] The above-mentioned traditional Chinese medicine composition for preventing and treating adverse reactions related to next-generation targeted and immunotherapy for tumors is a clinically acceptable formulation prepared according to existing processes. The formulation includes: decoction, granules, pills, and capsules, comprising the following steps:

[0013] Preparation method of decoction: (1) Take 10 parts of Astragalus membranaceus, 10 parts of Rehmannia glutinosa, 10 parts of Lithospermum erythrorhizon, 10 parts of Hedyotis diffusa, 10 parts of Tribulus terrestris, 10 parts of Geranium wilfordii, 6 parts of Galla chinensis, 10 parts of stir-fried Shenqu (medicated leaven), and 5 parts of raw Glycyrrhiza uralensis, mix them together, and soak them in water for half an hour. The ratio of the total weight of the Chinese medicinal materials to the weight of water can be (1-2):(10-15), and the specific amount of water added can be determined according to the weight of the medicinal materials. (2) Add all the medicinal materials and decoct for 40 minutes. The ratio of the total weight of the Chinese medicinal materials to the weight of water can be (1-2):(10-15), and the specific amount of water added can be determined according to the weight of the medicinal materials. (3) Filter the decoction obtained after decoction to obtain filtrate and residue. The first decoction is over. (4) Take out the residue and decoct again with water for 25 minutes. The ratio of the total weight of the Chinese medicinal materials to the weight of water can be (1-2):(5-10), and the specific amount of water added can be determined according to the weight of the medicinal materials. (5) Filter the decoction obtained after decoction to obtain filtrate and residue, and the second decoction is completed. (6) Mix the filtrate obtained from the first decoction with the filtrate obtained from the second decoction to obtain the Chinese medicinal composition decoction.

[0014] Granule preparation method: (1) Take 10 parts of Astragalus membranaceus, 10 parts of Rehmannia glutinosa, 10 parts of Lithospermum erythrorhizon, 10 parts of Hedyotis diffusa, 10 parts of Tribulus terrestris, 10 parts of Geranium wilfordii, 6 parts of Galla chinensis, 10 parts of stir-fried Shenqu (medicated leaven), and 5 parts of raw Glycyrrhiza uralensis, mix them together, and soak them in water for 30 minutes. The ratio of the total weight of the Chinese medicinal materials to the weight of water can be (1-2):(5-10), and the specific amount of water added can be determined according to the weight of the medicinal materials. (2) Add water and decoct three times. The first time, add water and decoct for 1.5 hours. The ratio of the total weight of the Chinese medicinal materials to the weight of water is 1:10, and the specific amount of water added can be determined according to the weight of the medicinal materials. (3) Add water and decoct for 1.5 hours in the second and third times. The ratio of the total weight of the Chinese medicinal materials to the weight of water is 1:8, and the specific amount of water added can be determined according to the weight of the medicinal materials. (4) Combine the filtrates obtained from the three filtrations and filter through 200 mesh to obtain the filtrate. (5) Concentrate under vacuum of -0.06 to -0.08 MPa and temperature of 70-80℃ until the relative density is 1.20-1.25 (50℃) to obtain a clear extract. (6) Use a one-step granulation method, with dextrin and mannitol in a ratio of 8:1 as the base material, spray the clear extract to obtain granules, and after packaging, obtain the granules of the Chinese herbal composition.

[0015] Preparation method of honey pills: (1) Take 10 parts of Astragalus membranaceus, 10 parts of Rehmannia glutinosa, 10 parts of Lithospermum erythrorhizon, 10 parts of Hedyotis diffusa, 10 parts of Tribulus terrestris, 10 parts of Geranium wilfordii, 6 parts of Galla chinensis, 10 parts of stir-fried Shenqu (medicated leaven), and 5 parts of raw Glycyrrhiza uralensis. (2) Mix and grind the above medicinal materials, and pass them through a 100-mesh or 120-mesh sieve to make extremely fine powder. Mix the powder and honey in a weight ratio of 1:1.2-1.8 to make honey pills. (3) Each pill is 3g, take 6g each time, twice a day.

[0016] Capsule preparation method: (1) Take 10 parts of Astragalus membranaceus, 10 parts of Rehmannia glutinosa, 10 parts of Lithospermum erythrorhizon, 10 parts of Hedyotis diffusa, 10 parts of Tribulus terrestris, 10 parts of Geranium wilfordii, 6 parts of Galla chinensis, 10 parts of stir-fried Shenqu (medicated leaven), and 5 parts of raw Glycyrrhiza uralensis. (2) After mixing and pulverizing the above-mentioned medicinal materials, pass them through a 100-mesh or 120-mesh sieve to make extremely fine powder, and then fill the powder into empty capsules. (3) Each capsule contains 0.3g, take 6 capsules each time, 3 times a day.

[0017] Meanwhile, traditional Chinese medicine compositions prepared using the traditional Chinese medicine composition provided by this invention as active ingredients for the prevention and treatment of adverse reactions related to targeted and immunotherapy are also within the scope of protection of this invention.

[0018] The medicinal materials used in this invention have the following effects and pharmacological properties:

[0019] Astragalus root is the dried root of *Astragalus mongholicus* or *Astragalus membranaceus*, both belonging to the legume family. It possesses the functions of tonifying qi and raising yang, consolidating the exterior and stopping sweating, promoting diuresis and reducing swelling, generating fluids and nourishing blood, promoting blood circulation and relieving pain, promoting pus drainage and detoxification, and astringing wounds and promoting tissue regeneration. It is used to treat qi deficiency edema, spontaneous sweating due to exterior deficiency, numbness and pain, carbuncles that are difficult to heal, and chronic ulcers that do not heal. Modern pharmacology shows that astragalus mainly contains chemical components such as astragaloside A and verbascoside, which can enhance immunity, lower blood pressure, improve blood circulation, and have antioxidant effects.

[0020] Rehmannia glutinosa, or raw rehmannia root, is the tuber of the plant Rehmannia glutinosa (family Scrophulariaceae) that has been slowly roasted to about 80% dryness. It has the effects of clearing heat and cooling blood, nourishing yin and promoting body fluids. It is used to treat conditions such as heat entering the blood level, febrile rashes, hematemesis, epistaxis, yin deficiency due to febrile diseases, red tongue with thirst, yin deficiency fever, bone steaming fever, and internal heat with thirst. Modern pharmacology shows that raw rehmannia root mainly contains rehmannia glycoside D, catalpol, and other chemical components, which can lower blood pressure, sedate, reduce inflammation, fight allergies, strengthen the heart, and promote diuresis.

[0021] Lithospermum erythrorhizon, the dried stem of *Lithospermum erythrorhizon* or *Lithospermum erythrorhizon*, belongs to the Boraginaceae family. It possesses the effects of clearing heat and cooling blood, promoting blood circulation and detoxifying, and promoting rash eruption and eliminating spots. It is used to treat conditions such as blood heat and toxicity, purplish-black rashes, incomplete measles eruption, sores, eczema, and burns. Modern pharmacology shows that Lithospermum erythrorhizon mainly contains naphthoquinones, monoterpenoid phenols and benzoquinones, phenolic acids and their salts, alkaloids, and other chemical components, which can inhibit bacteria, reduce inflammation, relieve pain, fight tumors, and stop bleeding.

[0022] Oldenlandia diffusa, an annual spreading herb, has the effects of clearing heat and detoxifying, relieving pain and dissipating nodules, and promoting diuresis and removing dampness. It is used to treat various types of inflammation, heat toxicity, jaundice, dysentery, etc. Modern pharmacology shows that Oldenlandia diffusa mainly contains vitamins, flavonoids, polysaccharides and other chemical components, which can enhance immune function, have antibacterial and antitumor effects, protect the liver and promote bile secretion, and enhance adrenal cortex function.

[0023] Tribulus terrestris, the dried, mature fruit of the plant Tribulus terrestris (family Zygophyllaceae), has the effects of calming the liver and relieving depression, promoting blood circulation and dispelling wind, improving eyesight, and relieving itching. It is used to treat headaches and dizziness, chest and rib pain, mastitis, red and pterygium, and itchy rashes. Modern pharmacology shows that Tribulus terrestris mainly contains saponins, flavonoids, alkaloids, polysaccharides, and other chemical components, which can enhance sexual function, resist aging, have antibacterial and antitumor effects, regulate blood lipids, and treat cardiovascular diseases.

[0024] Geranium, the dried aerial parts of Geranium wilfordii, Geranium spp., or Geranium wildense, all belonging to the Geraniaceae family, are used to treat rheumatic pain, numbness and contractures, muscle and bone pain, diarrhea, and dysentery. Modern pharmacology shows that Geranium wilfordii mainly contains tannins, flavonoids, organic acids, and volatile oils, which have antibacterial, anti-inflammatory, antidiarrheal, liver-protective, and antiviral properties.

[0025] Gallnut, also known as Chinese gallnut, is the gall bud found on the leaves of *Rhus chinensis* (also known as Chinese sumac or red sumac). It possesses properties that astringe the lungs and reduce inflammation, promote healing of sores and dampness, astringe the intestines, stop bleeding, strengthen essence, and reduce sweating. It is used to treat carbuncles, boils, skin ulcers, chronic cough due to lung deficiency, chronic diarrhea, hematochezia, seminal emission, spontaneous sweating, and night sweats. Modern pharmacology shows that the tannins in gallnut can combine with proteins to form large, water-insoluble precipitates, forming a film at the site of skin ulcers, thus exerting an astringent effect. Simultaneously, small blood vessels are compressed and constricted, causing blood clotting and achieving hemostasis. It also has anti-ulcer, antioxidant, detoxifying, and anti-cancer effects.

[0026] Shenqu, or fermented glutinous rice, is a fermented preparation made by adding ingredients such as Polygonum hydropiper, Artemisia annua, almond paste, red beans, and fresh Xanthium sibiricum to flour or wheat bran. It is produced throughout China. It has the effects of strengthening the spleen and stomach, promoting digestion, and is used to treat food stagnation, indigestion, abdominal distension, loss of appetite, vomiting, and diarrhea. Modern pharmacology shows that Shenqu is rich in yeast, amylase, and other enzymes, which can promote the digestion and absorption of food, thereby improving spleen and stomach function.

[0027] Raw licorice is the dried root and rhizome of *Glycyrrhiza uralensis*, *Glycyrrhiza inflata*, or *Glycyrrhiza glabra*, all belonging to the legume family. It has the effects of tonifying the spleen and replenishing qi, clearing heat and detoxifying, resolving phlegm and relieving cough, relieving spasms and pain, and harmonizing other herbs. It is used to treat spleen and stomach weakness, fatigue, palpitations, shortness of breath, cough with excessive phlegm, abdominal and limb spasms and pain, carbuncles, and boils. Modern pharmacology shows that licorice mainly contains triterpenoids, flavonoids, polysaccharides, coumarins, volatile oils, and amino acids, and has anti-tumor, antibacterial, antiviral, anti-inflammatory, immunomodulatory, antioxidant, anti-aging, and anti-fibrotic effects.

[0028] The above-mentioned herbs, when combined, work synergistically to nourish Yin and Qi, invigorate blood and dispel wind, and detoxify and eliminate turbidity. They can effectively prevent or alleviate systemic adverse reactions associated with targeted therapy and immunotherapy, primarily including rashes, gastroenteritis and diarrhea, proteinuria, hypertension, hypothyroidism, pneumonia, and myocarditis. Symptoms include itchy skin, rashes (in severe cases, blistering, peeling, or ulceration), diarrhea (even bloody and mucous stools), constipation, abdominal pain, abdominal distension, nausea, vomiting, fatigue, chills, hair loss, depression, chest tightness, shortness of breath, fever, chest pain, cough, and palpitations. This herbal composition is suitable for treating adverse reactions such as rashes, gastroenteritis and diarrhea, hypothyroidism, pneumonia, hypertension, proteinuria, and myocarditis caused by tumor targeted therapy and immunotherapy. It has significant effects in adjusting and restoring the physiological functions of the internal organs, prolonging the tolerance period of immunotherapy to enhance anti-tumor effects, improving prognosis, improving the quality of life of patients, and prolonging survival.

[0029] Detailed Implementation: The technical solution of the present invention will be further described in detail below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto. Detailed Implementation

[0030] The traditional Chinese medicine composition of the present invention will be further described below with reference to specific embodiments, so that those skilled in the art can better understand the present invention, but this does not limit the present invention.

[0031] All the Chinese medicinal materials used in the following examples comply with the relevant provisions of the Chinese Pharmacopoeia 2020 edition. Before feeding, each medicinal material was identified and confirmed to be consistent with its name, and its quality met the pharmacopoeia standards.

[0032] Example 1: Preparation of a decoction of a traditional Chinese medicine composition for preventing and treating adverse reactions related to next-generation targeted and immunotherapy for tumors.

[0033] The composition comprises the following components in parts by weight: Astragalus membranaceus 10 parts, Rehmannia glutinosa 10 parts, Lithospermum erythrorhizon 10 parts, Hedyotis diffusa 10 parts, Tribulus terrestris 10 parts, Geranium wilfordii 10 parts, Gallnut 6 parts, stir-fried Shenqu 10 parts, and raw licorice 5 parts. Take 81g of the above twelve medicinal herbs according to the prescription, mix them, add 400ml of water and soak for 30 minutes. Add 400ml of water to all the herbs and decoct for 40 minutes. Filter the decoction to obtain a filtrate and a residue; this completes the first decoction. Remove the residue, add 600ml of water again and decoct for 25 minutes. Filter the decoction to obtain a filtrate and a residue; this completes the second decoction. Mix the filtrate from the first decoction with the filtrate from the second decoction to obtain the decoction of the aforementioned Chinese herbal composition. Take it warm when using.

[0034] Example 2: Preparation of a traditional Chinese medicine composition granule for preventing and treating adverse reactions related to next-generation targeted and immunotherapy for tumors.

[0035] The composition comprises the following components in parts by weight: Astragalus membranaceus 10 parts, Rehmannia glutinosa 10 parts, Lithospermum erythrorhizon 10 parts, Hedyotis diffusa 10 parts, Tribulus terrestris 10 parts, Geranium wilfordii 10 parts, Gallnut 6 parts, stir-fried Shenqu 10 parts, and raw Glycyrrhiza uralensis 5 parts. Take 81g of the above twelve medicinal herbs according to the prescription, mix them, and decoct three times with water. For the first decoction, add 900ml of water and decoct for 1.5 hours; for the second and third decoctions, add 700ml of water and decoct for 1.5 hours each. Combine the filtrates obtained from the three filtrations and filter through a 200-mesh sieve to obtain the filtrate. Concentrate under a vacuum of -0.06 to -0.08 MPa and a temperature of 70-80℃ until the relative density is 1.20-1.25 (50℃) to obtain a clear extract. A one-step granulation method is used, with dextrin and mannitol in a ratio of 8:1 as the base material. The extract is sprayed in to obtain granules, which are then packaged to obtain the Chinese herbal composition granules. They can be taken by dissolving them in hot water.

[0036] Example 3: Preparation of a traditional Chinese medicine composition pill for preventing and treating adverse reactions related to next-generation targeted and immunotherapy for tumors.

[0037] The composition comprises the following components in parts by weight: Astragalus membranaceus 10 parts, Rehmannia glutinosa 10 parts, Lithospermum erythrorhizon 10 parts, Hedyotis diffusa 10 parts, Tribulus terrestris 10 parts, Geranium wilfordii 10 parts, Gallnut 6 parts, stir-fried Shenqu 10 parts, and raw Glycyrrhiza uralensis 5 parts. Take 81g of the above twelve medicinal herbs according to the prescription, mix and pulverize them, then pass them through a 100-mesh or 120-mesh sieve to obtain an extremely fine powder. Mix the powder with honey in a weight ratio of 1:1.2-1.8 to make honey pills, each weighing 3g. Take 6g each time, twice daily.

[0038] Example 4: Preparation of a capsule formulation of a traditional Chinese medicine composition for preventing and treating adverse reactions related to next-generation targeted and immunotherapy for tumors.

[0039] The composition comprises the following components in parts by weight: Astragalus membranaceus 10 parts, Rehmannia glutinosa 10 parts, Lithospermum erythrorhizon 10 parts, Hedyotis diffusa 10 parts, Tribulus terrestris 10 parts, Geranium wilfordii 10 parts, Gallnut 6 parts, stir-fried Shenqu 10 parts, and raw Glycyrrhiza uralensis 5 parts. Take 81g of the above twelve medicinal herbs according to the prescription, mix and pulverize them, then pass them through a 100-mesh or 120-mesh sieve to obtain an extremely fine powder. Fill the powder into empty capsules, each containing 0.3g. Take 6 capsules each time, three times a day.

[0040] Example 5: Typical Case:

[0041] The inventors of this invention treated patients with adverse reactions related to tumor-targeted and immunotherapy using traditional Chinese medicine (TCM). They observed changes in the grading of these adverse reactions before and after intervention, evaluated the clinical efficacy of the TCM preparations, and monitored the effects of TCM treatment on patients' blood, liver, and kidney function. No patients reported any issues with the safety of the TCM treatment. TCM preventative intervention significantly reduced uncommon and adverse reactions caused by immunotherapy drugs, effectively avoiding dosage reduction, discontinuation, and interruption due to drug toxicity, improving patient adherence to immunotherapy, ensuring the smooth implementation of tumor-targeted and immunotherapy drugs, and ultimately benefiting patients.

[0042] Case 1: (ADC Targeted Therapy) Ms. Sun, female, underwent left supraclavicular puncture at our hospital on December 22, 2021. Immunohistochemical results indicated classic Hodgkin lymphoma, tuberous sclerosis type. Immunohistochemical results: CD30 (1+), CD15 (3+), Pax-5 (2+), MUM1 (2+), OTC-2 (-), P53 (+95%), Ki-67 (+>50%), ALK (-), PD-L1 Neg (-), PD-L1 (22C3) (TPS=80%; CPS=100). On December 31, 2021, the patient received treatment at another hospital with doxorubicin, dacarbazine, vindesine, and brentuximab. During this period, a PET-CT scan was performed at our hospital. The results showed multiple lymph nodes in the bilateral deep cervical chains, posterior cervical region, supraclavicular region, left axilla and posterior pectoral muscles, mediastinal regions 1-6, hilar space, and retroperitoneum, some with slightly increased uptake. Multiple lymph nodes in the right upper deep cervical region and submandibular region showed mild uptake. There was a subcutaneous uptake lesion in the left groin. Multiple micronodules were found in both lungs, without increased uptake, the largest being approximately 0.4 cm. Current symptoms include: generalized rash, especially severe on the hands and feet, with many blisters; torrential itching; oral mucosal ulceration; dry skin, peeling of hands and feet, and dry and cracked toenails / nails; 2-6 bowel movements per day, unformed; normal urination; poor appetite, aversion to cold, dry mouth and bitter taste; pale tongue with white coating, and deep and thready pulse. After evaluation, the patient's rash was graded G2, and the KPS score was 75.

[0043] Analysis of the syndrome differentiation: The patient's vital energy is deficient, and the toxicity of the medication attacks the internal organs, penetrating deep into the blood, causing blood heat to circulate erratically and manifest as herpes on the skin surface. The combined pathogenic heat seeks its way through the orifices, causing ulceration of the oral mucosa, resulting in dry mouth and bitter taste. The heat damages Yin, leading to dry skin, peeling of the hands and feet, and cracked toenails / fingernails. The heat disturbs the intestines, and insufficient Qi in the middle Jiao results in frequent, unformed stools. However, the patient's examination reveals aversion to cold, pale tongue with a white coating, and a deep, thready pulse, indicating that the aforementioned pathogenic heat is actually deficiency heat, a sign of both Qi and Yin deficiency with excessive internal pathogenic toxins.

[0044] Diagnosis: Accumulation, rash

[0045] Treatment principle: Tonify Qi and nourish Yin, clear heat and detoxify. Prescription: Decoction as described in Example 1: Astragalus membranaceus 10g, Rehmannia glutinosa 10g, Lithospermum erythrorhizon 10g, Hedyotis diffusa 10g, Tribulus terrestris 10g, Geranium wilfordii 10g, Gallnut 6g, Fried Shenqu 10g, Licorice 5g. One dose daily, divided into morning and evening administrations, for 14 days. The patient's overall rash significantly improved, except for the rash on the outer parts of the hands and feet, which subsided. There was no itching, peeling of the hands and feet lessened, bowel movements were twice daily and formed, appetite improved, relative cold intolerance remained, and there was no significant dry mouth or bitter taste. The rash grade decreased from G2 to G1, and the KPS score was 85. A follow-up visit was conducted, and the previous consolidation treatment was continued for another 14 days, after which all symptoms disappeared.

[0046] Case 2: (Immunotherapy) Mr. Zhao, male, 75 years old, underwent endoscopic examination on February 13, 2024, which revealed esophageal lesions. Pathology indicated severe squamous epithelial dysplasia with localized carcinoma. He subsequently underwent 30 sessions of radiotherapy, which ended on April 3, 2024. After 6 cycles of capecitabine + camrelizumab treatment, he was on camrelizumab maintenance therapy when he visited on August 12, 2024. Current symptoms included: facial, neck, and chest rashes, without itching; fatigue; hoarseness; facial edema; difficulty swallowing; choking while drinking; poor appetite; hiccups; poor sleep; difficulty falling asleep and light sleep with frequent awakenings; dry stools; dry mouth and bitter taste, especially noticeable in the morning; red tongue with a thin white coating; and a wiry, slippery pulse. On August 12, a thyroid function test was performed, and the results showed: T3 0.53 ng / ml↓, T4 2.04 ug / dl↓, FT3 0.57 pmol / L↓, FT4 0.18 pmol / L↓, TSH 72.4 mu / L↑.

[0047] Differential diagnosis: In Traditional Chinese Medicine (TCM), hypothyroidism is called "goiter." This patient is elderly, and his kidney yang is already deficient. The deficiency of yang leads to water retention, resulting in facial edema. Kidney deficiency also affects the spleen, and the stagnation of spleen and stomach qi causes poor appetite, hiccups, and constipation. The deficiency of spleen and kidney yang is the root cause, hence the fatigue. In addition, the invasion of cancer toxins and the internal disturbance of radiotherapy and chemotherapy drugs have led to abnormal circulation of qi and blood. The combination of fire, qi stagnation, blood stasis, and phlegm has caused the disease. When it invades the upper part of the body, it manifests as rashes on the face, neck, and chest, dry mouth, bitter taste, and hoarseness. This is a case of both pathogenic factors and excess, a mixed deficiency and excess syndrome, which is further evidenced by the tongue and pulse.

[0048] Diagnosis: Accumulation, goiter, skin rash

[0049] Treatment principle: Strengthening the body's resistance and detoxifying. Prescription: Based on the decoction of Example 1, the following herbs were added according to the patient's condition: Astragalus membranaceus 12g, Rehmannia glutinosa 12g, Lithospermum erythrorhizon 10g, Hedyotis diffusa 12g, Tribulus terrestris 9g, Geranium wilfordii 9g, Galla chinensis 6g, stir-fried Shenqu 10g, Glycyrrhiza uralensis 6g, Pinellia ternata 9g, Citrus reticulata 10g, Bambusa textilis 10g, Atractylodes macrocephala 12g (for clearing heat, regulating qi, and resolving phlegm), Acorus tatarinowii 10g, Eupatorium fortunei 6g, Lycopus lucidus 6g (for aromatic dampness-resolving and calming the mind). One dose daily, divided into morning and evening administrations, for 28 days. Afterwards, the patient's rash subsided, itching and fatigue lessened, bowel movements became regular, appetite increased, the number of awakenings during sleep decreased, facial edema disappeared, and there was no significant dry mouth or bitter taste. On September 15, 2024, a follow-up thyroid function test showed improvement in all indicators: T3 0.74 ng / ml ↓, T4 8.23 ​​ug / dl, FT3 1.76 pmol / L ↓, FT4 1.11 pmol / L ↓, TSH 40.6 mu / L ↑. The previous treatment was continued with the removal of Pinellia ternata, Citrus reticulata peel, Bambusa textilis, Atractylodes macrocephala, Acorus tatarinowii, Eupatorium fortunei, and Lycopus lucidus. After 28 days of treatment, the thyroid function indicators returned to normal and did not affect the continuation of immunotherapy.

[0050] Case 3: (Targeted Therapy) Mr. Tian, ​​male, 56 years old, underwent surgery for medullary thyroid carcinoma more than 13 years ago. In 2020, he underwent surgery again for recurrence in his right submandibular region. In 2022, a follow-up examination revealed metastasis in the upper and middle segment of the right femur. In April 2022, he underwent resection of the right femoral tumor segment at our hospital. In July 2022, he began treatment with the targeted drug anlotinib. Due to proteinuria after taking anlotinib, the patient visited the Department of Traditional Chinese Medicine on February 29, 2024. Urine routine chemical analysis and urine formed element analysis on February 22, 2024, showed: urine specific gravity increased to 1.028, urine protein (3+); micrototal protein (mTP) measurement (24-hour urine) showed: micrototal protein in urine increased to 2.81g / 24H.

[0051] The patient presented with the following symptoms: foamy urine, aching and heavy pain in the lower back and abdomen, loose stools 2-3 times a day, mild lower abdominal pain, good appetite and sleep, normal urination, dark tongue with a yellow and greasy coating, and a slippery and rapid pulse. The patient has a history of hypertension, with a usual blood pressure of 150 / 90 mmHg.

[0052] Analysis of the syndrome: The patient's body shows metastatic tumor lesions, indicating that the cancerous toxins have not been cleared. In addition, the patient has a phlegm-dampness constitution and a preference for rich, greasy, and fatty foods, which leads to the accumulation of dampness and phlegm, causing qi stagnation and blood stasis. The dampness tends to descend, stagnating in the lower back, causing soreness and slight lower abdominal pain. The kidneys govern urination and defecation; the phlegm-dampness flowing to the lower abdomen prevents kidney water from rising, weakening the body's warming and metabolic abilities, resulting in protein in the urine and loose stools. Therefore, the patient presents with a syndrome of phlegm and blood stasis, further supported by the tongue and pulse diagnosis.

[0053] Diagnosis: Accumulation

[0054] Treatment principle: Detoxify, remove blood stasis, eliminate dampness and resolve phlegm. Prescription: Based on the decoction of Example 1, the following herbs were added according to the patient's condition: Astragalus membranaceus 30g, Rehmannia glutinosa 18g, Lithospermum erythrorhizon 15g, Hedyotis diffusa 15g, Tribulus terrestris 12g, Geranium wilfordii 10g, Galla chinensis 10g, stir-fried Shenqu 10g, Glycyrrhiza uralensis 6g, and stir-fried Atractylodes macrocephala 10g, Citrus reticulata 10g, and 10g each of the three roasted herbs (Horse, Hawthorn, and Malt) to invigorate the spleen and resolve dampness; Coptis chinensis 3g, Phellodendron chinense 5g, Prunus mume 5g, and Zingiber officinale 3g to clear heat from the upper body and warm the lower body. One dose was taken daily, divided into morning and evening doses, for 14 days. After this period, the patient reported reduced foam in urine, reduced lower back and abdominal soreness, disappearance of lower abdominal pain, increased appetite, and increased activity, but stools remained loose. Follow-up tests showed that the patient's urine protein decreased to (2+), and the total trace protein in the urine decreased to 1.12g / 24H. The patient returned for a follow-up visit and was prescribed "3g of Coptis chinensis, 5g of Phellodendron chinense, 5g of Prunus mume, and 3g of Zingiber officinale" for 14 days of consolidation treatment. The patient's test results returned to normal, bowel movements became formed, and occasional lower back and abdominal soreness occurred.

[0055] Case 4: (Targeted Therapy) Ms. Liu, female, 48 years old, underwent ovarian, hysterectomy, partial colectomy, and peritoneal resection at our hospital in April 2021. Postoperative pathology indicated high-grade serous carcinoma with a T53 gene mutation frequency of 21%, and she subsequently received niraparib treatment. A follow-up examination in December 2023 revealed localized thickening of the peritoneum in the abdominopelvic cavity, patchy shadows in the mesenteric region, some of which were newly observed, suggesting metastasis. Thickening of the right pleura and lymph nodes in the right hilum and lesser curvature of the gastric body were also observed, suggesting new metastasis. She subsequently underwent three cycles of bevacizumab targeted therapy. During the treatment process, she consulted the Traditional Chinese Medicine department on February 27, 2024. Symptoms included: lower abdominal pain, abdominal distension, loose stools 3-4 times a day, yellow urine, urinary frequency, urgency, and incomplete urination, normal appetite and sleep, numbness of the tongue, heat intolerance, normal sweating, and dry mouth and thirst. Her tongue was red with a yellow coating, and her pulse was thready and weak. The patient's white blood cell count was 15.08 x 10⁻⁸. 9 / L, absolute neutrophil count was 11.94 x 10⁹ / L. 9 Both were elevated, suggesting gastroenteritis.

[0056] Analysis of the syndrome differentiation: The patient's cancerous toxins have invaded the intestines and stomach, and the targeted drugs have severely damaged the spleen and stomach qi, leading to impaired digestion and absorption of food and fluids, resulting in diarrhea and bloating; qi stagnation causes obstruction, and obstruction causes pain, hence the patient's abdominal pain; the cancerous toxins have damaged yin, leading to yin deficiency and internal heat, causing dry mouth and thirst; the yin fluids of the bladder are depleted, resulting in yellow urine, frequent urination, urgency, and incomplete urination. Therefore, the patient presents with a syndrome of qi deficiency and intense toxicity, as evidenced by the tongue and pulse.

[0057] Diagnosis: Accumulation, diarrhea

[0058] Treatment principle: Tonify Qi and detoxify, nourish Yin and replenish deficiency. Prescription: Based on the decoction of Example 1, the following herbs were added and modified according to the patient's condition: Astragalus membranaceus 6g, Rehmannia glutinosa 6g, Lithospermum erythrorhizon 5g, Hedyotis diffusa 5g, Tribulus terrestris 5g, Geranium wilfordii 5g, Galla chinensis 3g, stir-fried Shenqu 10g, raw Glycyrrhiza uralensis 3g. Add Paeonia suffruticosa 5g and Gardenia jasminoides 5g to clear heat from the intestines; Angelica sinensis 5g, Poria cocos 6g, stir-fried Atractylodes macrocephala 5g, and chicken gizzard lining 5g to tonify the Qi and blood of the spleen and stomach, and enhance the spleen and stomach's digestive function; and Dalbergia odorifera 3g to resolve blood stasis, stop bleeding, regulate Qi, and relieve pain. One dose daily, divided into morning and evening administrations, for 7 days. Test results showed that the patient's white blood cell and neutrophil counts were normal. The patient reported relief from lower abdominal pain, disappearance of bloating, formed stools (1-2 times / day), slightly yellow urine, slightly frequent urination, and disappearance of urgency and incomplete urination. Dry mouth remained. At the follow-up visit, the previous prescription was modified by removing "gardenia, stir-fried atractylodes macrocephala, chicken gizzard lining, and sandalwood" and adding "6g of salted fennel and 9g of vinegar-processed turtle shell" to regulate qi and stomach, assist yang and reduce urination, nourish yin and clear heat. After 14 days of consolidation treatment, the lower abdominal pain disappeared, the urine color returned to normal, the dry mouth was relieved, and the appetite improved. The patient can continue chemotherapy combined with targeted therapy.

[0059] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A traditional Chinese medicine composition for preventing and treating adverse reactions related to a new generation of targeted and immunotherapy for tumors, characterized in that, The composition is composed of the following components in weight fraction: 3-20 parts of Astragalus, 3-18 parts of Rehmannia glutinosa, 3-15 parts of Arnebia, 3-20 parts of Oldenlandia, 3-20 parts of Tribulus terrestris, 3-18 parts of Geranium, 3-12 parts of Rhus, 3-20 parts of Fried God, and 3-10 parts of Raw licorice.

2. The traditional Chinese medicine composition for preventing and treating the adverse reactions related to the new generation of targeted and immunotherapy of tumors according to claim 1, characterized in that, The composition is composed of the following components in weight fraction: 5-15 parts of Astragalus, 5-12 parts of Rehmannia glutinosa, 5-10 parts of Arnebia, 5-15 parts of Oldenlandia, 5-15 parts of Tribulus terrestris, 5-12 parts of Geranium, 3-12 parts of Rhus, 3-20 parts of Fried God, and 3-8 parts of Raw licorice. 3.The traditional Chinese medicine composition for preventing and treating the adverse reactions of a new generation of targeted and immunotherapy for tumors according to claim 1, characterized in that, The composition is composed of the following components in weight fraction: 10 parts of Astragalus, 10 parts of Rehmannia glutinosa, 10 parts of Arnebia, 10 parts of Oldenlandia, 10 parts of Tribulus terrestris, 10 parts of Geranium, 6 parts of Rhus, 3-20 parts of Fried God, and 5 parts of Raw licorice.

4. The use of the traditional Chinese medicine composition according to any one of claims 1-3 in the preparation of a traditional Chinese medicine preparation for preventing and treating adverse reactions related to a new generation of targeted and immunotherapy for tumors, characterized in that, The preparation is water decoction, granules, pills or capsules, and the adverse reactions related to the new generation of tumor targeting and immunotherapy are skin rash, gastrointestinal inflammation and diarrhea, proteinuria, and hypothyroidism.