A fever-reducing traditional Chinese medicine decoction for treating acute phase fever patients with brucellosis

Abstract

The application discloses a fever-reducing traditional Chinese medicine decoction for treating acute fever of brucellosis, and relates to the technical field of traditional Chinese medicine.The decoction is composed of 15 kinds of traditional Chinese medicine decoction pieces, i.e., radix bupleuri, radix scrophulariae, radix paeoniae rubra, radix paeoniae alba, radix scrophulariae, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae alba, radix paeoniae

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine technology, and in particular to a traditional Chinese medicine decoction for treating fever in patients with acute brucellosis. Background Technology

[0002] Brucellosis is a zoonotic disease caused by Brucella bacteria. Clinically, it is mainly characterized by fever, excessive sweating, joint pain, and fatigue, with high fever in the acute phase being one of the typical symptoms. Currently, the main clinical treatment is combination antibiotic therapy, but this approach suffers from problems such as long treatment courses, high recurrence rates, and drug resistance. Traditional Chinese medicine (TCM) has unique advantages in antipyretics and immune regulation, especially in symptomatic intervention during the acute phase. However, there is currently a lack of TCM decoctions specifically targeting acute fever in brucellosis with rapid fever reduction as the core objective. Most related patents focus on vaccines, diagnostic reagents, or broadly defined treatment formulas, lacking precise intervention for the acute febrile stage.

[0003] A search revealed that patent CN116570666A discloses a Mongolian medicine and its preparation for treating brucellosis, composed of more than twenty medicinal herbs including long-haired anemone, chebula, scutellaria, and licorice. This formula focuses on a holistic approach of clearing heat and detoxifying, promoting blood circulation and relieving pain, and strengthening the body's resistance to pathogens. While it has shown some efficacy in clinical trials, it does not focus on the core symptom of high fever in the acute phase, nor does it clarify the synergistic effect of the various components in its antipyretic mechanism. Furthermore, the Mongolian medicine is administered in pill or powder form, limiting its onset of action and falling short of the clinical need for rapid fever reduction in acute-phase patients.

[0004] A further search revealed a patent with publication number CN105169005A that proposes a traditional Chinese medicine compound for treating brucellosis, containing local herbs such as Quercus acutissima, Lysimachia christinae, Clerodendrum trichotomum, and Achyranthes bidentata. While this formula claims to be safe and effective in treating brucellosis, it does not differentiate between disease stages, nor does it specifically address the pathophysiological mechanisms of fever in the acute phase. Furthermore, the patent lacks specific decoction techniques, dosage ratios, and antipyretic efficacy evaluation indicators, limiting its clinical operability. Additionally, the limited distribution of some medicinal resources hinders standardized production and widespread application.

[0005] The above analysis shows that existing traditional Chinese medicine (TCM) treatments for brucellosis generally emphasize the overall condition over staged illness and focus on treatment rather than symptomatic relief. In particular, they lack highly effective, rapid-acting, and repeatable antipyretic TCM decoctions specifically targeting the key symptom of fever in the acute phase. Therefore, this invention provides an antipyretic TCM decoction for treating patients with fever in the acute phase of brucellosis. Through the scientific formulation of TCM herbs with clear effects of relieving exterior symptoms, reducing fever, clearing heat and cooling the body, and using a decoction form to leverage its rapid onset of action, this invention aims to achieve rapid fever reduction, symptom relief, and a shorter course of illness, filling the gap in existing technologies for symptomatic treatment of acute brucellosis. Summary of the Invention

[0006] The purpose of this invention is to provide a traditional Chinese medicine decoction for treating fever in patients with acute brucellosis, in order to solve the problem of the lack of a rapid, effective, standardized and easy-to-promote symptomatic treatment plan for high fever symptoms in the acute phase of brucellosis in the existing technology.

[0007] To solve the above-mentioned technical problems, the present invention provides the following technical solution:

[0008] On the one hand, a traditional Chinese medicine decoction for treating fever in the acute phase of brucellosis is composed of the following Chinese medicinal herbs in parts by weight:

[0009] Bupleurum 12g to 18g, Scutellaria baicalensis 9g to 15g, Gypsum 30g to 60g, Anemarrhena asphodeloides 9g to 15g, Lonicera japonica 15g to 25g, Forsythia suspensa 12g to 20g, Rehmannia glutinosa 15g to 25g, Paeonia suffruticosa 9g to 15g, Paeonia lactiflora 9g to 15g, Glycyrrhiza uralensis 6g to 10g, Mentha haplocalyx 6g to 10g, Phragmites communis 15g to 30g, Lophatherum gracile 9g to 15g, Artemisia annua 12g to 20g, Pueraria lobata 12g to 18g.

[0010] In the above formula, Bupleurum and Pueraria lobata work synergistically to relieve muscle tension, promote sweating, and clear heat. Scutellaria baicalensis, Gypsum, Anemarrhena asphodeloides, Lonicera japonica, and Forsythia suspensa together form the core herb group for clearing heat from the Qi level, intervening in the mechanism of endotoxin-mediated upward shift of the body temperature set point. Rehmannia glutinosa, Paeonia suffruticosa, Paeonia lactiflora, and Artemisia annua form the herb group for cooling the blood and clearing heat, inhibiting the release of inflammatory factors and regulating the hypothalamic temperature center. Mentha haplocalyx, Phragmites communis, and Lophatherum gracile enhance the effects of clearing heat, generating fluids, and expelling heat. Glycyrrhiza uralensis harmonizes the herbs and moderates the cold nature of Gypsum. Within the dosage range, each component forms a multi-target, multi-pathway synergistic network, achieving precise intervention for fever symptoms in the acute phase of brucellosis.

[0011] The aforementioned traditional Chinese medicine decoction for treating fever in the acute phase of brucellosis is a compound decoction with a clear effect of relieving exterior symptoms, reducing fever, and clearing heat and cooling the body, formed by a specific combination of Chinese herbal medicines and a standardized decoction process. It is used for symptomatic intervention during the high fever stage of the acute phase of brucellosis.

[0012] On the other hand, a method for preparing a traditional Chinese medicine decoction for treating fever in the acute phase of brucellosis includes the following steps:

[0013] Step S10: Weigh out the following ingredients according to the stated weight proportions: Bupleurum, Scutellaria baicalensis, Gypsum, Anemarrhena asphodeloides, Lonicera japonica, Forsythia suspensa, Rehmannia glutinosa, Paeonia suffruticosa, Paeonia lactiflora, Glycyrrhiza uralensis, Mentha haplocalyx, Phragmites communis, Lophatherum gracile, Artemisia annua, and Pueraria lobata. Clean them separately to remove impurities and obtain clean medicinal slices.

[0014] Step S20: First, crush the gypsum into particles with a diameter of no more than 1 cm, place them in a decoction container, add 1000 ml of room temperature drinking water, bring to a boil over high heat, and then simmer over low heat for 30 minutes.

[0015] Step S30: Add all the medicinal slices except for the peppermint to the decoction container and continue to simmer over low heat for 20 minutes;

[0016] Step S40: Add the mint to the decoction container, simmer over low heat for 5 minutes, then turn off the heat;

[0017] Step S50: Filter the decoction, collect the filtrate, add 600 ml of water to the dregs, repeat steps S30 to S40, combine the two filtrates, concentrate to 400 ml, and divide into doses of 200 ml for morning and evening administration.

[0018] In step S10, all medicinal slices comply with the provisions of Part I of the 2020 edition of the Pharmacopoeia of the People's Republic of China, with a moisture content not exceeding 13% and a total ash content not exceeding 8%. In step S20, the gypsum is decocted for 25 to 35 minutes to ensure that calcium ions are fully dissolved and form a soluble calcium sulfate complex. In step S30, the decoction temperature is maintained at 95 to 100 degrees Celsius, and a gentle boil is maintained during the decoction process to avoid the loss of volatile components due to violent boiling. In step S40, the peppermint is added later, and the time is strictly controlled between 4 and 6 minutes to retain the bioactivity of effective components such as menthol and menthone in its volatile oil. In step S50, the filtrate is concentrated using a vacuum concentration device at 60 to 70 degrees Celsius and a vacuum degree of 0.08 to 0.09 MPa to prevent the degradation of heat-sensitive components.

[0019] The clinical method of using the antipyretic traditional Chinese medicine decoction for treating patients with fever in the acute phase of brucellosis is as follows: one dose per day, decocted in 400 ml of water, taken warm twice a day after meals, for 7 consecutive days as one course of treatment; during the medication period, spicy, greasy and allergenic foods should be avoided, as well as alcohol.

[0020] The oral temperature is controlled between 35 and 40 degrees Celsius to reduce irritation to the gastrointestinal tract and promote drug absorption; the administration time after meals is 30 to 60 minutes after meals to reduce direct irritation of the gastric mucosa and improve bioavailability.

[0021] The quality control method for the antipyretic traditional Chinese medicine decoction used to treat patients with acute brucellosis and fever includes the following detection indicators:

[0022] Indicator T10: The content of baicalin was determined by high performance liquid chromatography, and the content of baicalin in each milliliter of decoction shall not be less than 0.15 mg;

[0023] Indicator T20: The total flavonoid content is determined by ultraviolet-visible spectrophotometry, and the total flavonoid content, calculated as rutin, in each milliliter of decoction shall not be less than 0.30 mg;

[0024] Indicator T30: The calcium ion content is determined by atomic absorption spectrometry, and the calcium ion concentration in each milliliter of decoction shall not be less than 1.2 mg;

[0025] Indicator T40: The menthol content is determined by gas chromatography-mass spectrometry, and the menthol content shall not be less than 0.05 mg per milliliter of decoction;

[0026] Indicator T50: The microbial limit test shall comply with the provisions of General Chapters 1105 and 1106 of Part IV of the 2020 edition of the Chinese Pharmacopoeia. The total number of aerobic bacteria shall not exceed 1000 CFU per 1 ml, the total number of molds and yeasts shall not exceed 100 CFU per 1 ml, and Escherichia coli shall not be detected.

[0027] For the specified index T10, the chromatographic conditions are as follows: the chromatographic column is a C18 column with dimensions of 250 mm × 4.6 mm and 5 μm; the mobile phase is methanol-0.2% phosphoric acid solution in a ratio of 50:50; the flow rate is 1.0 mL / min; the detection wavelength is 280 nm; and the column temperature is 30 degrees Celsius.

[0028] In index T20, the detection wavelength is 510 nm, the linear range of the standard curve is 0.01 mg / mL to 0.10 mg / mL, and the correlation coefficient is not less than 0.999; In index T30, flame atomic absorption spectrometry is used with a wavelength of 422.7 nm and an acetylene-air flame, and the concentration range of the standard curve is 0.5 mg / L to 5.0 mg / L.

[0029] In the specified index T40, the chromatographic column is an HP-5MS quartz capillary column with dimensions of 30 m × 0.25 mm × 0.25 μm; the programmed temperature conditions are: initial temperature of 60 degrees Celsius held for 2 minutes, then increased to 200 degrees Celsius at a rate of 10 degrees Celsius / minute and held for 10 minutes; the injection port temperature is 250 degrees Celsius; and the ion source temperature is 230 degrees Celsius.

[0030] The stability assurance measures for the antipyretic traditional Chinese medicine decoction used to treat patients with acute brucellosis include:

[0031] Measure U10: The decoction should be stored at 4 to 8 degrees Celsius and its shelf life shall not exceed 48 hours.

[0032] Measure U20: The decoction should not be left at room temperature (25°C ± 2°C) for more than 4 hours;

[0033] Measure U30: The decoction is dispensed into sterile polypropylene medicine bottles, 200 ml per bottle, and then sealed and sterilized by moist heat at 121 degrees Celsius for 15 minutes.

[0034] In measure U10, the pH value shall be tested every 24 hours during refrigerated storage, and the pH value change shall not exceed ±0.3. In measure U30, the residual microbial limits after sterilization shall meet the following requirements: the total number of aerobic bacteria shall not exceed 10 CFU per 1 ml, and molds and yeasts shall not be detected.

[0035] The pharmacodynamic verification method for the antipyretic traditional Chinese medicine decoction used to treat patients with acute brucellosis includes:

[0036] Step V10: Establish a rabbit fever model induced by Brucella lipopolysaccharide. Intravenously inject 0.5 μg / kg of Brucella lipopolysaccharide and observe the changes in body temperature at 0.5 hours, 1 hour, 2 hours, 4 hours and 6 hours after administration.

[0037] Step V20: Set up a blank control group, a model control group, a positive control group using acetaminophen at 150 mg / kg, and the decoction group of the present invention converted to human dosage equivalent;

[0038] Step V30: The effective standard is a decrease in body temperature of ≥1.0 degrees Celsius and a duration of ≥4 hours. Record the effectiveness rate and onset time of each group.

[0039] In step V10, the rabbits weighed 2.5 kg to 3.0 kg, with half being male and half female, and were acclimatized for 7 days before the experiment; in step V20, the volume of the decoction group of the present invention was 10 ml / kg, administered by gavage, and the decoction was restored to 37 degrees Celsius before administration.

[0040] The clinical application criteria for the antipyretic traditional Chinese medicine decoction used to treat patients with acute brucellosis and fever include:

[0041] Standard W10: The patient's diagnosis meets the acute phase diagnostic criteria in the "Diagnosis of Brucellosis WS 269-2019";

[0042] Standard W20: Body temperature ≥38.5 degrees Celsius, lasting 2-4 weeks;

[0043] Standard W30: No severe liver or kidney dysfunction (ALT ≤ 3 times the upper limit of normal, Cr ≤ 1.5 times the upper limit of normal).

[0044] Standard W40: No other infectious or autoimmune diseases present;

[0045] Standard W50: Sign an informed consent form and voluntarily participate in treatment.

[0046] The diagnostic criteria in standard W10 include three aspects: epidemiological history, clinical manifestations, and laboratory tests. Epidemiological history refers to: close contact with livestock or livestock products suspected of being infected with Brucella before the onset of illness, or consumption of raw cow or sheep milk or meat products, or living in a Brucella epidemic area; or working in Brucella culture, testing, or Brucella vaccine production and use. Clinical manifestations include: fever (including low-grade fever), excessive sweating, fatigue, muscle and joint pain, etc., lasting for several days or even weeks. Laboratory diagnostic criteria are: Brucella isolation from any pathological material culture, such as blood, bone marrow, other body fluids, or excrement; a serum agglutination test (SAT) titer of 1:100++ or higher; a complement fixation test (CFT) titer of 1:10++ or higher; or a Coombs test titer of 1:400++ or higher. The acute phase is defined as: having the above clinical manifestations, a course of illness of less than 3 months, and a confirmed positive serological reaction;

[0047] In the aforementioned standard W20, body temperature is measured using an electronic thermometer under the armpit. Before each measurement, the patient sits quietly for 10 minutes, and the average value is taken from three consecutive measurements.

[0048] The adverse reaction monitoring protocol for the antipyretic traditional Chinese medicine decoction used to treat patients with acute brucellosis includes:

[0049] Monitoring measure X10: Record body temperature, heart rate, respiratory rate, and blood pressure daily during medication;

[0050] Monitoring measure X20: Blood routine, liver function (ALT, AST), and kidney function (Cr, BUN) were tested before medication and on the 3rd and 7th days of medication.

[0051] Monitoring measure X30: If adverse reactions such as nausea, vomiting, diarrhea, or rash occur, discontinue the medication immediately and record the time of occurrence, symptoms, duration, and treatment measures.

[0052] Monitoring measure X40: Establish an adverse reaction causality assessment form and conduct correlation assessment using WHO-UMC standards.

[0053] In monitoring measure X20, blood samples are collected in the morning on an empty stomach, and the amount of blood collected is not less than 5 ml. In monitoring measure X40, the causal relationship is divided into five levels: certain, very likely, possible, possibly irrelevant, and cannot be evaluated, and is assessed by two independent physicians using a blind method.

[0054] The guidelines for controlling the source of medicinal materials for the antipyretic traditional Chinese medicine decoction used to treat patients with fever during the acute phase of brucellosis include:

[0055] Standard Y10: Bupleurum is the dried root of Bupleurum chinense, a plant of the Apiaceae family, produced in Shanxi and Hebei provinces;

[0056] Standard Y20: Scutellaria baicalensis is the dried root of Scutellaria baicalensis, a plant of the Lamiaceae family, produced in Shandong and Shaanxi provinces;

[0057] Standard Y30: Gypsum is a sulfate mineral, anhydrite group gypsum, mainly containing hydrated calcium sulfate, and produced in Hubei and Anhui provinces;

[0058] Standard Y40: Honeysuckle is the dried flower bud of Lonicera japonica, a plant of the Caprifoliaceae family, and is produced in Shandong and Henan provinces.

[0059] Standard Y50: Peppermint refers to the dried aerial parts of the plant *Mentha haplocalyx*, belonging to the Lamiaceae family, and is produced in Jiangsu and Jiangxi provinces.

[0060] In the aforementioned standards Y10 to Y50, a traceability coding system is established for all medicinal materials, and each batch of medicinal materials is accompanied by a certificate of origin, harvesting time, initial processing method, and test reports on heavy metals and pesticide residues.

[0061] The required parameters for the decoction equipment for the antipyretic traditional Chinese medicine decoction used to treat patients with acute brucellosis include:

[0062] Requirement Z10: The decoction container shall be made of 304 stainless steel and have a volume of not less than 2000 ml;

[0063] Z20 requirement: Heating method is electromagnetic heating, with an adjustable power range of 500 watts to 1500 watts;

[0064] Z30 requirements: Equipped with a temperature sensor, accurate to ±1 degree Celsius, to display the cooking temperature in real time;

[0065] Z40 requirement: Equipped with a timing device, with an error not exceeding ±30 seconds;

[0066] Z50 should be equipped with an automatic stirring device with a speed of 10 to 30 rpm to prevent herbs from sticking to the bottom.

[0067] In requirement Z10, the inner wall roughness Ra value of the stainless steel container is not greater than 0.8 micrometers to prevent the adsorption and loss of effective ingredients; in requirement Z50, the stirring blades are made of polytetrafluoroethylene, which is heat-resistant and does not react with the medicinal ingredients.

[0068] Compared with the prior art, the beneficial technical effects of the present invention are as follows:

[0069] This invention targets the pathogenesis of fever in the acute phase of brucellosis. It uses Bupleurum and Pueraria to relieve exterior syndromes, Scutellaria, Gypsum, and Anemarrhena to clear heat from the Qi level, Rehmannia, Moutan, and Red Peony to cool the blood and clear heat, and Mentha and Phragmites to promote the release of heat and generate fluids. This creates a compound formula that works synergistically to relieve exterior syndromes and clear heat from the Qi level and cool the blood level. It can quickly reduce the patient's body temperature, relieve fever-related symptoms, and achieve precise intervention for acute fever.

[0070] This invention, through a standardized decoction process, clarifies key steps such as decocting gypsum first and adding mint later, and sets specific temperature, time, and concentration parameters, ensuring the stable dissolution and retention of effective components in the decoction, improving the consistency and reproducibility of the preparation quality, and providing a reliable process basis for large-scale preparation and clinical application.

[0071] This invention establishes a quality control system covering multiple indicators such as baicalin, total flavonoids, calcium ions, and menthol, and clarifies microbial limit requirements. Combined with stability assurance measures and medicinal material traceability standards, it achieves full-process quality control from raw materials to finished products, ensuring the safety and efficacy of the decoction are stable and controllable.

[0072] This invention provides clear clinical application standards, pharmacodynamic verification methods, and adverse reaction monitoring protocols, enhancing the standardization and safety of clinical use, facilitating individualized treatment and rational drug use, and providing a systematic evaluation framework for subsequent clinical research and application. Attached Figure Description

[0073] Figure 1 This is a schematic diagram of the composition and structure of the antipyretic traditional Chinese medicine decoction for treating patients with acute brucellosis with fever according to the present invention;

[0074] Figure 2 This is a flowchart illustrating the specific steps of preparing the antipyretic traditional Chinese medicine decoction for treating patients with acute brucellosis with fever, as described in this invention. Detailed Implementation

[0075] The various embodiments or implementation schemes in this specification are described in a progressive manner, with each embodiment focusing on the differences from other embodiments.

[0076] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "illustrative embodiment," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with an embodiment or example is included in at least one embodiment or example of this application. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0077] As mentioned in the background section above, acute brucellosis often presents with persistent high fever. Conventional antipyretic and analgesic drugs carry risks of adverse reactions such as liver and kidney burden and gastrointestinal irritation. Existing traditional Chinese medicine antipyretic formulas are mostly for common exogenous febrile diseases and lack specific intervention methods targeting the endotoxin-mediated fever mechanism of Brucella. Therefore, this invention provides an antipyretic traditional Chinese medicine decoction for treating acute brucellosis with fever, along with its preparation method, quality control methods, and clinical usage guidelines. Through specific formulation and standardized decoction processes, it achieves effective intervention for acute brucellosis with fever.

[0078] On the one hand, this invention provides a traditional Chinese medicine decoction for treating fever in patients with acute brucellosis, with reference to... Figure 1 It is composed of the following Chinese medicinal herbs in parts by weight: Bupleurum chinense 12 to 18g, Scutellaria baicalensis 9 to 15g, Gypsum fibrosum 30 to 60g, Anemarrhena asphodeloides 9 to 15g, Lonicera japonica 15 to 25g, Forsythia suspensa 12 to 20g, Rehmannia glutinosa 15 to 25g, Paeonia suffruticosa 9 to 15g, Paeonia lactiflora 9 to 15g, Glycyrrhiza uralensis 6 to 10g, Mentha haplocalyx 6 to 10g, Phragmites communis 15 to 30g, Lophatherum gracile 9 to 15g, Artemisia annua 12 to 20g, and Pueraria lobata 12 to 18g.

[0079] In some embodiments, the following ingredients are used: Bupleurum chinense 15g, Scutellaria baicalensis 12g, Gypsum fibrosum 45g, Anemarrhena asphodeloides 12g, Lonicera japonica 20g, Forsythia suspensa 16g, Rehmannia glutinosa 20g, Paeonia suffruticosa 12g, Paeonia lactiflora 12g, Glycyrrhiza uralensis 8g, Mentha haplocalyx 8g, Phragmites communis 25g, Lophatherum gracile 12g, Artemisia annua 16g, and Pueraria lobata 15g.

[0080] In some embodiments, the gypsum is first crushed into particles with a diameter of no more than 1 cm, and the remaining medicinal slices are cut into slices or segments with a thickness of 2 mm to 4 mm to facilitate the dissolution of the active ingredients.

[0081] In some implementations, all medicinal slices are cleaned before feeding to remove mud, sand, impurities and non-medicinal parts, with the moisture content controlled at 10% to 13% and the total ash content controlled at 6% to 8%, in accordance with the provisions of Part I of the 2020 edition of the Pharmacopoeia of the People's Republic of China.

[0082] On the other hand, a method for preparing a traditional Chinese medicine decoction for treating fever in the acute phase of brucellosis, referencing... Figure 2 This includes the following steps:

[0083] Step S10: Weigh out Bupleurum, Scutellaria baicalensis, Gypsum, Anemarrhena asphodeloides, Lonicera japonica, Forsythia suspensa, Rehmannia glutinosa, Paeonia suffruticosa, Paeonia lactiflora, Glycyrrhiza uralensis, Mentha haplocalyx, Phragmites communis, Lophatherum gracile, Artemisia annua, and Pueraria lobata, and clean them separately to remove impurities, thus obtaining clean medicinal slices.

[0084] Step S20: First, crush the gypsum into particles with a diameter of no more than 1 cm, place them in a decoction container, add 1000 ml of room temperature drinking water, bring to a boil over high heat, and then simmer over low heat for 30 minutes.

[0085] Step S30: Add all the medicinal slices except for the peppermint to the decoction container and continue to simmer over low heat for 20 minutes;

[0086] Step S40: Add the mint to the decoction container, simmer over low heat for 5 minutes, then turn off the heat;

[0087] Step S50: Filter the decoction, collect the filtrate, add 600 ml of water to the dregs, repeat steps S30 to S40, combine the two filtrates, concentrate to 400 ml, and divide into doses of 200 ml for morning and evening administration.

[0088] In some embodiments, in step S20, the gypsum is pre-cooked for 25 to 35 minutes, and a gentle boil is maintained during the cooking process, with the temperature kept between 95 and 100 degrees Celsius, to ensure that calcium ions are fully dissolved and form a soluble calcium sulfate complex.

[0089] In some embodiments, in step S30, the decocting temperature is maintained at 95 degrees Celsius to 100 degrees Celsius, and a gentle boil is maintained during the decocting process to avoid the loss of volatile components due to violent boiling. The decocting time is 20 minutes, with an error of no more than ±1 minute.

[0090] In some embodiments, in step S40, the time for adding peppermint is strictly controlled to be between 4 and 6 minutes, and the decocting temperature is maintained at 95 to 100 degrees Celsius in order to preserve the bioactivity of the effective components such as menthol and menthone in its volatile oil.

[0091] In some embodiments, in step S50, the filtrate concentration is carried out using a vacuum concentration device at 60 to 70 degrees Celsius and a vacuum of 0.08 to 0.09 MPa, with a final concentration volume of 400 ml and an error not exceeding ±10 ml.

[0092] A clinical method for using a traditional Chinese medicine decoction to treat fever in patients with acute brucellosis is as follows: one dose per day, decocted in 400 ml of water, taken warm twice a day after meals, for 7 consecutive days as one course of treatment; during the medication period, spicy, greasy and allergenic foods should be avoided, as well as alcohol.

[0093] In some implementations, the oral temperature is controlled between 35 and 40 degrees Celsius. The dispensed medicine is heated to the specified temperature using a constant temperature water bath device before being taken. The medicine is taken 30 to 60 minutes after a meal. Patients should sit quietly for 10 minutes before taking the medicine and avoid taking it immediately after strenuous exercise.

[0094] A quality control method for an antipyretic traditional Chinese medicine decoction used to treat patients with fever during the acute phase of brucellosis includes the following detection indicators:

[0095] Indicator T10: The content of baicalin was determined by high performance liquid chromatography, and the content of baicalin in each milliliter of decoction shall not be less than 0.15 mg;

[0096] Indicator T20: The total flavonoid content is determined by ultraviolet-visible spectrophotometry, and the total flavonoid content, calculated as rutin, in each milliliter of decoction shall not be less than 0.30 mg;

[0097] Indicator T30: The calcium ion content is determined by atomic absorption spectrometry, and the calcium ion concentration in each milliliter of decoction shall not be less than 1.2 mg;

[0098] Indicator T40: The menthol content is determined by gas chromatography-mass spectrometry, and the menthol content shall not be less than 0.05 mg per milliliter of decoction;

[0099] Indicator T50: The microbial limit test shall comply with the provisions of General Chapters 1105 and 1106 of Part IV of the 2020 edition of the Chinese Pharmacopoeia. The total number of aerobic bacteria shall not exceed 1000 CFU per 1 ml, the total number of molds and yeasts shall not exceed 100 CFU per 1 ml, and Escherichia coli shall not be detected.

[0100] In some implementations, the chromatographic conditions for index T10 are as follows: a C18 column with dimensions of 250 mm × 4.6 mm and 5 μm; a mobile phase of methanol-0.2% phosphoric acid solution in a ratio of 50:50; a flow rate of 1.0 mL / min; a detection wavelength of 280 nm; a column temperature of 30 °C; and an injection volume of 10 μL.

[0101] In some implementations, in index T20, the detection wavelength is 510 nm, the linear range of the standard curve is 0.01 mg / mL to 0.10 mg / mL, the correlation coefficient is not less than 0.999, and rutin is used as a reference standard.

[0102] In some implementations, for index T30, flame atomic absorption spectrometry is used at a wavelength of 422.7 nm with an acetylene-air flame. The standard curve concentration range is 0.5 mg / L to 5.0 mg / L. The sample is filtered through a 0.45 μm filter before injection.

[0103] In some implementations, in index T40, the chromatographic column is an HP-5MS quartz capillary column with dimensions of 30 m × 0.25 mm × 0.25 μm; the programmed temperature conditions are: initial temperature of 60 degrees Celsius held for 2 minutes, increased to 200 degrees Celsius at 10 degrees Celsius / min and held for 10 minutes, injection port temperature of 250 degrees Celsius, ion source temperature of 230 degrees Celsius, carrier gas is high-purity helium, and the flow rate is 1.0 mL / min.

[0104] A stability assurance measure for an antipyretic traditional Chinese medicine decoction used to treat patients with fever during the acute phase of brucellosis includes:

[0105] Measure U10: The decoction should be stored at 4 to 8 degrees Celsius and its shelf life shall not exceed 48 hours.

[0106] Measure U20: The decoction should not be left at room temperature (25°C ± 2°C) for more than 4 hours;

[0107] Measure U30: The decoction is dispensed into sterile polypropylene medicine bottles, 200 ml per bottle, and then sealed and sterilized by moist heat at 121 degrees Celsius for 15 minutes.

[0108] In some implementations, in measure U10, the pH value is tested every 24 hours during refrigerated storage, and the pH value change range shall not exceed ±0.3. The pH value is measured after calibration using a pH meter. In measure U30, the residual microbial limits after sterilization must meet the following requirements: the total number of aerobic bacteria shall not exceed 10 CFU per 1 ml, and molds and yeasts shall not be detected. The detection method is membrane filtration.

[0109] A pharmacodynamic verification method for an antipyretic traditional Chinese medicine decoction used to treat patients with fever during the acute phase of brucellosis includes:

[0110] Step V10: Establish a rabbit fever model induced by Brucella lipopolysaccharide. Intravenously inject 0.5 μg / kg of Brucella lipopolysaccharide and observe the changes in body temperature at 0.5 hours, 1 hour, 2 hours, 4 hours and 6 hours after administration.

[0111] Step V20: Set up a blank control group, a model control group, a positive control group using acetaminophen at 150 mg / kg, and the decoction group of the present invention converted to human dosage equivalent;

[0112] Step V30: The effective standard is a decrease in body temperature of ≥1.0 degrees Celsius and a duration of ≥4 hours. Record the effectiveness rate and onset time of each group.

[0113] In some embodiments, in step V10, the rabbits weigh 2.5 kg to 3.0 kg, with half males and half females, and are acclimatized for 7 days before the experiment. The ambient temperature is 22°C to 25°C, and the relative humidity is 50% to 60%. In step V20, the volume of the decoction group of the present invention is 10 ml / kg, administered by gavage. Before administration, the decoction is restored to 37°C, and the temperature is controlled by a constant temperature water bath device.

[0114] Clinical criteria for the use of a traditional Chinese medicine decoction for treating fever in the acute phase of brucellosis include:

[0115] Standard W10: The patient's diagnosis meets the acute phase diagnostic criteria in the "Diagnosis of Brucellosis WS 269-2019";

[0116] Standard W20: Body temperature ≥38.5 degrees Celsius, lasting 2-4 weeks;

[0117] Standard W30: No severe liver or kidney dysfunction (ALT ≤ 3 times the upper limit of normal, Cr ≤ 1.5 times the upper limit of normal).

[0118] Standard W40: No other infectious or autoimmune diseases present;

[0119] Standard W50: Sign an informed consent form and voluntarily participate in treatment.

[0120] The diagnostic criteria in standard W10 include three aspects: epidemiological history, clinical manifestations, and laboratory tests. Epidemiological history refers to: close contact with livestock or livestock products suspected of being infected with Brucella before the onset of illness, or consumption of raw cow or sheep milk or meat products, or living in a Brucella epidemic area; or working in Brucella culture, testing, or Brucella vaccine production and use. Clinical manifestations include: fever (including low-grade fever), excessive sweating, fatigue, muscle and joint pain, etc., lasting for several days or even weeks. Laboratory diagnostic criteria are: Brucella isolation from any pathological material culture, such as blood, bone marrow, other body fluids, or excrement; a serum agglutination test (SAT) titer of 1:100++ or higher; a complement fixation test (CFT) titer of 1:10++ or higher; or a Coombs test titer of 1:400++ or higher. The acute phase is defined as: having the above clinical manifestations, a course of illness of less than 3 months, and a confirmed positive serological reaction;

[0121] In the aforementioned standard W20, body temperature is measured using an electronic thermometer under the armpit. Before each measurement, the patient sits quietly for 10 minutes, and the average value is taken from three consecutive measurements.

[0122] A monitoring protocol for adverse reactions to an antipyretic traditional Chinese medicine decoction used to treat patients with fever during the acute phase of brucellosis includes:

[0123] Monitoring measure X10: Record body temperature, heart rate, respiratory rate, and blood pressure daily during medication;

[0124] Monitoring measure X20: Blood routine, liver function (ALT, AST), and kidney function (Cr, BUN) were tested before medication and on the 3rd and 7th days of medication.

[0125] Monitoring measure X30: If adverse reactions such as nausea, vomiting, diarrhea, or rash occur, discontinue the medication immediately and record the time of occurrence, symptoms, duration, and treatment measures.

[0126] Monitoring measure X40: Establish an adverse reaction causality assessment form and conduct correlation assessment using WHO-UMC standards.

[0127] In some implementations, in monitoring measure X20, blood samples are collected in the morning on an empty stomach, with a blood volume of not less than 5 ml. Whole blood is collected using EDTA anticoagulant tubes, and serum is separated and stored at -20 degrees Celsius for testing. In monitoring measure X40, causality is classified into five levels: certain, very likely, possible, possibly irrelevant, and cannot be evaluated. The causal relationship is assessed by two independent physicians using a blind method, and if the opinions differ, a third-party expert makes the final decision.

[0128] A set of guidelines for controlling the source of medicinal materials for an antipyretic traditional Chinese medicine decoction used to treat patients with fever during the acute phase of brucellosis, including:

[0129] Standard Y10: Bupleurum is the dried root of Bupleurum chinense, a plant of the Apiaceae family, produced in Shanxi and Hebei provinces;

[0130] Standard Y20: Scutellaria baicalensis is the dried root of Scutellaria baicalensis, a plant of the Lamiaceae family, produced in Shandong and Shaanxi provinces;

[0131] Standard Y30: Gypsum is a sulfate mineral, anhydrite group gypsum, mainly containing hydrated calcium sulfate, and produced in Hubei and Anhui provinces;

[0132] Standard Y40: Honeysuckle is the dried flower bud of Lonicera japonica, a plant of the Caprifoliaceae family, and is produced in Shandong and Henan provinces.

[0133] Standard Y50: Peppermint refers to the dried aerial parts of the plant *Mentha haplocalyx*, belonging to the Lamiaceae family, and is produced in Jiangsu and Jiangxi provinces.

[0134] In some implementation methods, in specifications Y10 to Y50, a traceability coding system is established for all medicinal materials. Each batch of medicinal materials is accompanied by a certificate of origin, harvesting time, initial processing method, and heavy metal and pesticide residue test reports. The total amount of heavy metals does not exceed 10 mg / kg, and the residues of hexachlorocyclohexane (HCH) and DDT do not exceed 0.1 mg / kg.

[0135] The equipment parameters for preparing a traditional Chinese medicine decoction for treating fever in the acute phase of brucellosis include:

[0136] Requirement Z10: The decoction container shall be made of 304 stainless steel and have a volume of not less than 2000 ml;

[0137] Z20 requirement: Heating method is electromagnetic heating, with an adjustable power range of 500 watts to 1500 watts;

[0138] Z30 requirements: Equipped with a temperature sensor, accurate to ±1 degree Celsius, to display the cooking temperature in real time;

[0139] Z40 requirement: Equipped with a timing device, with an error not exceeding ±30 seconds;

[0140] Z50 should be equipped with an automatic stirring device with a speed of 10 to 30 rpm to prevent herbs from sticking to the bottom.

[0141] In some embodiments, it is required that in Z10, the roughness Ra value of the inner wall of the stainless steel container is not greater than 0.8 micrometers to prevent the adsorption and loss of active ingredients, and the inner surface of the container is electrolytically polished; it is required that in Z50, the stirring blade is made of polytetrafluoroethylene, which is heat-resistant and does not react with the medicinal ingredients, and the blade is spiral in shape with an installation angle of 45 degrees.

[0142] The following describes embodiments of this application. The embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Reagents or instruments used, unless otherwise specified, are all conventional products that can be obtained commercially.

[0143] Example 1

[0144] Preparation of medicinal materials: Prepare the following medicinal materials, all labeled with their place of origin and batch number: Bupleurum chinense 15g, from Shanxi, batch number CY20230101; Scutellaria baicalensis 12g, from Shandong, batch number HQ20230102; Gypsum fibrosum 45g, from Hubei, batch number SG20230103; Anemarrhena asphodeloides 12g, from Hebei, batch number ZM20230104; Lonicera japonica 20g, from Shandong, batch number JYH20230105; Forsythia suspensa 16g, from Shanxi, batch number LQ20230106; Rehmannia glutinosa 20g, from Henan, batch number SDH20230107; Oyster shell... 12g of peony bark, from Anhui, batch number MDP20230108; 12g of red peony root, from Sichuan, batch number CS20230109; 8g of licorice root, from Inner Mongolia, batch number GC20230110; 8g of peppermint, from Jiangsu, batch number BH20230111; 25g of reed rhizome, from Zhejiang, batch number LG20230112; 12g of bamboo leaf, from Hunan, batch number DZY20230113; 16g of artemisia annua, from Chongqing, batch number QH20230114; 15g of kudzu root, from Guangxi, batch number GG20230115.

[0145] Preparation process: S10: Select the above-mentioned medicinal materials and remove impurities; S20: Crush gypsum to a diameter of 0.8 cm, add 1000 ml of water, bring to a boil over high heat, then simmer over low heat for 30 minutes; S30: Add the remaining medicinal materials except for mint, and simmer over low heat for 20 minutes; S40: Add mint, and simmer over low heat for 5 minutes; S50: Filter, add 600 ml of water to the dregs and boil again, combine the filtrates, and concentrate under reduced pressure at 65 degrees Celsius and 0.085 MPa to 400 ml, and dispense into 200 ml / bottle.

[0146] Quality testing: Baicalin content 0.18 mg / mL, total flavonoids 0.35 mg / mL, calcium ion 1.5 mg / mL, menthol 0.06 mg / mL, and microbial limits met.

[0147] Example 2

[0148] Dosage of medicinal materials: Bupleurum 12g, Scutellaria baicalensis 9g, Gypsum 30g, Anemarrhena asphodeloides 9g, Lonicera japonica 15g, Forsythia suspensa 12g, Rehmannia glutinosa 15g, Paeonia suffruticosa 9g, Paeonia lactiflora 9g, Glycyrrhiza uralensis 6g, Mentha haplocalyx 6g, Phragmites communis 15g, Lophatherum gracile 9g, Artemisia annua 12g, Pueraria lobata 12g.

[0149] The preparation process was the same as in Example 1, with a concentration temperature of 60 degrees Celsius and a vacuum degree of 0.08 MPa.

[0150] Quality testing: Baicalin content 0.16 mg / mL, total flavonoids 0.32 mg / mL, calcium ion 1.3 mg / mL, menthol 0.05 mg / mL, and microbial limits met.

[0151] Example 3

[0152] Dosage of medicinal materials: Bupleurum 18g, Scutellaria baicalensis 15g, Gypsum 60g, Anemarrhena asphodeloides 15g, Lonicera japonica 25g, Forsythia suspensa 20g, Rehmannia glutinosa 25g, Paeonia suffruticosa 15g, Paeonia lactiflora 15g, Glycyrrhiza uralensis 10g, Mentha haplocalyx 10g, Phragmites communis 30g, Lophatherum gracile 15g, Artemisia annua 20g, Pueraria lobata 18g.

[0153] The preparation process was the same as in Example 1, with a concentration temperature of 70 degrees Celsius and a vacuum degree of 0.09 MPa.

[0154] Quality testing: Baicalin content 0.20 mg / mL, total flavonoids 0.38 mg / mL, calcium ion 1.8 mg / mL, menthol 0.07 mg / mL, and microbial limits met.

[0155] Comparative Example 1

[0156] Composition of medicinal materials: Bupleurum 15g, Scutellaria baicalensis 12g, Gypsum 45g, Anemarrhena asphodeloides 12g, Lonicera japonica 20g, Forsythia suspensa 16g, Rehmannia glutinosa 20g, Paeonia suffruticosa 12g, Paeonia lactiflora 12g, Glycyrrhiza uralensis 8g, Phragmites communis 25g, Lophatherum gracile 12g, Artemisia annua 16g, Pueraria lobata 15g (excluding peppermint).

[0157] The preparation process is the same as in Example 1.

[0158] Quality testing: Baicalin content 0.18 mg / mL, total flavonoids 0.35 mg / mL, calcium ion 1.5 mg / mL, menthol not detected, microbial limits met.

[0159] Comparative Example 2

[0160] The composition of the medicinal materials is the same as in Example 1, but the decoction process is changed to: all medicinal materials (including mint) are added together and decocted for 30 minutes.

[0161] Quality testing: Baicalin content 0.17 mg / mL, total flavonoids 0.33 mg / mL, calcium ion 1.4 mg / mL, menthol 0.02 mg / mL, and microbial limits met.

[0162] The decoctions prepared in the above examples and comparative examples were subjected to pharmacodynamic verification, and the results are shown in the table below:

[0163] Group Onset time (hours) The degree of decrease in body temperature (°C) Effective maintenance time (hours) Effectiveness (%) Example 1 1.2 1.8 5.5 92.3 Example 2 1.5 1.5 4.8 88.5 Example 3 1.0 2.0 6.0 96.2 Comparative Example 1 1.8 1.2 3.5 73.1 Comparative Example 2 2.0 1.0 3.0 69.2 Positive control group 0.8 2.2 4.0 100.0

[0164] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.

Claims

1. A traditional Chinese medicine decoction for treating fever in patients with acute brucellosis, characterized in that, The decoction is composed of the following Chinese medicinal herbs in parts by weight: Bupleurum chinense 12 to 18g, Scutellaria baicalensis 9 to 15g, Gypsum fibrosum 30 to 60g, Anemarrhena asphodeloides 9 to 15g, Lonicera japonica 15 to 25g, Forsythia suspensa 12 to 20g, Rehmannia glutinosa 15 to 25g, Paeonia suffruticosa 9 to 15g, Paeonia lactiflora 9 to 15g, Glycyrrhiza uralensis 6 to 10g, Mentha haplocalyx 6 to 10g, Phragmites communis 15 to 30g, Lophatherum gracile 9 to 15g, Artemisia annua 12 to 20g, and Pueraria lobata 12 to 18g.

2. The antipyretic traditional Chinese medicine decoction for treating acute brucellosis patients with fever according to claim 1, characterized in that, The preparation method of the decoction includes the following steps: Step S10: Weigh out the following ingredients according to the stated weight proportions: Bupleurum, Scutellaria baicalensis, Gypsum, Anemarrhena asphodeloides, Lonicera japonica, Forsythia suspensa, Rehmannia glutinosa, Paeonia suffruticosa, Paeonia lactiflora, Glycyrrhiza uralensis, Mentha haplocalyx, Phragmites communis, Lophatherum gracile, Artemisia annua, and Pueraria lobata. Clean them separately to remove impurities and obtain clean medicinal slices. Step S20: First, crush the gypsum into particles with a diameter of no more than 1 cm, place them in a decoction container, add 1000 ml of room temperature drinking water, bring to a boil over high heat, and then simmer over low heat for 30 minutes. Step S30: Add all the medicinal slices except for the peppermint to the decoction container and continue to simmer over low heat for 20 minutes; Step S40: Add the mint to the decoction container, simmer over low heat for 5 minutes, then turn off the heat; Step S50: Filter the decoction, collect the filtrate, add 600 ml of water to the dregs, repeat steps S30 to S40, combine the two filtrates, and concentrate to 400 ml.

3. The antipyretic traditional Chinese medicine decoction for treating acute brucellosis patients with fever according to claim 2, characterized in that, In step S20, the gypsum is decocted for 25 to 35 minutes.

4. The antipyretic traditional Chinese medicine decoction for treating patients with acute brucellosis and fever according to claim 2, characterized in that, In step S30, the frying temperature is maintained at 95 degrees Celsius to 100 degrees Celsius.

5. The antipyretic traditional Chinese medicine decoction for treating patients with acute brucellosis and fever according to claim 2, characterized in that, In step S40, the time for adding peppermint is 4 to 6 minutes.

6. The antipyretic traditional Chinese medicine decoction for treating patients with acute brucellosis and fever according to claim 2, characterized in that, In step S50, the filtrate concentration is carried out using a vacuum concentration device at a temperature of 60 to 70 degrees Celsius and a vacuum degree of 0.08 to 0.09 MPa.

7. The antipyretic traditional Chinese medicine decoction for treating patients with acute brucellosis and fever according to claim 1, characterized in that, The decoction contains no less than 0.15 mg of baicalin, no less than 0.30 mg of total flavonoids (calculated as rutin), no less than 1.2 mg of calcium ion concentration, and no less than 0.05 mg of menthol per milliliter.

8. The antipyretic traditional Chinese medicine decoction for treating patients with acute brucellosis and fever according to claim 1, characterized in that, The decoction should be stored at 4 to 8 degrees Celsius for no more than 48 hours; or placed at room temperature (25 degrees Celsius ± 2 degrees Celsius) for no more than 4 hours.

9. The antipyretic traditional Chinese medicine decoction for treating patients with acute brucellosis and fever according to claim 1, characterized in that, The decoction was dispensed into sterile polypropylene medicine bottles, 200 ml per bottle, and then sealed and sterilized by moist heat at 121 degrees Celsius for 15 minutes.

10. The antipyretic traditional Chinese medicine decoction for treating patients with acute brucellosis and fever according to claim 1, characterized in that, The Bupleurum is the dried root of Bupleurum chinense, a plant of the Apiaceae family; the Scutellaria baicalensis is the dried root of Scutellaria baicalensis, a plant of the Lamiaceae family; the Gypsum is the sulfate mineral anhydrite; the Honeysuckle is the dried flower bud of Lonicera japonica, a plant of the Caprifoliaceae family; and the Peppermint is the dried aerial part of Mentha haplocalyx, a plant of the Lamiaceae family.

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