Traditional Chinese medicine composition for treating spontaneous peritonitis due to cirrhosis and preparation method thereof

Abstract

The invention discloses a traditional Chinese medicine composition for treating spontaneous peritonitis due to cirrhosis and a preparation method of the traditional Chinese medicine composition. In order to overcome the defect that in the prior art, a traditional Chinese medicine with an exact curative effect for treating spontaneous peritonitis (SBP) is lacked, the invention provides a traditional Chinese medicine compound which is prepared from 16-24 parts of vinegar-processed euphorbia kansui, 25-35 parts of semen pharbitidis, 25-35 parts of radix stephaniae tetrandrae, 25-35 parts of semen lepidii, 12-18 parts of radix scutellariae, 8-12 parts of rhizoma coptidis, 12-18 parts of fructus amomi, 18-23 parts of radix et rhizoma rhei, 18-23 parts of fructus aurantii immaturus, 18-23 parts of mirabilite and 8-12 parts of borneol. The monarch drugs (euphorbia kansui, semen pharbitidis, semen lepidii and radix stephaniae tetrandrae) synergistically exert the effects of draining water and expelling fluid retention, and inducing diuresis to reduce edema Ministerial drugs (baical skullcap root and coptis chinensis) have the effects of clearing heat, drying dampness and detoxifying, and are assisted with rhubarb and immature bitter orange have the effects of relaxing bowels and removing heat; the fructus amomi can promote qi circulation, remove dampness and promote diuresis. According to the composition, through multi-way synergistic effect, the symptoms of abdominal pain and abdominal distension of SBP patients are remarkably improved, ascites metabolism is promoted, inflammatory response is inhibited, the disease course is shortened, and a novel safe and effective traditional Chinese medicine scheme is provided for treatment of liver cirrhosis complications.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technologies, and particularly to a traditional Chinese medicine composition for treating spontaneous bacterial peritonitis in liver cirrhosis and a preparation method thereof. Background Art

[0002] Spontaneous Bacterial Peritonitis (SBP) is one of the most serious infectious complications in cirrhotic ascites patients. Its incidence rate is as high as 7%-30% in cirrhotic inpatients, and it has a significant recurrence feature (annual recurrence rate of 40%-70%). If SBP patients are not intervened in time, the condition can rapidly progress to septic shock, hepatorenal syndrome (HRS) or hepatic encephalopathy (HE), and the fatality rate is as high as 50%, seriously threatening the lives of patients. Although anti-infection treatment means have advanced in recent years, the high recurrence rate of SBP and the emergence of multi-drug resistant bacteria still pose challenges to clinical treatment.

[0003] At present, the core pathogenesis of SBP has not been fully elucidated, but Bacterial Translocation (BT) has been recognized as a key pathological link. Its specific manifestations are as follows: ① Intestinal microecological imbalance: intestinal flora disorder and excessive bacterial proliferation; ② Intestinal barrier function damage: increased intestinal mucosal permeability leads to the translocation of bacteria / endotoxins (such as lipopolysaccharide, bacterial DNA) to the abdominal cavity and circulatory system; ③ Immunodefense defect: the function of the mononuclear-macrophage system in cirrhotic patients is damaged and cannot effectively clear ectopic pathogens; ④ Inflammatory cascade amplification: pathogen-associated molecular patterns (PAMPs) activate immune cells, and pro-inflammatory factors (TNF-α, IL-6, IFN-γ, etc.) are released in excess, triggering systemic inflammatory response syndrome (SIRS).

[0004] At present, for the western medicine clinical treatment of this disease, early empirical antibiotic treatment (such as third-generation cephalosporins, quinolones) is the core, combined with albumin expansion, diuresis and symptomatic supportive treatment. However, this plan has significant defects: ① Risk of drug resistance: long-term use of antibiotics leads to the growth of drug-resistant strains, and the choice of second-line drugs is limited; ② Insufficient symptom control: about 30% of patients have insignificant relief of abdominal distension and pain symptoms after treatment, and the quality of life is difficult to improve; ③ High recurrence rate: even if the infection is temporarily controlled, the intestinal flora disorder and intestinal barrier damage are not fundamentally repaired, and the re-infection rate within 6 months exceeds 40%; ④ Increased burden on the liver and kidneys: the nephrotoxicity of some antibiotics may accelerate the progression of hepatorenal syndrome.

[0005] Traditional Chinese medicine theory holds that SBP belongs to the categories of "abdominal distension" and "abdominal pain". The pathogenesis is mainly due to the stagnation of dampness, heat, stasis and toxin in the triple energizer. The treatment principle emphasizes purging the bowels to remove turbidity and promoting blood circulation to induce diuresis. Modern pharmacological research has confirmed that traditional Chinese medicine compound can act through multiple targets: antibacterial and anti-inflammatory: inhibiting the proliferation of pathogens and regulating the balance of pro-inflammatory / anti-inflammatory factors; intestinal barrier repair: improving intestinal mucosal permeability and reducing bacterial translocation; immune regulation: enhancing the phagocytic function of macrophages and reconstructing immune homeostasis. However, existing traditional Chinese medicine preparations generally have problems such as empirical ingredient ratio, slow onset, insufficient inflammation control, and low efficiency of ascites excretion.

[0006] Based on the above background, there is an urgent need to develop a traditional Chinese medicine composition with scientific formula, rapid onset and convenient use, aiming to quickly relieve abdominal pain and distension, accelerate ascites excretion, reduce inflammatory response through multi-target synergistic effects, while repairing liver function and delaying the progression of the disease.

[0007] The information disclosed in this background art section is only used to deepen the understanding of the background art of the present disclosure, and should not be regarded as an admission or any form of implication that this information constitutes the prior art known to those skilled in the art. Summary of the Invention

[0008] Based on long-term clinical practice research of traditional Chinese medicine, the inventor believes that: based on the main clinical manifestations of SBP such as fever, abdominal pain, and abdominal distension, it should be classified into the categories of "abdominal distension", "abdominal pain", etc. It is mostly caused by exogenous dampness, heat and epidemic toxin, improper diet, emotional injury, insect toxin infection, and long-term liver disease. Pathological factors such as dampness, heat, toxin, and stasis are intertwined and interact with each other, resulting in the mutual struggle of qi stagnation, water dampness, dampness heat, phlegm stasis; during the progression of liver cirrhosis, the liver's failure to disperse and dredge affects the body's intestine's function of separating the clear from the turbid and transporting and transforming the dross, resulting in the internal binding of intestinal stasis toxin, obstruction of the qi of the bowel, and the invasion of dampness, heat, stasis, toxin and other pathogenic factors into the internal organs. "Disharmony of the liver, spleen and kidney, and mutual binding of dampness, heat, toxin and stasis" is its basic pathogenesis.

[0009] In view of this, the inventor believes that for the treatment of this disease, the formula should first clear heat and detoxify to relieve pain, promote diuresis and reduce swelling, so that pathogenic factors such as dampness, heat, toxin and stasis can find a way out. When the pathogenic factors are removed, the qi mechanism will be smooth, the blood vessels will be unobstructed, the water channels will be unobstructed, and the body fluid will be distributed, so as to quickly and effectively relieve the clinical symptoms and signs of abdominal pain and distension of patients, accelerate ascites excretion, improve the clinical treatment efficiency, reduce inflammatory response, accelerate liver function repair, and delay the progression of the disease. Therefore, the prescription is as follows (by weight): Euphorbia kansui processed with vinegar 16 - 24 parts, Pharbitis seed 25 - 35 parts, Stephania tetrandra 25 - 35 parts, Lepidium apetalum 25 - 35 parts, Scutellaria baicalensis 12 - 18 parts, Coptis chinensis 8 - 12 parts, Amomum villosum 12 - 18 parts, Rheum palmatum 18 - 23 parts, Aurantii Fructus Immaturus 18 - 23 parts, Natrii Sulfas 18 - 23 parts, Borneol 8 - 12 parts.

[0010] In some embodiments of the present disclosure, a traditional Chinese medicine for treating cirrhotic spontaneous peritonitis is prepared from the following raw medicinal materials: 18 - 22 parts of processed kansui root, 27 - 33 parts of pharbitis seed, 27 - 33 parts of Stephania tetrandra, 27 - 33 parts of Lepidium apetalum, 13 - 17 parts of Scutellaria baicalensis, 9 - 11 parts of Coptis chinensis, 13 - 17 parts of Amomum villosum, 19 - 22 parts of Rheum palmatum, 19 - 22 parts of Immature Bitter Orange, 19 - 22 parts of Mirabilite, 9 - 11 parts of Borneol.

[0011] In some embodiments of the present disclosure, a traditional Chinese medicine composition for treating cirrhotic spontaneous peritonitis is prepared from the following raw medicinal materials: 20 parts of processed kansui root, 30 parts of pharbitis seed, 30 parts of Stephania tetrandra, 30 parts of Lepidium apetalum, 15 parts of Scutellaria baicalensis, 10 parts of Coptis chinensis, 15 parts of Amomum villosum, 20 parts of Rheum palmatum, 20 parts of Immature Bitter Orange, 20 parts of Mirabilite, 10 parts of Borneol.

[0012] Based on the pathogenesis of "disharmony of the liver, spleen and kidney, and mutual binding of dampness - heat, toxin and stasis", with the therapeutic principles of purging water retention, clearing heat and detoxifying, and promoting qi flow in the intestines, the above formula contains four types of synergistic components: ① Main drugs (purging water retention): Processed kansui root, pharbitis seed, Lepidium apetalum, Stephania tetrandra, jointly exerting the effects of purging water retention and inducing diuresis to reduce swelling; ② Drugs for clearing damp - heat and detoxifying: Scutellaria baicalensis, Coptis chinensis, clearing away damp - heat and toxin; ③ Drugs for purging heat from the intestines: Rheum palmatum, Immature Bitter Orange, Mirabilite, promoting defecation and guiding stagnation, and promoting the excretion of toxins; ④ Drugs for promoting qi flow and relieving pain: Amomum villosum promoting qi flow and resolving dampness, Borneol clearing heat and reducing swelling, jointly regulating qi movement.

[0013] According to another aspect of the present disclosure, a preparation method of a traditional Chinese medicine composition (external application pack) for treating cirrhotic spontaneous peritonitis is provided: (1) Dosage form innovation: Each raw medicinal material is configured according to the raw material ratio, ground into fine powder of 80 - 150 meshes, and mixed with honey to form a paste, and then sealed with lotus leaf to make an external patch, with each pack weighing 220 - 300 g; (2) Acupoint - targeted application: Applied to the abdomen, covering acupoints such as Shenque and Tianshu, combining meridian transdermal absorption and drug penetration to achieve "synergy between acupoints and drugs"; (3) Process optimization: The lotus leaf seal has both air permeability and moisture retention, prolonging the drug release time, adapting to the characteristics of the open collateral circulation around the umbilicus of cirrhotic patients, and improving the bioavailability of the drug.

[0014] One or more technical solutions provided in the embodiments of the present application have at least any one of the following technical effects or advantages: 1. Trinity of pathogenesis - treatment method - formula: Aiming at the core pathogenesis of "mutual binding of dampness - heat, toxin and stasis", a four - dimensional compatibility of "purging water + clearing heat + promoting defecation + promoting qi flow" is first created, breaking through the limitations of traditional single - diuretic or heat - clearing methods, and achieving a way out for pathogenic factors and synchronous adjustment of visceral functions.

[0015] 2. Transdermal absorption enhancement mechanism: Combining the advantages of transdermal absorption at the Shenque acupoint (thin fat layer and rich venous network), and through the directional penetration of the lotus leaf pack, the drug can directly reach the abdominal cavity and blood circulation, with rapid onset.

[0016] 3. Advantages verified clinically: It can quickly relieve abdominal pain and distension, and the symptom relief rate reaches 81.6% within 24 hours; the ascites excretion speed is increased by more than 40%, and the average hospital stay is shortened by 5 - 7 days; the levels of serum inflammatory factors (such as TNF-α, IL-6) decrease by more than 50%, and the liver function indicators (ALT, AST) are significantly improved.

[0017] 4. Safety and economy: The raw materials are easily available, and the cost is reduced by more than 30%. The external preparation avoids the first-pass effect of the liver, and there are no reports of gastrointestinal irritation or liver and kidney toxicity.

[0018] 5. Application prospects: The present invention provides a safe, efficient and highly compliant external Chinese medicine solution for cirrhotic spontaneous peritonitis, which is suitable for clinical adjuvant treatment and community medical promotion, and has significant social and economic benefits. Detailed implementation mode

[0019] In order to better understand the technical solution of the present application, the above technical solution will be described in detail below in combination with specific implementation modes.

[0020] In the following examples, the Chinese medicine raw materials involved are all commercially available conventional raw materials without special instructions; the processing and preparation methods involved are all conventional methods without special instructions.

[0021] Example 1. A Chinese medicine composition for treating cirrhotic spontaneous peritonitis (lotus leaf pack of heat-clearing, pain-relieving and diuretic formula), and its raw material formula is as follows: 20 g of kansui tuber processed with vinegar, 30 g of pharbitis seed, 30 g of Stephania tetrandra root, 30 g of Lepidium apetalum willd, 15 g of Scutellaria baicalensis, 10 g of Coptis chinensis, 15 g of Amomum villosum, 20 g of Rheum officinale, 20 g of Fructus aurantii immaturus, 20 g of mirabilite, 10 g of borneol.

[0022] The preparation method of the above drugs includes the following steps: (1) Weigh each raw material drug according to the above raw material formula and set aside; (2) Grind into powder, make it into a paste with honey, and wrap it on the abdomen with a lotus leaf pack, once a day, 4 - 6 hours each time.

[0023] Example 2. A Chinese medicine composition for treating cirrhotic spontaneous peritonitis (lotus leaf pack of heat-clearing, pain-relieving and diuretic formula), and its raw material formula is as follows: 17 g of kansui tuber processed with vinegar, 26 g of pharbitis seed, 26 g of Stephania tetrandra root, 26 g of Lepidium apetalum willd, 14 g of Scutellaria baicalensis, 9 g of Coptis chinensis, 14 g of Amomum villosum, 17 g of Rheum officinale, 17 g of Fructus aurantii immaturus, 17 g of mirabilite, 9 g of borneol.

[0024] The preparation method is the same as that in Example 1.

[0025] Example 3: A traditional Chinese medicine composition for treating spontaneous bacterial peritonitis in liver cirrhosis (Lotus leaf pack of heat-clearing, pain-relieving and diuretic formula), and its raw material formula is as follows: 23 g of processed kansui root, 34 g of pharbitis seed, 34 g of Stephania tetrandra, 34 g of Lepidium apetalum, 16 g of Scutellaria baicalensis, 11 g of Coptis chinensis, 16 g of Amomum villosum, 23 g of Rheum officinale, 23 g of Immature Bitter Orange, 23 g of mirabilite, 11 g of borneol.

[0026] The preparation method is the same as that in Example 1.

[0027] Example 4: A traditional Chinese medicine composition for treating spontaneous bacterial peritonitis in liver cirrhosis (Lotus leaf pack of heat-clearing, pain-relieving and diuretic formula), and its raw material formula is as follows: 21 g of processed kansui root, 29 g of pharbitis seed, 32 g of Stephania tetrandra, 28 g of Lepidium apetalum, 14 g of Scutellaria baicalensis, 12 g of Coptis chinensis, 13 g of Amomum villosum, 22 g of Rheum officinale, 21 g of Immature Bitter Orange, 18 g of mirabilite, 9 g of borneol.

[0028] The preparation method is the same as that in Example 1.

[0029] Clinical application test cases: 1. Case selection 86 inpatients from the Department of Spleen, Stomach, Liver and Gallbladder Diseases of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine were randomly divided into an experimental group and a control group, with 43 cases in each group. Among them, 2 cases in the experimental group were excluded due to missing relevant test items, 1 case in the control group dropped out due to withdrawal midway, and 1 case was excluded due to not completing the observation period. Finally, a total of 82 cases were actually included in the analysis, 41 cases in the experimental group and 41 cases in the control group. There were no significant differences in terms of gender, age, ascites course, SBP history, co-existing liver cancer, alcohol history, Child-Pugh classification, etc. between the two groups of patients, and they were comparable, as shown in Table 1.

[0030] Table 1 Comparison of general data of two groups of cases .

[0031] Case inclusion criteria: (1) Those who meet the above Western medicine diagnostic criteria and syndrome differentiation criteria, 18 ≤ age ≤ 75 years old, gender is not limited; the subjects voluntarily participate in the study and sign the informed consent form.

[0032] (2) The Western medicine diagnostic criteria for liver cirrhosis SBP refer to the "Diagnosis and Treatment Guidelines for Liver Cirrhosis Ascites and Related Complications" formulated by the Liver Disease Branch of the Chinese Medical Association in 2017.

[0033] (3) Medical history: There is a clear history of liver cirrhosis in the past; (4) Any of the following symptoms or signs: ① Symptoms or signs of acute peritonitis: abdominal pain, abdominal tenderness or rebound pain, increased abdominal muscle tension; ② Manifestations of inflammatory response syndrome: fever or no fever, chills, tachycardia, tachypnea; ③ Deterioration of liver function without obvious cause; ④ Hepatic encephalopathy; ⑤ Shock; ⑥ Refractory ascites or sudden unresponsiveness to diuretics or renal failure.

[0034] (5) Any of the following laboratory abnormalities: ① PMN count in ascites ≥ 250 × 10 6 / L; ② Ascites bacterial culture is positive; ③ Serum procalcitonin (PCT)>0.5ng / ml, excluding infection in other parts.

[0035] The diagnostic criteria for TCM syndromes refer to the damp-heat accumulation syndrome in the "Expert Consensus on TCM Diagnosis and Treatment of Cirrhosis Ascites (2023)" formulated by the Spleen and Stomach Disease Branch of the Chinese Association of Traditional Chinese Medicine. Damp-heat accumulation and toxic stasis syndrome: (1) Main symptoms: ① Enlarged, hard and full abdomen with abdominal distension and pain; ② Abdominal pain that is resistant to pressure; ③ Yellow body and eyes.

[0036] (2) Secondary symptoms: ① fever; ② dry mouth, bitter taste in the mouth; ③ thirst without desire to drink; ④ short yellow urine; ⑤ constipation or loose stools; ⑥ exposed blue veins in the abdominal wall; ⑦ stabbing pain in the ribs, fixed and immovable.

[0037] (3) Tongue and pulse: ① The tongue is dark red with a greasy yellow coating; ② The pulse is stringy, slippery or rapid.

[0038] Among them, if the patient has main symptom ① + one other main symptom and two secondary symptoms, the diagnosis can be made by referring to the tongue and pulse.

[0039] Case exclusion criteria: ① Patients with bloody ascites; ② Patients with severe primary diseases of the heart, brain, kidney and other systems, or severe mental illness; ③ Patients with hepatorenal syndrome, acute upper gastrointestinal bleeding, shock, other organ failure or other critical and severe diseases; ④ Patients who have taken immunomodulators or intestinal microecological preparations in the past month; ⑤ Pregnant and lactating women; ⑥ Patients participating in other clinical trials.

[0040] 2. Treatment options The control group referred to the "Guidelines for the diagnosis and treatment of ascites and related complications of liver cirrhosis" formulated by the Chinese Medical Association Hepatology Branch in 2017: (1) Anti-infection treatment: The third-generation cephalosporins are preferred, and ascites culture and / or blood culture are performed at the same time. The antibiotic treatment plan is adjusted according to the drug sensitivity results; (2) Plasma and human albumin: When the patient's serum ALB is less than 30 g / L, plasma (200 ml / d) or human albumin injection (10 g / d) should be transfused; (3) Basic liver protection, choleretic and jaundice-relieving, antiviral and oral diuretics (furosemide, spironolactone), etc.

[0041] On the basis of the control group, the experimental group was combined with the Qingre Zhitong Lishui Decoction wrapped in lotus leaves. Prescription: 20 g of kansui processed with vinegar, 30 g of pharbitis seeds, 30 g of Stephania tetrandra, 30 g of semen lepidii, 15 g of Scutellaria baicalensis, 10 g of Coptis chinensis, 15 g of Amomum villosum, 20 g of Rheum officinale, 20 g of Aurantii Fructus Immaturus, 20 g of mirabilite, and 10 g of borneol. The drugs were dispensed by the Traditional Chinese Medicine Pharmacy of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine, ground into powder, made into a paste with honey, and then wrapped in lotus leaves and applied to the abdomen once a day for 4 - 6 hours each time. The treatment time for both groups was 2 weeks.

[0042] Observation indicators 3.1 Main efficacy indicators (1) Abdominal ascites volume (the deepest value of ascites) by color Doppler ultrasound: Before and after treatment, professionally trained researchers used Mindray ultrasound (RESONA 8) to detect the abdominal ascites volume of patients; (2) Time (h) for the disappearance of fever and abdominal pain: The time for the disappearance of fever and abdominal pain after treatment of patients; (3) Count of polymorphonuclear cells (PMN) in ascites.

[0043] The calculation formula for the PMN count in ascites is: the number of white blood cells in ascites × the percentage of polymorphonuclear cells. Under the positioning of abdominal color Doppler ultrasound, abdominal paracentesis was performed, and routine ascites, biochemical, and ascites bacterial culture were carried out. Then, 10 ml of ascites was aseptically extracted again. After collecting the ascites specimen, it was immediately sent to the Clinical Laboratory of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine for detection by professionally trained researchers.

[0044] 3.2 Secondary efficacy indicators (1) TCM syndrome score and syndrome efficacy; formulated with reference to the "Consensus Opinion on the Quantitative Standard of Spleen and Stomach Disease Symptoms". The main symptoms of fever, abdominal pain, abdominal distension, and jaundice of the body and eyes were graded as none, mild, moderate, and severe, and were scored as 0, 2, 4, and 6 points respectively; the symptoms of dry mouth, bitter taste, short and yellow urine, fatigue, and poor appetite were graded as none, mild, moderate, and severe, and were scored as 0, 1, 2, and 3 points respectively; the sum of the scores of each TCM clinical symptom before and after treatment was the total symptom score. According to the difference in the total symptom score before and after treatment, the efficacy was evaluated. The calculation formula used the Nimodipine method, and the efficacy score = (total score before treatment - total score after treatment) / total score before treatment × 100%. Marked effect: Symptoms and signs were significantly improved, and the syndrome score decreased by ≥70%; Effective: Symptoms and signs were both improved, and the syndrome score decreased by ≥30% but <70%. Ineffective: Symptoms and signs were not significantly improved, or even worsened, and the syndrome score decreased by <30%.

[0045] (2)Liver function indicators: total bilirubin (TBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB): At 6 - 7 am before treatment and at the end of treatment, 4 - 6 mL of fasting cubital venous blood was collected, and immediately sent to the biochemical laboratory of the First Affiliated Hospital of Henan University of Chinese Medicine for detection by professionally trained personnel.

[0046] (3)Infection indicators: percentage of neutrophils (%NEUT), C-reactive protein (CRP), procalcitonin (PCT). Before treatment and at the end of treatment, all study subjects underwent fasting (no food intake for 8 hours before blood collection) venous blood collection. 5 mL of venous blood was drawn into a red vacuum negative pressure blood collection tube and immediately sent to the clinical laboratory of the First Affiliated Hospital of Henan University of Chinese Medicine for detection by professionally trained personnel.

[0047] 3.3 Mechanism-related indicators (1)Inflammatory factors: human tumor necrosis factor a (TNF-a), human interleukin 6 (IL-6), human interleukin 10 (IL-10); (2)Intestinal mucosal barrier function evaluation indicators: endotoxin (ET), diamine oxidase (DAO), D-lactic acid (D-Lac), occludin, zonula occludens protein 1 (ZO-1).

[0048] For both inflammatory factors and intestinal mucosal barrier function evaluation indicators, at 6 - 7 am before treatment and at the end of treatment, 4 - 6 mL of fasting cubital venous blood was collected. After centrifuging at 2000 revolutions with a centrifuge to separate the serum, it was frozen in a -80 °C refrigerator and detected by enzyme-linked immunosorbent assay (ELISA). The reagent kits were provided by Jiangsu Enzyme Immunoassay Industry Co., Ltd. (human tumor necrosis factor α (TNF-α) ELISA research kit; human interleukin 6 (IL-6) ELISA research kit; human interleukin 10 (IL-10) ELISA research kit; human diamine oxidase (DAO) ELISA research kit; human D-lactic acid (D-Lactate) ELISA research kit; human zonula occludens protein 1 (ZO-1) ELISA research kit; human occludin ELISA research kit; human endotoxin (ET) ELISA research kit). The experimental operations were carried out strictly in accordance with the reagent kit instructions.

[0049] 3.4 Safety indicators Vital signs, blood routine, urine routine, stool routine, renal function, coagulation function, electrolytes, electrocardiogram, etc.

[0050] Efficacy evaluation criteria Western medicine clinical efficacy evaluation criteria: Referring to the "Diagnosis and Treatment Guidelines for Liver Cirrhosis Ascites and Related Complications" and the "Technical Guidelines for Clinical Research of New Chinese Medicines of Syndrome Categories", the criteria are formulated as follows: ① The PMN count in ascites is < 0.25×10 9 / L or the ascites disappears; ② The fever disappears; ③ The abdominal pain disappears. Those who meet all three conditions are clinically cured.

[0051] Evaluation criteria for the curative effect of TCM symptoms: Refer to the "Consensus on the Quantitative Criteria for Spleen and Stomach Disease Symptoms" and the "Technical Guidelines for Clinical Research of New Chinese Medicines for Syndrome Types".

[0052] Marked effect: Symptoms and signs are significantly improved, and the syndrome integral is reduced by ≥ 70%; Effective: Symptoms and signs are both improved, and the syndrome integral is reduced by ≥ 30% but < 70%. Ineffective: Symptoms and signs are not significantly improved or even worsened, and the syndrome integral is reduced by < 30%.

[0053] 5. Results 5.1 Comparison of the changes in the amount of ascites under color Doppler ultrasound in the two groups of patients Before treatment, there was no significant difference between the groups ( P > 0.05), and they were comparable; After treatment, the amount of ascites in both groups of patients was significantly reduced compared with that before treatment (experimental group t = 24.351, P = 0.000; Control group t = 20.838, P = 0.000, P < 0.05). After treatment, the reduction of the amount of ascites in the experimental group was more obvious than that in the control group ( t = -2.753, P = 0.007), and the difference was statistically significant ( P < 0.05), as shown in Table 2.

[0054] Table 2 Comparison of the changes in the amount of ascites (mm) under color Doppler ultrasound in the two groups of patients ( ±s ) Note: ▲ Comparison between the two groups before treatment P > 0.05; # Comparison between the two groups after treatment P < 0.05; ● Comparison within the two groups after treatment P < 0.05.

[0055] 5.2 Comparison of the disappearance time of fever and abdominal pain in the two groups of patients Among the 82 patients included, 60 patients had fever before treatment, 31 in the experimental group and 29 in the control group; 65 patients had abdominal pain before treatment, 34 in the experimental group and 31 in the control group; The difference in the disappearance time of fever and abdominal pain between the two groups of patients was statistically significant ( P(<0.05). The disappearance times of fever and abdominal pain in the experimental group were shorter than those in the control group, as shown in Table 3.

[0056] Table 3 Comparison of symptom disappearance times (h) after treatment between the two groups of patients ( ±s ) .

[0057] 5.3 Comparison of ascites PMN counts between the two groups of patients There was no significant difference in the ascites PMN counts between the two groups of patients before treatment ( P >0.05), and they were comparable. After 72 h of treatment, the ascites PMN counts in both groups were significantly lower than those before treatment (experimental group Z =-5.579, control group Z =-5.293, P <0.05). After 72 h of treatment, the decrease in ascites PMN counts in the experimental group was better than that in the control group, and the difference was statistically significant ( Z =-2.541, P =0.011, P <0.05), as shown in Table 4.

[0058] Table 4 Ascites PMN counts of the two groups of patients [M(P 25 ,P 75 ),(unit 10 6 / L)] .

[0059] 5.4 Comparison of single traditional Chinese medicine symptom scores between the two groups of patients Before treatment, there were no significant differences in the symptoms of fever, abdominal pain, abdominal distension, jaundice of the body and eyes, dry mouth, bitter taste in the mouth, short and yellow urine, fatigue, and poor appetite between the two groups of patients ( P >0.05), and they were comparable. After treatment in the experimental group, all symptoms were significantly improved compared with those before treatment, and the differences before and after treatment were statistically significant ( P <0.05); in the control group, the symptoms of fever, abdominal pain, abdominal distension, jaundice of the body and eyes, short and yellow urine, fatigue, and poor appetite were significantly improved compared with those before treatment, and the differences were statistically significant ( P <0.05), while the symptoms of dry mouth and bitter taste in the mouth were not significantly improved. After treatment, the improvements in the symptoms of fever, abdominal pain, and fatigue in the experimental group were comparable to those in the control group ( P >0.05), while the improvements in the symptoms of abdominal distension, jaundice of the body and eyes, dry mouth, bitter taste in the mouth, short and yellow urine, and poor appetite were better than those in the control group, and all were statistically significant ( P <0.05), as shown in Table 5.

[0060] Table 5 Comparison of single traditional Chinese medicine symptom scores before and after treatment between the two groups of patients [M(P25 , P 75 )] 。

[0061] 5.5 Comparison of the total scores of traditional Chinese medicine symptoms between the two groups of patients After treatment, the total scores of traditional Chinese medicine symptoms in both groups were significantly lower than those before treatment, and the differences were statistically significant ( P <0.05). After treatment, the reduction level of the total scores of traditional Chinese medicine symptoms in the experimental group was more significant than that in the control group ( t =-4.567, P =0.000), and the difference was statistically significant ( P <0.05), as shown in Table 6.

[0062] Table 6 Comparison of the total scores of traditional Chinese medicine symptoms in the two groups of patients before and after treatment ( ±s ) 。

[0063] 5.6 Comparison of the curative effects of traditional Chinese medicine symptoms between the two groups of patients The total effective rate of the curative effect of traditional Chinese medicine symptoms in the treatment group was 92.68%, which was significantly better than that in the control group ( P <0.05), as shown in Table 7.

[0064] Table 7 Comparison of the curative effects of traditional Chinese medicine symptoms in the two groups of patients [cases (%)]

[0065] 5.7 Comparison of the changes in liver function before and after treatment in the two groups of patients Before treatment, there were no statistically significant differences in TBIL, ALB, ALT, and AST between the two groups of patients ( P >0.05), and they were comparable. After treatment, the levels of TBIL, ALT, and AST in both groups of patients were significantly lower than those before treatment ( P <0.05), and ALB was significantly higher than that before treatment ( P <0.05). After treatment, the reduction of TBIL, ALT, and AST in the experimental group was better than that in the control group ( P <0.05), while the increase in ALB was comparable to that in the control group ( P <0.05), as detailed in Table 8.

[0066] Table 8 Comparison of the changes in liver function indexes before and after treatment in the two groups of patients [M(P 25 , P 75 )] 。

[0067] 5.8 Comparison of the changes in infection indexes between the two groups of patients There were no statistically significant differences in %NEUT, CRP, and PCT between the two groups of patients before treatment ( P > 0.05), and they were comparable. After treatment, the levels of serum infection indicators %NEUT, CRP, and PCT in both groups of patients were significantly improved compared with those before treatment ( P the values were all 0.000).

[0068] After treatment, the improvement of the levels of serum infection indicators %NEUT, CRP, and PCT in the experimental group was better than that in the control group ( P < 0.05), as shown in Table 9.

[0069] Table 9 Comparison of changes in infection indicators before and after treatment in two groups of patients [M(P 25 ,P 75 )] .

[0070] 5.9 Comparison of serum inflammatory factors TNF-α, IL-6, and IL-10 in two groups of patients There were no statistically significant differences in the levels of serum TNF-α, IL-6, and IL-10 before treatment ( P > 0.05), and they were comparable. After treatment, the levels of serum inflammatory factors TNF-α and IL-6 in both groups of patients were significantly decreased compared with those before treatment ( P < 0.05), and the levels of serum anti-inflammatory factor IL-10 were significantly increased compared with those before treatment ( P < 0.05). After treatment, the decrease levels of serum inflammatory factors TNF-α and IL-6 in the experimental group were better than those in the control group, TNF-α( t =-3.936, P =0.000), IL-6( t =-3.925, P =0.000), the increase level of serum anti-inflammatory factor IL-10 in the experimental group was better than that in the control group, IL-10( t =3.264, P =0.002), P < 0.05, see Table 10.

[0071] Table 10 Comparison of changes in serum TNF-α, IL-6, and IL-10 before and after treatment in two groups of patients ( ±s ) .

[0072] 5.10 Comparison of intestinal mucosal barrier function evaluation indicators in two groups of patients There were no statistically significant differences in the contents of serum ET, DAO, D-lac, Occludin, and ZO-1 before treatment ( P> 0.05), with comparability. After treatment, the contents of serum intestinal mucosal barrier function evaluation indicators ET, DAO, D-lac, Occludin, and ZO-1 in both groups of patients were significantly lower than those before treatment ( P＜0.05 ). After treatment, serum ET( t =-3.581, P =0.001), DAO( t =-3.593, P =0.001), D-lac( t =-4.433, P =0.000), Occludin( t =-4.682, P =0.000), ZO-1( t =-5.342, P =0.000) showed statistically significant differences in content( P <0.05), indicating that after treatment, the reduction levels of serum intestinal mucosal barrier function evaluation indicators ET, DAO, D-lac, Occludin, and ZO-1 in the experimental group of patients were more significant than those in the control group (see Table 11).

[0073] Table 11 Comparison of changes in intestinal mucosal barrier function evaluation indicators before and after treatment in two groups of patients ( ±s ) .

[0074] 6. Results of safety analysis During the implementation of this clinical trial, there were no obvious changes in safety indicators such as blood routine, urine routine, stool routine, renal function, electrolytes, and electrocardiogram in both groups of patients compared with those before treatment, and no other adverse reactions occurred, indicating that the traditional Chinese medicine triple therapy is safe for the treatment of patients with liver cirrhosis complicated with SBP.

[0075] The above results show that adding the heat-clearing and detoxifying and diuretic prescription shown in the present invention to the western medicine treatment for patients with liver cirrhosis complicated with spontaneous peritonitis can shorten the time for fever and abdominal pain to relieve, rapidly reduce the ascites PMN count level, improve the clinical effective rate, more significantly improve the clinical symptoms of patients, and at the same time inhibit the inflammatory response, and the effect of reducing hepatocyte damage is better than that of simple western medicine basic treatment, and it can improve the intestinal mucosal barrier. No adverse reactions were found in this trial, indicating that the medicine of the present invention is safe and the curative effect is stable and reliable.

[0076] Typical cases Case 1: Cao Mouxia, female, 54 years old, Han nationality, visited on July 3, 2024.

[0077] Chief complaint: Intermittent right rib pain for 10 years, aggravated with abdominal distension and abdominal pain for 2 d.

[0078] Western medicine diagnosis: decompensated liver cirrhosis after hepatitis B (portal hypertension, splenomegaly, ascites), spontaneous peritonitis.

[0079] Traditional Chinese medicine diagnosis: liver accumulation (syndrome of spleen deficiency and dampness excess).

[0080] Treatment: (1) Western medicine regimen: antiviral, anti-infection (piperacillin / tazobactam + levornidazole), diuresis (furosemide + spironolactone), liver protection (magnesium isoglycyrrhizinate). (2) Traditional Chinese medicine pack: Apply the lotus leaf pack described in Example 1 externally on the abdomen once a day for 4 - 6 hours each time, with a treatment course of 14 days.

[0081] Therapeutic effect: ① Symptom improvement: abdominal pain and distension disappeared, urine output increased, anorexia and fatigue were relieved. ② Laboratory indicators: CRP decreased from 135.0 mg / L to 4.6 ng / L, TBIL decreased from 51.7 μmol / L to 23.5 μmol / L, and ALB increased from 30.0 g / L to 35.8 g / L. ③ Imaging: ascites was completely absorbed and pleural effusion disappeared.

[0082] Case 2: Guo Mouxu, male, 60 years old, visited on June 30, 2024.

[0083] Chief complaint: abdominal distension and anorexia for more than 1 year, aggravated with disturbance of consciousness for 3 months.

[0084] Western medicine diagnosis: decompensated liver cirrhosis due to hepatitis B, spontaneous peritonitis.

[0085] Traditional Chinese medicine diagnosis: tympanites (syndrome of dampness - heat stasis and binding).

[0086] Treatment: (1) Western medicine regimen: anti - infection (piperacillin / tazobactam + ornidazole), correction of hypoproteinemia, diuresis and antiviral (entecavir). (2) Traditional Chinese medicine pack: Apply the lotus leaf pack described in Example 2 externally, with a treatment course of 14 days.

[0087] Therapeutic effect: ① Symptom improvement: abdominal pain, abdominal distension, jaundice and bilateral lower extremity edema were significantly reduced, and the state of consciousness recovered. ② Laboratory indicators: WBC decreased from 22.5×10 9 / L to 6.4×10 9 / L, TBIL decreased from 91.3 μmol / L to 38.8 μmol / L, PCT decreased from 1.44 ng / mL to <0.05 ng / mL. ③ Ascites volume: the depth of abdominal effusion decreased from 95 mm to 29 mm.

[0088] Case 3: Lou Mou, male, 60 years old, was admitted to the hospital on July 22, 2019.

[0089] Chief complaint: a history of hepatitis B for 1 year, intermittent fever and abdominal distension for more than 2 months.

[0090] Western medicine diagnosis: decompensated stage of hepatitis B cirrhosis, primary liver cancer, spontaneous peritonitis.

[0091] Traditional Chinese medicine diagnosis: liver accumulation, fever (qi deficiency syndrome).

[0092] Treatment: (1) Western medicine regimen: anti-infection (piperacillin / tazobactam), anti-virus (tenofovir alafenamide). (2) Traditional Chinese medicine packet application: Apply the lotus leaf packet described in Example 3 externally, with a treatment course of 14 days.

[0093] Therapeutic effect: ① Symptom improvement: Abdominal pain and distension disappeared, body temperature returned to normal, and bilateral lower limb edema subsided. ② Laboratory indicators: ALT decreased from 102.8 U / L to 42.2 U / L, AST decreased from 115.2 U / L to 36.1 U / L, and ascites white blood cells decreased from 552×10 6 / L to 131×10 6 / L. ③ Imaging: Ascites color Doppler ultrasound showed that the effusion disappeared.

[0094] Case 4: Niu Moucheng, male, 68 years old, was admitted to our hospital from the outpatient department on July 10, 2024.

[0095] Chief complaint: Liver cirrhosis for more than 2 months, with aggravated abdominal distension and lower limb edema.

[0096] Western medicine diagnosis: decompensated stage of hepatitis B cirrhosis, spontaneous peritonitis, hydronephrosis.

[0097] Traditional Chinese medicine diagnosis: liver accumulation (syndrome of spleen deficiency and dampness accumulation).

[0098] Treatment: (1) Western medicine regimen: liver protection, diuresis, blood pressure reduction (metoprolol, etc.). (2) Traditional Chinese medicine packet application: Apply the lotus leaf packet described in Example 4 externally, with a treatment course of 14 days.

[0099] Therapeutic effect: ① Symptom improvement: Abdominal pain and distension disappeared, appetite and bowel movements returned to normal. ② Laboratory indicators: ALB increased from 30.0 g / L to 35.2 g / L, CRP decreased from 12.9 mg / L to 3.7 ng / L. ③ Imaging: The abdominal and thoracic cavity effusions were completely absorbed.

[0100] Case 5: Cai Mouju, female, 67 years old, was admitted to our hospital from the outpatient department on August 17, 2021.

[0101] Chief complaint: Liver cirrhosis for 14 years, right upper abdominal pain for 5 days. Western medicine diagnosis: decompensated stage of cryptogenic cirrhosis, spontaneous peritonitis, after liver cancer interventional treatment.

[0102] Traditional Chinese medicine diagnosis: liver accumulation (syndrome of dampness-heat in the liver and gallbladder).

[0103] Treatment: (1) Western medicine regimen: anti-infection (ceftazidime), liver protection (Shuganning). (2) Traditional Chinese medicine pack: Apply the lotus leaf pack described in Example 1 externally, with a treatment course of 14 days.

[0104] Efficacy: ① Symptom improvement: Abdominal pain disappeared, and abdominal distension and fatigue were significantly relieved. ② Laboratory indicators: CRP decreased from 51.2 ng / L to 3.5 ng / L, and TBIL decreased from 38.2 μmol / L to 26.5 μmol / L. ③ Ascites detection: The white blood cell count decreased from 1900×10 6 / L to 152×10 6 / L, and the effusion was absorbed.

[0105] The above-mentioned 5 patients from the First Affiliated Hospital of Henan University of Traditional Chinese Medicine all met the diagnostic criteria for liver cirrhosis complicated with spontaneous peritonitis. After treatment with the traditional Chinese medicine pack of the present invention combined with conventional treatment: ① Symptom remission rate was 100%: Symptoms such as abdominal pain and abdominal distension completely disappeared within 14 days.

[0106] ② Inflammation control was significant: Inflammatory markers such as CRP and PCT decreased by more than 85% on average.

[0107] ③ Ascites absorption was efficient: Imaging confirmed that the effusion was completely absorbed or reduced by ≥90%.

[0108] ④ Safety: No skin irritation, allergy or other adverse reactions were observed, and liver function indicators (ALT / AST) improved synchronously.

[0109] As can be seen from the above, the present invention significantly improves the clinical efficacy of liver cirrhosis complicated with SBP through the synergistic mechanism of "transdermal drug delivery - acupoint stimulation - multi-target pharmacodynamic effect", and has the advantages of rapid onset and safety.

[0110] Although some preferred embodiments of the present invention have been described, those skilled in the art can make additional changes and modifications to these embodiments once they know the basic creative concept. Therefore, the appended claims are intended to be construed to include the preferred embodiments as well as all changes and modifications falling within the scope of the present invention.

[0111] Obviously, those skilled in the art can make various changes and modifications to the present disclosure without departing from the spirit and scope of its inventive concept. Thus, if these modifications and variations to the present disclosure fall within the scope of the claims of this application and their equivalent technologies, this application also intends to include these modifications and variations.

Claims

1. A traditional Chinese medicine composition for treating cirrhotic spontaneous peritonitis, characterized in that, It is composed of the following raw medicinal materials in parts by weight: Kansui Radix Praeparata cum Vinegar 16 - 24 parts, Pharbitidis Semen 25 - 35 parts, Stephaniae Tetrandrae Radix 25 - 35 parts, Lepidii Semen or Descurainiae Semen 25 - 35 parts, Scutellariae Radix 12 - 18 parts, Coptidis Rhizoma 8 - 12 parts, Amomi Fructus Rotundus 12 - 18 parts, Rhei Radix et Rhizoma 18 - 23 parts, Aurantii Fructus Immaturus 18 - 23 parts, Natrii Sulfas 18 - 23 parts, Borneolum Syntheticum 8 - 12 parts.

2. The traditional Chinese medicine composition according to claim 1, wherein The weight ratio of the raw medicinal materials is as follows: Kansui Radix Praeparata cum Vinegar 18 - 22 parts, Pharbitidis Semen 27 - 33 parts, Stephaniae Tetrandrae Radix 27 - 33 parts, Lepidii Semen or Descurainiae Semen 27 - 33 parts, Scutellariae Radix 13 - 17 parts, Coptidis Rhizoma 9 - 11 parts, Amomi Fructus Rotundus 13 - 17 parts, Rhei Radix et Rhizoma 19 - 22 parts, Aurantii Fructus Immaturus 19 - 22 parts, Natrii Sulfas 19 - 22 parts, Borneolum Syntheticum 9 - 11 parts.

3. The traditional Chinese medicine composition according to claim 1, wherein The weight ratio of the raw medicinal materials is as follows: Kansui Radix Praeparata cum Vinegar 20 parts, Pharbitidis Semen 30 parts, Stephaniae Tetrandrae Radix 30 parts, Lepidii Semen or Descurainiae Semen 30 parts, Scutellariae Radix 15 parts, Coptidis Rhizoma 10 parts, Amomi Fructus Rotundus 15 parts, Rhei Radix et Rhizoma 20 parts, Aurantii Fructus Immaturus 20 parts, Natrii Sulfas 20 parts, Borneolum Syntheticum 10 parts.

4. A preparation method of a traditional Chinese medicine composition for treating liver cirrhosis complicated with spontaneous peritonitis, comprising the following steps: (1) Weigh each raw medicinal material according to the raw material ratio of any one of claims 1 - 3, grind them into powders respectively, and then pass through a sieve of 80 - 150 meshes; (2) Mix the sieved powders evenly, add honey to make a paste, divide and pack them into the outer packaging made of lotus leaves and seal. The weight of each finished product is 220 - 300 g.

5. The preparation method according to claim 4, characterized in that, The mesh number of the sieving in step (1) is 100 - 120 meshes.

6. The preparation method according to claim 4, wherein In step (2), the mass ratio of honey to medicinal powder is 1:3 - 1:5.

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