Application of rheum officinale composition in preparation of medicine for treating, relieving or preventing non-alcoholic steatohepatitis hepatic fibrosis

Abstract

The invention belongs to the technical field of new application of medicines, and particularly relates to application of a Chinese rhubarb # imgabs0 # insect composition in preparation of medicines for treating, relieving or preventing non-alcoholic steatohepatitis hepatic fibrosis. According to the application of the Chinese rhubarb # imgabs1 # composition in preparing the medicine for treating, relieving or preventing the non-alcoholic steatohepatitis hepatic fibrosis, the Chinese rhubarb # imgabs2 # composition has the effects of removing blood stasis and promoting tissue regeneration and is mainly used for treating the symptoms of deficiency of five consumptions and internal stagnation of dry blood; the traditional Chinese medicine composition has the effects of slimming body, hypogalactia and spasm, abdominal pain and refusal to press, or non-reduction in press, abdominal fullness and less food intake, skin onychomycosis, dull eyes, dark orbits, ecchymosis on tongues, and astringent or slender pulse. The pharmacodynamic study of the Chinese rhubarb # imgabs3 # worm pill for treating the non-alcoholic steatohepatitis hepatic fibrosis is carried out, and the result shows that the Chinese rhubarb # imgabs4 # worm pill can reduce the liver visceral organ coefficient, the serum biochemical index and the hepatic fibrosis index of a non-alcoholic steatohepatitis hepatic fibrosis model mouse and improve the pathological change of the liver tissue, so that the Chinese rhubarb # imgabs3 # worm pill can be used for treating the non-alcoholic steatohepatitis hepatic fibrosis. The traditional Chinese medicine composition has an obvious treatment effect on non-alcoholic steatohepatitis hepatic fibrosis.

Description

Technical Field

[0001] The invention belongs to the technical field of new drug uses, and specifically relates to rhubarb Application of the insect composition in the preparation of a drug for treating, alleviating or preventing non-alcoholic fatty liver inflammatory liver fibrosis. Background Art

[0002] In the absence of excessive drinking, imaging or histology showing liver fibrosis of more than 5% is diagnosed as non-alcoholic fatty liver disease (NAFLD), including simple fatty degeneration, non-alcoholic steatohepatitis (NASH) and its related liver fibrosis and cirrhosis, which has become the main cause of chronic liver disease in adults. The global prevalence of NAFLD is 25%, and the prevalence of NASH in NAFLD patients is 59.10%, and the prevalence is increasing year by year. About 40% of patients may develop liver fibrosis and cirrhosis.

[0003] The current NASH population is very large, and it will inevitably lead to a high incidence of liver fibrosis and cirrhosis in a few decades. Long-term follow-up studies have confirmed that liver fibrosis is the most important predictive indicator affecting the prognosis of NAFLD, and it is also a key link in determining the prognosis of patients. However, since the pathogenesis of NASH liver fibrosis is not yet completely clear, the research and development of targeted drugs by major pharmaceutical companies around the world are mostly in the clinical trial stage, and no effective drugs have been approved by the FDA. Therefore, there is a great practical need to develop drugs to treat NASH liver fibrosis. Summary of the invention

[0004] Therefore, the technical problem to be solved by the present invention is to develop a drug for treating NASH liver fibrosis, thereby providing rhubarb Application of the insect composition in the preparation of a drug for treating, alleviating or preventing non-alcoholic fatty liver inflammatory liver fibrosis.

[0005] To this end, the present invention provides the following technical solutions.

[0006] In the treatment of NASH liver fibrosis, the current clinically recommended treatment plan is to change the lifestyle, such as improving the diet structure and work and rest time, and appropriately increase exercise, supplemented by drug treatment, such as insulin sensitizers, lipid-lowering drugs, antioxidants, etc. Western medicine has a single ingredient and clear targets. For complex metabolic diseases such as NASH liver fibrosis, it can often only improve some indicators and also produce some adverse reactions, such as increased serum transaminase, gastrointestinal discomfort, and increased liver burden. Traditional Chinese medicine has multi-target comprehensive treatment and has potential advantages.

[0007] According to clinical symptoms, NASH liver fibrosis is classified as "symptoms and masses", "dampness obstruction", "fullness", "flank pain", "liver problems" and other categories in traditional Chinese medicine. Non-alcoholic fatty liver fibrosis is mostly caused by overeating fatty and sweet foods, or emotional frustration, or long-term illness and physical weakness, which leads to liver failure, spleen failure, kidney essence deficiency, and accumulation of dampness, phlegm, and blood stasis. Clinically, it can be divided into qi stagnation and blood stasis type, spleen deficiency and phlegm dampness type, liver and kidney deficiency type and dampness and heat accumulation type, which can be treated by promoting blood circulation and regulating qi, strengthening the spleen and removing phlegm, clearing heat and removing dampness.

[0008] rhubarb Chongwan is a famous prescription in the Golden Chamber by Zhang Zhongjing, a famous doctor in the Eastern Han Dynasty. It is made of rhubarb, It is composed of twelve Chinese medicinal herbs, including insects, leeches, horseflies, peach kernels, dried lacquer, white peony, and licorice. In the formula, rhubarb and peach kernels can relieve diarrhea and heat, promote blood circulation and dissolve blood; rehmannia can nourish blood and yin; white peony can nourish blood and soften the liver, clear away heat and nourish yin; rhubarb and other herbs can clear away heat and reduce inflammation; insect herbs can promote blood circulation, soften and disperse nodules, and move into the collaterals; licorice can harmonize the herbs. The combination of the herbs can nourish the kidney and replenish qi, promote blood circulation and dissolve blood stasis, soften and disperse nodules, and clear away dampness, heat and detoxify. From the perspective of its formula, it has both attack and supplement, and the strong pills are taken, which is intended to slow down the attack, so as to achieve the effect of strengthening the body without leaving blood stasis, and removing blood stasis without hurting the body.

[0009] Clinical trials have found that rhubarb Chongwan can treat liver diseases such as chronic hepatitis B liver fibrosis and cirrhosis, primary liver cancer, hepatic encephalopathy and cirrhosis ascites, fatty liver disease or combined with other diseases, alcoholic liver fibrosis, etc. through different mechanisms and effects. It has good efficacy and is widely used in liver diseases. This drug has good effects in lowering blood lipids, improving liver function, inhibiting liver fibrosis, and resisting lipid peroxidation. A comprehensive analysis of rhubarb was conducted through drug formula analysis, functional indications and modern pharmacodynamics research. Chongwan has potential therapeutic effect on non-alcoholic fatty liver inflammatory liver fibrosis.

[0010] The first aspect of the present invention provides rhubarb Application of the insect composition in the preparation of a drug for treating non-alcoholic fatty liver inflammatory liver fibrosis.

[0011] The second aspect of the present invention provides rhubarb Application of an insect composition in the preparation of a drug for alleviating non-alcoholic fatty liver inflammatory liver fibrosis.

[0012] The third aspect of the present invention provides rhubarb Application of the insect composition in the preparation of a drug for preventing non-alcoholic fatty liver inflammatory liver fibrosis.

[0013] The fourth aspect of the present invention provides rhubarb The invention discloses an application of the insect composition in preparing a medicine capable of reducing serum ALT, liver organ coefficient, ColⅣ, HPCⅢ, HA and LN.

[0014] The medicament further includes a pharmaceutically acceptable excipient or carrier.

[0015] The form of the pharmaceutical preparation includes pharmaceutically acceptable preparations;

[0016] Preferably, the dosage form includes tablets, pills, capsules, powders, drops, lyophilisates, granules, suspensions, syrups or oral solutions.

[0017] Rhubarb The raw materials of the insect composition include: cooked rhubarb, earthworm, leech, horsefly, grub, dry lacquer, peach kernel, fried bitter almond, scutellaria, rehmannia root, white peony root and liquorice.

[0018] Rhubarb The raw materials of the insect composition include: 300g by weight of cooked rhubarb, 30g by weight of earthworm, 60g by weight of leech, 45g by weight of horsefly, 45g by weight of white grub, 30g by weight of dry lacquer, 120g by weight of peach kernel, 120g by weight of fried bitter almond, 60g by weight of scutellaria, 300g by weight of rehmannia, 120g by weight of white peony root and 90g by weight of liquorice.

[0019] rhubarb When the insect composition is used in the treatment, alleviation or prevention of non-alcoholic fatty liver inflammatory liver fibrosis, in pill form, rhubarb The dosage of worm pills is: 1 to 2 pills at a time, 1 to 2 times a day.

[0020] The technical solution of the present invention has the following advantages:

[0021] The rhubarb provided by the present invention Application of insect composition in the preparation of medicine for treating, alleviating or preventing non-alcoholic fatty liver inflammatory liver fibrosis, rhubarb Rhubarb has the effect of removing blood stasis and promoting new blood, and is mainly used to treat extreme weakness caused by five kinds of labor, dry blood stagnation syndrome; thin body, lower abdominal cramps, abdominal pain that refuses to be pressed, or does not reduce after pressing, abdominal distension and poor appetite, skin and nails, dull eyes, dark eye sockets, ecchymosis on the tongue, and deep and astringent or stringy pulse. The pharmacodynamic study of Chongwan in treating nonalcoholic fatty liver inflammatory fibrosis showed that rhubarb The Chongwan pill has a good effect of reducing the liver organ coefficient, serum biochemical indexes, liver fibrosis indexes, and improving liver tissue pathological changes in mice with non-alcoholic fatty liver inflammatory fibrosis, and has a significant therapeutic effect on non-alcoholic fatty liver inflammatory fibrosis. The present invention establishes a simple, stable and reliable non-alcoholic fatty liver inflammatory fibrosis mouse model, and clarifies the role of rhubarb in the treatment of non-alcoholic fatty liver inflammatory fibrosis. The therapeutic effects and characteristics of the insect compound have expanded the application of rhubarb The new use of the insect composition provides new therapeutic drugs and means for the intervention and treatment of non-alcoholic fatty liver inflammatory liver fibrosis, and provides technical support for the rational use of drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0023] Figure 1 The cell morphology of the samples in each experimental group of Example 1 of the present invention under a high-power microscope after HE staining, HE×200; wherein a is the blank group, b is the model group, and c is the rhubarb group Chongwan high dose group, d is rhubarb The medium dose group of Chongwan, e is rhubarb The low-dose group of insect pills;

[0024] Figure 2 The fiber deposition of the samples in each experimental group of Example 1 of the present invention after Masson staining under a high-power microscope, Masson × 200; a is the blank group, b is the model group, and c is the rhubarb group. Chongwan high dose group, d is rhubarb The medium dose group of Chongwan, e is rhubarb Low-dose group of Chongwan. DETAILED DESCRIPTION

[0025] The following examples are provided for a better understanding of the present invention, but are not intended to limit the best mode of implementation, nor to limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.

[0026] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the field can be used. If no manufacturer is specified for the reagents or instruments used, they are all conventional reagent products that can be obtained commercially.

[0027] Example 1

[0028] This embodiment provides rhubarb Application of Chongwan in preparing medicine for treating, alleviating and preventing non-alcoholic fatty liver inflammatory liver fibrosis.

[0029] 1.1 Establishment of animal model

[0030] 1.1.1 The non-alcoholic fatty liver inflammatory liver fibrosis mouse model was established by feeding the mouse with a high-fat diet produced by Deci Biotechnology (Wuxi) Co., Ltd. The therapeutic effect of Chongwan on nonalcoholic fatty liver inflammatory fibrosis.

[0031] Model experiment: C57BL / 6J male mice (SPF grade, weight 18-20g) were randomly divided into 5 groups after adaptive feeding: blank group, model group, rhubarb group There were 5 experimental groups with high, medium and low doses of Chongwan pills, and 12 mice in each group. Except for the blank group, the mice in other groups were fed high-fat diet every day to replicate the non-alcoholic fatty liver disease mouse model. The high, medium and low dose groups of Chongwan were given corresponding doses of rhubarb by gavage The model was established with the drug of worm pills for 6 weeks. The mice in the blank group were given ordinary maintenance feed (manufactured by Beijing Keao Xieli Feed Co., Ltd.) and drinking water. The mice in the model group did not take rhubarb. Insect pills. Among them, rhubarb The dosage of the high-, medium-, and low-dose groups of the insect pills was shown in Table 1, and the medication was administered once a day. During the establishment of the animal model, the mice were free to eat and drink water.

[0032] 1.1.2 Index determination method:

[0033] (1) One hour after the last dose, blood was collected from the inferior vena cava under anesthesia, and serum was collected by centrifugation to measure ALT and AST;

[0034] (2) Remove the mouse liver, weigh it, and calculate the mouse liver organ coefficient;

[0035] (3) A portion of the liver lobe was fixed in 4% paraformaldehyde, sliced, and then stained with Masson and HE to observe the degree of liver fibrosis and morphological changes of liver cells in mice;

[0036] (4) Determine the expression levels of liver fibrosis indicators such as ColⅣ, HPCⅢ, HA, and LN in liver tissue, and evaluate the effects of drugs on the liver fibrosis level of model mice.

[0037] 1.2 Experimental Results

[0038] 1.2.1 Liver organ coefficient

[0039] Table 1 shows the liver organ coefficients of mice in each experimental group. After the model group mice were fed with a high-fat diet, the liver organ coefficient increased significantly, which was significantly different from the blank group (p<0.01), indicating that the liver of mice was damaged after being fed with a high-fat diet. The liver organ coefficient of mice in the Chongwan group was significantly reduced, which was significantly different from that in the model group (all p<0.01), indicating that the drug had a significant improvement effect on the increased liver organ coefficient of model mice.

[0040] Table 1 Liver organ coefficients of mice in each experimental group

[0041]

[0042] Note: Compared with the model group: *P<0.01.

[0043] 1.2.2 Serum ALT and AST indicators

[0044] Table 2 shows the results of serum ALT and AST of mice in each experimental group. The serum ALT and AST of mice in the model group were significantly increased, and there was a significant difference compared with the blank group (all p<0.01), indicating that the mice in the model group had obvious liver damage. The serum ALT levels of mice in the high, medium and low dose groups of Chongwan were significantly reduced, and there were significant differences compared with the model group (p<0.05, p<0.05, p<0.01, respectively). Although there was no significant difference in serum AST levels between the high, medium and low dose groups of Chongwan and the model group (all p>0.05), there was a downward trend. Chongwan has a significant effect on improving the liver function of non-alcoholic hepatitis model mice.

[0045] Table 2 Serum ALT and AST indexes of mice in each experimental group

[0046] Note: Compared with the model group: *P<0.05; **P<0.01.

[0047] 1.2.3 Liver histopathology

[0048] HE staining: Figure 1 The cell morphology of the samples in each experimental group under a high-power microscope after HE staining. The results showed that the liver tissue of the mice in the model group was damaged, the liver lobule structure was unclear, the liver sinusoids were narrow, obvious vacuoles were seen in a large number of hepatocytes, the hepatocyte nuclei were squeezed to one side, some hepatocytes were dissolved, interstitial inflammatory cells infiltrated, cell necrosis and hepatocyte ballooning were seen, and the NAS score was significantly increased. The high and medium dose groups of Chongwan had a certain effect on relieving liver inflammatory cell infiltration, and the NAS score was significantly reduced. The worm pill has a certain protective effect on animal liver damage caused by the experimental conditions, mainly manifested in the inhibition of inflammatory cell infiltration. The worm pill has a certain protective effect on animal liver damage and a certain relief effect on liver inflammatory cell infiltration, especially when rhubarb The effect is more significant when the insect pills are taken in high or medium doses.

[0049] Masson staining: Figure 2 The results show that the fibrosis positive rate of liver samples in the model group increased, and the liver had obvious fibrosis. The high, medium and low dose groups of Chongwan Pills can significantly reduce the positive rate of liver fibrosis in model mice and improve the degree of inflammatory liver fibrosis in non-alcoholic fatty liver disease.

[0050] 1.2.4 Effects of ColⅣ, HPCⅢ, HA, and LN expression in liver tissue

[0051] Table 3 shows the effects of ColⅣ, HPCⅢ, HA, and LN expression in the liver tissue of mice in each experimental group. The expression levels of ColⅣ, HPCⅢ, HA, and LN in the liver tissue of mice in the model group were significantly increased, and there were significant differences compared with the blank group (all p<0.01), indicating that there was collagen deposition in the liver tissue of mice in the model group. The expression levels of ColⅣ and HA in the liver tissue of mice in the high, medium and low dose groups of Chongwan were significantly reduced, which was significantly different from that in the model group (all p<0.01); The expression level of LN in the liver tissue of mice in the high, medium and low dose groups of Chongwan was significantly reduced, which was significantly different from that in the model group (p<0.05, p<0.01, p<0.05, respectively); especially The expression level of HPCⅢ in the liver tissue of mice in the medium-dose Chongwan group was significantly reduced, and there was a significant difference compared with the model group (p<0.01). Chongwan can significantly inhibit liver collagen deposition and improve liver fibrosis.

[0052] Table 3 Expression of ColⅣ, HPCⅢ, HA and LN in liver tissue of mice in each experimental group

[0053]

[0054] Note: Compared with the model group: *P<0.05; **P<0.01.

[0055] The above results show that rhubarb The insect composition has a good effect of reducing the liver organ coefficient, serum biochemical indexes, liver fibrosis indexes and improving liver tissue pathological changes in mice with non-alcoholic fatty liver inflammatory fibrosis model, and has a significant therapeutic effect on non-alcoholic fatty liver inflammatory fibrosis.

[0056] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the scope of protection of the invention.

Claims

1. Rhubarb Application of the insect composition in the preparation of a drug for treating non-alcoholic fatty liver inflammatory liver fibrosis.

2. Rhubarb Application of an insect composition in the preparation of a drug for alleviating non-alcoholic fatty liver inflammatory liver fibrosis.

3. Rhubarb Application of the insect composition in the preparation of a drug for preventing non-alcoholic fatty liver inflammatory liver fibrosis.

4. Rhubarb The invention discloses an application of the insect composition in preparing a medicine capable of reducing serum ALT, liver organ coefficient, ColⅣ, HPCⅢ, HA and LN.

5. The use according to any one of claims 1 to 4, characterized in that: The medicament further includes a pharmaceutically acceptable excipient or carrier.

6. The use according to any one of claims 1 to 5, characterized in that: The form of the pharmaceutical preparation includes pharmaceutically acceptable preparations; Preferably, the dosage form includes tablets, pills, capsules, powders, drops, lyophilisates, granules, suspensions, syrups or oral solutions.

7. The use according to any one of claims 1 to 6, characterized in that: Rhubarb The raw materials of the insect composition include: cooked rhubarb, earthworm, leech, horsefly, grub, dry lacquer, peach kernel, fried bitter almond, scutellaria, rehmannia root, white peony root and liquorice.

8. The use according to claim 7, characterized in that: Rhubarb The raw materials of the insect composition include: 300g by weight of cooked rhubarb, 30g by weight of earthworm, 60g by weight of leech, 45g by weight of horsefly, 45g by weight of white grub, 30g by weight of dry lacquer, 120g by weight of peach kernel, 120g by weight of fried bitter almond, 60g by weight of scutellaria, 300g by weight of rehmannia, 120g by weight of white peony root and 90g by weight of liquorice.

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