Use of metyrosine

Abstract

The present application relates to the technical field of new application of compositions, in particular to the application of Jia Ga Song decoction. The Jia Ga Song decoction can be applied in the preparation of medicines for treating fatty liver, especially medicines for treating drug-induced fatty liver. The Jia Ga Song decoction can effectively inhibit the uptake of fatty acids in the liver, reduce the accumulation of lipids in the liver, and then effectively relieve or even treat fatty liver, especially having excellent inhibitory effect on drug-induced accumulation of liver fat.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of new application of compositions, in particular, to the application of Jiamasong Decoction. BACKGROUND

[0002] Drug-induced fatty liver (DIFL) is a disease caused by abnormal accumulation of lipids in liver cells. Although the number of cases is only a relatively small part of all fatty liver cases, in the context of the synchronous rapid prevalence of metabolic diseases and obesity in today's society, due to the changes in the baseline lipid content in the liver cells of the body and the cytochrome p450 enzymes and drug transport proteins, the population is more susceptible to drugs that affect liver lipid homeostasis. If the drug that causes fatty liver cannot be stopped due to treatment reasons, and timely intervention is not made, repeated liver damage may develop into hepatitis and even cirrhosis.

[0003] At present, there are orlistat, L-carnitine, vitamin E, thiazolidinediones and fibrates, statin lipid-lowering drugs and the like on the market for the treatment of lipid disorders and DIFL, but their curative effects are not ideal, and they all have adverse reactions. The commonly used treatment drugs, such as vitamin E and thiazolidinediones, are mainly used for the treatment of early liver lipid accumulation, and achieve the effect by regulating lipid metabolism and the oxidation and utilization link of fatty acids. The commonly used treatment drugs have the following shortcomings: (1) the curative effect is not ideal; (2) they have adverse reactions such as causing bone loss, increasing the risk of bone fracture, and causing body weight gain due to redistribution of body fat; (3) the safety of some drugs such as vitamin E is questioned. In view of the above, the drugs for treating DIFL have not been widely promoted due to limited curative effect and safety problems. Early drug intervention for DIFL caused by inability to stop taking drugs is extremely important (untimely intervention may lead to more serious cirrhosis, etc.), so finding the pathogenesis of DIFL caused by valproic acid and its drugs is a research hotspot and an urgent problem to be solved in the context of the synchronous rapid prevalence of metabolic diseases and obesity in today's society, and has important clinical and social significance.

[0004] The Tibetan prescription Jiamasong Decoction is recorded in the Tibetan medical classic book Four Medical Classics written in the 8th century AD. Jiamasong Decoction is also known as Sanwei Ganjiang Powder, and its prescription is 300g of dried ginger, 200g of nutmeg and 250g of amomum.

[0005] It can be used for cold and long liver diseases, and has definite curative effect, and is included in the Ministry of Health Drug Standard Tibetan Volume. However, the prior art does not record its therapeutic effect on fatty liver, especially drug-induced fatty liver.

[0006] In view of this, the present application is proposed. SUMMARY

[0007] The application aims to provide an application of Jia Gusong decoction. The Jia Gusong decoction provided by the application can effectively inhibit the uptake of fatty acids in the liver, reduce the accumulation of lipids in the liver, and then effectively relieve or even treat fatty liver, especially having excellent inhibitory effect on drug-induced accumulation of lipids in the liver.

[0008] The application is implemented in the following manner:

[0009] In a first aspect, the application provides an application of Jia Gusong decoction in the preparation of a medicine for treating fatty liver.

[0010] In an optional embodiment, the fatty liver is drug-induced fatty liver.

[0011] Preferably, the fatty liver is drug-induced fatty liver caused by antiepileptic drugs.

[0012] Preferably, the fatty liver is drug-induced fatty liver caused by valproic acid.

[0013] In an optional embodiment, the medicine is a medicine for reducing the uptake of lipids in the liver.

[0014] In a second aspect, the application provides an application of Jia Gusong decoction in the preparation of a medicine for improving lipid disorder in the liver.

[0015] In an optional embodiment, the lipid disorder in the liver is a disorder caused by excessive uptake of lipids.

[0016] In a third aspect, the application provides an application of Jia Gusong decoction in the preparation of a medicine for reducing the uptake of lipids in the liver.

[0017] In a fourth aspect, the application provides an application of Jia Gusong decoction in the preparation of a medicine for treating accumulation of lipids in the liver.

[0018] In an optional embodiment, the accumulation of lipids in the liver is accumulation of lipids in the liver caused by antiepileptic drugs.

[0019] Preferably, the accumulation of lipids in the liver is accumulation of lipids in the liver caused by valproic acid.

[0020] In a fifth aspect, the application provides an application of at least one of the following nine compounds in the preparation of a medicine for treating fatty liver.

[0021] 6-gingerol, 8-gingerol, 10-gingerol, 6-shogaol, 10-shogaol, eucalyptol, beta-caryophyllene, dehydrodiisoeugenol, and zingerone.

[0022] In an optional embodiment, the nine compounds are all derived from Jia Gusong decoction.

[0023] Preferably, the fatty liver is drug-induced fatty liver.

[0024] Preferably, the fatty liver is drug-induced fatty liver caused by antiepileptic drugs.

[0025] Preferably, the fatty liver is drug-induced fatty liver caused by valproic acid.

[0026] The drug is a drug for reducing liver lipid uptake.

[0027] The present application has the following beneficial effects: the Jia Gusong decoction and active ingredients thereof provided by the present application can effectively reduce liver lipid uptake, thereby reducing liver lipid accumulation, and have certain curative effects on fatty liver, in particular, excellent curative effects on drug-induced fatty liver. BRIEF DESCRIPTION OF DRAWINGS

[0028] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings needed in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present application, and therefore should not be considered as limiting the scope. For those skilled in the art, other related drawings can also be obtained without creative labor on the basis of these drawings.

[0029] Figure 1 The figure shows the results of triglyceride content in serum (left) and liver tissue (right) provided for Experimental Example 1 of the present application;

[0030] Figure 2 The figure shows the results of liver enzyme ALT (left) and AST (middle) content in serum and ALP content in liver tissue (right) provided for Experimental Example 1 of the present application;

[0031] Figure 3 The figure shows the pathological changes of mouse liver provided for Experimental Example 1 of the present application (n=6);

[0032] Figure 4 The figure shows the results of triglyceride content in serum (left) and liver (right) provided for Experimental Example 2 of the present application;

[0033] Figure 5 The figure shows the results of liver ALP content provided for Experimental Example 2 of the present application;

[0034] Figure 6 The figure shows the results of the improvement of JGST on pathological damage of mice with liver lipid metabolism disorder caused by VPA provided for Experimental Example 2 of the present application (n=6);

[0035] Figure 7 The figure shows the results of TG content in serum (left) and liver (right) provided for Experimental Example 3 of the present application;

[0036] Figure 8The results chart of the activity of liver function enzymes ALT (left), AST (middle) in serum and the content of ALP (right) in liver tissue provided for the experimental example 3 of the present application;

[0037] Figure 9 The TG test results chart provided for the experimental example 4 of the present application;

[0038] Figure 10 The MDA test results chart provided for the experimental example 4 of the present application;

[0039] Figure 11 The test results chart of ALT and AST provided for the experimental example 4 of the present application. DETAILED DESCRIPTION

[0040] In order to make the purpose, technical scheme and advantages of the embodiments of the present application more clear, the technical scheme in the embodiments of the present application will be described clearly and completely below. If the specific conditions are not indicated in the embodiments, the conventional conditions or the conditions suggested by the manufacturers are adopted. If the manufacturers of the reagents or instruments are not indicated, the conventional products that can be purchased in the market are adopted.

[0041] The present application provides a new application of Jiagasong decoction, which has certain curative effect on fatty liver, especially low drug-induced fatty liver, which is caused by anti-epileptic drugs, such as valproic acid-induced drug-induced fatty liver.

[0042] Valproic acid (VPA) is a first-line drug for treating epilepsy at present. Although its effectiveness and safety have been widely verified in clinical practice, studies have shown that VPA can cause anorexia, drowsiness, diarrhea, constipation, weight changes, liver toxicity and other adverse reactions, among which liver toxicity is the most attention clinical adverse reaction. And through the search of information, it is found that about 61% of the patients with epilepsy who receive long-term VPA treatment will cause DIFL, therefore, a kind of drug is needed to relieve or treat drug-induced fatty liver caused by VPA.

[0043] And the inventors found that Jiagasong decoction can reduce liver lipid uptake, and then reduce or avoid liver lipid accumulation, and then has good therapeutic effect on drug-induced fatty liver.

[0044] Further, the inventors further studied the active ingredients of Jiagasong decoction and found that 9 kinds of active ingredients such as 6-gingerol, 8-gingerol, 10-gingerol, 6-shogaol, 10-shogaol, eucalyptol, β-caryophyllene, dehydrodiisoeugenol and zingerone can also reduce liver lipid uptake, and then reduce or avoid liver lipid accumulation, and then have good therapeutic effect on drug-induced fatty liver.

[0045] The features and properties of the present application will be further described in detail below in combination with the embodiments.

[0046] Experimental Example 1 - Animal Model Building

[0047] Male C57 mice were divided into control group, 250mg / kg VPA group, 500mg / kg VPA group. The experimental group mice were given 25mg / mL or 50mg / mL VPA aqueous solution by gavage every day, and the control group was given the same volume of normal saline (0.1mL / 10g), for 15 consecutive days. The activities of serum liver enzymes ALT and AST, ALP in liver tissue, and the contents of TG in serum and liver were detected by biochemical kits, the pathological changes of liver were observed by HE staining, and the liver lipid deposition was observed by oil red O staining.

[0048] Results are shown in Figure 1 , Figure 2 and Figure 3 . Among them, Figure 1 represents the results of triglyceride content in serum (left) and liver tissue (right); Figure 2 represents the results of liver enzymes ALT (left) and AST (middle) in serum and ALP in liver tissue (right); Figure 3 represents the pathological changes of mouse liver (n=6), where liver oil red O staining; Control normal saline control group, VPA 250mg / kg valproic acid 250mg / kg treatment group, VPA 500mg / kg valproic acid 500mg / kg treatment group; magnification 400x.

[0049] According to Figure 1 and Figure 2 , after 15 days of modeling of two concentrations of VPA (250 and 500mg / kg), there was no significant difference in serum liver enzymes ALT and AST, and the contents of ALP in liver tissue, TG in serum and liver were significantly increased (P<0.05). The results are consistent with the literature reports, suggesting that after 15 days of treatment with these two concentrations of VPA, the liver lipid accumulation of mice increased, and the liver was damaged to a certain extent. According to Figure 3 the results of oil red O staining also showed that liver steatosis (red area in Figure 3 is lipid droplet) occurred in both VPA treatment groups.

[0050] Experimental Example 2 - Improving effect of methotrexate soup on VPA-induced liver lipid metabolism disorder

[0051] Male C57 mice were randomly divided into control group (Control), 500 mg / kg VPA model group (Model), compound glycyrrhizin tablet positive drug group (Compound glycyrrhizin, CG), 165 mg / kg Jiagamotang low-dose group (JGST-L), 330 mg / kg Jiagamotang medium-dose group (JGST-M), and 660 mg / kg Jiagamotang high-dose group (JGST-H). Daily modeling administration, for 15 consecutive days. The activities of serum liver enzymes ALT and AST, ALP in liver tissue, and the contents of TG in serum and liver were detected by biochemical kits, and the liver lipid deposition was observed by oil red O staining.

[0052] Results are shown in Figure 4 , Figure 5 and Figure 6 . Among them, Figure 4 indicates the results of triglyceride content in serum (left) and liver (right) of the administration group; Figure 5 indicates the results of liver ALP content; Figure 6 indicates the results of the improvement of JGST on pathological damage of VPA-induced liver lipid metabolism disorder mice (n=6).

[0053] According to Figure 4 and Figure 5 , compared with the control group, the ALP content in the liver tissue of the model group was extremely significantly increased (P<0.001), and showed a downward trend after administration, among which the high-dose group of JGST was significantly reduced (P<0.05). Compared with the control group, the contents of triglyceride in serum and liver of the model group were extremely significantly increased (P<0.001), and the contents of triglyceride in serum and liver of the administration group were significantly reduced (P<0.01 or P<0.001). It is shown that JGST has an improvement effect on VPA-induced liver lipid metabolism disorder and damage. According to Figure 6 The results of oil red O staining showed that the liver of the model group appeared fatty degeneration, and the accumulation of lipid droplets in the liver was significantly reduced after administration. The results show that JGST can improve the fatty degeneration of the liver caused by VPA.

[0054] Preparation of the above-mentioned compound glycyrrhizin tablet Jiagamotang

[0055] Preparation of JGST

[0056] Dry ginger, bean curd and nutmeg are ground into a 100-mesh sieve and stored in a dry jar for later use. Before use, mix according to the weight ratio of dry ginger: bean curd: nutmeg = 6:5:4, add distilled water and boil for 10 min to prepare a suspension of 66 mg / mL (high dose), 33 mg / mL (medium dose) and 16.5 mg / mL (low dose).

[0057] Preparation of compound glycyrrhizin tablet solution

[0058] Take one piece of compound glycyrrhizin tablet (Leep Pharmaceutical Co., Ltd.) and dissolve it in 7.326 mL of distilled water. Prepare a suspension containing 3.14 mg of ammonium glycyrrhizinate, 3.14 mg of glycine, and 3.14 mg of methionine per mL.

[0059] Experimental Example 3

[0060] SPF C57BL / 6 male mice were divided into a control group and an epilepsy group. The mice in the epilepsy group were injected intraperitoneally with kainic acid (dissolved in normal saline, 20 mg / kg), and the mice in the control group were injected with the same amount of normal saline. Within 14 days after the action of kainic acid, the mice were scored according to the racine classification at the same time every day.

[0061] The mice in the epilepsy group that successfully induced epilepsy and were scored as grade III or above were used for subsequent experiments and were randomly divided into an epilepsy + valproic acid group (500 mg / kg), an epilepsy + valproic acid + Jiagasong decoction low-dose group (165 mg / kg), an epilepsy + valproic acid + Jiagasong decoction medium-dose group (330 mg / kg), an epilepsy + valproic acid + Jiagasong decoction high-dose group (660 mg / kg), and an epilepsy + valproic acid + positive drug pioglitazone group (5 mg / kg). The Jiagasong decoction group and the pioglitazone group were given corresponding drugs by gavage, and the other groups were given the same amount of normal saline. Two hours after administration, valproic acid was given by gavage for treatment, and the control group and the epilepsy group were given the same amount of normal saline. Continuous administration was performed for 21 days, and samples were taken 4 hours after the last administration for detection of the corresponding indicators.

[0062] The results are shown in Figure 7 and Figure 8 . Among them, Figure 7 indicates the results of the TG content in the serum (left) and liver (right); Figure 8 indicates the results of the activity of liver enzymes ALT (left) and AST (middle) in the serum and the content of ALP (right) in the liver tissue.

[0063] According to Figure 7 and Figure 8 , the inventors found that the Jiagasong decoction can significantly improve the liver lipid accumulation and damage caused by VPA by detecting the activity of liver enzymes ALT and AST in the serum, the content of ALP in the liver tissue, and the content of TG in the serum and liver using biochemical kits, indicating that the Jiagasong decoction can alleviate liver lipid accumulation and has a certain effect on drug-induced fatty liver.

[0064] Experimental Example 4

[0065] By consulting the literature, the effective components of Jiagameng decoction which have not been confirmed yet, 6-gingerol, 8-gingerol, 10-gingerol, 6-shogaol, 10-shogaol, eucalyptol, β-caryophyllene, dehydrodiisoeugenol, zingerone, were screened out for research. The inventors conducted CCK8 test on the above active components to obtain the safe dosing range of each active component. Then, within the safe dosing range, a concentration gradient was set, and the VPA-modeled hepatocytes were dosed for 24 hours, after which the biochemical kit was used to detect the content of TG and MDA in the cells, and the components with good effects were selected to measure the activity of ALT and AST to observe the effect of the effective components of Jiagameng decoction on VPA-modeled hepatocytes.

[0066] Specifically, the concentration of each active component is set as follows:

[0067] blank, model (VPA: 15MM), 6-gingerol (6.25um, 12.5um, 25um), dehydrodiisoeugenol (5um, 10um, 20um), 6-shogaol (5um, 10um, 20um), zingerone (2.5um, 5um, 10um), 10-shogaol (3.125um, 6.25um, 12.5um), eucalyptol (2.5um, 5um, 10mm), B-caryophyllene (0.625um, 1.25um, 2.5um), 8-gingerol (3.75um, 7.5um, 15um), 10-gingerol (5um, 10um, 20um).

[0068] The results are shown in Figure 9 , Figure 10 and Figure 11 , wherein, Figure 9 represents the TG test result graph; Figure 10 represents the MDA test result graph; Figure 11 represents the ALT and AST test result graph.

[0069] According to Figure 9 and Figure 10 , the effective components of Jiagameng decoction, through the detection results of TG and MDA, we found that 6-gingerol, dehydrodiisoeugenol, 6-shogaol, zingerone, and 10-shogaol can more significantly improve the condition of liver lipid disorder caused by VPA at appropriate dosing concentrations. Therefore, we selected these components to further detect the activity of ALT and AST, and according to Figure 11 we found that they can indeed improve the condition of liver damage well.

[0070] The above merely provides the preferred embodiments of the present application, and is not used to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modifications, equivalent replacements, improvements, etc. made within the principles and technical scope of the present application shall fall into the scope of the present application.

Claims

1. Use of metagabene in the preparation of a medicament for treating fatty liver, characterized in that, The fatty liver is drug-induced fatty liver caused by valproic acid. ​ 2. Use according to claim 1, characterized in that, The active ingredient of the drug for treating fatty liver includes at least one of the following 9 compounds: 6-gingerol, 8-gingerol, 10-gingerol, 6-shogaol, 10-shogaol, eucalyptol, β-caryophyllene, dehydrodiisoeugenol and zingerone.

Images