A composition containing clausenamide and its application in preparing a medicine for treating liver damage

Abstract

The present invention relates to the field of biomedicine and specifically discloses a composition containing clausenamide and its use in preparing a medicament for treating liver damage. The clausenamide-containing composition comprises clausenamide and an active compound; the active compound is selected from ergolactone and / or isosaxifragine. Studies have shown that the composition has an effect on resisting alcoholic liver damage and, in addition, an effect on resisting hepatitis B virus. Therefore, using the composition of the present invention as an active ingredient in preparing a medicament for treating liver damage and a medicament for resisting hepatitis B virus has important application value.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a composition containing clausenamide and application thereof in preparing a medicine for treating liver damage. Background Art

[0002] The liver is the largest solid organ in the abdominal cavity and is responsible for important physiological functions of the human body. Liver injury refers to damage to the liver by various factors, resulting in abnormalities in its structure and function. Common liver injuries include drug-induced liver injury and alcoholic liver injury. The liver is the main metabolic organ of alcohol. It first metabolizes alcohol into acetaldehyde, then further metabolizes it into acetic acid, and finally metabolizes it into carbon dioxide and water, thus completing the metabolism of alcohol. However, excessive drinking or long-term alcoholism will increase the metabolic burden of the liver, thereby causing liver damage. If alcoholic liver injury is not treated, it will eventually be accompanied by cirrhosis, liver cancer, and viral hepatitis. Therefore, providing a drug for the treatment of alcoholic liver injury has important application value.

[0003] Clausinamide is a known compound isolated from the leaves of the Rutaceae plant, with the CAS number 103541-15-7. While prior art reports suggest its potential for treating drug-induced liver injury, its potential for treating alcoholic liver injury remains unknown, warranting further research. Summary of the Invention

[0004] In order to overcome at least one of the technical problems existing in the prior art, the present invention provides a composition containing clausenil and its use in preparing a medicament for treating liver damage.

[0005] The technical solutions of the present invention are as follows:

[0006] The present invention first provides a clausenamide-containing composition, which comprises clausenamide and an active compound; the active compound is selected from ergolactone and / or isosaxifen.

[0007] The inventors discovered that the combination of clausenamide and ergolactone resulted in a significantly enhanced anti-liver injury effect compared to clausenamide alone. The combination of clausenamide and isosaxifen also resulted in an enhanced anti-liver injury effect compared to clausenamide alone; however, the enhanced effect was not as significant as that of the combination of clausenamide and ergolactone.

[0008] The inventors further discovered that the composition obtained by combining clausenil with ergolactone or isosaxifen also has anti-HBV activity. Furthermore, the anti-HBV activity of the composition obtained by combining clausenil with isosaxifen is significantly higher than that of the composition obtained by combining clausenil with ergolactone.

[0009] Preferably, the mass ratio of clausenamide to the active compound is 1-5:1-5.

[0010] More preferably, the mass ratio of clausenamide to the active compound is 1-3:1-3.

[0011] Most preferably, the mass ratio of clausenamide to the active compound is 2:3.

[0012] Preferably, the composition comprises clausenil as well as ergolactone and isosaxifen.

[0013] In further research, the inventors found that the anti-liver damage effect of the composition consisting of clausenamide, ergolide and isosaxifen is much higher than that of clausenamide alone; it is also significantly higher than the composition obtained by combining clausenamide with ergolide and the composition obtained by combining clausenamide with isosaxifen. This may be the result that the combination of clausenamide, ergolide and isosaxifen can produce a synergistic anti-liver damage effect.

[0014] In addition, the inventors also found that the anti-hepatitis B virus effect of the composition consisting of clausenil, ergolide and isosaxifen is much higher than that of the composition obtained by combining clausenil and ergolide and the composition obtained by combining clausenil and isosaxifen; this may be the result that the combination of clausenil, ergolide and isosaxifen can produce a synergistic anti-hepatitis B virus effect.

[0015] More preferably, the mass ratio of clausenil to ergolactone to isosaxifen is 1-5:1-3:1-2.

[0016] Most preferably, the mass ratio of clausenil to ergolactone and isosaxifen is 2:2:1.

[0017] The present invention also provides a use of the above-mentioned clausenamide-containing composition in the preparation of a medicine for treating liver damage.

[0018] Preferably, the liver damage is alcoholic liver damage.

[0019] The present invention also provides a use of the above-mentioned clausenamide-containing composition in the preparation of a medicine having an anti-hepatitis B virus effect.

[0020] The present invention also provides a use of the above-mentioned clausenamide-containing composition in the preparation of a medicine having both anti-hepatitis B virus and liver damage treatment effects.

[0021] Preferably, the liver damage is alcoholic liver damage.

[0022] Beneficial Effects: This invention provides a novel composition. Studies have shown that this composition has anti-alcoholic liver damage and anti-hepatitis B virus effects. Therefore, using this composition as an active ingredient in the preparation of drugs for treating liver damage and anti-hepatitis B virus effects has important application value. In particular, the preparation of drugs that have both anti-hepatitis B virus and liver damage treatment effects has even greater application value. DETAILED DESCRIPTION

[0023] The present invention is further explained below with reference to specific examples, but the examples do not limit the present invention in any form.

[0024] The clausenil, ergolactone, and isosaxifen in the following examples are all compounds known in the art and are purchased through conventional channels. The CAS number of clausenil is 103541-15-7, the CAS number of ergolactone is 54999-07-4, and the CAS number of isosaxifen is 482-27-9.

[0025] Example 1 Preparation of a composition containing clasamide

[0026] Preparation method: Take clasamide and ergolactone, mix them evenly in a mass ratio of 2:3 to obtain the clasamide-containing composition.

[0027] Example 2 Preparation of a Composition Containing Clausamide

[0028] Preparation method: Take clasamide and isosaxifen, mix them evenly in a mass ratio of 2:3 to obtain the clasamide-containing composition.

[0029] Example 3 Preparation of a Composition Containing Clausamide

[0030] Preparation method: Take clausthamide, ergolactone and isosaxifen, mix them evenly in a mass ratio of 2:2:1 to obtain the clausthamide-containing composition.

[0031] Example 4 Preparation of a Composition Containing Clausamide

[0032] Preparation method: Take clasamide and ergolactone, mix them evenly in a mass ratio of 5:1 to obtain the clasamide-containing composition.

[0033] Example 5 Preparation of a Composition Containing Clausamide

[0034] Preparation method: Take clasamide and ergolactone, mix them evenly in a mass ratio of 1:5 to obtain the clasamide-containing composition.

[0035] Example 6 Preparation of a Composition Containing Clausamide

[0036] Preparation method: Take clasamide and isosaxifen, mix them evenly in a mass ratio of 1:3 to obtain the clasamide-containing composition.

[0037] Example 7 Preparation of a Composition Containing Clausamide

[0038] Preparation method: Take clasamide and isosaxifen, mix them evenly in a mass ratio of 3:1, and then obtain the clasamide-containing composition.

[0039] Example 8 Preparation of a Composition Containing Clausamide

[0040] Preparation method: Take clausthamide, ergolactone and isosaxifen, mix them evenly in a mass ratio of 5:1:1 to obtain the clausthamide-containing composition.

[0041] Example 9 Preparation of a Composition Containing Clausinamide

[0042] Preparation method: Take clausthamide, ergolactone and isosaxifen, mix them evenly in a mass ratio of 3:1:2 to obtain the clausthamide-containing composition.

[0043] Example 10 Preparation of a composition containing clasamide

[0044] Preparation method: Take clausthamide, ergolactone and isosaxifen, mix them evenly in a mass ratio of 1:3:1 to obtain the clausthamide-containing composition.

[0045] Example 1 Anti-liver damage experiment

[0046] KM male mice weighing 20 ± 2 g were divided into six groups, each consisting of 12 mice: a normal group, an alcohol model group, and drug groups 1 to 4. Except for the normal group, the alcohol model and drug groups received daily gavage with a 53% aqueous alcohol solution at a dose of 15 mL / kg / day. The drug group received a 15 mg / kg / day oral gavage of the test drug suspended in distilled water 2 hours before daily alcohol gavage. The other normal and alcohol model groups received an equal volume of distilled water 2 hours before daily alcohol gavage. This gavage continued for 14 days. Six hours after the last alcohol gavage, eyeballs were removed and blood was collected. Serum ALT and AST levels in each group were measured using an automated biochemical analyzer. The results are shown in Table 1.

[0047] Among them, the test drug tested in experimental group 1 is the composition prepared in Example 1; the test drug tested in experimental group 2 is the composition prepared in Example 2; the test drug tested in experimental group 3 is the composition prepared in Example 3; and the test drug tested in experimental group 4 is clathramide.

[0048] Table 1. Anti-liver damage experimental results

[0049]

[0050]

[0051] From the experimental results in Table 1, it can be seen that the ALT and AST levels in the serum of mice in experimental groups 1 to 3 are significantly or even substantially lower than those in the alcohol model group; this indicates that the clausenamide-containing compositions of the present invention have the effect of treating alcoholic liver damage.

[0052] As can be seen from the experimental results in Table 1, the ALT and AST levels in the serum of mice in Experimental Group 1 that were gavaged with the composition prepared in Example 1 were significantly lower than those in Experimental Group 4 that were gavaged with clausenil. This indicates that the composition obtained by combining clausenil with ergolactone has a significantly improved anti-alcoholic liver injury effect compared to clausenil alone.

[0053] As can be seen from the experimental results in Table 1, the ALT and AST levels in the serum of the mice in Experimental Group 2, which were gavaged with the composition prepared in Example 2, were also lower than those in Experimental Group 4, which were gavaged with clausenil. This indicates that the anti-alcoholic liver injury effect of the composition obtained by combining clausenil with isosaxifen is also improved compared to clausenil alone.

[0054] As can be seen from the experimental results in Table 1, the ALT and AST levels in the serum of the mice in Experimental Group 2 that were orally administered with the composition prepared in Example 2 were lower than those in Experimental Group 4 that were orally administered with clausenil, and the reduction was not significant, but the reduction was significantly lower than that in Experimental Group 1 that were orally administered with the composition prepared in Example 1. This indicates that the anti-alcoholic liver injury effects of clausenil and combinations of different active ingredients are different; the anti-alcoholic liver injury effect of the composition obtained by combining clausenil with ergolactone is significantly higher than that of clausenil alone in that of the composition obtained by combining clausenil with isosaxifen.

[0055] As can be seen from the experimental results in Table 1, the ALT and AST levels in the serum of the mice in Experimental Group 3 that were orally administered with the composition prepared in Example 3 were close to those in the normal group, and were significantly lower than those in the mice in Experimental Group 4 that were orally administered with clausenil, and also significantly lower than those in Experimental Groups 1 and 2. This indicates that the composition of clausenil, ergolactone, and isosaxifen has a very excellent effect in resisting alcoholic liver injury; its effect in resisting alcoholic liver injury is further significantly higher than that of clausenil alone; and also further significantly higher than that of the combination of clausenil and ergolactone and the combination of clausenil and isosaxifen. This may be the result that the combination of clausenil, ergolactone, and isosaxifen can produce a synergistic effect in resisting alcoholic liver injury.

[0056] Experimental Example 2: Anti-hepatitis B virus effect

[0057] Human hepatoma cells Hep G2.2.15 expressing HBV were seeded in 96-well plates (containing DMEM medium) with a cell content of 1×10 6 The cells were then placed in an incubator (5% CO2, 37°C) and cultured for 24 hours. After the culture, the experimental group replaced the culture medium with DMEM culture medium containing 300 μg / mL of the test drug, and the culture medium was replaced once every two days. The control group replaced the culture medium with DMEM culture medium without the test drug, and the culture medium was replaced once every two days. After 10 days of continuous culture, the supernatant was collected and the HBsAg and HBeAg levels were detected using ELISA kits. The inhibition rates of HBsAg and HBeAg in each group were calculated, and 5 parallel wells were set for each group. The test results are shown in Table 1.

[0058] Among them, the test drug tested in experimental group 1 is the composition prepared in Example 1; the test drug tested in experimental group 2 is the composition prepared in Example 2; and the test drug tested in experimental group 3 is the composition prepared in Example 3.

[0059] Table 2. Results of anti-HBV experiments

[0060]

[0061] From the experimental results in Table 2, it can be seen that experimental groups 1 to 3 all showed inhibitory effects on HBsAg and HBeAg; this indicates that the clausenamide-containing compositions of the present invention all have anti-hepatitis B virus effects.

[0062] From the experimental results in Table 2, it can be seen that the inhibition rate of experimental group 2 on HBsAg and HBeAg is significantly higher than that of experimental group 1; this shows that the anti-hepatitis B virus effect of the composition obtained by combining clavoline and isosaxifen is significantly higher than that of the composition obtained by combining clavoline and ergolactone.

[0063] From the experimental results in Table 2, it can be seen that the inhibition rate of experimental group 3 on HBsAg and HBeAg is further significantly higher than that of experimental groups 1 and 2; this shows that the anti-hepatitis B virus effect of the combination of clausenil, ergolide and isosaxifen is much higher than that of the combination of clausenil and ergolide and the combination of clausenil and isosaxifen; and it has excellent anti-hepatitis B virus effect; this may be the result that the combination of clausenil, ergolide and isosaxifen can produce synergistic anti-hepatitis B virus.

Claims

1. A composition containing clasamide, characterized in that The composition comprises clausenil, ergolide and isosaxifen; wherein the mass ratio of clausenil, ergolide and isosaxifen is 1-5:1-3:1-2.

2. The composition containing clausenamide according to claim 1, wherein The mass ratio of clausenil, ergolactone and isosaxifenesin is 2:2:

1.

3. Use of the composition containing clausenamide according to any one of claims 1 to 2 in the preparation of a medicament for treating alcoholic liver damage.

4. Use of the composition containing clausenamide according to any one of claims 1 to 2 in the preparation of a drug having an anti-hepatitis B virus effect.

5. Use of the composition containing clausenamide according to any one of claims 1 to 2 in the preparation of a medicament having both anti-hepatitis B virus and alcoholic liver damage effects.

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