CN111419838A - Use of ketones for the treatment of liver fibrosis - Google Patents
Use of ketones for the treatment of liver fibrosis Download PDFInfo
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- CN111419838A CN111419838A CN202010265354.4A CN202010265354A CN111419838A CN 111419838 A CN111419838 A CN 111419838A CN 202010265354 A CN202010265354 A CN 202010265354A CN 111419838 A CN111419838 A CN 111419838A
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- liver fibrosis
- liver
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- fibrosis
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- A61K31/33—Heterocyclic compounds
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- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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Abstract
The present invention provides the use of a pharmaceutical composition in the manufacture of a medicament for the treatment of liver fibrosis, wherein the pharmaceutical composition comprises a compound of the formulaShow
Ketone compounds:
wherein R is H or C1-C6 alkyl.
Description
Technical Field
The invention relates to the field of medicine, in particular to a pharmaceutical composition for treating hepatic fibrosis (especially alcoholic hepatic fibrosis), wherein the pharmaceutical composition comprises
A ketone compound.
Background
Hepatic fibrosis is a disease in which connective tissues in the liver are abnormally proliferated due to various pathogenic factors. Particularly, with the continuous improvement of living standard of people, the drinking mode, the drinking path and the drinking amount of people are greatly changed, and the situations of alcoholism and alcohol dependence are frequent, so that the possibility that people suffer from alcoholic liver diseases (hepatic fibrosis) and finally cause alcoholic cirrhosis is increased virtually.
Among hospitalized patients, the proportion of alcoholic liver disease patients tends to increase year by year, and the degree of pathological changes thereof increases in proportion to the total amount of drinking, and thus the patients have received extensive attention. Hepatic fibrosis is an important feature of alcoholic liver disease developing to cirrhosis, liver failure and liver cancer. According to related investigations, almost all people who drink more than 40 grams of alcohol per day are found to suffer from steatosis, and 10% to 35% of alcoholics have different degrees of alcohol consumptionOf the liver, about 10% to 15% of alcoholics suffer from cirrhosis1。
Acetaldehyde dehydrogenase 2(A L DH2) in mitochondria decomposes acetaldehyde to consume NAD + and generates active oxygen/nitrogen2In addition, acetaldehyde can cause the increase and accumulation of extracellular matrix through regulating matrix metalloproteinases, thereby promoting the development of fibrosis, and TGF- β plays an important promoting role in the synthesis process of the extracellular matrix, so that the search and screening of the anti-TGF- β inhibition drug becomes an important direction for the treatment of alcoholic liver fibrosis.
It is reported that chronic and acute alcohol-fed mice can significantly increase the number of neutrophils in the liver, after the alcohol is taken, the alcohol is combined with T L R receptor on the surface of hepatophagy cell to stimulate macrophage activation and release proinflammatory factors TNF- α, I L-1 β and I L-6, thereby inducing inflammatory response3。
When acute inflammation occurs, I L-6 is synthesized in the liver in a large amount, receptors I L-6R are combined to form a complex, an NF-KB signal path is activated, NF-KB is promoted to be transferred into a nucleus, so that inflammatory reaction is mediated, and the process of liver fibrosis is accelerated.
At present, the clinical treatment of alcoholic hepatic fibrosis mainly requires patients to abstain from alcohol, and no specific drug treatment exists. Therefore, there is still a need for effective drugs against liver fibrosis, especially alcoholic liver fibrosis.
Disclosure of Invention
The object of the present invention is to provide a container
Pharmaceutical compositions of ketone compounds and their use for treating liver fibrosis. The pharmaceutical composition has particularly good curative effect on hepatic fibrosis, in particular chronic alcoholic hepatic fibrosis. The pharmaceutical composition of the invention is superior to the commonly used clinical hepatoprotective medicine metadoxine in the treatment effect on hepatic fibrosis (especially chronic alcoholic hepatic fibrosis).
In order to achieve the purpose, the invention provides the following technical scheme:
use of a pharmaceutical composition in the manufacture of a medicament for treating liver fibrosis, wherein the pharmaceutical composition comprises a compound represented by the formula
Ketone compounds:
wherein R is H or C1-C6 alkyl. Preferably, the first and second electrodes are formed of a metal,
the ketone compound is a compound represented by the following formula:
preferably, the liver fibrosis is selected from at least one of liver fibrosis caused by viral hepatitis, alcoholic liver fibrosis, fatty liver fibrosis and liver fibrosis caused by autoimmune disease.
More preferably, the alcoholic liver fibrosis is chronic alcoholic liver fibrosis.
In one embodiment, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier or excipient, such as a diluent, disintegrant, binder, lubricant, stabilizer, or corrective agent.
Preferably, the diluent is a sugar derivative, a starch derivative or a cellulose derivative.
Preferably, the diluent is lactose.
Preferably, the medicament may be a drip, injection, powder, microgranule, granule, capsule or tablet.
More preferably, the auxiliary materials are selected from one or more of glucose, starch, lactose, silicon dioxide, dextrin and flavoring agents. In order to make the medicine have better taste, the medicine of the invention can also contain a flavoring agent with the total weight of two to three per thousand of the raw materials. For convenient use, the invention can also be prepared into preparations, the raw materials also comprise one third to two thirds of auxiliary materials in parts by weight, and the auxiliary materials are as follows: glucose, starch, lactose, silicon dioxide, dextrin and/or flavouring agents.
Methods for preparing these dosage forms and the adjuvants used are known to those skilled in the art and can be found, for example, in "pharmacy of Chinese medicine" (published by Shanghai science and technology Press, 11 months 1986), "grand universe of pharmaceutic adjuvants" (published by Sichuan science and technology Press, 1995, 1 month), "Chinese pharmacopoeia" (published by chemical industry Press, 2005, 1 month), and the like. The Chinese medicinal composition of the present invention is preferably prepared into granules.
The term "pharmaceutically acceptable" as used herein refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compounds described herein. Such a substance is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
The term "pharmaceutically acceptable carrier" as used herein includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorants, dyes, and the like, and combinations thereof, as are well known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences,18th ed. mack Printing Company,1990, pp.1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, use thereof is contemplated in the therapeutic or pharmaceutical compositions.
According to one embodiment of the invention, the pharmaceutical composition may further comprise one or more of prednisone, colchicine and metadoxine.
In this case, the medicament of the present invention can be prepared into a compound medicament. Those skilled in the art will appreciate that a combination of drugs may produce a synergistic effect, reducing the toxic side effects of the drugs and increasing the efficacy.
Preferably, the medicament of the present invention may contain 60% by weight or more
A ketone compound. When in use
When the content of the ketone compound is less than 60% by weight, the effect of effectively treating fatty liver may not be sufficiently produced.
In one embodiment of the process of the present invention,
the ketone compound can be derived from extract of at least one of swertia, pseudogentiana (e.g., gentiana acutifolia), gentiana and gentiana of gentianaceae. In particular, obtaining
The method of ketone compounds may comprise: extracting whole plant of Gentiana acuta (3kg) with 70 vol% ethanol under reflux to obtain extract 1053.4g, extracting with chloroform-water, treating water layer (670g) with D101 macroporous adsorbent resin (water-95 vol% ethanol solution-acetonitrile) to obtain water and 95 bodyVolume% ethanol solution and acetonitrile eluate 332.4g, 294.9g and 5.1g respectively, 95 volume% ethanol solution eluate (200g) was subjected to silica gel column chromatography to obtain 16 fractions in total, wherein fractions 9-6(3g) were subjected to HP L C to prepare the compound desmethyl bellidifolin (76.9 mg).
The pharmaceutical composition or the medicament can effectively treat, relieve or eliminate hepatic fibrosis of patients.
In this context, liver fibrosis may be liver fibrosis caused by viral hepatitis, alcoholic liver fibrosis, fatty liver fibrosis, liver fibrosis caused by autoimmune diseases, and drug-induced liver fibrosis. The medicine is especially suitable for treating, relieving or eliminating alcoholic hepatic fibrosis of a patient who drinks, especially chronic alcoholic hepatic fibrosis.
More preferably, the medicament of the invention is particularly suitable for treating, alleviating or eliminating chronic alcoholic liver fibrosis in a patient. The term "chronic alcoholic liver fibrosis" refers to a liver fibroproliferative disease caused by long-term heavy drinking.
In the attack process of chronic alcoholic liver fibrosis, liver cells can be damaged by long-term alcohol intake, and diffuse excessive deposition and abnormal distribution of extracellular matrix in the liver are caused when the liver cells are subjected to pathological repair. At present, no specific medicine exists in the market for treating chronic alcoholic hepatic fibrosis. The invention screens and develops the medicine with definite curative effect on preventing and treating the chronic alcoholic hepatic fibrosis from abundant traditional Chinese medicine resources, and the medicine is very suitable for clinical popularization and application, thereby having obvious clinical significance.
Brief description of the drawings
Exemplary embodiments of the invention are described in detail based on the following figures, wherein:
fig. 1 shows a: HE (hematoxylin-eosin) staining results of pathological sections of mouse liver; b in the polarizer, the result of sirius red staining of pathological section of mouse liver.
Fig. 2 shows a and B: the results of biochemical indexes of mouse serum of a blank control group, an alcohol model group, a metadoxine treatment group and DMB treatment groups with different dosages; and C and D: levels of superoxide dismutase (SOD) and Glutathione (GSH) in the livers of mice in the placebo group, the alcohol model group, the metadoxine-treated group, and the DMB-treated group at different doses.
Fig. 3A, B, C and D show the expression levels of different relevant inflammatory factors in mice of the blank control group, the alcohol model group, the metadoxine-treated group, and the DMB-treated group at different doses, respectively.
FIG. 4 shows the expression of TGF- β in mouse livers of a blank control group, an alcohol model group, a metadoxine-treated group, and a DMB-treated group at different doses.
Detailed Description
The technical solution and the beneficial effects of the present invention will be further described with reference to the following specific embodiments.
Examples
Heating and refluxing the whole gentiana acuta (3kg) in an ethanol solution with a net volume fraction of 70% to extract 1053.4g, extracting with chloroform-water, treating a water layer (670g) with D101 macroporous adsorption resin (water-ethanol solution with a volume fraction of 95% -acetonitrile) to obtain water, 95% ethanol solution and acetonitrile eluate, respectively 332.4g, 294.9g and 5.1g, separating the ethanol solution eluate with a volume fraction of 95% (200g) by silica gel column chromatography to obtain 16 components in total, wherein the components 9-6(3g) are separated by HP L C to prepare the compound desmethyl bellidifolinone (76.9mg), which can be used as an active ingredient of a medicament.
The method comprises the steps of adopting 5% alcohol liquid feed to manufacture an alcoholic liver fibrosis C57B L/6J mouse model formed by chronic drinking, continuously feeding an experimental control group and an administration group for 14 days by adopting the 5% alcohol liquid feed, simultaneously feeding the administration group with 10mg/kg and 20mg/kg DMB for intervention, using 300mg/kg clinical commonly used medicine-metadoxine as a positive medicine control, using 20mg/kg Bellidifolin (BDN) as a liver protection and drug effect control, feeding a blank control group by adopting isocaloric liquid feed, changing fresh feed every day and symmetrically taking the weight of the mouse, carrying out euthanasia on the mouse in the morning on day 15, taking serum for biochemical index detection, taking out the liver of the mouse, quickly freezing by using liquid nitrogen for subsequent relevant index detection, feeding the experimental animal in a circulating SPF level environment in the day 12 hours and night 12 hours, changing the weight of the mouse once every day, changing the new food every day, and freely taking the mouse for feeding.
The mouse livers collected above were pathologically sectioned and stained with HE (hematoxylin-eosin) and sirius red, respectively, and the sections were observed by a zeiss Imager D2 advanced upright microscope. The results are shown in FIGS. 1A and 1B, respectively. Specifically, as shown in the HE staining result of the pathological liver section of the mouse shown in fig. 1A, chronic alcohol induction can obviously cause pathological changes such as vacuolation of liver cells of the mouse, and after DMB treatment is given, pathological changes such as vacuolation of liver caused by chronic alcohol feeding can be obviously improved. As shown in fig. 2B, sirius red staining results showed that chronic alcohol induction caused significant deposition of collagen in the liver, particularly accumulation of type I and III collagen in the liver, under polariscope. After the DMB treatment is given, excessive deposition of liver collagen can be remarkably inhibited. Thereby inhibiting liver fibrosis caused by chronic alcohol induction. In addition, the anti-fibrosis effect of DMB is obviously superior to BDN, and later, the pharmacological effect of DMB anti-fibrosis is intensively discussed.
The biochemical indexes of the collected serum are detected by a Hitachi 7020 biochemical analyzer, the detection result is shown in figure 2, the biochemical indexes of the serum of the mouse show that the chronic alcohol feeding can obviously increase the level of glutamic-pyruvic transaminase and (A L T) glutamic-oxalacetic transaminase (AST) in the serum, and the metadoxine or DMB treatment can obviously reduce the level of AST and A L T in the serum (figures 2A and 2B), which indicates that the DMB treatment has obvious liver protection effect.
The harvested livers were also homogenized and tested with SOD and GSH test kits. The results are shown in FIGS. 2C and 2D. Specifically, in the assay of liver homogenates, DMB treatment was found to significantly increase the levels of superoxide dismutase (SOD) and Glutathione (GSH) in the liver following chronic ethanol induction (fig. 2C, 2D). The DMB can inhibit the process of alcoholic hepatic fibrosis caused by peroxidation by regulating and controlling an oxidative stress channel.
As shown in FIGS. 3A, B, C and D, ethanol induction can significantly up-regulate the expression of relevant inflammatory factors such as MCP-1, I L-1 β, I L-6, TNF α and the like, but the expression of the relevant inflammatory genes is significantly inhibited after DMB intervention, which indicates that DMB can play a role in inhibiting the chronic alcohol-induced inflammatory reaction by inhibiting the expression of the relevant inflammatory genes, thereby playing a significant role in improving the initiation and development of chronic alcohol-induced liver fibrosis.
The result of sirius red staining shows that DMB can obviously inhibit the excessive accumulation of chronic alcohol-induced collagen in liver, and the expression of TGF- β in liver is also detected in order to reveal the possible molecular mechanism of the collagen.
The above-described embodiment is merely a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, and other modifications may be made without departing from the spirit and scope of the invention as set forth in the appended claims. It is to be understood that the above embodiments are merely exemplary embodiments that are employed to illustrate the principles of the present disclosure, and that the present disclosure is not limited thereto. It will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope of the disclosure, and these are to be considered as the scope of the disclosure.
Reference documents:
1.Felix S,Christian D,Jochen H,et al.Pathophysiology and Managementof Alcoholic Liver Disease:Update 2016[J].Gut and Liver, 2017,11(2):173-188.
2.Hao L,Sun Q,Zhong W,et al.Mitochondria-targeted ubiquinone (MitoQ)enhances acetaldehyde clearance by reversing alcohol-inducedposttranslational modification of aldehyde dehydrogenase 2:A molecularmechanism of protection against alcoholic liver disease[J].Redox Biology,2018,14:626-636.
3. study on the action and mechanism of MicroRNA-29b in alcoholic liver disease [ D ]. university of Anhui medical science, 2019.
4.Fielding C A,Mcloughlin R M,Mcleod L,et al.IL-6 RegulatesNeutrophil Trafficking during Acute Inflammation via STAT3[J].The Journal ofImmunology,2008,181(3):2189-2195.
Claims (9)
1. Use of a pharmaceutical composition in the manufacture of a medicament for treating liver fibrosis, wherein the pharmaceutical composition comprises a compound represented by the formula
Ketone compounds:
wherein R is H or C1-C6 alkyl.
2. Use according to claim 1, characterized in that
The ketone compound is a compound represented by the following formula:
3. use according to claim 1 or 2, characterized in that the liver fibrosis is selected from at least one of liver fibrosis due to viral hepatitis, alcoholic liver fibrosis, fatty liver fibrosis and liver fibrosis due to autoimmune diseases.
4. Use according to claim 1 or 2, characterized in that the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or adjuvant.
5. Use according to claim 1 or 2, characterized in that the medicament is made in the form of a drip, injection, powder, microgranule, granule, capsule or tablet.
6. Use according to claim 1 or 2, characterized in that the pharmaceutical composition further comprises one or more of prednisone, colchicine and metadoxine.
7. Use according to claim 1 or 2, characterized in that the medicament comprises more than 60% by weight
A ketone compound.
8. Use according to claim 3, characterized in that the alcoholic liver fibrosis is chronic alcoholic liver fibrosis.
9. Use according to claim 1 or 2, characterized in that said
The ketone compound is obtained from extract of at least one plant of swertia, pseudogentian, gentian and Gentiana of Gentianaceae.
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Non-Patent Citations (2)
| Title |
|---|
| JUN FU LI ETC.: "Demethylbellidifolin Inhibits Proliferation and Activation of Hepatic Stellate Cells", 《JOURNAL OF INVESTIGATIVE SURGERY》 * |
| 陈雪晴: "印度獐牙菜乙酸乙酯部位抗肝纤维化活性成分研究", 《中国优秀博硕士学位论文全文数据库（硕士）医药卫生科技辑》 * |
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