CN100434075C - Usage of caffeine and its analogue in resistance of hepatitis B replication and use thereof in preparation of medicament for treating viral hepatitis - Google Patents
Usage of caffeine and its analogue in resistance of hepatitis B replication and use thereof in preparation of medicament for treating viral hepatitis Download PDFInfo
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- CN100434075C CN100434075C CNB2006101443892A CN200610144389A CN100434075C CN 100434075 C CN100434075 C CN 100434075C CN B2006101443892 A CNB2006101443892 A CN B2006101443892A CN 200610144389 A CN200610144389 A CN 200610144389A CN 100434075 C CN100434075 C CN 100434075C
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Abstract
The invention discloses an application of caffeine and analogue in the virus hepatitis drug, which is characterized by the following: improving antiviral effect; inhibiting the duplication of variation hepatitis B virus.
Description
Technical field
The present invention relates to the effect and the purposes in preparation treatment viral hepatitis medicine thereof of caffeine and analog resistance of hepatitis B replication thereof, belong to field of medicaments.
Background technology
Itself can not directly cause liver cell lesion hepatitis B virus (HBV), and the morbidity of hepatitis (being the necrosis and the inflammation of hepatic tissue) is because HBV infects the result that the back starts the human immunity reset procedure.If the immunologic mechanism of human body can not in time be removed HBV lasting existence and active duplicating in vivo, will cause the continuous progress of liver tissue injury.Therefore, want to stop the progressive injury of liver, must take the active drug removing or suppress duplicating of HBV, that is to say, antiviral therapy is a control chronic hepatitis B key measure.
The main medicine of domestic and international anti-HBV (hepatitis B virus) is that interferon (destroy, thereby reach the purpose of removing virus by the hepatocyte that its immunoregulation effect can cause infecting at present.), its effective percentage is 30-60%, but does not recommend to use for hepatocyte such as hepatitis gravis patient seldom.The one antiviral medicine is a nucleoside analog in addition, be primarily aimed at viral reverse transcriptase, it is effective for the HBV carrier of immunologic tolerance to carry out now Latin America's fluorine pyridine that clinical I, II phase test, but the HBV dna level raises again after the drug withdrawal, long-term prescription virus easily produces the drug resistance variation, purpose of the present invention is exactly a kind of special new drug target at hepatitis B virus duplication of exploitation, and this medicine can suppress duplicating of all hepatitis viroids.
Summary of the invention
Content of the present invention is to find and provide the effect and the purposes in preparation treatment viral hepatitis medicine thereof of resistance of hepatitis B replication.
We find can cause behind the hepatitis B virus infection activation of DNA damage approach first by research, the level of cell node kinases 1 (CHK1), cell node kinases 2 (CHK2), p53 phosphorylation increases behind the hepatitis B virus infection, MRE11, p21 albumen are degraded, and fluorescent quantitative PCR result shows after this approach is suppressed can directly influence duplicating of hepatitis B virus.We find that by experiment in vitro discovery caffeine and theophylline can suppress the emiocytosis hepatitis B surface antigen significantly after using caffeine and theophylline to handle by the cell of hepatitis B virus infection again, and this result does not similarly report at present both at home and abroad.
Caffeine (caffeine) is 1,2, and 7 trimethyl xanthines, described caffeine analog are that caffeine metabolite in vivo is such as theophylline (Theophylline), theobromine (theobromine), paraxanthine (paraxanthine) etc.There has been the analog of these caffeine of experiment confirm the same, can have suppressed the activity of ATM in the DNA damage approach with caffeine.Our experiment confirm caffeine and theophylline have suppressed duplicating of hepatitis B virus by the activation that suppresses the DNA damage approach, since and all analog of caffeine all can suppress the activation of DNA damage approach, therefore the analog of all these caffeine all should have function of resisting hepatitis B virus in theory.If other hepatitis viroid such as hepatitis C, hepatitis G virus etc. stimulate body DNA damage repair mechanism after having same infection, caffeine and analog etc. thereof should have the effect of anti-all hepatitis viroids in theory, make anti-hepatitis class medicine so caffeine and analog thereof can be developed.
One of the analog of caffeine theophylline is used for treating asthma clinical, so its pharmacology medicine band and toxic and side effects are perfectly clear, it suppresses on the effective basis of hepatitis B virus duplication at laboratory proofing, its clinical practice of expansion that can be very fast.
Described medicine is for being the preparation of active component with caffeine and/or its analog, promptly comprises as unique active component also comprising situation as the part active component.
Described preparation is oral formulations (as tablet) or intravenous administration formulation (as aqueous injection or lyophilized injectable powder).
Said preparation can be made into conventional tablet, conventional capsule, granule, slow releasing tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coatel tablets, enteric coated capsule, delayed-release tablet, regularly/position releasing piece, slow releasing capsule, controlled release capsule, the capsule that contains micropill or small pieces, the pH dependent form capsule that contains micropill or small pieces, granule, oral liquid, etc. dosage form.
Also contain the pharmaceutics acceptable carrier in the said preparation, can be made into common oral preparation, comprise conventional tablet, conventional capsule, granule etc., described pharmaceutically acceptable carrier includes excipient and the accessory drugs that helps reactive compound is mixed with pharmaceutical formulation when making tablet, compositions as one or more materials of starch, microcrystalline Cellulose, inorganic salts, sucrose, dextrin, lactose, Icing Sugar, glucose, sodium chloride, cysteine, citric acid and sodium sulfite etc. belongs to this area general knowledge.
Also contain the pharmaceutics acceptable carrier in the said preparation, can be made into slow releasing tablet, comprise excipient and adjuvant etc.Described excipient and adjuvant have comprised that the adjuvant of slow releasing function is solubility/insoluble salt and/or other adjuvant that plays slow releasing function of hypromellose and/or ethyl cellulose and/or polyacrylic resin class and/or polycarboxy ethene and/or alginic acid, the hypromellose employing includes the extensive stock of hydroxypropyl methylcellulose (HPMC) such as U.S. many elegant (Methocel) of all size, ethyl cellulose adopts the extensive stock that includes ethyl cellulose (EC), and the polyacrylic resin class adopts and includes polyacrylic resin II, the acrylic resin of III class or analog such as all size (Eudragit).Above-mentioned adjuvant is porogen, binding agent, lubricant, emulsifying agent, membrane material, solvent or other adjuvant, and porogen can adopt sucrose, mannitol, starch, Pulvis Talci, silicon dioxide etc.; Binding agent can adopt polyvinylpyrrolidone, hypromellose etc.; Wetting agent can adopt the ethanol-water solution of water, dehydrated alcohol, various concentration; Lubricant can adopt stearic acid, magnesium stearate, Pulvis Talci, starch, paraffin etc.; Solubilizing agent can be adopted tartaric acid, citric acid etc.; Emulsifying agent can adopt span80 span85 etc.; Membrane material can adopt polyvinyl alcohol, hydroxyl methylcellulose, hyetellose, hymetellose, methylcellulose etc.; Foaming agent can adopt basic magnesium carbonate, sodium bicarbonate etc.; Bleach activator can adopt hexadecanol, octadecanol, Cera Flava etc.; Solvent can adopt dehydrated alcohol, ethanol, water etc.
Also contain the pharmaceutics acceptable carrier in the said preparation, can be made into controlled release tablet, comprise that active medicine has reached the adjuvant of controlled release effect.The above-mentioned adjuvant that plays the controlled release effect is polyoxyethylene and/or hypromellose and/or ethyl cellulose and/or sodium chloride and/or lactose and/or mannitol and/or fructose and/or glucose and/or sucrose/or low-substituted hydroxypropyl cellulose and/or cross-linking sodium carboxymethyl cellulose and/or crospolyvinylpyrrolidone and/or cellulose acetate.Above-mentioned adjuvant is pharmaceutical carrier, expanding material, permeation-promoter, solubilizing agent, binding agent, wetting agent, lubricant, coloring agent, porogen, membrane material, antiplastering aid, plasticizer, lucifuge agent, solvent.Pharmaceutical carrier, expanding material can adopt polyoxyethylene, hypromellose, ethyl cellulose, Glyceryl Behenate class etc.; Permeation-promoter can adopt sodium chloride, lactose, mannitol, fructose, glucose, sucrose etc.; Solubilizing agent can be adopted sodium lauryl sulphate or poloxamer etc.; Binding agent can adopt polyvinylpyrrolidone, hypromellose etc.; Wetting agent can adopt the ethanol-water solution of water, dehydrated alcohol, various concentration; Lubricant can adopt stearic acid, magnesium stearate, Pulvis Talci, starch, paraffin etc.; Coloring agent can adopt iron oxide red, iron oxide yellow etc.; Porogen can adopt sucrose, mannitol, Polyethylene Glycol, titanium dioxide, Pulvis Talci, silicon dioxide etc.; Membrane material can adopt cellulose acetate, ethyl cellulose etc.; Solvent can adopt acetone, dehydrated alcohol, ethanol, water etc.
Also contain the pharmaceutics acceptable carrier in the said preparation, can be made into sublingual lozenge, oral cavity quick disintegrating slice or dispersible tablet etc., comprise excipient and adjuvant etc.Described excipient and adjuvant have low substituted hydroxy-propyl methylcellulose, microcrystalline Cellulose, carboxymethyl starch sodium, cross-linked carboxymethyl cellulose sodium, crospolyvinylpyrrolidone, processing agar and mannitol, lactose etc.
Also contain the pharmaceutics acceptable carrier in the said preparation; can be made into enteric coatel tablets or enteric coated capsule etc.; comprise excipient and adjuvant etc.; described excipient and adjuvant have starch; microcrystalline Cellulose; inorganic salts; hydroxypropyl emthylcellulose; ethyl cellulose; the polyacrylic resin class; polycarboxy ethene; the solubility of alginic acid/insoluble salt; octadecanol; stearic acid; sucrose; dextrin; lactose; Icing Sugar; glucose; sodium chloride; cysteine; the compositions of one or more materials of citric acid and sodium sulfite etc.; enteric-coating material comprises: Lac; the cellulose acetate phthalate ester; crylic acid resin (as Eudragit L and S type etc.); the polyvinyl acetate phthalic acid ester; phthalic acid hypromellose ester; succinic acid acetic acid hydroxypropyl methylcellulose, and plasticizer is (as diethyl phthalate; Polyethylene Glycol; propylene glycol; glycerol triacetate; dimethyl phthalate; dibutyl sebacate; triethyl citrate; tributyl citrate; CitroflexA-2; the acetylated monoglycerides of Oleum Ricini and percentage etc.) with various medicaments adjuvant such as porogen (as PEG6000 etc.).
Also contain the pharmaceutics acceptable carrier in the said preparation; can be made into delayed-release tablet or timing (position) releasing piece; comprise excipient and adjuvant; described excipient and adjuvant have starch; microcrystalline Cellulose; inorganic salts; hydroxypropyl emthylcellulose; ethyl cellulose; the polyacrylic resin class; polycarboxy ethene; the solubility of alginic acid/insoluble salt; octadecanol; stearic acid; sucrose; dextrin; lactose; Icing Sugar; glucose; sodium chloride; cysteine; the compositions of one or more materials of citric acid and sodium sulfite etc., described coating material that postpones release or regularly (position) release comprises: Lac; the cellulose acetate phthalate ester; ethyl cellulose; hydroxypropyl emthylcellulose; hydroxypropyl cellulose; crylic acid resin (as Eudragit L and S type etc.); the polyvinyl acetate phthalic acid ester; phthalic acid hypromellose ester; succinic acid acetic acid hydroxypropyl methylcellulose; hydroxypropylmethylcellulose acetate methylcellulose phthalate ester; and plasticizer is (as diethyl phthalate; Polyethylene Glycol; propylene glycol; glycerol triacetate; dimethyl phthalate; dibutyl sebacate; triethyl citrate; tributyl citrate; CitroflexA-2; acetylated monoglycerides of Oleum Ricini and percentage or the like) with various medicaments adjuvant such as porogen (as PEG6000 etc.).
Also contain the pharmaceutics acceptable carrier in the said preparation; can be made into slow releasing capsule; controlled release capsule; the capsule that contains micropill or small pieces; contain the pH dependent form capsule of micropill or small pieces etc.; comprise excipient and adjuvant; described excipient and adjuvant have starch; microcrystalline Cellulose; inorganic salts; hydroxypropyl emthylcellulose; ethyl cellulose; the polyacrylic resin class; polycarboxy ethene; the solubility of alginic acid/insoluble salt; octadecanol; stearic acid; sucrose; dextrin; lactose; Icing Sugar; glucose; sodium chloride; cysteine; the compositions of one or more materials of citric acid and sodium sulfite etc., coating material comprises Lac; cellulose acetate; the cellulose acetate phthalate ester; ethyl cellulose; hydroxypropyl emthylcellulose; hydroxypropyl cellulose; crylic acid resin (as Eudragit series); the polyvinyl acetate phthalic acid ester; phthalic acid hypromellose ester; succinic acid acetic acid hydroxypropyl methylcellulose; hydroxypropylmethylcellulose acetate methylcellulose phthalate ester; the single-stearic acid glyceride; and plasticizer is (as diethyl phthalate; Polyethylene Glycol; propylene glycol; glycerol triacetate; dimethyl phthalate; dibutyl sebacate; triethyl citrate; tributyl citrate; CitroflexA-2; acetylated monoglycerides of Oleum Ricini and percentage or the like) with various medicaments adjuvant such as porogen (as PEG6000 etc.).
Advantage of the present invention is:
1 antiviral effect is better:
From extracorporeal antivirus effect model HepG2 2215 experimental results, to compare with lamivudine with existing antiviral drugs such as interferon, the antiviral effect of this medicine is better.
2 hepatitis B virus duplications after can suppressing to make a variation
Existing medicine can't solve the problem of virus variation, and this medicine since at be host's albumen itself, so should be able to solve chemical sproof problem.
The present invention will be further described below in conjunction with the drawings and specific embodiments, is not limitation of the present invention.Every any this area of doing according to the disclosure of invention be equal to replacement, all belong to protection scope of the present invention.
Description of drawings
Fig. 1 can activate the DNA damage approach after showing hepatitis B virus infection.
Fig. 2 shows that caffeine can suppress the activation of DNA damage approach.
Fig. 3 shows that caffeine can suppress duplicating of hepatitis B virus: cell is used the hepatitis B virus infection cell after caffeine is handled, the different time collecting cell is done quantitative fluorescent PCR behind the cracking supernatant, and the group that does not add any drug treating is organized in contrast.
Fig. 4 shows that caffeine and theophylline can suppress HepG2 2215 emiocytosis hepatitis B surface antigens: different time was collected the secretory volume that supernatant utilizes surface antigen detection kit detection surface antigen after cell added medicine, and the concentration of caffeine and theophylline is 4mM suppression ratio=(matched group-experimental group)/experimental group %.
Fig. 5 shows that caffeine and theophylline are dose dependent to the excretory inhibitory action of HepG2 2215 cell hepatitis B surface antigens: the drug effect of cell adding variable concentrations collecting cell after 9 days, secretory volume suppression ratio=(matched group-experimental group)/experimental group % of detection surface antigen.
The specific embodiment
Embodiment 1: hepatitis B virus duplicate the activation that depends on the DNA damage approach
One. material
Consumptive materials such as Tissue Culture Plate are all available from magnificent company.The HL7702 cell is preserved the center available from the biochemical institute in Chinese Academy of Sciences Shanghai cell, and hepatitis B virus positive serum is provided by People's Armed Police hospital general clinical laboratory, is 5 * 10 through the HBV of fluorescence quantitative PCR detection serum DNA titre
7
Caffeine and theophylline are available from SIGMA company.All antibody are all available from cell signaling company.The hepatitis B virus DNA detection kit wins biological company limited available from east, Beijing.
Two. method
1. hepatitis B virus infection HL7702 cell: the HL7702 cell goes to 6CM and carried out the HBV infection experiment in dull and stereotyped back 24 hours, test divides negative converting according to group and infected group, matched group adds 2ML and contains normal 30%FCS/DMEM culture medium, infected group adds the FCS/DMEM that contains 30% hepatitis B virus positive serum, infecting the back different time cleans with PBS, collecting cell after washing 8 times altogether, be used for the detection of protein level after the part lysis, a part of cell is used for fluorescence quantitative PCR detection after boiling cracking in 5 minutes.
2.WB: prepare the SDS-PAGE electrophoresis on the sample behind the sample, change film behind the electrophoresis,, add one and resist that jog spent the night in 1 hour on shaking table with 5% defatted milk powder PBST sealing 1 hour, PBST gives a baby a bath on the third day after its birth inferior, each 5min adds two then and resisted on shaking table jog 1 hour, and PBST gives a baby a bath on the third day after its birth time, each 5min, add A liquid and B liquid among the ECL, the development of exposing to the sun after the exposure, photographic fixing.
Three. the result
Fig. 1-3 shows, the level of interior CHK1, CHK2 of cell, p53 phosphorylation increases behind the hepatitis B virus infection, MRE11, p21 albumen are degraded, after handling, caffeine carries out the infection of hepatitis B virus again, the discovery CHK1 phosphorylation level hepatitis B virus positive infected group simple with not adding any processing compared obvious reduction, and the caffeine drug treating group that is replicated in of HBV DNA viruses also obviously is suppressed.
Conclusion: HBV infects back DNA damage reparation approach and is activated, and the activation of DNA damage approach can promote duplicating of HBV virus.
Embodiment 2: caffeine and theophylline can suppress HepG2 2215 emiocytosis hepatitis B surface antigens
One. material
Caffeine and theophylline are available from SIGMA company;
The FBS hyclone is available from the Hangzhou Ilex purpurea Hassk.[I.chinensis Sims.The DMEM culture medium is available from GIBCOL company
HepG2 2-2-15 is preserved by this chamber.IFN-r available from triad because of, draw the miaow furan to sting available from good thing hall pharmacy.
Hepatitis B surface antigen and cAg diagnostic kit are available from Huamei Bio-Engrg Co..
Two. method
With HepG2 2-2-15 is cell model, with cell with 3 * 10
5/ cm
2Be inoculated in 24 well culture plates, every hole adds the DMEM 1ml that contains 10%FBS, removes above-mentioned training base next day, and every hole adds the DMEM culture medium 1ml that contains 5%FBS; Experimental group adds the positive control IFN-r of variable concentrations and the caffeine and the theophylline of variable concentrations respectively, and negative control group does not add medicine.Establish 3 multiple holes for every group.Every 3d collects culture supernatant HBsAg detection by quantitative to be measured.
Hepatitis B virus surface (core) detection of antigens: respectively get in 96 orifice plates of 50 μ l culture fluid adding surface antigen, add the corresponding enzyme mark of 50 μ l conjugate again, hatch 1h for 37 ℃.Corresponding washing liquid is washed plate 5 times, adds 50 μ l colour developing liquid A and 50 μ l colour developing liquid B more successively, and 37 ℃ of lucifuge colour developing 15min add 50 μ l stop buffers at last.(VIC2 TORTM Wallac 1420 Multilabel Counter Wallac) go up the mensuration 450nm 1s of place light absorption value A at the multiple labeling enzyme-linked immunosorbent assay instrument.
Suppression ratio=(control wells-experimental group)/matched group
Three. the result
Fig. 4 shows that caffeine and theophylline can suppress HepG2 2215 emiocytosis hepatitis B surface antigens, and along with the passing of drug treating time, this inhibitory action strengthens gradually, and the suppression ratio after the 9th day surpasses more than 60%.(the average inhibitory action that it is fixed that 5uM draws the miaow husband is 30%, and the average inhibitory action of 500IU r-interferon is 15%).
Fig. 5 shows that caffeine and theophylline are dose dependent to the excretory inhibitory action of HepG2 2215 cell hepatitis B surface antigens.
Conclusion: caffeine and theophylline can suppress HepG2 2,2 under experimental concentration, the expression of 15 cell surface antigens.
Claims (5)
- Caffeine and analog thereof the preparation anti-hepatitis B virus medicine in purposes, described caffeine analog is a theophylline.
- 2. caffeine according to claim 1 and analog thereof the purposes in the medicine of preparation anti-hepatitis B virus is characterized in that: described medicine is for being the preparation of active component with caffeine and/or its analog.
- 3. caffeine according to claim 2 and analog thereof the purposes in the medicine of preparation anti-hepatitis B virus, it is characterized in that: described preparation is oral formulations or intravenous administration formulation.
- 4. caffeine according to claim 3 and analog thereof the purposes in the medicine of preparation anti-hepatitis B virus, it is characterized in that: described oral formulations is a tablet.
- 5. caffeine according to claim 3 and analog thereof the purposes in the medicine of preparation anti-hepatitis B virus, it is characterized in that: described intravenous administration formulation is aqueous injection or lyophilized injectable powder.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07135923A (en) * | 1993-11-19 | 1995-05-30 | Takeo Tanabe | Composition for functional food |
| WO1996032952A1 (en) * | 1995-04-21 | 1996-10-24 | Oswald Edmonds Hooper | Caffeine composition as medicament and use thereof |
| US20050123560A1 (en) * | 2003-12-04 | 2005-06-09 | Sinnott Robert A. | High purity and water dispersible extract and formulations of larrea tridentata leaf resin, and methods of making and using the same |
| JP2006182737A (en) * | 2004-12-28 | 2006-07-13 | Kao Corp | Packed drink for improving hepatic function |
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2006
- 2006-12-05 CN CNB2006101443892A patent/CN100434075C/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07135923A (en) * | 1993-11-19 | 1995-05-30 | Takeo Tanabe | Composition for functional food |
| WO1996032952A1 (en) * | 1995-04-21 | 1996-10-24 | Oswald Edmonds Hooper | Caffeine composition as medicament and use thereof |
| US20050123560A1 (en) * | 2003-12-04 | 2005-06-09 | Sinnott Robert A. | High purity and water dispersible extract and formulations of larrea tridentata leaf resin, and methods of making and using the same |
| JP2006182737A (en) * | 2004-12-28 | 2006-07-13 | Kao Corp | Packed drink for improving hepatic function |
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