CN100402028C - Use of abedol in preparation of medicine for preventing and treating hepatitis B, HIV virus - Google Patents
Use of abedol in preparation of medicine for preventing and treating hepatitis B, HIV virus Download PDFInfo
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- CN100402028C CN100402028C CNB03159638XA CN03159638A CN100402028C CN 100402028 C CN100402028 C CN 100402028C CN B03159638X A CNB03159638X A CN B03159638XA CN 03159638 A CN03159638 A CN 03159638A CN 100402028 C CN100402028 C CN 100402028C
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- abiduoer
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Abstract
The present invention relates to application of abedol in preparing medicine for preventing and treating hepatitis B and HIV viruses. Through invitro experiments, the present invention proves that abedol has the obvious inhibiting effect for hepatitis B and HIV viruses. Therefore, a product of the present invention can be used as medicine for preventing and treating hepatitis B and HIV viruses to be clinically applied.
Description
Technical field
The present invention relates to the new medicinal usage of Abiduoer, particularly relate to the application of this chemical compound in preparing prevention and treatment hepatitis B, HIV virus drugs.
Background technology
HIV has the selection tropism to auxiliary T lymph, also can infect mononuclear cell, macrophage and central nervous system cell simultaneously.The HIV reproduction process needs 3 kinds of enzymes: protease, reverse transcriptase and intergrase, after entering cell, it is deoxyribonucleic (DNA) with viral ribonucleic acid (RNA) reverse transcription that HIV utilizes reverse transcriptase, subsequently under the intergrase effect, be incorporated in the chromosome of host cell, thereby the part and the cell that become human cel gene are bred together.Because these viruses can be hidden in human body cell, if Once you begin duplicate breeding, can cause patient's the auxiliary serious injures and deaths of lymphocyte of T, cause immunity degradation, and then bring out a series of relevant diseases.
After the hepatitis B virus actute infection, human body produces corresponding antibody to virus antigen, i.e. surface antibody, e antibody and core antibody etc.During these antibody are attempted in serum and hepatitis B virus and corresponding antigen thereof; The cellular immunization of human body starts on the other hand, cytotoxic T cell particularly, and it can aim at the hepatocyte (target cell) that has scurried into hepatitis B virus and attack.The cAg of virus manufacturing (also having surface antigen, e antigen or pro-S antigen etc.) all adopts on liver plasma membrane and the bonded attack of liver plasma membrane lipoprotein.The result is when removing this target antigen regulating liver-QI intracellular virus.Hepatocyte has become the victim.According to the destructive acute stage clinical sign that corresponding different weights how much just occur of hepatocyte.
Abiduoer is the non-nucleoside new antiviral drug, be a kind of efficient medicine of preventing and treating first type and influenza B and other acute respiratory virus infection, by activating 2, the 5-oligo-adenylate synthetase, specificity suppresses the fusion of virus envelope and host cell membrane, thereby blocks duplicating of influenza virus.Compare other class anti-influenza virus medicaments and have following characteristics: 1, to influenza virus A type, B-mode all effective.2, have direct inhibition virus replication and induce the dual function of endogenous interferon concurrently.3, toxicity is low, toleration is good.
Abiduoer has following pharmacodynamic properties:
1, resisiting influenza virus:
This product all has inhibitory action to first type and Influenza B virus.Elisa shows that it is respectively 80% and 60% to the suppression ratio of first type and Influenza B virus, and the antigenic subtype of all influenza A viruss is all had activity.
Domestic in vitro tests result shows the H of Abiduoer to influenza virus A type
1N
1, H
2N
2, clinical separation strain all has inhibitory action, it 50% suppresses virosis degree of thickening (IC
50) be respectively 1.22 ± 0.015,1.50 ± 0.056 and 1.65 ± 0.12 μ g/mL; Its therapeutic index (TI) is respectively 37.6 ± 0.48,30.6 ± 1.13 and 27.9 ± 1.94.Show that Abiduoer has direct anti-influenza A virus effect.
The in vivo test result shows: successive administration 7～8 times, Abiduoer 15～125mg/kg on average lives mice day obviously to prolong, mortality rate significantly reduces, pathological changes obviously alleviates, and its effect obviously is better than the positive control drug virazole.Show that Abiduoer has significant resisiting influenza virus effect to whole animal.
2, inducement interferon effect
After domestic result of the test shows that mouse stomach gives Abiduoer 31.3～125mg/kg or lumbar injection Abiduoer 15～45mg/kg, certain density IFN all appears in its serum, peak value appears at 18h after the administration, and later titre descends, and shows that Abiduoer has the inducement interferon effect.
Foreign literature report Abiduoer all has the inducement interferon effect to humans and animals, the visible maximum titre of administration 24h.Human oral Abiduoer 300mg/kg, 24 hours interferon titre is 160IU/mL.
3, immunoregulation effect
Domestic result of the test: Abiduoer gastric infusion 5d, dosage are that 25～100mg/kgd significantly increases normal Kunming mouse peritoneal macrophage phagocytic percentage and phagocytic index; Dosage is 50～100mg/kgd, making due to the hydrocortisone immunocompromised Kunming mouse carbon clean up the K value obviously increases, dosage is that 12.5～50mg/kgd increases caused by cyclophosphamide immunocompromised Kunming mouse DTH significant reaction, shows that giving the Abiduoer various dose all has certain facilitation to the normal cellular immune function that reaches non-specific immunity, humoral immune function and the immunocompromised mice of immunocompromised Kunming mouse.
Foreign literature report Abiduoer has tangible activation to macrophage phagocytic function in testing in vivo and in vitro, to cellular immune functions such as delayed hypersensitivity and host's allograft reactions, the humoral immune function of caused by cyclophosphamide immunocompromised mice all there is obvious facilitation.
This product toxicity is very low.Foreign literature report rat and the oral 2000mg/kg of the single agent of Cavia porcellus, well-tolerated shows that oral acute toxicity is very low, estimates LD
50＞3000mg/kg.The oral LD=340mg/kg chronic toxicity test of mice, rat 100～125mg/kg, Canis familiaris L. 25mg/kg, oral administration 6 months pathology all do not occur and changes.To rabbit and Cavia porcellus long-term prescription also is safe.
Internal and external test shows that all this product do not have mutagenesis.Rat breeding toxicity research shows that this product do not have teratogenesis.
Summary of the invention
Effect in view of above-mentioned Abiduoer, in order to understand the mechanism of action of Abiduoer in depth to a series of viruses, we pass through molecule, screening experiment on the cellular level proves that Abiduoer is to hepatitis B, whether HIV virus is responsive, whether to hepatitis B, HIV is effective, therefore be example with hepatitis B virus and HIV virus, hepatitis B virus (being comprised: HBsAg on molecule and cellular level by Abiduoer, HBeAg, the DNA speckle), the biological activity of hepatitis B virus DNA polymerase etc. and to the bioactive detection of HIV virus judges that with this Abiduoer is to hepatitis B virus, the therapeutic effect of HIV virus.Thereby obtain the medicine of treatment hepatitis B, HIV viral infection.Learn experiment, integral animal experiment by Abiduoer mechanism of action and existing cell in vitro, we have designed following two experiments:
In the experiment of the external anti-HIV-1 proteinase activity of Abiduoer, find that Abiduoer has an anti-HIV-1 protease activities external.
In the experiment of Abiduoer anti-hepatitis B virus, find that Abiduoer has the effect that suppresses emiocytosis HBsAg and HBV dna replication dna.
The specific embodiment
Abiduoer of the present invention is to prevention and treat hepatitis B, HIV virus effectively, by following description of test.
Embodiment 1, the external anti-HIV-1 proteinase activity of Abiduoer screening experiment
Test philosophy: HIV-1 protease can cut the fluorescent labeling substrates enzymes in optimum reaction condition and reaction system, and fluorescence intensity reflects the activity of enzyme in the measurement of enzymatic reaction products, adds the inhibitor that sample can be used for screening this enzyme in reaction system.
Test material and method:
1, HIV-1 protease: The National Center for Drug Screening extracts, and-85 preserve.
2, sample and processing: Abiduoer, sample face with before being dissolved in DMSO or distilled water is made into debita spissitudo, 2 times of dilutions, each 5 dilution factor.
3, positive control drug: indinavir (indinavir), Ge Lansu company provides.
4, substrate: MP company provides.
5, method of testing: add behind the diluted sample and contain in the reaction buffer of fluorescent labeling substrate, and add genetic engineering target enzyme, under optimum reaction condition, hatch, measure fluorescent value with FLUO star Galaxy luminoscope.
Test result:
Table 1: the sample of initial concentration 250 μ g/ml each experimental concentration suppression ratio and IC
50
| Sample and reference substance | 250 (μg/ml) | 125 (μg/ml) | 62.5 (μg/ml) | 31.25 (μg/ml) | 15.625 (μg/ml) | IC 50 (μg/ml) | 10 (nM) |
| Net compares Duo Er | 53.8 | 44.1 | 23.3 | 8.2 | 7.4 | 188.37 | |
| Indinavir | 92.1 |
Conclusion: Abiduoer is external to have inhibitory action to HIV-Pr, its IC
50Be 188.37 μ g/ml.
Embodiment 2, the experiment of Abiduoer anti-hepatitis B virus primary dcreening operation
Test philosophy: with the 2.2.15 cell is the hepatitis B poisonous carrier, and working sample suppresses second
Hepatitis virus is carried out dna replication dna and is produced the ability of HBsAg, HBeAg.
Test material and method:
1, cell strain: 2.2.15 cell; Provide by The National Center for Drug Screening.
2, sample and processing: Abiduoer, sample face with before being dissolved in DMSO and are made into debita spissitudo, and each sample is made 3 times of dilutions, totally 8 dilution factors with culture fluid during detection.
3, positive control drug: lamivudine (3TC), produce by Glaxo Wellcome company.
4, main agents: hepatitis B virus e antigen and s antigen are put immunoassay agent box, and the Beijing North biotechnology research provides;
32PdCTP, the auspicious biological engineering company limited of Chinese good fortune provides.
5, method of testing: 2.2.15 cell kind 96 well culture plates, add sample and positive control drug respectively by above dilution factor after 36 hours, establish cell control well simultaneously, change the sample culturing liquid that contains different diluted concentrations after 72 hours respectively, in kind of plate the 8th day difference collecting cell supernatant and 2.2.15 cell, adopt the RIA method to detect the secretory volume of HBsAg, HBeAg in the cell conditioned medium, the method for dot blot detects HBV dna replication dna degree in the cell, calculates IC respectively
50And SI.
Test result:
Table 2:
Annotate: "-" expression sample does not have antiviral activity at maximal non-toxic dosage in (1) table.
(2) TC
50: the poisonous concentration of pair cell half; IC
50To viral half-inhibition concentration;
SI: be selection index, SI=TC
50/ IC
50
Conclusion: Abiduoer has inhibitory action, IC to 2.2.15 emiocytosis HBsAg and HBV dna replication dna
50Be respectively: 22.25 and 11.48 μ g/ml; SI is respectively: 3.46 and 6.71.
Claims (2)
1. the application of Abiduoer in preparation prevention and treatment HIV virus drugs.
2. application according to claim 1 is characterized in that: Abiduoer has an anti-HIV-1 protease activities external.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB03159638XA CN100402028C (en) | 2003-09-19 | 2003-09-19 | Use of abedol in preparation of medicine for preventing and treating hepatitis B, HIV virus |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB03159638XA CN100402028C (en) | 2003-09-19 | 2003-09-19 | Use of abedol in preparation of medicine for preventing and treating hepatitis B, HIV virus |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200710007199A Division CN101011389B (en) | 2003-09-19 | 2003-09-19 | Application of arbidol in preparing medicaments for preventing and/or treating hepatitis B |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1596892A CN1596892A (en) | 2005-03-23 |
| CN100402028C true CN100402028C (en) | 2008-07-16 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB03159638XA Expired - Lifetime CN100402028C (en) | 2003-09-19 | 2003-09-19 | Use of abedol in preparation of medicine for preventing and treating hepatitis B, HIV virus |
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Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101564389B (en) * | 2009-06-05 | 2010-10-27 | 中国人民解放军军事医学科学院军事兽医研究所 | Application of arbidol hydrochloride in preparing medicine for preventing and treating canine distemper virus |
-
2003
- 2003-09-19 CN CNB03159638XA patent/CN100402028C/en not_active Expired - Lifetime
Non-Patent Citations (2)
| Title |
|---|
| 抗病毒药物现状及研究进展.. 陈本川.中国处方药，第6期. 2003 |
| 抗病毒药物现状及研究进展.. 陈本川.中国处方药，第6期. 2003 * |
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| CN1596892A (en) | 2005-03-23 |
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