CN103800343B - The application of chenodeoxycholic acid on preparation control poultry bird flu medicine - Google Patents
The application of chenodeoxycholic acid on preparation control poultry bird flu medicine Download PDFInfo
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- CN103800343B CN103800343B CN201410068806.4A CN201410068806A CN103800343B CN 103800343 B CN103800343 B CN 103800343B CN 201410068806 A CN201410068806 A CN 201410068806A CN 103800343 B CN103800343 B CN 103800343B
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Abstract
The invention provides the application of chenodeoxycholic acid on preparation control poultry bird flu medicine.Inventor studies discovery and has significant influenza and avian influenza toxic action for the chenodeoxycholic acid inside and outside of gallstone treatment clinically, has significant protective effect to infection bird flu virus chicken.Chenodeoxycholic acid of the present invention is for the preparation of the medicine of control bird flu, and its active ingredient is clear and definite, stable curative effect, quality controllable, safety non-toxic.And effective ingredient chenodeoxycholic acid plays a role mainly through regulating the inflammatory signals path of host cell, therefore not easily causes strains of influenza viruses to produce drug resistance.
Description
Technical field
The invention belongs to veterinary medicine field, be specifically related to the application of chenodeoxycholic acid on preparation control poultry bird flu medicine.
Background technology
Poultry bird flu is a kind of fowl acute respiratory disease with hyperinfection caused by bird flu virus (Avian Influenza Virus, AIV), has features such as propagating fast, high incidence and high mortality.Bird flu epidemic situation can cause wild fowl and the large quantities of death of poultry, and fertility performance reduces, Fowl meat egg product Quality Down, the sustainable health development of serious restriction aviculture.Highly pathogenic H5N1 subtype avian influenza virus as come from Southeast Asia the end of the year 2003 spreads the countries and regions, 3 15, continents to the world fast, makes thousands of poultry and wild fowl death.Although the virulence of H9N2 subtype avian influenza virus is lower than H5N1 hypotype, it is in recent years at poultry farms ubiquity, has a strong impact on the growth of poultry and the performance such as to lay eggs.Bird flu also can cross over species barrier, infects to mammal and people, threaten to the life and health of the mankind by fowl.Highly pathogenic H5N1 subtype avian influenza as 2003 causes nearly 400 people in the whole world to infect death, and case fatality rate is up to 60%.
Up to the present, inoculation avian influenza vaccine is the basic means of prevention poultry bird flu, and it can prevent the infection of homotype influenza virus, reduces mortality rate.But because the serotype of bird flu virus is numerous, antigen very easily occurs to drift about and produces new epidemic strain, then the reason such as the environment adding part plant is poor, mismanagement, cause the prevention effect not reaching expection after inoculating avian influenza vaccine clinically.Simultaneously, the Research and development and production cycle of new vaccine is longer, generally at least need 4-6 month, often lag behind the speed of virus variation, the epidemic situation be difficult to for newly breaking out provides vaccine (Bonhoeffer J in time, Bentsi-Enchill A, Chen R T, etal.Guidelines for collection, analysis and presentation of vaccine safety data insurveillance systems [J] .Vaccine, 2009,27 (16): 2289-2297.).Therefore, the control of bird flu can not rely on vaccine prevention completely.Medical treatment is the indispensable important means of avian influenza prevention.
Very deficient for the medicine preventing and treating influenza at present.Four kinds of Tamiflu that current American food and medicine administration (FDA) is ratified can be divided into two classes.The anti-influenza virus medicament that one class is is target with Influenza matrix albumen (M2), mainly contain amantadine and rimantadine, another kind of is the anti-influenza virus medicament that is target with influenza neuraminidase (NA), mainly contains GS-4104 (trade name: " oseltamivir phosphate capsule "), zanamivir and Peramivir.And the medicine being specifically designed to control bird flu does not also have at present, China does not ratify any medicine that can be used for poultry avian influenza prevention.The measure of current reply bird flu epidemic situation is the poultry slaughtering epidemic situation district.To a certain extent can quick control bird flu epidemic situation although slaughter, cause tremendous economic to lose to cultivation dealer, slaughter the process of a large amount of spoils of generation simultaneously and bury and bring harmful effect to environment.Therefore, new and effective control bird flu medicine is developed extremely urgent, very urgent.
Chenodeoxycholic acid (chenodeoxycholic acid, CDCA) is the primary bile acid all contained in many animals bile, is the main active of the poultry such as chicken, goose bile.Its chemistry is by name: 3 α, 7 alpha-dihydroxy--5-β-cholanic acids.Molecular formula: C
24h
40o
4, molecular weight: 392.57 is colorless needle crystals, and odorless, bitter in the mouth are water-soluble hardly, are soluble in ethanol, glacial acetic acid, are slightly soluble in chloroform.Chemical constitution is as follows:
CDCA Main Function is the saturation reducing bile inner cholesterol, is mainly used in treatment cholesterol type cholelithiasis etc. clinically.And in traditional medicine, Fel Gallus domesticus is used for treating respiratory system disease, as pertussis, tracheitis, pneumonia, pant, cough etc.Li Peifeng etc. once proved that CDCA had and relievingd asthma significantly and antiinflammatory action.Its mechanism of action and CDCA significantly can reduce the NO content in rat blood serum and tracheal tissue and the PGE2 content that reduces significantly in mice trachea and lung tissue relevant.(Li Peifeng, Guan Hong, Zhao Hongxia, Si Qin.Relievining asthma and Anti-inflammatory Mechanism research of chenodeoxycholic acid. CHINA JOURNAL OF CHINESE MATERIA MEDICA, Vol.29, Issue4:349-352).They also find that CDCA has obvious inhibitory action to staphylococcus aureus in vitro.(Li Peifeng, Haas Su Rong, Guan Hong, Cao Jinshan.The extraction of Fel Gallus domesticus active ingredient CDCA and T CDCA and antibacterial action research thereof.Agricultural University of the Inner Mongol's journal, Vol21 (4): 68-71).
Up to now, have no CDCA and suppress influenza virus and the report for preventing and treating bird flu, also have no the application for a patent for invention of CDCA for the preparation of control bird flu medicine.
Although containing chenodeoxycholic acid in poultry bile, the bile acid of animal self mainly circulates in liver sausage.The result of study of Zheng Rui etc. shows, after mice is filled with and feeds isotope-labeled chenodeoxycholic acid, its content in bile, intestinal stomach function regulating and content thereof is far away higher than the distribution (Zheng Rui in other tissue, Wang Zhenli, Yuan Ling, Li Naikuan. the research of the absorption of chenodeoxycholic acid in Mice Body, distribution and excretion. Acta Pharmaceutica Sinica, 1981, Vol16 (3): 235-237).Although there is no the report of CDCA acid content in poultry lung tissue so far, can infer that chenodeoxycholic acid is extremely humble at the content of the respiratory tract organs such as poultry lung by the result of study of Zheng Rui.
Summary of the invention
For solving the shortcoming and defect part of prior art, the object of the present invention is to provide the application of chenodeoxycholic acid on preparation control poultry bird flu medicine.
For achieving the above object, the present invention adopts following technical scheme:
The application of chenodeoxycholic acid on preparation control poultry bird flu medicine that a kind of structure is following:
Preferably, the spray, injection, water soluble powder or the granule that to be equipped with adjuvant using chenodeoxycholic acid as effective ingredient and to make is applied as described in.
Preferably, described poultry bird flu is the poultry bird flu disease that the influenza a virus infection comprising H9N2 hypotype and H5N1 hypotype causes.
Preferably, described poultry is the raising poultry comprising chicken, duck, goose and pigeon.
The molecular formula of chenodeoxycholic acid of the present invention: C
24h
40o
4, molecular weight: 392.57, its chemistry is by name: 3 α, 7 alpha-dihydroxy--5-β-cholanic acids.
Principle of the present invention: find a kind of effective ingredient chenodeoxycholic acid with influenza and avian influenza toxic action from animal bile, and verify its pharmacological mechanism.Obtain chenodeoxycholic acid by test in cell and chicken body, have significant suppression influenza and bird flu virus proliferation function, to infection bird flu virus chicken, there is remarkable protective effect, can be used for the medicine preparing control poultry bird flu.By further investigation, inventor finds that chenodeoxycholic acid can suppress the secretion of the cellular inflammation factor significantly reducing viral infection induction, suppress the inflammatory signals path of viral infection induced activation, and then suppress the assembling core and virion of virus nucleoprotein (NP), reduce virus propagation in vivo.Therefore, the present invention illustrates the mechanism of action of chenodeoxycholic acid resisiting influenza virus.
Although containing chenodeoxycholic acid in poultry bile, but the chenodeoxycholic acid of animal self mainly circulates in liver sausage, in the respiratory tract organs such as lung, content is extremely humble, and the administering mode such as spraying and injection makes this medicine can arrive pulmonary, significantly improve its concentration in respiratory system, thus play the effect of control bird flu.
Compared with prior art, the present invention has the following advantages and beneficial effect:
Chenodeoxycholic acid of the present invention is for the preparation of the medicine of control poultry bird flu, and active ingredient and mechanism of action are clearly, quality controllable, stable curative effect.Chenodeoxycholic acid clinical medicine has been used to treat cholelithiasis, therefore it in effective dosage ranges to humans and animals safety.
Medicine chenodeoxycholic acid of the present invention plays a role mainly through regulating the inflammatory signals path of host cell, therefore not easily causes avian influenza strain to produce drug resistance.
Accompanying drawing explanation
Fig. 1 is the inhibitory action that in embodiment 1, chenodeoxycholic acid (CDCA) is bred H5N1 subtype avian influenza virus different action time in cell;
Fig. 2 be in embodiment 2 variable concentrations chenodeoxycholic acid (CDCA) in cell to H9N2 subtype avian influenza virus propagation inhibitory action;
Fig. 3 be in embodiment 3 variable concentrations chenodeoxycholic acid (CDCA) in cell to H5N1 subtype avian influenza virus propagation inhibitory action;
Fig. 4 is that in embodiment 5, variable concentrations chenodeoxycholic acid (CDCA) infected by influenza nucleoprotein (NP) in cell goes out the inhibitory action of core;
Fig. 5 is the inhibitory action that in embodiment 6, the infection induced A549 cell of variable concentrations chenodeoxycholic acid (CDCA) infected by influenza produces inflammatory factor IL-6;
Fig. 6 is the inhibitory action that in embodiment 6, the infection induced A549 cell of variable concentrations chenodeoxycholic acid (CDCA) infected by influenza produces inflammatory factor IL-8;
Fig. 7 is the inhibitory action that in embodiment 6, the infection induced A549 cell of variable concentrations chenodeoxycholic acid (CDCA) infected by influenza produces inflammatory factor TNF-α.
Detailed description of the invention
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are not limited thereto.
Chenodeoxycholic acid used in following examples purchased from Guangzhou drug inspection in one's power Shaoxing according to Ke Mu Chemical Industry Science Co., Ltd.
The inhibitory action that embodiment 1 chenodeoxycholic acid is bred H5N1 subtype avian influenza virus different action time in cell
After A549 Growth of Cells to monolayer, add the H5N1 strain virus liquid (containing 100TCID50) diluted with basal medium, 100 μ L/ holes, hatch 1h, discard viral supernatants for 37 DEG C, PBS(phosphate buffer) liquid cleans one time, add the CDCA of 50 μ g, 100 μ L/ holes.Experiment establish simultaneously Normal group (do not add test medicine, do not add influenza virus liquid) and influenza virus matched group (not adding test medicine), each tested concentration establish three parallel.Cell continues to cultivate, and time respectively to 24h, 48h and 72h, stops cultivating, after observing its disease, in-80 DEG C and 4 DEG C of multigelation cell plates three times, make the abundant cracking of cell, cause intracellular virus all to discharge into cell conditioned medium, then collect each hole supernatant.According to Endpoint Dilution Method (Geiler J, Michaelis M, Naczk P, et al.N-acetyl-L-cysteine (NAC) inhibitsvirus replication and expression of pro-inflammatory molecules in A549cellsinfected with highly pathogenic H5N1influenza A virus [J] .Biochem Pharmacol, 2010, 79 (3): 413-420.), by collected cell conditioned medium basal medium 10 times of doubling dilutions, add the mdck cell growing to monolayer, continue to be placed in incubator and cultivate.After cultivating 72h, observe its CPE degree.Cell occurs that lesion degree is by following 6 grade standard records: "-" for Growth of Cells normal, occur without pathological changes; " ± " for cytopathy is less than whole cell monolayer 10%; "+" for cytopathy accounts for whole cell monolayer 25%; " ++ " for cytopathy accounts for whole cell monolayer 50%; " +++ " for cytopathy accounts for whole cell monolayer 75%; " ++++" accounts for more than 75% of whole cell monolayer for cytopathy.Virus titer (TCID50) value in each time period in each test group cell culture fluid is calculated by Reed-Muench method.As shown in Figure 1, H5N1 represents virus-infected controls group to experimental result, and CDCA represents chenodeoxycholic acid processed group.In figure, compare with virus-infected controls group, " * " represents significant difference (P<0.05).As can be seen from Figure 1, medicine chenodeoxycholic acid of the present invention under the concentration of 50 μ g/ml in A549 cell different action time all have significant inhibitory action to the propagation of H5N1 subtype influenza virus.
The inhibitory action that in embodiment 2A549 cell, variable concentrations chenodeoxycholic acid is bred H9N2 subtype avian influenza virus
The virus infected is the strain of H9N2 subtype influenza virus, and infection time is 2h, and to stopping during drug effect 48h cultivating, other experimental procedure is identical with embodiment 1.As shown in Figure 2, as can be seen from Figure 2, medicine chenodeoxycholic acid of the present invention has significant inhibitory action to the propagation of H9N2 subtype influenza virus in cell to experimental result in the concentration range of 12.5 ~ 50 μ g/ml, and presents good dose-effect relationship.
The inhibitory action that in embodiment 3A549 cell, variable concentrations chenodeoxycholic acid is bred H5N1 subtype avian influenza virus
Experimental procedure is identical with embodiment 1, stops cultivating, measure virus titer value during drug effect 48h.As shown in Figure 3, as can be seen from Figure 3, medicine chenodeoxycholic acid of the present invention has significant inhibitory action to the propagation of H5N1 subtype influenza virus in cell to experimental result in the concentration range of 12.5 ~ 50 μ g/ml, and presents good dose-effect relationship.
Embodiment 4 chenodeoxycholic acid is to the protective effect infecting H9N2 subtype avian influenza virus chicken
10 age in days egg inoculation H9N2 subtype avian influenza virus, collected chick embryo allantoic liquid after 2 days, were used as counteracting toxic substances and infected chicken virus liquid.Test chicken is 15 age in days H9N2 negative antibody Lingnan Yellow chickens, and intramuscular injection 0.4mL virus allantoic fluid under every chicken wing, sets up chicken and infect H9N2 bird flu virus disease model.Infected group generally starts to occur symptom the 3rd day part chicken, shows as: feed intake reduces, and body weight increases slow; Lassitude, depressed, feather is fluffy, becomes thin, necking down, slow-witted vertical; Larynx, nasal cavity flow out secretions sometimes, nasal sinuses swelling; Eye episcleral redness, flows out a small amount of secretions; Mouth breathing or dyspnea, ataxia, swollen eye or swollen head, cockscomb and wattle cyanosis.And it is dead temperature lower (<10 DEG C) situation lower part chicken.
Get chenodeoxycholic acid 20g, dissolve with the sodium bicarbonate aqueous solution of 100mL5%.Be the solution of 5% with normal saline by this solution dilution to chenodeoxycholic acid mass concentration, for chicken abdominal cavity and subcutaneous injection.Be the solution of 5% by this solution dilution to chenodeoxycholic acid mass concentration with water, for spray delivery.Spray delivery carries out in an airtight plastic box with atomising device.
Chenodeoxycholic acid infection virus the same day start administration, successive administration 5 days, test to the 11st day terminate.Result shows that different modes of administration can be protected to some extent and infects chicken, and significantly reduce chicken mortality rate, the chicken suppressing viral infection to cause loses weight, and administering mode, dosage and result of the test refer to table 1.
Table 1 chenodeoxycholic acid different modes of administration is to the protective effect infecting H9N2 subtype avian influenza virus chicken
* represent: compare with infection group and viral infection group, P ﹤ 0.05; * represents: compare with infection group and viral infection group, P < 0.01
△ △ represents: compared with normal group, P<0.01;
Embodiment 5 chenodeoxycholic acid infected by influenza nucleoprotein (NP) in A549 cell goes out the inhibitory action of core
By 1 × 10
4individual A549 cell dilution suspension adds in laser co-focusing culture dish (diameter at the bottom of glass is 15mm), 37 DEG C, volumetric concentration is 5%CO
2overnight incubation in incubator.Until cell cover with to about 50% time, abandon old liquid, PBS cleaning twice, add H5N1 subtype influenza virus diluent (MOI=0.1), 100 μ L, absorption 1h.After stopping cultivating, inhale and abandon virus liquid, PBS cleaning twice, adds the CDCA acid solution being dissolved in PBS, 37 DEG C, volumetric concentration is 5%CO
2continue in incubator to cultivate.Virus control group, solvent control group, 25 μ g/ml, 50 μ g/ml and 100 μ g/ml chenodeoxycholic acid groups are established in experiment.Desolventize matched group outer (PBS solution containing 0.4% dimethyl sulfoxide), other group all infects virus.8h after infection, stops cultivating.PBS cleans cell climbing sheet, every hole add mass concentration be 4% paraformaldehyde 500 μ l fix 10min; PBS cleans 3 times, and adding mass concentration is 0.25%Triton X-100 permeable membrane, 15min under room temperature; Adding mass concentration is that 5%BSA closes foreign protein, 4 DEG C of closed 2h; PBS cleans 3 times, adds Mus source NP monoclonal antibody (1:100 dilution), hatches 1h for 37 DEG C; PBS cleans 3 times, lucifuge add two anti-(
488 labelling goat anti-mouse IgG), 37 DEG C of lucifuges hatch 1h; PBS cleans 3 times, and lucifuge adds DAPI, and dyeing 10min, PBS clean; Glycerol mounting, observes under laser confocal microscope.The results are shown in Figure 4, the go out core of chenodeoxycholic acid to virus NP has remarkable inhibitory action as can be seen from FIG..
The inhibitory action of embodiment 6 chenodeoxycholic acid cellular inflammation factor of infected by influenza induction in A549 cell
Get the A549 cell being grown on logarithmic (log) phase to digest routinely, adjust its density to 2 × 10
6individual cell/mL is inoculated in 6 porocyte culture plates, cultivates 18-24h, treats that it is paved with Tissue Culture Dish, abandon old liquid, and PBS cleaning twice, adds the H5N1 influenza virus of 0.1MOI, 37 DEG C, volumetric concentration is 5%CO
2cultivate 1h, abandon virus liquid, PBS cleaning twice, adds SSa diluent, is placed in incubator, continues to cultivate 24h.Experimental group establishes the chenodeoxycholic acid test group of Normal group (do not add test medicine, without influenza virus stimulate), H5N1 virus matched group (not adding test medicine) and 250 μ g/ml, 50 μ g/ml and 100 μ g/ml, tri-concentration.Each tested concentration all establishes three parallel group.Cultivate after stopping, draw each hole culture supernatant, 4 DEG C centrifugal (1000r/min, 5min), measures the content of TNF-α, IL-6 and IL-8 in each sample according to Human TNF-α ELISA Kit, Human IL-6ELISA Kit and Human IL-8ELISA Kit description.The results are shown in Figure 5,6,7, can see from Fig. 5-7, the inflammatory factor that chenodeoxycholic acid infected by influenza infection induced A549 cell produces has significant inhibitory action.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (3)
1. the application of chenodeoxycholic acid on preparation control poultry bird flu medicine that a structure is following:
Described poultry bird flu is selected from the poultry bird flu disease that H9N2 hypotype and H5N1 hypotype cause at interior influenza a virus infection.
2. application according to claim 1, is characterized in that, described in be applied as and be equipped with adjuvant using chenodeoxycholic acid as effective ingredient and make spray, injection, water soluble powder or granule.
3. application according to claim 1, is characterized in that, described poultry is the raising poultry comprising chicken, duck, goose and pigeon.
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| CN101890048A (en) * | 2009-05-21 | 2010-11-24 | 上海凯宝药业股份有限公司 | Total bile acid extract of bear bile powder and preparation method and application of injection thereof |
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| CN101890048A (en) * | 2009-05-21 | 2010-11-24 | 上海凯宝药业股份有限公司 | Total bile acid extract of bear bile powder and preparation method and application of injection thereof |
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| 熊胆粉的药理作用及临床应用研究概述;连常宝;《海峡药学》;20081231;第20卷(第8期);71-75 * |
| 鹅去氧胆酸的平喘及抗炎作用机理研究;李培锋等;《中国中药杂志》;20040430;第29卷(第4期);349-352 * |
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