CN102697858B - Application of clove leaves or extract thereof in preparation of swine influenza virus resistant medicament - Google Patents
Application of clove leaves or extract thereof in preparation of swine influenza virus resistant medicament Download PDFInfo
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- CN102697858B CN102697858B CN201210186698.1A CN201210186698A CN102697858B CN 102697858 B CN102697858 B CN 102697858B CN 201210186698 A CN201210186698 A CN 201210186698A CN 102697858 B CN102697858 B CN 102697858B
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- folium caryophylli
- influenza virus
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Abstract
The invention discloses application of clove leaves or extract thereof in preparation of a swine influenza virus resistant medicament. In-vivo and in-vitro swine influenza virus resistant experiments show that the clove leaves or the extract thereof has a remarkable prevention or treatment effect on swine influenza viruses and can be prepared into the medicament for preventing or treating the swine influenza viruses.
Description
Technical field
The present invention relates to Folium Caryophylli extract a kind of new pharmacological use, relate in particular to Folium Caryophylli or its extract and preparing anti-swine flu virus (Swine influenza virus, SIV) purposes in medicine, belongs to the pharmacological use field of Folium Caryophylli or its extract.
Background technology
Swine flue (Swine influenza, SI) is the Acute respiratory infectious disease of the boar that caused by A type influenza virus (Swine influenza virus, SIV).SIV not only endangers health and the pig industry of pig, and occupies critical role in the genetic evolution of influenza virus distributes with ecology, particularly human health is had to great threat.
Folium Caryophylli is the dried leaves of Oleaceae genus syringa Syringa oblata oblata Lindl, Korea Flos Caryophylli Syringa diatata Nakai or foreign Flos Caryophylli Syringa vulgaris L.Folium Caryophylli is cold in nature, bitter in the mouth, attaches to the lung and stomach meridians, and has heat-clearing and toxic substances removing, the effect of anti-inflammtory anti-dysentery, and for acute bacillary dysentery, enteritis and upper respiratory tract infection, laryngopharynx swelling and pain, the bacterial infection diseases such as acute and chronic tonsillitis.Up to now, there is not yet the research report that relevant Folium Caryophylli infected by influenza has prevention or therapeutical effect.
Summary of the invention
Main purpose of the present invention is to provide a kind of new pharmacological use of Folium Caryophylli or its extract.
The present invention finds by the anti-anti-swine flu Viral experiment of in vitro and in vivo, and Folium Caryophylli or its extract have significant prevention and therapeutical effect to swine influenza virus, can be prepared into the medicine of prevention or treatment swine influenza virus.
First the present invention has measured the effect of Folium Caryophylli extract In Vitro Anti swine influenza virus, experimental result shows, the Folium Caryophylli extract of variable concentrations all has significant preventive effect, therapeutical effect, anti-adsorption and directly deactivation for swine influenza virus, along with the raising of Folium Caryophylli extract concentration, the effect of its anti-swine flu virus also strengthens thereupon.
On the basis of antiviral experiment, the present invention has carried out anti-swine flu Viral experiment in Folium Caryophylli extract body in vitro.Lungs titration of virus result shows, the virus titer of Folium Caryophylli extract high dose group contrasts the virus titer of (amantadine hydrochloride) and compares with positive drug, and difference is not remarkable.Folium Caryophylli extract shows the inhibitory action of mice pneumonia, it is not remarkable that the lung index of the height of Folium Caryophylli extract, middle dosage group and lung index and positive drug (amantadine hydrochloride) group are compared difference, and these three groups compared with Normal group, difference is not remarkable yet.The result of lung lesion degree shows (table 3), and it is not remarkable that the height of Folium Caryophylli ethanol extraction, middle dosage group and positive drug (amantadine hydrochloride) group are compared difference, illustrates that Folium Caryophylli extract can alleviate the lesion degree of pneumonia due to mice influenza virus.
" Folium Caryophylli " described in the present invention can be that Folium Caryophylli is pulverized to resulting Folium Caryophylli fine powder after porphyrize;
" Folium Caryophylli extract " described in the present invention can be according to the preparation-obtained extract of various extracting method of reporting in document, comprises water extract or the alcohol extract of Folium Caryophylli, is preferably alcohol extract;
As a reference, " Folium Caryophylli extract " of the present invention can be to obtain extract after Folium Caryophylli water or alcohols material are refluxed, and extract is filtered, concentrates and get final product; In order to reach better effect, further, can also be by adding distilled water in concentrated solution, standing, centrifugal, getting supernatant adsorbs with macroporous adsorbent resin column chromatography, after washing, successively with 0～50% ethanol elution and 50～90% ethanol, carry out eluting, collect 50～90% ethanol elution, concentrated, obtain Folium Caryophylli alcohol extract.
Wherein, described macroporous adsorbent resin is preferably HP-20 macroporous adsorbent resin; Described alcohols material is preferably ethanol or methanol.
Thus, the present invention also provides the pharmaceutical composition of a kind of prevention or treatment swine flue, the Folium Caryophylli fine powder by effective dose or Folium Caryophylli extract, consists of with pharmaceutically acceptable carrier or adjuvant.
" Folium Caryophylli fine powder or Folium Caryophylli extract " of the present invention can add after various adjuvants and pharmaceutically acceptable excipient or carrier required while preparing different dosage form, with conventional method of Chinese medicinal, be prepared into any suitable clinical preparation, such as being injection, oral liquid, powder etc.; Wherein, described adjuvant can be antioxygen chelating agent, filler etc.; Described pharmaceutically acceptable carrier is one or more in xylitol, mannitol, lactose, fructose, glucosan, glucose, polyvinylpyrrolidone, low molecular dextran, sodium chloride, calcium gluconate or calcium phosphate.
Accompanying drawing explanation
Fig. 1 mice average weight every day changes.
Fig. 2 Folium Caryophylli ethanol extraction affects infecting mouse lungs viral level.
The specific embodiment
Below in conjunction with specific embodiment, further describe the present invention, advantage and disadvantage of the present invention will be more clear along with description.But these embodiment are only exemplary, scope of the present invention are not formed to any restriction.It will be understood by those skilled in the art that lower without departing from the spirit and scope of the present invention and can the details of technical solution of the present invention and form be modified or be replaced, but these modifications and replacement all fall within the scope of protection of the present invention.
1. material and reagent
1.1 viruses and cell
H1N1 hypotype swine influenza virus (experiment of the swine influenza virus of relevant HINI hypotype need to complete in national influenza reference laboratory, and those of ordinary skills all can obtain the swine influenza virus of corresponding HINI hypotype and need to complete relevant experiment at this laboratory at this laboratory after the approval through leader), mdck cell are purchased from Yan Jing bio tech ltd, Shanghai.
1.2 cell culture fluids and maintenance medium
Cell culture fluid is the streptomycin of penicillin 100g/mL and the DMEM culture fluid of 10% hyclone containing 100U/mL;
Cell maintenance medium is except containing 2% hyclone, the same cell culture fluid of other composition.
Viral dilution liquid, for not containing serum, is the TPCK-pancreatin of 2 μ g/mL containing final concentration, the same cell culture fluid of other composition.
1.3 medicine
Supply reagent thing: (1) Folium Caryophylli ethanol extraction: (2) Folium Caryophylli water extract;
Positive drug contrast: amantadine hydrochloride.
1.4 reagent
MTT (3-(4,5-dimethylthiazole-2)-2,5-diphenyl tetrazole bromine salt), MTT is mixed with 5mg/mL solution, filtration sterilization ,-20 ℃ of preservations not contain the DMEM culture medium of serum; Dimethyl sulfoxide (DMSO); 1% Sanguis Gallus domesticus.
1.5 instrument
Superclean bench, ultra cold storage freezer, refrigerated centrifuger, electronic analytical balance, ether, gavage pin, plate, dissecting scissors, ophthalmic tweezers, disposable syringe etc.
The preparation of embodiment 1 Folium Caryophylli ethanol extract
Folium Caryophylli is pulverized and carried out reflux, extract, 1-3 time with the ethanol that percent concentration is 50-95%, by extracting liquid filtering concentrated; By adding distilled water in concentrated solution, standing, centrifugal, get supernatant macroporous adsorbent resin column chromatography and adsorb, after washing, successively use 0～50% ethanol elution and 50～90% ethanol, collect 50～90% ethanol elution, concentrated, obtain.
The preparation of embodiment 2 Folium Caryophylli water extracts
Folium Caryophylli is pulverized and used water boiling and extraction 1-3 time, decoction liquor is filtered, concentrated, obtain.
The infective determination experiment of experimental example 1 swine influenza virus
1, experimental technique
With viral dilution liquid, swine influenza virus is carried out to continuous 10 times of successives dilution, each dilution virus liquid is inoculated in the mdck cell of monolayer, 100 μ L/ holes, each dilution factor is parallel does 8 multiple holes, establish normal cell contrast simultaneously, cell control well does not add virus, only add diluent, after 37 ℃ of absorption 2h, careful suction is abandoned each hole virus liquid and is used maintenance medium continuation cultivation instead, after 72h, do hemagglutination test and record result, by Reed-Muench method, calculate viral half cell infection amount (TCID50).
2, experimental result
According to pressing Reed-Muench method, the TCID50 that calculates swine influenza virus is 10-7.2/0.1mL.
Experimental example 2 Folium Caryophylli alcohol extracts are to cytotoxicity experiment
1, experimental technique
Mdck cell suspension is inoculated in 96 well culture plates by 100 μ L/ holes, puts into 37 ℃, 5%CO
2in incubator, cultivate 24h, after cell covers with monolayer, discard original fluid.2 times of serial dilutions of cell maintenance medium for Folium Caryophylli alcohol extract, concentration is respectively 2000 μ g/mL, 1000 μ g/mL, 500 μ g/mL, 250 μ g/mL, 125 μ g/mL, 63 μ g/mL, 32 μ g/mL.The Folium Caryophylli alcohol extract of different extension rates is added in cell culture hole, and every hole 100 each concentration of μ L repeat 4 holes, establish cell control well (not dosing only adds culture fluid) simultaneously, put 37 ℃, 5%C O
2cultivate 72h in incubator, every day observation of cell pathological changes record.
2, experimental result
The maximal non-toxic concentration of the mdck cell that syringyl alcohol extract is right is 250 μ g/mL, cellular atrophy, cavity or come off when this concentration range is above.
Experimental example 3 Folium Caryophylli water extract are to cytotoxicity experiment
1, experimental technique
Mdck cell suspension is inoculated in 96 well culture plates by 100 μ L/ holes, puts into 37 ℃, 5%CO
2in incubator, cultivate 24h, after cell covers with monolayer, discard original fluid.2 times of serial dilutions of cell maintenance medium for Folium Caryophylli water extract, concentration is respectively 2000 μ g/mL, 1000 μ g/mL, 500 μ g/mL, 250 μ g/mL, 125 μ g/mL, 63 μ g/mL, 32 μ g/mL.The Folium Caryophylli water extract of different extension rates is added in cell culture hole, and every hole 100 each concentration of μ L repeat 4 holes, establish cell control well (not dosing only adds culture fluid) simultaneously, put 37 ℃, 5%CO
2cultivate 72h in incubator, every day observation of cell pathological changes record.
2, experimental result
Folium Caryophylli water extract the results are shown in Table 1 to the toxicity test of mdck cell.
The toxicity test result of table 1 Folium Caryophylli water extract to mdck cell
Note: ++++75% above cytopathy; +++ 75-50% cytopathy; ++ 50%-25% cytopathy; + 25% following cytopathy;-acellular pathological changes.
As can be seen from Table 1, the maximal non-toxic concentration of Folium Caryophylli water extract is 500 μ g/mL, cellular atrophy, cavity or come off when this concentration range is above.
Experimental example 4 Folium Caryophylli ethanol extract In Vitro Anti swine influenza virus experiments
1, experimental technique
The preventive effect of 1.1 pairs of viral infection
Get the drug dilution liquid (diluting with cell maintenance medium) that the 96 porocyte culture plates that cover with monolayer first add variable concentrations, concentration is respectively 250,125,63,32,16,8 μ g/mL,, 1 virus control and 1 normal control, respectively establish 4 parallel holes.First with drug dilution liquid, act on cell 2h, then abandon liquid, with PBS buffer washing 2 times, with the effect of 100TCID50 virus liquid, at 37 ℃, in 5%CO2 incubator, cultivate 72h again, abandon culture fluid supernatant, every hole adds 20 μ LMTT(5mg/mL) solution, mix gently, put in 37 ℃ of incubators and hatch after 4h, every hole adds 100 μ L DMSO, mixes gently low-speed oscillation 10min, put the OD value of measuring 490nm wavelength place in microplate reader, the preventive effect of checking medicine to swine influenza virus.
1.2 pairs of viral therapy effects
Get the 96 porocyte culture plates that cover with monolayer, first add 100TCID50 virus liquid and cytosis 2h, then add medicinal liquid, other is with above-mentioned 1.1 (preventive effect to viral infection).
The inhibitory action of 1.3 pairs of viruses adsorptions
Get the 96 porocyte culture plates that cover with monolayer, virus liquid and medicinal liquid add cell simultaneously.Other is with above-mentioned 1.1 (preventive effect to viral infection).
1.4 pairs of viral direct killing effect
Get the sample liquid of variable concentrations and mix and hatch 2h in 37 ℃ with virus stock solution used respectively, establish DMEM maintenance medium simultaneously and mix the experiment contrast group of placing 2h with virus stock solution used, be inoculated in 96 well culture plates that cover with cell monolayer.Other are with above-mentioned 1.1 (preventive effect to viral infection).
In above-mentioned experiment, the computing formula of viral suppression ratio is
Virus suppression ratio=[the average average OD value of OD value one virus control group of experimental group (medicine+virus)]/(the average OD value of the average OD value one virus control group of normal group) * 100%
2. In Vitro Anti swine influenza virus experimental result
Raising along with syringyl alcohol extract concentration, the effect of its anti-swine flu virus is also along with enhancing, when reaching 250 μ g/mL, syringyl alcohol extract all reaches 73.3%, 84.3%, 86.1% and 88.1% to the preventive effect of swine influenza virus, therapeutical effect, anti-adsorption and direct deactivation.
Table 2MTT method is measured the effect that syringyl alcohol extract is resisted swine influenza virus on mdck cell
| Concentration (μ g/mL) | Preventive effect | Therapeutical effect | Anti-adsorption | Directly deactivation |
| 250 | 73.3% | 84.3% | 86.1% | 88.1% |
| 125 | 50.4% | 81.3% | 81.9% | 83.5% |
| 63 | 38.4% | 76.2% | 76.5% | 78.4% |
| 32 | 16.6% | 70.5% | 63.6% | 69.7% |
| 16 | 6.9% | 53.7% | 56.9% | 64.8% |
| 8 | 0.6% | 49.1% | 50.2% | 52.9% |
Experimental example 5 Folium Caryophylli water extract In Vitro Anti swine influenza virus tests
One, experimental technique
Folium Caryophylli ethanol extract In Vitro Anti swine influenza virus experiment with experimental example 4.
Two, experimental result
Experimental result is in Table 3.
Table 3MTT method is measured Folium Caryophylli water extract inhibitory action result to swine influenza virus on mdck cell
Note: " medicine " described in table 3 is " Folium Caryophylli water extract ".
Virus suppression ratio: [the average average OD value of OD value one virus control group of experimental group (medicine+virus)]/(the average OD value of the average OD value-virus control of normal group group) * 100%
From experimental result, Folium Caryophylli water extract has significant inhibitory action for swine influenza virus, and along with the increase of Folium Caryophylli water extract concentration, its inhibitory action to swine influenza virus is remarkable rising, shows certain dose-effect relationship.
Anti-swine flu Viral experiment in experimental example 6 Folium Caryophylli ethanol extraction objects
1 experimental technique
1.1 experiment grouping and administrations
Ba lb/c mice is divided into Normal group, virus control group, amantadine hydrochloride group (dosage is 0.07g/kg/d) and the high, medium and low dosage group of Folium Caryophylli ethanol extraction at random, and (dosage is respectively 0.50g, 0.25g, 0.13g/kg/d), every group 10, before infecting, 1d starts administration, every day 2 times, gastric infusion, 0.2mL/10g.Normal group and model group give isometric(al) distilled water gavage.
1.2 infect virus
Each group is under the slight anesthesia of ether, with 10
6the viral intranasal inoculation mice of TCID50/50 μ L, 25 μ L/ nostrils.Weigh Mouse Weight record every day.
1.3 measure lung index
Infection mice was weighed in latter the 5th day and blood-letting is killed.Dissect mice, take out full lung, put into and fill PBS plate washed twice, absorbent paper is weighed after blotting.Calculate as follows lung index and suppression ratio:
Lung index=mouse lung weight/Mouse Weight * 100
Lung index=(the average lung index of average lung index one experimental group of virus control group) average lung index * 100% of/virus control group
One record pulmonary lesion integration simultaneously.Lung lesion degree is pressed following standard integral:
0 minute: lung tissue is normal;
1 minute: a small amount of inflammation or congested point appear in lung tissue;
2 minutes: block inflammation or congested piece (the full lung of pathological changes 1/4) appear in lung tissue;
3 minutes: half appears inflammation, congested piece or erosion (pathological changes 1/2 is complete more than lung) in lung tissue;
4 minutes: lung tissue most of inflammation, hyperemia or be liver-coloured (pathological changes 3/4 is complete more than lung).
1.4 measure lungs titration of virus
Take lung tissue according to conventional treatment, it is 2000U/mL that every g tissue adds 1mLPBS(to contain penicillin and streptomycin), after homogenate, 5000g/min is at 4 ℃ of centrifugal 5min, aseptic absorption supernatant.By mensuration, organize supernatant TCID50 to carry out titration to virus quantity.
1.5 statistical method
In this experiment, measurement data result all represents with mean ± standard deviation, adopts SPSS18.0 statistical package to carry out date processing.
2 experimental results
Mice viral infection starts to occur anorexia after 2 days, hair is matt, and the symptoms such as asthenia, weight loss are slow in action.As can be seen from Table 4, mouse infection influenza virus was cutd open and is killed after 4 days, and virus control group lung lesion degree compared with normal matched group is serious, and lung index is compared, difference tool significance (P<0.05), shows the murine pneumonia model modeling success due to swine influenza virus.Amantadine hydrochloride has obvious inhibitory action for influenza virus induced mice pneumonia, compares with virus control, and lung index is clearly better, and lung index is 43% her <0.01).
2.1 mice average weights change
Mice average weight changes in Table 4 and Fig. 1.
Table 4 mice average every day of body weight change table
2.2 lungs titration of virus results
Experimental result is in Table 5 and Fig. 2.
By table 5 and Fig. 2, can find out that the virus titer of Folium Caryophylli ethanol extraction high dose group contrasts (amantadine hydrochloride) virus titer with positive drug compares, difference is not remarkable.
Table 5 mouse lung disease of ZANG-organs poison titration results
The inhibitory action of 2.3 Folium Caryophylli ethanol extractions to mice pneumonia
Lung assessment of indices result shows (table 6), it is not remarkable that the lung index of the height of Folium Caryophylli ethanol extraction, middle dosage group and lung index and positive drug (amantadine hydrochloride) group are compared difference, and these three groups compared with Normal group, difference is not remarkable yet.The result of lung lesion degree shows (table 4), and it is not remarkable that the height of Folium Caryophylli ethanol extraction, middle dosage group and positive drug (amantadine hydrochloride) group are compared difference.Presentation of results Folium Caryophylli ethanol extraction can alleviate the lesion degree of pneumonia due to mice influenza virus thus, and the effect of its high dose group and positive drug (amantadine hydrochloride) are suitable.
The impact of table 6 Folium Caryophylli ethanol extraction on swine influenza virus infecting mouse lung lesion degree
Claims (1)
- Folium Caryophylli extract as unique active component for the preparation of the purposes in the medicine of anti-swine flu virus; The preparation method of described Folium Caryophylli extract comprises: after Folium Caryophylli is carried out reflux with methanol or ethanol, extraction obtains alcohol extract; Alcohol extract is filtered, concentrated, obtain concentrated solution; By adding distilled water in concentrated solution, standing, centrifugal, get supernatant and adsorb with macroporous adsorbent resin column chromatography, after washing, first use 0～50% ethanol elution, then use 50～90% ethanol elutions, collect 50～90% ethanol elution, concentrated, obtain.
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| CN101028314A (en) * | 2006-03-04 | 2007-09-05 | 周广刚 | Liquid coating against tumor, virus and bacterium |
| CN102166261A (en) * | 2011-04-13 | 2011-08-31 | 沈阳药科大学 | Clove leaf extract and method for preparing same |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101028314A (en) * | 2006-03-04 | 2007-09-05 | 周广刚 | Liquid coating against tumor, virus and bacterium |
| CN102166261A (en) * | 2011-04-13 | 2011-08-31 | 沈阳药科大学 | Clove leaf extract and method for preparing same |
Non-Patent Citations (1)
| Title |
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| Andrew G. Mercader，et al.QSAR study of flavonoids and biflavonoids as influenza H1N1 virus neuraminidase inhibitors.《European Journal of Medicinal Chemistry》.2010,(第45期),1724–1730. * |
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