CN1605335A - Antivirus dihydromyricetin and myricetin containing pharmaceutical composition - Google Patents
Antivirus dihydromyricetin and myricetin containing pharmaceutical composition Download PDFInfo
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Abstract
The present invention discloses the use of the composition containing myricitrin and dihydromyricitrin in preparing broad-spectrum antiviral medicine and medicine for raising immunity. The composition contains myricitrin in 2-80 wt% and dihydromyricitrin 20-98 wt%. The antiviral medicine composition is used in resisting hepatitis B virus, influenza virus and/or coronavirus.
Description
The invention belongs to drug world.
Document Walter Karrerr, Birkhauser Verlag, Bassel undstuttgart (1958), P.652, NO:1640 discloses the structural formula of dihydromyricetin,
But the activity of dihydromyricetin is not studied.Ampelopsin is a kind of compound known, and its structural formula is:
Nobody disclosed the composition and use thereof that contains dihydromyricetin and ampelopsin up to now.
The purpose of this invention is to provide a kind of new compositions, it contains dihydromyricetin and ampelopsin, and wherein the dihydromyricetin cellulose content is 20% to 98% weight ratio, and ampelopsin content is 2% to 80% weight ratio.Can also contain one or more in the present composition and be selected from following composition: arbutin, gallic acid and/or tea polyphenols.The content of arbutin preferably accounts for the 0-50wt% of dihydromyricetin and ampelopsin gross weight, the content of gallic acid preferably accounts for the 0-50wt% of dihydromyricetin and ampelopsin gross weight, and the content of tea polyphenols preferably accounts for the 0-50wt% of dihydromyricetin and ampelopsin gross weight.
The applicant is surprisingly found out that the compositions that contains dihydromyricetin and ampelopsin has purposes widely at pharmaceutical field and field of health care products.
The compositions that contains dihydromyricetin and ampelopsin of the present invention has broad-spectrum disease resistance toxic action, particularly anti-hepatitis virus, influenza virus and/or coronavirus.The compositions that contains dihydromyricetin and ampelopsin can directly be used as antiviral drugs, can also make the broad-spectrum antiviral medicament compositions with pharmaceutical acceptable carrier or mixed with excipients, the amount that contains the compositions of dihydromyricetin and ampelopsin in the pharmaceutical composition can be the 2-98% weight ratio.
The compositions that contains dihydromyricetin and ampelopsin of the present invention has blood sugar lowering and effect for reducing blood fat, can be prepared into blood sugar lowering and hypolipidemic.
Another object of the present invention provides the method for compositions that preparation the present invention contains dihydromyricetin and ampelopsin.Compositions of the present invention can also can be extracted from ampelopsis by described constituent monomers is mixed in proportion preparation.Described ampelopsis comprises ampelopsis cantoniensis, a leaf beautiful Fructus Vitis viniferae, Ampelopsis grossedentata, Cayratia japonica (Thunb.) Gagnep., Radix Ampelopsis, Northeastern Caulis seu folium ampelopsis brevipedunculatae and Vitis Amurensis.Described extracting method can be: decoct vitaceae by all kinds of solvents (water and/or organic solvent), decoct one or many, decoction liquor is through concentrating cooling, standing over night, detection precipitates the active ingredient with supernatant, gets to have active precipitation and/or obtain the present composition after further silica gel adsorption.Decoct used solvent preferred water, alcohols, esters, ketone, ethers and strong polar organic solvent, more preferably low-level chain triacontanol, low-grade fatty acid ester has ketone and ether and/or water, the most preferably methanol of 3-12 carbon atom, ethanol, propanol, isopropyl alcohol, n-butyl alcohol, isobutanol, sec-butyl alcohol, the tert-butyl alcohol, ethyl acetate, methyl acetate, Ethyl formate, acetone, methyl ethyl ketone, ether, methyl ethyl ether, methyl tertiary butyl ether(MTBE), dichloromethane, chloroform, carbon tetrachloride, dimethyl sulfoxine, N, dinethylformamide and/or water or the like.Separating the adsorbent that uses can be silica gel.
Principle of the present invention is to contain dihydromyricetin and ampelopsin compositions drug activity by setting up the tracking of pharmacological screening model, finds its pharmaceutical usage.Extracorporeal bacteria inhibitor test and antivirus test show that the present composition has anti-inflammation and broad-spectrum disease resistance toxic action, particularly anti-hepatitis virus, influenza virus and/or coronavirus.Test proves that also the compositions that contains dihydromyricetin and ampelopsin of the present invention has blood sugar lowering and effect for reducing blood fat, has the function of prevention and/or recovery alcoholic liver injury, has hepatoprotective, the function of enhance immunity systemic immunity power.
The compositions that contains dihydromyricetin and ampelopsin of the present invention can be mixed with pharmaceutical composition by conventional preparation technique of drug world and carrier, and the amount that contains the compositions of dihydromyricetin and ampelopsin in the pharmaceutical composition can be the 2-98% weight ratio.The present composition can be prepared into tablet, granule, capsule, medicine for external use.But those skilled in the art also can be mixed with other dosage form with technology well known in the art and carrier as required.The dosage that preferred active component is used the people is 0.01-5 gram/kg body weight/sky, but also can decide as the case may be, is not limited to this scope.
Describe the present invention in detail by the following examples.But should be appreciated that these embodiment just illustrate the present invention, rather than in office where face limits the scope of the invention.
Embodiment 1: prepare the present composition from dihydromyricetin and ampelopsin crystal
Get dihydromyricetin 80g, ampelopsin 20g gets mixture after said components is mixed in mixer.Perhaps get dihydromyricetin 98g, ampelopsin 2g gets mixture after said components is mixed in mixer.Perhaps get dihydromyricetin 20g, ampelopsin 80g gets mixture after said components is mixed in mixer.
Embodiment 2: prepare the present composition from dihydromyricetin and ampelopsin crystal
Get dihydromyricetin 20g, ampelopsin 80g, arbutin 2.5g, gallic acid 2.5g, tea polyphenols 2.5g, said components in mixer, mix mixture.Perhaps get dihydromyricetin 98g, ampelopsin 2g, arbutin 2.5g, gallic acid 2.5g, tea polyphenols 2.5g, said components in mixer, mix mixture.Perhaps get dihydromyricetin 85g, ampelopsin 15g, arbutin 25g, gallic acid 2g, said components in mixer, mix mixture.Perhaps get dihydromyricetin 50g, ampelopsin 50g, arbutin 25g, tea polyphenols 2.5g, said components in mixer, mix mixture.Perhaps get dihydromyricetin 70g, ampelopsin 30g, arbutin 5g, said components in mixer, mix mixture.
Embodiment 3: prepare the present composition from dihydromyricetin and ampelopsin crystal
Get first kind of compositions (or the third compositions of embodiment 2) 30g of embodiment 1 respectively, lactose 53g, sodium carboxymethyl cellulose 1.5g, magnesium stearate 0.5g, 50% ethanol 5ml, said components is mixed the back compacting in flakes in mixer.
Embodiment 4: prepare the present composition from dihydromyricetin and ampelopsin crystal
Get dihydromyricetin 115g, ampelopsin 15g, Icing Sugar 345g, dextrin 145g, ethanol 5ml, said components is mixed after drying, obtains electuary.
Embodiment 5: prepare the present composition from porcelain ampelopsis
Get the dry young stem and leaf 2kg of Ampelopsis grossedentata, with 95% ethanol (medical ethanol) reflux, extract, twice, each 2 hours, filter, merging filtrate is evaporated to dried, add 1200 milliliters of 85 ℃ of hot water, extractum is fully dissolved, elimination black insoluble matter, add silica gel (100 order) 200g in the filtrate, filtrate is heated to 60 ℃, take advantage of heat filtering, filtrate is cooled to room temperature, precipitation, standing over night, obtain yellow mercury oxide, productive rate: 11.2%.Dihydromyricetin cellulose content 74.8% weight ratio wherein, ampelopsin content 21.1% weight ratio, the content of arbutin is 2.8% weight ratio, the content of gallic acid is 1.3% weight ratio.Thin-layer chromatographic analysis polyamide thin layer chromatography, specification 8 * 8cm, developing solvent: methanol, developer: 4% ferric chloride-alcoholic solution, Rf gallic acid=0.72, Rf arbutin=0.54, Rf dihydromyricetin=0.50, Rf ampelopsin=0.21.
Perhaps get the dry young stem and leaf 2kg of Ampelopsis grossedentata, with 95% ethanol (medical ethanol) reflux, extract, twice, each 2 hours, filter, merging filtrate is evaporated to dried, add 1200 milliliters of 85 ℃ of hot water, extractum is fully dissolved, elimination black insoluble matter, filtrate is used twice of equal-volume ethyl acetate extraction, combined ethyl acetate solution, be evaporated to driedly, obtain yellow mercury oxide, productive rate: 10.25%.Dihydromyricetin cellulose content 76% weight ratio wherein, ampelopsin content 18% weight ratio, the content of arbutin is 3.0% weight ratio, and the content of gallic acid is 2% weight ratio, and all the other are the composition of Rf5=0.41 in the porcelain ampelopsis.Thin-layer chromatographic analysis polyamide thin layer chromatography, specification 8 * 8cm, developing solvent: methanol, developer: 4% ferric chloride-alcoholic solution, R
The f gallic acid=0.72, R
The f arbutin=0.54, R
The f dihydromyricetin=0.50, R
The f ampelopsin=0.21, R
F5=0.41.
Embodiment 6: prepare the present composition from the Northeastern Caulis seu folium ampelopsis brevipedunculatae plant
Under the room temperature, the Northeastern Caulis seu folium ampelopsis brevipedunculatae 1000 gram flush away dust with collecting add 4000 ml waters, supersound extraction 0.5 hour is filtered, and residue adds 1000 milliliters of propanol again, supersound extraction is 0.5 hour again, refilters, and filtrate merges, be concentrated into 2 milliliters, add 500 milliliters of 100 ℃ of hot water, be cooled to 60 ℃, leave standstill, filter.Filtrate is heated to 70 ℃ with silica gel (100 order) 100g absorption with filtrate, takes advantage of heat filtering, and filtrate is cooled to room temperature, precipitation, and standing over night obtains yellow mercury oxide, productive rate: 10.3%.Dihydromyricetin cellulose content 58% weight ratio wherein, ampelopsin content 14l weight ratio, the content of arbutin is 1.4% weight ratio, and the content of gallic acid is 1.7% weight ratio, and all the other are the composition of Rf5=0.43 in the Northeastern Caulis seu folium ampelopsis brevipedunculatae plant.Thin-layer chromatographic analysis polyamide thin layer chromatography, specification 8 * 8cm, developing solvent: methanol, developer: 4% ferric chloride-alcoholic solution, Rf gallic acid=0.76, Rf arbutin=0.55, Rf dihydromyricetin=0.54, Rf ampelopsin=0.22, Rf5=0.43.
Embodiment 7: the test of pesticide effectiveness that contains the outer anti-hepatitis virus of composition of dihydromyricetin and ampelopsin
Select 2215 cell strains of hepatitis B virus (HBV) DNA transfection, with the titre of HBsAg and HBeAg in its culture supernatant as the index of estimating anti-HBV effect, the anti-HBV effect of first kind of compositions of the research embodiment of the invention 5.The toxicity of tetramethyl azo azoles salt (MTT) colorimetric analysis detection of drugs pair cell is also adopted in this test, selects for use acyclovir as positive control.
1. materials and methods
1.1 active component
1.1.1 the compositions that the embodiment of the invention 6 obtains
1.1.2 sweet Thailand of positive drug or injection acyclovir (Acyclovir for Injection), lot number: 20,000,409 2, Hubei Qianjiang Pharmaceutical Co., Ltd. produces, and the accurate word (1991) of medicine is defended No. 000354 in Hubei Province.
1.2 cell and reagent
2215 cells go out this laboratory to be preserved, and culture fluid is DMEM (a Gibco company), contains 10% hyclone in the culture fluid, 38ug/mlG418 (Geneticin, Gibco company), 0.03%L-glutamine (magnificent import packing), various each 1000iu/ml of penicillin and streptomycin.
MTT (Switzerland Fluka company), dimethyl sulfoxide (DMSO) (Serva company)
HBsAg, HBeAg test kit are provided by Shanghai industry Hua Sheng Science and Technology Ltd..Lot number: 08-2000-03,06-2000-02
1.3 cell culture and experiment grouping
2215 cells are according to a conventional method with 10
3-10
4The concentration in individual/hole is inoculated 96 well culture plates, every hole 0.1ml, 5%CO
2, 37 ℃ remove culture fluid after cultivating 24h, proportionately contain the culture fluid of medicine, wherein first of embodiment 5 kind of compositions established 6 concentration: 95ug/ml, 195ug/ml, 385ug/ml, 750ug/ml, 1500ug/ml, 3100ug/ml, acyclovir is established 6 concentration, i.e. 62.5ug/ml, 125ug/ml, 250ug/ml, 500ug/ml, 1mg/ml, 2mg/ml, and each concentration is established 5 parallel holes, establish simultaneously that not add the medicine hole be matched group, cultivate and gather in the crops supernatant after 5 days.
1.4 the cytotoxic assay of medicine
After the medication 5 days, each hole supernatant exhausts, culture hole adds the culture fluid that contains MTT again, and making the MTT ultimate density is 0.5mg/ml, 37 ℃ of cultivation 4h, discards culture fluid, every hole adds 100ulDMSO, vibration 10min, 490nm measures the OD value on the microplate reader, with absorbance (survivaling cell the is 100%) comparison of corresponding control wells, calculating survivaling cell percentage ratio is determined the maximal non-toxic dose concentration of medicine pair cell.
1.5 detect
Release 4-5 dosage level forward according to the maximal non-toxic dose concentration of medicine pair cell, gather in the crops the detection that supernatant at different levels are used for HBsAg and HBeAg, detect and undertaken by operating instruction.
1.6 the evaluation methodology of the anti-HBV of medicine
With medicine the suppression ratio of HBsAg or HBeAg is estimated
2. result
2.1 the toxicity of medicine pair cell
Found that along with the raising with concentration, the toxicity of its pair cell increases, the maximal non-toxic concentration of pair cell (survivaling cell is at the drug level more than 90%) is 750ug/ml, and the positive drug acyclovir is 500ug/ml (table 1).
2.2 the anti-HBV effect of medicine
First kind of compositions of the embodiment of the invention 6 and positive drug the results are shown in Table 2 to the inhibition of 2215 emiocytosis HBsAg, HBeAg, as can be seen from the table, under the used concentration of this test: first kind of compositions of the embodiment of the invention 6 to the suppression ratio of HBsAg, HBeAg respectively between 15.68 ± 3.723%-54.65 ± 9.067% and 25.84 ± 1.705-45.38 ± 8.705%, along with its suppression ratio of increase of drug level increases gradually, when drug level reaches 750ug/ml, to the suppression ratio of HBsAg greater than 50%.
The positive drug acyclovir is respectively between 19.48 ± 9.86%-51.86 ± 7.14% and 20.42 ± 1.52%-28.44 ± 5.15% the secretion suppression ratio of HBsAg, HBeAg, when drug level is 500ug/ml, to the suppression ratio of HBsAg greater than 50%.
The toxicity of first kind of compositions pair cell of table 1 embodiment of the invention 6
Medicine name concentration (ug/ml) survivaling cell (%M ± S)
3100????????????????52.38±1.20
The present invention 1,500 88.40 ± 2.11
Embodiment 750 92.60 ± 1.82
5 obtain 385 93.31 ± 5.45
Compositions 195 95.68 ± 4.78
95??????????????????99.70±1.28
2000????????????????76.64±4.96
Ah 1000 87.40v1.51
Former times 500 92.54 ± 1.76
Lip river 250 92.76 ± 8.84
Wei 125 92.06 ± 4.87
62.5????????????????96.48±4.04
The external anti-HBV result of the test of the compositions that table 2 embodiment of the invention 6 obtains
Medicine name concentration (ug/ml) HbsAg suppression ratio HBeAg suppression ratio
(％M±S)????????(％M±S)
The present invention 95 15.68 ± 3.723 25.84 ± 1.705
Embodiment 195 23.68v2.213 28.39 ± 7.087
5 obtain 385 35.48 ± 8.705 31.49 ± 4.689
Compositions 750 54.65 ± 9.067 45.38 ± 8.705
Ah 62.5 19.48 ± 9.86 20.42 ± 1.52
Former times 125 25.88 ± 11.09 20.94 ± 10.55
Lip river 250 44.44 ± 5.94 21.62 ± 19.95
Wei 500 51.86 ± 7.14 28.44 ± 5.15
The compositions that above result shows the embodiment of the invention 6 has certain anti-hepatitis B activity external.Test with first kind of compositions of the compositions of the embodiment of the invention 5, embodiment 1 or the third compositions of embodiment 2, also obtained essentially identical result, these compositionss all have an anti-hepatitis B activity external.
Embodiment 8: the compositions that contains dihydromyricetin and ampelopsin in the duck body to the therapeutic effect of duck hepatitis B virus infection
Carry out therapeutic test in duck hepatitis B virus infection duck body, whether the compositions that the observation embodiment of the invention 1,2,5 and 6 obtains suppresses DHB.
An age in days Beijing duck intravenous injection DHB is adopted in experiment, begin after 7 days to the oral embodiment of the invention 1 of duck, 2,3 dosage groups 1.25 of 5 compositionss that obtain, 2.5 and 5.0g/kg, 1 day 2 times, administration 10 days (Bid * 10), observe medicine to toxicity of duck and the influence of the clear DHB DNA of Sanguis Anas domestica (DHBV-DNA), and compare with lamivudine.
Experiment shows, the embodiment of the invention 1,2,5.0g/kg is oral for the heavy dose of group of 5 compositionss that obtain, 1 day 2 times 10 days, avirulence, first experiment is by the pairing statistics, 5.0g/kg group, after the administration after the 5th, 10 day and the drug withdrawal 3 days clear DHBV-DNA of treatment group Sanguis Anas domestica have highly significant to descend (P＜0.01).By statistics in groups and matched group separately relatively, after the administration the 5th day, after the 10th day and the drug withdrawal 3 days, the clear DHBV-DNA of treatment group Sanguis Anas domestica had highly significant to descend (P＜0.01).2.5g/kg group, after the administration after the 5th, 10 day and the drug withdrawal 3 days clear DHBV-DNA of treatment group Sanguis Anas domestica (P＜0.05-0.01) is arranged significantly and highly significant decline.By statistics in groups and matched group separately relatively, after the administration after the 10th day and the drug withdrawal 3 days, the clear DHBV-DNA of treatment group Sanguis Anas domestica had highly significant to descend (P＜0.05).1.25g/kg group, after the administration the 5th day, by the pairing statistics, the clear DHBV-DNA of treatment group Sanguis Anas domestica had highly significant to descend (P＜0.01).By statistics in groups, after the administration the 5th day, the clear DHBV-DNA of treatment group Sanguis Anas domestica had remarkable decline, (P＜0.05).Second batch of experiment 5.0g/kg group, by the pairing statistics, after the administration the 5th day, 3 days clear DHBV-DNA of treatment group Sanguis Anas domestica had highly significant and significantly descend after the 10th day and the drug withdrawal, (P＜0.01-0.05).By statistics in groups and matched group separately relatively, after the administration the 5th day, the 10th day, the clear DHBV-DNA of treatment group Sanguis Anas domestica had highly significant and significantly descends, (P＜0.01-0.05).2.5g/kg group, by statistics in groups and matched group separately relatively, after the administration the 10th day, the clear DHBV-DNA of treatment group Sanguis Anas domestica had remarkable decline, (P＜0.05).1.25g/kg group, the unrestraint effect.The 3rd crowd of experiment 5.0g/kg, pairing statistics, after the administration the 5th, 10 day, the clear DHBV-DNA of treatment group Sanguis Anas domestica had highly significant and remarkable result.(P＜0.01-0.05)。By statistics in groups and matched group separately relatively, after the administration the 5th day, the clear DHBV-DNA of treatment group Sanguis Anas domestica had highly significant to descend (P＜0.01).2.5g/kg group, by pairing statistics, after the administration after the 5th, 10 day and the drug withdrawal 3 days, the clear DHBV-DNA of treatment group Sanguis Anas domestica had significantly and highly significant decline, (P＜0.05,0.01,0.05).Statistics in groups, after the administration the 5th day, the 10th day, the clear DHBV-DNA of treatment group Sanguis Anas domestica had significantly and highly significant decline, (P＜0.05-0.01).1.25g/kg group, the unrestraint effect.The lamivudine matched group has the highly significant effect, and illustrative experiment is credible.Prompting: the embodiment of the invention 1,2, or 5 compositionss that obtain are effective to duck hepatitis B virus infection in the 3.4-10.0g/kg group.
Material and method
(1) medicine
The compositions that the embodiment of the invention 5 obtains is prepared with normal saline.
The positive drug lamivudine is prepared with normal saline by Glaxo Wellcome drugmaker product.
(2) virus
DHB DHB DNA (DHBV-DNA) strong positive serum picks up from the Shanghai sheldrake ,-70 ℃ of preservations.
(3) animal
1. age in days Beijing duck is available from animal feeding field, progressive species duck field, Beijing.
(4) reagent
α-
32P-dCTP is available from the auspicious biotechnology of Beijing good fortune engineering company.The nick translation medicine box is available from Pu Luomaige company (Promega Co.); Sephadex G-50, Ficoll PVP is available from Sweden Pharmacia company; SDS West Germany Merck company product; Milt DNA, bovine serum albumin are Instite of Biophysics, Chinese Academy of Sciences's product; Nitrocellulose filter 0.45um Amersham company product.
(5) experimental technique
1. duck hepatitis B virus infection:
1 age in days Beijing duck, clear through the positive Sanguis Anas domestica of lower limb shin intravenous injection Shanghai sheldrake DHBV-DNA, every 0.2ml got blood in back 7 days in infection, separation of serum ,-70 ℃ of preservations are to be checked.
2. Drug therapy test:
DHBV infect duckling after 7 days random packet carry out the Drug therapy test, 6 every group, 3 dosage groups of administration component are respectively 1.25,2.5, the 5.0g/kg group is oral, 1 day 2 times, 10 days.If virus control group (DHBV) is with the physiologic saline for substitute medicine.The positive drug lamivudine, oral administration 50mg/kg, 1 day 2 times, 10 days.The 7th day is (T0) before the medication after infection, and medication the 5th day (T5) after medication the 10th day (T10) and the drug withdrawal the 3rd day (P3), is got blood from duck lower limb shin vein, separation of serum, and-70 ℃ of preservations are to be checked.
3. detection method:
It is clear to get above-mentioned Sanguis Anas domestica to be checked, and every batch with the time point film, measure Sanguis Anas domestica clear in the DHBV-DNA level dynamically, press nick translation test kit description method, usefulness
32P labelling DHBV-DNA probe, and make the clear dot blot hybridization of Sanguis Anas domestica, autoradiography diaphragm speckle is measured OD value (optical filter is 490nm) at enzyme mark detector, calculating serum DHBV-DNA density, with hybridization spot OD value as specimen DHBV-DNA level value.
(6) drug effect is calculated
1. calculate the meansigma methods (X ± SD) of every group of duck different time serum DNA OD value, and with (T0) OD value comparison before the 3rd day (P3) serum DHBV-DNA level after different time (T5, T10) and the drug withdrawal after every group of duck medication and the administration on the same group, adopt paired t-test, calculate t1, P1 value.Analyze the significance of difference, judge the inhibition effect of medicine viral infection.
2. calculate the inhibition % of different time (T5, T10) and the 3rd day (P3) serum of drug withdrawal DHBV-DNA after every group of duck medication, and mapping, respectively organize the clear DHBV-DNA suppression ratio of Sanguis Anas domestica dynamically.
The result
After (one) 1 age in days Beijing duck infected DHBV, serum DHBV-DNA was dynamic
The DHBV-DNA results of dot sees Table 3 behind the DHBV-DNA infected duck oral normal saline.78 serum DHBV-DNA of three batches of experimental infections total positives.18 ducklings of virus control group infect the 7th day serum DHBV-DNA total positives in back, test in omnidistance 21 days steady substantially behind the serum DHBV-DNA level infection for three batches.
(2) the positive drug lamivudine is to the influence of DHBV infected duck serum DHBV-DNA
The oral positive drug lamivudine of DHBV infected duck 50mg/kg, 1 day 2 times, 10 days.The results are shown in Table 3, table 4.Pair analysis, before administration the 10th day (T10) and the administration OD value of (T0) relatively, decline has highly significant (P＜0.01), after the administration to serum DHBV-DNA suppression ratio and virus control group, become group analysis administration the 10th day (T10) significant differences to be arranged, (P＜0.01).3 days (P3) not statistically significants after the drug withdrawal.Rebound phenomenon is arranged.
(3) first of the embodiment of the invention 5 kind of compositions in DHBV infected duck body to the influence of the clear DHBV-DNA of Sanguis Anas domestica
Three batches of experimental results show:
1. 3 dosage groups are selected in first experiment for use, see Table 3, Fig. 1.Be respectively 1.25,2.5 and 5.0g/kg group, after (T0) and the administration after the 5th day (T5), 10 days (T10) and the drug withdrawal 3 days (P3), get Sanguis Anas domestica before administration, separation of serum detects DHBV-DNA OD value, does self comparison.The result shows: 5.0g/kg organizes after the 5th day (T5) of administration, the 10th day (T10) and drug withdrawal the 3rd day (P3), before clear DHBV-DNAOD value of Sanguis Anas domestica and the administration (T0) relatively, pair analysis has the inhibitory action of highly significant.(P＜0.01)。Become group analysis, administration the 5th day, after 10 days (T10) and the drug withdrawal the 3rd day (P3), administration group and matched group relatively have the inhibitory action of highly significant.(P＜0.01)。2.5g/kg group, after the 5th day (T5) of administration, the 10th day (T10) and drug withdrawal the 3rd day (P3), (T0) compares before Sanguis Anas domestica clear DHBV-DNA OD value and the administration, and pair analysis has significantly and the inhibitory action of highly significant.(P＜0.05-0.01)。Become group analysis, after administration the 10th day (T10) and the drug withdrawal the 3rd day (P3), administration group and matched group comparison have significant inhibitory effect.(P＜0.05)。1.25g/kg group, (T0) compares before Sanguis Anas domestica clear DHBV-DNA OD value and the administration, and pair analysis in administration the 5th day (T5), has significant inhibitory effect.(P＜0.05)。Become group analysis, administration the 5th day (T5), administration group and matched group relatively have significant inhibitory effect.(P＜0.05)。
2. second batch of experimental result shows: see Table 3,4, Fig. 2.5.0g/kg group different time after administration, the clear DHBV-DNA of Sanguis Anas domestica, (T0) compares before OD value and the administration, the 5th day (T5), 10 days (T10) after the administration, with the 3rd day (P3) after the drug withdrawal, highly significant and remarkable inhibitory action are arranged, (P＜0.01-0.05), become group analysis, suppressing % with matched group analyzes, administration the 5th day (T5), the 10th day (T10) have highly significant and remarkable inhibitory action, (P＜0.01-0.05).2.5g/kg group, pair analysis, the 10th day (T10) has the highly significant inhibitory action after the administration, and (P＜0.01) becomes group analysis, suppresses % with matched group and analyzes, and administration the 10th day (T10) has remarkable inhibitory action, (P＜0.05).1.25g/kg group, inhibitory action is not obvious.
3. the 3rd crowd of repeated experiments result shows: see Table 3,4, Fig. 3.5.0g/kg after the group administration the 5th, 10 day, before DHBV-DNA and the administration relatively, pair analysis, highly significant and remarkable inhibitory action are arranged, and (P＜0.01-0.05), become group analysis suppresses % with matched group and analyzes, administration the 5th day (T5) has the highly significant inhibitory action, (P＜0.01).2.5g/kg group, pair analysis with comparison before the administration, after the 5th day (T5) of administration, the 10th day (T10) and the drug withdrawal the 3rd day (P3), has highly significant and remarkable inhibitory action, (P＜0.05,0.01,0.05).Become group analysis, suppress % with matched group and analyze, administration the 5th day (T5), the 10th day (T10) have significantly and the highly significant inhibitory action, (P＜0.05-0.01).1.25g inhibitory action is not obvious.
First kind of compositions of table 3 embodiment of the invention 5 duck hepatitis B virus infection duck interior therapeutic group with
The clear DHBV-DNA OD of viral infection matched group Sanguis Anas domestica value relatively
The clear DHBV-DNA OD490 of test dose duck number (only) Sanguis Anas domestica value (P3 of X ± SD)
Group
Batch g/kg bid * 10 T0 T5 T10
Normal saline 6 0.958 ± 0.06 0.926 ± 0.07 0.930 ± 0.07 0.910 ± 0.07
The invention process 1.25 6 0.938 ± 0.09 0.738 ± 0.10** 0.836 ± 0.13 0.783 ± 0.19
I
The the one 2.5 6 0.918 ± 0.06 0.775 ± 0.09*, 0.675 ± 0.08** 0.698 ± 0.05** of example 5
Plant compositions 5.0 6 1.291 ± 0.21 0.985 ± 0.23**, 0.916 ± 0.16**, 0.943 ± 0.09**
Normal saline 6 0.549 ± 0.05 0.528 ± 0.04 0.514 ± 0.03 0.515 ± 0.03
The invention process 1.25 6 0.638 ± 0.15 0.529 ± 0.09 0.526 ± 0.08 0.546 ± 0.09
II
The the one 2.5 6 0.731 ± 0.05 0.665 ± 0.09 0.576 ± 0.04** 0.656 ± 0.06 of example 5
Plant compositions 5.0 6 1.251 ± 0.38 0.675 ± 0.26**, 0.758 ± 0.28**, 0.810 ± 0.24*
Normal saline 6 0.802 ± 0.05 0.795 ± 0.06 0.755 ± 0.02 0.776 ± 0.08
The invention process 1.25 6 0.989 ± 0.05 0.985 ± 0.20 0.955 ± 0.21 0.896 ± 0.09
The the one 2.5 6 1.383 ± 0.23 1.005 ± 0.10*, 0.985 ± 0.09** 0.995 ± 0.13* of III example 5
Plant compositions 5.0 6 1.385 ± 0.09 0.679 ± 0.32**, 0.915 ± 0.39* 1.230 ± 0.29
3TC?????????0.05??????6????????????????1.554±0.17???????1.195±0.62??????0.657±0.20**?????1.742±0.14
Statistical disposition: t1, P1: (T5, T10, P3) the clear DHBV-DNA OD of Sanguis Anas domestica value compares (paired t-test) with preceding (T0) OD value of infection to administration group different time.
*p1＜0.05，
**p1＜0.01。
First kind of combination treatment of table 4. oral embodiment of the invention 5 in duck hepatitis B virus infection duck body
Group and viral infection matched group
The comparison of the horizontal suppression ratio of the clear DHBV-DNA of Sanguis Anas domestica
The test dose duck is counted suppression ratio (%)
Medicine
(only) T5 P3
Batch g/kg bid * 10 T10
Virus control 6 3.32 2.91 4.90
The embodiment of the invention 5
1.25??????????????6????????????????21.25*?????????10.25?????????16.18
First kind of compositions of I, 2.5 6 15.25*, 25.97 23.78*
5.0???????????????6????????????????23.13**????????29.15**???????26.35**
Virus control 6 3.51 5.86 5.62
The embodiment of the invention 5
1.25??????????????6????????????????16.96*?????????17.58?????????14.25
First kind of compositions of II
2.5???????????????6????????????????9.12???????????21.50*????????10.26
5.0???????????????6????????????????46.09**????????38.80*????????35.27*
Virus control 6 0.88 5.65 2.99
The embodiment of the invention 5
1.25??????????????6????????????????0.41???????????3.18??????????9.25
First kind of compositions
III
2.5???????????????6????????????????27.21*?????????28.69**???????27.86
5.0???????????????6????????????????50.98**????????33.98?????????11.56
3TC????????????????????50mg/kg???????????6????????????????23.88??????????56.67**???????-13.16
Virus control 6 3.32 2.91 4.90
The embodiment of the invention 5
1.25??????????????6????????????????19.57*?????????8.31??????????14.80
First kind of compositions of I
2.5???????????????6????????????????13.52??????????23.68?????????22.03*
5.0???????????????6????????????????19.39**????????26.76**???????23.96**
II virus control 6 3.51 5.86 5.62
The embodiment of the invention 5
1.25????????????6????????????????10.50???????????6.68????????????7.06
First kind of compositions
2.5?????????????6????????????????6.86????????????17.02*??????????6.16
5.0?????????????6????????????????36.35**?????????26.80*??????????20.01
Virus control 6 0.88 5.65 2.99
The embodiment of the invention 5
1.25????????????6????????????????-5.34???????????0.23????????????5.94
First kind of compositions
III
2.5?????????????6????????????????19.93*??????????26.39**?????????23.56
5.0?????????????6????????????????50.82**?????????32.87???????????9.53
3TC???????????????????50mg/kg?????????6????????????????23.88???????????56.67**?????????-13.16
Statistical disposition: t2, P2: (T5, T10, P3) the clear DHBV-DNA level of Sanguis Anas domestica suppresses % relatively (t checks in groups) with infection preceding (T0) inhibition % and virus control group relatively to administration group different time.
*p2＜0.05，
**p2＜0.01，
***p2＜0.001。
Sum up
First kind of compositions of the embodiment of the invention 5 tested at duck hepatitis B virus infection duck interior therapeutic, three batches of experimental results show: first kind of combination treatment of duck hepatitis B virus infection duck the 7th day oral embodiment of the invention 5 after infection, 5.0g/kg the inhibition effect to infected duck serum DHBV-DNA level had the highly significant effect in one day 2 times 10 days, (P＜0.01), non-toxic reaction; 2.5g/kg group administration the 5th, 10 day in experiment has certain inhibitory action.Remarkable and highly significant effect are arranged, (P＜0.05,0.01).The 1.25g/kg group does not have obvious inhibitory action in the experiment.The oral inhibitory action to DHBV-DNA of positive drug lamivudine has the inhibitory action of highly significant.With repeatedly experimental result was consistent in the past.Above experimental result shows: first kind of combination treatment duck hepatitis B virus infection duck of the embodiment of the invention 5 is effective, and effective dose is 2.5-5.0g/kg, one day 2 times 10 days.
Compositions with compositions, embodiment 2 compositionss and the embodiment 6 of embodiment 1 is carried out above-mentioned test, has also obtained essentially identical result, illustrates that these combination treatment duck hepatitis B virus infection ducks are effective.
Embodiment 9: contain the resisiting influenza virus experiment of the compositions of dihydromyricetin and ampelopsin:
Separation of influenza virus and mirror (dripping) are fixed
Embryo Gallus domesticus at present commonly used separates and carries out influenza virus, route of inoculation is the allantoic cavity of Embryo Gallus domesticus, occurs the characteristics of lesion of back chicken embryo death after 3 days and hemagglutinin occurs, to this, we adopt the method to carry out the evaluation of compositions that the embodiment of the invention 1,2 or 5 is obtained.We adopt the influenza virus of certain density extracting solution and 4 HAUs to mix at 1: 1, allow the two inject Embryo Gallus domesticus after 20 minutes again in the room temperature effect, and injection volume is every embryo 0.2ml.The Embryo Gallus domesticus of 9 to 11 ages in days is adopted in experiment, carry out the allantoic cavity inoculation, cultivate after 48 hours, placed liquid in 4 ℃, aseptic then its urine of getting, get supernatant through 1000rpm after centrifugal 10 minutes, packing is deposited for-20 ℃, the usefulness that is equipped with detection, the detection of urine divides blood clotting and blood to press down two kinds, and the erythrocyte of use comes prosperous cock, and method is a conventional method.
The antiviral experiment: the compositions that the embodiment of the invention 5,6,1 or 2 of usefulness variable concentrations obtains is carried out the antiviral experiment in Embryo Gallus domesticus
Table 5 hirst's hemagglutination inhibition test
Serum dilution stock solution 10 * 20 * 40 * 80 * 160 * 320 * 640 * 1280 *
Sample concentration
Stock solution 1 ++ ++ ++ ++ +++++ ++ ++ ++ ++ ++ ++
+
Stock solution 2 ++ ++ ++ ++ +++++ ++ ++ ++ ++ ++ ++
+
Stock solution 3 ++ ++ ++ ++ +++++ ++ ++ ++ ++ ++ ++ ++ ++
+
Stock solution 4 ++ ++ ++ ++ +++++ ++ ++ ++ ++ ++ ++ ++ ++
+
10
-5a????????++++?????????++++???????+++??????++++??????++++??????++++????????++++???????????++++????++
+
10
-5b????????++++?????????++++???????+++??????++++??????++++??????++++????????++++???????????++++????++
+
10
-5c????????++++?????????++++???????+++??????++++??????++++??????++++????????++?????????????++++
+
10
-5d????????++++?????????++++???????+++??????++++??????++++??????++++????????++++???????????++
+
10
-6a????????++++?????????++++???????+++??????++++??????++++??????++++????????++?????????????++++
+
10
-6b????????++++?????????++++???????+++??????++++??????++++??????++++????????++?????????????++++
+
10
-6c????????++++?????????++++???????+++??????++++??????++++??????++++????????++++???????????++
+
10
-6d????????++++?????????++++???????+++??????++++??????++++??????++++????????++++???????????++
+
Remarks: 1, stock solution refers to the dihydromyricetin 4mg/ml of initial concentration
2,10
-5With 10
-6Finger carries out the dilution factor of medicine from first kind of compositions stock solution of the embodiment of the invention 5
3, during result of determination by blood clotting intensity respectively with ++ ++, +++, ++ ,-expression coagulation appears with 50% erythrocyte ++ the blood clotting dilution factor be its blood clotting decline
Erythrocyte is the invalid main aperture of fine sand grain sample (pipe) end person +++, i.e. 100% coagulation; Erythrocyte evenly is laid on the end, hole (pipe), but the edge is whole to hole (pipe) end concentrator is not slightly +++, i.e. 75% coagulation; (pipe) end, form a ring-type to erythrocyte in the hole, has little coagulation piece person to be all around ++, i.e. 50% coagulation; (pipe) end, form wad to erythrocyte in the hole, but the edge is smooth inadequately, have slightly all around coagulation piece person for+, i.e. 25% coagulation; (pipe) end, form wad to erythrocyte in the hole, and the smooth neat person in edge is one, does not promptly have coagulation.
The compositions that above-mentioned experimental data proof contains dihydromyricetin and ampelopsin has the resisiting influenza virus effect.
Embodiment 10: the test of the function of the compositions enhance immunity systemic immunity power that contains dihydromyricetin and ampelopsin of the present invention
1. contain of the influence of the compositions of dihydromyricetin and ampelopsin to the Turnover of Mouse Peritoneal Macrophages phagocytic function
1.1 experiment purpose
Observation contains the influence of the compositions of dihydromyricetin and ampelopsin to the mice phagocytic function.
1.2 be subjected to the reagent thing
Title: the compositions that contains dihydromyricetin and ampelopsin
Solvent: hot distilled water
Consumption: 0.5ml/20g mice
1.3 control sample
Bifendate; Shanghai balance pharmaceutical factory, the accurate word (1995) of medicine is defended No. 3765-011 in Shanghai
1.4 animal
Mice, the Kunming kind, male, 19～21g.
Chicken red blood cell: 5% concentration
1.5 method
Kunming mouse, be divided into 5 groups at random, it is matched group, the compositions 75 that contains dihydromyricetin and ampelopsin, 150,300mg/kg, bifendate 150mg/kg, matched group gives normal saline, the equal oral administration of administration group, every day 1 time, totally 6 times, lumbar injection 0.5% lactoalbumin hydrolysate 1.5ml/ simultaneously of last administration, pneumoretroperitoneum was injected 5% chicken red blood cell 0.1ml in 24 hours, the blood-letting of breaking end after 30 minutes, use the normal saline flushing abdominal cavity, collect peritoneal macrophage and hatch half an hour for 37 ℃, centrifugal, the precipitate smear, dyeing, counting cells under the oil mirror calculates with following formula, and compares with matched group.
1.6 result
The results are shown in Table 6, the basic, normal, high dosage of compositions that contains dihydromyricetin and ampelopsin all can promote Turnover of Mouse Peritoneal Macrophages to engulf chicken red blood cell and increase phagocytic index, and bifendate 150mg/kg dosage group also can promote the Turnover of Mouse Peritoneal Macrophages phagocytic function.
Table 6. contains the compositions of dihydromyricetin and ampelopsin
To the influence of Turnover of Mouse Peritoneal Macrophages phagocytic function (± SD)
| Group | Dosage approach mg/kg | Number of animals (only) | Phagocytic percentage % | Phagocytic index |
| First kind of compositions of the embodiment of the invention 5 | 75???????po×6 | ??8 | ????32.5±3.5 ** | ????0.67±0.08 ** |
| 150??????po×6 | ??8 | ????43.7±3.9 ** | ????0.90±0.03 ** | |
| 300??????po×6 | ??8 | ????43.7±5.2 ** | ????0.84±0.08 ** | |
| Bifendate | 150??????po×6 | ??8 | ????40.1±4.5 ** | ????0.88±0.03 ** |
| Matched group | Coordinative solvent | ??8 | ????23.0±5.3 | ????0.39±0.12 |
*Compare with model control group P＜0.01
2. contain of the influence of the compositions of dihydromyricetin and ampelopsin to mice spleen lymphocytes proliferation
2.1 experiment purpose
Observation contains the influence of the compositions of dihydromyricetin and ampelopsin to mice spleen lymphocytes proliferation.
2.2 be subjected to the reagent thing
Title: the compositions that contains dihydromyricetin and ampelopsin
Solvent: hot distilled water
Consumption: 0.5ml/20g mice
2.3 control sample
Bifendate; Shanghai balance pharmaceutical factory, the accurate word (1995) of medicine is defended No. 3765-011 in Shanghai
2.4 animal
Mice, C
57BL/6, ♂, 19～21g.
2.5 other materials
Canavaline (ConA): Sigma product, 50 μ g/ml concentration
3H-TdR: Shanghai nuclear research institute, radioactive concentration 1mci/ml
Culture medium: RPMI-1640 includes 2.6 methods such as 15% calf serum, mercaptoethanol, Hepes
C
57The BL/6 mice, be divided into 5 groups at random, be the normal control group, contain compositions 75,150,300mg/kg, the bifendate 150mg/kg of dihydromyricetin and ampelopsin, every day, oral administration was 1 time, continuous 7 days, after administration finishes, put to death under the animal aseptic condition and get spleen, the counting splenocyte, and the adjustment cell concentration is 1 * 10
7/ ml, every hole adds cell suspension 100 μ l on 96 porocyte culture plates, ConA 50 μ l, and culture fluid, each group is all established three multiple pipes, 37 ℃, 5%CO
2Cultivated 48 hours under the condition, add
3H-TdR 0.5 μ ci/ hole continues to cultivate 18 hours, with bull cell harvestor collecting cell, surveys the CPM value on liquid scintillation instrument, and compares with matched group, the results are shown in Table 7.
2.7 result
Table 7. contains the compositions of dihydromyricetin and ampelopsin
Influence to mice spleen lymphocytes proliferation
| Group | Dosage approach mg/kg | Number of animals (only) | The CPM value (± SD) |
| First kind of compositions of the embodiment of the invention 5 | ??75?????po×7 | ??4 | ????11956±2178 ** |
| ??150????po×7 | ??4 | ????7869±1401 * | |
| ??300????po×7 | ??4 | ????7947±1321 * | |
| Bifendate | ??150????po×7 | ??4 | ????7188±1010 ** |
| Matched group | ??N.S. | ??4 | ????5448±917 |
*P＜0.05
*Compare with matched group P＜0.01
The result shows that the compositions that contains dihydromyricetin and ampelopsin has the effect of tangible promotion mice spleen lymphocytes proliferation, and strong than other two groups with the low dosage effect.
Compositions with embodiment 1, embodiment 2 and embodiment 6 is tested, and has obtained roughly the same result of the test, illustrates that these compositionss all have the function of enhancing immunity.
Claims (13)
1. the purposes of compositions in preparation broad-spectrum antiviral medicament compositions and/or raising immunity pharmaceutical composition that contains dihydromyricetin and ampelopsin.
2. the purposes of claim 1 is characterised in that in the wherein said compositions that contains dihydromyricetin and ampelopsin and contains the dihydromyricetin of 20% to 98% weight ratio and the ampelopsin of 2% to 80% weight ratio.
3. claim 1 or 2 purposes are characterised in that wherein said compositions also contains one or more and is selected from following composition: arbutin, gallic acid and/or tea polyphenols.
4. the purposes of claim 3, be characterised in that wherein the content of arbutin is the 0-50wt% of dihydromyricetin and ampelopsin gross weight, the content of gallic acid is the 0-50wt% of dihydromyricetin and ampelopsin gross weight, and the content of tea polyphenols is the 0-50wt% of dihydromyricetin and ampelopsin gross weight.
5. each purposes of claim 1-4 is characterised in that wherein said compositions extracts from ampelopsis.
6. the purposes of claim 5 is characterised in that wherein said ampelopsis comprises ampelopsis cantoniensis, a leaf beautiful Fructus Vitis viniferae, Ampelopsis grossedentata, Cayratia japonica (Thunb.) Gagnep., Radix Ampelopsis, Northeastern Caulis seu folium ampelopsis brevipedunculatae or Vitis Amurensis.
7. each purposes of claim 1-4 is characterised in that wherein said compositions is that described monomer obtains according to described mixed.
8. the purposes of one of claim 1 to 7, wherein drug prepared institute antiviral is hepatitis B virus, influenza virus and/or coronavirus.
9. a broad-spectrum antiviral medicament compositions is characterised in that it contains the compositions that contains dihydromyricetin and ampelopsin of antiviral effective dose.
10. the compositions of claim 9 is characterised in that in the wherein said compositions that contains dihydromyricetin and ampelopsin and contains the dihydromyricetin of 20% to 98% weight ratio and the ampelopsin of 2% to 80% weight ratio.
11. the compositions of claim 9 or 10 is characterised in that wherein said compositions also contains one or more and is selected from following composition: arbutin, gallic acid and/or tea polyphenols.
12. the compositions of claim 11, be characterised in that wherein the content of arbutin is the 0-50wt% of dihydromyricetin and ampelopsin gross weight, the content of gallic acid is the 0-50wt% of dihydromyricetin and ampelopsin gross weight, and the content of tea polyphenols is the 0-50wt% of dihydromyricetin and ampelopsin gross weight.
13. the compositions of one of claim 9 to 12, wherein said antiviral are anti-hepatitis virus, influenza virus and/or coronavirus.
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| CN 03123879 CN1605335A (en) | 2003-05-30 | 2003-05-30 | Antivirus dihydromyricetin and myricetin containing pharmaceutical composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102772398A (en) * | 2011-05-13 | 2012-11-14 | 贵州省生物研究所 | Application of dihydromyricetin in preparation of drug preventing and treating influenza |
| CN105506183A (en) * | 2016-01-21 | 2016-04-20 | 长江大学 | Method for screening antivirus plant ethanol extract |
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| CN102772398A (en) * | 2011-05-13 | 2012-11-14 | 贵州省生物研究所 | Application of dihydromyricetin in preparation of drug preventing and treating influenza |
| CN105506183A (en) * | 2016-01-21 | 2016-04-20 | 长江大学 | Method for screening antivirus plant ethanol extract |
| CN106822092A (en) * | 2017-02-21 | 2017-06-13 | 中国水产科学研究院长江水产研究所 | A kind of pharmaceutical composition for suppressing infected by Aeromonas hydrophila |
| CN106822092B (en) * | 2017-02-21 | 2019-08-06 | 中国水产科学研究院长江水产研究所 | A kind of pharmaceutical composition inhibiting infected by Aeromonas hydrophila |
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| CN115397410A (en) * | 2020-03-16 | 2022-11-25 | 环球生物生命有限公司 | Methods and compositions for treating, preventing, or limiting the occurrence of viral infections |
| CN113679701A (en) * | 2020-05-18 | 2021-11-23 | 中国科学院上海药物研究所 | Use of pyrogallol and its derivatives as covalent ligand reaction warhead |
| CN113679701B (en) * | 2020-05-18 | 2024-04-30 | 中国科学院上海药物研究所 | Use of pyrogallol and derivatives thereof as covalent ligand reaction warheads |
| WO2021243756A1 (en) * | 2020-06-03 | 2021-12-09 | 上海爱启医药技术有限公司 | Pharmaceutical use of myricetin in inhibition of novel coronavirus |
| CN112168899B (en) * | 2020-09-30 | 2022-07-01 | 上海中医药大学 | Ampelopsis grossedentata extract for inhibiting coronavirus 3CL proteolytic enzyme and application thereof |
| CN112168899A (en) * | 2020-09-30 | 2021-01-05 | 上海中医药大学 | Ampelopsis grossedentata extract for inhibiting coronavirus 3CL proteolytic enzyme and application thereof |
| CN112546038A (en) * | 2020-11-19 | 2021-03-26 | 澳门科技大学 | Application of myricetin in preparation of medicine for preventing or treating coronavirus and influenza virus |
| CN113244217A (en) * | 2021-06-25 | 2021-08-13 | 南开大学 | Application of dihydromyricetin in preparation of medicine for inhibiting new coronavirus or pulmonary fibrosis |
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