CN111228343A - Quzhao extract and application thereof in preparation of medicine for preventing and/or treating viral pneumonia - Google Patents
Quzhao extract and application thereof in preparation of medicine for preventing and/or treating viral pneumonia Download PDFInfo
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Abstract
The application discloses a Quzhang extract and application thereof in preparation of a medicament for preventing and/or treating viral pneumonia, wherein the active ingredients of the extract are stilbene substances mainly comprising Quzhang stilbene glucoside, polydatin, methyl polydatin, piceatannol and resveratrol. The extract has various pharmacological activities of resisting virus, resisting bacteria, resisting inflammation, scavenging free radicals, etc., can remarkably reduce lung index of mouse infected by coronavirus, and can resist shock, and can be used for preparing pharmaceutical preparation for preventing and treating viral pneumonia.
Description
Technical Field
The application relates to a quzhao extract and application thereof in preparation of a medicament for preventing and/or treating viral pneumonia, and belongs to the field of medicines.
Background
Viral pneumonia is highly contagious, and is easily infected by the elderly, infants, people with weak constitution and low immunity. Pneumonia can cause lung tissue necrosis to cause lung abscess, and lung infection can also cause various specific complications, for example, infection can spread to pleural cavity to cause empyema, and hematogenous spread can also cause pleuritis, endocarditis, pericarditis, arthritis, etc.
Severe pneumonia can sustain high fever, palpitation, shortness of breath, dyspnea, and may even be accompanied by shock, respiratory failure, respiratory distress syndrome, and multi-organ failure.
In recent years, coronavirus (Coronaviridae) having tropism for gastrointestinal tract, Respiratory tract and nervous system has many times caused severe acute Respiratory Syndrome abused worldwide, such as Severe Acute Respiratory Syndrome (SARS) in winter to 2003 spring in 2002, Respiratory Syndrome in middle east 2012 (MERS) and pneumonia caused by a novel coronavirus "2019-nCoV" in 2019. In recent years, severe viral pneumonia caused by SARS, MERS, H1N1, H5N1, H7N9, 2019-nCoV and other viruses causes great harm and loss to China.
Viral pneumonia has no ideal medicine at present. The only FDA approved drugs for the treatment of adult viral pneumonia are neuraminidase inhibitors. In viral pneumonia, antibacterial drugs are abused seriously, the use rate of antibiotics in respiratory tract infection of diseases in China is close to 100%, and flora disorder and micro-ecological imbalance can be caused by long-term use of broad-spectrum antibiotics. Viral pneumonia is also commonly used as an antiviral drug such as ribavirin, vidarabine and other broad-spectrum antiviral drugs, but the effect is not ideal, and the viral pneumonia is listed as a common urgent and critical disease which is difficult to treat in China. Therefore, in the aspect of preventing and treating viral pneumonia, the search for effective drugs for treating viral pneumonia is urgent need of clinical practice.
Quzha, a Tibetan medicine material, the plant source is Rheum lhasaense A.J. Li et P.K. Hsiao, which belongs to Rheum genus plant of Polygonaceae, is produced in east of Tibet, Sichuan and other places, and is introduced and domesticated successfully in Shandong botanical garden of Shanghai Shang of Shang Dynasty.
The existing research on the chemical components and pharmacological activity of the Lhasa rhubarb finds that the Lhasa rhubarb contains high-content stilbene compounds which mainly comprise Quzhazhigan, methyl polydatin and polydatin. Unlike other rhubarb plants, Quzha contains almost no anthraquinone chemical components with potentially serious toxic side effects.
Disclosure of Invention
The application provides a quzhu extract for solving the technical problems and application thereof in preparing a medicament for preventing and/or treating viral pneumonia.
The application provides an application of a quzhao extract in preparation of a medicament for preventing and/or treating viral pneumonia. The effective components of the extract of Quzhazhiza trifoliata include stilbene substances mainly including Quzhazhigan, polydatin, methyl polydatin, piceatannol and resveratrol.
The Quzhu extract has various pharmacological activities such as antiviral activity, antibacterial activity, anti-inflammatory activity, free radical removal activity and the like, can inhibit SARS virus in vitro and protect infected cells, has a remarkable protective effect on mouse viral pneumonia caused by influenza A virus H1N1, and can remarkably prolong the survival time of endotoxic shock rats. The Quzhao extract can be used for preparing medicine for preventing and treating viral pneumonia.
In the present application, "stilbene compound" refers to a compound containing stilbene structural units in the compound structure, and the chemical structure general formula of the stilbene compound is:
in the formula I, R is selected from-H, -OH and-OCH3At least one of, -O-glucosyl group and-O-substituted glucosyl group.
Preferably, the pathogen of viral pneumonia comprises a coronavirus.
Preferably, the treatment comprises reducing the viral load in the blood of a patient with viral pneumonia.
Preferably, the viral pneumonia comprises severe viral pneumonia with shock symptoms.
Preferably, the raw material for extracting the Quzhu extract is rhizomes of Rheum lhasaense; the Rheum lasianum is planted in wild or artificial mode; the medicinal material base source of the quzhao is wild or planted rhizome of Rheum lhasaense (Rheum lhasaense A.J.Li et P.K.Hsiao),
the medicine is oral preparation, inhalant or injection.
The Quzha extract can be made into oral preparation, inhalant or injection, specifically injection and aerosol, by conventional method. The injection has quick absorption and rapid action. Especially intravenous injection, the liquid medicine can directly enter blood circulation, and is more suitable for rescuing critical diseases. The spray administration is an important local administration way, and is direct and rapid for respiratory diseases, particularly patients with pneumonia, and is beneficial to the rapid prevention and treatment of diseases and severe diseases.
Another aspect of the present application also provides a koji extract used in the above application, comprising: 50 to 100 percent of Quzhazhigan in percentage by weight; preferably, the said extract of kozakha comprises: 50-100% of polydatin in percentage by weight; preferably, the said extract of kozakha comprises: 50-100% of methyl polydatin. The extract contains only one of Quzhazhigan, polydatin or methyl polydatin, and can be used for the above purpose.
Specifically, the chemical formula of the Quzhazhigan is (E) -1- (3, 5-dihydroxyphenyl) -2- (3-hydroxy-4-O-D-glucopyranosyl phenyl) ethylene or 3,5,3 ', 4 ' -tetrahydroxystilbene-3 ' -O- β -glucoside, and the structural formula is shown as formula II:
specifically, the polydatin has a chemical formula of 4 ', 5-dihydroxy-stilbene-3-O-glucoside (4', 5-dihydroxy-stilbene-3-O-glucoside, polydatin, piceid), and a structural formula of III:
specifically, the chemical formula of the methyl polydatin is 5-hydroxy-4 '-methoxystilbene-3-O-glucoside (4' -methoxy-5-hydroxy-stilbene-3-O-glucoside, deoxyhalophilic), and the structural formula is shown as formula IV:
preferably, the said extract of kozakha comprises: the Quzha extract comprises: the total content of the stilbene compounds is 50-100% in percentage by weight; preferably, the said extract of kozakha comprises: 20-55% of methyl polydatin, 5-35% of Quzhazhigan, 1-35% of resveratrol and 1-35% of piceatannol. The stilbene compounds are total extract of Quzhu.
Preferably, the said extract of kozakha comprises: 20-55% of methyl polydatin, 5-35% of Quzhazhigan, 5-9% of resveratrol and 1-30% of piceatannol.
Specifically, the structural formula of resveratrol is shown as formula V:
specifically, the structural formula of piceatannol is shown as formula VI:
preferably, the Quzhazhiza extract comprises 20-28 wt% of methyl polydatin, 5-35 wt% of (E) -5-O-methyl-resveratrol-3-O- β -glucoside, 1-35 wt% of resveratrol and 1-25 wt% of piceatannol.
The (E) -5-O-methyl-resveratrol-3-O- β -glucoside is prepared by extraction from Acer mono Maxim, see H.Yang, S.H.Sung and Y.C.Kim, J.Nat.Prod.,2005,68,101. No active report on the substance has been found in previous researches.
The extract of the quzhu is obtained by mixing the substances according to the proportion and is used as a medicament, so that the activity of virus in a human body can be well inhibited, SARS virus can be effectively inhibited, infected cells can be protected, the extract has a remarkable protection effect on mouse viral pneumonia caused by influenza A virus H1N1, and the survival time of endotoxic shock rats can be remarkably prolonged.
Preferably, the Quzhazhiza extract comprises 10-15 wt% of methyl polydatin, 40-55 wt% of (E) -5O-methyl-resveratrol-3-O- β -glucoside, 1-2 wt% of methyl resveratrol and 1-5 wt% of piceatannol.
The extract of the Quzhazha koidz provided by the application can inhibit SARS virus and protect infected cells, has a significant protective effect on mouse viral pneumonia caused by influenza A virus H1N1, and can significantly prolong the survival time of endotoxic shock rats no matter the extract is the total extract of the Quzhazha koidz or three stilbene glucoside monomeric compounds of the Quzhazhigan, the methyl polydatin and the polydatin are independently used as the extract. More unexpectedly, in a pharmacodynamic experiment, after the quzhu extract is used as an injection, the injection shows a very significant (P <0.01) effect of reducing the pulmonary index of a mouse with pneumonia caused by coronavirus H1N1 under the condition of a lower dose, has a good treatment effect on pulmonary edema caused by viral pneumonia, and has a very positive treatment significance for relieving the symptoms of patients with severe viral pneumonia.
In addition, the total extract of the quzhazhigan and the quzhazhigan injection have obvious effect of prolonging the survival time of the endotoxic shock rats and can obviously improve the survival rate of the shock rats for 6 hours (85%). The survival rate is improved, and the method is also of great significance for saving patients with severe shock. Therefore, the Quzhao extract can be used for preparing a medicine for preventing and treating viral pneumonia and has a positive effect on treating severe patients. The invention also finds that the effect of the total extract of the Quzha is better than that of a single stilbene glucoside component, and the pleiotropic effect of multiple components is more advantageous in the drug effect.
Specifically, the extraction method of each substance contained in the Quzhao extract comprises the following steps:
a. collecting underground rhizome of the plant of the quzha, washing with water to remove soil, hanging in a ventilation place, air-drying, and cutting;
b. soaking underground rhizome granules of the plant of the quzhu in 75% ethanol for 24 hours, and filling a percolation column with the volume of V (ethanol): w (weight of medicinal material) is 8: percolating with 1 time 75% ethanol at a flow rate of 20ml/min, mixing the extractive solutions, and concentrating under reduced pressure to obtain total extract of Quzhang; the total extract of Quzhang contains said methyl polydatin, Quzhazhigan, resveratrol, and piceatannol.
c. B, adding water into the total extract of the Quzhazhiza trifoliata in the step b for precipitation, collecting the precipitate, directly drying the precipitate or further crystallizing and refining the precipitate to obtain an extract of the methyl polydatin, wherein the content of the methyl polydatin is 50 to 100 percent by mass percent;
d. c, putting the water solution after precipitation in the step c on D101 macroporous resin, eluting by 10 times of 30 percent ethanol, and concentrating the eluent by 3 to 5 times of the volume under reduced pressure or further recrystallizing to obtain the extract enriched with the quzhazhigan, wherein the content of the methyl polydatin is 50 to 100 percent by mass percent; concentrating the 6-9 times volume of eluate under reduced pressure or further recrystallizing to obtain polydatin-enriched extract, wherein the content of methyl polydatin is 50% -100% by mass;
e. and d, mixing the total extract of the quzhao, the methyl polydatin obtained in the step c and the polydatin obtained in the step d to obtain the extract of the quzhao.
In the step b, the total extract of the quzhang is a mixture taking a stilbene compound as a main chemical component. It is understood that the content of different chemical components in the extract varies with the batch of raw materials and the processing parameters. Generally, the total extract contains about 50-100% of stilbene components, including Quzhazhigan, polydatin, resveratrol, piceatannol and methyl polydatin.
In the step c and the step d, the Quzhazhigan, the polydatin and the methyl polydatin are separated and enriched, and the content of 3 components in percentage by mass is 50-100% through repeated recrystallization.
And c, the steps b, c and d respectively give the extract of the quzhang koozhao, including the preparation steps of the total extract of the quzhang kozhang and the extract rich in the components of quzhang stilbene glucoside, polydatin and methyl polydatin.
The extract can also be prepared from other plant materials and/or methods to obtain three components including Quzhazhigan, polydatin and methyl polydatin.
The rhizomes of Rheum palmatum contain high content of stilbene compounds, and the total amount of stilbene compounds in the rhizomes of Quzhu can reach 5-14% (by dry weight) according to the harvesting season, the place and other factors. Therefore, the present application preferably uses the underground rhizomes of Rheum laparaense as the plant material for extraction.
The total extract of the Quzhazhiza trifoliata prepared by the method comprises the main effective components of stilbene compounds, and the total content of the stilbene compounds in the extract is 50-100% by weight, wherein the total content of the stilbene compounds in the extract comprises 20-55% of methyl polydatin, 5-35% of Quzhazhigan, 1-35% of resveratrol and 1-35% of piceatannol. Based on the extract, the stilbene component monomer compound with abundant content can be easily prepared or produced by common separation and purification means and techniques such as chromatography, recrystallization and the like. Such as the enriched extract and monomer (percentage content: 50-100%) of stilbene glycoside components of Quzhazhigan, methyl polydatin and polydatin, etc.
The ingredients in the Quzhazha extract can also be prepared from other plant materials such as edible rhubarb (Rheum rhaponticum L.) and giant knotweed (Polygonum cuspidatum Sieb. et Zucc.) or obtained by chemical synthesis.
The beneficial effects that this application can produce include:
1) the application of the Quzhu extract provided by the application is found to have application value in preventing and treating viral pneumonia, particularly pneumonia caused by coronavirus for the first time. Pharmacodynamic experiments show that the Quzhazha total extract is more advantageous in relieving symptoms of severe viral pneumonia patients, wherein the effect of the Quzhazha total extract is better than that of a single stilbene glucoside component. The extract has various pharmacological activities of resisting virus, resisting bacteria, resisting inflammation, scavenging free radicals, etc., can remarkably reduce lung index of mouse infected by coronavirus, and can resist shock, and can be used for preparing pharmaceutical preparation for preventing and treating viral pneumonia.
2) The application shows that the total extract of the kozak and the injection of the main monomer components in the total extract of the kozak and the injection have an inhibitory effect on SARS virus in vitro and can protect infected cells, have a significant protective effect on mouse viral pneumonia cells caused by influenza A virus H1N1, and can significantly prolong the survival time of rats with endotoxic shock caused by pneumonia.
3) Based on pharmacological activity and pharmacodynamic experiment results of the invention, the total extract of kozakhstan and/or the purified composition of kozakhstan, methyl polydatin and polydatin provided by the application has application value and prospect in the prevention and treatment of viral pneumonia, particularly pneumonia caused by coronavirus. Pharmacodynamic experiments in the application show that the total extract of the quzhang and the pharmaceutical composition thereof are more advantageous in relieving symptoms of severe viral pneumonia patients, wherein the effect of the total extract of the quzhang is better than that of disease prevention and treatment by only adopting a single stilbene glucoside component.
4) The extract composition obtained by replacing (E) -5-O-methyl-resveratrol-3-O- β -glucoside with Quzhazhigan can better play a role in inhibiting the activity of coronaviruses.
5) The extract contains high-activity stilbene components such as Quzhazhigan, methyl polydatin, polydatin and the like, and the components are clear and controllable. The extract of the invention contains abundant stilbene substances as the medicinal material source, can be used for preparing the raw material of the extract of the medicament without further purification and refining, has simple and easy preparation method, low production cost, continuous operation and strong practicability and application value.
Detailed Description
The present application will be described in detail with reference to examples, but the present application is not limited to these examples.
Examples
Unless otherwise specified, the raw materials, solvents and auxiliaries in the examples of the present application were purchased commercially and were not treated.
The instrumentation used was tested:
example 1: preparation of total extract of Quzhao
(1) Materials:
rhizome of Quzhao: planting in Shandong Li La high mountain plantation, removing impurities, cleaning, cutting into pieces or blocks, and drying in the sun. Batch number: 180902, 191003, 190903
Resin: d101 macroporous adsorption resin, a product of Hitachi Chemicals Limited, Tianjin, is pretreated according to the instructions of a production plant; 80-100 meshes of polyamide resin and a product of Zhejiang yellow rock resin chemical industry Limited company are pretreated according to the specification of a production plant.
(2) The preparation method comprises the following steps:
i) extraction of total extract of kozakh koidzumi
Washing collected plant with water to remove soil, hanging in ventilation place, air drying, separating underground rhizome and overground stem and leaf, and pulverizing into coarse particles respectively with pulverizer.
Collecting underground rhizome and above ground stem and leaf 100g, respectively cutting, soaking in 1L 75% ethanol for 24 hr, loading into percolation column (phi 8cm, L100 cm), percolating with 75% ethanol at percolation flow rate of 20ml/min, percolating with 2L 75% ethanol respectively, mixing percolates, concentrating under reduced pressure, and detecting content of stilbene compounds in the percolates by ultraviolet spectrophotometry. As a result: the total amount of stilbene compounds contained in underground rhizome and aerial stem leaf of Rheum palmatum of lot 050902 was 10% and 0.001%, respectively. The result shows that the content of stilbene compounds in underground rhizomes of the Rheum palmatum is rich.
ii) extraction:
3 parts of underground rhizomes of the Rheum palmatum L.of 600g each, are cut into pieces, and are extracted by taking 50 percent, 75 percent and 95 percent ethanol as extraction solvents respectively. Reflux-extracting the above medicinal materials with different extraction solvents for 3 times, 4.8L each time for 2 hr. Respectively combining the extracting solutions, detecting the content (A) of the total toluylene compounds in the extracting solutions by an ultraviolet spectrophotometry, and calculating the transfer rate (B) of the toluylene compounds: the average total amount of stilbene compounds in the extractive solution/total amount of stilbene compounds in the medicinal material is multiplied by 100 percent.
The results of the extraction test are shown in table 1.
Table 1: results of extraction tests with different extraction solvents
| Extract liquid | 50% ethanol | 75% ethanol | 95% ethanol |
| A | 56.94g | 57.18g | 53.82g |
| B | 94.9％ | 95.3％ | 89.7％ |
A: detecting the total stilbene compound content in the extracting solution by an ultraviolet spectrophotometry; b: transfer rate of stilbene compound
In the above extraction test, when 50%, 75% and 95% ethanol were used as the extraction solvent, the transfer rate of the stilbene compounds in the extraction step was 89% to 95%. Therefore, they can be used as the extraction solvent of the effective components of the kozak. Preferably 75% ethanol is used as the extraction solvent. The detection shows that the content of stilbene extracted from 75% ethanol of different batches of Quzhu medicinal materials and the percentage content of each component are shown in Table 2. The results show that different batches of Quzhazhigan extracts contain Quzhazhigan, polydatin, resveratrol, piceatannol and methyl polydatin, and the three stilbene glycoside components are taken as main components.
Table 2: test results of percentage contents of each component of total extract of medicinal materials of different batches
Example 2: extraction and detection of Quzhazhigan, methyl polydatin, piceatannol and resveratrol
(1) Materials:
rhizome of Quzhao: the rhizomes of Quzha are purchased from Lasa, Tibet, cleaned, cut into pieces or blocks and dried in the sun. Batch number: 190903
(2) Preparation of total extract of kozakh koidzumi
Total extract of kozak was prepared as described in example 1, using 75% ethanol as extraction solvent.
(3) Purification and extraction of resveratrol, methyl polydatin and piceatannol
200 g of total extract of the quzhu is heated and dissolved by 200mL of water, placed for 12 hours, centrifuged at 5000rpm for 10 minutes, the centrifugal precipitate is dissolved by 50mL of 45% ethanol, 2 g of activated carbon is refluxed at 80 ℃ for 15 minutes for decolorization, the decolorization is carried out while the extract is hot, the filtrate is placed at 4 ℃ for 4 hours for crystallization, and the crystals are dried in vacuum to obtain 62 g of white needle crystals, which are identified as methyl polydatin through the structure, and the purity is 85-100%. And (3) passing the crystallized mother liquor through D101 macroporous resin (150 multiplied by 1000mm), eluting by 30% ethanol, wherein each 1 column volume is 1 fraction, obtaining 20 fractions, concentrating fractions 1-8 to obtain light yellow solid 10g, recrystallizing by 30% ethanol to obtain white powdery solid, identifying the structure as piceatannol, concentrating fractions 11-19 to obtain light yellow solid 51g, recrystallizing by 50% ethanol to obtain white crystal, and identifying the structure as resveratrol.
(4) Purification and extraction of Quzhazhigan and polydatin
Centrifuging polyamide resin (150 × 1000mm) on a water phase, eluting with 35% ethanol, wherein 1 fraction is in each 1 column volume to obtain 18 fractions, concentrating the fractions 2-9 under reduced pressure to obtain light yellow solid 125 g, dissolving with 15% ethanol, refluxing 4 g of activated carbon at 80 ℃ for 15 min to decolorize, performing suction filtration while hot, standing the filtrate at 4 ℃ for 2h to crystallize, and performing vacuum drying on the crystals to obtain 102 g of white crystals, wherein the crystals are structurally identified as quzhazhigan; the fraction 11-15 is decompressed and concentrated to obtain 11 g of yellow solid, and the yellow solid is identified as polydatin through the structure.
(5) Performing structural identification on Quzhazhigan, methyl polydatin, piceatannol and resveratrol:
respectively carrying out UV, MS,1H NMR, UV, MS, and 1H NMR on the obtained Quzhazhigan, methyl polydatin, piceatannol, and resveratrol,13CNMR spectrogram, the obtained detection data is as follows:
polydatin methyl (methanol), blue-violet fluorescence under an ultraviolet lamp at mp.225-227 ℃. UV: λ max (MeOH) nm: 217,308,319; negative FAB MS [ M/z ]: 403[ M-H ] -, 227[ M + H-C6H11O6] -, 1H NMR (acet-d 6) δ ppm: 7.50(d, J ═ 8.0Hz), 7.11(s, J ═ 16.3Hz), 6.94(s, J ═ 16.3Hz), 6.93(d, J ═ 8.0Hz),6.80(s),6.67(s),6.48(s),4.83(1H, d, anomeric H),3.76(3H, yyrs, OCH3),3.2-3.9(4H, M, sugar-H ″),13 ″ (3501H, d, anomeric H),3.76(3H, OCH3),3.2-3.9(4H, M, sugar-H-13 ″), C7-32 ″, C (-70 ″, C7-32 ″, C7-13 ″, C7-34 ″, C7-13 ″, C7-H ″, C7-18 ″, C7-3-34 ″, C7-3-34 ″, C7-3', 6-13 ″, C7-3.
Polydatin white needles (30% ethanol), UV λ max (etoh), 217,307, 320. MS [ M/z, rel. ], 390[ M ] +, 228(100), 227(12.51), 211(6.38),181 (8.87); 1H NMR (acetone-d 6) δ ppm, 8.48(1H, s),8.40(1H, s),7.43(2H, d, J ═ 8.5Hz),7.10(1H, d, J ═ 16.0Hz),6.92(1H, d, J ═ 16.0Hz),6.85(2H, d, J ═ 8.5Hz),6.82-6.68(1H, s),6.47(1H, s),4.95(1H, d, 7.5J ═ 8.5Hz),6.82-6.68(1H, s),6.47(1H, s),4.95(1H, d, 7.5J ═ 8, 7.60 ═ 6.68 ═ 6.7H, 7.7.7 ″, 3.7.7H, 7.7 ″, 3.7.7.7.7.7.7.7.7H, 3-6.7.7.7.7 ″, 3.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.7.
Quzhazhigan: white hairy crystals (water), mp.220-225 ℃. The ultraviolet lamp emits blue-violet fluorescence. UV λ max (MetOH) 217(4.38),320 (4.48); EI-MS (M/z):406[ M]+,244[M-glycosy]+；negative FAB-MS(m/z):405[M-H]—，243[M-H-glycosy]—；1H NMR(CD3OD,500M Hz)δppm:7.44(1H,d,J＝2.0Hz,C2′-H),7.05(1H,dd,J1＝2.0Hz,J2＝8.0Hz,C6′-H),6.92(1H,d,J＝16.3Hz,Cα-H),6.83(1H,d,J＝16.3Hz,Cβ-H),6.82(1H,d,J＝8.3Hz,C5′-H),6.47(1H,d,J＝2.2Hz,C2,6-H),6.18(1H,t,J＝2.2Hz,C4-H),4.81(1H,d,J＝7.4Hz,anomeric H),3.95(1H,dd,J 1＝2.0,2.1Hz,J2＝12.2Hz,C6″-H),3.74(1H,dd,J 1＝6.0Hz,J2＝＝12.1Hz,C6″-H),3.41-3.56(4H,m sugar-H)；13C NMR(CD3OD,125M Hz)δppm：141.1(C-1),105.9(C-2,6),159.4(C-3,5),102.7(C-4),131.3(C-1′),116.6(C-2′),146.9(C-3′),148.1(C-4′),117.2(C-5′),123.0(C-6′),127.8(C-α),129.1(C-β),104.4(C-1″),74.9(C-2″),78.4(C-3″),71.4(C-4″),77.5(C-5″),62.5(C-6″)。
Piceatannol in the form of white crystal (15% ethanol), ESI-MS (M/z)243[ M-H]+,1H NMR(400MHz,Acetone-d6)δ7.07(d,J＝1.7Hz,1H),6.95(d,J＝16.3Hz,1H),6.90(dd,J＝8.0/1.7Hz,1H),6.82(d,J＝16.3Hz,1H),6.80(d,J＝8.0Hz,1H),6.52(d,J＝1.8Hz,2H),6.26(t,J＝1.8,1H).13C NMR(101MHz,Acetone-d6)δ159.50(C-3,5),146.040(C-3′,4′),140.77,0(C-1)130.600(C-1′),129.310(C-β),126.800(C-α),119.930(C-6′),116.180(C-2′),113.740(C-5′),105.580(C-2,6),102.560(C-4).
Resveratrol: white needle crystals (50% ethanol), EI-MS (M/z)228[ M [)]+,1H NMR(400MHz,Acetone-d6)δ8.51(s,1H),8.23(s,2H),7.41(d,J＝8.6Hz,2H),7.01(d,J＝16.3Hz,1H),6.88(d,J＝16.3Hz,1H),6.83(d,J＝8.6Hz,2H),6.53(d,J＝2.0Hz,2H),6.25(t,J＝2.0Hz,1H).13C NMR(101MHz,Acetone-d6)δ159.53(C-3,5),158.11(C-4′),140.80(C-1),130.01(C-1′),129.01(C-β),128.65(C-2′,6′),126.75(C-α),116.33(C-3′,5′),105.57(C-2,6),102.58(C-4)。
Example 3: preparation of Quzha extract samples 1-16
Mixing the materials according to the following table to obtain the extract samples 1-16 of the quzhang, wherein the extract samples are calculated according to weight percentage.
Example 4: preparation of Quzhu extract sample injection
(1) Prescription
(2) Method for producing
Weighing 2.50L of absolute ethyl alcohol, adding 1.50L of propylene glycol and phosphate buffer solution, mixing well, adding 100.00g of the quzhazhigan extract obtained in examples 1 and 2, performing ultrasonic dissolution, and fixing the volume of the buffer solution to scale. Filtering with 0.45 μm microporous membrane, and coarse filtering. The secondary filtrate is filtered through a 0.22 mu m microporous filter membrane and is filtered through a 1 ten thousand molecular weight cutoff polyether sulfone membrane to remove pyrogen. And filling nitrogen into the brown bottle for encapsulation.
Wherein the extract sample of the koji shea is 1-12.
Example 5: preparation of Quzha extract sample aerosol
(1) Prescription
(2) Method for producing
The preparation method comprises filling the prepared medicinal liquid into a container at room temperature, loading the valve, rolling, and pressing into a certain amount of propellant (preferably air in the container is removed). The liquefied propellant is filtered by a sand rod from an inlet and then enters a press-mounting machine. The operating pressure was 80.65 kPa. And (6) filling.
Wherein the extract sample of the koji shea is 1-12.
Example 6 anti-SARS virus activity of Quzhu extract injection and animal experiment for protection of virus infected cells
(1) Test method
Vero-E6 cells (susceptible cells) are inoculated into a 96-well culture plate according to the conventional method, and the culture plate is placed at 37 ℃ and 5% CO2Culturing, after SARS virus infects cells, adding samples with different dilution concentration, dividing the experiment into virus control, cell control, total extract of Quzhang, Quzhazhigan, methyl polydatin and polydatin injection (each injection prepared according to the method of example 3), preparing four samples into high (150ug/mL), middle (80ug/mL) and low ((6ug/mL)3 concentration test, observing every day, recording CPE (cell disease method) with "-" indicating the cell attachment form is complete and no obvious separation, with "+" indicating the degree of cell disease,<25% is "+", 25-50% is "+", 50-75% is "+ + +", and > 75% is "+ + + +""++++". After 48 hours, the OD value is measured by neutral red staining, the protection rate of the sample on SARS virus infected cells is calculated by referring to the control, the protection rate is more than 1.5 times, and the sample is considered to have certain protection effect on coronavirus infected cells.
(2) The experimental results are as follows: the protection effect of the extract injection of each quzhu on the virus activity and virus-infected cells is shown in table 3.
Table 3: quzhao extract with protective effect on SARS virus infected cell
| Group of | CPE | Rate of protection |
| Cell control group | — | |
| Virus control group | ++++ | |
| Quzhang extract sample 2 injection (150ug/mL) | + | 2.5 |
| Quzhang extract sample 2 injection (80ug/mL) | ++ | 2.2 |
| Quzha extract sampleProduct 2 injection (6ug/mL) | ++ | 2.2 |
| Quzhang extract sample 13 injection (150ug/mL) | ++ | 2.1 |
| Quzhang extract sample 13 injection (80ug/mL) | +++ | 2.0 |
| Quzhang extract sample 13 injection (6ug/mL) | ++++ | 1.9 |
| Quzhang extract sample 11 injection (150ug/mL) | ++ | 2.4 |
| Quzhang extract sample 11 injection (80ug/mL) | +++ | 2.1 |
| Quzhang extract sample 11 injection (6ug/mL) | +++ | 2.1 |
| Quzhang extract sample 10 injection (150ug/mL) | ++ | 2.2 |
| Quzhang extract sample 10 injection (80ug/mL) | ++ | 2.3 |
| Quzhang extract sample 10 injection (6ug/mL) | +++ | 2.1 |
| Quzhu extract sample 6 injection (80ug/mL) | ++ | 2.3 |
| Quzhang extract sample 8 injection (80ug/mL) | ++ | 2.3 |
According to the above table, each quzhang extract injection has anti-SARS virus effect and can protect infected cells at high, medium and low doses, wherein, the total extract of quzhang has better activity, and the extract sample obtained has better protection effect after (E) -5-O-methyl-resveratrol-3-O- β -glucoside is used for replacing quzhang stilbene glucoside.
Example 7: protection effect of quzhang extract sample injection on H1N1 influenza A virus infected mouse pneumonia model
(1) The experimental method comprises the following steps: the ICR mice are randomly divided into a normal group, a model group and a high, medium and low dose group (150, 50, 10 mg.kg) of the extract injection of the koozhaki-1) Quzhazhigan injection high and medium/low dosage group (150, 50, 10 mg/kg)－1) High and medium dosage group (150, 50, 10 mg/kg) of methyl polydatin injection－1) Each group had 8 individuals, each half of a female. Except for the normal group, the mice of each group were lightly anesthetized with ether, and 0.05 mL/mouse was infected nasally with 0.05mL of a solution of influenza virus mouse lung-adapted strain FM1 at a concentration of 15LD50, resulting in a model of influenza virus pneumonia in the mice. The groups are respectively administered by intravenous injection, and the normal group and the model group are injected into abdominal cavity on the same day of infectionThe same volume of purified water (0.1mL/10g) was administered 1 time daily for 5 consecutive days. After weighing the mice on day 6 of infection, the mice were fixed, dissected, and the whole lung was harvested and weighed. And calculating the lung index value and the lung index inhibition rate.
Lung index inhibition (%) of (model group lung index value-administration group lung index value mode)/(model group lung index value-normal group lung index value) × 100%
(2) And (5) experimental results. The results are shown in Table 4.
Table 4: influence of different Quzhu extracts on lung index of H1N1 influenza A virus infected mice ((x + -s, N ═ 8)
| Group of | Index of lung | Pulmonary index inhibition (%) |
| Normal group | 1.76±0.12 | - |
| Model set | 0.92±0.16△△ | 0 |
| Quzhang extract sample 2 injection (150 mg. kg)-1) | 1.08±0.21 | 80.95** |
| Quzhao extract sample 2 injection (50mg kg)-1) | 1.13±0.18 | 75.00** |
| Quzhang extract sample 2 injection (10 mg. kg)-1) | 1.21±0.22 | 65.48** |
| Quzhang extract sample 13 injection (150mg kg)-1) | 1.2±0.11 | 66.67** |
| Quzhao extract sample 13 injection (50mg kg)-1) | 1.28±0.25 | 57.14** |
| Quzhao extract sample 13 injection (10mg kg)-1) | 1.32±0.21 | 52.38** |
| Quzhang extract sample 11 injection (150 mg. kg)-1) | 1.35±0.20 | 48.81* |
| Quzhao extract sample 11 injection (50mg kg)-1) | 1.45±0.18 | 36.90* |
| Quzhang extract sample 11 injection (6 mg. kg)-1) | 1.51±0.23 | 29.76* |
| Quzhang extract sample 10 injection (150mg kg)-1) | 1.28±0.18 | 57.14** |
| Quzhao extract sample 10 injection (50mg kg)-1) | 1.37±0.21 | 46.43* |
| Quzhang extract sample 10 injection (10 mg. kg)-1) | 1.4±0.21 | 42.86* |
| Quzhao extract sample 6 injection (50mg kg)-1) | 1.23±0.17 | 63.10** |
| Quzhang extract sample 8 injection (50mg kg)-1) | 1.33±0.20 | 51.19** |
Note: in comparison with the normal group,△△p is less than 0.01; in comparison with the set of models,*P＜0.05，**P＜0.01
the results in Table 4 show that after influenza A virus infects mice, the pulmonary index value of the mice in the model group is obviously higher than that of the mice in the normal group (P is less than 0.01), and the pulmonary index of the mice in the high, medium and low dose groups of the total kozak extract, the quzhazhigan, the methyl polydatin and the polydatin injection is obviously reduced (P is less than 0.05 or P is less than 0.01) compared with that of the mice in the model group, which indicates that each administration group has obvious protective effect on the viral pneumonia of the mice caused by the influenza A H1N 1. The Quzhu extract has better protective effect (lung index inhibition rate of 65.48-80.95%), and has better effect than 3 stilbene glucoside monomer injections in each dose group.
Meanwhile, (E) -5-O-methyl-resveratrol-3-O- β -glucoside is used for replacing quzhazhigan, and the obtained extract sample also has a remarkable protective effect on mouse viral pneumonia caused by influenza A H1N1 virus.
Example 8 therapeutic Effect of different Quzhu extract injections on toxic shock in rats
(1) The experimental method comprises the following steps: SD rats are randomly divided into a normal group, a model group, a quzhang extract injection group and a quzhazhigan injection group (150, 50, 10 mg.kg)－1) Methyl polydatin injection (150, 50, 10 mg/kg)－1) Each group had 8 individuals, each half of a female. The rats in each group except the normal group are at a dose of 10 mg/kg-1Doses were injected intravenously with LPS (lipopolysaccharide) to create a mouse model of endotoxin shock. Then, each group was administered by intravenous injection, and the positive administration group was administered with 10 mg/kg-1The injection, normal group and model group were administered with the same volume of normal saline (0.15 ml. kg-1) by intraperitoneal injection, and the body temperature of the animals was kept at 37 ℃ during the test. The survival rate of the rats was recorded after 6h observation.
(2) The experimental results are as follows: the results are shown in Table 5.
Table 5: influence of different Quzhu extract injection on endotoxin shock rat survival rate of 6h ((x, n ═ 8)
| Group of | Survival rate of 6h |
| Normal group | 100％ |
| Model set | 25.0％△△ |
| Quzhao extract sample 2 injection | 87.5％** |
| Quzhao extract sample 13 injection | 75.0％** |
| Quzhao extract sample 11 injection | 37.5％ |
| Quzhang extract sample 8 injection | 62.5％** |
| Quzhao extract sample 9 injection | 50.0％* |
Note that △△ P was <0.01 in comparison with the normal group and △△ P was <0.01 in comparison with the model group,*P＜0.05，**P＜0.01
the experimental results showed 10 mg.kg compared to the model group－1The survival time of rats with endotoxin shock can be remarkably prolonged by intravenous injection of the dose of the total kozakh extract and the dry Quzhazhigan injection, wherein the survival rate of rats with endotoxin shock for 6h can reach 87.5 percent by the total kozakh extract.
Meanwhile, (E) -5-O-methyl-resveratrol-3-O- β -glucoside is used for replacing the quzhazhigan, and the obtained extract sample can also obviously prolong the survival time of the endotoxic shock rat.
Reference throughout this specification to "one embodiment," "another embodiment," "an embodiment," "a preferred embodiment," or the like, means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment described generally in this application. The appearances of the same phrase in various places in the specification are not necessarily all referring to the same embodiment. Further, when a particular feature, structure, or characteristic is described in connection with any embodiment, it is submitted that it is within the scope of the disclosure to effect such feature, structure, or characteristic in connection with other embodiments.
Although the present application has been described herein with reference to a number of illustrative embodiments thereof, it should be understood that numerous other modifications and embodiments can be devised by those skilled in the art that will fall within the spirit and scope of the principles of this disclosure. More specifically, various variations and modifications are possible in the component parts and/or arrangements of the subject combination arrangement within the scope of the disclosure and claims of this application. In addition to variations and modifications in the component parts and/or arrangements, other uses will also be apparent to those skilled in the art.
Claims (9)
1. Application of Quzhang extract in preparation of medicine for preventing and/or treating viral pneumonia is provided.
2. The use of claim 1, wherein the causative agent of viral pneumonia comprises a coronavirus.
3. The use of claim 1, wherein the treatment comprises reducing the viral load in the blood of a patient with viral pneumonia.
4. The use of claim 1, wherein the viral pneumonia comprises severe viral pneumonia with shock symptoms.
5. The use as claimed in claim 1, wherein the extract of Quzhaki extract is obtained from the rhizome of Rheum palmatum; the Rheum lasianum is planted in wild or artificial mode;
the medicine is oral preparation, inhalant or injection.
6. A Quzhazha extract for use according to any one of claims 1 to 5, wherein said Quzhazha extract comprises: 50 to 100 percent of Quzhazhigan in percentage by weight; preferably, the said extract of kozakha comprises: 50-100% of polydatin in percentage by weight; preferably, the said extract of kozakha comprises: 50-100% of methyl polydatin.
7. A Quzhang extract according to claim 6, wherein said Quzhang extract comprises: the total content of the stilbene compounds is 50-100% in percentage by weight; preferably, the said extract of kozakha comprises: 20-55% of methyl polydatin, 5-35% of Quzhazhigan, 1-35% of resveratrol and 1-35% of piceatannol.
8. A Quzhazha extract according to claim 6, wherein said Quzhazha extract comprises (by weight) methyl polydatin 20-28%, polydatin 5-35%, (E) -5O-methyl-resveratrol-3-O- β -glucoside 5-35%, resveratrol 1-35%, and piceatannol 1-25%.
9. A Quzhazha extract according to claim 6, wherein said Quzhazha extract comprises (by weight) 10-15% of methyl polydatin, 40-55% of polydatin, (E) -5-O-methyl-resveratrol-3-O- β -glucoside 20-45%, 1-5% of methyl resveratrol and 4-5% of piceatannol.
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| CN113533563A (en) * | 2021-07-07 | 2021-10-22 | 健民药业集团股份有限公司 | Method for simultaneously detecting contents of four components of liver-soothing, stomach-harmonizing and pain-relieving traditional Chinese medicine |
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