CN109700848A - Chinese medicine composition, the drug and preparation method thereof for treating dengue fever - Google Patents
Chinese medicine composition, the drug and preparation method thereof for treating dengue fever Download PDFInfo
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Abstract
The application provides a kind of Chinese medicine composition for treating dengue fever, drug and preparation method thereof, belongs to technical field of traditional Chinese medicine.The Chinese medicine composition of dengue fever is treated, in parts by weight, comprising: the pueraria lobata of the sweet wormwood of 15-30 parts by weight, the radix bupleuri of 10-20 parts by weight and 10-20 parts by weight.The preparation method for treating the drug of dengue fever, comprising: Chinese medicine composition is mixed into decoction with water.By above-mentioned preparation method, the drug of above-mentioned treatment dengue fever is prepared using above-mentioned Chinese medicine composition, can effectively treat dengue fever, there is good antipyretic response.
Description
Technical field
This application involves the technical field of traditional Chinese medicines for the treatment of dengue fever, in particular to a kind of Chinese medicine for treating dengue fever
Composition, drug and preparation method thereof.
Background technique
Dengue fever (dengue fever) is dengue virus by infectious disease caused by killing propagation.After dengue virus infection
It can lead to subclinical infection, dengue fever, dengue hemorrhagic fever etc..Removing from office hot Disease Clinical performance is mainly that onset is hurried, high fever, headache,
Muscle, Bones and joints are acutely ached.In the prior art, the method without effectively treating dengue fever.
Summary of the invention
The application's is designed to provide a kind of Chinese medicine composition for treating dengue fever, drug and preparation method thereof, obtains
Drug can effectively treat dengue fever.
In a first aspect, the embodiment of the present application provides a kind of Chinese medicine composition for treating dengue fever, and in parts by weight, packet
It includes: the pueraria lobata of the sweet wormwood of 15-30 parts by weight, the radix bupleuri of 10-20 parts by weight and 10-20 parts by weight.
Cooperated by the sweet wormwood, radix bupleuri and pueraria lobata of above-mentioned parts by weight, can effectively treat dengue fever, can be had very
Good antipyretic response.
With reference to first aspect, in another embodiment, the Chinese medicine composition of dengue fever is treated, in parts by weight, comprising:
The pueraria lobata of the sweet wormwood of 22.5 parts by weight, the radix bupleuri of 15 parts by weight and 15 parts by weight.The effect for treating dengue fever is more preferable, takes effect more
Fastly.
With reference to first aspect, in another embodiment, the Chinese medicine composition of dengue fever is treated, in parts by weight, is also wrapped
Include: the schizonepeta of 10-20 parts by weight, the radix saposhnikoviae of 10-20 parts by weight, the honeysuckle flower of 10-20 parts by weight, 10-20 parts by weight Fructus Forsythiae,
The campanulaceae of 10-20 parts by weight and the Radix Glycyrrhizae of 5-10 parts by weight.Heat can quickly drop, effectively treatment dengue fever.
With reference to first aspect, in another embodiment, the Chinese medicine composition of dengue fever is treated, in parts by weight, comprising:
The sweet wormwood of 22.5 parts by weight, the radix bupleuri of 15 parts by weight, the pueraria lobata of 15 parts by weight, the schizonepeta of 15 parts by weight, 15 parts by weight radix saposhnikoviae,
The Radix Glycyrrhizae of the honeysuckle flower of 15 parts by weight, the Fructus Forsythiae of 15 parts by weight, the campanulaceae of 15 parts by weight and 7.5 parts by weight.The effect for treating dengue fever
Fruit is more preferable, takes effect faster.
With reference to first aspect, in another embodiment, the Chinese medicine composition of dengue fever is treated, in parts by weight, is also wrapped
Include: the almond of 10-20 parts by weight, the Fructus Forsythiae of 10-20 parts by weight, the mulberry leaf of 10-20 parts by weight, 10-20 parts by weight radix scutellariae,
The White Chloe of the talcum of 10-20 parts by weight, the Poria cocos of 10-20 parts by weight and 5-10 parts by weight.
Dengue fever can not only effectively be treated, additionally it is possible to which there is certain analgesic effect.
With reference to first aspect, in another embodiment, the Chinese medicine composition of dengue fever is treated, in parts by weight, comprising:
The sweet wormwood of 22.5 parts by weight, the radix bupleuri of 15 parts by weight, the pueraria lobata of 15 parts by weight, the almond of 15 parts by weight, 15 parts by weight Fructus Forsythiae,
The White Chloe of the mulberry leaf of 15 parts by weight, the radix scutellariae of 15 parts by weight, the talcum of 15 parts by weight, the Poria cocos of 15 parts by weight and 7.5 parts by weight.
Cooling effect and analgesic effect are more preferable.
Second aspect, the embodiment of the present application provide a kind of preparation method of drug for treating dengue fever, comprising: by Chinese medicine group
It closes object and mixes decoction with water.For obtained drug for treating dengue fever, drop thermal effect is fine.
In conjunction with second aspect, in another embodiment, after decoction, filtrate is extracted, obtains medicinal extract after filtrate is concentrated.It is convenient for
It saves, to take at any time.
In conjunction with second aspect, in another embodiment, the density of medicinal extract is (1.1-1.2) g/cm3.So as to subsequent preparation
Granula.
The third aspect, the embodiment of the present application provide a kind of drug for treating dengue fever, by the drug of above-mentioned treatment dengue fever
Preparation method be prepared.Said medicine is taken, dengue fever can be effectively treated.
Detailed description of the invention
Technical solution in ord to more clearly illustrate embodiments of the present application, below will be to needed in the embodiment attached
Figure is briefly described, it should be understood that the following drawings illustrates only some embodiments of the application, therefore is not construed as pair
The restriction of range for those of ordinary skill in the art without creative efforts, can also be according to this
A little attached drawings obtain the protection scope that other relevant attached drawings also belong to the application.
Fig. 1 is the photomicrograph figure for the normal cell that the application experimental example 2 provides;
Fig. 2 is the model photomicrograph figure for the infection high dose dengue virus that the application experimental example 2 provides;
Fig. 3 is the drug that provides of the embodiment 1 that the application experimental example 2 provides in the case where upper concentration is 0.5mg/ml
Photomicrograph figure;
Fig. 4 is the drug that provides of the embodiment 1 that the application experimental example 2 provides the case where upper concentration is 0.25mg/ml
Under photomicrograph figure;
Fig. 5 is the drug that provides of the embodiment 1 that the application experimental example 2 provides the case where upper concentration is 0.125mg/ml
Under photomicrograph figure;
Fig. 6 is the drug that provides of the embodiment 3 that the application experimental example 2 provides in the case where upper concentration is 0.5mg/ml
Photomicrograph figure;
Fig. 7 is the drug that provides of the embodiment 3 that the application experimental example 2 provides the case where upper concentration is 0.25mg/ml
Under photomicrograph figure;
Fig. 8 is the drug that provides of the embodiment 3 that the application experimental example 2 provides the case where upper concentration is 0.125mg/ml
Under photomicrograph figure;
Fig. 9 is that the drug that the embodiment 1 that the application experimental example 2 provides provides is opposite to the intracellular dengue viral rna of Huh7
The influence of amount;
Figure 10 is that the drug that the embodiment 3 that the application experimental example 2 provides provides is opposite to the intracellular dengue viral rna of Huh7
The influence of amount.
Specific embodiment
It, below will be in the embodiment of the present application to keep the purposes, technical schemes and advantages of the embodiment of the present application clearer
Technical solution be clearly and completely described.The person that is not specified actual conditions in embodiment, according to normal conditions or manufacturer builds
The condition of view carries out.Reagents or instruments used without specified manufacturer is the conventional production that can be obtained by commercially available purchase
Product.
The preparation method for treating the drug of dengue fever, comprising: the Chinese medicine composition for treating dengue fever is mixed into decoction with water,
Filtrate is extracted, obtains medicinal extract after concentration.
In the present embodiment, the Chinese medicine composition of dengue fever is treated, in parts by weight, comprising: 15-30 parts by weight (such as:
15 parts by weight, 18 parts by weight, 20 parts by weight, 24 parts by weight, 28 parts by weight or 30 parts by weight) sweet wormwood, 10-20 parts by weight (example
Radix bupleuri such as: 10 parts by weight, 12 parts by weight, 15 parts by weight, 18 parts by weight or 20 parts by weight) and 10-20 parts by weight (such as: 10
Parts by weight, 12 parts by weight, 15 parts by weight, 18 parts by weight or 20 parts by weight) pueraria lobata.
After above-mentioned three kinds of Chinese medicines are used cooperatively by above-mentioned parts by weight, it can be good at treating dengue fever, and can
The infection of normal cell is avoided, dengue fever can be prevented.
Optionally, the Chinese medicine composition of dengue fever is treated, in parts by weight, comprising: the sweet wormwood of 22.5 parts by weight, 15 weights
Measure the radix bupleuri of part and the pueraria lobata of 15 parts by weight.The effect for treating dengue fever is more preferable, takes effect faster.
In another embodiment, the Chinese medicine composition of dengue fever is treated, in parts by weight, comprising: 15-30 parts by weight
The sweet wormwood of (such as: 15 parts by weight, 18 parts by weight, 20 parts by weight, 24 parts by weight, 28 parts by weight or 30 parts by weight), 10-20 weight
The radix bupleuri of part (such as: 10 parts by weight, 12 parts by weight, 15 parts by weight, 18 parts by weight or 20 parts by weight), 10-20 parts by weight (example
Pueraria lobata such as: 10 parts by weight, 12 parts by weight, 15 parts by weight, 18 parts by weight or 20 parts by weight), 10-20 parts by weight (such as: 10 weights
Measure part, 12 parts by weight, 15 parts by weight, 18 parts by weight or 20 parts by weight) schizonepeta, 10-20 parts by weight (such as: 10 parts by weight, 12
Parts by weight, 15 parts by weight, 18 parts by weight or 20 parts by weight) radix saposhnikoviae, 10-20 parts by weight (such as: 10 parts by weight, 12 parts by weight,
15 parts by weight, 18 parts by weight or 20 parts by weight) honeysuckle flower, 10-20 parts by weight (such as: 10 parts by weight, 12 parts by weight, 15 weight
Part, 18 parts by weight or 20 parts by weight) Fructus Forsythiae, 10-20 parts by weight (such as: 10 parts by weight, 12 parts by weight, 15 parts by weight, 18 weights
Measure part or 20 parts by weight) campanulaceae and 5-10 parts by weight (such as: 5 parts by weight, 8 parts by weight or 10 parts by weight) Radix Glycyrrhizae.It can
Quickly drop heat, effectively treatment dengue fever.
The Chinese medicine composition of dengue fever is treated, in parts by weight, comprising: the sweet wormwood of 22.5 parts by weight, 15 parts by weight
Radix bupleuri, the pueraria lobata of 15 parts by weight, the schizonepeta of 15 parts by weight, the radix saposhnikoviae of 15 parts by weight, the honeysuckle flower of 15 parts by weight, 15 parts by weight company
It sticks up, the Radix Glycyrrhizae of the campanulaceae of 15 parts by weight and 7.5 parts by weight.The effect for treating dengue fever is more preferable, takes effect faster.
In another embodiment, the Chinese medicine composition of dengue fever is treated, in parts by weight, comprising: 15-30 parts by weight
The sweet wormwood of (such as: 15 parts by weight, 18 parts by weight, 20 parts by weight, 24 parts by weight, 28 parts by weight or 30 parts by weight), 10-20 weight
The radix bupleuri of part (such as: 10 parts by weight, 12 parts by weight, 15 parts by weight, 18 parts by weight or 20 parts by weight), 10-20 parts by weight (example
Pueraria lobata such as: 10 parts by weight, 12 parts by weight, 15 parts by weight, 18 parts by weight or 20 parts by weight), 10-20 parts by weight (such as: 10 weights
Measure part, 12 parts by weight, 15 parts by weight, 18 parts by weight or 20 parts by weight) almond, 10-20 parts by weight (such as: 10 parts by weight, 12
Parts by weight, 15 parts by weight, 18 parts by weight or 20 parts by weight) Fructus Forsythiae, 10-20 parts by weight (such as: 10 parts by weight, 12 parts by weight,
15 parts by weight, 18 parts by weight or 20 parts by weight) mulberry leaf, 10-20 parts by weight (such as: 10 parts by weight, 12 parts by weight, 15 weight
Part, 18 parts by weight or 20 parts by weight) radix scutellariae, 10-20 parts by weight (such as: 10 parts by weight, 12 parts by weight, 15 parts by weight, 18 weights
Measure part or 20 parts by weight) talcum, 10-20 parts by weight (such as: 10 parts by weight, 12 parts by weight, 15 parts by weight, 18 parts by weight or
20 parts by weight) Poria cocos and 5-10 parts by weight (such as: 5 parts by weight, 8 parts by weight or 10 parts by weight) White Chloe.Can not only have
Effect treatment dengue fever, additionally it is possible to there is certain analgesic effect, and can be avoided the infection of normal cell, have centainly to dengue fever
Prevention effect.
The Chinese medicine composition of dengue fever is treated, in parts by weight, comprising: the sweet wormwood of 22.5 parts by weight, 15 parts by weight
Radix bupleuri, the pueraria lobata of 15 parts by weight, the almond of 15 parts by weight, the Fructus Forsythiae of 15 parts by weight, the mulberry leaf of 15 parts by weight, 15 parts by weight Huang
The White Chloe of a kind of reed mentioned in ancient books, the talcum of 15 parts by weight, the Poria cocos of 15 parts by weight and 7.5 parts by weight.Cooling effect and analgesic effect are more preferable.
In the present embodiment, the mode of decoction are as follows: decocting includes decocting to decoct with second for the first time;In decocting for the first time,
The mass ratio 1:(12-14 of Chinese medicine composition and water);In second of decoction, the mass ratio 1:(8-10 of Chinese medicine composition and water).
Be first 1:(12-14 according to mass ratio by Chinese medicine composition and water) ratio (such as: 1:12,1:13 or 1:14) it is mixed
It closes and impregnates 30min, then continue decoction 40-80min (such as: 40min, 50min, 60min, 70min or 80min) boiling after,
Filtering, obtains the first filtrate and the first filter residue, according to mass ratio is 1:(8-10 by the first filter residue and water) ratio (such as: 1:
8,1:9 or 1:10) mixing, continue to decoct 40-80min (such as: 40min, 50min, 60min, 70min or 80min) after boiling,
Filtering, obtains the second filtrate and the second filter residue, and the first filtrate and the second filtrate are mixed, carry out being concentrated under reduced pressure to give medicinal extract.
Optionally, the density of medicinal extract is (1.1-1.2) g/cm3, high temperature extrusion medicinal extract obtains granule.Obtained medicinal extract
Drug effect is preferable, and after high temperature extrusion, and the particle of obtained granule is more moderate, and does not need to be dried again and can be obtained
Granule.
Granule can be packaged into mono- bag of 10g, mono- bag of 15g or mono- bag of 20g is packed, three times a day, every secondary eclipse
The treatment of dengue fever is carried out with one bag.The drug for the treatment dengue fever being prepared by the above method can effectively treat Dengue
Heat, it is quick.
Embodiment 1
The preparation method for treating the drug of dengue fever includes:
(1), Chinese medicine composition is prepared, the pueraria lobata of the sweet wormwood of 22.5kg, the radix bupleuri of 15kg and 15kg is weighed.
(2), above-mentioned Chinese medicine composition is obtained into mixture in the water of 630kg and impregnated half an hour, by mixture boiled
After continue decoct 1h, filtering, obtain the first filtrate and the first filter residue, the first filter residue mixed with the water of 525kg and is boiled with subsequent
Continuous to decoct 1h, filtering obtains the second filtrate, and the first filtrate and the second filtrate are mixed, and being concentrated under reduced pressure to give density is 1.2kg/
m3Medicinal extract, high temperature extrusion medicinal extract obtains granule.
Embodiment 2
The preparation method for treating the drug of dengue fever includes:
(1), prepare Chinese medicine composition, weigh the sweet wormwood of 22.5kg, the radix bupleuri of 15kg, the pueraria lobata of 15kg, 15kg schizonepeta,
The radix saposhnikoviae of 15kg, the honeysuckle flower of 15kg, the Fructus Forsythiae of 15kg, the campanulaceae of 15kg and 7.5kg parts of Radix Glycyrrhizae.
(2), above-mentioned Chinese medicine composition is obtained into mixture in the water of 1620kg and impregnated half an hour, by mixture boiled
After continue decoct 1h, filtering, obtain the first filtrate and the first filter residue, the first filter residue mixed with the water of 1350kg and is boiled with subsequent
Continuous to decoct 1h, filtering obtains the second filtrate, and the first filtrate and the second filtrate are mixed, and being concentrated under reduced pressure to give density is 1.2kg/
m3Medicinal extract, high temperature extrusion medicinal extract obtains granule.
Embodiment 3
The preparation method for treating the drug of dengue fever includes:
(1), prepare Chinese medicine composition, weigh the sweet wormwood of 22.5kg, the radix bupleuri of 15kg, the pueraria lobata of 15kg, 15kg almond,
The Fructus Forsythiae of 15kg, the mulberry leaf of 15kg, the radix scutellariae of 15kg, the talcum of 15kg, the Poria cocos of 15kg and the White Chloe of 7.5kg.
(2), above-mentioned Chinese medicine composition is obtained into mixture in the water of 1800kg and impregnated half an hour, by mixture boiled
After continue decoct 1h, filtering, obtain the first filtrate and the first filter residue, the first filter residue mixed with the water of 1500kg and is boiled with subsequent
Continuous to decoct 1h, filtering obtains the second filtrate, and the first filtrate and the second filtrate are mixed, and being concentrated under reduced pressure to give density is 1.2kg/
m3Medicinal extract, high temperature extrusion medicinal extract obtains granule.
Experimental example 1
Use the drug effect for the drug that zoopery detection embodiment 1- embodiment 3 is prepared, concrete mode are as follows:
1.1 experimental material
1.1.1 sample and reference substance
The cloth that drug that drug that drug that embodiment 1 obtains, embodiment 2 obtain, embodiment 3 obtain, comparative example 1 provide
Ibuprofen piece: Xiuzheng Pharmaceutical Group Changchun Gaoxin Pharmaceutical Co., Ltd., lot number: 180402, specification: piece × 24 piece 0.2g//box.
1.1.2 experiment reagent
Lipopolysaccharides: L2880, SIGMA, lot number: 057M4013V.
Plum mountain high activity dried yeast: Hebei Ma Li Food Co., Ltd, lot number: ZB201809129845011457.
Glacial acetic acid: Aladdin, lot number: G1528005.
Sodium chloride injection: Hunan Cologne Pharmaceutical Co., Ltd, lot number: D17112204-1.
1.1.3 solvent is used in experiment
Title: pure water.Source: Science and Technology Industrial Park engineering center, Traditional Chinese Medicine University Of Guangzhou pure water system.
1.1.4 experimental animal
KM mouse, SPF grades, 140, half male and half female, weight 18-22g is mentioned by Nanfang Medical Univ's Experimental Animal Center
For experimental animal production licence number: SCXK (Guangdong) 2016-0041, Quality of Experimental Animals quality certification number:
No.44002100017742.The experiment of mouse fever is caused for lipopolysaccharides.
KM mouse, SPF grades, 140, half male and half female, weight 18-22g is mentioned by Nanfang Medical Univ's Experimental Animal Center
For experimental animal production licence number: SCXK (Guangdong) 2016-0041, Quality of Experimental Animals quality certification number:
No.44002100017743.Experiment for induced by yeast in mice fever.
KM mouse, SPF grades, 160, female, weight 18-22g is provided by Nanfang Medical Univ's Experimental Animal Center, real
Test animal productiong licensing number: SCXK (Guangdong) 2016-0041, Quality of Experimental Animals quality certification number: No.44002100017192.
The experiment of mice pain is caused for hot plate.
KM mouse, SPF grades, 140, half male and half female, weight 18-22g is mentioned by Nanfang Medical Univ's Experimental Animal Center
For experimental animal production licence number: SCXK (Guangdong) 2016-0041, Quality of Experimental Animals quality certification number:
No.44002100017191.The experiment of mice pain is caused for acetic acid.
1.1.5 adaptive feeding process
From reception, all animals carry out adaptive feeding observation, and observation 1 time, is observed continuously 3-7 days daily.
Observed content include: whether the state of mind good, behavioral activity whether normal, coat it is whether bright, whether there is or not loose stool, eyes whether there is or not
Congested and abnormal secretion, the urinary tract whether there is or not abnormal secretion and fester, whether there is or not death etc..The healthy animal of situation without exception is received
Enter formal test.
1.1.6 experimental animal feeding management and environmental condition
20-25 DEG C of experimental animal room room temperature, humidity 40%-70%, using 12h/12h, light and shade replaces round the clock for illumination.Experiment
Animal uses credit number: SYXK (Guangdong) 2013-0014.
1.1.7 feed and drinking water
1.1.7.1 feed: SPF grades of sterilizing mouse material are provided by Guangdong Medical Lab Animal Center.
1.1.7.2 water: pure water comes from laboratory animal room's pure water system.
1.1.8. major experimental instrument
Electronic balance, model: AX2202ZH, sensibility reciprocal: 0.01g, Ohaus Instrument (Changzhou) Co., Ltd..
Electronic balance, model: CP224C, sensibility reciprocal: 0.1mg, Ohaus Instrument (Changzhou) Co., Ltd..
Electronic thermometer, model: MC-347, Omron (Dalian) Co., Ltd.
Intelligent hot-plate instrument, model: RB-200, Chengdu TME Technology Co., Ltd..
1.1.9 dose design and grouping
The Nuprin Tablets clinic dose that reference examples 1 provide: 0.2g/ time, daily no more than 0.8g, i.e., 0.8g/ days, mouse
Equivalent dose be 0.12gkg-1·d-1。
The drug that embodiment 1-3 is provided uses basic, normal, high 3 dosage groups, is equivalent to clinical quasi- dosage respectively
0.5,1,2 times, by every kg body weight dosage conversions.
The clinic for the drug that embodiment 1 provides is intended with dosage being 35g/ days, i.e., the 3 of the drug of the offer of embodiment 1 are more preferable small
Mouse equivalent dose is respectively 2.63gkg-1·d-1、5.26g·kg-1·d-1、10.52g·kg-1·d-1。
The clinic for the drug that embodiment 2 provides is intended with dosage being 90g/ days, i.e. 3 mouse of the drug of the offer of embodiment 2
Equivalent dose is respectively 6.76gkg-1·d-1、13.52g·kg-1·d-1、27.04g·kg-1·d-1。
The clinic for the drug that embodiment 3 provides is intended with dosage being 95g/ days, i.e. 3 mouse of the drug of the offer of embodiment 3
Equivalent dose is respectively 7.14gkg-1·d-1、14.27g·kg-1·d-1、28.54g·kg-1·d-1, dosage is shown in Table 1,
The grouping of 1 mouse test of table and dose design
1.1.10 statistical analysis
With " means standard deviation" indicate.Test data is united using 17.0 statistics analysis software package of SPSS
Meter processing quantitative data comparison among groups use one-way analysis of variance (One-Way ANOVA), if between-group variance is neat, are examined with LSD
It tests and compare two-by-two between each group.
1.2 experimental methods and result
1.2.1 drug causes the influence of mouse fever to lipopolysaccharides
1.2.1.1 experimental method
18-22g health KM mouse 140, after adaptive feeding, after clinical thermometer smears vaseline are taken, mouse anus is measured
Temperature chooses the KM mouse fluctuated in the normal range, is randomly divided into blank control group (comparative example 2), (comparison of Nuprin Tablets group
Example 1), the high, medium and low dosage group of embodiment 1, the high, medium and low dosage group of embodiment 2, the high, medium and low dosage group of embodiment 3,
Every group 10, by 20mLkg-1·d-1Volume gastric infusion is respectively administered once before Yu Fare modeling and after fever modeling 4h.With
Physiological saline configures lipopolysaccharides reagent, with 250 μ g/kg intraperitoneal injection, 2 after injection, 4,6,8h, measures each group mouse temperature respectively
1 time.
1.2.1.2 experimental result
Temperature-measuring results such as table 2,
2 drug of table causes the influence of mouse fever to lipopolysaccharides
From table 2 it can be seen that after injection lipopolysaccharides 2h, compared with comparative example 2, the Nuprin Tablets group energy of the offer of comparative example 1
It significantly reduces mouse temperature (P ﹤ 0.01).
After injecting lipopolysaccharides 4h, compared with comparative example 2, the Bu Luo of high dose group, the offer of comparative example 1 that embodiment 1 provides
Fragrant piece group can significantly reduce mouse temperature (P ﹤ 0.01).
After injecting lipopolysaccharides 6h, compared with comparative example 2, each group can significantly reduce mouse temperature (P ﹤ 0.05 or P ﹤
0.01)。
After injecting lipopolysaccharides 8h, compared with comparative example 2, the high agent of high dose group, the offer of embodiment 3 that embodiment 2 provides
The Nuprin Tablets group that amount group, comparative example 1 provide can significantly reduce mouse temperature (P ﹤ 0.05 or P ﹤ 0.01).
So, it was therefore concluded that: the drug that embodiment 1 provides can significantly reduce mouse temperature after the 4h and 6h that generates heat;Implement
The drug that example 2 provides can significantly reduce mouse temperature after the 6h and 8h that generates heat;The drug that embodiment 3 provides is after the 6h and 8h that generates heat
It can significantly reduce mouse temperature.
1.2.2 the influence that drug generates heat to induced by yeast in mice
1.2.2.1 experimental method
18-22g health KM mouse 140, after adaptive feeding, after clinical thermometer smears vaseline are taken, mouse anus is measured
Temperature chooses the KM mouse fluctuated in the normal range, is randomly divided into blank control group (comparative example 2), (comparison of Nuprin Tablets group
Example 1), the high, medium and low dosage group of embodiment 1, the high, medium and low dosage group of embodiment 2, the high, medium and low dosage group of embodiment 3,
Every group 10, by 20mLkg-1·d-1Volume gastric infusion is respectively administered once before Yu Fare modeling and after fever modeling 4h.With
Physiological saline configures yeast reagent, is subcutaneously injected with 20mg/kg, 2 after injection, 4,6,8h, measures each group mouse temperature 1 respectively
It is secondary.
1.2.2.2 experimental result
Temperature-measuring results such as table 3,
The influence that 3 drug of table generates heat to induced by yeast in mice
From table 3 it can be seen that after injection yeast 2h, compared with comparative example 2, each group no difference of science of statistics (P ﹥ 0.05).
After injecting yeast 4h, compared with comparative example 2, the brufen of middle dose group, the offer of comparative example 1 that embodiment 3 provides
Piece group can significantly reduce mouse temperature (P ﹤ 0.05 or P ﹤ 0.01).
After injecting yeast 6h, compared with comparative example 2, the low dosage of high dose group, the offer of embodiment 3 that embodiment 2 provides
The Nuprin Tablets group that group, comparative example 1 provide can significantly reduce mouse temperature (P ﹤ 0.05 or P ﹤ 0.01).
After injecting yeast 8h, compared with comparative example 2, the middle dosage of the offer of embodiment 1, the high dose of the offer of embodiment 2, reality
Apply the low, middle and high dose groups of the offer of example 3, the Nuprin Tablets group that comparative example 1 provides can significantly reduce mouse temperature (P ﹤ 0.05
Or P ﹤ 0.01).
So, it was therefore concluded that: the middle dose group for the drug that embodiment 1 provides can significantly reduce Mice Body after the 8h that generates heat
Temperature;The high dose group for the drug that embodiment 2 provides can significantly reduce mouse temperature after the 6h and 8h that generates heat;What embodiment 3 provided
Drug can significantly reduce mouse temperature after generate heat 4h, 6h and 8h.
1.2.3 drug causes the influence of mice pain to hot plate
1.2.3.1 experimental method
18-22g health KM female mice 160 are taken, after adaptive feeding, mouse is placed in hot-plate instrument, temperature setting
It is 55 ± 0.5 DEG C, metapedes is licked as observation index using mouse, preselects the mouse for having pain reaction in 5-30s.Choose pre-selection qualification
KM mouse 140, be randomly divided into blank control group (comparative example 2), Nuprin Tablets group (comparative example 1), embodiment 1 it is high, medium and low
Dosage group, the high, medium and low dosage group of embodiment 2, the high, medium and low dosage group of embodiment 3, every group 10, by 20mLkg-1·
d-1Volume gastric infusion, 1 time a day, for three days on end.After 40min, 80min, 120min after the last administration, mouse is placed in heat
In plate instrument, temperature is 55 ± 0.5 DEG C, licks metapedes as observation index using mouse, mouse pain threshold is measured, if nothing in mouse 60s
Pain reaction is taken out immediately, calculates by 60s.
1.2.3.2 experimental result
Measurement result such as table 4,
4 drug of table causes the influence of mice pain to hot plate
From table 4, it can be seen that compared with comparative example 2, the low dose group that embodiment 3 provides can be mentioned significantly after administration 40min
High mouse pain threshold (P ﹤ 0.05).
After 80min is administered, compared with comparative example 2, each group no difference of science of statistics (P ﹥ 0.05).
After 120min is administered, compared with comparative example 2, each group no difference of science of statistics (P ﹥ 0.05).
So, it was therefore concluded that: the low dose group for the drug that embodiment 3 provides can significantly improve mouse after 40min is administered
Pain threshold.
1.2.4 drug Dichlorodiphenyl Acetate causes the influence of mice pain
1.2.4.1 experimental method
18-22g health KM mouse 140, after adaptive feeding are taken, blank control group (comparative example 2), Bu Luo are randomly divided into
Fragrant piece group (comparative example 1), embodiment 1 high, medium and low dosage group, the high, medium and low dosage group of embodiment 2, the height of embodiment 3,
In, low dose group, every group 10, by 20mLkg-1·d-1Volume gastric infusion, 1 time a day, for three days on end.Last dose
After 40min, 0.6% glacial acetic acid is configured with distilled water, glacial acetic acid is injected intraperitoneally only with 0.2ml/." S " is shrunk to mouse web portion
The behaviors such as shape, body twist, hindlimb extension and crawling be writhing index, observe and record mouse in 20min writhing incubation period and
Writhing number.
1.2.4.2 experimental result
Measurement result such as table 5,
The influence of 5 drug Dichlorodiphenyl Acetate of table cause mice pain
As can be seen from Table 5, compared with comparative example 2, the middle dosage of middle dose group, the offer of embodiment 2 that embodiment 1 provides
The Nuprin Tablets group that the middle dose group and comparative example 1 that group, embodiment 3 provide provide can significantly extend mouse writhing incubation period (P
﹤ 0.05 or P ﹤ 0.01).
Compared with comparative example 2, the middle dose group and comparative example 1 of high dose group, the offer of embodiment 3 that embodiment 2 provides are mentioned
The Nuprin Tablets group of confession can substantially reduce mouse writhing number (P ﹤ 0.05 or P ﹤
0.01)。
So, it was therefore concluded that: the middle dose group for the drug that embodiment 1 provides can significantly extend mouse writhing incubation period;It is real
The middle dose group for applying the drug of the offer of example 2 can significantly extend mouse writhing incubation period, and high dose can substantially reduce mouse writhing
Number;The middle dose group for the drug that embodiment 3 provides can significantly extend mouse writhing incubation period and reduce mouse writhing number.
So experimental example 1 the experimental results showed that, the drug that embodiment 1- embodiment 3 provides all has refrigeration function, real
The drug for applying the offer of example 3 also has certain analgesic activity.
Experimental example 2
Use the drug effect for the drug that experiment in vitro detection embodiment 1- embodiment 3 is prepared, concrete mode are as follows:
Cytotoxicity of 2.1 drugs to Huh cell
Experimental virus: Dengue II type
Experimental cell: Huh7 cell, culture medium are DMEM in high glucose culture medium, add 10% fetal calf serum, dual anti-.
Experimental procedure: it by cell recovery in 20ml culture bottle, is covered with after about 3 days, is then digested with pancreatin, be inoculated in 96
In orifice plate, density is 1 × 105/ml.Start to add medicine to after second day adherent.Upper concentration be 50mg/ml, 10mg/ml,
0.4mg/ml, 0.08mg/ml, 16ug/ml, 3.25ug/ml;Set up the Normal group that do not add medicine to and cell-free blank control
Group, every group of three holes.After drug effect 48 hours, detected with mtt assay.Possible maximum nothing is found in analysis according to testing result
Then malicious concentration range carries out 2 times of dilution medicine-feedings again, more accurately to determine highest non-toxic concn such as table 6,
The cytotoxicity experiment result (MTT detection) of 62 times of table diluted embodiment 1-3
Embodiment 1 | Embodiment 2 | Embodiment 3 | |
Dosage | OD570nm | OD570nm | OD570nm |
4 | 0.5762±0.0652 | 0.5412±0.0214 | 0.4875±0.0254 |
2 | 0.8653±0.0248 | 0.7867±0.0361 | 1.0658±0.0365 |
1 | 1.2584±0.1205 | 1.3687±0.1247 | 2.0654±0.1547 |
0.5 | 2.1556±0.2658 | 2.0785±0.1152 | 2.0745±0.1257 |
0.25 | 1.9857±0.0365 | 1.9547±0.2014 | 1.9254±0.2014 |
0.125 | 2.0347±0.1475 | 1.8547±0.1526 | 1.8845±0.1562 |
0.0625 | 2.0489±0.1356 | 2.3645±0.2034 | 2.1687±0.1423 |
0.03125 | 1.9985±0.1654 | 1.9214±0.1143 | 2.1624±0.2513 |
As can be seen from Table 6, the drug that embodiment 1 provides is 0.5mg/ml to the highest non-toxic concn of Huh7 cell, real
The drug for applying the offer of example 2 is 0.5mg/ml to the highest non-toxic concn of Huh7 cell, and the drug that embodiment 3 provides is to Huh7 cell
Highest non-toxic concn be 1mg/ml, carry out drug in use, can according to highest non-toxic concn carry out drug use.
Protective effect of 2.2 drugs to large dosage of dengue virus infection Huh7 cell
Experimental virus: Dengue II type
Experimental cell: Huh7 cell, culture medium are DMEM in high glucose culture medium, add 10% fetal calf serum, dual anti-.
Experimental procedure: infection high dose (seed culture of viruses 10-1Dilution) dengue virus, Huh7 cellular morphology can be caused to destroy dead.
By cell recovery in 20ml culture bottle, cover with after about 3 days, then digested with pancreatin, is inoculated in 24 orifice plates, density be 1 ×
105/ml.To second day adherent postoperative infection dengue virus and start to add medicine to.Set up virus control group.Upper concentration is 1mg/ml,
0.5mg/ml, 0.25mg/ml, 0.125mg/ml.Obtain result such as Fig. 1-Fig. 8, wherein Fig. 1 is the photomicrograph of normal cell
Figure, Fig. 2 are the model photomicrograph figure for infecting high dose dengue virus, and Fig. 3 is that the drug that embodiment 1 provides is in upper concentration
Photomicrograph figure in the case where 0.5mg/ml, Fig. 4 are the feelings that the drug that embodiment 1 provides is 0.25mg/ml in upper concentration
Photomicrograph figure under condition, Fig. 5 are micro- bat of the drug that provides of embodiment 1 in the case where upper concentration is 0.125mg/ml
According to figure, Fig. 6 is photomicrograph figure of the drug that provides of embodiment 3 in the case where upper concentration is 0.5mg/ml, and Fig. 7 is to implement
Photomicrograph figure of the drug that example 3 provides in the case where upper concentration is 0.25mg/ml, Fig. 8 are the drug that embodiment 3 provides
Photomicrograph figure in the case where upper concentration is 0.125mg/ml.Wherein, since the drug of the offer of embodiment 2 is without obvious thin
The effect of born of the same parents' protection, complete cell death, so, it does not take pictures.It can be seen that the drug that embodiment 1 provides from Fig. 1-Fig. 8
There is apparent cytoprotection in 0.5mg/ml and 0.25mg/ml dosage, the drug that embodiment 3 provides has in 0.5mg/ml
Obvious cytoprotection can prevent normal cell by equal virus infection.
Influence of 2.2 drugs to the intracellular dengue viral rna content of Huh7
Experimental virus: Dengue II type
Experimental cell: Huh7 cell, culture medium are DMEM in high glucose culture medium, add 10% fetal calf serum, dual anti-.
Experimental procedure: infection high dose (seed culture of viruses 10-3Dilution) dengue virus, Huh7 cellular morphology can be caused to destroy dead.
By cell recovery in 20ml culture bottle, cover with after about 3 days, then digested with pancreatin, is inoculated in 24 orifice plates, density be 1 ×
105/ml.To second day adherent postoperative infection dengue virus and start to add medicine to.Set up virus control group.Upper concentration is 1mg/ml
(embodiment 3 is without this dosage), 0.5mg/ml, 0.25mg/ml, 0.125mg/ml.As a result such as Fig. 9-Figure 10, wherein Fig. 9 is to implement
Influence of the drug that example 1 provides to the intracellular dengue viral rna relative quantity of Huh7, Figure 10 are the drug pair that embodiment 3 provides
The influence of the intracellular dengue viral rna relative quantity of Huh7.It can be seen that the drug and reality that embodiment 1 provides from Fig. 9 and Figure 10
The drug for applying the offer of example 3 has not significant impact the intracellular dengue viral rna relative quantity of Huh7.
So lower in virus attack, when without obvious cell damage, the drug that embodiment 1- embodiment 3 provides does not have
There is obvious inhibition dengue virus effect, but higher in virus challenge dose, under the dosage that cell can be killed completely, 1 He of embodiment
The drug that embodiment 3 provides has apparent cytoprotection.
Embodiments described above is some embodiments of the present application, instead of all the embodiments.The reality of the application
The detailed description for applying example is not intended to limit claimed scope of the present application, but is merely representative of the selected implementation of the application
Example.Based on the embodiment in the application, obtained by those of ordinary skill in the art without making creative efforts
Every other embodiment, shall fall in the protection scope of this application.
Claims (10)
1. a kind of Chinese medicine composition for treating dengue fever, which is characterized in that in parts by weight, comprising: the blueness of 15-30 parts by weight
Wormwood artemisia, the radix bupleuri of 10-20 parts by weight and 10-20 parts by weight pueraria lobata.
2. the Chinese medicine composition for the treatment of dengue fever according to claim 1 characterized by comprising 22.5 parts by weight
The pueraria lobata of the sweet wormwood, the radix bupleuri of 15 parts by weight and 15 parts by weight.
3. the Chinese medicine composition for the treatment of dengue fever according to claim 1, which is characterized in that further include: 10-20 parts by weight
Schizonepeta, the radix saposhnikoviae of 10-20 parts by weight, the honeysuckle flower of 10-20 parts by weight, the Fructus Forsythiae of 10-20 parts by weight, 10-20 parts by weight tangerine
The Radix Glycyrrhizae of stalk and 5-10 parts by weight.
4. the Chinese medicine composition for the treatment of dengue fever according to claim 3 characterized by comprising 22.5 parts by weight
The sweet wormwood, the radix bupleuri of 15 parts by weight, the pueraria lobata of 15 parts by weight, the schizonepeta of 15 parts by weight, 15 parts by weight
The radix saposhnikoviae, the honeysuckle flower of 15 parts by weight, the Fructus Forsythiae of 15 parts by weight, the campanulaceae of 15 parts by weight and 7.5 parts by weight
The Radix Glycyrrhizae.
5. the Chinese medicine composition for the treatment of dengue fever according to claim 1, which is characterized in that further include: 10-20 parts by weight
Almond, the Fructus Forsythiae of 10-20 parts by weight, the mulberry leaf of 10-20 parts by weight, the radix scutellariae of 10-20 parts by weight, 10-20 parts by weight cunning
The White Chloe of stone, the Poria cocos of 10-20 parts by weight and 5-10 parts by weight.
6. the Chinese medicine composition for the treatment of dengue fever according to claim 5 characterized by comprising 22.5 parts by weight
The sweet wormwood, the radix bupleuri of 15 parts by weight, the pueraria lobata of 15 parts by weight, the almonds of 15 parts by weight, 15 parts by weight
The Fructus Forsythiae, the mulberry leaf of 15 parts by weight, the radix scutellariae of 15 parts by weight, the talcums of 15 parts by weight, 15 parts by weight
The White Chloe of the Poria cocos and 7.5 parts by weight.
7. a kind of preparation method for the drug for treating dengue fever characterized by comprising will be described in claim any one of 1-6
The Chinese medicine composition for the treatment of dengue fever decoction is mixed with water.
8. the preparation method of the drug for the treatment of dengue fever according to claim 7, which is characterized in that after the decoction, mention
Filtrate is taken, medicinal extract will be obtained after filtrate concentration.
9. the preparation method of the drug for the treatment of dengue fever according to claim 8, which is characterized in that the density of the medicinal extract
For (1.1-1.2) g/cm3。
10. a kind of drug for treating dengue fever, which is characterized in that by the described in any item treatment dengue fever of claim 7-9
The preparation method of drug is prepared.
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104367941A (en) * | 2014-11-03 | 2015-02-25 | 山东瑞康生命科技有限公司 | Preparation method of traditional Chinese medicinal preparation for treating singapore hemorrhagic fever |
CN105168813A (en) * | 2015-09-13 | 2015-12-23 | 吴冬梅 | Exterior syndrome relieving and internal heat and detoxication relieving soup |
-
2019
- 2019-03-05 CN CN201910167374.5A patent/CN109700848B/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104367941A (en) * | 2014-11-03 | 2015-02-25 | 山东瑞康生命科技有限公司 | Preparation method of traditional Chinese medicinal preparation for treating singapore hemorrhagic fever |
CN105168813A (en) * | 2015-09-13 | 2015-12-23 | 吴冬梅 | Exterior syndrome relieving and internal heat and detoxication relieving soup |
Non-Patent Citations (5)
Title |
---|
伍炳彩: "杏仁汤临床运用举隅 ", 《江西中医药》 * |
曹彩云等: "寒温合方退高热——刘英锋教授运用柴胡杏仁汤的经验", 《上海中医药杂志》 * |
李开国: "青蒿煎剂治疗登革热疗效观察", 《中草药》 * |
陈宣等: "中西医结合治疗登革热37例", 《广东医学》 * |
高学敏: "《中国药典中药材及饮片彩色图鉴》", 31 March 2015, 山西科学技术出版社 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111388517A (en) * | 2020-02-24 | 2020-07-10 | 冼启福 | A Chinese medicinal composition for treating dengue fever and novel coronavirus pneumonia |
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