CN108478757A - The application of Shengjian Xiexin Tang diarrhea caused by treatment clostridium difficile infection - Google Patents
The application of Shengjian Xiexin Tang diarrhea caused by treatment clostridium difficile infection Download PDFInfo
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Abstract
The invention belongs to pharmaceutical technology fields, and in particular to the application of Shengjian Xiexin Tang diarrhea caused by treatment clostridium difficile infection.The present invention is furtherd investigate by many experiments on the basis of the existing pharmacological activity of Shengjian Xiexin Tang and screens its new clinical efficacy, the experimental results showed that：Shengjian Xiexin Tang has the purposes of diarrhea caused by treatment clostridium difficile infection.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to Shengjian Xiexin Tang diarrhea caused by treatment clostridium difficile infection
Using.
Background technology
Clostridium difficile (clostridium difficile, CD) is a kind of Gram-positive anaerobic spore-bearing bacilli, is passed through
Fecal oral route is propagated in crowd.As being widely used for extensive pedigree antibiotic is even abused, Intestinal Mucosal Injury in Patients Undergoing flora imbalance is held
Clostridium difficile infection (Clostridium difficile infection, CDI) is easily induced, and then diarrhea, enteritis occurs etc. one
Series of disease.Clostridium difficile infection has become global epidemiology problem (Clincal Infection
Diseases.2007,45(3):302–307.).It is estimated that can find clostridium difficile in 35% or so inpatient excrement,
Clostridium difficile infection illness rate may be up to 50% in the patient of long-term inpatients, and in about 3% healthy adult human faecal mass
Clostridium difficile (British Medical Journal.2010,340 can be turned out:c1296.).At present for clostridium difficile sense
There are two types of methods, respectively vancomycin and metronidazole for the standard care of dye.Through metronidazole and vancomycin treatment clostridium difficile
The Meta analysis results of infection validity show that for metronidazole compared with vancomycin, the two treats slight clostridium difficile infection
Effect is suitable, but more effectively (Li Rui metronidazoles and vancomycin treatment are difficult for the infection of vancomycin treatment severe clostridium difficile
The safety of clostridium infection and Meta analysis [D] the Medical University Of Chongqing of validity, 2016.).
Vancomycin and metronidazole treatment have the following problems：1. destroying intestinal beneficial flora；2. part clostridium difficile faces
Bed separation strains decline vancomycin and metronidazole sensitivity, resistant rate increases；3. symptoms recurrence rate is up to 15%-35% etc. and asks
Topic.It is shown through metronidazole and the Meta analysis results of vancomycin treatment clostridium difficile infection safety, two medicine combination therapies
Adverse reaction rate is single therapy more than 4 times.Therefore, the alternative medicine and therapeutic scheme for the treatment of clostridium difficile infection are found
Have become the important topic studied now.
Invention content
The purpose of the present invention is to provide a kind of clinical applications of classics recipe Shengjian Xiexin Tang；Another object of the present invention
It is to further provide for application of the classical bright side's Shengjian Xiexin Tang in terms of the caused induced diarrhea for the treatment of clostridium difficile infection.
Specifically, the present invention includes that Shengjian Xiexin Tang is being prepared for treating induced diarrhea caused by clostridium difficile infection
The application of drug etc..
The invention also includes application of the Shengjian Xiexin Tang in terms of improving intestinal flora, which excludes that disease is relevant controls
Treatment method.
The invention also includes Shengjian Xiexin Tangs in the application for preparing drug for improving intestinal flora etc..
The present invention also provides a kind of pharmaceutical compositions, including Shengjian Xiexin Tang and vancomycin.The pharmaceutical composition is available
The induced diarrhea caused by treatment clostridium difficile infection.
The prescription of Shengjian Xiexin Tang of the present invention is by the tuber of pinellia, rhizoma zingiberis, the coptis, radix scutellariae, ginseng, jujube, Radix Glycyrrhizae, ginger group
At.
Further, the prescription of Shengjian Xiexin Tang of the present invention is by tuber of pinellia 5-45g, rhizoma zingiberis 3-15g, coptis 3-15g, Huang
A kind of reed mentioned in ancient books 5-45g, ginseng 5-45g, jujube 5-45g, Radix Glycyrrhizae 5-45g, ginger 5-60g compositions.
Preferably, the prescription of Shengjian Xiexin Tang of the present invention is by tuber of pinellia 9g, rhizoma zingiberis 3g, coptis 3g, radix scutellariae 9g, ginseng
9g, jujube 9g, Radix Glycyrrhizae 9g, ginger 12g compositions.
Shengjian Xiexin Tang of the present invention can use this field conventional method to prepare.This field conventional method can also be used in medicinal material
Or the net system product or processed product that classical documents are recorded.
Chinese medicine mainly recognizes the understanding of infection in terms of bacterium and patient two, emphasizes the power of patient itself healthy tendency
With the relationship of disease, it is believed that and " healthy tendency deposit in then heresy can not do ", internal cause is basic, is not simple antibacterial.Natural resources of Chinese medicinal materials is abundant,
Studies have shown that most antibacterial Chinese medicines have broad-spectrum antibacterial action, seeks from traditional Chinese medicine to antibacterial active drug and grind
It is all feasible way to study carefully Chinese and Western medicine to be used in combination with the drug resistance for reducing bacterium.
Chinese medicine compound prescription Shengjian Xiexin Tang comes from classical Chinese medicine ancient books《The Treatise on Fevrile Diseases》It " cures the wound after cold sweating, gets along well in stomach, under the heart
Ruffian is hard, and gas is smelly, retention of fluid in the hypochondrium, the unfavorable person of active borhorygmus." party is by the tuber of pinellia, rhizoma zingiberis, the coptis, radix scutellariae, ginseng, jujube, sweet
Grass, ginger composition.Clinical research confirmation, Shengjian Xiexin Tang can effectively prevent (the Deng Chao gingers of late-onset diarrhea caused by Irinotecan
Mechanism study [D] the Beijing University of Chinese Medicine of late-onset diarrhea caused by Xiexin Tang prevention Irinotecan, 2017.).Ginger removing the heart-fire
Soup also has therapeutic effect to irritable bowel syndrome after infection.Shengjian Xiexin Tang can mitigate scorching property, change the work(of aproll gas, only
Rush down at the same again will not constipation, be prevent and auxiliary treatment clostridium difficile infection viable drug.By network pharmacology, computer
Chemical technology method consults classical Chinese medicine ancient books and combines the practical experience of clinical expert, reaches common understanding through being repeatedly expounded through peer review,
Think that Shengjian Xiexin Tang can be used as the candidate prescription for the treatment of clostridium difficile.
Using C57BL/6 mouse clostridium difficile infection models, the animal drugs that Shengjian Xiexin Tang infects clostridium difficile are carried out
Effect learns evaluation preliminary experiment, and research is found：(1) Shengjian Xiexin Tang is used alone strong not as good as the bacteriostasis of vancomycin, but still table
Certain therapeutic effect is revealed；(2) Shengjian Xiexin Tang middle dose group joint vancomycin group uses, and not only has direct antibacterial work
With, can also reduce be discontinued after vancomycin the death rate；(3) treatment of Shengjian Xiexin Tang works slower, but therapeutic effect is stablized,
And without recurrence sign, embody the action character and advantage of Chinese medicine.There are problems for preliminary experiment：(1) this model does not occur brighter
Aobvious diarrhea and a large amount of death, may be caused by the concentration of bacterium or quality；(2) Shengjian Xiexin Tang is used alone, and does not make agent
Dependence is measured, and opposite effect occurs in Shengjian Xiexin Tang high dose group；To confirm the dose-effect relationship of Shengjian Xiexin Tang；
(3) preliminary experiment animal number of elements is less, unfavorable to the difference for observing the death rate；(4) preliminary experiment only have weight, state, the death rate and
The pharmacodynamic indexs such as A/B toxin lack the data that immunology etc. discloses mechanism of action.
The key point of the present invention
1. Shengjian Xiexin Tang can mitigate scorching property, change the work(of aproll gas, antidiarrheal simultaneously again will not constipation, be to prevent and auxiliary
Help the viable drug for the treatment of clostridium difficile infection.
2. by network pharmacology, computer chemistry technical method, consulting classical Chinese medicine ancient books and combining clinical expert
Practical experience is reached common understanding through being repeatedly expounded through peer review, it is believed that Shengjian Xiexin Tang can be used as the candidate prescription for the treatment of clostridium difficile.
3. the present invention screens it on the basis of the existing pharmacological activity of Shengjian Xiexin Tang, by many experiments further investigation
New clinical efficacy, the experimental results showed that：Shengjian Xiexin Tang has the purposes of diarrhea caused by treatment clostridium difficile infection.
The effect of the present invention
Shengjian Xiexin Tang is classics recipe, comes from the written classical works of Eastern Han Dynasty's Zhang Zhongjing《The Treatise on Fevrile Diseases》, research finds this
Compound has the function of that therapeutic effect is stable, restores intestinal flora balance, adjusts immune and gut metabolism, and shuttle is distinguished for treatment difficulty
Bacterium infection patient outcome it is further preferred that.
Shengjian Xiexin Tang is specific as follows the advantages for the treatment of in terms of the caused diarrhea of clostridium difficile infection：
1. Shengjian Xiexin Tang totally embodies certain therapeutic effect, feature is embodied in：Early stage results are bad, far from
And vancomycin treatment significant effect；Treatment onset time is long compared with vancomycin, but its effect is stablized compared with vancomycin, and is not easy
There is rebound phenomenon, embody the treatment advantage of traditional Chinese medicine multicomponent, multiple target point, is provided for clostridium difficile infection a kind of possible
Therapeutic strategy；
2. Shengjian Xiexin Tang is to the adjustment effect of intestinal flora：Vancomycin can effectively inhibit the growth of clostridium difficile, but
The quantity and ratio of profitable strain are destroyed simultaneously it is larger, and Shengjian Xiexin Tang have in terms of the balance for restoring flora it is more apparent
Advantage；
3. influence of the Shengjian Xiexin Tang to gut metabolism：In terms of gut metabolism object level, using vancomycin to enteron aisle generation
It thanks and is affected, it is more difficult in a short time to restore to normal level；And be used alone Shengjian Xiexin Tang on gut metabolism influence it is milder,
And have the tendency that gradually to normally restoring.
Description of the drawings
Fig. 1 vancomycins+small intestine of Shengjian Xiexin Tang treatment group pathological change figure.
Small intestine of Fig. 2 Shengjian Xiexin Tang middle dosages treatment group pathological change figure.
Fig. 3 Shengjian Xiexin Tang low dose therapy groups small intestine pathological change figure.
Small intestine of Fig. 4 Shengjian Xiexin Tang very low doses treatment group pathological change figure.
Fig. 5 different time points mouse weight figure of changing；In Fig. 5, A:Normal group；B:Model group；C:It is mould through the ages
Extract for treating group；D:Vancomycin+Shengjian Xiexin Tang low dose group；E:Shengjian Xiexin Tang middle dose group；F:Low dose of Shengjian Xiexin Tang
Amount group；G:Shengjian Xiexin Tang very low dose group.M1:Before various antibiotic are intervened；M2：Various antibiotic dry prognosis；M3：Difficult shuttle
After bacterium infection；
T1：After treatment 1 day；T2：After treatment 3 days；T3：After treatment 5 days；O1：Withdrawal observation the 3rd day.
A＆B Mycotoxin identification result figures before the various antibiotic of Fig. 6 (M1) are intervened.
Fig. 7 (M2) antibiotic dry prognosis A＆B Mycotoxin identification result figures.
A＆B Mycotoxin identification result figures after Fig. 8 (M3) clostridium difficile infection；Vs blank (A) group, * * p ＜ 0.01.
A＆B Mycotoxin identification result figures after Fig. 9 (T1) is treated 1 day；Vs models (B) group, * * p ＜ 0.01.
A＆B Mycotoxin identification result figures after Figure 10 (T2) is treated 3 days；Vs models (B) group, * p ＜ 0.05, * * p ＜ 0.01.
A＆B Mycotoxin identification result figures after Figure 11 (T3) is treated 5 days；Vs models (B) group, * p ＜ 0.05.
Figure 12 (O1) stops the 3rd day A＆B Mycotoxin identification result figure of observation post administration；Vs models (B) group, * p ＜ 0.05.
In Fig. 6 to Figure 12, A:Normal group；B:Model group；C:Vancomycin treatment group；D:Vancomycin+ginger rushes down
Heart soup low dose group；E:Shengjian Xiexin Tang middle dose group；F:Shengjian Xiexin Tang low dose group；G:Shengjian Xiexin Tang very low dose
Group.
The trend chart of Figure 13 different time points model group and vancomycin treatment group A＆B endotoxin levels；In Figure 13, B:
Model group；C:Vancomycin treatment group；M1:Before various antibiotic are intervened；M2：Various antibiotic dry prognosis；M3：Clostridium difficile sense
After dye.
T1：After treatment 1 day；T2：After treatment 3 days；T3：After treatment 5 days；O1：Withdrawal observation the 3rd day
Figure 14 different time points vancomycin and Shengjian Xiexin Tang treatment group A＆B toxin figure of changing.In Figure 14, C:Ten thousand
Ancient mycin treatment group；D:Vancomycin+Shengjian Xiexin Tang low dose group；E:Shengjian Xiexin Tang middle dose group；F:Shengjian Xiexin Tang
Low dose group；G:Shengjian Xiexin Tang very low dose group；M1:Before various antibiotic are intervened；M2：Various antibiotic dry prognosis；M3：It is difficult
After difficult clostridium infection；T1：After treatment 1 day；T2：After treatment 3 days；T3：After treatment 5 days；O1：Withdrawal observation the 3rd day.
Figure 15 Alpha diversity analysis figures；In Figure 15, Nor：Normal group；Pretre：Pretreated group；Mode：Modeling
Group；Van5：Vancomycin treatment group 5 days；Comb5：Through the ages+Chinese medicine combination therapy 5 days；Chinz5：Chinese medicine middle dosage 5 days；
Chind5：Chinese medicine low dosage 5 days；Chindd5：Chinese medicine very low dose 5 days.
Figure 16 group differences examine figure；Note：Significant difference situation between the selected two groups of samples of this figure displaying, and it is aobvious to having
Write sex differernce two groups mark (0.01<p<=0.05 be labeled as *, 0.001<p<=0.01 is labeled as * *, p<=0.001
Labeled as * * *).Abscissa is packet name, the exponential average that ordinate is every group.
Figure 17 groups composition analysis Bar schemes (categorization levels：Door)；Note：Normal control, CDI modelings, is treated through the ages, Chinese medicine
Middle dosage, five groups of Chinese medicine low dosage compare.Deferrization bacillus door (Deferribacteres), wart germ door
(Verrucomicrobia), Proteobacteria (Proteobacteria), Bacteroidetes (Bacteroidetes), Firmicutes
(Firmicutes)。
Figure 18 groups composition analysis Bar schemes (categorization levels：Guiding principle)；Note：Normal control, antimicrobial treatment, CDI modelings, through the ages
Treatment, Chinese medicine middle dosage, five groups are compared；Wherein, ε-deformation Gammaproteobacteria Epsilonproteobacteria, δ-deformation Gammaproteobacteria
Deltaproteobacteria, deferrization bacillus guiding principle Deferribacteres, Erysipelotrichaceae guiding principle is (temporarily without Chinese
Title), bacillus guiding principle Bacilli, wart germ guiding principle Verrucomicrobiae, β-deformation Gammaproteobacteria
Betaproteobacteria, γ-deformation Gammaproteobacteria Gammaproteobacteria, clostridium guiding principle Clostridia, bacteroid guiding principle
Bacteroidetes。
Figure 19 PCoA analysis charts.
Specific implementation mode
The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention..It is not specified in embodiment specific
Technology or condition person carry out according to technology or condition described in document in the art, or according to product description.It is used
Production firm person is not specified in reagent or instrument, is the conventional products that can be commercially available by regular distributor.
Experimental example
1. material
1.1 drug
Vancomycin dosage：50mg/kg；Shengjian Xiexin Tang middle dosage：16.4g/kg, Shengjian Xiexin Tang low dosage：
8.2g/kg, Shengjian Xiexin Tang very low dose：4.1g/kg.
(explanation：Shengjian Xiexin Tang dosage is in terms of the quality of raw medicinal herbs, and wherein low dose group is equivalent to people's dosage
Equivalent dose, administering mode：Gavage).
1.2 animal
4-5 week old C57BL/6 mouse, 18 ± 2g of weight.
2. method and result
The prescription of Shengjian Xiexin Tang is：Tuber of pinellia 9g, rhizoma zingiberis 3g, coptis 3g, radix scutellariae 9g, ginseng 9g, jujube 9g (thumb), toast are sweet
Careless 9g, ginger 12g, preparation method are that the tuber of pinellia adds boiling water cleaning is rear several times to merge decoction with other 7 taste medicinal materials, and medical filtration is dense
It is reduced to certain volume to obtain the final product.
2.1 animal packets and administration and materials
Mouse 140 is taken, it is normal to raise 3-5 days to adapt to environment.Then, weight is recorded, is randomly divided into 7 groups, every group 20
Only, i.e.,：Normal group (A), model group (B), vancomycin treatment group (C), vancomycin+Shengjian Xiexin Tang low dose group
(D), Shengjian Xiexin Tang middle dose group (E), Shengjian Xiexin Tang low dose group (F), Shengjian Xiexin Tang very low dose group (G).
2.1.1 animal model
After grouping, in addition to normal group, modeling is carried out to other 6 groups of mouse.Modeling method：Antibiotic mixed liquor replaces drinking-water
3 days；After 3 days, normal water is replaced, continues 2 days, and weighed within the 2nd day with normal water, takes excrement detection clostridium difficile A/B
Toxin；Next day gives intragastric administration on mice clostridium difficile suspension, to mouse state is observed and recorded after bacterium at any time, including：Activity condition,
Excrement shape, death condition etc.；After 24 hours, excrement is taken to detect A/B toxin, comprehensive evaluation model replicates situation.
2.1.2 treatment phase is administered
After modeling success, successive administration 5 days, the normal group of physiological saline that same volume is given once daily.In the drug treatment phase
Between observe and record mouse state at any time, including：Activity condition, excrement shape, death condition etc.；Weight is weighed, and takes mouse excrement
Just A/B endotoxin levels are detected；Overall merit therapeutic effect.
After the last administration, 6 mouse are randomly selected for every group, eye socket takes blood, IL-1, TNF-α, the change of the inflammatory factors such as IL-6
Change situation；Solution takes colon, and pathological staining observes each group mouse pathological change situation；Mouse ileocecus liquid is taken, it is more different
The change situation of intervention group intestinal flora.
2.1.3 stop observation post administration
After administration, mouse state is observed and recorded at any time, including：Activity condition, excrement shape, death condition etc.；Often
It weighs weight, the next day take excrement to detect A/B endotoxin levels, observation continues 2-3 weeks, according to later observations phase mouse state and A/
B endotoxin level situations；Solution takes colon, and pathological staining observes each group mouse pathological change situation；Mouse ileocecus liquid is taken,
Compare the change situation of different intervention group intestinal floras.
2.2 experimental result
2.2.1 each group small intestine pathological change situation after treatment end
Vancomycin combines Shengjian Xiexin Tang treatment group (Fig. 1) epithelium of intestinal mucosa structural integrity, and part epithelial cell contaminates deeply,
A small amount of meronecrosis；The loose oedema of submucosa, telangiectasis.Vancomycin joint ginger removing the heart-fire is given after showing modeling
Soup is treated, and can improve damage of the clostridium difficile to mouse small intestine tissue to a certain degree.
Shengjian Xiexin Tang middle dosage treatment group (Fig. 2) intestinal mucosa layer structural integrity, has no ulcer and inflammatory cell infiltration, few
Measure mucomembranous epithelial cell karyopycnosis, deep dye；The visible spotty necrosis of enteraden epithelial cell.Show that giving middle dosage ginger after modeling rushes down
Heart soup is treated, and inflammatory conditions caused by clostridium difficile infection can be improved.
Shengjian Xiexin Tang low dose therapy group (Fig. 3) intestinal mucosa layer structural integrity, mucomembranous epithelial cell pyknosis, deep dye,；Portion
Enteraden epithelial cell is divided to contaminate deeply.Illustrate after modeling, give the treatment of low dosage Shengjian Xiexin Tang, clostridium difficile infection can be improved
The integrality of caused mouse small intestine tissue.
Shengjian Xiexin Tang very low dose treatment group (Fig. 4) intestinal mucosa layer structural integrity, the visible karyopycnosis of mucomembranous epithelial cell,
A small amount of meronecrosis；The visible necrosis of mucous layer.Illustrate after modeling, gives the treatment of very low dose Shengjian Xiexin Tang, can improve
The integrality of mouse small intestine tissue caused by clostridium difficile infection, but still have the necrosis of a small amount of meronecrosis and mucous layer.
2.2.2 after stopping observation post administration 1 week, each group mouse small intestine histo pathological change situation
2.2.3 mouse weight situation of change
Mouse weight situation of change as can be seen from Figure 5, each group mouse weight is totally in increasing in whole experiment process
Gesture, wherein to during second day drug therapy after giving clostridium difficile, each group mouse weight is decreased obviously, and illustrates clostridium difficile sense
It is affected to mouse weight after dye, but with the extension of time and gives each group mouse (including model group) body after drug therapy
Weight gradually slowly restores and constantly increases, and notable difference is not found out between each group.
2.2.4 clostridium difficile toxin A＆B situations of change
Clostridium difficile toxin A/B is the principal causative substance of the bacterium, and A/B endotoxin levels can be effective in stool in mice sample
Reflect the quantity and state of development that pathogenic bacteria breed in enteron aisle.
It can be seen that before giving various antibiotic and intervening from Fig. 6 results, in addition to blank group, each group mouse clostridium difficile
Mycotoxin identification result be it is negative (<, and no difference of science of statistics 0.13)；
Various antibiotic dry prognosis are given during can be seen that modeling from Fig. 7 results, there is the A＆B toxin water of some animals
It is flat to have presentation gray area (0.13-0.37), illustrate that mouse is likely to occur intestinal flora when the simulation mankind take various antibiotic
Variation, but each group does not have infection clostridium difficile toxin A＆B positive；
It can be seen that from Fig. 8 results except blank group, after other each groups give clostridium difficile for 24 hours, A＆B endotoxin levels are notable
It increases, all in positive section (＞ 0.37), and endotoxin level is higher, illustrates that clostridium difficile infection is more serious in Mice Body, from A＆B
Endotoxin level sees that the success of clostridium difficile infecting mouse model provides support for Subsequent pharmacological evaluation；
After Fig. 9 results can be seen that model success, gives different pharmaceutical and treat 1 day, vancomycin standard care group
(C) and vancomycin Combined with Chinese Herbal Shengjian Xiexin Tang treatment group (D) A＆B endotoxin levels significantly significantly reduce (＜ 0.37), with mould
Type group (B) and extremely significant difference (p ＜ 0.05), show preferable therapeutic effect；And after treatment 1 day, Shengjian Xiexin Tang list
The A＆B endotoxin levels of only treatment group (E, F, G) are higher, and notable difference is had no compared with model group, illustrates interim medicine before the treatment
Shengjian Xiexin Tang does not show therapeutic effect；
It can be seen that from Figure 10 results after giving different pharmaceutical treatment 3 days, the A＆B poison of vancomycin standard care group (C)
Plain horizontal significant decrease (＜ 0.37) has still shown preferably treatment with model group (B) and extremely significant difference (p ＜ 0.05)
Effect；Level after vancomycin Combined with Chinese Herbal Shengjian Xiexin Tang treatment group (D) relatively treats 1 day is on the rise, but and model
Group (B) shows certain therapeutic effect compared to still having significant difference (p ＜ 0.01)；And after treatment 3 days, ginger removing the heart-fire
The relatively treatment of the A＆B endotoxin levels of soup monotherapy group (E, F, G) has obvious downward trend in first day, and compared with model group
There were significant differences (p ＜ 0.05 or p ＜ 0.01), illustrates that Chinese medicine Shengjian Xiexin Tang shows certain treatment effect after treating 3 days
Fruit, but at this time effect still not as good as vancomycin；
It can be seen that and given after different pharmaceutical treats 5 days from Figure 11 results, vancomycin standard care group (C) and through the ages
Mycin Combined with Chinese Herbal Shengjian Xiexin Tang treatment group still shows preferable therapeutic effect, with model group (B) than there is significant difference
(p ＜ 0.05)；Also there were significant differences compared with model group for Shengjian Xiexin Tang monotherapy group (E, F) (p ＜ 0.05), illustrates controlling
Chinese medicine Shengjian Xiexin Tang (E, F) shows certain therapeutic effect after treating 5 days, and suitable with vancomycin treatment effect at this time；
It can be seen that from Figure 12 results after being discontinued the 3rd day, the endotoxin level of model group (B) has restored substantially to normal water
It is flat, and individually give vancomycin standard care group (D) and obvious rebound phenomena occur, endotoxin level may be up to 4 or so,
Significantly larger than positive boundary (being more than 0.37), clinical common rebound phenomenon may occur at this time in mouse, and vancomycin joins
The endotoxin level for closing Xiexin decoction group (D) and individually giving Xiexin decoction various dose group (E, F, G) remains at sun
Property boundary hereinafter, treatment it is more stable；
Model group (B) and vancomycin treatment group (C) are can be seen that before the modeling phase gives clostridium difficile from Figure 13 results
(M1, M2), A＆B endotoxin levels are in compared with normal level；After gavaging clostridium difficile for 24 hours (M3), two groups of A＆B endotoxin levels
Significantly increasing, significantly larger than positive boundary (＞ 0.37), over the course for the treatment of, vancomycin group endotoxin level is remarkably decreased, but
Model group does not give any drug therapy, and endotoxin level also has slow downward trend, illustrates model group mouse there are self and is extensive
Recurrent images；The endotoxin level of model group mouse continues on a declining curve after drug withdrawal, and vancomycin treatment group endotoxin level is then
It significantly increases suddenly, in fact it could happen that clinical common recurrence；
From Figure 14 results can be seen that vancomycin treatment group (C) and each treatment group of Chinese medicine (D, E, F, G) the modeling phase to
It gives (M1, M2) before clostridium difficile, A＆B endotoxin levels are in compared with normal level；After gavaging clostridium difficile for 24 hours (M3), respectively
Group A＆B endotoxin levels significantly increase, significantly larger than positive boundary (＞ 0.37), before the treatment phase (T1：After 1 day), vancomycin
Group (C) and vancomycin Combined with Chinese Herbal Shengjian Xiexin Tang group (D) endotoxin level are remarkably decreased, and Chinese medicine Shengjian Xiexin Tang is each at this time
Treatment group (E, F, G) endotoxin level is still higher, does not show therapeutic effect；Treat mid-term (T2：After 3 days), each group (C, D, E, F,
G) endotoxin level is relatively low, shows different degrees of therapeutic effect, but at this point, vancomycin treatment group (C) and vancomycin
Chinese medicine Shengjian Xiexin Tang each group (E, F, G) is relatively used alone in Combined with Chinese Herbal Shengjian Xiexin Tang treatment group (E) therapeutic effect；After treatment
Phase (T3：After 5 days), each group (C, D, E, F, G) endotoxin level is relatively low, different degrees of therapeutic effect is shown, at this point, each group
Therapeutic effect is suitable；It is discontinued and terminates observation, vancomycin treatment group (D) endotoxin level significantly increases, in fact it could happen that rebound phenomenon,
And vancomycin Combined with Chinese Herbal Shengjian Xiexin Tang group (D) and each Chinese medicine Shengjian Xiexin Tang treatment group (E, F, G) do not recur
Phenomenon, therapeutic effect are relatively stablized.
2.2.5 the change situation of intestinal flora
Sequencing data optimization information table
(1) Alpha diversity analysis Figure 15 the result shows that：
Normal group bacterial diversity Abundances highest, antibacterials processing group, vancomycin treatment group, combination therapy
The diversity abundance of group is relatively low, and the use of Chinese medicine promotes flora and restores diversity.
(2) group difference examine Figure 16 the result shows that：
Left figure CDI modelings make normal flora abundance be decreased obviously, while middle figure vancomycin treatment kills clostridium difficile
Further decline flora abundance, right figure Chinese medicine is substantially better than vancomycin to the improvement of flora abundance.
(3) group's composition analysis Bar Figure 17 (categorization levels：Door) the result shows that：
AW1 AL1 AR1 (Normal group mouse) intestinal flora constitute：Firmicutes Firmucutes (Grain-positives
Bacterium) 45-55% is accounted for, Bacteroidetes Bacteroidetes (Grain-negative anaerobic bacteria beneficial bacterium) accounts for 55-65%, pleomorphous bacteria door
Proteobacteria is consistent with document report less than 5%；
B1 B2 B3 (modeling group mouse)：After antibiotic pretreatment and clostridium difficile gavage, Bacteroidetes disappears, multiform
Bacterium door and Firmicutes dramatically increase；
C1/C2/C3 (vancomycin treatment group)：Vancomycin inhibits Firmicutes but does not act on pleomorphous bacteria door；
E1/2/3 and F1/2/3 (low dose group in Chinese medicine)：After Chinese medicine treatment, Firmicutes and pleomorphous bacteria door are pressed down
System, Bacteroidetes accounting example are restored, and Chinese medicine middle dose group is better than low dose group.After E group Chinese medicine middle dose groups are treated 5 days, bacterium
Group constitutes and has been approached A group Normal groups.
(4) group's composition analysis Bar Figure 18 (categorization levels：Guiding principle) the result shows that：
After antibacterials mixed solution (blocking that, celebrating is big, mostly viscous, through the ages, metronidazole) and clindamycin are handled, clostridium difficile
It draws materials before gavage, B41, C42, D43 mouse floras constitute display：Under the action of antibiotic, in mouse intestinal bacteroid guiding principle and
The ratio of clostridium guiding principle is remarkably decreased, and the γ-deformation Gammaproteobacteria (enterobacteria mesh, Pseudomonadales) deformed in Gammaproteobacteria is resistance to due to being also easy to produce
Pharmacological property or natural drug resistance become dominant bacteria.
(5) PCoA analysis charts 19 the result shows that：
PCoA is analyzed, i.e., principal coordinate analysis (principal co-ordinates analysis) is to the phase of different samples
It is analyzed like property and difference.Principal component 1 (PC1) and principal component 2 (PC2) are two maximum difference spies for causing sample to be grouped
Sign, contribution rate is respectively 39.05% and 17.83%.Vancomycin is the main reason for causing sample packet whether use：In figure
Four groups of right side is drawn materials when vancomycin treatment is not used, and left side is drawn materials when using vancomycin treatment.Illustrate ten thousand
The influence that ancient mycin constitutes intestinal flora is compared with clostridium difficile bigger.The flora of Chinese medicine middle dose group and Normal group is constituted most
It is close.
3. conclusion
(1) model evaluation：This experiment, through generally acknowledged modeling method, simulates clinical human infection's clostridium difficile using international
Phenomenon finds out after clostridium difficile infection, have the integrality of small intestine compared with havoc, go out simultaneously from the HE dyeing of small intestine pathology
Existing more serious inflammation damnification, in combination with A＆B Mycotoxin identifications as a result, illustrating that this Success in Experiment replicates C57/6 mouse infections
The animal model of clostridium difficile provides support for drug evaluation.
(2) vancomycin standard care effect：In terms for the treatment of phase A＆B endotoxin levels, vancomycin and vancomycin joint
Chinese medicine Shengjian Xiexin Tang treatment group shows stronger therapeutic effect, but finds vancomycin standard care group after being discontinued,
Endotoxin level significantly increases, and therapeutic effect is unstable, in fact it could happen that clinical common rebound phenomenon.
(3) Chinese medicine Shengjian Xiexin Tang therapeutic effect：From pathology HE dyeing as can be seen that Shengjian Xiexin Tang can be to a certain degree
Upper improvement institutional framework imperfection and inflammation damnification caused by clostridium difficile infection；Shengjian Xiexin Tang various dose group,
Treatment early period (the 1st day) does not show therapeutic effect, after treatment 3 days, shows certain therapeutic effect, but at this time effect still not as good as ten thousand
Ancient mycin；But phase (the 5th day) after the treatment, therapeutic effect is still stablized, and therapeutic effect is suitable with vancomycin at this time；It is discontinued
After continue to observe, the therapeutic effect of Chinese medicine Shengjian Xiexin Tang is stablized, and does not occur rebound phenomenon.
Chinese medicine Shengjian Xiexin Tang totally embodies certain therapeutic effect, and feature is embodied in：Early stage results are bad, much
Not as good as vancomycin treatment significant effect；Treatment onset time is long compared with vancomycin, but its effect is stablized compared with vancomycin, and not
Easily there is rebound phenomenon, embody the treatment advantage of traditional Chinese medicine multicomponent, multiple target point, a kind of possibility is provided for clostridium difficile infection
Therapeutic strategy.
(4) adjustment effect of the Chinese medicine Shengjian Xiexin Tang to intestinal flora：Vancomycin can effectively inhibit the life of clostridium difficile
It is long but larger to the quantity of profitable strain and ratio destruction simultaneously, and Shengjian Xiexin Tang has in terms of the balance for restoring flora
Obvious advantage.
Although above the present invention is described in detail with a general description of the specific embodiments,
On the basis of the present invention, it can be made some modifications or improvements, this will be apparent to those skilled in the art.Cause
This, these modifications or improvements, belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (8)
1. application of the Shengjian Xiexin Tang in terms of preparing the drug for treating induced diarrhea caused by clostridium difficile infection.
2. application of the Shengjian Xiexin Tang in terms of preparing the drug for immunoregulation effect.
3. application of the Shengjian Xiexin Tang in terms of preparing the drug for improving intestinal flora.
4. application of the Shengjian Xiexin Tang in terms of improving intestinal flora, which excludes the relevant therapy of disease.
5. a kind of pharmaceutical composition, including Shengjian Xiexin Tang and vancomycin.
6. the pharmaceutical composition described in claim 5 is preparing the drug for treating induced diarrhea caused by clostridium difficile infection
The application of aspect, or the application in terms of preparing the drug for immunoregulation effect, or inhibit main inflammatory factors preparing
Expression drug in terms of application, or the application in terms of preparing drug for improving intestinal flora, or improving enteron aisle
Application in terms of flora.
7. according to claim 1-4,6 any one of them applications, which is characterized in that the prescription of the Shengjian Xiexin Tang is by half
Summer, rhizoma zingiberis, the coptis, radix scutellariae, ginseng, jujube, Radix Glycyrrhizae, ginger composition；
Preferably, the prescription of the Shengjian Xiexin Tang is by tuber of pinellia 5-45g, rhizoma zingiberis 3-15g, coptis 3-15g, radix scutellariae 5-45g, ginseng
5-45g, jujube 5-45g, Radix Glycyrrhizae 5-45g, ginger 5-60g compositions；
It is further preferred that the prescription of the Shengjian Xiexin Tang is by tuber of pinellia 9g, rhizoma zingiberis 3g, coptis 3g, radix scutellariae 9g, ginseng 9g, big
Jujube 9g, Radix Glycyrrhizae 9g, ginger 12g compositions.
8. pharmaceutical composition according to claim 5, which is characterized in that the prescription of the Shengjian Xiexin Tang is by the tuber of pinellia, dry
Ginger, the coptis, radix scutellariae, ginseng, jujube, Radix Glycyrrhizae, ginger composition；
Preferably, the prescription of the Shengjian Xiexin Tang is by tuber of pinellia 5-45g, rhizoma zingiberis 3-15g, coptis 3-15g, radix scutellariae 5-45g, ginseng
5-45g, jujube 5-45g, Radix Glycyrrhizae 5-45g, ginger 5-60g compositions；
It is further preferred that the prescription of the Shengjian Xiexin Tang is by tuber of pinellia 9g, rhizoma zingiberis 3g, coptis 3g, radix scutellariae 9g, ginseng 9g, big
Jujube 9g, Radix Glycyrrhizae 9g, ginger 12g compositions.
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