CN113413379A - Application of senkyunolide I in medicine for treating sepsis and lung injury - Google Patents
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- CN113413379A CN113413379A CN202110718579.5A CN202110718579A CN113413379A CN 113413379 A CN113413379 A CN 113413379A CN 202110718579 A CN202110718579 A CN 202110718579A CN 113413379 A CN113413379 A CN 113413379A
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Abstract
The invention provides an application of senkyunolide I in a medicine for treating sepsis lung injury, belonging to the technical field of medical biology. The senkyunolide I has the effects of inhibiting inflammatory cytokines and oxidative stress level in the medicament for treating the lung injury caused by sepsis, inhibiting platelet activation in the medicament for treating the lung injury caused by sepsis, and inhibiting formation of a neutrophil extracellular trap network in the medicament for treating the lung injury caused by sepsis.
Description
Technical Field
The invention belongs to the technical field of medical biology, and particularly relates to application of senkyunolide I in a medicament for treating sepsis lung injury.
Background
Sepsis refers to organ dysfunction caused by infection, specifically, the clinical course of systemic inflammatory response caused by bacterial infection, is also a common complication after surgery of critically ill patients, and is one of the important causes of death of clinically critically ill patients. The lung is the organ most frequently affected by sepsis and is the most vulnerable target organ. Sepsis lung injury produces inflammation and oxidative stress in the lungs, and also activates the platelets in the lungs and forms a neutrophil extracellular trap. Oxygen therapy and mechanical ventilation are currently the most common techniques for treating septic lung injury, but the therapeutic drugs for this disease are very poor. Senkyunolide I is a lactone compound contained in traditional Chinese medicines such as Ligusticum chuanxiong of Umbelliferae, and is one of the active ingredients of Ligusticum chuanxiong. Modern pharmacological studies show that senkyunolide compounds have the effects of resisting oxidative damage, resisting inflammation, resisting platelet aggregation, relaxing blood vessels and the like, and a Chinese patent medicine Xuebijing taking ligusticum wallichii as one of the main components is widely applied to sepsis treatment in China.
The existing sepsis therapeutic medicine contains seven-component compound including senkyunolide I, namely, hydroxysafflor yellow A, paeoniflorin, albiflorin, oxypaeoniflorin, senkyunolide I, sodium danshensu and ferulic acid. Meanwhile, in the report about animal experiments, the therapeutic effect of the senkyunolide on the sepsis encephalopathy is disclosed.
It can be seen that the existing therapeutic drugs are mixed with a plurality of different compounds, the precise description of the therapeutic action of a single molecule is difficult, and the increase of the molecular components may increase the incidence of adverse drug reactions.
Disclosure of Invention
In order to solve the problems, the invention provides an application of senkyunolide I in a medicament for treating lung injury caused by sepsis, which adopts the following technical scheme:
the invention provides an application of senkyunolide I in a medicament for treating sepsis lung injury.
The application of the senkyunolide I in the sepsis lung injury treatment medicine provided by the invention can also have the characteristics that the sepsis lung injury treatment medicine comprises the senkyunolide I and a pharmaceutically acceptable carrier, and the weight percentage of the senkyunolide I in the sepsis lung injury treatment medicine is 0.1-99.9%.
The application of senkyunolide I in the medicine for treating lung injury caused by sepsis can also have the characteristics that the senkyunolide I also comprises pharmaceutically acceptable salts, solvates, polymorphic forms, enantiomers and racemic mixture thereof.
The application of the senkyunolide I in the sepsis lung injury treatment medicine provided by the invention can also have the characteristics that the sepsis lung injury treatment medicine is any one of tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquid, buccal agents, granules, medicinal granules, pills, powder, ointment, pellets, suspensions, powder, solutions, injections, suppositories, ointments, plaster, creams, sprays, drops and patches.
The application of the senkyunolide I in the medicine for treating the lung injury caused by sepsis can also have the characteristics that the administration route of the injection is intravenous injection or intravenous drip, and the using dosage range of the senkyunolide I is 1mg/kg to 200 mg/kg.
The application of the senkyunolide I in the medicine for treating the lung injury caused by sepsis can also have the characteristics that the senkyunolide I has the effects of inhibiting inflammatory cytokines and the oxidative stress level in the treatment of the lung injury caused by sepsis.
The application of senkyunolide I in the medicine for treating the lung injury caused by sepsis provided by the invention can also have the characteristic that senkyunolide I has the effect of inhibiting platelet activation in the treatment of the lung injury caused by sepsis.
The application of the senkyunolide I in the medicine for treating the lung injury caused by sepsis can also have the characteristic that the senkyunolide I has the effect of inhibiting the formation of a neutrophil extracellular capture net in the treatment of the lung injury caused by sepsis.
Action and Effect of the invention
In the medicament for treating the lung injury caused by the sepsis, the senkyunolide I not only inhibits the level of inflammatory cytokines and oxidative stress, but also inhibits the activation of platelets and inhibits the formation of a net captured outside neutrophils, thereby having accurate and efficient treatment effect on the lung injury caused by the sepsis. The sepsis lung injury treatment drug only has a treatment effect on sepsis lung injury through a single molecule of the senkyunolide I, and simultaneously reduces the incidence rate of adverse drug reactions caused by multiple molecular components of the existing treatment drug.
Drawings
FIG. 1 is a comparative lung tissue section of four groups of experimental mice in example two of the present invention;
FIG. 2 is a table comparing the pathological scores of lung tissue damage of four groups of experimental mice in example two of the present invention;
FIG. 3 is a table comparing the protein concentration of tracheal lavage fluid in four groups of experimental mice in example two of the present invention;
FIG. 4 is a graph showing a comparison of the number of MPO-positive cells in lung tissue in four groups of experimental mice in example two of the present invention;
FIG. 5 is a chart comparing the number of MPO positive cells in lung tissue of four groups of experimental mice in the second example of the present invention, wherein 5(A) is a bar graph comparing the number of MPO positive cells in lung tissue of four groups of experimental mice, and 5(B) is a chart comparing the number of MPO positive cells in lung tissue of four groups of experimental mice;
FIG. 6 is a table comparing the MDA levels of TNF- α, IL-1 β and IL-6 in lung tissues of four groups of experimental mice in the third example of the present invention;
FIG. 7 is a graph comparing the expression levels of CD42d/GP5 observed by immunofluorescence after lung tissue sections of four groups of experimental mice in the fourth example of the present invention;
FIG. 8 is a graph comparing the expression levels of CD42d/GP5 in lung tissues of four groups of experimental mice in the fourth example of the present invention, wherein 8(A) is a bar graph of the number of MPO positive cells in lung tissues of four groups of experimental mice, and 8(B) is a comparison graph of the number of MPO positive cells in lung tissues of four groups of experimental mice;
FIG. 9 is a comparative table of MPO-DNA levels in plasma and tracheal lavage fluid of four groups of experimental mice in five examples of the invention.
Detailed Description
In order to make the technical means, the creation characteristics, the achievement purposes and the efficacy of the invention easy to understand, the following embodiment specifically explains the application of the senkyunolide I in the medicine for treating the lung injury caused by sepsis.
< example one >
The embodiment provides application of senkyunolide I in a medicament for treating lung injury caused by sepsis.
The medicament for treating the lung injury caused by the sepsis comprises senkyunolide I and a pharmaceutically acceptable carrier.
The senkyunolide I accounts for 0.1-99.9% of the weight of the medicine for treating the lung injury caused by sepsis.
The chemical structure of senkyunolide I is as follows:
the molecular formula is C12H16O4And the molecular weight is 224.256.
The sepsis lung injury treatment drug dosage form is any one of tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquid, buccal agents, granules, medicinal granules, pills, powder, paste, pellets, suspensions, powder, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops and patches.
That is, the sepsis lung injury treatment drug dosage form can be in the forms of other preparations such as an oral preparation, an injection preparation and a smearing preparation, wherein the oral preparation can also be an oral solid preparation or an oral liquid preparation.
The preferable therapeutic drug dosage forms are tablet, powder, granule, tincture, pill, capsule, oral liquid, aerosol inhalant, and injection. The tablets may be coated if necessary.
Oral formulations may contain conventional excipients. Such as binders, fillers, diluents, tabletting agents, lubricants, disintegrating agents, colouring agents, flavouring agents and wetting agents. Among the suitable fillers are cellulose, mannitol, lactose and other similar fillers; suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives, wherein the starch derivative may be sodium starch glycolate; suitable lubricants may be magnesium stearate; a suitable wetting agent may be sodium lauryl sulphate.
Solid preparations for oral administration can be prepared by conventional methods of mixing, filling, tabletting and the like, and repeated mixing can distribute the active substance throughout those compositions which employ large amounts of filler.
Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, non-aqueous carriers and preservatives, and, if desired, conventional flavoring or coloring agents.
Conventional additives such as suspending agents and emulsifiers. The suspending agent can be sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fat; the emulsifier can be lecithin, sorbitan monooleate, or acacia.
Non-aqueous carriers may include edible oils such as almond oil, fractionated coconut oil, oily esters such as esters of glycerin, propylene glycol or ethyl alcohol.
The preservative may be p-hydroxy-methyl-benzoate, propyl-p-hydroxybenzoate or sorbic acid.
Injectable formulations, prepared in liquid unit dosage form, contain the active substance of this example, senkyunolide I, and a sterile carrier. Depending on the carrier and concentration, the active substance can be suspended or dissolved. Solutions are generally prepared by dissolving the active substance in a carrier, filter sterilising before filling it into a suitable vial or ampoule and then sealing. Adjuvants such as a local anaesthetic, preservatives and buffering agents may also be dissolved in the vehicle. To improve its stability, the composition can be frozen after filling into vials and the water removed under vacuum.
The senkyunolide I in the sepsis lung injury treatment medicine of the embodiment can contain not only the compound monomer thereof, but also pharmaceutically acceptable salts, solvates, polymorphic forms, enantiomers and racemic mixture thereof.
When the sepsis lung injury treatment drug is a traditional Chinese medicine preparation, a suitable pharmaceutically acceptable carrier can be selectively added during preparation of the drug, and the pharmaceutically acceptable carrier is selected from the following components: mannitol, sorbitol, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin C, EDTA disodium, calcium sodium EDTA, monovalent alkali metal carbonates, acetates, phosphates or aqueous solutions thereof, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acids, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and derivatives thereof, alginates, gelatin, polyvinylpyrrolidone, glycerol, Tween 80, agar, calcium carbonate, calcium bicarbonate, surfactants, polyethylene glycol, cyclodextrin, beta-cyclodextrin, phospholipid-based materials, kaolin, talc, calcium stearate, magnesium stearate, and the like.
When the sepsis lung injury treatment drug of the embodiment treats sepsis through an injection, the administration route is intravenous injection or intravenous drip administration, and the using dosage range of the senkyunolide is 1mg/kg to 200 mg/kg.
< example two >
This example is a pharmacodynamic study of the therapeutic effect of senkyunolide I on sepsis lung injury in an animal model of sepsis.
2.1 materials of the experiment
48 male cleaning grade C57BL/6 mice were divided into 4 groups of 12, 22-25g, senkyunolide I (purchased from Shanghai philosophy Biotech, Inc.), sevoflurane, dimethyl sulfoxide, hematoxylin eosin stain, BCA kit, MPO fluorescent antibody.
2.2 Experimental methods
After anesthesia of mice with sevoflurane, the cecum was dissected through the median abdominal incision, the cecum was exposed, ligated at 1/2, and passed through a 22G needle, and the abdominal wall was closed layer by layer after a small amount of intestinal contents were squeezed out. The control group exposed the cecum by the same procedure but did not ligate the cecum or puncture. The experimental mice are divided into a pseudo-surgery dimethyl sulfoxide group, a pseudo-surgery senkyunolide I group, a sepsis dimethyl sulfoxide group and a sepsis senkyunolide I group. Injecting dimethyl sulfoxide solvent (concentration less than 5%) or senkyunolide I (36mg/kg) dissolved in dimethyl sulfoxide solvent into abdominal cavity after abdominal closing. Mice were sacrificed 24 hours after observation and lung tissue or tracheal lavage fluid was taken. Lung tissue sections were stained with hematoxylin and eosin and with MPO fluorescence, and tracheal lavage fluid was used to measure protein concentration by BCA method.
2.3 results of the experiment
FIG. 1 is a comparative lung tissue section of four groups of experimental mice in example two of the present invention; FIG. 2 is a table comparing the pathological scores of lung tissue damage of four groups of experimental mice in example two of the present invention.
As shown in figure 1 and figure 2, the sepsis senkyunolide I group mice lung injury pathology score in the embodiment is obviously lower than that of the sepsis dimethyl sulfoxide group.
FIG. 3 is a table comparing the protein concentration of tracheal lavage fluid in four groups of experimental mice in example two of the present invention.
As shown in FIG. 3, the protein concentration of tracheal lavage fluid in mice in the sepsis senkyunolide I group was significantly lower than that in the sepsis dimethyl sulfoxide group.
FIG. 4 is a graph showing a comparison of the number of MPO-positive cells in lung tissue in four groups of experimental mice in example two of the present invention; FIG. 5 is a chart comparing the number of MPO positive cells in lung tissue of four groups of experimental mice in example two, wherein 5(A) is a bar chart of the number of MPO positive cells in lung tissue of four groups of experimental mice, and 5(B) is a chart comparing the number of MPO positive cells in lung tissue of four groups of experimental mice.
As shown in FIG. 4 and FIG. 5, in this example, the MPO positive cell number in lung tissue of mice in the sepsis senkyunolide I group was significantly decreased compared to the sepsis dimethylsulfoxide group.
Compared with sepsis dimethyl sulfoxide, sepsis senkyunolide I has the advantages that lung injury classification and tracheal lavage fluid protein concentration and lung tissue MPO positive cell number are obviously reduced, and the senkyunolide I can relieve sepsis-induced lung injury, and inhibit protein exudation in tracheal lavage fluid and neutrophil infiltration of lung tissue.
< example three >
This example is a pharmacodynamic study of the inhibition of lung tissue inflammatory factors and oxidative stress levels using senkyunolide I in an animal model of sepsis.
3.1 Experimental materials
24 male cleaning grade C57BL/6 mice were divided into 4 groups of 6 mice, 22-25g, senkyunolide I (purchased from Shanghai philosophy science and technology Co., Ltd.), sevoflurane, dimethyl sulfoxide, TNF-alpha, IL-1 beta, IL-6ELISA kit, MDA kit.
3.2 Experimental methods
After anesthesia of mice with sevoflurane, the cecum was dissected through the median abdominal incision, the cecum was exposed, ligated at 1/2, and passed through a 22G needle, and the abdominal wall was closed layer by layer after a small amount of intestinal contents were squeezed out. The control group exposed the cecum by the same procedure but did not ligate the cecum or puncture. The experimental mice are divided into a pseudo-surgery dimethyl sulfoxide group, a pseudo-surgery senkyunolide I group, a sepsis dimethyl sulfoxide group and a sepsis senkyunolide I group. Injecting dimethyl sulfoxide solvent (concentration less than 5%) or senkyunolide I (36mg/kg) dissolved in dimethyl sulfoxide solvent into abdominal cavity after abdominal closing. The mice were sacrificed 24 hours after observation, lung tissue was taken, after homogenization and centrifugation, supernatants were taken for measurement of inflammatory factors by ELISA, and MDA content was measured by MDA kit.
3.3 results of the experiment
FIG. 6 is a table comparing the MDA levels of TNF- α, IL-1 β, and IL-6 in lung tissues of four groups of experimental mice in the third example of the present invention.
As shown in figure 6, compared with sepsis dimethyl sulfoxide group, MDA levels of TNF-alpha, IL-1 beta and IL-6 in lung tissues of sepsis senkyunolide I group mice are obviously reduced, which indicates that senkyunolide can inhibit inflammation and oxidative stress reaction of lung of sepsis lung injury mice.
< example four >
This example is a pharmacodynamic study of inhibition of pulmonary platelet activation using senkyunolide I in an animal model of sepsis.
4.1 Experimental materials
24 male cleaning grade C57BL/6 mice were divided into 4 groups of 6 mice, 22-25g, senkyunolide I (purchased from Shanghai philosophy Biotech, Inc.), sevoflurane, dimethyl sulfoxide, CD42d/GP5 fluorescent antibody.
4.2 Experimental methods
After anesthesia of mice with sevoflurane, the cecum was dissected through the median abdominal incision, the cecum was exposed, ligated at 1/2, and passed through a 22G needle, and the abdominal wall was closed layer by layer after a small amount of intestinal contents were squeezed out. The control group exposed the cecum by the same procedure but did not ligate the cecum or puncture. The experimental mice are divided into a pseudo-surgery dimethyl sulfoxide group, a pseudo-surgery senkyunolide I group, a sepsis dimethyl sulfoxide group and a sepsis senkyunolide I group. Injecting dimethyl sulfoxide solvent (concentration less than 5%) or senkyunolide I (36mg/kg) dissolved in dimethyl sulfoxide solvent into abdominal cavity after abdominal closing. Mice were sacrificed 24 hours after observation, lung tissue sections were removed and CD42d/GP5 expression levels were observed by immunofluorescence.
4.3 results of the experiment
FIG. 7 is a graph comparing the expression levels of CD42d/GP5 observed by immunofluorescence after lung tissue sections of four groups of experimental mice in the fourth example of the present invention; FIG. 8 is a chart comparing the expression levels of CD42d/GP5 in lung tissues of four groups of experimental mice in the fourth example of the present invention, wherein 8(A) is a bar graph of the number of MPO positive cells in lung tissues of four groups of experimental mice, and 8(B) is a chart comparing the number of MPO positive cells in lung tissues of four groups of experimental mice.
As shown in fig. 7 and fig. 8, compared with the sepsis dimethyl sulfoxide group, the sepsis senkyunolide I group mice lung tissue CD42d/GP5 expression level is obviously reduced, which indicates that the senkyunolide I can inhibit the activation degree of the sepsis lung injury mice lung platelets.
< example five >
This example is a pharmacodynamic study of the inhibitory effect of senkyunolide I on neutrophil capture in an animal model of sepsis.
5.1 Experimental materials
24 male cleaning grade C57BL/6 mice were divided into 4 groups of 6 mice, 22-25g, senkyunolide I (purchased from Shanghai philosophy Biotech, Inc.), sevoflurane, dimethyl sulfoxide, MPO-DNA complex ELISA kits.
5.2 Experimental methods
After anesthesia of mice with sevoflurane, the cecum was dissected through the median abdominal incision, the cecum was exposed, ligated at 1/2, and passed through a 22G needle, and the abdominal wall was closed layer by layer after a small amount of intestinal contents were squeezed out. The control group exposed the cecum by the same procedure but did not ligate the cecum or puncture. The experimental mice are divided into a pseudo-surgery dimethyl sulfoxide group, a pseudo-surgery senkyunolide I group, a sepsis dimethyl sulfoxide group and a sepsis senkyunolide I group. Injecting dimethyl sulfoxide solvent (concentration less than 5%) or senkyunolide I (36mg/kg) dissolved in dimethyl sulfoxide solvent into abdominal cavity after abdominal closing. Mice were sacrificed 24 hours after observation and peripheral blood and tracheal lavage were taken for ELISA detection.
5.3 results of the experiment
FIG. 9 is a comparative table of MPO-DNA levels in plasma and tracheal lavage fluid of four groups of experimental mice in five examples of the invention.
As shown in figure 9, compared with sepsis dimethyl sulfoxide group, sepsis senkyunolide I group mice plasma and tracheal lavage fluid MPO-DNA levels were significantly reduced, indicating that senkyunolide I can inhibit the formation of neutrophil capture net in sepsis lung injury mice.
The above embodiments are preferred examples of the present invention, and are not intended to limit the scope of the present invention.
Claims (8)
1. Application of senkyunolide I in preparation of medicine for treating lung injury due to sepsis is provided.
2. The use of senkyunolide I in the preparation of a medicament for treating sepsis pulmonary injury, as defined in claim 1, wherein:
wherein the sepsis lung injury treatment drug comprises the senkyunolide I and a pharmaceutically acceptable carrier,
the senkyunolide I accounts for 0.1-99.9% of the weight of the sepsis lung injury treatment drug.
3. The use of senkyunolide I in the preparation of a medicament for treating sepsis pulmonary injury, as defined in claim 1, wherein:
wherein, the senkyunolide I also comprises pharmaceutically acceptable salts, solvates, polymorphic forms, enantiomers and racemic mixture thereof.
4. The use of senkyunolide I in the preparation of a medicament for treating sepsis pulmonary injury, as defined in claim 1, wherein:
the sepsis lung injury treatment drug dosage form is any one of tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquid, buccal agents, granules, medicinal granules, pills, powder, ointment, pellets, suspensions, powder, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops and patches.
5. The use of senkyunolide I in the treatment of sepsis lung injury as claimed in claim 4, wherein:
wherein the administration route of the injection is intravenous injection or intravenous drip,
the application dosage range of the senkyunolide I is 1mg/kg to 200 mg/kg.
6. The use of senkyunolide I in the preparation of a medicament for treating sepsis pulmonary injury, as defined in claim 1, wherein:
wherein, the senkyunolide I has the inhibiting effect on the proinflammatory cytokines in the treatment of the lung injury caused by sepsis,
the senkyunolide I has an inhibiting effect on the oxidative stress level in the treatment of sepsis lung injury,
the senkyunolide I has an inhibiting effect on inflammatory cytokines and oxidative stress level in treatment of sepsis lung injury.
7. The use of senkyunolide I in the preparation of a medicament for treating sepsis pulmonary injury, as defined in claim 1, wherein:
wherein, the senkyunolide I has an inhibiting effect on platelet activation in the treatment of sepsis lung injury.
8. The use of senkyunolide I in the preparation of a medicament for treating sepsis pulmonary injury, as defined in claim 1, wherein:
wherein, the senkyunolide I has an inhibiting effect on the formation of the neutrophil extracellular trap net in the treatment of the lung injury caused by sepsis.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01207233A (en) * | 1988-02-12 | 1989-08-21 | Tsumura & Co | Antiarteriosclerotic |
| US20040081631A1 (en) * | 2002-10-29 | 2004-04-29 | Kang-Tae Lee | Cosmetic composition for skin whitening comprising senkyunolide a as active ingredient |
| KR100681700B1 (en) * | 2005-12-28 | 2007-02-15 | 주식회사 코리아나화장품 | Cosmetic composition for skin whitening comprising senkyunolide a and gluconic acid as active ingredients |
| CN112891362A (en) * | 2021-03-01 | 2021-06-04 | 天津红日药业股份有限公司 | Pharmaceutical composition for treating sepsis and application thereof |
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2021
- 2021-06-28 CN CN202110718579.5A patent/CN113413379A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01207233A (en) * | 1988-02-12 | 1989-08-21 | Tsumura & Co | Antiarteriosclerotic |
| US20040081631A1 (en) * | 2002-10-29 | 2004-04-29 | Kang-Tae Lee | Cosmetic composition for skin whitening comprising senkyunolide a as active ingredient |
| KR100681700B1 (en) * | 2005-12-28 | 2007-02-15 | 주식회사 코리아나화장품 | Cosmetic composition for skin whitening comprising senkyunolide a and gluconic acid as active ingredients |
| CN112891362A (en) * | 2021-03-01 | 2021-06-04 | 天津红日药业股份有限公司 | Pharmaceutical composition for treating sepsis and application thereof |
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| Title |
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| 沈燕: "血必净对脓毒症患者肺损伤和炎症因子的影响", 《现代生物医学进展》 * |
| 王亚亚: "抗脓毒症中药注射剂血必净新型质量评价方法的建立及其多批次质量波动性分析", 《中国优秀博硕士学位论文全文数据库（硕士）医药卫生科技辑》 * |
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