WO2009000150A1

WO2009000150A1 - The use of sanchinoside in treating septicemia

Info

Publication number: WO2009000150A1
Application number: PCT/CN2008/001170
Authority: WO
Inventors: Jingyan Han; Jiying Yang; Kai Sun; Chuanshe Wang; Yuying Liu
Original assignee: Tianjin Tasly Pharmaceutical Co. Ltd.
Priority date: 2007-06-21
Filing date: 2008-06-17
Publication date: 2008-12-31
Also published as: CN101327235A; CN101327235B

Abstract

The use of sanchinoside in treating septicemia, especially the use of Panax notoginsenosides in treating and/or preventing septicemia is provided in the prevent invention.

Description

Application of Panax notoginseng saponin in the treatment of sepsis

Technical field

The invention relates to new uses of traditional Chinese medicine products, in particular to the application of Panax notoginseng saponins in the treatment and/or prevention of sepsis. Background technique

Panax notoginseng (Burk. ) FH Chen, PN ) is the root of the traditional Chinese medicine Sanqi after air drying. Panax notoginseng saponins (also known as: notoginsenosides) are the main active ingredients of Panax notoginseng, including one or two or more saponins contained in traditional Chinese medicine Panax notoginseng, and the total saponins of Panax notoginseng include the traditional Chinese medicine Panax notoginseng Various saponins, which are widely used clinically to treat cardiovascular diseases and liver dysfunction. Panax notoginseng has been listed in the National Pharmacopoeia, and there are corresponding preparation products listed, such as: Xuesaitong for injection. Chinese patent CN200410058111.4 describes a preparation method of Panax notoginseng saponins: extracting water from Sanqi, concentrating the extract, precipitating with ethanol, removing the ethanol in the supernatant, dissolving in water, and using the macroporous resin HPD400 for column After chromatographic treatment, the impurities are removed by water elution, and then eluted with 90% ethanol until the active ingredient is completely eluted, and the alcohol eluate is recovered and dried. Specifically, it can be obtained by the following method: pulverizing the medicinal material into a coarse powder, adding 10 times the weight of the medicinal material to 70% ethanol, refluxing and extracting 2 times, each time for 25 hours, filtering, combining the second extract, 70 ° C The solvent was recovered under reduced pressure to the right and left to a flow extract having a specific gravity of 1.10 to 1.12. Dilute with water, carry out adsorption on a macroporous resin HPD400 adsorption column, elute with water, elute with 90% ethanol, and recover the solvent under reduced pressure at 70 °C in 90% ethanol. To the above-mentioned panax notoginseng saponin solution, MgO ₂ .Al ₂ O _{3 was added to} decolorize, and the filtrate was filtered, and the filtrate was vacuum dried at 80 ° C under reduced pressure to be pulverized to obtain a pale yellow panax saponin product. Sepsis is an acute systemic infection caused by pathogenic bacteria or conditional pathogens invading the blood circulation, producing toxins and other metabolites. It is characterized by chills, fever, rash, joint pain and hepatosplenomegaly. Some may have septic shock and migratory lesions. The causes of sepsis are: First, human factors:

1. When the skin and mucous membranes are damaged or have suppurative inflammation, the bacteria easily invade the body. 2. The human immune response can be divided into two types: non-specific immune response and specific immune response. The latter can be divided into cellular immunity and humoral immunity. When the body's immune function declines, it can't fully exert its phagocytosis and kill bacteria. Even if the amount of invading bacteria is small and the pathogenicity is not strong, it can cause sepsis.

3. The iatrogenic infection caused by conditional pathogens is also increasing. Second, the bacterial factors:

Mainly related to the virulence and quantity of pathogens. Virulent or large numbers of pathogenic bacteria enter the body, which is more likely to cause sepsis. The main symptoms of sepsis are:

1. Primary inflammation: The primary inflammation caused by various pathogens is related to its distribution in the human body. Primary inflammation is characterized by localized redness, swelling, heat, pain, and dysfunction.

2. Symptoms of Toxemia: The onset is more rapid. Frequent chills, high fever, and fever are mostly relaxation heat and/or intermittent heat. They can also be caused by heat retention, irregular heat and bimodal fever. The latter are caused by sepsis of Gram-negative bacilli. Fever is accompanied by varying degrees of symptoms of toxemia such as headache, nausea, vomiting, bloating, abdominal pain, general discomfort, and muscle and joint pain.

3. Rash: Seen in some patients, the most common defects are distributed in the trunk, limbs, conjunctiva, oral mucosa, etc., not many.

4. Joint symptoms: may have large joint redness, swelling, heat, pain and limited mobility, and even complicated with joint fluid, empyema, more common in Gram-positive cocci, meningococcal, Alcaligenes and other sepsis in.

5. Infectious shock: About 1/5~1/3 of patients with sepsis, manifested as irritability, rapid pulse rate, cold limbs, skin spots, decreased urine output and decreased blood pressure, etc. Caused by severe toxemia.

6. Hepatosplenomegaly: Generally only mild swelling. According to the study, lipopolysaccharide (LPS) is one of the components of the cell wall of Gram-positive bacteria, causing multiple manifestations of human sepsis and septic shock caused by Gram-positive bacteria. Microcirculatory disorders that occur during sepsis are systemic inflammation caused by excessive release of LPS The response is mediated by a number of activators such as adhesion molecules, reactive oxygen species (ROS), and inflammatory precursor mediators such as tumor necrosis factor-a (TNF-ct), interleukin-6 (IL-6), and interference. Prime-gamma (INF-γ LPS-induced microcirculatory disorders play a key role in organ dysfunction in sepsis, during which white blood cells rotate along the vascular endothelium and adhere to the vascular endothelium, which produces hydrogen peroxide and Mast cell degranulation is a key step in the literature. The main clinical treatments for sepsis include volume recovery, catecholamine use and antibiotic compensation. These methods can increase the survival rate of patients with sepsis, but clinically lead to elevated blood glucose. And blood pressure and blood calcium decline, and bleeding occurs. Clinical studies suggest that anti-TNF-α treatment may be helpful in the treatment of sepsis. However, recent studies have shown that this method can not cure sepsis, and will increase the death of patients with severe sepsis Therefore, looking for prevention of severe microcirculatory disorders in LPS-induced sepsis The method is still a challenge. In the course of research on Panax notoginseng saponins, the inventors found that post-treatment of Panax notoginseng saponins can inhibit leukocyte adhesion to the blood vessel wall, inhibit mast cell degranulation and inhibit cytokine release, and improve LPS-induced Microcirculatory disorders have obvious therapeutic effects on sepsis.

Accordingly, the present invention provides a novel therapeutic use of notoginsenoside, §: The present invention provides the use of panax notoginseng in the preparation of a medicament for the treatment and/or prevention of sepsis. The notoginsenosides described in the present invention may be panax notoginseng saponins. The panax notoginseng saponins described in the present invention preferably meet the following criteria: loss on drying 5%;

Hot residue 0.5%;

Ginsenoside Rbl 30% _;

Ginsenoside Rgl 20%;

The total saponin content is 88%. Further, the notoginsenoside of the present invention may also be a pharmaceutical composition containing notoginsenoside. The pharmaceutical composition containing notoginsenoside is based on panax notoginsenoside as a pharmaceutically active ingredient, and a pharmaceutically acceptable carrier, wherein the weight percentage of notoginsenoside in the composition is 0.1 to 99.9%, and the rest It is a pharmaceutically acceptable carrier. According to the use of the present invention, the sepsis is an acute systemic infection caused by pathogenic bacteria or conditional pathogens invading into the blood circulation to produce toxins and other metabolites. According to the use of the present invention, the notoginsenoside can treat and/or alleviate microcirculatory disorders caused by sepsis caused by a systemic inflammatory response caused by excessive release of LPS. According to the use of the present invention, the notoginsenoside can reduce the number of white blood cells induced by LPS to adhere to the wall of the small vein. According to the use of the present invention, the notoginsenoside inhibits LPS-induced degranulation of mast cells. According to the use of the present invention, the notoginsenoside inhibits an increase in LPS-induced blood plasma IL-6 and INF-γ concentrations. According to the use of the present invention, the notoginsenoside inhibits an increase in LPS-induced neutrophil CD1 lb expression. detailed description

The Panax notoginseng saponin according to the present invention may be Panax notoginseng saponins, and the main components thereof are ginsenoside Rb, Rg, notoginsenoside Rl, R2, R3 o The notoginsenosides according to the present invention may be commercially available or may be commercially available. It can be prepared according to the prior art and meets the medicinal standards. For example, it can be the following standard Panax notoginseng supplied by Yunnan Ruibao Natural Pigment Co., Ltd. - Appearance: Light yellow amorphous powder

Loss on drying 5%

Hot residue 0.5%

Ginsenoside Rbl 30%

Ginsenoside Rgl 20%

Total saponin content 88% Or Panax notoginseng saponins prepared according to the national standard WS3-B-3590-2001 (Z). The medicament of the present invention is a pharmaceutical composition prepared by using the above-mentioned notoginsenoside as a pharmaceutically active ingredient. The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier as needed, wherein the notoginsenoside is used as a pharmaceutically active ingredient, and the weight percentage in the preparation may be 0.1 to 99.9%, and the rest is a pharmaceutically acceptable carrier. . The pharmaceutical composition of the present invention is present in unit dosage form, which means a unit of the preparation, such as each tablet, each capsule, each vial of oral solution, granules per bag, each injection, and the like. The pharmaceutical composition of the present invention may be in any pharmaceutically acceptable dosage form, including tablets (for example, sugar-coated tablets, film-coated tablets and enteric coated tablets), capsules (for example, hard capsules, soft capsules), orally. Liquid, buccal, granules, granules, pills, powders, ointments, dandruffs, suspensions, powders, solutions, injections, suppositories, ointments (eg ointments, plasters), creams, sprays, drops Agents, patches, etc. The pharmaceutical composition of the present invention, which is orally administered, may contain conventional excipients such as a binder, a filler, a diluent, a tablet, a lubricant, a disintegrant, a coloring agent, a flavoring agent, and a moisturizing agent. The tablet can be coated if necessary. Suitable fillers include cellulose, mannitol, lactose and other similar fillers. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable humectants include sodium decyl sulfate. The solid oral composition can be prepared by a conventional method such as mixing, filling, tableting or the like. Repeated mixing allows the active ingredient to be distributed throughout the composition containing a substantial amount of filler. The oral liquid preparation may be in the form of, for example, an aqueous or oily suspension, solution, emulsion, syrup or elixir, or may be a dry product which may be formulated with water or other suitable carrier before use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fat; An emulsifier such as lecithin, sorbitan monooleate or gum arabic; a non-aqueous carrier (which may include edible oils), such as almond oil, fractionated coconut oil, An oily ester such as a glyceride, propylene glycol or ethanol; a preservative such as p-hydroxybenzyl or propylparaben or sorbic acid, and if desired, may contain a conventional flavoring or coloring agent. For injection, the liquid unit dosage form prepared contains the active ingredient of the invention and a sterile vehicle. The compound can be suspended or dissolved depending on the carrier and concentration. The solution is usually prepared by dissolving the active ingredient in a carrier, sterilizing it by filtration before filling it into a suitable vial or ampoule, and then sealing. Excipients such as a local anesthetic, preservative and buffer may also be dissolved in such a carrier. To increase its stability, the composition can be frozen after filling the vial and the water removed under vacuum. The pharmaceutical composition of the present invention may optionally be added to a suitable pharmaceutically acceptable carrier when prepared as a medicament, the pharmaceutically acceptable carrier being selected from the group consisting of: mannitol, sorbitol, sodium metabisulfite, sodium hydrogen sulfite , sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin C, disodium EDTA, calcium EDTA, monovalent alkali metal carbonate, acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid , sulfuric acid, phosphoric acid, amino acid, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and Derivatives, alginate, gelatin, polyvinylpyrrolidone, glycerin, Tween 80, agar, calcium carbonate, calcium bicarbonate, surfactant, polyethylene glycol, cyclodextrin, β-cyclodextrin, Phospholipid materials, kaolin, talc, calcium stearate, magnesium stearate, and the like. When using the preparation of the present invention, the dosage can be determined according to the condition of the patient, and can be taken three times a day, 1~20 doses per time. Depending on the dosage form, the "agent" can be such as a bag, a granule, a tablet, etc., each dose. The active ingredient of the drug, notoginsenoside, is from 1 to 1000 mg. The therapeutic use of the present invention is demonstrated by the following experiment. The results show that after 30 minutes after LPS injection, post-treatment with Panax notoginseng saponins can significantly reduce the number of white blood cells adhering to the wall of the small vein and reduce the number of degranulated mast cells. Inhibition of LPS-induced increase in CD lb expression in neutrophils and inhibition of LPS-induced increase in plasma IL-6 and INF-γ concentrations, these results indicate that post-treatment with Panax notoginseng can inhibit LPS-induced leukocyte adhesion , can improve LPS-induced microcirculatory disorders under the conditions of this experiment. This result suggests that treatment with the drug of the present invention will be effective after sepsis or septic shock. Experimental purpose

After the formation of LPS-induced microcirculatory disorders, the effects of Panax notoginseng saponins on sepsis were examined.

2. Materials and methods

2.1 Preparation of LPS and Panax notoginseng saponins

LPS is derived from the Escherichia coli O55:B5 plasma type obtained from Sigma (St Louis, MO), and Panax notoginseng is supplied by Tianjin Tianshili Group (Tianjin, China). Both are soluble in the saline solution.

2.2 Animal preparation

Male sprague-dawley (SD) rats, weighing between 200 and 250 grams, were provided by the Animal Center of Peking University Medical School. SD rats were fasted for 12 hours before the test. The test animals were anesthetized with urethane (1.25 mg/kg body weight, i.m.). The test animals were divided into control group (n=6), LPS group (n=6) and LPS+ notoginsenoside group (n=6). For the control group, after 10 minutes of basal observation, the left jugular vein and the left femoral vein were placed, and then saline was injected for 60 minutes. For the LPS group, the test animals received the same treatment as the control group, except that the LPS solution (2 mg/kg/hr) was continuously injected through the left femoral vein for 60 minutes without a 10-minute basic observation. For the LPS+ Panax notoginseng group, after 10 minutes of basic observation, LPS solution (2 mg/kg/hr) was continuously injected through the left femoral vein, and continuous injection of Panax notoginseng saponin solution through the left jugular vein was started 20 minutes after the injection of LPS solution. (5mg/kg/hr) until the end of the observation.

2.3 In vivo observation of mesenteric microcirculation

For each animal, the abdominal cavity was incision using a median incision (incision 2 to 3 cm long). The ileocecal portion of the mesentery (10 to 15 cm from the tail of the mesentery) was carefully separated, and the mesentery was removed from the abdominal cavity and laid flat on a transparent plastic table. The temperature and humidity of the mesentery are maintained by continuous surface perfusion of TC saline. The microcirculation of the mesentery was observed using an inverted microscope (Leica, DM-IRB, Germany) using a transilluminator. A TV camera (Japan, Toshiba Jk-TU53H) was mounted on the microscope, and the image was transmitted to a color display (Korea, TCL, J2118A), and the transmitted image was recorded by a DVD tape recorder (China, Malata DVR-R25). The time to start injecting LPS is set to TV timer (TV timing) 0 o'clock at VTG-55B, FOR-A, Japan).

2.4 Image Analysis

A single vein with no branching and no obvious curvature was selected for the following test. The diameter of the small vein was between 30 and 50 μm, and the length was about 200 μm.

2.4.1 Determination of venule diameter

Vessel diameters were determined using Image-Pro Plus 5.0 (Media Cybernetic, USA) software for images recorded at 0, 20, 30, 40, 50, and 60 minutes after LPS injection. The vessel diameter was measured three times at the same position and then averaged.

2.4.2 Determination of red blood cell flow rate

Converting the monitor's CCD to a high-speed TV camera system (FASTCAM-ultima APX, photron, Japan) Recording the flow rate of red blood cells in the venule at 2000 frames per second, then replaying the stored high-speed image at 25 frames per second. . The flow rate of erythrocytes in the venules at 0 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, and 60 minutes after LPS injection was measured using Image-Pro Plus 5.0 software (Media Cybernetic, USA).

2.4.3 Determination of shear rate

The venous wall shear rate (SR) is estimated based on the formula SR = 2.12x8x [V/D], where D represents the mean diameter of the vessel, V is the mean flow rate of red blood cells, and 2.12 is the median value of the empirical correction factor.

2.4.4 Determination of adherent white blood cells

To observe white blood cells adhering to the vessel wall, the dynamic behavior of the leukocytes was reviewed by replaying the recorded images. In the present study, adherent white blood cells were defined as white blood cells that adhered to the ipsilateral vascular wall for more than 10 seconds. The number of adherent white blood cells was counted by randomly selecting the recorded images, and the number of adhered white blood cells was expressed as the number of adherent cells/200 μηι venules.

2.4.5 Determination of DHR intensity in the wall of small veins

Partially added Η ₂ Ο ₂ sensitive fluorescent probe dihydronobamine 123 (DHR, molecular probe) to the mesenteric surface to observe the oxidative capacity of the venular wall. Fluorescence of a wavelength of 455 mm generated by excitation with a mercury lamp (100 W) was applied to an inverted fluorescence microscope (DM-IRB, Leica, Germany ) Observe fluorescence. Fluorescence images were then recorded at 0, 20, 30, 40, 50, and 60 minutes after LPS injection using a CD recorder. Image-Pro Plus 5.0 software was used to measure the fluorescence of the intervenous wall of the small vein and the small vein. strength. The difference between the fluorescence intensity of the venular wall and the venous interstitial at 0 minutes was taken as the baseline value, and the DHR was obtained by calculating the ratio of the difference between the venous wall and venous interstitial fluorescence intensity at each time point and the baseline value. Fluorescence intensity ratio.

2.4.6 Determination of albumin leaking from mesenteric venules

In another rat test group, FITC-labeled bovine plasma albumin (50 mg/kg) was slowly injected through the left jugular vein. After a 10-minute baseline observation, a mercury lamp (100W) was excited to produce a fluorescence of 455 mm to an inverted fluorescence microscope (DM-IRB, Leica, Germany) for fluorescence observation using a CD recorder at 0 minutes after LPS injection. Fluorescence images were recorded at 20 minutes, 30 minutes, 40 minutes, 50 minutes, and 60 minutes, and the fluorescence intensity of the venule wall and venules was measured using Image-Pro Plus 5.0 software. The ratio of the fluorescence intensity of the venular wall to the venous interstitial at 0 minutes was taken as the baseline value, and the ratio of the fluorescence intensity of the venule wall to the venous interstitial at each time point was divided by the baseline value to calculate the FITC fluorescence intensity. The ratio is calculated as R _t =P _t /P _c , where:

R _t : FITC fluorescence intensity ratio at time t;

P _t : ratio of fluorescence intensity of the venular wall and venous interstitial at time t;

The ratio of the fluorescence intensity of the venule wall to the venule interstitial at time P ₀ : 0, the baseline value.

2.4. Determination of mast cell degranulation

60 minutes after the injection of LPS, tissue staining was performed with 0.1% toluidine blue for 1 minute and then bleached with saline. The degranulated mast cells were identified as having cells that release intracellular particles into the surrounding tissue, and the number of cells in the circular field of view of the microscope microscope was counted to determine the number of such cells. There are five mesenteric windows per window for assessing the field of view along the microvasculature. The number of degranulated and non-degranulated mast cells was recorded, and then the proportion of degranulated mast cells was calculated.

2.4.8 Determination of CDllb/CD18 expression

After observing the mesenteric microcirculation, blood was collected from the abdominal aorta of each test animal and anticoagulated with heparin (20 units/ml blood), followed by lg FITC-labeled anti-CD llb and anti-CD 18 Antibodies (BD Biosciences Pharmingen, USA) were co-cultured for 20 minutes at room temperature. The cells were lysed with hemolysin (BD Biosciences Immunocytometer Systems, USA) and washed twice with PBS. The mean fluorescence intensity was measured using a flow cytometer (FACS Calibur, BD Co, USA). Neutrophils were selected using the FSC-SSC scatter plot. 5,000 neutrophils were required per sample and the average fluorescence intensity of each group was calculated.

2.4.9 Determination of plasma cytokine concentration

After observing the mesenteric microcirculation, blood samples from the test animals were collected via the abdominal aorta for heparin anticoagulation (20 units/ml blood). The plasma is then centrifuged. 50 μl plasma and standard material were co-cultured with 50 μl capture beads for 1 hour at room temperature, then mixed with 50 μl of TNF-a and IL-6 detection antibodies, and co-cultured for 2 hours at room temperature to form a sandwich composite. Things. After co-cultivation, 1 ml of elution buffer (BD Biosciences Pharmingen, USA) was added to each tube, and the mean fluorescence intensity was measured using a flow cytometer (FACS Calibur, B.D. Co, USA). Data analysis was performed using BD Cytometric Bead Array analysis software.

2.5 Statistical analysis

All values are expressed as the mean ± S.E ( N = 6). Statistical significance was calculated using analysis of variance and - test. set up? A value of <0.05 is significant.

3. Results

3.1 Number of white blood cells adhering to the wall of the small vein

The control group found only a small amount of adherent white blood cells during the entire 60-minute observation period. After 10 minutes of baseline observation, no adherent leukocytes were observed in the LPS and LPS + notoginsenoside groups. In the LPS group, injection of LPS for 20 minutes and LPS for 60 minutes resulted in the adhesion of a large number of white blood cells to the vessel wall. In the LPS + Panax notoginseng group, the number of white blood cells adhering to the wall of the small vein was significantly increased 20 minutes after the injection of LPS, and then the post-treatment of Panax notoginseng saponins was started, resulting in a significant decrease in the number of adherent white blood cells. Only a small amount of adherent white blood cells were found in the control group during the 60-minute observation period. In contrast, the number of white blood cells adhering to the wall of the small veins in the LPS group was progressively increased and linearly correlated with time, 5.0 ± 0.8 cells / 200 μπι at 20 minutes after LPS injection, and as high as 12.7 ± 1.4 cells at 60 minutes. 200μηι. Post-treatment of Panax notoginseng saponins for 30 minutes significantly inhibited LPS induction 8 001170 Adhesion of leukocytes to the vessel wall.

3.2 mast cell degranulation

In the control group, the percentage of degranulated mast cells was 23.91 ± 5.21%, which represents the spontaneous degeneration of mast cells in this test. After 60 minutes of LPS injection, the degranulated mast cells increased to 51.20 ± 5.86%. Post-treatment of Panax notoginseng saponins significantly inhibited LPS-induced degranulation of mast cells, which reached 23.96±6.12%.

3.3 Expression of neutrophil adhesion molecules CDl lb and CD18

The values of CDl lb and CD 18 in the control group were 27.36 ± 2.33 and 44.31 ± 4.09, respectively. After LPS stimulation, the fluorescence intensity of CDl lb and CD18 increased significantly, with values of 54.98 ± 4.14 and 65.83 ± 4.12, respectively. Post-treatment of Panax notoginseng saponins inhibited the fluorescence intensity of CD1 lb, indicating that Panax notoginseng was used to inhibit LPS-induced increase in CD1 lb concentration in neutrophils, but had no effect on LPS-induced CD18 expression.

3.4 Plasma cytokine concentration

In the control group, the concentrations of TNF-a, IL-6 and INF-γ were 17.68±2.64, 22.01±4.60 and 1.91±0.1 ng/L, respectively. After LPS stimulation, all measured cytokines increased rapidly, reaching 252.22±64.10, 647.83±182.80 and 2.63±0.11 ng/L, respectively. Post-treatment of Panax notoginseng significantly inhibited the production of IL-6 and INF-γ, and inhibited the release of TNF-α to a certain extent, but did not reach a significant level. The results of this experiment show that after 20 minutes after LPS injection, the use of Panax notoginseng saponin treatment can significantly reduce the number of white blood cells adhering to the wall of the small vein, reduce the number of degranulated mast cells, and inhibit LPS-induced neutrophil CD l Increased expression of lb, and inhibition of LPS-induced increase in plasma IL-6 and INF-γ concentrations, these results indicate that post-treatment with panax notoginseng can inhibit LPS-induced leukocyte adhesion and improve LPS induction under the conditions of this experiment. Microcirculatory disorders. This result suggests that treatment with the drug of the present invention will be effective after sepsis or septic shock. In summary, the experiments of the present invention show that the post-treatment of Panax notoginseng saponins can improve LPS-induced microcirculatory disorders by inhibiting leukocyte adhesion to the blood vessel wall, inhibiting mast cell degranulation, and release of cytokines. These results provide a new alternative to the clinical treatment of LPS-induced sepsis. Example

The invention is further illustrated by the following examples, which are not intended to limit the invention. Preparation Example 1 Tablet

Panax notoginseng saponin 100g, calcium sulphate 150g, microcrystalline cellulose 50g, micronized silica gel 3g, magnesium stearate 1.5g Take the above raw materials through a 100 mesh sieve; take notoginsenoside, calcium sulfate, microcrystalline cellulose, mix, Use 60% (v/v) ethanol as binder, make soft material; pass 20 mesh sieve, granulate; 60 Ό dry, take out, pass 30 mesh sieve, whole grain; add micro-silica gel and magnesium stearate, mix Evenly, tablet, made into 1000 pieces, that is. Preparation Example 2 Tablet

Panax notoginseng saponin 75g, calcium sulfate 1 12g, microcrystalline cellulose 37g, micronized silica gel 2.3g, magnesium stearate l. lg Take the above raw materials through a 100 mesh sieve; take notoginsenoside, calcium sulfate, microcrystalline cellulose, Mix well, use 60% (v/v) ethanol as the binder, make soft material; pass 20 mesh sieve, granulate; 60. C dry, take out, pass 30 mesh sieve, whole grain; add appropriate amount of micro-silica gel and magnesium stearate, mix, compress, and make 1000 pieces, that is. Preparation Example 3 Tablet

Panax notoginseng 133g, calcium sulfate 200g, microcrystalline cellulose 66g, micronized silica gel 4g, magnesium stearate 2g take the above raw materials through a 100 mesh sieve; take notoginsenoside, calcium sulfate, microcrystalline cellulose, mix, use 60 % ( v / v ) Ethanol as a binder, soft material; 20 mesh sieve, granulation; 60 Ό dry, taken out, passed through 30 mesh sieve, whole grain; add appropriate amount of micro-silica gel and magnesium stearate, mixed Evenly, tablet, made into 1000 pieces, that is. Preparation Example 4 Capsules

Take 30g of Sanqi saponin, add appropriate amount of starch, magnesium stearate and other auxiliary materials, granulate, whole, and put into the No. 1 capsule, that is. Preparation Example 5 Oral solution

Take 5g of saponins, add appropriate amount of sucrose, preservative, add water to 1000ml, and pack into 10ml / support, that is, oral solution. Preparation Example 6 Granules

Take 30g of saponins, add appropriate amount of dextrin, stevia, dry granulation, whole granules, and dispense. Preparation Example 7 Injection

Take 50g of notoginsenoside, add water to dissolve, and dissolve sodium chloride and ethyl p-hydroxybenzoate in water by heating, mix and adjust the pH value. The water for injection is diluted to 1000 ml, filtered through a hollow fiber membrane, filled, and sterilized. Application Example 1 Treatment of sepsis

Typical case: Patient Wang xx, male, 45 years old, civil servant, with headache, nausea, vomiting, bloating, abdominal pain, general discomfort, muscle and joint pain, etc., diagnosed with sepsis, injection of Panax notoginseng saponin injection, specification O. lg / support, three times a day, three at a time. After half a month, the symptoms have improved significantly. There were no adverse reactions during the medication.

Claims

Claim

1 . The use of panax notoginseng in the preparation of a medicament for treating and/or preventing sepsis.

2. The use of claim 1 wherein the notoginsenoside is panax notoginseng saponin.

3. The use according to claim 2, wherein the Panax notoginseng saponins meet the following criteria:

Loss on drying 5%;

Hot residue 0.5%;

Ginsenoside Rbl 30%;

Ginsenoside Rgl 20% _;

The total saponin content is 88%.

4. The use according to claim 1, wherein the notoginsenoside is a pharmaceutical composition containing notoginsenoside.

The use according to claim 4, wherein the pharmaceutical composition comprises notoginsenoside as a pharmaceutically active ingredient, and a pharmaceutically acceptable carrier, wherein the weight percentage of notoginsenoside in the composition is 0.1~ 99.9%, the remainder being a pharmaceutically acceptable carrier.

The use according to any one of claims 1 to 5, wherein the sepsis is an acute systemic infection caused by pathogenic bacteria or conditional pathogens invading into the blood circulation to produce toxins and other metabolic products.

The use according to any one of claims 1 to 5, wherein the notoginsenoside can treat and/or alleviate microcirculatory disorders caused by sepsis caused by excessive release of LPS Caused by systemic inflammatory response.

The use according to claim 6 or 7, wherein said notoginsenoside reduces the number of leukocytes induced by LPS adhesion to the wall of the small vein.

The use according to claim 6 or 7, wherein said notoginsenoside inhibits LPS-induced degranulation of mast cells.

The use according to claim 6 or 7, wherein said notoginsenoside inhibits an increase in LPS-induced plasma IL-6 and INF-γ concentrations.

The use according to claim 6 or 7, wherein said notoginsenoside inhibits LPS-induced increase in CD1 lb expression of neutrophils.