WO2008154794A1 - Utilisation d'extrait de salvia miltiorrhiza pour la préparation d'un médicament pour le traitement de la septicémie - Google Patents

Utilisation d'extrait de salvia miltiorrhiza pour la préparation d'un médicament pour le traitement de la septicémie Download PDF

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WO2008154794A1
WO2008154794A1 PCT/CN2008/000876 CN2008000876W WO2008154794A1 WO 2008154794 A1 WO2008154794 A1 WO 2008154794A1 CN 2008000876 W CN2008000876 W CN 2008000876W WO 2008154794 A1 WO2008154794 A1 WO 2008154794A1
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Prior art keywords
lipopolysaccharide
lactic acid
salvia miltiorrhiza
use according
acid
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PCT/CN2008/000876
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English (en)
Chinese (zh)
Inventor
Jing-Yan Han
Jun Guo
Kai Su
Chuan-She Wang
Yu-Ying Liu
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Tianjin Tasly Pharmaceutical Co. Ltd.
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Publication of WO2008154794A1 publication Critical patent/WO2008154794A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/537—Salvia (sage)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the present invention relates to new uses of traditional Chinese medicine products, and in particular to the use of Salvia miltiorrhiza extract for the treatment and/or prevention of sepsis. Background technique
  • Salvia miltiorrhiza is a traditional Chinese medicine in China. It was first seen in Shennong Bencaojing and was listed as top grade. Salvia miltiorrhiza is used as a dry root and rhizome of Salviami Itior2rhiza Bunge, a perennial herb of the genus Salicidae. Alias red ginseng, purple salvia miltiorrhiza Danshen is mainly produced in Shanxi, Sichuan, Anhui, Hebei, Jiangsu, Shandong, Zhejiang and other provinces. Danshen tastes bitter, slightly cold, into the heart, pericardium, liver.
  • Isotanshinone I , II A, II B
  • Isotanshinone I , II
  • cryptotanshinone hydroxy tanshinone II A
  • cryptotanshinone salvia miltiorrhiza
  • L-dihydrotanshinone I methyl tanshinate
  • the water-soluble component of Salvia miltiorrhiza is mainly dihydroxyphenyl lactic acid (DLA, see Figure 1A).
  • AKA Danshensu _D (+) f3 - (3, 4_Dihydroxyphenyl) lactic acid (1) is the basic structural component of the water-soluble various components of Salvia miltiorrhiza. It has been proven to have anti-oxidation and anti-fibrosis effects. .
  • Salvianolic acid compounds have strong inhibition of lipid peroxidation, scavenging superoxide anion and hydroxyl free The role of the base. Among them, salvianolic acid A and B have the strongest activity. Salvianolic acid B significantly inhibited mitochondrial damage and neuronal apoptosis induced by cerebral ischemia-reperfusion injury. It can inhibit the apoptosis of PCI2 cells with high anti-Caspase-3 expression, and also inhibit the formation of B amyloid protein (A f3 1-40) and the mitochondrial damage and apoptosis of PC12 cells induced by A ⁇ 1-40. It is a strong antioxidant and can eliminate intracellular calcium overload.
  • 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. There may be septic shock and migratory lesions.
  • the causes of sepsis are:
  • the human immune response can be divided into two types: non-specific immune response and specific immune response, and the latter can be divided into cellular immunity and humoral immunity.
  • non-specific immune response When the immune function of the body declines, the effect of phagocytosis and killing of bacteria cannot be fully exerted. Even if the amount of invading bacteria is small, the pathogenicity is not strong and can cause sepsis.
  • Pathogenic bacteria Mainly related to the virulence and quantity of pathogens. Pathogenic bacteria with high virulence or a large number of bacteria enter the body, which is more likely to cause sepsis.
  • 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.
  • Symptoms of Toxemia The onset is more rapid. Often there are chills, high fever, and fever, which are mostly relaxation heat or intermittent heat. They can also be caused by heat retention, irregular heat and bimodal fever. The latter are caused by sepsis-negative bacilli sepsis. The fever is accompanied by varying degrees of symptoms of toxemia such as headache, nausea, vomiting, bloating, abdominal pain, generalizedness, and muscle and joint pain.
  • Rash Seen in some patients, the most common defects are distributed in the trunk, limbs, conjunctiva, oral mucosa, etc., not many.
  • Joint symptoms There may be large joint redness, swelling, heat, pain and limited mobility, even complicated with joint fluid and empyema. It is more common in the course of sepsis such as Gram-positive cocci, meningococcal, and Alcaligenes. .
  • 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., and DIC can occur; Severe toxemia To.
  • lipopolysaccharide 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.
  • the microcirculatory disorder that occurs during sepsis is a systemic inflammatory response caused by excessive release of LPS, mediated by a number of activated factors such as adhesion molecules, reactive oxygen species (R0S), and inflammatory precursor mediators such as tumors.
  • TNF- ⁇ necrosis factor-a
  • IL-6 interleukin-6
  • IFN- ⁇ interferon-Y
  • the microcirculatory disorder induced by LPS plays a key role in organ dysfunction during sepsis. During this process, white blood cells rotate along the endothelium and adhere to the vascular endothelium. Hydrogen peroxide and mast cell degranulation are produced in the vessel wall.
  • the main clinical treatments for current sepsis include volume recovery, the use of catecholamines, and antibiotic-compensatory treatment. These methods can increase the survival rate of patients with sepsis, but clinically lead to an increase in blood sugar and a decrease in blood pressure and blood calcium, and bleeding. Clinical studies suggest that anti-TNF- ⁇ therapy may be helpful in the treatment of sepsis. However, recent studies have shown that this method does not cure sepsis and increases mortality in patients with severe sepsis. Thus, finding a way to prevent severe microcirculation in LPS-induced sepsis remains a challenge.
  • dihydroxyphenyl lactic acid and salvianolic acid B significantly improved lipopolysaccharide-induced rat mesenteric micros in the study of two important extracts of dihydroxyphenyl lactic acid and salvianolic acid B in Salvia miltiorrhiza. Circulatory disorders, and inhibition of lipopolysaccharide-induced CDl lb and CD18 expression and neutrophil production of ⁇ 2 and H 2 0 2 , have significant therapeutic effects on sepsis. Summary of the invention:
  • the present invention provides a novel therapeutic use of Salvia miltiorrhiza extract.
  • the new therapeutic use is the treatment of sepsis caused by microcirculatory disorders with salvia miltiorrhiza extract.
  • the present invention provides a new use of a medicament for preparing a medicament for treating and/or preventing sepsis using Salvia miltiorrhiza extract.
  • the Salvia miltiorrhiza extract of the present invention is selected from two important extracts, dihydroxyphenyl lactic acid and salvianolic acid B.
  • the dihydroxyphenyl lactic acid and salvianolic acid B according to the present invention are prior art, are commercially available, can also be prepared according to the prior art, and can meet pharmaceutical standards.
  • the purity is > 50%, more preferably the purity is > 90%, Most preferably, the purity is > 98%.
  • the medicament prepared by the present invention is a pharmaceutical preparation composition prepared by using the above-mentioned salvia miltiorrhiza extract as a pharmaceutically active ingredient.
  • the medicinal composition of the present invention may comprise a pharmaceutically acceptable carrier, wherein the salvia miltiorrhizae extract may be 0. 1-99. Accepted carrier.
  • the pharmaceutical preparation composition of the present invention is in the form of a unit dosage form, which means a unit of the preparation, such as each tablet of the tablet, each capsule of the capsule, each bottle of the oral solution, granules per bag, injection Every one of them.
  • the pharmaceutical preparation composition of the present invention may be in any pharmaceutically acceptable dosage form, and includes: a tablet, a sugar-coated tablet, a film-coated tablet, an enteric coated tablet, a capsule, a hard capsule, a soft capsule, orally. Liquid, buccal, granule, granule, pill, powder, ointment, dandruff, suspension, powder, solution, injection, suppository, ointment, plaster, cream, spray, drops, patch .
  • the preparation for oral administration may contain common excipients such as a binder, a filler, a diluent, a tablet, a lubricant, a disintegrant, a coloring agent, a flavoring agent and a wetting agent.
  • a binder such as a binder, a filler, a diluent, a tablet, a lubricant, a disintegrant, a coloring agent, a flavoring agent and a wetting agent.
  • Suitable fillers include cellulose, mannitol, lactose and other similar fillers.
  • Suitable disintegrating agents include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium decyl sulfate.
  • the solid oral composition can be prepared by a usual method such as mixing, filling, tableting or the like. Repeated mixing allows the active material to be distributed throughout those compositions that use large amounts 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 or hydrogenated edible fats.
  • Emulsifiers such as lecithin, sorbitan monooleate or gum arabic; non-aqueous carriers (which may include edible oils), such as almond oil, fractionated coconut oil, oily esters of esters such as glycerol, propylene glycol or ethanol;
  • the agent for example, p-hydroxybenzyl or propylparaben or sorbic acid, and if desired, may contain conventional flavoring or coloring agents.
  • the liquid unit dosage form prepared contains the active substance of the invention and a sterile vehicle.
  • the carrier and the concentration can be suspended or dissolved.
  • the solution is usually prepared by dissolving the active substance 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.
  • the composition can be frozen after filling the vial and the water removed under vacuum.
  • the traditional Chinese medicine preparation of the present invention can be selectively added to a suitable pharmaceutically acceptable carrier when prepared as a medicament, and the pharmaceutically acceptable carrier is selected from the group consisting of: mannitol, sorbitol, sodium metabisulfite, sodium hydrogen sulfite, thio Sodium sulfate, 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 thereof , alginate, gelatin, polyvinylpyrrolidone,
  • the preparation of the present invention is used according to the condition of the patient at the time of use, and can be taken three times a day for 1 20 doses, such as: 1-20 bags or tablets or tablets, each dose of lmg-1000 mg.
  • 1 20 doses such as: 1-20 bags or tablets or tablets, each dose of lmg-1000 mg.
  • the therapeutic use of the present invention is demonstrated by the following experiments:
  • FITC-binding mouse anti-rat CD1 lb monoclonal antibody FITC-binding mouse anti-rat CD18 monoclonal antibody
  • FITC-binding mouse IgA, ⁇ and FITC-binding mouse IgG! ⁇ are purchased from BD Bioscience System (San Diego, CA). Hemolysin was purchased from the BD Bioscience Immunocytometer system (Silicon Valley, California, USA). The mono-Pol separation liquid was purchased from Dainippon Co., Ltd. (Osaka, Japan). RPMI 1640 and fetal calf serum were purchased from Hydone (Fagan, Utah). All other chemical reagents used in the test are the best commercial grade reagents.
  • mice Male Sprague-Dawley rats weighing 200-250 g were provided by the Experimental Animal Center of Peking University Medical School. All studies were approved and all experimental animals were processed following the guidelines of the Peking University Laboratory Animal Research Committee.
  • mice were fasted for 12 hours before the test and were given free access to water.
  • Experimental animals were anesthetized with urethane (1.25 mg/kg body weight, intramuscularly).
  • the catheter was inserted into the left jugular vein and the right femoral vein for injection of various experimental drugs.
  • the ileocecal of the 20 cm mesenteric tail was gently removed from the abdomen by a 20- 30 mm incision through the midline of the abdomen and placed on a transparent plastic rat experimental bench.
  • the mesentery was maintained at 37 ° C with a thermostat, and physiological saline was continuously dropped on the surface to maintain moisture.
  • DM-IRB Leica, Wetzlar, Germany
  • a camera Jk-TU53H, Toshiba Corporation, Tokyo, Japan
  • J2118A, TCL, Huizhou, China is mounted on a microscope to reflect images to a color monitor (J2118A, TCL, Huizhou, China), using DVD (DVR-R25, Malata, Xiamen, China) ) Record images.
  • the venules used for the measurement parameters in the study should be single, non-branched, without obvious bending, with a diameter range of 30 ⁇ -50 ⁇ and a length of 200 ⁇ .
  • Rats were randomly divided into 4 groups of 6 each. After observing the basic hemodynamics of the rat mesenteric microvascular system for 10 minutes, a vehicle (physiological saline solution) or a test drug was administered. From the beginning of the experiment (0th minute) to the end of the experiment (60th minute), the experimental animals were perfused with saline solution (8ml/kg body weight/hr) from the left jugular vein; from the start of the experiment (0th minute) to the end of the test (60th minute), lipopolysaccharide (2 mg/kg body weight/hrin saline solution) was continuously perfused from the left femoral vein of the experimental group of the lipopolysaccharide group.
  • saline solution 8ml/kg body weight/hr
  • the left jugular vein was infused with dihydroxyphenyl lactic acid from 20 minutes before the end of the observation period to the end of observation. 5 mg/kg body weight/hrin saline solution).
  • the lipopolysaccharide + salvianolic acid group B was treated in the same manner as the lipopolysaccharide + dihydroxyphenyl lactic acid group, and only the salvianolic acid B (5 mg/kg body weight / hrin saline solution) was used instead of the dihydroxyphenyl lactic acid.
  • the total infusion volume was the same for the four experimental groups.
  • the venule diameter was measured at 30 and 50 minutes.
  • Vein red blood cell flow rate measurement Record the venous red blood flow rate, adjust the monitor to the high speed camera system via CCD (FAST CAM-ultima APX, photron, San Diego, California), adjust the speed to 2000 frames per second (frames per second), replay at 25 frames per second Save images at high speed.
  • CCD FAST CAM-ultima APX, photron, San Diego, California
  • the venous red blood cell flow rates at 0, 10, 30 and 50 minutes were measured using Image-Pro Plus 5.0 software.
  • Y 8 (average velocity of venule/venule diameter RBCs).
  • Adherent granulocytes mean that granulocytes are attached to the same site for more than 10 seconds when the DVD image is replayed.
  • the observed 0, 10, 30 and 50 minute images were randomly selected for 200 ⁇ venules, and then the number of adherent granulocytes was counted along the venules.
  • Leukocyte chemotaxis is the number of granulocytes per 200 ⁇ ⁇ , and images were randomly selected at 0, 10, 30 and 50 minutes.
  • the tissue was partially stained with 0.1% toluidine blue for 1 minute and then washed with physiological saline.
  • the number of mast cells and degranulated mast cells without degranulation in the field of view was enlarged by 20 ⁇ , and 5 fields of view were evaluated for each experimental animal.
  • the ratio of the number of degranulated mast cells to the total number of mast cells is the percentage of degranulated mast cells.
  • the samples were incubated in a 37 ° C water bath for 2 hours, then using ⁇ g/ml FITC-binding mouse anti-rat CD1 lb antibody, lg/ml FITC-binding mouse anti-rat CD 18 antibody or FITC-binding
  • the isotype (mouse IgA, Kfor CD 11 b, mouse IgG, KtheCD 18) was labeled for 20 minutes at room temperature. Then, according to the manufacturer (BD Bioscience System, US Plus State Silicon Valley) Description, red blood cells are dissolved with hemolysin, and phosphorus residual cells are washed twice with an acid buffer solution.
  • neutrophils were classified using a FACS Calibur flow cytometer (BD Biosciences System, Silicon Valley, California, USA), and 5,000 singularities in each sample were evaluated. Granulocytes, measuring mean fluorescence intensity.
  • the nitrate portion of 2'-V-dichlorofluorescein diacetate is cleaved by intracellular esterase, releasing 2',7'-dichlorofluorescein which cannot pass through the cell membrane and is oxidized to 2' by H 2 0 2 , 7'-dichlorofluorescein (DCF) emits fluorescence; on the other hand, Hydroethidium can be directly oxidized by '0 2 - to phenanthridine bromide (EB), which fluoresces after being embedded in nucleic acid.
  • EB phenanthridine bromide
  • the cells were then treated with dihydroxyphenyl lactic acid (0.5 mg/ml) or salvianolic acid B (0.5 mg/ml) and stimulated with lipopolysaccharide (2 yg/ml). After incubation for 20 minutes in ice, the resulting H 2 0 2 and '0 2 were measured by flow cytometry, and the emission wavelengths were measured at 525 nm (FL1, forDCF) and 590 nm.
  • Table 2 shows the mesenteric venous shear rate observed in four experimental groups at different time points.
  • Mesenteric venules were significantly reduced after administration of lipopolysaccharide, becoming more pronounced after 30 minutes, and this decrease was maintained until 50 minutes after the end of lipopolysaccharide infusion.
  • Figure 4 shows the percentage of degranulated mast cells in the venules of the four experimental groups. A small amount of degranulated mast cells can be detected even in the control group. After 60 minutes of lipopolysaccharide infusion, the number of degranulated mast cells began to increase, and the dihydroxyphenyl lactate or salvianolic acid B treatment group significantly inhibited lipopolysaccharide-induced degranulation of mast cells.
  • Figure 5B shows a similar trend in the adhesion molecule CD18: the neutrophil surface CD18 fluorescence intensity is significantly increased after lipopolysaccharide treatment, using a concentration of 0.2 mg/ml, dihydroxyphenyl lactic acid or salvianolic acid This effect is inhibited after B treatment.
  • dihydroxyphenyl lactic acid and salvianolic acid B on the production of '0 2 - and 0 2 in neutrophil cells: Detection of resistance of dihydroxyphenyl lactic acid and salvianolic acid B by flow cytometry oxidation.
  • neutrophils After the cells were stimulated by lipopolysaccharide, neutrophils produced a large amount of '0 2 —, and after adding 0.5 mg/ml of dihydroxyphenyllactate or salvianolic acid B, the cells were significantly inhibited from producing '0 2 — (see Figure 6A). . Compared with the control group, the neutrophil 0 2 fluorescence intensity almost doubled after lipopolysaccharide stimulation, and this effect was significantly reduced after treatment with 0.5 mg/ml dihydroxyphenyl lactic acid or salvianolic acid B (see Figure 6B). ).
  • the venous red blood cell flow rate was measured at 0, 10, 30 and 50 minutes after infusion of saline solution or lipopolysaccharide, with or without administration of dihydroxyphenyl lactic acid or salvianolic acid B, as described in Materials and Methods. Data are expressed as the mean S. E. M of 6 rats. Vein RBCsi velocity (mm/sec)
  • Lipopolysaccharide + salvianolic acid 1.90 ⁇ 0.33 1.93 ⁇ 0.32 1.94 ⁇ 0.35 1.78 ⁇ 0.33 B (n 6) Rats in the control group were perfused with vehicle (saline solution) (8 ml / kg body weight / hr) ; Polysaccharide (2 mg/kg body weight/hr); Lipopolysaccharide + dihydroxyphenyl lactic acid group Experimental animals were perfused with dihydroxyphenyl lactic acid (5 mg/kg body weight/hr) 20 minutes before infusion of lipopolysaccharide (2 mg/kg body weight/hr).
  • lipopolysaccharide + salvianolic acid B experimental animals infused with lipopolysaccharide (2 mg / kg body weight / hr) 20 minutes before infusion of Dan Phenolic acid B (5mg/kg body weight/hr) ⁇
  • the venous shear rate was measured at 0, 10, 30 and 50 minutes after the infusion of saline solution or lipopolysaccharide with or without the administration of dihydroxyphenyl lactic acid or salvianolic acid B according to the methods described in the materials and methods. .
  • Data are average ⁇ S.E.M of 6 rats. Said.
  • Rats in the control group were perfused with vehicle (saline solution) (8 ml/kg body weight/hr); lipopolysaccharide group was perfused with lipopolysaccharide (2 mg/kg body weight/hr) ; lipopolysaccharide + dihydroxyphenyl lactic acid group Rat perfusion
  • Rats in the control group were perfused with saline solution for 60 minutes (8 ml/kg body weight/hr), and rats in the lipopolysaccharide group were perfused with lipopolysaccharide (2 mg/kg body weight/hr) for 60 minutes.
  • rats were infused with lipopolysaccharide (2 mg/kg body weight/hr) intravenously for 2 minutes before intravenous injection of dihydroxyphenyl lactate (5 mg/kg body weight/hr) or salvianolic acid B (5 mg/kg body weight). /hr), continuous infusion until the end of the observation.
  • the total infusion volume was the same for the four experimental groups.
  • the number of chemotactic leukocyte chemotaxis was counted and the results were expressed as the number of cells per 200 ⁇ venule. Data are mean SEM representation of 6 rats. * p ⁇ 0.05 compared with the control group. , ⁇ and lipopolysaccharide ⁇ ⁇ 0.05.
  • Figure 3 Time-course intervention of dihydroxyphenyl lactic acid and salvianolate on the changes in the number of granulocytes in the venules of rats after infusion of lipopolysaccharide. Rats in the control group were perfused with saline solution for 60 minutes (8 ml/kg body weight/hr), and rats in the lipopolysaccharide group were perfused with lipopolysaccharide (2 mg/kg body weight/hr) for 60 minutes.
  • rats were injected with lipopolysaccharide (2 mg/kg body weight/hr) intravenously for 2 minutes before intravenous injection of dihydroxyphenyl lactate (5 mg/kg body weight/hr) or salvianolic acid B (5 mg/kg body weight). /hr), continuous infusion until the end of the observation.
  • the total infusion volume was the same for the four experimental groups.
  • the number of chemotactic leukocyte chemotaxis was counted and the results were expressed as the number of cells per 200 ⁇ m venule.
  • Data The mean SE M of 6 rats is expressed. * p ⁇ 0.05 compared with the control group. , ⁇ and lipopolysaccharide comparison p ⁇ 0.05.
  • FIG. 4 Intervention of dihydroxyphenyl lactic acid and salvianolic acid B on degranulation of microvessel mast cells after lipopolysaccharide in rats.
  • Rats in the control group were perfused with saline solution for 60 minutes (8 ml/kg body weight/hr), and rats in the lipopolysaccharide group were perfused with lipopolysaccharide (2 mg/kg body weight/hr) for 60 minutes.
  • Rats were infused with lipopolysaccharide (2 mg/kg body weight/hr) intravenously with dihydroxyphenyl lactate (5 mg/kg body weight/hr) or salvianolic acid B (5 mg/kg body weight) 20 minutes prior to the method described in Materials and Methods.
  • FIG. 5 Intervention of dihydroxyphenyl lactic acid and salvianolic acid B on lipopolysaccharide-stimulated neutrophil adhesion molecules CD11b (A) and CD18 (B) expression in vitro.
  • CD11b and CD18 expression were analyzed using flow cytometry. Blood samples were incubated with lipopolysaccharide (24 g/ml) with or without various concentrations of dihydroxyphenyl lactic acid or salvianolic acid B and then incubated with the corresponding antibodies. Red blood cells were lysed, neutrophils were classified, and evaluated by flow cytometry, and the average fluorescence intensity was measured. Data The average soil SE M of 6 rats is expressed. * p ⁇ 0.05 compared with the control group.
  • Preparation method Take the original and auxiliary materials through 100 mesh sieves separately; take notoginsenoside, microcrystalline cellulose, mix well, use 60% ethanol as the binder to make soft materials, pass 20 mesh sieve particles, 60 ⁇ dry, Take out, sift through 30 mesh, add micro-silica gel and magnesium stearate, mix and compress, and make 1000 pieces.
  • Preparation method Take the original and auxiliary materials through 100 mesh sieves separately; take notoginsenoside, calcium sulfate, microcrystalline cellulose, mix well, use 60% ethanol as the binder to make soft materials, and filter the particles through 20 mesh. Dry at 60 ° C, take out, sift through 30 mesh, add appropriate amount of micro-silica gel and magnesium stearate, mix and compress, and make 1000 pieces.
  • Capsules take dihydroxyphenyl lactic acid or salvianolic acid BlOOmg, add appropriate amount of starch, magnesium stearate and other accessories, granulate, whole, into the No. 1 capsule, that is.
  • Oral solution take dihydroxyphenyl lactic acid or salvianolic acid BlOOmg, add appropriate amount of sucrose, preservative, add water to 1000ml, dispense into 10ml - branch, that is, get oral liquid.
  • Granules taking dihydroxyphenyl lactic acid or salvianolic acid BlOOmg, adding appropriate amount of dextrin, stevioside, dry granulation, whole granules, and dispensing, that is, obtained.
  • Patient Sun X X male, 30 years old, printer, has headache, nausea, vomiting, bloating, abdominal pain, general discomfort, muscle and joint pain, etc., diagnosed as sepsis

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Abstract

La présente invention concerne l'utilisation d'un extrait de salvia miltiorrhiza, en particulier un acide dihydroxyphényl lactique A ou un acide salvianolique B, pour la préparation d'un médicament pour le traitement de la septicémie.
PCT/CN2008/000876 2007-06-21 2008-04-29 Utilisation d'extrait de salvia miltiorrhiza pour la préparation d'un médicament pour le traitement de la septicémie WO2008154794A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN1174065A (zh) * 1997-07-16 1998-02-25 迟经惠 障碍贫血针剂
CN1957982A (zh) * 2005-11-04 2007-05-09 天津天士力制药股份有限公司 丹参提取物、制剂及其制备方法
WO2007084419A2 (fr) * 2006-01-13 2007-07-26 The Feinstein Institute For Medical Research Inhibition de la production de cytokine inflammatoire par les tanshinones

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1174065A (zh) * 1997-07-16 1998-02-25 迟经惠 障碍贫血针剂
CN1957982A (zh) * 2005-11-04 2007-05-09 天津天士力制药股份有限公司 丹参提取物、制剂及其制备方法
WO2007084419A2 (fr) * 2006-01-13 2007-07-26 The Feinstein Institute For Medical Research Inhibition de la production de cytokine inflammatoire par les tanshinones

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