WO2009000149A1 - Utilisation de la notoginsenoside r1 dans la préparation du médicament destiné au traitement de lésions hépatiques - Google Patents

Utilisation de la notoginsenoside r1 dans la préparation du médicament destiné au traitement de lésions hépatiques Download PDF

Info

Publication number
WO2009000149A1
WO2009000149A1 PCT/CN2008/001169 CN2008001169W WO2009000149A1 WO 2009000149 A1 WO2009000149 A1 WO 2009000149A1 CN 2008001169 W CN2008001169 W CN 2008001169W WO 2009000149 A1 WO2009000149 A1 WO 2009000149A1
Authority
WO
WIPO (PCT)
Prior art keywords
liver
reperfusion
use according
ischemia
notoginsenoside
Prior art date
Application number
PCT/CN2008/001169
Other languages
English (en)
Chinese (zh)
Inventor
Jingyan Han
Weixing Chen
Fang Wang
Yuying Liu
Original Assignee
Tianjin Tasly Pharmaceutical Co. Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tianjin Tasly Pharmaceutical Co. Ltd. filed Critical Tianjin Tasly Pharmaceutical Co. Ltd.
Publication of WO2009000149A1 publication Critical patent/WO2009000149A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses

Definitions

  • the present invention relates to a novel pharmaceutical use of Panax notoginseng saponin R1, an active ingredient of traditional Chinese medicine Sanqi, and particularly relates to the use of notoginsenoside R1 for the treatment and/or prevention of liver damage.
  • Background technique
  • PN Panax notoginseng (Burk. ) FH Chen
  • PN is a dry root of A liaceae (Sanqi), widely used in China, Korea, Japan and other Asian countries for the treatment of microcirculation.
  • Disorder-related diseases such as cardiovascular disease, cerebrovascular disease, and liver dysfunction.
  • Sanqi contains more than 30 different types of saponin compounds, of which ginsenoside Rgl (Rgl), ginsenoside Rbl (Rbl) and notoginsenoside Rl (R1) are more common.
  • the structure of R1 is as follows:
  • Liver injury is a common disease, and hepatitis virus, liver cirrhosis, drug abuse, alcohol abuse, and chemical poison contact are the main causes of liver damage.
  • the liver is the "life tower" of the human body.
  • the various metabolic, detoxification and immune functions of the human body are borne by the liver. Any adverse effects on hepatocytes and intrahepatic blood flow can damage liver tissue.
  • Common liver injuries include liver infection caused by viral infection or cirrhosis, drug liver injury, alcoholic liver injury, chemical liver injury, liver damage caused by ischemia-reperfusion, and the like. Liver damage caused by viral infection and cirrhosis mainly causes liver cell damage through the immune response of the human body.
  • liver injury is caused by the formation of oxygen free radicals by drug metabolites, lipid peroxidation, drugs Metabolism produces electrophilic products, superoxide ions, leading to liver cell damage. Alcoholic liver injury affects the blood supply to the liver and increases the burden on the liver, leading to alcoholic hepatitis, fatty liver, and cirrhosis. Chemical liver damage is caused by chemical poisons destroying liver cells, and liver function is abnormal.
  • Ischemia-reperfusion injury refers to the damage of tissues and organs caused by reperfusion of blood perfusion or oxygen supply in ischemic tissues or organs.
  • Hepatic ischemia-reperfusion injury Hepatic ischemia reperfusion injury (HIRI) can reduce liver metabolic detoxification ability and increase microcirculation resistance. In severe cases, liver failure can be caused. In liver transplantation, primary nonfunction (PNF) is observed. PNF is one of the leading causes of death in liver transplant patients.
  • Ischemia-reperfusion (I/R) can occur in many situations, such as trauma, vasoconstriction, PTCA, thrombolytic therapy, organ transplantation, and resuscitated hypovolemic shock.
  • Ischemia-reperfusion can cause microcirculation to be damaged, often accompanied by epithelial cell damage, enhanced granulocyte adhesion, macromolecular efflux, oxygen free radical production and mast cell degranulation, according to hepatic ischemia-reperfusion
  • the mechanism of injury can take many preventive and therapeutic methods.
  • Passive defense can be used during surgery, preoperative and postoperative, as well as adding drugs or active ingredients to the preservation solution.
  • Antioxidant free radical drugs such as allopurinol and glutathione Peptides, Ca 2+ antagonists, etc. have been used in clinical practice, and domestic researchers have also achieved good results by reasonably adding Chinese medicine preparations to the preservation solution.
  • notoginsenoside R1 can improve intestinal microcirculation disturbance induced by intestinal ischemia-reperfusion, thereby treating and/or preventing liver damage, and the present invention provides a novel therapeutic use of notoginsenoside R1. Summary of the invention
  • the present invention provides a novel therapeutic use of notoginsenoside R1.
  • the new therapeutic use is to treat and/or prevent liver damage, particularly ischemia-reperfusion-induced liver damage, with notoginsenoside R1.
  • the present invention provides a novel use of a drug, that is, the use of notoginsenoside R1 or a pharmaceutical composition thereof for the preparation of a medicament for treating and/or preventing liver damage.
  • the notoginsenoside R1 is obtained by extracting from the traditional Chinese medicine Panax notoginseng, the purity is >50%, preferably the purity is >90%, more preferably the purity is >98%.
  • the pharmaceutical composition of the present invention has notoginsenoside R1 as a pharmaceutically active ingredient, and the weight percentage in the preparation may be 0.1 to 99.9%, and the balance is a pharmaceutically acceptable carrier.
  • the notoginsenoside R1 in the present invention may be administered to a patient in the form of a pharmaceutical composition which is in the form of any pharmaceutically acceptable preparation, preferably an injection, which may be a solution or a lyophilized powder injection.
  • the liver injury is selected from liver damage caused by viral infection or cirrhosis, drug liver damage, alcoholic liver damage, chemical liver damage, liver damage caused by ischemia-reperfusion.
  • the liver injury is liver damage caused by ischemia-reperfusion.
  • the treatment and/or prevention of liver damage is achieved by ameliorating microcirculatory disorders including a decrease in venule diameter, a decrease in red blood cell flow rate, a decrease in the number of perfused sinusoids, and leukocyte Rolling and adhesion increase.
  • the treatment and/or prevention of liver damage is achieved by reducing the expression of hepatic vascular E-selectin and intercellular adhesion molecule-1.
  • the treatment and/or prevention of liver damage is achieved by reducing the expression of CD18 and CD1 lb on the surface of neutrophils.
  • FIG. 1 Chemical structure of notoginsenoside (R1).
  • Figure 2 R1 treatment of the diameter of the hepatic venules in the superior mesenteric artery ischemia-reperfusion mice, the detection time is 0 minutes before ischemia (basal value), 15 minutes and 30 minutes after reperfusion.
  • A The diameter of the terminal venule.
  • B Central vein diameter.
  • the abscissa represents the ratio of the diameter value to the base value at any point in time.
  • the results are the mean ⁇ SE values of 6 experimental animals. Compared with the control group, a P ⁇ 0.05; compared with the ischemia-reperfusion (I/R) group, e P ⁇ 0.05.
  • FIG. 3 R1 to the flow velocity of hepatic venule erythrocytes in the mesenteric artery ischemia-reperfusion mice Intervention, the time point of detection was 0 minutes before ischemia (basal value) and 15 and 30 minutes after reperfusion.
  • A The flow rate of red blood cells in the terminal venules.
  • B Red blood cell flow rate in the central vein.
  • the abscissa represents the ratio of the red blood cell flow rate value to the base value at any time point.
  • the results are the mean ⁇ SE values of 6 experimental animals.
  • a P ⁇ 0.05 compared with the ischemia-reperfusion (I/R) group, C P ⁇ 0.05.
  • FIG. 4 Intervention of R1 on perfusion of the sinusoids in the superior mesenteric artery ischemia-reperfusion mice at the 0th minute before ischemia (basal value) and 15 minutes and 30 minutes after reperfusion.
  • A sinusoidal perfusion in the terminal venule region.
  • B sinusoidal perfusion in the central venous area.
  • the abscissa represents the ratio of the sinusoids perfused at any point in time to the baseline value.
  • the results are the mean ⁇ SE values of 6 experimental animals. Compared with the control group, a P ⁇ 0.05; compared with the ischemia-reperfusion group (I/R), e P ⁇ 0.05.
  • Figure 5 Intervention of R1 on hepatic venous leukocyte rolling in the ischemic-reperfused mesenteric artery.
  • the time of detection was 0 minutes before ischemia (basal value) and 15 minutes and 30 minutes after reperfusion.
  • A The number of rolling granulocytes in the terminal venules.
  • B Number of rolling granulocytes in the central vein.
  • the abscissa represents the number of rolling granulocytes in each 200 ⁇ m 2 field of view.
  • the results are the mean ⁇ SE values of 6 experimental animals. Compared with the control group, a P ⁇ 0.05; compared with the ischemia-reperfusion group (I/R), e P ⁇ 0.05.
  • Figure 6 Intervention of R1 on hepatic venous leukocyte rolling in the ischemic-reperfused mesenteric artery.
  • the time of detection was 0 minutes before ischemia (basal value) and 15 minutes and 30 minutes after reperfusion.
  • A
  • ⁇ The number of granulocytes attached to the terminal venules.
  • ⁇ The number of granulocytes attached to the central vein.
  • the abscissa represents the number of granulocytes attached per 200 ⁇ 2 field of view.
  • the results are the mean ⁇ SE values of 6 experimental animals.
  • a P ⁇ 0.05 compared with the control group, a P ⁇ 0.05 ; compared with the ischemia-reperfusion (I/R) group, c P ⁇ 0.05 o Figure 8 R1 on leukocyte adhesion in the sinusoids of the superior mesenteric artery ischemia-reperfusion mice
  • the time point of detection is ischemia (basic value) before 0 minutes, after reperfusion 15 minutes and 30 minutes.
  • A The number of granulocytes attached to the sinusoids of the terminal venules.
  • B Number of granulocytes attached to the sinusoid in the central venous region.
  • the abscissa represents the number of granulocytes attached per 200 ⁇ 2 field of view.
  • the result was the mean SE value of 6 experimental animals.
  • a P ⁇ 0.05 compared with the control group, a P ⁇ 0.05; compared with the ischemia-reperfusion (I/R) group, c P ⁇ 0.05 o Figure 9 R1 on the hepatic vascular E-selectin and the mesenteric artery ischemia-reperfusion in mice Intervention of expression of intercellular adhesion molecule-1.
  • liver tissues were immunofluorescently stained.
  • the results are the mean ⁇ SE values of 6 experimental animals. Compared with the control group, a P ⁇ 0.05; compared with the ischemia-reperfusion (I/R) group, e P ⁇ 0.05.
  • Figure 10 Intervention of R1 on the expression of CD18 and CD1 lb on neutrophil surface in mice with superior mesenteric ischemia-reperfusion. At 30 minutes after reperfusion, neutrophils were isolated and subjected to flow cytometry.
  • the results are the mean ⁇ SE values of 6 experimental animals. Compared with the control group, a P ⁇ 0.05; compared with the ischemia-reperfusion (I/R) group, e P ⁇ 0.05.
  • Figure 12 in the serum of the superior mesenteric artery ischemia-reperfusion mice, tumor necrosis factor- ⁇ (TNF- ⁇ ), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) The concentration of intervention. At 30 minutes after reperfusion, serum was separated and subjected to flow cytometry. The results are the mean ⁇ SE values of 6 experimental animals. Compared with the control group, a P ⁇ 0.05; compared with the ischemia-reperfusion (I/R) group, e P ⁇ 0.05. detailed description
  • the notoginsenoside R1 of the present invention is a component of the traditional Chinese medicine Panax notoginseng, and is not particularly limited as long as it meets the medicinal standard.
  • the notoginsenoside R1 can be purchased from the market, such as products produced by Nanjing Qingze Pharmaceutical Technology Development Co., Ltd. and Shanghai Kangjiu Chemical Co., Ltd.; it can also be prepared according to the prior art, for example, Chinese patent 01136697.4 from Sanqisheng A method for extracting and separating notoginsenoside Rl, ginsenoside Re, and notoginseng by powder extraction.
  • the notoginsenoside R1 preferably has a purity of >50%, more preferably a purity of >90%, and most preferably a purity of >98%.
  • the medicament according to the present invention is a pharmaceutical composition prepared by using the above-mentioned notoginsenoside R1 as a pharmaceutically active ingredient.
  • the pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier as needed, wherein notoginsenoside R1 is a pharmaceutically active ingredient, and the weight percentage in the preparation may be 0.1 to 99.9%, and the others are 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.
  • the pharmaceutical composition of the present invention may contain a usual excipient such as a binder, a filler, a diluent, a tablet, a lubricant, a disintegrant, a coloring agent, a flavoring agent. And humectants, if necessary, the tablets can be coated.
  • 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 pharmaceutically acceptable wetting agents include sodium decyl sulfate.
  • the solid oral composition can be prepared by a conventional method such as mixing, filling, tableting or the like. The repeated mixing of the active ingredients allows the active ingredient to be distributed throughout the composition containing a large 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; 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 such as glycerides, propylene glycol or ethanol; preservatives, Such as p-hydroxybenzyl ester or pair Propyl hydroxybenzoate or sorbic acid, and if desired, may contain conventional flavoring or coloring agents.
  • the liquid unit dosage form prepared contains the active ingredient of the invention and a sterile vehicle.
  • This 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 prior to 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 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
  • the injection is preferably a solution or a lyophilized powder injection.
  • the pharmaceutical composition of the present invention determines the usage amount according to the condition of the patient at the time of use.
  • the therapeutic use of the present invention will be described by taking the ischemia-reperfusion liver injury as an example, but the present invention is not limited to the embodiment.
  • Notoginsenoside R1 (referred to as Rl, purity >98%) was provided by Tianjin Tianshili Group (Tianjin, China).
  • mice (batch number: 6538, Santa Cruz Biotechnology, Inc., USA); mouse monocyte chemotactic protein-l (MCP-l) freely set (flex set) (batch number: 558342, BD bio Scientific System, USA); Mouse Tumor Necrosis Factor-a (TNF-a) Free Combination Pack (Batch No.: 558299, BD Bioscience System, USA); Mouse Interleukin-6 (IL-6) Free Combination Pack (Batch Number: 558301, BD Bioscience Systems, USA).
  • MCP-l mouse monocyte chemotactic protein-l
  • TNF-a Mouse Tumor Necrosis Factor-a
  • IL-6 Mouse Interleukin-6 Free Combination Pack
  • mice were purchased from the Experimental Animal Center of Peking University Medical School, weighing 22 ⁇ 26g, age 8 ⁇ 10 weeks, laboratory animal certificate number SCXK 2002-2001.
  • the experimental animals were housed in a temperature of 24 ⁇ 1 ° C, humidity of 50 ⁇ 5%, 12 hours of light and dark cycle environment, fasting for 12 hours before the test, free to drink water. All experimental animals were processed following the guidelines of the Peking University Laboratory Animal Management Committee. In vivo microscopy
  • mice were anesthetized with 20% urethane (10 ml/kg body weight).
  • the cannula was inserted into the left jugular vein and the test drug was perfused with a PE tube having a diameter of 0.96 mm.
  • the mice were placed in the lateral position on the observation table.
  • the liver was placed in a temperature-controlled (37 ° C) observation box on an adjustable Plexiglas microscope stage and carefully treated to reduce the effects of respiratory motion.
  • the left lobe of the liver was observed by an inverted biomicroscope (DM-IRB, Leica, Germany) through a 3CCD color camera (JK-TU53H, 3CCD camera, Toshiba Corporation, Japan).
  • physiological saline at 37 ° C was used to drip the liver surface to maintain the moisture of the liver, and the observation area around the liver surface was covered with physiologically wet cotton gauze.
  • the superior mesenteric artery was ligated with a polyethylene tube (1.00 mm in diameter) for 15 minutes. After ischemia, the ligation is gently released and reperfusion is performed. Immediately before ischemia (baseline), venule diameter, erythrocyte flow rate, sinusoidal reperfusion, and leukocyte rolling and adhesion were measured, and the above indicators were observed every 15 minutes within half an hour after reperfusion. Test plan
  • mice in the ischemia-reperfusion group were continuously perfused with physiological saline solution through the left neck vein.
  • Mice in the R1 + ischemia-reperfusion (I/R) group were continuously perfused with R1 (10 mg/kg/h) 10 minutes before ischemia-reperfusion to the end of observation.
  • Mice in the mock surgery control group were treated in the same manner as the blood-reperfusion group, but the superior mesenteric artery was not ligated. There were 6 mice in each group (3 males and 3 females).
  • the DVD image was replayed using Image-Pro Plus 5.0 software, and the terminal venule diameter and central vein diameter were measured.
  • the measurement results are expressed as the ratio of the measured value at the 15th minute or the 30th minute after reperfusion to the base value, and the results are shown in Fig. 2.
  • the monitor was tuned to a high-speed camera system (FASTCAM-ultima ⁇ , photon, Japan) by CCD, and the red blood cell flow rate in the terminal venules and central veins of the liver was recorded at 1000 frames per second, and the image was saved at 25 frames at high speed. / second speed replay.
  • Red blood cell flow rates were measured using Image-Pro Plus 5.0 software. The red blood cell flow rate is expressed in ⁇ ⁇ /sec.
  • the measurement results are expressed as the ratio of the measured value to the base value at the 15th or 30th minute after reperfusion.
  • the results are shown in Figure 3.
  • the number of liver sinusoids in the terminal venules and central veins of the liver was recorded.
  • the number of hepatic sinusoids is expressed as a perfused sinusoid in each field of view (250 ⁇ > 300 ⁇ ).
  • the measurement results are expressed as the ratio of the measured value to the base value at the 15th minute or the 30th minute after reperfusion, and the results are shown in FIG.
  • rhodamine 6G rhodamine 6G in physiological saline at a concentration of 0.5 mg/ml
  • rhodamine 6G in physiological saline at a concentration of 0.5 mg/ml rhodamine 6G in physiological saline at a concentration of 0.5 mg/ml
  • a 20-inch fluorescent objective lens, argon laser beam irradiation (wavelength 543 nm), recorded the rolling and adhesion of granulocytes in the terminal venules and central veins of the liver.
  • the results are shown in Figures 5 to 8.
  • the granulocytes that stayed in the terminal venules and central veins of the liver for less than 10 seconds were rolling granulocytes, expressed as the number observed per 200 ⁇ m 2 field of view, and the results are shown in Fig. 5. Scanning at a rate of 1 frame/second, a total of 10 consecutive frames are recorded at each time point, and the granulocytes that appear at the same position during the scanning of 10 consecutive frames are adherent granulocytes.
  • the granulocytes adhering to the terminal venules and central veins of the liver are expressed as the number of granulocytes observed per 200 ⁇ m 2 field of view, and the results are shown in Fig. 7.
  • the adherent granulocytes in the sinusoids of the liver are expressed in terms of the number of granulocytes observed per 200 ⁇ 2 field of view, and the results are shown in Fig. 8.
  • the liver was fixed by perfusion of 4% paraformaldehyde, the liver was taken out, frozen with liquid nitrogen, and then cut into 6 ⁇ thick slices using a cryostat (LEICACM1800, Leica Co., Germany). The sections were fixed again with 4% paraformaldehyde for 10 minutes at room temperature and finally rinsed with phosphate buffer solution. The samples were then subjected to conventional immunohistochemical staining. Goat anti-mouse ⁇ -selectin polyclonal antibody or goat anti-mouse intercellular adhesion molecule-1 polyclonal antibody was diluted (dilution factor 1: 50).
  • mice at 30 minutes and 60 minutes after reperfusion were taken from the inferior vena cava and anticoagulated with heparin (20 units/ml whole blood). Serum was separated by centrifugation (Allegra TM 64R Centrifuge, Beckman Coultertm, Germany) rotating at 4,000 revolutions / minute, placed in a 4 ° C 10 min, then stored at -20 ° C environment.
  • centrifugation Allegra TM 64R Centrifuge, Beckman Coultertm, Germany
  • Figure 3 shows the effect of R1 on the flow rate of red blood cells in the terminal venules and central veins of the liver after ischemia and reperfusion of the superior mesenteric artery in mice.
  • red blood cell flow rate in the blood vessels was significantly reduced in a time-dependent manner.
  • the decrease of red blood cell flow rate in the two types of blood vessels after ischemia-reperfusion was restored to some extent, and the effect was 30 minutes after ischemia-reperfusion.
  • the recovery of red blood cell flow in the terminal venules was more pronounced (see Figure 3A).
  • Figure 6 shows a typical image of microcirculation in the central venous region at 30 minutes after ischemia-reperfusion of the superior mesenteric artery. Some granulocytes can be observed to adhere to the central vein and sinusoids.
  • Figure 7 shows R1 adhesion to granulocytes induced by ischemia-reperfusion of superior mesenteric artery Intervention. Ischemia-reperfusion of the superior mesenteric artery greatly increases the amount of granulocyte adhesion in the terminal venules and central veins of the liver. After R1 treatment, the number of increased adherent granulocytes was reduced after ischemia-reperfusion, and the terminal venules were more significantly reduced (see Figure 7A).
  • Figure 8 shows the effect of R1 on leukocyte adhesion in the terminal venous and central sinusoids of the liver.
  • Figure 8 shows the effect of R1 on leukocyte adhesion in the terminal venous and central sinusoids of the liver.
  • Figure 8 shows the effect of R1 on leukocyte adhesion in the terminal venous and central sinusoids of the liver.
  • Figure 8 shows the effect of R1 on the expression of hepatic vascular E-selectin and intercellular adhesion molecule-1 in mice at 30 minutes after reperfusion.
  • E-selectin expression is significantly enhanced at the 30th minute after reperfusion, and has no effect on the expression of intercellular adhesion molecule-1.
  • R1 the expression of E-selectin increased after ischemia-reperfusion of the superior mesenteric artery completely disappeared, and the expression of intercellular adhesion molecule-1 was also reduced.
  • blood samples were taken to evaluate the effect of R1 on the expression of peripheral neutrophil adhesion molecules CD18 and CD1 lb in mice.
  • CD18 expression was significantly enhanced and CDl lb expression was slightly enhanced at 30 minutes after reperfusion.
  • R1 treatment significantly reduced the increase in mean fluorescence intensity of CD18 and CD1 lb induced by ischemia-reperfusion.
  • the present invention demonstrates that R1 treatment can significantly reduce hepatic microcirculatory disturbance induced by ischemia-reperfusion of the superior mesenteric artery, including a decrease in venule diameter, a decrease in red blood cell flow rate, and a decrease in the number of perfused sinusoids. As well as the rolling and adhesion of white blood cells.
  • the improved effect of R1 on microcirculatory disorders implies a protective effect on ischemia-reperfusion-induced liver injury.
  • the notoginsenoside Rl 5g is dissolved in water, and sodium chloride and ethyl p-hydroxybenzoate are dissolved in water by heating, mixed, and adjusted to pH.
  • the water for injection is diluted to 1000 ml, filtered through a hollow fiber membrane, filled, and sterilized.
  • the notoginsenoside Rl lg is dissolved in water, and sodium chloride and ethyl p-hydroxybenzoate are dissolved in water by heating, mixed, and adjusted to pH.
  • the water for injection is diluted to 1000 ml, filtered through a hollow fiber membrane, filled, and sterilized.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Virology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Oncology (AREA)
  • Biotechnology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de la notoginsenoside R1 dans la préparation du médicament destiné au traitement de lésions hépatiques, en particulier des lésions hépatiques d'ischémie-reperfusion.
PCT/CN2008/001169 2007-06-21 2008-06-17 Utilisation de la notoginsenoside r1 dans la préparation du médicament destiné au traitement de lésions hépatiques WO2009000149A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200710111276.7 2007-06-21
CN200710111276.7A CN101327220B (zh) 2007-06-21 2007-06-21 三七皂苷r1在制备治疗肝损伤的药物中的应用

Publications (1)

Publication Number Publication Date
WO2009000149A1 true WO2009000149A1 (fr) 2008-12-31

Family

ID=40185174

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2008/001169 WO2009000149A1 (fr) 2007-06-21 2008-06-17 Utilisation de la notoginsenoside r1 dans la préparation du médicament destiné au traitement de lésions hépatiques

Country Status (2)

Country Link
CN (1) CN101327220B (fr)
WO (1) WO2009000149A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111024471A (zh) * 2019-12-17 2020-04-17 浙江殷欣生物技术有限公司 一种用于宫颈癌筛查的液基细胞检测试剂盒及使用方法
CN114432494A (zh) * 2022-01-12 2022-05-06 宁波市第一医院 负载三七素的水凝胶和制备方法
CN115105492A (zh) * 2021-03-17 2022-09-27 南方医科大学南方医院 岩芹酸的新用途

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105147753B (zh) * 2015-10-23 2018-06-22 云南大学 三七总皂苷在制备直接抗丙型肝炎病毒药物中的应用
CN106511365A (zh) * 2016-12-17 2017-03-22 郑州郑先医药科技有限公司 一种治疗肝硬化的西药组合物
CN109288853A (zh) * 2018-11-21 2019-02-01 浙江中医药大学 三七皂苷r1在制备预防或治疗肝损伤药物中的应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
LI Y. ET AL.: "The protective effect of panax notoginseng saponins on the transplanted liver during ischemia-reperfusion injury in rat with orthotopic liver transplantation", CHINESE JOURNAL OF GENERAL SURGERY, vol. 15, no. 7, 2006, pages 508 - 511 *
LI Z. ET AL.: "Pharmacological study and clinical application on Panax Notoginseng in the treatment of hepatic lesion", INNER MONGOLIA MED. J., vol. 36, no. 6, 2004, pages 426 - 428 *
ZHAO P. ET AL.: "Effect of saponin in protecting against alcoholic liver injury", CHINESE JOURNAL OF CLINICAL REHABILITATION, vol. 8, no. 30, 2004, pages 6686 - 6687 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111024471A (zh) * 2019-12-17 2020-04-17 浙江殷欣生物技术有限公司 一种用于宫颈癌筛查的液基细胞检测试剂盒及使用方法
CN115105492A (zh) * 2021-03-17 2022-09-27 南方医科大学南方医院 岩芹酸的新用途
CN115105492B (zh) * 2021-03-17 2023-08-25 南方医科大学南方医院 岩芹酸的新用途
CN114432494A (zh) * 2022-01-12 2022-05-06 宁波市第一医院 负载三七素的水凝胶和制备方法

Also Published As

Publication number Publication date
CN101327220B (zh) 2014-04-23
CN101327220A (zh) 2008-12-24

Similar Documents

Publication Publication Date Title
US7438935B2 (en) Pharmaceutical composition for the treatment of cardiovascular and cerebrovascular diseases
USRE49035E1 (en) Traditional Chinese medicine composition, and preparation and application thereof
US20160143976A1 (en) Traditional chinese medicine composition, and preparation and application thereof
CN100999470A (zh) 一种丹参丹酚酸a及制剂的制备方法和用途
WO2009000149A1 (fr) Utilisation de la notoginsenoside r1 dans la préparation du médicament destiné au traitement de lésions hépatiques
US9034398B2 (en) Traditional Chinese drug comprising Danshen extracts and Sanqi extracts and use thereof
JP7390106B2 (ja) アテローム性動脈硬化症の治療用医薬の調製におけるトリアセチル－３－ヒドロキシフェニルアデノシンの応用
JP5120848B2 (ja) 血管新生阻害剤及び血管新生を伴う疾病に対する予防又は治療剤並びに食品
ZA200603160B (en) Use of agomelatine in obtaining medicaments intended for the treatment of bipolar disorders
WO2009135433A1 (fr) Utilisation d'acide salvianolique total, de notoginsenosides panax et d'une combinaison de ces composés dans le traitement de la septicémie
CN110169971A (zh) 一种包含3乙酰-α、β乳香酸的药物及其在预防、治疗胰腺炎中的应用
Zaiats et al. Ultrastructure of alveolar macrophages in case of experimental acute renal failure
RU2795163C2 (ru) Триацетил-3-гидроксифениладенозин для получения фармацевтических препаратов для уменьшения количества циркулирующих в крови моноцитов
US9101640B2 (en) Use of Danshensu, Notoginsenoside R1 or their combination in preparation of medicaments for preventing and treating diseases caused by microcirculation disorder
WO2008154794A1 (fr) Utilisation d'extrait de salvia miltiorrhiza pour la préparation d'un médicament pour le traitement de la septicémie
CN117257781A (zh) 美金刚通过靶向心房心肌细胞谷氨酸受体有效干预房颤
JP2024510653A (ja) 急性虚血性脳卒中を治療するｄｃ００９
CN113143922A (zh) Dhc在制备动脉粥样硬化治疗制剂中的应用
JP2007161686A (ja) 糖尿病網膜症治療剤及び眼局所投与用製剤
WO2008154795A1 (fr) Utilisation de sanchinosides pour le traitement de la septicémie
CN103027904A (zh) 咖啡酸用于制备抑制白细胞Src的活化的药物中的应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08772962

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08772962

Country of ref document: EP

Kind code of ref document: A1