CN102038698A - New application of morroniside - Google Patents
New application of morroniside Download PDFInfo
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- CN102038698A CN102038698A CN2009100192852A CN200910019285A CN102038698A CN 102038698 A CN102038698 A CN 102038698A CN 2009100192852 A CN2009100192852 A CN 2009100192852A CN 200910019285 A CN200910019285 A CN 200910019285A CN 102038698 A CN102038698 A CN 102038698A
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- morroniside
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- ethanol
- endotoxin
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Abstract
The invention discloses new application of morroniside, which provides the application of the morroniside in the preparation of medicines for treating or preventing sepsis. The intravenous injection of the morroniside can reduce the levels of sepsis rat serum HMGB1 (High-mobility Group-Box 1protein), TNF (Tumor Necrosis Factor)-alpha, IL (Interleukin)-6, endotoxin and TREM (Triggering Receptor Expressed on Myeloid Cells)-1.
Description
Technical field
The present invention relates to a kind of new purposes of morroniside, be specifically related to morroniside in preparation treatment or prevent application in the pyemic medicine.
Background technology
Sepsis (sepsis), i.e. pyemia.It is a kind of clinical syndrome that causes by infection.Suppurative pathogen is invaded blood flow and a large amount of therein breedings, and spreads to whole body with blood flow, the new multiple suppurative focus that causes at histoorgan.Sepsis is often with following sign: body temperature is higher or lower than normally, and leukocytosis or minimizing, tachycardia, rapid breathing or per minute ventilation raise unusually, as occurring wherein two or two above symptoms clinically, gets final product the diagnosis of sepsis mass formed by blood stasis; As the organ failure of occurring together, promptly be called serious symptom pyemia (severe sepsis).There is 500,000 pyemia patients every year in the U.S., survival rate only 55%～65%.
Sepsis is a common complication after severe trauma, burn, shock, the major operation, also is one of important cause of death of surgery critical patient.Research at present generally believes that lipopolysaccharide (LPS) is one of the crucial medium of generation inflammatory reaction in the toxic shock generating process [StaffM, WeintraubA, Widmalm G, et al.Structure determination oftheo-antigenic polysacchanide from the enteroinvasive Escherichia coli 1036.Eur JBiochem, 1999,263 (3): 65].Inflammatory mediator IL-6, TNF-α, HMGB-1 also play pivotal role [Cohen J.The immunopathogenesis of sepsis.Nature 2002,420 (6917): 885-891 in sepsis; WangH, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J.HMG-1 as a late mediatorof endotoxin lethality in mice.Science 1999,285 (5425): 248-251; Andersson U, TraceyKJ.HMGB1 in sepsis.Scand J Infect Dis 2003,35 (9): 577-584.].Myeloid cell triggers and is subjected to
Body (TREM-1) is sensitive indicator [the Ching LL that sepsis takes place, Wen YH, Ch LW, Hsu TK, Yen TL.Triggering receptor expressed on myeloid cells-1 in pleural effusions:A marker ofinflammatory disease.Resp Med 2007; 101:903-9.; Knapp S, Gibot S, de Vos A, VersteegHH, Colonna M, van der Poll T.Cutting edge:expression patterns of surface and solubletriggering receptor expressed on myeloid cells-1 in human endotoxemia.J Immunol 2004; 173:7131-4.; Gibot S, Kolopp-Sarda MN, B é n é MC, Bollaert PE, Lozniewski A, Mory F, Levy B, Faure GC.A soluble form of the triggering receptor expressed on myeloidcells-1 modulates the inflammatory response in murine sepsis.J Exp Med 2004; 200:1419-26.; Bouchon A, Facchetti F, Weigand MA, Colonna M.TREM-1 amplifies inflammationand is a crucial mediator of septic shock.Nature 2001; 410:1103-7.].
Morroniside is to extract the water miscible iridoid obtain from the Chinese medicine Fructus Corni, bibliographical information Fructus Corni water extract have blood sugar lowering, immunosuppressant, antiinflammatory, shock, heart tonifying,, effects such as arrhythmia, resisting fatigue, defying age and memory reinforcing.But morroniside is in the preparation treatment or prevent pyemic pharmacological action not appear in the newspapers.The inventor discovers that by a large amount of morroniside can trigger receptor (TREM-1) by the inflammation-inhibiting factor and myeloid cell and express, thus in and the serum endotoxin aspect prevention or the treatment sepsis tangible effect is being arranged.Based on this, the inventor provides morroniside by the inflammation-inhibiting factor expression, thus in and the serum endotoxin suppress pyemic and develop so that prevention or treatment sepsis.
Summary of the invention
The invention provides morroniside in preparation treatment or prevent application in the pyemic medicine.
Medicine provided by the invention is when being used to prevent sepsis, and the using dosage scope is 25mg～1000mg during its injection, preferred 25～500mg.
The present invention also provides the pharmaceutical composition of being made up of morroniside and pharmaceutically acceptable carrier or adjuvant, and said composition can be prepared into injection, freeze-dried powder with the pharmacy conventional method.
Morroniside provided by the invention prepares by the following method: the Fructus Corni pulverizing medicinal materials, add 6～12 times of water, and soaked 2 hours, decoct 2～3 times, decocted 1～2 hour at every turn, filter, the united extraction filtrate, being evaporated to relative density is 1.05～1.2, adds ethanol, stir, to concentration of alcohol be 60%～90%, left standstill 1～12 hour, filter alcoholic solution, small amount of ethanol washing filtering residue discards filtering residue, filtrate is concentrated into no ethanol, and is standby.Select the macroporous resin of nonpolar～low pole for use, regulator solution pH value to 1～3, last sample, absorption, 3～9 times of column volumes of water elution, 10%～50% alcoholic solution eluting, segmentation receives, elution volume is 3～15 times of column volumes, and the morroniside enriching section concentrates, and is standby.With sample on nonpolar～semipolar macroporous resin, get morroniside solution, the low-temperature reduced-pressure drying.Crystallization.
The inventor has confirmed the application of morroniside in treatment or prevention sepsis by following test, but effect is not limited thereto.
The specific embodiment
The preparation of embodiment 1 morroniside
Morroniside medical material 50Kg adds water 500L, soaks 2 hours, heating decocts 3 times, each 2 hours, filters, the united extraction filtrate, concentrating under reduced pressure is to relative density 1.20 (40 ℃ of mensuration), add 95% ethanol, stir, to concentration of alcohol be 80%, left standstill 2 hours, and filtered alcoholic solution, small amount of ethanol washing filtering residue, discard filtering residue, filtrate is concentrated into does not have alcohol, and regulating pH value is 2, last sample adsorbs 3 times of column volumes of 10% alcoholic solution eluting to the AB-8 macroporous resin column, 3 times of column volumes of 30% alcoholic solution eluting, 3 times of column volumes of 40% alcoholic solution eluting, 3 times of column volumes of 50% alcoholic solution eluting, segmentation receives, after testing, the person is concentrated into no ethanol to be rich in the morroniside.Sample adsorbs to the HPD300 resin column on this concentrated solution, 3 times of column volumes of purification washing, and 10% liquid alcoholic solution is washed 3 times of column volumes, and segmentation receives, and detects, and the person concentrates no ethanol, low-temperature reduced-pressure drying to be rich in the morroniside.Weigh, make morroniside 150g, content 91%, recrystallization in the ethanol, content 98.3%.
The preparation of embodiment 2 morronisides
Monot's medical material 50Kg adds water 500L, soaks 2 hours, heating decocts 3 times, each 2 hours, filters, the united extraction filtrate, concentrating under reduced pressure is to relative density 1.15 (40 ℃ of mensuration), add 95% ethanol, stir, to determining alcohol be 80%, left standstill 6 hours, and filtered alcoholic solution, wash filtering residue with small amount of ethanol, discard filtering residue, filtrate is concentrated into no ethanol.It is 2 that concentrated solution is regulated PH, and last sample adsorbs 3 times of column volumes of 10% ethanol elution to the HZ-818 macroporous resin column, 3 times of column volumes of 20% ethanol elution, 3 times of column volumes of 30% ethanol elution, 3 times of column volumes of 40% ethanol elution, segmentation receives, and after testing, the person is concentrated into no ethanol to be rich in the morroniside.Sample is to the HPD300 post on this concentrated solution, and 3 column volumes are washed in absorption, and 10% ethanol is washed 3 times of column volumes, and segmentation receives, and detects, and the person concentrates no ethanol to be rich in the morroniside.The low-temperature reduced-pressure drying.Crystallization is weighed, and makes morroniside 140g, content 92%, recrystallization in the ethanol, content 98.7%.
The preparation of embodiment 3 morroniside injection
Prescription:
Method for making:
Measure morroniside 2.5g by prescription, sodium chloride 225g with water for injection 25000ml dissolving, stirs; Add active carbon 25g, stirred 20 minutes, solution is clear and bright through filtering with microporous membrane, be sub-packed in the 250ml infusion bottle, and sterilization, packing gets final product after the passed examination.
Other checks that item should meet Pharmacopoeia of People's Republic of China version injection in 2005 project demand.
The preparation of embodiment 4 morroniside freeze-dried powders
Prescription:
Method for making:
Get morroniside 125g, being dissolved in 10000ml contains in the aqueous solution for injection of 1.25% mannitol, add active carbon 10g, stirred 30 minutes, solution obtains pyrogen-free settled solution through filtering with microporous membrane, be sub-packed in the 10ml cillin bottle, 2ml/ props up, and presses the lyophilizing of freeze-dried powder technology, makes every freeze-dried powder that contains 25mg.
Test the influence of the sepsis rat that 1 morroniside causes cecal ligation and perforation
1.1 medicine and reagent
Morroniside is by preparation example 1 preparation
Tachypleus amebocyte lysate test kit (the biochemical Industrial Co., Ltd of Foochow, Fujian Province Xin Bei, lot number: 080430)
High-mobility group-box 1protein (HMGB1), TNF-α, IL-6ELISA test kit (Shanghai Xi Tang biotech company)
Myeloid cell triggers receptor (TREM-1) ELISA test kit (Shanghai Hu Feng bio tech ltd)
Laboratory animal: SPF level Sprague Dawley rat, male, body weight 150g-200g, Shandong Luye Pharmaceutical Co., Ltd. is real
Testing animal center provides, and the animal quality certification number is: SYXK (Shandong) 20030020.
1.2 experimental technique and result
1.2.1 the preparation of cecal ligation and perforation (CLP) rat
Dorsal position is got in operation rat fasting in early morning on the same day behind the etherization, 75% ethanol disinfection abdominal part along the otch of hunter's line stage casing work one long 1.5cm, is cut off skin and flesh layer, detects the abdominal cavity and separates caecum; No. 1 silk thread is apart from cecum 1cm place (ileocecal valve far-end) ligation, and No. 16 puncture needle runs through caecum 3 times (triangular in shape) at ligation place far-end, the about 3mm of pin hole spacing, and extrude a little content; Caecum Hui Na abdominal cavity, layer-by-layer suture is closed the abdominal cavity.
1.2.2 grouping administration
60 of CLP rats are divided into 6 groups at random, and promptly model group, morroniside intravenous injection 2.5mg/kg, 5mg/kg, 25mg/kg, 50mg/kg, 100mg/kg get 10 normal rats in addition and organize in contrast.1 hour each group of CLP operation gives relative medicine.Blood was got in the CLP operation in 20 hours, measured serum HMGB1, TNF-α, IL-6, endotoxin.Serum HMGB, TNF-α, IL-6 measure and use the ELISA test kit, and the serum endogenous toxin uses plain tachypleus amebocyte lysate kit measurement.
1.2.3 experimental result
Morroniside intravenous injection 2.5mg/kg, 5mg/kg, 25mg/kg, 50mg/kg, 100mg/kg group obviously reduce sepsis rat blood serum HMGB1, TNF-α, IL-6, endotoxin, TREM-1 level (p＜0.05 or p＜0.01).Morroniside intravenous injection 50mg/kg group reduces relatively there was no significant difference of sepsis rat blood serum HMGB1, TNF-α, IL-6, endotoxin, TREM-1 level and morroniside intravenous injection 100mg/kg group.
The influence (n=10) of the sepsis rat that the intravenous injection of table 1 morroniside causes cecal ligation and perforation
*, p＜0.05,
*, compare with model group p＜0.01
Test of the influence of 2 morronisides to the endotoxemia rat
2.1 material
Morroniside is by preparation example 1 preparation
Endotoxin: microorganism teaching and research room of Shanghai The 2nd Army Medical College, lot number: 070412
D-galactosamine (import packing, 5g/ bottle, Beijing chemical reagents corporation, lot number: 070412)
Tachypleus amebocyte lysate test kit (the biochemical Industrial Co., Ltd of Foochow, Fujian Province Xin Bei, lot number: 070430)
Laboratory animal: SPF level Sprague Dawley rat, male, body weight 150g-200g, Shandong Green Leaf Pharmaceutical Co., Ltd's Experimental Animal Center provides, and the animal quality certification number is: SYXK (Shandong) 20030020.
2.2 experimental technique and result
Rat is divided into NS group, dexamethasone 5mg/kg group, intravenous injection morroniside 100mg/kg group, 50mg/kg group, 25mg/kg group, 5mg/kg group, 2.5mg/kg group, 10 every group at random.Rat fasting 16h before the experiment can't help water.During experiment through tail vein injection D-galactosamine (300mg/kg), carry out modeling through intragastric infusion endotoxin (20mg/kg) immediately, respectively organize administration immediately, the NS group gives the NS with volume, each group is got blood respectively at 24h eye socket after the modeling, get 10 normal rats simultaneously and get blood, measure level of endotoxin in the blood plasma.Plasma endotoxin is measured with adopting the tachypleus amebocyte lysate chromogenic substrate method, and statistical procedures is carried out in the T check between group.
Table 2 result of the test shows that morroniside intravenous injection 2.5mg/kg, 5mg/kg, 25mg/kg, 50mg/kg, 100mg/kg group can significantly reduce level of endotoxin in the endotoxemia rat plasma and (compare with the NS group, P＜0.01), intravenous injection morroniside 10mg/kg can obviously reduce level of endotoxin in the endotoxemia rat plasma (comparing P＜0.05 or P＜0.01 with model group).Morroniside intravenous injection 50mg/kg group reduces sepsis rat blood serum level of endotoxin and morroniside intravenous injection 100mg/kg group compares there was no significant difference.
Table 2 morroniside is to level of endotoxin influence (n=10) in the endotoxemia rat plasma
Compare with the NS group,
*: p＜0.05;
*: p＜0.01.
Claims (1)
1. morroniside is in preparation treatment or prevent application in the pyemic medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100192852A CN102038698A (en) | 2009-10-14 | 2009-10-14 | New application of morroniside |
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| CN2009100192852A CN102038698A (en) | 2009-10-14 | 2009-10-14 | New application of morroniside |
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| CN102038698A true CN102038698A (en) | 2011-05-04 |
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| CN2009100192852A Pending CN102038698A (en) | 2009-10-14 | 2009-10-14 | New application of morroniside |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110025626A (en) * | 2019-05-10 | 2019-07-19 | 厦门大学 | Application of the morroniside in preparation treatment chordapsus drug |
| US11186636B2 (en) | 2017-04-21 | 2021-11-30 | Amgen Inc. | Anti-human TREM2 antibodies and uses thereof |
-
2009
- 2009-10-14 CN CN2009100192852A patent/CN102038698A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11186636B2 (en) | 2017-04-21 | 2021-11-30 | Amgen Inc. | Anti-human TREM2 antibodies and uses thereof |
| CN110025626A (en) * | 2019-05-10 | 2019-07-19 | 厦门大学 | Application of the morroniside in preparation treatment chordapsus drug |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EM01 | Change of recordation of patent licensing contract |
Change date: 20101223 Contract record no.: 2010320000507 Assignee after: Nanjing Luye Pharmaceutical Co., Ltd. Assignee before: Kanghai Pharmaceutical Co., Ltd., Nanjing |
|
| C06 | Publication | ||
| PB01 | Publication | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Assignee: Nanjing Luye Pharmaceutical Co., Ltd. Assignor: Luye Natural Medicinal Research Developing Co., Ltd., Shandong Prov. Contract record no.: 2010320000507 Denomination of invention: New application of morroniside License type: Exclusive License Open date: 20110504 Record date: 20100430 |
|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20110504 |