CN101057840A - Application of Vam3 in preparing medicine for treating chronic obstructive disease of lung - Google Patents
Application of Vam3 in preparing medicine for treating chronic obstructive disease of lung Download PDFInfo
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Abstract
The invention discloses the novel use of Vam 3 (Amurensin H) with a general formula (I) in preparing medicament for preventing and/or treating chronic obstructive pulmonary disease.
Description
Technical field
The present invention relates to the novel medical use of the Vam3 shown in the formula (I) (Amurensin H).
Background technology
Chronic obstructive pulmonary disease (chronic obstructive pulmonary disease, COPD) be common chronic disease in a kind of global range, in the global cause of death, be number four at present, predict according to World Health Organization (WHO), to the year two thousand twenty, COPD will be number five in global disease incidence, be number three in the cause of death.
COPD is a kind of disease of incomplete reversible flow limitation feature, and relevant to harmful gas or poisonous particulate abnormal inflammatory reaction with pulmonary, its chronic inflammatory reaction spreads all over air flue, pulmonary parenchyma and lung blood vessel.The cell that participates in COPD has inflammatory cells such as neutrophilic granulocyte, T lymphocyte and macrophage, discharges multiple inflammatory mediator after cell is activated, as leukotriene B
4(LTB
4), interleukin 8 (IL-8), RANTES, Eotaxin, tumor necrosis factor (TNF α), matrix metalloproteinase 9 (MMP-9) etc., participate in inflammatory reactions such as pulmonary parenchyma destruction, lung blood vessel.The pathological change feature shows as alveolar space inflammatory cell (as macrophage) infiltration, bronchia and bronchioles kitchen range inflammatory cell infiltration on every side, the alveolar space expansion of lung tissue edge, destruction, alveolar wall broadens, and its epithelial cell swelling, change circle, part come off.COPD and chronic bronchitis and emphysema are closely related, but definition is upward different, and bronchial asthma is relevant with atopic allergy, its flow limitation tool reversibility (it is not exclusively reversible to occur flow limitation when merging with chronic tracheitis).Now still do not have the sexual development that carries out that medicine can be contained the COPD state of an illness, the progress of its Drug therapy is quite slow, and the clinical medicine that usually will treat asthma is used for the treatment of COPD at present, because the pathogenesis of COPD is different from asthma, is difficult to obtain satisfied curative effect.
Vam3 (Amurensin H), obtain by the applicant's separation first from the Vitis amurensis Rupr ethanol extraction, but chemosynthesis now, and structural formula is suc as formula shown in (I), preparation method is seen " purposes of Vitis Amurensis extract for treating inflammation disease " (application number 03134647.2, publication number CN1600304).The effect of the anti-COPD of Vam3 does not now appear in the newspapers.
Summary of the invention
Long-term smoking is modal human COPD paathogenic factor, and we induce simulation mice COPD model with medicated cigarette by laboratory, intend the mitigation of research Vam3 to the inductive mice COPD of medicated cigarette.
The object of the invention is to provide synthetic or the application of semi-synthetic composition in the anti-COPD disease medicament of preparation.Vam3 is gastric infusion under dosage 50,100,200mg/kg, and the generation of inflammatory cytokine TNF α, IL-8 among the inductive COPD mice of the medicated cigarette BALF is had inhibitory action; Secretion to chemotactic factor RANTES, Eotaxin has inhibitory action; To inflammatory cell among the BALF, mainly be the inhibitory action of having raised of neutrophilic granulocyte and macrophage; Pathological change has reverse effect to mouse lung.
The specific embodiment
Method: the male BALB/c mouse of SPF level, 18-20g is divided into normal control group, model control group, positive controls (terbutaline at random, 10mg/kg, gastric infusion), drug treating group (Vam3 50,100,200mg/kg, gastric infusion), 10 every group.Mice is placed in the 4L container, sootiness every day (Jinjian board medicated cigarette, tar content is less than 16mg), Friday time, continuously around, preceding 1 hour gastric infusion of sootiness every day.Mice after the last sootiness 1 hour is with sodium phenobarbital anesthesia, with PBS buffer (pH7.0) the pulmonary perfusion of 0.6mL pre-cooling, wash 3 times, sucking-off bronchoalveolar lavage fluid (BALF), the centrifugal 10min of 250 * g, supernatant is used to analyze the content of TNF α, IL-8, RANTES, Eotaxin.Cell is resuspended with the PBS buffer, and counting is used Rui Shi-Giemsa staining behind the cell smear, the variation of inflammatory cell sum and neutrophilic granulocyte, macrophage quantity among the analysis BALF.
Embodiment 1 Vam3 generates inhibitory action to inflammatory mediator in the COPD mouse bronchial bronchoalveolar lavage fluid (BALF)
(1) Vam3 generates inhibitory action to TNF α among the COPD mice BALF
The startup factor in the pathogenic process that preceding inflammatory cytokine TNF α is COPD.COPD patient's TNF alpha levels is higher than the normal person, but the bronchial epithelial cell of cultivation contacts TNF secretion α with the smog of medicated cigarette.TNF α can impel neutrophilic granulocyte to take off granule, induces and plays mucomembranous cell hypertrophy and high secretion, increases epithelial cell IL-8 and generates, and increases the macrophage matrix metalloproteinase and generates, and promotes airway hyperreactivity.This experiment purpose is to investigate Vam3 to the influence that TNF α among the COPD mice BALF generates, and the results are shown in Table 1.
The influence that table 1 Vam3 generates TNF α among the COPD mice BALF
| Chemical compound | Dosage (mg/kg) | The content (pg/ml) of TNF α among the COPD mice BALF |
| Vam3 terbutaline model contrast normal control | 50 100 200 10 | 19.9±4.2(61.2 *) 15.9±4.9(74.3 *) 13.1±5.5(83.3 **) 19.4±2.6(62.9 *) 38.5±3.9 ## 8.0±0.6 |
Annotate: be inhibition percentage rate (IR%) in the bracket;
*P＜0.05 is compared with model control group;
##P＜0.01 is compared with the normal control group.n＝10。
Result: Vam3 to COPD model mice gastric infusion, can reduce the generation of TNF α among the mice BALF under dosage 50,100,200mg/kg.
(2) Vam3 generates inhibitory action to IL-8 among the COPD mice BALF
Pulmonary epithelial cells, fibroblast, endotheliocyte and pulmonary alveolar macrophage can be expressed IL-8 under the inducing of medicated cigarette, IL-8 is neutrophilic granulocyte chemotactic, endothelial cell adhesion and degranulated important medium, IL-8 can activate neutrophilic granulocyte 5-lipoxygenase, chemotactic CD8
+The T cell plays a significant role in the COPD pathological process.This experiment purpose is to investigate Vam3 to the influence that IL-8 among the COPD mice BALF generates, and the results are shown in Table 2.
Table 2 Vam3 is to the influence of IL-8 among the COPD mice BALF
| Chemical compound | Dosage (mg/kg) | The content (pg/ml) of IL-8 among the COPD mice BALF |
| Vam3 terbutaline model contrast normal control | 50 100 200 10 | 14.7±0.6(38.3) 9.3±0.6(67.5 *) 6.5±0.4(82.5 *) 11.8±2.5(53.6) 21.7±5.6 ## 3.3±2.0 |
Annotate: be inhibition percentage rate (IR%) in the bracket;
*P＜0.05 is compared with model control group;
##P＜0.01 is compared with the normal control group.n＝10。
Result: Vam3 to COPD model mice gastric infusion, can reduce the generation of IL-8 among the mice BALF under dosage 50,100,200mg/kg.
(3) Vam3 is to RANTES secretion inhibition among the COPD mice BALF
The migration of inflammatory cell is subjected to the adjusting of chemotactic factor, and various structure cells and inflammatory cell all can be secreted these small molecular proteins, and the RANTES secretion increases chemotactic Monocytes, T lymphocyte, oxyphil cell in the COPD pathogenic process.This experiment purpose is to investigate Vam3 to the excretory influence of RANTES among the COPD mice BALF, the results are shown in Table 3.
Table 3 Vam3 is to the excretory influence of RANTES among the COPD mice BALF
| Chemical compound | Dosage (mg/kg) | The content (pg/ml) of RANTES among the COPD mice BALF |
| Vam3 | 50 100 | 30.9±18.5(74.7) 22.4±6.5(87.0 *) |
| Terbutaline model contrast normal control | 200 10 | 15.6±6.0(96.9 **) 39.0±19.8(62.9) 82.3±8.1 ## 13.5±2.8 |
Annotate: be inhibition percentage rate (IR%) in the bracket;
*P＜0.05 is compared with model control group,
*P＜0.01 is compared with model control group;
##P＜0.01 is compared with the normal control group.n＝10。
Result: Vam3 to COPD model mice gastric infusion, can reduce the secretion of RANTES among the mice BALF under dosage 50,100,200mg/kg.
(4) Vam3 is to Eotaxin secretion inhibition among the COPD mice BALF
The high expressed chemokine receptors of the cell in allergic inflammation district, Eotaxin plays an important role in the inflammation district raises the eosinophilic granulocyte by interacting with its specific receptor.In addition, many documents report that also Eotaxin relevant effector lymphocyte, works in the migration as pulmonary alveolar macrophage and basophilic granulocyte.This experiment purpose is to investigate Vam3 to the excretory influence of Eotaxin among the COPD mice BALF, the results are shown in Table 4.
Table 4 Vam3 is to the excretory influence of Eotaxin among the COPD mice BALF
| Chemical compound | Dosage (mg/kg) | The content (pg/ml) of Eotaxin among the COPD mice BALF |
| Vam3 terbutaline model contrast normal control | 50 100 200 10 | 131±25.2(55.2) 74±5.2(82.1 *) 47±10.0(94.3 *) 205±35.1(20.8) 250±34.9 ## 35.0±5.0 |
Annotate: be inhibition percentage rate (IR%) in the bracket;
*P＜0.05 is compared with model control group;
##P＜0.01 is compared with the normal control group.n＝10。
Result: Vam3 to COPD model mice gastric infusion, can reduce the secretion of Eotaxin among the mice BALF under dosage 50,100,200mg/kg.
The inhibitory action that embodiment 2 Vam3 raise inflammatory cell among the COPD mice BALF
(1) Vam3 inhibitory action that total inflammatory cell among the COPD mice BALF is raised
COPD is a feature to spread all over air flue, pulmonary parenchyma and pulmonary vascular chronic inflammatory disease, and this inflammation shows as neutrophilic granulocyte, T lymphocyte and macrophage and increases in lung.Activated inflammatory cell discharges a series of inflammatory mediators, comprises LTB
4, IL-8, TNFa and other media that can destroy lung structure or keep the neutrophilic granulocyte inflammation.This experiment purpose is to investigate the influence that Vam3 raises total inflammatory cell among the COPD mice BALF, the results are shown in Table 5.
The influence that table 5 Vam3 raises total inflammatory cell among the COPD mice BALF
| Chemical compound | Dosage (mg/kg) | Inflammatory cell grand total (10 among the COPD mice BALF 5cell/ml) |
| Vam3 terbutaline model contrast normal control | 50 100 200 10 | 5.15±1.85(25.8) 4.53±1.77(34.7) 3.97±1.59(42.8 *) 4.82±1.91(30.5) 6.94±2.23 ## 0.51±0.29 |
Annotate: be inhibition percentage rate (IR%) in the bracket;
*P＜0.05 is compared with model control group;
##P＜0.01 is compared with the normal control group.n＝10。
Result: Vam3 to COPD model mice gastric infusion, can reduce among the mice BALF raising of total inflammatory cell under dosage 50,100,200mg/kg.
(2) Vam3 inhibitory action that neutrophilic granulocyte among the COPD mice BALF is raised
Neutrophilic granulocyte has important function in the COPD morbidity, it can discharge two kinds of serine proteases, elastoser and cysteinyl proteinase-3, and induced animal produces the pathological change of human emphysema sample.Neutrophilic granulocyte life is of short duration, and the process that air flue and crossing gap chamber are recruited in its circulation is very rapid.Pathological study proves in some COPD patient bronchial tissue that the neutrophilic granulocyte number increases that to get degree relevant with airflow obstruction.The neutrophilic granulocyte number increases in the COPD patient airway of smoking, and particularly those are with the patient of chronic bronchitis.Influencing the principal element that neutrophilic granulocyte is raised in COPD patient's lung strengthens for the IL-8 chemotactic activity.This experiment purpose is to investigate the influence that Vam3 raises neutrophilic granulocyte among the COPD mice BALF, the results are shown in Table 6.
The influence that table 6 Vam3 raises neutrophilic granulocyte among the COPD mice BALF
| Chemical compound | Dosage (mg/kg) | Neutrophilic granulocyte counting (* 10 among the COPD mice BALF 5cell/ml) |
| Vam3 terbutaline model contrast normal control | 50 100 200 10 | 0.61±0.21(53.8 *) 0.45±0.09(65.9 *) 0.29±0.07(78.0 **) 0.33±0.04(75.0 *) 1.32±0.38 ## 0.02±0.005 |
Annotate: be inhibition percentage rate (IR%) in the bracket;
*P＜0.05 is compared with model control group,
*P＜0.01 is compared with model control group;
##P＜0.01 is compared with the normal control group.n＝10。
Result: Vam3 to COPD model mice gastric infusion, can reduce raising of neutrophilic granulocyte among the mice BALF under dosage 50,100,200mg/kg.
(3) Vam3 inhibitory action that macrophage among the COPD mice BALF is raised
Macrophage increases than normal person group's level in smoker and the COPD patient's lung, accumulates in alveolar, bronchioles and little air flue more.Alveolar wall macrophage number and light moderate emphysema and COPD patient's small airway disease degree is proportionate.Lesion tissue can be seen COPD with damage location, and slowly progress is parallel with chronic pathological changes and the long-term increase of macrophage.Macrophage may cause the Elastic tissue degradation capability to increase unusually by the release matrix metalloproteases, brings out emophysematous generation.This experiment purpose is to investigate the influence that Vam3 raises macrophage among the COPD mice BALF, the results are shown in Table 7.
The influence that table 7 Vam3 raises macrophage among the COPD mice BALF
| Chemical compound | Dosage (mg/kg) | Macrophage counting (* 10 among the COPD mice BALF 5cell/ml) |
| Vam3 terbutaline model contrast normal control | 50 100 200 10 | 4.42±1.36(19.2) 3.97±0.89(27.4) 3.49±1.02(36.2 *) 4.22±1.26(22.8) 5.47±1.73 ##0.41±0.08 |
Annotate: be inhibition percentage rate (IR%) in the bracket;
*P＜0.05 is compared with model control group;
##P＜0.01 is compared with the normal control group.n＝10。
Result: Vam3 to COPD model mice gastric infusion, can reduce raising of macrophage among the mice BALF under dosage 50,100,200mg/kg.
Embodiment 3.Vam3 is to the reverse effect of COPD mouse lung pathological change
To the mouse lung pathological observation as seen, the model group alveolar wall broadens, and the swelling of alveolar wall epithelial cell becomes circle, and part comes off, kitchen range inflammatory cell infiltration around the visible macrophage of alveolar space, bronchia and bronchioles, the expansion of lung tissue edge alveolar space.The swelling of Vam3 group alveolar wall epithelial cell, visible a small amount of macrophage of alveolar space and granulocyte soak into, and do not see lymphocytic infiltration, mouse lung organize do not see hemorrhage.
Conclusion: Vam3 is gastric infusion under dosage 50,100,200mg/kg, and the inductive mice chronic obstructive of medicated cigarette pulmonary venous pleonaemia, inflammatory cell infiltration etc. are had certain therapeutical effect.
Claims (1)
1, the chemical compound shown in the formula (I) prevents and/or treats application in the medicine of chronic obstructive pulmonary disease in preparation
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104546820A (en) * | 2013-10-09 | 2015-04-29 | 中国医学科学院药物研究所 | Application of stilbene dimer in preventing and curing hematopoietic stem cell radioactive damage |
| CN109897021A (en) * | 2017-12-07 | 2019-06-18 | 中国医学科学院药物研究所 | The plain derivative of grapevine penta, its preparation method and pharmaceutical composition and purposes |
| CN109893522A (en) * | 2017-12-08 | 2019-06-18 | 中国医学科学院药物研究所 | Amurensin H derivative is treating and preventing the application in Chronic Obstructive Pulmonary Disease |
| CN110433153A (en) * | 2018-05-03 | 2019-11-12 | 中国医学科学院药物研究所 | A kind of Amurensin H derivative is treating and preventing the application in liver related disease |
| CN113304139A (en) * | 2021-06-30 | 2021-08-27 | 贵州医科大学 | Application of Viniferifuran in preparation of xanthine oxidase inhibition drugs |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1600304A (en) * | 2003-09-23 | 2005-03-30 | 中国医学科学院药物研究所 | Application of extractive of ussurian grape on curing inflammatory disease |
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2006
- 2006-04-21 CN CN2006100762994A patent/CN101057840B/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104546820A (en) * | 2013-10-09 | 2015-04-29 | 中国医学科学院药物研究所 | Application of stilbene dimer in preventing and curing hematopoietic stem cell radioactive damage |
| CN109897021A (en) * | 2017-12-07 | 2019-06-18 | 中国医学科学院药物研究所 | The plain derivative of grapevine penta, its preparation method and pharmaceutical composition and purposes |
| CN109897021B (en) * | 2017-12-07 | 2021-09-14 | 中国医学科学院药物研究所 | Grapevine pentalin derivative, preparation method thereof, pharmaceutical composition and application |
| CN109893522A (en) * | 2017-12-08 | 2019-06-18 | 中国医学科学院药物研究所 | Amurensin H derivative is treating and preventing the application in Chronic Obstructive Pulmonary Disease |
| CN110433153A (en) * | 2018-05-03 | 2019-11-12 | 中国医学科学院药物研究所 | A kind of Amurensin H derivative is treating and preventing the application in liver related disease |
| CN113304139A (en) * | 2021-06-30 | 2021-08-27 | 贵州医科大学 | Application of Viniferifuran in preparation of xanthine oxidase inhibition drugs |
| CN113304139B (en) * | 2021-06-30 | 2022-04-29 | 贵州医科大学 | Application of Viniferifuran in preparation of xanthine oxidase inhibition drugs |
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