CN105520934A - Application of micheliolide dimethylamine - Google Patents
Application of micheliolide dimethylamine Download PDFInfo
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- CN105520934A CN105520934A CN201410515925.XA CN201410515925A CN105520934A CN 105520934 A CN105520934 A CN 105520934A CN 201410515925 A CN201410515925 A CN 201410515925A CN 105520934 A CN105520934 A CN 105520934A
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- pulmonary fibrosis
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- dimethyl amine
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Abstract
The invention provides application of micheliolide dimethylamine (ACT001) to preparation of medicines for treating pulmonary fibrosis. The micheliolide dimethylamine (ACT001) is capable of decreasing pulmonary coefficients of pulmonary fibrosis mice to be approximate to normal level, reversing and inhibiting pulmonary fibrosis level of organisms, inhibiting pulmonary extracellular matrix overdeposition, improving lung blood supply, increasing lung blood supply quantity and relieving dyspnea, thereby being remarkably effective in treatment of pulmonary fibrosis.
Description
Technical field
The present invention relates to medicinal chemistry art, in particular to the application of with a smile lactone dimethyl amine.
Background technology
With a smile lactone dimethyl amine is the derivant of lactone with a smile, is be that waste comes by natural extract parthenolide, in this article by it referred to as ACT001.Parthenolide is a kind of Sesquiterpene compound be purified into from draft class plant tansy, has the features such as antiinflammatory, antitumor, antiplatelet aggregation.Diseases such as mainly concentrating on treatment skin infection, migraine, rheumatism and treatment tumor is studied at present about ACT001.Research shows that ACT001 and parthenolide have the features such as antiinflammatory, antitumor, antiplatelet aggregation, the propagation of suppression vascular smooth muscle cell, the activity of suppression osteoclast, it passes through expression of Tumor suppression necrosin (TNF-α), il-1 (interleukin-1, IL-1), IL-12 and Transitional cell carcinomas (COX-2) etc. and has antiinflammatory action; Promoted the apoptosis of cancerous cell by the activation and phosphorylation suppressing NF-к B, suppress the generation of L-8, VEGF (vascularendothelialgrothfactor, VEGF) simultaneously, play antineoplastic action;
Up to the present, the application of ACT001 in pulmonary fibrosis there is no and clearly report.The cytokine relevant with pulmonary fibrosis has transforming growth factor (transforminggrowthfactor-β, TGF-β), epidermal growth factor (epidermalgrowthfactor, EGF), platelet derived growth factor (plateletderivedgrowthfactor, PDGF), insulin like growth factor (insulin-likegrowthfactors, IGF-1), interleukin (interleukin, IL), Connective Tissue Growth Factor (connectivetissuegrowthfactor, CTGF), tumor necrosis factor (tumornecrosisfactor α, TNF-α) matrix metalloproteinase (matrixmetalloproteinases, MMPs) etc.The feature of pulmonary fibrosis is fibroblastic hypertrophy in lung interval, causes ECM to deposit, and is therefore suppressed to the important step that fibroblast growth is development anti-fibrosis medicine.
The clinical manifestation of pulmonary fibrosis is dyspnea, during slight pulmonary fibrosis, dyspnea be everlasting strenuous exercise time occur, when pulmonary fibrosis is in progress, also dyspnea occurring when tranquillization, can there is Progressive symmetric erythrokeratodermia dyspnea in serious pulmonary fibrosis patients, the serious consequence of pulmonary fibrosis, cause normal lung tissue's structural change, afunction; When not having the fibrous tissue of gas exchange function to replace alveolar in a large number, gas exchange capacity in pulmonary is weakened, causes oxygen not enter blood, patient respiratory is smooth, anoxia, acidosis, disability, severe patient finally can cause death.The feature of pulmonary fibrosis is fibroblastic hypertrophy in lung interval, and the deposition of extracellular matrix is excessive.Fibrocyte can not replace alveolar cell to carry out gas exchange, and the alluvial of pulmonary blood can cause harmful substance can not metabolism in time in pulmonary, and then can cause damage to alveolar cell, forms a vicious cycle; The over-deposit of extracellular matrix causes compressing to blood capillary, causes pulmonary blood to circulate not smooth, causes pulmonary blood to deposit, and then causes declining for blood level of pulmonary, causes the problems such as dyspnea.
The pneumonopathy caused by pulmonary fibrosis is frequently-occurring disease, because pulmonary fibrosis is caused by the injury of lung of persistence, therefore once there is pulmonary fibrosis, is then difficult to cure, the very large harm that can cause human health.The treatment of pulmonary fibrosis does not have specific medicament at present.The measure such as anti-inflammatory agent and/or immunosuppressant, anti-fibrosis medicine, anticoagulation medicine, lung transplantation is mainly adopted to treat clinically, conventional medicine comprises glucocorticoid, nitroimidazole sulfur pyrimidine, ciclosporin, mycophenolate, and can affect colchicine that collagen formed and penicillamine etc.Glucocorticoid medicine is used for the treatment of idiopathic pulmonary fibrosis and has history more than 50 years, and gather discovery to the result of every clinical research, the obvious effective rate of glucocorticoid medicine to idiopathic pulmonary fibrosis is the highest is no more than 16%.Azathioprine is used for the treatment of idiopathic pulmonary fibrosis more than more than 20 years, and its effectiveness still exists dispute.Also there is dispute in varying degrees in other drug effectiveness clinically.Pulmonary fibrosis disease is safeguarded seriously, case fatality rate is high, clinical treatment measure deficient, therefore extremely urgent at the medicine of the treatment pulmonary fibrosis of understanding development of new on its pathogenetic basis in depth.
Summary of the invention
The object of the present invention is to provide the application of lactone dimethyl amine in the medicine of preparation treatment pulmonary fibrosis with a smile.
The invention provides the application of lactone dimethyl amine in the medicine of preparation treatment pulmonary fibrosis with a smile, wherein, the molecular structural formula of described lactone dimethyl amine is with a smile:
In above-mentioned application, comprising: the application that described lactone dimethyl amine with a smile reverses in preparation and suppresses the pulmonary fibrosis level of body, suppresses lung cells epimatrix over-deposit and improve in the medicine of pulmonary's blood supply.
In above-mentioned application, the medicine for the treatment of pulmonary fibrosis comprises: lactone dimethyl amine, with a smile lactone dimethyl amine pharmaceutically acceptable salt, ester, hydrate or their combination and adjuvant with a smile.
In above-mentioned application, the dosage form of the medicine for the treatment of pulmonary fibrosis is selected from tablet, capsule, pill, suppository, aerosol, oral liquid, granule, powder, injection, syrup, medicated wine, tincture, distillate medicinal water, membrane or their combination.
In above-mentioned application, the administering mode of medicine for the treatment of pulmonary fibrosis comprises: oral, injection, implantation, external, spraying, suction or their combination.
The advantage for the treatment of pulmonary fibrosis medicine provided by the invention is: lactone dimethyl amine (ACT001) can reverse and suppress the pulmonary fibrosis level of body, suppresses lung cells epimatrix over-deposit, improve pulmonary's blood supply, increases lung amount of blood supply thus alleviate dyspnea with a smile, to pulmonary fibrosis, there is good therapeutic effect, in addition, this medicine patient is not only acceptant, and toxic and side effects is little, cheap, wide material sources, easily obtain, be also convenient to understand patient to the reaction of medicine.In addition, ACT001 will change the market structure of existing treatment pulmonary fibrosis medicine, and becoming one can long-term taking, and effectively suppresses pulmonary fibrosis, improves the clinical medicine of pulmonary function.
ACT001 used in the present invention is ACT001 fumarate, white powder, and by Tianjin, Shang Deyao edge Science and Technology Co., Ltd. provides, lot number: the chemical structural formula of 20131112, ACT001 fumarate is:
Accompanying drawing explanation
Tu1Shi normal mouse lung tissue section schemes;
Fig. 2 is mouse pulmonary fibrosis modeling the 3rd week mouse lung tissue dicing effect figure;
Fig. 3 A is design sketch under second week mouse lung tissue formalness stereoscopic microscope after ACT001 administration;
Fig. 3 B is second week mouse lung tissue dicing effect figure after ACT001 administration;
Fig. 4 A is design sketch under the 3rd week mouse lung tissue formalness stereoscopic microscope after ACT001 administration; And
Fig. 4 B is the 3rd week mouse tissue dicing effect figure after ACT001 administration.
Detailed description of the invention
Below in conjunction with the accompanying drawing in the embodiment of the present invention, be clearly and completely described the technical scheme in the embodiment of the present invention, obviously, described embodiment is only the present invention's part embodiment, instead of whole embodiments.Based on the embodiment in the present invention, the every other embodiment that those of ordinary skill in the art obtain, all belongs to the scope of protection of the invention.
The test material that the present invention uses and source thereof comprise:
(1) mice
kunming mice(male): provided by Academy of Military Medicine, PLA's experimental animal center and Beijing Vital River Experimental Animals Technology Co., Ltd..
After animal arrives, animal is received in two corridors barrier environment Mice Residence 2 by special messenger, fill in " experimental animal receiving record table " (BG-017-V00), during reception, animal general condition is observed, and randomly draw animal and weigh, guarantee experimental animal and introduction standard substantially identical.Laboratory animal occupancy permit number: SYXK (Tianjin) 2012-0003.
(2) test sample
ACT001 fumarate: white powder, purchased from Tianjin Shang Deyao edge Science and Technology Co., Ltd., lot number 20131112.
Methyl viologen hydrate: white crystal, purchased from Beijing lark prestige Science and Technology Ltd., manufacturer: lark prestige Science and Technology Ltd., brand: J & K, purity: 98%, production code member: 6045559, MDL:MFCD00150001, No. CAS: 1910-42-5.
Test sample is preserved: 4 DEG C
(3) compound method of medicine used and reagent comprises:
A) preparation of ACT001 solution: take ACT001 powder 1g, be dissolved in 0.9% normal saline solution of 100mL, be mixed with 10mg/mL solution, after it fully dissolves, with 0.22 μm of degerming rear use of frit, matching while using during each use.Preparation and the use of solution all should operate in sterile biological safety cabinet.
B) configuration of methyl viologen hydrate soln: take methyl viologen hydrate 2g, be dissolved in 0.9% normal saline of 100ml, be configured to the solution of 20mg/ml, after it fully dissolves, with 0.22 μm of degerming rear use of frit, matching while using during each use.Preparation and the use of solution all should operate in sterile biological safety cabinet.
C) configuration of 10% formalin fixative: the pure water of the formalin of 100ml and 900ml is mixed.
The foundation of embodiment 1 mouse pulmonary fibrosis model and ACT001 pharmacodynamics detect
Experimental technique and step:
1. the foundation of mouse pulmonary fibrosis model and drug treatment
The foundation of 1.1 mouse pulmonary fibrosis models
36 mices are divided into three groups at random, normal group, matched group (pulmonary fibrosis model group), ACT001 group (after modeling administration ACT001), often organize 12.0.9% normal saline of the every only disposable gavage 0.15mL of normal group; The aqueous solution of matched group and the every only methyl viologen hydrate of disposable gavage 0.15mL of ACT001 group.
The drug treatment of 1.2 pulmonary fibrosis mices
After modeling the 3rd week, give mice Drug therapy, normal group and matched group used the normal saline gavage of 0.9% of 0.1mL at every turn, the ACT001 aqueous solution gavage of each 0.1mL of ACT001 group.Every 2 days once.
The pathology detection of 1.3 mouse pulmonary fibrosis
At the 3rd week of modeling, after administration after second week, administration the 3rd week, respectively from normal group, matched group, ACT001 group often group get four mices, disconnected neck is put to death, and gets its lung tissue, fixing two days later through 10% formalin, fall the fixative on lung tissue surface with running water, with pathological tissue dehydrating machine, processed is carried out to lung tissue, embed through paraffin, investing tissue is cut into slices, through H.E dyeing, cover plate, examines under a microscope the change of lung tissue.
Experimental result and evaluation
1) result set up by model
As shown in Figure 1, Tu1Shi normal mouse lung tissue section figure.As shown in Figure 2, Fig. 2 is mouse pulmonary fibrosis modeling the 3rd week mouse lung tissue dicing effect figure.As can be seen from Figure 2, there is obvious pulmonary fibrosis in modeling group: extracellular matrix components deposits in alveolar and interstitial, and fibrous tissue is excessively repaired, lung fibroplasia, interstitial pulmonary fibrosis, collagen deposition, and alveolar structure changes.
2) ACT001 pharmacodynamics detects
After administration ACT001 second week, mice is dissected, detect ACT001 to the drug effect of pulmonary fibrosis.The lung tissue of mice is observed after dissecting, result as shown in Figure 3A, Fig. 3 A is design sketch under second week mouse lung tissue formalness stereoscopic microscope after ACT001 administration, from Fig. 3 A: compared with matched group, the lung tissue of administration ACT001 group is more ruddy, and lung tissue blood supply obviously improves, and lung tissue color is scarlet, lung tissue surface is more ruddy, quite apparent with normal group mice; And modeling not administration group mouse lung tissue surface color is dim, lung tissue surface is not ruddy.Visible administration is had a smile on one's face lactone dimethyl amine (ACT001) and is organized mouse lung tissue blood supply and obviously improve.Visible administration ACT001 can improve pulmonary's blood supply, thus can alleviate the symptoms such as the dyspnea of body.
Stereomicroscopy Microscopic observation lung, and modeling not administration group lung tissue surface color is pale, lung tissue marginal vessel is tiny and rare, and consolidation appears in lung tissue, has fibroplasia alveolar structure in a big way to destroy obviously in pulmonary parenchyma.
The lung tissue section of mice as shown in Figure 3 B, Fig. 3 B is second week mouse lung tissue dicing effect figure after ACT001 administration, from Fig. 3 B: compared with healthy normal mouse, after injection methyl viologen hydrate obviously there is fibrosis in matched group (i.e. not administration group) lung; Administration ACT001 group, there is not consolidation in lung tissue, in pulmonary parenchyma without fibroplasia phenomenon, alveolar structure is not destroyed; The fibrosis of pulmonary obviously improves, and interstitial lung deposition obviously reduces, and alveolar tissue recovers normal.
As shown in fig. 4 a and 4b, wherein Fig. 4 A is design sketch under the 3rd week mouse lung tissue formalness stereoscopic microscope after ACT001 administration to the picture of the lung tissue picture of ACT001 administration after the 3rd week and lung tissue section; Fig. 4 B is the 3rd week mouse tissue dicing effect figure after ACT001 administration, from Fig. 4 A and Fig. 4 B, administration group is compared with matched group, and the pulmonary fibrosis degree of administration ACT001 group is obviously improved, the lung fibrosis level of mice obviously reduces, quite apparent with the lung of normal group.
In addition, in administration after the 3rd week, the Mouse Weight of normal group, matched group and administration ACT001 group is observed, and calculates the paragonimus cyst of each group.Each group of average mice body weight is as follows: the average weight of normal group mice is 49.2352g, and the average weight of control group mice is 45.4575, and the average mice body weight of administration ACT001 group is 47.576.The average lung of each group of mice is heavily: the average lung of normal group mice is heavily 0.4012g, and the average lung of control group mice is heavily 0.5983g, and the average lung of the mice of administration ACT001 group is heavily 0.4034g.According to formula: paragonimus cyst=lung weight in wet base (mg)/body weight (g) * 100%, as calculated, the paragonimus cyst of each group of mice is respectively: the average paragonimus cyst of normal group mice is 0.81%, the average paragonimus cyst of control group mice is 1.32%, and the average paragonimus cyst of administration ACT001 group is 0.85%.The paragonimus cyst of matched group apparently higher than normal group, the paragonimus cyst of administration ACT001 group and the paragonimus cyst no significant difference of normal group.Because paragonimus cyst represents pulmonary fibrosis degree, compared to matched group, the average paragonimus cyst of administration ACT001 group is 0.85%, reduce 0.47%, close to the average paragonimus cyst 0.81% of normal group mice, show that ACT001 can reverse and improve the Fibrosis levels of pulmonary thus, improve extracellular matrix over-deposit, suppress the hyperplasia of lung fibrosis cell.
Above embodiment shows: ACT001 can reverse and suppress the pulmonary fibrosis level of body, suppresses lung cells epimatrix over-deposit, improves pulmonary's blood supply increase lung amount of blood supply and alleviate dyspnea, has the effect for the treatment of pulmonary fibrosis.
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (5)
1. have a smile on one's face the application of lactone dimethyl amine in the medicine of preparation treatment pulmonary fibrosis, wherein, the molecular structural formula of described with a smile lactone dimethyl amine is:
2. application according to claim 1, is characterized in that, comprising: the application that described lactone dimethyl amine with a smile reverses in preparation and suppresses the pulmonary fibrosis level of body, suppresses lung cells epimatrix over-deposit and improve in the medicine of pulmonary's blood supply.
3. application according to claim 1, is characterized in that, the medicine of described treatment pulmonary fibrosis comprises: described lactone dimethyl amine with a smile, described lactone dimethyl amine pharmaceutically acceptable salt, ester, hydrate or their combination and adjuvant with a smile.
4. the application according to any one of claim 1-3, it is characterized in that, the dosage form of the medicine of described treatment pulmonary fibrosis is selected from tablet, capsule, pill, suppository, aerosol, oral liquid, granule, powder, injection, syrup, medicated wine, tincture, distillate medicinal water, membrane or their combination.
5. application according to claim 4, is characterized in that, the administering mode of the medicine of described treatment pulmonary fibrosis comprises: oral, injection, implantation, external, spraying, suction or their combination.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108484550A (en) * | 2018-05-07 | 2018-09-04 | 中国人民解放军第四军医大学 | One kind having a smile on one's face lactone derivatives and its preparation method and application |
| CN110856716A (en) * | 2018-08-22 | 2020-03-03 | 龙海波 | Application of compound and pharmaceutical composition thereof in prevention and treatment of renal fibrosis |
| CN111434336A (en) * | 2019-01-11 | 2020-07-21 | 深圳尚德药业科技有限公司 | Application of compound and pharmaceutical composition thereof in prevention and treatment of peritoneal fibrosis |
| CN111494366A (en) * | 2019-01-31 | 2020-08-07 | 洛阳尚德药缘科技有限公司 | Application of dimethylamino michelia lactone in preparing anti-aging drugs |
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| US20130109749A1 (en) * | 2010-04-23 | 2013-05-02 | Nankai University | Micheliolide derivatives, medicinal composition, producing method and usage thereof |
| CN103417532A (en) * | 2012-05-16 | 2013-12-04 | 天津尚德药缘科技有限公司 | Sesquiterpene lactone compound and uses of derivative thereof in preparation of drugs |
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| CN102234259A (en) * | 2010-04-23 | 2011-11-09 | 天津尚德药缘科技有限公司 | Sphaelactone derivatives, their pharmaceutical compositions, preparation method thereof and application thereof |
| US20130109749A1 (en) * | 2010-04-23 | 2013-05-02 | Nankai University | Micheliolide derivatives, medicinal composition, producing method and usage thereof |
| CN103417532A (en) * | 2012-05-16 | 2013-12-04 | 天津尚德药缘科技有限公司 | Sesquiterpene lactone compound and uses of derivative thereof in preparation of drugs |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108484550A (en) * | 2018-05-07 | 2018-09-04 | 中国人民解放军第四军医大学 | One kind having a smile on one's face lactone derivatives and its preparation method and application |
| CN110856716A (en) * | 2018-08-22 | 2020-03-03 | 龙海波 | Application of compound and pharmaceutical composition thereof in prevention and treatment of renal fibrosis |
| CN111434336A (en) * | 2019-01-11 | 2020-07-21 | 深圳尚德药业科技有限公司 | Application of compound and pharmaceutical composition thereof in prevention and treatment of peritoneal fibrosis |
| CN111494366A (en) * | 2019-01-31 | 2020-08-07 | 洛阳尚德药缘科技有限公司 | Application of dimethylamino michelia lactone in preparing anti-aging drugs |
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Effective date of registration: 20200511 Address after: Dongting Road 300457 in Tianjin Binhai Economic and Technological Development Zone No. 220 Co-patentee after: Xinyi Suntech Pharmaceutical Co., Ltd. Patentee after: TIANJIN INTERNATIONAL JOINT ACADEMY OF BIOMEDICINE Address before: Dongting Road 300457 in Tianjin Binhai Economic and Technological Development Zone No. 220 Co-patentee before: ACCENDATECH Co.,Ltd. Patentee before: TIANJIN INTERNATIONAL JOINT ACADEMY OF BIOMEDICINE |
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