CN107714688A - The application of Decahydro-3,6,9-tris(methylene)azuleno[4,5-b and its preparation in anti-fibrosis drug is prepared - Google Patents
The application of Decahydro-3,6,9-tris(methylene)azuleno[4,5-b and its preparation in anti-fibrosis drug is prepared Download PDFInfo
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- CN107714688A CN107714688A CN201711013335.7A CN201711013335A CN107714688A CN 107714688 A CN107714688 A CN 107714688A CN 201711013335 A CN201711013335 A CN 201711013335A CN 107714688 A CN107714688 A CN 107714688A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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Abstract
The invention discloses the application of Decahydro-3,6,9-tris(methylene)azuleno[4,5-b and its preparation in anti-fibrosis drug is prepared, experiment proves, Decahydro-3,6,9-tris(methylene)azuleno[4,5-b substantially mitigates the pulmonary alveolitis and pulmonary fibrosis degree of the pulmonary fibrosis model mouse of bleomycin structure, the secretion of collagen and deposition in the lung tissue of fibrosis can be suppressed, so as to prevent, treat pulmonary fibrosis.
Description
Technical field
The present invention relates to the application of Decahydro-3,6,9-tris(methylene)azuleno[4,5-b, is being prepared more particularly, to Decahydro-3,6,9-tris(methylene)azuleno[4,5-b and its preparation
Application in anti-fibrosis drug.
Background technology
Idiopathic pulmonary fibrosis (idiopathic pulmonary fibrosis, IPF) refer to alveolar epithelial cells by
Repaired extremely after damage, cause proliferation of lung fibroblast to be converted to myofibroblast, Extracellular Matrix Secretion is excessive, collagen
Deposition, alveolar structure change, and ultimately form fibrosis.Not yet completely clearly, research at present is thought should with oxidation for its pathogenesis
Sharp, inflammatory reaction, Humoral immunity feritin-angiotensins-RAAS (RAAS) are closely related.Oxidative stress produced
More ROS causes pulmonary epithelial cells necrosis to induce inflammatory reaction and cytokine network imbalance promotion interleukins, conversion life
The increase such as long factor-beta 1 (TGF-β 1), CTGF (CTGF), inflammatory reaction can produce active oxygen metabolic product again
And a series of inflammatory mediators aggravate inflammation and pulmonary epithelial cells necrosis, form vicious circle, aggravate pulmonary fibrosis progressive.Mesh
Before think that RAAS systems are played an important role in pulmonary fibrosis process, angiotensin converting enzyme (Angiotensin
Converting enzyme, ACE) angiotensinⅠ (Angiotensin I, Ang I) can be hydrolyzed to angiotensins
II (Angiotensin II, Ang II), Ang II play an important role in the generation, evolution of various inflammation.
And aldosterone can stimulate cell mitogen and collage synthesis, promotion organization cell increases, and increases collagen deposition, enhancing
The repair ability of tissue.Patient is diagnosed as IPF, and less than 3 years from respiratory failure to death, survival rate is about 20% within 5 years,
Treatment is still without specific drug at present.
Decahydro-3,6,9-tris(methylene)azuleno[4,5-b (dehydrocostus lactone) is by China feverfew banksia rose (Aucklandia
Lappa Decne.) dry root in the main component isolated, be terpenoid.
At present, there has been no the report that dehydro-α-curcumene is applied in anti-fibrosis drug is prepared.
The content of the invention
The purpose of the present invention is overcome the deficiencies in the prior art, there is provided dehydro-α-curcumene is preparing anti-fibrosis drug
In application.
Second object of the present invention is to provide the pharmaceutical preparation containing dehydro-α-curcumene and is preparing anti-fibrosis medicine
In application.
Technical scheme is summarized as follows：
Application of the Decahydro-3,6,9-tris(methylene)azuleno[4,5-b in anti-fibrosis drug is prepared.
Application of the pharmaceutical preparation containing Decahydro-3,6,9-tris(methylene)azuleno[4,5-b in anti-fibrosis medicine is prepared.
The formulation of the pharmaceutical preparation is preferably tablet, capsule, granule or injection.
It is demonstrated experimentally that Decahydro-3,6,9-tris(methylene)azuleno[4,5-b substantially mitigates the pulmonary alveolitis of the pulmonary fibrosis model mouse of bleomycin structure
And pulmonary fibrosis degree, the secretion of collagen and deposition in the lung tissue of fibrosis can be suppressed, so as to prevent, treat pulmonary fibrosis.
Brief description of the drawings
Fig. 1 is mouse lung tissue pathological section (× 200) after Decahydro-3,6,9-tris(methylene)azuleno[4,5-b acts on 7 days.
Fig. 2 is mouse lung tissue pathological section (× 200) after Decahydro-3,6,9-tris(methylene)azuleno[4,5-b acts on 21 days.
Fig. 3 is mouse lung tissue pathological section scoring after Decahydro-3,6,9-tris(methylene)azuleno[4,5-b effect.
Fig. 4 is mouse lung tissue Masson dyeing observations (× 200) after Decahydro-3,6,9-tris(methylene)azuleno[4,5-b acts on 7 days.
Fig. 5 is mouse lung tissue Masson dyeing observations (× 200) after Decahydro-3,6,9-tris(methylene)azuleno[4,5-b acts on 21 days.
Fig. 6 is mouse lung tissue Masson dyeing scorings after Decahydro-3,6,9-tris(methylene)azuleno[4,5-b effect.
Embodiment
With reference to specific embodiment, the present invention is further illustrated.
Shown in Decahydro-3,6,9-tris(methylene)azuleno[4,5-b such as formula (I)：
Pharmacological experimental data：
1. materials and methods
Material
4 week old SPF levels male mouse of kunming 80 (Beijing Vital River Experimental Animals Technology Co., Ltd.), body weight (21
±2.0)g；
Dehydro-α-curcumene powder (commercially available), normal saline is used before administration.
Pirfenidone：Tianjin Kingyork Pharmaceutical Co., Ltd. (Chinese medicines quasi-word H12020392)；
Hydrochloride for injection bleomycin, Nippon Kayaku K. K, lot number 640412, import of drugs registration certificate number：
H20090885；Superoxide dismutase (SOD) testing cassete, glutathione (GSH) kit and hydroxyproline (HYP) kit
It is purchased from Nanjing and builds up Graduate School of Engineering；
Method
1.1 packets and modeling mouse are randomly divided into 5 groups：Control group (N), model group (M), positive drug pirfenidone
(50mg·kg-1·d-1) group (P), the low (10mgkg of Decahydro-3,6,9-tris(methylene)azuleno[4,5-b-1·d-1) group (2 (10)), Decahydro-3,6,9-tris(methylene)azuleno[4,5-b
Height (20mgkg-1·d-1) group (2 (20)), every group 16.
N groups tracheal strips instill 0.9% sodium chloride injection, and remaining each group mouse transtracheal gives bleomycin solution
5mg·kg-1·d-1Establish pulmonary fibrosis model.
The 2nd day each group gives pirfenidone (50mgkg respectively after modeling-1·d-1), Decahydro-3,6,9-tris(methylene)azuleno[4,5-b (10,
20mg·kg-1·d-1) gavage.N groups fill isometric 0.9% sodium chloride injection with M groups.
1.2 samples obtain with analyze the 7th day after treatment, the 21st day every group put to death 8 materials.Each group eyeball of mouse
Blood is taken, serum is left and taken and detects.Then take off neck and put to death quick opening mouse thoracic cavity, cut the middle lobe of right lung, 4% neutral formalin is consolidated
It is fixed, do HE dyeing and Masson coloring pathological sections.Remaining -80 DEG C of lung tissue, which freezes, makees index of correlation measure.
1.3 pathologic state colonies observation observation pulmonary morphology, with reference to the methods of Szapiel, dyes to lung tissue HE and ties
Fruit carries out alveolar inflammation scoring.
Pulmonary alveolitis is classified and standards of grading:
0 grade：Without pulmonary alveolitis, 0 point is remembered；
1 grade：Slight pulmonary alveolitis, alveolar septa infiltration is seen under mirror and is thickened, but extent of disease is no more than full lung 20%, alveolar knot
Significant change does not occur for structure, remembers 1 point；
2 grades：Moderate pulmonary alveolitis, alveolar inflammation lesion area account for the 20%-50% of full lung, remember 2 points；
3 grades：Severe pulmonary alveolitis, extent of disease exceed the 50% of full facies pulmonalis cordis product, the visible inflammatory cell of alveolar space and red blood cell,
3 points of note.
Graphical analysis is carried out to Masson coloration results with Image ProP lus softwares, every section randomly selects 5
Not overlapped view (× 200), evaluate pulmonary fibrosis degree.Pulmonary fibrosis degree=pulmonary fibrosis area/lung tissue area ×
100%.
1.4 statistical procedures carry out single factor test side using statistic software SPSS 17.0 to the experimental data at same time point
Difference is analysed, P<0.05 is that difference is statistically significant.
2. result
As shown in Figure 1, 2, 3, each time point alveolar structure of N group mouse is clear for 2.1 mouse lung tissue HE dyeing and inflammatory score
Clear, alveolar septum is normal.M groups mouse was destroyed in the 7th day alveolar structure, and inflammatory cell infiltration, alveolar septum is broadening, was had a small amount of red
Cell oozes out, and has substantial amounts of macrophage, the significantly raised (P of alveolar inflammation scoring<0.05)；Alveolar inflammation has subtracted within 21st day
Gently, but still there is massive inflammatory cells infiltrated.Compared with M groups, Decahydro-3,6,9-tris(methylene)azuleno[4,5-b group and positive controls pirfenidone group are small
Mouse alveolar structure, which destroys, to be mitigated, and alveolar inflammation degree mitigates (P<0.05).(Fig. 1,2,3).
Performance lung compared with control group under 2.2 mouse lung tissue Masson dyeing and Rating Model group mouse lung tissue light microscopic
It is broadening to steep interstitial, extracellular matrix also obvious hyperplasia, has and largely contaminates green collagen fiber hyperplasia deposition, form extensive fiber
Change；And Decahydro-3,6,9-tris(methylene)azuleno[4,5-b group and positive controls mouse pulmonary fibrosis degree significantly mitigate compared with model group；Dehydrogenation wood
Fragrant hydrocarbon lactone group mouse lung tissue Collagen fiber deposition and positive controls (pirfenidone group) no difference of science of statistics (Fig. 4,5,
6)。
In summary, Decahydro-3,6,9-tris(methylene)azuleno[4,5-b substantially mitigates the pulmonary alveolitis of the pulmonary fibrosis model mouse of bleomycin structure
And pulmonary fibrosis degree, the secretion of collagen and deposition in the lung tissue of fibrosis can be suppressed, so as to prevent, treat pulmonary fibrosis.
According to《Chinese Pharmacopoeia》Described in common medicinal supplementary material, it will be apparent to those skilled in the art that Decahydro-3,6,9-tris(methylene)azuleno[4,5-b
It can be combined with various pharmaceutically acceptable pharmaceutic adjuvants, the pharmaceutical preparation of pharmaceutically available various formulations, such as piece is made
Agent, capsule, granule or injection etc., and said preparation equally has effect to preventing or treating pulmonary fibrosis.
One embodiment of invention is described in detail above, but the content is only the preferable implementation of the present invention
Example, it is impossible to be considered as the practical range for limiting the present invention.All equivalent changes made according to the present patent application scope and improvement
Deng, all should still belong to the present invention patent covering scope within.
Claims (3)
1. application of the Decahydro-3,6,9-tris(methylene)azuleno[4,5-b in anti-fibrosis drug is prepared.
2. application of the pharmaceutical preparation containing Decahydro-3,6,9-tris(methylene)azuleno[4,5-b in anti-fibrosis medicine is prepared.
3. application according to claim 2, it is characterised in that the formulation of the pharmaceutical preparation is tablet, capsule, particle
Agent or injection.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711013335.7A CN107714688A (en) | 2017-10-25 | 2017-10-25 | The application of Decahydro-3,6,9-tris(methylene)azuleno[4,5-b and its preparation in anti-fibrosis drug is prepared |
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| CN201711013335.7A CN107714688A (en) | 2017-10-25 | 2017-10-25 | The application of Decahydro-3,6,9-tris(methylene)azuleno[4,5-b and its preparation in anti-fibrosis drug is prepared |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140271923A1 (en) * | 2013-03-14 | 2014-09-18 | Christopher Brian Reid | Compositions & formulations for preventing and treating chronic diseases that cluster in patients such as cardiovascular disease, diabetes, obesity, polycystic ovary syndrome, hyperlipidemia and hypertension, as well as for preventing and treating other diseases and conditions |
| CN107041882A (en) * | 2016-10-31 | 2017-08-15 | 中国人民武装警察部队后勤学院 | Application of the corter pseudolaricis acetic acid in anti-fibrosis drug is prepared |
-
2017
- 2017-10-25 CN CN201711013335.7A patent/CN107714688A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140271923A1 (en) * | 2013-03-14 | 2014-09-18 | Christopher Brian Reid | Compositions & formulations for preventing and treating chronic diseases that cluster in patients such as cardiovascular disease, diabetes, obesity, polycystic ovary syndrome, hyperlipidemia and hypertension, as well as for preventing and treating other diseases and conditions |
| CN107041882A (en) * | 2016-10-31 | 2017-08-15 | 中国人民武装警察部队后勤学院 | Application of the corter pseudolaricis acetic acid in anti-fibrosis drug is prepared |
Non-Patent Citations (2)
| Title |
|---|
| 于红: "核转录因子NF-κB与肺纤维化", 《中国实用内科杂志》 * |
| 魏华等: "木香有效成分及药理作用研究进展", 《中草药》 * |
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Application publication date: 20180223 |