CN110251677A - For treating the pharmaceutical composition and its application of pulmonary fibrosis - Google Patents
For treating the pharmaceutical composition and its application of pulmonary fibrosis Download PDFInfo
- Publication number
- CN110251677A CN110251677A CN201910698156.4A CN201910698156A CN110251677A CN 110251677 A CN110251677 A CN 110251677A CN 201910698156 A CN201910698156 A CN 201910698156A CN 110251677 A CN110251677 A CN 110251677A
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- China
- Prior art keywords
- pharmaceutical composition
- administration group
- receptor antagonist
- converting enzyme
- nmda receptor
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 37
- 208000005069 pulmonary fibrosis Diseases 0.000 title claims abstract description 26
- 229940099433 NMDA receptor antagonist Drugs 0.000 claims abstract description 21
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 claims abstract description 21
- 239000005541 ACE inhibitor Substances 0.000 claims abstract description 19
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 claims abstract description 15
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 claims abstract description 15
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 claims description 12
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 claims description 12
- 229960004949 glycyrrhizic acid Drugs 0.000 claims description 12
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 claims description 12
- 239000001685 glycyrrhizic acid Substances 0.000 claims description 12
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- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
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- 239000007921 spray Substances 0.000 claims description 2
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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
- A61K31/13—Amines
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of for treating the pharmaceutical composition of pulmonary fibrosis, belongs to drug field.Pharmaceutical composition includes nmda receptor antagonist and angiotensin converting enzyme inhibitor.The weight proportion of the nmda receptor antagonist and angiotensin converting enzyme inhibitor is 1:1-100.The present invention also provides the related preparations comprising described pharmaceutical composition and its applications.
Description
Technical field
The present invention relates to a kind of for treating the pharmaceutical composition of pulmonary fibrosis, belongs to drug field.
Background technique
Pulmonary fibrosis (pulmonaryfibrosis, PF) is a kind of severe pulmonary disease, caused by being various different pathogenies
The final final result of interstitial lung disease (interstitiallungdisease, ILD) disease progression.The unknown ILD of a lot of reasons suffers from
Person finally makes a definite diagnosis and connective tissue disease (connectivetissuedisease, CTD) is related, referred to as between connective tissue disease correlation
Matter tuberculosis, wherein with systemic sclerosis disease incidence highest, up to 60-70%.Once there is pulmonary fibrosis in patient, in advance
It is very poor afterwards, it can be dead because of severe infection and/or respiratory failure in a short time.
The exact pathogenesis of present pulmonary fibrosis is unclear；But generally believe its with inflammatory reaction, cell factor,
Oxidative stress, alveolar epithelial cells damage are related with fibroblast proliferation.
Lung transplantation is the current treatment most effective means of pulmonary fibrosis, and single lung transplantation can improve symptom and life is delayed to improve
Quality of life.However, due to donated organs resource shortage, rejection, infection, complication and somewhat expensive, many patients without
Method carries out organ transplant, limits its application.
For not can be carried out the patient of lung transplantation treatment, clinically the drug therapy of lung fiber mainly has at present: sugared cortex
Hormone, immunosuppressor (cyclophosphamide), colchicin, cytokine class and its inhibitor, Angiotensin-Converting inhibit
Agent (captopril) and antioxidant etc..But the clinical study results of pulmonary fibrosis treatment show either cortin or exempt from
Epidemic disease inhibitor and other treatments, the curative effect for treating interstitial lung disease are poor；Said medicine treatment can not be effectively improved lung
The prognosis of fibrosis patients and life cycle.
Since the mechanism that pulmonary fibrosis occurs is complicated, participation factor is numerous, at present the still not breakthrough progress for the treatment of.
With the application of modern molecular biology technique, the research that deepens continuously of mechanism and pathophysiological change to the disease, no
The new trend of pulmonary fibrosis treatment will be become with the multiple target point synergistic treatment of access.
Summary of the invention
The first aspect of the present invention is to provide a kind of for treating the pharmaceutical composition of pulmonary fibrosis；It includes nmda receptor
Antagonist and angiotensin converting enzyme inhibitor.
In one embodiment, the nmda receptor antagonist is selected from: MK-801, ketamine, Memantine hydrochloride and/or Chinese mugwort
Fragrant ground that.Preferably, the nmda receptor antagonist is Memantine hydrochloride.
In another embodiment, the angiotensin converting enzyme inhibitor is selected from: captopril, enalapril,
Benazepil and/or Ramipril.Preferably, the angiotensin converting enzyme inhibitor is Ramipril.
In further carrying out scheme, the weight of the nmda receptor antagonist and angiotensin converting enzyme inhibitor
Proportion is 1:1-100.Preferably, the weight proportion of the nmda receptor antagonist and angiotensin converting enzyme inhibitor is 1:
5-20.It is highly preferred that the weight proportion of the nmda receptor antagonist and angiotensin converting enzyme inhibitor is 1:10.
It is preferably carried out in scheme at one, described pharmaceutical composition；It includes nmda receptor antagonist, angiotensins
Converting enzyme inhibitor and glycyrrhizic acid.The weight of the nmda receptor antagonist, angiotensin converting enzyme inhibitor and glycyrrhizic acid
Proportion is 1:5-20:0.1-10.Preferably, the nmda receptor antagonist, angiotensin converting enzyme inhibitor and glycyrrhizic acid
Weight proportion be 1:10:0.5-2.
The second aspect of the present invention is to provide a kind of pharmaceutical preparation comprising described pharmaceutical composition comprising the drug
Composition and pharmaceutically acceptable carrier.
In one embodiment, the pharmaceutical preparation is oral preparation, ejection preparation or spray.
The third aspect of the present invention is to provide application of the described pharmaceutical composition in preparation treatment pulmonary fibrosis medicine.
Present invention discover that nmda receptor antagonist and angiotensin converting enzyme inhibitor are inhibiting lung fibroblast to increase
Grow, alveolar epithelial cells damage conversion aspect produce apparent synergistic effect, after adding glycyrrhizic acid, it is this act synergistically into
The enhancing of one step.Described pharmaceutical composition has biggish market Development volue, can be used as treatment pulmonary fibrosis medicine and carries out deep layer
Secondary research and development.
Specific embodiment
Also the present invention further can be understood by embodiment, wherein the embodiment illustrates some preparations or user
Method.It is to be appreciated, however, that these embodiments do not limit the present invention.The change of the invention of currently known or further exploitation
Change is considered within the scope of the invention described herein and claimed below.
In the present invention, the synergistic effect generally refers to the biological effect after group subassembly, with based on be used alone
Expectation generates content required by given biological effect and compares when single component, and the activity of composition is apparently higher than single component
Synergistic effect.For popular, i.e., composition produces the biological effect of 1+1 > 2.
It is theoretical based on above-mentioned synergistic effect, can according to non-patent literature Chou T C.Theoretical basis,
experimental design,and computerized simulation of synergism and antagonism
In drug combination studies. [J] .Pharmacological Reviews, 2006,58 (3): in 621-681.
Whether there is collaboration, addition or antagonism, the multicomponent collaboration between the specific compound component of the standard places of proposition
Effect is calculated using following formula:
CI=A/Ae+B/Be+C/Ce
A, B and C refers to the dosage of three kinds of compound components in pharmaceutical composition, Ae、BeAnd CeRefer to individually using unification
The dosage of single component needed for polymer component reaches the inhibition efficiency of pharmaceutical composition, as CI (Combination Index)
When value is less than 1, and the smaller synergistic effect illustrated between component of CI value is stronger, illustrates that component has synergistic effect, CI value etc.
Illustrate that component has equivalent or antagonism in 1 or greater than 1 when.For specific experimental data processing, Calcusyn can be passed through
V2.0 (BIOSOFT, MO, USA) carries out related synergistic effect and calculates
Influence of the example 1 drug composition to proliferation of lung fibroblasts in rat
Induced lung fibroblast cell primary culture: 1-4 days after life Wistar suckling mouses are taken out, suckling mouse is impregnated in alcohol
After take out, be transferred in the glass culture dish on super-clean bench, taken out suckling mouse lung tissue by performing the operation after disinfection.It is placed in and fills
In the glass dish of PBS (containing 200U/ml mycillin), blood is washed.Lung is divided into several lobes of the lung with eye scissors, uses tweezers
The blood clot and fibr tissue for removing periphery cut off bronchus and blood vessel at hilus pulumonis with eye scissors, then with containing dual anti-PBS
It rinses 1 time.Lung tissue is shredded into 1mm3Size is added and contains dual anti-PBS, and the piping and druming of lung tissue block is opened, 15min is stood
Afterwards, the PBS more renewed.Aspirates tissue block is inoculated in culture bottle, every bottle of 20-25 block or so, every fritter spacing 0.5cm or so.
After tissue block places, gently culture bottle is overturn, allows bottom of bottle upward, the culture solution that 2ml or so is added into bottle (contains 10%
The DMEM low sugar culture medium of FBS, Hyclone, the U.S.), bottle cap is covered, by culture bottle slant setting in incubator, dry doubling wall 3h
Afterwards, culture bottle is slowly overturn and is laid flat, continue stationary culture.After the adherent 72h of paste block, visible a large amount of fibroblast is climbed under mirror
Out, tissue block is removed, continues culture 2-3 days, covers with, can pass on to cell.The lung fibroblast is spindle shape shape
State is often grown in circinate；Logarithmic growth phase cell is in for subsequent experimental after taking for 5 generations.
Test method: by the rat primary lung fibroblast of acquisition with 5 × 104A/ml is inoculated in 96 hole cell culture
In plate, every hole 200ul；Blank group directly adds DMEM culture medium, and administration group adds pastille culture medium, and (every group is added U.S. dollar respectively
Rigid amine and/or Ramipril), every group of 5 holes contain 5%CO at 37 DEG C2It is cultivated in incubator for 24 hours, cell is then measured using mtt assay
Activity calculates each group inhibiting rate.
Inhibiting rate=(blank group OD value-administration group OD value)/blank group OD value × 100%
Concrete outcome is as follows:
| Memantine hydrochloride | Ramipril | Inhibiting rate (%) | CI | |
| Blank group | - | - | 0 | - |
| Administration group 1 | 0.25ug/ml | - | 1.3±0.6 | - |
| Administration group 2 | 0.5ug/ml | - | 4.1±0.3 | - |
| Administration group 3 | 1ug/ml | - | 7.4±0.4 | - |
| Administration group 4 | - | 1ug/ml | 10.9±0.8 | - |
| Administration group 5 | - | 5ug/ml | 33.2±1.7 | - |
| Administration group 6 | - | 10ug/ml | 48.9±1.3 | - |
| Administration group 7 | 1ug/ml | 5ug/ml | 53.6±1.9 | 0.499 |
| Administration group 8 | 0.5ug/ml | 5ug/ml | 55.8±1.6 | 0.424 |
| Administration group 9 | 0.25ug/ml | 5ug/ml | 50.3±1.1 | 0.535 |
For pulmonary fibrosis disease, although pathogenic mechanism is still not very clear at present, its Major Clinical presentation is
Fibroblast hyper-proliferative and irradiation in all of pulmonary parenchyma cells are reduced in alveolar damage, lung tissue.Therefore how to inhibit lung at fiber finer
Born of the same parents' hyper-proliferative is the important target spot for treating pulmonary fibrosis.
ACEI is clinically more commonly to treat pulmonary fibrosis medicine at present, we combine document tune on this basis
It grinds, multiple pathway inhibitors that may play therapeutic effect to lung fiber has been screened, we have found that nmda receptor is short of money in preliminary experiment
Anti-agent and ACEI can produce certain synergistic effect, therefore our further detailed examination nmda receptor antagonist and ACEI
Synergy.It can be seen from the results above that the use in conjunction of nmda receptor antagonist and ACEI are to rat primary lung at fibre
The Proliferation Ability of dimension cell produces apparent synergistic effect, and best with weight ratio 1:10 effect.
On the basis of the above results, we have further investigated the joint of nmda receptor antagonist, ACEI and glycyrrhizic acid
Medication effect, method are same as above, and concrete outcome is as follows:
| Memantine hydrochloride | Ramipril | Glycyrrhizic acid | Inhibiting rate | CI | |
| Blank group | - | - | 0 | - | |
| Administration group 1 | - | - | 0.05ug/ml | 0.3 ± 0.1% | - |
| Administration group 2 | - | - | 0.25ug/ml | 1.2 ± 0.3% | - |
| Administration group 3 | - | - | 1ug/ml | 2.3 ± 0.6% | - |
| Administration group 7 | 0.5ug/ml | 5ug/ml | 0.05ug/ml | 57.4 ± 2.1% | 0.396 |
| Administration group 8 | 0.5ug/ml | 5ug/ml | 0.25ug/ml | 64.9 ± 1.8% | 0.283 |
| Administration group 9 | 0.5ug/ml | 5ug/ml | 1ug/ml | 65.2 ± 1.4% | 0.280 |
The above results show after adding glycyrrhizic acid in pharmaceutical composition that synergistic effect further enhances, wherein with U.S. dollar
Just, for the weight proportion of Ramipril and glycyrrhizic acid between 1:10:0.5-2, synergy is best.
The influence for people's alveolar epithelial cells fibrosis model that 2 pharmaceutical composition of embodiment induces TGF-β 1
For pulmonary fibrosis disease, fibroblast proliferation a part derives from its self duplication, and another part comes
Derived from alveolar epithelial cells under damaging condition, fibroblast is converted into through cytokine induction.Therefore in the examination of embodiment 1
It tests on the basis of result, we have further investigated people's alveolar epithelial cells fibrosis model that pharmaceutical composition induces TGF-β 1
Influence.
Test method: people's alveolar epithelial cells strain (A549) in logarithmic growth phase is taken, with 5 × 103A/ml is inoculated in
In 96 porocyte culture plates, every hole 200ul；It is placed in the DMEM culture medium containing 10%FBS and cultivates for 24 hours；Final concentration is added later
The TGF-β 1 (model group) of 10ng/ml, blank group addition are free of the equivalent culture medium of TGF-β 1, and after incubator culture 5 days, digestion is mentioned
Part cell tissue is taken, grinding then is carried out to cell tissue and is crushed and extracts albumen, and then is each using ELISA kit measurement
The content of I-type collagen and fibronectin in histone is carried out next with verifying whether model succeeds after as a result confirming
Step test.
To addition TGF-β 1 cell hole be grouped, administration group add various concentration pharmaceutical composition, model group and
Blank group adds equivalent culture medium, is then incubated for 72h.
1) using the influence of mtt assay measurement drug cell proliferation inhibiting rate.
Inhibiting rate=(model group OD value-administration group OD value)/model group OD value × 100%
2) using I-type collagen (ColI) and fibronectin in ELISA kit measurement group of cells supernatant
(FN) expression quantity
Experimental result:
1, the expression quantity variation of I-type collagen (ColI) and fibronectin (FN) after TGF-β 1 induces
| ColI | FN | |
| Blank group | 0.5±0.2ng/ml | 1.4±0.1ng/ml |
| Model group | 3.2±0.7ng/ml | 5.9±0.4ng/ml |
I-type collagen (ColI) and fibronectin (FN) are the weights that alveolar epithelial cells is converted to fibroblast
The marker wanted illustrates modeling it can be seen that ColI and FN expression quantity is significantly increased after the TGF-β 1 of 10ng/ml induces
Success can carry out the evaluating drug effect test of next step.
2, pharmaceutical composition induces TGF-β 1 influence of alveolar epithelial cells fibrosis
| Memantine hydrochloride | Ramipril | Glycyrrhizic acid | Inhibiting rate | CI | |
| Model group | - | - | - | 0 | - |
| Administration group 1 | 0.5ug/ml | - | - | 8.3 ± 0.6% | - |
| Administration group 2 | - | 5ug/ml | - | 40.8 ± 1.1% | - |
| Administration group 3 | - | - | 0.25ug/ml | 5.2 ± 0.4% | - |
| Administration group 4 | 0.5ug/ml | 5ug/ml | - | 62.9 ± 1.9% | 0.409 |
| Administration group 5 | 0.5ug/ml | 5ug/ml | 0.25ug/ml | 75.3 ± 1.6% | 0.233 |
3, pharmaceutical composition induces ColI the and FN expression quantity of alveolar epithelial cells to influence TGF-β 1
| ColI | FN | |
| Model group | 3.6±0.4ng/ml | 6.3±0.9ng/ml |
| Administration group 1 | 3.3±0.3ng/ml | 5.8±0.4ng/ml |
| Administration group 2 | 1.9±0.6ng/ml* | 2.7±0.5ng/ml** |
| Administration group 3 | 3.5±0.5ng/ml | 6.1±0.4ng/ml |
| Administration group 4 | 1.2±0.3ng/ml** | 2.1±0.6ng/ml** |
| Administration group 5 | 0.8±0.1ng/ml** | 1.6±0.3ng/ml** |
It is examined through Oneway-ANOVA, compared with model group, * and * * represents P < 0.05 and P < 0.01
ColI and FN is not only fibroblastic transformation marker object, and it is also lung tissue extracellular matrix ECM
Important component, and ECM is also an important pathogenesis of pulmonary fibrosis.It can be seen from the results above that pharmaceutical composition
The fibroblast proliferation converted through alveolar epithelial cells can not only be inhibited and or inhibit fibroblasts to secrete
ColI and FN.
The influence for the Model of Bleomycin-induced Pulmonary Fibrosis that 3 pharmaceutical composition of embodiment induces bleomycin
Test method: taking the Wistar rat of 200g or so, random to be grouped, respectively control group, model group and administration group；
Rat Fast starts modeling after one night, all rats are faced upward rat after anesthesia using the chloral hydrate anesthesia of intraperitoneal injection 10%
Clinostatism is fixed on mouse plate, cuts the skin of neck, and blunt separation musculi colli sufficiently exposes tracheae, model group and administration group
To the bleomycin of intratracheal disposable injection 5mg/kg, medical fluid is made to be evenly distributed in intrapulmonary, establishes big popular pulmonary fibrosis model,
The physiological saline of control group injection equivalent.After rat is awake, start intraperitoneal injection, once a day, model group and control group
Same amount of normal saline is injected, successive administration 3 weeks, rat is put to death and lung tissue is taken to carry out coherent detection.
Each administration group dosage is as follows:
| Memantine hydrochloride | Ramipril | Glycyrrhizic acid | |
| Administration group 1 | 10mg/kg | ||
| Administration group 2 | 10mg/kg | ||
| Administration group 3 | 10mg/kg | ||
| Administration group 4 | 0.91mg/kg | 9.09mg/kg | |
| Administration group 5 | 0.87mg/kg | 8.7mg/kg | 0.43mg/kg |
Testing index:
1) before putting to death rat, lavation is carried out to the left lung of rat with Sterile Saline, is flushed three times, collect bronchoalveolar lavage
Liquid, after the sample filtered through gauze of part, centrifugation obtains cell mass, smear, and Rui Shi-Giemsa stain is taken to be added dropwise in being coated with cell
On slide, it is placed at room temperature for rear microscopy, obtains the percentage of lymphocyte and neutrophil leucocyte.Another irrigating solution sample uses
BCA measures protein content.
2) after taking lung tissue, weighing calculates paragonimus cyst.
3) after calculating paragonimus cyst, lung tissue segment is taken, grinding is broken, collects albumen, measures hydroxyl dried meat using ELISA kit
The content of amino acid.
As a result as follows:
1, pharmaceutical composition influences the BAL fluid of Model of Bleomycin-induced Pulmonary Fibrosis
| Lymphocyte (%) | Neutrophil leucocyte (%) | |
| Control group | 2.7±1.5 | 5.3±2.3 |
| Model group | 17.2±4.1## | 14.3±3.6## |
| Administration group 1 | 15.7±2.9 | 12.8±2.5 |
| Administration group 2 | 11.2±3.2* | 10.7±3.4 |
| Administration group 3 | 16.7±2.6 | 13.6±4.2 |
| Administration group 4 | 8.4±3.7** | 8.9±2.2** |
| Administration group 5 | 6.3±3.4** | 7.1±0.4** |
It is examined through Oneway-ANOVA, compared with model group, * and * * represents P < 0.05 and P < 0.01
2, pharmaceutical composition influences the BAL fluid of Model of Bleomycin-induced Pulmonary Fibrosis
| Total protein (g/L) | |
| Control group | 0.17±0.06 |
| Model group | 1.34±0.19## |
| Administration group 1 | 1.22±0.14 |
| Administration group 2 | 0.85±0.17* |
| Administration group 3 | 1.28±0.21 |
| Administration group 4 | 0.53±0.09** |
| Administration group 5 | 0.38±0.11** |
| Paragonimus cyst | |
| Control group | 7.21±0.74 |
| Model group | 16.37±1.82## |
| Administration group 1 | 15.14±1.58 |
| Administration group 2 | 12.61±2.03* |
| Administration group 3 | 15.82±1.94 |
| Administration group 4 | 10.53±1.16** |
| Administration group 5 | 8.81±1.49** |
It is examined through Oneway-ANOVA, compared with model group, * and * * represents P < 0.05 and P < 0.01
3, influence of the pharmaceutical composition to paragonimus cyst
It is examined through Oneway-ANOVA, compared with model group, * and * * represents P < 0.05 and P < 0.01
4, the influence that pharmaceutical composition expresses hydroxyproline
| Hydroxyproline (g/mg) | |
| Control group | 1.17±0.32 |
| Model group | 5.61±0.86## |
| Administration group 1 | 5.03±0.91 |
| Administration group 2 | 4.52±0.53* |
| Administration group 3 | 5.23±0.61 |
| Administration group 4 | 3.17±0.44** |
| Administration group 5 | 2.04±0.39** |
It is examined through Oneway-ANOVA, compared with model group, * and * * represents P < 0.05 and P < 0.01
Hydroxyproline content in collagen is most, and collagen is the main of collagenous fibres in composition connective tissue
Ingredient.Therefore hydroxyproline content can be shown that the distribution situation of collagen in lung tissue.The above results show pharmaceutical composition
Group significantly inhibits in inhibiting hydroxyproline expression, and is substantially better than simple group.
The content of present invention merely illustrates claimed some specific embodiments, one of them or more skill
Documented technical characteristic can be combined with arbitrary one or more technical solutions in art scheme, these are combined and obtain
Technical solution also in the application protection scope, the technical solution just as obtained from these are combined is disclosed in the present invention
It is specifically recorded in content the same.
Claims (10)
1. a kind of for treating the pharmaceutical composition of pulmonary fibrosis；It includes nmda receptor antagonist and Angiotensin-Converting
Inhibitor.
2. pharmaceutical composition according to claim 1, which is characterized in that the nmda receptor antagonist is selected from: MK-801,
Ketamine, Memantine hydrochloride and/or ifenprodil.Preferably, the angiotensin converting enzyme inhibitor is Ramipril.
3. pharmaceutical composition according to claim 1, which is characterized in that the angiotensin converting enzyme inhibitor choosing
From: captopril, enalapril, benazepil and/or Ramipril.Preferably, the angiotensin converting enzyme inhibitor
For Ramipril.
4. pharmaceutical composition according to claim 1, which is characterized in that the nmda receptor antagonist and angiotensins
The weight proportion of converting enzyme inhibitor is 1:1-100.
5. pharmaceutical composition according to claim 4, which is characterized in that the nmda receptor antagonist and angiotensins
The weight proportion of converting enzyme inhibitor is 1:5-20.
6. pharmaceutical composition according to claim 1, which is characterized in that described pharmaceutical composition；It includes nmda receptor
Antagonist, angiotensin converting enzyme inhibitor and glycyrrhizic acid.
7. pharmaceutical composition according to claim 6, which is characterized in that the nmda receptor antagonist, angiotensins
The weight proportion of converting enzyme inhibitor and glycyrrhizic acid is 1:5-20:0.1-10.
8. a kind of pharmaceutical preparation comprising claim 1-7 described pharmaceutical composition comprising described pharmaceutical composition and pharmacy
Upper acceptable carrier.
9. pharmaceutical preparation according to claim 8, which is characterized in that the pharmaceutical preparation is oral preparation, ejection preparation
Or spray.
10. application of the claim 1-7 described pharmaceutical composition in preparation treatment pulmonary fibrosis medicine.
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