CN106138061B - The compound and its preparation and purposes of prevention or decrease pulmonary fibrosis - Google Patents
The compound and its preparation and purposes of prevention or decrease pulmonary fibrosis Download PDFInfo
- Publication number
- CN106138061B CN106138061B CN201510158487.0A CN201510158487A CN106138061B CN 106138061 B CN106138061 B CN 106138061B CN 201510158487 A CN201510158487 A CN 201510158487A CN 106138061 B CN106138061 B CN 106138061B
- Authority
- CN
- China
- Prior art keywords
- group
- tki
- gefitinib
- pulmonary fibrosis
- melbine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
The present invention relates to a kind of biguanides and the compound of EGFR-TKI or ALK-TKI and application thereof, the compound can be used for preventing or slowing down interstitial pneumonia, the interstitial pneumonia generated when especially EGFR-TKI or ALK-TKI treatment non-small cell lung cancer, it can avoid the complication generated when EGFR-TKI or ALK-TKI treatment non-small cell lung cancer, the therapeutic effect for effectively improving EGFR-TKI or ALK-TKI reduces the generation and development of complication for patients.
Description
Technical field
The invention belongs to field of medical application, the in particular to compound and its preparation and use of prevention or decrease pulmonary fibrosis
On the way.
Background technique
Lung cancer is the highest malignant tumour of morbidity and mortality in global range；Non-small cell lung cancer (Non Small
Cell Lung Cancer, NSCLC) Zhan Suoyou cases of lung cancer 80%~85%.EGF-R ELISA (Epidermal
Growth factor receptor, EGFR) and anaplastic lymphoma kinase (anaplasticlymphoma kinase, ALK)
It plays an important role during the occurrence and development of NSCLC.EGFR tyrosine kinase inhibitor (Tyrosine kinase
Inhibitor, TKI) and ALK-TKI be representative targeted drug significant curative effect is achieved to specific NSCLC patient, still
Occur serious complication in TKI therapeutic process -- interstitial pneumonia；Although its disease incidence is low, once occur often to patient
Generate detrimental effects.
Gefitinib (gefitnib, Iressa) is the EGFR-TKI of representative, is by multinational approval and to be widely applied at present
Improving advanced stage with highly selective and hypotoxicity advantage in progress or the small molecule targeted drug of intractable NSCLC
The nearly late result of NSCLC and the effect in quality of life show encouraging prospects.Recent III phase clinical research knot
Fruit shows the NSCLC patient being mutated to EGFR, and a line can be mentioned compared with a line conventional chemotherapy using targeted drug Tarceva
High nearly 3 times of the Progression free survival time.
Interstitial pneumonia is Gefitinib and the rare but fatal adverse reaction of Tarceva.Japanese scholars Okamoto et
Al, which reports the first, leads to serious interstitial pneumonia due to the case of death because taking Gefitinib.It is exhaled after patient medication 8d
Difficulty is inhaled, it is dead after 13d is administered although giving large dosage of Patients Treated with Steroid.U.S. FDA the study found that
The U.S. is 1% using the incidence of patient's interstitial lung disease of Gefitinib, wherein about 1/3 patient dies of interstitial pneumonia.
Preventing interstitial pneumonia caused by EGFR-TKIs is the key that improve such patient's prognosis.Cortin is this kind of interstitial for the treatment of
One of property most important measure of pneumonia, but curative effect is unsatisfactory and side effect is larger.Therefore, if can find a kind of new, effectively
Measure prevention interstitial pneumonia generation, then for enhance TKI safety, improve patient's prognosis all will be with important section
Learn meaning and clinical value.
Research has shown that pulmonary fibrosis is the most basic pathological change of interstitial pneumonia, pathogenesis mainly includes into
The aggregation of fibrocyte and extracellular matrix excess deposition etc..Clinically majority is by preventing or weakening pulmonary fibrosis at present
It generates, to prevent the generation of interstitial pneumonia.
Melbine is a kind of classical drug for treating diabetes, and economic security, tolerance are good, due to its hypoglycemic mechanism
It is the intake for inhibiting gastrointestinal tract glucose, increases surrounding tissue to the sensibility of insulin, the glycogen for inhibiting liver, kidney excessive is different
It is raw, therefore to normal person without hypoglycemic effect；With going deep into for research, prior art discloses many melbine and other compositions
Combined compound；For example, CN103271907 discloses a kind of group for the treatment of diabetes being made of jamaicin and melbine
Close object；CN103860532 disclose it is a kind of by Memantine and melbine form for treating alzheimer dementia disease
Composition；In addition, technology is also disclosed by melbine and meglitinides or is formed with DPP-4 inhibitor etc. now
Compound.But the prior art yet there are no about the biguanides and Gefitinib etc. based on melbine
EGFR-TKI or ALK-TKI combination treats the report of interstitial pneumonia for preventing or weakening pulmonary fibrosis.
Summary of the invention
The present invention provides one kind for preventing or weakening by production when EGFR-TKI or ALK-TKI treatment non-small cell lung cancer
The compound and its preparation of raw pulmonary fibrosis.
The present invention provides a kind of compound prevented or weaken pulmonary fibrosis, wherein the compound includes that parts by weight are
The TKI of 2-4 parts of biguanides and 2-5 part；The TKI is selected from EGFR-TKI or ALK-TKI.
Further to improve, biguanides are selected from melbine and its salt, insoral or chloroguanide；The EGFR-TKI
Selected from Gefitinib, Tarceva, Conmana, Afatinib, AZD9291, CO-1686 or HM61713；The ALK-TKI
Buddhist nun or Ceritinib are replaced selected from gram azoles.
When biguanides are melbine, EGFR-TKI is Gefitinib, also, the parts by weight of melbine are 3
Part, it is the most obvious to the decrease effect of pulmonary fibrosis when the parts by weight of Gefitinib are 2 parts.
Another aspect of the present invention provides the oral preparation made of compound and auxiliary material, preferably tablet.
The tablet is the bilayer tablet being made of the release layer of label and package label, and the label is by melbine and assigns
Shape agent is made；The release layer is made of Gefitinib and auxiliary material.
Preferably, auxiliary material is powdered cellulose, beta-cyclodextrin, Arabic gum, crospovidone and superfine silica gel powder；Excipient
For lactitol, polyethylene maleic anhydride, ethylene glycol monostearate, crospovidone and myristyl alcohol；The bilayer tablet
Parts by weight are as follows:
Label:
Release layer:
After the present invention is by being made bilayer tablet for compound, after entering the tablet in vivo, Gefitinib is first played
Effect, later, melbine slowly plays a role, and the two plays the role for the treatment of non-small cell lung cancer, while can also be pre-
Generation that is anti-or weakening pulmonary fibrosis.After Gefitinib is mixed with powdered cellulose and beta-cyclodextrin, Gefitinib can be reduced
The precipitating of drug in aqueous solution, improves the bioavilability of Gefitinib；Simultaneously by melbine and slow-release material polyethylene
After sustained release label is made in maleic anhydride and ethylene glycol monostearate, label is made to dissolve out hundred in accumulation in 1,2,6,12 and 24 hour
Point rate respectively reaches 30-32%, 65-67%, 80-82%, 85-88% and 90% or more, make the double-layer tablets have drug release it is steady,
The effect slowly to release the drug, and the purpose that releases the drug for 24 hours to obtain can be reached.
Another aspect of the present invention provides the purposes of the compound, in preparation prevention or the drug for weakening pulmonary fibrosis
Application.The preferably described pulmonary fibrosis is by generating when EGFR-TKI or ALK-TKI treatment non-small cell lung cancer.
Compound provided by the invention can also be used in preparation prevention or slow down the drug of interstitial pneumonia, the chromic fibrous lung
Inflammation is the complication by generating when EGFR-TKI or ALK-TKI treatment non-small cell lung cancer.
Another aspect of the present invention additionally provides the application of tablet, which can be used for preparing prevention or weaken pulmonary fibrosis
Drug.Preferably, pulmonary fibrosis is by generating when EGFR-TKI or ALK-TKI treatment non-small cell lung cancer.
The beneficial effects of the present invention are, the present invention to provide a kind of biguanides and the compound of TKI and application thereof, should
Compound generates when can be used for preventing or weakening pulmonary fibrosis, especially EGFR-TKI or ALK-TKI treatment non-small cell lung cancer
Pulmonary fibrosis, thus play prevention or weaken interstitial pneumonia generation, can avoid EGFR-TKI or ALK-TKI treatment it is non-
The complication generated when Small Cell Lung Cancer effectively improves the therapeutic effect of EGFR-TKI or ALK-TKI, reduces complication for patients
Generation and development.
Detailed description of the invention
Fig. 1 is the result that immunofluorescence technique detects fibrosis indices in hepatic α-actin expression；
Fig. 2 is the expression that western blot technology detects Fibrosis Markers α-actin and COL1A1, detects TGF-β
The result of the expression of downstream key signal pathway protein；
Fig. 3 is the result that HE is dyed and Masson is dyed；
Fig. 4 is the result that Elisa method detects hydroxyproline content；
Fig. 5 is the result that immunohistochemistry detects α-actin expression；
Fig. 6 is the expression that western blot detects COL1A1, α-actin and TGF-β downstream key signal pathway protein
Result.
Specific embodiment mode
The compound of a kind of prevention of embodiment 1 or decrease pulmonary fibrosis
The compound includes the melbine of 3 parts by weight and the Gefitinib of 2 parts by weight.
A kind of bilayer tablet of embodiment 2
Label:
Release layer:
A kind of bilayer tablet of embodiment 3
Label:
Release layer:
Zoopery
1 melbine of experimental example, which is obviously reduced Gefitinib, stimulates the research of caused pulmonary fibrosis
1.1 experimental method
It is 6 groups, respectively control group by lung fibroblast strain HFL-1 point, P9-CM group, P9-CM+ Gefitinib group,
P9-CM+ Gefitinib+melbine group, R9-CM group, R9-CM+ melbine group；
Control group is without specially treated；P9-CM group gives the processing of the conditioned medium from PC-9 cell cell 48h；PC-9+
The conditioned medium that Gefitinib group gives the PC-9 cell handled from 30 μM of Gefitinib handles cell 48h；PC-9+ Ji is non-
The conditioned medium for giving the PC-9 cell handled from 30 μM of Gefitinib for Buddhist nun+melbine group combines 20 μM of melbine
Handle cell 48h；R9-CM group gives the processing of the conditioned medium from PC-9GR cell cell 48h；R9-CM+ melbine group
Give conditioned medium joint 20 μM of processing cell 48h of melbine from PC-9GR cell；
After 48h, using the expression of immunofluorescence technique detection fibrosis indices in hepatic α-actin；Using western blot skill
The expression of art detection Fibrosis Markers α-actin, COL1A1 and TGF-β downstream key signal pathway protein.
2.2 experimental result
From figure 1 it appears that compared with the control group, at P9-CM group, R9-CM group and P9-CM+ Gefitinib group
After the HFL-1 cell 48h of reason, the expression of α-actin albumen is obviously increased；Compared with P9-CM group, by P9-CM+ Gefitinib
After the HFL-1 cell 48h of group processing, the expression of α-actin albumen is also obviously increased, it follows that, Gefitinib is not only able to
The content of pulmonary fibrosis marker α-actin albumen is significantly improved, and P9-CM group can be further increased treated HFL-
The content of 1 intracellular α-actin albumen；Compared with P9-CM+ Gefitinib group, by P9-CM+ Gefitinib+melbine
The expression of group treated HFL-1 cell, α-actin albumen significantly reduces；It is double by R9-CM+ diformazan compared with R9-CM group
The expression of guanidine group treated HFL-1 cell, α-actin albumen significantly reduces；It follows that melbine not only can be significant
Weaken pulmonary fibrosis mark caused by the conditioned medium from PC-9 cell strain and the conditioned medium from PC-9GR cell strain
The expression of will object α-actin albumen；And pulmonary fibrosis marker α-actin egg caused by Gefitinib pierces can be obviously reduced
White expression.
From figure 2 it can be seen that compared with the control group, the HFL-1 handled by R9-CM group and P9-CM+ Gefitinib group
After cell 48h, the expression of COL1A1, α-actin, pSmad2, pSmad3, pSTAT3, pAKT and dpERK1/2 albumen obviously increase
Add；Compared with P9-CM group, after the HFL-1 cell 48h of P9-CM+ Gefitinib group processing, COL1A1, α-actin,
The expression of pSmad2, pSmad3, pSTAT3, pAKT and dpERK1/2 albumen obviously increases；Compared with P9-CM+ Gefitinib group,
By in P9-CM+ Gefitinib+melbine group treated HFL-1 cell, COL1A1, α-actin, pSmad2,
The expression of pSmad3, pSTAT3, pAKT and dpERK1/2 albumen is substantially reduced；It is double by R9-CM+ diformazan compared with R9-CM group
In guanidine group treated HFL-1 cell, COL1A1, α-actin, pSmad2, pSmad3, pSTAT3, pAKT and dpERK1/2 egg
White expression is substantially reduced；It follows that melbine can be obviously reduced Gefitinib and the condition from PC-9GR cell strain
The expression of pulmonary fibrosis marker α-actin and COL1A1 albumen caused by culture medium, significantly inhibit TGF-β signal path key
The expression of downstream albumen significantly inhibits the key mechanism of pulmonary fibrosis.
1.3 conclusion
From above it can be concluded that melbine can be obviously reduced pulmonary fibrosis caused by Gefitinib.
2 melbine of experimental example is obviously reduced the research of pulmonary fibrosis caused by the bleomycin of Gefitinib exacerbation
2.1 experimental material
6 week old health male SD rats 75 (are purchased from Third Military Medical University great Ping hospital Experimental Animal Center), weight
200g-210g；
Gefitinib is purchased from Britain Tocris Bioscience company；
Melbine is purchased from U.S. sigma company；
HE and Masson staining kit steps Newbiotics Inc's production by Foochow；
Enzyme-linked Immunosorbent Assay (enzyme linked immunosorbent assay, ELISA) kit, it is excellent by Wuhan
The production of Er Sheng company.
The preparation and grouping of 2.2 animal models
By 75 one Zhou Yihou of SD rat adaptable fed, it is divided into control group, bleomycin by the method for table of random number
Group, melbine group, Gefitinib group and Gefitinib co-administrated metformin group, every group each 15；
After 75 SD rats are used 1% yellow Jackets intraperitoneal injection of anesthesia respectively, lies on the back and be fixed on mouse plate, neck is gone
Ethanol disinfection after hair, longitudinal incision throat skin, exposure tracheae after chorista；
Wherein, control group injects 200 μ l of sterile saline, remaining each group to intratracheal injection bleomycin (5mg/kg,
5g/L), rapidly that animal is upright after injection, rotation makes medical fluid be evenly distributed in intrapulmonary；
Each experimental group rat starts also to need continuous gavage 21 days on the day of intratracheal injection, wherein control group and rich Lay are mould
Plain group is given physiological saline 2ml stomach-filling, and Gefitinib group gives Gefitinib 200mg/kg stomach-filling；Melbine group gives diformazan
Biguanides 300mg/kg stomach-filling；Gefitinib co-administrated metformin group gives Gefitinib 200mg/kg joint melbine 300mg/
Kg stomach-filling；The 21st day after intratracheal injection, kills mouse and take lung；
2.3 observation index
Left pneumolith wax slice row HE dyeing and Masson dyeing；The expression of immunohistochemistry detection α-actin；Take right lung
Elisa method detects hydroxyproline content；Western blot detects COL1A1, α-actin and TGF-β downstream key signal is logical
The expression of road albumen.
2.4 experimental result
From figure 3, it can be seen that after HE decoration method, compared with the control group, by bleomycin group and Gefitinib group
After the lung for handling mouse, lung septal thickening, pulmonary interstitial edema and fibrosis capillary injection amount are dramatically increased；It is next mould with winning
Plain group is compared, and after the lung of Gefitinib group processing mouse, lung septal thickening, pulmonary interstitial edema and fibrosis capillary fill
Blood volume also dramatically increases；Compared with bleomycin group, after the lung of melbine group processing mouse, between lung septal thickening, lung
Matter oedema and fibrosis capillary injection amount significantly reduce；Compared with Gefitinib group, by Gefitinib melbine
After combination group handles the lung of mouse, lung septal thickening, pulmonary interstitial edema and fibrosis capillary injection amount are significantly reduced；By
This show that melbine can significantly reduce lung septal thickening, pulmonary interstitial edema and fibrosis capillary injection, is obviously reduced lung
Degree of tissue damage；It can be obtained through masson dyeing, it is compared with the control group, small by bleomycin group and the processing of Gefitinib group
After the lung of mouse, lung fibrosis degree is aggravated；Compared with bleomycin group, after the lung of Gefitinib group processing mouse,
Lung fibrosis degree also aggravates；Compared with bleomycin group, after the lung of melbine group processing mouse, lung tissue is fine
Dimensionization degree obviously weakens；Compared with Gefitinib group, after the lung of Gefitinib co-administrated metformin group processing mouse, lung
Tissue fibrosis degree obviously weakens；It follows that melbine has been obviously reduced the degree of fibrosis of lung tissue.
Figure 4, it is seen that compared with the control group, by the lung of bleomycin group and Gefitinib group processing mouse
Afterwards, the content of hydroxyproline dramatically increases；Compared with bleomycin group, after the lung of Gefitinib group processing mouse, hydroxyl dried meat
The content of propylhomoserin also dramatically increases；Compared with bleomycin group, after the lung of melbine group processing mouse, hydroxyproline
Content significantly reduces；Compared with Gefitinib group, after the lung of Gefitinib co-administrated metformin group processing mouse, hydroxyl dried meat ammonia
The content of acid significantly reduces；It follows that melbine can significantly reduce the content of hydroxyproline, it is heavy to be obviously reduced tissue collagen
Product.
From figure 5 it can be seen that compared with the control group, after the lung of bleomycin group processing mouse, α-actin albumen
Expression obviously increase；Compared with bleomycin group, after the lung of Gefitinib group processing mouse, the table of α-actin albumen
Up to also obviously increasing, it follows that, Gefitinib can aggravate pulmonary fibrosis marker α-actin albumen caused by bleomycin
Expression；Compared with bleomycin group, after the lung of melbine group processing mouse, the expression of α-actin albumen is substantially reduced；
Compared with Gefitinib group, after the lung of Gefitinib co-administrated metformin group processing mouse, the expression of α-actin albumen is aobvious
Writing reduces；It follows that melbine can not only be obviously reduced pulmonary fibrosis marker α-actin egg caused by bleomycin
White expression；And pulmonary fibrosis marker α-actin egg caused by the bleomycin of Gefitinib exacerbation can be obviously reduced
White expression.
From fig. 6 it can be seen that compared with the control group, by the lung of bleomycin group and Gefitinib group processing mouse
Afterwards, the expression of COL1A1, α-actin, pSmad2, pSTAT3, pAKT and dpERK1/2 albumen obviously increase；With bleomycin group
Compare, after the lung of Gefitinib group processing mouse, COL1A1, α-actin, pSmad2, pSmad3, pSTAT3 and pAKT egg
White expression obviously increases；Compared with bleomycin group, after the lung of melbine group processing mouse, COL1A1, α-
The expression of actin, pSmad2, pSTAT3, pAKT and dpERK1/2 albumen is substantially reduced；Compared with Gefitinib group, by Ji
After the non-lung for Buddhist nun's co-administrated metformin group processing mouse, COL1A1, α-actin, pSmad2, pSTAT3, pAKT and dpERK1/
The expression of 2 albumen is substantially reduced；It follows that melbine can be obviously reduced pulmonary fibrosis marker α-caused by bleomycin
The expression of actin and COL1A1 albumen；And pulmonary fibrosis caused by the bleomycin of Gefitinib exacerbation can be obviously reduced
The expression of marker α-actin and COL1A1 albumen；And the expression of TGF-β signal path key downstream albumen is significantly inhibited,
Significantly inhibit the key mechanism of pulmonary fibrosis.
2.5 conclusion
From above it can be concluded that melbine can be obviously reduced pulmonary fibrosis caused by bleomycin；And it is obviously reduced
Pulmonary fibrosis caused by the bleomycin that Gefitinib aggravates.
Claims (3)
1. a kind of tablet, the tablet is made of the compound and auxiliary material for preventing or weakening pulmonary fibrosis, which is characterized in that described
Tablet is the bilayer tablet being made of the release layer of label and package label, and the label is made of melbine and excipient,
Excipient is lactitol, polyethylene maleic anhydride, ethylene glycol monostearate, crospovidone and myristyl alcohol；The quick-release
Layer is made of Gefitinib and auxiliary material, and auxiliary material is powdered cellulose, beta-cyclodextrin, Arabic gum, crospovidone and micro mist silicon
Glue；The parts by weight of the bilayer tablet are as follows:
Label:
Release layer:
2. a kind of application of tablet described in claim 1 in preparation prevention or the drug for weakening pulmonary fibrosis.
3. application as claimed in claim 2, which is characterized in that the pulmonary fibrosis is treated by EGFR-TKI or ALK-TKI
It is generated when non-small cell lung cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510158487.0A CN106138061B (en) | 2015-04-03 | 2015-04-03 | The compound and its preparation and purposes of prevention or decrease pulmonary fibrosis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510158487.0A CN106138061B (en) | 2015-04-03 | 2015-04-03 | The compound and its preparation and purposes of prevention or decrease pulmonary fibrosis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106138061A CN106138061A (en) | 2016-11-23 |
| CN106138061B true CN106138061B (en) | 2019-06-04 |
Family
ID=57337520
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510158487.0A Active CN106138061B (en) | 2015-04-03 | 2015-04-03 | The compound and its preparation and purposes of prevention or decrease pulmonary fibrosis |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106138061B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017205459A1 (en) | 2016-05-26 | 2017-11-30 | Kalyra Pharmaceuticals, Inc. | Egfr inhibitor compounds |
| CN109806262A (en) * | 2019-03-05 | 2019-05-28 | 大连医科大学 | Pyrimidine heterocyclic class compound, composition and its purposes for treating pulmonary fibrosis disease |
| CN113143925B (en) * | 2021-04-16 | 2022-03-25 | 浙江大学智能创新药物研究院 | Application of metformin hydrochloride in preparation of preparation for treating crizotinib cardiotoxicity |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1582928A (en) * | 2004-06-08 | 2005-02-23 | 天津药物研究院 | Medicinal composition and its use in treatment of diabetes |
| CN101772346A (en) * | 2007-04-02 | 2010-07-07 | 帕金森氏病研究院 | Methods and compositions for reduction of side effects of therapeutic treatments |
| CN102008472A (en) * | 2010-10-18 | 2011-04-13 | 中国科学院上海药物研究所 | Compound pioglitazone hydrochloride/metformin hydrochloride bilayer osmotic pump controlled release preparation and preparation method thereof |
| CN103316344A (en) * | 2013-04-07 | 2013-09-25 | 中国人民解放军第三军医大学第三附属医院 | EGFR-TKI compound for delaying or reversing drug-resistance in lung cancer treatment, and preparation thereof |
| CN103316343A (en) * | 2013-04-07 | 2013-09-25 | 中国人民解放军第三军医大学第三附属医院 | Application of biguanide based medicament in medicaments for delaying or reversing acquired drug-resistance of NSELC treated by EGFR-TKI |
-
2015
- 2015-04-03 CN CN201510158487.0A patent/CN106138061B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1582928A (en) * | 2004-06-08 | 2005-02-23 | 天津药物研究院 | Medicinal composition and its use in treatment of diabetes |
| CN101772346A (en) * | 2007-04-02 | 2010-07-07 | 帕金森氏病研究院 | Methods and compositions for reduction of side effects of therapeutic treatments |
| CN102008472A (en) * | 2010-10-18 | 2011-04-13 | 中国科学院上海药物研究所 | Compound pioglitazone hydrochloride/metformin hydrochloride bilayer osmotic pump controlled release preparation and preparation method thereof |
| CN103316344A (en) * | 2013-04-07 | 2013-09-25 | 中国人民解放军第三军医大学第三附属医院 | EGFR-TKI compound for delaying or reversing drug-resistance in lung cancer treatment, and preparation thereof |
| CN103316343A (en) * | 2013-04-07 | 2013-09-25 | 中国人民解放军第三军医大学第三附属医院 | Application of biguanide based medicament in medicaments for delaying or reversing acquired drug-resistance of NSELC treated by EGFR-TKI |
Non-Patent Citations (4)
| Title |
|---|
| AMPK与肺部炎症研究进展;玄玲玲;《药学学报》;20141231;第49卷(第8期);第1089-1096页 * |
| M. Kato1 等.Metformin Inhibits Bleomycin-Induced Pulmonary Fibrosis In Mice.《American Journal of Respiratory and Critical Medicine》.2014,第1962页. * |
| Metformin Inhibits Bleomycin-Induced Pulmonary Fibrosis In Mice;M. Kato1 等;《American Journal of Respiratory and Critical Medicine》;20140524;第1962页 * |
| Metformin inhibits TGF-b-induced myofibroblast differentiation through AMPK activation;Naoki Takasaka 等;《European Respiratory Journal》;20141231;第44卷;第3854页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106138061A (en) | 2016-11-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2155188B1 (en) | Methods and compositions for treating recurrent cancer | |
| RU2576609C2 (en) | Methods of treating pancreatic cancer | |
| JP6429292B2 (en) | Methods for the treatment of HER2 amplifying cancer | |
| KR20130109025A (en) | Methods of treating bladder cancer | |
| TWI750051B (en) | Composition for preventing or treating sars coronavirus 2 infection disease | |
| CN101829061A (en) | Taxol nanoparticle composition and preparation method thereof | |
| CN108348538A (en) | Include the cancer therapeutics and kit of gemcitabine liposome composition | |
| CN106138061B (en) | The compound and its preparation and purposes of prevention or decrease pulmonary fibrosis | |
| Wen et al. | Dual-ligand supramolecular nanofibers inspired by the renin-angiotensin system for the targeting and synergistic therapy of myocardial infarction | |
| WO2018113684A1 (en) | Use of fullerene structure in preparation of drug for treating leukemia | |
| EP2862575A1 (en) | Application of piceatannol-3'-o-b-d-glucopyranoside in preparation of medicaments for improving microcirculation block | |
| Wang et al. | Implantation of hydrogel-liposome nanoplatform inhibits glioblastoma relapse by inducing ferroptosis | |
| EP3969001A1 (en) | Bisfluoroalkyl-1,4-benzodiazepinone compounds for treating notch-activated breast cancer | |
| CN111920788B (en) | Medicine for inhibiting brain tumor and application thereof | |
| CN111773390B (en) | Application of medicine in preparing medicine for treating brain metastasis tumor and related diseases | |
| WO2013012771A2 (en) | Clinical applications of a recombinant human endostatin adenovirus (e10a) injection | |
| CN109481688A (en) | Pharmaceutical composition containing chemotherapeutics and Berbamine hydrochloride | |
| Milluzzo et al. | Cancer drugs and diabetic retinopathy: a dangerous, underestimated association | |
| WO2021143754A1 (en) | Combination for the treatment of cancer and application thereof | |
| CN110327354B (en) | Application of diosgenin in treatment and prevention of psoriasis | |
| CN102406641A (en) | Application of sorafenib to treatment of fibrosis | |
| CN115887473A (en) | Application of verbascoside compound or derivative thereof in preparation of bladder cancer resistant medicines | |
| WO2022179592A1 (en) | Combination therapeutic drug for acute myeloid leukemia | |
| TW202337469A (en) | Methods of treating small cell lung cancer | |
| CN101161234A (en) | Erlotinib sustained-release implants for treating entity knub |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |