CN106138020A - Biguanides prevents in preparation or weakens the application in the medicine of pulmonary fibrosis - Google Patents
Biguanides prevents in preparation or weakens the application in the medicine of pulmonary fibrosis Download PDFInfo
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Abstract
The present invention relates to the new application of a kind of biguanides, prevent or slow down the application in the medicine of pulmonary fibrosis particularly to biguanides in preparation, wherein, this pulmonary fibrosis is the complication produced during EGFR-TKI or ALK-TKI treatment nonsmall-cell lung cancer；It can avoid the complication that EGFR-TKI or ALK-TKI produces when treating nonsmall-cell lung cancer, is effectively improved the therapeutic effect of EGFR-TKI or ALK-TKI, reduces generation and the development of complication for patients.
Description
Technical field
The invention belongs to field of medical application, in preparation prevention or weaken particularly to biguanides
Application in the medicine of pulmonary fibrosis.
Background technology
Pulmonary carcinoma is the malignant tumor that M & M is the highest in global range.Nonsmall-cell lung cancer
(Non Small Cell Lung Cancer, NSCLC) accounts for the 80%-85% of all cases of lung cancer；
EGF-R ELISA (Epidermal growth factor receptor, EGFR) and
Anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (anaplasticlymphoma kinase, ALK) is NSCLC's
Occur evolution plays an important role.EGFR tyrosine kinase inhibitor (Tyrosine
Kinase inhibitor, TKI) and targeted drug that ALK-TKI is representative to specific NSCLC
Patient achieves significant curative effect, but it was discovered by researchers that there will be tight in TKI therapeutic process
Complication--the interstitial pneumonia of weight；There is no clinically at present effective prevention EGFR-TKI and
ALK-TKI causes the measure of interstitial pneumonia.Thus, it is found that effectively prevent arranging of interstitial pneumonia
Execute the safety applications for improving TKI, improve patient's prognosis there is very important scientific meaning
And clinical value.
Showing after deliberation, pulmonary fibrosis is the pathological change that interstitial pneumonia is most basic, its morbidity
Mechanism mainly includes fibroblastic gathering and extracellular matrix excess deposition etc..The most clinical
Upper majority is the generation by preventing or weaken pulmonary fibrosis, prevents the generation of interstitial pneumonia.
It is the treatment that representational biguanides is widely used in type 2 diabetes mellitus with metformin；
Along with deepening continuously of research, CN103371991 also discloses metformin and has prevention or treatment
The effect of hepatocarcinoma；CN103446080 discloses metformin and has reduction hepatitis B virus
The effect of sAg levels；CN102743364 discloses metformin and has treatment parkinson disease
Effect, etc..
Not yet it is found to have the document report biguanides based on metformin at present pre-in preparation
Anti-or weaken the application in the medicine of pulmonary fibrosis.
Summary of the invention
The present invention provides the new application of a kind of biguanides, i.e. biguanides in preparation prevention
Or weaken the application in the medicine of pulmonary fibrosis.
The biguanides that the present invention provides can prevent or weaken pulmonary fibrosis, can play further
Prevent or slow down generation and the development of interstitial pneumonia.
The biguanides of the present invention is selected from metformin and salt, phenformin or proguanil.
During the preferred metformin of biguanides, pre-to pulmonary fibrosis especially interstitial pneumonia
Anti-and to weaken effect more significantly.
Wherein, described pulmonary fibrosis is to be treated nonsmall-cell lung cancer by EGFR-TKI or ALK-TKI
Shi Yinqi's.
EGFR-TKI or ALK-TKI there will be serious complication in treatment NSCLC patient--
Interstitial pneumonia；Pulmonary fibrosis is the pathological change that interstitial pneumonia is most basic；In order to effectively
Control generation and the development of interstitial pneumonia, prevent or weaken the generation of pulmonary fibrosis, be to improve
Hidden danger in EGFR-TKI or ALK-TKI therapeutic process so that it is the effective measures that medication is safer.
The present invention is drawn by substantial amounts of experiment, and biguanides can prevent or weaken sending out of pulmonary fibrosis
Raw.
EGFR-TKI class medicine includes a lot, and the EGFR-TKI of the present invention is non-selected from the Ji of the first generation
For Buddhist nun, Erlotinib or Conmana；The Afatinib of the second filial generation；And the AZD9291 of the third generation,
CO-1686 or HM61713；ALK-TKI replaces Buddhist nun or Ceritinib selected from gram azoles.
Preferably, described EGFR-TKI is gefitinib.
The present invention is found surprisingly that, when the using dosage scope of metformin is 250-2000mg,
It is preferably 500-1000mg；Pulmonary fibrosis is weakened by it and preventive effect becomes apparent from.
Moreover, when the using dosage of metformin is 750mg, it is to lung fiber
Weakening of changing is the most obvious with preventive effect.
The slow releasing preparation that another aspect of the present invention provides metformin and adjuvant is made, this slow release
Preparation also can prevent or weaken pulmonary fibrosis.
Preferably slow releasing preparation is slow releasing tablet, and this slow releasing tablet includes metformin and adjuvant；Used
Adjuvant includes maltose alcohol, lauric acid, slow-release material, disintegrating agent and lubricant, wherein, slow
Releasing material is methyl methacrylate and the mixture of sorbitol anhydride tristearate, and disintegrating agent is
Microcrystalline Cellulose and the mixture of POLY-karaya, lubricant is magnesium stearate, and described slow releasing tablet is each
The weight portion of composition is as follows:
The Metformin Extended-release Tablets that the present invention provides adds maltose alcohol and lauric mixing
Thing, can make this slow releasing tablet have good stability, verifies through accelerated test and long term test
The character of this slow releasing tablet, the amount containing metformin, there are related substance, disintegration and dissolution equal
It is not changed in；In slow releasing tablet, add methyl methacrylate and sorbitol anhydride tristearate mixes
The slow-release material of compound, makes this slow releasing tablet the accumulation dissolution hundred of 1,2,6,12 and 24 hours
Point rate respectively reaches 33-35%, 68-70%, 80-82%, 87-89% and more than 90%, this slow release
Sheet has that release is steady, the effect of slow release, and can reach 24h release；At slow release
The microcrystalline Cellulose and the POLY-karaya that add in sheet can make this slow releasing tablet fater disintegration, during disintegrate
Limit, in 10min, arrives internal rapid-onset.
The beneficial effects of the present invention is:
1. the present invention provides the new application of a kind of biguanides, and this biguanides can be used for pre-
Preventing or weaken pulmonary fibrosis, biguanides not only can be obviously reduced transforming growth factor β
The pulmonary fibrosis that (TGF-β) causes, it is also possible to notable EGFR-TKI or ALK-TKI treatment is non-
The pulmonary fibrosis produced during small cell lung cancer, can be obviously reduced simultaneously EGFR-TKI or
The pulmonary fibrosis that the bleomycin that ALK-TKI increases the weight of causes；Thus play prevention or slow down chromic fibrous
The effect of pneumonia, it can avoid EGFR-TKI or ALK-TKI to produce when treating nonsmall-cell lung cancer
Complication, be effectively improved the therapeutic effect of EGFR-TKI or ALK-TKI, reduce patient also
Send out the generation of disease and send out.
Accompanying drawing explanation
Fig. 1 is the result that immunofluorescence technique detection pulmonary fibrosis index α-actin expresses；
Fig. 2 is for using western blot technology for detection pulmonary fibrosis mark α-actin and COL1A1
Expression and the result of expression of detection TGF-β downstream key signal pathway protein；
Fig. 3 is the result that immunofluorescence technique detection fibers index α-actin expresses；
Fig. 4 is the table of western blot technology for detection Fibrosis Markers α-actin and COL1A1
Reach, the result of the expression of detection TGF-β downstream key signal pathway protein；
Fig. 5 is HE dyeing and the result of Masson dyeing；
Fig. 6 is the result of Elisa method detection hydroxyproline content；
Fig. 7 is the result that SABC detection α-actin expresses；
Fig. 8 is western blot detection COL1A1, α-actin and TGF-β downstream key signal
The result of the expression of pathway protein.
Detailed description of the invention
1 one kinds of Metformin Extended-release Tablets of embodiment
Conventionally prepare.
2 one kinds of Metformin Extended-release Tablets of embodiment
Conventionally prepare.
Zoopery
Experimental example 1 metformin is obviously reduced the lung fibre that transforming growth factor β (TGF-β) causes
The research of dimensionization
1.1 experimental technique
Lung fibroblast strain HFL-1 is randomly divided into four groups, respectively matched group, TGF-β
Group, metformin group and TGF-β+metformin group；
Matched group is without special handling；TGF-β group gives TGF-β process, and (10 μ g/L, during effect
Between 48h)；Metformin group gives metformin and processes (10 μMs, action time 48h)；TGF-
β+metformin group gives TGF-β associating metformin and processes (10 μ g/L+10 μM, effect
Time 48h)；
After 48h, use the expression of immunofluorescence technique detection pulmonary fibrosis index α-actin；
Use western blot technology for detection pulmonary fibrosis mark α-actin, COL1A1 and TGF-
The expression of β downstream key signal pathway protein.
1.2 experimental result
From figure 1 it appears that compared with matched group, the lung fibroblast that TGF-β processes
After strain HFL-148h, the expression of α-actin albumen substantially increases；And it is only given metformin
After process, the expression of α-actin albumen does not has significant change；Compare with TGF-β group, TGF-
After β associating metformin processes, the expression of α-actin albumen significantly reduces；It follows that
Metformin can be obviously reduced the pulmonary fibrosis mark that transforming growth factor β (TGF-β) causes
The expression of thing α-actin albumen.
From figure 2 it can be seen that compared with matched group, the lung fibroblast that TGF-β processes
After strain HFL-148h, COL1A1, α-actin, pSmad3, pSTAT3, pAKT and dpERK1/2
The expression of albumen substantially increases；And after being only given metformin process, the expression of these albumen is bright
Aobvious reduction；Compare with TGF-β group, after TGF-β associating metformin processes, COL1A1,
α-actin, the expression of pSmad3, pSTAT3, pAKT and dpERK1/2 albumen significantly reduce；
It follows that metformin can be obviously reduced the lung that transforming growth factor β (TGF-β) causes
Fibrosis Markers α-actin and the expression of COL1A1 albumen, significantly inhibit TGF-β signal
The expression of path key downstream albumen, significantly inhibits the key mechanism of pulmonary fibrosis.
1.3 conclusion
From showing that metformin can be obviously reduced transforming growth factor β (TGF-β) above
The pulmonary fibrosis caused.
Experimental example 2 metformin is obviously reduced gefitinib stimulates the research of the pulmonary fibrosis caused
2.1 experimental technique
Lung fibroblast strain HFL-1 is divided into 6 groups, respectively matched group, P9-CM group,
P9-CM+ gefitinib group, P9-CM+ gefitinib+metformin group, R9-CM group, R9-CM+
Metformin group；
Matched group is without special handling；P9-CM group gives at the conditioned medium of PC-9 cell
Reason cell 48h；PC-9+ gefitinib group gives the PC-9 processed from gefitinib 30 μMs
The conditioned medium of cell processes cell 48h；PC-9+ gefitinib+metformin group give from
At the conditioned medium associating metformin 20 μMs of the PC-9 cell that gefitinib 30 μMs processes
Reason cell 48h；R9-CM group gives to process cell 48h from the conditioned medium of PC-9GR cell；
R9-CM+ metformin group gives to combine metformin from the conditioned medium of PC-9GR cell
20 μMs process cell 48h；
After 48h, use the expression of immunofluorescence technique detection fibers index α-actin；Adopt
With western blot technology for detection Fibrosis Markers α-actin, COL1A1 and TGF-β
The expression of downstream key signal pathway protein.
2.2 experimental result
From figure 3, it can be seen that compared with matched group, through P9-CM group, R9-CM group and
After the HFL-1 cell 48h that P9-CM+ gefitinib group processes, the expression of α-actin albumen is bright
Aobvious increase；Compare with P9-CM group, through the HFL-1 cell that P9-CM+ gefitinib group processes
After 48h, the expression of α-actin albumen the most substantially increases, it follows that, gefitinib is not only
The content of pulmonary fibrosis mark α-actin albumen can be significantly improved, and can be further
Improve the content of the HFL-1 intracellular α-actin albumen after P9-CM group processes；With
P9-CM+ gefitinib group compares, after P9-CM+ gefitinib+metformin group processes
HFL-1 cell, the expression of α-actin albumen significantly reduces；Compare with R9-CM group, pass through
HFL-1 cell after the process of R9-CM+ metformin group, the expression of α-actin albumen is significantly dropped
Low；It follows that the condition that metformin not only can be obviously reduced from PC-9 cell strain is trained
The pulmonary fibrosis mark that foster base and the conditioned medium from PC-9GR cell strain cause
The expression of α-actin albumen；And gefitinib can be obviously reduced and sting the pulmonary fibrosis caused
The expression of mark α-actin albumen.
Figure 4, it is seen that compared with matched group, non-through R9-CM group and P9-CM+ Ji
For Buddhist nun's group process HFL-1 cell 48h after, COL1A1, α-actin, pSmad2, pSmad3,
The expression of pSTAT3, pAKT and dpERK1/2 albumen substantially increases；Compare with P9-CM group, warp
After crossing the HFL-1 cell 48h that P9-CM+ gefitinib group processes, COL1A1, α-actin,
The expression of pSmad2, pSmad3, pSTAT3, pAKT and dpERK1/2 albumen substantially increases；With
P9-CM+ gefitinib group compares, after P9-CM+ gefitinib+metformin group processes
In HFL-1 cell, COL1A1, α-actin, pSmad2, pSmad3, pSTAT3, pAKT
Expression with dpERK1/2 albumen substantially reduces；Compare with R9-CM group, through R9-CM+ diformazan
Biguanide group process after HFL-1 cell in, COL1A1, α-actin, pSmad2, pSmad3,
The expression of pSTAT3, pAKT and dpERK1/2 albumen substantially reduces；It follows that metformin
Can be obviously reduced gefitinib and lung that the conditioned medium from PC-9GR cell strain causes is fine
Dimensionization mark α-actin and the expression of COL1A1 albumen, significantly inhibit TGF-β signal and lead to
The expression of key downstream, road albumen, significantly inhibits the key mechanism of pulmonary fibrosis.
2.3 conclusion
From showing that metformin can be obviously reduced the lung fiber that gefitinib causes above
Change.
Experimental example 3 metformin is obviously reduced the pulmonary fibrosis that the bleomycin that gefitinib increases the weight of causes
Research
3.1 experiment material
6 week old health male SD rats 75 are (dynamic purchased from the experiment of great Ping hospital of Third Military Medical University
Thing center), body weight 200g-210g；
Gefitinib, purchased from Tocris Bioscience company of Britain；
Metformin, purchased from sigma company of the U.S.；
HE and Masson staining kit, is stepped Newbiotics Inc by Foochow and produces；
Enzyme-linked Immunosorbent Assay (enzyme linked immunosorbent assay, ELISA) tries
Agent box, is produced by Wuhan You Ersheng company.
The preparation of 3.2 animal models and packet
After 75 SD rat adaptabilities are fed one week, it is divided into by the method for table of random number
Matched group, bleomycin group, metformin group, gefitinib group and gefitinib metformin
Combination group, often organizes each 15；
By 75 SD rats respectively with after 1% pentobarbital sodium intraperitoneal injection of anesthesia, lie on the back fixing
On Mus plate, ethanol disinfection after cervical region unhairing, longitudinal incision throat skin, sudden and violent after chorista
Leak pipe；
Wherein, matched group injects physiological saline solution 200 μ l, and remaining each group is injected to tracheal strips
Bleomycin (5mg/kg, 5g/L), rapidly that animal is upright after injection, rotate, make medicinal liquid
It is evenly distributed in lung；
Each experimental group rat started also to need continuous gavage 21 days in intratracheal injection the same day, wherein,
Matched group and bleomycin group give normal saline 2ml gavage, and gefitinib group gives Ji Fei and replaces
Buddhist nun's 200mg/kg gavage；Metformin group gives metformin 300mg/kg gavage；Ji Fei replaces
Buddhist nun's co-administrated metformin group gives gefitinib 200mg/kg associating metformin 300mg/kg and fills
Stomach；After intratracheal injection the 21st day, kill Mus and take lung；
3.3 observation index
The dyeing of left pneumolith wax slice row HE and Masson dyeing；SABC detection α-actin
Expression；Take right lung Elisa method detection hydroxyproline content；Western blot detects
COL1A1, α-actin and the expression of TGF-β downstream key signal pathway protein.
3.4 experimental result
From figure 5 it can be seen that after HE staining, compared with matched group, through rich next mould
After element group and gefitinib group process the lung of mice, lung septal thickening, pulmonary interstitial edema and fiber
Change capillary injection amount all to dramatically increase；Compare with bleomycin group, through gefitinib group
After processing the lung of mice, lung septal thickening, pulmonary interstitial edema and fibrosis capillary injection amount
Also dramatically increase；Compare with bleomycin group, after the lung that metformin group processes mice,
Lung septal thickening, pulmonary interstitial edema and fibrosis capillary injection amount all significantly reduce；With Ji
Non-compare for Buddhist nun's group, after the lung that gefitinib co-administrated metformin group processes mice, between lung
Every thickening, pulmonary interstitial edema and fibrosis capillary injection amount all significantly reduce；It follows that
Metformin can significantly reduce lung septal thickening, pulmonary interstitial edema and fibrosis capillary injection,
It is obviously reduced lung injury degree；Can draw through masson dyeing, compared with matched group, warp
After crossing the lung of bleomycin group and gefitinib group process mice, lung fibrosis degree increases the weight of；
Compare with bleomycin group, after the lung that gefitinib group processes mice, lung fibrosis
Degree also increases the weight of；Compare with bleomycin group, after the lung that metformin group processes mice,
Lung fibrosis degree substantially weakens；Compare with gefitinib group, through gefitinib diformazan
After biguanide combination group processes the lung of mice, lung fibrosis degree substantially weakens；It follows that
Metformin has been obviously reduced the fibrosis of lung tissue.
From fig. 6 it can be seen that compare with matched group, through bleomycin group and gefitinib
After group processes the lung of mice, the content of hydroxyproline dramatically increases；Compare with bleomycin group,
After the lung that gefitinib group processes mice, the content of hydroxyproline also dramatically increases；With rich
Bleomycin group compares, and after the lung that metformin group processes mice, the content of hydroxyproline shows
Write and reduce；Compare with gefitinib group, process mice through gefitinib co-administrated metformin group
Lung after, the content of hydroxyproline significantly reduces；It follows that metformin can significantly reduce
The content of hydroxyproline, is obviously reduced tissue collagen deposition.
It can be seen from figure 7 that compared with matched group, process mice through bleomycin group
After lung, the expression of α-actin albumen substantially increases；Compared with bleomycin group, non-through Ji
Organize the lung of process mice for Buddhist nun after, the expression of α-actin albumen the most substantially increases, it follows that,
Gefitinib can increase the weight of the table of the pulmonary fibrosis mark α-actin albumen that bleomycin causes
Reach；Compare with bleomycin group, after the lung that metformin group processes mice, α-actin
The expression of albumen substantially reduces；Compare with gefitinib group, join through gefitinib metformin
Process the lung of mice by group after, the expression of α-actin albumen significantly reduces；It follows that two
First biguanide not only can be obviously reduced the pulmonary fibrosis mark α-actin egg that bleomycin causes
White expression；And the lung fiber that the bleomycin that gefitinib increases the weight of causes can be obviously reduced
Change the expression of mark α-actin albumen.
As can be seen from Figure 8, compared with matched group, through bleomycin group and gefitinib
Group process mice lung after, COL1A1, α-actin, pSmad2, pSTAT3, pAKT and
The expression of dpERK1/2 albumen substantially increases；Compare with bleomycin group, through gefitinib group
After processing the lung of mice, COL1A1, α-actin, pSmad2, pSmad3, pSTAT3 and pAKT
The expression of albumen substantially increases；Compared with bleomycin group, process mice through metformin group
Lung after, COL1A1, α-actin, pSmad2, pSTAT3, pAKT and dpERK1/2 albumen
Expression substantially reduce；Compared with gefitinib group, through gefitinib co-administrated metformin group
After processing the lung of mice, COL1A1, α-actin, pSmad2, pSTAT3, pAKT and dpERK1/2
The expression of albumen substantially reduces；Cause it follows that metformin can be obviously reduced bleomycin
Pulmonary fibrosis mark α-actin and the expression of COL1A1 albumen；And can significantly subtract
The pulmonary fibrosis mark α-actin that the bleomycin that weak gefitinib increases the weight of causes and
The expression of COL1A1 albumen；And significantly inhibit the table of TGF-β signal path key downstream albumen
Reach, significantly inhibit the key mechanism of pulmonary fibrosis.
3.5 conclusion
From showing that metformin can be obviously reduced the lung fiber that bleomycin causes above
Change；And it is obviously reduced the pulmonary fibrosis that the bleomycin that gefitinib increases the weight of causes.
The impact of the pulmonary fibrosis that bleomycin is caused by the metformin of experimental example 4 various dose
4.1 experiment material
6 week old health male SD rats 90 are (dynamic purchased from the experiment of great Ping hospital of Third Military Medical University
Thing center), body weight 200g-210g；
Gefitinib, purchased from Tocris Bioscience company of Britain；
Metformin, purchased from sigma company of the U.S.；
HE and Masson staining kit, is stepped Newbiotics Inc by Foochow and produces；
Enzyme-linked Immunosorbent Assay (enzyme linked immunosorbent assay, ELISA) tries
Agent box, is produced by Wuhan You Ersheng company.
The preparation of 4.2 animal models and packet
After 90 SD rat adaptabilities are fed one week, it is divided into by the method for table of random number
Matched group, bleomycin group, metformin 1 group, metformin 2 groups, metformin 3 groups,
Metformin 4 groups, metformin 5 groups, metformin 6 groups and metformin 7 groups, often group
Each 10；
By 90 SD rats respectively with after 1% pentobarbital sodium intraperitoneal injection of anesthesia, lie on the back fixing
On Mus plate, ethanol disinfection after cervical region unhairing, longitudinal incision throat skin, sudden and violent after chorista
Leak pipe；
Wherein, matched group injects physiological saline solution 200 μ l, and remaining each group is injected to tracheal strips
Bleomycin (5mg/kg, 5g/L), rapidly that animal is upright after injection, rotate, make medicinal liquid
It is evenly distributed in lung；
Each experimental group rat started also to need continuous gavage 21 days in intratracheal injection the same day, wherein,
Matched group and bleomycin group give normal saline 2ml gavage；Metformin 1 group gives diformazan
Biguanide 200mg gavage；Metformin 2 groups gives metformin 250g gavage；Metformin 3
Group gives metformin 500mg gavage；Metformin 4 groups gives metformin 750mg gavage；
Metformin 5 groups gives metformin 1000mg gavage；Metformin 6 groups gives metformin
2000mg gavage；Metformin 7 groups gives after metformin 2250mg gavage intratracheal injection
21 days, kill Mus and take lung；Weigh, calculate Lung Exponent, morphological change classification alveolitis and lung fine
Dimensionization classification.
Alveolitis and pulmonary fibrosis degree are divided into 4 grades: 0 grade without significant change；1 grade of slight change
Changing, extent of disease is less than the 20% of full lung；2 grades of moderates change, and extent of disease accounts for full lung
20-50%；3 grades of severes change, and extent of disease accounts for more than the 50% of full lung.Elisa method detects
Hydroxyproline content.
4.3 experimental result
The impact of the pulmonary fibrosis that bleomycin is caused by the metformin of various dose is shown in Table 1.
The impact of the pulmonary fibrosis that bleomycin is caused by the metformin of table 1 various dose
Compared with bleomycin group, P*0.05, Pa0.01.
As can be seen from the table, metformin 1 group can be slight reduction Lung Exponent, fibrosis
Hydroxyproline content in classification and lung tissue；And metformin 2 groups can to metformin 7 groups
Significantly reduce hydroxyproline content in Lung Exponent, fibrosis grade and lung tissue；That is, along with two
The increase of first biguanide amount, in Lung Exponent, fibrosis grade and lung tissue, hydroxyproline content reduces
The most obvious, and when the consumption of metformin reaches 750mg, Lung Exponent, fibrosis grade
And the level that in lung tissue, hydroxyproline content reduces is already close to matched group, continue increments,
Little on hydroxyproline content impact in Lung Exponent, fibrosis grade and lung tissue.
Claims (10)
1. biguanides prevents in preparation or weakens the application in the medicine of pulmonary fibrosis.
Apply the most as claimed in claim 1, it is characterised in that described biguanides is pre-in preparation
Anti-or slow down the application in the medicine of interstitial pneumonia.
3. the application as described in claim 1-2 is arbitrary, it is characterised in that described biguanides selects
From metformin and salt, phenformin or proguanil.
Apply the most as claimed in claim 3, it is characterised in that described biguanides is that diformazan is double
Guanidine.
Apply the most as claimed in claim 1, it is characterised in that described pulmonary fibrosis is by EGFR-TKI
Or cause during ALK-TKI treatment nonsmall-cell lung cancer；Described EGFR-TKI non-replaces selected from lucky
Buddhist nun, Erlotinib, Conmana, Afatinib, AZD9291, CO-1686 or HM61713；
Described ALK-TKI replaces Buddhist nun or Ceritinib selected from gram azoles.
Apply the most as claimed in claim 5, it is characterised in that described EGFR-TKI is gefitinib.
Apply the most as claimed in claim 4, it is characterised in that the using dosage of described metformin
For 250-2000mg；It is preferably 500-1000mg.
Apply the most as claimed in claim 7, it is characterised in that the using dosage of described metformin
For 750mg.
Apply the most as claimed in claim 4, it is characterised in that described metformin and adjuvant are made
Slow releasing preparation in preparation prevention or the application in weakening the medicine of pulmonary fibrosis.
10. the slow releasing preparation prevented or weaken pulmonary fibrosis, it is characterised in that described slow release system
Agent is slow releasing tablet；Described slow releasing tablet includes metformin and adjuvant.
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| 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 |
| US10513509B2 (en) | 2016-05-26 | 2019-12-24 | Recurium Ip Holdings, Llc | EGFR inhibitor compounds |
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| US11098030B2 (en) | 2016-05-26 | 2021-08-24 | Recurium Ip Holdings, Llc | 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 |
| CN113143925A (en) * | 2021-04-16 | 2021-07-23 | 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 |
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