CN109512826A - Labetalol prevents and treats the purposes in fibrotic disease drug in preparation - Google Patents
Labetalol prevents and treats the purposes in fibrotic disease drug in preparation Download PDFInfo
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- CN109512826A CN109512826A CN201811514048.9A CN201811514048A CN109512826A CN 109512826 A CN109512826 A CN 109512826A CN 201811514048 A CN201811514048 A CN 201811514048A CN 109512826 A CN109512826 A CN 109512826A
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Abstract
The invention belongs to pharmaceutical technology fields, are related to labetalol in preparation and treat and prevent the purposes in fibrotic disease drug.The labetalol is labetalol or its medicinal derivative.The fibrotic disease includes pulmonary fibrosis, liver fibrosis, kidney fibrosis, cardiac fibrosis, endometrium fibrosis, eye fibrosis, pancreatic fibrosis, spleen Fibrotic proliferative disorders, myeloproliferative disorders or the disease induced by fibrosis.The labetalol can form pharmaceutical composition with one or more pharmaceutical carriers.Labetalol or its pharmaceutical composition can be used alone or be used in combination with other drugs.And its have the advantages that in terms for the treatment of fibrotic disease significant in efficacy, toxic side effect is few, using safe.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to labetalol in the drug that preparation prevents and treats fibrotic disease
Purposes.
Background technique
Fibrosis (Fibrosis) refers to since inflammation causes parenchymatous disease cell to necrose, and organizes extracellular matrix
The pathologic process of abnormal increase and over-deposit.Essential co-fibration is the reparation reaction after tissue is damaged, to protect group
Knit the relative fullness of organ.Although the fibrous connective tissue of hyperplasia has repaired defect, but it is substantially thin not have original organ
The structure and function of born of the same parents.If this reparation overreact, it is too strong and out of control when, will cause organ fibrosis and lead to device
The function reduction of official.
Fibrosis can betide the important organs such as a variety of organs, including lung, liver, kidney and heart.Main pathological change
Increase for the formation of myofibroblast lesion in organ-tissue, fibrous connective tissue and parenchyma is reduced, continuing advances
Organ structure destruction and hypofunction or even failure can be caused, human health and life are seriously threatened.In worldwide, group
Textured fiber is the main reason for many diseases disable, is lethal, and related statistics proves, the disease lethal because of various diseases
In people, tissue fibers proliferative disease can be attributed to close to 45%.
Transforminggrowthfactor-β1 (TGF-β 1) is the principal element for driving fibrosis, inhibits TGF-β 1 or signal is logical downstream
Road can inhibit the progress of limitation multiple fiber disease pathology model.1 signal of TGF-β for flesh in pulmonary fibrosis pathologic process at
The formation of fibrocyte plays a crucial role, and the main action target spot of clinical anti-fibrosis drug at present.
The inhibitor of 1 signal of TGF-β can be used for the prevention and treatment of different types of fiber disease, such as 1 signal inhibitor pyrrole of TGF-β
Non- Buddhist nun's ketone to different types of fibrotic disease, such as pulmonary fibrosis, liver fibrosis, kidney fibrosis and cardiac fibrosis have it is good
Good preventive and therapeutic effect.Important function based on 1 signal of TGF-β during fibrillatable pathological, current external fibrosis model
It is with TGF-β 1 mostly for inducer, the activation of 1 signal of TGF-β also plays very important reuse in internal fibrosis model,
Model above is widely used in the research of fibrillatable pathological mechanism and the activity rating of anti-fibrosis medicine.
Clinic is based primarily upon the association of immune response, inflammatory reaction in fibrotic processes to the therapeutic scheme of fibrotic disease
Same-action, be used in combination it is anti-inflammatory, immunosuppressive drug to delay progression of fibrosis, the program because its curative effect uncertainty and
Adverse reaction is more and fails to be widely applied.And although organ transplant is fibrosis latter stage the only effective treatment means, but it is same
Sample faces organ donor shortage, and operation survival rate is low, postoperative the problems such as being difficult to recover.It can be seen that high specificity, it is curative for effect and
The discovery of anti-fibrosis medicine without obvious adverse reaction is significant, but clinic still lacks safely and effectively anti-fibrosis at present
Drug.
Summary of the invention
The technical problem to be solved in the present invention is to for the drug for lacking effective prevention and treatment fibrotic disease
Deficiency provides a kind of new application of labetalol, i.e., labetalol is in preparation for effectively preventing or treating fibrotic disease
Application in drug.
The technical proposal adopted by the invention to solve the above technical problems is that:
Purposes of the labetalol in the drug that preparation prevents and treats fibrotic disease.
Further, the fibrotic disease includes pulmonary fibrosis, liver fibrosis, kidney fibrosis, cardiac fibrosis, uterus
The fibrosis such as intimal fibrosis, eye fibrosis, pancreatic fibrosis, spleen Fibrotic proliferative disorders, myelofibrosis and fibrosis of skin
Disease or the disease induced by fibrosis.
The pulmonary fibrosis disease is drug induced pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), sarcoidosis, pneumoconiosis, mistake
The pulmonary fibrosis of the inductions such as quick property pneumonia and radioactive ray, the unknown pulmonary fibrosis of other causes of disease, and induced by pulmonary fibrosis
Disease.
The liver fibrosis be virus hepatitis, alcoholic hepatitis, autoimmune disease, fatty liver, malnutrition,
Hepatic fibrosis-renal tubular ectasia syndrome caused by the difference reason such as chronic congestive heart failure and drug, the unknown hepatic fibrosis-renal tubular ectasia syndrome of other causes of disease,
And the disease induced by liver fibrosis.
The kidney fibrosis is hypertension, glomerulonephritis, systemic loupus erythematosus, chorionitis, renal transplant rejection, kidney
Renal fibrosis caused by the reasons such as nephropyelitis, kidney stone, hyperlipidemia, diabetes, hyperuricuria, hypercalciuria, other diseases
Because of unknown renal fibrosis, and the disease induced by kidney fibrosis.
The cardiac fibrosis is ischemic heart disease, hypertension, vital myocarditis, metabolic cardiomyopathy, Keshan
Cardiac fibrosis caused by the reasons such as disease, dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy and arrhythmia cordis, the heart
Dirty reconstruct and myocardial hypertrophy, the unknown cardiac fibrosis of other causes of disease, and the disease induced by cardiac fibrosis.
The endometrium fibrosis is endometrium fibrosis lesion caused by different reasons, and by endometrium
The disease that fibrosis induces.
The eye fibrosis is eyes retina Fibrotic proliferative disorders caused by eye injury, ocular surgical and diabetes,
And the disease induced by eye fibrosis.
In the present invention, the labetalol is labetalol or its medicinal derivative, and the labetalol is medicinal to spread out
Biology is the medicinal salt or ester of labetalol.
The labetalol can be used alone or be used in combination with other drugs.
The labetalol drug can be prepared into pharmaceutical composition, and the composition is drawn including at least a kind of active constituent
Labetalol and a kind of pharmaceutical carrier.
Further, the pharmaceutical composition, including 0.1~99% (quality) labetalol and 0.1~99% (matter
Amount) pharmaceutical carrier, preferably 1~99% (quality) labetalol and 1~99% (quality) pharmaceutical carrier.
Labetalol of the present invention or its pharmaceutical composition can be prepared into tablet, capsule, granule, injection or
It is transfused agent, is administered for being administered orally, and through vein, muscle, rectum, the intradermal or modes such as subcutaneous.
The pharmaceutical composition can also be aqueous solution, non-aqueous solution or suspension.
In the present invention, in the labetalol or its pharmaceutical composition, dosage root of the labetalol in treatment
Depending on the age of patient and the state of an illness, common daily dosage is about 1~5000mg, preferably 10~3000mg, more preferable 20~
2000mg.Administration number of times is once a day or for several times.
The present invention investigates tested material labetalol in pulmonary fibrosis, liver fiber by preparing internal, external fibrosis model
Purposes in the prevention and treatment of the fibrotic diseases such as change, kidney fibrosis and cardiac fibrosis.Test result show labetalol or its
Pharmaceutical composition can obviously inhibit lung, liver, kidney and cardiac fibrosis pathogenesis.
Detailed description of the invention:
Fig. 1 is pulmonary fibrosis, liver fibrosis, kidney fibrosis and the core fiber that labetalol can inhibit the stimulation of TGF-β 1 in vitro
Change the up-regulation of marker protein α-SMA expression.
Wherein A, B, C and D are followed successively by the pulmonary epithelial cells handled in advance with 30 μM of labetalols or solvent (Control)
A549 cell, hepatic stellate cells LX2, renal cells CD3 and primary cardiac fibroblasts are pierced through the TGF-β 1 of 10ng/mL
The variation of markers of fibrosis protein alpha-SMA expression after swashing.##P < 0.01, compared with control group；* P < 0.01, with TGF-β
1 group is compared.
Fig. 2 is pulmonary fibrosis, liver fibrosis, kidney fibrosis and the core fiber that labetalol can block TGF-β 1 to stimulate in vitro
Change the change of effector cell's surface hardness.
Wherein A, B, C and D are followed successively by the pulmonary epithelial cells handled in advance with 30 μM of labetalols or solvent (Control)
A549 cell, hepatic stellate cells LX2, renal cells CD3 and primary cardiac fibroblasts are pierced through the TGF-β 1 of 10ng/mL
The variation of cell surface hardness after swashing.##P < 0.01, compared with control group；* P < 0.01, compared with 1 group of TGF-β.
Fig. 3 is the pathological examination for the mouse pulmonary fibrosis model that labetalol intraperitoneal injection induces bleomycin
As a result.
A is HE Coloration experiment as a result, B is the result of Masson dyeing detection collagen expression.
Specific embodiment
Embodiment 1, the external pulmonary fibrosis resistant of labetalol based on markers of fibrosis protein alpha-SMA, liver fibrosis, kidney are fine
Dimensionization and cardiac fibrosis Effect study.
Pulmonary epithelial cells A549 cell, hepatic stellate cells LX2, renal cells CD3 and primary cardiac fibroblasts
In advance with 30 μM of labetalols or vehicle treated, then the TGF-β 1 through 10ng/mL stimulates above-mentioned four kinds of cells to flesh at fiber
The outer lung of cell transition and construct, liver, kidney and cardiac fibrosis model, with the journey of markers of fibrosis protein alpha-SMA characterization fibrosis
Degree.As shown in Figure 1, the TGF-β 1 of 10ng/ml stimulates human squamous lung cancer A549, hepatic stellate cells LX2, renal cells
After CD3 and Primary mouse cardiac fibroblasts 48h, the obvious up-regulation (P < 0.01) of markers of fibrosis protein alpha-SMA proves classics
Lung, liver, kidney and cardiac fibrosis model successful building.The fibrosis that 30 μM of labetalol can obviously block TGF-β 1 to induce
It is inhibited to lung, liver, kidney and cardiac fibrosis pathogenesis to show labetalol for the up-regulation of marker protein α-SMA.
Embodiment 2, cell hardness are that Fibrosis Markers investigate the external pulmonary fibrosis resistant of labetalol, liver fibrosis, kidney
Fibrosis and cardiac fibrosis effect.
Our early-stage study results prove that cell hardness can be used as the biomarker of characterization degree of fibrosis.Lung epithelial
Cell A549 cell, hepatic stellate cells LX2, renal cells CD3 and primary cardiac fibroblasts use 30 μM of drawing shellfishes in advance
Luo Er or vehicle treated, then the TGF-β 1 through 10ng/mL stimulates above-mentioned four kinds of cells to make the transition and construct to myofibroblast
External lung, liver, kidney and cardiac fibrosis model, atomic force microscope detect above-mentioned four kinds of cells cell hardness after the stimulation of TGF-β 1
Variation, with cell hardness (Young's modulus) be marker characterize fibrosis degree.The result shows that (Fig. 2), fine in above-mentioned lung
In dimensionization, liver fibrosis, kidney fibrosis and cardiac fibrosis model, labetalol can obviously block the cell hardness of the induction of TGF-β 1
Increase, further demonstrate labetalol in vitro and can produce pulmonary fibrosis resistant, liver fibrosis, kidney fibrosis and core fiber and be turned into
With.
Anti-fibrosis effect is studied in embodiment 3, labetalol body.
1, model preparation and administration:
Bull C57 mouse between weight 20-24g is selected, blank control group (physiological saline), model is set separately
Group, reagent group (labetalol, 10mg/kg, intraperitoneal injection), every group of 10 animals.Bleomycin is by 3mg/kg through gas
Pipe perfusion administration prepares mouse pulmonary fibrosis model；It gives different test medicines within the 7th day after bleomycin modeling, is administered daily one
It is secondary, successive administration 21 days.
2, pathological tissue is drawn materials:
The 28th day after administration, mouse peritoneal injected 0.1ml/10g chloral hydrate anesthesia, opens thoracic cavity, cuts off atrium sinistrum,
It is slowly injected into heart from right ventricle with the physiological saline of pre-cooling, transpulmonary circumfusion is cut left lung and put until lungs whiten
It is fixed for 24 hours to enter 4% paraformaldehyde, is sliced after paraffin embedding, remaining lung tissue is housed in spare in liquid nitrogen.The isotonic physiology of sample
Salt water thaws, and homogenate is made and stores in -20 DEG C.
3, the preparation of mouse lung tissue pathological slice and fibrosis evaluation index:
Above-mentioned histopathology sample impregnates ethanol dehydration for 24 hours, paraffin embedding, eosin haematoxylin using 4% paraformaldehyde
It dyes, Masson trichrome stain, carries out Histological evaluation under light microscopic.Evaluation index include: alveolar cavity volume, alveolar wall thickness,
Neutrophil leucocyte and collagen content etc..
4, the internal pulmonary fibrosis resistant evaluation of effect result of labetalol:
Experimental result is shown in Fig. 3.HE Coloration experiment has no the results show that clear in structure in blank control group animal lung tissue
Fibrosis performance.Bleomycin model group mouse lung tissue is sliced has severe fibrosis, shows as alveolar structure and destroys or disappear, fine
Connective tissue filling is tieed up, and with inflammatory cell infiltration；The obvious oedema of alveolar spaces is broadening, a large amount of fibroblasts and collagen group
Knit deposition.Labetalol administration group mouse lung tissue structure is relatively complete compared with model group, and apparent inflammatory cell is had no in alveolar,
There are a small amount of fiber stove, degree of fibrosis is substantially reduced.Masson coloration result is shown, in blank control group animal lung tissue
There is a small amount of collagen distribution.Around bleomycin model group bronchial wall and alveolar septa region, it is seen that blue collagenous fibres obviously increase
It is more.Compared with model group, Collagen fiber deposition significantly reduces labetalol administration group mouse.Above histopathologic slide's result is aobvious
Show, apparent anti-fibrosis effect is generated in labetalol body.
Claims (10)
1. labetalol prevents and treats the purposes in fibrotic disease drug in preparation.
2. purposes as described in claim 1, which is characterized in that the fibrotic disease include pulmonary fibrosis, liver fibrosis,
Kidney fibrosis, cardiac fibrosis, endometrium fibrosis, eye fibrosis, pancreatic fibrosis, spleen Fibrotic proliferative disorders, myleo
The disease changing disease or being induced by fibrosis.
3. purposes as claimed in claim 2, which is characterized in that the pulmonary fibrosis disease is drug induced pulmonary fibrosis, special
The pulmonary fibrosis of hair property, the pulmonary fibrosis that sarcoidosis, pneumoconiosis, hylactic pneumonia or radioactive ray induce, the unknown lung of other causes of disease are fine
Dimensionization, and the disease induced by pulmonary fibrosis；The liver fibrosis is virus hepatitis, alcoholic hepatitis, autoimmunity
Property disease, fatty liver, malnutrition, chronic congestive heart failure or drug-induced hepatic fibrosis-renal tubular ectasia syndrome, other causes of disease are unknown
Hepatic fibrosis-renal tubular ectasia syndrome, and by liver fibrosis induce disease；The kidney fibrosis is hypertension, glomerulonephritis, system
Property lupus erythematosus, chorionitis, renal transplant rejection, pyelonephritis, kidney stone, hyperlipidemia, diabetes, hyperuricuria, hypercalciuria
Renal fibrosis caused by disease, the unknown renal fibrosis of other causes of disease, and the disease induced by kidney fibrosis；The heart
Fibrosis be ischemic heart disease, hypertension, vital myocarditis, metabolic cardiomyopathy, Keshan disease, dilated cardiomyopathy,
Cardiac fibrosis caused by hypertrophic cardiomyopathy, restrictive cardiomyopathy or arrhythmia cordis, cardiac remodeling and myocardial hypertrophy, other diseases
Because of unknown cardiac fibrosis, and the disease induced by cardiac fibrosis；The endometrium fibrosis is that different reasons cause
Endometrium fibrosis lesion, and the disease induced by endometrium fibrosis；The eye fibrosis be eye injury,
Eyes retina Fibrotic proliferative disorders caused by ocular surgical or diabetes, and the disease induced by eye fibrosis.
4. purposes described in -3 any one according to claim 1, which is characterized in that the labetalol be used alone or
It is used in combination with other drugs.
5. the purposes as described in claim 1-4 any one, which is characterized in that the labetalol be labetalol or its
Medicinal derivative.
6. purposes as claimed in claim 5, which is characterized in that the labetalol medicinal derivative is the medicine of labetalol
With salt or ester.
7. the purposes as described in claim 1-6 any one, which is characterized in that the labetalol and pharmaceutical carrier composition
Pharmaceutical composition.
8. purposes as claimed in claim 7, which is characterized in that the pharmaceutical composition includes that quality is 0.1~99%
Labetalol and 0.1~99% pharmaceutical carrier.
9. purposes as claimed in claim 7 or 8, which is characterized in that the pharmaceutical composition be aqueous solution, non-aqueous solution or
Suspension, or be prepared into tablet, capsule, granule, injection or infusion agent, for taking orally, vein, muscle, rectum, it is intradermal or
Subcutaneous administration.
10. the purposes as described in any one of claim 1-9, which is characterized in that the labetalol daily dosage is 1
~5000mg, preferably 10~3000mg, more preferable 20~2000mg.
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| US20170128457A1 (en) * | 2003-10-08 | 2017-05-11 | Palo Alto Investors | Treatment of Conditions Through Pharmacological Modulation of the Autonomic Nervous System |
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| US20170128457A1 (en) * | 2003-10-08 | 2017-05-11 | Palo Alto Investors | Treatment of Conditions Through Pharmacological Modulation of the Autonomic Nervous System |
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