CN104083386A - Use of amprenavir in preparation of medicines for preventing or treating acute lung injury/acute respiratory distress syndrome and pulmonary fibrosis - Google Patents
Use of amprenavir in preparation of medicines for preventing or treating acute lung injury/acute respiratory distress syndrome and pulmonary fibrosis Download PDFInfo
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Abstract
The invention provides a new medical use of amprenavir and specifically relates to a use of the amprenavir for inhibiting the apoptosis of type I alveolar epithelial cells, promoting the expression of the receptor for advanced glycation endproducts of the type I alveolar epithelial cells, further inhibiting the occurrence and development of the ALI/ARDS and the pulmonary fibrosis and finally preventing or treating acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and pulmonary fibrosis. In the use, the dosage of the amprenavir ranges from 120mg to 6000mg, preferably from 240mg to 3000mg.
Description
Technical field
The present invention relates to that amprenavir suppresses acute lung injury/acute respiratory distress syndrome (ALI/ARDS) thereby and the generation of pulmonary fibrosis development prevention or treat ALI/ARDS and pulmonary fibrosis; Be specifically related to amprenavir by suppressing I type alveolar epithelial cells apoptosis, promote glycosylated end-product receptor (the receptor for advanced glycation endproducts of I type alveolar epithelial cells, RAGE) expression, so that prevention or treatment ALI/ARDS and pulmonary fibrosis.
Background technology
Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a kind of common critical illness, and case fatality rate is high, and serious threat patient with severe symptoms's life also affects its life quality.ALI/ARDS is in the non-Cardiac disease processes such as severe infections, shock, wound and burn, PCEC and alveolar epithelial cells damage cause diffusivity interstitial lung and intra-alveolar edema, the acute hypoxia respiratory insufficiency or the exhaustion that cause, with lung volume reducing, lung compliance reduces, and serious ventilation/blood flow is out of proportion is pathophysiological features.Clinical manifestation is carrying out property hypoxemia and respiratory distress, and lung image is learned the exudative process that shows as heterogencity.At present the case fatality rate of ARDS is higher, bibliographical information ARDS patient's case fatality rate in 50% left and right [serious symptom medical science branch of Chinese Medical Association. acute lung injury/acute respiratory distress syndrome diagnosis and treatment guide. Chinese critical illness emergency medicine .2006; 18 (12): 706-710].Alveolar I type epithelial cell claims again " film alveolar cell ", is cells maximum in alveolar epithelium, and its form is flat, and it is oblate that nucleus is, slightly outstanding to alveolar space.I type alveolar epithelial cells nearly cover all alveolar spaces, is closely affixed with contiguous capillary wall, and be the basic place of carrying out gas exchange.In ALI/ARDS, there is obvious apoptosis in I type alveolar epithelial cells, increases invalid epithelization (because I type alveolar epithelial cells is without multiplication capacity, the position of dead I type alveolar epithelial cells is filled up by the II type alveolar epithelial cells of breeding), make alveolar wall impaired, impact ventilation.Glycosylated end-product receptor (receptor for advanced glycation endproducts, RAGE) at I type alveolar epithelial cells high expressed, the reduction that suppresses RAGE can reduce the inflammatory reaction of lung, alleviate pulmonary parenchyma damage [Zhang H, Tasaka S, Shiraishi Y.Role of soluble receptor for advanced glycation end-products on endotoxin-induced lung injury.Am J Respir Crit Care Med2008; 178:356-362.].
Idiopathic pulmonary fibrosis (idiopathic pulmonary fibrosis, IPF) be called again hidden source property fibrosis alveolitis (cryptogenicfibrosing alveolitis, CFA), it is a kind of chronic inflammation interstitial disease, the plain edition interstitial pneumonia (usual interstitialpneumonia, UIP) of take is characteristic pathological change and etiology unknown.Main manifestations is that the appearance of fibroblast kitchen range (fibroblastic foci) causes a large amount of extracellular matrixs (extracellular matrix, ECM) heavy, collagen gathers, alveolar structure destroys, finally cause normal lung tissue's structural damage, be a kind of chronic, carrying out property, irreversible be also modal a kind of mortality lung disease [King TJ, Pardo A, Selman M.Idiopathic pulmonary fibrosis[J] .Lancet, 2011,378 (9807): 1949-1961.].Clinical manifestation is for carrying out property dyspnea and with zest dry cough, and pulmonary function is restrictive ventilatory disorder, and the state of an illness generally continues to worsen, finally because respiratory failure is dead.Epidemiological study shows, I PF sickness rate is continuous ascendant trend, be about at present 16.3/100,000, and acute exacerbation incidence rate is 20.7%[Navaratnam V in 3 years, Fleming KM, West J et al.The rising incidence of idiopathic pulmonary fibrosis in the UK[J] .Thorax, 2011,66 (6): 462-467.; Song JW, Hong SB, Lim CM et al.Acute exacerbation of idiopathic pulmonary fibrosis:incidence.risk factors and outcome[J] .Eur Respir J, 2011,37 (2): 356-363.].Known pulmonary fibrosis be mainly after damaged lung tissue, repair to regulate out of control, rebuild abnormal caused pathological changes, in this process, the abnormal expressions such as a series of cytokines and somatomedin, inflammatory reaction participate in the pathogenic process of pulmonary fibrosis.Cause thus that epithelial cell is damaged, the major lesions such as fibroblast proliferation and ECM gather, final result is that fibroblast has substituted alveolar epithelial cells (the alveolar epithelial cells that exercises normal function, AECs), caused Fibrotic generation.
Amprenavir (having another name called An Ruinawei) is a kind of new anti-reversion hiv protease inhibitor, there is anti-HIV-1 and the effect of HIV-2 protease, the ripe necessary protein precursor division of HIV capable of blocking, the growth course of viral interference, discharges the immature communicable viruses molecule that do not have then.Prolonged application amprenavir can reduce the HIV viral load in blood, increases CD
4the counting of cell, the chance of reduction aids infection, improves the quality of living, extending life, but amprenavir has no report in the pharmacological action of prevention or treatment ALI/ARDS and pulmonary fibrosis.The inventor finds that by a large amount of research amprenavir can be by suppressing the apoptosis of I type alveolar epithelial cells, thereby the RAGE that increases I type alveolar epithelial cells expresses and having obvious effect aspect prevention or treatment ALI/ARDS and pulmonary fibrosis.Based on this, the inventor has invented amprenavir by suppressing the apoptosis of I type alveolar epithelial cells, thereby the RAGE that increases I type alveolar epithelial cells expresses and suppresses developing of ALI/ARDS and pulmonary fibrosis, so that prevention or treatment ALI/ARDS and pulmonary fibrosis.
Summary of the invention
The invention provides the application of amprenavir in the medicine of preparation prevention or treatment ALI/ARDS and pulmonary fibrosis.
The invention provides the application of amprenavir in the medicine of preparation prevention or treatment ALI/ARDS.
The invention provides the application of amprenavir in the medicine of preparation prevention or treatment pulmonary fibrosis.
The invention provides the application in the medicine of amprenavir I type alveolar epithelial cells apoptosis in suppressing acute and chronic injury of lung.
The invention provides the application in the amprenavir medicine that I type alveolar epithelial cells RAGE expresses in increasing acute and chronic injury of lung.
The medicine that the amprenavir that the present invention also provides can form with pharmaceutically acceptable carrier or adjuvant, this medicine can be prepared into tablet, capsule, drop pill with pharmacy conventional method, preferably with capsule form, exists.
The amprenavir that invention provides is when for ALI/ARDS and pulmonary fibrosis, and it orally uses dosage range is 120mg～6000mg; Preferred 240～3000mg.
The specific embodiment
Embodiment 1 amprenavir capsule preparation
After taking 120.0g amprenavir and the abundant mix homogeneously of 120.0g carboxymethyl starch sodium, cross 100 mesh sieves, add appropriate 3%PVP
k30aqueous solution is soft material processed in right amount, and 20 mesh sieves are granulated, and 60 ℃ are dried 3 hours, and 18 mesh sieve granulate, add 2.0g magnesium stearate, encapsulated, and every about 240mg, obtains.
Specific embodiment
The impact of test example 1 amprenavir on people I type alveolar epithelial cells cell strain apoptosis and RAGE expression
1.1 experiment material
DMEM culture medium is Gibco company product, new-born calf serum is Hangzhou Ilex purpurea Hassk.[I.chinensis Sims company product, TGF-β 1 is purchased from PeproTech company, people I type alveolar epithelial cells cell strain (AT I) is purchased from Chinese Typical Representative culture collection center, by the low sugar DMEM culture medium (GIBCO company) containing 10% hyclone (Hyclone company), cellar culture is in 5% CO
2, in 37 ℃ of artificial culture casees, cell is adherent growth.
RAGE primary antibodie is bought the company in sigma.
Amprenavir (purity 99.5% is bought Han Xiang bio tech ltd, Shanghai)
1.2 test method
When Growth of Cells merges to 70%-80%, with the hungry 24h of serum-free medium, change fresh medium, amprenavir is dissolved with DMSO, with culture medium, is diluted to respective concentration.The AT I cell going down to posterity is divided into 2 parts, includes: (1) negative control group; (2) TGF-β 1 processed group (3 μ g/L 24h action time); (3) TGF-β 1 processed group (3 μ g/L 24h action time)+amprenavir 0.15 μ M; (4) TGF-β 1 processed group (3 μ g/L 24h action time)+amprenavir 0.5 μ M; (5) TGF-β 1 processed group (3 μ g/L 24h action time)+amprenavir 1.5 μ M; (6) TGF-β 1 processed group (3 μ g/L 24h action time)+amprenavir 5 μ M.First's cultured cells is with cells were tested by flow cytometry apoptosis, first's cultured cells lysis, BCA protein determination kit (Pierce company) is measured after protein concentration, getting 50 μ g sample proteins carries out 10% dodecyl sodium sulfate 2 polyacrylamides (SDS-PAGE) gel degeneration electrophoresis, then goes to polyvinylidene fluoride (PVDF) film, add RAGE primary antibodie, β-actin makes internal reference, and Western blot detects the expression of cell rage protein.With TGF-β 1 not stimulating group in contrast, count 100% of corresponding protein, analyze each concentration medicine and the differential expression of simple TGF-β 1 stimulating group to rage protein.Between group, carry out T check.
Table 1 amprenavir stimulates the apoptosis of AT I cell and RAGE to express impact (n=5) on TGF-β 1
*, P < 0.05,
*, P < 0.01, with simple TGF-β 1 stimulating group comparison
Table 1 result can find out, TGF-β 1 stimulates AT I cell 24 hours, and AT I apoptosis obviously increases, and RAGE expresses and obviously declines, and adds after amprenavir 0.15-5 μ M 24 hours, and AT I apoptosis obviously declines, and RAGE expresses obviously and rises.Illustrate that amprenavir can suppress AT I apoptosis, alleviate in acute lung injury/acute respiratory distress syndrome the damage that the exhaustion because of AT I cell causes.
The impact of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) rat model that experimental example 2 amprenavir cause cecal ligation and perforation
2.1 medicines and reagent
Amprenavir (purity 99.5% is bought Han Xiang bio tech ltd, Shanghai)
Tachypleus amebocyte lysate test kit (the biochemical Industrial Co., Ltd of Foochow, Fujian Province Xin Bei, lot number: 080430)
Anti-Aquaporin5 antibody (abcam company, ab104751)
RAGE primary antibodie is bought the company in sigma.
Laboratory animal: SPF level Sprague Dawley rat, male, body weight 150g-200g, Shandong Green Leaf Pharmaceutical Co., Ltd's Experimental Animal Center provides, and the animal quality certification number is: SYXK (Shandong) 20030020.
2.2 experimental techniques and result
2.2.1 the preparation of cecal ligation and perforation (CLP) rat
Operation rat fasting in early morning on the same day, gets dorsal position after etherization, 75% ethanol disinfection abdominal part, along the otch of hunter's line stage casing work one long 1.5em, is cut off skin and flesh layer, detects the separated caecum in abdominal cavity; No. 1 silk thread is apart from cecum 1cm place (ileocecal valve far-end) ligation, and No. 16 puncture needle runs through caecum 3 times (triangular in shape) at ligation place far-end, the about 3mm of pin hole spacing, and extrude a little content; Caecum Hui Na abdominal cavity, layer-by-layer suture is closed abdominal cavity.
2.2.2 the administration of dividing into groups
50 of CLP rats, are divided into 5 groups at random, i.e. model group, amprenavir gastric infusion 12mg/kg, 24mg/kg, 300,600mg/kg group.Get in addition 10 normal rats as a control group.1 hour each group of CLP operation gives relative medicine.Blood is got in CLP operation for 24 hours, measures serum endotoxin, and serum endogenous toxin is used plain tachypleus amebocyte lysate kit measurement.Get lung, weigh, measure lung coefficient, get a fresh leaf lung, homogenate, BCA protein determination kit (Pierce company) is measured after protein concentration, getting 50 μ g sample proteins carries out 10% dodecyl sodium sulfate 2 polyacrylamides (SDS-PAGE) gel degeneration electrophoresis, then goes to polyvinylidene fluoride (PVDF) film, add RAGE primary antibodie, β-actin makes internal reference, and Western blot detects the expression of cell rage protein.Get in addition a leaf lung, prepare pathology sheet, row Aquaporin5 (characteristic indication of I type alveolar epithelial cells) immunohistochemical staining, 200 times of light microscopics are taken pictures, calculate Aquaporin5 positive cell number under each visual field, Aquaporin5 positive cell number with normal group counts 100%, relatively the difference of each administration group and model group.Between group, carry out T check.
2.2.3 experimental result
Table 2 result shows amprenavir gastric infusion 12mg/kg, 24mg/kg, 300mg/kg, 600mg/kg group obviously reduce ALI/ARDS rat blood serum level of endotoxin, suppress lung tissue RAGE and express decline, suppress Aquaporin5 positive cell quantity decline (p < 0.05 or p < 0.01).Amprenavir 300mg/kg group suppresses ALI/ARDS rat blood serum endotoxin and raises, and suppresses lung tissue RAGE expression and declines, and suppresses relatively there was no significant difference of Aquaporin5 positive cell quantity decline level and amprenavir 600mg/kg group.
The impact (n=6) of the ALI/ARDS rat that the administration of table 2 amprenavir causes cecal ligation and perforation
*, p < 0.05,
*, p < 0.01, with model group comparison
The impact of test example 3 amprenavir on the pulmonary fibrosis model rat of bleomycin (BLM) induction
3.1 experiment material
Bleomycin is purchased from Bai Li bio tech ltd, Shanghai
Hydroxyproline assay test kit builds up Bioengineering Research Institute purchased from Nanjing
Laboratory animal: SPF level Sprague Dawley rat, male, body weight 150g-200g, Shandong Green Leaf Pharmaceutical Co., Ltd's Experimental Animal Center provides, and the animal quality certification number is: SYXK (Shandong) 20030020.
Amprenavir (purity 99.5% is bought Han Xiang bio tech ltd, Shanghai)
3.2 test method
50 rats, 10% chloral hydrate anesthesia (350mg/kg, ip), adopts injection bleomycin (5mg/kg) induction pulmonary fibrosis model in bronchus.The grouping afterwards in 21 days of modeling type, is divided into model group, amprenavir gastric infusion 12mg/kg, amprenavir gastric infusion 24mg/kg, amprenavir gastric infusion 300mg/kg, amprenavir gastric infusion group 600mg/kg, successive administration 3 weeks.Put to death animal, get lung, weigh, calculate lung index, document [Szapiel S V is pressed in morphological change classification alveolitis and pulmonary fibrosis classification, Elson N A, Fulmur J D.Bleomycin induced interstitial pulmonary disease in the nude, athymic mouse[J] .Am Rev Respir Dis, 1979,120:893-899], the degree of alveolitis and pulmonary fibrosis is divided into 4 grades: 0 grade of nothing obviously changes; 1 grade of MC, extent of disease is less than 20% of full lung; 2 grades of moderates change, and extent of disease accounts for 20%～50% of full lung; 3 grades of severes change, and extent of disease accounts for the more than 50% of full lung.Measure body weight and lung weight, calculate lung index, get lung, hydrolysis, measures lung tissue hydroxyproline content.
The impact of table 3 amprenavir on the pulmonary fibrosis model rat of bleomycin (BLM) induction
*, P < 0.05,
*, P < 0.01, with model group comparison.
Table 3 result shows that amprenavir gastric infusion 12,24,300 and 600mg/kg successive administration can obviously reduce lung index in 3 weeks, reduce fibrosis classification, reduce lung tissue hydroxyproline content, illustrate that amprenavir gastric infusion can suppress developing of pulmonary fibrosis.Amprenavir 300mg/kg group reduces lung index, reduces fibrosis classification, reduces lung tissue hydroxyproline content and amprenavir 600mg/kg group relatively, there was no significant difference.
Claims (6)
1. the invention provides the application of amprenavir in the medicine of preparation prevention or treatment acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and pulmonary fibrosis.
2. application according to claim 1, amprenavir is by suppressing I type alveolar epithelial cells apoptosis, increase I type alveolar epithelial cells glycosylated end-product receptor (receptor for advanced glycation endproducts, RAGE) and express the application in the medicine of prevention or treatment ALI/ARDS and pulmonary fibrosis.
3. application according to claim 2, ALI/ARDS can be prevented or treat to amprenavir.
4. application according to claim 2, amprenavir prevention or treatment pulmonary fibrosis.
5. according to the application described in claim 3 and 4, when amprenavir is used for ALI/ARDS and pulmonary fibrosis, it orally uses dosage range is 120mg～6000mg; Preferred 240～3000mg.
6. application according to claim 5, the medicine that amprenavir and pharmaceutically acceptable carrier or adjuvant form, this medicine can be prepared into tablet, capsule, drop pill with pharmacy conventional method, preferably with capsule form, exists.
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Cited By (5)
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| CN106139154A (en) * | 2016-08-18 | 2016-11-23 | 滨州医学院 | Amprenavir strengthens the new medical use of glucocorticoid antiinflammatory action |
| CN106389496A (en) * | 2016-11-17 | 2017-02-15 | 郑州郑先医药科技有限公司 | Western medicine composite preparation for treating pneumonia |
| CN106619635A (en) * | 2017-03-06 | 2017-05-10 | 滨州医学院 | Application of elvitegravir to preparation of drugs for preventing or treating ALI/ARDS (acute lung injury/acute respiratory distress syndrome) and PF (pulmonary fibrosis) |
| CN106728404A (en) * | 2016-11-17 | 2017-05-31 | 郑州郑先医药科技有限公司 | A kind of compound preparation for treating pneumonia |
| US11364239B2 (en) | 2020-04-29 | 2022-06-21 | Cfd Research Corporation | Compositions and methods for mitigating aflatoxin B1-induced liver injury |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106139154A (en) * | 2016-08-18 | 2016-11-23 | 滨州医学院 | Amprenavir strengthens the new medical use of glucocorticoid antiinflammatory action |
| CN106389496A (en) * | 2016-11-17 | 2017-02-15 | 郑州郑先医药科技有限公司 | Western medicine composite preparation for treating pneumonia |
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| US11364239B2 (en) | 2020-04-29 | 2022-06-21 | Cfd Research Corporation | Compositions and methods for mitigating aflatoxin B1-induced liver injury |
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