CN104083373A - Use of lopinavir in preparation of medicines for preventing or treating acute lung injury/acute respiratory distress syndrome and pulmonary fibrosis - Google Patents
Use of lopinavir 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 lopinavir and specifically relates to a use of the lopinavir in preventing or treating acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and pulmonary fibrosis by 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 ALI/ARDS and the pulmonary fibrosis and finally preventing or treating ALI/ARDS. In the use, the dosage of the lopinavir ranges from 100mg to 6000mg, preferably from 240mg to 3000mg.
Description
Technical field
The present invention relates to that Lopinavir 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 Lopinavir 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, taking plain edition interstitial pneumonia (usual interstitialpneumonia, UIP) as 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 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.
Lopinavir and ritonavir share the treatment that (trade name gram force sesame) infects for HIV/AIDS clinically, also can be with other antiretroviral drugs coupling in adult and more than 6 months child's HIV treatment of infection, but Lopinavir has no report in prevention or the pharmacological action for the treatment of ALI/ARDS and pulmonary fibrosis.The inventor finds that by a large amount of research Lopinavir 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 Lopinavir 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 Lopinavir in the medicine of preparation prevention or treatment ALI/ARDS and pulmonary fibrosis.
The invention provides the application of Lopinavir in the medicine of preparation prevention or treatment ALI/ARDS.
The invention provides the application of Lopinavir in the medicine of preparation prevention or treatment pulmonary fibrosis.
The invention provides the application of Lopinavir in the medicine that suppresses I type alveolar epithelial cells apoptosis in acute and chronic injury of lung.
The invention provides Lopinavir in the application increasing in the medicine that in acute and chronic injury of lung, I type alveolar epithelial cells RAGE expresses.
The Lopinavir that the present invention also provides can with the medicine of pharmaceutically acceptable carrier or adjuvant composition, this medicine can be prepared into tablet, capsule with pharmacy conventional method, preferably exists with tablet form.
The Lopinavir that invention provides is when for ALI/ARDS and pulmonary fibrosis, and its using dosage scope is 100mg～6000mg; Preferably 200～3000mg.
Detailed description of the invention
Embodiment 1 Lopinavir tablet preparation
After taking 120.0g Lopinavir and the abundant mix homogeneously of 80.0g 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 DEG C are dried 3 hours, and 18 mesh sieve granulate, add 2.0g magnesium stearate, tabletting after mix homogeneously, and the heavily about 200mg of adjustment sheet, to obtain final product.
Specific embodiment
The impact of test example 1 Lopinavir on people I type alveolar epithelial cells cell strain apoptosis and RAGE expression
1.1 experiment material
DMEM culture medium is Gibco company product, and 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 DEG C of artificial culture casees, cell is adherent growth.
RAGE primary antibodie is bought the company in sigma.
Lopinavir (purity 99.5% is bought in 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, Lopinavir dissolves with DMSO, is diluted to respective concentration with culture medium.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)+Lopinavir 0.22 μ M; (4) TGF-β 1 processed group (3 μ g/L 24h action time)+Lopinavir 0.67 μ M; (5) TGF-β 1 processed group (3 μ g/L 24h action time)+Lopinavir 2 μ M; (6) TGF-β 1 processed group (3 μ g/L 24h action time)+Lopinavir 6 μ M.Part I cultured cells is with cells were tested by flow cytometry apoptosis, the lysis of Part I cultured cells, 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 Westernblot 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 inspection.
Table 1 Lopinavir 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 Lopinavir 0.22-6 μ M 24 hours, and AT I apoptosis obviously declines, and RAGE expresses obviously and rises.Illustrate that Lopinavir can suppress AT I apoptosis, alleviates the damage causing because of the exhaustion of AT I cell in acute lung injury/acute respiratory distress syndrome.
The impact of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) rat model that experimental example 2 Lopinavirs cause cecal ligation and perforation
2.1 medicines and reagent
Lopinavir (purity 99.5% is bought in 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 1.5cm, is cut off skin and flesh layer, detects abdominal cavity and separates caecum; 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, Lopinavir gastric infusion 10mg/kg, 20mg/kg, 300,600mg/kg group.Get in addition 10 normal rats as a control group.Each group of CLP operation 1 hour gives relative medicine.Blood is got in CLP operation for 24 hours, measures serum endotoxin, and serum endogenous toxin uses 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%, the difference of more each administration group and model group.Between group, carry out T inspection.
2.2.3 experimental result
Table 2 result shows Lopinavir gastric infusion 10mg/kg, 20mg/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).Lopinavir 300mg/kg group suppresses ALI/ARDS rat blood serum endotoxin and raises, and suppresses lung tissue RAGE expression and declines, and suppresses Aquaporin5 positive cell quantity decline level and relatively there was no significant difference of Lopinavir 600mg/kg group.
The shadow noon (n=6) of the ATI/ARDS rat that the administration of table 2 Lopinavir causes cecal ligation and perforation
*, p < 0.05,
*, p < 0.01, with model group comparison
The impact of the pulmonary fibrosis model rat of test example 3 Lopinavirs on 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.
Lopinavir (purity 99.5% is bought in 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, Lopinavir gastric infusion 10mg/kg, Lopinavir gastric infusion 20mg/kg, Lopinavir gastric infusion 300mg/kg, Lopinavir 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 the pulmonary fibrosis mould shape rat of table 3 Lopinavir on bleomycin (BLM) induction
*, P < 0.05,
*, P < 0.01, with model group comparison.
Table 3 result shows that Lopinavir gastric infusion 10,20,300 and 600mg/kg successive administration can obviously reduce lung index in 3 weeks, reduce fibrosis classification, reduce lung tissue hydroxyproline content, illustrate that Lopinavir gastric infusion can suppress developing of pulmonary fibrosis.
Claims (6)
1. the invention provides the application of Lopinavir 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, Lopinavir 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, Lopinavir can prevent or treat ALI/ARDS.
4. application according to claim 2, Lopinavir prevention or treatment pulmonary fibrosis.
5. according to the application described in claim 3 and 4, when Lopinavir is used for ALI/ARDS and pulmonary fibrosis, its using dosage scope is 100mg～6000mg; Preferably 200～3000mg.
6. application according to claim 5, the medicine of Lopinavir and pharmaceutically acceptable carrier or adjuvant composition, this medicine can be prepared into tablet, capsule with pharmacy conventional method, preferably exists with tablet form.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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) |
| WO2018202792A1 (en) * | 2017-05-04 | 2018-11-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for the prediction of acute respiratory distress syndrome |
| EP4163379A4 (en) * | 2020-12-22 | 2024-08-14 | Inst Zoology Cas | Method for identifying and/or regulating senescence |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1838930A (en) * | 2003-06-20 | 2006-09-27 | 病毒基因混和公司 | Compositions and methods for treating HIV |
| WO2006108666A1 (en) * | 2005-04-13 | 2006-10-19 | Proteosys Ag | Mefloquine, nelfinavir and saquinavir as novel agents for neurodegenerative and (neuro-) inflammatory diseases |
| CN1938017A (en) * | 2004-01-30 | 2007-03-28 | 辉瑞有限公司 | Therapeutic combinations |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1838930A (en) * | 2003-06-20 | 2006-09-27 | 病毒基因混和公司 | Compositions and methods for treating HIV |
| CN1938017A (en) * | 2004-01-30 | 2007-03-28 | 辉瑞有限公司 | Therapeutic combinations |
| WO2006108666A1 (en) * | 2005-04-13 | 2006-10-19 | Proteosys Ag | Mefloquine, nelfinavir and saquinavir as novel agents for neurodegenerative and (neuro-) inflammatory diseases |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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) |
| WO2018202792A1 (en) * | 2017-05-04 | 2018-11-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for the prediction of acute respiratory distress syndrome |
| EP4163379A4 (en) * | 2020-12-22 | 2024-08-14 | Inst Zoology Cas | Method for identifying and/or regulating senescence |
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Application publication date: 20141008 |