CN104138374A - Application of atazanavir sulfate in preparation of medicine for preventing or treating endoxemia and pyemia - Google Patents
Application of atazanavir sulfate in preparation of medicine for preventing or treating endoxemia and pyemia Download PDFInfo
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- CN104138374A CN104138374A CN201410379453.XA CN201410379453A CN104138374A CN 104138374 A CN104138374 A CN 104138374A CN 201410379453 A CN201410379453 A CN 201410379453A CN 104138374 A CN104138374 A CN 104138374A
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- sulphuric acid
- acid atazanavir
- atazanavir
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Abstract
The invention provides a new function of atazanavir sulfate, and particularly relates to application of the atazanavir sulfate in preparation of medicine for preventing or treating endoxemia and pyemia. According to the application of the atazanavir sulfate, the atazanavir sulfate can inhibit generation and development of endoxemia and pyemia by inhibiting expression of high mobility group protein B1 (HMGB1), and accordingly endoxemia and pyemia can be prevented or treated. In the application, the injection dosage range of the atazanavir sulfate is 50mg-2000mg and is preferably 50-1000mg, and the oral dosage range of the atazanavir sulfate is 100mg-6000mg and is preferably 200-3000mg.
Description
Technical field
Thereby the present invention relates to sulphuric acid atazanavir and suppress pyemic generation development prevention or treatment endotoxemia and sepsis; Be specifically related to sulphuric acid atazanavir by suppressing the expression of high mobility group protein B 1 (high mobility group protein, HMGB1), thus prevention or treatment endotoxemia and sepsis.
Background technology
Sepsis (sepsis), i.e. pyemia.It is a kind of clinical syndrome being caused by infection.Suppurative pathogen is invaded blood flow a large amount of breeding therein, and with blood flow, to whole body, spreads the new multiple suppurative focus causing at histoorgan.Sepsis is often with following sign: body temperature is higher or lower than normally, and leukocytosis or minimizing, tachycardia, rapid breathing or ventilation per minute raise extremely, as occurred clinically wherein two or two above symptoms, and can diagnosis of sepsis mass formed by blood stasis; As the organ failure of occurring together, be called serious symptom pyemia (severe sepsis).The U.S. has 500,000 patients with sepsis every year, survival rate only 55%～65%.
Sepsis is common complication after severe trauma, burn, shock, major operation, is also one of important cause of death of surgery critical patient.Research at present thinks that HMGB-1 also plays pivotal role [Wang H in sepsis, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J.HMG-1 as a late mediator of endotoxin lethality in mice.Science 1999,285 (5425): 248-251; Andersson U, Tracey KJ.HMGB1 in sepsis.Scand J Infect Dis 2003,35 (9): 577-584.].
Sulphuric acid atazanavir capsule is used treatment HIV-1 to infect for combining with other antiretroviral drugs clinically,, but sulphuric acid atazanavir has no report at prevention or treatment endotoxemia and pyemic pharmacological action.The inventor finds that by a large amount of research thereby expression that sulphuric acid atazanavir can be by suppressing people's peritoneal macrophage HMGB1 that lipopolysaccharide stimulates has obvious effect at prevention or treatment endotoxemia and sepsis.Based on this, thus the inventor invented sulphuric acid atazanavir by suppress macrophage HMGB1 expression suppress pyemic and develop, thereby prevention or treatment endotoxemia and sepsis.
Summary of the invention
The invention provides the application of sulphuric acid atazanavir in preparation prevention or treatment endotoxemia and pyemic medicine.
The invention provides the application in the medicine of sulphuric acid atazanavir HMGB1 in suppressing endotoxemia and sepsis.
The invention provides the application of sulphuric acid atazanavir in the medicine of preparation prevention or treatment endotoxemia.
The invention provides sulphuric acid atazanavir in preparation prevention or treat the application in pyemic medicine.
The sulphuric acid atazanavir that invention provides is when for sepsis, and its injection using dosage scope is 50mg～2000mg; Preferred 50～1000 mg; It orally uses dosage range is 100mg～6000mg; Preferred 200～3000mg.
The medicine that the sulphuric acid atazanavir that the present invention also provides can form with pharmaceutically acceptable carrier or adjuvant, this medicine can be prepared into injection, freeze-dried powder, tablet, capsule with pharmacy conventional method, preferably with freeze-dried powder and capsule form, exists.
The specific embodiment
Embodiment 1 sulphuric acid atazanavir freeze-dried powder preparation
Get sulphuric acid atazanavir 50.0g, inject water 2000ml it is dissolved, with mannitol 8g, stirring and dissolving, ultrafiltration, obtains apyrogenic clear liquor, pours in 10ml cillin bottle, 2ml/ only, by the lyophilizing of freeze-dried powder technique, makes the freeze-dried powder of every sulfur acid atazanavir 50.0mg.
Embodiment 2 sulphuric acid atazanavir capsule preparations
After taking 200.0g sulphuric acid atazanavir and the abundant mix homogeneously of 100.0g carboxymethyl starch sodium, cross 100 mesh sieves, add appropriate 3%PVPK30 aqueous solution soft material processed in right amount, 20 mesh sieves are granulated, 60 ℃ are dried 3 hours, 18 mesh sieve granulate, add 2.0g magnesium stearate, encapsulated after mix homogeneously, regulate the heavily about 200mg of capsule, obtain.
Specific embodiment
The impact that people's peritoneal macrophage HMGB1 that test example 1 sulphuric acid atazanavir stimulates lipopolysaccharide expresses
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
Lipopolysaccharide (LPS) is purchased from Sigma company
The strain of people's peritoneal macrophage is purchased from Chinese Typical Representative culture collection center, and 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.HMGB1 primary antibodie is bought the company in sigma.
Sulphuric acid atazanavir (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, the people's peritoneal macrophage going down to posterity is divided into: (1) negative control group; (2) LPS processed group (2 μ g/L h action times 24); (3) LPS processed group (2 μ g/L h action times 24)+sulphuric acid atazanavir 0.3 μ M; (4) LPS processed group (2 μ g/L 24h action time)+methanesulfonic acid Sha Kuilawei 1 μ M; (5) LPS processed group (2 μ g/L h action times 24)+sulphuric acid atazanavir 3 μ M; (6) LPS processed group (2 μ g/L h action times 24)+sulphuric acid atazanavir 10 μ M.Cultured cells is carried out cracking, BCA protein determination kit (Pierce company) is measured after protein concentration, getting 50 μ g sample proteins carries out dodecyl sodium sulfate-polyacrylamide (SDS-PAGE) gel degeneration electrophoresis of 10%, then goes to polyvinylidene fluoride (PVDF) film, add HMGB1 primary antibodie, β-actin makes internal reference, and Western blot detects the expression of cell HMGB1 albumen.With LPS not stimulating group in contrast, count 100% of corresponding protein, analyze each concentration medicine and the differential expression of simple LPS stimulating group to HMGB1 albumen.Between group, carry out T check.
People's peritoneal macrophage HMGB1 that table 1 sulphuric acid atazanavir stimulates lipopolysaccharide expresses impact (n=5)
*, P < 0.05,
*, P < 0.01, with the comparison of simple LPS stimulating group
Table 1 result can be found out, LPS stimulating expression of macrophage 24 hours, and HMGB1 expresses obviously and rises, and adds after sulphuric acid atazanavir 0.3-10 μ M 24 hours, and HMGB1 expresses obviously and declines.Illustrate that sulphuric acid atazanavir can suppress the HMGB1 expression of macrophage, alleviates endotoxemia and sepsis damage.
The impact of the rats with sepsis that test example 2 sulphuric acid atazanavirs cause cecal ligation and perforation
2.1 medicines and reagent
Sulphuric acid atazanavir (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: 130430)
High-mobility group-box 1 protein (HMGB1) test kit (Shanghai Xi Tang biotech company)
Laboratory animal: SPF level Sprague Dawley rat, male, body weight 150 g-200 g, 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 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
90 of CLP rats, be divided at random 6 groups, be model group, sulphuric acid atazanavir intravenous injection 5mg/kg, 25mg/kg, 100mg/kg, 200mg/kg, sulphuric acid atazanavir gastric infusion 10mg/kg, 50mg/kg, 300mg/kg, 600mg/kg, get in addition 10 normal rats as a control group.Each group of CLP operation 1h gives relative medicine.CLP operation 20h gets blood, measures serum HMGB1 and endotoxin.Serum HMGB measures and uses ELISA test kit, and serum endogenous toxin is used plain tachypleus amebocyte lysate kit measurement.Get blood complete, observe the survival condition of animal in 144h, if not dead in 144h, the time-to-live is designated as 144h.Data are used
represent, to organize a t check, carry out statistical procedures.
2.2.3 experimental result
The impact (n=10) of the rats with sepsis that the intravenous injection of table 2 sulphuric acid atazanavir causes cecal ligation and perforation
*, p < 0.05,
*, p < 0.01, with model group comparison
Result is as shown in table 2, sulphuric acid atazanavir intravenous injection 5mg/kg, 25mg/kg, 100mg/kg, 200mg/kg, sulphuric acid atazanavir gastric infusion 10mg/kg, 50mg/kg, 300mg/kg, 600mg/kg group obviously reduce rats with sepsis serum HMGB1 and level of endotoxin, extend the time-to-live (p < 0.05 or p < 0.01).Sulphuric acid atazanavir intravenous injection 100mg/kg group reduces rats with sepsis serum HMGB1 and level of endotoxin, extends relatively there was no significant difference of time-to-live and sulphuric acid atazanavir intravenous injection 200mg/kg group; Sulphuric acid atazanavir gastric infusion 300mg/kg group reduces rats with sepsis serum HMGB1 and level of endotoxin, extends relatively there was no significant difference of time-to-live and sulphuric acid atazanavir gastric infusion 600mg/kg group.
Test the impact of 3 sulphuric acid atazanavir endotoxemia rats
3.1 material
Sulphuric acid atazanavir (purity 99.5% is bought in Han Xiang bio tech ltd, Shanghai)
Endotoxin: Sigma company, lot number: 20130412
D-galactosamine (import subpackage, 5g/ bottle, Beijing chemical reagents corporation, lot number: 120912)
Tachypleus amebocyte lysate test kit (the biochemical Industrial Co., Ltd of Foochow, Fujian Province Xin Bei, lot number: 130430)
Laboratory animal: SPF level Sprague Dawley rat, male, body weight 150 g-200 g, 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
Rat is divided into model group, sulphuric acid atazanavir intravenous injection 5mg/kg, 25mg/kg, 100mg/kg, 200mg/kg, sulphuric acid atazanavir gastric infusion 10mg/kg, 50mg/kg, 300mg/kg, 600mg/kg, 10 every group at random.Rat fasting 16h before experiment, can't help water.During experiment through tail vein injection D-galactosamine (300mg/kg), through intragastric infusion endotoxin (20mg/kg), carry out modeling immediately, respectively organize immediately administration, model group gives the normal saline of same volume, each group respectively at modeling after 24h eye socket get blood, get 10 normal rats simultaneously and get blood, measure level of endotoxin in blood plasma.Plasma endotoxin is measured with adopting tachypleus amebocyte lysate chromogenic substrate method, and between group, T check, carries out statistical procedures.
Level of endotoxin impact (n=10) in table 3 sulphuric acid atazanavir endotoxemia rat plasma
With model group comparison,
*p < 0.05;
*p < 0.01
Table 3 result of the test shows that sulphuric acid atazanavir intravenous injection 5mg/kg, 25mg/kg, 100mg/kg, 200mg/kg, sulphuric acid atazanavir gastric infusion 10mg/kg, 50mg/kg, 300mg/kg, 600mg/kg group can significantly reduce level of endotoxin in Endotoxemia blood plasma (with model group comparison, p < 0.05 or p < 0.01).Sulphuric acid atazanavir intravenous injection 100mg/kg group reduces Endotoxemia serum endotoxin level and sulphuric acid atazanavir intravenous injection 200mg/kg group compares there was no significant difference; Sulphuric acid atazanavir gastric infusion 300mg/kg group reduces Endotoxemia serum endotoxin level, compares there was no significant difference with sulphuric acid atazanavir gastric infusion 600mg/kg group.
Claims (6)
1. the invention provides the application of sulphuric acid atazanavir in preparation prevention or treatment endotoxemia and pyemic medicine.
2. application according to claim 1, sulphuric acid atazanavir is to reach prevention or treatment endotoxemia and sepsis by suppressing HMGB1.
3. application according to claim 2, sulphuric acid atazanavir can prevent or treat endotoxemia.
4. application according to claim 2, the prevention of sulphuric acid atazanavir or treatment sepsis.
5. according to the application described in claim 3 and 4, when sulphuric acid atazanavir is used for endotoxemia and sepsis, its injection using dosage scope is 50mg～2000mg; Preferred 50～1000mg; It orally uses dosage range is 100mg～6000mg; Preferred 200～3000mg.
6. application according to claim 5, the medicine that sulphuric acid atazanavir and pharmaceutically acceptable carrier or adjuvant form, this medicine can be prepared into injection, freeze-dried powder, tablet, capsule, thin membrane coated tablet with pharmacy conventional method, preferably with freeze-dried powder and capsule form, exists.
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| CN102112876A (en) * | 2008-05-28 | 2011-06-29 | 普罗瑟拉生物制剂有限责任公司 | Preparation and composition of inter-alpha inhibitor proteins from blood |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102112876A (en) * | 2008-05-28 | 2011-06-29 | 普罗瑟拉生物制剂有限责任公司 | Preparation and composition of inter-alpha inhibitor proteins from blood |
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