CN106139154A - Amprenavir strengthens the new medical use of glucocorticoid antiinflammatory action - Google Patents
Amprenavir strengthens the new medical use of glucocorticoid antiinflammatory action Download PDFInfo
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- CN106139154A CN106139154A CN201610687345.8A CN201610687345A CN106139154A CN 106139154 A CN106139154 A CN 106139154A CN 201610687345 A CN201610687345 A CN 201610687345A CN 106139154 A CN106139154 A CN 106139154A
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- amprenavir
- glucocorticoid
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- prednisolone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
Abstract
The invention provides the new medicine use of amprenavir, be specifically related to the application in the medicine of the antiinflammatory action that amprenavir strengthens glucocorticoid with glucocorticosteroidsin in combination use.In above-mentioned application, it orally uses dosage range is 40mg～1600mg；Preferably 40～800mg.
Description
Technical field
The invention belongs to chemical medicine, be specifically related to anti-HIV protease inhibitors amprenavir and glucocorticoid
It is used in combination, strengthens glucocorticoid in glucocorticoid anti-inflammatory effect and treatment acute respiratory distress syndrome treatment and make for a long time
With the tolerance caused.
Background technology
Glucocorticoid (Glucocorticoid, GC) is by a class steroid hormone of adrenocortical secretion.Sugar cortex
Hormone has antiinflammatory action quick, powerful and nonspecific.The most effective to various inflammation.At the inflammation initial stage, GC suppresses blood capillary
Enlargement of pipe, alleviates and oozes out and edema, suppresses again infiltration and the phagocytosis of leukocyte, and the symptom that reduces inflammation.In the inflammation later stage, press down
Blood capillary processed and the hypertrophy of fibroblast, delay the generation of granulation tissue.And alleviate the inflammatory sequelae such as cicatrix and adhesion.
Glucocorticoid is treatment acute respiratory distress syndrome and the common drug of asthma, but in life-time service or heavy dose of application
Time, the phenomenon that the curative effect of glucocorticoid declines, referred to as glucocorticoid tolerance occur.Glucocorticoid combines glucocorticoid
Receptor (GR), in the GR rapid translocation of activation to nucleus, transcriptional activation or Transcription inhibition subtract oligogenic expression.Transcriptional activation
GR combine glucocorticoid responsive element (GRE), transcribing, such as the synthesis of lipocortin-1 of induction antiinflammatory target gene.Sugar
Corticosteroid therapy suggestion was less than 14 days [Steinberg KB, Hudson LD, Goodman RB, et al.Effi cacy
and safety of corticosteroids for persistent acute respiratory distress
syndrome.N Engl J Med 2006；354:1671-1684], reason is that high dose glucocorticoid life-time service causes
Glucocorticoid tolerates, i.e. glucocorticoid can not effectively be combined, i.e. with its Receptor Glucocorticoids receptor alpha (GR α) effectively
In cytoplasm, GR α declines.The transcriptional activity of GR α is then suppressed, it is impossible to transcribing of suppression inflammation-related gene, causes antiphlogistic effects
Weaken, tolerate.
Adult respiratory distress syndrome (acute respiratory distress syndrome, ARDS) refers to the non-heart
Inside and outside the various lungs of source property, paathogenic factor causes serious Acute Hypoxic respiratory failure, clinically with respiratory distress, intractable
Hypoxemia and non cardiogenic pulmonary edema are characterized.The most basic pathological change of ARDS pulmonary is lung endothelium and lung epithelial urgency
Property diffusivity damage and hyaline membrane.ARDS risk factors both may be from the coup injury of lung, also may be from indirect injury
[The ARDS Definition Task Force,Ranieri VM,Rubenfeld GD,Thompson BT,Ferguson
ND,Caldwell E,Fan E,Camporota L,Slutsky AS:Acute Respiratory Distress
Syndrome:The Berlin Definition2012,307:2526–2533].In the U.S., adult ARDS patient morbidity is
Annual 100000 people have 7 people's morbidities, although the management of ARDS had major progress, according to the clinical studies show 28 days of nearly 3 years
Inside there is 20-40% dead, it addition, the also patient of 15-20% dead [Rosuvastatin for sepsis-in 12 months
associated acute respiratory distress syndrome.N Engl J Med 2014；370:2191–
200.；Sweeney RM,McAuley DF.Acute respiratory distress syndrome.Lancet.2016Apr
28.pii:S0140-6736(16)00578-X.].Find the medicine used with glucocorticosteroidsin in combination to improve glucocorticoid
Tolerance necessary.
Anti-HIV protease inhibitors (protease inhibitor) amprenavir (Amprenavir) is a kind of clinically
New anti-reflective turns hiv protease inhibitor, has anti-HIV-1 and HIV-2 protease effect, can block necessary to HIV maturation
Protein precursor divides, the growth course of viral interference, then discharges and immature does not have communicable viruses molecule.Long
Phase applies this product, generally can reduce the inhibition of HIV load in blood, increases CD4The counting of cell, reduces the machine of aids infection
Meeting, improves the quality of living, extending life, but anti-HIV protease inhibitors uses with glucocorticosteroidsin in combination, prevents or treats sugar
The pharmacological action of the tolerance that 17-hydroxy-11-dehydrocorticosterone life-time service causes has no report.The present inventor finds AntiHIV1 RT activity by substantial amounts of research
Protease inhibitor uses with glucocorticosteroidsin in combination, can substantially suppress the decline of GR α in target cell slurry, reduce sugar skin
The tolerance that matter hormone life-time service causes, strengthens the anti-inflammatory effect of glucocorticoid in ARDS treatment.Based on this, Crinis Carbonisatus of the present invention
Understand that anti-HIV protease inhibitors amprenavir uses with glucocorticosteroidsin in combination, reduce glucocorticoid life-time service and cause
Tolerance, thus strengthen the curative effect of glucocorticoid, extend the use of glucocorticoid.
Summary of the invention
The invention provides anti-HIV protease inhibitors amprenavir to use with glucocorticosteroidsin in combination, treat acute exhaling
Inhale the tolerance that in Distress Syndrome treatment, glucocorticoid life-time service causes, strengthen the medicine of the antiinflammatory action of glucocorticoid
In application.
The anti-HIV protease inhibitors amprenavir that the present invention provides uses with glucocorticosteroidsin in combination, and suppression is acute
In respiratory distress syndrome treatment, in target cell slurry, declining of GR α treats the tolerance that glucocorticoid life-time service causes.
The glucocorticoid that the present invention provides includes middle effect glucocorticoid and Glucocorticoid.
The Glucocorticoid that the present invention provides includes can being dexamethasone, fluticasone propionate.
The middle effect glucocorticoid that the present invention provides can be Urbason Solubile (prednisolone), prednisolone
The preferred Urbason Solubile of the middle effect glucocorticoid (prednisolone) that the present invention provides.
The amprenavir using dosage scope that the present invention provides is 100mg～2400mg, preferably 100mg～1200mg
Specific embodiment
Experimental example 1 anti-HIV protease inhibitors amprenavir stimulates GR α and the phosphoric acid of PMEC (Pulmonary Microvascular Endothelial Cells) to LPS
Change the impact of NF-κ B
1.1 medicines and reagent
DMEM culture medium is Gibco Products, and new-born calf serum is Hangzhou Ilex purpurea Hassk.[I.chinensis Sims Products
LPS (Sigma Products is bought in Dalian Mei Lun Bioisystech Co., Ltd)
Amprenavir (purity 99.2% is bought in Han Xiang bio tech ltd, Shanghai)
GR Alpha antibodies (Glucocorticoid Receptor (D8H2)Rabbit mAb, cellsignal company, goods
Number: 3660s)
Human pulmonary microvascular endothelial cells (Chinese Academy of Sciences's cell bank)
Prednisolone (methylprednisolone sodium succinate for injection, Pfizer produces, 500mg/ bottle)
1.2 experimental techniques and result
When PMEC (Pulmonary Microvascular Endothelial Cells) growth is fused to 70%-80%, change fresh medium, the people's organs except lungs that will pass on
Endotheliocyte packet includes: (1) negative control group；(2) prednisolone process group (30 μMs action time 96h)；(3) prednisolone processes
Group (30 μMs action time 96h)+amprenavir (1 μM action time 96h)；(4) prednisolone process group (30 μMs action time 96h)
+ amprenavir (3 μMs action time 96h)；(5) prednisolone process group (30 μMs action time 96h)+amprenavir (10 μMs of effects
Time 96h)；The cell cracking cultivated, extracts total protein and nucleus group with total protein extraction reagent and nucleus extraction reagent
Point, after BCA protein determination kit (Pierce company) measures protein concentration, take 50 μ g sample proteins and carry out the dodecane of 10%
Base sodium sulfonate 2 polyacrylamide (SDS-PAGE) gel denaturing electrophoretic, then go to polyvinylidene fluoride (PVDF) film, add respectively
Entering GR Alpha antibodies, β-actin makees internal reference, GR α protein expression in Westernblot detection cell cytosol.Group is not stimulated to make with LPS
For comparison, it is calculated as the 100% of corresponding albumen, analyzes anti-HIV protease inhibitors+prednisolone with simple prednisolone process group to GR
The differential expression of α, carries out T inspection between group.
Table 1 amprenavir stimulates the impact (n=5) of the GR α of PMEC (Pulmonary Microvascular Endothelial Cells) to LPS
| Group | GR α (%) |
| Normal group | 100±14 |
| LPS stimulation group | 25±6 |
| LPS+ prednisolone group | 14±4* |
| LPS+ prednisolone+amprenavir 1 μM group | 28±8**# |
| LPS+ prednisolone+amprenavir 3 μMs group | 39±6**## |
| LPS+ prednisolone+amprenavir 10 μMs group | 53±8**## |
*, p < 0.05,**, p < 0.01, stimulate with LPS and compare；#, p < 0.05,##, p < 0.01, compares with LPS+ prednisolone group
Adult respiratory distress syndrome (the ALI/ that LPS is caused by experimental example 2 anti-HIV protease inhibitors amprenavir
ARDS) impact of rat model
2.1 medicines and reagent
LPS (Sigma Products is bought in Dalian Mei Lun Bioisystech Co., Ltd)
Amprenavir (purity 99.5% is bought in Han Xiang bio tech ltd, Shanghai)
Prednisolone (methylprednisolone sodium succinate for injection, Pfizer produces, 500mg/ bottle)
GR Alpha antibodies (GlucocorticoidReceptor (D8H2)RabbitmAb, cellsignal company, goods
Number: 3660s)
Laboratory animal: SPF level Sprague Dawley rat, male, body weight 150g-200g, Shandong greenery pharmacy share
Company limited's Experimental Animal Center provides, and the animal quality certification number is: SYXK (Shandong) 20030020.
2.2 experimental techniques and result
2.2.1 endotoxin two-hit ARDS rat model is prepared, is grouped and is administered
Male rat 70, body weight 180-220g, take 60 lumbar injection LPS 2mg/kg, 10% hydration chlorine after 16 hours
Aldehyde is anaesthetized, and separates trachea, and tracheal strips instills LPS normal saline solution, volume 0.2mL/, dosage: 5mg/kg.It is randomly divided into 6
Group, i.e. model group, prednisolone intramuscular injection 20mg/kg group, prednisolone intramuscular injection 20mg/kg+ amprenavir gastric infusion
4mg/kg group, prednisolone intramuscular injection 20mg/kg+ amprenavir gastric infusion 20mg/kg group, prednisolone intramuscular injection 20mg/
Kg+ amprenavir gastric infusion 80mg/kg group, prednisolone intramuscular injection 20mg/kg+ amprenavir gastric infusion 160mg/kg
Group.Additionally take 10 rats as a control group.Tracheal strips instills and within LPS24 hour, starts to be administered, and successive administration 5 days is given daily 1
Secondary, last is administered and terminates 24 hours, puts to death animal, takes lung, weigh, and measures paragonimus cyst, takes a leaf lung, and pathology is prepared in HE dyeing
Sheet, carries out pathological score, and pathological score is according to list of references [Matute-Bello, G.et al.Acute Lung Injury
in Animals Study Group.An official American Thoracic Society workshop report:
features and measurements of experimental acute lung injury in animals.Am J
Respir Cell Mol Biol 44,725-738 (2011) .] mark.Relatively amprenavir adds prednisolone group and model
Group and the difference of simple prednisolone group.T inspection is carried out between group.
2.2.2 experimental result
Table 2 result display prednisolone intramuscular injection 20mg/kg group can obviously reduce the paragonimus cyst of ARDS rat model, reduces
Lung pathology scoring (comparing with model group, p < 0.05 or p < 0.01)；Prednisolone intramuscular injection 20mg/kg+ amprenavir gavage is given
Medicine 4mg/kg group, prednisolone intramuscular injection 20mg/kg+ amprenavir gastric infusion 20mg/kg group, prednisolone intramuscular injection
20mg/kg+ amprenavir gastric infusion 80mg/kg group, prednisolone intramuscular injection 20mg/kg+ amprenavir gastric infusion
160mg/kg group significantly reduces the paragonimus cyst of ARDS rat model, reduces lung pathology scoring (comparing, p < 0.01) with model group；With
Prednisolone intramuscular injection 20mg/kg group compares, prednisolone intramuscular injection 20mg/kg+ amprenavir gastric infusion 5mg/kg group, first
Strong dragon intramuscular injection 20mg/kg+ amprenavir gastric infusion 20mg/kg group, prednisolone intramuscular injection 20mg/kg+ amprenavir
Gastric infusion 80mg/kg group, prednisolone intramuscular injection 20mg/kg+ amprenavir gastric infusion 160mg/kg group significantly reduce
The paragonimus cyst of ARDS rat model, reduces lung pathology scoring (comparing, p < 0.05 or p < 0.01) with prednisolone group, illustrates to pacify Pune
Wei is used in combination with prednisolone, hence it is evident that strengthen the anti-ARDS effect of prednisolone.Prednisolone intramuscular injection 20mg/kg+ amprenavir
Gastric infusion 160mg/kg group reduces the paragonimus cyst of ARDS rat model, reduces lung pathology scoring and prednisolone intramuscular injection
20mg/kg+ amprenavir gastric infusion 80mg/kg group compares, and there was no significant difference.
The impact (n=10) on ARDS rat model paragonimus cyst and lung pathology of table 2 amprenavir
| Group | Paragonimus cyst | Lung pathology is marked |
| Matched group | 0.48±0.04 | --- |
| Model group | 1.14±0.10 | 0.85±0.08 |
| Prednisolone group | 1.02±0.08* | 0.71±0.08** |
| Prednisolone+amprenavir 4mg/kg group | 0.91±0.10**# | 0.60±0.10**# |
| Prednisolone+amprenavir 20mg/kg group | 0.79±0.10**## | 0.48±0.10**## |
| Prednisolone+amprenavir 80mg/kg group | 0.69±0.08**## | 0.33±0.06**## |
| Prednisolone+amprenavir 160mg/kg group | 0.68±0.09**## | 0.32±0.07**## |
*, p < 0.05,**, p < 0.01, compares with model group；#, p < 0.05,##, p < 0.01, compares with prednisolone group.
Claims (7)
1. a new medical use for amprenavir, is specifically related to amprenavir and uses enhancing sugar cortex with glucocorticosteroidsin in combination
Application in the medicine of the antiinflammatory action of hormone.
Application the most according to claim 1, it is characterised in that amprenavir and glucocorticosteroidsin in combination use treatment acute
Respiratory distress syndrome, strengthens the antiinflammatory action of glucocorticoid.
Application the most according to claim 2, it is characterised in that glucocorticoid is middle effect glucocorticoid and long-acting sugar skin
Matter hormone.
Application the most according to claim 2, it is characterised in that middle effect glucocorticoid includes Urbason Solubile,
Prednisolone.
Application the most according to claim 4, it is characterised in that middle effect glucocorticoid is Urbason Solubile.
6. according to the application described in claim 2-5 any claim, it is characterised in that the using dosage scope of amprenavir
It is 40mg～1600mg.
Application the most according to claim 6, it is characterised in that the using dosage scope of amprenavir is 40mg～800mg.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106727592A (en) * | 2017-03-06 | 2017-05-31 | 滨州医学院 | De Tegewei strengthens the new medical use of glucocorticoid antiinflammatory action |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104083386A (en) * | 2014-07-08 | 2014-10-08 | 滨州医学院 | Use of amprenavir in preparation of medicines for preventing or treating acute lung injury/acute respiratory distress syndrome and pulmonary fibrosis |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104083386A (en) * | 2014-07-08 | 2014-10-08 | 滨州医学院 | Use of amprenavir in preparation of medicines for preventing or treating acute lung injury/acute respiratory distress syndrome and pulmonary fibrosis |
Non-Patent Citations (3)
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| 国家食品药品监督管理局执业药师资格认证中心编写: "《药学综合知识与技能》", 31 January 2011, 中国医药科技出版社 * |
| 宁光: "糖皮质激素临床应用基本原则", 《中国实用内科杂志》 * |
| 李淑英等: "糖皮质激素治疗急性呼吸窘迫综合征的疗效观察", 《中国医药指南》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106727592A (en) * | 2017-03-06 | 2017-05-31 | 滨州医学院 | De Tegewei strengthens the new medical use of glucocorticoid antiinflammatory action |
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