CN106176751A - Indinavir strengthens the new medical use of glucocorticoid antiinflammatory action - Google Patents
Indinavir strengthens the new medical use of glucocorticoid antiinflammatory action Download PDFInfo
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- CN106176751A CN106176751A CN201610702265.5A CN201610702265A CN106176751A CN 106176751 A CN106176751 A CN 106176751A CN 201610702265 A CN201610702265 A CN 201610702265A CN 106176751 A CN106176751 A CN 106176751A
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- glucocorticoid
- indinavir
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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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
Abstract
The invention provides the new medicine use of indinavir, be specifically related to the application in the medicine of the antiinflammatory action that indinavir strengthens glucocorticoid with glucocorticosteroidsin in combination use.In above-mentioned application, it orally uses dosage range is 400mg～4800mg；Preferably 400～2400mg.
Description
Technical field
The invention belongs to chemical medicine, be specifically related to anti-HIV protease inhibitors indinavir sulfate and sugar cortex
Hormons uses, and strengthens glucocorticoid in glucocorticoid anti-inflammatory effect and treatment acute respiratory distress syndrome treatment long
Phase uses 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.2016
Apr 28.pii:S0140-6736(16)00578-X.].Find the medicine used with glucocorticosteroidsin in combination to improve sugar cortex
The tolerance of hormone is necessary.
Anti-HIV protease inhibitors (protease inhibitor) indinavir sulfate (Indinavir clinically
Sulfate) indication, for being used in combination with other antiretroviral drugs, is used for treating adult and child HIV-1 infects.
The clinical research of adult proves to slow down the development process of acquired immune deficiency syndrome (AIDS) or the lethal danger died, and increases overall survival rate, makes serum
Viral ribonucleic acid is in persistency low-level, make cd4 cell counting in persistency raise, but anti-HIV protease inhibitors with
Glucocorticosteroidsin in combination uses, and prevents or treat the pharmacological action of the tolerance that glucocorticoid life-time service causes to have no report.
By substantial amounts of research, the present inventor finds that anti-HIV protease inhibitors uses with glucocorticosteroidsin in combination, can substantially suppress
In target cell slurry, the decline of GR α, reduces the tolerance that glucocorticoid life-time service causes, and strengthens sugar cortex in ARDS treatment
The anti-inflammatory effect of hormone.Based on this, the present inventor has invented anti-HIV protease inhibitors indinavir sulfate and glucocorticoid
It is used in combination, reduces the tolerance that glucocorticoid life-time service causes, thus strengthen the curative effect of glucocorticoid, extend sugar cortex
The use of hormone.
Summary of the invention
The invention provides anti-HIV protease inhibitors indinavir sulfate to use with glucocorticosteroidsin in combination, treatment is anxious
Property respiratory distress syndrome treatment in the tolerance that causes of glucocorticoid life-time service, strengthen the antiinflammatory action of glucocorticoid
Application in medicine.
The anti-HIV protease inhibitors indinavir sulfate that the present invention provides uses with glucocorticosteroidsin in combination, suppresses
What during in acute respiratory distress syndrome treatment, target cell is starched, the decline treatment glucocorticoid life-time service of GR α caused is resistance to
It is subject to.
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 using dosage scope of the indinavir that the present invention provides is 400mg～4800mg, preferably 400mg～2400mg.
Specific embodiment
Experimental example 1 anti-HIV protease inhibitors indinavir sulfate to LPS stimulate PMEC (Pulmonary Microvascular Endothelial Cells) GR α and
The impact of phosphorylation 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)
Indinavir sulfate (purity 99.1% 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)+indinavir sulfate (1 μM action time 96h)；(4) prednisolone process group (30 μMs of action times
96h)+indinavir sulfate (3 μMs action time 96h)；(5) prednisolone process group (30 μMs action time 96h)+sulphuric acid indenes ground that
Wei (10 μMs action time 96h)；The cell cracking cultivated, extracts total protein with total protein extraction reagent and nucleus extraction reagent
And nuclear components, after BCA protein determination kit (Pierce company) measures protein concentration, take 50 μ g sample proteins and carry out
Dodecyl sodium sulfate 2 polyacrylamide (SDS-PAGE) the gel denaturing electrophoretic of 10%, then go to polyvinylidene fluoride
(PVDF) film, is separately added into GR Alpha antibodies, and β-actin makees internal reference, GR α protein expression in Western blot detection cell cytosol.
Do not stimulate group as comparison using LPS, be calculated as the 100% of corresponding albumen, analyze anti-HIV protease inhibitors+prednisolone with simple
The prednisolone process group differential expression to GR α, carries out T inspection between group.
Table 1 indinavir sulfate stimulates the impact (n=5) of the GR α of PMEC (Pulmonary Microvascular Endothelial Cells) to LPS
*, p < 0.05,**, p < 0.01, stimulate with LPS and compare；#, p < 0.05,##, p < 0.01, compares with LPS+ prednisolone group
The adult respiratory distress syndrome that LPS is caused by experimental example 2 anti-HIV protease inhibitors indinavir sulfate
(ALI/ARDS) impact of rat model
2.1 medicines and reagent
LPS (Sigma Products is bought in Dalian Mei Lun Bioisystech Co., Ltd)
Indinavir sulfate (purity 99.1% is bought in Han Xiang bio tech ltd, Shanghai)
Prednisolone (methylprednisolone sodium succinate for injection, Pfizer produces, 500mg/ bottle)
GR Alpha antibodies (Glucocorticoid Receptor (D8H2)Rabbit mAb, cellsignal company, goods
Number: 3660s) laboratory animal: SPF level Sprague Dawley rat, male, body weight 150g-200g, Shandong greenery pharmacy stock
Part company limited 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+ indinavir sulfate gavage is given
Medicine 40mg/kg group, prednisolone intramuscular injection 20mg/kg+ indinavir sulfate gastric infusion 80mg/kg group, prednisolone muscle are noted
Penetrate 20mg/kg+ indinavir sulfate gastric infusion 240mg/kg group, prednisolone intramuscular injection 20mg/kg+ indinavir sulfate fills
Stomach is administered 480mg/kg group.Additionally take 10 rats as a control group.Tracheal strips instills LPS to start to be administered for 24 hours, gives continuously
Medicine 5 days, is given daily 1 time, and last is administered and terminates 24 hours, puts to death animal, takes lung, weigh, and measures paragonimus cyst, takes a leaf lung,
Pathology sheet is prepared in HE dyeing, 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 sulphuric acid indenes ground
That Wei group adds prednisolone 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+ indinavir sulfate fills
Stomach is administered 40mg/kg group, prednisolone intramuscular injection 20mg/kg+ indinavir sulfate gastric infusion 80mg/kg group, prednisolone flesh
Meat injection 20mg/kg+ indinavir sulfate gastric infusion 240mg/kg group, prednisolone intramuscular injection 20mg/kg+ sulphuric acid indenes ground that
Wei gastric infusion 4800mg/kg group significantly reduces the paragonimus cyst of ARDS rat model, reduces lung pathology and marks (with model group ratio
Relatively, p < 0.01)；Comparing with prednisolone intramuscular injection 20mg/kg group, prednisolone intramuscular injection 20mg/kg+ indinavir sulfate fills
Stomach is administered 40mg/kg group, prednisolone intramuscular injection 20mg/kg+ indinavir sulfate gastric infusion 80mg/kg group, prednisolone flesh
Meat injection 20mg/kg+ indinavir sulfate gastric infusion 240mg/kg group, prednisolone intramuscular injection 20mg/kg+ sulphuric acid indenes ground that
Wei gastric infusion 480mg/kg group significantly reduces the paragonimus cyst of ARDS rat model, reduces lung pathology and marks (with prednisolone group ratio
Relatively, p < 0.05 or p < 0.01), illustrate that indinavir sulfate is used in combination with prednisolone, hence it is evident that the anti-ARDS strengthening prednisolone makees
With.Prednisolone intramuscular injection 20mg/kg+ indinavir sulfate gastric infusion 480mg/kg group reduces the lung system of ARDS rat model
Number, reduces lung pathology scoring and compares with prednisolone intramuscular injection 20mg/kg+ indinavir sulfate gastric infusion 240mg/kg group,
There was no significant difference.
The impact (n=10) on ARDS rat model paragonimus cyst and lung pathology of table 2 indinavir sulfate
*, 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 indinavir, is specifically related to indinavir 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 indinavir 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 indinavir
It is 400mg～4800mg.
Application the most according to claim 6, it is characterised in that the using dosage scope of indinavir be 400mg～
2400mg。
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610702265.5A CN106176751A (en) | 2016-08-18 | 2016-08-18 | Indinavir strengthens the new medical use of glucocorticoid antiinflammatory action |
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| CN201610702265.5A CN106176751A (en) | 2016-08-18 | 2016-08-18 | Indinavir strengthens the new medical use of glucocorticoid antiinflammatory action |
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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 |
|---|---|---|---|---|
| CN1353573A (en) * | 1999-05-14 | 2002-06-12 | 加利福尼亚大学董事会 | Anti-inflammatory therapy for inflammatory mediated infection |
-
2016
- 2016-08-18 CN CN201610702265.5A patent/CN106176751A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1353573A (en) * | 1999-05-14 | 2002-06-12 | 加利福尼亚大学董事会 | Anti-inflammatory therapy for inflammatory mediated infection |
Non-Patent Citations (3)
| Title |
|---|
| 国家食品药品监督管理局执业药师资格认证中心: "《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 |
|---|---|---|---|---|
| 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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| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20161207 |
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