CN106309445A - New medical application of Nelfinavir to enhancement of anti-inflammatory action of glucocorticoid - Google Patents
New medical application of Nelfinavir to enhancement of anti-inflammatory action of glucocorticoid Download PDFInfo
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- CN106309445A CN106309445A CN201610688592.XA CN201610688592A CN106309445A CN 106309445 A CN106309445 A CN 106309445A CN 201610688592 A CN201610688592 A CN 201610688592A CN 106309445 A CN106309445 A CN 106309445A
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- Prior art keywords
- glucocorticoid
- group
- prednisolone
- viracept see
- see nelfinaivr
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
-
- 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
-
- 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
Abstract
The invention provides new medicine application of Nelfinavir, and in particular relates to application of Nelfinavir to enhancement of anti-inflammatory action of glucocorticoid through combined use of the Nelfinavir and the glucocorticoid. In the application, the oral dosage range is 250 to 4500 mg, preferably, 250 to 2250 mg.
Description
Technical field
The invention belongs to chemical medicine, be specifically related to anti-HIV protease inhibitors viracept see nelfinaivr 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 Definition 2012,307:2526–2533].In the U.S., be grown up ARDS patient morbidity
For annual 100000 people have 7 people's morbidities, although the management of ARDS had major progress, according to the clinical studies show 28 of nearly 3 years
There is 20-40% dead in it, it addition, the also patient of 15-20% dead [Rosuvastatin in 12 months
sepsis-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 and make with glucocorticosteroidsin in combination
Medicine necessary with the tolerance improving glucocorticoid.
Anti-HIV protease inhibitors (protease inhibitor) viracept see nelfinaivr cures mainly adult's HIV-I infection clinically,
Effectively press down for human immunodeficiency virus-1 (HIV-1) and the oral of human immunodeficiency virus-2 (HIV-2) aspartic protease
Preparation, blocks this enzymatic and makes in generation morphology the polyprotein needed for ripe HIV granule, makes HIV granule thus is maintained at into
Ripe state, thus HIV spreading in cell of slowing down, to prevent generation that a new round infects and to postpone advancing of disease, but
Anti-HIV protease inhibitors uses with glucocorticosteroidsin in combination, prevents or treat the tolerance that glucocorticoid life-time service causes
Pharmacological action have no report.By substantial amounts of research, the present inventor finds that anti-HIV protease inhibitors joins with glucocorticoid
Close and use, can substantially suppress the decline of GR α in target cell slurry, reduce the tolerance that glucocorticoid life-time service causes,
Strengthen the anti-inflammatory effect of glucocorticoid in ARDS treatment.Based on this, it is the most non-that the present inventor has invented anti-HIV protease inhibitors
That Wei uses with glucocorticosteroidsin in combination, reduces the tolerance that glucocorticoid life-time service causes, thus strengthens glucocorticoid
Curative effect, extend glucocorticoid use.
Summary of the invention
The invention provides anti-HIV protease inhibitors viracept see nelfinaivr 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 viracept see nelfinaivr 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 using dosage scope of the viracept see nelfinaivr that the present invention provides is 250mg～4500mg, preferably 250mg～2250mg.
Specific embodiment
Experimental example 1 anti-HIV protease inhibitors viracept see nelfinaivr 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)
Viracept see nelfinaivr (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)+viracept see nelfinaivr (1 μM action time 96h)；(4) (3) prednisolone process group (30 μMs of action times
96h)+viracept see nelfinaivr (3 μMs action time 96h)；(5) (3) prednisolone process group (30 μMs action time 96h)+viracept see nelfinaivr (10
μM action time 96h)；The cell cracking cultivated, extracts total protein with thin with total protein extraction reagent and nucleus extraction reagent
Karyon component, after BCA protein determination kit (Pierce company) measures protein concentration, takes 50 μ g sample proteins and carries out 10%
Dodecyl sodium sulfate 2 polyacrylamide (SDS-PAGE) gel denaturing electrophoretic, then go to polyvinylidene fluoride (PVDF) film,
Being separately added into GR Alpha antibodies, β-actin makees internal reference, GR α protein expression in Western blot detection cell cytosol.Do not sting with LPS
Swash group conduct comparison, be calculated as the 100% of corresponding albumen, analyze anti-HIV protease inhibitors+prednisolone and process with simple prednisolone
The group differential expression to GR α albumen, carries out T inspection between group.
Table 1 viracept see nelfinaivr stimulates the impact (n=5) of the GR α of PMEC (Pulmonary Microvascular Endothelial Cells) to LPS
| Group | GR α (%) |
| Normal group | 100±16 |
| LPS stimulation group | 26±5 |
| LPS+ prednisolone group | 15±4* |
| LPS+ prednisolone+viracept see nelfinaivr 1 μM group | 30±5**## |
| LPS+ prednisolone+viracept see nelfinaivr 3 μMs group | 39±6**## |
| LPS+ prednisolone+viracept see nelfinaivr 10 μMs group | 51±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 viracept see nelfinaivr
ARDS) impact of rat model
2.1 medicines and reagent
LPS (Sigma Products is bought in Dalian Mei Lun Bioisystech Co., Ltd)
Viracept see nelfinaivr (purity 99.2% 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 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+ viracept see nelfinaivr gastric infusion
25mg/kg group, prednisolone intramuscular injection 20mg/kg+ viracept see nelfinaivr gastric infusion 75mg/kg group, prednisolone intramuscular injection 20mg/
Kg+ viracept see nelfinaivr gastric infusion 225mg/kg group, prednisolone intramuscular injection 20mg/kg+ viracept see nelfinaivr gastric infusion 450mg/kg
Group.Additionally take 10 rats as a control group.Tracheal strips instills LPS to start to be administered for 24 hours, and successive administration 5 days is given daily
1 time, 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.AcuteLung 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 Biol44,725-738 (2011) .] mark.Relatively viracept see nelfinaivr 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+ viracept see nelfinaivr gavage is given
Medicine 25mg/kg group, prednisolone intramuscular injection 20mg/kg+ viracept see nelfinaivr gastric infusion 75mg/kg group, prednisolone intramuscular injection
20mg/kg+ viracept see nelfinaivr gastric infusion 225mg/kg group, prednisolone intramuscular injection 20mg/kg+ viracept see nelfinaivr gastric infusion
450mg/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+ viracept see nelfinaivr gastric infusion 25mg/kg group,
Prednisolone intramuscular injection 20mg/kg+ viracept see nelfinaivr gastric infusion 75mg/kg group, prednisolone intramuscular injection 20mg/kg+ Nai Feina
Wei gastric infusion 225mg/kg group, prednisolone intramuscular injection 20mg/kg+ viracept see nelfinaivr gastric infusion 450mg/kg group significantly reduce
The paragonimus cyst of ARDS rat model, reduces lung pathology scoring (comparing with prednisolone group, p < 0.05 or p < 0.01), Nai Feina is described
Wei is used in combination with prednisolone, hence it is evident that strengthen the anti-ARDS effect of prednisolone.Prednisolone intramuscular injection 20mg/kg+ viracept see nelfinaivr
Gastric infusion 450mg/kg group reduces the paragonimus cyst of ARDS rat model, reduces lung pathology scoring and prednisolone intramuscular injection
20mg/kg+ DRV ethylate gastric infusion 225mg/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 viracept see nelfinaivr
| Group | Paragonimus cyst | Lung pathology is marked |
| Matched group | 0.49±0.04 | --- |
| Model group | 1.10±0.11 | 0.82±0.11 |
| Prednisolone group | 0.98±0.09* | 0.69±0.09** |
| Prednisolone+viracept see nelfinaivr 25mg/kg group | 0.87±0.09**# | 0.57±0.10**# |
| Prednisolone+viracept see nelfinaivr 75mg/kg group | 0.78±0.09**## | 0.44±0.11**## |
| Prednisolone+viracept see nelfinaivr 225mg/kg group | 0.69±0.08**## | 0.33±0.08**## |
| Prednisolone+viracept see nelfinaivr 450mg/kg group | 0.68±0.08**## | 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 viracept see nelfinaivr, is specifically related to viracept see nelfinaivr 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 viracept see nelfinaivr 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 viracept see nelfinaivr
It is 250mg～4500mg.
Application the most according to claim 6, it is characterised in that the using dosage scope of viracept see nelfinaivr be 250mg～
2250mg。
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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 CN201610688592.XA patent/CN106309445A/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 |
|---|
| 宁光: "糖皮质激素临床应用基本原则", 《中国实用内科杂志》 * |
| 曹元华 等: "《中国女性皮肤病学》", 31 December 2009, 中国协和医科大学出版社 * |
| 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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