CN106310280A - New medical use of darunavir ethanolate for enhancing anti-inflammatory action of glucocorticoid - Google Patents
New medical use of darunavir ethanolate for enhancing anti-inflammatory action of glucocorticoid Download PDFInfo
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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
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Abstract
The invention provides new medical use of darunavir ethanolate, particularly relates to the medical use that the combined use of darunavir ethanolate and glucocorticoidis enhances anti-inflammatory action of glucocorticoid. According to the application, the Oral dosage range is from 100 milligrams to 3000 milligrams, and the preferred range is from 100 milligrams to 1500 milligrams.
Description
Technical field
The invention belongs to chemical medicine, be specifically related to anti-HIV protease inhibitors DRV 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.2016 Apr 28.pii:S0140-6736(16)00578-X.].Find and glucocorticosteroidsin in combination
The medicine used is necessary with the tolerance improving glucocorticoid.
Anti-HIV protease inhibitors (protease inhibitor) DRV (Darunavir clinically
Ethanolate) cure mainly adult HIV-I to infect, for human immunodeficiency virus-1 (HIV-1) and human immunodeficiency virus-2 (HIV-
2) oral effective inhibitor of aspartic protease, blocks this enzymatic and makes gathering needed for ripe HIV granule in generation morphology
Albumen, makes HIV granule thus is maintained at immature state, thus HIV spreading in cell of slowing down, to prevent new round sense
The generation of dye and delay advancing of disease, 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 DRV 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 DRV 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 DRV 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 DRV that the present invention provides is 100mg～3000mg, preferably 100mg～1500mg.
Specific embodiment
Experimental example 1 anti-HIV protease inhibitors DRV 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)
DRV ethylate (purity 99.5% is bought in Han Xiang bio tech ltd, Shanghai)
GR Alpha antibodies (Glucocorticoid Receptor (D8H2)Rabbit mAb, cellsignal company,
Article No.: 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)+DRV ethylate (1 μM action time 96h)；(4) prednisolone process group is (during 30 μMs of effects
Between 96h)+DRV ethylate (3 μMs action time 96h)；(5) prednisolone process group (30 μMs action time 96h)+ground auspicious that
Wei ethylate (10 μMs action time 96h)；The cell cracking cultivated, extracts with total protein extraction reagent and nucleus extraction reagent
Total protein and nuclear components, after BCA protein determination kit (Pierce company) measures protein concentration, take 50 μ g sample proteins
Carry out dodecyl sodium sulfate 2 polyacrylamide (SDS-PAGE) the gel denaturing electrophoretic of 10%, then go to gather inclined difluoro second
Alkene (PVDF) film, is separately added into GR Alpha antibodies, and β-actin makees internal reference, GR α albumen table in Western blot detection cell cytosol
Reach.Do not stimulate group as comparison using LPS, be calculated as the 100% of corresponding albumen, analyze anti-HIV protease inhibitors+prednisolone and list
The pure prednisolone process group differential expression to GR α albumen, carries out T inspection between group.
Table 1 DRV stimulates the impact (n=5) of the GR α of PMEC (Pulmonary Microvascular Endothelial Cells) to LPS
| Group | GR α (%) |
| Normal group | 100±12 |
| LPS stimulation group | 23±5 |
| LPS+ prednisolone group | 15±4* |
| LPS+ prednisolone+DRV 1 μM group | 27±5**## |
| LPS+ prednisolone+DRV 3 μMs group | 35±6**## |
| LPS+ prednisolone+DRV 10 μMs group | 47±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 DRV
ARDS) impact of rat model
2.1 medicines and reagent
LPS (Sigma Products is bought in Dalian Mei Lun Bioisystech Co., Ltd)
DRV ethylate (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 (Glucocorticoid Receptor (D8H2)Rabbit mAb, cellsignal company,
Article No.: 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+ DRV ethylate gavage
It is administered 10mg/kg group, prednisolone intramuscular injection 20mg/kg+ DRV ethylate gastric infusion 30mg/kg group, prednisolone flesh
Meat injection 20mg/kg+ DRV ethylate gastric infusion 150mg/kg group, prednisolone intramuscular injection 20mg/kg+ DRV
Ethylate gastric infusion 300mg/kg group.Additionally take 10 rats as a control group.Tracheal strips instill within LPS24 hour, start to
Medicine, successive administration 5 days, it is given daily 1 time, last is administered and terminates 24 hours, puts to death animal, takes lung, weigh, and measures paragonimus cyst,
Taking 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.Comparatively
Rui Nawei ethylate 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+ DRV ethylate
Gastric infusion 10mg/kg group, prednisolone intramuscular injection 20mg/kg+ DRV ethylate gastric infusion 30mg/kg group, first are strong
Dragon intramuscular injection 20mg/kg+ DRV ethylate gastric infusion 150mg/kg group, prednisolone intramuscular injection 20mg/kg+ ground are auspicious
That Wei ethylate gastric infusion 300mg/kg group significantly reduces the paragonimus cyst of ARDS rat model, reduces lung pathology and marks (with mould
Type group compares, p < 0.01)；Compare with prednisolone intramuscular injection 20mg/kg group, prednisolone intramuscular injection 20mg/kg+ DRV
Ethylate gastric infusion 10mg/kg group, prednisolone intramuscular injection 20mg/kg+ DRV ethylate gastric infusion 30mg/kg
Group, prednisolone intramuscular injection 20mg/kg+ DRV ethylate gastric infusion 150mg/kg group, prednisolone intramuscular injection 20mg/
Kg+ DRV ethylate gastric infusion 300mg/kg group significantly reduces the paragonimus cyst of ARDS rat model, reduces lung pathology and comments
Divide (comparing with prednisolone group, p < 0.05 or p < 0.01), illustrate that DRV ethylate is used in combination with prednisolone, hence it is evident that strengthen
The anti-ARDS effect of prednisolone.Prednisolone intramuscular injection 20mg/kg+ DRV ethylate gastric infusion 300mg/kg group reduces
The paragonimus cyst of ARDS rat model, reduces lung pathology scoring and prednisolone intramuscular injection 20mg/kg+ DRV ethylate gavage
It is administered 150mg/kg group to compare, there was no significant difference.
The impact (n=10) on ARDS rat model paragonimus cyst and lung pathology of table 2 DRV
| Group | Paragonimus cyst | Lung pathology is marked |
| Matched group | 0.49±0.04 | --- |
| Model group | 1.16±0.11 | 0.86±0.11 |
| Prednisolone group | 1.04±0.09* | 0.73±0.09** |
| Prednisolone+DRV 10mg/kg group | 0.93±0.09**# | 0.61±0.10**# |
| Prednisolone+DRV 30mg/kg group | 0.87±0.09**## | 0.50±0.11**## |
| Prednisolone+DRV 150mg/kg group | 0.76±0.08**## | 0.32±0.08**## |
| Prednisolone+DRV 300mg/kg group | 0.75±0.08**## | 0.31±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 DRV, is specifically related to DRV 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 DRV 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 DRV
It is 100mg～3000mg.
Application the most according to claim 6, it is characterised in that the using dosage scope of DRV be 100mg～
1500mg。
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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 (3)
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| CN102811730A (en) * | 2010-02-08 | 2012-12-05 | 杜涛 | Methods for the use of progestogen as a glucocorticoid sensitizer |
| CN103989689A (en) * | 2014-05-28 | 2014-08-20 | 滨州医学院 | Application of darunavir ethanolate in preparing medicine for preventing or treating acute lung injury/acute respiratory distress syndrome and pulmonary fibrosis |
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2016
- 2016-08-18 CN CN201610681444.5A patent/CN106310280A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1163571A (en) * | 1994-09-28 | 1997-10-29 | 比克·古尔顿·劳姆贝尔格化学公司 | Compositions containing at least one glucocorticoid in combination with pulmonary surfactant for treatment of IRDS and ARDS |
| CN102811730A (en) * | 2010-02-08 | 2012-12-05 | 杜涛 | Methods for the use of progestogen as a glucocorticoid sensitizer |
| CN103989689A (en) * | 2014-05-28 | 2014-08-20 | 滨州医学院 | Application of darunavir ethanolate in preparing medicine for preventing or treating acute lung injury/acute respiratory distress syndrome and pulmonary fibrosis |
Non-Patent Citations (4)
| Title |
|---|
| KRISTIN H.S.BUSSE & SCOTT R.PENZAK: "Darunavir:A second-generation protease inhibitor", 《AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY》 * |
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| 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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