CN109091473A - Application of the benserazide hydrochloride in preparation treatment acute lung injury drug - Google Patents
Application of the benserazide hydrochloride in preparation treatment acute lung injury drug Download PDFInfo
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- CN109091473A CN109091473A CN201811298432.XA CN201811298432A CN109091473A CN 109091473 A CN109091473 A CN 109091473A CN 201811298432 A CN201811298432 A CN 201811298432A CN 109091473 A CN109091473 A CN 109091473A
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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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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Abstract
The present invention relates to application of the benserazide hydrochloride in preparation treatment ALI drug, belong to biomedicine technical field.The present invention passes through animal experiment study therapeutic effect of the benserazide hydrochloride to ALI, benserazide hydrochloride can be relieved injury of lungs caused by mouse ALI and pulmonary edema as the result is shown, inhibit the release of a variety of pro-inflammatory cytokines, to have the function that mouse ALI caused by treating lipopolysaccharides.ALI model is constructed especially by lipopolysaccharide-induced C57BL/6 mouse, it is treated using the benserazide hydrochloride of various concentration, as a result, it has been found that benserazide hydrochloride can reduce lung injury caused by C57BL/6 mouse ALI, pulmonary edema and the secretion for inhibiting a variety of pro-inflammatory cytokines.The various preparations that benserazide hydrochloride is prepared into clinical needs by adding pharmaceutically acceptable carrier, the beneficial effect is that: a kind of new way is provided for preparation treatment ALI drug.
Description
Technical field
The present invention relates to application of the benserazide hydrochloride in preparation treatment acute lung injury drug, belong to biological medicine technology
Field.
Background technique
Acute lung injury (acute lung injury, ALI) is anxious as caused by the various pathogenic factors other than cardiogenic
Property, the hypoxic respiratory failure of progressive, it is characterised in that non cardiogenic pulmonary edema, expiratory dyspnea are clinically dead at present
Rate is high, it is difficult to cure.Inflammation is that the group rich in blood vessel is woven in a kind of physiological reaction occurred after local damage.In the process,
Various soluble mediators and inflammatory cell are played a role together in the form of system, to eliminate the factor meter for causing body injury
It is now red, swollen, hot, pain and dysfunction.But when inflammatory reaction is excessive, inflammatory mediator will generate abnormal somatic reaction,
Further when uncontrolled inflammation, serious tissue damage will lead to.The essence of ALI is uncontrolled inflammatory reaction, mistake
Degree or inflammatory reaction out of control will lead to the damage of bubble epithelial cell and endothelial cell, and the edematous fluid rich in protein enters lung
Bubble, in turn results in the oedema of lung.If the state of an illness is not effectively controlled during ALI, alveolar-capillary it is penetrating
Property continues to increase, finally will lead to acute respiratory distress syndrome (acute respiratory distress syndrome,
ARDS).Serious acute inflammatory reaction, a large amount of apoptosis of alveolar epithelial cells, alveolar-capillary permeability are continuously increased
It will lead to the slowly formation of pulmonary fibrosis.On a cellular level, the formation with development process of ALI are complete with alveolar capillary membrane
The destruction of whole property, the generation and secretion of excessive neutrophil migration and pro-inflammatory cytokine have close ties.
Benserazide hydrochloride (benserazide hydrochloride) is a kind of periphery decarboxylase inhibitors, is being cured at present
Medicine often combines the treatment that compound formulation Benserazide is made for Parkinson's disease with levodopa in the market, records in Chinese Pharmacopoeia
Version (ChP 2010) in 2010, European Pharmacopoeia 7.0 editions (EP7.0) and day pharmacopeia 16 editions (JP16) of version.Benserazide hydrochloride property pole
It is unstable, it is extremely sensitive to the variation of solvent PH, light, temperature and humidity.There has been no benserazide hydrochlorides to be used as treatment ALI at present
The report of drug.
Summary of the invention
The object of the present invention is to provide application of the benserazide hydrochloride in preparation treatment ALI drug.
The present invention passes through animal experiment study therapeutic effect of the benserazide hydrochloride to ALI, as the result is shown benserazide hydrochloride
Injury of lungs caused by mouse ALI and pulmonary edema can be alleviated, while inhibiting the release of a variety of pro-inflammatory cytokines, to reach
To the effect of mouse ALI caused by treatment lipopolysaccharides.ALI model is constructed particular by lipopolysaccharide-induced C57BL/6 mouse, is adopted
It is treated with the benserazide hydrochloride of various concentration, as a result, it has been found that benserazide hydrochloride can reduce C57BL/6 mouse ALI institute
Caused by lung injury, pulmonary edema and inhibit a variety of pro-inflammatory cytokine such as tumor necrosis factor (TNF-α), leucocyte
The secretion of -1 β of interleukin (IL-1 β) and interleukin-6 (IL-6).Benserazide hydrochloride is pharmaceutically acceptable by adding
Carrier is prepared into the various preparations of clinical needs, the beneficial effect is that: a kind of new way is provided for preparation treatment ALI drug.
Detailed description of the invention
Fig. 1 is blank control group mouse lung tissue HE dyeing microscopic examination figure.
Fig. 2 is model control group mouse lung tissue HE dyeing microscopic examination figure.
Fig. 3 is positive drug control group mouse lung tissue HE dyeing microscopic examination figure.
Fig. 4 is benserazide hydrochloride high dose group mouse lung tissue HE dyeing microscopic examination figure.
Fig. 5 is benserazide hydrochloride middle dose group mouse lung tissue HE dyeing microscopic examination figure.
Fig. 6 is benserazide hydrochloride low dose group mouse lung tissue HE dyeing microscopic examination figure.
Fig. 7 is data statistic analysis result figure of the hydrochloric acid benzyl silk various dose group to mouse lung edema therapeutic effect.
Fig. 8 is the ELISA result of IL-1 β secretion in mice serum.
Fig. 9 is the ELISA result of TNF-α secretion in mice serum.
Figure 10 is the ELISA result of IL-6 secretion in mice serum.
Specific embodiment
The present invention will be further described combined with specific embodiments below, but the present invention should not be limited by the examples.
Embodiment
Establish C57BL/6 mouse ALI animal model and drug treatment
All mouse are raised in SPF grades of animal houses, and take the feeding manner of free choice feeding and drinking-water.By 60
C57BL/6 mouse (be purchased from Nanjing University model organism research institute) is randomly divided into six groups, and every group 10, respectively blank control
Group, model control group, positive drug control group, benserazide hydrochloride high dose group (30mg/kg/d), benserazide hydrochloride middle dose group
(20mg/kg/d), benserazide hydrochloride low dose group (10mg/kg/d).
To above-mentioned six groups of mouse using after basal feed adaptable fed 7 days, benserazide hydrochloride low dose group mouse is injected
Benserazide hydrochloride 10mg/kg/d, benserazide hydrochloride middle dose group mouse injection benserazide hydrochloride 20mg/kg/d and benserazide hydrochloride
High dose group mouse injects benserazide hydrochloride 30mg/kg/d, and positive drug control group mouse injects dexamethasone
(Dexamethasone, DEX) 4mg/kg/d, blank control group and model control group then inject the physiological saline of respective volume.Even
Continuous drug treatment is after 7 days, jejunitas 12h, later model control group, positive drug control group, benserazide hydrochloride high dose group, hydrochloric acid benzyl
Silk hydrazine middle dose group, benserazide hydrochloride low dose group inject 10mg/kg lipopolysaccharides, and blank control group mouse injects respective volume
Physiological saline.8h puts to death mouse after taking blood, obtains lung tissue sample, then carries out ELISA experiment, dry and wet reevaluating pulmonary edema
Situation and HE dyeing.
HE Coloration experiment
It after experiment, takes lungs and is fixed in 10% formalin solution, conventional to draw materials, dehydration, paraffin embedding is cut
Piece (4 microns of thickness).HE dyeing: (1) paraffin section routinely dewaxes: dimethylbenzene (I) 15min → dimethylbenzene (II) (answering fully transparent)
10min；(2) downlink graded ethanol impregnates aquation: 100% ethyl alcohol (I) ethyl alcohol of 2min → 100% (II) second of 2min → 95% step by step
The ethyl alcohol of alcohol 2min → 80% 2min → tap water rinses a moment；(3) it dyeing: distilled water develops a film quarter → haematoxylin liquid dye core 5min →
It is anti-blue that tap water rinses the differentiation of a moment → 1% acidic alcohol 30s (mention insert several under) → flowing water flushing a moment → weak ammonia liquor aqueous solution
Several seconds → flowing water rinses 10min → sets in 0.5% Yihong aqueous solution and redyes 10min；(4) ascending gradient ethanol dehydration step by step: from
Water flushing a moment (differentiation Yihong) → 95% ethyl alcohol (I) ethyl alcohol of 2min → 95% (II) ethyl alcohol of 2min → 100% (I) 2min →
100% ethyl alcohol (II) 2min；(5) transparent: dimethylbenzene (I) 5min → dimethylbenzene (II) 5min；(6) fixed, mounting: under coverslip
Resinene fixes, mounting.(6) it is checked under optical microscopy.
Optical microphotograph microscopic observation result: blank control group, lung tissue is by alveolar, intrapulmonary bronchial tree and interstitial group
At, clear in structure, alveolar wall, which has no, to be thickened, alveolar epithelial cells structural integrity, alveolar wall without in congested, alveolar space without exudation
Object.Intrapulmonary bronchial epithelial cells at different levels are without obvious denaturation, necrosis or fall off, such as Fig. 1.Model control group, lung tissue structure are same
Normal group, structure is still clear, but alveolar collapse, and alveolar septum is broadening, the cell infiltration based on lymphocyte, and interstitial is intravascular
Minute quantity or a small amount of leukocytic margination are seen, with slight or hyporrhea, such as Fig. 2 around interstitial blood vessel.Positive drug control group,
With normal group, structure is still clear for lung tissue structure, slight or slight pulmonary alveolitis, and interstitial lung is intravascular to see minute quantity or on a small quantity white
Cell keeps to the side, wherein 3 with slight around interstitial blood vessel or hyporrhea, such as Fig. 3.Benserazide hydrochloride high dose group, lung group
Structure is knitted with normal group, structure is still clear, and the lesion of this group of mouse lung tissue is consistent with model group, and lesion degree is bright compared with model group
It is aobvious to mitigate, such as Fig. 4.Benserazide hydrochloride middle dose group, with normal group, structure is still clear for lung tissue structure, this group of mouse lung tissue
Lesion it is consistent with model group, lesion degree higher dosage group is slightly heavy, such as Fig. 5.Benserazide hydrochloride low dose group, lung tissue structure
With normal group, structure is still clear, and the lesion of this group of mouse lung tissue is consistent with model group, and lesion degree is slightly heavy compared with middle dose group,
Such as Fig. 6.
Dry and wet weight method assesses pulmonary edema
It separates the left lung of every mouse and weighs immediately, record numerical value is its weight in wet base；It is dried two days later at 95 DEG C, then
Secondary weighing assesses the severity of mouse pulmonary edema based on the ratio of weight in wet base and dry weight to obtain dry weight.The results show that positive
Medicine control group and benserazide hydrochloride various dose administration group can decline the wet dry weight ratio of lung in the ALI mouse of LPS induction, subtract
The slow intracorporal pulmonary edema of mouse, wherein benserazide hydrochloride high dose group has significant difference, such as Fig. 7.
Internal inflammatory reaction
ELISA detects IL-1 β in mice serum, TNF-α, IL-6 expression variation
After blood specimen collection, it is immediately placed on ice.After 2h, 4 DEG C of 3000r/min centrifugations, time 15min.It mentions
After taking serum, ELISA detection is carried out according to the operational manual of kit.(1) it is loaded: diluted blood final proof in accordance with the appropriate ratio
Different groups of blood serum sample is added in pre-coating plates by product, every 100 μ L of hole, every group of at least three multiple holes of setting.(2) add
Detect antibody: biotinylated antibody working solution is added in 50 μ L/well.After mixing, sealing plate film is covered, 37 DEG C are incubated for 90 minutes.(3)
Board-washing: button removes liquid in hole, and cleaning solution is added in 300 μ L/well；Liquid in hole is discarded after stopping 1 minute.It is repeated 4 times, each time
It is buckled on filter paper dry.(4) enzyme: 100 μ L/well Streptavidin-HRP working solutions.Sealing plate film is covered, 37 DEG C are incubated for 30 points
Clock.(5) board-washing: step 3 is repeated.(6) develop the color: 100 μ L/well be added TMD, 37 DEG C Incubation in dark 5-30 minutes, according in hole
The depth (navy blue) of color is reacted to determine to terminate.Usually colour developing 10-20 minutes.(7) terminate reaction: 100 μ L/well are rapid
Terminate liquid is added and terminates reaction.IL-1 β, TNF-α, IL-6 express result of variations such as Fig. 8, Fig. 9, Figure 10 respectively in mice serum,
After benserazide hydrochloride is added, the expression of three kinds of proinflammatory cytokines has the decline of conspicuousness, shows that benserazide hydrochloride can inhibit
The release of pro-inflammatory cytokine, to have the function that improvement and inhibit acute lung injury, the wherein high agent of benserazide hydrochloride
The effect of amount group is best.
In addition to above-mentioned implementation, the present invention can also have other embodiments.It is all to be formed using equivalent substitution or equivalent transformation
Technical solution, fall within the scope of protection required by the present invention.
Claims (4)
1. purposes of the benserazide hydrochloride in preparation treatment acute lung injury drug.
2. purposes of the benserazide hydrochloride in preparation treatment acute lung injury drug according to claim 1, it is characterised in that:
The various preparations that the benserazide hydrochloride is prepared into clinical needs by adding pharmaceutically acceptable carrier.
3. purposes of the benserazide hydrochloride in preparation treatment acute lung injury drug according to claim 2, it is characterised in that:
The additive amount of the benserazide hydrochloride is 10-30mg/kg/d.
4. purposes of the benserazide hydrochloride in preparation treatment acute lung injury drug according to claim 3, it is characterised in that:
The additive amount of the benserazide hydrochloride is 30mg/kg/d.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811298432.XA CN109091473A (en) | 2018-10-26 | 2018-10-26 | Application of the benserazide hydrochloride in preparation treatment acute lung injury drug |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811298432.XA CN109091473A (en) | 2018-10-26 | 2018-10-26 | Application of the benserazide hydrochloride in preparation treatment acute lung injury drug |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111743884A (en) * | 2019-03-26 | 2020-10-09 | 深圳先进技术研究院 | Use of benserazide or derivatives thereof |
| CN115919823A (en) * | 2022-08-15 | 2023-04-07 | 浙江艾特为生物科技有限公司 | Application of benserazide hydrochloride in preparation of medicine for treating diseases caused by respiratory syncytial virus |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106727470A (en) * | 2016-12-09 | 2017-05-31 | 中国药科大学 | Application of the benserazide hydrochloride in the medicine for preparing treatment acute inflammation |
-
2018
- 2018-10-26 CN CN201811298432.XA patent/CN109091473A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106727470A (en) * | 2016-12-09 | 2017-05-31 | 中国药科大学 | Application of the benserazide hydrochloride in the medicine for preparing treatment acute inflammation |
Non-Patent Citations (1)
| Title |
|---|
| 吴桂英: "《临床儿科急危重症诊疗新进展》", 30 November 2014, 西安交通大学出版社 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111743884A (en) * | 2019-03-26 | 2020-10-09 | 深圳先进技术研究院 | Use of benserazide or derivatives thereof |
| CN115919823A (en) * | 2022-08-15 | 2023-04-07 | 浙江艾特为生物科技有限公司 | Application of benserazide hydrochloride in preparation of medicine for treating diseases caused by respiratory syncytial virus |
| CN115919823B (en) * | 2022-08-15 | 2024-04-05 | 浙江艾特为生物科技有限公司 | Application of benserazide hydrochloride in preparing medicament for treating diseases caused by respiratory syncytial virus |
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Application publication date: 20181228 |