CN102973546A - Application of acetyl-trans-resveratrol in preparation of medicine for preventing and/or treating pulmonary fibrosis diseases - Google Patents
Application of acetyl-trans-resveratrol in preparation of medicine for preventing and/or treating pulmonary fibrosis diseases Download PDFInfo
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- CN102973546A CN102973546A CN2012104983991A CN201210498399A CN102973546A CN 102973546 A CN102973546 A CN 102973546A CN 2012104983991 A CN2012104983991 A CN 2012104983991A CN 201210498399 A CN201210498399 A CN 201210498399A CN 102973546 A CN102973546 A CN 102973546A
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- resveratrol
- pulmonary fibrosis
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Abstract
The invention discloses the application of acetyl-trans-resveratrol in the preparation of medicine for preventing and/or treating pulmonary fibrosis diseases. The pulmonary fibrosis model of a mice is copied by injecting bleomycin in an intratracheal manner, and the influence of the acetyl-trans-resveratrol to the pulmonary tissue pathologic change and related indexes of the mice can be studied, so that the pulmonary fibrosis resistance of the acetyl-trans-resveratrol is confirmed, and the basis is provided for using the acetyl-trans-resveratrol to prepare the medicine for preventing and treating pulmonary fibrosis.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to the medical usage of acetylation resveratrol.
Background technology
Pulmonary fibrosis is one of most important common pathological change of various heterogeneous interstitial lung diseases, is to cause the lungs dysfunction, does not even reversibly develop into respiratory failure, main causes of death.The pulmonary fibrosis pathological process is substantially clear, and minute earlier damage, inflammatory and immune response, one-tenth fibrosis three phases, the participation factors in each stage determine progressively that also research is illustrated but the concrete mechanism of action of each participation factors is still needed.The many factors such as pathogenic microorganism, dust, medicine, chemicals, lonizing radiation all can be induced the generation of pulmonary fibrosis, but its detailed mechanism it be unclear that.Pulmonary fibrosis can betide any age, and global sickness rate is 7-10/10 ten thousand, and patient's mean survival time is 3-4, and with advancing age, sickness rate increases gradually and the mean survival time shortens gradually.Up to now, there is no effective medicine.
The medicine of pulmonary fibrosis resistant mainly contains at present: 1) glucocorticoid be the main selection of present clinical treatment, but this class Drug side reaction is large, has a strong impact on body's immunity, increases the probability of secondary infection; 2) interferon gamma, untoward reaction is more, easily brings out tolerance; 3) cytotoxic drug (AZA, cyclophosphamide etc.), medicine poor selectivity, untoward reaction are many; 5) other drug, colchicine, pyrrole coffee ketone etc.
The acetylation resveratrol is the prodrug of resveratrol.Resveratrol is a kind of polyphenolic substance of non-flavonoid, has widely biological activity, can antitumor, protection cardiovascular, antioxidation, antibiotic and antiinflammatory etc., can be widely used in the fields such as medicine, health care, food, cosmetics.
Summary of the invention
The purpose of this invention is to provide the acetylation resveratrol and prevent and/or treat new purposes in the pulmonary fibrosis disease medicine in preparation.
Implementation procedure of the present invention is as follows:
Because resveratrol is unstable, absorption in body, metabolism, elimination are rapid, and bioavailability is low.For the pharmacokinetic characteristics of resveratrol, the inventor has compared pharmacokinetic parameter and the interior distribution of body of resveratrol and acetylation resveratrol.Discovery is in the tissue distribution experiment; gavage that resveratrol concentration is significantly higher than the lung tissue of rats that gavages resveratrol in the lung tissue of rats of acetylation resveratrol; up to 20 times more than; illustrate that the acetylation resveratrol has certain targeting for lung tissue, also can cause resveratrol at the savings of pulmonary simultaneously.Investigate the pulmonary fibrosis resistant effect of acetylation resveratrol, find that the acetylation resveratrol has potential pulmonary fibrosis resistant effect.
The specific embodiment
Below be part pharmacodynamics test and the result of the acetylation resveratrol pulmonary fibrosis resistant disease that provides of inventor.
The acetylation resveratrol can be bought its CAS NO:42206-94-0, another name/chemical name: triacetyl resveratrol, molecular formula/structural formula: C by existing document preparation or commercial channel
20H
18O
6, molecular weight: 354.35.
1 laboratory animal
80 of the healthy Kunming mouses of cleaning level, body weight 18～22 g are provided by The Fourth Military Medical University's Experimental Animal Center, and adaptability is fed and was used for afterwards experiment in 3 days.
2 animal model methods
With 0.1% pentobarbital sodium intraperitoneal injection of anesthesia (0.1 ml/10g body weight), mice lies on the back and is fixed on the Mus platform, successively separate behind the cervical region alcohol disinfecting and expose trachea, syringe enters trachea through the tracheal cartilages czermak space towards heart terminal spine, then slowly inject 0.05 ml BLM normal saline solution (5 mg/kg) or normal saline solution, immediately with the upright also left rotation and right rotation of animal, medicinal liquid is evenly distributed in lung behind the notes.Experimental session, mice freely drinks water and takes food.
The grouping of 3 animals and processing method
Kunming mouse is divided into 4 groups at random: normal group, model group, resveratrol (RES) treatment group and acetylation resveratrol (TARES) treatment group, 20 every group.Second day after the Kunming mouse modeling is respectively to each group mice normal saline, TARES and RES.The RES treatment group in the modeling second day to RES 100 mg/kg gavages, RES 155.5 mg/kg gavages, normal group and model group give isometric normal saline gavage.The cervical vertebra dislocation in 21 days after administration of normal group, model group, RES treatment group and TARES treatment group is put to death, and isolates two lungs, gets right lung and places 4% formalin fixing, routine paraffin wax section, HE dyeing; Lung tissue segment is made 5% homogenate and freezing preservation under condition of ice bath, be used for Biochemical Indexes; The freezing preservation of lung tissue segment is used for hydroxyproline content and measures.
4 acetylation resveratrols are on the impact of pulmonary fibrosis mice lung tissue disease disease
Pathological study: get right lung, 4% formalin is fixed, the dehydration of routine pathology method, embedding, section, HE dyeing.According to method evaluation alveolar inflammation and pulmonary fibrosis degree such as Szapiel.Alveolar inflammation and Fibrotic judgement: 0 grade: without alveolitis or fibrosis; 1 grade: extent of disease accounts for below 20% of full lung; 2 grades: extent of disease accounts for 20%～50% of full lung; 3 grades: extent of disease surpasses 50% of full lung.
Histopathology changes: as seen HE dyes microscopic examination: the model group alveolar structure destroys, and fibrosis is obvious, proves the modeling success.Compare with model group, acetylation resveratrol treatment group experiment mice alveolar structure destroy and fibrosis aspect all have in various degree and alleviate (P＜0.01) (seeing Table 1).
5 impacts on hydroxyproline content in the pulmonary fibrosis mice lung tissue
The essence of pulmonary fibrosis is because the synthetic and degraded of collagen and other extracellular matrixs (ECM) is unbalance, causes ECM excess deposition in lung.In the normal physiological situation, synthetic and the degraded of the various compositions of ECM are in poised state.The tissue injury that a variety of causes causes all can make ECM metabolism disequilibrium.Hydroxyproline (HyP) is that proline hydroxylase forms the hydroxylation of proline residue in front α-peptide chain, accounts for 10% of collagen peptide chain amino acid.In ECM, contain a small amount of HyP(about 1% except elastin laminin), HyP all do not contained.Because HyP mainly is present in collagen, the mensuration of HyP content can reflect collagen content indirectly, and therefore, the content of measuring HyP often is used to the research of pulmonary fibrosis.
Lung tissue HyP assay: lung tissue HyP content adopts the sample acid-hydrolysis method to carry out by HyP assay test kit description.
TARES compares with normal group with the RES group with the impact of RES on pulmonary fibrosis mice lung tissue HyP content: TARES, and the model group mouse lung is organized HyP content significance rising (P＜0.01); Compare with model group, Res treatment group lung tissue HyP content significance reduces (P＜0.01); TARES group and RES group comparison there was no significant difference (P〉0.05).
6 impacts on mda content in the pulmonary fibrosis mice lung tissue
Oxygen-derived free radicals can be attacked the polyunsaturated fatty acid in the biomembrane, form lipid peroxide, mainly be malonaldehyde (MDA), the height of its content can reflect the snperoxiaized degree of body inner lipid, indirectly reflect the cell injury degree, therefore measure the value that MDA estimates antioxidant radical.
The mensuration of lung tissue MDA content: the related assays test kit that lung tissue MDA content builds up according to Nanjing is measured.
TARES compares with normal group with the RES group with the impact of RES on pulmonary fibrosis mice lung tissue MDA content: TARES, and the model group mouse lung is organized MDA content significance rising (P＜0.01); Compare with model group, Res treatment group lung tissue MDA content significance reduces (P＜0.01); TARES group and RES group comparison there was no significant difference (P〉0.05).
Tissue distribution dynamic experiment and the comparison of acetylation resveratrol and resveratrol
36 SD rats are equally divided into 6 groups, male and female half and half.With 0.5 % CMC-Na acetylation resveratrol and resveratrol such as are made respectively at the mole suspension, rat is waited respectively molar dose 438 μ molkg
-1Resveratrol or acetylation resveratrol gastric infusion.Three groups of rats gavaged resveratrols, 5,15,60 min after administration, each time point to one group of rat aorta sacrificed by exsanguination after, core immediately, liver, spleen, lung, kidney, brain, stomach, intestinal, gonad be (female: ovary; Testis) male: the tissue such as; Other three groups of rats gavaged acetylation resveratrols; after 15,90,180 each time point of min after the administration are to one group of rat aorta sacrificed by exsanguination; core immediately, the tissue such as liver, spleen, lung, kidney, brain, stomach, intestinal, ovary, testis ,-80 ℃ of airtight preservations.
With normal saline tissue samples is made homogenate (0.2 g tissue adds 1 mL normal saline), add respectively mark in 0.1 mL, add 1.0 mL extracts behind the mixing, vortex 3 min that vibrate, 12000 rpm * 10 min, draw upper organic phase solution in another 5 mL point end test tube, extracting twice merges organic phase solution, volatilize in the fume hood, with 50 μ L dissolve with methanol residues, get 20 μ L sample introduction analyses behind the mixing, the results are shown in Table 4 and table 5.
Oral resveratrol and the acetylation resveratrol pharmacokinetic property in SD rat body relatively
1.1 dosage regimen and sample collecting and processing
12 SD rats are equally divided into two groups, male and female half and half.With 0.5 % carboxymethylcellulose sodium solution resveratrol or acetylation resveratrol are made equimolar suspension.Rat is waited respectively molar dose 438 μ molkg
-1Resveratrol (100 mgkg
-1) or acetylation resveratrol (150 mgkg
-1) gastric infusion.The rat that gavages resveratrol is after administration 2,5,10,15,30,60,120,180, and 240,360,480,720 min eye sockets are got blood; The rat that gavages the acetylation resveratrol is after administration 15,30,45,60,90,120,180,240, and 360,480,720,1440 min eye sockets are got blood.Get blood 1 mL at every turn, anticoagulant heparin, 3000 rpm * 10 min are centrifugal, pipette blood plasma, and-20 ℃ are frozen for subsequent use.
Get above-mentioned sample blood plasma 0.2 mL, add 10 μ L internal standard substance phloretin methanol solution (640 μ gmL
-1), vortex 30 s that vibrate add 1 mL ethyl acetate, vortex 3 min.12000 rpm * 10 min are centrifugal, draw upper organic phase solution 800 μ L in another point end test tube, and nitrogen current dries up in the fume hood, add methanol 80 μ L, vortex 3 min that vibrate, 12000 rpm * 10 min are centrifugal, get supernatant 20 μ L and carry out HPLC and analyze.
1.2 data analysis and pharmacokinetic parameter calculate
C-T data are carried out automatic computing with DAS (the Drug And Statistics) statistical software of clinical evaluation of drug center, Anhui Province exploitation, at first the C-T data of every rat are carried out intelligent processing method match compartment model, then the C of six rats-T data are carried out batch processing, obtained pharmacokinetic parameter (table 6 and table 7).
As seen, resveratrol absorbs in the rat gastrointestinal rapidly, can detect the original shape medicine behind rat oral gavage 2 min from blood, can reach peak concentration about 10 min, and peak concentration is 2.815 ± 0.246 μ gmL
-1, the half-life is 289.0 ± 23.6 min, AUC
(0-∞)Be 475.77 ± 52.852 mg
.h
.L
-1
Behind the acetylation resveratrol gastric infusion, 15 min can measure the catabolite resveratrol, show that the acetylation resveratrol absorbs and it is all rapider to decompose, but than resveratrol absorb slower; Peak time is 90 min, is far longer than the resveratrol peak time, but its C
MaxBe 1.187 ± 0.084 μ gmL
-1Be lower than resveratrol, illustrate that the absorption of acetylation resveratrol distributes comparatively more steady than resveratrol; Half-life is 394.7 ± 106.5 min, is 1.34 times of resveratrol half-life, illustrates that the acetylation resveratrol can effectively prolong the action time of resveratrol; AUC
(0-∞)Be 544.55 ± 58.98 mg
.h
.L
-1, be 1.15 times of resveratrol AUC, illustrate that its bioavailability increases.
Claims (1)
1. the acetylation resveratrol prevents and/or treats application in the pulmonary fibrosis disease medicine in preparation.
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|---|---|---|---|
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109820841A (en) * | 2019-04-01 | 2019-05-31 | 辽宁大学 | Application of the resveratrol in preparation treatment Bronchial Epithelial Cells drug |
| CN111728962A (en) * | 2019-03-25 | 2020-10-02 | 泰州华元医药科技有限公司 | Resveratrol derivative and medical application of resveratrol derivative in anti-fibrosis |
-
2012
- 2012-11-30 CN CN2012104983991A patent/CN102973546A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| RECEP AKGEDIK, ET AL: "Effect of Resveratrol on Treatment of Bleomycin-Induced Pulmonary Fibrosis in Rats", 《INFLAMMATION》 * |
| 梁力: "乙酰化白藜芦醇和白藜芦醇在SD大鼠体内药代动力学研究", 《万方数据知识服务平台》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111728962A (en) * | 2019-03-25 | 2020-10-02 | 泰州华元医药科技有限公司 | Resveratrol derivative and medical application of resveratrol derivative in anti-fibrosis |
| CN111728962B (en) * | 2019-03-25 | 2024-04-30 | 绍兴君科臻元医药科技有限公司 | Resveratrol derivative and medical application thereof in resisting fibrosis |
| CN109820841A (en) * | 2019-04-01 | 2019-05-31 | 辽宁大学 | Application of the resveratrol in preparation treatment Bronchial Epithelial Cells drug |
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Application publication date: 20130320 |