CN1989973A - Application of amygdalin in preparation of amygdalin preparation for promoting the blood circulation of heart, brain, pancreas and wound - Google Patents
Application of amygdalin in preparation of amygdalin preparation for promoting the blood circulation of heart, brain, pancreas and wound Download PDFInfo
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Abstract
The invention discloses the use of bitter apricot seed glycosides in preparing preparations for blood circulation of heart, brain, pancreas and wound positions, wherein the preparation can be used for preventing and treating cerebral ischemia, cardiac function prostration, acute adenitis, for promoting skin tissue microcirculation blood flow and wound healing.
Description
Technical field
The present invention relates to contain the medical usage of the pharmaceutical product of organic effective ingredient, specifically being a kind of preparation method of amygdaloside and amygdaloside promotes application in heart, brain, pancreas and the sanguimotor amygdaloside preparation of wound in preparation.
Background technology
Semen Persicae, Semen Armeniacae Amarum are the kind that Chinese Pharmacopoeia is included, aboundresources.
Semen Armeniacae Amarum belongs to Rosaceae (Rosaceae) bitter in the mouth, and tepor is slightly poisonous.Has relieving cough and asthma, the function of loosening bowel to relieve constipation.After this product oral administration of therapeutic dose, its effective ingredient amygdaloside is slowly hydrolysis in vivo, generates micro-hydrocyanic acid gradually, and the latter is sedation to respiratory center, makes respiratory movement be tending towards quiet and effect that present antitussive and relieving asthma.Be cough-relieving, the Chinese medicine of relievining asthma commonly used.Its chemical constituent: contain amygdaloside (amygdalin), fatty oil, emulsin (emulsin), amygdalase (amydgalase), prunase (prunase), estrone, alpha-estradiol, desmosterol etc.
Often Semen Armeniacae Amarum being made dosage forms such as pill, tablet, syrup clinically uses.
Semen Persicae belongs to Rosaceae (Rosaceae), and bitter but sweet flavor is flat.Function cures mainly: blood stasis removing and clots absorbing, moisturize laxation.Control amenorrhea, calentura blood-retention, migratory arthralgia, malaria, traumatic injury, swelling and pain due to blood stasis, the dry constipation of blood.Its chemical constituent: contain amygdaloside (amygdalin), emulsin (emulsin), fatty wet goods.
Semen Persicae also is one of raw material of using always in Chinese patent medicine preparation.
Chinese patent 1319431 discloses a kind of " containing enhancement method unit and the thing and the evaluation methodology of amygdaloside material anti-tumor activity ", be by infraredly bake, distillers yeast fermentation and dope promote anticancer functions such as containing amygdaloside Folium Eriobotryae seed.Under the concentration conditions of the product that adds and increase the treated mistake that contains amygdaloside, in system, increase the formation of lipid peroxide by ultraviolet radiation two carbon acids.Lipid peroxide forms manyly more, and the anticancer function in evaluation and the prediction oral route is strong more.The effect that contains the amygdaloside material with the method evaluation.
Chinese patent 1365979 discloses a kind of " extraction separation of effective ingredient amygdaloside and process for purification " is that Semen Armeniacae Amarum squeezing is deoiled, and adds the ethanol extraction 3 times that 3-6 doubly measures, filtration under diminished pressure, merging filtrate, amygdaloside is placed, separated out to decompression recycling ethanol, filter crude product; The amygdaloside crude product through dissolve with ethanol, filtration, cold preservation, place, separate out white bunch shape crystallization, filtration under diminished pressure with a small amount of ether and washing with alcohol, must purity be the quantitative reference substance of amygdaloside more than 99%.This invention has solved for a long time amygdaloside and has made the difficult problem that effective ingredient is destroyed, curative effect reduces with emulsin enzymolysis or hydrolysis.Reference substance gets the purity height, has extensive use and is worth.
Summary of the invention
The present invention is in order to solve the medical effect that effective ingredient had in the Chinese medicine Semen Persicae, and provide a kind of medicine source more widely amygdaloside promote application in heart, brain, pancreas and the sanguimotor amygdaloside preparation of wound in preparation; A kind of preparation method of amygdaloside also is provided simultaneously.
The principle of the invention:
Though Semen Persicae, Semen Armeniacae Amarum have difference in function aspect curing mainly, but its contained chemical constituent has great common point.After determining the clear and definite function of promoting blood circulation to disperse blood clots of Semen Persicae by the quadrature screening, determine to extract the main component-amygdaloside in the Semen Persicae, and qualitative analysis amygdaloside and assay have been carried out, because amygdaloside also is present in the Semen Armeniacae Amarum, and Semen Armeniacae Amarum technology of overvoltage oil when medicinal, therefore it is more convenient to extract processing, so in the experimentation of amygdaloside, all use from the Semen Armeniacae Amarum cake and extract amygdaloside.
Amygdalate main effective ingredient is an amygdaloside, amygdaloside easily is stored in heterocellutate emulsin enzymolysis in the Semen Armeniacae Amarum together, its chemical property is for being soluble in hot ethanol, be insoluble in ethanol, so select for use and squeeze the almond cookie of removing overwhelming majority oil, adopt the further defat of ether, the method for alcohol reflux is obtained through refining amygdaloside fast, simply.
The preparation method of amygdaloside:
The Semen Armeniacae Amarum 1Kg of squeezing after the deoiling 4000-5000ml that adds diethyl ether divides 2 reflux defats, filters standby; Add 95% alcohol reflux three times after medicinal residues are waved most ether, each 3000-5000ml, filtered while hot, merging filtrate, decompression recycling ethanol is doubly measured volume to the 1-2 of crude drug amount, is placed to room temperature, adds the ether of 1/2 amount again, the container bottom chromatography goes out to be stained with the oily precipitation of wall, produce supernatant, place, separate out crystallization, sucking filtration gets the amygdaloside crude product; The amygdaloside crude product is added 20-40 times of dissolve with ethanol, filtration, places, separates out the crystallization of amygdaloside white plates, and filtration under diminished pressure with the crystallization of 100-200mL washing with alcohol, promptly gets the pure product of amygdaloside, and yield is more than 4%, and purity reaches more than 90%.
Described preparation method, but its amygdaloside crude product repeated treatments 1-2 time, but each amount of alcohol must reduce by half.
A kind of application in the amygdaloside preparation of preparation promotion cerebral blood circulation effect.
One. amygdaloside is to the effect of cerebral blood circulation.
1. treatment is because of the cerebral ischemia of blood viscosity due to raising.The circulation blood flow at the input all can increasing of amygdaloside vein rat's pial and brain essence two positions illustrates that the vasodilation reaction at two positions has synchronicity; Effect manifests later, and after the intravenous injection 30 minutes, effect is increase progressively, in the time of 60 minutes and before the administration notable difference is arranged.For this reason, before causing the blood flow reduction, give amygdaloside, the pathogenic effects of energy antagonism glucosan.
2. to the influence of cerebral microcirculation disturbance.Be used for prevention and treatment as injection epinephrine, pituitrin and mesencephalic arteries ligation.
A kind of application in the amygdaloside preparation of preparation treatment heart failure.
Semen Armeniacae Amarum is done and can be kept contract power and contraction frequency of isolated rat heart coronary flow, the heart in a long time and remain unchanged.Use the amygdaloside perfusion and can make isolated heart in the long period, keep the heart normal function, cardiac failure is had protective effect.
A kind of application in the amygdaloside preparation of preparation treatment acute pancreatitis.
Amygdaloside has influence preferably to pancreatic blood flow and oxygen consumption, and leukocyte rolls and the increase of adhesion number in the time of reducing heavy acute pancreatitis, can increase velocity of blood flow and wall is cut rate; By suppressing leukocyte endotheliocyte excessive adhesion, reduce leukocyte in in-house gathering, thereby the outer internal organs of pancreas are shielded; The transition of rat blood serum NO raises during to acute pancreatitis the reduction effect.
A kind of application in the amygdaloside preparation of preparation promotion wound healing.
Improve the subcutaneous tissue partial pressure of oxygen, increase the skin histology microcirculation blood flow, the quickening that cicatrizes a wound improves the otch fracture strength, is of value to the healing of ischemia skin incision.
Zhi Bei amygdaloside productive rate height, purity height, preparation method is easy like this.
As above Zhi Bei amygdaloside shows to have prevention and treatment because of the cerebral ischemia of blood viscosity due to raising through zoopery, and cardiac failure is had protective effect, to treatment of acute pancreatitis with promote the effect of wound healing, and has significant effect.Therefore, the present invention provides a kind of new pharmaceutical preparation for clinical medicine, and provides new medical usage for said preparation.
Description of drawings
Fig. 1 is sample chromatogram figure of the present invention
Fig. 2 is the reference substance chromatogram
Fig. 3 be normal saline to rat's pial (on) and the microcirculatory influence of brain essence (descending).
Fig. 4 be amygdaloside to rat's pial (on) and the microcirculatory influence of brain essence (descending).
The rat's pial that Fig. 5 causes for the macromolecule glucosan (on) and the variation of brain essence (descending) microcirculation.
The rat's pial that Fig. 6 causes the macromolecule glucosan for amygdaloside (on) and the preventive effect of brain essence (descending) microcirculation disturbance.
Fig. 7 a is that the YHI+ amygdaloside organizes microcirculation to change to pancreas.
Fig. 7 b is that normal saline organizes microcirculation to change to pancreas.
The specific embodiment
Directly get almond cookie 1Kg, suitably pulverize the back and cross 20 mesh sieves, the 4000mL that adds diethyl ether divides 2 reflux defats, filter, add 95% alcohol reflux three times, each 5000mL after medicinal residues are waved most ether, filtered while hot, merging filtrate, decompression recycling ethanol is to 1500mL, be placed to room temperature slightly, add the ether of 1/2 amount again, place, the container bottom chromatography goes out to be stained with the oily mater of wall, and supernatant is produced, and continues to place, separate out crystallization, sucking filtration gets amygdaloside crude product 61g.The amygdaloside crude product is added 1200mL ethanol heating for dissolving, filtration, places, separates out the crystallization of amygdaloside white plates, and filtration under diminished pressure is used the small amount of ethanol wash crystallization, uses 200mL washing with alcohol 2 times, gets the pure product 41g of amygdaloside, and purity reaches more than 90%.
Pharmaceutical dosage form: injection powder preparation.
The clinical using dosage of recommendation of injection amygdaloside powder preparation is 2ml/kg/h, and the conversion method of a transfusion dosage and an implantation dosage is undetermined.
One. the qualitative and detection by quantitative of amygdaloside:
1. thin layer chromatography:
Get amygdaloside standard substance (Chinese biological goods calibrating institute, lot number 820-9401), be mixed with the solution that 1mL contains 2mg with methanol, in contrast product solution.Get the amygdaloside that the present invention obtains through refining, be mixed with the solution that 1mL contains 2mg with methanol equally, as need testing solution.Draw above-mentioned two kinds of solution 10uL respectively, point is on same silica GF254 lamellae (Yantai Chemical Industry Research Inst.), developing solvent is the water saturation chloroform: methanol (2: 1), launch, take out, dry, put under the uviol lamp (UV254) and inspect, in the test sample chromatograph, with the corresponding position of reference substance chromatograph on show the skin dark stain point of same color.
2.HPLC method is measured amygdaloside content:
Chromatographic condition: with octadecylsilane chemically bonded silica is filler; Mobile phase is the water that contains 0.1% phosphoric acid: methanol (80: 20); The detection wavelength is 210nm, and flow velocity is 0.9mL/min, and theoretical cam curve is calculated by amygdaloside should be not less than 5000.
Get amygdaloside standard substance (lot number 820-9401), be mixed with the solution that 1mL contains about 0.2mg with methanol, in contrast product solution.Get the present invention again and make amygdaloside and be mixed with the solution that 1mL contains about 0.2mg, as need testing solution with methanol.
The drafting of standard curve: by above-mentioned chromatographic condition, sample introduction 4ul, 8ul, 10ul, 12ul, 16ul draw the area integral value respectively, with ug is abscissa, and area is a vertical coordinate, the drawing standard curve chart, be a straight line, linear equation is Y=8.893e-007X+1.686e-002, R=0.9999
Press the external standard method test sample, sample introduction 10ul, reference substance is consistent with the liquid chromatogram retention time of test sample.Amygdaloside content is 98.4%.
Adopt the normalization method of high-efficient liquid phase technique to carry out purity test, with the above-mentioned content basically identical of surveying.Standard substance content is 97.70%, and the amygdaloside content that the present invention obtains through refining is 99.18%.
Two. the pharmacological action of amygdaloside:
(1) promote cerebral blood circulation, treatment is because of the cerebral ischemia of blood viscosity due to raising.
1. to the influence of brain microcirculation
Purpose: for measuring the input of amygdaloside vein to rat's pial and the microcirculatory influence of brain essence.
Method: 40 of healthy II level Wistar rats are divided into 4 groups, 10 every group.During experiment with rat with 10% urethane intraperitoneal injection of anesthesia (1ml/100g body weight), head is worn out cerebral dura mater after vowing strong seam both sides sphenotresia, inserts laser-Doppler microcirculation electrode respectively, measures pia mater encephali and brain essence blood flow.The stable back of blood flow in each group respectively vein input normal saline (matched group) and basic, normal, high dosage amygdaloside (1.5%, 3% and 6%, 2ml/h).Observing two position microcirculation blood flows changed 1 hour.
The result: normal saline does not have influence, and three dosage amygdalosides all can increase by two position blood flows, and are the most obvious with effect of high dosage.
Conclusion: the input of amygdaloside vein can increase rat's pial and brain essence microcirculation blood flow.(table 1,2)
Table 1 amygdalosides etc. are to the influence of rat's pial microcirculation blood flow (PU) (x ± s)
| Group | Before the administration | After the administration (branch) | |||
| 5 | 15 | 30 | 60 | ||
| Matched group (7) administration I group (7) administration II group (10) is cheated medicine III group (9) | 216.62±131.73 143.69±104.28 180.57±43.25 151.87±74.24 | 208.51±139.19 132.68±69.27 175.70±44.26 162.11±90.96 | 198.05±137.99 138.38±69.30 179.98±46.34 168.23±87.85 | 197.25±136.12 151.76±89.00 210.40±62.69 174.15±100.96 | 207.28±140.61 182.93±125.93 * 222.40±75.60 * 188.84±102.41 * |
With before the administration relatively:
*P＜0.05 () number of animals
Table 2 amygdalosides etc. are to the influence of rat brain essence microcirculation blood flow (PU) (x ± s)
| Group | Before the administration | After the administration (branch) | |||
| 5 | 15 | 30 | 60 | ||
| Dosage group (10) high dose I group (9) in matched group (7) low dose group (7) | 130.79±40.11.. 145.19±104.82 103.21±26.40 110.13±30.46 | 130.35±32.77 144.36±109.55 101.88±29.76 108.68±31.77 | 141.30±6.30 146.18±110.16 103.53±32.90 110.41±34.36 | 134.99±44.55 154.53±133.75 108.14±33.06 115.10±41.04 | 122.94±62.55 161.79±145.62 * 112.20±29.76 * 128.09±53.55 * |
With before the administration relatively:
*P＜0.05 () number of animals
2. to the influence of cerebral microcirculation disturbance
Purpose: the protective effect of the rat brain microcirculation disturbance that the research amygdaloside causes the macromolecule glucosan.
Method: use 10% glucosan tail vein injection (9ml/kg) and cause the rat brain microcirculation disturbance, the amygdaloside of (treatment group) or preceding 30min (prevention group) tail vein input is meanwhile observed its treatment and preventive effect to cerebral microcirculation disturbance.Cerebral blood flow change application laser Doppler flowmetry (LDF, Sweden, 5001 series) is measured.
The result: the macromolecule glucosan obviously reduces the rat brain microcirculation, and amygdaloside does not show obvious therapeutic action, but significant preventive effect is arranged.
Conclusion: amygdaloside has tangible preventive effect to the rat brain microcirculation disturbance that the macromolecule glucosan causes.(table 3,4; Fig. 5,6)
Table 3 amygdaloside changes (x ± s) to cerebral microcirculation disturbance rat's pial microcirculation blood flow (PU)
| Group | Before the administration | After the administration (branch) | |||
| 5 | 15 | 30 | 60 | ||
| Matched group (7) model group (8) treatment group (11) prevention group (9) | 216.62±131.73 150.77±63.49 141.37±68.52 142.36±28.22 | 208.51±139.19 122.11±48.77 109.17±74.04 144.02±32.85 | 198.05±137.99 115.23±64.38 102.78±49.66 * 136.99±33.85 | 197.25±136.12 107.60±66.04 ** 87.03±45.86 ** 133.44±35.82 | 207.28±140.61 90.60±46.79 ** 90.13±55.67 ** 142.14±43.81 |
With before the administration relatively:
*P＜0.05;
*P＜0.01 () number of animals
Table 4 amygdaloside changes (x ± s) to cerebral microcirculation disturbance rat brain essence microcirculation blood flow (PU)
| Group | Before the administration | After the administration (branch) | |||
| 5 | 15 | 30 | 60 | ||
| Matched group (7) model group (8) treatment group (11) prevention group (9) | 130.79±40.11.. 132.37±36.07 143.87±34.58 143.87±19.64 | 130.35±32.77 106.59±36.36 ** 128.92±41.14 151.55±41.59 | 141.30±6.30 91.33±30.67 ** 98.75±33.46 ** 149.07±63.30 | 134.99±44.55 84.60±22.05 *** 89.63±31.52 ** 143.64±83.21 | 122.94±62.55 84.46+24.63 *** 90.51±36.52 ** 159.33+124.44 |
With before the administration relatively:
*P＜0.05;
*P＜0.01 () number of animals
(2). the treatment heart failure
Purpose: observed amygdaloside to the contract influence of power, coronary flow and contraction frequency of the isolated rat heart heart.
Method: using modified Langendorff isolated heart perfusion method.Behind the stable phase, carry out perfusion, observe desired indicator and change with the perfusate that contains amygdaloside.
The result: matched group (isolated heart perfusate) is because the condition restriction matched group of isolated perfusion specimen is promptly seen coronary flow decline after 10 minutes, and amygdaloside administration group (application contains the perfusate perfusion of amygdaloside) just begins to descend to testing latter stage (50,60 minutes) coronary flow.Then can to keep coronary flow in 60 minute observation period constant if share with the Radix Paeoniae Rubra extracting solution; Amygdaloside does not have influence substantially to heart contraction frequency and contractility.
Conclusion: with the continuity of perfusion time, the heart coronary flow reduces gradually, gives amygdaloside and can keep contract power and contraction frequency of isolated rat heart coronary flow, the heart in a long time and remain unchanged.(table 5)
Table 5 amygdalosides etc. are to the influence of isolated rat perfusion heart coronary flow
| Group | Number of animals | Before the administration | After the | ||||||||
| 5 | 10 | 15 | 20 | 25 | 30 | 40 | 50 | 60 | |||
| Control group compound injection of red sage root peach kernel extract radix paeoniae rubrathe extract peach kernel+radix paeoniae rubrathe | 8 8 9 11 9 | 4.54 ± 1.17 4.46 ± 1.51 4.78 ± 1.05 5.77 ± 2.35 5.41 ± 3.31 | 4.88 ± 1.32 4.84 ± 1.47 4.98 ± 1.07 5.70 ± 2.07 5.67 ± 3.20 | 4.26 ± 1.10 * 4.46 ± 1.22 4.87 ± 0.83 5.66 ± 2.20 5.39 ± 2.98 | 4.19 ± 1.10 * 4.24 ± 1.17 4.76 ± 0.79 5.75 ± 2.27 5.34 ± 3.05 | 4.00± 1.13 ** 4.15± 1.17 4.71± 0.88 5.91± 2.42 5.37± 3.13 | 4.06± 1.02 * 4.08± 1.14 4.66± 0.98 5.81± 2.50 5.46± 3.20 | 3.93± 1.08 ** 4.16± 1.21 4.60± 0.93 5.74± 2.58 5.40± 3.08 | 3.95± 1.08 * 4.04± 1.08 4.37± 0.93 5.44± 2.28 5.23± 2.94 | 3.96± 1.24 * 3.90± 1.02 4.14± 0.90 * 5.05± 2.24 * 5.23± 3.91 | 4.09± 1.22 3.71± 1.00 * 4.12± 0.69 * 4.73± 2.25 ** 4.77± 2.41 |
Annotate:
*With comparison P＜0.05 before the administration
*With comparison P＜0.01 before the administration
(3). the treatment acute pancreatitis
1. to the pancreatitic protective effect of the impatient property of rabbit experiment
Using heavy acute pancreatitis (SAP) model of rabbit proves, press down enzyme injection (YHI) and amygdaloside and merge intravenous injection (1g/kg, be dissolved in the 10mL normal saline and give), the trend (matched group 33.3% that increases rabbit time-to-live and five days survival rates is arranged; Treatment group 83.3%).Medicine makes animal serum amylase obviously descend (table 6).Pancreas organizes microcirculation obviously to improve (Fig. 7), and makes SAP seriousness index IL-6 be starkly lower than matched group (table 7).Pathological examination results shows that also leukocyte infiltration, fat necrosis, index such as hemorrhage all are light (table 8) than matched group.The experiment prompting, YHI and amygdaloside use in conjunction have protective effect to rabbit SAP.
Table 6 presses down enzyme injection (YHI) and amygdaloside to the influence of Severe Acute Pancreatitis SAP rabbit anteserum amylase (U/L) (x ± s)
| Group | Before the AP | Behind the AP (my god) | ||
| 1 | 3 | 5 | ||
| Treatment group matched group | 867.67±374.62(6) 838.17±189.12(6) | 6320.83±2614.12〔6〕 7856.67±3745.03〔5〕 ** | 4774.0±1859.36(5) ** 7038.0±3687.41〔4〕 ** | 15966±76050(5) 2095.0±1081.87〔2〕 * |
*With comparison P＜0.01 before the SAP;
*With comparison P＜0.02 before the AP; () number of animals () survival number
Table 7YHI and amygdaloside are to the influence of SAP rabbit anteserum IL-6 level (x ± s)
| Group | Before the AP | Behind the AP (my god) | ||
| 1 | 3 | 5 | ||
| Treatment group matched group | 32.37±9.11〔6〕 34.0±16.40〔6〕 | 69.75±19.18〔5〕 59.50±17.59〔6〕 | 72.25±10.14〔4〕 50.33±16.57〔5〕 * | 70.25±10.34〔2〕 46.50±14.94〔5〕 * |
Interleukin-6 unit: U/mL () number of animals
*Compare P＜0.05 with matched group
Table 8 presses down the influence to the pathological change of Severe Acute Pancreatitis SAP rabbit of enzyme injection (YHI) and amygdaloside
| Matched group | The | |
| 1 leaflet structure, 2 acinuses, 3 pancreatic ducts: 4 adipose tissues, 5 inflammatory cells, 6 hemorrhagic focus, 7 interstitial fibers hyperblastosises, 8 pancreas islet between the leaflet endite | The remaining abscess of destroying fully of destruction heavy damage forms large stretch of few nothing of measuring around abscess and slough fully | To have more complete leaflet atrophy to exist expansion to exist light-and the moderate damage abscess is few, and the little and few more existence of hyperplasia around abscess and slough of leukocyte infiltration kitchen range is arranged in the remaining leaflet in a small amount |
Amygdaloside is to intestinal blood flow and the strongest medicine of oxygen consumption effect, after experiment confirm also has influence preferably to pancreatic blood flow and oxygen consumption through the orthogonal experiment proof.This experiment is share the acute heavy pancreatitis of treatment rabbit with pressing down enzyme injection and amygdaloside, obtains satisfied result, and this suppresses pancreatin with them, and it is relevant to improve the pancreas blood circulation.(table 8)
2. mechanism analysis
(1) to the influence of leukocyte adhesion
1. amygdaloside is to the microcirculatory influence of living rats
Purpose: observe amygdaloside to the microcirculatory influence of rat mesentery live body.
Method: open abdomen behind the rat anesthesia, find out nearly colon portion mesojejunum and be laid on the special insulation Mus version, carry out microscopic examination.Observed blood capillary posterior vein microcirculation is recorded in video-tape gives over to analysis.Amygdaloside tail vein injection (2ml/kg), heavy acute pancreatitis (SAP) are used ductus pancreaticus injection sodium taurocholate method and are caused.
Result: SAP obviously worsens the every index of microcirculation (leukocyte rolling number, adhesion number, mean blood flow velocity, He Bi cut rate), gives amygdaloside and can prevent microcirculation disturbance when the AP modeling
Conclusion: leukocyte when amygdaloside can reduce rat SAP rolls and adheres to number to be increased, and can increase velocity of blood flow and wall is cut rate.(table 9)
Table 9 amygdaloside is to the microcirculatory influence of SAP rat mesentery live body (x ± s)
| Before the AP | Behind the AP+ amygdaloside (min) | ||||||
| 20 | 40 | 60 | 80 | 100 | 120 | ||
| Adhere to (8) rolling (8) bore (8) flow velocity (8) wall and cut (8) | 0.13±0.35 6.88±5.17 25.98±3.18 193.79±15.18 38.07±4.21 | 0.50±0.76 8.00±7.62 26.23±2.80 191.24±24.95 35.87±4.82 | 0.25±0.46 9.50±11.77 25.95±2.66 197.42±19.33 37.08±4.75 | 0.25±0.46 12.50±13.34 26.07±2.80 194.42±23.54 36.70±5.01 | 0.25±0.46 13.13±13.96 26.08±2.80 194.02±23.54 36.70±5.01 | 0.13±0.15 14.88±16.27 26.08±2.80 196.95±20.90 37.15±4.70 | 0.13±0.35 15.25±16.48 26.08±2.80 196.95±20.90 37.15±4.70 |
Annotate: only behind the AP 0min and 10min wall cut with AP before relatively, P＜0.05, () number of animals
2. amygdaloside is to the influence of acute heavy pancreatitis (SAP) pancreas in rat, lung leukocyte recruitment
Purpose: the leukocyte recruitment to experimental SAP pancreas in rat, lung carries out quantitative study.
Method: the SAP modeling method injects through jugular vein before the modeling with 1.
99mThe leukocyte of Tc labelling, the radioactivity of pancreas, lung is measured each internal organs myeloperoxidase (MPO) (MPO) activity behind the record SAP, and it is quantitative to carry out leukocyte recruitment, and the tissues observed pathological change.
The result: the SAP rat in the time of 3 hours pancreas, lung leukocyte recruitment obviously increase, and increase gradually.Amygdaloside can obviously resist the gathering of leukocyte at pancreas, lung.
Conclusion: amygdaloside adheres to by suppressing the leukocyte endotheliocyte, reduces the gathering of leukocyte at tissue, thereby the outer internal organs of pancreas are shielded.(table 10)
Table 10SAP lung tissue of rats exit dose changes (%ID/G)
| Group | 3h | 6h | 12h | 24h |
| Sham operated rats SAP group SAP+ Radix Salviae Miltiorrhizae SAP+ amygdaloside | 0.545±0.010 0.512±0.014 0.232±0.018 * | 0.532±0.014 0.528±0.018 0.240±0.016 ** | 0.164±00.11 ** 0.529±0.010 0.537±0.011 0.240±0.015 ** | 0.540±0.011 0.540±0.024 0.0241±0.020 ** |
Compare with SAP group, SAP+ Radix Salviae Miltiorrhizae group
*P＜0.05,
*P＜0.01,
3. amygdaloside is to the influence of SAP rat CD11b/CD18 expression
Purpose: the influence that the research amygdaloside is expressed SAP rat CD11b/CD18.To inquire into the mechanism that it regulates leukocyte recruitment.
Method: rat is divided into model group, treatment group at random.The treatment group is got lung and pancreatic tissue specimen causing SAP after jugular vein input amygdaloside 0.1ml/100g put to death animal in 1,3,6 and 24 hour after the treatment, and the SABC method is measured CD118/CD18 and expressed.
The result: each is organized and is not all measured activity in the pancreatic tissue, and 3 hours lungs are expressed and increased after the model group animal sees SAP, and the treatment treated animal is treated and seen that lung CD11b expressed obvious decline in back 1 hour, further reduces in 3,6,12 hours.
Conclusion: the lung CD11b/CD18 that amygdaloside can make the SAP rat raise expresses obviously and reduces.Inference thinks that it is regulated leukocyte raising at least in tissue and expresses relevant (table 11,12) with adhesion molecule CD11b/CD18.
Each treated animal lung tissue CD11b of table 11 expresses (positive cell/visual field)
| Group | 1h | 3h | 6h | 12h | 24h |
| Sham operated rats SAP group SAP+ Radix Salviae Miltiorrhizae SAP+ amygdaloside | 14.2±6.8 12.8±6.4 4.5±2.3※ | 26.7±8.1★ 24.7±8.6 6.9±4.5※※ | 45.7±11.8★★ 43.5±12.9 8.3±4.9※※ | 3.3±2.5 ** 73.7±13.8★★ 70.2±13.7 11.5±5.8※※ | 79.8±14.9 71.9±16.5 9.0±5.6※※ |
*Compare P＜0.01 with SAP group, SAP+ Radix Salviae Miltiorrhizae group;
★ compares P＜0.05 with previous time period; ★ ★ compares P＜0.01 with previous time period;
※ compares P＜0.05 with SAP group, SAP+ Radix Salviae Miltiorrhizae group; ※ ※ compares P＜0.01 with SAP group, SAP+ Radix Salviae Miltiorrhizae group.
Each treated animal lung tissue CD18 of table 12 expresses (positive cell/visual field)
| Group | 1h | 3h | 6h | 12h | 24h |
| Sham operated rats SAP group SAP+ Radix Salviae Miltiorrhizae SAP+ amygdaloside | 17.1±7.3 16.5±5.5 4.7±3.0※※ | 30.8±8.6★ 25.8±7.3 7.0±3.9※※ | 47.1±14.7★★ 47.4±12.6 8.2±5.5※※ | 4.8±2.8 ** 75.7±16.1★★ 71.8±13.7 11.9±5.2※※ | 82.2±19.4 69.5±20.8 9.3±5.2※※ |
The same
4. amygdaloside is to the influence of induced lung microvascular endothelial and leukocyte adhesion rate
Purpose: the In vitro culture induced lung microvascular endothelial that the observation amygdaloside pair cell factor is brought out and the influence of leukocyte adhesion.
After the result shows PMEC (Pulmonary Microvascular Endothelial Cells) and contains the tumor factor and IL-1 β culture medium and hatch jointly, the remarkable mutual adhesive attraction of leukocyte increasing and endotheliocyte.Add amygdaloside or amygdaloside pastille serum in culture medium after, adhesion rate obviously descends.
Conclusion: the excessive adhesion that suppresses the leukocyte endotheliocyte is one of important mechanism of action of amygdaloside.(table 13)
Table 13 induced lung microvascular endothelial and leukocyte adhesion rate
| Group | n | Adhesion rate (%) |
| Normal group TNF-α group TNF-α+amarogentin (1) group TNF-α+amarogentin (2) group TNF-α+red sage root group IL-1 group IL-1+ amarogentin (1) group IL-1+ amarogentin (2) group IL-1+ red | 6 6 6 6 6 6 6 6 6 | 12.72±1.91 32.53±3.22 ** 16.27±1.80 *△△ 17.23±2.48 *△△ 24.81±2.02 **△△▲▲ 31.89±4.35 ** 17.27±2.05 *△△ 18.22±2.66 *△△ 24.4±2.63 |
*Compare P＜0.05 with the normal control group
*Compare P＜0.01 with the normal control group
△ △ compares P＜0.01 with the corresponding model group
▲ ▲ compare P＜0.01 with the amygdaloside group
(2) to the influence of serum levels of nitric oxide
Purpose: NO is the important vessel active factors, but its excessive rising is also unfavorable to blood fortune.This is tested in acute pancreatitis in rats and has observed the influence of amygdaloside to serum levels of nitric oxide (NO) concentration.
Method: the method for using retrograde injection sodium taurocholate in the bile duct causes rat acute pancreatitis, collects blood specimen and measures kit measurement treatment front and back Serum concentration of NO with NO.
The result: amygdaloside can make it obvious reduction.
Conclusion: the excessive rising of rat blood serum NO has the reduction effect during amygdaloside acute pancreatitis.(table 14)
Table 14 amygdaloside is to the influence (x ± s, μ mol/L) of acute pancreatitis in rats Serum concentration of NO
| n | Before the treatment | After the treatment | |
| Matched group Radix Salviae Miltiorrhizae group Radix Paeoniae Rubra group amygdaloside group amygdaloside | 6 4 4 6 6 | 1.28±0.55 1.30±0.67 1.00±0.30 1.18±0.81 2.68±0.55 | 3.22±0.79 ** 3.09±1.28 * 1.80±1.40 0.41±0.29 * 1.16±0.33 ** |
Annotate: with comparison before the pancreatitis,
*P＜0.05,
*P＜0.01
(4) promote wound healing
Ischemia is the important adverse effect factor in the wound healing process, and this experimental applications rabbit ear ischemia skin incision model is studied the effect of wound healing amygdaloside.
Model and method: 12 of rabbit, with side rabbit ear depilation, make the portion's ischemia model of picking up the ears after the anesthesia by the WUShi method.Make a 5cm, vertical, the surgery breach that is deep to cartilage again in this ear side, use the 5# silk suture.Postoperative was measured the skin microcirculation (laser doppler flowmetry method) and the subcutaneous tissue partial pressure of oxygen (tissue oxygen meter method) of next-door neighbour's notching edge in 3,5,7,10,14 and 28 days respectively, got otch skin in the 28th day, carefully cut fat, use three sections wide skin grafts of 8mm and measure tissue segments big powers degree with simplified method.
Result: experimental results show that amygdaloside can improve the subcutaneous tissue partial pressure of oxygen, increase the skin histology microcirculation blood flow, wound healing is accelerated, improve the disconnected big powers of otch degree.
1. ordinary circumstance, ischemia rabbit ear matched group to 12 day are recovered the skin normal color not yet, and the amygdaloside group is changeed blush in the 10th day skin by purple.
2. subcutaneous tissue partial pressure of oxygen (PO
2) cause ischemia after matched group obviously reduce, recovery is arranged in the time of 10 days slightly.Before still being lower than operation in 14-28 days, treatment is organized in the 7th day and is begun to recover, and recovers normal substantially during to 10 days.(table 15)
3. microcirculation inspection: see that all skin microcirculation obviously reduces after causing ischemia model for two groups, matched group recovered to postoperative in 10 days yet, and the treatment group was then obviously recovered in postoperative in 10 days, recovered normal substantially during to 14 days.(table 16)
4. otch fracture strength: treatment group otch fracture strength is apparently higher than matched group in the time of the 28th day.(table 17)
Conclusion: amygdaloside is of value to the healing of ischemia skin incision.
Table 15 skin histology partial pressure of oxygen (PO
2) change (x ± s)
| Group | Before the ischemia | Behind the ischemia (my god) | |||||
| 3 | 5 | 7 | 10 | 14 | 28 | ||
| Matched group (mmHg) treatment group (mmHg) | 51.6±2.4 52.0±2.1 | 25.0±2.8* 25.2±2.8* | 24.7±2.7* 24.0±2.9* | 26.0±3.1* 43.0±4.2* | 27.2±2.3* 40.5±3.6 | 34.5±5.1* 49.0±3.0 | 35.5±5.1* 49.3±2.8* |
*With preceding relatively P＜0.05 of treatment
The variation of table 16 rabbit ear skin microcirculation blood flow (x ± s)
| Group | Before the ischemia | Behind the ischemia (my god) | |||||
| 3 | 5 | 7 | 10 | 14 | 28 | ||
| Matched group (mmHg) treatment group (mmHg) | 22.5±1.9 22.6±1.0 | 12.5±1.9 * 13.5±1.9 * | 13.6±2.8 * 15.3±2.9 * | 15.0±2.6 * 19.8±1.2 * | 15.2±2.4 * 21.3±1.4 | 14.8±2.9 * 21.0±1.6 | 16.6±2.2 * 21.6±1.2 |
*With preceding relatively P＜0.05 of treatment
Table 17 skin incision fracture strength (x ± s)
| Matched group (gram) | Treatment group (gram) |
| 10.66±2.50 | 16.0±2.76 * |
*Compare P＜0.05 with matched group
The amygdaloside of the present invention preparation is through Tianjin combination of Chinese and Western medicine acute abdomen institute Pathophysiology research department, the toxicity test done of Tianjin combination of Chinese and Western medicine acute abdomen institute drug research chamber is reported as follows.
One. the amygdaloside acute toxicity test
1. experimental technique:
The preliminary experiment result shows that the Cmax amygdaloside does not generally have lethal, so adopt Cmax, maximum volume dose regimen.And proof amygdaloside maxima solubility is 19%.
Get 20 of healthy Kunming mouses, male and female half and half.Experiment day every mice was observed seven days continuously through tail vein injection 19% amygdaloside 0.5ml.
Medicine is faced with preceding and is prepared with normal saline by the drug research chamber preparation of this institute.
2. experimental result:
At once do not see after the administration that animal has acute poisoning symptoms such as dyspnea, tic, gatism, animal wool is smooth, activity freely, investigatory reaction is arranged.Animal appetite is good in seven days observation processes, can take food naturally, intake, and does not see vomiting, diarrhoea phenomenon, and last the weight of animals increased (average 27.05 ± 1. grams before the administration, average 30.9 ± 1.91 grams after the administration) in seven days.No any animal dead in seven days whole observation processes.
3. conclusion: mice is 19% to the maximum tolerated dose of amygdaloside, 0.5ml.By the mice average weight is 25 grams/only calculating, and always giving dose is 3.8g/kg, once gives (inject in about 5 seconds and finish).Clinical recommendation consumption is 3%, 2ml/kg/h, promptly 2.7 * 10
-3Ml/kg/5sec, just 8.3 * 10
-5G/kg.Therefore 45783.13 times of the quite clinical recommendation consumption of this experiment gained mice maximum tolerated dose.(above is rough calculation, will not import the cumulative action of medicine continuously and estimate interior.
Two. the amygdaloside long term toxicity test
(1) animal and material
1. animal: 80 of healthy wistar rats (cleaning level), available from four of Military Medical Science Institutes, about body weight 250 grams.Test is divided into 4 groups, and 20 every group, male and female half and half.Observe a week record appetite and body weight before the test.
2. trial drug: amygdaloside, white powder, by the drug research chamber preparation of this institute, before the test with the normal saline wiring solution-forming.
(2) test method
1. test grouping: test is divided into four groups, promptly blank 9 (not adding processing), matched group (normal saline group), high dose group (9% amygdaloside), the low dose group (3% amygdaloside) organized.
2. medication: three treated animal every days of back are respectively through intraperitoneal injection of saline, each 1ml of amygdaloside, continuous two weeks.
3. observation index: observe every day diet, two just, hair and active situation.The next day measure body weight.Test end is the rat sacrificed by decapitation, get blood specimen and measure liver, renal function and hemogram and change, and core, liver, spleen, lung, kidney, testis and ovary tissue specimen carry out the pathological tissue inspection, the calculating organ coefficient of weighing.
(3) result of the test
1. hemogram: 14 days rat red blood cell count(RBC) (RBC), numeration of leukocyte (WBC), hemoglobin (HGB), cell specific volume (HCT), MCV (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC)s (MCHC) more all do not have significant difference with blank group after the administration, only platelet count (PLT) changes, and low dose group obviously raises, and (827 ± 89.8vs 670 ± 174 * 10
9/ μ l, p=0.01), (805.4 ± 88.92vs 670 ± 174 * 10 but the normal saline group also raises than blank group
9/ μ l p=0.038), therefore may be accidental variation.(table 18,19)
2. liver function: intraperitoneal is injected two weeks of amygdaloside continuously to rats'liver function free of toxic effects, and the test end is respectively organized visible glutamate pyruvate transaminase and reduced, and comprises that normal saline group (p＜0.05), total protein and albumin raise.The total bilirubin no change.(table 20)
3. renal function: intraperitoneal is injected two weeks of amygdaloside does not continuously have any toxic action to the kidney of rats function, and blood urea nitrogen and kreatinin and blank treated animal relatively do not have significant difference.(table 21)
4. body weight: two week of amygdaloside lumbar injection the back rat body weights obviously increase, normal saline treated animal body weight also increases, only matched group is not obvious, but increase trend is also arranged.(table 22)
5. organ weights and organ coefficient
Each organ coefficient between each group does not have significant difference.(table 23)
Table 21. amygdaloside long term injections is to the influence of kidney of rats function
| Urea(mmo/l) | Cr(umol/l) | |||||||
| Blank | NS | High dose | Low dosage | Blank | NS | High dose | Low dosage | |
| Average value standard deviation P value | 7.5475 2.865 | 6.563 0.7498 0.3049 | 5.9555 0.6195 0.086 | 6.1409 1.0482 0.1399 | 33.738 8.8343 | 28.99 3.743 0.13 | 25.911 4.0444 0.0138 | 29.34 3.4408 0.1373 |
Annotate: Urea carbamide; The Cr kreatinin
Table 22. amygdaloside long term injections is to the influence (gram) of rat body weight
| Group | NS | High dose | Low dosage | Contrast | ||||
| Before the test | After the test | Before the test | After the test | Before the test | After the test | Before the test | After the test | |
| The p value | 250.0 29.51 | 271.6 41.59 0.001 | 247.45 33.60 | 262.09 38.19 0.0002 | 245.4 42.9 | 260.17 39.34 0.00036 | 258.3 43.98 | 263.33 40.06 0.8 |
P value: compare before and after the test
Table 18 amygdaloside long term injections is to the influence of rat hemogram
| RBC(10 9/L) | WBC(10 12/L) | HGB(g/L) | PLT(10 9/uL) | |||||||||||||
| Blank | NS | High dose | Low dosage | Blank | NS | High dose | Low dosage | Blank | NS | High dose | Low dosage | Blank | NS | High dose | Low dosage | |
| Average value standard deviation P value | 8.185 0.5948 | 8.371 0.3175 0.3857 | 8.3055 0.2232 0.5384 | 8.5073 0.4834 0.171 | 10.242 1.8278 | 10.28 2.143 0.964 | 10.645 1.647 0.585 | 10.627 3.6598 0.7491 | 153.42 10.638 | 155.6 3.502 0.543 | 156.9 4.989 0.543 | 158.5 8.347 0.223 | 670 174 | 805.4 88.92 0.038 | 719.6 103.6 0.423 | 827 89.8 0.01 |
Annotate: the RBC red blood cell count(RBC); The WBC numeration of leukocyte; The HGB hemoglobin; The PLT platelet
Table 19 amygdaloside long term injections is to the influence of rat hemogram
| HCT(％) | MCV(fL) | MCH(pg) | MCHC(g/L) | |||||||||||||
| Blank | NS | High dose | Low dosage | Blank | NS | High dose | Low dosage | Blank | NS | High dose | Low dosage | Blank | NS | High dose | Low dosage | |
| Average value standard deviation P value | 46.708 2.8353 | 48.37 1.1889 0.0998 | 47.973 1.3799 0.1949 | 48.445 2.8115 0.1554 | 57.142 2.1377 | 57.77 1.217 0.42 | 57.782 1.4063 0.4105 | 56.955 1.4638 0.8107 | 18.75 0.6245 | 18.61 0.576 0.594 | 18.88 0.615 0.612 | 18.65 0.216 0.604 | 329 15.1 | 322.1 8.569 0.243 | 327.1 6.625 0.766 | 327 6.91 0.78 |
Annotate: HCT blood cell specific volume; The MCV MCV; The MCH mean corpuscular hemoglobin; The MCHC mean corpuscular hemoglobin concentration (MCHC)
Table 20 amygdaloside long term injections is to the influence of rats'liver function
| ALT(U/L) | TP(g/l) | ALB(g/l) | T-BILumol/l) | |||||||||||||
| Blank | NS | High dose | Low dosage | Blank | NS | High agent dish | Low dosage | Blank | NS | High agent dish | Low dosage | Blank | NS | High dose | Low dosage | |
| Average value standard deviation P value | 168.5 72.393 | 114.1 24.786 0.0351 | 98.818 24.624 0.0064 | 100 23.277 0.0069 | 67.983 4.9101 | 75.65 5.609 0.003 | 75.355 5.6828 0.0031 | 76.273 5.4575 0.001 | 38.825 2.5385 | 41.26 2.851 0.047 | 41.74 2.953 0.019 | 41.1 2.717 0.05 | 0.95 0.76 | 0.648 0.291 0.248 | 0.564 0.479 0.162 | 0.84 0.44 0.67 |
Annotate: the ALT alanine aminotransferase; The TP total protein; The ALB albumin; T-BIL is total-bilirubin
Table 23 amygdaloside long term injections is to the influence of rat heart coefficient (x ± s)
| Internal organs | Matched group | Normal saline | High dose | Low dosage |
| Heart liver spleen lungs kidney testis ovary | 0.0034±0.00043 0.035±0.0023 0.0024±0.0002 0.0095±0.0023 0.0065±0.0005 0.0092±0.0005 0.0006±0.0001 | 0.0034±0.00026 0.034±0.0023 0.0024±0.0003 0.0076±0.0018 0.0066±0.0003 0.0096±0.0006 0.0004±0.0003 | 0.0033±0.00024 0.029±0.01 0.0024±0.0003 0.0053±0.0008 0.0067±0.0004 0.0080±0.0039 0.0006±0.0009 | 0.0035±0.00031 0.026±0.01 0.0061±0.0089 0.0062±0.0013 0.0066±0.0006 0.0091±0.0019 0.0006±0.0001 |
6. pathological tissue check result:
Blank group, normal saline group and amygdaloside is low and the heart of high dose group animal, liver,spleen,kidney and gonad (testis or ovary) all do not have any pathological change.Intra-alveolar hemorrhage (may be the result that disconnected neck sucks when putting to death), slight interstitial cell hyperplasia, alveolar septum broadening, organizing consolidation etc. all to exist to some extent in each group, therefore think the problem of animal itself, is not the chronic toxicity effect of amygdaloside.
Four. conclusion
The continuous lumbar injection of amygdaloside, 1ml/d. (3% or 9%) in totally 2 weeks, does not produce chronic toxicity effect * to rat.
* to recommend clinical using dosage be that this uses the dosage of chronic toxicity test once to inject as 1ml to 2ml/kg/h (still use dosage for experiment at present, carry out the clinical trial treatment and the time also must further weigh), so dosage is possible bigger than normal to amygdaloside.Lung pathology checks that the finding slight abnormality is perhaps relevant therewith.The conversion method of a transfusion dosage and an implantation dosage is still very not clear and definite.The applied dosage of chronic toxicity test is because may be bigger than normal, gained result of the test (free of toxic effects) thereby more reliable.
Claims (4)
1. the application of amygdaloside in the amygdaloside preparation of preparation promotion cerebral blood circulation effect.
2. the application of amygdaloside in the amygdaloside preparation of preparation treatment heart failure.
3. the application of amygdaloside in the amygdaloside preparation of preparation treatment acute pancreatitis.
4. the application of amygdaloside in the amygdaloside preparation of preparation promotion wound healing.
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| CN102133175A (en) * | 2011-03-09 | 2011-07-27 | 天津市南开医院 | Amygdalin gel and preparation method and medicinal application thereof |
| CN103948612A (en) * | 2012-05-14 | 2014-07-30 | 中国人民解放军第四军医大学 | Application of amygdalin in protection of ischaemic heart |
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| CN103948612A (en) * | 2012-05-14 | 2014-07-30 | 中国人民解放军第四军医大学 | Application of amygdalin in protection of ischaemic heart |
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