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CN1654040A - Novel medical uses of perennial sowthistle and preparing method for intermediate thereof - Google Patents

Novel medical uses of perennial sowthistle and preparing method for intermediate thereof Download PDF

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CN1654040A
CN1654040A CN 200410021125 CN200410021125A CN1654040A CN 1654040 A CN1654040 A CN 1654040A CN 200410021125 CN200410021125 CN 200410021125 CN 200410021125 A CN200410021125 A CN 200410021125A CN 1654040 A CN1654040 A CN 1654040A
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extract
liquid
lepidium
raw material
tap water
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CN100462081C (en
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徐绥绪
宋少江
封锡志
曹颖林
路金才
徐琲琲
邹大光
张国刚
陈兆国
张梅
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Wei Zhenlin
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Wei Zhenlin
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Abstract

The present invention is the new application of denticulate ixeris herb in treating cardiac and cerebral vascular diseases and leukaemia and the preparation process of its medicinal intermediate. The extract of denticulate ixeris herb contains sesquiterpene lactone and phenoloid and thus has the functions of increasing blood flow rate of coronary artery, improving myocardial circulation, inhibiting thrombocyte aggregation, raising the activity of plasmin, etc. The preparation process of the medicinal intermediate includes water or alcohol extraction and chromatographic purification in combined macroporous resin and polyamide column. The intermediate has total content of total flavone and total lactone of 60-95 %.

Description

The preparation method of gutweed Lepidium new medical use and pharmaceutical intermediate thereof
Technical field:
Technical field of the present invention belongs to pharmaceutical sanitary field.
Background technology:
Compositae (Compositae) gutweed Lepidium (Ixeris genus) plant, kind surplus the whole world has 50, kind surplus China just has 20 is abounded with in northern China; Ground such as northeast, North China and the Inner Mongol.Effect with heat-clearing and toxic substances removing, antiinflammatory, pain relieving.
Herba Ixeritis Denticulatae platymiscium (Herba Ixeritis Sonchifoliae Ixeris sonchifolia (Bge.) Hance for example; Another name is Herba Ixeritis Sonchifoliae, Caulis et folium pavettae hongkongensis, autumn Herba Ixeritis Sonchifoliae Ixeris sonchifolia (Bge.) Hance Var.Serotina (Maxin.) Kitag, mutation, Herba Ixeritis Denticulatae Ixeris denticulate (Houtt.) Stebb, Herba Ixeritis chinensis dish Ixeris chinensis (Thunb.) Nakai for Herba Ixeritis Sonchifoliae, call little hardship and sell dish, HUOXUECAO etc.), in China long medicinal history is arranged, be applied to treat appendicitis, enteritis, headache, toothache etc., main pharmacological has the activity of antitumor, antiinflammatory, analgesia, calmness and cardiovascular aspect; Division is as follows: 1. antitumor action: a lot of plants have antineoplastic action in the gutweed Lepidium.Ixerislaciniata uses as the antitumor medical herbs among the people, and people such as Bi Zhiming show its chemical constituent and the result of study of pharmacologically active, chemical compound 11 β, and 13-dihydrolactucin acetate has stronger cytotoxic activity.The methanolic extract of Herba Ixeritis Sonchifoliae has the activity of inhibition to Ehrlich carcinoma JEG-3.The Korea S scholar finds that the methanolic extract of Ixeris dentata has stronger inhibition activity to MG63 human osteosarcoma cell strain.2. to the pharmacological action of cardiovascular system: people such as Feng Yushu prove that the extract of Herba Ixeritis Sonchifoliae has the increase coronary flow, increase the myocardial nutrition blood flow, reduce myocardial oxygen consumption, improve effects such as cardiac muscle circulation; To the remarkable anticoagulant function of blood system energy, obviously increase the activity of fibrinolysin, and these effects are the bases that prevent and treat thrombosis.The extract of Herba Ixeritis Sonchifoliae no matter at aerobic, in various degree under anoxia and the oxygen free condition, myocardium lactic acid content is reduced, this will alleviate or prevent the myocardial cell acidosis, help the recovery of myocardial cell function, this is the another main cause that Herba Ixeritis Sonchifoliae is used for the treatment of myocardial infarction.3. analgesic activity: pharmacological evaluation shows, after giving male mice lumbar injection KUDIEZI ZHUSHEYE, measure the threshold of pain with hot plate method and improve percentage rate, the administration treated animal threshold of pain is significantly increased than matched group, show that KUDIEZI ZHUSHEYE has 4. sedation of analgesic activity: experimental results show that, KUDIEZI ZHUSHEYE has obvious sedation, the mice autonomic activities is significantly reduced, and can produce synergism, but central stimulant leptazol and caffeine sodium benzoate are not seen that tangible antagonism is arranged with the hypnotic pentobarbital sodium.5. cholesterol reducing effect: the Korea S scholar finds the effect that the chloroform extract of Herba Ixeritis Denticulatae (Ixeris dentata) has significant cholesterol reducing level.It is further studied the back find that active component is the mixture of triterpene and sterol: α-Amyrin, β-Amyrin, lupeol, pseudo-taraxasterol, taraxasterol, cupreol, stigmasterol etc.6. antimutagenesis: the Korea S scholar Herba Ixeritis Denticulatae (Ixerisdentata) with behind the methanol extraction, use cyclohexane extraction respectively, chloroform, ethyl acetate, n-butyl alcohol extracts successively, will extract each layer then and test with the mutation due to aspergillus flavus resisting toxin B (aflatoxin B) is carried out in the water-bearing layer.The selection result finds that the activity of chloroform layer is the strongest, and suppression ratio is 74%.
Since the eighties in 20th century, the various countries scholar has carried out a series of research to the chemical constituent of Herba Ixeritis Denticulatae platymiscium, finds to mainly contain kind of chemical constituent surplus sesquiterpene lactones class, triterpenes and flavonoid, coumarin, sterol, lignanoid, vitamin, aminoacid and the saccharide etc. 200.
Wherein being developed to new drug closely has the stem hardship of embracing to sell dish, and this plant extract of bibliographical information has effects such as the coronary flow of increasing, the circulation of improvement cardiac muscle to blood circulation; To significantly anticoagulant effect of blood system, obviously increase the activity of fibrinoclase, be developed to new drug " dish arteries and veins spirit injection " because clinical practice for many years in late 1980s through research for many years, determined curative effect, be upgraded to national standard on 1st in December in 2002, be renamed as " KUDIEZI ZHUSHEYE " (Kudiezi Zhusheye) authentication code and be promoting blood circulation and stopping pain, heat clearing away blood stasis dispelling for its function of issue in " WS-10354 (ZD-0354)-2002 " standard cures mainly.The thoracic obstruction, the card that is used for the blood stasis impatency seen, uncomfortable in chest, pained, bitter taste, tongue is dark red or deposit ecchymosis etc.Be applicable to that coronary heart disease, angina pectoris see above-mentioned condition of illness person, also available cerebral infarction person.The intermediate method for making of stipulating in the standard is classical " stone sulfur method "
Other three kinds of medicinal plants only have the reports such as isolation identification of former plant amedica with report and application record among the people and chemical constituent thereof.In a word, do not find that so far gutweed Lepidium (except that Herba Ixeritis Sonchifoliae) is to treatment cardiovascular and cerebrovascular disease and leukemic purposes.
Summary of the invention:
The present invention solves existing gutweed Lepidium treatment cardiovascular and cerebrovascular vessel and leukemic new purposes and preparation method thereof do not found.
New medical use:
1. leukaemia K 562Activity:
From gutweed Lepidium Herba Ixeritis chinensis [Ixeris chinensis (Thunb) Nakai], separate obtain Luteolin-7-O-gentiobiside (Luteolin-7-O-gentiobiside) (I) apigenin-7-O-beta-D-glucuronide (apigenin-7-O-D-glucuronopyranoside) (II) and luteolin-7-O-β-D-glucuronide (luteolin-7-O-glucuronopyranoside) (III) to human leukemia cell K 562By stronger inhibitory action, K 562Cell is made substrate and is cultivated and obtain with containing the clear pMRI1640 of 5% calf fetal blood, utilizes mtt assay, measures above three kinds of chemical compounds, result such as following table.
The leukemia cell K of effective ingredient in the table 2 gutweed Lepidium 562Activity
??Sample ??Con.c/mM ????OD(±s) (nhibitory?Ratel％) ????P
?? ??Control ????(I)?? ?? ?? ????(II)? ? ????(III) Salt solution 0.085 0.170 0.340 0.056 0.112 0.224 0.041 0.082 0.164 ????2.983±0.19 ????1.764±0.28 ????1.465±0.24 ????1.266±0.26 ????1.258±0.42 ????0.662±0.08 ????0.452±0.12 ????2.287±0.08 ????1.772±0.29 ????1.240±0.12 ?? ????37.3 ????41.3 ????55.7 ????56.8 ????77.5 ????84.5 ????28.1 ????40.0 ????58.4 ?? ????＜0.01 ????＜0.01 ????＜0.01 ????＜0.01 ????＜0.01 ????＜0.01 ????＜0.01 ????＜0.01 ????＜0.01
2. the cardiovascular effect of Herba Ixeritis Denticulatae genus plants extract
(1) research of the anti-myocardial ischemia effect of Herba Ixeritis Sonchifoliae extract intravenously administrable
Tried mice with 72 and be divided into 6 groups at random, every group of 12 male and female half and half, to be tried mice and be used urethane (1.2g/kg) intraperitoneal injection of anesthesia, fixing, throat portion surgical exposure and free trachea, link to each other with the mice extremity through pin type electrode with MS302 multimedization bio signal record analysis system, gather mark II lead electrocardiogram, tail venipuncture drug administration by injection, the 1st group of matched group injecting normal saline, the 2nd, 3,4 groups is Herba Ixeritis Sonchifoliae extract senior middle school low dose group, and dosage is respectively 40mg/kg, 20mg/kg, 10mg/kg, the 5th group is Herba Ixeritis Sonchifoliae extract gastric infusion group, and dosage is 20mg/kg, holds one's breath in folder and manages preceding 30 minutes gastric infusions.The 6th group is DIEMAILING ZHUSHEYE intravenous injection group, and dosage is 1.625mg/kg, and each is organized the administration volume and is 0.2ml/10g, and injection speed is that 0.02ml/s is mixed with desired concn with 0.9%NaCl before test.Tried to put into the wide mouthed bottle that contains soda lime after the mice administration, bottleneck is sealed, the death time (min) of record mice with vaseline.The testing data significance test is handled with the t-test of pairing data, result of the test is as shown in table 3, in selected dosage range, Herba Ixeritis Sonchifoliae extract intravenous administration and oral administration all obviously prolong the mice time-to-live, relatively have significantly and highly significant difference with matched group.
The intravenous injection of table 3 Herba Ixeritis Sonchifoliae extract is to the influence of white mice time-to-live (min) (X ± SD)
Group Dosage (mg/kg) Number of animals (only) Death time (min)
Control group ixeri sonhifolia extract iv ixeri sonhifolia extract iv ixeri sonhifolia extract iv ixeri sonhifolia extract ig ixeri sonhifolia extract iv ????0.9％NaCl ????(0.2ml/kg) ????40 ????20 ????10 ????20 ????1.625 ????10 ????10 ????10 ????10 ????10 ????10 ????35.3±4.08 ????46.62±9.65 **????45.9±11.1 *????44.12±9.30 *????44.0±9.80 *????45.0±10.26 *
Each administration group and matched group are relatively *P＜0.05 *P＜0.01
(2) research of Herba Ixeritis Sonchifoliae extract function of resisting myocardial ischemia
1. to the influence of anesthetized dog acute myocardial ischemia:
Get 30 hybrid dogs, body weight is at the 11.0-13.0 kilogram, every group of 5 male and female dual-purposes, divide 6 groups at random, be respectively the 0.9%NaCl matched group, high, normal, basic 3 the dosage groups of Herba Ixeritis Sonchifoliae extract intravenously administrable, dosage are respectively 8.8mg/kg, 4.4mg/kg, 2.2mg/kg and 4.4mg/kg through duodenal administration group and DIEMAILING ZHUSHEYE 0.33mg/kg intravenously administrable group.Each administration group is all prepared the desired concn medicinal liquid with 0.9%NaCl before administration.
Animal subject is cut a side femoral vein earlier open and is equipped with administrable under pentobarbital sodium (30mg/kg) intravenous anesthesia, circulation of qi promoting cannula again, and artificial respiration, respiratory frequency are 30 times/minute, and ratio is 1.5: 1 during breathing, and tidal volume is 300ml.Animal is under the right arm reclining artificial respiration, in between the left side 4-5 side of body, open breast,, cut off pericardium parietale along vagus nerve and do outstanding bed (being sewn in thoracic wall) exposure heart at distance vagus nerve 2cm place, at nearly 1/2 place of left anterior descending coronary artery, be equipped with ligation from the following lead-in wire of coronary artery and use.Epicardial lead is sewn on the visceral pericardium, is connected on the automatic electrocardiograph of EK10 type single track, the record epicardial electrogram through band switch [5], (∑-ST) and ST displacement surpass the number (N-ST) that leads of 1mV being to be worth before the administration 15 minutes the time after the ligation to calculate the summation of 30 ST displacements of leading.Each is organized dog and is subjected to the reagent thing from what femoral vein splashed into corresponding dosage respectively, and the administration volume is 3ml/kg.Injection speed is the 2ml/ branch.Write down 30,60,120,180 minutes epicardial electrogram after the administration simultaneously, calculate ∑ ST, N-ST and rate of change thereof; Before coronary artery ligation, after the ligation 60 minutes, 120 minutes and 180 respectively from femoral vein blood chemical examination creatine kinase (CK), lactic acid dehydrogenase (LDH) vigor.After the administration 3 hours, take off and wipe out after heart is weighed that atrium and right ventricle claim that left chamber is heavy, freezing 30-40 minute,, with coronary sulcus parallel 5 slice of ventricular muscles being cut into uniform thickness following in coronary ligation point, place 37 ℃ of 1%N-BT dye liquors, jolting dyeing to take out in 15 minutes 5 ventricular muscles, infarcted region is dyed light red, non-infarcted region is a kermesinus, calculates the percentage ratio that infarcted region accounts for ischemia ventricle, cardiac weight.
Result of the test shows that the Herba Ixeritis Sonchifoliae extract intravenously administrable is to the effect of having clear improvement of coronary artery ligation dog myocardial ischemia, show as: 1. epicardial electrogram ST section moves summation (∑ ST) and ST displacement and surpasses 1mV and lead and highly significant or significant difference are arranged, (seeing table 4,5 for details) between the above-mentioned two indexes rate of change of each corresponding time point of rate of change and matched group of number (N-ST) after each administration group administration.2. each administration group also has highly significant or significant difference (seeing table 6,7 for details) between different time points CK, LDH rate of change and the matched group respective points CK of administration behind the ligation coronary artery, LDH rate of change.3. the quantitative tissue of myocardial infarct size is learned measurement result and shown: each administration group infarcted myocardium weight/ventricular weight percentage ratio, infarcted myocardium weight/percentage by weight is starkly lower than matched group whole-heartedly, and highly significant or significant difference (seeing table 8 for details) are arranged therebetween
Table 4 Herba Ixeritis Sonchifoliae extract intravenous administration to anesthetized open-chest dog ligation arteria coronaria after epicardial electrogram S-T section summation (∑ ST) influence (mv, X ± SD, n=6)
Group Dosage mg/kg statistical indicator Before the administration After the administration
?60???????????????120???????????????180
Quiet ixeri sonhifolia extract of quiet ixeri sonhifolia extract of quiet ixeri sonhifolia extract of control group ixeri sonhifolia extract is through quiet of duodenal administration ixeri sonhifolia extract 0.9%NS 1.0ml/kg rate of change (%) 8.8 rates of change (%) 4.4 rates of change (%) 2.2 rates of change (%) 4.4 rates of change (%) 0.33 rates of change (%) ??41.24±11.72 ??44.97±24.62 ??42.67±28.58 ??37.14±7.90 ??43.08±26.74 ??43.90±29.68 ?47.08±14.23?????49.90±15.05??????48.25±14.62 ?13.83±5.76??????20.83±8.63???????16.83±8.45 ?39.50±18.89?????28.99±13.43??????28.60±03.18 ?-10.05±5.90 **??-33.97±9.37 **???-34.79±8.95 **?39.11±26.38?????36.97±22.90??????36.22±22.07 ?-8.91±5.43 **???-11.64±3.51 **???-13.14±4.18 **?35.29±7.37??????34.30±7.23???????34.64±7.03 ?-4.89±0.91 **???-7.60±1.21 **????-6.57±3.08 **?41.29±25.46?????45.67±26.97??????44.17±25.58 ?-3.69±4.12 **???7.84±9.80????????4.68±9.61 ?39.00±23.56?????33.60±16.25??????35.56±17.26 ?-8.62±5.26 **???-17.14±12.21 **??-12.27±14.12 **
Each administration group and normal saline matched group compare rate of change=(being worth * 100% before the value/administration before the value-administration after the administration) ratio with rate of change before and after the time point administration *P＜0.05 *P＜0.01
Table 5 Herba Ixeritis Sonchifoliae extract intravenous administration to anesthetized open-chest dog ligation arteria coronaria after the epicardial electrogram N-ST (influence of mv X ± SD)
Group Dosage mg/kg Statistical indicator Before the administration After the administration
????60???????????????120???????????180
Quiet ixeri sonhifolia extract of quiet ixeri sonhifolia extract of quiet ixeri sonhifolia extract of control group ixeri sonhifolia extract is through quiet of duodenal administration Diemailing injection ????0.9％NaCl ????1.0ml/kg ????8.8 ????4.4 ????2.2 ????4.4 ????0.33 ??? X±SD ????％ ??? X±SD ????％ ??? X±SD ????％ ??? X±SD ????％ ??? X±SD ????％ ??? X±SD ????17.2±3.9 ????18.2±4.0 ????17.0±7.0 ????16.2±5.3 ????16.0±5.1 ????14.0±7.4 ?????19.2±5.5 ?????10.0±11.0 ?????16.6±4.5 ?????-9.1±9.6 *?????16.0±8.3 ?????-9.5±17.4 ?????14.4±5.0 ?????-11.2±9.1 *?????16.0±4.4 ?????1.3±6.8 ?????13.4±7.1 ?????-4.1±4.6 * ????20.6±5.6????????19.6±5.0 ????18.51±12.0??????13.4±12.5 ????9.4±6.9?????????9.6±6.0 ????-51.6±31.5 **???-49.5±25.9 **????13.4±8.9????????13.4±9.3 ????-27.4±19.6 **???-28.1±22.1 **????14.4±5.6????????14.0±5.3 ????-11.9±9.7 **????-14.5±7.2 **????16.8±4.6????????16.8±4.6 ????6.5±8.2?????????6.5±8.2 ????12.0±5.2????????12.4±5.1 ????-11.1±8.6 **????-7.7±13.5 *
Each administration group and normal saline matched group compare rate of change=(being worth * 100% before the value/administration before the value-administration after the administration) ratio with rate of change before and after the time point administration *P＜0.05 *P＜0.01
Table 6 Herba Ixeritis Sonchifoliae extract intravenously administrable is to the influence of dog serum kreatinase CK
Group dosage Statistical indicator Before the medicine Behind the medicine (min)
??60 ????180
Quiet 2.2 ixeri sonhifolia extracts of quiet 4.4 ixeri sonhifolia extracts of quiet 8.8 ixeri sonhifolia extracts of control group 0.9%NaCl 10ml/kg ixeri sonhifolia extract are annotated 0.33 through the spirit of 4.4 duodenal administration dish arteries and veins and are penetrated quiet of liquid X ± SD rate of change (%) X ± SD rate of change (%) X ± SD rate of change (%) X ± SD rate of change (%) X ± SD rate of change (%) X ± SD rate of change (%) ????811.8±6.7.6 ????966.0±73.9 ????745.8±91.1 ????699.4±100.5 ????748.2±88.7 ????741.8±74.6 ??1442.2±84.3 ??77.9±4.5 ??1306.2±63.4 ??35.5±5.7 **??1238.4±88.2 ??66.9±8.7 *??1221.2±117.8 ??75.6±9.2 ??1254.8±99.5 ??68.4±8.7 ??1268.4±109.8 ??71.3±8.1 ????2732.4±160.7 ????237.1±9.6 ????2403.2±298.6 ????148.0±13.4 **????1608.6±115.7 ????117.6±24.8 ????2019.6±272.9 ????189.3±10.4 *????2201.0±343.8 ????193.1±14.1 *????2104.0±215.2 ????183.7±11.6 **
Relatively thin with contrast *P＜0.05, *P＜0.01
Table 7 Herba Ixeritis Sonchifoliae extract intravenously administrable is to the influence of ligation coronary artery dog lactic acid dehydrogenase
Group dosage Statistical indicator Before the medicine Behind the medicine (min)
????60 ????180
Quiet 2.2 injection dish Maitongs of quiet 4.4 injection dish Maitongs of quiet 8.8 injection dish Maitongs of control group 0.9%NaCl 1ml/kg injection dish Maitong are through 4.4 X ± SD rate of change (%) X ± SD rate of change (%) X ± SD rate of change (%) X ± SD rate of change (%) X ± SD ????122.2±30.2 ????135.6±7.6 ????120.2±23.4 ????109.8±23.9 ????127.6±18.5 ????171.2±323.2 ????42.9±18.7 ????167.0±20.1 ????22.8±8.5 *????150.4±28.0 ????25.4±8.2 ????153.8±19.7 ????42.9±16.8 ????158.8±22.3 ????296.8±37.4 ????150.9±44.8 ????291.8±27.2 ????114.8±9.1 ????244.6±18.0 ????108.7±38.2 ????246.0±14.5 ????132.6±50.8 ????276.4±21.6
The spirit of duodenal administration dish arteries and veins is annotated 0.33 and is penetrated quiet of liquid Rate of change (%) X ± SD rate of change (%) ?? ????110.0±33.6 ????24.6±2.2 ????131.1±35.9 ????19.6±10.6 * ????118.4±21.2 ????267.1±29.8 ????156.3±70.9
Compare with matched group *P＜0.05, *P＜0.01
Table 8 Herba Ixeritis Sonchifoliae extract intravenous administration is to the influence of ligation coronary artery dog myocardial infarction area (X ± SD n=5)
Group Dosage/(mg/kg) Infarcted myocardium weight/chamber heavy (%) Infarcted myocardium weighs/heavy (%) whole-heartedly
Quiet ixeri sonhifolia extract of quiet ixeri sonhifolia extract of quiet ixeri sonhifolia extract of control group ixeri sonhifolia extract is through quiet of duodenal administration Diemailing injection ????0.9％NaCl ????1.0mg/kg ????8.8 ????4.4 ????2.2 ????4.4 ????0.33 ????30.61±4.65 ????15.36±2.96 **????19.41±3.85 **????22.97±4.10 *????25.76±3.22 ????20.75±1.99 ** ????18.99±3.00 ????8.71±2.10 **????11.72±1.79 **????13.39±2.36 *????16.33±3.17 ????11.62±1.86 **
Compare with matched group, *P＜0.05 *P＜0.01
2. the influence of the Acute Myocardial Ischemia in Rats that isoproterenol is brought out is respectively model control group with 10 every group of 60 rat random packet; The quiet notes administration of autumn Herba Ixeritis Sonchifoliae extract senior middle school low dose group dosage is respectively 30mg/kg, 15mg/kg, 7.5mg/kg; 15mg/kg gastric infusion group; Positive controls is mg/kg for DIEMAILING ZHUSHEYE dosage, the quiet notes of matched group 0.9%NaCl.Be subjected to reagent thing and matched group all to be mixed with desired concn with 0.9%NaCl, the administration volume is 10ml/kg, and injection speed is 2ml/min.
Animal subject is with urethane intraperitoneal injection of anesthesia (1.2g/kg), is dorsal position and fixes, links to each other with photoelectricity 6511 type electrocardiographs to write down with pin type electrode and mark II and lead and V 1Lead.By being the subcutaneous injection isoproterenol behind the above-mentioned dosage intravenously administrable, dosage is 2mg/kg.Observe after the administration the 5th ', 10 ', 20 ', the height of ST field offset baseline in 30 ' electrocardiogram., add up and significance test as the observation index of weighing the myocardial damage degree with average.
The result shows that intravenous injection autumn Herba Ixeritis Sonchifoliae extract causes that to the isoproterenol subcutaneous injection myocardial metabolism reinforcement causes the skew of myocardial ischemia ST section that obvious mitigation is arranged.See table 9 for details.
The Herba Ixeritis Sonchifoliae extract intravenous injection of table 9 autumn to isoproterenol bring out myocardial ischemia influence (X ± SD, n=10)
Group Dosage (mg/kg) The mark II ∑ S-T total drift value mv that leads
Control group autumn ixeris sonchifolia hance extract iv autumn ixeris sonchifolia hance extract iv autumn ixeris sonchifolia hance extract iv autumn ixeris sonchifolia hance extract ig Diemailing injection ????0.9％NaCl ????5.0mg/kg ????30 ????15 ????7.5 ????15 ????0.33 ????0.73±0.15 ????0.38±0.24 **????0.48±0.24 **????0.51±0.24 *????0.44±0.13 **????0.46±0.23 **
Each administration group and matched group are relatively *P＜0.05, *P＜0.01
3. we have carried out the test of cytotoxic activity to sell 22 chemical compounds that separation obtains the Lepidium plant from hardship the bitter cytotoxic activity of selling Lepidium plant monomer chemical compound, and structure activity relationship has been carried out preliminary discussion.
Experiment material and cell culture
A375 (human melanoma cell), L929 (mouse lung epithelial cell), HeLa (human cervical carcinoma cell) all derives from U.S. ATCC (American Tissue Culture Collection), all cultivate, add 10% hyclone, 1% antibiotic (10 with the RPMI-1640 culture fluid, 100U/ml penicillin and 10,000 μ g/ml streptomycin), the 2mM glutamine places 4%CO 2Cultivate in the incubator.Sample: sell each monomeric compound of extraction separation the Lepidium plant from hardship: Sonchifolactone A (sonchifolactone A) (1), Sonchifolactone B (sonchifolactone B) (2), Sonchifolactone C (sonchifolactone C) (3), Sonchifolactone D. (sonchifolactone D) (4), Sonchifolignan A. (sonchifolignan A) (5), Sonchifolignan B. (sonchifolignan B) (6), Sonchifolinin. (sonchifolinin) (7), luteolin-7-O-β-D-glucuronide ethyl ester (luteolin-7-O-β-D-glucuronopyranoside ethyl ester) (8), taraxerane-20-alkene-3 β, 16 alpha-dihydroxy-s-3-ethyl ester (taraxastane-20-ene-3 β, 16 α-dihydroxy-3-acetate) (9), lxeris saponin A (ixeris saponin A) (10), lxeris saponin B (ixeris saponin B) (11), lxeris saponin C (ixeris saponin C) (12), lxeris saponin D (ixeris saponin D) (13), luteolin (luteolin) (14), luteolin-7-O-β-D-glucoside (luteolin-7-O-β-D-glucopyranoside) (15), luteolin-7-O-β-D-glucuronide (luteolin-7-O-β-D-glucuronopyranoside) (16), Luteolin-7-O-gentiobiside (luteolin-7-O-gentiobiside) (18), apigenin (apigenin) (20), apigenin 7-O-β-D-glucoside (apigenin-7-O-β-D-glucopyranoside) (21), apigenin 7-O-β-D-glucuronide (apigenin-7-O-β-D-glucuronopyranoside) (22), 5,7-dihydroxy-4 '-methoxy flavone-7-O-rutin glucosides (5,7-dihydroxy-4 '-methoxy-flavone-7-O-rutinoside) (24), oleanolic acid (oleanlic acid) (25), taraxasterol acetas (taraxasterylacetate) (26).
Compound concentration is successively: 1 μ g/ml, 5 μ g/ml, 20 μ g/ml, 50 μ g/ml, 100 μ g/ml.Tetrazolium bromide (MTT): the precious Imtech in Beijing; RPMI-1640:Gibco company, the U.S.; Hyclone (FBS): Dalian biological reagent factory; Penicillin and streptomycin: North China pharmacy joint-stock company; Trypsin: the north is with positive company; Glutamine: the precious Imtech in Beijing.
22 kinds of monomeric compounds are carried out the anti-tumor activity in-vitro screening, the results are shown in Table 10.
As can be seen from the table, hardship is sold in the classes of compounds in the Lepidium plant, sesquiterpene lactones class (as chemical compound 2) and triterpene saponin componds (as chemical compound 11) have than the obvious in-vitro anti-tumor activity, and flavonoid, lignanoids and triterpenoid sapogenin do not have anti-tumor activity substantially.
In the sesquiterpene lactones compounds, the strongest (IC of activity of chemical compound 2 5011.0 about μ g/ml), to chemical compound 1,2,3,4 structure compares, and infers that chemical compound 2 is that activity is stronger owing to have the structure of α-methene-gamma lactone in its aglycon structure.After two keys were reduced, activity greatly reduced, IC 50Value is reduced to 30-40 μ g/ml (as chemical compound 1,3).
In triterpene saponin componds, chemical compound 11 and 12 active obviously than 10 and the last 13.Find when analyzing their structure, be likely 11 with 12 structure in to become the ester glycosides and caused specific activity C-28 in the C-28 position be the saponin 10 and the last 13 of free hydroxyl group.
In flavone compound, except luteolin-7-O-β-D-glucoside (15) was medium cytotoxicity, other chemical compound comprised that aglycon, monoglycosides, bioside all do not have activity.Chemical compound 7 shows significant cytotoxicity, and therefore, we utilize fluorescent staining method to carry out further research.Found that chemical compound 7 can induce the HeLa apoptosis.DAPI is a kind of fluorescent dye, and it can combine with cell DNA is specific, and sends green fluorescence under the exciting of the ultraviolet light of certain wavelength.After will carrying out DAPI dyeing through the HeLa cell that chemical compound 7 is handled, find the HeLa cell shrinkage, the nucleus distortion, chromatic agglutination is typical apoptosis feature; And the cell growth condition of negative control group is good.
Table?10?Cytotoxic?Activity?of?Natural?Products?against?Tumor?Cell?Lines?in?vitro(IC 50，μ
g/ml)
????Compound ????A375 ????L929 ????HeLa
????1 ????2 ????3 ????4 ????5 ????6 ????7 ????8 ????9 ????10 ????11 ????12 ????13 ????14 ????15 ????16 ????18 ????20 ????21 ????24 ????25 ????26 ????CPM ????34.8±11.2 ????13.2±1.6 ????28.2±11.5 ????38.5±13.2 ????＞100 ????＞100 ????5.2±0.1 ????＞100 ????＞100 ????43.2 ????8.8±2.6 ????32.3±14.8 ????＞100 ????＞100 ????36.7±9.2 ????＞100 ????＞100 ????＞100 ????＞100 ????＞100 ????＞100 ????＞100 ????1.10±0.2 ????35.2±8.8 ????10.5±2.2 ????32.8±8.4 ????31.9±8.4 ????＞100 ????＞100 ????4.1±2.2 ????- ????- ????＞100 ????12.1±4.5 ????45.2±5.3 ????＞100 ????＞100 ????55.2±25.7 ????＞100 ????＞100 ????＞100 ????＞100 ????＞100 ????＞100 ????＞100 ????0.85±0.4 ????- ????- ????- ????- ????- ????- ????4.6±0.4 ????- ????- ????＞100 ????- ????- ????- ????- ????42.6±13.7 ????- ????- ????- ????- ????- ????- ????- ????0.46±0.2
Noval chemical compound in sesquiterpene lactones and the phenoloid
Table 1 Constituents isolated from Ixeris genus
Figure A20041002112500181
Hardship is sold the process that Lepidium extracts the preparation intermediate
A, medical material soak and decoct
(A) hardship is sold Lepidium raw material (medical material) cutting, by the weight fraction ratio of raw material and tap water is 1: 9～15 to add tap water in raw material, and soak at room temperature 1～3 hour is then with both mixture heated to 70 ℃～100 ℃, after being incubated 1～3 hour, residue obtained liquid.
(B) the weight fraction ratio of selling Lepidium raw material and tap water by described hardship is to add tap water in 1: 6～10 slags that leach to the A step (A), and with both mixture heated to 70 ℃～100 ℃, be incubated 1～2.5 hour after, residue obtained liquid.
(C) the weight fraction ratio of selling Lepidium raw material and tap water by described hardship is to add tap water in 1: 6～8 slags that leach to the A step (B), and with both mixture heated to 70 ℃～100 ℃, is incubated after 1～1.5 hour residue obtained liquid.
(D) or adopt 50～95% ethanol and methanol extract liquid, reclaim alcohol and do not contain below the alcohol amount to there being alcohol flavor or 10%.
B, liquid concentration
The liquid mixing that will be respectively produce by described each A step (A), (B), (C), (D) is the back concentrating under reduced pressure together, till the ratio of its weight and described raw material weight is 1: 1～5.
C, absorption, eluting
Macroporous resin column after making liquid after concentrating by activated processing makes the total flavones in the liquid be adsorbed by resin column, and discards effluent, presses 1: 1～3 distilled water flushing resin column of raw material weight again, discards effluent.Continuing with concentration is that 10～60% ethanol cleans resin column, and collects eluent.With the polyamide column of this eluent, and, collect effluent and eluent with 80% ethanol elution of 1～2 times of material quantity by having handled well.
D, roguing
With the eluent of collecting among the C, be that 95% ethanol adds wherein with concentration, be 80% until the concentration of alcohol of eluent, then, this mixed liquor is filtered by clear slag plate, roguing is also collected filtrate.
E, finished product reclaim, drying
Recovery process D makes the ethanol in the filtrate, after the remaining material drying, can obtain preparing the finished product of intermediate.
Compared with the prior art the present invention has the following advantages after realizing:
1. cost is low
2. impurity content is low
3. process stabilizing, easy operating is easy to realize
4. production process environmentally safe
Intermediate preparation embodiment
Embodiment 1 (raw material is sold dish for embracing the stem hardship)
A, immersion and decoction
(A) the Herba Ixeritis Sonchifoliae herb 10Kg that gets cutting adds in the container, adds 150 liters in tap water again in container, soak at room temperature 2 hours, and then, the mixture heated to 100 ℃ with both is incubated 2 hours.
(B) add 100 liters in tap water in the slag that leaches to A step (A), and both are mixed
Thing is heated to 95 ℃, be incubated 1 hour after, residue obtained liquid.
(C) add 80 liters in tap water in the slag that leaches to A step (B), and with both mixture
Be heated to 95 ℃, be incubated 1 hour after, residue obtained liquid.
B, liquid concentration
Will be respectively by above-mentioned each liquid of producing of (A), (B), (C) in step, after being mixed, concentrating under reduced pressure is concentrated into 20 until it and is upgraded to and ends.
C, absorption, eluting
Macroporous resin column after making liquid after concentrating by activated processing makes the total flavones in the liquid be adsorbed by resin column, and discards effluent, 0.5 liter of distilled water flushing resin column of reuse, discard effluent, continue with the ethanol cleaning resin column of concentration 60%, and collect eluent.With the polyamide column of this eluent, and, collect effluent and eluent with 80% ethanol elution of 2 times of material quantities by having handled well.
D, roguing
With the eluent of collecting among the C, be that 95% ethanol adds wherein with concentration, be 80% until the concentration of alcohol of eluent, this mixed liquor is filtered by clear slag plate, roguing is also collected filtrate.
E, finished product reclaim, drying
Recovery process D makes the ethanol in the filtrate, after the remaining material drying, can obtain preparing intermediate.
Embodiment 2 (raw material is the autumn Herba Ixeritis Sonchifoliae)
A, immersion and decoction
(A) the autumn Herba Ixeritis Sonchifoliae herb 10Kg that gets cutting adds in the container, adds 120 liters in tap water again in container, soak at room temperature 2 hours, and then, the mixture heated to 100 ℃ with both is incubated 2 hours.
(B) add 100 liters in tap water in the slag that leaches to A step (A), and both are mixed
Thing is heated to 90 ℃, be incubated 1.5 hours after, residue obtained liquid.
(C) add 80 liters in tap water in the slag that leaches to A step (B), and with both mixture
Be heated to 85 ℃, be incubated 1 hour after, residue obtained liquid.
B, liquid concentration
Will be respectively by above-mentioned each liquid of producing of (A), (B), (C) in step, after being mixed, concentrating under reduced pressure is concentrated into 20 until it and is upgraded to and ends.
C, absorption, eluting
Macroporous resin column after making liquid after concentrating by activated processing makes the total flavones in the liquid be adsorbed by resin column, and discards effluent, 0.5 liter of distilled water flushing resin column of reuse, discard effluent, continue with the ethanol cleaning resin column of concentration 50%, and collect eluent.With the polyamide column of this eluent, and, collect effluent and eluent with 70% ethanol elution of 2 times of material quantities by having handled well.
D, roguing
With the eluent of collecting among the C, be that 95% ethanol adds wherein with concentration, be 80% until the concentration of alcohol of eluent, this mixed liquor is filtered by clear slag plate, roguing is also collected filtrate.
E, finished product reclaim, drying
Recovery process D makes the ethanol in the filtrate, after the remaining material drying, can obtain preparing intermediate.
Embodiment 3 (raw material is a Herba Ixeritis Denticulatae)
A, immersion and decoction
(A) the Herba Ixeritis Denticulatae herb 10Kg that gets cutting adds in the container, adds 150 liters in tap water again in container, soak at room temperature 2 hours, and then, the mixture heated to 95 ℃ with both is incubated 1.5 hours.
(B) add 100 liters in tap water in the slag that leaches to A step (A), and both are mixed
Thing is heated to 90 ℃, be incubated 2 hours after, residue obtained liquid.
(C) add 60 liters in tap water in the slag that leaches to A step (B), and with both mixture
Be heated to 80 ℃, be incubated 1.5 hours after, residue obtained liquid.
B, liquid concentration
Will be respectively by above-mentioned each liquid of producing of (A), (B), (C) in step, after being mixed, concentrating under reduced pressure is concentrated into 20 until it and is upgraded to and ends.
C, absorption, eluting
Macroporous resin column after making liquid after concentrating by activated processing makes the total flavones in the liquid be adsorbed by resin column, and discards effluent, 0.5 liter of distilled water flushing resin column of reuse, discard effluent, continue with the ethanol cleaning resin column of concentration 55%, and collect eluent.
D, roguing
With the eluent of collecting among the C, be that 95% ethanol adds wherein with concentration, be 80% until the concentration of alcohol of eluent, this mixed liquor is filtered by clear slag plate, roguing is also collected filtrate.
E, finished product reclaim, drying
Recovery process D makes the ethanol in the filtrate, after the remaining material drying, can obtain preparing intermediate.
Embodiment 4 (raw material is the Herba Ixeritis chinensis dish)
A, immersion and decoction
(A) the Herba Ixeritis chinensis dish herb 10Kg that gets cutting adds in the container, adds 100 liters in tap water again in container, soak at room temperature 2.5 hours, and then, the mixture heated to 100 ℃ with both is incubated 2 hours.
(B) add 100 liters in tap water in the slag that leaches to A step (A), and both are mixed
Thing is heated to 95 ℃, be incubated 2 hours after, residue obtained liquid.
(C) add 60 liters in tap water in the slag that leaches to A step (B), and with both mixture
Be heated to 80 ℃, be incubated 1.5 hours after, residue obtained liquid.
B, liquid concentration
Will be respectively by above-mentioned each liquid of producing of (A), (B), (C) in step, after being mixed, concentrating under reduced pressure is concentrated into 20 until it and is upgraded to and ends.
C, absorption, eluting
Macroporous resin column after making liquid after concentrating by activated processing makes the total flavones in the liquid be adsorbed by resin column, and discards effluent, 0.5 liter of distilled water flushing resin column of reuse, discard effluent, continue with the ethanol cleaning resin column of concentration 50%, and collect eluent.
D, roguing
With the eluent of collecting among the C, be that 95% ethanol adds wherein with concentration, be 80% until the concentration of alcohol of eluent, this mixed liquor is filtered by clear slag plate, roguing is also collected filtrate.
E, finished product reclaim, the dried recovered step D makes the ethanol in the filtrate, after the remaining material drying, can obtain preparing intermediate.
The dosage form of medicine of the present invention:
1. injection Herba Ixeritis Sonchifoliae (lyophilizing)
Herba Ixeritis Sonchifoliae extract intermediate 50～200g
(quite total flavones, total lactone total content labelled amount 90～110%)
Mannitol is made proppant in right amount
Make 1000 of lyophilized injectable powders
Method for making: (or in the superpurgative working table operation) with recipe quantity extract and proppant, adds the injection water under aseptic condition, and heating for dissolving adds the injection active carbon, heating and filtering, 1000 of-40 ℃ of packing, freezing after, heat up, till the lyophilizing.
Character: this product is grey yellow-white amorphous powder or porous solid shape thing, bitter and puckery flavor, have necessarily draw moist.
Function with cure mainly: promoting blood circulation and stopping pain, heat clearing away blood stasis dispelling are used for coronary heart disease, angina pectoris card and see that uncomfortable in chest, pained, bitter taste, the dark red work of tongue deposits ecchymosis etc., also available and cerebral infarction person.
2. Herba Ixeritis Sonchifoliae infusion solution
Herba Ixeritis Sonchifoliae extract intermediate 50～200g
(quite labelled amount 90～110%)
Excipient such as glucose are an amount of
Make 1000 of PVP plastic bag or infusion bottles
Method for making: the side of going out is measured intermediate and excipient, solvent, adds injection water, heating for dissolving, adds injection active carbon, heating, filtration, packing promptly.
Character: this product is pale yellow light color clear liquid, bitter and puckery flavor.
Function with cure mainly with embodiment 1.
3. anti-brain patch
Intermediate 80～400g that Herba Ixeritis Denticulatae extracts
(contain lactone, phenol thing content accounts for more than 50%)
The excipient amount of being (lactose, starch)
Make 1000
Method for making: with recipe quantity intermediate (extract) and excipient mixing, wet method or one-step palletizing, if wet granulation 60～80 ℃ of dryings, is pressed into 1000 with adding the moderate lubrication agent behind the granule granulate, color clothing or thin film color clothing are promptly.
Character: behind uncoating or the thin film pale brown toner end, bitter in the mouth is puckery.Function with cure mainly: with example 1,2.In addition applicable to antiinflammatory, the pain relieving of chronic appendicitis.
4. the white flat capsule of blood
Intermediate 80～400g that Herba Ixeritis chinensis is extracted
(contain the lactone total flavones more than 50%, be labelled amount 90～110%)
Excipient is an amount of
Make 1000
Method for making: recipe quantity intermediate mixing obtained makes granule, in incapsulating promptly.
Character: this product content is the amorphous or porous solid granular substance of yellowish-brown, bitter and puckery flavor, have draw moist.Function with cure mainly: heat clearing away, detoxifcation, reducing swelling and alleviating pain, dissipating blood stasis.Be used for coronary heart disease, angina pectoris and cerebral infarction card and see uncomfortable in chest, hands acroanesthesia and leukemic auxiliary treatment etc.
5. heart and brain Shu Ping mediating recipe (oral liquid)
Intermediate 80～400g that the autumn Herba Ixeritis Sonchifoliae extracts
Excipient (Mel, lactose etc.) is an amount of
Make 1000
Method for making: with recipe quantity intermediate and excipient, add suitable quantity of water, heating for dissolving adds simple syrup and antiseptic such as Mel, benzoic acid, it is an amount of to add water again, filters to divide to be filled to 10000ml, cold preservation, filter, be sub-packed in the 10ml peace bottle or in the 50ml peace bottle, with 100 ℃ aseptic 30 minutes promptly.
Function with cure mainly: with embodiment 1
6. Herba Ixeritis Sonchifoliae granule (Sugarless type)
Intermediate 80～400g that Herba Ixeritis Sonchifoliae extracts
(contain lactone and total flavones amount, labelled amount 90～110%) more than 50%
Excipient is an amount of
Make 1000 bags
Method for making: with the intermediate and the excipient mixing of recipe quantity extract, wet granulation or one-step palletizing, if during wet granulation in 60～80 ℃ of dryings, dried granule is carried out being sub-packed in 1000 bags promptly after granulate handles.
Character: this product is yellow shallow brown white loose shape granule bitter in the mouth, puckery.
Function with cure mainly: with embodiment 1.
Content assaying method and index
(1) sells with hardship that index composition adenosine and luteolin 7-O-glucosides are reference substance in the Lepidium, set up the thin layer chromatography discrimination method of plant extract.
(2) employing HPLC method is carried out assay to the active ingredient Sonchifolactone A of this genus medicinal substances extract intermediate, and with colorimetric method for determining the general flavone content of preparation, effective ingredient adds with content and can survey more than 80% in the intermediate, and the content of extract intermediate Sonchifolactone A must not be less than 1%.
(3) be object of reference with luteolin 7-O-glucosides, formulated the finger printing of medical material, intermediate.The quality standard of being formulated has guaranteed the controllability and the repeatability of drug quality.

Claims (4)

1. gutweed Lepidium new medical use, it is characterized in that plant extract, contain sesquiterpene lactones and phenol thing (containing flavone), having increases coronary flow, improves the cardiac muscle circulation, the anticoagulant effect, obviously increases effects such as the activity of fibrinous lyase, anti-cerebral infarction blood circulation.
2. nine kinds of All new compounds in the gutweed Lepidium are as follows:
3. the preparation method of gutweed Lepidium pharmaceutical intermediate is characterized in that the preparation of intermediate adopts water or alcohols to extract, by macroporous resin and the preparation of polyamide columns in series chromatographic process.
4. the preparation method of gutweed Lepidium pharmaceutical intermediate according to claim 2 is characterized in that:
A, medical material soak and decoct
(A) hardship is sold Lepidium raw material (medical material) cutting, by the weight fraction ratio of raw material and tap water is 1: 9～15 to add tap water in raw material, and soak at room temperature 1～3 hour is then with both mixture heated to 70 ℃～100 ℃, after being incubated 1～3 hour, residue obtained liquid.
(B) the weight fraction ratio of selling Lepidium raw material and tap water by described hardship is to add tap water in 1: 6～10 slags that leach to the A step (A), and with both mixture heated to 70 ℃～100 ℃, be incubated 1～2.5 hour after, residue obtained liquid.
(C) the weight fraction ratio of selling Lepidium raw material and tap water by described hardship is to add tap water in 1: 6～8 slags that leach to the A step (B), and with both mixture heated to 70 ℃～100 ℃, is incubated after 1～1.5 hour residue obtained liquid.
(D) or adopt 50～95% ethanol and methanol extract liquid, reclaim alcohol and do not contain below the alcohol amount to there being alcohol flavor or 10%.
B, liquid concentration
The liquid mixing that will be respectively produce by described each A step (A), (B), (C), (D) is the back concentrating under reduced pressure together, till the ratio of its weight and described raw material weight is 1: 1～5.
The macroporous resin column of liquid after C, absorption, eluting make and concentrate after by activated processing makes the total flavones in the liquid be adsorbed by resin column, and discards effluent, presses 1: 1～3 distilled water flushing resin column of raw material weight again, discards effluent.Continuing with concentration is that 10～60% ethanol cleans resin column, and collects eluent.With the polyamide column of this eluent, and, collect effluent and eluent with 80% ethanol elution of 1～2 times of material quantity by having handled well.
D, roguing
With the eluent of collecting among the C, be that 95% ethanol adds wherein with concentration, be 80% until the concentration of alcohol of eluent, then, this mixed liquor is filtered by clear slag plate, roguing is also collected filtrate.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102526150A (en) * 2010-12-24 2012-07-04 苏州宝泽堂医药科技有限公司 Method for preparing total elecampane sesquiterpene lactone extract
CN112341515A (en) * 2020-11-20 2021-02-09 榆林学院 Method for extracting taraxasterol from sow thistle
CN115109067A (en) * 2022-07-11 2022-09-27 山东省果树研究所 Sesquiterpenoids and preparation method and application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1190205C (en) * 2001-06-24 2005-02-23 华玉强 Diemailing injection and its preparing process

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102526150A (en) * 2010-12-24 2012-07-04 苏州宝泽堂医药科技有限公司 Method for preparing total elecampane sesquiterpene lactone extract
CN112341515A (en) * 2020-11-20 2021-02-09 榆林学院 Method for extracting taraxasterol from sow thistle
CN115109067A (en) * 2022-07-11 2022-09-27 山东省果树研究所 Sesquiterpenoids and preparation method and application thereof
CN115109067B (en) * 2022-07-11 2023-08-08 山东省果树研究所 Sesquiterpenoids and preparation method and application thereof

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