CN1138984A - Anti-thrombosis glucoside medicine - Google Patents
Anti-thrombosis glucoside medicine Download PDFInfo
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- CN1138984A CN1138984A CN 95106768 CN95106768A CN1138984A CN 1138984 A CN1138984 A CN 1138984A CN 95106768 CN95106768 CN 95106768 CN 95106768 A CN95106768 A CN 95106768A CN 1138984 A CN1138984 A CN 1138984A
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- 239000003814 drug Substances 0.000 title claims abstract description 9
- 230000002785 anti-thrombosis Effects 0.000 title claims abstract description 8
- 229930182478 glucoside Natural products 0.000 title abstract description 4
- 150000008131 glucosides Chemical class 0.000 title abstract description 3
- 229930182470 glycoside Natural products 0.000 claims abstract description 27
- 150000002338 glycosides Chemical class 0.000 claims abstract description 18
- ZQEKBPUAGJKEQO-UHFFFAOYSA-N isoeruboside b Chemical compound O1C2(OCC(C)CC2)C(C)C(C2(CCC3C4(C)CC5)C)C1CC2C3CC(O)C4CC5OC(C(C1O)O)OC(CO)C1OC(C1OC2C(C(O)C(O)C(CO)O2)O)OC(CO)C(O)C1OC1OC(CO)C(O)C(O)C1O ZQEKBPUAGJKEQO-UHFFFAOYSA-N 0.000 claims abstract description 15
- WXBBQBYCUTXTJQ-FUIZFARNSA-N 7-[(2s,3r,4r,5s,6s)-3,5-dihydroxy-6-methyl-4-[(2r,3s,4r,5r,6s)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-3,5,8-trihydroxy-2-(4-hydroxyphenyl)chromen-4-one Chemical compound O([C@@H]1O[C@H]([C@@H]([C@@H](O[C@@H]2[C@H]([C@H](O)[C@@H](O)[C@H](CO)O2)O)[C@H]1O)O)C)C(C=1O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C=C1 WXBBQBYCUTXTJQ-FUIZFARNSA-N 0.000 claims abstract description 14
- -1 glucoside compounds Chemical class 0.000 claims abstract description 11
- CIAXXTSXVCLEJK-JOEVVYSCSA-N rhodionin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC1=CC(O)=C2C(=O)C(O)=C(C=3C=CC(O)=CC=3)OC2=C1O CIAXXTSXVCLEJK-JOEVVYSCSA-N 0.000 claims abstract description 11
- WYWLHHWQKOHXHW-UHFFFAOYSA-N protoisoeruboside b Chemical compound O1C(CO)C(O)C(O)C(O)C1OCC(C)CCC(C(C1C2(C)CCC3C4(C)CC5)C)(O)OC1CC2C3CC(O)C4CC5OC(C(C1O)O)OC(CO)C1OC(C1OC2C(C(O)C(O)C(CO)O2)O)OC(CO)C(O)C1OC1OC(CO)C(O)C(O)C1O WYWLHHWQKOHXHW-UHFFFAOYSA-N 0.000 claims abstract description 8
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- WXBBQBYCUTXTJQ-WITOOHFNSA-N rhodiosin Natural products O([C@@H]1[C@H](O)[C@H](Oc2c(O)c3OC(c4ccc(O)cc4)=C(O)C(=O)c3c(O)c2)O[C@@H](C)[C@@H]1O)[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 WXBBQBYCUTXTJQ-WITOOHFNSA-N 0.000 claims abstract description 8
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 9
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
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- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 1
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- SYXUBXTYGFJFEH-UHFFFAOYSA-N oat triterpenoid saponin Chemical compound CNC1=CC=CC=C1C(=O)OC1C(C=O)(C)CC2C3(C(O3)CC3C4(CCC5C(C)(CO)C(OC6C(C(O)C(OC7C(C(O)C(O)C(CO)O7)O)CO6)OC6C(C(O)C(O)C(CO)O6)O)CCC53C)C)C4(C)CC(O)C2(C)C1 SYXUBXTYGFJFEH-UHFFFAOYSA-N 0.000 description 1
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- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention discovers for the first that garlic saponin proto-iso-eruboside-B and iso-eruboside-B, rhodiola flavone glycoside rhodionin and rhodiosin, and Rhizoma bolbostemmae glucoside A, B, C separated from Rhizoma bolbostemmae total glycoside and their cellulase-enzymolyzed derivatives has strong activity in checking the coagulation of platelet, raising dissolution of fibrin and prolonging blood clotting time, and that these glucoside compounds may be used in the prevention and cure of thrombosis. The new anti-thrombosis medicine is prepated with the monomer or the mixture of the above-said compounds as effective component.
Description
The present invention relates to Bulbus Allii Saponin, Herbacetin 7-O-.alpha.-L-rhamnopyranoside, tubeimoside and derivant thereof is the novel antithrombotic reagent of a class that main component is made for the new purposes of control thrombotic disease with it.
Bulbus Allii is the bulb of Liliaceae allium Bulbus Allii (Allium sativum L.).A large amount of modern pharmacologies and clinical research find that Bulbus Allii has stronger anticoagulant effect, and antilipemic is raise and the raising fibrinolytic, thereby have antithrombotic, antiatherogenic effect (Chen Jingbo etc., the Chinese Pharmacological circular, 1991,7 (2): 88; Han Jinxiang etc., foreign medical science Chinese medicine fascicle, 1990,12 (1): 1).About the chemical research of Bulbus Allii water soluble ingredient, Japanese scholar Matsuura report derives from the Furost saponine proto-eruboside-B of Bulbus Allii, sativoside-B
1And two steroid saponin sativoside-R
1, sativoside-R
2Structure (Matsuura H, et al., Chem Pharm Bull, 1988,36:3659; Chem Pharm Bull, 1989,37 (10): 2741).As for its pharmacological action, do not see bibliographical information as yet.
Radix Rhodiolae Rhodiola crenulata SH.Fu is a kind of of Radix Rhodiolae, and forefathers reported once that its chemical constituent had rhodioloside, butyl alcohol, rhodionin, and rhodiosin (Wang Shu etc., Acta Pharmaceutica Sinica, 1992,27 (2): 117; Peng Jiangnan etc., Chinese herbal medicine, 1995,26 (4): 177) etc., wherein afterwards both are Radix Rhodiolae medium-height grass quality flavonoids, have more characteristic.Its pharmacological action someone is as yet studied.
Rhizoma Bolbostematis is the dry tuber of cucurbitaceous plant Rhizoma Bolbostematis Bolbostemma paniculatum (Maxim.) Franquet.Function with eliminating stagnation, detumescence, detoxifcation is used for the treatment of acute mastitis scrofula, mastitis, the tuberculosis of cervical lymph nodes, chronic lymphadenitis, hypertrophic rhinitis (90 editions the 11st page of the Pharmacopoeia of the People's Republic of China).The macro ring triterpenoid saponin is the bigger composition of content in the Rhizoma Bolbostematis, specific examples of such components complex structure uniqueness, and that has now identified has Rhizoma Bolbostematis glycoside first, second and third (Kong Fanhua etc., chemical journal 1988,46, a 772-778; 1988,46,409-411) etc. (structure sees Table 3).People such as Yu Lijian find that Rhizoma Bolbostematis glycoside first has very strong active anticancer and cancer is urged strong inhibitory action (Planta Medica1994,60, the 204-208 of process; Science Bulletin 1991, (18): 1421-1424), but the effect to cardiovascular system does not appear in the newspapers as yet about tubeimoside up to now.
The objective of the invention is to study of the effect of above-mentioned glycoside compound, seek the active drug of control thrombotic disease cardiovascular system.
The present invention finds Bulbus Allii Saponin proto-iso-eruboside-B (I) and iso-eruboside-B (II), Herbacetin 7-O-.alpha.-L-rhamnopyranoside rhodionin (III) and rhodiosin (IV) first and get Tubeimuside I (V) from the Rhizoma Bolbostematis general glycoside, second (VI) and third (VII) and solve derivant 1 (VIII) through cellulose enzyme, (structure sees Table 1 for 2 (IX) and 3 (X), 2 and 3) all have very strong anticoagulant effect and raising fibrinolytic activity, and can obviously prolong blood coagulation time (the results are shown in Table 4).Prompting, this compounds can be used as the control of thrombotic disease (as cerebral thrombosis, myocardial infarction, atherosclerosis etc.).
With above-mentioned arbitrary effective monomer or by its mixture of forming is raw material, and the medicine that is made can be various dosage forms, comprises oral and two kinds of approach of injection.Dosage range can be 3-200mg/ kg body weight/day, and consumption is 3-50mg/ kg body weight/day preferably, and preferable amount is 5-25mg/ kg body weight/day.
Embodiment:
1. the preparation technology of various glycoside compounds
The fresh bulb of Bulbus Allii, Radix Rhodiolae tuber and Rhizoma Bolbostematis tuber, each 2 kilograms, pulverize separately, aqueous alcohol (can be aqueous methanol, ethanol) lixiviate 4 times (4000ml * 4), each 24 hours, merge concentrated solution, remove wherein alcohols under reduced pressure to 2500ml.Gained extracting solution chloroform extraction three times (1000ml, 500ml, 500ml).
Water layer again with n-butyl alcohol distribute three times (1300ml, 1200ml, 500ml).Merge the n-butanol layer concentrating under reduced pressure and get the n-butanol extraction position, soluble in water, lyophilizing gets the total Saponin of Bulbus Allii (TSG, yield 0.58%), Radix Rhodiolae general glycoside (TSR, yield 4.34%) and Rhizoma Bolbostemmatis total saponins (TSB, yield 2.75%) respectively.Character: equal water soluble, methanol.
Each general glycoside sample separates the preparation monomer through Prep.HPLC.Condition is as follows: and the ODS post (7.8mm * 250mm); Mobile phase: MeOH-H
2O (70: 30 → 55: 45); Detect: RI (decay 1024) or UV; Flow velocity: 1.0ml/min; Sample size: 0.7ml/ time; Analysis time: 35-45min/ pin; Chart speed: 0.25cm/min.From the Bulbus Allii general glycoside, get proto-iso-eruboside-B (I) and iso-eruboside-B (II) (seeing Table 1) respectively; From the Radix Rhodiolae general glycoside, get two flavonoid glycoside rhodionin (III) and rhodiosin (IV) (seeing Table 2); From the Rhizoma Bolbostematis general glycoside, get Tubeimuside I (V), second (VI) and third (VII); Tubeimuside I, second and third solve derivant 1 (VIII) through cellulose enzyme respectively, 2 (IX) and 3 (X) (seeing Table 3).
2. structure is identified
Mainly utilize spectrum, comprise infrared, ultraviolet, nuclear magnetic resoance spectrum (
1H-NMR,
13C-NMR, DEPT,
1H-
1H,
1H-
13C COSY and HMBC) and the FAB-MS analysis, its structure identified.Utilization enzymolysis, acid hydrolysis, aqueous alkali is released and sugar alcohol acetate GC-MS analytical technology has solved the order of connection and the link position that contains sugar in the more Saponin of sugar.
3. biological activity determination
(1) antiplatelet aggregation experiment
Get healthy intravenous rabbit blood, centrifugal (1000rpm) 20min, getting supernatant is PRP (platelet rich plasma), and remainder is through centrifugal (3000rpm) 10min, and getting supernatant is PPP (platelet poor plasma).It is in the 6mm cuvette that the testing sample solution (according to dissolubility with normal saline or dissolve with methanol) of getting different volumes with sampler is inserted diameter, put into automatic cell, quantitatively get PRP and PPP, platelet count is transferred to 28-30 ten thousand/μ l, in 37 ℃ of cultivations, add 2 μ M ADP (0.05ml) and induce, the turbidimetry for Determination platelet aggregation calculates suppression ratio and IC
50Used instrument is that Japan produces Aggregometer PAM-8T platelet aggregation analyzer.
(2) blood coagulation time is measured
Get healthy intravenous rabbit blood, 0 ℃ of centrifugal (3000rpm) 10min, getting supernatant is PPP, gets testing sample solution (DMSO dissolving) 30 μ l with sampler, to wherein adding 150 μ l PPP, cultivates 50 seconds, and adds 150 μ l 0.025M CaCl again for 37 ℃
2Solution, rotation is stirred, and treats that rotation stops, and is blood coagulation time, is the time lengthening rate that blank calculates blood coagulation with the solvent, measures IC with the variable concentrations sample solution
50Used instrument is that Japan produces the blood coagulation time analyzer.
(3) fibrinolytic is measured
(a) making of agar culture dish:
Phosphate buffer (pH7.4) 400ml adds agar 4.8g, NaN
3The straight fire boiling of 200mg, 5ml is divided in 60-80 ℃ of water bath heat preservation in the test tube, in order to avoid solidify.With phosphate buffer thrombin (thrombin) furnishing 100u/ml (1 5ml phosphate buffer) is not made foaming, put on labelling.The right hand is taken agar 5ml (50 ℃), left hand takes Fibrinogen (fibrinogen) (derive from calf serum, hold field pharmacy commercial firm) 5ml to add together in the culture dish, rotates moving (7-10 circle) mixing of heavy curtain rapidly by hand, in order not allow foaming, can support by the arm above-mentioned thrombin solution (5 times).Make a call to six foveolas with a tubule by diagonal in above-mentioned culture dish, a foveola is made a call at the center, and the agar in the hole is removed.
(b) sample determination of activity:
Different samples (2mg) dissolve with 100 μ l phosphate buffers when insoluble (use DMSO), add urokinase (Urokinase) (being dissolved into 500IU/ml with phosphate buffer) 15 μ l.Get above-mentioned sample solution 10 μ l and add in the hole, two holes of each sample, the hole, center is a blank sample, cultivates 18 hours for 37 ℃.In culture dish, inject the 5%NaCl aqueous solution, placed 20 minutes, repeatable operation 2 times, next step is cleaned with Purified Water, same repeatable operation 2 times.After cleaning, 60 ℃ of dryings (needing 3 hours approximately).With the dyeing of 0.2%Coomassie Brilliant BlueR-250 dyeing liquor, place and dyeing liquor was outwelled in 20 minutes, add ablution (EtOH: EtOAc: H in the dish
2O=45: 10: 45) places 20 minutes, the processing of decolouring, 60 ℃ of dryings 3 hours.Measure the hole diameter, reference area is obtained the area ratio with the blank group, draws fibrinolytic raising rate: (sample area/matched group area-1) * 100%, with the repeated measurement of variable concentrations sample solution, calculate its IC
50
The result of above-mentioned biological activity test shows that Bulbus Allii general glycoside TSG has antiplatelet aggregation and improves fibrinolytic; Proto-iso-eruboside-B (I) has significant raising fibrinolytic; Iso-eruboside-B (II) has tangible prolongation blood coagulation time and improves fibrinolytic; Rhodionin in the Radix Rhodiolae (III) has antiplatelet aggregative activity, and can prolong blood coagulation time, and rhodiosin (IV) then has platelet aggregation inhibitory activity; And Rhizoma Bolbostematis general glycoside TSB and tubeimoside (V-X) all have very strong platelet aggregation inhibitory activity, obviously prolong blood coagulation time and improve fibrinolytic (seeing Table 4).Adenosine then has platelet aggregation inhibitory activity and improves fibrinolytic as positive control in this experiment.
Table 1 derives from the structure of the glycoside compound of Bulbus Allii
Proto-iso-eruboside-B (I)
Iso-eruboside-B (II)
Table 2 derives from the structure of the glycoside compound of Radix Rhodiolae
Rhodionin (III)
Rhodiosin (IV)
Table 3 derives from the structure of the glycoside compound of Rhizoma Bolbostematis
Tubeimuside I (V) R
1=-β-D-Xyl R
2=-H R
3=1 Ara 4 Rhizoma Bolbostematis glycoside second (VI) R
1=-β-D-Xyl R
2=-OH R
3=1 Ara 4 Rhizoma Bolbostematis glycoside third (VII) R
1=-β-D-Xyl R
2=-OH R
3=1 Glc 6 derivant 1 (VIII) R
1=-H R
2=-H R
3=1 Ara 4 derivant 2 (IX) R
1=-H R
2=-OH R
3=1 Ara 4 derivant 3 (X) R
1=-H R
2=-OH R
3=1 Glc 6
Table 4 biological activity test result
The anticoagulant experiment prolongs the blood coagulation time experiment and improves fibrinolytic experiment glycoside sample IC
50* IC
50* IC
50*
mg/ml ( mM ) mg/ml ( mM ) mg/ml ( mM ) 1.9 ( 7.1 ) ------25 ( 93.6 ) TSG 27.3-----13I-----------13 ( 10.5 ) II------1.5 ( 1.4 ) 19 ( 17.6 ) III 3.7 ( 8.2 ) 6.8 ( 15.2 ) ------IV 7.5 ( 12.3 ) ------------TSB 3.6 1.5 15V 1.8 ( 1.3 ) 2.6 ( 1.9 ) 14 ( 10.6 ) VI 0.3 ( 0.2 ) 2.5 ( 1.8 ) 14 ( 10.3 ) VII 0.5 ( 0.3 ) 2.3 ( 1.6 ) 13 ( 9.3 ) VIII 5.2 ( 4.3 ) 5.7 ( 4.8 ) 21 ( 17.7 ) IX 4.1 ( 3.3 ) 4.4 ( 3.6 ) 30 ( 24.3 ) X 2.7 ( 2.1 ) 3.6 ( 2.8 ) 28 ( 22.2 ) *,；------is not strong for activity, does not survey IC50Sample number 4-6
Claims (6)
1, two kinds of steroid saponin proto-iso-eruboside-B (I) that get from Bulbus Allii and iso-eruboside-B (II), structure vides infra.
2, the novel antithrombotic reagent of a class, it is characterized in that with Bulbus Allii Saponin proto-iso-eruboside-B (I) and iso-eruboside-B (II), Herbacetin 7-O-.alpha.-L-rhamnopyranoside rhodionin (III) and rhodiosin (IV) and from the Rhizoma Bolbostematis general glycoside, get Tubeimuside I (V), second (VI) and third (VII) and solve derivant 1 (VIII) through cellulose enzyme, the arbitrary effective monomer in 2 (IX) and 3 (X) (structure vides infra) or be effective ingredient by wherein several mixture of forming.
3, the described medicine of claim 2 can be various dosage forms, comprises oral and two kinds of approach of injection.
4, the dosage range of the described medicine of claim 2 can be 3-200mg/ kg body weight/day, and consumption is 3-50mg/ kg body weight/day preferably, and preferable amount is 5-25mg/ kg body weight/day.
5, the purposes of the described medicine anti thrombotic action of claim 2.
6, the purposes of glycoside compound I-X anti thrombotic action.
Derive from the structure of the glycoside compound of Bulbus Allii
Proto-iso-eruboside-B (I)
Iso-eruboside-B (II)
Derive from the structure of the glycoside compound of Radix Rhodiolae
Rhodionin(III)
Rhodiosin(IV)
Derive from the structure of the glycoside compound of Rhizoma Bolbostematis
Tubeimuside I (V) R
1=-β-D-Xyl R
2=-H R
3=1 Ara 4 Rhizoma Bolbostematis glycoside second (VI) R
1=-β-D-Xyl R
2=-OH R
3=1 Ara 4 Rhizoma Bolbostematis glycoside third (VII) R
1=-β-D-Xyl R
2=-OH R
3=1 Glc 6 derivant 1 (VIII) R
1=-H R
2=-H R
3=1 Ara 4 derivant 2 (IX) R
1=-H R
2=-OH R
3=1 Ara 4 derivant 3 (X) R
1=-H R
2=-OH R
3=1 Glc 6
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 95106768 CN1138984A (en) | 1995-06-26 | 1995-06-26 | Anti-thrombosis glucoside medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 95106768 CN1138984A (en) | 1995-06-26 | 1995-06-26 | Anti-thrombosis glucoside medicine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1138984A true CN1138984A (en) | 1997-01-01 |
Family
ID=5076028
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 95106768 Pending CN1138984A (en) | 1995-06-26 | 1995-06-26 | Anti-thrombosis glucoside medicine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1138984A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6399116B1 (en) * | 2000-04-28 | 2002-06-04 | Rulin Xiu | Rhodiola and used thereof |
| EP1024146A4 (en) * | 1997-09-26 | 2006-02-08 | Inst Radiation Med Amms Pla | The use of steroid saponin compounds to prevent senility, and novel steroid saponin compounds |
| WO2007003957A3 (en) * | 2005-07-06 | 2007-05-31 | Btg Int Ltd | Steroidal glycoside compounds as core 2 glcnac- t inhibitors |
| US7906493B2 (en) | 2003-12-22 | 2011-03-15 | Btg International Limited | Core 2 GlcNAc-T inhibitors |
| CN102504006A (en) * | 2011-09-26 | 2012-06-20 | 李国玉 | Steroid saponin compound in siberian fritillary bulb |
| CN107820427A (en) * | 2016-11-24 | 2018-03-20 | 泰州永恒生物科技有限公司 | Application of herbal element or its composition in the preparation of medicines for preventing and treating cardiovascular and cerebrovascular diseases |
-
1995
- 1995-06-26 CN CN 95106768 patent/CN1138984A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1024146A4 (en) * | 1997-09-26 | 2006-02-08 | Inst Radiation Med Amms Pla | The use of steroid saponin compounds to prevent senility, and novel steroid saponin compounds |
| US6399116B1 (en) * | 2000-04-28 | 2002-06-04 | Rulin Xiu | Rhodiola and used thereof |
| US7906493B2 (en) | 2003-12-22 | 2011-03-15 | Btg International Limited | Core 2 GlcNAc-T inhibitors |
| WO2007003957A3 (en) * | 2005-07-06 | 2007-05-31 | Btg Int Ltd | Steroidal glycoside compounds as core 2 glcnac- t inhibitors |
| CN102504006A (en) * | 2011-09-26 | 2012-06-20 | 李国玉 | Steroid saponin compound in siberian fritillary bulb |
| CN102504006B (en) * | 2011-09-26 | 2013-12-25 | 李国玉 | Steroid saponin compound in siberian fritillary bulb |
| CN107820427A (en) * | 2016-11-24 | 2018-03-20 | 泰州永恒生物科技有限公司 | Application of herbal element or its composition in the preparation of medicines for preventing and treating cardiovascular and cerebrovascular diseases |
| WO2018094640A1 (en) * | 2016-11-24 | 2018-05-31 | 泰州永恒生物科技有限公司 | Applications of herbacetin or composition thereof in preparing medicament for preventing and treating cardiovascular and cerebrovascular diseases |
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