CN1569011A - Application of 20(R)-ginsenoside-Rg3 in the preparing process of medicine for treating or preventing cardiovascular and cerebrovascular disease - Google Patents
Application of 20(R)-ginsenoside-Rg3 in the preparing process of medicine for treating or preventing cardiovascular and cerebrovascular disease Download PDFInfo
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Abstract
The invention relates to the application of 20(R)-ginsenoside-Rg3 in the preparing process of medicine for treating or preventing hypertension, in preparing medicine for treating or preventing myocardial ischemia, and in preparing medicament for prevention or treatment of heart failure.
Description
Technical field
The present invention relates to 20 (R)-ginsenoside-Rg
3Application in the medicine of preparation treatment or prevention cardiovascular and cerebrovascular disease.
Background technology
Along with the acceleration of aged tendency of population process and the change of life style, cardiovascular and cerebrovascular disease has become a global health problem, the mortality rate of coronary heart disease, apoplexy occupies the 1st, 3 respectively at world wide, and hypertension is considered to the main hazard factor of apoplexy always.The exploitation that novel and effective is prevented and treated the cardiovascular and cerebrovascular vessel medicine is very urgent.
20 (R)-ginsenoside-Rg
3It is the tetracyclic triterpenes panoxadiol type saponin monomer of separation and Extraction from Radix Ginseng.
20 (R)-ginsenoside-Rg
3Structural formula (R:-glu-o-glu; R
1:-CH
3R
2:-OH)
It is reported Rg
3Have antitumor, suppress effects such as new vessels generation, antiinflammatory, but about 20 (R)-ginsenoside-Rg
3Effect with prevention or treatment cardiovascular and cerebrovascular disease does not appear in the newspapers; Given this, the inventor is surprised to find 20 (R)-ginsenoside-Rg by a large amount of experimentatioies
3Medical usage with prevention or treatment cardiovascular and cerebrovascular disease.
Summary of the invention
The invention provides 20 (R)-ginsenoside-Rg
3Application in the medicine of preparation treatment or prevention cardiovascular and cerebrovascular disease.
The invention provides 20 (R)-ginsenoside-Rg
3Application in the medicine of preparation treatment or prevention of brain damage.
The invention provides 20 (R)-ginsenoside-Rg
3Application in the medicine of preparation treatment or prevention myocardial ischemia.
The invention provides 20 (R)-ginsenoside-Rg
3Application in preparation treatment or prevention congestive heart failure medicine.
The invention provides and contain 20 (R)-ginsenoside-Rg
3The pharmaceutical composition of treatment cardiovascular and cerebrovascular disease.
20 (R)-ginsenoside-Rg of the present invention
3When being used for above-mentioned arbitrary purposes, its using dosage scope is 10mg～400mg, and the preferred dose scope is 30mg～200mg.
20 (R)-ginsenoside-Rg3 that use among the present invention can use separately or use with pharmaceutical compositions.Pharmaceutical composition comprises 20 (R)-ginsenoside-Rg3 and pharmaceutical carriers as active component.This pharmaceutical composition can be by oral, Sublingual, percutaneous, through muscle or subcutaneous, mucocutaneous, urethra, vagina or intravenous route administration.Pharmaceutical composition can exist with the form of tablet, pill, granule, capsule, suspension, solution, syrup, injection.Various pharmaceutical dosage form provided by the present invention all can be prepared from the pharmacy conventional method.
The inventor has confirmed that by following test 20 (R)-ginsenoside-Rg3 have the effect of treatment or prevention cardiovascular and cerebrovascular disease disease, but is not limited to this test.Testing 20 used (R)-ginsenoside-Rg3 is provided by natural drug Engineering Technical Research Centre pharmaceutical chemistry research department, Shandong Province, and through HPLC detection level 90%, reference substance is provided by the natural drug Engineering Technical Research Centre chamber of analysis and research, Shandong Province.
The inventor has carried out following test and has confirmed that 20 (R)-ginsenoside-Rg3 are the drug effect of preparation treatment or prevention cardiovascular and cerebrovascular disease (the following examples are used for more detailed description the present invention, but and do not mean that the present invention only limits to this).
The specific embodiment:
Preparation embodiment 1: injection preparation prepares embodiment
Take by weighing 1.00g 20 (R)-ginsenoside-Rg
3, the propylene glycol that adds 20ml n-butyl alcohol and 30ml melts saponin fully, and the citric acid of 0.15g tetracaine hydrochloride, 0.02g is joined in the 40ml water for injection, makes dissolving fully, and above-mentioned aqueous solution is joined in the drug solution mix homogeneously; Regulating pH value with Borax and boric acid is 5.5 ± 1.0; 85 ℃ of insulations of the needle-use activated carbon of adding 0.1% 30 minutes, G
3Sintered glass funnel filters, the filtering with microporous membrane of 0.22um; Filtrate is sub-packed in the 7ml cillin bottle, and (directly tamponade of the injection that branch installs, jewelling cover into injection to every loading amount 2ml; Or make freeze-dried powder through the freeze dryer lyophilizing.)。
Test the influence of routine 1:20 (R)-ginsenoside-Rg3 to the damage of rat local cerebral ischemia
(1) material:
20 (R)-ginsenoside-Rg3: provide by natural drug Engineering Technical Research Centre pharmaceutical chemistry research department, Shandong Province.
Red tetrazolium: U.S. Sigma company product, face with preceding and be made into 4% solution with normal saline.
Laboratory animal: regular grade Wistar rat, male, body weight 280g-350g, natural drug Engineering Technical Research Centre zoopery center, Shandong Province provides.The quality certification number: No. 200106005, Shandong kinoplaszm word.
(2) method and result:
Animal is divided into sham operated rats at random, model control group (waiting the capacity solvent), nimodipine group (Nim, 1.5mg/kg), 20 (R)-ginsenoside-Rg3 small dose group (1mg/kg), dosage group (4mg/kg) among 20 (R)-ginsenoside-Rg3, the heavy dose of group of 20 (R)-ginsenoside-Rg3 (40mg/kg), 10 every group.After the fasting 12 hours, and chloral hydrate (350mg/kg, i.p.) anesthesia separates left carotid, and folder closes in the neck, common carotid artery, external carotid artery proximal part and distal end ligation, cut off the centre.The external carotid artery free-end is pulled to internal carotid artery in alignment, bolt line (selecting diameter 0.24mm nylon wire for use, length 5.0cm) is inserted into intracranial by external carotid artery, stop when meeting slight resistance, insertion depth is about 2cm.Ligation external carotid artery opening, and open the common carotid artery bulldog clamp, the disinfection and stitching wound causes left side middle cerebral artery ischemia model; Sham operated rats is only carried out the separation (above experiment is all carried out at 23～25) of left carotid, internal carotid artery, external carotid artery.Each treated animal intravenous drip (injecting) relative medicine (administration volume 3ml, 30min drips off) of postoperative with infusion pump.Press document [Liu Xiaoguang, Xu Lina, a kind of rat brain medium-sized artery model that can estimate thrombolytic and anti-thrombolytic after 24 hours, Acta Pharmaceutica Sinica, 1995,30:662] described method and standard is observed and the behavior disorder of record rat: (A) carry the Mus tail and observe forelimb flexing situation, stretch to ground as two forelimb symmetries, count 0 fen, the wrist flexing occurs as operation offside forelimb and count 1 fen, the elbow flexing is counted 2 fens, the shoulder inward turning is counted 3 fens, existing wrist flexing and/or elbow flexing have shoulder inward turning person again, count 4 fens.(B) animal is placed on the plane earth, push away both shoulders respectively, check resistance to side shifting.As bilateral resistance equity and strong, count 0 fen, as resistance descender when the operation offside promotes, according to decline degree difference be divided into gently, in, weigh three degree, count 1,2 and 3 fen respectively.(C) the two forelimbs of animal are put on the wire netting, observed the muscular tension of two forelimbs.Two muscle of anterior limb tension force equities and strong person count 0 fen.Count 1,2 and 3 fen according to operation offside muscular tension decline degree difference equally.(D) animal has ceaselessly to a side person of turn-taking, and counts 1 fen.According to the standard scoring, full marks are 11 minutes, and mark is high more, and expression animal behavior obstacle is serious more.
Put to death rat behind the behavior scoring, get brain, remove olfactory bulb, cerebellum and low brain stem, crownly be cut into 5, the brain sheet takes on a red color after normal structure is dyed with red tetrazolium (TTC) dyeing, and blocking tissue is white in color, taking a picture in dyeing back, asks the infarct size ratio with Chinese Aero-Space university pathological image analysis software.Data are represented with X scholar S, carry out statistical procedures with t check between group.
The result is as shown in table 1, and ischemia is after 24 hours, and rat shows tangible behavior disorder, and tangible kitchen range shape ischemic region also appears in rat cerebral tissue, reaches about 25% of full brain; Give 20 (R)-ginsenoside-Rg3 of various dose, the animal behavior obstacle has alleviating in various degree, and the rat cerebral ischemia district also takes an evident turn for the better, and is dose dependent.
The influence that table 1 20 (R)-ginsenoside-Rg3 damages the rat local cerebral ischemia (n=10, X ± s)
Group behavior disorder ischemic areas (%)
Sham operated rats 00
Model control group 10.50 ± 1.31 24.41 ± 4.22
Nim group 6.97 ± 2.35
*13.34 ± 7.56
*
The heavy dose of group 6.24 ± 1.88 of 20 (R)-ginsenoside-Rg3
*12.37 ± 4.45
*
Dosage group 7.61 ± 3.01 among 20 (R)-ginsenoside-Rg3
*16.27 ± 2.76
*
20 (R)-ginsenoside-Rg3 small dose group 7.66 ± 2.65
*18.57 ± 3.65
*
Compare with model control group
*P＜0.05,
*P＜0.01
Test routine 2:20 (R)-ginsenoside-Rg3 the rat heart muscle ischemia influenced this test (1) material:
20 (R)-ginsenoside-Rg3: provide by natural drug Engineering Technical Research Centre pharmaceutical chemistry research department, Shandong Province.
Chlorination nitro blue tetrazolium (N-BT) is provided by Military Medical Science Institute medical supply station.
Laboratory animal: regular grade Wistar rat, male, body weight 280g-350g, natural drug Engineering Technical Research Centre zoopery center, Shandong Province provides.The quality certification number: No. 200106005, Shandong kinoplaszm word.
(2) method and result:
Rat is divided into sham operated rats at random, model control group (waiting the capacity solvent), 20 (R)-ginsenoside-Rg3 small dose group (1mg/kg), dosage group (4mg/kg) among 20 (R)-ginsenoside-Rg3, the heavy dose of group of 20 (R)-ginsenoside-Rg3 (40mg/kg), 10 every group.After the fasting 12 hours, the limb lead electrocardiogram is surveyed in ip urethane (1.2g/kg) anesthesia.Cut off left front fur, iodine tincture and alcohol disinfecting, along left border of sternum 1cm place, cut off thoracic wall muscle and two ribs, open the thoracic cavity rapidly, expose heart, the ligation left coronary artery is put back to heart immediately between arterial cone and left auricle, squeezes the thoracic cavity air, use the mosquito forceps closed-chest, cause Model Rats with Acute Myocardial Ischemia.Each treated animal intravenous drip (injecting) relative medicine (administration volume 3ml, 30min drips off) of postoperative with infusion pump.Record postoperative 0,2, the 6h electrocardiogram takes out heart subsequently, after cleaning with cold saline ,-20 refrigerator freeze overnight.Next day, refrigerated heart is cut into 5 by ligation place to apex uniform thickness, immerse in the freshly prepared 0.5%N-BT phosphate buffer (pH 7.4).37 water-bath joltings, 10～15min.Blot the dyeing liquor of slice surface with filter paper, separate the coloured portions and the part of being unstained, weigh the compute infarct size.Infarct size (%)=infarction part weight/(non-infarction part weight+infarction part weight) * 100%.
The result is as shown in table 2, and 20 (R)-ginsenoside-Rg3 of various dose obviously reduce the myocardial infarction area that Acute Myocardial Ischemia in Rats causes due to the ligation coronary artery, and can reduce the rising of the limb lead electrocardiogram J point that is caused by myocardial ischemia.
Table 2 20 (R)-ginsenoside-Rg3 is to the influence of rat heart muscle ischemic injuries (n=10, X ± s)
Infarction face J point rising (mV)
Grouping
Long-pending (%) normal 0h 2h 6h
Model control group 24 ± 4 0.8 ± 0.6 6.7 ± 2.3 5.8 ± 2.0 5.1 ± 1.4
Radix Salviae Miltiorrhizae Injection group 17 ± 6 0.8 ± 0.6 6.0 ± 1.5
*5.1 ± 1.8
*4.1 ± 1.3
*
The heavy dose of group 13 ± 7 0.7 ± 0.6 4.3 ± 1.3 of 20 (R)-ginsenoside-Rg3
*3.4 ± 1.1
*3.2 ± 1.2
*
Dosage group 16 ± 5 0.7 ± 0.4 5.4 ± 1.6 among 20 (R)-ginsenoside-Rg3
*4.3 ± 1.3
*3.4 ± 1.3
*
20 (R)-ginsenoside-Rg3 small dose group 17 ± 6 0.7 ± 0.5 5.8 ± 1.7
*4.9 ± 1.4
*4.2 ± 1.3
*
Compare with model control group
*P＜0.05,
*P＜0.01
Test the therapeutical effect of routine 3:20 (R)-ginsenoside-Rg3 to the experimental heart failure of cat
(1) material:
20 (R)-ginsenoside-Rg3: provide by natural drug Engineering Technical Research Centre pharmaceutical chemistry research department, Shandong Province.
The Powerlab/8sp physiograph: Australian InStruments company produces.
Electromagnetic flowmeter (MFV-3200 type): Japanese photoelectricity company produces.
Laboratory animal: healthy adult cat body weight 2.5～3.5kg, natural drug Engineering Technical Research Centre zoopery center, Shandong Province provides.
(2) method:
Cat is divided into model control group (waiting the capacity solvent) at random, 20 (R)-ginsenoside-Rg3 small dose group (0.5mg/kg), dosage group (2mg/kg) among 20 (R)-ginsenoside-Rg3, the heavy dose of group of 20 (R)-ginsenoside-Rg3 (20mg/kg), 6 every group.After the fasting 12 hours, intravenous injection pentobarbital sodium 40mg/kg anesthesia, tracheal intubation, artificial respiration, monitoring aortic pressure (AP) and electrocardiogram.Breast is opened in the left side, plugs in conduit to left ventricle from the apex of the heart, surveys left constant pressure and rate of pressure change (± dp/dt thereof
Max).Waltan-Brodie strain bow is implanted the left ventricle antetheca, measure myocardial contraction.With electromagnetic flowmeter determination ascending aorta blood flow.As cardiac output (CO), calculate cardiac index (CI), the index (SI) of whenever fighting, the work done (SW) of whenever fighting, left heart work done (LVW) and total peripheral vascular resistance (SVR) with the ascending aorta flow.Parameters is recorded in the Powerlab/8sp physiograph.Postoperative half an hour, it is stable that parameters reaches.From femoral vein constant speed gasing injection pentobarbital sodium (0.5ml/kgmin), with ± dp/dt
MaxDropping to about 1000mmHg/s is that leading indicator forms acute heart failure.After treating the heart failure model stability, each treated animal intravenous drip (injecting) relative medicine (administration volume 10ml, 30min drips off) with infusion pump.
(3) result:
A, 20 (R)-ginsenoside-Rg3 is to the influence of heart failure cat heart rate and blood pressure
The result is as shown in table 3, and instillation various dose 20 (R)-ginsenoside-Rg3 can reduce heart failure cat blood pressure in various degree, and particularly evident to the effect of diastolic pressure.
Table 3 20 (R)-ginsenoside-Rg3 is to the influence of heart failure cat blood pressure (n=6, X ± s)
Dosage mean arterial pressure (mmHg) systolic pressure (mmHg) diastolic pressure (mmHg)
Grouping
(mg/kg) before the administration after the administration before the administration after the administration before the administration after the administration
Model control group 57 ± 4 53 ± 6 71 ± 11 69 ± 10 45 ± 8 44 ± 6
20 (R)-ginsenosides
20 56±5 39±5
**## 73±13 64±7
*# 47±7 28±3
**##
The heavy dose of group of-Rg3
20 (R)-ginsenosides
2 58±5 44±8
*# 70±8 67±9 42±6 31±5
**##
Dosage group among the-Rg3
20 (R)-ginsenosides
0.5 63±4 46±7
* 73±13 67±8 42±7 36±5
*#
-Rg3 small dose group
With comparison before the administration
*P＜0.05,
*P＜0.01; Compare with model control group
#P＜0.05,
##P＜0.01
B, 20 (R)-ginsenoside-Rg3 is to the influence of heart failure cat cardiac work
The result is as shown in table 4, and instillation various dose 20 (R)-ginsenoside-Rg3 can increase SW and the LVW of heart failure cat, with before the administration, model control group relatively has significant difference.
Table 4 20 (R)-ginsenoside-Rg3 is to the influence of heart failure cat cardiac work (n=6, X ± s)
The dosage left heart work done of work done (gm/beat) (kgm/min) of whenever fighting
Grouping
(mg/kg) before the administration after the administration before the administration after the administration
Model control group 0.98 ± 0.34 0.87 ± 0.57 0.064 ± 0.035 0.059 ± 0.035
20 (R)-ginsenosides
20 0.86±0.42 1.23±0.58
**## 0.066±0.035 0.088±0.044
**##
The heavy dose of group of-Rg3
20 (R)-ginsenosides
2 0.89±0.33 1.08±0.43
*# 0.059±0.037 0.078±0.034
*#
Dosage group among the-Rg3
20 (R)-ginsenosides
0.5 0.93±0.36 1.01±0.55
# 0.061±0.033 0.071±0.027
#
-Rg3 small dose group
With comparison before the administration
*P＜0.05,
*P＜0.01; Compare with model control group
#P＜0.05,
##P＜0.01
C, 20 (R)-ginsenoside-Rg3 is to the influence of the total peripheral vascular resistance of heart failure cat
The result is as shown in table 5, and instillation various dose 20 (R)-ginsenoside-Rg3 can reduce the total outer vascular resistance of heart failure cat, with before the administration, model control group relatively has significant difference.
Table 5 20 (R)-ginsenoside-Rg3 is to the influence of the total peripheral vascular resistance of heart failure cat (n=6, X ± s)
The total peripheral vascular resistance of dosage (mmHg/min/kg)
Grouping
(mg/kg) after the preceding administration of administration
Model control group 79 ± 28 82 ± 32
The heavy dose of group 20 81 ± 31 51 ± 21 of 20 (R)-ginsenoside-Rg3
* ##
Dosage group 2 83 ± 27 64 ± 31 among 20 (R)-ginsenoside-Rg3
* ##
20 (R)-ginsenoside-Rg3 small dose group 0.5 82 ± 31 71 ± 34
* #
With comparison before the administration
*P＜0.05,
*P＜0.01; Compare with model control group
#P＜0.05,
##P＜0.01
D, 20 (R)-ginsenoside-Rg3 is to the kinemic influence of heart failure cat
The result is as shown in table 6, and instillation various dose 20 (R)-ginsenoside-Rg3 can increase the cardiac output of heart failure cat, with before the administration, model control group relatively has significant difference.
Table 6 20 (R)-ginsenoside-Rg3 is to the kinemic influence of heart failure cat (n=6, X ± s)
Dosage stroke volume index (ml/beatm
2) cardiac output index (L/minm
2)
Grouping
(mg/kg) before the administration after the administration before the administration after the administration
Model control group 4.5 ± 0.8 4.1 ± 1.1 0.65 ± 0.16 0.59 ± 0.17
20 (R)-ginsenosides
20 4.4±1.1 8.1±3.6
**## 0.67±0.21 0.88±0.24
**##
The heavy dose of group of-Rg3
20 (R)-ginsenosides
2 5.1±1.7 7.2±3.2
**## 0.66±0.16 0.79±0.17
*#
Dosage group among the-Rg3
20 (R)-ginsenosides
0.5 4.8±0.8 5.9±1.2
*# 0.67±0.22 0.73±0.17
#
-Rg3 small dose group
With comparison before the administration
*P＜0.05,
*P＜0.01; Compare with model control group
#P＜0.05,
##＜0.01
Claims (9)
1. the application of 20 (R)-ginsenoside-Rg3 in the medicine of preparation treatment or prevention cardiovascular and cerebrovascular disease.
2. application according to claim 1 is characterized by the application in the medicine that preparation is treated or prevention of brain is damaged.
3. application according to claim 1 is characterized by the application in the medicine for preparing treatment or prevention myocardial ischemia.
4. application according to claim 1 is characterized by the application in the medicine for preparing treatment or prevention congestive heart failure.
5. according to the arbitrary described application of claim 1-4, the using dosage scope that it is characterized in that 20 (R)-ginsenoside-Rg3 is 10mg～400mg.
6. application according to claim 5 is characterized in that the using dosage of 20 (R)-ginsenoside-Rg3 is preferably 30mg～200mg.
7. the pharmaceutical composition that is used for the treatment of or prevents cardiovascular and cerebrovascular disease that contains 20 (R)-ginsenoside-Rg3.
8. pharmaceutical composition according to claim 7, said composition can be by oral, Sublingual, percutaneous, through muscle or subcutaneous, mucocutaneous, urethra, vagina or intravenous route administration.
9. according to claim 7 or 8 described pharmaceutical compositions, it is characterized in that said composition can exist with forms such as tablet, pill, granule, capsule, suspension, solution, syrup, injection, cream, ointment, spray, chewing agent or patches.
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| WO2007134534A1 (en) * | 2006-05-22 | 2007-11-29 | Li Fu | WATER SOLUTION OF 20(R)-GINSENOSIDE Rg3 PHARMACEUTICAL COMPOSITION AND PROCESS THEREOF |
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| CN106822157A (en) * | 2015-12-07 | 2017-06-13 | 上海中医药大学 | The therapeutic action of Ginsenoside compound K acute myocardial infarction |
| CN111514156A (en) * | 2015-12-07 | 2020-08-11 | 上海中医药大学 | Application of ginsenoside Rg3 in treating acute myocardial infarction |
| CN115337317A (en) * | 2021-05-14 | 2022-11-15 | 中国科学院大连化学物理研究所 | 20 Application of (S) -ginsenoside Rg3 and medicine or GPR35 receptor antagonist |
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