CN1403470A - Astragalus saponin A with the function of resisting myocardial fibrillation - Google Patents
Astragalus saponin A with the function of resisting myocardial fibrillation Download PDFInfo
- Publication number
- CN1403470A CN1403470A CN 01126609 CN01126609A CN1403470A CN 1403470 A CN1403470 A CN 1403470A CN 01126609 CN01126609 CN 01126609 CN 01126609 A CN01126609 A CN 01126609A CN 1403470 A CN1403470 A CN 1403470A
- Authority
- CN
- China
- Prior art keywords
- myocardial
- mmhg
- group
- mercury
- index
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Abstract
The present invention relates to the field of Chinese medicine technology, and provides astragalus saponin A as the effective component in astragalus root. The effective component has excellent function of resisting myocardial fibrillation.
Description
Technical field
The invention belongs to technical field of traditional Chinese medicines.Be specifically related to a kind of astragalus saponin 1 with function of resisting myocardial fibrillation.
Background technology
The Radix Astragali (Astragalus membranaceus) belongs to leguminous plants, and sweet, the tepor of nature and flavor is returned spleen, lung channel, and main effect is an invigorating QI to consolidate the body surface resistance, diuresis holder poison, apocenosis, and expelling pus and promoting granulation is one of most important medicine in the Chinese medicine Qi-tonifying drug.The modern medicine study proof Radix Astragali has the immunologic function of adjusting, delays senility, promotes marrow hemopoiesis and hemopoietic.At present, to Radix Astragali research at most, the most extensive and the most deep be aspect the cardiovascular effect.Numerous clinical observations and experimental study show that the Radix Astragali has good protective action to heart, can be used for the treatment of coronary heart disease and angina pectoris, heart failure, hypertension, ypotension, viral myocarditis, irregular pulse etc. clinically.The chemical research of the Radix Astragali shows that activeconstituents main in the Radix Astragali is flavonoid, saponin class, polyose and amino acid, phosphatide and trace element.Main flavones in the Radix Astragali has nearly 20 kinds of onocol, calycosin, Radix Astragali isoflavan glucoside etc.
Although the Radix Astragali is sure to cardiovascular effect, with regard to present research, the Radix Astragali is unclear to the effective substance of cardiovascular effect aspect.Therefore, be necessary on existing research basis, to carry out deep research, illustrate the effective substance and the mechanism of action of the Radix Astragali aspect treating cardiovascular disease.
Summary of the invention
Technical problem to be solved by this invention is the effective constituent in the Radix Astragali is further studied, and exploitation has the medicine of function of resisting myocardial fibrillation.
The invention provides a kind of astragalus saponin 1 with function of resisting myocardial fibrillation.
Have following structural:
Astragalus saponin 1 (Astragaloside IV) MW=802
The HPLC collection of illustrative plates of astragalus saponin 1 of the present invention is seen Figure 11.
The result of study of the function of resisting myocardial fibrillation of astragalus saponin 1 of the present invention is as follows:
Experimental subjects is a Sprague-Dawley kind rat, uses the narrow aorta abdominalis of silver brain clip of 0.6mm diameter, causes the myocardial hypertrophy model of traffic overload.After the modeling behind 1 first quarter moon, beginning administration, time 1 first quarter moon, 3 months experimental periods.Experiment is divided into control group (sham operated rats), model group, Western medicine (Ramipril, Ramipril) control group (oral Ramipril, 1mg/Kg, 0.33mg/ml), astragalus saponin 1 (Astragaloside IV, AS-IV) organize (oral and abdominal injection 0.3mg/Kg, 0.1mg/ml).Experimental index is Hemodynamics, Left ventricular mass index, myocardium morphology (Electronic Speculum and light microscopic) and circulation internal secretion (endothelin, Angiotensin II, cAMP).The results are shown in Table 1-table 6.
Table 1.AS-IV is to the influence of myocardial hypertrophy rat heart muscle ponderal index (x ± s)
Group n cardiac muscle ponderal index (mg/100g) sham operated rats 12 2.01 ± 0.08
*Oral group 20 2.43 ± 0.15 of model group 26 2.79 ± 0.12AS-IV
*AS-IV abdominal injection group 15 2.34 ± 0.09
*Ramipril group 12 2.14 ± 0.09
*
Compare with model group:
*P＜0.05,
*P＜0.01
Table 2.AS-IV is to the influence of myocardial hypertrophy rat peripheral arterial blood pressure (x ± s)
Arteriotony (mmHg)
Group n
Oral group 20 146 ± 14.8 of systolic pressure diastolic pressure sham operated rats 12 145 ± 11.8 97 ± 12.9 model group 26 171 ± 18.9 121 ± 17.9AS-IV
*87 ± 18.5
*AS-IV abdominal injection group 15 161 ± 26.8 107 ± 22.3 Ramipril groups 12 129 ± 17.4
*85 ± 15.0
*
Compare with model group:
*P＜0.05,
*P＜0.01
Table 3.AS-IV is to the hemodynamic influence of myocardial hypertrophy rat heart (x ± s)
(mmHg) (mmHg/s) (BPM) for intraventricular pressure left ventricular end diastolic presssure intraventricular pressure differential heart rate group n (mmHg)
LVSP LVDEP+dp/dt
Max-dp/dt
MinHR sham operated rats 12 173 ± 16.6 2.8 ± 1.03 6780 ± 1,511 4180 ± 873 380 ± 31.7 model group 26 175 ± 19.0 1.5 ± 0.63 6250 ± 1,645 3970 ± 789 427 ± 23.9AS-IV oral group 20 172 ± 20.7 3.2 ± 1.26
*6810 ± 1,602 3692 ± 664 406 ± 28.6AS-IV abdominal injection groups 15 185 ± 27.8 2.5 ± 1.38 8107 ± 1283
*4290 ± 1,117 407 ± 34.2 Ramipril group 12 158 ± 20.2 2.8 ± 0.85
*6750 ± 2,174 3274 ± 612 373 ± 14.9
Compare with model group:
*P＜0.05,
*P＜0.01
Table 4.AS-IV is to the morphologic influence of myocardial hypertrophy rat (x ± s)
Om observation group n electron microscopic observation
(fibrosis is kept the score
*)
No plastosome swelling, no ischemic band does not have myocardium sham operated rats 8 0.25 (2/8)
Fibrosis
Mitochondrial swelling has obvious ischemic band, myocardial model group 8 1.63 (13/8)
Fibrosis is more obvious
Plastosome mild swelling, part have the ischemic band, oral group 6 1.00 (6/6) of AS-IV
Cardiac muscle has fibrosis to exist
Plastosome mild swelling, part have the ischemic band, AS-IV abdominal injection group 6 0.33 (2/6)
Myocardial fibrosis has improvement
The plastosome mild swelling, the ischemic band obviously improves, Ramipril group 8 0.00 (0/8)
The rarer fibrosis of cardiac muscle exists
*The fibrosis scoring system:
Fibrosis account for high power field below 1/3 the note 1 minute;
Fibrosis accounts for 2 minutes (below 2/3) of note more than 1/3 of high power field;
Fibrosis account for high power field more than 2/3 the note 3 minutes;
High power field does not have fibrosis note 0 minute down substantially
Table 5.AS-IV is to the influence of myocardial hypertrophy rat ET, cAMP (x ± s)
The cAMP of cardiac muscular tissue
Group n blood plasma ET (pg/L)
(pmol/mg) sham-operation group 5 155 ± 22.2 507 ± 82.8 model group 6 243 ± 49.7 354 ± 77.9AS-IV oral group 5 232 ± 43.2 363 ± 77.8AS-IV lumbar injection groups, 5 229 ± 42.5 380 ± 59.4 Ramipril group 5 239 ± 77.2 355 ± 48.9
The ELISA method is measured, and each sample repeats 2 times
Table 6.AS-IV is to the influence of myocardial hypertrophy rat serum angiotensin (AngII) (x ± s)
Ang?II
Group n
Blood plasma (pmol/L) cardiac muscular tissue (pmol/mg) sham operated rats 5 32 ± 6.2
*122 ± 28.0
*Model group 6 69 ± oral group 5 59 ± 7.1 292 ± 22.6AS-IV of 16.6 349 ± 66.6AS-IV abdominal injection group 5 49 ± 6.2
*245 ± 28.4
*Oral group 5 31 ± 9.4 of Ramipril group
*130 ± 20.1
*
Compare with model group:
*P＜0.05,
*P＜0.01
The ELISA method is measured, and each sample is surveyed 1 time
These results show that astragalus saponin 1 can obviously reduce Left ventricular mass index, alleviates myocardial hypertrophy; Reduce peripheral arterial blood pressure and left ventricular end diastolic presssure, improve cardiac diastolic function; Myocardial mitochondria swelling when improving heart failure, alleviate myocardial fibrosis; Reduce the content of blood plasma and the nervous plain II of cardiac muscular tissue's medium vessels.The crucial problem that will solve of this research has 4 aspects.1. whether Radix Astragali active substance I can alleviate heart failure rat left chamber ponderal index (improving myocardial remodelling).2. whether can bring high blood pressure down; 3. whether can reduce the content of Angiotensin II in the body.4. to the improvement of left chamber function.Has the effect that improves every index more than the heart failure rat from the present astragalus saponin 1 that studies show that.Further work be intended to illustrate whether astragalus saponin 1 suppresses or antagonist in angiotensin-ii receptor and to myocardial cell and fibroblastic fibrosis effect.
Because Ramipril class medicine is reversing myocardial hypertrophy (resisting myocardial fibrillation) simultaneously, can suppress granulocytic generation, contraction kidney blood vessel and life-time service and cause heart function to descend, limited being extensive use of of it.And AS-IV can not produce above-mentioned side effect.AS-IV may suppress hepatic fibrosis, renal fibrosis, pulmonary fibrosis etc., equally so AS-IV has the very big market DEVELOPMENT PROSPECT except the effect with resisting myocardial fibrillation.
Description of drawingsThe HPLC collection of illustrative plates of oral group of medicine group of the left chamber of cardiac muscle pathological section (HE dyeing) Fig. 2 sham-operation rat left chamber myocardial ultrastructure (Electronic Speculum) Fig. 3 myocardial hypertrophy rat model cardiac muscle pathological section (HE dyeing) the left chamber of Fig. 4 myocardial hypertrophy rat model myocardial ultrastructure (Electronic Speculum) Fig. 5 Ramipril medicine control rats left chamber cardiac muscle pathological section (HE dyeing) Fig. 6 Ramipril medicine control rats left chamber myocardial ultrastructure (Electronic Speculum) Fig. 7 AM-1 of Fig. 1 sham-operation rat left chamber cardiac muscle pathological section (HE dyeing) Fig. 8 Ramipril medicine control rats left chamber myocardial ultrastructure (Electronic Speculum) Fig. 9 AM-1 of rat left chamber lumbar injection group medicine group cardiac muscle pathological section (HE dyeing) Figure 10 AM-1 lumbar injection group medicine group rat left chamber's myocardial ultrastructure (Electronic Speculum) Figure 11 of rat left chamber astragalus saponin 1
Specific embodimentThe single example experiment of the resisting myocardial fibrillation of astragalus saponin 1 (reverse myocardial hypertrophy) effect sham-operation rat 1. myocardium ponderal index and haemodynamics
Index unit numerical value body weight (HW) gram (g) the 388 left hearts heavy (LVW) gram (g) 1.20 left heart ponderal indexs (LVWI) milligram/gram (mg/g) 1.92 femoral artery systolic pressures (SBP millimetres of mercury (mmHg) 152 femoral artery diastolic pressure (DBP) millimetres of mercury (mmHg) 102 left ventricular systolic pressures (LVSP) millimetress of mercury (mmHg) 179 left chamber diastolic pressure (LVDEP) millimetress of mercury (mmHg) 5.00 left ventricular pressure differential maximum (+dp/dtMax) mm Hg per second as (mmHg/s) 6120 left ventricular pressure differential minimum value (dp/dt
Min) mm Hg per second as (mmHg/s) 3340 hearts rate (BP) are inferior/minute (BPM) 396
2. myocardium morphological change
2.1 left chamber cardiac muscle pathological section (HE dyeing) is seen Fig. 1: Non Apparent Abnormality changes, normal morphology
2.2 Fig. 2 is seen in left chamber myocardial ultrastructure (Electronic Speculum): no mitochondria swelling; No ischemic band, no myocardial fibrosis 3. Circulation Endocrine index index unit numerical value cardiac muscle ring gland glycosides (cAMP) pmol/mg 548 endothelin level (ET) pg/L 164 myocardial vascular Angiotensin Converting Enzyme II (AngII) pmol/mg 124 plasma angiotensinogen II (AngII) pmol/L 25 models (myocardial hypertrophy) rats 1. myocardial Mass Measured index and haemodynamics
Index unit numerical value body weight (HW) gram (g) the 418 left hearts heavy (LVW) gram (g) 1.21 left heart ponderal indexs (LVWI) milligram/gram (mg/g) 2.89 femoral artery systolic pressures (SBP millimetres of mercury (mmHg) 175 femoral artery diastolic pressure (DBP) millimetres of mercury (mmHg) 119 left ventricular systolic pressures (LVSP) millimetress of mercury (mmHg) 177 left chamber diastolic pressure (LVDEP) millimetres of mercury (mmHg)-4.00 left ventricular pressure differential maximum (+dp/dtMax) mm Hg per second as (mmHg/s) 6520 left ventricular pressure differential minimum value (dp/dt
Min) mm Hg per second as (mmHg/s) 3140 hearts rate (BP) are inferior/minute (BPM) 4392. myocardium morphological change 2.1 left chamber cardiac muscle pathological sections (HE dyeing) see Fig. 3: proliferation of fibrous tissue under the myocardium inner membrance, cardiac muscle is seen fibrosis.2.2 Fig. 4 is seen in left chamber myocardial ultrastructure (Electronic Speculum): the sarcoplasmic reticulum expansion, the ischemic band appears in mitochondrial swelling, interstitial collagen protofibril hyperplasia.3. circulation endocrine indexes
Nervous plain II (AngII) pmol/mg of index value cardiac muscle ring gland glycosides (cAMP) pmol/mg 324 endothelin level (ET) pg/L 234 myocardial vasculars 357 plasma angiotensinogen II (AngII) pmol/L 71 medicines contrast (Ramipril) rat 1. myocardium ponderal index and haemodynamics
Index unit numerical value body weight (HW) gram (g) the 384 left hearts heavy (LVW) gram (g) 1.04 left heart ponderal indexs (LVWI) milligram/gram (mg/g) 2.11 femoral artery systolic pressures (SBP millimetres of mercury (mmHg) 139 femoral artery diastolic pressure (DBP) millimetres of mercury (mmHg) 78 left ventricular systolic pressures (LVSP) millimetress of mercury (mmHg) 160 left chamber diastolic pressure (LVDEP) millimetress of mercury (mmHg) 2 left ventricular pressure differential maximum (+dp/dtMax) mm Hg per second as (mmHg/s) 6720 left ventricular pressure differential minimum value (dp/dt
Min) mm Hg per second as (mmHg/s) 3890 hearts rate (BP) are inferior/minute (BPM) 3842. myocardium morphological change 2.1 left chamber cardiac muscle pathological sections (HE dyeing) see Fig. 5:the Non Apparent Abnormality variation; Fig. 6 is seen in basic normal morphology left chambers myocardial ultrastructure (Electronic Speculum) 2.2:the cell Mild edema; Morphological structure is normal substantially, and a matter is not seen the collagen fibril hyperplasia.3. Circulation Endocrine index index unit numerical value cardiac muscle ring gland glycosides (cAMP) pmol/mg 388 endothelin level (ET) pg/L 204 myocardial vascular Angiotensin Converting Enzyme II (AngII) pmol/mg 134 plasma angiotensinogen II (AngII) pmol/L, 32 medicine groups (oral group of AM-1) rats 1. myocardial Mass Measured index and haemodynamics
Index unit numerical value body weight (HW) gram (g) the 412 left hearts heavy (LVW) gram (g) 0.99 left heart ponderal index (LVWI) milligram/gram (mg/g) 2.40 femoral artery systolic pressures (SBP millimetres of mercury (mmHg) 141 femoral artery diastolic pressure (DBP) millimetres of mercury (mmHg) 79 left ventricular systolic pressures (LVSP) millimetress of mercury (mmHg) 158 left chamber diastolic pressure (LVDEP) millimetress of mercury (mmHg) 1.00 left ventricular pressure differential maximum (+dp/dtMax) mm Hg per second as (mmHg/s) 6920 left ventricular pressure differential minimum value (dp/dt
Min) mm Hg per second as (mmHg/s) 2930 hearts rate (BP) are inferior/minute (BPM) 3812. myocardium morphological change 2.1 left chamber cardiac muscle pathological sections (HE dyeing) see Fig. 7: local small amount of fibers kitchen range.2.2 Fig. 8 is seen in left chamber myocardial ultrastructure (Electronic Speculum): the plastosome mild swelling, the interstitial collagen protofibril is slightly many.3. circulation endocrine indexes
Index unit numerical value cardiac muscle ring gland glycosides, (cAMP) pmol/mg 346 endothelin level, (ET) the nervous plain II of pg/L 231 myocardial vasculars, (AngII) pmol/mg 299 plasma angiotensinogen II, (AngII) pmol/L 57 medicine groups-2, (AM-1 abdominal injection group) rat 1. myocardium ponderal index and haemodynamics
Index unit numerical value body weight (HW) gram (g) the 382 left hearts heavy (LVW) gram (g) 0.89 left heart ponderal index (LVWI) milligram/gram (mg/g) 2.33 femoral artery systolic pressures (SBP millimetres of mercury (mmHg) 151 femoral artery diastolic pressure (DBP) millimetres of mercury (mmHg) 94 left ventricular systolic pressures (LVSP) millimetress of mercury (mmHg) 180 left chamber diastolic pressure (LVDEP) millimetress of mercury (mmHg) 0.50 left ventricular pressure differential maximum (+dp/dtMax) mm Hg per second as (mmHg/s) 8100 left ventricular pressure differential minimum value (dp/dt
Min) mm Hg per second as (mmHg/s) 4560 hearts rate (BP) are inferior/minute (BPM) 4142. myocardium morphological change 2.1 left chamber cardiac muscle pathological sections (HE dyeing) see Fig. 9: the myocardial cell is more very thin, and surplus nothing obviously changes.2.2 Figure 10 is seen in left chamber myocardial ultrastructure (Electronic Speculum): morphological structure is normal substantially, and a matter is not seen the collagen fibril hyperplasia.3. circulation endocrine indexes
Nervous plain II (AngII) pmol/mg of index unit numerical value cardiac muscle ring gland glycosides (cAMP) pmol/mg 366 endothelin level (ET) pg/L 225 myocardial vasculars 254 plasma angiotensinogen II (AngII) pmol/L 48
Claims (2)
1. astragalus saponin 1 with function of resisting myocardial fibrillation is characterized in that having following structural:
Astragalus saponin 1 MW=802
2. the application of astragalus saponin 1 as claimed in claim 1 in the medicine of preparation function of resisting myocardial fibrillation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011266090A CN1164608C (en) | 2001-08-31 | 2001-08-31 | Astragalus saponin A with the function of resisting myocardial fibrillation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011266090A CN1164608C (en) | 2001-08-31 | 2001-08-31 | Astragalus saponin A with the function of resisting myocardial fibrillation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1403470A true CN1403470A (en) | 2003-03-19 |
| CN1164608C CN1164608C (en) | 2004-09-01 |
Family
ID=4666621
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB011266090A Expired - Fee Related CN1164608C (en) | 2001-08-31 | 2001-08-31 | Astragalus saponin A with the function of resisting myocardial fibrillation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1164608C (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102370699A (en) * | 2010-08-11 | 2012-03-14 | 天津天士力制药股份有限公司 | Application of qi-tonifying dripping pill containing radix astragali and root of red-rooted salvia to preparation of medicament for improving myocardial fibrosis and myocardial hypertrophy |
| US20120196816A1 (en) * | 2005-06-23 | 2012-08-02 | Nuliv Holding Inc. | Method for enhancing nutrient absorption with astragalosides |
| EP2548880A3 (en) * | 2003-06-23 | 2013-06-19 | Geron Corporation | Compositions for increasing telomerase activity |
-
2001
- 2001-08-31 CN CNB011266090A patent/CN1164608C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2548880A3 (en) * | 2003-06-23 | 2013-06-19 | Geron Corporation | Compositions for increasing telomerase activity |
| US8759304B2 (en) | 2003-06-23 | 2014-06-24 | Telomerase Activation Science, Inc. | Compositions and methods for increasing telomerase activity |
| US20120196816A1 (en) * | 2005-06-23 | 2012-08-02 | Nuliv Holding Inc. | Method for enhancing nutrient absorption with astragalosides |
| US20120196817A1 (en) * | 2005-06-23 | 2012-08-02 | Nuliv Holding Inc. | Method for enhancing nutrient absorption with astragalosides |
| CN102370699A (en) * | 2010-08-11 | 2012-03-14 | 天津天士力制药股份有限公司 | Application of qi-tonifying dripping pill containing radix astragali and root of red-rooted salvia to preparation of medicament for improving myocardial fibrosis and myocardial hypertrophy |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1164608C (en) | 2004-09-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20090169660A1 (en) | A composition of radix codonopsis and radix astragali, a method for preparation thereof and its application | |
| CN102908583B (en) | Traditional Chinese medicine composition for treating chest stuffiness and pains as well as preparation method, quality detection method and application of composition | |
| CN1201776C (en) | Medicines composition for treating diabetes and its prepn | |
| CN1403470A (en) | Astragalus saponin A with the function of resisting myocardial fibrillation | |
| CN1709469A (en) | Ginseng-astragalus dispersion tablet formulation, and its preparing process | |
| CN100339111C (en) | Medicine for treating coronary heart disease and its prepn | |
| CN1403452A (en) | Astragalus calycosin and its glycoside with the function of resisting myocardial ischemia | |
| CN1958001A (en) | Medication for treating high blood pressure | |
| CN1254252C (en) | Medicine for treating ischemic angiocardiopathy and cerebrovascular disease and its preparation method | |
| CN100337615C (en) | Oral disintegration tablet prepared from general saponin of notoginseng for treating thrombosis, and preparing technique | |
| CN1299718C (en) | Medicine for treating cardio-cerebral vascular disease and its preparing method | |
| CN1231568C (en) | Meridians-activating and kidney-nourishing wine | |
| CN1235611C (en) | Chinese medicinal composition for treating hypertension | |
| CN1425379A (en) | Traditional Chinese medicine active part compound preparation for curing cardiac and cerebral vascular diseases and its preparing method | |
| CN1256093C (en) | Application of skimming in the preparing process of medicine for preparing and treating kidney function failure | |
| CN1121869C (en) | Zhengtang capsule for treating diabetes | |
| CN1251717C (en) | Traditional Chinese medicine composition for treating coronary heart disease and angina pectoris | |
| CN1615956A (en) | Ginseng sini injection four treating cold limbs and preparing method | |
| CN1537547A (en) | Applicaton of chinese angelica-root for preparing medicine for treating hypertension disease | |
| CN1269517C (en) | Acquired immuno-deficiency syndrome resistant oral liquid | |
| CN105311208A (en) | Traditional Chinese medicine composition used for protecting livers | |
| CN1140285C (en) | Medicine for treating high blood pressure and preventing cerebral hemorrhage and its preparing method | |
| CN1328829A (en) | Medicine for curing angiocardiopathy | |
| CN109381450A (en) | Danshenxinkun C is preparing the application in anti-hypertension myocardial fibrosis drug | |
| CN1330930A (en) | Medicine for treating cardiovascular disease |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20040901 Termination date: 20170831 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |