CN1785299A - Applicntion of ligusticum containing medicine in preparation of thenting aspirin resistant medicine - Google Patents
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- 239000003814 drug Substances 0.000 title claims abstract description 69
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 title claims abstract description 68
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Abstract
A Chinese medicine for treating the aspirin-resistant cardiovascular disease is prepared from Chuan-xiong rhizome, evodia fruit and borneol.
Description
Technical field
The present invention relates to field of medicaments, specifically, the present invention relates to the application of a kind of medicine in preparation treatment resistant medication of aspirin.
Background technology
Aspirin (Aspirin) claim aspirin or aspirin again, is applied to clinical existing more than 80 year history, is a kind of ancient analgesic, analgesic.Along with the going deep into of prostaglandin research, aspirin there has been new understanding again in recent years: analgesic except being used for traditionally clinically, analgesia, the antiinflammatory, also be used for antiplatelet aggregation etc.Clinical trial shows that aspirin is the effective antiplatelet drug of cardiovascular and cerebrovascular disease high-risk patient primary prevention, and is also effective to the secondary prevention of myocardial infarction and ischemic vascular events.
But use the aspirin of therapeutic dose at present clinically, still there is part cardiovascular and cerebrovascular disease patient that coronary artery thrombus and apoplexy have taken place, strengthen therapeutic dose, not only fail to reach treatment and prevention purpose, and untoward reaction increases, this phenomenon be called " aspirin resistance " (Aspirin Resistance, AR).
Through long term follow-up, reason is as follows; First platelet is by other pathway activation, can not be blocked [Valles J by aspirin, Santos MT, Aznar J, et al.Erythrocyte Promotion of platelet reactivity decreases the effectivenessof aspirin as an antithrombotic therapeutic modality:the effect of low-dose aspirin is less thanoptimal in patients with vascular disease due to prothrombotic effects of erythrocytes on plateletreactivity.Circulation, 1998; 97:350-355]; The dosage that second some needs of patients is bigger than routine dose just can obtain best thromboembolism preventing effect, there is not evidence to show relevant [the Patrono C.Prevention ofmyocardial infarction and stroke by aspirin:different mechanisms of aspirin thromboembolism preventing effect with dosage? Different dosage? Thromb.Res., 1998; 92:S7-S12]; Although using the routine dose aspirin, the 3rd some patient also can generate TXA
2[Tayllor DW, Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy:arandomized controlled trail; ASA and Carotid Endarterectomy (ACE) Trial Collaborators.Lancet, 1999; 353:2179-2184].
Studies show that the generation of AR is relevant with following mechanism.
Erythrocyte improves platelet response
Platelet-erythrocyte interacts influence platelet response, synthesizes and platelet is raised and caused aspirin resistance by platelet release reaction, eicosanoids.Erythrocyte causes TXA
2Synthetic increasing, 5-HT, β-TG and ADP discharge, generation [the Valles J that shows erythrocyte adjusting platelet eicosanoids, et al.Erythrocyte metabolically enhancescollagen-induced platelet responsiveness via increased thromboxane production, adenosinediphosphate release, and recruitment.Blood, 1991; 78:154-162].
Arachidonic acid (PGF
2
) metabolism
Arachidonic acid produces a series of bioactive PGF that have through lipid peroxidation
2See complex.F
2-isoprostanes is the important new predictor of angiopathy.Unstable angina, stable angina pectoris, ariant angina patient and healthy people take aspirin 100mg/d and measure 8-iso-PGF
2(mark of matter fat peroxidation) and 11 dehydrogenations-TXA
2(TXA
2Studies show that biosynthetic mark), unstable angina patient 8-iso-PGF
2Urinary excretion is apparently higher than stablizing patient with angina pectoris and matched group; TXA
2Excretion apparently higher than stable patient with angina pectoris.Unstable angina patient's oxidant stress increases, 8-iso-PGF
2Increase, platelet is to the increased response of other agonist.
Smoking stimulates
Smoking is the cardiovascular disease principal risk factor.Data shows that aspirin can the anticoagulant rate reduce platelet aggregation [the Davis JW that causes, et al.Cigarette smoking-induced enhancement of platelet function:lack ifprevention by aspirin in men with coronary artery disease.J Lab Clin Med, 1982; 126:637-639].Platelet aggregation rate reduces after the smoking.Take aspirin before non-smoker and the smoking addiction person smoking and can prevent that platelet aggregation rate from descending.
The catecholamine levels platelet increasing is assembled to be increased
External platelet shows adrenergic sensitivity and has contact [Larsson PT et al between platelet activation that catecholamine causes and the acute coronary syndrome, Norepinephrine-induced human platelet activation in vivo is only partlycounteracted by aspirin.Circulation, 1994; 89:1951-1957].40 patients of acute myocardial infarction are divided into warfarin group and aspirin group at random.Get blood before and after the bicycle ergometor exercise, relatively two groups baseline characteristic, movement time and maximum heart rate.The warfarin group obviously reduces than aspirin group platelet aggregation rate when baseline, illustrates that aspirin has the effect of antiplatelet aggregation.Two groups platelet aggregation rate all reduces during motion, shows that the platelet aggregation ability increases.Its reason may be that the noradrenaline levels increase causes platelet activation.
Platelet increases the sensitivity of collagen
Collagen is the agonist of physiological important platelet aggregation.Two experimental study aspirin reply and collagen between relation.Before aspirin 324mg/kg is taken in a test (n=8 healthy male), measure the bleeding time after taking medicine 2 hours, distinguish aspirin respondent and nonresponder.87 of philtrums have participated in second test, give collagen 0.15-4 μ g/ml and determine aspirin respondent and the nonresponder's platelet sensitivity to collagen.Among 8 patients of first test, 5 aspirin respondents, 3 nonresponders.Aspirin respondent and the nonresponder preceding bleeding time indifference [(408 ± 121) and (330 ± 30) second, P＞0.05] of taking medicine has significant difference [(720 ± 225) and (330 ± 52) second] after taking medicine.Among 7 patients of second test, 4 aspirin respondents, 3 nonresponders.Aspirin respondent and the nonresponder preceding bleeding time indifference [(405 ± 52) and (357 ± 31) second of taking medicine, P＞0.05], significant difference [(623 ± 189) and (345 ± 54) second] [Kawasaki T is arranged after taking medicine, el at.Incresed platelet sensitivity to cllagen in individuals resistant to low aspirin.Stroke, 2000; 31:591-595].
Cycloxygenase-2 (COX-2) (p900)
Cox is the synthetic rate-limiting enzyme of prostaglandin.Cox-1 expresses in most cells and tissue.In the great majority tissue, can not detect under the mRNA of Cox-2 and the protein normal condition.[Weber AA, et al.Cyclooxygenase-2 in human platelet as a possible factor in aspirin resistance.Lancet, 1993 such as nearest Webr; 353:900] report that protein and the mRNA of Cox-2 express in healthy people's circulation platelet, this may be a reason of aspirin resistance.
Drug interaction
The interaction of aspirin and other nonsteroidal anti inflammatory medicines (NSAIDS) can weaken aspirin to hematoblastic effect.Aspirin needs at first to combine lysine-the 120th, the coefficient site of all NSAIDS with lysine-120 to the acetylation of serine residue.NSAIDS is stronger to the affinity of lysine-120, thereby has stoped the inhibitory action of aspirin to platelet Cox-1.
More than set forth possible mechanisms of aspirin resistance.Clear and definite platelet activation mechanism and reversible risk factor help to reduce the generation of aspirin resistance, improve patient's prognosis.
Aspirin resistance can not effectively stop thromboxane A after being meant and taking aspirin
2Synthetic, promptly aspirin has lost the protective effect to cardio-cerebrovascular, this phenomenon is referred to as aspirin resistance.Concerning Most patients, aspirin can make cardiovascular danger reduce by 25%, but the patient of aspirin resistance uses the aspirin for treatment cardiovascular disease, can not prevent the generation of cardiovascular event, can increase the incidence rate of heart infarction and apoplexy on the contrary, these find the use of restriction aspirin.Therefore, these cardiovascular disease are referred to as aspirin repellency cardiovascular disease in the middle of the present invention, particularly refer to coronary heart disease, the angina pectoris of using aspirin for treatment invalid.The present invention will be referred to as the medicine of anti-aspirin resistance to the medicine that aspirin repellency cardiovascular disease has a therapeutical effect, and this therapeutical effect is referred to as anti-aspirin resistance effect.
At present, the report for the treatment aspirin resistance also is not a lot.YusufS etc. [Effects of pretreatment withclopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneouscoronary intervention:the PCI-CURE study.Lancet, 2001] have reported to add on the basis of aspirin for treatment and have adjoined Gray with chlorine and can reduce the incidence rate that Acute Coronary Syndrome Patients comprises the early stage and secular serious cardiovascular incident of patient of percutaneous coronary intervention (pci).
The Chinese medicine blood-regulating drug, particularly the blood-activating stasis-removing kind medicine is the medicine that ancient Chinese medicine doctor is used always, this class medicine has the effect of promoting blood flow to regulate menstruation, removing blood stasis Xiao Disorder, blood-activating analgetic, detumescence and promoting granulation, modern pharmacology confirms, blood-regulating drug has the expansion coronary artery, increases coronary flow, reduce myocardial oxygen consumption, reduce peripheral vascular resistance, anticoagulant, microcirculation improvement, suppress thrombosis, fortifying fibre protein dissolution activity, anticoagulation system, microcirculation improvement, effects such as smooth muscle spasm are alleviated in blood pressure lowering.The clinical effect of Rhizoma Chuanxiong in the blood-regulating drug, Radix Salviae Miltiorrhizae, Herba Leonuri, Semen Persicae, Flos Carthami, Hirudo etc. is constantly expanded, and particularly the research of Radix Salviae Miltiorrhizae is particularly outstanding.
Find that through secular clinical research the traditional Chinese medical science thinks that the etiology and pathology of coronary heart disease is many because " imbalance of YIN and YANG, mechanism of qi be contrary to cause disorderly that the painstaking effort stasis of blood stagnates, blockage of the cardiac vessels, stagnation of QI and blood may bring about pain ".According to mentioned above principle, the someone has chosen Rhizoma Chuanxiong, Fructus Evodiae, Borneolum Syntheticum and has made preparation, and said preparation has blood circulation promoting and blood stasis dispelling, eleminating phlegm and freeing channels, the function of promoting the circulation of QI to relieve pain.The paralysis due to windstroke that is used for blood stasis or phlegm-damp impatency meridians; present research mainly concentrates on: in the clinical research of pharmaceutical composition of the present invention to Ischemia-reperfusion Injury rat serum brain barrier protection experimental study of effect, paralysis due to windstroke, the effect of relevant said preparation treatment aspirin resistance does not appear in the newspapers as yet.In order to alleviate the phenomenon that can produce aspirin resistance when cardio-cerebral vascular disease patient uses aspirin Drug therapy cardiovascular and cerebrovascular disease, some researchers are being sought the medicine that can substitute or alleviate the aspirin resistance phenomenon at present, the present invention tests at present more present medicines just on this basis, in the hope of finding its new medicine use, easily produce the aspirin resistance phenomenon to solve present aspirin medication.
Summary of the invention
The object of the present invention is to provide the application of a kind of pharmaceutical composition in the medicine of the anti-aspirin resistance of preparation.
Described Chinese medicine composition is by comprising that following crude drug makes: Rhizoma Chuanxiong, Fructus Evodiae, Borneolum Syntheticum, and preferred described Chinese medicine composition is by comprising that following crude drug makes: 1～20 part of Rhizoma Chuanxiong, 1～20 part of Fructus Evodiae, 1～10 part of Borneolum Syntheticum; Further preferred described Chinese medicine composition is by comprising that following crude drug makes: 5～10 parts of Rhizoma Chuanxiongs, 5～10 parts of Fructus Evodiaes, 1.5～3.5 parts of Borneolum Syntheticums, best described Chinese medicine composition is by comprising that following crude drug makes: 8 parts of Rhizoma Chuanxiongs, 8 parts of Fructus Evodiaes, 2 parts of Borneolum Syntheticums.
The preparation of the effective ingredient of described Chinese medicine composition can be adopted following method: water extraction, decoction and alcohol sedimentation technique, extraction, infusion process, percolation, reflux extraction, continuous backflow extraction method, macroreticular resin absorbing method preparation.For example, these crude drug pulverize mix homogeneously can be made powder takes after mixing it with water; Also can be with these medicines decocting together, the condensed water decocting liquid is made oral liquid then; But, preferably adopt following technology to extract, but this can not limit protection scope of the present invention to raw material in order to make each crude drug of this medicine bring into play drug effect better.
Get flavour of a drug such as Rhizoma Chuanxiong, Fructus Evodiae, Borneolum Syntheticum,, make the condensed water honeyed pill, promptly through suitable processing, the process of preparing Chinese medicine, pulverizing, mixing.
Described Chinese medicine composition can be made drop pill, granule, capsule, tablet, electuary, powder, oral liquid formulations form.
More than form when producing and to increase or to reduce according to corresponding ratio, as large-scale production can be unit with kilogram or with the ton, small-scale production can be unit with the gram also, and weight can increase or reduce, but the crude drug material weight proportion constant rate between each composition.
In order to understand essence of the present invention better,, its new purposes in pharmaceutical field is described below by the result of the test of this pharmaceutical composition of clinical observation at anti-" aspirin resistance ".
The present invention adopts the research method to aspirin resistance commonly used at present, uses immune enzyme linked immunosorbent assay mensuration patient urine sample is provided, and is used for analyzing 11-dehydrogenation thromboxance B
2(TXB
2) variation of level, judge whether the patient has the effect that reduces aspirin resistance after taking medicine of the present invention, the present invention passes through clinical research observation, proved the application of medicine of the present invention in the medicine of the anti-aspirin resistance of preparation, medicine of the present invention has the effect of anti-aspirin resistance, in order to understand the present invention better, the clinical test results with pharmaceutical composition of the present invention illustrates its new purposes in pharmaceutical field below.
Experimental example pharmaceutical composition of the present invention (preparing gained according to embodiment 2 methods) reduces aspirin resistance effect experiment
Retrospective approach is adopted in this research: normal value with reference to Australia about the aspirin resistance result of study
Physical data
This is organized 90 routine patients and is selected from the outpatient, and is the cardiovascular patient that has the aspirin resistance tendency through measuring.Male 66 people wherein, women 24 people.70 years old～85 years old age, 77 years old mean age.Clothes aspirin person 30 people; Take pharmaceutical composition 30 people of the present invention; Sharer 30 people (all patient took medicine more than half a year at least continuously to the day of sampling).
Materials and methods
Institute's urine sample of adopting is urina sanguinis stage casing for the first time, drop into immediately after getting in the liquid nitrogen, after be stored in-86 ℃ of cryogenic refrigerators standby.Use immune enzyme linked immunosorbent assay and detect 11-dehydrogenation TXB
2, test kit adopts Cayman Chemical company product, and all experiment is finished in the biological institute of sky scholar's power academy, and patient's packet conditions is carried out double blinding to lab assistant and later data statistician.
The result
As shown in table 1.
Table 1. is respectively organized patient's urine value 11-dehydrogenation TXB
2(ng/mmol) X ± SD
| Aspirin (n=30 example) | Pharmaceutical composition of the present invention (n=30 example) | Aspirin and pharmaceutical composition of the present invention share (n=30 example) |
| Urine value 11-dehydrogenation TXB 2(ng/mmol) | Urine value 11-dehydrogenation TXB 2(ng/mmol) | Urine value 11-dehydrogenation TXB 2(ng/mmol) |
| 26.11±10.42 | ?22.46±9.87 | ?20.31±9.99 |
Conclusion: obvious significant difference is arranged, p＜0.05 between the TXB2 excretion in the urine between pharmaceutical composition of the present invention and aspirin combination group and aspirin use group separately group; No obvious significant difference between the TXB2 excretion in urinating between pharmaceutical composition group of the present invention and aspirin group group, p＞0.05; No obvious significant difference between the TXB2 excretion during pharmaceutical composition group of the present invention and pharmaceutical composition of the present invention share and urinate between aspirin group group, p＞0.05.
This experimental result proves that pharmaceutical composition of the present invention and aspirin share, and can make the TXB2 excretion in the urine reduce thromboxane A promptly capable of blocking in vivo
2(TXA
2) formation, reduce hematoblastic sticking and blood coagulation, thereby anticoagulant, reduce the generation of arteriosclerosis, myocardial infarction, the TXB2 excretion reduces in the urine though pharmaceutical composition list of the present invention is with making, but compare not statistically significant with the aspirin group with single, presentation of results pharmaceutical composition of the present invention and aspirin share has anti-aspirin resistance effect, the cardiovascular patient invalid to aspirin, pharmaceutical composition of the present invention and aspirin be shared still the effect that improves life index.Whether this medicine reduces aspirin resistance by other mechanism of action, the further research of still needing.
Medicine of the present invention is to be prepared from by following examples, and following specific embodiment is an explanation of the invention, can not limit the present invention.
The specific embodiment
Embodiment 1:
Get Rhizoma Chuanxiong 150g, Fructus Evodiae 150g, Borneolum Syntheticum 2g is standby;
Rhizoma Chuanxiong, Fructus Evodiae carry out supercritical CO respectively
2Extract, through suitable processing, the process of preparing Chinese medicine, pulverizing, Borneolum Syntheticum is pulverized, stasis of blood said medicine extract mixing is made the condensed water honeyed pill, promptly.
Embodiment 2
Get Rhizoma Chuanxiong 50g, Fructus Evodiae 35g, Borneolum Syntheticum 2g is standby;
Rhizoma Chuanxiong, Fructus Evodiae water extract 3 times, merge three times extracting solution, and concentrating under reduced pressure with the concentrated extract spray drying, adds and pulverizes Borneolum Syntheticum, mixing, and condensed water honeyed pill method is made the condensed water honeyed pill routinely, promptly.
Embodiment 3
Get Rhizoma Chuanxiong 89g, Fructus Evodiae 40g, Borneolum Syntheticum 1g is standby;
Flavour of a drug such as Rhizoma Chuanxiong, Fructus Evodiae, Borneolum Syntheticum through suitable processing, the process of preparing Chinese medicine, pulverizing, mixing, are made the condensed water honeyed pill, promptly.
Embodiment 4
Get 20g, Fructus Evodiae 20g, Borneolum Syntheticum 1g is standby;
Flavour of a drug such as Rhizoma Chuanxiong, Fructus Evodiae, Borneolum Syntheticum through suitable processing, the process of preparing Chinese medicine, pulverizing, mixing, are made powder, promptly.
Embodiment 5
Get 20g, Fructus Evodiae 15g, Borneolum Syntheticum 2.5g is standby;
Flavour of a drug such as Rhizoma Chuanxiong, Fructus Evodiae, Borneolum Syntheticum, processing, the process of preparing Chinese medicine, pulverizing, mixing through suitable incapsulate, promptly.
Embodiment 6
Get 10g, Fructus Evodiae 10g, Borneolum Syntheticum 1.5g is standby;
Flavour of a drug such as Rhizoma Chuanxiong, Fructus Evodiae, Borneolum Syntheticum through suitable processing, the process of preparing Chinese medicine, pulverizing, mixing, are made the condensed water honeyed pill, promptly.
Embodiment 7
Get 5g, Fructus Evodiae 10g, Borneolum Syntheticum 3.5g is standby;
Flavour of a drug such as Rhizoma Chuanxiong, Fructus Evodiae, Borneolum Syntheticum through suitable processing, the process of preparing Chinese medicine, pulverizing, mixing, are made the condensed water honeyed pill, promptly.
Embodiment 8
Get Rhizoma Chuanxiong 8g, Fructus Evodiae 8g, Borneolum Syntheticum 2g is standby;
Flavour of a drug such as Rhizoma Chuanxiong, Fructus Evodiae, Borneolum Syntheticum through suitable processing, the process of preparing Chinese medicine, pulverizing, mixing, are made the condensed water honeyed pill, promptly.
Claims (8)
1, the application of a kind of pharmaceutical composition in the low medicine that resists of the anti-aspirin of preparation, wherein the composition of said composition comprises: Rhizoma Chuanxiong, Fructus Evodiae, Borneolum Syntheticum.
2, application as claimed in claim 1, wherein the composition of said composition comprises: 1～20 part of Rhizoma Chuanxiong, 1～20 part of Fructus Evodiae, 1～10 part of Borneolum Syntheticum.
3, application as claimed in claim 2, wherein the composition of said composition comprises: 5～10 parts of Rhizoma Chuanxiongs, 5～10 parts of Fructus Evodiaes, 1.5～3.5 parts of Borneolum Syntheticums.
4, application as claimed in claim 3, wherein the composition of said composition comprises: 8 parts of Rhizoma Chuanxiongs, 8 parts of Fructus Evodiaes, 2 parts of Borneolum Syntheticums.
5,, it is characterized in that described compositions is a kind of of granule, capsule, tablet, electuary, powder, oral liquid formulations form as claim 1,2,3 or 4 described application.
6,, it is characterized in that the application of this pharmaceutical composition in the medicine of preparation treatment aspirin repellency cardiovascular and cerebrovascular disease as claim 1,2,3 or 4 described application.
7, application as claimed in claim 6 is characterized in that said aspirin repellency cardiovascular and cerebrovascular disease is meant the invalid cardiovascular and cerebrovascular disease of use aspirin for treatment.
8, application as claimed in claim 7 is characterized in that said aspirin repellency cardiovascular and cerebrovascular disease is meant invalid coronary heart disease, the angina pectoris of use aspirin for treatment.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410093842 CN1785299A (en) | 2004-12-06 | 2004-12-06 | Applicntion of ligusticum containing medicine in preparation of thenting aspirin resistant medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410093842 CN1785299A (en) | 2004-12-06 | 2004-12-06 | Applicntion of ligusticum containing medicine in preparation of thenting aspirin resistant medicine |
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| Publication Number | Publication Date |
|---|---|
| CN1785299A true CN1785299A (en) | 2006-06-14 |
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ID=36782967
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|---|---|---|---|
| CN 200410093842 Pending CN1785299A (en) | 2004-12-06 | 2004-12-06 | Applicntion of ligusticum containing medicine in preparation of thenting aspirin resistant medicine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023173581A1 (en) * | 2022-03-18 | 2023-09-21 | 广州白云山奇星药业有限公司 | New use of huatuo zaizao pill |
-
2004
- 2004-12-06 CN CN 200410093842 patent/CN1785299A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023173581A1 (en) * | 2022-03-18 | 2023-09-21 | 广州白云山奇星药业有限公司 | New use of huatuo zaizao pill |
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