CN1714828A - Use of injection in preparing medicine for breating anti aspirin - Google Patents
Use of injection in preparing medicine for breating anti aspirin Download PDFInfo
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- CN1714828A CN1714828A CN 200410019847 CN200410019847A CN1714828A CN 1714828 A CN1714828 A CN 1714828A CN 200410019847 CN200410019847 CN 200410019847 CN 200410019847 A CN200410019847 A CN 200410019847A CN 1714828 A CN1714828 A CN 1714828A
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- 229960001138 acetylsalicylic acid Drugs 0.000 title claims description 64
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides the new use of a kind of medicine composition. The medicine composition consists of red sage, safflower, sodium chloride for injection, etc. Clinical test shows that the medicine composition has the property of improving aspirin resistance and may be used in treating aspirin resistance cardiac vascular diseases to raise the life quality of the aspirin resistance cardiac vascular disease patient.
Description
Technical field
The present invention relates to field of medicaments, specifically, the present invention relates to a kind of application of injection in preparation treatment resistant medication of aspirin that contains Radix Salviae Miltiorrhizae.
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.[Effects of pretreatment withclopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneouscoronary intervention:the PCI-CURE study.Lancet, 2001] such as Yusuf S have been reported to add on the basis of aspirin for treatment and have been 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.And the clinical effect of the Rhizoma Chuanxiong in the blood-regulating drug, Radix Salviae Miltiorrhizae, Herba Leonuri, Semen Persicae, Flos Carthami, Hirudo etc. is constantly expanded.
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 and has got Radix Salviae Miltiorrhizae, Flos Carthami, raw materials such as sodium chloride for injection are made preparation, and said preparation has the effect of blood circulation promoting and blood stasis dispelling, are used for the treatment of the thoracic obstruction and apoplexy that the blood stasis impatency is caused clinically, disease is seen: chest pain, uncomfortable in chest, cardiopalmus, facial hemiparalysis, the not smoothgoing plug of speech, numb limbs and tense tendons, movable symptom such as unfavorable: coronary heart disease, angina pectoris, myocardial infarction, blood stasis type pulmonary heart disease, ischemic encephalopathy, cerebral thrombosis.The research to the preparation made by Radix Salviae Miltiorrhizae, Flos Carthami, sodium chloride for injection at present mainly concentrates on aspects such as coronary heart disease, angina pectoris, and the effect of relevant said preparation treatment aspirin resistance does not appear in the newspapers as yet.
Summary of the invention
The objective of the invention is to propose a kind of application of injection in preparation treatment resistant medication of aspirin that contains Radix Salviae Miltiorrhizae.
Under the situation that the cardiovascular disease incidence rate remains high at present, how can more effective treatment and prevention cardiovascular and cerebrovascular disease, it is very important thing, clinical aspirin commonly used is in the process of treatment and prevention cardiovascular and cerebrovascular disease, the aspirin resistance phenomenon occurred, the inventor is just under this prerequisite condition, to the medicine that is used for the treatment of cardiovascular and cerebrovascular disease commonly used at present, particularly Chinese medicine or compositions are screened, and find a kind of medicine that is used for anti-aspirin resistance.Pharmaceutical composition of the present invention through clinical observation under doses separately or the associating aspirin use together, can obviously improve " aspirin resistance " patient's symptom.The result shows that the former pharmaceutical composition of the present invention that is used for the treatment of coronary heart disease, angina pectoris, myocardial ischemia has the effect of anti-" aspirin resistance ".
Following drug component of the present invention is formed, consumption all has the low anti-curative effect of anti-preferably aspirin: the composition of compositions comprises gets Radix Salviae Miltiorrhizae, Flos Carthami, sodium chloride for injection; Preferred each amounts of components is Radix Salviae Miltiorrhizae 50～100g, Flos Carthami 15～40g, sodium chloride for injection 3.5～20g; Further preferred each amounts of components is Radix Salviae Miltiorrhizae 65～85g, Flos Carthami 20～30g, sodium chloride for injection 5～10g; Each best amounts of components is Radix Salviae Miltiorrhizae 75g, Flos Carthami 25g, sodium chloride for injection 7g.
Medicine of the present invention can adopt following step preparation:
1. get Radix Salviae Miltiorrhizae 75g, Flos Carthami 25g, sodium chloride for injection 7g is standby;
2. above two flavor medical materials, Radix Salviae Miltiorrhizae each 1 hour, filters filtrate for later use with Diluted Alcohol warm macerating secondary; Medicinal residues mix with Flos Carthami, add water temperature and soak secondary, each 1 hour, filter, merging filtrate, being concentrated into relative density is the clear paste of 1.05～1.15 (65 ℃), add sodium chloride for injection and ooze, regulate pH value to 5.5～7.0, filter to waiting, filtrate cold preservation 24 hours, add the injection water to ormal weight, filter embedding, sterilization, promptly.
Medicine of the present invention can be made into dosage forms such as injection, drip liquid, granule, capsule, tablet, electuary, powder, oral liquid, drop pill.
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 red sage formulation, 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 medicine of the present invention illustrates its new purposes in pharmaceutical field below.Following medicine of the present invention is called the DANHONG drip liquid.
Experimental example 1 DANHONG drip liquid 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 120 routine patients and is selected from the outpatient, and is the cardiovascular patient that has the aspirin resistance tendency through measuring.Male 85 people wherein, women 35 people.70 years old～85 years old age, 78 years old mean age.Clothes aspirin person 40 people; Take DANHONG drip liquid 40 people; Sharer 40 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=40 example) | DANHONG drip liquid (n=40 example) | Aspirin and DANHONG drip liquid are share (n=40 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) |
| 25.16±10.41 | 22.14±9.26 | 20.83±9.12 |
Conclusion: obvious significant difference is arranged, p＜0.05 between the TXB2 excretion in the urine between DANHONG drip liquid and aspirin combination group (pellet+Ah) and aspirin use group separately group; There is not obvious significant difference, p＞0.05 between the TXB2 excretion in the urine between DANHONG drip liquid group and aspirin group group; No obvious significant difference between the TXB2 excretion during DANHONG drip liquid group and DANHONG drip liquid are share and urinated between aspirin (pellet+Ah) group group, p＞0.05.
This experimental result proves that the DANHONG drip liquid is share aspirin 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, presentation of results DANHONG drip liquid is share aspirin and is had anti-aspirin resistance effect, the cardiovascular patient invalid to aspirin, the DANHONG drip liquid still has 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
EXAMPLE l: the preparation method of DANHONG ZHUSHEYE
1. get Radix Salviae Miltiorrhizae 75g, Flos Carthami 25g, sodium chloride for injection 7g is standby;
2. above two flavor medical materials, Radix Salviae Miltiorrhizae each 1 hour, filters filtrate for later use with Diluted Alcohol warm macerating secondary; Medicinal residues mix with Flos Carthami, add water temperature and soak secondary, each 1 hour, filter, merging filtrate, being concentrated into relative density is the clear paste of 1.05～1.15 (65 ℃), add sodium chloride for injection and ooze, regulate pH value to 5.5～7.0, filter to waiting, filtrate cold preservation 24 hours, add the injection water to ormal weight, filter embedding, sterilization, promptly.
Embodiment 2: the preparation method of DANHONG ZHUSHEYE
1. Radix Salviae Miltiorrhizae 50g, Flos Carthami 15g, sodium chloride for injection 3.5g is standby;
2. according to the preparation of embodiment 1 preparation method, add the injection water, filter to ormal weight, embedding, sterilization, promptly.
Embodiment 3: the preparation method of DANHONG ZHUSHEYE
1. get Radix Salviae Miltiorrhizae 100g, Flos Carthami 30g, sodium chloride for injection 20g is standby;
2. according to the preparation of embodiment 1 preparation method, add the injection water, filter to ormal weight, embedding, sterilization, promptly.
Embodiment 4: the preparation method of DANHONG ZHUSHEYE
1. get 65g, Flos Carthami 30g, sodium chloride for injection 10g is standby;
2. according to the preparation of embodiment 1 preparation method, add the injection water, filter to ormal weight, embedding, sterilization, promptly.
Embodiment 5: the preparation method of DANHONG ZHUSHEYE
1. get 85g, Flos Carthami 30g, sodium chloride for injection 5g is standby;
2. according to the preparation of embodiment 1 preparation method, add the injection water, filter to ormal weight, embedding, sterilization, promptly.
Claims (8)
1, the application of a kind of pharmaceutical composition in the low medicine that resists of the anti-aspirin of preparation is characterized in that the composition of said composition comprises Radix Salviae Miltiorrhizae, Flos Carthami, sodium chloride for injection.
2, application as claimed in claim 1 is characterized in that the composition of said composition comprises Radix Salviae Miltiorrhizae 50～100g, Flos Carthami 15～40g, and sodium chloride for injection 3.5～20g is standby.
3, application as claimed in claim 1 is characterized in that the composition of said composition comprises Radix Salviae Miltiorrhizae 65～85g, Flos Carthami 20～30g, and sodium chloride for injection 5～10g is standby.
4, application as claimed in claim 1 is characterized in that the composition of said composition comprises Radix Salviae Miltiorrhizae 75g, Flos Carthami 25g, and sodium chloride for injection 7g is standby.
5,, it is characterized in that described compositions is a kind of of injection, drip liquid, granule, capsule, tablet, electuary, powder, oral liquid, dropping pill formulation form as any one described application in the claim 1～4.
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 any one described application in the claim 1～4.
7, application as claimed in claim 6 is characterized in that described 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 6 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 200410019847 CN1714828A (en) | 2004-06-30 | 2004-06-30 | Use of injection in preparing medicine for breating anti aspirin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410019847 CN1714828A (en) | 2004-06-30 | 2004-06-30 | Use of injection in preparing medicine for breating anti aspirin |
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| CN1714828A true CN1714828A (en) | 2006-01-04 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105412226A (en) * | 2015-11-30 | 2016-03-23 | 南京中医药大学 | Application of salviae miltiorrhizae and flos carthami composition to enhancement of antithrombotic function of aspirin |
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2004
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105412226A (en) * | 2015-11-30 | 2016-03-23 | 南京中医药大学 | Application of salviae miltiorrhizae and flos carthami composition to enhancement of antithrombotic function of aspirin |
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