CN1872177A - Application of medication of containing red sage root in resistant medication anti aspirin - Google Patents
Application of medication of containing red sage root in resistant medication anti aspirin Download PDFInfo
- Publication number
- CN1872177A CN1872177A CN 200510013589 CN200510013589A CN1872177A CN 1872177 A CN1872177 A CN 1872177A CN 200510013589 CN200510013589 CN 200510013589 CN 200510013589 A CN200510013589 A CN 200510013589A CN 1872177 A CN1872177 A CN 1872177A
- Authority
- CN
- China
- Prior art keywords
- aspirin
- application
- medicine
- salviae miltiorrhizae
- standby
- 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.)
- Pending
Links
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 title claims abstract description 71
- 229960001138 acetylsalicylic acid Drugs 0.000 title claims abstract description 69
- 239000003814 drug Substances 0.000 title claims abstract description 66
- 229940079593 drug Drugs 0.000 title claims abstract description 30
- 240000007164 Salvia officinalis Species 0.000 title abstract 3
- 235000005412 red sage Nutrition 0.000 title abstract 3
- 239000000203 mixture Substances 0.000 claims abstract description 14
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 13
- 241000628997 Flos Species 0.000 claims description 21
- 238000011282 treatment Methods 0.000 claims description 19
- 239000007788 liquid Substances 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 16
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 10
- 239000008187 granular material Substances 0.000 claims description 9
- 239000007921 spray Substances 0.000 claims description 9
- 206010002383 Angina Pectoris Diseases 0.000 claims description 8
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 7
- 208000029078 coronary artery disease Diseases 0.000 claims description 5
- 239000002674 ointment Substances 0.000 claims description 4
- 239000006187 pill Substances 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 239000003826 tablet Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000008298 dragée Substances 0.000 claims description 2
- 239000006196 drop Substances 0.000 claims description 2
- -1 electuary Substances 0.000 claims description 2
- 239000002662 enteric coated tablet Substances 0.000 claims description 2
- 239000007941 film coated tablet Substances 0.000 claims description 2
- 239000007902 hard capsule Substances 0.000 claims description 2
- 239000011505 plaster Substances 0.000 claims description 2
- 239000007901 soft capsule Substances 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- 239000007940 sugar coated tablet Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 abstract description 2
- 244000020518 Carthamus tinctorius Species 0.000 abstract 1
- 235000003255 Carthamus tinctorius Nutrition 0.000 abstract 1
- 244000170916 Paeonia officinalis Species 0.000 abstract 1
- 235000006484 Paeonia officinalis Nutrition 0.000 abstract 1
- 208000025870 aspirin resistance Diseases 0.000 description 37
- 230000000694 effects Effects 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 239000000706 filtrate Substances 0.000 description 14
- 239000000341 volatile oil Substances 0.000 description 14
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 12
- 238000005469 granulation Methods 0.000 description 8
- 230000003179 granulation Effects 0.000 description 8
- 239000004375 Dextrin Substances 0.000 description 7
- 229920001353 Dextrin Polymers 0.000 description 7
- 230000004520 agglutination Effects 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 235000019425 dextrin Nutrition 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000007654 immersion Methods 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- 235000019640 taste Nutrition 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 210000003743 erythrocyte Anatomy 0.000 description 6
- 230000000391 smoking effect Effects 0.000 description 6
- 102000008186 Collagen Human genes 0.000 description 5
- 108010035532 Collagen Proteins 0.000 description 5
- 239000003146 anticoagulant agent Substances 0.000 description 5
- 229920001436 collagen Polymers 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 230000010118 platelet activation Effects 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 208000032843 Hemorrhage Diseases 0.000 description 4
- 208000006011 Stroke Diseases 0.000 description 4
- 230000000202 analgesic effect Effects 0.000 description 4
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 4
- 230000004087 circulation Effects 0.000 description 4
- 230000001737 promoting effect Effects 0.000 description 4
- 230000035945 sensitivity Effects 0.000 description 4
- 206010002388 Angina unstable Diseases 0.000 description 3
- 208000007814 Unstable Angina Diseases 0.000 description 3
- 230000000740 bleeding effect Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000002131 composite material Substances 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 2
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 2
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 2
- 101150071146 COX2 gene Proteins 0.000 description 2
- 101100496968 Caenorhabditis elegans ctc-1 gene Proteins 0.000 description 2
- 101100114534 Caenorhabditis elegans ctc-2 gene Proteins 0.000 description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 description 2
- 208000005189 Embolism Diseases 0.000 description 2
- 206010021703 Indifference Diseases 0.000 description 2
- 206010061216 Infarction Diseases 0.000 description 2
- 101100221647 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cox-1 gene Proteins 0.000 description 2
- 101150062589 PTGS1 gene Proteins 0.000 description 2
- 101150000187 PTGS2 gene Proteins 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 208000001435 Thromboembolism Diseases 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000000702 anti-platelet effect Effects 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 229940114079 arachidonic acid Drugs 0.000 description 2
- 235000021342 arachidonic acid Nutrition 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 238000013172 carotid endarterectomy Methods 0.000 description 2
- 150000003943 catecholamines Chemical class 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000007574 infarction Effects 0.000 description 2
- 230000033001 locomotion Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 230000004089 microcirculation Effects 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 238000007427 paired t-test Methods 0.000 description 2
- 238000013146 percutaneous coronary intervention Methods 0.000 description 2
- 230000003405 preventing effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000011287 therapeutic dose Methods 0.000 description 2
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 208000019553 vascular disease Diseases 0.000 description 2
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical group OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 2
- 229960005080 warfarin Drugs 0.000 description 2
- 206010059245 Angiopathy Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 1
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 101000947178 Homo sapiens Platelet basic protein Proteins 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102100036154 Platelet basic protein Human genes 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 208000007718 Stable Angina Diseases 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 229940067131 aspirin 100 mg Drugs 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000001851 biosynthetic effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 150000002066 eicosanoids Chemical class 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 210000000088 lip Anatomy 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 238000012153 long-term therapy Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000036284 oxygen consumption Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000005325 percolation Methods 0.000 description 1
- 230000036513 peripheral conductance Effects 0.000 description 1
- 238000005502 peroxidation Methods 0.000 description 1
- 230000009862 primary prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000003331 prothrombotic effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 230000009863 secondary prevention Effects 0.000 description 1
- 238000007560 sedimentation technique Methods 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000006441 vascular event Effects 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
An application of the medicinal composition consisting of 5 Chinese-medicinal materials including red sage root, red peony root, red sage root, safflower, Chuan-xiong rhizome, etc in preparing the medicines for treating the aspirin-resistant cardiovascular disease is disclosed.
Description
Technical field
The present invention relates to field of medicaments, specifically, the present invention relates to a kind of application of medicine in resistant medication anti 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.
The said aspirin resistance of the present invention 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.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 Radix Paeoniae Rubra, Radix Salviae Miltiorrhizae, Lignum Dalbergiae Odoriferae, Flos Carthami, Rhizoma Chuanxiong and has made preparation, and said preparation has blood circulation promoting and blood stasis dispelling, and the effect of promoting the circulation of QI to relieve pain is used for angina pectoris, and arrhythmia is improved diseases such as coronary heart disease symptom.Because its determined curative effect, untoward reaction is few, is clinical treatment Chinese patent medicine commonly used uncomfortable in chest, anginal.Research to said preparation at present mainly concentrates in the research of angina pectoris, and 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 Chinese medicine composition in the medicine of the anti-aspirin resistance of preparation.
Described Chinese medicine composition is by comprising that following crude drug makes: Radix Paeoniae Rubra 1500～6000g, Radix Salviae Miltiorrhizae 3000～10000g, Lignum Dalbergiae Odoriferae 1200～3500g, Flos Carthami 1500～6000g, Rhizoma Chuanxiong 1500～6000g; Preferred described Chinese medicine composition is by comprising that following crude drug makes: Radix Paeoniae Rubra 2500～4000g, Radix Salviae Miltiorrhizae 5000～7000g, Lignum Dalbergiae Odoriferae 1800～2500g, Flos Carthami 2500～4000g, Rhizoma Chuanxiong 2500～4000g; Best described Chinese medicine composition is by comprising that following crude drug makes: Radix Paeoniae Rubra 3354g, Radix Salviae Miltiorrhizae 6708g, Lignum Dalbergiae Odoriferae 2236g, Flos Carthami 3354g, Rhizoma Chuanxiong 3354g.
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.
The preparation method of described Chinese medicine composition can adopt following steps:
Get Radix Paeoniae Rubra 3354g, Radix Salviae Miltiorrhizae 6708g, Lignum Dalbergiae Odoriferae 2236g, Flos Carthami 3354g, Rhizoma Chuanxiong 3354g is standby;
The above five tastes, Radix Paeoniae Rubra, Radix Salviae Miltiorrhizae decoct with water twice, and 2 hours for the first time, 1 hour for the second time, decocting liquid filtered, and merging filtrate is standby; Cataclasm Lignum Dalbergiae Odoriferae and Rhizoma Chuanxiong extract volatile oil, use dissolve with ethanol, and standby, residue decocts with water 2 hours, and decocting liquid filters, and is standby; Flos Carthami adds water temperature and soaks twice, and 2 hours for the first time, 1 hour for the second time, merge immersion, filter, standby; Above-mentioned each filtrate is merged, be condensed into relative density and be 1.30～1.32 thick paste, get 1 part of thick paste, 2.1 parts of Icing Sugar, 0.7 part in dextrin is mixed, alcohol granulation, drying sprays into volatile oil, and granulate is made 1000 bags, promptly.
Described Chinese medicine composition can be made any preparation on the pharmaceutics; Preferably make tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, solution, ointment, plaster, spray, drop pill, oral cavity disintegration tablet, effervescent tablet.
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, by measuring platelet aggregation rate, 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 (according to the preparation of embodiment 1 preparation method) reduces aspirin resistance effect experiment
We filter out 86 of aspirin resistance patients (56 of men, 30 of woman, 70.9 ± 10.9 years old age) altogether from outpatient service, find that the aspirin resistance incidence rate is about 15.6%.The aspirin resistance patient is divided into (55 of combination group; Unite and use aspirin and pharmaceutical composition of the present invention), single with pharmaceutical composition group of the present invention (31, the aspirin of stopping using is singly used pharmaceutical composition of the present invention), measure the platelet maximum agglutination rate once more after treating for 2 weeks.
Method:
One. inclusion criteria
1. take low-dosage aspirin continuously and surpass 2 all persons
2. use U.S. CHRON-LOG AGGREGOMETER 540VS and detect the platelet maximum agglutination rate of its arachidonic acid-induction greater than 30%
Meeting above-mentioned two persons simultaneously can be selected in
Two. exclusion standard:
1. disease in the blood system hemorrhage especially;
2. cancer
3. chronic obstructive pulmonary disease
The person promptly is excluded to meet the one
Three. grouping:
Combination group: select 55 aspirin resistance patients at random, continue to use aspirin, add simultaneously with 2 all pharmaceutical compositions of the present invention, one time 1 bag, 3 times on the one.
Single with pharmaceutical composition group of the present invention: select 31 aspirin resistance patients at random, inactive aspirin is used pharmaceutical composition of the present invention instead, and is oral, one time 1 bag, 3 times on the one, 2 weeks.
Four. curative effect determinate standard
Produce effects: the platelet maximum agglutination rate is less than 30% (effect is equal to normal aspirin effect)
Effectively: the platelet maximum agglutination rate is greater than 30%, but is lower than for 80% (the platelet activation value normally suppresses effect but be lower than aspirin in normal range)
Invalid: the maximum agglutination rate excursion is ± 10% before and after the treatment
Raise: treatment back platelet aggregation rate raises more than 10%
Effective percentage=(produce effects number+effective number)/total number of persons
The result
One, aspirin resistance aspirin and pharmaceutical composition of the present invention are united use
1. treatment effective percentage
| Therapeutic effect | Number | Ratio % |
| Produce effects is effective | 40 5 | 72 9 |
| Invalid rising | 8 2 | 15 4 |
The total effective rate that aspirin and pharmaceutical composition of the present invention are united use reaches 81% (45/55)
2. compare before and after the platelet maximum agglutination rate:
Before the treatment (65.4 ± 26.5), treatment 2 week backs (29.6 ± 19.7) are through paired t-test: p＜0.01; The average range of decrease of platelet aggregation rate is 49.22%.
Annotate: value before reduction amplitude=(being worth after value-medication before the medication)/medication
Two. aspirin resistance stops aspirin, list pharmaceutical composition of the present invention
1. treatment effective percentage
| Therapeutic effect | Number | Ratio % |
| The produce effects enabledisable raises | 11 4 9 7 | 35 13 29 23 |
Stop aspirin, list pharmaceutical composition of the present invention, the total effective rate that aspirin resistance is treated reaches 48% (15/31)
2. compare before and after the platelet maximum agglutination rate:
Before the treatment (80.7 ± 24.6), treatment 2 week backs (60.1 ± 29.2) are through paired t-test: p＜0.05; The average range of decrease of platelet aggregation rate is 19.05%.
Annotate: value before reduction amplitude=(being worth after value-medication before the medication)/medication
Conclusion: to the aspirin resistance person, use aspirin and medicine composite for curing of the present invention can obviously lower platelet aggregation rate simultaneously, effective percentage is 81%, and the average range of decrease is 49.22%; Single its effective percentage is 48% with medicine composite for curing aspirin resistance of the present invention, and the average range of decrease is 19.05%.Presentation of results is to the invalid cardiovascular patient of independent use aspirin for treatment, pharmaceutical composition of the present invention and aspirin share has the effect of good curing aspirin resistance, use medicine composite for curing aspirin resistance of the present invention that effect is preferably also arranged separately, but the effect not as good as with the aspirin combination group, whether pharmaceutical composition of the present invention 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 Radix Paeoniae Rubra 3354g, Radix Salviae Miltiorrhizae 6708g, Lignum Dalbergiae Odoriferae 2236g, Flos Carthami 3354g, Rhizoma Chuanxiong 3354g is standby;
The above five tastes, Radix Paeoniae Rubra, Radix Salviae Miltiorrhizae decoct with water twice, and 2 hours for the first time, 1 hour for the second time, decocting liquid filtered, and merging filtrate is standby; Cataclasm Lignum Dalbergiae Odoriferae and Rhizoma Chuanxiong extract volatile oil, use dissolve with ethanol, and standby, residue decocts with water 2 hours, and decocting liquid filters, and is standby; Flos Carthami adds water temperature and soaks twice, and 2 hours for the first time, 1 hour for the second time, merge immersion, filter, standby; Above-mentioned each filtrate is merged, be condensed into relative density and be 1.30～1.32 thick paste, get 1 part of thick paste, 2.1 parts of Icing Sugar, 0.7 part in dextrin is mixed, alcohol granulation, drying sprays into volatile oil, and granulate is made 1000 bags, promptly.
Embodiment 2:
Get Radix Paeoniae Rubra 1500g, Radix Salviae Miltiorrhizae 10000g, Lignum Dalbergiae Odoriferae 1200g, Flos Carthami 6000g, Rhizoma Chuanxiong 1500g is standby;
The above five tastes, Radix Paeoniae Rubra, Radix Salviae Miltiorrhizae decoct with water twice, and 3 hours for the first time, 2 hours for the second time, decocting liquid filtered, and merging filtrate is standby; Cataclasm Lignum Dalbergiae Odoriferae and Rhizoma Chuanxiong extract volatile oil, use dissolve with ethanol, and standby, residue decocts with water 3 hours, and decocting liquid filters, and is standby; Flos Carthami adds water temperature and soaks twice, and 3 hours for the first time, 1 hour for the second time, merge immersion, filter, standby; Above-mentioned each filtrate is merged, be condensed into relative density and be 1.05～1.32 thick paste, get 1 part of thick paste, 3 parts of Icing Sugar, 1 part in dextrin is mixed, alcohol granulation, drying sprays into volatile oil, and granulate is made 1000 bags, promptly.
Embodiment 3:
Get Radix Paeoniae Rubra 6000g, Radix Salviae Miltiorrhizae 3000g, Lignum Dalbergiae Odoriferae 3500g, Flos Carthami 1500g, Rhizoma Chuanxiong 6000g is standby;
The above five tastes, Radix Paeoniae Rubra, Radix Salviae Miltiorrhizae decoct with water twice, and 2.5 hours for the first time, 1.5 hours for the second time, decocting liquid filtered, and merging filtrate is standby; Cataclasm Lignum Dalbergiae Odoriferae and Rhizoma Chuanxiong extract volatile oil, use dissolve with ethanol, and standby, residue decocts with water 2 hours, and decocting liquid filters, and is standby; Flos Carthami adds water temperature and soaks twice, and 2.5 hours for the first time, 1.5 hours for the second time, merge immersion, filter, standby; Above-mentioned each filtrate is merged, be condensed into relative density and be 1.10～1.22 thick paste, get 1 part of thick paste, 4 parts of Icing Sugar, 2 parts in dextrin is mixed, alcohol granulation, drying sprays into volatile oil, and granulate is made 1000 bags, promptly.
Embodiment 4:
Get Radix Paeoniae Rubra 2500g, Radix Salviae Miltiorrhizae 5000g, Lignum Dalbergiae Odoriferae 1800g, Flos Carthami 2500g, Rhizoma Chuanxiong 2500g is standby;
The above five tastes, Radix Paeoniae Rubra, Radix Salviae Miltiorrhizae decoct with water twice, and 2 hours for the first time, 1 hour for the second time, decocting liquid filtered, and merging filtrate is standby; Cataclasm Lignum Dalbergiae Odoriferae and Rhizoma Chuanxiong extract volatile oil, use dissolve with ethanol, and standby, residue decocts with water 2 hours, and decocting liquid filters, and is standby; Flos Carthami adds water temperature and soaks twice, and 2 hours for the first time, 1 hour for the second time, merge immersion, filter, standby; Above-mentioned each filtrate is merged, be condensed into relative density and be 1.30～1.32 thick paste, get 1 part of thick paste, 2.1 parts of Icing Sugar, 0.7 part in dextrin is mixed, alcohol granulation, drying sprays into volatile oil, and granulate is made capsule, promptly.
Embodiment 5:
Get Radix Paeoniae Rubra 2500g, Radix Salviae Miltiorrhizae 7000g, Lignum Dalbergiae Odoriferae 1800g, Flos Carthami 4000g, Rhizoma Chuanxiong 2500 is standby;
The above five tastes, Radix Paeoniae Rubra, Radix Salviae Miltiorrhizae decoct with water twice, and 2 hours for the first time, 1 hour for the second time, decocting liquid filtered, and merging filtrate is standby; Cataclasm Lignum Dalbergiae Odoriferae and Rhizoma Chuanxiong extract volatile oil, use dissolve with ethanol, and standby, residue decocts with water 2 hours, and decocting liquid filters, and is standby; Flos Carthami adds water temperature and soaks twice, and 3 hours for the first time, 2 hours for the second time, merge immersion, filter, standby; Above-mentioned each filtrate is merged, be condensed into relative density and be 1.25～1.40 thick paste, get 1 part of thick paste, 1 part of Icing Sugar, 1.5 parts in dextrin is mixed, alcohol granulation, drying sprays into volatile oil, and granulate is made electuary, promptly.
Embodiment 6:
Get Radix Paeoniae Rubra 4000g, Radix Salviae Miltiorrhizae 5000g, Lignum Dalbergiae Odoriferae 1800g, Flos Carthami 4000g, Rhizoma Chuanxiong 2500g is standby;
The above five tastes, Radix Paeoniae Rubra, Radix Salviae Miltiorrhizae decoct with water twice, and 5 hours for the first time, 2 hours for the second time, decocting liquid filtered, and merging filtrate is standby; Cataclasm Lignum Dalbergiae Odoriferae and Rhizoma Chuanxiong extract volatile oil, use dissolve with ethanol, and standby, residue decocts with water 3 hours, and decocting liquid filters, and is standby; Flos Carthami adds water temperature and soaked twice, the one 52 hour, and 3 hours for the second time, merge immersion, filter, standby; Above-mentioned each filtrate is merged, be condensed into relative density and be 1.30～1.32 thick paste, get 1 part of thick paste, 5 parts of Icing Sugar, 2 parts in dextrin is mixed, alcohol granulation, drying sprays into volatile oil, and granulate is made 1000 bags, promptly.
Claims (7)
1, the application of a kind of pharmaceutical composition in the low anti-medicine of the anti-aspirin of preparation, wherein this drug composition is by comprising that following crude drug makes: Radix Paeoniae Rubra 1500～6000g, Radix Salviae Miltiorrhizae 3000～10000g, Lignum Dalbergiae Odoriferae 1200～3500g, Flos Carthami 1500～6000g, Rhizoma Chuanxiong 1500～6000g.
2, application as claimed in claim 1, wherein this drug composition is by comprising that following crude drug makes: Radix Paeoniae Rubra 2500～4000g, Radix Salviae Miltiorrhizae 5000～7000g, Lignum Dalbergiae Odoriferae 1800～2500g, Flos Carthami 2500～4000g, Rhizoma Chuanxiong 2500～4000g.
3, application as claimed in claim 1, wherein this drug composition is by comprising that following crude drug makes: Radix Paeoniae Rubra 3354g, Radix Salviae Miltiorrhizae 6708g, Lignum Dalbergiae Odoriferae 2236g, Flos Carthami 3354g, Rhizoma Chuanxiong 3354g.
4,, it is characterized in that described compositions is tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, sucks agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, solution, ointment, plaster, spray, drop pill as any one described application in the claim 1～3.
5,, 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 1～3.
6, application as claimed in claim 5 is characterized in that said aspirin repellency cardiovascular and cerebrovascular disease is meant the invalid cardiovascular and cerebrovascular disease of use aspirin for treatment.
7, 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 200510013589 CN1872177A (en) | 2005-06-01 | 2005-06-01 | Application of medication of containing red sage root in resistant medication anti aspirin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510013589 CN1872177A (en) | 2005-06-01 | 2005-06-01 | Application of medication of containing red sage root in resistant medication anti aspirin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1872177A true CN1872177A (en) | 2006-12-06 |
Family
ID=37482886
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510013589 Pending CN1872177A (en) | 2005-06-01 | 2005-06-01 | Application of medication of containing red sage root in resistant medication anti aspirin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1872177A (en) |
-
2005
- 2005-06-01 CN CN 200510013589 patent/CN1872177A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1714859A (en) | Use of composition containing red-rooted salvia root in preparing medicine for treating anti-aspirin | |
| CN1745768A (en) | Use of medicine containing Milkvetch Root against aspirin | |
| CN1714836A (en) | Application of a kind of medicine in preparation of medicine for treating aspirin resistance | |
| CN1714837A (en) | Use of medicine containing haw in preparing medicine for treating anti-aspirin | |
| CN1872315A (en) | Application of medication of containing spatholobus stem in resistant medication anti aspirin | |
| CN1872317A (en) | Application of medication of containing red sage root in resistant medication anti aspirin | |
| CN1872177A (en) | Application of medication of containing red sage root in resistant medication anti aspirin | |
| CN1785271A (en) | Applicalsion of medicine containing salvia in anriaspirin medicine | |
| CN1872312A (en) | Application of medication of containing red sage root in resistant medication anti aspirin | |
| CN1723974A (en) | Application of medicine contg. ligusticum wallichii for preparing medicine of anti-aspirn-resistance | |
| CN1724046A (en) | Application of medicine contg. sealwort for preparing medicine of anti-aspirin-resistance | |
| CN1872316A (en) | Medication of containing astragalus root in application for treating resistant medication of aspirin | |
| CN1714822A (en) | Use of medicine containing ligusticum vallichii in preparing medicine for treating anti-aspirin | |
| CN1724026A (en) | Application of medicinal composition for preparing medicine for treating aspirin-resistance | |
| CN1723993A (en) | Application of medicine used in anti-aspirin-resistance medicine | |
| CN1745767A (en) | Use of depot containing Chuanxiong against aspirin | |
| CN1745764A (en) | Use of depot containing safflower against aspirin | |
| CN1872313A (en) | Medication of containing curcuma root in application for treating resistant medication of aspirin | |
| CN1872314A (en) | Application of medication of containing spatholobus stem in resistant medication anti aspirin | |
| CN1872176A (en) | Application of medication of containing red sage root in treating resistant medication of aspirin | |
| CN1872249A (en) | Application of medication of containing red peony root in resistant medication anti aspirin | |
| CN1714825A (en) | Use of composition in preparing medicine for treating anti-aspirin | |
| CN1714831A (en) | Use of medicinal composition in preparing medicine for treating anti aspirin | |
| CN1724035A (en) | Application of medicine contg. wilsonii used for anti aspirin resistance | |
| CN1872296A (en) | Application of medication composition in preparation for treating resistant medication of aspirin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |