小檗碱抗富含血小板血浆凝块收缩的作用及其机制

对小檗碱抗富含血小板血浆凝块收缩的作用进行研究，结果表明①小檗碱（ＢＲ）浓度为０．２９～０．８７ｍｍｏｌ·Ｌ－１时．有非常显著的抑制凝块收缩的作用。②ＢＲ浓度为０．５～２．０ｍｍｏｌ·Ｌ－１时．对血小板ｃＡＭＰ水平无影响．提示ＢＲ抑制凝块收缩的作用与ｃＡＭＰ无关．③当外加Ｃａ２＋浓度自０增加到１１．４７ｍｍｏｌ·Ｌ时，凝块收缩率随Ｃａ２＋内流增加而上升。同样条件下．ＢＲ浓度自０增加到０．６ｍｍｏｌ·Ｌ－１时．凝块收缩率显著或非常显著地下降。提示ＢＲ抑制凝块收缩的机制可能是由于直接抑制了Ｃａ２＋内流所致。     

慢性肺心病急性发作期t—PA,PAI活性的变化

测定３２例肺心病急性发作期组织型纤溶酶原激活物（ｔ－ＰＡ）、纤溶酶原激活物抑制物（ＰＡＩ）、纤溶酶原（Ｐｇ）及纤维蛋白原降解产物（ＦＤＰ）。结果表明，肺心病患者ｔ－ＰＡ、ＰＡＩ、Ｐｇ明显下降，而ＦＤＰ明显升高，表明肺心病急性发作期处于高凝、低纤溶状态。ｔ－ＰＡ、Ｐｇ的变化与ＰａＯ２呈明显正相关，而ＦＤＰ与ＰａＯ２呈明显负相关。     

参三七皂甙Rg1对实验性血栓形成的影响及其机制探讨

用大鼠动静脉血栓形成模型，研究参三七皂甙Ｒｇ１抗血栓作用。结果表明，参三七皂甙Ｒｇ１可明显降低实验性血栓形成，对大鼠血浆纤溶系统亦有明显作用，可升高血浆中组织纤溶酶原激活物（ｔＰＡ）活性和活性型ｔＰＡ百分比，降低组织纤溶酶原激活物抑制剂（ＰＡＩ）活性。同时利用培养大鼠血管内皮细胞实验，发现Ｒｇ１可以剂量依赖性提高血管内皮细胞一氧化氮（ＮＯ）释放。提示Ｒｇ１抗血栓作用与增强纤溶系统活性，促进血管内皮ＮＯ释放有关     

不稳定型心绞痛的药物治疗

不稳定型心绞痛（ＵＡＰ）是介于稳定型心绞痛和急性心肌梗塞（ＡＭＩ）之间的一组综合征,是一种具有潜在危险的急重症状态,易导致ＡＭＩ或猝死,对其必须采取及时有效的治疗。ＵＡＰ的药物治疗,除经典的硝酸酯类、β－受体拮抗剂、钙离子通道阻滞剂及抗血小板聚集药物外,现主张使用抗凝或溶栓治疗［１］。现将在治疗ＵＡＰ过程中,抗凝或溶栓疗效较好的部分药物综述如下。１　小剂量尿激酶、肝素联合应用 尿激酶是纤溶酶原激活剂。纤溶酶的快速纤溶作用可将新鲜血栓及其机化物溶解清除,使冠状动脉血流量增加而显示其对ＵＡＰ的高效作…     

青心酮对妊高征模型兔血浆纤溶相关因子和血小板功能的影响

采用缩窄腹主动脉下段的方法造成家兔实验性妊高征模型，并采用比浊法和发色底物分解产色法检测了注射青心酮（３，４－Ｄｉｈｙｄｒｏｘｙａｃｅｔｏｐｈｅｎｏｎｅ，ＤＨＡＰ）的模型兔血小板聚集性（ＰＡｇ）、血浆组织型纤溶酶原激活物（ｔＰＡ）及其抑制物（ＰＡＩ－１）活性。结果显示ＤＨＡＰ可显著降低模型兔ＰＡｇ；对血浆ＰＡＩ－１活性的抑制作用明显强于对ｔＰＡ的作用，因此，ＤＨＡＰ对血小板功能和血纤溶活性的作用可能是其改善子宫胎盘血循环的作用机制之一。     

慢性肾衰病人胰岛素和纤维蛋白溶解活性变化的观察

为探讨慢性肾衰（ＣＲＦ）病人胰岛素代谢异常和纤溶活性降低间的内在关系,采用邻苯胺法、放射免疫法和发色物显色法检测ＣＲＦ病人空腹血糖（ＦＢＳ）、血清Ｃ－肽（Ｃ－Ｐ）、胰岛素（ＩＮＳ）、纤溶酶原活性抑制物（ＰＡＩ）和组织型纤溶酶原激活剂９ｔ－ＰＡ）的变化。结果表明,ＣＲＦ病人ＦＢＳ、Ｃ－Ｐ、ＩＮＳ－ＰＡＩ均明显增高,而ｔ－ＰＡ明显降低。ＩＮＳ水平与ＦＢＳ、Ｃ－Ｐ及ＰＡＩ呈直线正相关。结论：ＣＲＦ病人Ｉ     

蚯蚓溶栓酶制剂的致突变研究

蚯蚓溶栓酶制剂的致突变研究山西医学院（０３０００１）孙天佑，谭佩娇，刘志艳，白桂花蚯蚓溶栓酶制剂是由双胸蚓组织中提取制备的多组分酶蛋白，含有多种纤维蛋白溶解酶及纤溶酶原激活物，具有抗凝、促纤溶作用，改善血液流变学功效（降低全血、血浆粘度及血小板聚集性...     

蝎毒活性肽对内皮细胞释放t-PA和PAI的影响

血管内皮细胞 (ｖａｓｃｕｌａｒｅｎｄｏｔｈｅｌｉａｌｃｅｌｌｓ,ＶＥＣ)能合成和分泌组织型纤溶酶原激活物 (ｔｉｓｓｕｅｐｌａｓｍｉｎｏｇｅｎａｃｔｉｖａｔｏｒ ,ｔ ＰＡ) ,使纤溶酶原激活为纤溶酶 ,促进局部血栓溶解 ,ＶＥＣ还可分泌纤溶酶原激活物抑制剂 ( ｐｌａｓｍｉｎｏｇｅｎａｃｔｉｖａｔｏｒｉｎ ｈｉｂｉｔｏｒ,ＰＡＩ) ,当机体处于正常情况下ｔ ＰＡ与ＰＡＩ保持动态平衡 ,这对于维持血液纤溶和凝血系统的稳定至关重要 ,因此 ,血管内皮细胞在调节血栓的形成和溶解方面具有十分重要的作用。全蝎是名贵中药材 ,有祛风、…     

糖尿病视网膜病变与血浆纤溶酶原激活物抑制物-1活性水平的关系

为探讨血浆纤溶酶原激活物抑制物 - 1与糖尿病视网膜病变的关系。本文选取 12 6例糖尿病视网膜病变患者 ,6 6例其它眼病患者 (非血管性疾病 ) ,10 0例健康自愿者 ,用发色底物法测定其血浆纤溶酶原激活物抑制物 - 1活性。12 6例患者的血浆纤溶酶激活物抑制物 -活性显著高于其它眼病患者和正常人群。糖尿病视网膜病变与血液的高凝状态密切相关。血浆纤溶酶原激活物抑制物 - 1(Ｐｌａｓｍｉｎｏｇｅｎａｃｔｉｖａｌｏｒｉｎｈｉｂｉｔｏｒ- 1,以下简称ＰＡＩ- 1)在血纤溶活性的调节过程中发挥重要作用。近期研究结果表明 :ＰＡＩ - 1活性升高…     

巴曲抗栓酶临床应用进展

巴曲抗栓酶是通过生物工程ＤＮＡ合成的单一酶,选择性地作用于凝血因子ＩＡ２链,释放血纤维蛋白肽Ａ,使纤维蛋白分解,并促使组织纤溶酶原激活物（ＴＰＡ）释放和活性增加．促进纤维蛋白溶酶生成,减少纤溶酶原激活抑制物（ＰＡＩ）和抗纤溶酶,促使血栓溶解,防止血栓继续生成,根据巴曲抗栓酶的上述药理作用,临床应用日趋广泛,现综述如下。１缺血性脑血管疾病［１］ 巴曲抗栓酶具有分解凝血因子Ｉ（ＦＧ）抑制血栓形成、诱发ＴＰＡ释放、增强ＩＰＡ的作用,促进纤维蛋白溶酶的生成,减少纤维蛋白溶酶抑制物（ａ２—ＰＩ）和 ＰＡＩ的…     

Combining antiplatelet and thrombolytic therapies for stroke

Pharmacological therapy for acute nonhaemorrhagic stroke has become a reality over the last 5 years. Mechanistically, both thrombolytic (tissue plasminogen activator and urokinase) and antiplatelet (aspirin) monotherapy have demonstrated efficacy. However, unintended actions limit the extent of clinical improvement in each circumstance. For example, in addition to excess bleeding, tissue plasminogen activator therapy has been associated with complement activation, neuronal toxicity and laminin degradation, while aspirin may reduce nitric oxide synthase activity and cerebral blood flow. Attention is now directed toward improving the therapeutic index for each class of agents. Generally, while thrombolytic therapy is focused on developing agents with greater fibrin specificity and safety (that is, a reduction in intracranial haemorrhage rate), the development of antiplatelet agents is primarily focused on achieving greater potency. The latter is being investigated by combining agents with different mechanisms (aspirin and dipyridamole, aspirin and clopidogrel) as well as agents designed to block the glycoprotein IIb/IIIa receptor, the final common pathway for platelet aggregation. Thus, combination therapy using both thrombolytic and antiplatelet agents will further attempt to improve the therapeutic index by increasing potency and improving the safety profile. Anecdotal case studies support the merits of this approach and are consistent with the data reported for myocardial ischaemia and interventional strategies. It is anticipated that drug therapy directed at both thrombolytic and antiplatelet targets will ultimately result in a widened therapeutic window that will allow acute stroke therapy to be administrated to a much greater number of patients than is currently possible.     

Combining antiplatelet and thrombolytic therapies for stroke

Pharmacological therapy for acute nonhaemorrhagic stroke has become a reality over the last 5 years. Mechanistically, both thrombolytic (tissue plasminogen activator and urokinase) and antiplatelet (aspirin) monotherapy have demonstrated efficacy. However, unintended actions limit the extent of clinical improvement in each circumstance. For example, in addition to excess bleeding, tissue plasminogen activator therapy has been associated with complement activation, neuronal toxicity and laminin degradation, while aspirin may reduce nitric oxide synthase activity and cerebral blood flow. Attention is now directed toward improving the therapeutic index for each class of agents. Generally, while thrombolytic therapy is focused on developing agents with greater fibrin specificity and safety (that is, a reduction in intracranial haemorrhage rate), the development of antiplatelet agents is primarily focused on achieving greater potency. The latter is being investigated by combining agents with different mechanisms (aspirin and dipyridamole, aspirin and clopidogrel) as well as agents designed to block the glycoprotein IIb/IIIa receptor, the final common pathway for platelet aggregation. Thus, combination therapy using both thrombolytic and antiplatelet agents will further attempt to improve the therapeutic index by increasing potency and improving the safety profile. Anecdotal case studies support the merits of this approach and are consistent with the data reported for myocardial ischaemia and interventional strategies. It is anticipated that drug therapy directed at both thrombolytic and antiplatelet targets will ultimately result in a widened therapeutic window that will allow acute stroke therapy to be administrated to a much greater number of patients than is currently possible.     

Protective effect of Foeniculum vulgare essential oil and anethole in an experimental model of thrombosis.

In a previous screening work, Foeniculum vulgare essential oil emerged from a pool of 24 essential oils for its antiplatelet properties and its ability to destabilize the retraction of the coagulum. In the present work the main component of the oil, anethole, tested in guinea pig plasma was as potent as fennel oil in inhibiting arachidonic acid-, collagen-, ADP- and U46619-induced aggregation (IC(50) from 4 to 147 microg ml(-1)). It also prevented thrombin-induced clot retraction at concentrations similar to fennel oil. The essential oil and anethole, tested in rat aorta with or without endothelium, displayed comparable NO-independent vasorelaxant activity at antiplatelet concentrations which have been proved to be free from cytotoxic effects in vitro. In vivo, both F. vulgare essential oil and anethole orally administered in a subacute treatment to mice (30 mg kg(-1)day(-1) for 5 days) showed significant antithrombotic activity preventing the paralysis induced by collagen-epinephrine intravenous injection (70% and 83% protection, respectively). At the antithrombotic dosage they were free from prohemorrhagic side effect at variance with acetylsalicylic acid used as reference drug. Furthermore, both F. vulgare essential oil and anethole (100 mg kg(-1) oral administration) provided significant protection toward ethanol induced gastric lesions in rats. In conclusion, these results demonstrate for F. vulgare essential oil, and its main component anethole, a safe antithrombotic activity that seems due to their broad spectrum antiplatelet activity, clot destabilizing effect and vasorelaxant action.     

Thrombolytic therapy for acute myocardial infarction. A review .

In the past 10 years, thrombolytics have become standard therapy for acute myocardial infarction. Although the ability of streptokinase to lyse clot was first recognised in the 1930s, thrombolytic therapy was not used to treat acute myocardial infarction until the early 1980s, when the importance of thrombosis in the pathogenesis of acute infarction was fully recognised. In addition to streptokinase and urokinase, recombinant human tissue plasminogen activator (tPA) and anistreplase were developed and widely used in the 1980s. Saruplase (prourokinase) and BM-06022 (recombinant plasminogen activator) have also undergone human clinical studies. All of these agents are effective at achieving clot lysis and coronary patency. Large, randomised clinical trials have demonstrated that thrombolytic therapy reduces mortality in patients with ST elevation treated within the first 6 to 12 hours of acute infarction, with an approximately 0.5% risk of intracranial haemorrhage. Recent data have more clearly identified which patients benefit from thrombolytic therapy. Efforts have been made to improve the speed of reperfusion, decrease reocclusion, simplify administration and reduce adverse effects. The characteristics of fibrin specificity and more rapid clot lysis with tissue plasminogen activator have not yet been translated into overall clinical benefit compared with the less expensive streptokinase. The lack of close association of improved early patency and improved global left ventricular function with improved survival challenges the very paradigm which led to the use of thrombolytic therapy for acute myocardial infarction. The need for development of additional methods for evaluation of new thrombolytic agents is evident.     

Antiplatelet and antithrombotic activities of essential oil from wild Ocotea quixos (Lam.) Kosterm. (Lauraceae) calices from Amazonian Ecuador.

Ocotea quixos essential oil was shown to possess significant inhibitory activity of platelet aggregation and clot retraction in rodent plasma. This study is aimed at fully characterizing the antiplatelet activity of the whole essential oil and its main components trans-cinnamaldehyde and methyl cinnamate also in human plasma, at investigating the mechanism underlying such activity and at evaluating the potential antithrombotic activity of subacute treatment of mice with Ocotea essential oil. In vitro Ocotea essential oil and trans-cinnamaldehyde inhibited arachidonic acid-, U46619-, ADP-, phorbol12-myristate13-alcetate-, collagen-induced platelet aggregation and thrombin-induced clot retraction in human and rodent plasma; Ocotea oil and trans-cinnamaldehyde competitively antagonized contractions induced by thromboxane A2 receptor agonist U46619 in rat isolated aortic ring (K(B) = 18 and 3.2 microg ml(-1), respectively). In vivo Ocotea oil, orally administered in a subacute treatment (30-100 mg kg(-1) day(-1) for 5 days) to mice, prevented acute thrombosis induced by collagen-epinephrine intravenous injection. This antithrombotic activity was not accompanied by pro-haemorragic side effect, as detected by the inactivity in bleeding test, thus showing a favourable safety profile compared to the conventional antiplatelet agent, acetylsalicylic acid. Present findings indicate that Ocotea essential oil possesses potent and safe antithrombotic activity attributable to its antiplatelet and vasorelaxant effects. The main constituent trans-cinnamaldehyde seems to be the primary responsible for this activity through a putative mechanism involving the inhibition of thromboxane A2 receptors.     

Selective fibrinolytic activity of recombinant non-glycosylated human pro-urokinase (single-chain urokinase-type plasminogen activator) from bacteria

To assess their therapeutic value recombinant non-glycosylated human pro-urokinase (cPUK) and recombinant non-glycosylated human low molecular mass urokinase (cLUK) both obtained from genetically transformed bacteria were compared with respect to their thrombolytic efficacy and their potential to induce systemic plasminogen activation which impairs the coagulation system. The investigations were performed in in vitro and in vivo test systems. In vitro, both substances significantly and concentration-dependently lysed radiolabelled human thrombi in rotating loops of tubes (Chandler-loops) with equivalent efficacy. Fibrinolytic activity of cLUK was accompanied by a decrease in alpha 2-antiplasmin, plasminogen and fibrinogen. In contrast, cPUK did not change the plasminogen and fibrinogen levels and induced a substantially smaller decline in alpha 2-antiplasmin than cLUK. In the lysis of pulmonary embolized radiolabelled blood clots in anesthetized rabbits cPUK and cLUK dose-dependently exerted significant effects of similar extent. Whereas cLUK significantly decreased plasma levels of alpha 2-antiplasmin, plasminogen and fibrinogen, cPUK caused only a marginal decrease in alpha 2-antiplasmin and left the plasminogen and fibrinogen levels unchanged. The results indicate that cPUK exerts fibrinolytic efficacy without systemic plasminogen activation and breakdown of fibrinogen. Therefore, cPUK might be expected to be a more specific and safer thrombolytic agent than urokinase and other traditional fibrinolytics.     

Plasminogen activation-based thrombolysis for ischaemic stroke: the diversity of targets may demand new approaches

The plasminogen activating enzyme system has been exploited and harnessed for therapeutic, mainly thrombolytic benefit for many years. While plasminogen activator-based thrombolysis turned out to be a resounding success, it has become apparent that the "plasminogen activating system" per se is not only designed to simply remove fibrin and some other matrix proteins. Indeed, the plasminogen activators and the plasminogen activator inhibitors have important effects on cell signalling through both proteolytic and non-proteolytic means and can promote unwanted side effects, particularly in the brain. Tissue type plasminogen activator (t-PA) was heralded as a fibrin-selective plasminogen activator and subjected to clinical development in the early 1980's initially for the treatment of patients with myocardial infarction. t-PA was given FDA approval in the mid 1990's for use in ischaemic stroke patients, but it could only be administered within a short 3h window post- stroke as later use was associated with an increased risk of intracerebral haemorrhage. Hence only a small percentage of these patients were eligible for thrombolysis to restore blood flow to the brain. Since t-PA-mediated plasmin generation is not only impacting on the cerebral blood clot, extending the therapeutic time window for thrombolysis is not a simple task. The ultimate success will depend on how well the future generation of thrombolytic agents promote efficacious removal of a fibrin clot without promoting collateral damage particularly in the brain.     

Thrombolytics: drug interactions of clinical significance.

Thrombolytic agents activate plasminogen and induce a systemic fibrinolytic and anticoagulant state. Interaction of fibrinolysis with coagulation and platelet aggregation might be important for synergistic interactions with other antiplatelet or anticoagulant drugs. Thrombolytic agents are most often used in patients with coexisting cardiovascular medication, including various antihypertensives, beta-blocking agents, nitrates and aspirin (acetylsalicylic acid). In acute coronary syndromes, anticoagulants and antiplatelet compounds such as clopidogrel or glycoprotein IIb/IIIa receptor antagonists might be given. Inducers or inhibitors of the cytochrome P450 system are not reported to affect the pharmacokinetics of any thrombolytic agent. Since the elimination of the recombinant plasminogen activators saruplase and alteplase is dependent on liver blood flow, drugs affecting hepatic blood flow could theoretically affect the hepatic clearance of these agents. In fact, a reduction in thrombolytic activity has only been demonstrated for alteplase with nitroglycerin (glyceryl trinitrate). Pharmacodynamic interactions occur more often. The additive and beneficial effect of aspirin as concomitant therapy to thrombolysis has been demonstrated without excessive bleeding rates. No data are available on the interaction between ticlopidine or clopidogrel and thrombolytic agents in humans. Anticoagulation by heparin concomitantly with thrombolysis improves the patency rate of the occluded coronary vessel, but bleeding complications are seen more frequently. Although there has been no controlled study on the interaction between oral anticoagulants and thrombolytic agents, patients with myocardial infarction who were taking an oral anticoagulant before admission seem to be at higher risk for intracranial haemorrhage during thrombolytic therapy. Currently, no recommendations can be given for possible dose adjustment of thrombolytic therapy in patients receiving antiplatelet comedication. For comedication with heparin, it has been advised to monitor activated partial thromboplastin time frequently and to avoid values >2.5-fold normal. Patients receiving thrombolytic treatment should be monitored frequently for bleeding and the physician should be aware of any comedication exerting antiplatelet (e.g. aspirin, clopidogrel and ticlopidine) or anticoagulant (e.g. warfarin) effects.     

Drug Treatment of Acute Ischemic Stroke

Acute ischemic stroke (AIS) is the fourth leading cause of death and the leading cause of adult disability in the USA. AIS most commonly occurs when a blood vessel is obstructed leading to irreversible brain injury and subsequent focal neurologic deficits. Drug treatment of AIS involves intravenous thrombolysis with alteplase (recombinant tissue plasminogen activator [rtPA]). Intravenous alteplase promotes thrombolysis by hydrolyzing plasminogen to form the proteolytic enzyme plasmin. Plasmin targets the blood clot with limited systemic thrombolytic effects. Alteplase must be administered within a short time window to appropriate patients to optimize its therapeutic efficacy. Recent trials have shown this time window may be extended from 3 to 4.5 hours in select patients. Other acute supportive interventions for AIS include maintaining normoglycemia, euthermia and treating severe hypertension. Urgent anticoagulation for AIS has generally not shown benefits that exceed the hemorrhage risks in the acute setting. Urgent antiplatelet use for AIS has limited benefits and should only promptly be initiated if alteplase was not administered, or after 24 hours if alteplase was administered. The majority of AIS patients do not receive thrombolytic therapy due to late arrival to emergency departments and currently there is a paucity of acute interventions for them. Ongoing clinical trials may lead to further medical breakthroughs to limit the damage inflicted by this devastating disease.