Safe Thrombolytic Agent Research Articles

Thrombogenic and Inflammatory Reactions to Biomaterials in Medical Devices.

Blood-contacting medical devices of different biomaterials are often used to treat various cardiovascular diseases. Thrombus formation is a common cause of failure of cardiovascular devices. Currently, there are no clinically available biomaterials that can totally inhibit thrombosis under the more challenging environments (e.g., low flow in the venous system). Although some biomaterials reduce protein adsorption or cell adhesion, the issue of biomaterial associated with thrombosis and inflammation still exists. To better understand how to develop more thrombosis-resistant medical devices, it is essential to understand the biology and mechano-transduction of thrombus nucleation and progression. In this review, we will compare the mechanisms of thrombus development and progression in the arterial and venous systems. We will address various aspects of thrombosis, starting with biology of thrombosis, mathematical modeling to integrate the mechanism of thrombosis, and thrombus formation on medical devices. Prevention of these problems requires a multifaceted approach that involves more effective and safer thrombolytic agents but more importantly the development of novel thrombosis-resistant biomaterials mimicking the biological characteristics of the endothelium and extracellular matrix tissues that also ameliorate the development and the progression of chronic inflammation as part of the processes associated with the detrimental generation of late thrombosis and neo-atherosclerosis. Until such developments occur, engineers and clinicians must work together to develop devices that require minimal anticoagulants and thrombolytics to mitigate thrombosis and inflammation without causing serious bleeding side effects.

SMTP-7, a new thrombolytic agent, decreases hemorrhagic transformation after transient middle cerebral artery occlusion under warfarin anticoagulation in mice

Stachybotrys microspora triprenyl phenol-7 (SMTP-7) is a new thrombolytic agent that exhibits anti-inflammatory effects. We previously demonstrated that the hemorrhagic transformation was fewer with SMTP-7 than with recombinant tissue plasminogen activator (rt-PA) following ischemia-reperfusion in animal models. We hypothesized that SMTP-7 may decrease hemorrhagic transformation after ischemia-reperfusion under the warfarin-treated condition. Transient middle cerebral artery occlusion (MCAO) was induced for 3h using an intraluminal suture in warfarin-treated mice to produce hemorrhagic transformation. Warfarin was administered orally for a 24-h feeding period before MCAO through bottled drinking water (5mg in 375ml tap water), resulting in a mean INR of 5.6±0.2. Mice were treated with vehicle, rt-PA, or SMTP-7 5h before reperfusion. Twenty percent of vehicle-treated and 50.0% of rt-PA-treated mice died 24h after reperfusion, while all SMTP-7-treated mice survived. Hemorrhagic severity in SMTP-7-treated mice was significantly lower than that in rt-PA-treated mice. Neurological deficit was significantly lower in SMTP-7-treated mice than vehicle- and rt-PA-treated mice. These results indicate that SMTP-7 decreases mortality, hemorrhagic transformation, and neurological deficits, and can be a safe thrombolytic agent following MCAO under the warfarin-treated condition.

Identifying needs and opportunities for advancing translational research in cardiovascular disease

In Western Europe, as in the USA, mortality of cardiovascular disease (CVD) has declined significantly in the last 30 years. Life expectancy for patients with coronary heart disease in the USA increased on average by 3 years between 1970 and 2000.1 Several epidemiological analyses support this positive evolution. An analysis of the underlying causes identifies improvements in quality of care and treatment as a major cause, accounting from 50 up to 75% of the success depending on the study samples, the remainder being accounted for by changes in lifestyle and prevention.2 Research and development in several areas of CVD have contributed to this success. In acute coronary events, the identification and development of efficient and safe thrombolytic agents followed by percutaneous coronary intervention with stent implantation were milestones in the reduction of acute mortality and salvage of myocardium.3–5 Statins have brought a major advance in preventing the progression of atherosclerotic disease and have been recognized for their wide mode of action.6 In heart failure (HF), beta-blockers and ACE-inhibitors have increased life expectancy by a leap.7 Some of these improvements have been the result of a classic bench-to-bedside development of a targeted treatment, such as the statins, others have known a more serendipitous development, such as beta-blockers. In other areas, progress in terms of treatment has been less spectacular and fraught with difficulties. Development of antiarrhythmic agents received a large boost from basic insights into cardiac ion channel structure and function, but translation into pharmacology unveiled unexpected pro-arrhythmia risks of some of the highly specific ion channel blockers in class III.8 Automatic defibrillators have taken an important role in the treatment of life-threatening arrhythmias and save lives, but are not without burden and come at a high cost.9 This latter example is …

Toward Safer Thrombolytic Agents in Stroke: Molecular Requirements for NMDA Receptor-Mediated Neurotoxicity

Current thrombolytic therapy for acute ischemic stroke with tissue-type plasminogen activator (tPA) has clear global benefits. Nevertheless, evidences argue that in addition to its prohemorrhagic effect, tPA might enhance excitotoxic necrosis. In the brain parenchyma, tPA, by binding to and then cleaving the amino-terminal domain (ATD) of the NR1 subunit of N-methyl-D-aspartate (NMDA) glutamate receptors, increases calcium influx to toxic levels. We show here that tPA binds the ATD of the NR1 subunit by a two-sites system (K(D)=24 nmol/L). Although tenecteplase (TNK) and reteplase also display two-sites binding profiles, the catalytically inactive mutant TNKS478A displays a one-site binding profile and desmoteplase (DSPA), a kringle 2 (K2) domain-free plasminogen activator derived from vampire bat, does not interact with NR1. Moreover, we show that in contrast to tPA, DSPA does not promote excitotoxicity. These findings, together with three-dimensional (3D) modeling, show that a critical step for interaction of tPA with NR1 is the binding of its K2 domain, followed by the binding of its catalytic domain, which in turn cleaves the NR1 subunit at its ATD, leading to a subsequent potentiation of NMDA-induced calcium influx and neurotoxicity. This could help design safer new generation thrombolytic agents for stroke treatment.

Natto and Its Active Ingredient Nattokinase: A Potent and Safe Thrombolytic Agent

Natto and Its Active Ingredient Nattokinase: A Potent and Safe Thrombolytic Agent

New developments in thrombolytic therapy

Summary Large efforts have been undertaken to develop more effective and safer thrombolytic agents than those currently used in clinical practice. In addition, the value of adjunctive agents influencing thrombotic and thrombolytic processes could be shown and newer agents are under active investigation. This review focuses on theoretical and practical aspects of optimizing thrombolytic therapy and mainly on genetically engineered, third generation plasminogen activators. Optimized thrombolytic therapy may make this form of therapy available to patients that are currently considered ineligible and it will lead to earlier, more complete reperfusion of infarct-related coronary arteries. The benefits and risks of optimized thrombolytic regimens relative to mechanical reperfusion strategies will have to be constantly reassessed as both forms of treatment develop.

The future of thrombolysis in the treatment of acute myocardial infarction.

The ability of thrombolytic therapy to lower mortality in patients with acute myocardial infarction was first demonstrated in 1986 by the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico. In the ensuing 10 years, large efforts have been undertaken to develop more effective and safer thrombolytic agents. In addition, the value of adjunctive agents influencing thrombotic and thrombolytic processes was demonstrated, and newer agents are under active investigation. This review focuses on theoretical and practical aspects of optimizing thrombolytic therapy and on genetically engineered third generation plasminogen activators. Optimized thrombolytic therapy may make this form of therapy available to patients who are currently considered ineligible, and it will lead to earlier, more complete reperfusion of infarct-related coronary arteries. The benefits and risks of optimized thrombolytic regimens relative to those of mechanical reperfusion strategies will require constant reassessment while both forms of treatment develop.

Saruplase in Myocardial Infarction.

Saruplase is an unglucosylated single-chain recombinant urokinase-type plasminogen activator. Dose finding studies in patients with acute myocardial infarction indicated that a dose of 80 mg of saruplase, given as a bolus of 20 mg and iv infusion of 60 mg in one hour, led to excellent patency figures.Saruplase is most effective when combined with a bolus of 5000 IU heparin followed by an iv heparin infusion for at least 24 hours.When saruplase is compared to other thrombolytic agents (streptokinase, alteplase, urokinase), it becomes apparent that its profile is excellent. Early patency rates are at least comparable to alteplase. Further reocclusion rates of saruplase after one day are lower than those of streptokinase and alteplase. Patency rates 24-72 hours after start of medication are comparable between saruplase and urokinase.The large database in over 6000 patients shows that saruplase, in comparison to the other thrombolytic agents, is safe. Its bleeding complication rate is significantly lower than streptokinase, and a trend to lower in-hospital mortality is observed when compared to urokinase.Summarizing, when comparing to the presently available thrombolytic agents, saruplase is a fast acting, effective and safe thrombolytic agent.

Tissue plasminogen activator: an evaluation of clinical efficacy in acute myocardial infarction.

Recombinant tissue plasminogen activator (t-PA) is a synthetic fibrinolytic protein which activates plasminogen or converts plasminogen to plasmin specifically in the presence of fibrin. With its "clot-selectivity", t-PA is capable of lysing clots without having a significant effect on circulating plasminogen. In contrast, activation by streptokinase and urokinase is non-specific and affects circulating as well as thrombus plasminogen. These agents, therefore, have a greater potential to induce bleeding than does t-PA. Plasma levels of t-PA following intravenous administration are generally proportional to the dose, but there can be significant interpatient variation. The drug is eliminated primarily by hepatic metabolism and is then excreted in the urine. Half-life of circulating t-PA ranges from 2-8 minutes. Most clinical trials of t-PA have evaluated its use in acute myocardial infarction. Indeed, its current indication is for thrombolysis in evolving MI. Short-term benefits of t-PA administration include a prompt reperfusion and restoration of coronary artery patency in patients with total coronary artery occlusion. The degree to which the heart benefits from thrombolysis is unknown, but electrocardiographic changes, changes in cardiac enzymes and alterations in the pattern of chest pain indicate that rapid reperfusion may limit the size of the infarct. Overall, t-PA appears to be a relatively safe thrombolytic agent. Bleeding is the most significant adverse effect reported with t-PA administration. In most cases, however, bleeding has been minor. Other reported adverse effects include reperfusion arrhythmias, bradycardia, and chest pain. Allergic reactions were not observed in clinical trials.

Achievement of coronary artery patency by use of anisoylated plasminogen streptokinase activator complex in acute myocardial infarction.

Anisoylated plasminogen streptokinase activator complex (APSAC) is a recently developed thrombolytic agent with high fibrin-binding potential and sustained release pharmacokinetics (plasma half-life 70 minutes). Following studies of its intracoronary use, the efficacy was examined, in an open study using coronary angiography, of a single bolus dose of 30U given intravenously to 94 patients within 6 hours (mean 2.97 hours) from the onset of symptoms of myocardial infarction. After thrombolytic therapy, patency of the left anterior descending artery was demonstrated in 32 of 42 patients with anterior infarctions (76%), and in 12 of 13 patients with circumflex (92%) and 28 of 36 with right coronary artery infarcts (78%) in the inferior infarction group. The overall incidence of reocclusion was 24%, which occurred within the first 12 days after hospitalisation. Successful thrombolysis was associated with rapid resolution of the acute ST segment change, and an early peak of creatine phosphokinase (CK) compared with patients whose vessels remained occluded. No major systemic bleeding complications were experienced. Single dose intravenous APSAC appears to be a highly effective and relatively safe thrombolytic agent which has the major advantage over other such agents of easier administration. This makes it suitable for use in district hospitals and in the community, as well as in specialised cardiac centres.