Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Unfractionated heparin has enjoyed the sole anticoagulant status for almost half a century. Besides an effective anticoagulant, this drug has been used in several additional indications. Despite the development of newer anticoagulant drugs, unfractionated heparin has remained the drug of choice for surgical anticoagulation and interventional cardiology. In the area of hematology and transfusion medicine, unfractionated heparin has continued to play a major role as an anticoagulant drug. The development of low-molecular-weight heparins (LMWHs) represents a refinement for the use of heparin. These drugs represent a class of depolymerized heparin derivatives with a distinct pharmacologic profile that is largely determined by their composition. These drugs produce their major effects by combining with antithrombin and exerting antithrombin and anti-Xa inhibition. In addition, the LMWHs also increase non-antithrombin-dependent effects such as TFPI release, modulation of adhesion molecules, and release of profibrinolytic and antithrombotic mediators from the blood vessels. The cumulative effects of each of the different LMWHs differ and each product exhibits a distinct profile. Initially these agents were developed for the prophylaxis of postsurgical deep-vein thrombosis. However, at this time these drugs are used not only for prophylaxis, but also for the treatment of thrombotic disorders of both the venous and arterial type. To a large extent, the LMWHs have replaced unfractionated heparin in most subcutaneous indications. With the use of these refined heparins, outpatient anticoagulant management has gone through a dramatic evolution. For the first time, patients with thrombotic disorders can be treated in an outpatient setting. Thus, the introduction of LMWHs represents a major advance in improving the use of heparin. The development of the oral formulation of heparin and LMWHs also provides an important area that may impact on the use of heparin and LMWHs. The increased awareness of heparin-induced thrombocytopenia has necessitated the development of newer methods to identify patients at risk of developing this catastrophic syndrome. Furthermore, a strong interest has developed in alternate drugs or the management of patients with this syndrome. Despite the development of alternate anticoagulants that are mostly antithrombin derived (hirudins, hirulog), these agents have failed to provide similar clinical outcome as heparin in many indications. However, antithrombin drugs are useful in the anticoagulant management of heparin-compromised patients. The FDA has approved a recombinant hirudin (Refludan) and a synthetic antithrombin agent, argatroban (Novastan), for this indication. The development of synthetic heparin pentasaccharide and anti-Xa agents may have an impact on the prophylaxis of thrombotic disorders. However, these monotherapeutic agents do not mimic the polytherapeutic actions of heparin. Furthermore, these agents do not inhibit thrombin. Heparin and LMWHs are capable of inhibiting not only factor Xa and thrombin, but other serine proteases in the coagulation network. The only way the newer drugs can mimic the actions of heparin is in combination modalities (polytherapeutic approaches). It has been suggested that newer antiplatelet drugs also exhibit anticoagulant actions. While these drugs may exhibit weak effects on thrombin generation, none of the currently available antiplatelet drugs exhibit any degree of antithrombin actions. It is likely that heparins synergize or augment the effects of the new antiplatelet drugs. Currently, combination approaches are used to anticoagulate patients in these studies. The dosage of heparins has been arbitrarily reduced. This may not be an optimal procedure. Additional clinical studies are needed to study these combinations where the alterations of these drugs are compared. Such combinations will require newer monitoring approaches. The development of oral thrombin agents, GP IIb
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PMID:An update on heparins at the beginning of the new millennium. 1101 2

When endothelial cells are exposed to thrombin, they become perturbed and acquire thrombogenic properties. Argatroban is an arginine derivative, synthetic small molecule that binds to the active site of thrombin and inhibits its catalytic activity. Therefore, the effects of argatroban on endothelial cells, which had been injured by thrombin, were investigated. The established endothelial cell line, TKM-33, which had been cloned from human umbilical vein endothelial cells, was used. Endothelial cells produce plasminogen activator (PA) to prevent thrombosis and maintain the blood flow. When the endothelial cells were injured by thrombin, secretion of plasminogen activator inhibitor-1 (PAI-1) increased and then the PA activity proportionally decreased. The treatment of endothelial cells with argatroban after thrombin injury did not restore their reduced PA activity. However, the treatment of endothelial cells with argatroban prior to thrombin injury resulted in inhibiting the induction of PAI-1 secretion. Thus, pretreatment of endothelial cells with argatroban suppresses the inhibition of their PA activity by thrombin. Since the effect of thrombolytic agent may be modified by the fibrinolytic factors produced by the endothelial cells, the activity of staphylokinase (SAK) was measured in the presence of endothelial cells that had been injured by thrombin. SAK is a newly developed thrombolytic agent. SAK activity in the presence of injured endothelial cells by thrombin was lower than that in the presence of endothelial cells without thrombin injury. However, treatment of endothelial cells with argatroban prior to thrombin injury revealed higher SAK activity than that after thrombin injury. These findings indicate that argatroban pretreatment prevents thrombin injury of endothelial cells, which may then maintain their physiological function.
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PMID:The effect of argatroban on injured endothelial cells by thrombin. 1108 83

Argatroban is a direct thrombin inhibitor synthesised to bind to the catalytic site of the thrombin molecule. It binds rapidly and reversibly to both clot-bound and soluble thrombin. The relatively short elimination half-life of argatroban (39 to 51 minutes) and its reversible binding allow rapid achievement of therapeutic effect on initiation of therapy and rapid restoration of normal haemostasis upon cessation of therapy. Argatroban produces a predictable dose response that is well correlated with changes in anticoagulant parameters. Argatroban, given to patients with heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia with thrombosis (HITTS) in a large scale, nonrandomised, prospective trial, reduced a combined end-point of morbidity and mortality when compared with historical controls. Argatroban was well tolerated in clinical trials of patients with HIT and caused no increase in bleeding risk compared with historical controls.
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PMID:Argatroban. 1132 81

The disturbance of microcirculation following cerebral ischemia leads to an enlargement of cerebral infarct volume. Endogenous thrombin may play a role in this disturbance of microcirculation following cerebral ischemia. Therefore, the inhibition of thrombin may improve neurodegeneration and the accumulation of cerebral edema following cerebral ischemia in gerbils. The effects of thrombin inhibitor (argatroban) on cerebral ischemia were investigated in comparison with thromboxane A2 synthase inhibitor (ozagrel) and cyclooxygenase inhibitor (aspirin) following bilateral common carotid artery occlusion and reperfusion (CCA:O/R) in male Mongolian gerbils. This study consisted of three experiments: (1) morbidity and survival ratio (n=40 for each), (2) histopathology (n=12 for each), and (3) mean arterial blood pressure, local cerebral blood flow (CBF), and cerebral specific gravity (n=8 for each). Argatroban treatment improved survival ratio and stroke index, and decreased ischemically injured cell numbers in cortex and hippocampus and cerebral edema in cortex compared with aspirin and saline, in concert with the fast recovery of local CBF without reactive hyperemia following bilateral CCA:O/R. Ozagrel treatment also improved those factors compared with saline, in concert with the fast recovery of local CBF with reactive hyperemia. Aspirin treatment improved survival ratio and stroke index, and decreased ischemically injured cell numbers in cortex. Thrombin inhibition with argatroban decreases neurodegeneration and cerebral edema following bilateral CCA:O/R in gerbils.
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PMID:Thrombin inhibition attenuates neurodegeneration and cerebral edema formation following transient forebrain ischemia. 1138 20

Argatroban, a direct thrombin inhibitor, has been used in Japan since the early 1980's and was recently approved for use in the United States for patients with heparin-induced thrombocytopenia. However, its use has been studied in other clinical settings including, myocardial infarction, percutaneous coronary intervention and cerebral thrombosis. The doses used in the different clinical situations vary, but argatroban offers the advantage of not requiring renal adjustment. Because of its small molecular weight, argatroban has the ability to inhibit both clot bound and soluble thrombin. This paper provides a comprehensive review of both indicated and off label uses of argatroban. Pharmacology, pharmacokinetics, adverse events and drug interactions with argatroban are also discussed.
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PMID:A synopsis of the clinical uses of argatroban. 1172 65

Heparin-induced thrombocytopenia (HIT) is an immune-mediated syndrome that can lead to limb- and life-threatening thrombosis. Argatroban, a small synthetic molecule (Argatroban; GlaxoSmithKline, Philadelphia, PA), and lepirudin, a protein of non-human origin (Refludan; Aventis, Bridgewater, NJ), are direct thrombin inhibitors that have been used successfully for anticoagulant therapy in HIT patients. It has been reported that between 44-74% of lepirudin-treated HIT patients develop drug-specific antibodies that either enhance or suppress the anticoagulant activity of lepirudin. By contrast, there have been no reported patient experiences suggestive of unexpected loss or enhancement of argatroban's anticoagulant effect in clinical trials, including those in HIT patients, or in postmarketing safety surveillance of over 4,800 patients treated in Japan. To confirm the lack of antibodies in argatroban-treated patients with HIT, we examined plasma for anticoagulant-altering activity and reviewed dosing patterns of re-exposed patients. Paired, pre-therapy and post-therapy (> or =7 days) plasma pools exhibited comparable in vitro anticoagulant responses (aPTT and antithrombin activity) to argatroban supplementation. Argatroban at 5 microg/mL similarly prolonged aPTTs of normal plasma pretreated with IgG isolated from pre-therapy versus post-therapy plasma (P>0.6). In trials, mean argatroban doses during initial therapy versus re-exposure were not different among individuals anticoagulated for the treatment or prophylaxis of thrombosis (P=0.60) or during percutaneous coronary interventions (P=0.79), with no discernable pattern of suppression or enhancement of argatroban anticoagulation. Consistent with the lack of reported patient experiences suggestive of unexpected loss or enhancement of argatroban's anticoagulant effect across clinical trials and post-marketing safety surveillance, these data support the lack of anti-argatroban antibodies that affect drug activity in argatroban-treated HIT patients.
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PMID:Argatroban therapy does not generate antibodies that alter its anticoagulant activity in patients with heparin-induced thrombocytopenia. 1206 41

Argatroban is the smallest anticoagulant molecule of direct thrombin inhibitors. The main attributes of this synthetic drug are its rapid onset of anti-thrombin action, the rapid reversibility of its anticoagulant effect, potent inhibition of clot-bound thrombin, the absence of antibody formation and no need for dosage adjustment in patients with renal impairment. It is eliminated by hepatic metabolism. These properties make argatroban a predictable anticoagulant with intravenous use in a routine clinical setting. Argatroban is approved in the US and Canada for both prophylaxis and treatment of thrombosis in patients with heparin-induced throm-bocytopenia (HIT) and in the US as an antithrombotic agent during percutaneous coronary interventions in patients with HIT or a history of HIT. Preliminary reports document the feasibility of using argatroban for anticoagulation during hemodialysis and as adjunct to thrombolysis for treatment of myocardial infarction. Current recommendations for argatroban monitoring are to use the aPTT (activated partial thromboplastin time) for low doses and the ACT (activated clotting time) for high doses. The specific inhibition of thrombin can be measured with the ECT (ecarin clotting time).
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PMID:[Experimental and clinical results with the thrombin inhibitor Argatroban]. 1221 62

We have previously confirmed, using a rat mesenteric arteriole thrombolysis model, that thrombin inhibition induces endogenous thrombolysis in vivo. In addition, we have shown that thrombin-activatable fibrinolysis inhibitor (TAFI) plays a role in the down regulation of endogenous thrombolysis. However, the mechanism of endogenous thrombolysis or spontaneous plasmin generation in vivo remains unclear. It has been shown in an in vitro system that plasma kallikrein activates pro-urokinase (pro uPA) and/or plasminogen, resulting in plasmin generation. These findings suggest that spontaneous fibrinolysis might be mediated by tPA and plasma kallikrein-dependent uPA. The aim of the present study was to examine whether these mechanisms play a dominant role in endogenous thrombolysis in vivo, using our rat mesenteric arterial thrombolysis model. Argatroban infusion enhanced endogenous thrombolysis. PKSI-527, anti uPA and anti tPA IgGs suppressed argatroban-induced thrombolysis. Also, the antibody IgG preparations suppressed endogenous thrombolysis in the absence of argatroban. In the presence of PKSI-527, anti tPA IgG was more effective than anti uPA IgG in suppressing argatroban-induced thrombolysis. The results suggested that both tPA and plasma kallikrein-mediated uPA activation and tPA release contribute to endogenous fibrinolytic or thrombolytic mechanisms.
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PMID:Suppression of argatroban-induced endogenous thrombolysis by PKSI-527, and antibodies to TPA and UPA, evaluated in a rat arterial thrombolysis model. 1271 78

Whereas heparin is the most widely used intravenous anticoagulant in the US for the treatment of thromboembolic disease and is a seminal adjunct to many clinical procedures, its use can cause serious adverse events. Heparin-induced thrombocytopenia (HIT) has emerged as one of the most frequently seen complications of heparin therapy and can be a life-threatening immunohematological challenge for patients requiring cardiopulmonary bypass (CPB) with obligatory heparin exposure. Unfortunately, lack of convenient monitoring techniques and the presence of HIT and other comorbidities in the complex patient frequently limits or precludes the use of most alternatives to heparin anticoagulation during CPB. This case report describes the successful use of the celite activated clotting time and high-dose thrombin time, while using the direct thrombin inhibitor Argatroban as an alternative to heparin anticoagulation during CPB in a high-risk patient presenting with type II HIT, end-stage renal failure, and ischemic cardiomyopathy with ventricular fibrillatory arrest.
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PMID:Successful use of Argatroban as a heparin substitute during cardiopulmonary bypass: heparin-induced thrombocytopenia in a high-risk cardiac surgical patient. 1273 90

Argatroban is a small molecule direct thrombin inhibitor. The main attributes of this synthetic drug are its rapid onset of anti-thrombin action, rapid reversibility of its anticoagulant effect, potent inhibition of clot-bound thrombin, absence of antibody formation and no need for initial dosage adjustment in patients with renal impairment. It is eliminated by hepatic metabolism. These properties make argatroban a predictable anticoagulant with intravenous use in a routine clinical setting. Argatroban is approved in the US and Canada for both prophylaxis and treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT); and it is approved in Japan and Korea for treatment of various thrombotic disorders. Argatroban has been shown in limited trials to provide reliable anticoagulation during percutaneous coronary interventions on HIT and non-HIT patients. Preliminary reports document the feasibility of using argatroban for anticoagulation during peripheral vascular interventions, hemodialysis and as adjunct to thrombolysis for treatment of myocardial infarction. Current recommendations for argatroban monitoring are to use the activated partial thromboplastin time for low doses and the activated clotting time for high doses. The ease of monitoring argatroban, its 'turn-on/turn-off' characteristic and its consistent safety profile provide the rationale to continue studies of argatroban as an anticoagulant in clinical settings.
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PMID:An overview of the direct thrombin inhibitor argatroban. 1281 Oct 6


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