Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.6 (thromboplastin)
 13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We sought to determine the efficacy of the combination of argatroban, a direct thrombin inhibitor, and G4120, a platelet glycoprotein (GP) IIb/IIIa blocker, to enhance thrombolysis with alteplase. Platelet-rich thrombus in the rabbit arterial thrombosis model is relatively resistant to alteplase despite the addition of aspirin and heparin. The adjunctive use of either direct thrombin inhibitors or GP IIb/IIIa inhibitors in thrombolysis has been investigated with encouraging, but limited, success. The usefulness of combining both agents as adjunctive therapy to thrombolysis has not been fully explored. Following platelet-rich thrombus formation in the rabbit, argatroban (3 mg/kg), G4120 (0.5 mg/kg), G4120 plus heparin (200 U/kg), or G4120 plus argatroban were intravenously infused over 60 minutes. Alteplase was given as intravenous boluses (0.45 mg/kg) at 15-minute intervals up to 4 doses or until reperfusion. Blood flow and bleeding time were monitored for 2 hours. The combination of G4120 plus argatroban resulted in a persistent patency in 5 of 7 animals compared with 0 of 6 for argatroban alone (p=0.02), 1 of 6 for G4120 alone (p=0.08), and 2 of 6 for G4120 plus heparin (p=0.2). Although during the infusion the bleeding times were longer in the groups that received G4120 (26+/-7.7 minutes vs. 14+/-10 minutes, p<0.05), by the end of the experiment there were no statistically significant differences. Similarly, during the infusion the activated partial thromboplastin times (aPTT) was higher in groups that received heparin or argatroban (99+/-51 seconds vs. 32+/-7.6 seconds, p<0.001), but by the end of the experiment the aPTTs had returned to close to baseline in all groups except the G4120 plus heparin group. These results suggest that lysis of platelet-rich thrombus with alteplase requires the addition of both potent platelet and thrombin inhibitors. Specifically designed agents, G4120 and argatroban, are effective without additional increased risk for bleeding.
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PMID:Combination of a direct thrombin inhibitor and a platelet glycoprotein IIb/IIIa blocking peptide facilitates and maintains reperfusion of platelet-rich thrombus with alteplase. 1100 41

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

To define the interaction of fibrinolytic components with platelets or coagulation factors on thrombus formation, we investigated mouse deficient in tissue plasminogen activator (tPA -/-) or urokinase plasminogen activator (uPA -/-) and in their wild-type control (tPA +/+, uPA +/+). A thrombus was induced in the murine carotid artery using photochemical reaction. Blood flow was monitored and the time needed before the vessel became completely obstructed was within 12 min in all types of mice. When DX-9065a, a selective factor Xa inhibitor, or GR144053, a platelet glycoprotein (GP) complex IIb/IIIa antagonist was applied, the time required to occlusion was prolonged in a dose-dependent manner in all types of mice. When a factor Xa inhibitor was injected in tPA -/- mice, the estimated ED50 was not changed. However, when GR144053 was injected in tPA -/- mice, the most significant changes were observed: the estimated ED51 was 19.6 times higher than the one in tPA +/+ mice. Platelet aggregation, hemostasis tests, and bleeding times were not significantly different among the different types of mice. In conclusion, the antithrombotic effect of platelet inhibition by a GPIIb/IIIa antagonist, is severely affected by the absence or presence of tPA production. On the contrary, the inhibition of factor Xa shows a stable antithrombotic effect with or without tPA. Thus the lack of tPA, but not of uPA, significantly affects antithrombotic efficacy.
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PMID:tPA, but not uPA, significantly affects antithrombotic therapy by a glycoprotein IIb/IIIa antagonist, but not by a factor Xa inhibitor. 1111 78

Enoxaparin, a low-molecular-weight heparin, and tirofiban, an intravenous platelet glycoprotein IIb/IIIa receptor antagonist, have each been shown to be effective in reducing cardiac ischemic events compared to unfractionated heparin alone in separate trials of patients with unstable angina and non-Q wave myocardial infarction. The combination of these agents may offer further therapeutic benefit. In a pilot study (ACUTE I), fifty-five patients with non-Q wave myocardial infarction were randomized to receive double-blind treatment with tirofiban (0.1 microg/kg/min intravenously) for 48/108 hours co-administered with either enoxaparin (1 mg/kg sc q 12 hours) (n = 26) or unfractionated heparin (intravenous, adjusted to activated partial thromboplastin time) (n = 27). Co-administration of tirofiban and enoxaparin was generally well tolerated. Plasma clearance of tirofiban was similar for enoxaparin and unfractionated heparin-treated patients. When combined with tirofiban, enoxaparin, relative to unfractionated heparin, resulted in less variability and a trend toward greater inhibition of platelet aggregation using 5 microM adenosine phosphate agonist. More patients achieved target inhibition of platelet aggregation (> 70%) in the tirofiban and enoxaparin group (84% versus 65%; p = 0.19). Median bleeding time was 21 minutes for tirofiban and enoxaparin versus 30 minutes for tirofiban and unfractionated heparin (p = non-significant). For a given level of inhibition of platelet aggregation, bleeding time was less prolonged with tirofiban and enoxaparin than tirofiban and unfractionated heparin (adjusted mean bleeding time 19.6 versus 24.9 minutes, respectively; p = 0.02). There were no major or minor bleeding events in either group by the TIMI criteria. The more consistent inhibition of platelet aggregation and lower adjusted bleeding time of tirofiban and enoxaparin versus tirofiban and unfractionated heparin support the therapeutic potential of combining these two agents. These observations have now been extended to more than 500 patients.
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PMID:Initial experience with the low-molecular-weight heparin, enoxaparin, in combination with the platelet glycoprotein IIb/IIIa blocker, tirofiban, in patients with non-ST segment elevation acute coronary syndromes. 1115 22

There exists incontrovertible scientific evidence that vascular endothelial cell dysfunction and atheromatous plaque disruption are causative pathobiologic events governing the clinical expression of disease in humans with coronary arteriosclerosis. A comprehensive understanding of vascular biology, platelet behavior, and coagulation protein bioamplification sequences forms the scientific basis for pharmacotherapy in acute coronary syndromes (ACS), and identifies the platelet as an attractive target. The three Food and Drug Administration-approved glycoprotein (GP) IIb/IIIa antagonists effectively prevent platelet aggregation. In vitro experiments also showed a dose-dependent decrease in prothrombinase activity and thrombin generation revealing that the GP IIb/IIIa antagonists possess anticoagulant properties as well. Combination pharmacotherapy in ACS is supported by the contribution of platelets and coagulation proteins to coronary artery thrombosis. While unfractionated heparin (UFH) is commonly used conjunctively with GP IIb/IIIa antagonists, several inherent limitations exist, including unpredictable pharmacodynamics, no established therapeutic standards, and the fact that the use of UFH has been associated with platelet activation. Low-molecular-weight heparin preparations offer several potential advantages over UFH: a greater degree of Xa inhibition; more predictable pharmacokinetic profile; the absence of significant platelet activation; and the confirmation of clinical superiority in several large-scale clinical trials. Randomized trials will be required to establish the full clinical impact of combined pharmacotherapy in ACS.
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PMID:The scientific basis for combined platelet and thrombin-directed pharmacotherapy in acute coronary syndromes. 1115 25

Antibody-derived GPIIb-IIIa antagonists, such as the c7E3 Fab fragment abciximab, have been shown to inhibit platelet procoagulant activity as well as platelet aggregation. Whether low-molecular-weight peptide-derived and peptidomimetic antagonists also inhibit platelet procoagulant activity in a similar manner has not been fully investigated. We compared the effects of the antibody-derived antagonists c7E3 Fab and m10E5 IgG, the peptide-derived antagonists eptifibatide, MK-852 and RGDS, and the peptidomimetic RO44--9883 on platelet procoagulant activity and on the stimulated cytosolic calcium increases that promote procoagulant activity. Procoagulant activity was measured as prothrombinase activity in gel-filtered platelets, activated by collagen plus thrombin or collagen alone, with and without stirring. The stimulated increases in cytosolic calcium were measured in parallel samples of platelets loaded with fura-2AM. Both c7E3 and m10E5 inhibited prothrombinase activity by 40--50% under all conditions of activation tested and inhibited cytosolic calcium increases to a similar extent in stirred, but not unstirred, platelets. The low-molecular-weight antagonists caused significantly less inhibition of prothrombinase activity in collagen plus thrombin-stimulated platelets, and produced no inhibition but rather a slight enhancement of activity in platelets stimulated by collagen alone. These antagonists also had little or no effect on the cytosolic calcium increases in stirred platelets. These differential effects of antibody-derived versus non-antibody GPIIb-IIIa antagonists on procoagulant activity may be a factor contributing to the differing anti-thrombotic effects of these antagonists seen in clinical trials.
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PMID:Greater inhibition of platelet procoagulant activity by antibody-derived glycoprotein IIb--IIIa inhibitors than by peptide and peptidomimetic inhibitors. 1132 83

It is known that a low-molecular-weight heparin (LMWH) is more effective than unfractionated heparin in unstable angina/non-Q-wave myocardial infarction (UA/NQMI) and the platelet GPIIb/IIIa receptors play an important role in acute myocardial infarction (AMI). Therefore, enoxaparin might have a similar advantage over heparin when used with a GPIIb/IIIa antagonist (RPR109891) in coronary thrombolysis. After induction of coronary thrombosis in anesthetized dogs, infusion of saline, enoxaparin, heparin, RPR109891, enoxaparin+RPR109891, or heparin+RPR109891 was initiated followed 15 min later by recombinant tissue plasminogen activator (rt-PA). The incidence of reperfusion in the enoxaparin+RPR109891- and the heparin+RPR109891-treated groups was similar, but time to reperfusion tended to be shorter for enoxaparin versus heparin. Only 43% of the vessels reoccluded in the enoxaparin+RPR109891 group, compared to 100% vessels in the heparin+RPR109891 group. Enoxaparin+RPR109891 maintained flow for a significantly longer time compared to saline, enoxaparin, heparin, and heparin+RPR109891. Enoxaparin+RPR109891 and heparin+RPR109891 increased the template bleeding time by 2- and 3-fold and activated partial thromboplastin time (APTT) by 1.3- and 3-fold, respectively. These data suggest that enoxaparin is more effective and potentially safer than heparin when combined with a GPIIb/IIIa receptor antagonist during rt-PA-induced coronary thrombolysis.
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PMID:Superiority of enoxaparin over heparin in combination with a GPIIb/IIIa receptor antagonist during coronary thrombolysis in dogs. 1136 20

We compared the antithrombotic efficacy of a potent factor Xa inhibitor, FXV673, to heparin and RPR109891, a GPIIb/IIIa antagonist, when used as adjunctive therapy in a canine model of rt-PA-induced coronary thrombolysis. Thrombus formation was induced by electrolytic injury to stenosed coronary artery. After thrombotic occlusion, a 135 min infusion of saline (n=8), FXV673 (10, 30 or 100 microg kg(-1)+1, 3, or 10 microg kg(-1) min(-1), respectively; n=8 per dose), heparin (60 u kg(-1)+0.7 u kg(-1) min(-1), n=8), or RPR109891 (30 microg kg(-1)+0.45 microg kg(-1) min(-1), n=8), was initiated. Aspirin (5 mg kg(-1), i.v.) was administered to all animals. Fifteen minutes after the start of drug infusion, rt-PA was administered (100 microg kg(-1)+20 microg kg(-1) min(-1) for 60 min). The incidence of reperfusion in the high dose FXV673 (8/8, 100%) was significantly greater than that in the heparin group (4/8, 50%), with a trend to faster reperfusion (23+/-5 min for FXV673 versus 41+/-11 min for heparin). Only 2/8 (25%) of the vessels reoccluded in the high dose FXV673 group, compared to 4/4 (100%) and 5/5 (100%) vessels in the heparin and RPR109891 groups, respectively (P<0.05). Throughout the protocol, blood flow was higher in the FXV673 treated group compared to other groups. FXV673 enhanced vessel patency in a dose-dependent manner. Compared to vehicle and heparin groups, the thrombus mass was decreased by 60% in the high dose FXV673. FXV673, heparin and RPR109891 increased the bleeding time by 2.7, 1.7 and 4 fold, and APTT by 2.8, 2.7 and 1.2 fold, respectively. In conclusion, FXV673 is more effective than heparin and at least as effective as RPR109891 when used as an adjunct during rt-PA-induced coronary thrombolysis.
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PMID:Antithrombotic efficacy of a novel factor Xa inhibitor, FXV673, in a canine model of coronary artery thrombolysis. 1148 31

Thrombosis is a major cause of mortality in the industrialized world. Therefore, the control of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (fXa), the enzyme directly responsible for thrombin generation. In this review we describe our approaches in the design and synthesis of small molecule, noncovalent fXa inhibitors. Rational drug design and selective screening of our GPIIb/IIIa library afforded several lead compounds for our fXa program. Following-up the leads in the isoxazoline series led to potent fXa inhibitors such as SF303 and SK509 with only one basic group. The isoxazole series was then designed to remove the chiral center in the isoxazoline ring, and this effort led to SA862 which has subnanomolar fXa affinity. Optimizing the core structure generated a series of novel five-membered ring heterocycles substituted with benzamidine, which are potent fXa inhibitors. Further optimization in the pyrazole series resulted in the discovery of fXa inhibitors such as SN429 with picomolar fXa affinity. Efforts to improve the oral bioavailability by lowering the basicity of these compounds, while simultaneously maintaining potency against fXa, culminated in the discovery of DPC 423. DPC 423 was selected for clinical evaluation as a potent and orally bioavailable fXa inhibitor.
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PMID:The design and synthesis of noncovalent factor Xa inhibitors. 1189 49

Cross-reactivity with integrins other than glycoprotein IIb/IIIa (GP IIb/IIIa) is discussed as a potential reason for the overall clinical benefits of the GP IIb/IIIa-blocking antibody-fragment abciximab. We evaluated whether abciximab binds to the leukocyte integrin Mac-1, whether it inhibits binding of the distinct ligands and thereby may modulate inflammation, cell proliferation and coagulation. Binding of fluorescence-labelled abciximab to phorbolmyristate acetate-stimulated monocytes and to a monocytic cell line (THP-1) could be detected in flow cytometry. The binding of fibrinogen, the inactivated complement factor 3b (iC3b), and the coagulation factor X to Mac-1 could be inhibited by abciximab (10 microg/ml) in vitro. As a functional consequence, the conversion of factor X to factor Xa mediated by Mac-1, as detected by the chromogenic substrate SZ-2222, was impaired by abciximab. Adhesion of THP-1 cells to immobilized intercellular adhesion molecule 1 (ICAM-1) and to fibrinogen was reduced significantly by abciximab. Fibrinogen-mediated cell aggregation was also impaired. In conclusion, we describe binding of abciximab to Mac-1 on stimulated monocytes. Thereby, abciximab inhibits binding of the ligands fibrinogen, ICAM-1, iC3b and factor X. Furthermore, we demonstrated that Mac-1-dependent conversion from factor X to factor Xa is impaired by abciximab, arguing for the direct modulation of the coagulation cascade by abciximab. Overall, the inhibition of Mac-1 could provide additional clinical benefits of abciximab beyond the well-described blockade of GP IIb/IIIa.
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PMID:The GP IIb/IIIa inhibitor abciximab (c7E3) inhibits the binding of various ligands to the leukocyte integrin Mac-1 (CD11b/CD18, alphaMbeta2). 1243 77


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