Antithrombotic effects

Dipyridamole exerts its effect by inhibition of platelet phosphodiesterase E5, increasing cyclic guanosine monophosphate and cyclic adenosine monophosphate (cAMP). By inhibiting its uptake and metabolism by erythrocytes, dipyridamole also increases the availability of adenosine within blood vessels, promoting inhibition of platelet aggregation and local vasodilatation. " Dipyridamole may also inhibit cAMP phosphodiesterase in platelets, which further increases cAMP levels and may enhance endothelial nitric oxide production, contributing to its antithrombotic effect. Existing trials of dipyridamole in stroke have focused on secondary prevention and will be discussed briefly. 

Because of interplay of the foregoing interactions with those mediated by antithrombin,509 the antithrombotic effect in vivo does not necessarily reflect the in vitro anticoagulant activities, as measured either by wholeclotting502 or anti-Xa assays.510... 

Lipo-PGI2. Prostacyclin (PGI2) is more potent than PGEj in antiplatelet and antithrombotic effects, and is expected to be very useful in the treatment of various thrombotic diseases (70,77). However, it causes more adverse reactions, such as hypotension and facial flushes, because of its vasodilation and possible suppression of feed-back mechanisms. Many attempts at clinical applications have failed. We have conducted studies on methylated TEI9090 (Figure 2), a chemically stable and... 

The most commonly used oral anticoagulant drug in the U.S. is warfarin. It acts by altering vitamin K so that it is unavailable to participate in synthesis of vitamin K-dependent coagulation factors in the liver (coagulation factors II, VII, IX, and X). Because of the presence of preformed clotting factors in the blood, the full antithrombotic effect of warfarin therapy may require 36 to 72 h. 

In an in vivo thrombosis model, these products displayed antithrombotic effects that were generally lower than those of the corresponding azoamidoximes. This is probably due to a rather slow cleavage of the prodrugs 136 to the drugs 134. The most potent oxadiazol-5-one proved to be the phenyl derivative (136, Ar=QH5). 

Unstable angina pectoris As above Antithrombotic effects... 

Protein C exerts an antithrombotic effect by inhibiting Factors Va and Villa. In vitro data indicate that it has indirect prohbri-nolytic activity through its abhity to inhibit plasminogen activator inhibitor-1 (PAI-1) and to hmit production of activated throm-bin-activatable-hbrinolysis inhibitor. In vitro data also indicate that Activated Protein C may exert an anti-inflammatory effect by inhibiting human tumor necrosis factor production by monocytes, by blocking leukocyte adhesion to selectins, and by hmiting thrombin-induced inflammatory responses within the microvascular endothehum. 

In addition to the presence of natural coumarin derivatives, phytochemical analysis found that dong quai also contains ferulic acid and osthole as ingredients. Ferulic acid was reported to have antithrombotic activity (38). Similarly, study using the closely related Angelica pubescens also found osthole to be antithrombotic (39). These two chemical constituents exert their antithrombotic effects by interfering with different pathways responsible... 

The antithrombotic effects of NO are also mediated by NO-dependent inhibition of platelet aggregation. Both endothelial cells and platelets contain eNOS, which acts to regulate thrombus formation. Thus, endothelial dysfunction and the associated decrease in NO generation may result in abnormal platelet function. As in vascular smooth muscle, cGMP mediates the effect of NO in platelets. NO may have an additional inhibitory effect on blood coagulation by enhancing fibrinolysis via an effect on plasminogen. 

The indirect thrombin inhibitors are so-named because their antithrombotic effect is exerted by their interaction with a separate protein, antithrombin. Unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and the... 

Clopidogrel has fewer adverse effects than ticlopidine and is rarely associated with neutropenia. Thrombotic thrombocytopenic purpura associated with clopidogrel has been reported. Because of its superior side effect profile and dosing requirements, clopidogrel is preferred over ticlopidine. The antithrombotic effects of clopidogrel are dose-dependent within 5 hours after an oral loading dose of 300 mg, 80% of platelet activity will be inhibited. The maintenance dose of clopidogrel is 75 mg/d, which achieves maximum platelet inhibition. The duration of the antiplatelet effect is 7-10 days. 

Hauptmann J, Kaiser B, Vowak G, Struzebecher J, Markwardt F. Comparison of the anticoagulant and antithrombotic effects of synthetic thrombin and factor Xa inhibitors. Throm Haemostas 1990 63 220-223. 

TFPI, when administered to rabbits, has been shown to have an antithrombotic effect when thromboplastin was used as a thrombogenic challenge (I 10). TFPI was also shown to be an effective inhibitor when thrombosis was induced in rabbit jugular veins by endothelial destruction and restricted blood flow. The antithrombotic and antiprotease actions of TFPI have been tested in several other animal models. Warn-Cramer et al. investigated the effect of immunodepletion of TFPI in factor Vila and Xa induced coagulation in rabbits (III). These rabbits were observed to be sensitized to the procoagulant effects of factor Vila, but not factor Xa in the absence of factor Vila. Two studies have indicated that TFPI administration reduces the lethal effects of . coli administration in a septic shock model in baboons (I 12). These studies also indicated that TFPI may have an anti-inflammatory effect, as an attenuation of the IL-6 response was also observed. Administration of TFPI has been observed to prevent... 

Ulutin ON. Antithrombotic effect and clinical potential of defi-brotide. Semin Thromb Hemost 1993 19 186-191. 

Goto S. Cilostazol potential mechanism of action for antithrombotic effects accompanied by a low rate of bleeding. Atheroscler Suppl 2006 6 3-1 I,... 

Elg M, Gustafsson D, Carlsson S. Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat. Thromb Res 1999 94 187-197. 

Sarich TC, Osende Jl, Eriksson UG, et al, Acute antithrombotic effects of ximelagatran, an oral direct thrombin inhibitor, and r-hirudin in a human ex vivo model of arterial thrombosis, J Thromb Haemost 2003 1 999— 1004. 

The first evidence for the ex vivo antithrombotic effects of a direct factor Xa inhibitor in humans was provided in the Badimon chamber (71). Healthy volunteers received escalating... 

Shimbo D, Osende J, Chen J, et al. Antithrombotic effects of DX-9065a, a direct factor Xa inhibitor a comparative study in humans versus low molecular weight heparin. Thromb Haemost 2002 88 733-738. 

Antithrombotic effects Decreased matrix metalloproteinases Increased tissue inhibitor of metalloproteinase 1 Increased collagen and fewer inflammatory cells in atherosclerotic plaque Reduced tissue factor expression and thrombin generation... 

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