Thrombin, direct inhibitors

L-Dihydroxyphenylalanine 4-Dihydroxyphenylethylamine Dimeric Transcription Factors Dioxins Dipeptidase Dipeptidylpeptidase Dipeptidylpeptidase IV Direct Thrombin Inhibitors Discharge of Neurons... 

Figure 24.4 The decision-analytic model shows the three strategies that were examined by Arnold and researchers [22] to evaluate the financial implications of the direct thrombin inhibitor argatroban for early treatment (<48 hours after thrombocytopenia onset), compared with delayed treatment, of heparin-induced thrombocytopenia (HIT) with or without thrombosis.

Arnold R, Kim R, Zhou Y, Tang B. Budgetary impact of heparin-induced thrombocytopenia with thrombosis and treatment with the direct thrombin inhibitor Argatroban (P401E). ASHP 39th Midyear Clinical Meeting. Orlando, FL, 2004. 

Given that thrombin is the central mediator of coagulation and amplifies its own production, it is a natural target for pharmacologic intervention. Direct thrombin inhibitors (DTIs) bind thrombin and prevent interactions with its substrates (Fig. 7-7). Several injectable DTIs are approved for use in the United States including lepirudin, bivalirudin, arga-troban, and desirudin. Several oral DTIs are currently in... 

FIGURE 7-7. Mechanism of action of direct thrombin inhibitors. 

Small-molecule direct thrombin inhibitors have been structurally modified for oral administration. Approximately... 

Activated partial thromboplastin time aPTT is performed by adding calcium phospholipids and kaolin to citrated blood and measures the time required for a fibrin clot to form. In this manner, aPTT measures the activity of intrinsic and common pathways. Prolongation of aPTT may be due to a deficiency or inhibitor for factors II, V, VIII, IX, X, XI, and XII. It also may be due to heparin, direct thrombin inhibitors, vitamin K deficiency, liver disease, or lupus anticoagulant. 

Bivalent inhibitors of thrombin have been synthesized to bind the anion-binding exosite and active (catalytic) site of thrombin simultaneously. By coupling the carboxy terminal fragment of hirudin to a tripeptide (D-Phe-Pro-Arg) by including a spacer molecule, both the anion exosite and the catalytic site are blocked. An example of such a molecule is Hirulog, which has 20 amino acids and has a Kj of 2 nM (61). Its ability to block the active site has been questioned, since thrombin has been shown to cleave the Arg-Pro bond of Hirulog slowly in vivo (58). In addition to hirudin and hirudin-like compounds, three other classes of site-directed thrombin inhibitors deserve mention. 

Direct thrombin inhibitors such as hirudin, Hirulog, the peptide aldehyde efegatran, and peptidomimetic compound argatroban have undergone clinical trials. Their application in the prevention and treatment of deep vein thrombosis contin-... 

Finally, with the use of direct thrombin inhibitors such as hirudin for anticoagulant therapy, laboratory tests such as APTT may not be sensitive enough to follow therapy. 

Lefkovits J., Topol E. J. Direct thrombin inhibitors in cardiovascular medicine. Circulation 1994 90, 1522-36. 

Eriksson, B. I., Arfwidsson, A. C., Frison, L., Eriksson, U. G., Bylock, A. et al, A dose-ranging study of the oral direct thrombin inhibitor,... 

Contraindications are similar to those of other antithrombotic drugs, and hemorrhage is the most common and serious adverse effect. For all agents in this class, a CBC should be obtained at baseline and periodically thereafter to detect potential bleeding. There are no known agents that reverse the activity of direct thrombin inhibitors. 

AstraZeneca first launch for AstraZeneca s Exanta (TM) (ximelagatran) the first oral anticoagulant in new class of direct thrombin inhibitors (DTIs), AstraZeneca. 

Bivalirudin (55 Angiomax ) Hirudin Peptide Synthetic congener Animal Antittirombotic Specific and reversible direct thrombin inhibitor (DTI) 479 91... 

Gladwell TD. (2002) Bivalirudin A direct thrombin inhibitor. Clin Ther 24 38-58. 

Xiao Z, Theroux P. (1998) Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular weight heparin and with a direct thrombin inhibitor. Circulation 97 251-256. 

Reiffel JA. Will direct thrombin inhibitors replace warfarin for preventing embolic events in atrial fibrillation Curr Opin Cardiol 2004 19 58-63. 

Mechanism of action - Argatroban is a synthetic, direct thrombin inhibitor that reversibly binds to the thrombin active site. It inhibits thrombin-catalyzed or induced reactions, including fibrin formation activation of coagulation factors V, VIII, and XIII protein C and platelet aggregation. 

Another type of anticoagulant are the direct thrombin inhibitors. Current members of this class include argatroban, lepirudin, and bivalirudin. 

Di Nisio M, Middeldorp S, BUller HR. Direct thrombin inhibitors. N Engl J Med 2005 353(10) 1028-40. 

SSR-182289 is a direct thrombin inhibitor, stmcturally related to argotroban. It is undergoing Phase E clinical trials for thromboembohc disease treatment. 

Lepirudin is a recombinant derivative of hirudin (direct thrombin inhibitor secreted by salivary glands of leech). It inhibits thrombin directly and is mainly used in heparin induced thrombocytopenia. 

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