Disease relevance of argatroban

• The combination of aspirin and argatroban may prove to be an effective therapeutic strategy in the prevention of coronary thrombosis [1].
• We describe our experience with argatroban, a direct thrombin inhibitor, in patients with HIT or HIT with thrombosis (HITTS) [2].
• Treatment with a direct thrombin inhibitor, such as lepirudin or argatroban, is an effective strategy in reversing the thrombocytopenia associated with HIT and reducing its complications [3].
• OBJECTIVES: This study examined the effect of a small-molecule, direct thrombin inhibitor, argatroban, on reperfusion induced by tissue plasminogen activator (TPA) in patients with acute myocardial infarction (AMI) [4].
• In the systemic high dose group (n = 10), angiographic thrombotic stenosis was < 5% after high dose drug delivery (p < 0.05 vs. control segments, 37.4% for heparin, 43% for argatroban) [5].

High impact information on argatroban

• Enoxaparin had only minor effects on platelet activation in vivo and ex vivo, and argatroban, evaluated ex vivo, had no detectable effects [6].
• Argatroban induced a dose-dependent prolongation of the thrombin time and the activated partial thromboplastin time (aPTT). aPTT had returned to its pretreatment value 1 hour after stopping the infusion of argatroban [1].
• Furthermore, argatroban did not increase the bleeding time when given alone and did not further prolong the bleeding time when combined with aspirin [1].
• Argatroban given alone increased thrombin time by 454 +/- 18% and aPTT by 160 +/- 3% [1].
• To address this possibility, we examined the effect of argatroban [MCI9038, (2R,4R)-4-methyl-1-[N alpha-(3-methyl-1,2,3,4-tetrahydro-8- quinolinesulfonyl)-L-arginyl]-2-piperidinecarboxylic acid], a specific thrombin inhibitor, on the response to tissue-type plasminogen activator in a closed-chest canine model of coronary thrombosis [7].

Chemical compound and disease context of argatroban

• The dose required for 50% inhibition of thrombus formation was 0.27 mg/kg/h. DX-9065a did not prolong transection bleeding time up to 7.78 mg/kg/h. Argatroban and AT III-dependent anticoagulants also inhibited both thrombus formation and TAT elevation, but prolonged bleeding time at a slightly higher dose than the effective dose [8].
• A multicenter clinical trial of the thrombin inhibitor argatroban (Novastan; Texas Biotechnology, Houston, TX; Smith-Kline Beecham Pharmaceuticals, Philadelphia, PA) was recently conducted in patients with heparin-induced thrombocytopenia (HIT) and HIT that had progressed to thrombosis (HITTS) [9].
• Antithrombotic effects of FK419, a novel nonpeptide platelet GPIIb/IIIa antagonist, in a guinea pig photochemically induced middle cerebral artery thrombosis model: comparison with ozagrel and argatroban [10].
• Transitioning from argatroban to warfarin therapy in patients with heparin-induced thrombocytopenia [11].
• We investigated the antithrombotic effects of a combination of argatroban and ticlopidine in the rat venous thrombosis model [12].

Biological context of argatroban

• Patency of femoral arterial segments was maintained after the end of the intra-arterial heparin and intravenous or intra-arterial argatroban infusion for up to 3 hours despite normalization of the thrombin time and partial thromboplastin time [13].
• Analysis of the argatroban dose-response data with a competitive inhibition model has yielded IC50 values in the low micromolar range [14].
• This study demonstrates the differential effects of DX-9065a and argatroban on thrombin generation, which in turn results in a differential acceleration of fibrinolysis as well as TAFI activation in the clots formed under the influence of these compounds [15].
• Platelet counts recovered more rapidly in argatroban-treated patients than in controls [2].
• We show that clot-associated thrombin induces platelet aggregation, is resistant to heparin:antithrombin III, less so to recombinant hirudin (rHV2Lys47) but not to argatroban, an active-site directed thrombin inhibitor [16].

Anatomical context of argatroban

• Heparin (30 U/kg), an antithrombin agent (argatroban, 0.05 mg/kg body weight) or a defibrinogenating drug (batroxobin, 0.05 U/kg) was locally infused into one side of the canine iliac artery after injury by balloon inflation [5].
• Argatroban dialytic clearance by high-flux membranes is clinically insignificant [17].
• Synergistic antithrombotic properties of G4120, a RGD-containing synthetic peptide, and argatroban, a synthetic thrombin inhibitor, in a hamster femoral vein platelet-rich thrombosis model [18].
• CONCLUSIONS: Argatroban suppressed leukocyte-endothelial cell interactions and blood-retinal barrier breakdown after scatter laser photocoagulation, suggesting that argatroban prevents postlaser macular edema [19].
• Effects of a thrombin inhibitor, argatroban, on ischemic brain damage in the rat distal middle cerebral artery occlusion model [20].

Associations of argatroban with other chemical compounds

• TAME derived noncovalent thrombin inhibitors argatroban, napsagatran, and UK 156,406 have entered clinical trials as anticoagulants, the latter as an orally active agent [21].
• The effects of argatroban, a direct thrombin inhibitor, on the International Normalized Ratio (INR), activated partial thromboplastin time (aPTT) and functional factor X during warfarin co-administration were established to provide means to interpret INRs during argatroban/warfarin co-therapy [22].
• Four direct thrombin inhibitors (DTIs), lepirudin, bivalirudin, argatroban, and melagatran, differ in their ability to prolong the prothrombin time (PT) [23].
• Suppression of argatroban-induced endogenous thrombolysis by PKSI-527, and antibodies to TPA and UPA, evaluated in a rat arterial thrombolysis model [24].
• Antithrombotic effects of TAK-029, a novel GPIIb/IIIa antagonist, in guinea pigs: comparative studies with ticlopidine, clopidogrel, aspirin, prostaglandin E1 and argatroban [25].

Gene context of argatroban

• Enhancement of endogenous plasminogen activator-induced thrombolysis by argatroban and APC and its control by TAFI, measured in an arterial thrombolysis model in vivo using rat mesenteric arterioles [26].
• Argatroban, a direct thrombin inhibitor, is metabolized in vitro by CYP3A4/5 and therefore may be susceptible to clinically relevant CYP3A drug interactions [27].
• Thrombin-induced FN secretin was also inhibited by thrombin inhibitors, such as antithrombin III, hirudin and argatroban [28].
• Here, it appears that argatroban may be effective in controlling disorders linked to thrombin-induced VEGF production in neuronal cells [29].
• PKSI-527, anti uPA and anti tPA IgGs suppressed argatroban-induced thrombolysis [24].

Analytical, diagnostic and therapeutic context of argatroban

• Scanning electron microscopy/morphometric analyses demonstrated that permeation with argatroban had no significant effects on clot structure [14].
• The antithrombotic activity of argatroban has been quantified in fibrin clot permeation and fibrin clot perfusion systems as a function of clot age and composition [14].
• CONCLUSIONS: Argatroban, as compared with heparin, appears to enhance reperfusion with TPA in patients with AMI, particularly in those patients with delayed presentation [4].
• The slope depended on the argatroban dose and on the International Sensitivity Index (ISI) of the PT reagent, the steepest slope (i.e., the largest difference between INR (ARG+VKA) and INR (VKA alone)) was seen with the highest ARG dose and the PT reagent with an ISI of 2.13 [30].
• Systemic argatroban clearance increased approximately 20% during hemodialysis, without clinically significantly affecting ACTs [17].

References