Inhibition of the amplification reactions of blood coagulation by site-specific inhibitors of <i>α</i>-thrombin

Ofosu, Frederick A.; Fenton, John W.; Maraganore, John M.; Blajchman, Morris A.; Yang, Xi; Smith, Louisa; Anvari, N; Buchanan, Michael R.; Hirsh, Jack

doi:10.1042/bj2830893

Cited by 42 publications

(22 citation statements)

References 28 publications

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“…It is im portant that clinically developed drugs are compared sys tematically side by side in the same systems, since only then do the differences in their action become apparent. Such limited studies have been previously reported, [1][2][3] but comparisons between several different thrombin in hibitors (as opposed to comparisons between structural analogues of the same agent) are lacking. Protease gener ation inhibition assays using biochemically defined sys tems provide a useful profile on the modulatory actions of newer antithrombin agents.…”

Section: Discussionmentioning

confidence: 99%

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Comparative Studies on the Anticoagulant and Protease Generation Inhibitory Actions of Newly Developed Site-Directed Thrombin Inhibitory Drugs

Callas¹,

Hoppensteadt²,

Fareed³

1995

Semin Thromb Hemost

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Site-directed thrombin inhibitors are being currently assessed clinically for their antithrombotic efficacy. Although these agents are claimed to be specific and direct thrombin inhibitors, their mechanism of inhibition varies. The objective of these studies was to compare four such agents in in vitro systems and to assess their relative anticoagulant efficacy. The four agents utilized in these studies were argatroban, Efegatran, hirulog, and hirudin. While hirulog and hirudin are specific irreversible inhibitors of thrombin, argatroban and Efegatran are reversible. All four agents were found to have a concentration-dependent anticoagulant effect when supplemented into normal human plasma, as assessed in the global clotting tests (PT, APTT, and Heptest). The most potent anticoagulant on a molar basis was hirudin in all three tests. The other three agents had similar anticoagulant actions. All four agents were also capable of inhibiting the generation of thrombin and factor Xa as determined by an amidolytic method after intrinsic or extrinsic activation of fibrinogen-deficient human plasma. Except for hirulog, all agents inhibited the extrinsic generation of thrombin, with hirudin being the most potent agent. The intrinsic generation of thrombin was blocked by the reversible thrombin inhibitors (argatroban and Efegatran) but not by the irreversible inhibitors (hirulog and hirudin). While all agents were capable of inhibiting the intrinsic generation of factor Xa at very low concentrations, only Efegatran was capable of blocking the extrinsic generation of the same factor.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionmentioning

confidence: 99%

“…Although the role of thrombin in catalyzing the conversion of fibrinogen to fibrin has been established, more information about thrombin's role in feedback am plification loops in the coagulation cascade is becoming available. [1][2][3][4] Until recently only limited information was available on the feedback regulatory actions of formed thrombin.…”

mentioning

confidence: 99%

Comparative Studies on the Anticoagulant and Protease Generation Inhibitory Actions of Newly Developed Site-Directed Thrombin Inhibitory Drugs

Callas¹,

Hoppensteadt²,

Fareed³

1995

Semin Thromb Hemost

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“…Other authors have already reported in detail on the biochemical and bio logical properties of both substances [2,7,11], In a series of in vitro and in vivo test systems the superiority of both inhibitors over heparins was demonstrated [ 13,[27][28][29]. However, there are only few comparative studies of rhi rudin and this analogue [12,13].…”

Section: Discussionmentioning

confidence: 99%

“…This bivalent inhibitor has been termed 'hirulog-1' by Maraganore et al [11]. Few comparative studies of rhirudin and its analogues have as yet been carried out [12][13][14], We examined both anti coagulants in vitro and in animal models. The results demonstrate marked differences be tween the two compounds.…”

Section: Introductionmentioning

confidence: 99%

Comparison of in vitro and in vivo Properties of rHirudin (HBW 023) and a Synthetic Analogous Peptide

Römisch

Diehl²,

Hoffmann³

et al. 1993

Pathophysiol Haemos Thromb

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Recombinant hirudin and a shortened synthetic analogue, with the amino acid sequence of D-Phe-Pro-Arg-Pro-(Gly)₄-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu, are specific thrombin inhibitors which in a concentration-dependent manner inhibit thrombus formation as well as clot propagation both in vitro and in vivo. In comparison to the analogue, lower molar concentrations of rhirudin affected doubling of aPTT and TT as well as inhibition of thrombin amidolytic activity or thrombin-induced platelet aggregation in vitro. In the rat wire coil-induced thrombosis model, a 50% thrombo-protective effect may be brought about with doses of 0.043 μmol/kg of rhirudin and 1.43 μmol/kg of the synthetic peptide. However, doubling of bleeding times is caused, on average, by dosages of between 0.143 and 0.43 μmol/kg rhirudin or approximately 0.143 μmol/kg of the analogue. Treatment groups included animals revealing significant prolongation of bleeding times as well as nonresponders. Despite the 10-fold longer impact on aPTT after application of rhirudin, the extent of mean bleeding time prolongation is identical to that of the analogue.

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“…Some patents on lepirudin argatroban and bivalirudin were reported [90][91][92][93][94][95][96][97]. Three parenteral DTI are currently approved for use in the United States: lepirudin [90,98], argatroban [91][92][93]99], and bivalirudin [95,100]. Ximelagatran and dabigatran are oral DTI that are being investigated for the prevention and treatment of TED.…”

Section: Direct Thrombin Inhibitorsmentioning

confidence: 99%

Recent Developments in Antithrombotic Therapy: Will Sodium Warfarin Be a Drug of the Past?

Desai¹,

Massad²,

DiDomenico³

et al. 2006

PRC

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Warfarin and heparin have formed the mainstay in the prophylaxis of deep vein thrombosis (DVT), stroke prevention in atrial fibrillation, and treatment of thromboembolic disease (TED). However, these choices are hampered by difficult administration, interactions with other medications, side effect profile, and limited indications for treatment. Anti-factor Xa (anti-Xa) inhibitors have already entered the drug market with the drug Fondaparinux being the first anti-Xa inhibitor to be approved for use in the U.S. by the Food and Drug Administration (FDA), and other drugs such as idraparinux being currently in development. A new class of medications, known as direct thrombin inhibitors (DTI), includes the parental agents lepirudin, argatroban and bivalirudin which have been approved by the FDA and the oral agents ximelagatran, melagatran and dabigatran. The latter three drugs which are oral DTIs may soon replace warfarin and heparin as the preferred medications for DVT prophylaxis and for reducing the relative risk of stroke. These drugs do not rely on blocking serine proteases nor do they require a co-factor (antithrombin III) like unfractionated heparin (UFH) or low molecular weight heparin (LMWH). DTIs are rapid in onset, easy to administer, do not interact with other medications or foods, have limited side effects, and can be administered in a fixed dose. The DTI ximelagatran has already been approved in several European and Asian countries, and over a dozen randomized clinical trials have been conducted demonstrating its performance to be on par with warfarin. However, approval by the FDA in the U.S. remains pending in view of reported incidences of elevations in hepatic enzymes that are currently under evaluation. This review examines the role of DTIs in the prevention and treatment of TED and the recent patents reported in the literature.

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Inhibition of the amplification reactions of blood coagulation by site-specific inhibitors of α-thrombin

Cited by 42 publications

References 28 publications

Comparative Studies on the Anticoagulant and Protease Generation Inhibitory Actions of Newly Developed Site-Directed Thrombin Inhibitory Drugs

Comparative Studies on the Anticoagulant and Protease Generation Inhibitory Actions of Newly Developed Site-Directed Thrombin Inhibitory Drugs

Comparison of in vitro and in vivo Properties of rHirudin (HBW 023) and a Synthetic Analogous Peptide

Recent Developments in Antithrombotic Therapy: Will Sodium Warfarin Be a Drug of the Past?

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