Inhibition by D-MePhe-Pro-Arg-H (GYKI-14766) of Thrombus Growth in Experimental Models of Thrombosis

Bagdy, D; Szabó, Gabriella; Barabás, Éva; Bajusz, S.

doi:10.1055/s-0038-1656336

Cited by 31 publications

(3 citation statements)

References 15 publications

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“…This agent inhibits thrombin by accelerating AT III binding to tluombin. In addition, several direct (i.e., AT Ill-independent) and low molecular weight inhibitors of thrombin such as hirudin and its analogs (2)(3)(4), argatroban (5)(6)(7)(8) and tripeptide type inhibitors (9)(10)(11)(12) have demonstrated antithrombotic effects in experimental thrombosis models.…”

mentioning

confidence: 99%

Antithrombotic and Hemorrhagic Effects of DX-9065a, a Direct and Selective Factor Xa Inhibitor: Comparison with a Direct Thrombin Inhibitor and Antithrombin Ill-Dependent Anticoagulants

et al. 1997

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Summary(+)-2S-2-[4-[[(3S)-l-acetimidoyl-3- pyrrolidinyl]oxy]phenyl]-3-[7-amidino-2-naphthyl]propanoic acid hydrochloride pentahydrate (DX- 9065a) is an antithrombin III (AT III)-independent and selective inhibitor of activated blood coagulation factor X (FXa). The aim of the present study was to compare the antithrombotic and hemorrhagic effects of DX-9065a with a direct thrombin inhibitor and AT Ill-dependent anticoagulants in rat models of thrombosis and bleeding.Rats were administered intravenously DX-9065a (0.1-1 mg/kg/h), argatroban (0.1-1 mg/k/h), low molecular weight heparin (25-100 anti- XaU/kg/h), unfractionated heparin (25-100 anti-XaU/kg/h) or Orgaran (30-300 anti-XaU/kg/h) for 1 h. DX-9065a dose-dependently inhibited both thrombus formation and elevation in plasma thrombin-AT III complex (TAT) level in a copper wire-inserted arteriovenous (AV) shunt model in rats. 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 Ill-dependent anticoagulants also inhibited both thrombus formation and TAT elevation, but prolonged bleeding time at a slightly higher dose than the effective dose. These results suggest that direct and selective inhibition of factor Xa by DX-9065a is preferable for the treatment of thrombosis in the aspect of lack of compromising primary hemostasis.

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mentioning

confidence: 99%

Antithrombotic and Hemorrhagic Effects of DX-9065a, a Direct and Selective Factor Xa Inhibitor: Comparison with a Direct Thrombin Inhibitor and Antithrombin Ill-Dependent Anticoagulants

et al. 1997

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“…Furthermore, the method of bleeding time determination, although it has been fairly standardized and accepted, may not be very exact (35,42). There are initial reports, which describe the effects of other 'orally available' thrombin inhibitors on thrombus growth and fibrinolysis (43)(44)(45)(46). However, all these compounds are slow binding thrombin inhibitors, which narrows their therapeutic intervals and therefore limits their potential clinical applicability.…”

Section: Discussionmentioning

confidence: 99%

Successful Attenuation of Venous Thrombus Growth in Rabbits after the Administration of a Novel Oral Thrombin Inhibitor

Friederich

Keller²,

Biemond³

et al. 2000

Thromb Haemost

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SummaryCurrent antithrombotic compounds have several limitations in clinical practice. The present study was designed to investigate a novel orally available direct thrombin inhibitor, BSF 208791. Intravenous administration of BSF 208791 showed superior antithrombotic properties as compared with Polyethylenglycol-Hirudin (PEG-Hirudin) and low molecular weight heparin (LMWH) in a model of venous thrombosis in rabbits. The thrombus growth was 22%, 30%, 37% and 50% after BSF 208791, PEG-Hirudin, LMWH, and saline administration, respectively. Moreover, bleeding time was less affected after administration of BSF 208791 as compared with PEG-Hirudin. The oral administration of BSF 208791 resulted in adequate bioavailability and significantly reduced venous thrombus growth to 36% as compared with 60% in the saline treated rabbits. The antithrombotic effect of BSF 208791 appears to be superior to PEG-Hirudin and LMWH without affecting the bleeding time. BSF 208791 is an orally available agent that might be a promising candidate for future antithrombotic therapy.

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“…Inogatran also has oral bioavailability, but the oral availability of melagatran is higher than that of inogatran (24). Only a few other 'orally available' thrombin inhibitors have been described so far (15,25,26) but these are all slow-binding inhibitors.…”

Section: Oral Bioavailabilitymentioning

confidence: 99%

Effects of Melagatran, a New Low-molecular-weight Thrombin Inhibitor, on Thrombin and Fibrinolytic Enzymes

Gustafsson¹,

Antonsson²,

Bylund³

et al. 1998

Thromb Haemost

190

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SummaryMelagatran, a new, competitive and rapid inhibitor of thrombin with a molecular mass of 429 Da is described. Melagatran is well tolerated when administered in very high doses, and the oral bioavailability in the dog is relatively high. The aim of the study was to determine, in the preclinical setting, the degree of selectivity against the fibrinolytic system required for entering the clinical development phase. Melagatran was compared with two structurally similar thrombin inhibitors, inogatran and H 317/86. The potent inhibition of thrombin by melagatran was demonstrated by a low inhibition constant (Ki) for thrombin (0.002 μmol/l) and prolongation of clotting time to twice the control value in coagulation assays at low concentrations (0.010, 0.59 and 2.2 μmol/l for thrombin time, activated partial thromboplastin time and prothrombin time, respectively). Furthermore, thrombin-induced platelet aggregation was inhibited at the same concentration (IC50-value 0.002 μmol/l) as the Ki-value for thrombin. In two assays of global fibrinolysis, inhibition was observed at a concentration of 1.1 μmol/l in a euglobulin plasma fraction model, while no inhibition was observed at a concentration of ≤10 μmol/l in a plasma model. In an in vivo model of endogenous fibrinolysis in the rat, inhibition of fibrinolysis was observed at ≥1.0 μmol/l. In all assays, except the Ki-ratio determinations, the compounds could be graded with regard to selectivity against the fibrinolytic system: inogatran > melagatran > H 317/86. For melagatran, inhibition of fibrinolysis was not observed at concentrations below the upper limit of the proposed therapeutic plasma concentration interval (<0.5 μmol/l). Thus, melagatran seems to have a sufficient selectivity against the fibrinolytic system, while H 317/86 was considered to be insufficient for clinical development.

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Inhibition by D-MePhe-Pro-Arg-H (GYKI-14766) of Thrombus Growth in Experimental Models of Thrombosis

Cited by 31 publications

References 15 publications

Antithrombotic and Hemorrhagic Effects of DX-9065a, a Direct and Selective Factor Xa Inhibitor: Comparison with a Direct Thrombin Inhibitor and Antithrombin Ill-Dependent Anticoagulants

Antithrombotic and Hemorrhagic Effects of DX-9065a, a Direct and Selective Factor Xa Inhibitor: Comparison with a Direct Thrombin Inhibitor and Antithrombin Ill-Dependent Anticoagulants

Successful Attenuation of Venous Thrombus Growth in Rabbits after the Administration of a Novel Oral Thrombin Inhibitor

Effects of Melagatran, a New Low-molecular-weight Thrombin Inhibitor, on Thrombin and Fibrinolytic Enzymes

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