The antithrombotic and anticoagulant effects of a synthetic tripeptide and recombinant hirudin in various animal models.
The pharmacologic activities of two thrombin inhibitors (D-MePhe-Pro-Arg-H, recombinant-hirudin) were compared in two animal models. The antithrombotic effect was investigated in vivo in rabbits using a modified Wessler stasis thrombosis model. During these experiments, blood was drawn for ex vivo testing to determine the coagulation profile and to determine plasma concentrations using pre-constructed calibration curves. A dose-dependent antithrombotic effect was observed for both agents. On an equigravimetric basis (100 micrograms/kg i.v.), r-hirudin showed a stronger antithrombotic effect than the tripeptide, which correlated well with the ex vivo anticoagulant effect. No adverse reactions were observed during this study. In a rabbit ear bleeding model, a dose and time dependent hemorrhagic effect was observed for both agents. Only slight bleeding effects were observed at 1.0 mg/kg dosages. These studies show that the tripeptide D-MePhe-Pro-Arg-H and r-hirudin are specific thrombin inhibitors with potent antithrombotic effects and a high therapeutic (antithrombotic/hemorrhagic) index. Furthermore, the results of these two animal models and ex vivo analyses can be used to determine the therapeutic index of thrombin inhibitors.
Bacher
P
P
Hemostasis Research Laboratories, Loyola University Medical Center, Maywood, IL 60153.
Walenga
J M
JM
Iqbal
O
O
Bajusz
S
S
Breddin
K
K
Fareed
J
J
D000595:Amino Acid Sequence; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D024764:Hirudin Therapy; D006629:Hirudins / Q000031:analogs & derivatives*; D007601:Jugular Veins; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D011994:Recombinant Proteins / Q000627:therapeutic use; D013927:Thrombosis / Q000188:drug therapy*
D000925:Anticoagulants; D005343:Fibrinolytic Agents; D006629:Hirudins; D009842:Oligopeptides; D011994:Recombinant Proteins; C060225:desirudin; C064289:efegatran