Abstract
The novel recombinant hirudin analog CX-397 was investigated with respect to its pharmacological activity and antithrombin profiles in vivo and in vitro. In three different types of thrombosis models in rats, including stasis and thrombin-induced venous, glass surface-activated arterio-venous shunt, and ferric chloride-induced arterial thrombosis models, CX-397 and rHV-1 elicited potent antithrombotic effects, where the minimum effective doses of rHV-1 tended to be higher than those of CX-397 in the arterio-venous shunt and arterial thrombosis models. The hemorrhagic risk of CX-397 in template bleeding in rats was not higher than that of rHV-1, indicating that CX-397 is superior to rHV-1 for treating the platelet-dominant type of thrombosis. However, no differences were detected between CX-397 and rHV-1 in their effects on in vitro coagulation times and thrombin-induced platelet aggregation, suggesting the possibility that some unknown mechanisms other than simple thrombin inhibition are also involved in their antithrombotic actions.
MeSH terms
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Amino Acid Sequence
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Animals
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Arginine / analogs & derivatives
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Arterial Occlusive Diseases / chemically induced
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Arterial Occlusive Diseases / drug therapy
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Arterial Occlusive Diseases / prevention & control*
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Arteriovenous Shunt, Surgical
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Chlorides
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Drug Evaluation, Preclinical
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Ferric Compounds / toxicity
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Fibrinolytic Agents / pharmacology*
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Fibrinolytic Agents / therapeutic use
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Fibrinolytic Agents / toxicity
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Glass
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Hemorrhage / chemically induced
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Heparin / pharmacology
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Heparin / therapeutic use
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Heparin / toxicity
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Hirudin Therapy
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Hirudins / analogs & derivatives*
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Hirudins / chemistry
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Hirudins / pharmacology
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Hirudins / toxicity
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Molecular Sequence Data
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Pipecolic Acids / pharmacology
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Pipecolic Acids / therapeutic use
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Pipecolic Acids / toxicity
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Platelet Aggregation / drug effects
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Platelet Aggregation Inhibitors / pharmacology
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Platelet Aggregation Inhibitors / therapeutic use
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Platelet Aggregation Inhibitors / toxicity
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Rats
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Recombinant Proteins / chemistry
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Recombinant Proteins / pharmacology
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Recombinant Proteins / therapeutic use
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Recombinant Proteins / toxicity
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Sequence Alignment
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Sequence Homology, Amino Acid
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Serine Proteinase Inhibitors / pharmacology
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Serine Proteinase Inhibitors / therapeutic use
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Serine Proteinase Inhibitors / toxicity
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Sulfonamides
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Thrombin / antagonists & inhibitors
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Thrombin / pharmacology
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Thrombosis / chemically induced
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Thrombosis / drug therapy
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Thrombosis / prevention & control*
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Vena Cava, Inferior
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Venous Thrombosis / drug therapy
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Venous Thrombosis / prevention & control*
Substances
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CX 397
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Chlorides
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Ferric Compounds
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Fibrinolytic Agents
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Hirudins
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Pipecolic Acids
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Platelet Aggregation Inhibitors
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Recombinant Proteins
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Serine Proteinase Inhibitors
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Sulfonamides
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Heparin
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Arginine
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Thrombin
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argatroban
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desirudin
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ferric chloride