cgp-39393 and Disseminated-Intravascular-Coagulation

The naturally occurring anticoagulant from medicinal leeches, hirudin, which we isolated and biochemically analyzed 30 years ago as a miniprotein with specific antithrombin activity, has afterwards been employed for scientific and diagnostic purposes in hematology. Pure hirudin proved to be an antithrombotic agent of high quality that displays an antithrombotic action dependent upon its blood level. After intravenous injection, it is distributed in the extracellular space and is almost completely eliminated through the kidneys by glomerular filtration in a biologically active form. The efficacy of hirudin in preventing venous and arterial thrombosis and disseminated intravascular coagulation was demonstrated in various animal models. Clinical pharmacological studies corroborated the specific pharmacodynamic and pharmacokinetic properties of hirudin found in animal experiments. Genetic engineering led to the availability of sufficient quantities of recombinant hirudin (r-hirudin) for clinical purposes. Pharmacologic profiling of r-hirudin showed that both its pharmacokinetic and pharmacodynamic characteristics are very similar to those of native hirudin. Clinical pharmacological studies with r-hirudin revealed that, at single therapeutically relevant doses, r-hirudin is a well-tolerated and potent anticoagulant without any detectable side effects and allergic reactions. Further preclinical studies of r-hirudin should concentrate on identifying possible indications for use, on the development of r-hirudin preparations and derivatives, and on the development of antidotes for hirudin.

Topics: Amino Acid Sequence; Animals; Disseminated Intravascular Coagulation; Dogs; Fibrinolytic Agents; Hirudin Therapy; Hirudins; History, 20th Century; Humans; Leeches; Molecular Sequence Data; Rabbits; Rats; Recombinant Proteins; Sequence Homology, Nucleic Acid; Swine; Swine, Miniature; Thrombolytic Therapy; Thrombosis

Various reactions of disseminated intravascular coagulation (DIC) were experimentally induced by infusion of thrombokinase in rats, by administration of endotoxin in rabbits and pigs and by infusion of adrenaline and thrombin in dogs. Low plasma concentrations of recombinant hirudin (r-hirudin; 20-200 ng/ml) were sufficient for the inhibition of the different triggering mechanisms. The studies on the pharmacological profile of r-hirudin in DIC therapy confirm the efficacy of this specific tight-binding thrombin inhibitor.

Topics: Animals; Disease Models, Animal; Disseminated Intravascular Coagulation; Dogs; Endotoxins; Epinephrine; Factor Xa; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Hemodynamics; Hirudin Therapy; Hirudins; Lipid A; Male; Platelet Count; Rabbits; Rats; Rats, Inbred Strains; Recombinant Proteins; Species Specificity; Swine; Thrombin; Thrombolytic Therapy; Thrombosis; Viscera