title: Comparative pharmacology of site directed antithrombin agents. Implication in drug development.
abstract: Beside the direct inhibition of thrombin and its regulatory functions, many of the newer antithrombin agents produce several additional effects, unrelated to their anticoagulant actions. Synthetic peptide inhibitors are capable of producing fibrinolytic compromise by virtue of their actions on fibrinolytic enzymes such as t-PA, plasmin, urokinase and protein Ca. In addition, the low molecular weight arginine-containing peptides are also known to produce hemodynamic and hemostatic deficits. The designs of the ongoing clinical trials are largely empirical because of the non-availability of valid pharmacologic and toxicologic data on thrombin inhibitors. In contrast to heparin, none of the thrombin inhibitors produce endogenous release of tissue factor pathway inhibitor (TFPI) in the experimental and clinical settings. These observations suggest that beside the direct inhibition of thrombin, these agents also produce multiple additional effects that can significantly contribute to their pharmacologic and toxicologic profile.
authors.affiliation: Department of Pharmacology, Loyola University Medical Center, Maywood, IL 60153, USA.
authors.forename: D
authors.initials: D
authors.lastname: Callas
authors.forename: J
authors.initials: J
authors.lastname: Fareed
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000991:Antithrombins / Q000009:adverse effects / Q000145:classification / Q000494:pharmacology* / Q000627:therapeutic use; D052157:Aptamers, Nucleotide; D002986:Clinical Trials as Topic; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005342:Fibrinolysis / Q000187:drug effects; D005544:Forecasting; D006470:Hemorrhage / Q000139:chemically induced; D024764:Hirudin Therapy; D006629:Hirudins / Q000009:adverse effects / Q000494:pharmacology; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009841:Oligonucleotides; D010446:Peptide Fragments / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D011119:Polynucleotides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D011817:Rabbits; D011994:Recombinant Proteins / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000502:physiology
chemical_list: D000991:Antithrombins; D052157:Aptamers, Nucleotide; D006629:Hirudins; D008074:Lipoproteins; D009841:Oligonucleotides; D010446:Peptide Fragments; D011119:Polynucleotides; D011480:Protease Inhibitors; D011994:Recombinant Proteins; C051928:lipoprotein-associated coagulation inhibitor; C081676:thrombin aptamer; D013917:Thrombin