bivalirudin and acetylphenylalanyl-prolyl-boroarginine

In addition to its pivotal role in blood coagulation, thrombin is one of the most important agonists for platelet recruitment and aggregation. Thrombin inhibitors impede thrombin-induced platelet aggregation but have no effect on aggregation induced by other agonists. A review is presented of selective thrombin inhibitors now in clinical investigation, some of which are also orally active.

Topics: Administration, Oral; Adult; Animals; Antithrombins; Arginine; Blood Platelets; Boron Compounds; Clinical Trials as Topic; Dogs; Drug Evaluation, Preclinical; Glycine; Hirudin Therapy; Hirudins; Humans; Naphthalenes; Oligopeptides; Peptide Fragments; Pipecolic Acids; Piperidines; Recombinant Proteins; Sulfonamides; Thrombin

Topics: Antifibrinolytic Agents; Antithrombin III; Antithrombins; Aprotinin; Arginine; Binding Sites; Boron Compounds; Enzyme Activation; Fibrinolysis; Heparin; Hirudins; Humans; Oligopeptides; Peptide Fragments; Pipecolic Acids; Protein C; Recombinant Proteins; Sulfonamides; Thrombin

111Indium-labelled platelets were continuously monitored in the cranial vasculature of anaesthetised rabbits and thrombin inhibitors and anti-coagulants were tested on the sustained platelet accumulation induced by intracarotid injection of thrombin (90 U/kg). Pretreatment, commencing 30 min prior to thrombin, with a 1-h intracarotid infusion of D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK; 0.25-1.0 micrograms/kg per min), unfractionated heparin (Multiparin; 5-20 U/kg bolus + 0.75-3.0 U/kg per min infusion) or low molecular weight heparin (Fragmin; 2.4-9.6 U/kg per min) produced dose-related reductions in platelet accumulation. Continuous infusion of acetyl-D-phenylalanyl-prolyl-boroarginine (DuP-714 ester; 30 micrograms/kg per min) for 30 min induced marked accumulation of platelets in the pulmonary circulation in the absence of thrombin. Bolus intracarotid injection, 1 min before thrombin, of Hirulog (0.05-0.2 mg/kg), PPACK (10-30 micrograms/kg), Multiparin (25-100 U/kg), Fragmin (150 U/kg) or DuP-714 ester (15-30 micrograms/kg) caused significant reductions in platelet accumulation. When injected 1 min after thrombin, Hirulog (1 mg/kg), PPACK (100 micrograms/kg), Fragmin (150 U/kg) and DuP-714 ester (30 micrograms/kg) had no significant effect and Multiparin (100 U/kg) increased platelet accumulation. The results demonstrate that pretreatment with a range of thrombin inactivators, acting via different mechanisms, can inhibit thrombin-induced cerebral thromboembolism in the rabbit.

Topics: Amino Acid Chloromethyl Ketones; Animals; Anticoagulants; Antithrombins; Blood Platelets; Boron Compounds; Dalteparin; Dose-Response Relationship, Drug; Fibrinolytic Agents; Heparin; Hirudin Therapy; Hirudins; Indium; Infusions, Intra-Arterial; Intracranial Embolism and Thrombosis; Isotope Labeling; Male; Molecular Weight; Oligopeptides; Peptide Fragments; Platelet Aggregation; Platelet Aggregation Inhibitors; Pulmonary Circulation; Rabbits; Recombinant Proteins; Structure-Activity Relationship; Thrombin