bivalirudin and melagatran

The coagulation cascade, and particularly thrombin, plays a very important role in arterial and venous thrombosis. Thereby, it is clear that thrombin inactivation is an optimal strategy for thrombotic disease prevention and treatment. The direct thrombin inhibitors are a new class of anticoagulant drugs directly binding thrombin and blocking its interaction with fibrinogen. The group of direct thrombin inhibitors includes recombinant hirudin (lepirudin and desirudin), bivalirudin, melagatran and its oral precursor, ximelagatran, argotraban and dabigatran. These drugs have several advantages compared to other anticoagulant drugs, and the particular pharmacokinetic properties of some of them could be very important for future management of thromboembolic prophylaxis. The efficacy and safety of these new drugs are evaluated in several clinical trials; however today only few clinical indications are available for the majority of them.

Topics: Anticoagulants; Antithrombins; Azetidines; Benzylamines; Clinical Trials as Topic; Drug Therapy, Combination; Fibrinolytic Agents; Hirudins; Humans; Peptide Fragments; Recombinant Proteins; Thromboembolism; Treatment Outcome

Thromboembolic diseases are a major cause of morbidity and mortality, particularly in the Western world, which has stimulated enormous research efforts by the pharmaceutical industry to introduce new antithrombotic therapies. One strategy is the development of direct inhibitors of the serine protease thrombin, which holds a central position in the final steps of the blood coagulation cascade and in platelet activation. At present there is only limited clinical use of some parenteral preparations of thrombin inhibitors in acute situations, especially when the common antithrombotic drugs heparin, warfarin and aspirin are ineffective or associated with side effects. However, for use in prophylaxis of thrombotic diseases such inhibitors should be orally available, must be safe to avoid bleeding complications and should have an appropriate half-life, allowing once or twice daily dosing to maintain adequate antithrombotically effective blood levels. Details of several new and potent thrombin inhibitors have been published during the last years. For some of them oral bioavailability is claimed and they are effective in in vitro coagulation assays. However, most of them showed only limited efficacy in animal studies with respect to the doses administered. For that reason, effort is concentrated on the evaluation and optimisation of the overall physicochemical characteristics of the inhibitors in order to improve the pharmacokinetics and, thus, the development of promising drug candidates. Nevertheless, only careful clinical studies can give clear answers about the true therapeutical benefit of new developments in this field. This review summarises the current status of direct thrombin inhibitors which are already in clinical use and clinical development and gives an overview on recently published and promising new compounds.

Topics: Arginine; Azetidines; Benzylamines; Clinical Trials as Topic; Glycine; Hirudin Therapy; Hirudins; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombin

Inhibiting thrombin as a key enzyme of the coagulation cascade is therapeutically useful in thromboembolic diseases. In coronary thrombosis, direct thrombin inhibitors promise to be useful for an efficacious therapy. Hirudin and recombinant or synthetic mimetics like hirulog, argatroban and melagatran have proven their efficacy in clinical studies.. Therapy with direct thrombin inhibitors such as hirudin and analogous substances reduces coronary events. Moreover, the agents are useful for therapy of thromboembolic diseases, especially in the case of heparin induced thrombocytopenia type II.

Topics: Acute Disease; Angina, Unstable; Angioplasty, Balloon, Coronary; Animals; Anticoagulants; Antithrombins; Arginine; Azetidines; Benzylamines; Fibrinolytic Agents; Glycine; Hirudin Therapy; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Pipecolic Acids; Platelet Aggregation Inhibitors; Rabbits; Recombinant Proteins; Sulfonamides; Syndrome; Thrombin; Thromboembolism; Thrombosis; Time Factors

Four direct thrombin inhibitors (DTIs), lepirudin, bivalirudin, argatroban, and melagatran, differ in their ability to prolong the prothrombin time (PT). Paradoxically, the DTI in clinical use with the lowest affinity for thrombin (argatroban) causes the greatest PT prolongation. We compared the effects of these DTIs on various clotting assays and on inhibition of human and bovine factor Xa (FXa). On a mole-for-mole basis, lepirudin was most able to prolong the PT, activated partial thromboplastin time (APTT), and thrombin clotting time (TCT), whereas argatroban had the least effect. At concentrations that doubled the APTT (argatroban, 1 micromol/l; melagatran, 0.5 micromol/l; bivalirudin, 0.25 micromol/l; lepirudin, 0.06 micromol/l), the rank order for PT prolongation was: argatroban > melagatran > bivalirudin > lepirudin. Although the Ki's associated with inhibition of human FXa by melagatran (1.4 micromol/l) and argatroban (3.2 micromol/l) approach their therapeutic concentrations, inhibition of FXa did not appear to be a major contributor to PT prolongation, since argatroban also prolonged the PT of bovine plasma (despite a Ki for bovine FXa of 2,600 micromol/l). Only melagatran inhibited prothrombinase-bound FXa. We conclude that the differing effects of the DTIs on PT prolongation are primarily driven by their respective molar plasma concentrations required for clinical effect. DTIs with a relatively low affinity for thrombin require high plasma concentrations to double the APTT; these higher plasma concentrations, in turn, quench more of the thrombin generated in the PT, thereby more greatly prolonging the PT.

Topics: Animals; Anticoagulants; Arginine; Azetidines; Benzylamines; Blood Coagulation; Cattle; Dose-Response Relationship, Drug; Factor Xa; Factor Xa Inhibitors; Glycine; Hirudins; Humans; In Vitro Techniques; Partial Thromboplastin Time; Peptide Fragments; Pipecolic Acids; Prothrombin Time; Recombinant Proteins; Species Specificity; Sulfonamides; Thrombin; Thrombin Time; Thromboplastin

Thrombotic disorders can lead to uncontrolled thrombin generation and clot formation within the circulatory system leading to vascular thrombosis. Direct inhibitors of thrombin have been developed and tested in clinical trials for the treatment of a variety of these thrombotic disorders. The bleeding complications observed during these trials have raised questions about their clinical use. The development of a computer-based model of coagulation using the kinetic rates of individual reactions and concentrations of the constituents involved in each reaction within blood has made it possible to study coagulation pathologies in silico. We present an extension of our initial model of coagulation to include several specific thrombin inhibitors. Using this model we have studied the effect of a variety of inhibitors on thrombin generation and compared these results with the clinically observed data. The data suggest that numerical models will be useful in predicting the effectiveness of inhibitors of coagulation.

Topics: Anticoagulants; Arginine; Azetidines; Benzylamines; Blood Coagulation; Computer Simulation; Dose-Response Relationship, Drug; Glycine; Hirudins; Humans; Kinetics; Models, Cardiovascular; Oligopeptides; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides; Thrombin

The relation between the antithrombotic effect in vivo, and the inhibition constant (Ki) and the association rate constant (k(on)) in vitro was investigated for eight different thrombin inhibitors. The carotid arteries of anaesthetized rats were exposed to FeCl3 for 1 h, and the thrombus size was determined from the amount of incorporated 125I-fibrinogen. The thrombin inhibitors were given intravenously, and complete concentration- and/or dose-response curves were constructed. Despite a 50,000-fold difference between the Ki-values comparable plasma concentrations of hirudin and melagatran were needed (0.14 and 0.12 micromol l(-1), respectively) to obtain a 50% antithrombotic effect (IC50) in vivo. In contrast, there was a comparable in vitro (Ki-value) and in vivo (IC50) potency ratio for melagatran and inogatran, respectively. These results can be explained by the concentration of thrombin in the thrombus and improved inhibition by the low-molecular-weight compounds. For all eight thrombin inhibitors tested, there was an inverse relationship between k(on)-values in vitro and the slope of the dose response curves in vivo. Inhibitors with k(on)-values of < 1 x 10(7) M(-1) s(-1) gave steep dose response curves with a Hill coefficient > 1. The association time for inhibition of thrombin for slow-binding inhibitors will be too long to give effective antithrombotic effects at low plasma concentrations, but at increasing concentrations the association time will decrease, resulting in a steeper dose-response curve and thereby a more narrow therapeutic interval.

Topics: Amino Acid Chloromethyl Ketones; Animals; Anticoagulants; Arginine; Azetidines; Benzylamines; Carotid Artery Thrombosis; Dose-Response Relationship, Drug; Fibrinolytic Agents; Glycine; Hemodynamics; Heparin; Hirudin Therapy; Hirudins; Kinetics; Male; Oligopeptides; Partial Thromboplastin Time; Peptide Fragments; Pipecolic Acids; Piperidines; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Sulfonamides; Thrombin; Thrombin Time