fondaparinux and melagatran

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Azetidines; Benzylamines; Clinical Trials, Phase III as Topic; Fibrinolytic Agents; Fondaparinux; Glycine; Humans; Polysaccharides; Postoperative Complications; Pulmonary Embolism; Thromboembolism; Venous Thrombosis

Topics: Angina, Unstable; Animals; Anticoagulants; Azetidines; Benzylamines; Fondaparinux; Glycine; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Thrombosis

Topics: Anticoagulants; Arginine; Azetidines; Benzylamines; Fondaparinux; Glycine; Heparin; Hirudin Therapy; Humans; Pipecolic Acids; Polysaccharides; Prodrugs; Sulfonamides; Thrombin; Venous Thrombosis

A new generation of antithrombotic agents that target a single enzyme within the procoagulant cascade is making its way into mainstream clinical practice. Borrowing selectively from the properties of their parent anticoagulant, unfractionated heparin, as well as from those of peptide anticoagulants from reptile or insect venoms, designers of the new drugs have created targeted inhibitors of thrombin, factor Xa, or other specific factors in the procoagulant pathways. These new agents promise efficacy and safety profiles far more favorable than those of conventional anticoagulants for thromboprophylaxis after major orthopedic surgery and require no laboratory monitoring of drug efficacy in this setting. Ximelagatran, the oral "prodrug" of the direct thrombin inhibitor melagatran, is in phase III of clinical development. Clinical trials using various dosages of ximelagatran, sometimes preceded by subcutaneous melagatran, as thromboprophylaxis after total hip or knee replacement surgery have suggested efficacy equal to or better than that of warfarin and enoxaparin. The best dosing regimen and optimal timing of first dose for melagatran and ximelagatran remain to be determined, as do the mechanism and impact of drug disturbance of hepatic function. Fondaparinux, a selective, synthetic inhibitor of factor Xa, has been shown in large clinical trials to be superior to low-molecular-weight heparins and is approved as a fixed once-daily subcutaneous 2.5-mg dose for thromboprophylaxis for hip or knee replacement surgery and after hip fracture repair. Fixed-dose fondaparinux 2.5 mg initiated 6 to 8 hours after surgery achieved superior efficacy and comparable safety in head-to-head comparisons with enoxaparin for the prevention of venous thromboembolism after major orthopedic surgery. Fondaparinux is the only agent approved for use in hip fracture patients in the United States at this time and has recently gained approval for extended prophylaxis in this patient population.

Topics: Anticoagulants; Azetidines; Benzylamines; Clinical Trials as Topic; Factor Xa Inhibitors; Fondaparinux; Glycine; Heparin; Heparin, Low-Molecular-Weight; Humans; Models, Biological; Orthopedics; Polysaccharides; Postoperative Complications; Thromboembolism; Thrombolytic Therapy

The current management of thrombotic and vascular disorders has been strongly influenced by the introduction of several new drugs. 1. One of the major impact in the management of venous thromboembolic disorders has been the LMWHs. The newest, third generation heparin, the pentasaccharide inhibits specifically FXa. The elimination half-life of pentasaccharide is about 17 h, which allows a convenient once-daily dosing regime. The effects of pentasaccharide needs antithrombin. 2. Melagatran dipeptid is a specific, reversible direct thrombin inhibitor. It inhibits free and clot bound thrombin. Ximelagatran is a prodrug of melagatran. It is the first clinically used orally acting direct thrombin inhibitor. 3. Recombinant human activated protein C (rh-APC) has some advantages in patients with septic DIC. Qualities of the three new anticoagulants and clinical experiences with them have been summarized.

Topics: Anticoagulants; Azetidines; Benzylamines; Fondaparinux; Glycine; Humans; Polysaccharides; Protein C; Pulmonary Embolism; Recombinant Proteins; Venous Thrombosis

Two new classes of anticoagulants are actually developed which would change in the near future our strategies for the prevention and the treatment of venous thromboembolic events. These two classes are the anti-factor Xa and anti-factor IIa (direct antithrombin) agents. Among the anti factor Xa, the pentasaccharides are initiating their clinical use. Fondaparinux is a synthetic form of the natural pentasaccharide, its pharmacokinetics allows one s.c. administration/24 hours. It is active in prevention and treatment of venous thromboembolic and coronary thrombotic events. A modified form (idraparinux) whose pharmacokinetics allows one administration only once a week should have the same type of efficacy. Among direct antithrombin agents, hirudin and derivatives have been developed in the past decade with a limited use due to several drawback. More recently synthetic direct antithrombins modified to allow oral route have been developed, the most advanced in development, melagatran, is active in the prevention and treatment of venous thromboembolic and coronary thrombotic events. It could allow (if confirmed by clinical trials) a complete oral treatment of deep vein thrombosis without any biological monitoring. Melagatran is also active in the prevention of arterial thromboembolic events on atrial fibrillation. But other molecular forms of synthetic orally active direct antithrombin are also in development. Besides these important changes in our therapeutics which should appear in a near future, molecules aimed at other target are also tested: the most advanced are those antagonizing the initial phase of tissue factor activation of factor VII but other strategies are being tested such as stimulation of fibrinolysis. These new drugs at our disposal to treat venous thromboembolism should modify completely our handling of the patients. But additionally the numerous clinical trials necessary to prove the efficacy of the drugs, modify our understanding in the implication of the coagulation and in the physiopathogeny of thrombotic events.

Topics: Administration, Oral; Azetidines; Benzylamines; Clinical Trials as Topic; Coronary Thrombosis; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Glycine; Hirudin Therapy; Humans; Orthopedics; Polysaccharides; Prodrugs; Prothrombin; Research; Thrombin; Thromboembolism; Time Factors; Venous Thrombosis

Unfractionated heparin, low molecular weight heparin and vitamin K antagonists are anticoagulants currently used for the prevention and treatment of deep vein thrombosis and pulmonary embolism. Considerable limitations of these agents, such as a narrow therapeutic window, a variable dose response or lack of oral bioavailability, created the need for new anticoagulants. Numerous new compounds with different mechanisms of action have been developed and some have been already approved for clinical use. Quite recently, fondaparinux, an indirect anti-factor Xa inhibitor, has been licensed in Europe and in the US for prevention of VTE in patients undergoing hip or knee replacement surgery. In addition, lepirudin, a recombinant hirudin derivative, and the heparinoid danaparoid, have been approved in Austria for treatment of heparin-induced thrombocytopenia. Recombinant nematode anticoagulant protein c2, the orally available thrombin inhibitor ximelagatran and ART-123, a recombinant soluble thrombomodulin, are in advanced stages of clinical development. This article reviews mechanisms and sites of action, and the current state of preclinical and clinical research of these and various other agents with respect to the prevention and treatment of venous thromboembolism).

Topics: Anticoagulants; Azetidines; Benzylamines; Blood Coagulation Factors; Drugs, Investigational; Fondaparinux; Glycine; Heparin; Heparin, Low-Molecular-Weight; Humans; Polysaccharides; Pulmonary Embolism; Research; Thrombin; Venous Thrombosis; Vitamin K

Heparin and Vitamin K antagonists have been the only available anticoagulants for several decades. Their use has lead to significant achievements in all fields of medicine despite various shortcomings and bleeding complications. With the objective of an improved benefit-/risk ratio selective inhibitors of factor Xa (Fondaparinux) and factor IIa (Ximelagatran) have been developed. Ximelagatran can also be orally administered. The results obtained from various clinical trials with these compounds are extremely encouraging. Thus, a significant improvement of antithrombotic treatment may be expected by their future use in the clinical and out-patient setting.

Topics: Administration, Oral; Anticoagulants; Azetidines; Benzylamines; Biological Availability; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Glycine; Humans; Meta-Analysis as Topic; Polysaccharides; Prodrugs; Risk Factors; Stroke; Thrombosis