Jawed FAREED, Rakesh WAHİ, Debra A. HOPPENSTEADT

An update on new anticoagulant drugs

Abstract. The conventional management of thrombotic and cardiovascular disorders is based on the use of heparin, oral anticoagulants and aspirin. Despite remarkable progress in life sciences, these drugs still remain a challenge and mystery to us, and their use is far from optimized. The development of low molecular weight heparins and the synthesis of heparinomimetics, such as the chemically synthesized pentasaccharide, represent a refined use of heparin. Additional drugs from this knowledge will continue to develop; however, none of these drugs will match the polypharmacology of heparin. Aspirin still remains the leading drug in the management of thrombotic and cardiovascular disorders. The newer antiplatelet drugs such as ADP receptor inhibitors, GPIIb/IIIa inhibitors and other specific inhibitors have limited effects and have been tested in patients who have already been treated with aspirin. Warfarin provides a convenient and affordable approach in the long-term outpatient management of thrombotic disorders. The optimized use of these drugs still remains to be the approach of choice to manage thrombotic disorders. The new anticoagulant targets, including specific sites in the hemostatic network such as tissue factor, individual clotting factors (IIa, VIIa, IXa, Xa, XIIa and XIIIa), recombinant forms of serpins (antithrombin, heparin co-factor II and tissue factor pathway inhibitors), recombinant activated protein C, thrombomodulin and site specific serine proteases inhibitors complexes have also been developed. There is a major thrust on the development of orally bioavailable anticoagulant drugs (anti-Xa and IIa agents), which are slated to replace oral anticoagulants. Both the anti-factor Xa ( Rivaroxaban and Apixaban) antithrombin (Dabigatran) agents have been developed for oral use and have provided impressive clinical outcomes in sponsor trials for the post surgical prophylaxis of venous thrombosis; however, safety concerns related to liver enzyme elevations and thrombosis rebound have been reported with their use. For these reasons the US FDA did not approve the orally active antithrombin agent Ximelagatran for several indications. More recently the Columbian health authorities reject dabigatran for similar reasons. The synthetic pentasaccharide (Fondaparinux) has undergone an aggressive clinical development. Unexpectedly, Fondaparinux also produced major bleeding problems at minimal dosages. Fondaparinux represents only one of the multiple pharmacologic effects of heparins. Thus, its therapeutic index will be proportionately narrower. The methylated pentasaccharide, namely Idraparinux, is effective for long term prophylaxis, but its use is associated with bleeding. Other forms of pentasaccharide such as the biotinylated form which can be reversed with fucoidin are also developed. The newer antiplatelet drugs have added a new dimension in the management of thrombotic disorders. The favorable clinical outcomes with aspirin and Clopidogrel have validated COX-1 and P2Y12 receptors as targets for new drug development. Prasugrel, a novel thienopyridine, Cangrelor and AZD 6140 represent newer P2Y12 antagonists. Cangrelor and AZD 6140 are direct inhibitors, whereas Prasugrel requires metabolic activation. While clinically effective, recent results have prompted a closure of a large clinical trial with Prasugrel due to bleeding. The newer anticoagulant and antiplatelet drugs are attractive for several reasons; however, none of these are expected to replace the conventional drugs in poly-therapeutic approaches. Heparins, warfarin and aspirin will continue to play a major role in the management of thrombotic and cardiovascular disorders beyond 2010. Key word: New anticoagulant drugi

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