The therapeutic potential of novel anticoagulants.
Conventional anticoagulant therapy has been based on indirect inhibition of coagulation factors with heparin and warfarin. These agents display liabilities prompting the development of new anticoagulants over the last two decades. The first to be developed was a series of low molecular weight heparins(LMWHs). Their favourable pharmacokinetic profiles and risk/benefit ratios led to widespread use in Europe and, more recently, approval for their use in the USA. Paralleling the development of LMWHs has been the pursuit of a different strategy focused on direct rather than indirect inhibition of enzymes in the coagulation cascade. In contrast to heparin, LMWHs, or other glycosaminoglycans, direct inhibitors exert their effects independent of either antithrombin III (ATIII) or heparin cofactor II (HCII) and more effectively inhibit clot-bound thrombin or FXa. Highly potent, selective (versus other serine proteases)direct thrombin and FXa inhibitors have been identified and isolated from natural sources, such as leeches, ticks and hookworms. The recombinant forms and analogues of the senatural proteins have been produced using molecular biology techniques, i.e., rHirudin, Hirulogs, recombinant tick anticoagulant peptide (rTAP), recombinant antistasin (rATS) and recombinant nematode anticoagulant peptide-5 (rNAP-5). The design of novel structures or the modification of existing chemicals has led to the synthesis of many non-peptide, low molecular weight inhibitors of thrombin and FXa. Some of them are orally active and may be suitable for long-term clinical use. In addition, considerable progress has been made in developing specific TF/VIIa complex inhibitors. The anticoagulation properties of the new agents are being characterised in experimental studies. Some of them have been advanced to large scale clinical trials and their effectiveness, and sometimes relative ineffectiveness,in arterial and venous thromboembolic disorders has been demonstrated. They are being tested for their potential as new antithrombotic agents that act via direct enzyme inhibition. Thus,the clinician should in future be able to target different thrombotic conditions with proven, specific anticoagulant interventions.
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Vascular and Cardiac Diseases and Drug Development, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.
Rogers
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Uprichard
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Gallagher
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