Current trends in the development of anticoagulant and antithrombotic drugs.

Developments in biotechnology, synthetic chemistry, and extraction methods have contributed significantly to provide many newer antithrombotic and anticoagulant drugs. Many of these drugs exhibit mechanisms of actions distinct from heparin and oral anticoagulants. The depolymerization of heparin has resulted in the development of LMWHs. These drugs have now attained the agent of choice status for the prophylaxis of postsurgical and medical thrombotic disorders. LMWHs are now being clinically evaluated for the treatment of established thrombosis and prevention of post-acute angioplasty occlusion and reocclusion. Many newer applications of these agents will be proposed in coming years. Synthetic and recombinant antithrombin agents, such as hirudin and hirulog, have been claimed to exhibit effective anticoagulant and antithrombotic actions. The clinical data, however, are rather limited, and additional validation studies are needed. These agents, however, provide an alternate anticoagulation approach in patients who are refractory to the actions of heparin or who developed heparin-induced thrombocytopenia. Both hirudin and peptide conjugates are undergoing extensive clinical trials throughout the world in various indications. Once validated, their optimized use will provide physicians and surgeons an alternate anticoagulant approach for heparin-compromised patients. Glycosaminoglycans, such as dermatan sulfate, heparan sulfate, and other mixtures, have been developed for various indications. These drugs, however, are relatively inferior to LMWHs for the prophylaxis of thromboembolism. Although these agents have been used for phlebitis and other indications, well-designed objective clinical trials are not available at this time. Because these agents exhibit other effects, such as the effect on smooth muscle cell proliferation, these may be of some value in the control of post-percutaneous transluminal coronary angioplasty restenosis. Several synthetic analogs of heparin and related glycosaminoglycans have also been developed. One of these agents is a synthetic pentasaccharide that represents the AT-III binding site in the heparin molecule. This agent produces a strong anti-Xa effect and is devoid of any antithrombin actions. This agent is currently being developed for the prophylaxis of thromboembolism. The synthetic pentasaccharide is devoid of any effects on platelets and thus does not produce any thrombocytopenic effects. Thus it may be useful in those patients who develop thrombocytopenia and white clot syndrome. A hypersulfated lactobionic acid analog has also been developed as an antithrombotic agent. This agent was initially found to produce its antithrombotic action via HC-II. More recent data, however, show that it also releases TFPI from endogenous sites.(ABSTRACT TRUNCATED AT 400 WORDS)