Antithrombotic agent

Fondaparinux, the factor Xa-binding pentasaccharide (Arixtra, MW 1,728 Da), is prepared synthetically, unlike UFH, LMWH and danaparoid, which are obtained from animal sources. Despite only inactivating free factor Xa, clinical trials indicate that fondaparinux is an effective antithrombotic agent, both for venous thromboembolism prophylaxis and treatment, as well as for acute coronary syndrome and ST elevation myocardial infarction [4]. 

The PDE3 inhibitor, cilostazol, has been used as an antithrombotic agent and is currently being used in patients being treated for intermittent claudication. Cilostazol is also used for the prevention of restenosis after treatments such as angioplasty. Another PDE3 selective inhibitor, milrinone, has been used in the treatment of congestive heart failure. Milrinone also has been shown to increase the conductance of the CFTR transporter in vitro. 

Fibrinolytic agents have prothrombotic properties as well. The plasmin generated by thrombolysis leads to the production of thrombin, which is a potent platelet activator and converts fibrinogen to fibrin. Indeed, studies have shown early reocclusion in as many as 17% of the patients treated with lAT and 34% of the patients treated with IV rt-PA. Therefore, a strong rationale exists for the adjuvant use of antithrombotic agents. 

Aspirin is maximally effective as an antithrombotic agent at the comparatively low dose of 81 to 325 mg per day. (The antipyretic dose of aspirin in adults is 325 to 650 mg every 4 h.) Higher doses of aspirin are actually contraindicated in patients prone to thromboembolism. At higher doses, aspirin also reduces synthesis of prostacyclin, another arachidonic acid metabolite. Prostacyclin normally inhibits platelet aggregation. The prophylactic administration of low-dose aspirin has been shown to increase survival following myocardial infarction, decrease incidence of stroke, and assist in maintenance of patency of coronary bypass grafts. 

Warfarin is the antithrombotic agent of first choice for secondary prevention in patients with atrial fibrillation and a presumed cardiac source of embolism. 

The patent literature covers many pyridazine derivatives claimed as blood platelet aggregation inhibitors and antithrombotic agents. The interest has been focused mainly on 6-aryl-4,5-dihydro-3(2//)-pyridazinones. In these compounds the aryl substituent has been varied within a wide range. Thus, dihydro-pyridazinones bearing a substituted or heterocycle-fused phenyl group at C-6 (60, R R2,R3 = H, alkyl Ar = substituted Ph) [34, 110-112,205-233] as well as various heteroaryl substituted congeners (61, R1, R2, R3 = H, alkyl Ar = pyridyl, thienyl, pyrrolyl, pyrazolyl) [234-241] have been prepared in search of novel antithrombotics. 

Additional reports on dihydropyridazinones as antithrombotic agents have been published [260-264]. 

Also some 4(l//)-pyridazinones [121] and several 3-(aminoalkylthio)-6-chloropyridazines [269] have been claimed as useful antithrombotic agents. In... 

The fatal complications caused by toxin-LR in mice are unusual. Toxin-LR is a potent thrombogenic agent. Generally, such agents bring about symptoms of illness within a few minutes of injection of a lethal dose. However, toxin-LR produces no overt signs of illness until about one-half hour has elapsed. Moreover, pretreatment of mice with known antithrombotic agents does not affect the lethality of the toxin. 

F. Bellamy, D. Horton, J. Millet, F. Picart, S. Samreth, and J. B. Chazan, Glycosylated derivatives of benzophenone, benzhydrol and benzhydril as potential venous antithrombotic agents,./. Med. Chem., 36 (1993) 898-903. 

Heparin is biosynthesized in mast cells as a PG with approximately 10 GAG side chains (5). When mast cells degranulate, PG heparin is enzymatically degraded to GAG heparin (Fig. 1). Exogenous heparin is used primarily as an anticoagulant/antithrombotic agent. Heparin is produced from mast-cell-rich tissues, such as lung and intestinal mucosa, in metric ton quantities yearly for use as a pharmaceutical agent. 

Aprotinin (Trasylol) [Antithrombotic Agent/Protease Inhibitor]... 

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