title: Ximelagatran: direct thrombin inhibitor.
abstract: Warfarin sodium is an effective oral anticoagulant drug. However, warfarin has a narrow therapeutic window with significant risks of hemorrhage at therapeutic concentrations. Dosing is difficult and requires frequent monitoring. New oral anticoagulant agents are required to improve current anticoagulant therapy. Furthermore, while warfarin is effective in venous disease, it does not provide more than 60% risk reduction compared with placebo in venous thrombosis prophylaxis and considerably lower risk reduction in terms of arterial thrombosis. Ximelagatran is an oral pro-drug of melagatran, a synthetic small peptidomimetic with direct thrombin inhibitory actions and anticoagulant activity. As an oral agent, ximelagatran has a number of desirable properties including a rapid onset of action, fixed dosing, stable absorption, apparent low potential for medication interactions, and no requirement for monitoring of drug levels or dose adjustment. It has a short plasma elimination half-life of about 4 hours in cases of unexpected hemorrhage or need for reversal. Its main toxicity relates to the development of abnormal liver biochemistry and/or liver dysfunction with "long-term" use of the drug. This usually occurs within the first 6 months of commencing therapy, with a small percentage of patients developing jaundice. The biochemical abnormality usually resolves despite continuation of the drug. The cause of this toxicity remains unknown. Clinical studies to date have shown that ximelagatran is noninferior to warfarin in stroke prevention in patients with nonvalvular atrial fibrillation, noninferior to standard therapy as acute and extended therapy of deep vein thrombosis (DVT), and superior to warfarin for the prevention of venous thromboembolism post-major orthopedic surgery. It has also been shown to be more effective than aspirin alone for prevention of recurrent major cardiovascular events in patients with recent myocardial infarction.
authors.affiliation: Department of Clinical Haematology, Cancer Care Centre, St George Hospital, Gray St, Kogarah, NSW 2217, Australia. Shir-Jing.Ho@sesiahs.health.nswgov.au
authors.forename: Shir-Jing
authors.initials: SJ
authors.lastname: Ho
authors.forename: Tim A
authors.initials: TA
authors.lastname: Brighton
mesh_terms: D000208:Acute Disease; D000284:Administration, Oral; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000150:complications / Q000188:drug therapy; D001384:Azetidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001596:Benzylamines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006331:Heart Diseases / Q000188:drug therapy; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D019637:Orthopedic Procedures / Q000009:adverse effects; D010349:Patient Compliance; D017060:Patient Satisfaction; D010974:Platelet Aggregation / Q000187:drug effects; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020521:Stroke / Q000150:complications / Q000517:prevention & control; D013577:Syndrome; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013923:Thromboembolism / Q000209:etiology / Q000517:prevention & control; D016896:Treatment Outcome; D020246:Venous Thrombosis / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control
chemical_list: D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D011355:Prodrugs; C109573:melagatran; C426686:ximelagatran; D013917:Thrombin