Anticoagulant - ximelagatran
The formation of blood clots in the veins can lead to pulmonary embolism or arterial thrombosis, either of which can be a precursor to unstable angina or peripheral arterial occlusion. The result of this is a myocardial infarction or thrombotic stroke.
Antithrombotic drugs, which reduce blood clotting, are the usual treatment for these conditions. Interventions can be made at any of several points in the clotting process, but of interest are the thrombin inhibitors. Thrombin is a trypsin-like serine protease, and the final enzyme in the coagulation cascade. It induces platelet aggregation, and enhances its own production by activating factors Va, VIIIa and XI. However, its most important function is catalysing the reaction which turns fibrinogen into fibrin, which polymerises to form the structure of the clot.
Standard thrombin inhibitors, including warfarin and heparin, are both macromolecules, and a selective thrombin inhibitor that is a small molecule and binds directly to the active site of thrombin would have clear therapeutic advantages.
One such molecule being developed by AstraZeneca is ximelagatran. It is a double pro-drug for the peptide thrombin inhibitor melagatran, which has very poor oral availability. Ximelagatran is hydrolysed extremely quickly following oral dosing into the active form melagatran.
A group of 1,916 patients under going knee or hip replacement surgery were given melagatran subcutaneously, or dalteparin or placebo, before surgery, and then further oral doses for seven to ten days afterwards.1,2 The highest dose of ximelagatran proved better than dalteparin at clot prevention.
Similarly, in a randomised double blind double dummy parallel group trial in 2,788 patients, 3mg subcutaneous melagatran was given four to 12 hours after surgery, then further oral 24mg doses of ximelagatran administered to patients undergoing hip or knee replacement.3 It was shown to be comparable to enoxaparin in the study.
A further study into a treatment for pulmonary embolism has been demonstrated in an open label pilot study in 12 haemodynamically stable patients.4 It was well tolerated and gave an improvement in symptoms of both pulmonary embolism and deep vein thrombosis, with neither severe bleeding nor death being reported.
Ximelagatran is being developed for both the prevention and treatment of venous thrombosis, and also to prevent stroke in patients with atrial fibrillation, and is currently undergoing Phase III trials.