ximelagatran and Inflammation

Topics: Anti-Inflammatory Agents; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Humans; Inflammation; International Normalized Ratio; Stroke; Thrombin; Warfarin

Thrombin plays a central role in thrombus formation through its conversion of fibrinogen to fibrin and activation of platelets as well as amplifying its own generation by feedback activation via factors V, VIII, and XI. Consequently, thrombin represents a logical and promising target for therapeutic interventions against arterial and venous thromboembolic disorders. Ximelagatran is the first oral agent in the new class of direct thrombin inhibitors and is rapidly absorbed and bioconverted to the active moiety, melagatran, which inhibits fluid-phase and clot-bound thrombin with similar high potency. Binding to the active site of thrombin is direct and competitive and does not require the presence of co-factors. Inhibition of thrombin generation and platelet activation has been demonstrated in vitro with melagatran as well as ex vivo after oral administration of ximelagatran to healthy human volunteers. Oral ximelagatran dose dependently reduced the total thrombus area in an ex vivo flow chamber model of arterial thrombosis, reflecting the cumulative effect of inhibition of thrombin activity, thrombin generation, and platelet activation. Melagatran has also been shown to reduce thrombin-mediated inflammation in vitro. The combination of antithrombotic and anti-inflammatory activity with the practicality of oral dosing provided by ximelagatran represents an important new option for the treatment of arterial and venous thromboembolic disorders.

Topics: Administration, Oral; Anti-Inflammatory Agents; Anticoagulants; Azetidines; Benzylamines; Blood Coagulation; Humans; Inflammation; Platelet Activation; Thrombin; Thromboembolism; Thrombosis

Thrombin has a role not only in the coagulation process but also in inflammatory responses. Oral direct thrombin inhibitors (DTIs) are currently being evaluated in patients with thromboembolic diseases.. To investigate whether an oral DTI affects markers for platelet and inflammatory activity after myocardial infarction (MI).. A total of 518 patients with MI were randomly assigned to ximelagatran treatment (four different dose groups) in combination with aspirin, or aspirin alone for 6 months. The levels of soluble (s) P-selectin, soluble tissue factor, C-reactive protein (CRP), interleukin (IL)-10 and IL-18 were analysed in serial blood samples.. sP-selectin concentration increased after 1 week and persisted at an elevated level for 6 months in all study groups (P < 0.001). In the two highest ximelagatran dose groups, there was a reduced increase in sP-selectin compared to treatment with lower doses of ximelagatran and aspirin alone (P = 0.01 and P = 0.002, respectively). IL-18 levels did not change in the aspirin alone treatment group. By contrast, there was an elevation in IL-18 level in the lower and higher ximelagatran dose groups after 6 months (P = 0.006 and P < 0.001, respectively). Ximelagatran increased IL-10 levels (P = 0.002) and reduced the decrease in CRP levels after 6 months compared to treatment with aspirin alone (P = 0.002).. A persistent elevation of platelet activity is found in patients with a recent MI after the cessation of acute antithrombotic treatment, and the addition of an oral DTI at higher doses decreases the activity. By contrast, long-term treatment with a DTI increases the levels of several markers of inflammation. Further studies with prolonged exposure of oral DTIs are needed for evaluation of the effect on inflammatory processes and to determine whether these agents influence clinical outcomes.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antithrombins; Aspirin; Azetidines; Benzylamines; Biomarkers; Blood Platelets; C-Reactive Protein; Comorbidity; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Inflammation; Interleukin-10; Interleukin-18; Male; Middle Aged; Myocardial Infarction; P-Selectin; Platelet Activation; Risk Factors; Thromboplastin; Time Factors; Treatment Outcome