Oral Direct Thrombin Inhibitors

Oral thrombin inhibitors, such as megalatran, ximelagatran, and CI-1028, are currently being developed as potential agents for the prophylaxis and treatment of thrombosis. The first of the direct thrombin inhibitors to be used was hirudin; however, direct inhibitors with low molecular weights have since been developed (e.g., DuP 714, PPACK, efegatran), and these have an enhanced ability to inhibit clot-bound thrombin and the processes of thrombosis taking place at sites of arterial damage (78,79). For many of the available oral direct thrombin inhibitors, suboptimal gastrointestinal absorption is an evident problem. H376/95 is a new oral direct thrombin inhibitor. It is a prodrug with two protective residues attached to the direct thrombin inhibitor mega-latran. Gustafsson et al. (80) undertook a 3-part study comparing the intestinal absorption properties of melagatran on its own and in the H376/95 prodrug form, and also studied the affect of the prodrug on an experimental thrombosis model in rats. In the melagatran portion of the study, healthy male volunteers were given escalating single oral doses of the agent (57-200 mg) in an aqueous solution after an overnight fast. Four people were used at each dose level. In the prodrug study, healthy male volunteers were given escalating single oral doses between 5 and 98 mg, with 5 subjects at each dose level. By converting melagatran into the prodrug, the oral absorption of melagatran was between 2.7 and 5.5X higher than after oral administration of unaltered melagatran. It was concluded that, by using the prodrug principle in this way, melagatran becomes endowed with the pharmacokinetic properties necessary for oral administration without compromising the pharmacodynamic properties of the agent, thereby providing an oral direct thrombin inhibitor of use in a clinical setting. In the rat model, oral H 376/95 was found to be more effective in preventing thrombosis than was the LMWH, dalteparin.

Using a rat model, Mikulski et al. (81) assessed the effect of pretreatment with mela-gatran and inogatran for cerebral infarction. Ischemic stroke was induced in rats photo-chemically. A single oral dose of melagatran (30 imol/kg) was found to significantly reduce the vol of the cortical infarct by 53% (p < 0.05) compared with control animals. Additionally, after administration of intravenous (6 imol/kg) or oral (100 imol/kg) ino-gatran, there was a decrease in cortical infarct vol of 83 and 19%, respectively, compared with controls. Therefore, the study demonstrated that experimental focal ischemic infarction, brought about by photochemically induced endothelial cell damage, can be significantly reduced with direct thrombin inhibitors given in oral form.

McClanahan et al. (78) have conducted a study with the objective of evaluating the efficacy of CI-1028, a direct thrombin inhibitor that is orally bioavailable, in a canine electrolytic injury model of venous and arterial thrombosis. Animals received either saline or CI-1028 in doses of 10, 15, 20, or 30 mg/kg. Maximum blood CI-1028 concentrations were generally achieved between 15 and 30 min of oral administration. The drug was found to increase time to occlusion (TTO). In the 20 mg/kg treatment group (n = 8), TTO was significantly longer than in controls both in arteries (p = 0.05) and in veins (p < 0.05). Likewise, at the 30 mg/kg dose (n = 8), TTO was significantly prolonged. Although surgical blood loss and template bleeding times had a tendency to increase in a dose-dependent fashion, this only reached statistical significance at the highest dose. Consistent with the agents' mechanism of action, dramatic changes in thrombin time were noted. Hardly any changes were detected in prothrombin time. Maximum aPTT and activated clotting time (ACT) were achieved at approx 30 min after administration, and they were in the region of 2- and 5-fold baseline values, respectively, at the 30 mg/kg dose. These findings demonstrate that CI-1028 provides a dose-dependent antithrombotic effect following oral administration in the canine model described.

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