Contribution of in vivo models of thrombosis to the discovery and development of novel antithrombotic agents

Cardiovascular and cerebrovascular diseases continue to be the leading caus e of death throughout the world. Over the past two decades, great advances have been made in the pharmacological treatment and prevention of thromboti c disorders (e.g., tissue plasminogen activators, platelet GPIIb/IIIa antag onists, ADP receptor antagonists such as clopidogrel, low-molecular weight heparins, and direct thrombin inhibitors). New research is leading to the n ext generation of antithrombotic compounds such as direct coagulation FVIIa inhibitors, tissue factor pathway inhibitors, gene therapy, and orally act ive direct thrombin inhibitors and coagulation Factor Xa (FXa) inhibitors. Animal models of thrombosis have played a crucial role in discovering and v alidating novel drug targets, selecting new agents for clinical evaluation, and providing dosing and safety information for clinical trials. In additi on, these models have provided valuable information regarding the mechanism s of these new agents and the interactions between antithrombotic agents th at work by different mechanisms. This review briefly presents the pivitol p reclinical studies that led to the development of drugs that have proven to be effective clinically. The role that animal models of thrombosis are pla ying in the discovery and development of novel antithrombotic agents is als o described, with specific emphasis on FXa inhibitors. The major issues reg arding the use of animal models of thrombosis, such as the use of positive controls, appropriate pharmacodynamic markers of activity, safety evaluatio n, species-specificity, and pharmacokinetics, are highlighted. Finally, the use of genetic models in thrombosis/hemostasis research and pharmacology i s presented using gene-therapy for hemophilia as an example of how animal m odels have aided in the development of these therapies that are now being e valuated clinically. In summary, animal models have contributed greatly to the discovery of currently available antithrombotic agents and will play a primary role in the discovery and characterization of the novel antithrombo tic agents that will provide safe and effective pharmacological treatment f or life-threatening thrombotic diseases. (C) 2000 Elsevier Science Inc. All rights reserved.