| Abstrakt: |
Coronary heart disease leading to heart attack and ischemic stroke are the two most prevalent causes of mortality and morbidity in the United States. Thrombosis is the most important pathological mechanism underlying heart attack and stroke. The key role of platelets in arterial thrombosis was recognized for some time and a variety of antiplatelet agents have been developed as successful therapeutic agents for treating thrombotic diseases. Those include orally active ADP antagonists, intravenous GIIbIIIa antagonists, intravenous thrombin inhibitors and orally active cAMP phosphodiesterase 3 (PDE3) inhibitors. Antiplatelet agents being developed include inhibitors of coagulation factors Xa and VIIa, orally active thrombin inhibitors and proteinase-activated receptor 1 (PAR1) antagonists. On the other hand, for deep vein thrombosis where fibrin formation plays a major role, anticoagulants such as Coumarin, heparin and heparin-like small molecules have been therapeutically used. This issue of CPD presents the collection of the state of art reviews on various current and future antithrombotic agents as well as the molecular targets for potential novel antithrombotic agents. The first article by Kambayashi et al. [1] provides a comprehensive but clear review on antithrombotic actions of Cilostazol with its unique antithrombotic and vasodilatory properties. Cilostazol is the only PDE3 inhibitor approved in Japan for treatment of artierial occlusive diseases and very recently for stroke. Despite its remarkable antiplatelet properties, Cilostazol is not recognized as an antithrombotic agent in the U.S. due to the performance of most studies on this drug in Japan and the negative clinical outcomes of this class of compounds. The second article contributed by Kunapuli et al. [2] presents a comprebensive review on the pharmacology of several ADP receptors (P2Y1, P2Y12 and P2X1) in relation to platelet aggregation as well as summaries of clinical studies with clopidogrel and several new generations of ADP antagonists. Kunapuli suggests a dual inhibition of P2Y1 and P2Y12 as an attractive approach for development of a more efficacious antithrombotic agent. The third article by Mousa [3] highlights the role of the various antiplatelet therapies, especially GPIIbIIIa, and the need for combination therapies in thrombotic disorders. In view of the failed clinical trials with orally active GPIIbIIIa antagonists, he provides profiles of ideal GPIIbIIIa antagonists, which also apply to thrombin inhibitors. The fourth article by Linhardt and his coworkers [4] presents a comprehensive review on anticoagulant properties of synthetic oligosaccharides as heparin-mimetics. So far only a single approved drug, the pentasaccharide Fondaparinux, resulted from the efforts for developing heparin-mimetics as antithrombotic agents Linhardt believes more research warranted for the discovery of the next generation of heparin oligosaccharide antalogs with an improved side effect potential compared to low molecular weight heparin and Fondaparinux. In the fifth article Gould and Leadley [5] discuss recent advances in the development of inhibitors of coagulation factor Xa (FXa) as antithrombotic agents and present promising clinical data on some of non-oral, direct FXa inhibitors with a good efficacy and relative safety profile. The sixth article by Ahn et al. [6] focuses on the development as an antithrombotic agent and preclinical pharmacological properties of thrombin receptor proteinase-activated receptor 1 (PAR1) antagonists. This approach, unlike direct thrombin enzyme inhibitors, only inhibits the cellular action of thrombin on platelets and other target cells, leaving thrombin-mediated fibrin generation intact. Petidomimetic and nonpeptide PAR1 antagonists are being developed. The antithrombotic efficacy of the peptidomimetic PAR1 antagonists has recently been demonstrated in nonprinate models of thrombosis, providing proof of principle for clinical trials of an orally available nonpeptide PAR1 antagonist, when available. The last but very important article by Gruber and Hanson [7] identifies multiple new targets for development of safer antithrombotic agents by using strict criteria that targets inhibition should be compatible with normal life but have antithrombotic effects. Approaches thus identified include inhibition of intrinsic coagulation pathway and reduction of platelet counts. The rapid advances in our understanding of pharmacological actions of the current and second generation of antithrombotic drugs together with the promising preclinical data on new antithrombotic agents with novel mechanisms of action provide us with a very good prospect for delivery of new antithrombotic drugs with improved efficacy and safety profile in the next 5 to 10 years. I would like to thank all contributing authors for their very good review articles in the fields of antithrombotic agents and the managing editor for his patience and advice to me in preparing this issue. References [1] Kambayashi J, Liu Y, Sun B, Shakur Y, Yoshitake M. Cilostazol as a Unique Antithrombotic Agent. Curr Pharm Design 2003; 9(28): 2289-2302. [2] Kunapuli SP, Ding Z, Dorsam RT, Kim S, Murugappan S, Quinton TM. ADP Receptors-Targets for Developing Antithrombotic Agents. Curr Pharm Design 2003; 9(28): 2303-2316. [3] Mousa SA. Antiplatelet Therapies: Platelet GPIIb / IIIa Antagonists and Beyond. Curr Pharm Design 2003; 9(28): 2317-2322. [4] Avci FY, Karst NA, Linhardt RJ. Synthetic Oligosaccharides as Heparin-Mimetics Displaying Anticoagulant Properties. Curr Pharm Design 2003; 9(28): 2323-2335. [5] Gould WR, Leadley RJ. Recent Advances in the Discovery and Development of Direct Coagulation Factor Xa Inhibitors. Curr Pharm Design 2003; 9(28): 2337-2347. [6] Ahn H-S, Chackalamannil S, Boykow G, Graziano MP, Foster C. Development of Proteinase- Activated Receptor 1 Antagonists as Therapeutic Agents for Thrombosis, Restenosis and Inflammatory Diseases. Curr Pharm Design 2003; 9(28): 2349-2365. [7] Gruber A, Hanson SR. Potential New Targets for Antithrombotic Therapy. Curr Pharm Design 2003; 9(28): 2367-2374. |
