https://scholars.lib.ntu.edu.tw/handle/123456789/564132
標題: | NP-184[2-(5-methyl-2-furyl) benzimidazole], a novel orally active antithrombotic agent with dual antiplatelet and anticoagulant activities | 作者: | Kuo H.-L. Lien J.-C. Chung C.-H. Chang C.-H. SHYH-CHYI LO Tsai I.-C. Peng H.-C. Kuo S.-C. TUR-FU HUANG |
公開日期: | 2010 | 卷: | 381 | 期: | 6 | 起(迄)頁: | 495-505 | 來源出版物: | Naunyn-Schmiedeberg's Archives of Pharmacology | 摘要: | The established antiplatelet and anticoagulant agents show beneficial effects in the treatment of thromboembolic diseases; however, these drugs still have considerable limitations. The effects of NP-184, a synthetic compound, on platelet functions, plasma coagulant activity, and mesenteric venule thrombosis in mice were investigated. NP-184 concentration-dependently inhibited the human platelet aggregation induced by collagen, arachidonic acid (AA), and U46619, a thromboxane (TX)A2 mimic, with IC50 values of 4.5±0.2, 3.9±0.1, and 9.3±0.5 μM, respectively. Moreover, NP-184 concentration-dependently suppressed TXA2 formations caused by collagen and AA. In exploring effects of NP-184 on enzymes involved in TXA2 synthesis, we found that NP-184 selectively inhibited TXA2 synthase activity with an IC50 value of 4.3±0.2 μM. Furthermore, NP-184 produced a right shift of the concentration-response curve of U46619, indicating a competitive antagonism on TXA2/prostaglandin H2 receptor. Intriguingly, NP-184 also caused a concentration-dependent prolongation of the activated partial thromboplastin time (aPTT) with no changes in the prothrombin and thrombin time, indicating that it selectively impairs the intrinsic coagulation pathway. Oral administration of NP-184 significantly inhibited thrombus formation of the irradiated mesenteric venules in fluorescein sodium-treated mice without affecting the bleeding time induced by tail transection. However, after oral administration, NP-184 inhibited the ex vivo mouse platelet aggregation triggered by collagen and U46619 and also prolonged aPTT. Taken together, the dual antiplatelet and anticoagulant activities of NP-184 may have therapeutic potential as an oral antithrombotic agent in the treatment of thromboembolic disorders. ? 2010 Springer-Verlag. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/564132 | ISSN: | 281298 | DOI: | 10.1007/s00210-010-0505-x | SDG/關鍵字: | 15 hydroxy 11alpha,9alpha epoxymethanoprosta 5,13 dienoic acid; 2 (5 methyl 2 furyl)benzimidazole; anticoagulant agent; arachidonic acid; np 184; thromboxane A2; unclassified drug; animal experiment; animal model; anticoagulation; antiplatelet activity; article; bleeding time; controlled study; drug activity; drug antagonism; drug efficacy; drug safety; enzyme activity; ex vivo study; human; human cell; IC 50; male; mouse; nonhuman; partial thromboplastin time; protein synthesis; thrombocyte aggregation; thrombocyte function; thrombosis; Administration, Oral; Animals; Anticoagulants; Benzimidazoles; Blood Coagulation; Dose-Response Relationship, Drug; Fibrinolytic Agents; Humans; Inhibitory Concentration 50; Male; Mice; Mice, Inbred ICR; Platelet Aggregation; Platelet Aggregation Inhibitors; Venous Thrombosis |
顯示於: | 藥理學科所 |
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