摘要
目的 综述抗血小板药物的应用现状和研究进展。方法 在总结国内外文献的基础上,对临床上现有的抗血小板药物以及正在研究中的新的抗血小板药物及其新靶标进行总结和分析。结果与结论 抗血小板药物开发是一个热门的研究领域,当前对血小板生物学以及对血小板黏附、活化和聚集相关的机制以及药物作用的潜在靶点有了越来越多的了解,笔者主要从影响血小板黏附、活化扩增,抑制血小板聚集及抗血小板作用新靶点等方面进行综述,并对未来开发出具有临床作用的新靶点的抗血小板药物,为血栓栓塞性疾病提供安全、有效的药物治疗进行展望。
关键词
血小板 /
血栓 /
抗血小板药物 /
血栓素 /
凝血酶
{{custom_keyword}} /
杨宏艳 王晓良 .
抗血小板药物研究进展[J]. 中国药学杂志, 2012, 47(4): 250-254
Progress in Development of Antiplatelet Agents[J]. Chinese Pharmaceutical Journal, 2012, 47(4): 250-254
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] SIVARAMAN B, LATOUR R A. Delineating the roles of the GPIIb/IIIa and GP-Ib-IX-V platelet receptors in mediating platelet adhesion to adsorbed fibrinogen and albumin[J]. Biomaterials, 2011, 32(23): 5365-5370.
[2] DE MEYER S F, VANHOORELBEKE K, ULRICHTS H, et al. Development of monoclonal antibodies that inhibit platelet adhesion or aggregation as potential anti-thrombotic drugs[J]. Cardiovasc Hematol Disord Drug Targets,2006, 6(3):191-207.
[3] FIRBAS C, SILLER-MATULA J M, JILMA B. Targeting von Willebrand factor and platelet glycoprotein Ib receptor[J]. Expert Rev Cardiovasc Ther,2010, 8(12):1689-1701.
[4] GROTHUSEN C, UMBREEN S, KONRAD I, et al. EXP3179 inhibits collagen-dependent platelet activation via glycoprotein receptor-VI independent of AT1-receptor antagonism: potential impact on atherothrombosis[J]. Arterioscler Thromb Vasc Biol,2007, 27(5):1184-1190.
[5] VANHOORELBEKE K, ULRICHTS H, SCHOOLMEESTER A, et al. Inhibition of platelet adhesion to collagen as a new target for antithrombotic drugs[J]. Curr Drug Targets Cardiovasc Haematol Disord,2003, 3(2):125-140.
[6] MAYANGLAMBAM A, DANGELMAIER C A, THOMAS D, et al. Curcumin inhibits GPVI-mediated platelet activation by interfering with the kinase activity of Syk and the subsequent activation of PLCgamma2[J]. Platelets,2010, 21(3):211-220.
[7] VAN LOON J E, DE JAEGERE P P, ULRICHTS H, et al. The in vitro effect of the new antithrombotic drug candidate ALX-0081 on blood samples of patients undergoing percutaneous coronary intervention[J]. Thromb Haemost,2011, 106(1):165-171.
[8] ULRICHTS H, SILENCE K, SCHOOLMEESTER A, et al. Antithrombotic drug candidate ALX-0081 shows superior preclinical efficacy and safety compared with currently marketed antiplatelet drugs[J]. Blood,2011, 118(3):757-765.
[9] DIENER J L, DANIEL LAGASSE H A, DUERSCHMIED D, et al. Inhibition of von Willebrand factor-mediated platelet activation and thrombosis by the anti-von Willebrand factor A1-domain aptamer ARC1779[J]. J Thromb Haemost,2009, 7(7):1155-1162.
[10] PATRONO C, ROCCA B. Drug insight: aspirin resistance--fact or fashion?[J]. Nat Clin Pract Cardiovasc Med,2007, 4(1):42-50.
[11] CHO H J, NAM K S. Inhibitory effect of ginkgolide B on platelet aggregation in a cAMP- and cGMP-dependent manner by activated MMP-9[J]. J Biochem Mol Biol,2007, 40(5):678-683.
[12] KIM Y S, PYO M K, PARK K M, et al. Antiplatelet and antithrombotic effects of a combination of ticlopidine and ginkgo biloba ext (EGb 761)[J]. Thromb Res,1998, 91(1):33-38.
[13] XU L N, YU W G, TIAN J Y, et al. Effect of sodium ferulate on arachidonic acid metabolism[J]. Acta Pharm Sin(药学学报),1990, 25(6):412-416.
[14] JANTAN I, RAWEH S M, SIRAT H M, et al. Inhibitory effect of compounds from Zingiberaceae species on human platelet aggregation[J]. Phytomedicine,2008, 15(4):306-309.
[15] CRESCENTE M, JESSEN G, MOMI S, et al. Interactions of gallic acid, resveratrol, quercetin and aspirin at the platelet cyclooxygenase-1 level. Functional and modelling studies[J]. Thromb Haemost,2009, 102(2):336-346.
[16] VILAHUR G, CASANI L, BADIMON L. A thromboxane A2/prostaglandin H2 receptor antagonist (S18886) shows high antithrombotic efficacy in an experimental model of stent-induced thrombosis[J]. Thromb Haemost,2007, 98(3):662-669.
[17] ERLINGE D. P2Y receptors in health and disease[J]. Adv Pharmacol,2011, 61:417-439.
[18] YOUSUF O, BHATT D L. The evolution of antiplatelet therapy in cardiovascular disease[J]. Nat Rev Cardiol,2011, 8(10):547-559.
[19] HECHLER B, NONNE C, ROH E J, et al. MRS2500 [2-iodo-N6-methyl-(N)-methanocarba-2′-deoxyadenosine-3′,5′-bisphosphate], a potent, selective, and stable antagonist of the platelet P2Y1 receptor with strong antithrombotic activity in mice[J]. J Pharmacol Exp Ther,2006, 316(2):556-563.
[20] HECHLER B, MAGNENAT S, ZIGHETTI M L, et al. Inhibition of platelet functions and thrombosis through selective or nonselective inhibition of the platelet P2 receptors with increasing doses of NF449 [4,4′,4″,4-(carbonylbis(imino-5,1,3-benzenetriylbis-(carbonylimino)))t etrakis-benzene-1,3-disulfonic acid octasodium salt][J]. J Pharmacol Exp Ther,2005, 314(1):232-243.
[21] PRZYKLENK K, FRELINGER A L, 3RD, LINDEN M D, et al. Targeted inhibition of the serotonin 5HT2A receptor improves coronary patency in an in vivo model of recurrent thrombosis[J]. J Thromb Haemost,2010, 8(2):331-340.
[22] TAKANO S. Role of 5-hydroxytryptamine in platelet thrombus formation and mechanisms of inhibition of thrombus formation by 5-hydroxytryptamine2A antagonists in rabbits[J]. Arch Int Pharmacodyn Ther,1995, 330(3):297-308.
[23] MOERLAND M, KEMME M, DIJKMANS A, et al. Modulation of vasoactivity and platelet aggregation by selective 5-HT receptor antagonism in humans[J]. J Cardiovasc Pharmacol,2011,58(6):575-580.
[24] SHINOHARA Y, NISHIMARU K, SAWADA T, et al. Sarpogrelate-Aspirin comparative clinical study for efficacy and safety in secondary prevention of cerebral Infarction (S-ACCESS): A randomized, double-blind, aspirin-controlled trial[J]. Stroke,2008, 39(6):1827-1833.
[25] WU C C, WU S Y, LIAO C Y, et al. The roles and mechanisms of PAR4 and P2Y12/phosphatidylinositol 3-kinase pathway in maintaining thrombin-induced platelet aggregation[J]. Br J Pharmacol,2010, 161(3):643-658.
[26] FALKER K, HAGLUND L, GUNNARSSON P, et al. Protease-activated receptor 1 (PAR1) signalling desensitization is counteracted via PAR4 signalling in human platelets[J]. Biochem J,2011, 436(2):469-480.
[27] BURKE F M, WARNOCK M, SCHMAIER A H, et al. Synthesis of novel peptide inhibitors of thrombin-induced platelet activation[J]. Chem Biol Drug Des,2006, 68(5):235-238.
[28] KOGUSHI M, MATSUOKA T, KAWATA T, et al. The novel and orally active thrombin receptor antagonist E5555 (Atopaxar) inhibits arterial thrombosis without affecting bleeding time in guinea pigs[J]. Eur J Pharmacol,2011, 657(1-3):131-137.
[29] KOSOGLOU T, REYDERMAN L, TIESSEN R G, et al. Pharmacodynamics and pharmacokinetics of the novel PAR-1 antagonist vorapaxar (formerly SCH 530348) in healthy subjects[J]. Eur J Clin Pharmacol,2011, DOI: 10.1007/s00228-011-1120-6.
[30] LEE S. Discovery of an orally available PAR-1 antagonist as a novel antiplatelet agent[J]. Arch Pharm Res,2011, 34(4):515-517.
[31] VERGARA-JIMENEZ J, TRICOCI P. Safety and efficacy of abciximab as an adjunct to percutaneous coronary intervention[J]. Vasc Health Risk Manag,2010, 6:39-45.
[32] KARABULUT A, CAKMAK M. Position of tirofiban in ST segment elevation myocardial infarction treatment: more than an adjunctive therapy[J]. Blood Coagul Fibrinolysis,2011, 22(5):449-450.
[33] MEMON M Z, NATARAJAN S K, SHARMA J, et al. Safety and feasibility of intraarterial eptifibatide as a revascularization tool in acute ischemic stroke[J]. J Neurosurg,2011, 114(4):1008-1013.
[34] FROJMOVIC M, LABARTHE B, LEGRAND C. Inhibition and reversal of platelet aggregation by alphaIIbbeta3 antagonists depends on the anticoagulant and flow conditions: differential effects of Abciximab and Lamifiban[J]. Br J Haematol,2005, 131(3):348-355.
[35] STARNES H B, PATEL A A, STOUFFER G A. Optimal use of platelet glycoprotein IIb/IIIa receptor antagonists in patients undergoing percutaneous coronary interventions[J]. Drugs,2011, 71(15):2009-2030.
[36] WINCHESTER D E, WEN X, BREARLEY W D, et al. Efficacy and safety of glycoprotein IIb/IIIa inhibitors during elective coronary revascularization: a meta-analysis of randomized trials performed in the era of stents and thienopyridines[J]. J Am Coll Cardiol,2011, 57(10):1190-1199.
[37] SHINOHARA Y, KATAYAMA Y, UCHIYAMA S, et al. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial[J]. Lancet Neurol,2010, 9(10):959-968.
[38] LEE J H, CHA J K, LEE S J, et al. Addition of cilostazol reduces biological aspirin resistance in aspirin users with ischaemic stroke: a double-blind randomized clinical trial[J]. Eur J Neurol,2010, 17(3):434-442.
[39] THEORET J F, CHAHROUR W, YACOUB D, et al. Recombinant P-selectin glycoprotein-ligand-1 delays thrombin-induced platelet aggregation: a new role for P-selectin in early aggregation[J]. Br J Pharmacol,2006, 148(3):299-305.
[40] THEORET J F, YACOUB D, HACHEM A, et al. P-selectin ligation induces platelet activation and enhances microaggregate and thrombus formation[J]. Thromb Res,2011, 128(3):243-250.
[41] BEDARD P W, CLERIN V, SUSHKOVA N, et al.. Characterization of the novel P-selectin inhibitor PSI-697 [2-(4-chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[h] quinoline-4-carboxylic acid] in vitro and in rodent models of vascular inflammation and thrombosis[J]. J Pharmacol Exp Ther,2008, 324(2):497-506.
[42] HUANG A, MORETTO A, JANZ K, et al. Discovery of 2-[1-(4-chlorophenyl)cyclopropyl]-3-hydroxy-8-(trifluoromethyl)quinoline-4 -carboxylic acid (PSI-421), a P-selectin inhibitor with improved pharmacokinetic properties and oral efficacy in models of vascular injury[J]. J Med Chem,2010, 53(16):6003-6017.
[43] PAMUKCU B, LIP G Y, SNEZHITSKIY V, et al.The CD40-CD40L system in cardiovascular disease[J]. Ann Med,2011, 43(5):331-340.
[44] FURMAN M I, KRUEGER L A, LINDEN M D, et al. Release of soluble CD40L from platelets is regulated by glycoprotein IIb/IIIa and actin polymerization[J]. J Am Coll Cardiol,2004, 43(12):2319-2325.
[45] LIEVENS D, ZERNECKE A, SEIJKENS T, et al. Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis[J]. Blood,2010, 116(20):4317-4327.
[46] MIRABET M, BARRABES J A, QUIROGA A, et al. Platelet pro-aggregatory effects of CD40L monoclonal antibody[J]. Mol Immunol,2008, 45(4):937-944.
[47] EKMAN C, STENHOFF J, DAHLBACK B. Gas6 is complexed to the soluble tyrosine kinase receptor Axl in human blood[J]. J Thromb Haemost,2010, 8(4):838-844.
[48] ANGELILLO-SCHERRER A, BURNIER L, FLORES N, et al. Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy[J]. J Clin Invest,2005, 115(2):237-246.
[49] MAREE A O, JNEID H, PALACIOS I F, et al. Growth arrest specific gene (GAS) 6 modulates platelet thrombus formation and vascular wall homeostasis and represents an attractive drug target[J]. Curr Pharm Des,2007, 13(26):2656-2661.
[50] ANGELILLO-SCHERRER A, DE FRUTOS P, APARICIO C, et al. Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis[J]. Nat Med,2001, 7(2):215-221.
[51] SALLER F, BURNIER L, SCHAPIRA M, et al. Role of the growth arrest-specific gene 6 (gas6) product in thrombus stabilization[J]. Blood Cells Mol Dis,2006, 36(3):373-378.
[52] FAN H Y, FU F H, YANG M Y, et al. Antiplatelet and antithrombotic activities of salvianolic acid A[J]. Thromb Res,2010, 126(1):e17-22.
[53] XU H L, FENG Y P. Effect of 3-n-butylphthalide (NBP) on thrombosis for-mation and platelet function in rats[J]. Acta Pharm Sin(药学学报),2001, 36(5):329-333.
{{custom_fnGroup.title_cn}}
脚注
{{custom_fn.content}}