【溶栓药物研究现状的文献综述2000字】

溶栓药物研究现状的文献综述1.1国内外溶栓药物发展国内外对脑血栓、肺血栓和心肌梗塞等疾病临床使用的典型溶血栓药物是单链尿激酶型纤溶酶原激活剂（Singlechainurokinasetypeplasminogenactivator,scu-PA）、组织型纤溶酶原激活剂变异体（Recombinantvariantsoftissuetypeplasminogenactivator,rt-PA）和阿昔单抗（Abciximab），作为第二代或第三代溶血栓药物scu-PA、rt-PA、Abciximab通过刺激纤溶酶原变成纤溶酶或结合于血小板膜糖蛋白IIb/IIIa受体（glycoproteinIIb/IIIareceptor）的药理作用实现溶解血栓，这些药物尽管已经明显克服了第一代溶血栓药物如尿激酶（urokinase，UK）和链激酶（Streptokinase，SK）的出血危险性及继发性再灌注的再栓塞的风险，但仍然存在的微弱出血性（Hemorrhage）和血小板减少（Thrombocytopenia）等副作用也是不容忽视的问题。随着科学不断地进步，人们已经不再单纯的满足现有的溶栓药物，想研究出一种有合适的半衰期，给药方便，特异性强，安全无副作用的新型溶栓药物，并已经取得了不错的成绩。替奈普酶（Tenecteplase）是t-PA的多点突变变异体，具有高纤维蛋白特异性，无促凝血作用，纤溶酶原下降少。替奈普酶和rt-PA可治疗心肌梗死，在颅内出血风险无显著差异，非颅内出血显著降低ADDINEN.CITE<EndNote><Cite><Author>Tanswell</Author><Year>2002</Year><RecNum>150</RecNum><DisplayText><styleface="superscript">[11]</style></DisplayText><record><rec-number>150</rec-number><foreign-keys><keyapp="EN"db-id="rv2a2z2vgew2t6e05tap05ter20vzdtzt5sr"timestamp="1459713563">150</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Tanswell,Paul</author><author>Modi,Nishit</author><author>Combs,Dan</author><author>Danays,Thierry</author></authors></contributors><titles><title>Pharmacokineticsandpharmacodynamicsoftenecteplaseinfibrinolytictherapyofacutemyocardialinfarction</title><secondary-title>Clinicalpharmacokinetics</secondary-title></titles><periodical><full-title>Clinicalpharmacokinetics</full-title></periodical><pages>1229-1245</pages><volume>41</volume><number>15</number><dates><year>2002</year></dates><isbn>0312-5963</isbn><urls></urls></record></Cite></EndNote>[\o"Tanswell,2002#150"11]。孟替普酶（Monteplase）是t-PA的突变体，研究表明该药可以使心肌梗死患者冠状动脉再通率大，临床上孟替普酶静脉注射治60min再开通率达79.4%，孟替普酶具有再通时间短，且无致命出血并发症的危险，能够显著地改善患者的心肌供血等优良特点ADDINEN.CITE<EndNote><Cite><Author>Inoue</Author><Year>2005</Year><RecNum>151</RecNum><DisplayText><styleface="superscript">[12]</style></DisplayText><record><rec-number>151</rec-number><foreign-keys><keyapp="EN"db-id="rv2a2z2vgew2t6e05tap05ter20vzdtzt5sr"timestamp="1459713644">151</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Inoue,Teruo</author><author>Nishiki,Ryoichi</author><author>Kageyama,Manabu</author><author>Chida,Ryuji</author><author>Hayashi,Terumi</author><author>Takayanagi,Kan</author><author>Hikichi,Yutaka</author><author>Node,Koichi</author></authors></contributors><titles><title>Long-termbenefitsofmonteplasebeforecoronaryangioplastyinacutemyocardialinfarction</title><secondary-title>TheAmericanjournalofcardiology</secondary-title></titles><periodical><full-title>TheAmericanjournalofcardiology</full-title></periodical><pages>506-508</pages><volume>95</volume><number>4</number><dates><year>2005</year></dates><isbn>0002-9149</isbn><urls></urls></record></Cite></EndNote>[\o"Inoue,2005#151"12]。1.2溶栓药物的研究方向1.2.1天然来源的溶栓药物天然来源的溶栓剂是目前发现新型溶栓剂的一个重要方向。如近年研制的水蛭素、从纳豆中分离出的一种纳豆激酶等，都属于天然的溶栓药物，且溶栓要效果好，来源安全可靠。他们作用机理是直接和血栓或者纤维蛋白油起降解作用。葡激酶(SaK)是金黄色葡萄球菌分泌的一种含有136个氨基酸残基的多肽，作用机制与SK（链激酶）相似，与其他类似的溶栓药物相比较，具有不引起变态反应、小分子多肽等显著优点ADDINEN.CITE<EndNote><Cite><Author>翟中金</Author><Year>1998</Year><RecNum>152</RecNum><DisplayText><styleface="superscript">[13]</style></DisplayText><record><rec-number>152</rec-number><foreign-keys><keyapp="EN"db-id="rv2a2z2vgew2t6e05tap05ter20vzdtzt5sr"timestamp="1459713788">152</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>翟中金</author></authors></contributors><titles><title>葡激酶的研究进展</title><secondary-title>国外医学:临床生物化学与检验学分册</secondary-title></titles><periodical><full-title>国外医学:临床生物化学与检验学分册</full-title></periodical><pages>156-158</pages><volume>19</volume><number>4</number><dates><year>1998</year></dates><urls></urls></record></Cite></EndNote>[\o"翟中金,1998#152"13]。蚓激酶(LK)是一个多酶组分，是从蚯蚓的体内分离出来的，它的溶栓作用可以分为两方面，一是可以直接降解血栓或者蛋白块，二是还可以刺激内皮细胞产生t-PA激活纤溶酶原变成纤溶酶增强纤溶能力。蛇毒纤溶酶原激活剂(TSV-PA)是一种能直接或间接溶解纤维蛋白(原)的酶类，是近年来蛇毒纤溶酶的研究重点。 1.2.2RGD靶向溶栓药物RGD序列（即Arg-Gly-Asp序列，精氨酸-甘氨酸-天冬氨酸序列）靶向溶栓剂利用血小板糖膜蛋白（glycoprotein，GP）Ⅱb/Ⅲa受体是RGD序列的特异性配体，而且GPⅡb/Ⅲa受体的活化是血小板聚集的最终共用通道，在血栓形成中起到重要作用，因此RGD序列具有抗血小板聚集作用和血栓靶向性。Mo等ADDINEN.CITE<EndNote><Cite><Author>Chen</Author><Year>2007</Year><RecNum>154</RecNum><DisplayText><styleface="superscript">[14]</style></DisplayText><record><rec-number>154</rec-number><foreign-keys><keyapp="EN"db-id="rv2a2z2vgew2t6e05tap05ter20vzdtzt5sr"timestamp="1459714419">154</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Chen,Hongshan</author><author>Mo,Wei</author><author>Su,Huabo</author><author>Zhang,Yanling</author><author>Song,Houyan</author></authors></contributors><titles><title>Characterizationofanovelbifunctionalmutantofstaphylokinasewithplatelet-targetedthrombolysisandantiplateletaggregationactivities</title><secondary-title>BMCmolecularbiology</secondary-title></titles><periodical><full-title>BMCmolecularbiology</full-title></periodical><pages>1</pages><volume>8</volume><number>1</number><dates><year>2007</year></dates><isbn>1471-2199</isbn><urls></urls></record></Cite></EndNote>[\o"Chen,2007#154"14]在动物模型中进行验证实验，发现由Su等ADDINEN.CITE<EndNote><Cite><Author>Su</Author><Year>2004</Year><RecNum>153</RecNum><DisplayText><styleface="superscript">[15]</style></DisplayText><record><rec-number>153</rec-number><foreign-keys><keyapp="EN"db-id="rv2a2z2vgew2t6e05tap05ter20vzdtzt5sr"timestamp="1459714017">153</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Su,Hua-Bo</author><author>Zhang,Yu-Gao</author><author>He,Jin-Tian</author><author>Mo,Wei</author><author>Zhang,Yan-Ling</author><author>Tao,Xian-Mei</author><author>Song,Hou-Yan</author></authors></contributors><titles><title>Constructionandcharacterizationofnovelstaphylokinasevariantswithantiplateletaggregationactivityandreducedimmunogenecity</title><secondary-title>ActabiochimicaetbiophysicaSinica</secondary-title></titles><periodical><full-title>ActabiochimicaetbiophysicaSinica</full-title></periodical><pages>336-342</pages><volume>36</volume><number>5</number><dates><year>2004</year></dates><isbn>1672-9145</isbn><urls></urls></record></Cite></EndNote>[\o"Su,2004#153"15]构建的葡激酶突变体RGD-SAK具有较强的溶栓作用，效果比SAK更为显著。王成涛等ADDINEN.CITE<EndNote><Cite><Author>王成涛</Author><Year>2010</Year><RecNum>155</RecNum><DisplayText><styleface="superscript">[16]</style></DisplayText><record><rec-number>155</rec-number><foreign-keys><keyapp="EN"db-id="rv2a2z2vgew2t6e05tap05ter20vzdtzt5sr"timestamp="1459714634">155</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>王成涛</author><author>籍保平</author><author>曹雁平</author><author>孙宝国</author><author>刘旭东</author></authors></contributors><titles><title>豆豉纤溶酶RGDS-载酶脂质体的体内溶栓效果和靶向性评价</title><secondary-title>生物医学工程学杂志</secondary-title></titles><periodical><full-title>生物医学工程学杂志</full-title></periodical><pages>332-336</pages><volume>27</volume><number>2</number><dates><year>2010</year></dates><urls></urls></record></Cite></EndNote>[\o"王成涛,2010#155"16]制备了RGDS-豆豉纤溶酶脂质体，在体外试验中，RGDS载酶脂质体很好的发挥了靶向溶栓作用。1.2.3小分子溶栓药物近年来，具有纤溶活性作用的小分子溶栓化合物成了研究心脑血管疾病的药物热点，以期研制成高效、特异、安全、副作用小的溶栓药物。Wu等ADDINEN.CITE<EndNote><Cite><Author>Wu</Author><Year>2009</Year><RecNum>156</RecNum><DisplayText><styleface="superscript">[17]</style></DisplayText><record><rec-number>156</rec-number><foreign-keys><keyapp="EN"db-id="rv2a2z2vgew2t6e05tap05ter20vzdtzt5sr"timestamp="1459714725">156</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Wu,Wenhui</author><author>Hasumi,Keiji</author><author>Peng,Hui</author><author>Hu,Xianwen</author><author>Wang,Xichang</author><author>Bao,Bin</author></authors></contributors><titles><title>Fibrinolyticcompoundsisolatedfromabrownalga,Sargassumfulvellum</title><secondary-title>Marinedrugs</secondary-title></titles><periodical><full-title>Marinedrugs</full-title></periodical><pages>85-94</pages><volume>7</volume><number>2</number><dates><year>2009</year></dates><urls></urls></record></Cite></EndNote>[\o"Wu,2009#156"17]发现α-D-葡萄糖甘油二酯(1-O-Palmitoyl-2-O-oleoyl-3-O-(α-D-glucopyranosyl)-glycerol，以下简称POGG)（结构式见图1-1），在异硫氰酸荧光素-肺血栓动物模型中，血浆荧光值迅速升高，在一定范围内，随着POGG的浓度的增加，血浆中的萤光值越高，说明POGG具有明显的溶解血栓作用。Wang等ADDINEN.CITE<EndNote><Cite><Author>Wang</Author><Year>2015</Year><RecNum>157</RecNum><DisplayText><styleface="superscript">[18]</style></DisplayText><record><rec-number>157</rec-number><foreign-keys><keyapp="EN"db-id="rv2a2z2vgew2t6e05tap05ter20vzdtzt5sr"timestamp="1459714834">157</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Wang,Ge</author><author>Wu,Wenhui</author><author>Zhu,Quangang</author><author>Fu,Shiqing</author><author>Wang,Xiaoyu</author><author>Hong,Shaotong</author><author>Guo,Ruihua</author><author>Bao,Bin</author></authors></contributors><titles><title>IdentificationandFibrinolyticEvaluationofanIsoindoloneDerivativeIsolatedfromaRareMarineFungusStachybotryslongisporaFG216</title><secondary-title>ChineseJournalofChemistry</secondary-title></titles><periodical><full-title>ChineseJournalofChemistry</full-title></periodical><pages>1089-1095</pages><volume>33</volume><number>9</number><dates><year>2015</year></dates><isbn>1614-7065</isbn><urls></urls></record></Cite></EndNote>[\o"Wang,2015#157"18]发现，在体外溶栓试验中，相比较POGG，FGFC1（结构式见图1-2）的溶栓能力提高了至少4倍。滕佳等ADDINEN.CITE<EndNote><Cite><Author>滕佳</Author><Year>2009</Year><RecNum>158</RecNum><DisplayText><styleface="superscript">[19]</style></DisplayText><record><rec-number>158</rec-number><foreign-keys><keyapp="EN"db-id="rv2a2z2vgew2t6e05tap05ter20vzdtzt5sr"timestamp="1459714917">158</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>滕佳</author><author>董跃伟</author><author>崔琳</author><author>纪芳</author><author>张小超</author><author>沈志强</author></authors></contributors><titles><title>Corilagin抗PAF诱导血管内皮细胞损伤的保护作用</title><secondary-title>昆明医学院学报</secondary-title></titles><periodical><full-title>昆明医学院学报</full-title></periodical><pages>14-18</pages><volume>30</volume><number>6</number><dates><year>2009</year></dates><urls></urls></record></Cite></EndNote>[\o"滕佳,2009#158"19]实验结果表明，Corilagin（结构式见图1-2）对血栓没有直接的降解作用，但是可抑制PAI-1的分泌，而对t-PA的水平无明显影响，以此来调节t-PA/PAI-1平衡来，增强溶栓活性。图1-1POGG的分子结构Fig1-1chemicalstructuralformulaofPOGG图1-2FGFC1的分子结构图1-3Corilagin的分子结构Fig.1-2chemicalstructuralformulaofFGFC1Fig.1-3chemicalstructuralformulaofCorilagin参考文献[1] 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