治疗缺血性脑卒中的自由基清除剂类药物研究进展

CN341206/R,ISSN10092501Email:[e-mail]2011Apr;16(4):461-46720110308收稿20110320修回中央高校基本科研业务费专项资助(JKP2009007);基金项目十一五重大新药创制项目资助(2009ZX09304001);十二五重大新药创制项目资助(2011ZX0910200302)王晓金,女,硕士研究生,研究方向:药物代谢动力学王广基,通信作者,男,教授,研究方向:药物代谢动力学Email:[e-mail]孙建国,男,副教授,研究方向:药物代谢动力学Email:[e-mail]治疗缺血性脑卒中的自由基清除剂类药物研究进展王晓金,孙建国,彭英,王广基中国药科大学药物代谢动力学重点实验室,南京210009,江苏缺血性脑卒中已成为世界上导致人类死亡的第二大疾病,大量研究证明,缺血及再灌注过程中产生的自由基在脑损伤中起关键作用,使得自由基清除剂成为治疗缺血性脑血管病的研究热点,很多自由基清除剂类药物被合成并先后进入临床试验,包括代表药物依达拉奉成功在日本上市本文将综述有关治疗缺血性脑卒中的自由基清除剂的最新研究进展,探讨此类药物在研究过程中所遇到的问题并展望此类药物在治疗缺血性脑卒中疾病中的治疗前景自由基;自由基清除剂;缺血性脑卒中:R969:A:10092501(2011)04046107,[1],,,/,[2],,,,,,,,;,[3],,,,,,11.120014,,,60%,[4],72h24h,64.8%73.8%,32.0%25.6%,,[5-6],,MitsubishiTanabePharma461(AIS)a[7],,AIS,,Unno[8],,1000mg,,,1000mg2000mg,,,,[9-10]1.2(phenyltertbutyl,PBN),,1.2.1NXY059PBN,,3~6h,NXY059NXY059[11],NXY059,SAINT(StrokeAcuteIschaemicNXY059Treatment)I(,,),SAINTII()[12-13]Diener[14],SAINTISAINTII,6hNXY059,(),1.2.2STAZNSTAZN(stilbazulenylnitrone)42%~72%,NXY0591/300~1/600[15]ley[16]STAZN,(MCAo)0.7mg/kg,STAZN,1.2.3TBNTBN[17],(TMP),,,1.321,,(Tirilazad),24h48h,,48%[18],[19-20],,3,,,,,,,1.4(ebselen),(GSHPx),,NADPHNOS,,Salom,1[21],2001,394,,[22]1.5,,,SODFetmpypFetppsThiyagarajan462ChinJClinPharmacolTher2011Apr;16(4)[23]6hAEOL10113AEOL10150[24],35%,(COPD)12,,SOD(CAT)GSHPx,:2.1SOD,,(6min),SOD(PEG),,SOD(PCSOD)[25]SOD(SODNPs)[26],2.2(melatonin,MT),5-,,[27],SODmRNA,,,,,,[28]Kilic[29],,30%~35%,,Chen[27],,52%,tPA,4632011Apr;16(4),[30],,,,2.3(estrogen),,,Fe2+[31][32],,NO,,[30],;,[33],,,,,,,[34],[35],(),2.4(UA),Chamorro[36]rtPA3h[37][38]rtPA,rtPA[39],4.5h(3h)rtPA,,2.5ECE,;C,,[40],C(SVCT2),C,;B,400CE,,,,[41-42]3,,,,,,,,catechol,,,,[43],,;,,[44],,,SOD,(MDA),[45],,Kuang[46],NO;(OA),Rong[47],OASODGSHPx,MDA,,OA;,,,Shin[48],;464ChinJClinPharmacolTher2011Apr;16(4),[49],,,,,4,,,,,(,,NXY059),:[50],,,,,,,,,,;,,6h[51],,TBN,,,,,,,,,,,,,[1]LopezAD,MathersCD,EzzatiM,etal.Globalandregionalburdenofdiseaseandriskfactors,2001:systematicanalysisofpopulationhealthdata[J].Lancet,2006,367(9524):1747-1757.[2]DoeppnerTR,HermannDM.Freeradicalscavengersandspintrapstherapeuticimplicationsforischemicstroke[J].BestPractice&ResearchClinicalAnaesthesiology,2010,24(2010):511-520.[3],.[J].,2010,12(3):534-536.[4]OtomoE,TohgiH,KogureK,etal.Effectofanovelfreeradicalscavenger,edaravone(MCI186),onacutebraininfarction.Randomized,placebocontrolled,doubleblindstudyatmulticenters[J].CerebrovascDis,2003,15(3):222-229.[5]AbeM,KaizuK,MatsumotoK.Acasereportofacuterenalfailureandfulminanthepatitisassociatedwithedaravoneadministrationinacerebralinfarctionpatient[J].TherApherDial,2007,11(3):235-240.[6]HishidaA.Clinicalanalysisof207patientswhodevelopedrenaldisordersduringoraftertreatmentwithedaravonereportedduringpostmarketingsurveillance[J].ClinExpNephrol,2007,11(4):292-296.[7]MitsubishiTanabePharmaCorporation.SafetyandpharmacokineticsofMCI186insubjectswithacuteischemicstroke[EB/OL].2010;Availablefrom:[8]UnnoY,KatayamaM,ShimizuH.Doesfunctionaloutcomeinacuteischaemicstrokepatientscorrelatewiththeamountoffreeradicalscavengertreatment?Aretrospectivestudyofedaravonetherapy[J].ClinDrugInvestig,2010,30(3):143-155.[9]KikuchiK,KawaharaK,MiyagiN,etal.Edaravone:anewtherapeuticapproachforthetreatmentofacutestroke[J].MedHypotheses,2010,75(6):583-585.[10]WatanabeT,TaharaM,TodoS.Thenovelantioxidantedaravone:frombenchtobedside[J].CardiovascTher,2008,26(2):101-114.[11]HessDC.NXY059:ahopefulsigninthetreatmentofstroke[J].Stroke,2006,37(10):2649-2650.4652011Apr;16(4)[12]ShuaibA,LeesKR,LydenP,etal.NXY059forthetreatmentofacuteischemicstroke[J].NEnglJMed,2007,357(6):562-571.[13]WangCX,ShuaibA.Neuroprotectiveeffectsoffreeradicalscavengersinstroke[J].DrugsAging,2007,24(7):537-546.[14]DienerHC,LeesKR,LydenP,etal.NXY059forthetreatmentofacutestroke:pooledanalysisoftheSAINTIandIITrials[J].Stroke,2008,39(6):1751-1758.[15]GinsbergMD,BeckerDA,BustoR,etal.Stilbazulenylnitrone,anovelantioxidant,ishighlyneuroprotectiveinfocalischemia[J].AnnNeurol,2003,54(3):330-342.[16]LeyJJ,BelayevL,SaulI,etal.NeuroprotectiveeffectofSTAZN,anovelazulenylnitroneantioxidant,infocalcerebralischemiainrats:doseresponseandtherapeuticwindow[J].BrainRes,2007,1180:101-110.[17]SunY,JiangJ,ZhangZ,etal.AntioxidativeandthrombolyticTMPnitronefortreatmentofischemicstroke[J].BioorgMedChem,2008,16(19):8868-8874.[18]SchmidElsaesserR,ZausingerS,HungerhuberE,etal.Monotherapywithdextromethorphanortirilazadbutnotacombinationofbothimprovesoutcomeaftertransientfocalcerebralischemiainrats[J].ExpBrainRes,1998,122(1):121-127.[19]vanderWorpHB,KappelleLJ,AlgraA,etal.Theeffectoftirilazadmesylateoninfarctvolumeofpatientswithacuteischemicstroke[J].Neurology,2002,58(1):133-135.[20]ZhangS,WangL,LiuM,etal.Tirilazadforaneurysmalsubarachnoidhaemorrhage[J].CochraneDatabaseSystRev,2010(2):CD006778.[21]SalomJB,PerezAsensioFJ,BurgueteMC,etal.Singledoseebselendoesnotaffordsustainedneuroprotectiontoratssubjectedtoseverefocalcerebralischemia[J].EurJPharmacol,2004,495(1):55-62.[22]GreenAR,Shuaib