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0 rpc_queries腾讯十二周年抽奖活动是真的吗＠腾讯十四周年庆典活动 - 育儿问答
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腾讯十二周年抽奖活动是真的吗＠腾讯十四周年庆典活动
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腾讯十二周年抽奖活动是真的吗＠腾讯十四周年庆典活动
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13高一致性药物诱导的体外细胞毒作用的一种新的细胞为基础的模式使用高含量的测定筛选人肝-2
appliedto611drugs:42drug；Comparisonontheperforman；Althoughnoneoftheconvent；Table1Predictivityofdrug；4973Glutathionedepletion；10928Combinationofabovet；Regulatoryanimaltoxicity；52；Se
　appliedto611drugs:42drugscausingseverehepato-toxicity,283drugscausingmoderatehepatoxicityand286non-hepatotoxicdrugs.Table1demonstratesthattheseassayshaveonlyhalfthesensitivitythatregulatoryanimaltestshave.Althoughtheinvitroassayswerestillrelativelyinsensitiveatdetectinghepatotoxicity,theywerehighlyspeci?c,sothatwhendrugstestedpositiveintheseassaystherewashighprobabilitythatthedrugproducedhumantoxicity.Comparisonontheperformanceoftheconventionalcytotoxicityassayswiththenewmultiparametricassay(Table2)onidenticalcompoundsindicatedsimilarre-sultsaswhentheconventionalassayswereappliedtothelargerdatasetof611drugs.Althoughnoneoftheconventionalassaysforcyto-toxicityhadadequateconcordancewithinvivohumantoxicity,therewerenotabledi?erencesbetweenassays.Theassaywithgreatestsensitivity,19%,fordetectionofhumantoxicitypotentialwasglutathionedepletion,beingtwiceassensitiveasthenextmoste?ectiveassays,namelyDNAsynthesis,asassessedbytritiatedthymi-dineincorporation,andcellviability,asassessedbymitochondrialredoxcyclingactivity.Thecaspase-3inductiontestforapoptosis,proteinsynthesis,super-oxideinductiontestforoxidativestressandthemem-braneintegritytestweresimplyine?ective.Table1Predictivityofdrug-inducedhumanhepatotoxicitybyconventional,invitrocytotoxicityassaysandbyregulatoryanimaltestinginvivoSl.no.PredictivetestSensitivitySpeci?city1DNAsynthesis10922Proteinsynthesis4973Glutathionedepletion19854Superoxideinduction1975Caspase-3induction5956Membraneintegrity2997Cellviability10928Combinationofabovetests1,3,725839Regulatoryanimaltoxicitystudies52CSensitivity(percentageofhepatotoxicdrugsdetected)andspeci-?city(percentageofdrugstestingpositivethatarehepatoxic)aretabulatedforsevenconventional,cytotoxicityinvitroassays,fortheoptimalcombinationoftheseassays,andforregulatory,invivo,animaltoxicitystudies.Theinvitrotestswereappliedto611drugs,including:(a)42drugscausingseverehumanhepatotoxicity,de?nedasproducingmorethan1%frequencyofincreasedserumALTplusatleasttwoofeitherjaundice,morethanthreereportsofliverfailu(b)283drugsproducingmoderatehumanhepatotoxicity,de?nedasproducing0.1C1%frequencyofincreasedserumALT,plusjaundiceoralabelofoccurrenceofadversee?ectand(c)286drugsproducingnegligiblehumanhepatotoxicity,de?nedaslessthan0.1%frequencyofin-creasedALTandabsenceofclinicalsymptoms.Sensitivityforregulatoryanimaltoxicitystudiesisbasedonretrospectiveexam-inationofoutcomesinanimalstudiesfordrugsfoundinclinicalstudiestoproducehumanhepatotoxicity(Olsonetal.2000)585Cellulare?ectsintheHCS,sublethal,cytotoxicityassayWhencellswereseededpriortoincubationwithdrugs,3,000cellswereaddedperwell.Thiscorrespondstoabout500cellsinten?eldsatthe10?objectiveusedforthecellcount.Thisnumberdidnotchangesigni?cantlyonthefollowingdaywhenincubationbegan,indicatingthatthestressesofplatinghadacytostatice?ect.InthefourChannelAssayusinga20?objectivethisseedingdensitycorrespondsto12cellsper?eld.Thisdatacanbeusedtoassesswhetheradrugismerelyhaltingcellsintheircellcycle,oractuallykillingthem(i.e.cytostaticversuscytotoxic).CellcountsatDay0(i.e.24hafterplating)wereslightlymorethanthetheoreticalamountthatshouldbecountedwhentheyare?rstplated.TypicalcytotoxicchangesareillustratedinFig.1.SeeHCSanalyserspeci?cationsandsettingsfordetailsonsettingsandproceduresforimageanalysis.Fura-zolidone-induceddecreasesincellnumber,nuclearareaandmitochondrialmembranepotentialarereadilyvisi-ble,asaretheincreasesincellcalciumandplasmamembranepermeability.E?ectsofdurationonpreincubationofcellswithdrugsoncytotoxicityHCSassaysfordrug-inducedcytotoxicityconductedon23toxicdrugsand6non-toxicdrugsatconcentrationsupto100lMwerefarmoree?ectivewhencellswerepreincubatedwithdrugspriortotesting.Assaysinwhichcellshadnotbeenpreincubatedwiththedrug,producedpositivetestresultsforonly17%ofthetoxicdrugs(Fig.2,top).However,cytotoxicitywasseenfor70%ofthesetoxicdrugsafterpreincubationatupto100lMfor3days(Fig.2,bottom).Toxice?ectswereinducedafter3dayspreincubationbyamodiaquine,cerivastatin,diclofenac,fen?uramine,furazolidone,kanamycin,pamidronate,primaquine,pyrmethamine,rosiglitazone,tacrineandzidovudine.Cytotoxicitywasnotseen,evenafter3daysofincubationwithupto100lM,foracetaminophen,cisapride,erythromycin,isoniazide,lamivudine,sulphanilamideandvidaribine.However,insubsequentstudies(Table2)inwhichthesesixdrugsweretestedtohigherconcentrationsofupto30-foldtheCmax,cytotoxicitywasalsodetectedforacetaminophen,erythromycinandlamivudine.Therewerenoe?ectsdetectedforanyofthenon-toxicdrugstested:?ufenamate,?umazenil,glimepirideandzom-epirac.E?ectswerenotfoundforfoscarnetnorprimi-done,althoughinlaterstudiesinwhichthesecompoundsweretestedto30-foldCmax,theirtoxicitywasrevealed.Preincubationofcellswithtoxicdrugsfor3daysproducedafourfoldgreaterfrequencyofchangethanwhencellswerenotpreincubatedwithdrugs.Toxicityofthefollowingdrugswasnotdetectablewithoutprein-cubationwithcellsfor3days:amodiaquine,cerivasta-tin,diclofenac,fen?uramine,foscarnet,furazolidone,Table2Cytotoxice?ectsofdrugscausinghumantoxicityOldtestsTIPPB(%)HCStestFirstsignalCellnumberMitochondrialpotentialCaMempermNuclearareaCmax(lM)Mechanism586Sl.noDrugToxicity+OSIM3624OPIMM,Ca,ApOS+++++++++++++++++.IMOP,ApMOSMSynIMMMIM,OSIM,MIM,OSIMMIMMSynM,OPSyn15769962IM,M++++MIM,OS,MIMIMMIM,OSOS,MOSSeverelyhepatotoxicdrugsi,r1Acetaminophen2Aminosalycilate3Amitryptilline4Amiodarone5Amodiaquine6Cerivastatin7CyclosporinA8Danazol9Dantrolenei,rDiclofenac1011Didanosine12Disul?ram13Efavirenz14Etoposidei,rFelbamate1516Fialuridine17Flutamide18Indomethacin19ImipraminerIsoniazide2021Itraconazole22Ketoconazole23Ketorolac24Labetalol25Lamivudine26Mercaptopurine27Methapyrilene28Methotrexatei,rMethyldopa29iMinocycline3031Niacin32NimesulideiNitrofurantoin3334Novobiocin35PhenylbutazonerPiroxicam3637Propythiouracil38Pyrazinamide49StavudineiSulindac40i,rValproate4142Zileutonààà++ND+àààND+NDNDàNDààààND+ààà+àNDNDàNDNDàààààNDNDààND+++500?4,000?24?750?136?25?250.1?1.6??2??C?100?125CC0.?,00.1?0.8?2?50?100?.225?100?220?50?CC150C?13,000?160C,000?CCC6CC50C50CC2522050CCCC330CC,600CCC500CCCCC004C220100CCCC330CCCCCC1,000C4,000C7,800C125?C2?50C313?50?C0.0?C5?CCC570?8,000C.810.420.030.20.167.94.70.0.0.520...382620%ààà100%Str++HiTIàM,C,N##6,,300C1,6,0C0.50.Str++StrStrStrStrStrStrStr+StrStrStrStrStrStr+Str++StrStrStr+++StrStr+++StrStr++++StrStrStr+####C#,MM#,N######,NM##,C,M,PN#MMNM,N,CPN#NM#,NAll##,N#,NN#,P#,M,C#,N###M##394X,FH,HI,Ht0.005,W,XJ&10,H,C,LD0.25,BBW,HWd,FH,HIWd,I,H&3,C,Ht50,W0.012,BBW,H,X,LD0.04,W,H,FH,J65,BBW,H,FH,XH,FH,X8,Ht20,H,HI,BBW,X,FH,HWd,X,Ht&1,w,H,C,J,X,FHW,FH,X,I&22,H,LD,C20,BBW,X,FH,HX40,BW,X,H,CBW,FH,H,CW,I,H,FH,X,C,HI4,BBW,X,40,W,HtBW,Ht,I,Ci,FW,I,H,FHW,I,H,B&5,W,FH,C,JX,HtW,X,HBBW,IWd2,W,H,X&30,W,H,FH,JW,I,BBW,H,FH&1,W,H,X44,BBW,B,XW,HtSensitivityModerately434445hepatotoxicdrugsAspirinAzathioprineBupropionI,H,Ht&1,B,Ht&1,W,C,H,LDOS,MOSTable2(Contd.)OldtestsTIPPB(%)HCStestFirstsignalCellnumberMitochondrialpotentialCaMempermNuclearareaCmax(lM)MechanismSl.noDrugToxicityOSIM,MMM981799OS,MMOSCCMMMC48C13CCCCC0.1CC100CC1,CC270CCC48C13CCCCC0.1CCCCC1,C100CCC55?110?48C6CC0.12,300?C0.41.6C?75CC990IMIM,MIMM,ApIMIMIMMApIMSynM98.799.58.9490625598C,.,100C?25?.10.8?25?00.4?0.2?50?C1,100??CC13CCCCC506.3C.CCC50CCC6CCCCC100C6CCC?C?13C?0.4?1.6?6?0.2?0.9?3?CC.4?25?C24C25C7,100?CCC1?2?1.6?50?C503C5?CC?C13C630?C?1.6?3?0.2?0.9?3?50??100?.30.20..0.4.30.20..010..10..01..00...40..61301CaptoprilCeftazidimeChloramphenicolChlorpromazineCipro?brateClo?brateColchicineCyclophosphamideDiethylcarbamazineDoxorubicinEnalaprilrErythromycinEthylestrenolrEstradiolFamotidineFeno?brateFurazolidonerFurosemideFusidicAcidGlyburidei,rHydralazineIbuprofenIfosfamideIsotretinoinKetoprofeni,rLe?unomideLovastatinMesalamineMethacyclineNaproxenNizatidineNor?oxacinPaclitaxelParoxetinePravastatinrProcainamidePyrimethamineQuinacrineQuinidineQuinineiRifampicinRosuvastatinSimvastatinrSulfamethizolerSulfamethoxazolerSulfaphenazolerTacrinerTamoxifenW,I,H,BI,CC,J,HI0.75,I,H,HII,Hm,CHI,JX,H,HI&1,H,CW,I,H,B,CW,I,H,c,J,LDHtW,C,J&1,C,J0.063,W,H,CC,HIC,JB,Ht,CI,H,C0.005,HHI,C,&1,H,J0.03,B,C0.15,W,HH,C,LD0.05,W,B0.019,W,H,CI,H,B,FH,C,HIH,C&1,FH,HI,CI,H,HI,C1.6,H0.19,B,HII,H,FH,HI0.045,W,H,B,HII,H,CC,J,HIHH,HI,HtHW,I,H&0.5,0.05,W,HW,HW,H,B,C,J,HIM,Ca,ApM,IMIM,MOS,MM0.29,W,H,B,HtW,I,H,B,C,HIà+àNDààNDàà+NDàà+ààààààNDààNDà+NDààNDààND+NDNDND+ND+++NDààNDà++Str+Str+Str+++++Weak+Str++++HiTIà+Str+Str+Str+++Str++++Str+++++HiTIà+Str+Str+Str+HiTIàStr+Str+Str+Str+Str+++++++Str+Str+N####M#,N#,N##,C,PN,M###,NM##MMM#,N###,MM#N##M,NNN###N#CC#,P,C,NNN#,M,NM#NNN587588Table2(Contd.)ToxicityTIPPB(%)99CAIMOldtestsNDHCStestFirstsignalCellnumberMitochondrialpotentialCaMempermNuclearareaCmax(lM)MechanismSl.noDrugi,rC,J,Ht,LDI,H,C,JI,Ht,CCX,C,JH,CI,H,C,JW,HtBW,H,HIààà+àNDà24%HICCCCC88%804536C63CC6CCC100C.020.052,Str+HiTIà+++HiTIà++Str+#CM,C,PN#C#,M,NM,N#Terbina?neTerfenadineTetracyclineTolazamideTolbutamideTri?uoperazineWarfariniZar?rlukastZidovudineIMM19536687798.845MI(possAlerg)CCCCCM#,N#CC#,MM,N##PMH(1case),CCC#,P#C#,P,CM996828MHI100SensitivityNon-toxicdrugs103Acetylcysteine104Aminobenzoate105Bambuterol106Betaine107Biotin108Bisacodyl109Buspirone110Carbidopa111Citicoline112Cromolyn113Cyanocobalamin114Dexamethasone115Dimethylsulfoxide116Diphenhydramine117Flumazenil118Eserine119Fexofenadine120Folate121Folinicacid122Glimepiride123Isoproterenol124Isosorbidedinitrate125Ketotifen126Moxisylyte127Myo-inositol128Oxyphenonium129Pargyline130Picotamide131Pinacidil132Pioglitazone133Praziquantel134Propranolol135Pyridoxine136Rosiglitazone137ThiamineààààààND+ààààNDà+NDNDNDNDàNDààNDNDNDNDNDNDààCNDNDNDM,N#M#,M,NCCC,P,NC#CCCCCCC.1,300CCCCCCCCC50C100CCC0.850?70,CCCCCCCC100CC100C6?100?CC25C80CCCCCC100CCCC0.,500C6?CCCCCC100?100?C100C2100CCCC100CCCCCCCCCCCCCC2,500CCCCCCCC50CCCC100CCC25CCCCCCCCCCCCCCC70,CCCC100CC50CCCC100CCC25CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC+CCCCCCC1,940&10.150.0.,.220.573.430.730...30..80.11.10.676.8&1&30&6,700&30&260&30&6,4,&175&30&30&137x21,500,000&61&588&38&x10&30MTable2(Contd.)ToxicityTIPPB(%)Oldtests88%CAIMyoI,R,OI,HI617298603090992028MCAIM,AgCardRM,SynM,ApRRRM,OSIMTransIM97%IMMOSHCStestFirstsignalCellnumberMitochondrialpotentialCaMempermNuclearareaCmax(lM)MechanismSl.noDrugI,H,CAI,HI,LD0.011,W,Myo5,RR,O.6&.H,D,GIHI,R,OCNSNPanI,Ht0..480.250..360.21160.450.65OSApCa5WdCNSRTransRLA20IR,O6CC2,500?C130.4?6?6?C64C5095?2?CC25?2,500C?0.2?CC100?25?3?C100?1...110..NA150.150Speci?cityDrugstoxic18218370508BM+àNDàND+NDNDàààààNDNDàNDNDNDNDàààNDà+NDNDNDNDNDNDàNDND+àààNDàNDàààà?650CC641,,0C111,C630.4?6?C270.1,600C25CC50C3?CC0.0266CCC?100?3C2,000C?13?50?8,700?10.2?0.4?3?6C0.4CCCC6CCCC0.82,200185CCCC2,0.46CC25C100CC625CC50CCCCCC6CC2,500C13CCC2,C61.68,700185CCCC2,CC625CC50CCC100CCHiTIà+++Str+Str+++HiTI-+++Str+Str+Str+++++Falseà++Str+++Str++Str+Str++++Str+++Str+++Str+Str++???++All##,C###,CNMC#,N#,P#M,N#,PCC,NNN#C#,MM#MN#N#NM#####,M#,C,P#,#MNMN#M,PM#tootherorgansAstemizoleBeza?brateBupivacaineCa?eineCapreomycinChloroquineChlorpheniramineCiglitizoneCisaprideClioquinolDipyroneFen?uramineFlufenamateFlucytosineFluvastatinFoscarnetGentamycinHalothaneIndoprofenIsoxicamKanamycinLidocaineMemantineMetforminMetoclopramideMenadioneMevastatinMibefradilNialamideNicotineNocodazoleNomifensinePamidronatePhenacetinPhenforminPimozidePrimaquinePrimidonePropythiouracilSodiumchloride,mMStreptomycinStreptozocinSulfabenzamideSulfanilamideTelenzipineTemozolomideIMSyn589包含各类专业文献、中学教育、外语学习资料、幼儿教育、小学教育、生活休闲娱乐、行业资料、文学作品欣赏、专业论文、13高一致性药物诱导的体外细胞毒作用的一种新的细胞为基础的模式使用高含量的测定筛选人肝等内容。　
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