Apixabanisahighlyselective,reversIBLeinhibitorofFactorXawithKiof0.08nMand0.17nMinhumanandrabbit,respectively.DescriptionApixabanisahighlyselective,reversibleinhibitorofFactorXawithKiof0.08nMand0.17nMinhumanandrabbit,respectively.IC50&TargetIC50:0.08nM(HumanFactorXa),0.17nM(RabbitFactorXa)InVitroApixabanexhibitsahighdegreeofpotency,selectivity,andefficacyonFactorXawithKiof0.08nMand0.17nMforHumanFactorXaandRabbitFactorXa,respectively[1].Invitro,Apixabanprolongstheclottingtimesofnormalhumanplasmawiththeconcentrations(EC2x)of3.6μM,0.37μM,7.4μM,and0.4μM,whicharerequiredrespectivelytodoubletheprothrombintime(PT),modifiedprothrombintime(mPT),activatedpartialthromboplastintime(APTT)andHepTest.Besides,Apixabanshowsthehighestpotencyinhumanandrabbitplasma,butlesspotencyinratanddogplasmainboththePTandAPTTassays[2].InVivoApixabanshowstheexcellentpharmacokineticswithverylowclearance(Cl:0.02L/kg/h),andlowvolumeofdistribution(Vdss:0.2L/kg)inthedogs.Besides,Apixabanalsoexhibitsamoderatehalf-life(T1/2:5.8hours)andgoodoralbioavailABIlity(F:58%)[1].Inthearteriovenous-shuntthrombosis(AVST),venousthrombosis(VT)andelectricallymediatedcarotidarterialthrombosis(ECAT)rabbitmodels,Apixabanproducesdose-dependentantithromboticeffectswithEC50of270nM,110nMand70nM,respectively[2].ApixabansignificantlyinhibitsfactorXaactivitywithIC50of0.22μMinrabbitexvivo[3].Inchimpanzee,Apixabanalsoshowssmallvolumeofdistribution(Vdss:0.17L/kg),lowsystemicclearance(Cl:0.018L/kg/h),andgoodoralbioavailability(F:59%)[4].ClinicalTrialViewMoreCollapseReferences[1].PintoDJ,etal.Discoveryof1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide(apixaban,BMS-562247),ahighlypotent,selective,efficacious,andorallybioavailableinhibitorofblo[2].WongPC,etal.Apixaban,anoral,directandhighlyselectivefactorXainhibitor:invitro,antithromboticandantihemostaticstudies.JThrombHaemost.2008May;6(5):820-9.[3].ZhangD,etal.Metabolism,pharmacokineticsandpharmacodynamicsofthefactorXainhibitorapixabaninrabbits.JThrombThrombolysis.2010Jan;29(1):70-80.[4].HeK,etal.Preclinicalpharmacokineticsandpharmacodynamicsofapixaban,apotentandselectivefactorXainhibitor.EurJDrugMetabPharmacokinet.2011Sep;36(3):129-39.PreparingStockSolutionsConcentrationVolumeMass1mg5mg10mg1mM2.1763mL10.8814mL21.7628mL5mM0.4353mL2.1763mL4.3526mL10mM0.2176mL1.0881mL2.1763mLPleaserefertothesolubilityinformationtoselecttheappropriatesolvent.KinaseAssay[2]PurifiedFXaisobtainedafteractivationwithRussell’svipervenomfollowedbyaffinitychromatography.TheresultingFXais>95%pureasjudgedbysodiumdodecylsulfatepolyacrylamidegelelectrophoresis.ThesubstrateaffinityvaluesforFXa,expressedastheMichaelis-Menten-Henriconstant(Km),forhuman,rabbit,ratanddogFXaaredeterminedusingthechromogenicsubstrateS-2765,andare36,60,240and70μM,respectively.Thesubstratehydrolysisismonitoredbymeasuringabsorbanceat405nmat25°Cforupto30minusingaSpectraMax384PlusplatereaderandSoftMax.FXaactivityforeachsubstrateandinhibitorconcentrationpairisdeterminedinduplicate.TheKivaluesarecalculatedbynon-linearleast-squaresfittingofthesteady-statesubstratehydrolysisratestotheequationforcompetitiveinhibition(Equation1)usingGRAFIT,wherevequalsreactionsvelocityinODmin−1,Vmaxequalsmaxiumumreactionvelocity,Sequalssubstrateconcentration,andIequalsinhibitorconcentration.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalAdmiNISTration[2]Apixabanisformulatedinvehicle(10%N,N-dimethylacetamide;30%1,2-propanediol;60%water).Briefly,maleNewZealandWhiterabbitsareanesthetizedwithketamine(50mg/kgi.m.)andxylazine(10mg/kgi.m.),andtheirfemoralartery,jugularveinandfemoralveinarecatheterized.Theseanestheticsaresupplementedasneeded.Thrombosisisinducedbyanarteriovenous(AV)-shuntdevicecontainingasilkthread.BloodflowedfromthefemoralarteryviatheAVshuntintotheoppositefemoralveinfor40min.Theshuntisthendisconnectedandthesilkthreadcoveredwiththrombusisweighed.Asapixabanhasanoralbioavailabilityof50value(dosethatproduced50%inhibitionofthrombusformation)isdeterminedasdescribedbelow.Theapixabangrouptreatmentconsistsofvehicle(10%N,N-dimethylacetamide;30%1,2-propanediol;60%water)(n=4),andapixaban(mg/kg/h)at0.03(n=7),0.1(n=7),0.3(n=7),1(n=7),and3(n=3).Thefondaparinuxgrouptreatmentconsistsofvehicle(saline)(n=6),andfondaparinux(mg/kg/h1)at0.01(n=5),0.03(n=5),0.1(n=5),0.3(n=5),and1(n=5).Thewarfaringrouptreatmentconsistsofvehicle(water)(n=6),andwarfarin(mg/kg/day)at0.1(n=6),0.3(n=6),1(n=6),and3(n=6).MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.References[1].PintoDJ,etal.Discoveryof1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide(apixaban,BMS-562247),ahighlypotent,selective,efficacious,andorallybioavailableinhibitorofblo[2].WongPC,etal.Apixaban,anoral,directandhighlyselectivefactorXainhibitor:invitro,antithromboticandantihemostaticstudies.JThrombHaemost.2008May;6(5):820-9.[3].ZhangD,etal.Metabolism,pharmacokineticsandpharmacodynamicsofthefactorXainhibitorapixabaninrabbits.JThrombThrombolysis.2010Jan;29(1):70-80.[4].HeK,etal.Preclinicalpharmacokineticsandpharmacodynamicsofapixaban,apotentandselectivefactorXainhibitor.EurJDrugMetabPharmacokinet.2011Sep;36(3):129-39.MolecularWeight459.5FormulaC₂₅H₂₅N₅O₄CASNo.503612-47-3StoragePowder-20°C3years 4°C2yearsInsolvent-80°C6months -20°C1monthShippingRoomtemperatureincontinentalUS;mayvaryelsewhereSolvent&SolubilityDMSO:14.25mg/mL;H2O：*"

托烷司琼临床评价药物相关作用适应症托烷司琼CAS号:89565-68-4英文名称:Tropisetron英文同义词:icf205-930;TROPICACID;TROPISETRON;SS-TROPISETRON;BETA-TROPISETRON;Tropisetron(ICS205930);TROPISHTRONHYDROCHLORIDE;Indole-3-carbonylchloride;3-Tropanylindole-3-carboxylate;lαH，5Αh-Tropan-3α-ylindole-3-carboxylate中文名称:托烷司琼中文同义词:托普西隆;托普西龙;曲匹西龙;托烷司琼;Β-托烷司琼;CS-348;Β-内托烷司琼;吲哚-3-甲酰氯;Β-托烷司琼(光学异构体);Β-托烷司琼,托烷司琼异构体CBNumber:CB3236404分子式:C17H20N2O2分子量:284.35MOLFile:89565-68-4.mol化学性质安全信息用途供应商112化学性质安全信息用途供应商112托烷司琼化学性质熔点:201-202°C沸点:448.5±35.0°C(Predicted)密度:1.26储存条件:2-8°C溶解度:H2O:soluble形态:solid酸度系数(pKa):15.38±0.30(Predicted)颜色:whiteCAS数据库:Chemicalbook89565-68-4(CASDataBaseReference)安全信息WGKGermany:3托烷司琼化学药品说明书托烷司琼|药物应用信息托烷司琼性质、用途与生产工艺临床评价Sorbe等报道本品对含顺铂(剂量50～89mg/m2)化疗方案引起的急性呕吐完全控制率为63%。58例恶性肿瘤化疗所致恶心、呕吐者，应用托烷司琼或昂丹司琼8mg分别在同一病人前后2个化疗周期的第1d给药前30min静脉注射，并用地塞米松10mg静脉滴注。结果两药控制急性及迟发性恶心、呕吐的疗效基本相似，均可达81%～100%。本品对强致吐化疗药物顺铂的止吐疗效突出。药物相关作用饮食可略为延长本品的吸收。本品与利福平、苯巴比妥等肝酶诱导药同时使用，可加快代谢，故快代谢型者需增加剂量，慢者则不必。西咪替丁等肝酶抑制药对本品血药浓度无明显影响。适应症托烷司琼临床用于预防和治疗癌症化疗引起的恶心和呕吐。化学性质结晶，熔点201-202℃(二氯甲烷-乙酸乙酯)。单盐酸托烷司琼(TropisetronMonohydroehloride)：C17H20N2O2?HCI。[105826-92-4]。熔点283-285℃(分解)。用途有高效性和选择性的5-HT3受体拮抗剂。用于化疗所致的呕吐。用途为5-羟色胺拮抗药生产方法托品醇(I)和酰氯(Ⅱ)反应，可得托烷司琼。托烷司琼上下游产品信息上游原料托品醇下游产品