天普洛安剂量及安全性探讨-2003

危重症患者乌司他丁临床应用剂量探讨天普洛安®（乌司他丁）剂量及安全性探讨内容提要体内乌司他丁与疾病或炎症反应的关系天普洛安®（乌司他丁）的量效关系天普洛安®（乌司他丁）的安全性Ken-ichiroInoue.etal,J.Clin.Biochem.Nutr.,43,139–142,November2008炎症反应促进Bikunin和乌司他丁大量释放，

从而抑制蛋白酶活性这是一项用乌司他丁天然缺失（-/-）与正常表达两种基因型小鼠所进行的对比性研究。分别在这两种基因型的小鼠腹腔内注射1mg/kg内毒素以诱导全身炎症反应。然后对比这两种动物血液学和组织学的变化。KEN-ICHIROINOUE，etal:ProtectiveRoleofUrinaryTrypsinInhibitorinAcuteLungInjuryInducedbyLipopolysaccharide,ExpBiolMed230:281–287,2005Ken-IchiroInoue,etal:UrinaryTrypsinInhibitorProtectsagainstSystemicInflammationInducedbyLipopolysaccharide,MolPharmacol67:673–680,2005机体内缺失乌司他丁会……?Closedsymbols:UTI(-/-)miceOpensymbols:WTmiceAnimalswereharvested72hafteri.p.injectionofvehicleorLPS*P＜

0.05versusvehicle-treatedmice**P＜

0.01versusvehicle-treatedmice#P＜

0.05versusLPS-treatedWTmice##P＜

0.01versusLPS-treatedWTmicelung

vehicleLPSvehicleLPSkidney

vehicleLPSvehicleLPSlivervehicleLPSvehicleLPS在乌司他丁缺陷动物，大量白细胞被羁押在各器官kidneyliverlung乌司他丁缺陷动物，各器官细胞损伤明显加重UTInull(-/-)miceinjectedwithLPS;WTmiceinjectedwithLPS(C)UTInull(-/-)miceinjectedwithvehicle;(D)WTmiceinjectedwithvehicleKen-IchiroInoue,etal:UrinaryTrypsinInhibitorProtectsagainstSystemicInflammationInducedbyLipopolysaccharide,MolPharmacol67:673–680,2005天普洛安前体浓度与疾病严重程度及死亡率相关TheJournalofInfectiousDiseases2003,188:919–26病情越严重，血浆和尿液中乌司他丁水平越低SHIDELIN,etal.JournalofGastroenterologyandHepatology(2004)19,327–332Child-PushC级患者的血浆和尿液UTI水平显著低于A级和B级患者肝硬化患者肝细胞癌患者*P<0.05;**P<0.01严重疾病患者乌司他丁水平不足以消除被激活的酶Insufficientproductionofurinarytrypsininhibitorforneutrophilelastasereleaseaftercardiacarrest.SHOCK2008,29(5):549-552Controlgroup:8位健康志愿者Shortcardiacarrest:11位心脏骤停后30分钟内复苏患者Longcardiacarrest:25位心脏骤停后超过30分钟复苏患者NE:粒细胞弹性蛋白酶ARDS患者肺泡中乌司他丁浓度不足以灭活PMNEARDSgroup(n=8)Controlgroup(n=8)Inconclusion,PMNEactivityintheBALFofpost-surgericalARDSisnotinhibitedbythesmallamountofUTIthatispresentintheBALFSurgToday,JpnJSurg(1999)29:1030-33乌司他丁是保护机体免受炎性损害的重要机制当疾病进展到一定程度，体内乌司他丁水平严重不足小结乌司他丁抑制炎症的效果与其浓度有密切依赖关系HumanmonocyteswerepreincubatedwithUTI(1,000U/ml)for30minandthenstimulatedwithLPS(100ng/ml).〇

control;□UTIwithoutLPS;●LPS;■,LPS+UTI.*P0.01vs.control;†P0.01vs.LPS.HumanmonocyteswerepreincubatedwithvariousconcentrationsofUTIfor30minandthenstimulatedwithLPS(100ng/ml).Fourhoursafterstimulation,PerenleiMolor-Erdene,etal.

AmJPhysiolHeartCircPhysiol288:H1265–H1271,2005.高浓度的乌司他丁对溶酶体膜稳定作用更明显Effectsofulinastatin(UT;U/ml)onN-acetyl-b-D-glucosaminidase(NAG)releasefromL2cellsaftertreatmentwith2uMantimycinA(A2).*P<0.05vs.A2;**P<0.05vs.control.PulmonaryPharmacology&Therapeutics(1999)12,1–6天普洛安对LPS肺损伤的保护作用具有剂量相关性EffectsofUTIonLPS-inducedchangesintheconcentrationofinterleukin-8inbronchoalveolarlavagefluid(BALF)andwet/dryweight(W/D)ratio.BALFandlunglobewerecollected6hafterthestartofthesalineorLPSinfusion.Eachvaluerepresentsmean±SDfromsevenrabbits.*P<0.05versusgroupSaline-Only,†P<0.05vs.groupLPS-Only,‡P<0.01vs.groupLPS-Only.EffectsofUrinaryTrypsinInhibitoronLipopolysaccharide-InducedAcuteLungInjuryinRabbitsInflammation2011EffectsofUTIonlungtissuedamageinrabbitsat6hafterthestartofsalineorLPSinfusion.RepresentativehotomicrographiesshowinghematoxylinandeosinstainingsampleswithmedianvaluesinagroupSaline-Only,bgroupLPS-Only,andcgrouppre-UTI-High.Originalprintmagnifications×200.Lunginjuryscored:lunginjurywasscoredfrom0(nodamage)to4+(severedamage)accordingto