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1页Signature:MedSciMonit,2003;9(1):BR37-42签名：医学信息，2003；9（1）：溴37-42PMID:12552235分类号：12552235收到:2002.03.27Accepted:2003.01.03接受:2003.01.03Published:2003.01.28发表:2003.01.28Authors’Contribution:作者的贡献:AStudyDesignA个研究设计BDataCollectionB数据收集CStatisticalAnalysisC统计分析DDataInterpretationD维数据解释EManuscriptPreparationE手稿准备FLiteratureSearchF文献检索GFundsCollectionPharmacokineticsstudiesandtoxicityprofile药代动力学研究和毒性ofraltitrexedusedbyintraperitonealroute雷替曲塞腹腔路线innormothermiainapigmodel在常温的猪模型DiemNguyen1abcde,吴庭艳阮1份专题ClaudeEmond1abcde,克劳德等1份专题YvesE.Leclerc1abcde,伊夫·勒克莱尔1份专题IgorSherman2abcde,伊戈尔·谢尔曼2份专题PierreDubé1abcde皮埃尔·杜布1份专题DepartmentofSurgery,Maisonneuve-RosemontHospital,UniversityofMontreal,Montreal,Canada外科学系,麦松尼喔-罗斯医院,大学蒙特利尔,加拿大蒙特利尔AstraZenecaCanada阿斯利康加拿大G基金集合Sourceofsupport:AstraZenecaCanadaInc.资源的支持由:阿斯利康加拿大公司。Background背景Material/Methods材料/方法Results结果Summary摘要Todefinethepharmacokineticandtoxicityprofileofraltitrexedadministeredbyintraperi-tonealrouteinanormothermicpigmodel.定义的药代动力学和毒性雷替曲噻由腹腔腹膜路线性常温猪模型。Twenty-onefemalepigsweredividedinthreegroups.Undergeneralanesthesia,pigsingroups1and2underwentlaparotomywithresectionofasmallhepaticwedge,bowelanasto-mosisandportalandsystemicveincatheterization.Thiswasfollowedbyanintraperitionealdeliveryofraltitrexed:adoseof1mgwasgiventogroup1pigs,whereasgroup2received2mg.Serialsamplingofportalblood,systemicbloodandperitonealfluidwasthenundertakeninbothgroupsforpharmacokineticsstudies.Pigswerefolloweddailyforaperiodof10daysaftersurgerywithrecordingsofsignsoftoxicity.21只猪随机分为三组。在全身麻醉下，在组1头猪和组2行剖腹探查术，小肝楔形切除术，肠吻合门静脉和全身静脉插管。其次是腹腔交付雷替曲塞：剂量为1毫克组1头猪，而2毫克组2。串行静脉采血，全身的血液和腹腔液后进行，在两组的药代动力学研究。猪每天随访期为10天的毒性症状，记录术后。Onday10,anexploratorylaparotomywasundertakenoneachpiginordertoassessperitonealtoxicityafterwhichtheywereeutha-nized.Pigsingroup3wereusedforbioavailabilityevaluation.10天，剖腹探查术，进行了以每头猪腹腔毒性评估后，他们状态是安乐死。在组3头猪用于生物利用度的评价。Threedeathswererecordedwithin24hoursofsurgery;atechnicalproblemwasidentifiedinallcasesandnodeathsweretheresultsofraltitrexedtoxicity.Aperitoneo-plasmagradientof100:1wasobtained.Cmaxinplasmawereof28ng/mland54ng/mlforgroup1and2,respectively.Tmaxwere180minforbothgroups.AUCplasmaticwasdoubleinthe2mggroupcomparedtothe1mggroup.3例死亡记录在24小时的手术,一个技术问题是确定在所有情况下,没有死亡的结果雷替曲塞毒性。得到100:1腹血浆梯度。最大浓度在等离子体28ng/ml和54ng/ml组1和2,分别。两组的最高温度是180分钟。药时曲线下面积的2倍在2毫克组比1毫克组。Conclusion结论keywords关键词RaltitrexedadministeredbyIProuteinpigsisnon-toxic.Pharmacologically,therearefewinterindividualvariationsandthesmallfirst-pasteffectdidnotsignificantlyalterthehighperitoneo-plasmaticgradient.雷替曲塞由IP路由在猪是无毒的。药物,很少有个体间变化和以前小的效应不显著改变高腹血浆梯度。intraperitonealchemotherapy•raltitrexed•pig,normothermia•carcinomatosis•cancer腹腔化疗•雷替曲塞•猪，常温•癌病•癌Full-textPDF全文PDFWordcount:字计数：Tables:表：Figures:人物：References:参考文献：Author’saddress作者的地址医学监测（网址）24683116PierreDubé,MD,HôpitalMaisonneuve-Rosemont,5415Boulevardl’Assomption,Montréal(Québec),CanadaH1T杜布石头、医学博士、医院、检察、,麦松尼喔-罗斯大道第5415次,加拿大蒙特利尔(魁北克H1T）2M4,email:LREC@videotron.ca2页BACKGROUND背景Peritonealcarcinomatosis(PC)isadiseasewhichcarriesadismalprognosiswithamedian6-monthsurvivalof10%[1].Upto30%percentofcolorectalcancerpatientswillbeaffectedbythisentityduringthecourseoftheirdisease.In15%ofthesecases,thediseasewillbelocal-izedtotheperitonealsurfaces.Thepastdecadehasbroughtnewlocallyaggressiveandperhapscurativetreatmentmodalitiesforthislastsubgroupofpatients[2,3].Treatmentconsistsinacombinationofcytoreduc-tivesurgeryfollowedbyintraperitoneal(IP)fluo-areaof0.5m2[0.47to0.52m2]wereusedforexperi-mentation.Femaleswerechosentoavoidurinecontam-inationintotheabdominalcavityduringlaparotomy.ExperimentswereperformedbetweenAugust1999andDecember1999inourlaboratoryofexperimentalsurgery.Weproceededundergeneralanesthesiawithendotrachealintubationandmechanicalventilation.Inductionofanesthesiawasachievedwithaproportion-altoweightintramuscularinjectionofatropine,atro-ventandketamine.MaintenanceofanesthesiawaskeptwithIVadministrationofpentobarbital.HydrationwasassuredwithIVRinger`slactatesolutionthroughoutsurgeryat60ml/hinrightearvein.面积0.5平方米(0.47到0.52平方米)被用于试验心理状态。雌性选择避免尿液污染rouracil-basedchemotherapy[4].Themainadvantageofthisapproachistoallowdirectaccesstoresidualmicroscopicdisease,permittinghighdrugconcentra-tionstoreachtumorcellspriortoadhesionformationandentrapmenteffects.腹膜癌扩散(PC)是一种疾病的预后与平均6个月生存率为10%[1]。多达30%的结直肠癌患者将受此影响实体的过程中他们的疾病。在15%的情况下,疾病将局部腹膜表面。过去十年带来了新的本地咄咄逼人,也许对这一亚组病人治疗治疗[2、3]。在于结合肿瘤细胞减灭术手术治疗腹腔内化疗(IP)氟尿嘧啶为基础的紧随其后[4]。这种方法的主要优点是允许直接访问残留微小的疾病,允许高药物浓度达到肿瘤细胞粘附形成之前和诱捕效果。Thesuccessofthistreatmenthasbeenpartiallypreclud-edbyitsassociatedmorbiditywhichmayinpartbeduetothelackofspecificityoffluorouracil,thecompoundmostfrequentlyusedbyIPchemotherapytreatmentofPCfromcolorectalorigin[5–7].Fluorouracilexertsitsantitumoreffectsbyinteractingwiththymidilatesyn-thase(TS),anenzymeknowntobeexpressedincol-orectaltumorcells[8].TSisessentialforthereductivemethylationofdUMPtoTMPforitsincorporationintoDNA.Thus,theinhibit