【doc】用吡喹酮早期治疗小鼠的血吸虫感染

【doc】用吡喹酮早期治疗小鼠的血吸虫感染 用吡喹酮早期治疗小鼠的血吸虫感染 BIBLIDjISSN0253—9756中国琦理AcLaP^舢c.咖szice1903Nov}14i0)j533—538 Earlytreatmentofschistosomalinfectionwithpraziquantelinmice XIAOShu—Hua,YOUJi—Qing'MEIJing—Yan'JIAOPei—Ying (InstitutePavaaiticDiseages?ChineseAcademyPreventiveMegiciae,W0fd6d渤P CentreforMalaria.8chl.miasisangFilariasis.s^anghat200025.China) ABb~fRACTThefirstsingledoseofpraziquantel (Pra)wa3givenigtomiceonthedayofinfectionwith '?.m口,oaicumcercariae?or7d,l4d,and21 dafterlnfectionAfterwards.thesamedoseofPra wasgivenoncest1—3wkintervalfor2—3times. TheprophylacticeffectWaSestimatedbythereduction ofaverageauraberoftotaland旱worms,theflumber ofmicewithout旱worm,andthegrosschangeofthe liver.WhenmiceweretreatedwithPra300—500mg *kginitiallyond2lafterinfectionandrepeatedonce every1—2wkfor2--3times,almostidlthe早worms lodgedintheh08twerekilled—showingthateitherthe hostwasproteCtedfromthemfectionofschistosomes or8greatdeCreaseintheintensityoftheinfectionre— sulted. KEYWORDS8chiaommaonicumIschistosomula praziquantel}artemether;combinationdrugtherapy Theeffectofpraziquante1(Pra)olldiffer— entdevelopmentalstagesofSch~aosoma0n— cmhasbeenstudies.Apartfromitseffect onadultworms.Prawasexhibitedtohaveef- fect0ncercariaeinvadingtheskinofthehost, 3h—oldand2l-d.oldschistosomulaet1-43. Basedontheantischistosomalactivitiesof Pra,wesuggestifPraisgivenonceatappro- priateintervalsforseveraltimestothehost startedatearlystageofinfection,themajority orevenal1ofthe旱wormsareexpectedtobe killedbeforetheirsexualmaturity.Thus, theappropriateregimencouldbeselectedand usedf0rcontrolofacuteschIstosomiasisorre. Reeel~d1992-12-16Accepted1993—08—11 TheE~hJ8Five—yearResearchprogramofChina.? 859170208-projectsupporledinpartbyJointResearchMan— asementCommitteefromBWorldBankLoanforSchistosomi- i0j目- ducedtheintensitvofinfection.BesidesPra. studiesontheeffectofartemether'Art).a derivativeofqinghaosu,indicatedthatArt wasmoreeffectiveagainst7-d-.oldschistoso.. mula.Therefore.thecornbinedtreatmeat withPraandArtwasalsotestedinearlytreat— mentofschistosomalinfectiontomeasurethe possibilityofsynergicactionofthetwodrugs? MATERIALSANDMETHODS Parasite~Schi~oaomaJ印onieumeercarlae(An— hui扭olate).obtainedfromintectedO~tcomeLa*t^ $博,wasprovidedbyourInstitute. MiceKunmingstrainmiceofeitherSeXweighing 】8土2gweremaintainedoffarodentfeedandwater ad西mtheanimaIcarefacilitiesoftheInstitute. InfectionandtherapyEachmousewitsinfected with48—52cercariaeviatheshavedabdominalskin andtreatediswithPraatl一3wkintervalsfor1—5 times.Themicewerekilled4——5wkaftertreatment forcolleCtionofresidualwormsbyperfusion-The therapeuticefficacywasevaluatedbytotalworm reductionrate.单wormreductionratetthenumber ofmicewithout早worm?andthegrosschangeof theliver. Effectolleggproductionof旱wormMicein- fectedwithcercariaefor21dweretreatedwithPra 500mg?kg,.Groupsof2--3miceWerekilled3?7, 14.and2ldaftertreatmentandtheschistosomes lodgedthehostwereflushedoutwithicecold Hankhaianeedsaltsolution(HBSS)fromtheliver andmesentericveins.Thewormswerefixedin70 ethanolandstaedwithacidc盯mine.Thereproduc? tiresystemofthe早wormswasexaminedundera lishtmicroscopeandtheeggspre~entmtheuterus werecounted.Inuntreatedmiceoffd…d,andd36 单wormswereexa1~edRscontroIs. s.?thticalmethodAlldataobtainedfrOmtheex— perimentswereanalyzedwithftest? ?534?BIBLID|ISSN0253—9796中目药理Aeta户^口?伽啪5inWu1993Nov;14(6) RESULTS Treatmentstartedond.Whenmicewere treatedigwithPra500mS?kg,ondo,theto— taland早wormreductionrateswere80.3 and83.7,respectively.4/20micewere freefrom早worm,butnoneofthemicewas cured-Inothergroups?miceweretreatedig withPra500mg?kg,ond.andthenonceatI 一 3wkintervalsfor2—4times.Theaverage numbersoftotaland旦wormineachgroup weresireliar.butmuchlessthanthoseofthe above—mentionedgrouptreatedonlyoncewith Pra.AfterthemiceweretreatedigwithPra forseveraltimes,partoftheliversshowed normalappearance'purpl~hredincolorand softConsistency,whileotherpartsweretight redincolorwithsomedispersedeggtubercles onthesurface.Inthese3treatedgroupsover' halfofthemicewasfree丹om早wormsanda fewofthemwerecured(Tab1).' TreatmentstattedonI一3wkafterinlet- tionWhenPrawasgivenigtomice1wkaf- tOTinfectionatadailydoseofGO0mg?kg一for' 3d,noapparentefficacywasseen.Inabove— mentionedmicetreatedigwithPra500mg ?kg_.weekIyfor3wk?theaveragenumberof totalwormswasleasthanthatintheCOntrol. butwhichwasnotthecaseintheaverage' numberof旱worms.Inother2groupsof mice,the2ndandthe3rddosesofPrawere, givenat2—3wkintervalsfollowingthefirst dosingwhichtookplace1wkafterinfection, resultinginanapparentloweringoftheaver— agenumberoftotMwormsand早wormsas comparedwiththeabove-mentioned2groups, Tab1?MiceinfeCtedwithSchLq~}up--cot~triteandl~eatedwithlgprazlquantelgo0mg?kg 一.givenon dH2ereathafterinfection.i?$'P>O.O;,P<O.0;'P<O.el?control WRR;wormreductionrateFWRR;femalewormreductionrate. 一 {normal;土:nolmalcolor,needlepofrt~一likeeggtuberclesseenoccasionallyin1— 2lobesoftheliver}+tlight redcolor,eggtubercleslargerthanneedlepointdispersedonthewholeliversurface}++:mark edredColoregg tuberele~fusedtogetherwithmillet-likeinsizedistributedextensivelyontheliversurface. B1BLID-ISSN0259—9756中茸药理AclaP洲d?岬Ec4删]993Nov)14(6)?535? andhalfofthemicebeingfreefromworms (Tab1)+ inmicetreatediSwithPra500mg?kg dailyfor3dstarted14dafterinfection.no apparenteffectwasfound.WhenPrawas givenweeklyfor3wkstartedond14.theav- eragenumbersoftotalwormsandworms weresignificantlylowerthanthoseofthecon— trolwitha旱wormreductionrateof67.3. Inother2groups.the2ndand3rddosesof Praweregivenat2--3wkintervalsfollowing thefirstdosingstartedoild14,theaverage numbersoftotaland旱wormswerelessthan thoseoftheabove—mentioned2groupswith thesame早wormsreductionratesof96.9. Nevertheless,75ofmicetreated.nthese2 groupswerefreefrom旱worms(Tab1). WhenmiceweretreatedigwithPraat3 wkafterinfectionat500mg?kg一?d一×3d. thetotalandwormreductionrateswere 89.8and82.7,respectivelywithoile— thirdofmicewithout早worms.inmice treatedigwithPra500mg?kg一onceaweek for3wkstartedon3wkafterinfection,the averagenumbersoftotaland旦wormswere lessthanthoseoftheabove-mentionedgroup andthe早wormreductionratewas94.9+ WhenPrawasgivenonceevery2--3wkfor3 times,thetoralwormreductionratewasstill hisherandthewormreductionratewas98 一 l00+Noapparentdifferenceintheaver— agenumberofwormswasseenbetweenthe groupstreatedwithPraonceeveryl0r2wk (Tab1).IngroupstreatedjgwithPraatl or2wkintervals.mostoftheliverswereSoft andredincolorandonly1/6ofthemshowed sparsefineeggtubercles.Theliversinthe grouptreatedwithPraat3wkintervalswere slightlyharderwithsomefibrouseggtuber— cles(Tab1). EffectofvariousdosesAt3wkafterin— fectionthemiceweretreatedigwithPra300 or500mg?kg一.Afterwards.thesamedose ofPrawasgivenweeklyfortwice.Thetotal andwormreductionratesof300mg?kg一 groupwere70+8and80+8,respectively, buttheaveragenumbersoftotaland wormsinthisgroupweresis;nificantlyhigher andthenumbersofmicewithout旱wormor curedwerelessthanthoseinthe500mg?kg一 group+Inthe300mg?kg一group.abouthalf ofthemiceshowednormallivers.whlieoth— ersmanifestedsomelargereggtuberclesinthe darkredlivers.Inthe500mg?kg,group. mostofthemiceshowednormalliversapart fromsomefineeggtuberclesinafewofmice. Whenthe2ridandthe3rddosesofPra300mg ?kg一weregiventothemiceat3wkintervals afterthefirstdosingstarred0n3wkafterin— fection,theaveragenumbersoftotaland旱 wormswerestillhigherthanthoseofthe500 mg?kg,group.Inthisgroup.9/l3mice wereireefromwormwithatotalworm一 ductionrateof96+2andthegrosspatholog— icalchangesoftheliverweresimilartothose ofthe500mg?kggroup(Tab2). Inanotherexperiment,miceweretreated igwithPra300mg?kgatl一3intervalsand asingledose(200mg?kg)ofartemether (Art)wasgiven0nd7afterinfection.Noap- parentincreaseofefficacywasnoted?Onthe otherhand,whenadoseofPrawasaddedin theregimenofdH,d2s,dss,andgivenond afterinfection,theefficacyofPraincreased sisnificantly,asshownbythefindingthat旱 wormreductionratereached98.6and早 wormsdisappearedinl3/17mice(Tab2). AIternativeadministrationofPraand artemetherWhenmiceweretreatedigwith Pra500mg?kg一orArt300mg?kg一ondo andd7,respectively,thea~eragenumbersof totalworrusinthese2groupsweresimilar' butlessthanthatinthecontrol+Inmice treatedigwithPraondoandArtondrord1(' ? 536?BIBLID_ISSN0253—9750中圆药理^"4Phcrma~toets…1993Nov?14(6) Tab2-Miceinfectedwith&hm』o|l蛔ceresrlaeandtreatedwithpraziquantelCera)orIncombtnl— ttonwithartemetber(Art)igondifferentdaysafterinfection.i土&'P>0.05..P<0.05,.P<0.01嗨the eorresponding?group. WRR:wormreductionrate-FWRR:如maIewormreductionr=te. 一:normal;士Inormalcolor,needlepoint—likeeggtuberclesseenoccasionallyin1--2lobesoftheliverf+:1ight redcolor'eggtubercleslargerthanneed~pointdispersedonthewholeliversurfaoel++lmarke dredcolor,egg tuberclesfusedtogetherwithmillet—likeinsizedistributedextensivelyontheHversurface. noapparentincreaseinefficacywasseen. WhenmiceweretreatedigwithArtond7and Praond21,lessaveragenumbersoftotaland 早wormswereobtained,butthedifference wasn0tgignjficant$th.grouptfeatedwith ? eitherPraorArtalone(Tab3). Tabl?Effectsp?芏Iqu-胁I(Pra)combinedwithartemether(Art)givenalternalelytomiceondifferentdays afterInfectionwith&岫如鲫埘j'apo~umcerearlae.i土s.'P>0.Og,.P<0.Og,'P<0.OI侣?group ;II 一 BIBLIDIISSN0253—9755中圆药理AerePk~rma~lo9iNs?c1993Nov)14(6)-537? EffectofPraoneggproductionofd2I早 wormWhenmiceweretreatedigwithPra 500mg?kg-.ond2lafterinfection,3to7d later,the旱wormsshowedapparentshrink— ageinsize,depigmentationoftheintestine, degeneratjonofthevitell/negland,atrophyof theovary,anddisappearanceofeggsin uteros.Indz日control旱worms,eggswere seeninallofthewormsexaminedwithana eragenumberof84-4-47/早worm.Ond14 aftertreatment,21/34早worms(61.8) examinedshowednoeggintheiruteriorno apparentrecoveryoftheirdamagedreproduc- tireglands.Theother13wormsshowed recoveryoftheirreproductiveglandsinvari- OUSdegreesandtheeggswerefoundinthe uteruswithanaveragenumberof40-4-45/早 worm,whichwassignificantlylessthanthat ofds5control旱wormwithaneggreduction rateof80.4%.On21daftertreatment, mostoftheresidual旱wormsshowedappar— entrecoveryoftheirreproductiveglandswith anaverageeggnumberof93-4-55/早worm, whichwasreducedto54.5ofthatfoundin thecontrol早worms(Tab4). Tab1.EggproductionotwoTmsharboredinmice infectedwithSch~o*omajapordcum~ercarlaefor2ld andtreatedwithIgprazlquantelntnsingledoseof$00 mg?kg,.i士s.'P<0.gI懈l5-dcontro1.'懈 28-dcomro1. DlSCUssIoN Althoughhighertotaland早wormre- ductionrateswereseenwhenasingledoseof Prawasgiventomiceondo,lessefficacywas foundinrabbitstreatedwithPraonthesame timeafterinfection(TobePobitshed).In viewoftheabove-mentionedresultsandthe inaccess|b'l|lyofdeliveryofthedrugtothepi- lotareaonthedayofinfection,theregimen hasnotbeenfurtherstudied. WhenmiceweretreatedigwithPraon d7,ord1dafterinfectionatadailydosefor3 d,noneoronlyaslighteffectwasseen.The samewastruewhonthesamedoseofPrawas givenweekly.However,ifthesecondand thethirddosesweregivenat2—3wkinter— vals,higher旱wormreductionrateswere seen.Sinced7andd14schistosomulawereon- susceptibletoPra(.onlythedruggivenon d2l—dssmightdisplaythelethaleffectonadult worms,ie.the旱wormsWOO1dmatoreand layeggsbeforetheywereaffectedbythe drug.Therefore,inspiteofhigher早worm reductionrateandabouthalfoftheanimals treatedwereireefrom旱worms,theliverof eachmousestillshowedtracesofdamage causedbyeggs. Amongtheregimenstested,themost promisingonewasthatPrawasgiveninitially tothehostond21afterinfeorion,followedby therepeateddosingat1—2wkintervalfor2 — 3times.Wjththisearlytreatmentregimen theaveragenumbersoftotaland早worms, andthenumbarofmicewithoutwormwere somewhatlessthanthosein3wkgroup.A1一 thoughallmicewerefreefrom早worminthe lattergroup,tracesofgrosspathological changesoftheliverinducedbyeggswasseen ineachmouse.Onthecontrary.in1and2 wkgrouptracesofeggtuberclescouldhardly befoundintheliverinmostofthemicewith ? 538?BIBLIDIISSN0253-9756中国莳理ActaPj…??icasl…1993Nov=14(6) anapperancesimilartothatofthenon—.infect—. edmice.thestudyontheeffectofPraonegg productionofd2t苹wormnotedthatthe ovipositionofwormswasinhibitedsignifi— cantlyorevencompletelyduringthe2wkaf- tertreatment,indicatingtherationalityof above-mentionedrecommendedregimens. Apreviouspaperindicatedthatcombined PraandArtdidnotshowanysynergeticeffect# evenathigherdosesandwithlongertreat-~ mentcourses(. Sinced7,anddo,d2【schisto— somulaweremoresusceptibletorespective ArtandPrawhilegivenseparately",the2学科学院寄生虫病研究所.世界卫生组织疟疾,血吸 drugswerethengivenalternatively-Using虫病和丝虫病合作中心,上海200025,中国) thisregimen,theefficacyonlyincreasednegli一. gIblyandjtseemedmeaninglesstousethis,^摘要小鼠于感染血吸虫尾蚴后不同时问给予首剂毗 regimenjnpractice.~M(Pra)30O--500mg'kg--t-然后每隔1—5wkig1 ..敬相同剂量的Pra,共给2—3敬,并根据残存虫数和肝 REFERENCES脏变化评价疗技.结果认为宿主自感染后d:,开始用 1.sH,YuewJ.MejJY.AnayBb0fpt.p"yI州kf Prd治疗t每隔1—2wk给药敬,共蛤2--3扶时,可 feet.f口.?.I…k.抽fet.d_th鲫..杀灭宿主体内绝大部分或全部旱虫,从而达到保护宿 japotie~m.^嘲P~aTmaceu】985,2o:641—46.主或降低宿主感程度的目的- 2Y…WJY…JOMfiJY.ProobyIXCtictivitof0船 _qu圳.-帅.m:一.抽fe.ans……:.关蕾调巳奎:哩血吸虫童虫兰里-苎苎 ^c"P啪s'^1985{B198—9.联合药物疗法 《第四届全国生物医药色谱学术会议》通知 中国化学会色谱委员会和中国色谱学会决定于1994年9月23—27日在西安召开《第四届全国生 物医药色谱学术会议》,通知如下: l征文:液相色谱,气相色谱,毛细管色谱,薄层色谱超临界流体色谱,毛细管电泳等在 生物医药学方面的理论,有关技术及其应用.已在全国性会议上及刊物上发过的论文,请勿提 交. (以邮戳日期为准). 2征文截止日期:1994年3月31日 3征文要求:应征文稿请写成1500字以内的详细摘要(包括必要的数据,图表).字迹应清 晰工整,有绘图纸按正式出版物要求绘制插图,一式三份.挂号邮寄至:北京大学化学系爱今 收,邮编:100871.未录取稿件不予退回.会议期间同时举行产品展销会,欢迎有关厂商参展.