Fexinidazole A Potential New Drug Candidate for Chagas Disease 英文参考文献.docVIP

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Fexinidazole A Potential New Drug Candidate for Chagas Disease 英文参考文献.doc

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Fexinidazole A Potential New Drug Candidate for Chagas Disease 英文参考文献

Fexinidazole:APotentialNewDrugCandidatefor ChagasDisease MariaTerezinhaBahia1*,IsabelMayerdeAndrade1,TassianeAss?′riaFontesMartins1,Alvaro′ Fernando daSilvadoNascimento1,L?′viadeFigueiredoDiniz1,IvoSantanaCaldas1,Andre′ Talvani1 ,Bernadette BourdinTrunz2,ElsTorreele2,IsabelaRibeiro2 1Laborato′riodeDoenc?a deChagas,DepartamentodeCie?nciasBiolo′gicasNu′cleodePesquisasemCie?nciasBiolo′gicas,UniversidadeFederaldeOuroPreto,Campus Universita′rio, MorrodoCruzeiro,OuroPreto,Brazil,2DrugsforNeglectedDiseaseinitiative(DNDi),Geneva,Switzerland Abstract Background: New safe and effective treatments for Chagas disease (CD) are urgently needed. Current chemotherapy optionsforCDhavesignificantlimitations,includingfailuretouniformlyachieveparasitologicalcureorpreventthechronic phaseofCD,andsafetyandtolerabilityconcerns.Fexinidazole,a2-subsituted5-nitroimidazoledrugcandidaterediscovered followingextensivecompoundminingbytheDrugsforNeglectedDiseasesinitiativeandcurrentlyinPhaseIclinicalstudy forthetreatmentofhumanAfricantrypanosomiasis,wasevaluatedinexperimentalmodelsofacuteandchronicCDcaused bydifferentstrainsofTrypanosomacruzi. MethodsandFindings:WeinvestigatedtheinvivoactivityoffexinidazoleagainstT.cruzi,usingmiceashosts.TheT.cruzi strains used in the study were previously characterized in murine models as susceptible (CL strain), partially resistant (Y strain),andresistant(ColombianandVL-10strains)tothedrugscurrentlyinclinicaluse,benznidazoleandnifurtimox.Our resultsdemonstratedthatfexinidazolewaseffectiveinsuppressingparasitemiaandpreventingdeathininfectedanimals for all strains tested. In addition, assessment of definitive parasite clearance (cure) through parasitological, PCR, and serologicalmethodsshowedcureratesof80.0%againstCLandYstrains,88.9%againstVL-10strain,and77.8%against Colombian strain among animals treated during acute phase, and 70% (VL-10 strain) in those treated in chronic phase. Benznidazolehadasimilareffectagainstsusceptibleandpartiallyresis