Optimization of Topical Therapy for Leishmania major Localized Cutaneous Leishmaniasis Using a Reliable C57BL6 Model 英文参考文献.docVIP

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Optimization of Topical Therapy for Leishmania major Localized Cutaneous Leishmaniasis Using a Reliable C57BL6 Model 英文参考文献.doc

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Optimization of Topical Therapy for Leishmania major Localized Cutaneous Leishmaniasis Using a Reliable C57BL6 Model 英文参考文献

OptimizationofTopicalTherapyforLeishmaniamajor LocalizedCutaneousLeishmaniasisUsingaReliable C57BL/6Model Herve′ Lecoeur1,PierreBuffet2,GloriaMorizot2,SophieGoyard1,GhislaineGuigon3,Genevie`veMilon1, ThierryLang1* 1Unite′d’ImmunophysiologieetParasitismeIntracellulaire,InstitutPasteur,Paris,France,2Unite′deRechercheClinique,InstitutPasteur,Paris,France,3Plate-formeSante′ Publique,InstitutPasteur,Paris,France Abstract Background: Becausetopicaltherapyiseasyandusuallypainless,itisanattractivefirst-lineoptionforthetreatmentof localizedcutaneousleishmaniasis(LCL).Promisingointmentsareinthefinalstagesofdevelopment.Onemainobjective wastohelpoptimizethetreatmentmodalitiesofhumanLCLwithWR279396,atopicalformulationofaminoglycosidesthat wasrecentlyproventobeefficientandsafeforuseinhumans. Methodology/Principal Findings: C57BL/6 mice were inoculated in the ear with luciferase transgenic L. major and then treatedwithWR279396.Thetreatmentperiodspannedlesiononset,andtheevolutionofclinicalsignsandbioluminescent parasiteloadscouldbefollowedforseveralmonthswithoutkillingthemice.Asjudgedbyclinicalhealinganda1.5-3log parasiteloaddecreaseinlessthan2weeks,the94%efficacyof10dailyapplicationsofWR279396inmicewasverysimilar to what had been previously observed in clinical trials. When WR279396 was applied with an occlusive dressing, parasitologicalandclinicalefficacywassignificantlyincreasedandnoreboundofparasiteloadwasobserved.Inaddition,5 applicationsunderocclusionweremoreefficientwhendoneeveryotherdayfor10daysthandailyfor5days,showingthat lengthoftherapyisamoreimportantdeterminantoftreatmentefficacythanthetotaldosetopicallyapplied. Conclusions/Significance:Occlusionhasasignificantadjuvanteffectonaminoglycosideointmenttherapyofexperimental cutaneaousleishmaniasis(CL),aconceptthatmightapplytootherantileishmanialorantimicrobialointments.Generatedin alaboratorymouse-basedmodelthatcloselymimicsthecourseofLCLinhumans,ourresultssupportaschedulebasedon discontinuousapplicationsforafewweeksrathe