Preclinical Assessment of the Treatment of Second-Stage African Trypanosomiasis with Cordycepin and Deoxycoformycin 英文参考文献.docVIP

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Preclinical Assessment of the Treatment of Second-Stage African Trypanosomiasis with Cordycepin and Deoxycoformycin 英文参考文献.doc

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Preclinical Assessment of the Treatment of Second-Stage African Trypanosomiasis with Cordycepin and Deoxycoformycin 英文参考文献

PreclinicalAssessmentoftheTreatmentofSecond-Stage AfricanTrypanosomiasiswithCordycepinand Deoxycoformycin SumanK.Vodnala1,MarcelaFerella2,HildaLunde′n-Miguel1,EvansBetha3,NickvanReet4,DanielNdem Amin5,BoOberg¨ 6,Bjo¨rnAndersson2,KristerKristensson5,HansWigzell1,MartinE.Rottenberg1* 1Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden, 2Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden, 3Tropical Diseases Research Center, Ndola Central, Ndola, Zambia, 4Institute of Tropical Medicine, Antwerp, Belgium, 5Department of Neurosciences,KarolinskaInstitute,Stockholm,Sweden,6MedivirAB,Huddinge,Sweden Abstract Background:Thereisanurgentneedtosubstitutethehighlytoxiccompoundsstillinusefortreatmentoftheencephalitic stage of human African trypanosomiasis (HAT). We here assessed the treatment with the doublet cordycepin and the deaminaseinhibitordeoxycoformycinforthisstageofinfectionwithTrypanosomabrucei(T.b.). Methodology/Principal Findings: Cordycepin was selected as the most efficient drug from a direct parasite viability screeningofacompoundlibraryofnucleosideanalogues.Theminimalnumberofdosesandconcentrationsofthedrugs effective for treatment of T.b. brucei infections in mice were determined. Oral, intraperitoneal or subcutaneous administrations of the compounds were successful for treatment. The doublet was effective for treatment of late stage experimentalinfectionswithhumanpathogenicT.b.rhodesienseandT.b.gambienseisolates.Latestageinfectiontreatment diminished the levels of inflammatory cytokines in brains of infected mice. Incubation with cordycepin resulted in programmed cell death followed by secondary necrosis of the parasites. T.b. brucei strains developed resistance to cordycepinafterculturewithincreasingconcentrationsofthecompound.However,cordycepin-resistantparasitesshowed diminishedvirulenceandwerenotcross-resistanttootherdrugsusedfortreatmentofHAT,i.e.pentamidine,suraminand melarsopro