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Preclinical assessment of the treatment of second-stage African trypanosomiasis with cordycepin and deoxycoformycin

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Show simple item record Vodnala, S. K. Ferella, M. Lundén-Miguel, H. Betha, E. van Reet, N. Amin, D. N. Öberg, B. Andersson, B. Kristensson, K. Wigzell, H. Rottenberg, M. E. 2009-08-24T09:26:51Z 2009-08-24T09:26:51Z 2009
dc.identifier.issn 1935-2735
dc.identifier.other ABSTRACT
dc.identifier.other ITG-P5B
dc.identifier.other PARAS
dc.identifier.other U-SEROL
dc.identifier.other JIF
dc.identifier.other ELECTRONIC
dc.identifier.other DOI
dc.identifier.other UPD16
dc.identifier.other FTA
dc.description.abstract BACKGROUND: There is an urgent need to substitute the highly toxic compounds still in use for treatment of the encephalitic stage of human African trypanosomiasis (HAT). We here assessed the treatment with the doublet cordycepin and the deaminase inhibitor deoxycoformycin for this stage of infection with Trypanosoma brucei (T.b.). METHODOLOGY/PRINCIPAL FINDINGS: Cordycepin was selected as the most efficient drug from a direct parasite viability screening of a compound library of nucleoside analogues. The minimal number of doses and concentrations of the drugs 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 experimental infections with human pathogenic T.b. rhodesiense and T.b. gambiense isolates. Late stage infection treatment 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 cordycepin after culture with increasing concentrations of the compound. However, cordycepin-resistant parasites showed diminished virulence and were not cross-resistant to other drugs used for treatment of HAT, i.e. pentamidine, suramin and melarsoprol. Although resistant parasites were mutated in the gene coding for P2 nucleoside adenosine transporter, P2 knockout trypanosomes showed no altered resistance to cordycepin, indicating that absence of the P2 transporter is not sufficient to render the trypanosomes resistant to the drug. CONCLUSIONS/SIGNIFICANCE: Altogether, our data strongly support testing of treatment with a combination of cordycepin and deoxycoformycin as an alternative for treatment of second-stage and/or melarsoprol-resistant HAT. en
dc.language English en
dc.subject Protozoal diseases en
dc.subject Trypanosomiasis, African en
dc.subject Trypanosoma brucei en
dc.subject Encephalitic stage en
dc.subject Antiprotozoal agents en
dc.subject Cordycepin en
dc.subject Deoxycoformycin en
dc.subject Combination therapy en
dc.subject Treatment outcomes en
dc.subject Efficacy en
dc.title Preclinical assessment of the treatment of second-stage African trypanosomiasis with cordycepin and deoxycoformycin en
dc.type Article-E en
dc.citation.issue 8 en
dc.citation.jtitle PLoS Neglected Tropical Diseases en
dc.citation.volume 3 en
dc.citation.pages e495 en
dc.citation.jabbreviation PLoS Negl Trop Dis en

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