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Preclinical Assessment of the Treatment of Second-Stage African Trypanosomiasis with Cordycepin and Deoxycoformycin

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...

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Autores principales: Vodnala, Suman K., Ferella, Marcela, Lundén-Miguel, Hilda, Betha, Evans, van Reet, Nick, Amin, Daniel Ndem, Öberg, Bo, Andersson, Björn, Kristensson, Krister, Wigzell, Hans, Rottenberg, Martin E.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2713411/
https://www.ncbi.nlm.nih.gov/pubmed/19652702
http://dx.doi.org/10.1371/journal.pntd.0000495
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author Vodnala, Suman K.
Ferella, Marcela
Lundén-Miguel, Hilda
Betha, Evans
van Reet, Nick
Amin, Daniel Ndem
Öberg, Bo
Andersson, Björn
Kristensson, Krister
Wigzell, Hans
Rottenberg, Martin E.
author_facet Vodnala, Suman K.
Ferella, Marcela
Lundén-Miguel, Hilda
Betha, Evans
van Reet, Nick
Amin, Daniel Ndem
Öberg, Bo
Andersson, Björn
Kristensson, Krister
Wigzell, Hans
Rottenberg, Martin E.
author_sort Vodnala, Suman K.
collection PubMed
description 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.
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spelling pubmed-27134112009-08-04 Preclinical Assessment of the Treatment of Second-Stage African Trypanosomiasis with Cordycepin and Deoxycoformycin Vodnala, Suman K. Ferella, Marcela Lundén-Miguel, Hilda Betha, Evans van Reet, Nick Amin, Daniel Ndem Öberg, Bo Andersson, Björn Kristensson, Krister Wigzell, Hans Rottenberg, Martin E. PLoS Negl Trop Dis Research Article 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. Public Library of Science 2009-08-04 /pmc/articles/PMC2713411/ /pubmed/19652702 http://dx.doi.org/10.1371/journal.pntd.0000495 Text en Vodnala et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Vodnala, Suman K.
Ferella, Marcela
Lundén-Miguel, Hilda
Betha, Evans
van Reet, Nick
Amin, Daniel Ndem
Öberg, Bo
Andersson, Björn
Kristensson, Krister
Wigzell, Hans
Rottenberg, Martin E.
Preclinical Assessment of the Treatment of Second-Stage African Trypanosomiasis with Cordycepin and Deoxycoformycin
title Preclinical Assessment of the Treatment of Second-Stage African Trypanosomiasis with Cordycepin and Deoxycoformycin
title_full Preclinical Assessment of the Treatment of Second-Stage African Trypanosomiasis with Cordycepin and Deoxycoformycin
title_fullStr Preclinical Assessment of the Treatment of Second-Stage African Trypanosomiasis with Cordycepin and Deoxycoformycin
title_full_unstemmed Preclinical Assessment of the Treatment of Second-Stage African Trypanosomiasis with Cordycepin and Deoxycoformycin
title_short Preclinical Assessment of the Treatment of Second-Stage African Trypanosomiasis with Cordycepin and Deoxycoformycin
title_sort preclinical assessment of the treatment of second-stage african trypanosomiasis with cordycepin and deoxycoformycin
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2713411/
https://www.ncbi.nlm.nih.gov/pubmed/19652702
http://dx.doi.org/10.1371/journal.pntd.0000495
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