title: Preclinical assessment of the treatment of second-stage African trypanosomiasis with cordycepin and deoxycoformycin.
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.).
  
  
  RESULTS
  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
  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.
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
authors: Suman K
authors: SK
authors: Vodnala
authors: Marcela
authors: M
authors: Ferella
authors: Hilda
authors: H
authors: Lundén-Miguel
authors: Evans
authors: E
authors: Betha
authors: Nick
authors: N
authors: van Reet
authors: Daniel Ndem
authors: DN
authors: Amin
authors: Bo
authors: B
authors: Oberg
authors: Björn
authors: B
authors: Andersson
authors: Krister
authors: K
authors: Kristensson
authors: Hans
authors: H
authors: Wigzell
authors: Martin E
authors: ME
authors: Rottenberg