Evaluation of trypanocidal drugs used for human African trypanosomosis against<i>Trypanosoma lewisi</i>

Dethoua, Mariette; Nzoumbou‐Boko, Romaric; Truc, Philippe; Daulouède, Sylvie; Courtois, Pierrette; Bucheton, Bruno; Cuny, G; Semballa, Silla; Vincendeau, Philippe

doi:10.1051/parasite/2013038

Cited by 10 publications

(4 citation statements)

References 25 publications

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“…3-AB, the inhibitor reported to diminish T. cruzi growth, was also tested. Nifurtimox was also included in the panel of compounds as a positive control due to its extensively proven trypanocidal activity [ 37 , 38 ]. None of the PARP inhibitors tested were able to negatively affect parasite growth in culture (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Surprisingly, only Rucaparib at the highest concentration (15 μM) rendered a visible impact on the growth rate of procyclic parasites in the conditions tested here. This concentration was in a range similar to that exerted by Nifurtimox, a compound that has been recently incorporated as a combination therapy against Sleeping Sickness [ 37 , 38 ].…”

Section: Discussionmentioning

confidence: 95%

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Disrupted ADP-ribose metabolism with nuclear Poly (ADP-ribose) accumulation leads to different cell death pathways in presence of hydrogen peroxide in procyclic Trypanosoma brucei

et al. 2016

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BackgroundPoly(ADP-ribose) (PAR) metabolism participates in several biological processes such as DNA damage signaling and repair, which is a thoroughly studied function. PAR is synthesized by Poly(ADP-ribose) polymerase (PARP) and hydrolyzed by Poly(ADP-ribose) glycohydrolase (PARG). In contrast to human and other higher eukaryotes, Trypanosoma brucei contains only one PARP and PARG. Up to date, the function of these enzymes has remained elusive in this parasite. The aim of this work is to unravel the role that PAR plays in genotoxic stress response.MethodsThe optimal conditions for the activity of purified recombinant TbPARP were determined by using a fluorometric activity assay followed by screening of PARP inhibitors. Sensitivity to a genotoxic agent, H2O2, was assessed by counting motile parasites over the total number in a Neubauer chamber, in presence of a potent PARP inhibitor as well as in procyclic transgenic lines which either down-regulate PARP or PARG, or over-express PARP. Triplicates were carried out for each condition tested and data significance was assessed with two-way Anova followed by Bonferroni test. Finally, PAR influence was studied in cell death pathways by flow cytometry.ResultsAbolition of a functional PARP either by using potent inhibitors present or in PARP-silenced parasites had no effect on parasite growth in culture; however, PARP-inhibited and PARP down-regulated parasites presented an increased resistance against H2O2 treatment when compared to their wild type counterparts. PARP over-expressing and PARG-silenced parasites displayed polymer accumulation in the nucleus and, as expected, showed diminished resistance when exposed to the same genotoxic stimulus. Indeed, they suffered a necrotic death pathway, while an apoptosis-like mechanism was observed in control cultures. Surprisingly, PARP migrated to the nucleus and synthesized PAR only after a genomic stress in wild type parasites while PARG occurred always in this organelle.ConclusionsPARP over-expressing and PARG-silenced cells presented PAR accumulation in the nucleus, even in absence of oxidative stress. Procyclic death pathway after genotoxic damage depends on basal nuclear PAR. This evidence demonstrates that the polymer may have a toxic action by itself since the consequences of an exacerbated PARP activity cannot fully explain the increment in sensitivity observed here. Moreover, the unusual localization of PARP and PARG would reveal a novel regulatory mechanism, making them invaluable model systems.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1461-1) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 95%

Disrupted ADP-ribose metabolism with nuclear Poly (ADP-ribose) accumulation leads to different cell death pathways in presence of hydrogen peroxide in procyclic Trypanosoma brucei

et al. 2016

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“…cruzi (6), T. lewisi (8), and Leishmania donovani (9). Clinical studies have been performed in both Chagas disease and visceral leishmaniasis patients.…”

Section: Textmentioning

confidence: 99%

Pharmacokinetic-Pharmacodynamic Assessment of the Hepatic and Bone Marrow Toxicities of the New Trypanoside Fexinidazole

Watson

Strub-Wourgraft

Tarral

et al. 2019

Antimicrob Agents Chemother

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Fexinidazole is a novel oral treatment for human African trypanosomiasis caused by Trypanosoma brucei gambiense (g-HAT). Fexinidazole also has activity against T. cruzi, the causative agent of Chagas disease. During the course of a dose ranging assessment in patients with chronic indeterminate Chagas disease, delayed neutropenia and significant increases in hepatic transaminases were observed and clinical investigations were suspended. We retrospectively analyzed all available pharmacokinetic and pharmacodynamic data on fexinidazole in normal healthy volunteers and in patients with Chagas disease and g-HAT to assess the determinants of toxicity. A population pharmacokinetic model was fitted to plasma concentrations (n = 4,549) of the bioactive fexinidazole sulfone metabolite, accounting for the majority of the bioactive exposure, from three phase 1 studies, two g-HAT phase 2/3 field trials, and one Chagas disease phase 2 field trial (n = 462 individuals in total). Bayesian exposure-response models were then fitted to hematological and liver-related pharmacodynamic outcomes in Chagas disease patients. Neutropenia, reductions in platelet counts, and elevations in liver transaminases were all found to be exposure dependent and, thus, dose dependent in patients with Chagas disease. Clinically insignificant transient reductions in neutrophil and platelet counts consistent with these exposure-response relationships were observed in patients with g-HAT. In contrast, no evidence of hepatotoxicity was observed in patients with g-HAT. Fexinidazole treatment results in a dose-dependent liver toxicity and transient bone marrow suppression in Chagas disease patients. Regimens of shorter duration should be evaluated in clinical trials with patients with Chagas disease. The currently recommended regimen for sleeping sickness provides exposures within a satisfactory safety margin for bone marrow suppression and does not cause hepatotoxicity.

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“…Extensive phase 2 & 3 studies of fexinidazole in g -HAT infections have shown excellent efficacy and good tolerability. This class of drugs also has good in vitro and in vivo (murine model) activity against other kinetoplastid parasites: T. cruzi (5), T. lewisi (7) and Leishmania donovani (8). Clinical studies have been performed in both Chagas disease and visceral leishmaniasis.…”

Section: Introductionmentioning

confidence: 99%

A pharmacokinetic-pharmacodynamic assessment of the hepatic and bone-marrow toxicities of the new trypanoside fexinidazole

Watson

Strub-Wourgraft

Tarral

et al. 2018

Preprint

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1Fexinidazole is a novel oral treatment for Trypanosoma brucei gambiense human African trypanoso-2 miasis: g-HAT. Fexinidazole is also active against other kinetoplastid parasites, notably T. cruzi 3 the causative agent of Chagas disease.During the course of a dose ranging assessment in chronic in-4 determinate Chagas disease, delayed neutropenia and significant increases in hepatic transaminases 5 were observed and clinical investigations were suspended. We retrospectively analyzed all available 6 pharmacokinetic and pharmacodynamic data on fexinidazole in normal healthy volunteers and in 7 patients with chronic Chagas disease and g-HAT, in order to assess the determinants of toxicity. 8 A population pharmacokinetic model was fitted to plasma concentration data on the bioactive 9 fexinidazole sulfone metabolite from three phase 1 studies, two g-HAT phase 2/3 field trials and one 10 Chagas phase 2 field trial (462 individuals in total). Bayesian exposure-response models were then 11 fitted to hematological and liver related pharmacodynamic outcomes in chronic Chagas patients. 12 Neutropenia, reductions in platelet counts, and elevations in liver transaminases were all found 13 to be exposure and thus dose dependent in patients with chronic Chagas disease. Clinically insignif-14 icant transient reductions in neutrophil and platelet counts consistent with these exposure-response 15 relationships were observed in the g-HAT trials. In contrast, no evidence of hepatotoxicity was 16 observed in the g-HAT trials. 17 Fexinidazole treatment results in a dose dependent liver toxicity and transient bone marrow 18 suppression in Chagas disease. Regimens of shorter duration should be trialled for Chagas. The 19 currently recommended regimen for sleeping sickness provides exposures within a satisfactory safety 20 margin for bone marrow suppression and does not cause hepatotoxicity. 21 1 Abbreviations 22 ALT alanine aminotransferase 23 AST aspartate aminotransferase 24 AUlogC area under the log plasma concentration time curve 25 CNS central nervous system 26 CSF cerebrospinal fluid 27 DBS dry blood spot 28 g -HAT Trypanosoma brucei gambiense human African trypanosomiasis 29 M2 fexinidazole sulfone metabolite 30 NECT Nifurtimox-Eflornithine combination therapy 31 NHV normal healthy volunteers 32 OVL overlapping coefficient 33 PK-PD pharmacokinetics-pharmacodynamics 34 Introduction 35The nitroimidazole fexinidazole is a promising new treatment for sleeping sickness (human African 36 trypanosomiasis caused by Trypanosoma brucei gambiense: g-HAT). Fexinidazole has the potential 37 to replace current first-line therapies (1; 2; 3) as it is an oral treatment for both the blood stage and 38 the central nervous system (CNS) stages of the disease. Fexinidazole is metabolized extensively in 39 vivo to two biologically active metabolites, a sulfoxide (M1) and a more slowly eliminated sulfone 40 (M2) (4; 5). The sulfone metabolite accounts for the majority of bioactive exposure during the ten 41 days of fexinidazole treatment currently rec...

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Evaluation of trypanocidal drugs used for human African trypanosomosis againstTrypanosoma lewisi

Cited by 10 publications

References 25 publications

Disrupted ADP-ribose metabolism with nuclear Poly (ADP-ribose) accumulation leads to different cell death pathways in presence of hydrogen peroxide in procyclic Trypanosoma brucei

Disrupted ADP-ribose metabolism with nuclear Poly (ADP-ribose) accumulation leads to different cell death pathways in presence of hydrogen peroxide in procyclic Trypanosoma brucei

Pharmacokinetic-Pharmacodynamic Assessment of the Hepatic and Bone Marrow Toxicities of the New Trypanoside Fexinidazole

A pharmacokinetic-pharmacodynamic assessment of the hepatic and bone-marrow toxicities of the new trypanoside fexinidazole

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