Treatment options for second-stage gambiense human African trypanosomiasis

Epéron, Gilles; Balasegaram, Manica; Potet, Julien; Mowbray, Charles E.; Valverde, Olaf; Chappuis, François

doi:10.1586/14787210.2014.959496

Cited by 91 publications

(79 citation statements)

References 56 publications

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“…Clearly, with solid tissue cancers, there are greater challenges-the effects of soluble and cell-based signaling systems add a further complexity. The trypanocidal drug α-difluoromethylornithine (DFMO) is widely used to cure latestage sleeping sickness in people in West Africa, despite being a failed candidate anticancer drug (86). Perhaps taking a broader evolutionary perspective will promote a greater understanding of the origins of both protozoan and metazoan cancers and lead to the development of new cures for both cancers and parasitic infections.…”

Section: Resultsmentioning

confidence: 99%

Cancer in the parasitic protozoans Trypanosoma brucei and Toxoplasma gondii

Lun

Lai

Wen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cancer is a general name for more than 100 malignant diseases. It is postulated that all cancers start from a single abnormal cell that grows out of control. Untreated cancers can cause serious consequences and deaths. Great progress has been made in cancer research that has significantly improved our knowledge and understanding of the nature and mechanisms of the disease, but the origins of cancer are far from being well understood due to the limitations of suitable model systems and to the complexities of the disease. In view of the fact that cancers are found in various species of vertebrates and other metazoa, here, we suggest that cancer also occurs in parasitic protozoans such as Trypanosoma brucei, a blood parasite, and Toxoplasma gondii, an obligate intracellular pathogen. Without treatment, these protozoan cancers may cause severe disease and death in mammals, including humans. The simpler genomes of these single-cell organisms, in combination with their complex life cycles and fascinating life cycle differentiation processes, may help us to better understand the origins of cancers and, in particular, leukemias.

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Section: Resultsmentioning

confidence: 99%

Cancer in the parasitic protozoans Trypanosoma brucei and Toxoplasma gondii

Lun

Lai

Wen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Fexinidazole, an orally available drug from imidazole group has shown excellent antitrypanosomal activity in the African subcontinents. This compound has shown negligible toxicity along with inhibitory activity for human African trypanosomiasis and second stage gambience human African trypanosomiasis (Eperon et al, 2014). This drug has shown minimal side effect with antileishmanial activity in animal model, when it was administered orally (Wyllie, Patterson, & Fairlamb, 2013;Wyllie et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Developing imidazole analogues as potential inhibitor forLeishmania donovanitrypanothione reductase: virtual screening, molecular docking, dynamics and ADMET approach

Pandey

Sharma

Bhatt

et al. 2015

Journal of Biomolecular Structure and Dynamics

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Visceral leishmaniasis (VL) affects Indian subcontinent, African and South American continent, and it covers 70 countries worldwide. Visceral form of leishmaniasis is caused by Leishmania donovani in Indian subcontinent which is lethal if left untreated. Extensive resistance to antileishmanial drugs such as sodium stibogluconate, pentamidine and miltefosine and their decreased efficacy has been reported in the endemic region. Amphotericin B drug has shown good antileishmanial activity with significant toxicity, but its cost of treatment has limited the outreach of this treatment to affected people living in endemic zone. So, there is an urgent need to identify new antileishmanial drugs with excellent activity and minimal toxicity issues. Trypanothione reductase, a component of antioxidant system, is necessary for parasite growth and survival to raise infection. To develop potential inhibitor, we docked nine hundred and eighty-four 5-nitroimidazole analogues along with clomipramine which is a well-known inhibitor for TR. Total one hundred and forty-seven 5-nitroimidazole analogues with better docking score than clomipramine were chosen for ADMET and QikProp studies. Among these imidazole analogues, total twenty-four imidazole analogues and clomipramine were chosen on the basis of their ADMET, QikProp, and prime MM-GBSA study. Later on, two analogues with best MM-GBSA dG bind were undergone molecular dynamic simulation to ensure protein-ligand interactions. Using above approach, we confirm that ethyl 2-acetyl-5-[4-butyl-2-(3-hydroxypentyl)-5-nitro-1H-imidazol-1-yl]pent-2-enoate can be a drug candidate against L. donovani for the treatment of VL in the Indian subcontinent.

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“…1,4,[7][8][9] Five trypanocidal drugs (pentamidine, suramin, melarsoprol, nifurtimox and eflornithine) are used alone or in combinations specifically for one or another form or stage of HAT, but their relatively high cost, the requirement for longlasting parenteral administration, often impracticable in the affected poor rural settings, the associated toxicity and emergence of parasite resistance, the two latter especially in the case of the arsenical melarsoprol, 10 challenge the widespread, safe and efficacious use of these drugs. 11,12 The emergence of resistance is the cause of the loss of effectivenes of chloroquine, after decades of being the mainstay for malaria treatment, and it starts to challenge also the effectiveness of the current first-line treatments based on artemisinin. 1 In this scenario, it is of critical importance the enrichment of trypanocidal and antimalarial drug development pipelines with novel candidates that are devoid of the important flaws of existing drugs, i.e.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal–antiplasmodial activity

Sola

Castellà

Viayna

et al. 2015

Bioorganic & Medicinal Chemistry

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Dual submicromolar trypanocidal-antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. Inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers but likely it is not their main biological target within Trypanosoma brucei. Regarding their antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis and cerebral malaria. Future optimization should mainly focus on decreasing cytotoxicity and acetylcholinesterase inhibitory activity.

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Treatment options for second-stage gambiense human African trypanosomiasis

Cited by 91 publications

References 56 publications

Cancer in the parasitic protozoans Trypanosoma brucei and Toxoplasma gondii

Cancer in the parasitic protozoans Trypanosoma brucei and Toxoplasma gondii

Developing imidazole analogues as potential inhibitor forLeishmania donovanitrypanothione reductase: virtual screening, molecular docking, dynamics and ADMET approach

Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal–antiplasmodial activity

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