NECT Is Next: Implementing the New Drug Combination Therapy for Trypanosoma brucei gambiense Sleeping Sickness

Yun, Oliver; Priotto, Gérardo; Tong, Jacqueline; Flévaud, Laurence; Chappuis, François

doi:10.1371/journal.pntd.0000720

Cited by 119 publications

(97 citation statements)

References 21 publications

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“…Drugs are the only option for combatting this infection, but their use is often problematic (2). One treatment that targets the cerebral stage of this disease is nifurtimox-eflornithine combination therapy (3,4). In this medication, eflornithine acts as an inhibitor of ornithine decarboxylase, blocking polyamine biosynthesis (5,6), while nifurtimox is converted to a toxic metabolite following activation by a type I nitroreductase (NTR) (7,8).…”

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confidence: 99%

Evaluating 5-Nitrothiazoles as Trypanocidal Agents

O’Shea

Shahed

Aguilera‐Venegas

et al. 2016

Antimicrob Agents Chemother

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bThe growth-inhibitory properties of a 5-nitrothiazole series were evaluated against Trypanosoma brucei. A subset of related compounds displayed the greatest potency toward the parasite while exhibiting little cytotoxic effect on mammalian cells, with this antiparasitic activity dependent on expression of a type I nitroreductase by the trypanosome. We conclude that the 5-nitrothiazole class of nitroheterocyclic drugs may represent a new lead in the treatment of human African trypanosomiasis.

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confidence: 99%

Evaluating 5-Nitrothiazoles as Trypanocidal Agents

O’Shea

Shahed

Aguilera‐Venegas

et al. 2016

Antimicrob Agents Chemother

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“…Transmitted by the tsetse fly, the disease mainly affects rural populations in sub-Saharan Africa and is fatal if untreated. Although according to the World Health Organization the number of new cases has dropped to just over 7,000 during 2010 (39), very few drugs are available to treat HAT (2,4,42). Pentamidine and suramin, both developed in the first half of the 20th century, are used against first-stage disease, while melarsoprol and eflornithine are used to treat second-stage disease.…”

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confidence: 99%

Induction of Oxidative Stress in Trypanosoma brucei by the Antitrypanosomal Dihydroquinoline OSU-40

Dayton

Kuppusamy

et al. 2012

Antimicrob Agents Chemother

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In the present study, we sought to provide further support for the hypothesis that OSU-40 kills trypanosomes through oxidative stress. Inducible RNA interference (RNAi) was applied to downregulate key enzymes in parasite antioxidant defense, including T. brucei trypanothione synthetase (TbTryS) and superoxide dismutase B (TbSODB). Both TbTryS RNAi-induced and TbSODB RNAi-induced cells showed impaired growth and increased sensitivity toward OSU-40 by 2.4-fold and 3.4-fold, respectively. Decreased expression of key parasite antioxidant enzymes was thus associated with increased sensitivity to OSU-40, consistent with the hypothesis that OSU-40 acts through oxidative stress. Finally, the dose-dependent formation of free radicals was observed after incubation of T. brucei with OSU-40 utilizing electron spin resonance (ESR) spectroscopy. These data support the notion that the mode of antitrypanosomal action for this class of compounds is to induce oxidative stress. H uman African trypanosomiasis (HAT) is a vector-borne parasitic disease caused by the Trypanosoma brucei subspecies T. b. rhodesiense and T. b. gambiense.The trypanosome proliferates in the host's hemolymphatic system during the first stage of HAT and invades the central nervous system in the second stage. Transmitted by the tsetse fly, the disease mainly affects rural populations in sub-Saharan Africa and is fatal if untreated. Although according to the World Health Organization the number of new cases has dropped to just over 7,000 during 2010 (39), very few drugs are available to treat HAT (2, 4, 42). Pentamidine and suramin, both developed in the first half of the 20th century, are used against first-stage disease, while melarsoprol and eflornithine are used to treat second-stage disease. These drugs are far from satisfactory due to limitations such as severe toxicity, poor efficacy, acquired resistance, rising failure rates, and lack of availability (2, 4, 42). With high efficacy and a good safety profile, nifurtimox-eflornithine combination therapy (NECT) was introduced as a first-line treatment for second-stage HAT caused by T. b. gambiense in 2009 (4, 22, 42). However, administration of NECT is relatively complicated, and its efficacy toward T. b. rhodesiense is still questionable (4, 42). Thus, new drugs are needed against HAT that are safe, affordable, easy to administer, active against first-and second-stage disease, and effective against both subspecies of T. brucei (4, 42).From a previous synthetic medicinal chemistry study, we discovered several N1-substituted 1,2-dihydroquinoline-6-ols displaying nanomolar 50% inhibitory concentrations (IC 50 s) in vitro against T. b. rhodesiense and selectivity indexes (SI) up to Ͼ18,000 (11). OSU-40 (1-benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate) (Fig. 1) showed a potency (IC 50 , 0.014 M; SI, 1,700) close to that of melarsoprol (IC 50 , 0.008 M; SI, 1,000) against T. b. rhodesiense STIB900 in vitro. In an early treatment mouse model of acute African trypanosomiasis, OSU-40 prolonged the life s...

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“…However, the problems related to current therapies have stimulated a renewed interest in using nitroaromatic compounds to target T. brucei (41,42,44), with NECT being added to the WHO Essential Medicines List for the treatment of West African trypanosomiasis (11). Here, we conducted a screening program against BSF T. brucei, making use of a 5-nitrofuran series that was originally developed for use against Chagas disease (33)(34)(35)(36).…”

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confidence: 99%

“…However, concerns about gastrointestinal (GI) tract and central nervous system (CNS) toxicity, the refractory nature of some T. cruzi strains, and the limited efficacy and genotoxicity of nifurtimox led to the withdrawal of its use as an anti-Chagasic chemotherapy in Brazil, Argentina, Chile, and Uruguay; this resulted in reduced demand and the cessation of production (10). Following successful trials of a nifurtimox-eflornithine combination therapy (NECT) and its subsequent addition to the WHO Essential Medicines List as a treatment against the cerebral stage of West African trypanosomiasis (11), coupled with emerging reports about its effectiveness against pediatric neuroblastoma (12), the manufacture of nifurtimox has recommenced with Bayer HealthCare AG, guaranteeing supplies until 2017.…”

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confidence: 99%