Prescription of concomitant medications in patients treated with Nifurtimox Eflornithine Combination Therapy (NECT) for T.b. gambiense second stage sleeping sickness in the Democratic Republic of the Congo

Kuemmerle, Andrea; Schmid, Caecilia; Kande, Victor; Mutombo, Wilfried; Ilunga, Médard; Lumpungu, Ismael; Mutanda, Sylvain; Nganzobo, Pathou; Ngolo, Digas; Kisala, Mays; Mordt, Olaf Valverde

doi:10.1371/journal.pntd.0008028

Cited by 10 publications

(10 citation statements)

References 14 publications

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“…All rights reserved Similarly to BZN, NF is hydrophobic, highly liposoluble and distributes widely to tissues, including the central nervous system 90 , a useful property for the treatment of T. cruzi CNS infections. It has a rapid absorption from gut (Ka 0.77/h), but undergoes extensive first-pass elimination (much higher than BZN), leading to only a small fraction of orally administered NF reaching systemic circulation 91,92 . NF is administered orally and reaches peak plasma concentrations after 2 to 4 hours 32,90,93 with a relatively short half-life (approximately 3 hours in adults, and similar in children based on very limited data) 94,95 .…”

Section: Nifurtimox Clinical Pharmacologymentioning

confidence: 99%

Review of pharmacological options for the treatment of Chagas disease

Lascano

Bournissen

Altcheh

2021

Brit J Clinical Pharma

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Introduction: Chagas disease (CD) is a worldwide problem, with over 8 million people infected in both rural and urban areas. CD was first described over a century ago, but only two drugs are currently available for CD treatment, benznidazole (BZN) and nifurtimox (NF). Treating CD infected patients, especially children and women of reproductive age, is vital in order to prevent long term sequelae, such as heart and gastrointestinal dysfunction, but this aim is still far from being accomplished. Currently, the strongest data to support benefit-risk considerations come from trials in children. Finally, treatment response biomarkers need further development as serology is being questioned as the best method to assess treatment response.Areas covered: This article is a narrative review on the pharmacology of drugs for CD, particularly BZN and NF. Data on drug biopharmaceutical characteristics, safety and efficacy of both drugs are summarized from a clinical perspective. Current data on alternative compounds under evaluation for CD treatment, and new possible treatment response biomarkers are also discussed. Conclusion:Early diagnosis and treatment of CD, especially in pediatric patients, is vital for an effective and safe use of the available drugs (i.e. BZN and NF). New biomarkers for CD are urgently needed for the diagnosis and evaluation of treatment efficacy, and to guide efforts from academia and pharmaceutical companies to accelerate the process of new drugs development.

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Section: Nifurtimox Clinical Pharmacologymentioning

confidence: 99%

Review of pharmacological options for the treatment of Chagas disease

Lascano

Bournissen

Altcheh

2021

Brit J Clinical Pharma

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“…Convulsions, gastrointestinal symptoms such as nausea, vomiting, and diarrhea; Genotoxicity, neurotoxicity (Burri, 2010;Yun et al, 2010;Kuemmerle et al, 2020) Fexinidazole First and second stage of T. b. gambiense infection…”

Section: Intravenousmentioning

confidence: 99%

Trypanosomatid-Caused Conditions: State of the Art of Therapeutics and Potential Applications of Lipid-Based Nanocarriers

Muraca¹,

Berti

Sbaraglini³

et al. 2020

Front. Chem.

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Trypanosomatid-caused conditions (African trypanosomiasis, Chagas disease, and leishmaniasis) are neglected tropical infectious diseases that mainly affect socioeconomically vulnerable populations. The available therapeutics display substantial limitations, among them limited efficacy, safety issues, drug resistance, and, in some cases, inconvenient routes of administration, which made the scenarios with insufficient health infrastructure settings inconvenient. Pharmaceutical nanocarriers may provide solutions to some of these obstacles, improving the efficacy–safety balance and tolerability to therapeutic interventions. Here, we overview the state of the art of therapeutics for trypanosomatid-caused diseases (including approved drugs and drugs undergoing clinical trials) and the literature on nanolipid pharmaceutical carriers encapsulating approved and non-approved drugs for these diseases. Numerous studies have focused on the obtention and preclinical assessment of lipid nanocarriers, particularly those addressing the two currently most challenging trypanosomatid-caused diseases, Chagas disease, and leishmaniasis. In general, in vitro and in vivo studies suggest that delivering the drugs using such type of nanocarriers could improve the efficacy–safety balance, diminishing cytotoxicity and organ toxicity, especially in leishmaniasis. This constitutes a very relevant outcome, as it opens the possibility to extended treatment regimens and improved compliance. Despite these advances, last-generation nanosystems, such as targeted nanocarriers and hybrid systems, have still not been extensively explored in the field of trypanosomatid-caused conditions and represent promising opportunities for future developments. The potential use of nanotechnology in extended, well-tolerated drug regimens is particularly interesting in the light of recent descriptions of quiescent/dormant stages of Leishmania and Trypanosoma cruzi, which have been linked to therapeutic failure.

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“…Eflornithine, an inhibitor of ornithine decarboxylase [ 20 ], is a multifunctional drug as it is used topically (15% eflornithine cream) against unwanted facial hair (hirsutism) [ 21 ], as a treatment for malignant gliomas [ 22 ], and as an intravenous cocktail in combination with nifurtimox, approved by the EMA against African trypanosomiasis (sleeping sickness) caused by Trypanosoma brucei gambiense [ 23 , 24 ]. Beckmann et al showed an antifungal activity against A. fumigatus in agar diffusion assays [ 25 ], which potentially could be enhanced by active transport into the hyphae via MirB.…”

Section: Introductionmentioning

confidence: 99%

Antifungal Siderophore Conjugates for Theranostic Applications in Invasive Pulmonary Aspergillosis Using Low-Molecular TAFC Scaffolds

Pfister

Petřík

Bendova

et al. 2021

JoF

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Invasive pulmonary aspergillosis (IPA) is a life-threatening form of fungal infection, primarily in immunocompromised patients and associated with significant mortality. Diagnostic procedures are often invasive and/or time consuming and existing antifungals can be constrained by dose-limiting toxicity and drug interaction. In this study, we modified triacetylfusarinine C (TAFC), the main siderophore produced by the opportunistic pathogen Aspergillus fumigatus (A. fumigatus), with antifungal molecules to perform antifungal susceptibility tests and molecular imaging. A variation of small organic molecules (eflornithine, fludioxonil, thiomersal, fluoroorotic acid (FOA), cyanine 5 (Cy5) with antifungal activity were coupled to diacetylfusarinine C (DAFC), resulting in a “Trojan horse” to deliver antifungal compounds specifically into A. fumigatus hyphae by the major facilitator transporter MirB. Radioactive labeling with gallium-68 allowed us to perform in vitro characterization (distribution coefficient, stability, uptake assay) as well as biodistribution experiments and PET/CT imaging in an IPA rat infection model. Compounds chelated with stable gallium were used for antifungal susceptibility tests. [Ga]DAFC-fludioxonil, -FOA, and -Cy5 revealed a MirB-dependent active uptake with fungal growth inhibition at 16 µg/mL after 24 h. Visualization of an A. fumigatus infection in lungs of a rat was possible with gallium-68-labeled compounds using PET/CT. Heterogeneous biodistribution patterns revealed the immense influence of the antifungal moiety conjugated to DAFC. Overall, novel antifungal siderophore conjugates with promising fungal growth inhibition and the possibility to perform PET imaging combine both therapeutic and diagnostic potential in a theranostic compound for IPA caused by A. fumigatus.

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Prescription of concomitant medications in patients treated with Nifurtimox Eflornithine Combination Therapy (NECT) for T.b. gambiense second stage sleeping sickness in the Democratic Republic of the Congo

Cited by 10 publications

References 14 publications

Review of pharmacological options for the treatment of Chagas disease

Review of pharmacological options for the treatment of Chagas disease

Trypanosomatid-Caused Conditions: State of the Art of Therapeutics and Potential Applications of Lipid-Based Nanocarriers

Antifungal Siderophore Conjugates for Theranostic Applications in Invasive Pulmonary Aspergillosis Using Low-Molecular TAFC Scaffolds

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