Snapshot Profiling of the Antileishmanial Potency of Lead Compounds and Drug Candidates against Intracellular Leishmania donovani Amastigotes, with a Focus on Human-Derived Host Cells

2区 · 医学

Article

作者: Patterson, Stephen ; Seifert, Karin ; Wyllie, Susan ; Koniordou, Markela

ABSTRACT This study characterized the in vitro potencies of antileishmanial agents against intracellular Leishmania donovani amastigotes in primary human macrophages, obtained with or without CD14-positive monocyte enrichment, phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cells, and mouse peritoneal exudate macrophages (PEMs). Host cell-dependent potency was confirmed for pentavalent and trivalent antimony. Fexinidazole was inactive against intracellular amastigotes across the host cell panel. Fexinidazole sulfone, ( R )-PA-824, ( S )-PA-824, and VL-2098 displayed similar potency in all of the host cells tested.

2016-10-01·Bioanalysis4区 · 医学

A DBS Method for Quantitation of The New Oral Trypanocidal Drug Fexinidazole and its Active Metabolites

4区 · 医学

Article

作者: Abgrall, Audrey ; Mordt, Olaf Valverde ; Sanderink, Ger-Jan ; Souchaud, Marie ; Blesson, Séverine ; Pellissier, Franck ; Filali-Ansary, Aziz ; Augé, Cécile

Aim: Fexinidazole (FEX) is a nitroimidazole being developed as a new trypanocide treatment for human African trypanosomiasis/sleeping sickness. Its main metabolites, fexinidazole sulfoxide (M1) and fexinidazole sulfone (M2), show the same in vitro pharmacological activity as FEX. Methods & results: An LC–MS/MS assay was developed for quantitation of FEX in DBS, collected via finger-prick from healthy subjects. The DBS assay was specific, accurate and reproducible for FEX, M1 and M2 when validated against the current plasma assay. DBS samples were stable for 24 h at 37°C with 95% relative humidity, and 58 weeks desiccated at room temperature. Conclusion: DBS finger-prick sampling offers a simple, practical method for determining FEX, M1 and M2 concentrations in clinical studies in Africa.

2009-08-01·ELECTROPHORESIS3区 · 生物学

Simultaneous enantioselective determination of fenamiphos and its two metabolites in soil sample by CE

3区 · 生物学

Article

作者: Philippe Morin ; Marie Lecoeur-Lorin ; Raphaël Delépée

AbstractThe enantioseparation of fenamiphos and its two main metabolites (fenamiphos sulfoxide and fenamiphos sulfone) were simultaneously achieved by CE by using a dual CD system. A mixture of 25 mM carboxymethyl‐β‐CD and 10 mM hydroxypropyl‐α‐CD was added to the acetic acid/ammonia (ionic strength=50 mM, pH 5) buffer and was suitable for the baseline resolution of all stereoisomers of analytes. A further addition of 5% methanol to the BGE increased significantly the resolution between the diastereoisomers of fenamiphos sulfoxide. An overimposed pressure (0.2 psi) was applied during the analysis in order to have better peak efficiencies and small run time. The composition of the sample solvent was found to be a crucial parameter. An amount of 15% MeOH added to the sample was a good alternative to ensure the total solubility of fenamiphos and the baseline separation of fenamiphos sulfoxide enantiomers. The extraction of pesticides from soil samples was also investigated. A methanolic extraction allowed recovering 50–75% of pesticides, which were detected by CE at the parts per million concentration level (3–100 mg/kg) with a good precision (5.1–13.2% RSD). This method was applied to soil samples and was found to be suitable to monitor the enantiomeric degradation of fenamiphos in environmental samples.

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适应症	最高研发状态	国家/地区	公司	日期
利什曼病	临床2期	-	University of Basel	-
利什曼病	临床2期	-	Swansea University	-
利什曼病	临床2期	-	Drugs for Neglected Diseases initiative	-
利什曼病	临床2期	-	Swiss Tropical & Public Health Institute	-