ABSTRACT The intestinal parasites Giardia lamblia and Entamoeba histolytica are major causes of morbidity and mortality associated with diarrheal diseases. Metronidazole is the most common drug used to treat giardiasis and amebiasis. Despite its efficacy, treatment failures in giardiasis occur in up to 5%–40% of cases. Potential resistance of E. histolytica to metronidazole is an increasing concern. Therefore, it is critical to search for more effective drugs to treat giardiasis and amebiasis. We identified antigiardial and antiamebic activities of the rediscovered nitroimidazole compound, fexinidazole, and its sulfone and sulfoxide metabolites. Fexinidazole is equally active against E. histolytica and G. lamblia trophozoites, and both metabolites were 3- to 18-fold more active than the parent drug. Fexinidazole and its metabolites were also active against a metronidazole-resistant strain of G. lamblia . G. lamblia and E. histolytica cell extracts exhibited decreased residual nitroreductase activity when metabolites were used as substrates, indicating nitroreductase may be central to the mechanism of action of fexinidazole. In a cell invasion model, fexinidazole and its metabolites significantly reduced the invasiveness of E. histolytica trophozoites through basement membrane matrix. A q.d. oral dose of fexinidazole and its metabolites at 10 mg/kg for 3 days reduced G. lamblia infection significantly in mice compared to control. The newly discovered antigiardial and antiamebic activities of fexinidazole, combined with its FDA-approval and inclusion in the WHO Model List of Essential Medicines for the treatment of human African trypanosomiasis, offer decreased risk and a shortened development timeline toward clinical use of fexinidazole for treatment of giardiasis or amebiasis.

01 Aug 2019·Journal of Antimicrobial ChemotherapyQ2 · MEDICINE

Optimal kinetic exposures for classic and candidate antitrypanosomals

Q2 · MEDICINE

Article

Author: Shapiro, Theresa A ; Meyers, David J ; Meyer, Kirsten J

AbstractObjectivesEfficacy is determined not only by size, but also by shape, of drug exposure. Here the critical importance of the temporal pattern of drug concentrations (pharmacokinetic profile) is examined for antitrypanosomals in vitro.MethodsAn in vitro hollow-fibre cartridge system was used to study contrasting drug profiles with four clinically used agents and two experimental candidates against the deadly parasite Trypanosoma brucei. Artificial kinetics were employed intentionally to favour either high peak concentration or sustained duration of drug.ResultsChanging the shape of drug exposure significantly impacted drug efficacy. Suramin, melarsoprol and pentamidine were concentration-driven and therefore more efficacious when applied as short-lived high peaks. In contrast, difluoromethylornithine (DFMO) was time-driven, and therefore maximally effective as a constant infusion. Kinetic preference was robust over a wide range of drug exposures. Promising clinical candidates SCYX-7158 (acoziborole) and fexinidazole (parent and sulfone) were concentration-driven, suggesting optimal clinical regimens would involve relatively high but intermittent dosing.ConclusionsAntitrypanosomals have an intrinsic pharmacokinetic driver for optimal efficacy, with important implications for clinical management and future candidate development.

01 Apr 2019·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: Ribeiro, Isabela ; Watson, James A. ; Tarral, Antoine ; White, Nicholas J. ; Tarning, Joel ; Strub-Wourgraft, Nathalie

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Leishmaniasis	Phase 2	-	University of Basel	-
Leishmaniasis	Phase 2	-	Swiss Tropical & Public Health Institute	-
Leishmaniasis	Phase 2	-	Drugs for Neglected Diseases initiative	-
Leishmaniasis	Phase 2	-	Swansea University	-

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