In vitro activity and in vivo efficacy of fexinidazole against New World Leishmania species

Abstract

Objectives To evaluate the in vitro activity and in vivo efficacy of fexinidazole against the main species that cause visceral and cutaneous New World leishmaniasis. Methods The inhibitory concentrations of fexinidazole against Leishmania (Leishmania) infantum chagasi, Leishmania (Leishmania) amazonensis and Leishmania (Viannia) braziliensis in amastigotes were determined by in vitro activity assays. For the in vivo evaluation, animals were infected with L. (L.) infantum chagasi, L. (L.) amazonensis, L. (V.) braziliensis or Leishmania (Viannia) guyanensis and divided into groups: (i) control; and (ii) treated with oral fexinidazole, from 50 to 300 mg/kg/day. For cutaneous leishmaniasis, the size of the lesion was determined weekly after the beginning of the treatment. Upon completion, parasites were recovered from the spleen and liver, or skin lesion and spleen, and evaluated by a limiting dilution assay. Results All Leishmania isolates were susceptible to fexinidazole in the in vitro assays. The viable parasites in the liver and spleen were reduced with 100 and 300 mg/kg/day, respectively, for L. (L.) infantum chagasi. For the species causing cutaneous leishmaniasis, the viable parasites in lesions and the size of the lesions were reduced, starting from 200 mg/kg/day. The viable parasites in the spleen were also reduced with 200 and 300 mg/kg/day for L. (V.) braziliensis and L. (L.) amazonensis. Conclusions Considering the defined parameters, fexinidazole showed in vitro and in vivo activity against all tested species. This drug may represent an alternative treatment for the New World species.

Recent strategies for the development of oral medicines for the treatment of visceral leishmaniasis

“…Fexinidazole showed in vitro activity against intracellular L. infantum amastigote forms with IC 50 of 14.7 μM. Oral administration in murine VL models resulted in a reduction of 99% of hepatic (200 mg/kg/day) and splenic (300 mg/kg/day) viable parasites (de Morais‐Teixeira et al, 2019). Miransertib has also been evaluated for its antileishmanial activity, because protein kinase B (AKT) inhibitors prevent the suppression of immune activation caused by the parasite as a survival mechanism (Nandan et al, 2018).…”

Exploring Innovative Leishmaniasis Treatment: Drug Targets from Pre‐Clinical to Clinical Findings

“…Morais‐Teixeira et al . evaluated fexinidazole (S20) in vitro and in vivo studies against L. infantum , L. amazonensis , L. braziliensis and L. guyanensis [74] . Fexinidazole is a nitroimidazole that was developed in the 1980s against trypanosomes.…”

Efficacy of Spironolactone Treatment in Murine Models of Cutaneous and Visceral Leishmaniasis

“…Drugs that are currently on the market have already undergone pharmacokinetic and toxicity testing and have been proven to be clinically safe, thus obviating the problematic testing bottleneck of the drug discovery pipeline. One recent example of the successful use of this approach is the demonstration of fexinidazole's leishmanicidal activity in vitro and in vivo against Leishmania infantum, L. amazonensis, and L. braziliensis (Wyllie et al, 2012;de Morais-Teixeira et al, 2019).…”