The genus Trichuris includes parasites of major relevance in veterinary and human medicine. Despite serious economic losses and enormous impact on public health, treatment options against whipworms are very limited. Additionally, there is an obvious lack of appropriately characterized experimental infection models. Therefore, a detailed parasitological characterization of a Trichuris muris isolate was performed in C57BL/10 mice. Subsequently, the in vivo efficacies of the aminophenylamidines amidantel, deacylated amidantel (dAMD) and tribendimidine as well as the cyclooctadepsipeptides emodepside and in particular PF1022A were analyzed. This was performed using various administration routes and treatment schemes targeting histotropic and further developed larval as well as immature and mature adult stages.
Duration of prepatent period, time-dependent localization of larvae during period of prepatency as well as the duration of patency of the infection were determined before drugs were tested in the characterized trichurosis model. Amidantel showed no effect against mature adult T. muris. Tribendimidine showed significantly higher potency than dAMD after oral treatments (ED 50 values of 6.5 vs. 15.1 mg/kg). However, the opposite was found for intraperitoneal treatments (ED 50 values of 15.3 vs. 8.3 mg/kg). When emodepside and PF1022A were compared, the latter was significantly less effective against mature adults following intraperitoneal (ED 50 values of 6.1 vs. 55.7 mg/kg) or subcutaneous (ED 50 values of 15.2 vs. 225.7 mg/kg) administration. Only minimal differences were observed following oral administration (ED 50 values of 2.7 vs. 5.2 mg/kg). Triple and most single oral doses with moderate to high dosages of PF1022A showed complete efficacy against histotropic second stage larvae (3×100 mg/kg or 1×250 mg/kg), further developed larvae (3×10 mg/kg or 1×100 mg/kg) and immature adults (3×10 mg/kg or 1×100 mg/kg). Histotropic first stage larvae were only eliminated after three doses of PF1022A (3×100 mg/kg) but not after a single dose.
Treatment options against whipworm infections of humans and livestock are very limited and even anthelmintics recently introduced into the market do not significantly improve the situation. Here, we evaluated members of two relatively new drug classes, the aminophenylamidines (amidantel, deacylated amidantel, tribendimidine) and the cyclooctadepsipeptides (PF1022A, emodepside) in a murine trichurosis model. While tribendimidine is licensed for the treatment of human helminthosis caused by hookworms, pinworms and roundworms in China, emodepside is the nematocidal component of dewormers for cats and dogs. With the exception of amidantel, all drugs showed good efficacies against adult whipworms using three consecutive doses. Due to considerations regarding drug safety and price, PF1022A was further evaluated against histotropic first and second stage larvae, further developed larvae, immature and mature adults using a single or three consecutive doses. Three doses eliminated all stages while a single dose was inefficient against histotropic first stage larvae. In general, higher doses were required for early stages in comparison to stages protruding into the gut lumen. Since only a very basic formulation of drugs was tested, further improvement can be expected from optimized formulations. Cyclooctadepsipeptides should therefore be considered as candidates for evaluation to treat Trichuris spp. infections in livestock and humans.
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