Efficacy of Cyclooctadepsipeptides and Aminophenylamidines against Larval,
Immature and Mature Adult Stages of a Parasitologically Characterized
Trichurosis Model in Mice
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 (ED50 values of
6.5 vs. 15.1 mg/kg). However, the opposite was found for intraperitoneal
treatments (ED50 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 (ED50 values of 6.1 vs. 55.7 mg/kg) or
subcutaneous (ED50 values of 15.2 vs. 225.7 mg/kg) administration. Only
minimal differences were observed following oral administration (ED50 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. These results indicate
that the cyclooctadepsipeptides are a drug class with promising candidates for
further evaluation for the treatment of trichurosis of humans and livestock
animals in single dose regimens