Efficacy of Cyclooctadepsipeptides and Aminophenylamidines against Larval, Immature and Mature Adult Stages of a Parasitologically Characterized Trichurosis Model in Mice

Abstract

BackgroundThe 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.Methodology/Principal FindingsDuration 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.Conclusions/SignificanceThese 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.

Recent advances in candidate-gene and whole-genome approaches to the discovery of anthelmintic resistance markers and the description of drug/receptor interactions

“…The parent compound, PF1022A, which is much cheaper than emodepside, has recently been compared with emodepside for treatment of Trichuris muris , as a model for the human whipworm ( T. trichiura ), which is the dose-limiting gastrointestinal nematode in humans and particularly problematic due to its long period of prepatency. Although emodepside was much more effective than PF1022A after intraperitoneal and subcutaneous application, only a small difference was detected after oral application ( Kulke et al, 2014 ). It was also shown to be able to eliminate all stages of T. muris including histotropic L1.…”

In Vitro and In Vivo Drug-Drug Interaction Study of the Effects of Ivermectin and Oxantel Pamoate on Tribendimidine

“…Little is known about tribendimidine DDIs. Several in vitro and in vivo studies using nematode models have suggested possible effects of interactions between tribendimidine and other antiparasitic compounds, including albendazole, levamisole, ivermectin, cyclooctadepsipeptide PF1022A, emodepside, and crystal proteins (22)(23)(24)(25). Whether drug effects were additive, synergistic, or antagonistic varied widely depending on the compound and the parasite and in some cases reversed between in vitro and in vivo models.…”

Potential new drug targets and therapeutic approaches for parasitic nematode infections

“…The anthelmintic potential of PF1022A and emodepside has been reported in numerous in vitro and in vivo Source: Harder et al, 2003, p. 320. studies (Harder & von Samson-Himmelstjerna, 2001;Kulke et al, 2013a;Kulke et al, 2013b;Kulke et al, 2014;Zahner et al, 2001a;Zahner et al, 2001b). Interestingly, PF1022A and emodepside have a broad spectrum of activity against several nematode species including those that are resistant to benzimidazoles, levamisole and ivermectin (von Samson-Himmelstjerna et al, 2005).…”

“…emodepside can directly open these channels ( Kulke et al, 2014) and that emodepside action on this splice variant of the channel does not require the presence of additional receptors like the latrophilin receptors for an emodepside effect (Willson et al, 2004). It does not however, rule out a contribution of latrophilin receptors to the overall mode of action of emodepside in parasites as indicated by the interaction of Lat-1 and emodepside (Saeger et al, 2001).…”

“…In addition, the regulator of the K + channel conductance (RCK) domains (S7, S8) contains high and low affinity calcium binding sites. The SLO-1 α-subunits show alternative splicing, producing channels with different calcium sensitivities; in C. elegans there are up to 15 splice variants (including SLO-1a, SLO-1b and SLO-1c ( Kulke et al, 2014 andWang et al, 2001)). Each α-subunit of the channel has at least two high affinity calcium binding sites and one low affinity calcium/magnesium binding site.…”