Activity of Oxantel Pamoate Monotherapy and Combination Chemotherapy against Trichuris muris and Hookworms: Revival of an Old Drug

Abstract

BackgroundIt is widely recognized that only a handful of drugs are available against soil-transmitted helminthiasis, all of which are characterized by a low efficacy against Trichuris trichiura, when administered as single doses. The re-evaluation of old, forgotten drugs is a promising strategy to identify alternative anthelminthic drug candidates or drug combinations.MethodologyWe studied the activity of the veterinary drug oxantel pamoate against Trichuris muris, Ancylostoma ceylanicum and Necator americanus in vitro and in vivo. In addition, the dose-effect of oxantel pamoate combined with albendazole, mebendazole, levamisole, pyrantel pamoate and ivermectin was studied against T. muris in vitro and additive or synergistic combinations were followed up in vivo.Principal FindingsWe calculated an ED50 of 4.7 mg/kg for oxantel pamoate against T. muris in mice. Combinations of oxantel pamoate with pyrantel pamoate behaved antagonistically in vitro (combination index (CI) = 2.53). Oxantel pamoate combined with levamisole, albendazole or ivermectin using ratios based on their ED50s revealed antagonistic effects in vivo (CI = 1.27, 1.90 and 1.27, respectively). A highly synergistic effect (CI = 0.15) was observed when oxantel pamoate-mebendazole was administered to T. muris-infected mice. Oxantel pamoate (10 mg/kg) lacked activity against Ancylostoma ceylanicum and Necator americanus in vivo.Conclusion/SignificanceOur study confirms the excellent trichuricidal properties of oxantel pamoate. Since the drug lacks activity against hookworms it is necessary to combine oxantel pamoate with a partner drug with anti-hookworm properties. Synergistic effects were observed for oxantel pamoate-mebendazole, hence this combination should be studied in more detail. Since, of the standard drugs, albendazole has the highest efficacy against hookworms, additional investigations on the combination effect of oxantel pamoate-albendazole should be launched.

Development of an in vitro drug sensitivity assay for Trichuris muris first-stage larvae

“…The results obtained with the motility assay based on L1 correspond to findings observed with adult T. muris [10,12,24]. However, generally, L1 seem to be more sensitive to the drugs studied than older T. muris stages.…”

Basic and clinical pharmacology contribution to extend anthelmintic molecules lifespan

“…The three drug combinations showing a strongly synergistic effect ex vivo (albendazole-mebendazole, albendazole-ivermectin and mebendazole-ivermectin) also induced a synergism in vivo (Keiser et al, 2012). Furthermore, a synergistic effect was observed in both ex vivo and in vivo (T. muris infected-mice) experiments for the combination oxantel pamoate-mebendazole (Keiser et al, 2013). In contrast, combinations containing either pyrantel pamoate or levamisole combined with ivermectin (Keiser et al, 2012) or oxantel pamoate combined with either levamisole, albendazole or ivermectin (Keiser et al, 2013) were found to be antagonistic in vivo.…”

“…Furthermore, a synergistic effect was observed in both ex vivo and in vivo (T. muris infected-mice) experiments for the combination oxantel pamoate-mebendazole (Keiser et al, 2013). In contrast, combinations containing either pyrantel pamoate or levamisole combined with ivermectin (Keiser et al, 2012) or oxantel pamoate combined with either levamisole, albendazole or ivermectin (Keiser et al, 2013) were found to be antagonistic in vivo. The synergistic effect observed after in vivo experiments in the mouse model (Keiser et al, 2012) had some success to predict the real situation in humans naturally infected with T. trichiura.…”

Exposure of Heligmosomoides polygyrus and Trichuris muris to albendazole, albendazole sulfoxide, mebendazole and oxantel pamoate in vitro and in vivo to elucidate the pathway of drug entry into these gastrointestinal nematodes

“…We also included oxantel pamoate in our studies, because it is a promising drug for the treatment of trichuriasis (Speich et al., 2015). We used two helminth-mouse models: the H. polygyrus -NMRI model, which is a model for hookworm infections (Tritten et al., 2012) and the T. muris -C57BL/10 model, which is an established model for trichuriasis (Keiser et al., 2013). Several procedures used in this study were validated for their quantitative (e.g.…”

“…Oxantel pamoate was recently shown to be a useful addition to the current drug armamentarium given its high trichuricidal activity (Speich et al., 2015, Keiser et al., 2013). …”