BackgroundFew effective drugs are available for soil-transmitted helminthiases and drug resistance is of concern. In the present work, we tested the efficacy of the veterinary drug monepantel, a potential drug development candidate compared to standard drugs in vitro and in parasite-rodent models of relevance to human soil-transmitted helminthiases.MethodologyA motility assay was used to assess the efficacy of monepantel, albendazole, levamisole, and pyrantel pamoate in vitro on third-stage larvae (L3) and adult worms of Ancylostoma ceylanicum, Necator americanus and Trichuris muris. Ancylostoma ceylanicum- or N. americanus-infected hamsters, T. muris- or Ascaris suum-infected mice, and Strongyloides ratti-infected rats were treated with single oral doses of monepantel or with one of the reference drugs.Principal FindingsMonepantel showed excellent activity on A. ceylanicum adults (IC50 = 1.7 µg/ml), a moderate effect on T. muris L3 (IC50 = 78.7 µg/ml), whereas no effect was observed on A. ceylanicum L3, T. muris adults, and both stages of N. americanus. Of the standard drugs, levamisole showed the highest potency in vitro (IC50 = 1.6 and 33.1 µg/ml on A. ceylanicum and T. muris L3, respectively). Complete elimination of worms was observed with monepantel (10 mg/kg) and albendazole (2.5 mg/kg) in A. ceylanicum-infected hamsters. In the N. americanus hamster model single 10 mg/kg oral doses of monepantel and albendazole resulted in worm burden reductions of 58.3% and 100%, respectively. Trichuris muris, S. ratti and A. suum were not affected by treatment with monepantel in vivo (following doses of 600 mg/kg, 32 mg/kg and 600 mg/kg, respectively). In contrast, worm burden reductions of 95.9% and 76.6% were observed following treatment of T. muris- and A. suum infected mice with levamisole (200 mg/kg) and albendazole (600 mg/kg), respectively.Conclusions/SignificanceMonepantel reveals low or no activities against N. americanus, T. muris, S. ratti and A. suum in vivo, hence does not qualify as drug development candidate for human soil-transmitted helminthiases.

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.

Introduction: The triggering receptor expressed on myeloid cells 1 (TREM-1) signaling pathway is stimulated by bacteria and, together with its putative ligand peptidoglycan recognition protein 1 (PGLYRP1), propagates proinflammatory responses. Objectives: We aimed to evaluate the TREM-1/PGLYRP1/interleukin (IL)–1β regulation in response to biofilm accumulation and removal in an experimental human gingivitis model. Methods: The study (n = 42 participants, mean age: 23.8 ± 3.7 y) comprised a recruitment step (day –14) followed by experimentally induced biofilm formation (induction [I] phase, day 0 to +21) and a 2-wk resolution (R) phase (day +21 to +35). Plaque was recorded by the Modified Quigley and Hein Plaque Index (TQHPI), while records of gingival inflammation were based on the Modified Gingival Index (MGI). Unstimulated whole saliva supernatants (n = 210, 5 time points) were tested for TREM-1, PGLYRP1, and IL-1β by enzyme-linked immunosorbent assay. Results: During the I-phase, concentrations of all analytes showed a tendency for downregulation at day +7 compared to day 0. TREM-1 (P = 0.019) and PGLYRP1 (P = 0.007) increased significantly between day +7 and day +21. Although all analyte levels decreased during the R-phase, the difference was not significant except TREM-1 being at borderline significance (P = 0.058). Moreover, TREM-1, PGLYRP1, and IL-1β showed significant positive correlations (P < 0.0001) with each other. The study participants were grouped into “fast” and “slow” responders based on clinical gingival inflammation scores. At each time point, fast responders showed significantly higher concentrations of TREM-1 (P < 0.025), PGLYRP1 (P < 0.007), and IL-1β (P < 0.025) compared to slow responders. Mixed-effects multilevel regression analyses revealed that PGLYRP1 (P = 0.047) and IL-1β (P = 0.005) showed a significant positive association with the MGI scores. Conclusion: The study demonstrated that TREM-1 and PGLYRP1 are regulated in response to biofilm accumulation and removal, and fast responders demonstrated higher levels of these analytes compared to slow responders. Knowledge Transfer Statement: The results of this study demonstrated the suitability of salivary TREM-1 and PGLYRP1 to reflect biofilm accumulation and removal and PGLYRP1 to monitor the progression and resolution of inflammation in gingivitis-susceptible individuals (fast responders). Combined with conventional risk factors, the molecular toolbox proposed here should be further validated in future studies to confirm whether it can be used for population-based monitoring and prevention of gingivitis.