In Vitro and In Vivo Efficacy of Monepantel (AAD 1566) against Laboratory Models of Human Intestinal Nematode Infections

Abstract

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.

In vitro Screening of Compounds against Laboratory and Field Isolates of Human Hookworm Reveals Quantitative Differences in Anthelmintic Susceptibility

“…[10][11][12][13][14][15][16] Therefore, the correlation between the anthelmintic activity of compounds against laboratory and field isolates of human hookworms remains largely unknown.…”

“…[6][7][8][9] However, novel compounds identified using small animal models of hookworm infection are rarely screened for comparable activity against field isolates of human hookworms. [10][11][12][13][14][15][16] Therefore, the correlation between the anthelmintic activity of compounds against laboratory and field isolates of human hookworms remains largely unknown.…”

Bacillus subtilis Strain Engineered for Treatment of Soil-Transmitted Helminth Diseases

“…For example, a 10-mg/kg (49 mol/kg) dose of levamisole results in a 60% reduction of A. ceylanicum burdens in hamsters, a 10-mg/kg (17 mol/ kg) dose of pyrantel results in an 87% reduction in A. ceylanicum burdens, a 10-mg/kg (22 mol/kg) dose of tribendimidine results in a 75% reduction of A. ceylanicum burdens, and a 1.25-mg/kg (4.7 mol/kg) dose of albendazole results in an 88% reduction of A. ceylanicum burdens (46,47). In addition to excellent efficacy, Cry5B has a different mechanism of action from that of chemical anthelmintics; it is a pore-forming protein that binds to invertebrate-specific glycolipids and attacks the plasma membrane of the nematode intestine (34,35,(48)(49)(50).…”

An automated high-throughput system for phenotypic screening of chemical libraries onC. elegansand parasitic nematodes

“…Manual scoring of motility, growth or viability has been effective and used to 64 screen libraries of up to 67,000 compounds (Burns et al, 2015;Tritten et al, 2011Tritten et al, , 2012. Automated 65 systems offer the potential of higher throughput and greater reliability.…”

“…Trichuris muris, which infects mice, is a widely used laboratory model for investigating trichuriasis 339 and has been used as a system for ex vivo and in vivo testing of anthelmintic candidates for activity 340 against whipworm (Hurst et al, 2014;Tritten et al, 2011;Wimmersberger et al, 2013). We tested the 341 ability of the INVAPP / Paragon system to quantify the activity of the anthelmintic levamisole on 342 adult T. muris.…”