Evaluation of Commercially Available Anthelminthics in Laboratory Models of Human Intestinal Nematode Infections

Abstract

Drug repurposing from veterinary to human medicine has been the main strategy to develop the four recommended human anthelminthics, albendazole, mebendazole, levamisole, and pyrantel pamoate, for the treatment of soil-transmitted helminthiasis. A systematic, head-to-head comparison of the anthelminthic activity profile of derivatives of these drugs and other anthelminthics developed in succession has not been conducted to date. We studied eight benzimidazoles, five macrocyclic lactones, tribendimidine, levamisole, and pyrantel pamoate in laboratory models of human intestinal nematode infections. In vitro studies were performed on Trichuris muris L1 larval stage and adults, as well as Ancylostoma ceylanicum, Necator americanus, Heligmosomoides polygyrus, and Strongyloides ratti L3 larvae and adults. The benzimidazoles showed pronounced differences against larval and adult stages, with low activity against larvae and the highest activity observed against adult N. americanus (IC 50 of flubendazole 1.1 μM). The macrocyclic lactones, on the other hand, revealed a higher activity on the larval stages, with the lowest IC 50 values observed against N. americanus L3 (IC 50 values of 0.03−3 μM). In vivo studies were performed in the T. muris and H. polygyrus mice models, with moxidectin and milbemycin oxime showing the highest activity against H. polygyrus (ED 50 values of 0.009 and 0.006 mg/kg, respectively) and moxidectin and abamectin being the most effective drugs against T. muris (ED 50 values of 0.2 and 0.5 mg/kg, respectively). Laboratory models for soil-transmitted helminthiasis can assist characterizing potential drug candidates. Drugs should be evaluated against different species, and both the adult and larval stages as activities could differ considerably.

Susceptibility of Angiostrongylus cantonensis Larvae to Anthelmintic Drugs

“…Albendazole and mebendazole are the most widely used anthelmintics in humans, with a higher efficacy observed for albendazole ( Moser et al, 2017 ), in line with findings from this model. Results of this study with macrocyclic lactones, levamisole and pyrantel pamoate are also consistent with previously reported results ( Keiser and Häberli, 2021 ), which showed the in vitro antiparasitic activity against the larval stage of different nematode species, highlighting the importance of A. cantonensis L1 in the field of anthelmintic studies. Since A. cantonensis laboratory rodent models do exist, this may be the more logical option for a comparative efficacy study and may address the urgent need for new treatments so that goals set by WHO can be achieved.…”

“…Most anthelmintics have a broad spectrum of activity ( Geary et al, 2010 ; Choudhary et al, 2022 ). However, the usefulness of any anthelmintic is limited by the characteristics of the parasite (e.g., susceptibility of the life stage, or susceptibility to the drugs), and these compounds have specific activities for each species ( Geary et al, 2010 ; Keiser and Häberli, 2021 ). While the benzimidazoles mebendazole and fenbendazole lacked activity against A. cantonensis L1, albendazole showed good activity.…”

Preclinical and Clinical Characteristics of the Trichuricidal Drug Oxantel Pamoate and Clinical Development Plans: A Review

“…In an in vivo experiment, different doses of oxantel pamoate, ranging from 1 to 10 mg/kg, were administered to mice infected with T. muris. The oral administration of 10 mg/kg achieved the highest worm burden reduction (93%) and worm expulsion rate (88%) and an ED 50 value of 4 mg/kg was calculated [10], which is significantly lower than the one of other standard anthelminthics [11]. Following oral administration, oxantel pamoate acts locally in the human gastrointestinal tract by binding to the parasite's nicotinic acetylcholine receptor (nAChR; neuronal (N)-type).…”

Assessment of FDA-approved drugs against Strongyloides ratti in vitro and in vivo to identify potentially active drugs against strongyloidiasis

“…Since several of the active compounds are for topical use only (e.g., Gentian violet or cetrimonium bromide) (see Table 1 ) or are rather toxic (e.g., coumaphos or sodium nitroprusside), only three of the 14 compounds, namely levamisole, morantel, and prasterone, were selected for IC 50 determination and in vivo studies. The activity of ivermectin in in vivo studies was presented in earlier work [ 11 , 12 ].…”