An Extensive Comparison of the Effect of Anthelmintic Classes on Diverse Nematodes

Abstract

Soil-transmitted helminths are parasitic nematodes that inhabit the human intestine. These parasites, which include two hookworm species, Ancylostoma duodenale and Necator americanus, the whipworm Trichuris trichiura , and the large roundworm Ascaris lumbricoides , infect upwards of two billion people and are a major cause of disease burden in children and pregnant women. The challenge with treating these diseases is that poverty, safety, and inefficient public health policy have marginalized drug development and distribution to control infection in humans. Anthelmintics (anti-worm drugs) have historically been developed and tested for treatment of non-human parasitic nematodes that infect livestock and companion animals. Here we systematically compare the in vitro efficacy of all major anthelmintic classes currently used in human therapy (benzimidazoles, nicotinic acetylcholine receptor agonists, macrocyclic lactones, nitazoxanide) against species closely related to human parasitic nematodes-Ancylostoma ceylanicum, Trichuris muris , and Ascaris suum --- as well as a rodent parasitic nematode used in veterinary drug discovery, Heligmosomoides bakeri , and the free-living nematode Caenorhabditis elegans. Extensive in vitro data is complemented with single-dose in vivo data in three rodent models of parasitic diseases. We find that the effects of the drugs in vitro and in vivo can vary greatly among these nematode species, e.g., the efficacy of albendazole is strong on A. ceylanicum but weak on H . bakeri . Nonetheless, certain commonalities of the in vitro effects of the drugs can be seen, e.g., nitazoxanide consistently shows an all-or-nothing response. Our in vitro data suggest that further optimization of the clinical efficacy of some of these anthelmintics could be achieved by altering the treatment routine and/or dosing. Most importantly, our in vitro and in vivo data indicate that the hookworm A. ceylanicum is a particularly sensitive and useful model for anthelmintic studies and should be incorporated early on in drug screens for broad-spectrum human soil-transmitted helminth therapies.

Repurposing of Anthelminthics as Anticancer Drugs

“…Several drugs investigated for repurposing in oncology are anthelminthics which have been in clinical use against different worms for several decades [6,7]. Anticancer activities of anthelminthics were reported for mebendazole by Mukhopadhyay et [8][9][10].…”

“…Helminths are parasitic nematodes that inhabit the human intestine [6,7]. Anthelminthics were initially developed for treating veterinary parasites and have advanced from treatment of livestock to first clinical applications for patients.…”

“…In detail, agents such as mebendazole and flubendazole induce the loss of cytoplasmic microtubules of the tegumental and intestinal cells of the helminths, and this is followed by loss of transport of secretory vesicles, a decreased glucose uptake and an increased utilization of stored glycogen [12]. The salicylanilides such as rafoxanide, oxyclozanide and closantel and the substituted phenol, nitroxynil, are proton ionophores [6,7]. Other functionally distinct compounds are classified as nicotinic anthelmintics, glutamate-gated chloride channel potentiators or macrolides.…”

“…(Methyl N-(5-benzoyl-1H--benzimidazol-2-yl)-carbamate) is a broad-spectrum antihelminthic of the benzimidazole type which came into use in 1971 [6,7]. It is indicated for the treatment of nematode infestations and the intestinal form of trichinosis.…”

“…The fraction eliminated in urine was up to 25% and the rest was eliminated with feces. Salicylanilides are very lipophilic and may shuttle protons across membranes, particularly the inner mitochondrial membrane, thus removing the proton gradient and uncouple oxidative phosphorylation [6,7,15].…”