Anthelmintics: The best way to predict the future is to create it

Abstract

‘The best way to predict the future is to create it.’ When we look at drugs that are used to control parasites, we see that new knowledge has been created (discovered) about their modes of action. This knowledge will allow us to predict combinations of drugs which can be used together rationally to increase the spectrum of action and to slow the development of anthelmintic resistance. In this paper we comment on some recent observations of ours on the modes of action of emodepside, diethylcarbamazine and tribendimidine. Emodepside increases the activation of a SLO-1 K+ current inhibiting movement, and diethylcarbamazine has a synergistic effect on the effect of emodepside on the SLO-1 K+ current, increasing the size of the response. The combination may be considered for further testing for therapeutic use. Tribendimidine is a selective cholinergic nematode B-subtype nAChR agonist, producing muscle depolarization and contraction. It has different subtype selectivity to levamisole and may be effective in the presence of some types of levamisole resistance. The new information about the modes of action may aid the design of rational drug combinations designed to slow the development of resistance or increase the spectrum of action.

Advances in our understanding of nematode ion channels as potential anthelmintic targets

“…Parasite ion channels have been the subject of in-depth research as targets for anthelmintic drugs. Some of the most successful anthelmintic agents act on these channels and help alleviate the parasitic burden, which is a significant public health issue and threatens global food-security ( Wolstenholme, 2012 ; Greenberg, 2014 ; Martin et al, 2015 ; Abongwa et al, 2017 ).

Fig.

…”

“…Many of the current anthelmintics target nematode cys-loop ligand-gated ion channels; macrocyclic lactones act on glutamate-gated chloride channels (GluCls) while the cholinomimetics (such as pyrantel, levamisole, tribendimidine) act on nicotinic acetylcholine receptors (nAChRs) ( Wolstenholme, 2012 ; Holden-Dye et al, 2013 ; Greenberg, 2014 ; Martin et al, 2015 ; Abongwa et al, 2017 ). These membrane-bound channels face an extracellular matrix, making them easily accessible to drug molecules and are thus ‘druggable’ targets.…”

Control of helminth ruminant infections by 2030

“…These screens have benefited from knowledge discovered about the modes of action of anthelmintics. This knowledge allowed prediction of combinations of drugs that can be used together rationally to increase the spectrum of action and to slow the development of AR (Martin et al 2015). However, the disappointing return on investment in this area has led to renewed focus on high-throughput screening platforms that employ readily available stages of important parasites in phenotypic formats (Geary et al 2015).…”

Mind the gaps in research on the control of gastrointestinal nematodes of farmed ruminants and pigs

“…Since the mid-1960s, the control of GI nematodes in livestock has heavily relied on anthelmintics (Coles, 2002). The three major anthelmintic families are (i) the BZ, including albendazole, which is still widely Anthelmintic actives with a new mode of action, either stand alone or in combination, or novel combinations of actives against GI nematodes belonging to the currently available classes would greatly assist in managing AR (Martin et al, 2015;Smith, 2014). In this respect, differentiation needs to be made between combination products incorporating two or more constituent actives to expand efficacy against helminth parasites belonging to a different phylum (e.g., GI nematodes and liver fluke), and combinations of two or more actives targeting only GI nematodes.…”