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Title: An extensive comparison of the effect of anthelmintic classes on diverse nematodes

item HU, Y - University Of California
item ELLIS, B - University Of California
item YIU, Y - University Of California
item MILLER, M - University Of California
item Urban, Joseph
item SHI, L - University Of California
item AROIAN, R - University Of California

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/20/2013
Publication Date: 7/15/2013
Citation: Hu, Y., Ellis, B.L., Yiu, Y.Y., Miller, M.M., Urban Jr., J.F., Shi, L.Z., Aroian, R.V. 2013. Comprehensive comparison of anthelmintic classes on diverse nematodes. PLoS One. DOI: 10.1371/journal.pone.0070702.

Interpretive Summary: Parasitic worms infect humans and livestock worldwide with negative effects on health and productivity. The discovery and development of new anti-worm drugs (athelmintics) has been limited because of economic and social constraints on the cost effectiveness of global distribution of these new drugs.Nevertheless, anthelmintic resistance is a developing concern to livestock producers and human health professionals because the efficacy of the existiing drugs are diminishing as more resistant parasite strains are selected in nature. One of the cost factors in developing new drugs is the expense of testing in the target species such as humans and livestock. Screening of new drug compounds would be aided by reliable procedures that could evaluate parasite killing in the laboratory with mixtures of new drugs and parasite stages tested in culture systems. The next level of testing could then be through the use of small animal models that affirm efficacy of the test compounds when administered to parasite infected rodents or small mammals. This report demonstrates the feasibility of this approach by testing a number of established anti-parasitic drugs first on parasite in culture and then in infected rodent models. This relatively easy and inexpensive strategy could be used to encourage cost effective testing of new compounds that can then be developed for use in humans and livestock. The report will be useful to scientists in academia, government, and industry with an interest in developing new drug strategies to control parasitic infections.

Technical 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 (benzimidazoles, nicotinic acetylcholine receptor agonists, macrocyclic lactones, nitazoxanide) against closely related species of 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 soiltransmitted helminth therapies.