Abstract
Macrocyclic lactone (ML) anthelmintics are the most important class of anthelmintics because of our high dependence on them for the control of nematode parasites and some ectoparasites in livestock, companion animals and in humans. However, resistance to MLs is of increasing concern. Resistance is commonplace throughout the world in nematode parasites of small ruminants and is of increasing concern in horses, cattle, dogs and other animals. It is suspected in Onchocerca volvulus in humans. In most animals, resistance first arose to the avermectins, such as ivermectin (IVM), and subsequently to moxidectin (MOX). Usually when parasite populations are ML-resistant, MOX is more effective than avermectins. MOX may have higher intrinsic potency against some parasites, especially filarial nematodes, than the avermectins. However, it clearly has a significantly different pharmacokinetic profile. It is highly distributed to lipid tissues, less likely to be removed by ABC efflux transporters, is poorly metabolized and has a long half-life. This results in effective concentrations persisting for longer in target hosts. It also has a high safety index. Limited data suggest that anthelmintic resistance may be overcome, at least temporarily, if a high concentration can be maintained at the site of the parasites for a prolonged period of time. Because of the properties of MOX, there are reasonable prospects that strains of parasites that are resistant to avermectins at currently recommended doses will be controlled by MOX if it can be administered at sufficiently high doses and in formulations that enhance its persistence in the host. This review examines the properties of MOX that support this contention and compares them with the properties of other MLs. The case for using MOX to better control ML-resistant parasites is summarised and some outstanding research questions are presented.
Highlights
Moxidectin (MOX) belongs to the macrocyclic lactone (ML) family of antiparasitic endectocides
MOX may act on the same receptors as other MLs, but there appear to be significant differences in the characteristics of MOX and avermectin interactions, presumably due to the unique chemical properties and structural characteristics of MOX compared with avermectins and other milbemycins
Additional information pertinent to safety, pharmacokinetics and efficacy has become available since these publications and is reviewed briefly, as it is relevant for efforts to control parasitic nematodes in the face of developing resistance
Summary
Moxidectin (MOX) belongs to the macrocyclic lactone (ML) family of antiparasitic endectocides. Discovery of the macrocyclic lactones, including the milbemycins (milbemycin oxime and moxidectin) and the avermectins (ivermectin, abamectin, eprinomectin, doramectin and selamectin). In 1972, the 16-membered ML structure of the active compound was elucidated and identified as milbemycin and from this discovery, the anthelmintic milbemycin oxime was derived (Takiguchi et al, 1983). Ivermectin (IVM), the most commonly used avermectin, is a chemically reduced 22,23-dihydro derivative of abamectin, and is a mixture of 22,23-dihydroavermectin B1a (> 90%) and 22,23-dihydroavermectin B1b (< 10%) (Fig. 2), differing from the components of abamectin by a single methylene group at the 26 position (Campbell, 1989). The structural differences, related to the presence or absence of various substituents, affect the pharmacokinetics, pharmacodynamics and toxicity of MOX compared with the avermectins, and compared with milbemycin oxime. Physicochemical properties are important in modulating the rate of drug exchange between the tissues and the blood stream
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