Perspectives on the utility of moxidectin for the control of parasitic nematodes in the face of developing anthelmintic resistance

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.

Preventive efficacy of four or six monthly oral doses of 24 µg/kg moxidectin compared to six monthly doses of Heartgard® Plus or Interceptor® Plus against macrocyclic lactone-resistant heartworm (Dirofilaria immitis) strains in dogs

“…A review of the reported efficacy data has shown moxidectin to be the most potent of the MLs in preventing the development of D. immitis in dogs [4]. Moxidectin generally has a longer elimination half-life and a larger volume of distribution than both ivermectin and milbemycin, which allow for a longer persistence and greater distribution of moxidectin in host tissues, including adipose tissue where it is active against migrating D. immitis larvae [6]. These attributes make moxidectin an attractive molecule to optimize in new heartworm preventative products in the face of emerging ML heartworm resistance.…”

“…Moxidectin is a ML that is available in heartworm preventative products worldwide with 100% efficacy reported against ML-susceptible D. immitis strains [4]. Moxidectin has unique attributes that make it an attractive molecule for use as a heartworm preventative in the face of emerging resistance [6]. Recent reports showed that increasing the oral monthly dosage of moxidectin and the number of consecutive monthly doses administered improved its efficacy against MLresistant D. immitis, and that 24 µg/kg was selected as the optimal dosage for further commercial development [4].…”

Repurposing anthelmintic agents to eradicate resistant leukemia

“…46 )). Moreover, the chemical structure of moxidectin with high lipophilicity increases the half-life of the drug 47 , an observation that may be linked to its higher drug efficiency, as compared to other anthelmintic agents. Ivermectin on the other hand has been safely used in immunocompromised patients to treat scabies 48,49 .…”

“…The potential of these agents to improve the response to steroids also in good responding cases and potentially to decrease toxicity could be tested in a clinical trial. In nematodes, anthelmintic agents target glutamategated chloride channels to increase intracellular chloride concentrations, which is lethal to the parasites 47 . Since these chloride channels are lacking in humans, anthelmintics must have alternative targets to activate cell death.…”

Ivermectin, a potential anticancer drug derived from an antiparasitic drug

“…Ivermectin(IVM) is a macrolide antiparasitic drug with a 16-membered ring derived from avermectin that is composed of 80% 22,23-dihydroavermectin-B1a and 20% 22,23-dihydroavermectin-B1b [ 1 ]. In addition to IVM, the current avermectin family members include selamectin, doramectin and moxidectin [ [2] , [3] , [4] , [5] ] ( Fig. 1 ).…”