Avermectins and milbemycins against Fasciola hepatica: in vivo drug efficacy and in vitro receptor binding.
Few studies have examined activity against trematodes for the avermectin/milbemycin class of anthelmintics. To gain insight into this, 12 different members of the avermectin/milbemycin mode of action class were tested against juvenile Fasciola hepatica in a mouse model. The compounds chosen were Avermectin A1, Avermectin A2, Avermectin B1, Avermectin B2, Ivermectin, Ivermectin monosaccharide, Ivermectin aglycone, 13-deoxy ivermectin aglycone, Moxidectin, 13-O-methoxyethoxymethyl ivermectin aglycone, 4"-deoxy-4"-epi-methylamino avermectin B1, and 4"-deoxy-4"-epi-acetylamino avermectin B1 5-oxime. Each of these compounds was administered orally to 4 mice at 2.0 mg kg-1. These mice had been administered 3 metacercariae of F. hepatica 14 days prior to treatment and all mice were necropsied 4 days after treatment. At necropsy, none of the individual avermectin or milbemycin-treated groups showed any significant activity (P > 0.05) against juvenile F. hepatica relative to a vehicle-treated control. In a receptor binding study, adult F. hepatica that had been obtained from sheep were homogenized, their membranes incubated in the presence of 3H-ivermectin, and then measured for high affinity binding sites. The same was done with the free-living nematode, Caenorhabditis elegans. While the C. elegans membranes displayed high affinity 3H-ivermectin binding sites over the range of ivermectin concentrations tested (5-100 nM), no significant 3H-ivermectin binding sites were detected in the F. hepatica membranes. Based on these data, it seems unlikely that any avermectin or milbemycin will show activity against F. hepatica, and certainly makes one pessimistic about possible activity of this mode of action class against trematodes in general.
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Merck Research Laboratories, Rahway, NJ 07065-0900, USA.
Ostlind
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Rohrer
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Mickle
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Haines
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Michael
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Mrozik
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Fisher
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D000818:Animals; D000900:Anti-Bacterial Agents; D000980:Antiplatyhelmintic Agents / Q000378:metabolism* / Q000627:therapeutic use*; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D005210:Fasciola hepatica / Q000302:isolation & purification / Q000502:physiology; D005211:Fascioliasis / Q000188:drug therapy*; D007559:Ivermectin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000627:therapeutic use*; D008099:Liver / Q000469:parasitology; D018942:Macrolides / Q000378:metabolism / Q000627:therapeutic use; D051379:Mice; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D000980:Antiplatyhelmintic Agents; D018942:Macrolides; D007559:Ivermectin; C027837:moxidectin