AVERMECTINS AND MILBEMYCINS AGAINST FASCIOLA-HEPATICA - IN-VIVO DRUG EFFICACY AND IN-VITRO RECEPTOR-BINDING

Few studies have examined activity against trematodes for the avermert in/milbemycin class of anthelmintics. To gain insight into this, 12 di fferent members of the avermectin/milbemycin mode of action class were tested against juvenile Fasciola hepatica in a mouse model. The compo unds chosen were Avermectin A(1), Avermectin A(2), Avermectin B-1, Ave rmectin B-2, Ivermectin, Ivermectin monosaccharide, Ivermectin aglycon e, 13-deoxy ivermectin aglycone, Moxidectin, 13-O-methoxyethoxymethyl ivermectin aglycone, 4 ''-deoxy-4 ''-epi-methylamino avermectin B-1, a nd 4 ''-deoxy-4 ''-epi-acetylamino avermectin B-1 5-oxime. Each of the se 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 pri or to treatment and all mice were necropsied 4 days after treatment. A t necropsy, none of the individual avermectin or milbemycin-treated gr oups showed any significant activity (P > 0.05) against juvenile F. he patica relative to a vehicle-treated control. In a receptor binding st udy, adult F. hepatica that had been obtained from sheep were homogeni zed, their membranes incubated in the presence of H-3-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 H-3-ivermectin binding sites over t he range of ivermectin concentrations tested (5-100 nM), no significan t H-3-ivermectin binding sites were detected in the F. hepatica membra nes. Based on these data, it seems unlikely that any avermectin or mil bemycin will show activity against F. hepatica, and certainly makes on e pessimistic about possible activity of this mode of action class aga inst trematodes in general.