Avermectins and milbemycins against Fasciola hepatica: In vivo drug efficacy and in Vitro receptor binding

• Published in: International journal for parasitology 1995-08, Vol.25 (8), p.923-927
• Main Authors: Shoop, W.L., Ostlind, D.A., Rohrer, S.P., Mickle, G., Haines, H.W., Michael, B.F., Mrozik, H., Fisher, M.H.
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Antiplatyhelmintic Agents - metabolism; Antiplatyhelmintic Agents - therapeutic use; Avermectins; Binding Sites; Biological and medical sciences; Caenorhabditis elegans - metabolism; Cell Membrane - metabolism; efficacy; F. hepatica; Fasciola hepatica - isolation & purification; Fasciola hepatica - physiology; Fascioliasis - drug therapy; Ivermectin - analogs & derivatives; Ivermectin - metabolism; Ivermectin - therapeutic use; Liver - parasitology; Macrolides - metabolism; Macrolides - therapeutic use; Medical sciences; Mice; milbemycins; Pharmacology. Drug treatments; receptor binding; Structure-Activity Relationship
• ISSN: 0020-7519; 1879-0135
• DOI: 10.1016/0020-7519(95)00026-X

Few studies have examined activity against trematedes 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 juvemile Fasciola hepatica in a mouse model. The compounds chosen were Avermectin A 1, Avermectin A 2, Avermectin B 1, Avermectin B 2, Ivermectin, Ivermectin monosaccharide, Ivermectin aglycone, 13-deoxy invermectin aglycone, Moxidectin, 13-O-methoxyethoxymethyl ivermectin aglycone, 4″-deoxy-4″-epi-methylamino avermectin B 1, and 4″-deoxy-4″-epi-acetylamino avermectin B 1 5-oxime. Each of these compounds was administered orally to 4 mice at 2.0 mg kg −1. These mice had been administered 3 metacercarine 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.