An Investigation of the Mechanism of Ivermectin Resistance in the Nematode Parasite, Haemonchus contortus
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Authors
Musser, Sara E.
Issue Date
1996
Type
Thesis
Language
en_US
Keywords
Alternative Title
Abstract
Haemonchus contortus and Ascaris suum are parasitic nematodes that
pose a considerable challenge to veterinary medicine. Unfortunately, the
utility of each of the three major classes of broad-spectrum anthelmintic used
to treat parasitic nematode infections (macrocyclic lactones, imidazothiazoles/
tetrahydropyrimidines, and benzimidazoles) is gradually eroding due to the
emergence of strains of parasites that are resistant to the actions of these
drugs. Mechanisms of drug resistance have been proposed for the
benzimidazoles and the imidazothiazoles/ tetrahydropyrimidines (Prichard,
1990). However, the mechanism(s) for resistance to the macrocyclic lactones,
such as ivermectin, in parasitic nematodes is still unknown.
Recent studies suggest that multiple drug resistance (MDR) Pglycoproteins,
transmembranous proteins that reduce the cytotoxic effects of
drugs by actively transporting these compounds from cells, may underlie the
mechanism of ivermectin resistance in parasitic nematodes (Sangster, 1993;
Broeks et al., 1995; Sangster, 1995). In the present study, automated motility
recordings and ivermectin absorption/disappearance kinetics in H. contortus
along with ivermectin tissue distribution in A. suum were assessed in an
effort to delineate this mechanism. Results of the motility recordings
indicated an approximately 15-fold difference in ivermectin sensitivity
between the wild-type and ivermectin-resistant strains of H. contortus in
vitro; however, there was no significant difference in ivermectin absorption
or disappearance kinetics between the two strains. The MDR inhibitor,
cyclosporin A, had no significant effect on the kinetics of ivermectin in either
strain of H. contortus. Additionally, there was no preferential distribution of
ivermectin in the gut (or other tissues) of A. suum that would suggest MDR
involvement. On the basis of these studies, we conclude that MDR Pglycoproteins
are probably not responsible for ivermectin resistance in H.
contortus and other parasitic nematodes.
Description
ix, 47 p.
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