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Evaluation of the mode of action of albendazole against Giardia duodenalis and other parasitic protozoa

Oxberry, Megan E. (1997) Evaluation of the mode of action of albendazole against Giardia duodenalis and other parasitic protozoa. PhD thesis, Murdoch University.

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Abstract

Previous work has shown that albendazole, a member of the benzimidazole group of anthelmintics, is extremely effective against several protozoan parasites including Giardia duodenalis. In view of this potency it seemed appropriate to evaluate the mode of action of the benzimidazoles as knowledge of the drugs' action will help to optimise treatment of giardiasis, aid in the development of a single-dose treatment regime and reveal possible improvements which could be made to the benzimidazoles. The hypothesis of the study was that albendazole acts by binding to tubulin and preventing it polymerising to form microtubules, the accepted mode of action of the benzimidazole drugs in helminth parasites. Several approaches were taken to test this hypothesis, these included: electron microscopic studies of ultrastructural effects occurring in G. duodenalis and related protozoan parasites at different drug concentrations; the use of antibodies raised against albendazole and its principal metabolites to determine if and where albendazole was binding within or on the parasite; binding studies on the proteins of G. duodenalis to determine whether tubulin was involved in benzimidazole activity; displacement studies which measured benzimidazole binding to G. duodenalis proteins in the presence of competitors; and receptor protection studies in which colchicine was allowed to bind to G. duodenalis trophozoites in vitro, to determine whether its presence had an effect on albendazole binding and efficacy. It was concluded that the benzimidazoles do bind to G. duodenalis tubulin causing damage to the ventral disk structure of the parasite. It was also shown that other benzimidazoles are capable of displacing mebendazole from the tubulin binding site and that G. duodenalis is capable of metabolising albendazole. It could not be determined from the receptor protection studies whether albendazole binds to the colchicine binding site on the tubulin molecule.

Item Type: Thesis (PhD)
Murdoch Affiliation: School of Veterinary Studies
Notes: Note to the author: If you would like to make your thesis openly available on Murdoch University Library's Research Repository, please contact: repository@murdoch.edu.au. Thank you.
Supervisor(s): Reynoldson, James and Thompson, Andrew
URI: http://researchrepository.murdoch.edu.au/id/eprint/53151
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