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Development and application of a rat malaria model to investigate the pharmacology of microtubule antagonists as antimalarials

Dow, Geoffrey S. (2000) Development and application of a rat malaria model to investigate the pharmacology of microtubule antagonists as antimalarials. PhD thesis, Murdoch University.

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Abstract

Malaria, caused by Plasmodium spp. is a disease responsible for significant morbidity and mortality around the world. Resistance of malaria parasites to conventional antimalarial drugs is rapidly leading to a lack of useful antimalarial compounds. There is an urgent need to develop new antimalarial drugs which exploit novel parasite targets. Microtubules represent a potential drug target in malaria because of their essential role in maintenance of cellular integrity and parasite replication.

Albendazole is a benzimidazole anthelmintic used in human and veterinary medicine whilst trifluralin is a dinitroaniline herbicide. Both compounds are microtubule antagonists, and have activity against malaria parasites in vitro. The purpose of the present study was to evaluate their potential usefulness as antimalarial drugs using a P. berghei-rat model of malaria. This approach enabled simultaneous analysis of toxicology, pharmacokinetics, in vitro and in vivo efficacy data with respect to the same host-parasite system.

In in vivo studies, albendazole exhibited antimalarial activity against P. berghei in rats after oral administration to rats at higher dose rates than those used in humans. Pharmacokinetic and in vitro drug screening studies indicated that albendazole and its key metabolites exhibited no activity against P. berghei at concentrations detectable in blood. Toxicology studies found that at effective dose rates, albendazole treatment impaired haematopoietic responses to malaria and depleted young red blood cells essential for P. berghei proliferation. These data suggested an indirect mode of action for albendazole against P. berghei.

Trifluralin exhibited negligible in vivo activity against P. berghei after oral administration to rats, even when given at the maximum dose rates tolerated by the host. However in vitro studies indicated that trifluralin and related dinitroaniline herbicides exhibited activity against P. berghei at high nanomolar to low micromolar concentrations. The discrepancy between these data was resolved following a pharmacokinetic evaluation, in which plasma trifluralin concentrations were found to be below those necessary for antimalarial activity in vitro.

Due to the indirect mode of action of albendazole, and the poor absorption of trifluralin it is unlikely that these compounds will be used clinically as antimalarials. Other benzimidazole derivatives currently in use are less potent antimalarial agents than albendazole and are thus not realistic candidates. However dinitroaniline herbicides such as oryzalin retain their antimalarial activity in vitro and have significantly better pharmacokinetics than trifluralin and may prove to be more useful antimalarials in vivo.

Item Type: Thesis (PhD)
Murdoch Affiliation: Division of Veterinary and Biomedical Sciences
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/53155
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