In vitro flubendazole-induced damage to vital tissues in adult females of the filarial nematode Brugia malayi
The use of a microfilaricidal drug for the control of onchocerciasis and lymphatic filariasis necessitates prolonged yearly dosing. Prospects for elimination or eradication of these diseases would be enhanced by availability of a macrofilaricidal drug. Flubendazole (FLBZ), a benzimidazole anthelmint...
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doaj-9e065a672466429db361cf63c28593b22020-11-24T22:26:00ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072015-12-015313514010.1016/j.ijpddr.2015.06.002In vitro flubendazole-induced damage to vital tissues in adult females of the filarial nematode Brugia malayiMaeghan O'Neill0James F. Geary1Dalen W. Agnew2Charles D. Mackenzie3Timothy G. Geary4Institute of Parasitology and Centre for Host-Parasite Interactions, McGill University, Ste-Anne-de-Bellevue, QC H9X 3V9, CanadaDepartment of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824, USADepartment of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824, USADepartment of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824, USAInstitute of Parasitology and Centre for Host-Parasite Interactions, McGill University, Ste-Anne-de-Bellevue, QC H9X 3V9, CanadaThe use of a microfilaricidal drug for the control of onchocerciasis and lymphatic filariasis necessitates prolonged yearly dosing. Prospects for elimination or eradication of these diseases would be enhanced by availability of a macrofilaricidal drug. Flubendazole (FLBZ), a benzimidazole anthelmintic, is an appealing candidate macrofilaricide. FLBZ has demonstrated profound and potent macrofilaricidal effects in a number of experimental filarial rodent models and one human trial. Unfortunately, FLBZ was deemed unsatisfactory for use in mass drug administration (MDA) campaigns due to its markedly limited oral bioavailability. However, a new formulation that provided sufficient bioavailability following oral administration could render FLBZ an effective treatment for onchocerciasis and LF. This study characterized the effects of FLBZ and its reduced metabolite (FLBZ-R) on filarial nematodes in vitro to determine the exposure profile which results in demonstrable damage. Adult female Brugia malayi were exposed to varying concentrations of FLBZ or FLBZ-R (100 nM–10 μM) for up to five days, after which worms were fixed for histology. Morphological damage following exposure to FLBZ was observed prominently in the hypodermis and developing embryos at concentrations as low as 100 nM following 24 h exposure. The results indicate that damage to tissues required for reproduction and survival can be achieved at pharmacologically relevant concentrations.http://www.sciencedirect.com/science/article/pii/S221132071530004XFilariasisMacrofilaricideBenzimidazoleHistologyReproduction |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Maeghan O'Neill James F. Geary Dalen W. Agnew Charles D. Mackenzie Timothy G. Geary |
spellingShingle |
Maeghan O'Neill James F. Geary Dalen W. Agnew Charles D. Mackenzie Timothy G. Geary In vitro flubendazole-induced damage to vital tissues in adult females of the filarial nematode Brugia malayi International Journal for Parasitology: Drugs and Drug Resistance Filariasis Macrofilaricide Benzimidazole Histology Reproduction |
author_facet |
Maeghan O'Neill James F. Geary Dalen W. Agnew Charles D. Mackenzie Timothy G. Geary |
author_sort |
Maeghan O'Neill |
title |
In vitro flubendazole-induced damage to vital tissues in adult females of the filarial nematode Brugia malayi |
title_short |
In vitro flubendazole-induced damage to vital tissues in adult females of the filarial nematode Brugia malayi |
title_full |
In vitro flubendazole-induced damage to vital tissues in adult females of the filarial nematode Brugia malayi |
title_fullStr |
In vitro flubendazole-induced damage to vital tissues in adult females of the filarial nematode Brugia malayi |
title_full_unstemmed |
In vitro flubendazole-induced damage to vital tissues in adult females of the filarial nematode Brugia malayi |
title_sort |
in vitro flubendazole-induced damage to vital tissues in adult females of the filarial nematode brugia malayi |
publisher |
Elsevier |
series |
International Journal for Parasitology: Drugs and Drug Resistance |
issn |
2211-3207 |
publishDate |
2015-12-01 |
description |
The use of a microfilaricidal drug for the control of onchocerciasis and lymphatic filariasis necessitates prolonged yearly dosing. Prospects for elimination or eradication of these diseases would be enhanced by availability of a macrofilaricidal drug. Flubendazole (FLBZ), a benzimidazole anthelmintic, is an appealing candidate macrofilaricide. FLBZ has demonstrated profound and potent macrofilaricidal effects in a number of experimental filarial rodent models and one human trial. Unfortunately, FLBZ was deemed unsatisfactory for use in mass drug administration (MDA) campaigns due to its markedly limited oral bioavailability. However, a new formulation that provided sufficient bioavailability following oral administration could render FLBZ an effective treatment for onchocerciasis and LF. This study characterized the effects of FLBZ and its reduced metabolite (FLBZ-R) on filarial nematodes in vitro to determine the exposure profile which results in demonstrable damage. Adult female Brugia malayi were exposed to varying concentrations of FLBZ or FLBZ-R (100 nM–10 μM) for up to five days, after which worms were fixed for histology. Morphological damage following exposure to FLBZ was observed prominently in the hypodermis and developing embryos at concentrations as low as 100 nM following 24 h exposure. The results indicate that damage to tissues required for reproduction and survival can be achieved at pharmacologically relevant concentrations. |
topic |
Filariasis Macrofilaricide Benzimidazole Histology Reproduction |
url |
http://www.sciencedirect.com/science/article/pii/S221132071530004X |
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