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 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.
Institute of Parasitology and Centre for Host-Parasite Interactions, McGill University, Ste-Anne-de-Bellevue, QC H9X 3V9, Canada.
Maeghan
M
O'Neill
Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824, USA.
James F
JF
Geary
Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824, USA.
Dalen W
DW
Agnew
Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824, USA.
Charles D
CD
Mackenzie
Institute of Parasitology and Centre for Host-Parasite Interactions, McGill University, Ste-Anne-de-Bellevue, QC H9X 3V9, Canada.
Timothy G
TG
Geary
D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D017178:Brugia malayi / Q000187:drug effects*; D005260:Female; D008463:Mebendazole / Q000031:analogs & derivatives* / Q000494:pharmacology
D000871:Anthelmintics; D008463:Mebendazole; C018945:flubendazole
Benzimidazole; Filariasis; Histology; Macrofilaricide; Reproduction