title: An In Vitro/In Vivo Model to Analyze the Effects of Flubendazole Exposure on Adult Female Brugia malayi.
abstract: Current control strategies for onchocerciasis and lymphatic filariasis (LF) rely on prolonged yearly or twice-yearly mass administration of microfilaricidal drugs. Prospects for near-term elimination or eradication of these diseases would be improved by availability of a macrofilaricide that is highly effective in a short regimen. Flubendazole (FLBZ), a benzimidazole anthelmintic registered for control of human gastrointestinal nematode infections, is a potential candidate for this role. FLBZ has profound and potent macrofilaricidal effects in many experimental animal models of filariases and in one human trial for onchocerciasis after parental administration. Unfortunately, the marketed formulation of FLBZ provides very limited oral bioavailability and parenteral administration is required for macrofilaricidal efficacy. A new formulation that provided sufficient oral bioavailability could advance FLBZ as an effective treatment for onchocerciasis and LF. Short-term in vitro culture experiments in adult filariae have shown that FLBZ damages tissues required for reproduction and survival at pharmacologically relevant concentrations. The current study characterized the long-term effects of FLBZ on adult Brugia malayi by maintaining parasites in jirds for up to eight weeks following brief drug exposure (6-24 hr) to pharmacologically relevant concentrations (100 nM-10 μM) in culture. Morphological damage following exposure to FLBZ was observed prominently in developing embryos and was accompanied by a decrease in microfilarial output at 4 weeks post-exposure. Although FLBZ exposure clearly damaged the parasites, exposed worms recovered and were viable 8 weeks after treatment.
authors.affiliation: Institute of Parasitology, McGill University, Ste-Anne-de-Bellevue, Quebec, Canada.
authors.forename: Maeghan
authors.initials: M
authors.lastname: O'Neill
authors.affiliation: TRS Labs, Athens, Georgia, United States of America.
authors.forename: Abdelmoneim
authors.initials: A
authors.lastname: Mansour
authors.affiliation: TRS Labs, Athens, Georgia, United States of America.
authors.forename: Utami
authors.initials: U
authors.lastname: DiCosty
authors.affiliation: Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Geary
authors.affiliation: TRS Labs, Athens, Georgia, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Dzimianski
authors.affiliation: TRS Labs, Athens, Georgia, United States of America.
authors.forename: Scott D
authors.initials: SD
authors.lastname: McCall
authors.affiliation: TRS Labs, Athens, Georgia, United States of America.
authors.forename: John W
authors.initials: JW
authors.lastname: McCall
authors.affiliation: Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Mackenzie
authors.affiliation: Institute of Parasitology, McGill University, Ste-Anne-de-Bellevue, Quebec, Canada.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Geary
mesh_terms: D000818:Animals; D000969:Antinematodal Agents / Q000494:pharmacology*; D017178:Brugia malayi / Q000187:drug effects*; D005260:Female; D005849:Gerbillinae; D008297:Male; D008463:Mebendazole / Q000031:analogs & derivatives* / Q000494:pharmacology; D010529:Peritoneal Cavity / Q000469:parasitology
chemical_list: D000969:Antinematodal Agents; D008463:Mebendazole; C018945:flubendazole