title: In vivo preliminary investigations of the effects of the benzimidazole anthelmintic drug flubendazole on rat embryos and fetuses.
abstract: Flubendazole, in a new formulation with high systemic bioavailability, has been proposed as a macrofilaricide against filarial diseases. To investigate embryotoxic activity, the new flubendazole formulation was administered orally to Sprague Dawley rats at 2, 3.46, 6.32mg/kg/day on gestation day (GD) 9.5 and 10.5. Embryos/fetuses were evaluated on GD 11.5, 12.5 or 20. At 6.32mg/kg/day (Cmax=0.801μg/mL after single administration), flubendazole initially induced an arrest of embryonic development followed by a generalized cell death that led to 100% embryolethality by GD 12.5. At 3.46mg/kg/day (Cmax=0.539μg/mL after single administration), flubendazole markedly reduced embryonic development by GD 12.5 without causing cell death. On GD 20, 80% of fetuses showed malformations. At 2mg/kg/day (Cmax=0.389μg/mL after single administration), it did not interfere with rat embryofetal development.
authors.affiliation: Accelera S.r.l., Viale Pasteur 10, 20014 Nerviano (MI), Italy. Electronic address: monica.longo@accelera.org.
authors.forename: Monica
authors.initials: M
authors.lastname: Longo
authors.affiliation: Accelera S.r.l., Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Zanoncelli
authors.affiliation: Accelera S.r.l., Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Messina
authors.affiliation: DNDi (Drug for Neglected Diseases initiative), Geneva, Switzerland.
authors.forename: Ivan
authors.initials: I
authors.lastname: Scandale
authors.affiliation: Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Mackenzie
authors.affiliation: Institute of Parasitology, McGill University, Montreal, Canada.
authors.forename: Timothy
authors.initials: T
authors.lastname: Geary
authors.affiliation: AbbVie Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.affiliation: AbbVie Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lindley
authors.affiliation: Independent Consultant, Aux Fermes de Bosne, F 39230 Mantry, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Mazué
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000097:blood / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000187:drug effects*; D047108:Embryonic Development / Q000187:drug effects; D005260:Female; D005333:Fetus / Q000187:drug effects*; D008463:Mebendazole / Q000031:analogs & derivatives* / Q000097:blood / Q000633:toxicity; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000871:Anthelmintics; D008463:Mebendazole; C018945:flubendazole
keywords: Benzimidazole anthelmintic; Embryolethality; Eye development; Filarial diseases; Flubendazole; Teratogenicity