title: Effects of the benzimidazole anthelmintic drug flubendazole on rat embryos in vitro.
abstract: Filarial diseases affect millions of people in poverty-stricken areas. In 2011, an investigation of the potential of flubendazole as a safe, highly efficacious, and field-usable macrofilaricidal drug was begun by Drug for Neglected Diseases initiative. As part of the preclinical development program, whole embryo culture was used to investigate the potential embryotoxicity of flubendazole and its metabolites, reduced and hydrolyzed flubendazole. Albendazole was included as a comparator. Flubendazole and albendazole showed similar potency in affecting rat embryonic development in vitro, inducing retardation of growth and dysmorphogenic effects at concentrations ≥0.5 μg/mL. The head, optic and otic systems, branchial arches and posterior body portion were affected. Diffuse areas of cell death were seen in various embryonic districts. The No Observed Effect Level (NOEL) was 0.25 μg/mL for both drugs. Reduced and hydrolyzed flubendazole were less embryotoxic than the parent compound, with NOELs 4-fold and >40-fold higher than that of flubendazole, respectively.
authors.affiliation: Accelera S.r.l., Viale Pasteur 10, 20014 Nerviano, Milan, Italy. monica.longo@accelera.org
authors.forename: Monica
authors.initials: M
authors.lastname: Longo
authors.forename: Sara
authors.initials: S
authors.lastname: Zanoncelli
authors.forename: Paolo Angelo
authors.initials: PA
authors.lastname: Colombo
authors.forename: Michael Oscar
authors.initials: MO
authors.lastname: Harhay
authors.forename: Ivan
authors.initials: I
authors.lastname: Scandale
authors.forename: Charles
authors.initials: C
authors.lastname: Mackenzie
authors.forename: Timothy
authors.initials: T
authors.lastname: Geary
authors.forename: Nicole
authors.initials: N
authors.lastname: Madrill
authors.forename: Guy
authors.initials: G
authors.lastname: Mazué
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000196:embryology* / Q000473:pathology; D000015:Abnormalities, Multiple / Q000139:chemically induced* / Q000196:embryology / Q000473:pathology; D000818:Animals; D000871:Anthelmintics / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D001711:Biotransformation; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004477:Ectogenesis / Q000187:drug effects*; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000187:drug effects*; D005260:Female; D006868:Hydrolysis; D008463:Mebendazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D019055:No-Observed-Adverse-Effect Level; D009994:Osmolar Concentration; D010084:Oxidation-Reduction; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens / Q000032:analysis / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D018675:Toxicity Tests
chemical_list: D000871:Anthelmintics; D013723:Teratogens; D008463:Mebendazole; C018945:flubendazole