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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.
AuthorsMonica Longo, Sara Zanoncelli, Paolo Angelo Colombo, Michael Oscar Harhay, Ivan Scandale, Charles Mackenzie, Timothy Geary, Nicole Madrill, Guy Mazué
JournalReproductive toxicology (Elmsford, N.Y.) (Reprod Toxicol) Vol. 36 Pg. 78-87 (Apr 2013) ISSN: 1873-1708 [Electronic] United States
PMID23287076 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier Inc. All rights reserved.
Chemical References
  • Anthelmintics
  • Teratogens
  • Mebendazole
  • flubendazole
Topics
  • Abnormalities, Drug-Induced (embryology, pathology)
  • Abnormalities, Multiple (chemically induced, embryology, pathology)
  • Animals
  • Anthelmintics (administration & dosage, metabolism, pharmacokinetics, toxicity)
  • Biotransformation
  • Cell Death (drug effects)
  • Dose-Response Relationship, Drug
  • Ectogenesis (drug effects)
  • Embryo, Mammalian (abnormalities, drug effects)
  • Female
  • Hydrolysis
  • Mebendazole (administration & dosage, analogs & derivatives, metabolism, pharmacokinetics, toxicity)
  • No-Observed-Adverse-Effect Level
  • Osmolar Concentration
  • Oxidation-Reduction
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Teratogens (analysis, metabolism, pharmacokinetics, toxicity)
  • Toxicity Tests

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