title: The emerging threat of superwarfarins: history, detection, mechanisms, and countermeasures.
abstract: Superwarfarins were developed following the emergence of warfarin resistance in rodents. Compared to warfarin, superwarfarins have much longer half-lives and stronger affinity to vitamin K epoxide reductase and therefore can cause death in warfarin-resistant rodents. By the mid-1970s, the superwarfarins brodifacoum and difenacoum were the most widely used rodenticides throughout the world. Unfortunately, increased use was accompanied by a rise in accidental poisonings, reaching >16,000 per year in the United States. Risk of exposure has become a concern since large quantities, up to hundreds of kilograms of rodent bait, are applied by aerial dispersion over regions with rodent infestations. Reports of intentional use of superwarfarins in civilian and military scenarios raise the specter of larger incidents or mass casualties. Unlike warfarin overdose, for which 1-2 days of treatment with vitamin K is effective, treatment of superwarfarin poisoning with vitamin K is limited by extremely high cost and can require daily treatment for a year or longer. Furthermore, superwarfarins have actions that are independent of their anticoagulant effects, including both vitamin K-dependent and -independent effects, which are not mitigated by vitamin K therapy. In this review, we summarize superwarfarin development, biology and pathophysiology, their threat as weapons, and possible therapeutic approaches.
authors.affiliation: Department of Anesthesiology, University of Illinois, Chicago, Illinois.|Jesse Brown VA Medical Center, Chicago, Illinois.
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Feinstein
authors.affiliation: Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, North Carolina.
authors.forename: Belinda S
authors.initials: BS
authors.lastname: Akpa
authors.affiliation: Department of Medicine, University of Illinois, Chicago, Illinois.
authors.forename: Manuela A
authors.initials: MA
authors.lastname: Ayee
authors.affiliation: Department of Anesthesiology, University of Illinois, Chicago, Illinois.|Jesse Brown VA Medical Center, Chicago, Illinois.
authors.forename: Anne I
authors.initials: AI
authors.lastname: Boullerne
authors.affiliation: Department of Anesthesiology, University of Illinois, Chicago, Illinois.
authors.forename: David
authors.initials: D
authors.lastname: Braun
authors.affiliation: Department of Pathology, the Ohio State University, Columbus, Ohio.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Brodsky
authors.affiliation: Department of Physics and the Center for the Molecular Study of Condensed Soft Matter, Illinois Institute of Technology, Chicago, Illinois.
authors.forename: David
authors.initials: D
authors.lastname: Gidalevitz
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois, Chicago, Illinois.
authors.forename: Zane
authors.initials: Z
authors.lastname: Hauck
authors.affiliation: Department of Anesthesiology, University of Illinois, Chicago, Illinois.
authors.forename: Sergey
authors.initials: S
authors.lastname: Kalinin
authors.affiliation: Department of Anesthesiology, University of Illinois, Chicago, Illinois.
authors.forename: Kathy
authors.initials: K
authors.lastname: Kowal
authors.affiliation: X-ray Science Division, Argonne National Laboratory, Lemont, Illinois.
authors.forename: Ivan
authors.initials: I
authors.lastname: Kuzmenko
authors.affiliation: Department of Anesthesiology, University of Illinois, Chicago, Illinois.
authors.forename: Kinga
authors.initials: K
authors.lastname: Lis
authors.affiliation: Department of Anesthesiology, University of Illinois, Chicago, Illinois.
authors.forename: Natalia
authors.initials: N
authors.lastname: Marangoni
authors.affiliation: Department of Physics and the Center for the Molecular Study of Condensed Soft Matter, Illinois Institute of Technology, Chicago, Illinois.|X-ray Science Division, Argonne National Laboratory, Lemont, Illinois.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Martynowycz
authors.affiliation: Department of Anesthesiology, University of Illinois, Chicago, Illinois.|Department of Medicine, University of Illinois, Chicago, Illinois.
authors.forename: Israel
authors.initials: I
authors.lastname: Rubinstein
authors.affiliation: Department of Anesthesiology, University of Illinois, Chicago, Illinois.
authors.forename: Richard
authors.initials: R
authors.lastname: van Breemen
authors.affiliation: Department of Pathology, the Ohio State University, Columbus, Ohio.
authors.forename: Kyle
authors.initials: K
authors.lastname: Ware
authors.affiliation: Department of Anesthesiology, University of Illinois, Chicago, Illinois.|Jesse Brown VA Medical Center, Chicago, Illinois.
authors.forename: Guy
authors.initials: G
authors.lastname: Weinberg
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects / Q000032:analysis / Q000737:chemistry; D015415:Biomarkers / Q000032:analysis; D004781:Environmental Exposure / Q000032:analysis; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D009420:Nervous System / Q000187:drug effects / Q000473:pathology; D014859:Warfarin / Q000009:adverse effects* / Q000032:analysis* / Q000737:chemistry / Q000506:poisoning
chemical_list: D000925:Anticoagulants; D015415:Biomarkers; D014859:Warfarin
keywords: HPLC; brodifacoum; intralipid; lipid membrane; nephrotoxicity; neuropathology; superwarfarins