title: The combination of cobinamide and sulfanegen is highly effective in mouse models of cyanide poisoning.
abstract: BACKGROUND
  Cyanide is a component of smoke in residential and industrial fires, and accidental exposure to cyanide occurs in a variety of industries. Moreover, cyanide has the potential to be used by terrorists, particularly in a closed space such as an airport or train station. Current therapies for cyanide poisoning must be given by intravenous administration, limiting their use in treating mass casualties.
  
  
  OBJECTIVE
  We are developing two new cyanide antidotes--cobinamide, a vitamin B(12) analog, and sulfanegen, a 3-mercaptopyruvate prodrug. Both drugs can be given by intramuscular administration, and therefore could be used to treat a large number of people quickly. We now asked if the two drugs would have an augmented effect when combined.
  
  
  METHODS
  We used a non-lethal and two different lethal models of cyanide poisoning in mice. The non-lethal model assesses neurologic recovery by quantitatively evaluating the innate righting reflex time of a mouse. The two lethal models are a cyanide injection and a cyanide inhalation model.
  
  
  RESULTS
  We found that the two drugs are at least additive when used together in both the non-lethal and lethal models: at doses where all animals died with either drug alone, the combination yielded 80 and 40% survival in the injection and inhalation models, respectively. Similarly, drug doses that yielded 40% survival with either drug alone, yielded 80 and 100% survival in the injection and inhalation models, respectively. As part of the inhalation model, we developed a new paradigm in which animals are exposed to cyanide gas, injected intramuscularly with an antidote, and then re-exposed to cyanide gas. This simulates cyanide exposure of a large number of people in a closed space, because people would remain exposed to cyanide, even after receiving an antidote.
  
  
  CONCLUSIONS
  The combination of cobinamide and sulfanegen shows great promise as a new approach to treating cyanide poisoning.
authors: Department of Medicine, University of California-San Diego, 9500 Gilman Dr., La Jolla,CA 92093-0652, USA.
authors: Adriano
authors: A
authors: Chan
authors: Daune L
authors: DL
authors: Crankshaw
authors: Alexandre
authors: A
authors: Monteil
authors: Steven E
authors: SE
authors: Patterson
authors: Herbert T
authors: HT
authors: Nagasawa
authors: Jackie E
authors: JE
authors: Briggs
authors: Joseph A
authors: JA
authors: Kozocas
authors: Sari B
authors: SB
authors: Mahon
authors: Matthew
authors: M
authors: Brenner
authors: Renate B
authors: RB
authors: Pilz
authors: Timothy D
authors: TD
authors: Bigby
authors: Gerry R
authors: GR
authors: Boss
mesh_terms: D000818:Animals; D000931:Antidotes / Q000008:administration & dosage*; D003038:Cobamides / Q000008:administration & dosage*; D003486:Cyanides / Q000506:poisoning*; D003545:Cysteine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011355:Prodrugs / Q000008:administration & dosage*
chemical_list: D000931:Antidotes; D003038:Cobamides; D003486:Cyanides; D011355:Prodrugs; C017142:cobinamide; C008366:3-mercaptopyruvic acid; D003545:Cysteine