title: Protection against nerve agent poisoning by a noncompetitive nicotinic antagonist.
abstract: The acute toxicity of organophosphorus (OP) nerve agents arises from accumulation of acetylcholine (ACh) and overstimulation of ACh receptors. The mainstay of current pharmacotherapy is the competitive muscarinic antagonist, atropine. Nicotinic antagonists have not been used due to the difficulties of administering a dose of a competitive neuromuscular blocker sufficient to antagonise the effects of excessive ACh, but not so much that it paralyses the muscles. An alternative approach would be to use a noncompetitive antagonist whose effects would not be overcome by increasing ACh concentrations. This study demonstrates that the compound 1,1'-(propane-1,3-diyl)bis(4-tert-butylpyridinium), which blocks open nicotinic ion channels noncompetitively, is able to reverse the neuromuscular paralysis after nerve agent poisoning in vitro and to protect guinea pigs against poisoning by nerve agents when used as part of a therapeutic drug combination including a muscarinic antagonist. In contrast to the oxime HI-6, this compound was equally effective in protecting against poisoning by sarin or tabun. Further studies should identify more effective compounds with this action and optimise doses for protection against nerve agent poisoning in vivo.
authors.affiliation: Biomedical Sciences Department, Dstl Porton Down, Salisbury SP40JQ, Wiltshire, UK.
authors.forename: S R
authors.initials: SR
authors.lastname: Turner
authors.forename: J E
authors.initials: JE
authors.lastname: Chad
authors.forename: M
authors.initials: M
authors.lastname: Price
authors.forename: C M
authors.initials: CM
authors.lastname: Timperley
authors.forename: M
authors.initials: M
authors.lastname: Bird
authors.forename: A C
authors.initials: AC
authors.lastname: Green
authors.forename: J E H
authors.initials: JE
authors.lastname: Tattersall
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002619:Chemical Warfare Agents / Q000506:poisoning*; D003964:Diaphragm / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D018733:Nicotinic Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D062025:Organophosphate Poisoning; D010755:Organophosphates; D011041:Poisoning / Q000517:prevention & control; D011726:Pyridinium Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D012524:Sarin / Q000506:poisoning; D012999:Soman / Q000506:poisoning
chemical_list: D002619:Chemical Warfare Agents; D018733:Nicotinic Antagonists; D010755:Organophosphates; D011726:Pyridinium Compounds; D012999:Soman; D012524:Sarin; C009374:tabun