Toxicology and pharmacology of bispyridium oximes--insight into the mechanism of action vs Soman poisoning in vivo.
HI-6 was the least toxic and the most efficacious oxime examined against Soman poisoning with a high safety ratio between 26-30. Reactivation of peripheral acetylcholinesterase following Soman poisoning was more important in the beneficial therapeutic action of HI-6 than reactivation of central acetylcholinesterase. HI-6 reactivated Sarin-inhibited but not Tabun-inhibited acetylcholinesterase both peripherally and centrally. HI-6 passes the blood brain barrier as evidenced by its reactivation centrally of Sarin-inhibited acetylcholinesterase. Soman-inhibited enzyme was not aged in vivo by 30 min. In vivo diaphragm acetylcholinesterase was inhibited to a greater extent by Soman, Sarin and Tabun than intercostal muscle acetylcholinesterase. In vitro diaphragm and intercostal muscle acetylcholinesterase had similar IC50 values for Soman. HI-6 has antimuscarinic and antinicotinic activity in addition to its previously reported ganglion blocking activity (Lundy and Tremblay, 1979). These additional pharmacological actions of HI-6 may play a role in the therapeutic action of HI-6 (at the higher concentrations). The results suggest that peripheral acetylcholinesterase in the rat diaphragm is the primary lesion in Soman poisoning. The beneficial action of HI-6 in rats versus Soman poisoning is due to reactivation of diaphragm acetylcholinesterase.
D000110:Acetylcholinesterase / Q000032:analysis; D000818:Animals; D000931:Antidotes / Q000494:pharmacology* / Q000627:therapeutic use; D001285:Atropine / Q000627:therapeutic use; D001921:Brain / Q000201:enzymology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009469:Neuromuscular Junction / Q000187:drug effects; D062025:Organophosphate Poisoning; D010091:Oximes / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D011220:Pralidoxime Compounds / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology; D011950:Receptors, Cholinergic / Q000187:drug effects; D012999:Soman / Q000506:poisoning*; D013329:Structure-Activity Relationship
D000931:Antidotes; D010091:Oximes; D011220:Pralidoxime Compounds; D011726:Pyridinium Compounds; D011950:Receptors, Cholinergic; C003027:HS 6; D001285:Atropine; D012999:Soman; D000110:Acetylcholinesterase; C022870:asoxime chloride