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.