The treatment of Soman poisoning and its perspectives.
Soman is a highly toxic organophosphorus chemical warfare nerve agent which is characterized by (1) extremely rapid ageing of the phosphonylated enzyme, (2) poor reactivation of inhibited AChE due to a steric factor, (3) pronounced CNS effects, and (4) tentative direct toxic biochemical effects. By studies of Soman and its thiocholine-like analog (which yield the same type of phosphonylated enzyme), it has been established that (1) the steric factor is at least as responsible as ageing in the failure of oximes to reactivate effectively AChE inhibited by Soman, (2) that its dealkylation is catalyzed by the anionic site of the enzyme, and (3) that the velocity of reactivation and ageing of AChE is dependent on the orientation of the phosphonyl group at the enzyme surface. It has been found that PiMeP-Cl (O-pinacolyl methylphosphonochloridate) may serve as a good model in the evaluation of Soman toxicity and in the selection of adequate oximes in the treatment of its poisoning. The opposite effects of TMB-4 and HI-6, as group representatives, on PiMeP-Cl toxicity in mice (strong potentiation by TMB-4 and antagonism by HI-6) were mainly ascribed to the rates of decomposition of their corresponding O-pinacolyl methylphosphonylated products formed in vivo. They are considered to be slow with potentiators and instantaneous with antagonists, respectively. This assumption was confirmed by the finding that the most powerful oximes in Soman poisoned mice were HI-6, HGG-42 and BDB-27, which, contrary to TMB-4, possess an oxime group in position 2 and the CH2-O-CH2 linking chain. The remarkable influence of diazepam and sodium n-dipropylacetate on the survival time in Soman poisoned rats treated by atropine and bis-pyridinium oximes points to their antagonistic action at the biochemical level (decrease of elevated cGMP in CNS), not possessed by atropine. Essential antidotes in experimental treatment of Soman poisoning today are the powerful reactivators of Soman-inhibited AChE (e.g. HI-6, HGG-42 and BDB-27) and atropine. The treatment may be further improved by the use of symptomatic agents capable of counteracting biochemical changes in Soman poisoning not antagonized by atropine (e.g. diazepam), and theoretically for now, by retardation of ageing and by overcoming steric disturbances.
D000818:Animals; D000931:Antidotes / Q000627:therapeutic use*; D001285:Atropine / Q000627:therapeutic use; D002800:Cholinesterase Inhibitors / Q000506:poisoning; D003975:Diazepam / Q000627:therapeutic use; D004357:Drug Synergism; D008297:Male; D051379:Mice; D062025:Organophosphate Poisoning; D010091:Oximes / Q000627:therapeutic use / Q000633:toxicity; D051381:Rats; D012999:Soman / Q000506:poisoning*; D013329:Structure-Activity Relationship
D000931:Antidotes; D002800:Cholinesterase Inhibitors; D010091:Oximes; D001285:Atropine; D012999:Soman; D003975:Diazepam