Oximes: Reactivators of phosphorylated acetylcholinesterase and antidotes in therapy against tabun poisoning.
One of the therapeutic approaches to organophosphate poisoning is to reactivate AChE with site-directed nucleophiles such as oximes. However, pyridinium oximes 2-PAM, HI-6, TMB-4 and obidoxime, found as the most effective reactivators, have limiting reactivating potency in tabun poisoning. We tested oximes varying in the type of ring (pyridinium and/or imidazolium), the length and type of the linker between rings, and in the position of the oxime group on the ring to find more effective oximes to reactivate tabun-inhibited human erythrocyte AChE. Three of our tested pyridinium oximes K027, K048, K074, along with TMB-4, were the most promising for AChE reactivation. Promising oximes were further tested in vivo on tabun poisoned mice not only as antidotes in combination with atropine but also as pretreatment drug. Herein, we showed that a promising treatment in tabun poisoning by selected oximes and atropine could be improved if oximes are also used in pretreatment. Since the reactivating efficacy of the oximes in vitro corresponded to their therapeutic efficacy in vivo, it seems that pharmacological effect of these oximes is indeed primarily related to the reactivation of tabun-phosphorylated AChE.
Kovarik
Zrinka
Z
Institute for Medical Research and Occupational Health, Ksaverska c. 2, Zagreb, Croatia. zrinka.kovarik@imi.hr
Calić
Maja
M
Sinko
Goran
G
Bosak
Anita
A
Berend
Suzana
S
Vrdoljak
Ana Lucić
AL
Radić
Bozica
B
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D000931:Antidotes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002800:Cholinesterase Inhibitors / Q000506:poisoning*; D004793:Enzyme Reactivators / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D062025:Organophosphate Poisoning; D010755:Organophosphates; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation; D011041:Poisoning / Q000188:drug therapy
D000931:Antidotes; D002800:Cholinesterase Inhibitors; D004793:Enzyme Reactivators; D010755:Organophosphates; D010091:Oximes; D000110:Acetylcholinesterase; C009374:tabun