Pharmacological effects of oximes: how relevant are they?
The increased international concern about the threat of military and terroristic use of nerve agents, prompted us to critically consider the expected value of the currently available oxime treatment of nerve agent poisoning. Although oximes have been designed to reactivate the inhibited acetylcholinesterase (AChE), clinical experience has indicated that they are not always very effective as reactivators and at this very moment none of them can be regarded as a broad-spectrum antidote. In spite of this drawback, oximes are worth further investigating, since recent data derived from soman or tabun lethally intoxicated non-human primates suggest that the oxime HI-6 may exert a pharmacological effect that is not related to reactivation of inhibited AChE, but still leads to survival. This pharmacological effect causes recovery of neuronal transmission in the respiratory centres of the brain and recovery of neuromuscular transmission in the diaphragm. These findings have stimulated research to reveal the pharmacological basis of these effects in order to find drugs which could be more effective and less toxic than the available oximes. Since cholinergic drugs were able to exert this effect, a new concept for further treatment is suggested: maintenance of neuronal transmission in spite of continued AChE-inhibition by pharmacological manipulation of the cholinergic receptor. This should renew interest in the diverse pharmacological effects of oximes to reach a more effective treatment in the future.
Department of Pharmacology, TNO Prins Maurits Laboratory, Rijswijk, The Netherlands.
H P
HP
van Helden
R W
RW
Busker
B P
BP
Melchers
P L
PL
Bruijnzeel
D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D002619:Chemical Warfare Agents / Q000506:poisoning*; D002800:Cholinesterase Inhibitors / Q000506:poisoning; D002801:Cholinesterase Reactivators / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D062025:Organophosphate Poisoning; D010755:Organophosphates; D010091:Oximes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011041:Poisoning / Q000188:drug therapy* / Q000401:mortality; D011726:Pyridinium Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011950:Receptors, Cholinergic / Q000187:drug effects; D012119:Respiration / Q000187:drug effects; D012999:Soman / Q000506:poisoning; D009435:Synaptic Transmission / Q000187:drug effects*
D000931:Antidotes; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010755:Organophosphates; D010091:Oximes; D011726:Pyridinium Compounds; D011950:Receptors, Cholinergic; D012999:Soman; C022870:asoxime chloride; C009374:tabun