Pharmacological effects of oximes: how relevant are they?

Abstract

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.

Adenosine A1Receptor AgonistN6-Cyclopentyladenosine Affects the Inactivation of Acetylcholinesterase in Blood and Brain by Sarin

“…This cholinergic hyperactivity rapidly evolves into a more generalized neuroexcitability, which triggers seizure activity in susceptible brain areas (Kadar et al, 1995;Shih and McDonough, 1997;Van Helden and Bueters, 1999). Novel treatment strategies are currently under development, because the current therapy (atropine, oxime, and diazepam) seemed inadequate with respect to the suppression of the seizure activity and subsequent brain pathology in primates (Hayward et al, 1990;Van Helden et al, 1996;Shih and McDonough, 1997;Lallement et al, 1998). In this respect, a possible role for the adenosine A 1 receptor-mediated inhibition of ACh release in the brain was explored recently (Van Helden et al, 1998;Van Helden and Bueters, 1999;Bueters et al, 2002).…”

A comparison of the reactivating efficacy of a novel bispyridinium oxime K203 with currently available oximes in VX agent-poisoned rats

“…The relatively high therapeutic potency of the oxime HI-6 may be due to various antidotal mechanisms based on reactivation of phosphonylated AChE, direct antimuscarinic and ganglion blocking actions, restoration of neuromuscular transmission, retardation of the formation of the aged inhibitor-enzyme complex and inhibition of acetylcholine release 22 . Thus, only the oxime HI-6 appears to be able to sufficiently protect experimental animals from VX-induced adverse effects and improve survival of VX-poisoned animals due to the highest ability to reactivate VX-inhibited AChE in the blood, diaphragm and brain 3,4,20 .…”

Comparison of Reactivating and Therapeutic Efficacy of Two Salts of the Oxime HI‐6 against Tabun, Soman and Cyclosarin in Rats

“…Nevertheless, HI-6-induced recovery of the brain AChE activity is not sufficient to eliminate overstimulation of the cholinergic nervous system (especially in the case of soman poisoning) because both salts of HI-6 have limited access to the brain [4]. The high therapeutic potency of the oxime HI-6 may be also due to other antidotal mechanisms based on direct antimuscarinic and ganglionblocking actions, restoration of neuromuscular transmission, retardation of the formation of the aged inhibitor-enzyme complex and inhibition of acetylcholine release besides its reactivating potency [6,20]. On the other hand, the oxime HI-6 seems to be weak reactivator of tabun-inhibited AChE in comparison with other currently available oximes (obidoxime, trimedoxime) as it was demonstrated by the methods in vitro [21] and in vivo [19,22].…”