Jiri Bajgar 1
1 Department of Toxicology, Faculty of Military Health Sciences, University of Defense, Trebesska 1575, Hradec Kralove, Czech Republic
Abstract
Basic mechanism of action of organophosphates (OP)/nerve agents is based on acetylcholinesterase (AChE) inhibition and subsequent accumulation of neuromediator acetylcholine at the cholinergic synapses, either peripheral or central, causing cholinergic hyperstimulation and development of symptoms of poisoning, followed by metabolic dysbalance and, without eff ective prophylaxis/treatment leading to death. The treatment of nerve agents poisoning consists of administration of parasympatholytics (preferably atropine), cholinesterase reactivators (oximes) and anticonvulsants (usually diazepam). Th e choice of reactivators is not so simple. Th eir administration alone is not eff ective but simultaneous administration with atropine potentiates their antidotal eff ects based on AChE reactivation at the cholinergic nerve synapses. AChE reactivation at the peripheral nervous system is indisputable; however, their passing the blood-brain-barrier facilitating their central eff ect is discussed. On the basis of our own and literature data, central reactivation effi cacy of some oximes in vivo is demonstrated. Though the research is very intensive, unfortunately, up to now, there is not universal reactivator suffi ciently eff ective against all nerve agents/OP. A possible direction solving this problem is discussed – it is the use of combination of more reactivators. Th e good raectivating and therapeutic eff ect of combination of trimedoxime and HI-6 against tabun poisoning in rats is demonstrated. Prophylaxis against nerve agent intoxication is based on various approaches: Keeping AChE, key enzyme for toxic action of OP/nerve agents intact (protection of cholinesterases) is a basic requirement for eff ective prophylaxis. Detoxifi cation realised by administration of the enzymes splitting the OP or evaluating specifi c enzymes (cholinesterases) is another possibility (stoichiometric and catalytic scavengers). Th e antidotes currently used for the treatment of OP poisoning including reactivators are to be tested as prophylactics. Th is principle can be considered as a „treatment in advance”. Th e problem with use of reactivators is the timing, duration and achievement of suffi cient levels of these antidotes after the administration. Transdermal administration of reactivators solves these diffi culties. As a result of this research, prophylactic antidote TRANSANT (transdermal patch containing HI-6) was developed as the prophylactic mean and introduced into the Czech Armed Forces. Future development will be focused on scavengers (cholinesterases and other enzymes) acting before the binding of nerve agent to the target sites, and to other drugs either reversible cholinesterase inhibitors (e.g. huperzine A, physostigmine, acridine derivatives etc.) or other compounds. However, it will be necessary to study basic neuropharmacologic problems in general, i.e. • binding of diff erent ligands to cholinesterases for elucidation of cholinergic nerve transmission, • prevention of neuronal cells death due to seizures, • treatment of non-specifi c eff ects, • the choice of reactivators/their combinations and parasympatholytics including their timing, • evaluation of more informations dealing with long term eff ect of low doses, • the gene expression profi le after intoxication and its prophylaxis/treatment, • new drugs including combination of scavengers with classic prophylactics/antidotes.