Chemical aspects of pharmacological prophylaxis against nerve agent poisoning.
Prophylactic approaches against intoxication with organophosphates (OP)/nerve agents can be based on following principles: keeping acetylcholinesterase (AChE), the key enzyme for toxic action of OP/nerve agents, intact (protection of cholinesterases) is a basic requirement for effective prophylaxis. It can be reached using simple chemicals such as reversible inhibitors (preferably carbamates), which are able to inhibit AChE reversibly. AChE inhibited by carbamates is resistant to OP/nerve agent inhibition. After spontaneous recovery of the activity, normal AChE serves as a source of the active enzyme. Detoxification is realised by administration of the enzymes splitting the OP or exploitating specific enzymes (cholinesterases). OP/nerve agent is bound to the exogenously administered proteins (enzymes) and, thus, the agent level in the organism is decreased ("scavenger" effect). The antidotes currently used for the treatment of OP poisoning (also simple chemicals) can be tested as prophylactics. This principle can be considered as a treatment "in advance". The problem with their use is the timing, duration and achievement of sufficient levels of these antidotes after the administration. At present, PYRIDOSTIGMINE seems to be common prophylactic antidote; prophylactics PANPAL (tablets with pyridostigmine, trihexyphenidyle and benactyzine), TRANSANT (transdermal patch containing HI-6) are other means introduced into different armies as prophylactics. Future development will be focused on scavengers (cholinesterases and other enzymes) acting before the binding of nerve agent to the target sites, and on other drugs reversible cholinesterase inhibitors (e.g. huperzine A, physostigmine, acridine derivatives etc.) including non-traditional routes of administration.
Bajgar
Jiri
J
Department of Toxicology, Faculty of Military Health Sciences, University of Defense, Trebesska 1575, Hradec Kralove, Czech Republic. bajgar@pmfhk.cz
Fusek
Josef
J
Kassa
Jiri
J
Kuca
Kamil
K
Jun
Daniel
D
D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000737:chemistry / Q000506:poisoning*; D018680:Cholinergic Antagonists / Q000737:chemistry / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000506:poisoning*; D002801:Cholinesterase Reactivators / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D062025:Organophosphate Poisoning; D010755:Organophosphates / Q000737:chemistry; D011041:Poisoning / Q000517:prevention & control
D002619:Chemical Warfare Agents; D018680:Cholinergic Antagonists; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010755:Organophosphates; D000110:Acetylcholinesterase