Pharmacological prophylaxis against nerve agent poisoning: experimental studies and practical implications
Abstrakt
Prophylaxis against intoxication with organophosphate (OP) nerve agents is based on various approaches. Protection of acetylcholinesterase (AChE), the target enzyme for toxic action of OP nerve agents, is a basic requirement for effective prophylaxis.
This can be achieved by using reversible AChE inhibitors, preferably carbamates (CMs). AChE inhibited by CMs is resistant to the action of an OP nerve agent for a transient period.
After spontaneous recovery of the activity, normal AChE serves as a source of the active enzyme. Detoxification is carried out by the administration of enzymes hydrolyzing the OPs or evaluating specific enzymes (cholinesterases).
The OP nerve agent is bound to the exogenously administered enzyme, and thus the OP level in the organism is decreased (""scavenger"" effect). The administration of enzymes such as AChE and butyrylcholinesterase (BuChE) as scavengers seems to be very promising, as the enzyme acts at the very beginning of the toxic action, and without interaction with target tissues and without side effects.
The antidotes currently used for the treatment of OP poisoning can be tested as prophylactics. This principle can be considered as a treatment in advance.
Standard antidotes were studied in this respect; i.e., anticholinergics, enzyme reactivators, anticonvulsants, and others. The problem with their use is the timing, duration, and achievement of sufficient levels of these antidotes after administration.
At present, pyridostigmine seems to be a common prophylactic antidote, while PANPAL (tablets with pyridostigmine, trihexyphenidyle, and benactyzine) and TRANSANT (transdermal patch containing HI-6) are the prophylactics. Future drug development will be focused on scavengers (cholinesterases and other enzymes) acting prior to the binding of the 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.