Existing medical countermeasures target the molecular interactions between nerve agents and proteins involved in neural signaling. Neurons can communicate with each other or stimulate muscle cells by releasing a chemical called acetylcholine. Nerve agents and organophosphate pesticides bind and inhibit a protein called acetylcholinesterase (AChE), which normally breaks down acetylcholine after a stimulated neuron has released it. The acute symptoms of nerve agent and organophosphate exposure are due to excess acetylcholine that persists after its release and continues to stimulate nerve endings in the brain, muscles, and secretory glands. Although this route of nerve excitation is considered to be the major focus for drug intervention, other neurotransmission pathways in the body that can be affected by toxic chemicals may need to be assessed separately for the development of potential interventions.
The U.S. military adopted pyridostigmine bromide (PB), an FDA-approved treatment for myasthenia gravis (an autoimmune disease characterized by extreme muscle weakness), for the pretreatment of soman (a nerve gas) poisoning. PB competes with the nerve agent by reversibly attaching to AChE prior to nerve agent exposure, thus avoiding the toxic effects of excessive acetylcholine stimulation. PB has limited usefulness after exposure to a nerve agent and is approved for use in military populations against only one of several nerve agents that could be used in an attack.
The standard treatment for nerve agent and organophosphate poisoning includes a 2-PAM, and benzodiazepine anticonvulsants, such as diazepam. Atropine blocks acetylcholine receptors in certain tissues, drying secretions and reducing smooth muscle contraction. Oximes free AChE from the chemical nerve agent and have their most marked effect on skeletal muscle strength. The only oxime approved for use in the United States against nerve agents is pralidoxime chloride (2-PAM). This oxime is also indicated as an antidote for organophosphate insecticide poisoning and to control overdosage of anticholinesterase drugs in the treatment of myasthenia gravis. The Strategic National Stockpile CHEMPACKs, which have been distributed around the United States for deployment in case of a chemical attack or accident, contain military “Mark I” adult autoinjectors with atropine and 2-PAM, diazepam autoinjectors, pediatric atropine autoinjectors, and multi-use vials of 2-PAM and diazepam.
These current treatments for nerve agent or organophosphate exposure have significant disadvantages. Multiple doses of atropine and 2-PAM may be necessary in order to be effective. Atropine does not relieve nerve agent effects on skeletal muscles. Oximes are ineffective once the AChE-nerve agent complex has undergone “aging,” a chemical change that permanently inactivates AChE. Aging can happen within minutes of exposure to some of the nerve agents, such as soman. Although diazepam is an effective treatment for nerve agent-induced seizures during about the first 40 minutes after exposure, it is less useful later. Benzodiazepine anticonvulsants also carry risks of excessive sedation and respiratory depression. No treatments are currently available to prevent or reduce neurodegeneration resulting from prolonged seizures, anoxia, or the direct effects of chemical agents.
Diagnosis following an acute exposure to a nerve agent is generally based on clinical observations of specific symptoms. Environmental sensors may provide valuable information on probable chemical exposure. One of the greatest challenges in diagnosis is determining whether an individual exposed to a nerve agent is experiencing chemically induced seizure activity in the absence of visible convulsions, since the chemicals that trigger seizures may also cause unconsciousness or paralysis. Sustained seizure activity that is uncontrolled can result in permanent brain injury and death. The standard test for seizure activity involves placing electrodes on the scalp to record electrical activity in the brain using electroencephalography (EEG). Such devices are not portable and have limited practical value in evaluating patients in a mass casualty situation.
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Last Updated February 29, 2008