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Nervous System

Potential Medical Coutermeasures

Alternative oximes, such as trimedoxime (TMB4), Toxogonin, and HI-6 (an H-series oxime), are available in other countries for the treatment of nerve agent-induced injuries. Some of these have been or are in the process of being evaluated for use by the U.S. military, but none have been evaluated for possible use in U.S. civilian populations. Several promising new oxime candidates also have been identified and will require further investigation.

Proteins such as the enzyme butyrlcholinesterase (BChE), which have a similar structure to AChE, represent another potential therapeutic approach. They can act as “bioscavengers,” sequestering nerve agent molecules in the bloodstream. Plasma-derived human BChE shows some promise as a prophylactic countermeasure for military personnel, but it remains uncertain whether this product can be administered efficiently in a large enough volume to be fully effective. Several studies are underway and more are needed to determine if this, and similar bioscavenger-like proteins, could be effective treatments for civilians after exposure to a nerve agent has already occurred. Alternative forms of BChE have been produced through genetic engineering. They appear to be effective as pretreatments in animal models, and it may be possible to develop these enzymes as treatments for the civilian population or pretreatments for first responders.

Several promising anticonvulsant drugs for the treatment of nerve agent poisoning are on the horizon. New anticonvulsant drugs that have been or are being developed for the treatment of epilepsy in pediatric and adult populations may also be useful for treating chemically induced injuries. Alternative or more expeditious delivery routes for anticonvulsant drugs already approved to treat seizures may also be desirable in the event of mass casualties.

The benzodiazepine midazolam, currently Food and Drug Administration (FDA)-approved as an intravenous sedative and anesthetic, may also be very effective in the treatment of seizures. Midazolam is being investigated to replace diazepam as the immediate anticonvulsant treatment for nerve agent-induced seizures. The potential use of midazolam, administered intramuscularly, to treat nerve agent-induced seizures will require clinical trials to test its effectiveness and gain FDA approval. Different benzodiazepines and other classes of drugs that antagonize various neuronal excitation pathways mediated by the neurotransmitter glutamate and neurosteroids, are also candidates to treat chemically induced seizures. The development of these potential therapies will also require preclinical and clinical studies.

Other promising research strategies may lead to treatments for chemically induced, long-term damage to the nervous system, or neurodegeneration. Recent studies have shown that the immunosuppressant drug cyclosporine dramatically reduced organophosphate-induced seizures and brain damage, and preserved memory and learning ability in rodents. Clinical trials are planned or underway with several drugs that appear to slow or stop the process of neurodegeneration due to stroke, traumatic brain injury, and chronic nervous system diseases. Some of these drugs may be candidates to prevent chemically induced neurodegeneration.

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Last Updated February 29, 2008