News Release

Scientist says recent UNC research suggests better nerve agent treatment

Peer-Reviewed Publication

University of North Carolina at Chapel Hill

CHAPEL HILL - Research conducted at the University of North Carolina at Chapel Hill in rats suggests that a promising new treatment for nerve agent toxicity may exist, and scientists involved in the experiments say further work should reveal the most appropriate conditions and timing for its use.

Such efforts are important, they say, because of the war with Iraq and fears of possible chemical terrorism.

"Centrally active cholinesterase inhibitors, which block breakdown of the neurochemical acetylcholine are used therapeutically to treat Alzheimer's disease," said Dr. David Janowsky, professor and former chair of Psychiatry at the UNC School of Medicine. "Cholinesterase inhibitors in higher or more potent doses, such as VX, sarin and soman, have been developed for purposes of warfare as nerve agents."

Evidence indicates that such nerve agents are lethal, in part due to increasing acetylcholine in the brain, Janowsky said. Death from high-dose nerve agents occurs via seizures, as well as effects on the heart and lungs.

"The usual treatment for nerve agent toxicity is atropine plus a cholinesterase re-activator," he said. "In previous publications, we have shown in mice that the centrally acting anti-motion sickness agent scopolamine, which blocks the effects of acetylcholine in low doses, is markedly more effective than atropine, which does not affect the brain, in antagonizing the central effects of up to six times the lethal dose of physostigmine, the prototypic nerve agent and cholinesterase inhibitor.

Other studies have shown that low-dose physostigmine, given as pre-treatment, is effective against more powerful and tenacious nerve agents."

New experiments Janowsky and UNC colleague Dr. David Overstreet have conducted demonstrated that the popular anti-Alzheimer’s drug donezepil (Aricept) is effective in decreasing the actions of the irreversible nerve agent-like cholinesterase inhibitor DFP on rats’ body temperature, activity and bowel excretion. That had never been demonstrated before.

"Specifically, we have shown that over six hours, pre-treatment with scopolamine plus donezepil blocked the drop in temperature and the amount of diarrhea and reduced locomotor activity that DFP causes," he said.

"Although these changes in the mice were not the same as death, a consistent effect of low doses of cholinesterase inhibitors is hypothermia, hypoactivity and diarrhea, and high doses do cause death.

"Our results in rats suggest that prior blockage of central cholinesterase sites by a relatively low dose of a reversible, centrally acting cholinesterase inhibitor such as donezepil, which is currently used clinically, might have protective effects on the brain against nerve agents in humans," Janowsky said.

Overstreet and he presented their findings at a recent meeting of the Society for Neuroscience and plan to publish them in a scientific journal.

Because of concerns about terrorists one day using such deadly nerve agents as sarin, soman, tabun and VX, the two are urging the government and medical researchers to investigate potentially more effective treatments.

In the early 1980s, Janowsky performed his research on increases in acetylcholine (physostigmine) not because of concern about nerve gases but because of his interest in depression, which tiny amounts of the compound produce, he said.

"I wrote a new paper last year about it because no one seems to have picked up on the suggestion that scopolamine might work better than atropine does against nerve agents and because the threat of a nerve agent attack has intensified recently," Janowsky said. "It is definitely worth further investigation. Right now in emergency rooms they would use atropine, a drug that is unlikely to work well in many people following a serious high-dose nerve agent attack."

Scopolamine already is available in many emergency rooms for other reasons but has not been evaluated for use against nerve agents, he said. A report in the medical literature from the early 1970s described the case of a person accidentally poisoned by a nerve agent and treated successfully with scopolamine.

Donezepil, like scopolamine, also gets into the brain, which may make it more effective than similar drugs that do not affect the brain. For example, pyridostigmine, which does not enter the brain but is similar to donezepil, was extensively used as an antidote in the last Gulf War but has subsequently been found ineffective against the brain effects of nerve agents.

"We hope that these drugs will never need to be used as treatments in humans, but if a nerve agent attack comes against the military or civilians, as it did in the Japanese subway system in the early 1990s, we could have every opportunity to see if they work," Janowsky said. Nerve agents greatly increase the natural neurotransmitter acetylcholine in the body, he said.

Normally, acetylcholine causes a parasympathetic response. The heart slows, blood pressure drops, pupils constrict and the gastrointestinal tract becomes active. That neurotransmitter is the functional opposite of adrenalin, which generally revs up the body, causing a fight response. Massive amounts of acetylcholine accumulate after nerve agent exposure causing breathing to become labored or stop and the heart to stop, the physician said. Because of effects on the brain, seizures occur, and death can follow quickly.

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Note: Janowsky can be reached at (919) 966-0167 or david_janowsky@med.unc.edu
Contact: David Williamson, (919) 962-8596


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