EXPOSURE TO PYRIDOSTIGMINE BROMIDE
During the Gulf War of 1990-91 the United States Military conducted the largest experimental drug evaluation in its history. The compound Pyridostigmine Bromide (PB) was considered by the Pentagon as a possible prophylactic for a soldier's exposure to chemical warfare (CW) nerve agents. The Iraqi army's use of nerve agents during the 10 year war with Iran gave Pentagon planners reasonable cause to believe U.S. forces would be exposed to CW agents if war arose with Iraq.
The use of an experimental CW nerve agent prophylactic was and is controversial, but it's use in addition to the extensively tested gas mask and chemical protective over garment ensemble is unprecedented. With no particular definable deficit in the existing CW protection, the rational for conducting this large-scale experimental drug test on military personnel, without informed consent, is highly questionable.
Soldiers in the Gulf War theater of operations (South West Asia) were required to take PB on a constant schedule, several times a day, and the administration of the drug was closely supervised by the chain of command to insure all soldiers ingested it. Soldiers consumed PB upon arrival in theater, during the Desert Shield force buildup, and during the combat phase of Operation Desert Storm.
GENERAL NEUROLOGICAL EFFECTS
PB interacts with specific neurological sites and processes1 in nerve tissues that chemically communicates impulses from one part of the body to another. Nerve tissues have one-way synapse gaps made of neuron cells. Neuron cells have axons, which transmit chemicals and dendrites, which receive chemicals. The neuron cells temporarily chemically bridge the synapse gap when stimulated by a neurological impulse, allowing the nerve impulse to travel through the synapse gap.
The actual synapse gap is bridged by the neuro-chemical transmitter Acetylcholine2, which is released from the neuron cell axon and bridges the gap to the opposing neuron cell or muscle cell dendrite. The Acetylcholine bridging the gap is then neutralized by the dendrite's release of the enzyme Acetyl cholinesterase. Neutralizing the Acetylcholine opens the synapse gap and thus controls the flow of nerve impulse communication throughout the body.
PB is an anticholinesterase drug that inactivates the cholinesterase enzyme. Without this neutralizing enzyme the synapse gap-bridging Acetylcholine accumulates in the nerve tissue in substantial quantity, creating neurological complications. The neurological complications of building Acetylcholine levels has observable symptoms3 ranging from mild to severe:MILD SYMPTOMS
PB can be grouped with other anticholinesterase chemical compounds that also cause this range of symptoms. Those compounds most notably include organophosphorus insecticides4 such as Parathion, Malathion, Tetraethyl Pyrophosphate, among many. The most potent anticholinestrase chemical compounds are the CW nerve agents, such as GB/Saren5, GD/Soman6, GA/Tabun7, and the more modern VX8.
PB had only been approved prior to the Gulf War for treatment of Myasthenia Gravis9, a rare neurological disease. The disease is thought to be caused from a defect in the neuromuscular junction that reduces or stops the Acetylcholine simulation of muscle cell dendrites. The disease is characterized by:
Treatment of Myasthenia Gravis using PB temporarily inhibits the neutralization of Acetylcholine allowing higher accumulations of the neuro-transmitter and an increased function in neuromuscular activity. In treating Myasthenia Gravis with PB there are minor and major side effects. Minor side effects include abdominal cramps, diarrhea, and an increase in Myasthenia Gravis symptoms. The major side effect using PB is the generation of muscular weakness that itself cannot be clinically differentiated from the disease.
NEUROLOGICAL EFFECTS ON THE BRAIN
The probable intention for selecting PB as a nerve agent prophylactic was to saturate the body's neuron and muscle cell synapse dendrites with an Anticholinesterase molecule similar to CW nerve agents, but thought to be less volatile and possibly reversible in effect. This prophylactic tactic was also considered early in the Cold War for protecting the thyroid gland from radioactive iodine by the ingestion of potassium iodine to saturate the gland and block the uptake of the radioactive element. The reversibility consideration of the PB Anticholinestrase effect is probably based on observations in the treatment of Myasthenia Gravis. A reversible effect10 is considered to last minutes to hours, an irreversible effect lasts days to weeks. Unfortunately there was no large-scale clinical study on the effects of a continuous large dose of PB administered to a healthy population, and the long-term effects.
It was believed that the Anticholinestrase effects of PB would not affect the body's most important neurological system, the brain. Under normal conditions the capillary endothelium and astrocytic sheath, the blood-brain barrier, blocks and restricts the flow of certain chemical compounds and disease organisms from entering the brain tissue11. However during periods of stress the barrier passes PB into the brain tissue allowing the Anticholinestrase effect on the most important neuron synapse gaps. Clearly this interference with the normal function of brain neurons may explain the variety of mental impairments seen in gulf war veterans, such as:
This proven permeability of the brain12 to PB may also be a one-way permeability. With the elimination of daily dosages and the physiological stress necessary for PB brain absorption, the effects of Anticholinestrase effecting neurological interference are still seen long after initial exposure. The PB molecules may be trapped within the brain by the blood-brain barrier, or more vigorously attached to the neurons then ever anticipated. The brain's natural processes of chemical metabolism may be insufficient or ineffective against PB inside the brain.
An additional consideration for the tenacity of PB within brain tissue, and neurological tissue in general, is the mixing and possible chemical bonding with additional Anticholinestrase compounds from environmental exposure. During the Gulf War the population exposed to PB have been proven to be exposed to unknown levels of Anticholinestrase pesticides and CW nerve agents. The possible bonding of these molecules at the neuron dendrites may have an enhanced resistance to the natural processes of chemical metabolism.
PB TOXICITY AND TREATMENT
PB is also a bromide compound, which manifests additional symptoms of toxicity13 separate from the neurological symptoms of excess accumulation of Acetylcholine. Bromide compounds are water-soluble salts found in several proprietary prescription drugs used for inducing sleep or in the treatment of Epilepsy. The bromides act to displace chlorides from the blood plasma and from cells, depressing the central nervous system. The symptoms of bromide poisoning range from chronic to acute, the principal manifested symptom is mental confusion, but pathological symptoms may include pneumonia and pulmonary edema. The range of symptoms are:CHRONIC POISONING
The toxicity of bromides including PB can be treated14 with an antidote of sodium chloride (salt). Conventional detoxification for bromide compounds are based on blood serum toxicity levels above 150mg./100ml. Therapy consists of 1 gram (15 grains) of sodium chloride orally every hour in water or tablet, until blood serum levels drop to 50mg./100ml. The prognosis for conventional bromide toxicity is complete recovery in 1 to 6 months.
The principal difference of PB from conventional bromides are the compound's Anticholinestrase effect and location in the synapse dendrites. Because of the molecules design structure normal levels of sodium chloride in the blood serum may be insufficient to remove PB from its synapse location. The previously mentioned possibility of chemical bonding with additional Anticholinestrase compounds may further retard PB metabolism from nerve tissue by normal sodium chloride levels.
Therapy for PB exposure may be as simple as elevating the blood serum levels of sodium chloride to 2 to 3 times normal for an extended period of time, and combined with water and diuretics. If the elevated sodium levels lead to the excretion of PB in the exposed population, a reduction of symptoms could result. Also in light of the possibility of PB compounding with CW nerve agent Anticholinestrase molecules, excretion of this compounded PB would be the first treatment for reversing the effects of exposure to the Anticholinestrase CW nerve agents.
THE EXPOSED POPULATION
Since the end of the gulf war in the early 90's veterans exposed to the war's chemical environment have manifested many of the symptoms discussed here. Their symptoms are often persistent and sometimes profound, but all deserve consideration of their chemical exposure and subsequent treatment. And if the treatment may be as simple as outlined, it should be undertaken with as much zeal as was the decision to experimentally expose this population.
1. Berkow, Robert, M.D. (ed.), 1982, The Merck Manual of Diagnosis and Therapy, 14th edition, Merck Sharp & Dohme Research Labratories, Rahway, New Jersey, pg. 2353.
2. Ibid., pg. 2345.
3. Dreisbach, Robert H., M.D., Ph.D., 1971, Handbook of Poisoning: Diagnosis & Treatment, 7th edition. Lange Medical Publications, Palo Alto, California, pg. 107.
4. Ibid., pg. 103.
5. Windholz, Martha, (ed.), 1976, The Merck Index - An Encyclopedia of Chemicals and Drugs, 9th edition. Merck & Co. Inc., Rahway, New Jersey, pg. 1084.
6. Ibid., pg. 1125.
7. Ibid., pg. 1170.
8. U.S. Department of the Army, 1977, NBC (Nuclear, Biological, and Chemical) Defense. Field Manual FM-21-40 (14 October). Headquarters, Department of the Army, Washington, D.C., chapter 1 pgs. 15-17.
9. Berkow, The Merck Manual, pg. 1395.
10. Ibid., pg. 2353.
11. Ibid., pg. 2259.
12. Friedman et al. (Friedman, A., Kaufer-Nachum, D., Shemer, J., Heindler, I., Soreq, H., and Tur-Kaspa, I.) 1996. Pyridostigmine brain penitration under stress enhances neuronal excitability and induces early immediate transcriptional response. Nature Medicine 2:1382-1385.
13. Dreisbach, Handbook of Poisoning, pg. 20.
14. Ibid., pg. 291.