Many veterans, on returning from service in the Gulf War subsequently complained of a variety of symptoms which were more or less debilitating. These symptoms came to be known by several terms, the most prevalent being "Gulf War Syndrome" (GWS). In an attempt to determine the cause of GWS, or if indeed such a disease actually existed, a wide variety of retrospective studies on Gulf War veterans were carried out. The data generated as a result of these studies were examined by several different panels of experts, e.g., a panel appointed by the USŐs NIH and "The Presidential Advisory Committee on Gulf Veterans' Illnesses." These panels, as well as similar panels in other countries, were given the task of gathering and interpreting evidence to determine if a GWS actually existed, and if so, which were the likely causative factors.
The panels examined etiological factors that might be considered to contribute to long term illnesses of the type being reported. Factors unique to the Gulf veterans experience included immunizations given to the troops against the ever present threat of biological warfare, smoke from oil well fires, diesel exhaust fumes, sand flies, depleted uranium, pesticides, exposure to chemical and biological weapons, and the topic of this short review, pyridostigmine, a drug given to most Gulf soldiers as a pretreatment against possible exposure to the nerve agents known to be weaponized by Iraq.
Acetylcholinesterase (AChE) is an enzyme that metabolizes acetylcholine; the neurotransmitter whose uncontrolled accumulation is responsible for the toxic symptoms resulting from exposure to nerve agents. Nerve agents produce their effects through irreversible cholinesterase inhibition and elevation of acetylcholine levels. Pyridostigmine is a carbamate, one of a group of acetylcholinesterase inhibitors differing from the nerve agents because the inhibition is reversible; the enzyme is inhibited for a short period of time. The protective properties of pyridostigmine appear to be due to its ability to shield the active site of the enzyme from attack and subsequent irreversible inhibition by the nerve agents. The unreacted nerve agents may then be distributed and irreversibly bound at non-specific sites within the body, where they are not lethal. Pyridostigmine is a quaternary compound, which does not normally gain access to the brain, and therefore, until recently, it has been believed to have no CNS effects. The dose of pyridostigmine selected for protection of humans from nerve agents was determined from animal experiments. It is known that inhibiting or shielding about 30% of the total peripheral enzyme leads to no significant side effects in normal humans, but leads to significant increases in protection from the nerve agents. Since pyridostigmine is a short acting enzyme inhibitor, it quickly "falls off" the enzyme (AChE), which on regaining activity hydrolyzes the acetylcholine. Pyridostigmine, if given with a cholinolytic such as atropine and an oxime type of cholinesterase reactivator such as HI-6, produces much higher protection than atropine and oxime treatment alone. Pyridostigmine is therefore a very important integral part of our ability to ensure the best protection available from nerve agent induced lethality.
The panels of experts originally examined the possibility that pyridostigmine could be responsible for some of the long term GWS symptoms. The fact that pyridostigmine is an approved drug and appears in the formularies of most western countries, indicates that it has undergone considerable safety testing. Furthermore, pyridostigmine is used in several medical conditions, the most prevalent being myasthenia gravis (MG), in doses of 10-50 times higher than those taken by soldiers who fought in the Gulf War [The Persian Gulf Experience and Health 1994]. In addition to these high doses, myasthenic patients take pyridostigmine for life, whereas soldiers took this compound for a few weeks at most. The NIH panel concluded that pyridostigmine was essentially a safe drug. The presidential advisory committee concluded that whatever side effects might be due to pyridostigmine, they "disappear when individuals stop taking pyridostigmine bromide." Furthermore, they concluded that the health effects reported as GWS were unlikely to be due to pyridostigmine.
Certain recent studies have indicated that under given conditions, such as concurrent exposure to stress, pyridostigmine might gain access to the brain. These studies implicate a possible new role for pyridostigmine in the etiology of the veterans' complaints. They also may lead at least to the perception that pyridostigmine might become more toxic under stressful conditions, such as found on the battlefield. These perceptions could raise questions concerning the suitability of pyridostigmine for future military use. We would like to critically examine the available data concerning centrally mediated side effects of pyridostigmine, to ensure that decisions concerning the future use of pyridostigmine, are based on all of the information that is available to the medical and military communities.
Interest in the CNS effects of pyridostigmine are due in part to a recent study suggesting that in mice, stress activated mechanisms are responsible for increased access of what are normally impermeant molecules, such as pyridostigmine, into the central nervous system [Friedman et al 1996]. FriedmanŐs results showed that when pyridostigmine was given to stressed mice, more pyridostigmine breached the blood brain barrier than occurred in unstressed mice. This is an interesting finding of considerable potential importance, especially if it can be shown that similar mechanisms operate with all other quaternary compounds. From these data however, the authors, as well as the author of an accompanying commentary on the paper [Hanin 1996], suggest that a stress induced mechanism might be the explanation for the high incidence of CNS effects found in a group of Israeli soldiers who took pyridostigmine as a nerve agent pretreatment, during the Gulf War [Sharabi et al 1991]. Studies of this group of soldiers revealed that they had a considerably higher incidence of cental effects when compared to a similar group who took pyridostigmine, but who were not under these stresses. The increases in CNS effects were attributed to the interaction of stress with pyridostigmine and the results have been discussed under this assumption [Sharabi et al 1991, Friedman et al 1996, Hanin et al 1996]. However, there are several reasons to doubt such a relationship. In the Sharabi study, as the authors point out, no appropriate control group was included consisting of soldiers who were under stress, but who did not take pyridostigmine. Therefore the study did not account for the role of stress alone, in the production of the CNS effects. It is impossible to determine if the increased CNS effects reported in the soldiers taking pyridostigmine (fear, insomnia, headaches, etc.) were the result of pyridostigmine in addition to stress or, as was pointed out by Sharabi, were due to the state of anxiety often accompanying war situations. In such case, stress related CNS effects among soldiers fearing chemical/biological attack surely would be expected
There is a large body of evidence suggesting that pyridostigmine administered to Gulf War soldiers failed to result in any appreciable increase in CNS side effects, whether stress was or was not involved. In a very large retrospective study, which included 284,000 man days (over 41,000 soldiers) of pyridostigmine treatment, pyridostigmine was shown to induce an acceptable increase in the incidence of gastrointestinal side effects, but no increase in CNS effects [Keeler et al 1991]. This survey, as pointed out by Keeler, was carried out as a "worst case estimate," since the symptoms that were examined could well have been due to stress (see above) rather than due to pyridostigmine. Notwithstanding these results, a recent publication [Abou-Donia et al 1996] documenting the combined toxicity of a number of substances to which soldiers had been exposed, claimed that their results "may explain--unexplained neurological complaints of some of the Persian Gulf War veterans [Keeler et al 1991]." However, no increases in CNS effects were demonstrated to occur in Keeler's study.
It should be pointed out, that several studies have been carried out in humans who were administered pyridostigmine, under a variety of stressful conditions. Pyridostigmine has been administered under conditions of hypoxic stress and stress related to rapid decompression [Kurtz et al 1987, Parker et al 1987], during real or simulated flight situations, [Izraeli et al 1990, Schiflett et al 1987], during operations at altitude [Schiflett et al 1987] and under conditions of both exercise and heat stress [Epstein et al 1990, Arad et al 1992]. Authors of these reports, although not always specifically examining CNS activity in their subjects, failed to report any unusual CNS effects. It is also interesting that MG patients, who routinely take many times the dose of pyridostigmine that was used in soldiers, generally tolerate these large doses well. As far as we are aware, no clinical reports of increased CNS side effects during stress in these patients exist. On the other hand, no reports appear to have addressed the possibilities that stress and pyridostigmine may interact over longer periods of time, perhaps several days or even weeks of pyridostigmine treatment and prolonged stress.
The possible interaction of stress with pyridostigmine appears to require more carefully balanced study. It should be kept in mind that conclusions concerning the safety of pyridostigmine should be arrived at with care, due to the important role that it can play in preventing the extremely lethal effects of organophosphate nerve agents in humans. If soldiers are to be at risk of chemical attack, we must be assured that they are provided with the most efficient methods of protection available, while maintaining high safety levels.
Abou-Donia, M.B. Wilmarth, K.R., Abel-Rahman, A.A. Jensen, K.F. Oehme, F.W. and Kurt, K.F. (1996) Increased Neurotoxicity Following Concurrent Exposure to Pyridostigmine Bromide, DEET, and Chlorpyrifos. Fund. Appl. Toxicol. 34. 201.
Arad, M. Varssano, D. Moran, D. Arnon, R. Vazina, A. and Epstein, Y. (1992) Effects of Heat exercise Stress, NBC Clothing, and Pyridostigmine Treatment on Psychomotor and Subjective Measures of Performance. Mil. Med. 157, 210
Epstein, Y., Seidman, D.S. Moran, C. e t.al. (1990) Heat Exercise Performance of Pyridostigmine-Treated Subjects Wearing Chemical Protective Clothing. Aviat. Space Environ. Med. 61, 310
Friedman, A, Kaufer, D. Shemer, J. Hendler, I. Soreq,H. and Tur-Kaspa, I. (1996) Pyridostigmine Brain Penetration Under Stress Enhances Neuronal Excitability and Induces Early Immediate Transcriptional Response. Nature Med: 2 1382.
Hanin, I. (1996) The Gulf War, Stress And A Leaky Blood- Brain Barrier. Nature Med. 2: 1307.
Izraeli, S. Avgar, D. Almog, S. Shochat, I. Tochner, M.D. Tamir, A. Ribak, J. (1990) The Effect of Repeated Doses of 30 Mg Pyridostigmine Bromide on Pilot Performance in an A-4 Flight Simulator. Aviat. Space Environ. Med.61: 430.
Keeler, J.R. Hurst,C.G. and Dunn, M.A. (1991) Pyridostigmine Used as a Nerve Agent Pretreatment Under Wartime Conditions. JAMA 266, 693
Kurtz, jr. R.W. Burton, R.R. Schiflett, S. Holden, R. and Fischer, J. (1987) Interaction Of Pyridostigmine Bromide with Mild Hypoxia and Rapid Decompression. Proc. 6th. Med. Chem. Biosci. Rev. 601
Parker, F.R. Jr. Barber, J.A. Forster, E.M. and Whinnery, J.E. (1987) Chemical Warfare Prophylaxis: Pyridostigmine Bromide Levels and Acetylcholinesterase Activity in Single and Multiple Dose Protocols. Proc. 6th. Med. Chem. Biosci. Rev. 661
Schiflett, S.G. Miller, J.C. and Gawron, V.J. (1987) Pyridostigmine Bromide Effects On Performance Of Tactical Transport Aircrews. Proc. 6th. Med. Chem. Biosci. Rev. 609-611
Schiflett, S.G. Stranges, S.F. Slater, T. and Jackson, M.K. (1987) Interactive Effects of Pyridostigmine and Altitude on Performance. Proc. 6th. Med. Chem. Biosci. Rev. 605
Sharabi,Y. Danon, Y.L. Berkenstadt, H. Almog, S. Mimouni-Bloch, Dani,S. and Atsmon, J. (1991) Survey of Symptoms Following Intake of Pyridostigmine During The Persian Gulf War. Isr. J. Med. 27, 656
No Author, The Persian Gulf Experience and Health. National Institutes of Health Technology Assessment Workshop Statement 1994 Final Report Presidential Advisory Committee on Gulf War Veterans' Illnesses.
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