Gulf War Veteran' Illnesses.

Toxic Exposures: Pyridostigmine Bromide Part 1.

                                                                                                by Louise Kosta
                                                                                                Chief writer, The Human Ecologist

We know that some troops who served in the Gulf War took the anti-nerve-gas drug pyridostigmine bromide. We don't know exactly how many may have taken the drug, or for how long. We *do* know that over half of the veterans who have participated in the Department of Defense Comprehensive Clinical Evaluation Program (CCEP) *report* that they took it. These veterans have chosen to participate in the CCEP either because they believe they already have a health condition related to Gulf War service, or because they have long-term concerns about health effects from the war.

When people with myasthenia gravis take PB, they get the most out of the acetylcholine they do have. PB temporarily blocks acetylcholinesterase activity by binding temporarily to it. This activity is called cholinesterase inhibition, and PB is called a cholinesterase inhibitor.

Like other drugs, it can have unpleasant side effects. Symptoms of adverse reactions to PB include slowed heartbeat, weakness, headache, sweating, rash, nausea, vomiting, diarrhea, muscle cramps, visual disturbances, increased bronchial secretions, and bronchospasm. _The Merck Manual of Diagnosis and Therapy_, a standard medical reference, notes:"Excessive ... dosage causes weakness that cannot be differentiated clinically from the myasthenia itself." The principal symptom of myasthenia gravis is muscle weakness, particularly post-exercise muscle fatigue.

Doctors familiar with PB and its effects knew prior to the Gulf War that some myasthenia patients are more likely than others to experience adverse reactions to PB. These people appear to have a genetic variable in their receptors for acetylcholine that narrows the difference between a dose of PB that is helpful and a dose that is harmful. No one knew whether or not healthy people also vary in their acetylcholine receptors. If they do, doses of PB that might be fine for some people might be harmful to others.

Although PB was known to be active in the nervous system, prior to the Gulf War researchers believed that its effects were limited. They thought that PB couldn't get into the central nervous system. They expected that any adverse effects from PB would be confined to the peripheral nervous system. And they thought that all of the effects of PB, both good and bad, were reversible.

In order to understand what follows, it's important to remember this: Pyridostigmine bromide (PB) is a cholinesterase inhibitor, and cholinesterase inhibitors are toxic to the nervous system. Some pesticides work by inhibiting cholinesterase. And so do some chemical warfare nerve agents.

The rationale for using PB in the Gulf 

At the time Desert Shield began, everyone knew that Iraq not only had chemical weapons, but also had actually used them. The Pentagon wanted to make sure US troops had all the protection possible against chemical weapons attack.. They wanted PB to be available for troops to use in the Gulf. Does it make sense to use a cholinesterase inhibitor to *protect* against cholinesterase inhibiting chemical weapons?

The rationale goes like this: Chemical weapon nerve agents irreversiblybind to cholinesterase and deactivate it. The result is that acetylcholine remains operative instead of being deactivated, and poisoning results. Some victims die, while others may be impaired for life.

PB *also* binds to cholinesterase. However, its effects wear off in a brief time. When PB is taken prior to exposure to nerve agents, it locks onto the sites in the body that nerve agents attack and crowds them out. PB also enhances the effectiveness of the drugs commonly given *after* exposure to nerve agents. The person who takes PB is thus more likely than someone who has not taken the drug to survive an exposure to nerve agent without lasting harm. In order to work against nerve agents, PB has to be taken at least eight hours prior to chemical weapons exposure and at eight hour intervals during exposure or threat of exposure. If it is taken afteran exposure it offers no protection from that exposure.

The Defense Department wanted to give the (presumably healthy) troops half the lowest dose of PB that myasthenia gravis suffers take. They claimed that the side-effects of PB at the dosage level they wanted to use in the Gulf would be minimal, transitory and primarily a nuisance. DOD did not anticipate lasting problems from PB use. They argued that the long history of use in treating myasthenia gravis was evidence of PB's safety. On the other hand, DOD anticipated many casualties and deaths from nerve agent attack on unprotected troops. As portrayed by DOD, giving PB to the troops looked as if it could help a lot, without hurting much.

So, at the request of the Department of Defense, the Food and Drug Administration granted a special status to PB to enable the military to give it to troops serving in the Gulf. This status is called IND: investigational new drug. PB wasn't a new drug, but DOD wanted to use it in a new way, and on a different group of people than had taken PB before. That was a new use, and a new population-and so, IND.

FDA routinely grants IND status to drugs when they are used on people who participate in clinical trials. The drug itself may not be new, but a clinical trial can test a new use for an existing drug approved for other uses. Sometimes clinical trial participants are healthy volunteers who take the drug for pay. Other times the participants are sick people willing to try a new drug that has not yet been approved for use against their disease.

FDA requires all those who run drug trials to inform all trial participants about the nature of the drug, the nature of the trial, and the risks they might have to take along with the drug. This is called informed consent.

FDA waived informed consent for the military's use of PB. So no one told the troops that PB was "investigational" the way they were taking it. No one told them that there was little evidence that healthy humans could take PB without lasting harm. The troops were told it would protect them from harm.

Why did FDA cooperate with the military about PB?

The Senate Committee hearing report contained copies of documents that reveal how the FDA decided that it was a good idea to cooperate with the Pentagon's pyridostigmine requests.

NOTE: Much of what follows is drawn from the Committee proceedings, supplemented with other materials contemporary with the DOD request to use PB in the Gulf. You'll keep reading that, "there was no evidence" that FDA and DOD discussed certain matters. This doesn't mean that they *didn't* discuss those matters. It means that the discussions, if any, didn't leave tracks in sources used to compile this article.

A source at FDA said that a lot of what went on back then happened in meetings, and no records were kept. At one point, the source said that they didn't *want*records of some of the meetings. This probably sounds worse than it was: Most of the missing material, if it existed, would exculpate FDA, DOD or both regarding the questions raised. Here's what seems to have happened.

DOD sounds the alarm 

The Pentagon initially approached FDA about PB during Desert Shield, well before the ground war in Kuwait began. At that time, DOD told FDA that NATO issued PB to its troops for protection against nerve agents.

The sources consulted for this article did not indicate that FDA ever inquired whether NATO troops had ever actually usedPB in combat, and if they had, what the result had been. Without information about use in combat, FDA had little reason to suppose NATO-approved use proved that PB would be both safe for troops and effective in battlefield conditions.

There *is* evidence that at the time, both the military and FDA could have known- and should have known- that PB would have limited usefulness against nerve agent weapons. PB is used against nerve agents as a "pretreatment." By itself, PB doesn't offer effective protection, but it *does*enhance the effectiveness of other treatments used for nerve agent exposure. These include drugs in the regular issue nerve agent antidote kit carried by troops in the Gulf. The kit contains the drugs atropine and pralidoxime chloride or 2-PAM. A DOD memorandum contained in the Senate hearing proceedings clearly states: "Pyridostigmine used alone does nothing for a person poisoned by a nerve agent."

The effectiveness of PB against nerve agents depends on several factors. First, the troops would have to have the drug, and they would have to take it properly. The military and the FDA focused on this aspect. But FDA seemed to forget that the drug would not be effective unless the troops also had (and used) the nerve agent antidote kit. Did the military have enough of the regular kits?

There was no evidence that FDA asked this question. *After* the war, in 1993, the General Accounting Office reported to Congress about medical matters and the Gulf War. They found that throughout the Gulf troop buildup, military medical suppliers had the most difficulty meeting demand for the nerve agent antidote kit, and atropine injectors (part of the kit), as well as PB itself. This indicates that when DOD and FDA were discussing use of PB in the Gulf, the military could have known (and certainly should have known) that the nerve agent antidote kit and its contents were in short supply. This should have entered into discussions of approving PB for use in the Gulf.

In addition to being used properly, PB also has to be used against the *right* nerve agent. At the time FDA was considering the Pentagon's proposal about PB, there was clear evidence that PB was not equally effective against all nerve agents. Forty years ago, a drug similar to PB, physostigmine, enhanced the activity of atropine in test animals exposed to the nerve agent sarin. (This is the agent that Iraq apparently stored at Khamisiyah, and that was released when the munitions dump there was demolished after the war.)

Physostigmine turned out to be impractical for field use by the military. In the 1970's, pyridostigmine (PB) was found to be effective without the drawbacks of the earlier drug. However, PB was found to be most effective, not against sarin, but against the nerve agent soman. Tests showed that PB was no more effective against sarin than atropine alone. The contents of the military nerve agent antidote kit (atropine and 2-PAM) were effective against sarin (at least in test animals). Researchers knew this in the 1960's.
Therefore, PB's usefulness in Gulf depended not on troop exposure to nerve agents generally, but on troop exposure to soman in particular. There was no evidence in the material examined for this article that FDA had asked how likely soman exposure would be in the event of war against Iraq. There was no indication of an assurance from the DOD that according to their intelligence reports, soman exposure was likely to occur.

What did FDA and DOD know about the safety of PB? 

In deciding whether or not to approve PB for use in the Gulf, FDA had to consider a variety of issues. One of them was safety. At the time of the approval, it was known that when PB is used with atropine and 2-PAM, it makes those who take it *more* vulnerable to some agents. There was no indication that FDA was aware, or that DOD informed FDA, that when people take this combination of drugs, they become moresusceptible to poisoning from carbamates, sarin and VX (another nerve agent believed to be in Iraq's arsenal). This clearly changes the risk profile for PB, and increases the need for FDA to know *which* chemical weapons the troops were likely to encounter.

In order to be effective, troops issued PB and directed to take it needed to know when to take the drug and when to use the antidote kit. This in turn depended on the reliability of information available to the troops under attack. In the Gulf War, the military used chemical weapons detection systems. But there was no evidence in the material examined for this article of an inquiry from FDA about the military's ability to provide reliable information to the troops about chemical weapons attack. There was also no DOD description of chemical weapons detection systems. There was no evidence of discussions about whether or not the detection systems could tell the difference between nerve agents in battlefield environments (they couldn't).

The subject of false alarms apparently never came up in the DOD/FDA discussions of PB's proposed use in the Gulf. As it turned out, "false alarms" about chemical weapons attack were a feature of the Gulf War. What should the troops have done when the alarms sounded? Use the nerve agent kit immediately without waiting for attack confirmation? Which would be better for troop health- ongoing PB plus atropine/2-PAM in the event of an alarm, or ongoing PB and no post-alarm treatment? There was no evidence that anyone raised these questions either before the war or afterwards, though they were important questions from both the military and the health points of view.

At the time DOD and FDA were discussing PB use in the Gulf, what reasons did they have for thinking that the drug was safe for use in healthy people? There was extremely limited evidence that PB was safe to use in *healthy* humans. There were few studies of adverse effects from PB administered to healthy humans. Tests of PB in healthy people mostly had few, all male, young participants. Most of the information about PB's safety and effectiveness against nerve agents came from animal studies and these limited human studies. And there were no studies of long-term effects from multiple dose low-level PB ingestion by healthy people-the type of use DOD was proposing.

The military argued that PB's long use in the treatment of myasthenia gravis indicated its overall safety. There was no evidence in the material examined for this article that DOD or FDA ever mentioned that people with myasthenia vary in their response to PB, and that for some, there is little difference between a dose of PB that is helpful and one that is toxic.

The effects of PB in people without myasthenia gravis could be affected by other conditions. DOD proposed give PB to troops of mixed sex, mixed age, and potentially mixed state of health. Remember that many Reserve troops served in the Gulf. Reservists tend to be older than regular military enlisted personnel, though DOD considers them to be "worldwide deployable." Remember too that the military now includes substantial numbers of young women.

A military technical memorandum current at the time of the Gulf War even pointed out that some soldiers who are "world-wide deployable" also could have any of a number of conditions that could make taking PB risky. PB could cause untoward effects in asthmatics, hypertensives (especially those taking beta-blockers) and people with glaucoma. People who took both PB and antimalaria drugs could have adverse effects from the combination. There are people who have low plasma cholinesterase, from genetics or from taking birth control pills or corticosteroid drugs. These people could risk having prolonged reactions to anesthetics if they were injured and treated while PB was in their systems. People with overactive thyroid glands were at risk of heart fibrillation from taking PB.

There was no evidence in the material examined for this article that FDA had obtained and used information about how many of the troops had health factors that could make taking PB dangerous, before they allowed the military to issue it to the troops. I found no evidence that this information was either requested by FDA or forthcoming from DOD.

The material used for this article contained no evidence that the issue of concurrent exposures was discussed by FDA and DOD, or that questions about this issue were even raised. PB acts in the nervous system. Common sense should have dictated questions be asked about troop exposures to other substances that act on the nervous system. When DOD discussed PB with FDA, scientists knew that PB increases susceptibility to carbamate poisoning and to some organophosphates. I found no indications that FDA inquired about pesticide use by the military. Some pesticide exposures almost certainly happened while the troops were taking PB. If FDA had asked, they would have learned that at least some of the troops were likely to encounter fuels, metals, solvents, pesticides, and therapeutic drugs that could affect the nervous system.

What about health care in the Gulf?

Participants in meetings between FDA and DOD discussed the role of military medical personnel deployed in the Gulf. Since PB was to be given investigational new drug status, there had to be investigators, and in the Gulf, medical personnel were the military's obvious investigators. They would collect whatever data would be collected about PB used in the Gulf. There was no indication that FDA inquired about the medical personnel capability of the military- that is, the actual people who would be collecting the data.

As it turns out, they should have. The General Accounting Office later found many inadequacies in the military mobilization and deployment of medical personnel during Desert Shield/Desert Storm. GAO said, "Most medical units had not been trained in the treatment of chemical casualties. This deficiency was recognized early in the operation, and a training team was sent to the Persian Gulf to train 1,400 doctors and nurses in the management of chemical casualties. This was initial - not refresher- training." (DOD had an opportunity to respond to this comment but did not.)

GAO also reported other deficiencies in medical personnel in the Gulf. These included lack of training in battlefield medicine, lack of experience with military field medical equipment, and lack of credentials for the medical assignments needed. GAO found that the military was unprepared to fulfill military medical missions in the Gulf. Medical personnel in the Gulf were unlikely to have been able to take on the added duty of following up on the effects PB on combat troops.

It is unclear now who knew what at the time FDA and DOD were discussing using PB in the Gulf. Certainly, there is good evidence that questions should have been asked, and information offered, about the safety and effectiveness of PB if used in the Gulf the manner proposed by DOD.
Whatever the state of knowledge at the time, DOD got what it wanted. FDA granted IND status to PB for use in the Gulf, and gave DOD a waiver of informed consent to enable them to distribute it to the troops and order its use. PB was on its way to the Persian Gulf.

Opinions expressed are those of the author *only* and do not reflect the position of HEAL, its Governing Board, its staff, contractors or others.

For more information about Gulf War illnesses and service-related exposures, contact HEAL about "Gulf War Syndrome: Exposures in the line of duty [print only]." This three part series began with the Fall 1997 issue of The Human Ecologist and will conclude in March 1998. Articles include complete list of sources consulted, for the convenience of readers.

SOURCES

• Annas, GJ, Legal issues in medicine: changing the consent rules for Desert Storm. New England Journal of Medicine 326, March 12, 1992.
• Berkow, R (ed), The Merck Manual. Rahway NJ: Merck Research Laboratories, 1992.
• Blanck, RR et al., Unexplained illnesses among Desert Storm veterans: a search for causes, treatment, and cooperation. Archives of Internal Medicine 155, 262-268, February 13, 1995.
• C&I Magazine, Medics uncover neurological evidence. 15 April 1996
• CIA (US), Public Affairs. Press statement 03-97. February 26, 1997
• DOD(US), 970123_DOC_147_NERVE_AGENT_PYRIDOSTIGMINE _PRETREATMENT. (No clear date; clearly names Operation Desert Storm; posted by DOD in documents relating to the Gulf War. LK)
• DOD (US), Comprehensive Clinical evaluation program (CCEP) for Gulf War veterans, Report on 18,598 participants. April 1996.
• Ember, L. Chemical warfare agent detectors probe the fogs of war. Chemical & Engineering News, August 1, 1994.
• Friedman, A et al., Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response. Nature Medicine 2(12),1383-1385. December 1996.
• Haley, RW et al., Self-reported exposure to neurotoxic chemical combinations in the Gulf War. Journal of the American Medical Association 277 (30, 231-237. January 15, 1997.
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• Joseph, SC, Prepared remarks of Dr. Stephen C. Joseph, assistant secretary of defense for health affairs, to the Military Personnel Subcommittee, House National Security Committee, February 11, 1997. Reprinted in Defense Issues Vol. 12, #6.
• Lashof, JC, Testimony before the Senate Veterans Affairs Committee, January 1997
• Leikin, JB and Paloucek, FP, American Pharmaceutical Association Clinical Reference Library: Poisoning and Toxicology Handbook 1995-96. Hudson OH: Lexicomp 1995
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• US Army Medical Research Institute of Chemical Defense. Technical Memorandum 90-4. Clinical Notes on Chemical Casualty Care. November 1990.
• US Army Medical Research Institute of Chemical Defense. Countermeasures against chemical warfare agents. Additional information on pyridostigmine. January 8, 1991.
• US CFR, 21 CFR Part 50 Subpart B: Protection of human subjects.
• US General Accounting Office. Operation Desert Storm: Full Army Medical Capability Not Achieved. GAO/NSIAD-92-175. August 1992.
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• Zuckerman, D and Olson P. Preliminary Staff Findings extract, to Senator Rockefeller: Is military research hazardous to veterans' health: lessons from the Persian Gulf War. Pyridostigmine bromide. May 6, 1994