Extract From Preliminary Staff Findings

Efficacy Pyridostigmine does not protect against warfare nerve agents when taken alone; it only works in combination with other drugs. Similarly, pyridostigmine administered after exposure to a warfare agent is not effective. 7 Two antidotes to nerve agents, atropine and pyridine-2-aldoxime methochloride (2-PAM), are enhanced if pyridostigmine has already been given. Atropine and 2-PAM were included in the nerve agent antidote kits (Mark 1) which were given to US troops. It should be noted that 2-PAM itself may intensify the effects of carbamate poisoning, so that if a soldier had an adverse reaction to pyridostigmine, the use of 2-PAM could make the reaction worse.

In research studies, animals given pyridostigmine, atropine and 2-PAM were more likely to survive exposure to soman. Because pyridostigmine is unable to enter and protect the brain, animals exposed to soman can still suffer from convulsions despite the pyridostigmine pre treatment. To protect against brain damage from ongoing seizure activity, valium may also be required following exposure to a lethal warfare agent.

Although pyridostigmine may improve the survival of animals exposed to soman when treated with antidote enhancers, pyridostigmine pre treatment makes individuals more vulnerable to other nerve agents, such as VX and sarin.8 The DoD scientists who studied pyridostigmine and sarin therefore concluded that pyridostigmine should only be used when the chemical warfare threat is soman.9

Unfortunately, the Pentagon had no reason to believe that the Iraqis were more likely to use soman rather than sarin. According to a recent report by the Persian Gulf War Veterans Coordinating Board, Iraq had several chemical weapons, including sarin. 10 Moreover, at a briefing for Senators and staff on November 10, 1993, Under Secretary of Defence John Deutch stated that the Czechoslovakian military detected low levels of sarin in the Saudi theatre during the opening days of the air war against Iraq. The statement was repeated by Joseph Corrivean, US Army Foreign Science and Technology Centre, on April 27, 1994, at an NIH workshop on Persian Gulf War illness.

When phase 2 study of pyridostigmine began, it was noted that the atropine and 2-PAM did not seem to improve survival when animals were exposed to soman. As a result, the dose of atropin was increased to 0.40 mg/kg, which according to FDA increased the survival of Rhesus monkeys exposed to soman. 11 However, when the DoD developed a treatment regimen for US troops during the Persian Gulf War, it was based on the inadequate dose of atropine in the animal studies (0.096 mg/kg) rather than the higher, effective dose. 12 Therefore, even if Persian Gulf soldiers had been exposed to soman, it is questionable if the pyridostigmine pre treatment would have provided any protection, since the dose of atropine was apparently inadequate.

Safety Pyridostigmine bromide is approved by the FDA for treating myasthenia gravis, a neurological disease characterized by extreme weakness. The disease occurs when individuals develop antibodies that prevent ACh from facilitating muscle impulses. Therefore, treatment with relatively high doses of pyridostigmine (180 to 540 mg one or two times a day) increases ACh to levels that are able to overcome the "block" created by antibodies. However, giving similar levels of pyridostigmine to healthy humans could cause serious side effects, similar to those of nerve agent poisoning. A good analogy is the use of insulin for diabetes; very high doses of insulin are sometimes necessary to treat diabetics, but similar doses could be fatal for non-diabetic individuals.

Pyridostigmine is also approved to reverse the effect of neuromuscular blocking agents after surgery. The dose is relatively small (15 mg) and not repeated. The treatment does not provide relevant information about the safety of repeated use of pyridostigmine by healthy individuals.

Pyridostigmine is not FDA approved for repeated use in healthy individuals for any reason. Since it would be unethical to expose individuals to potentially lethal chemical weapons in order to evaluate the efficacy of pyridostigmine, this use has only been studied on animals. The product is therefore an investigational drug when used as an antidote enhancer for treating nerve gas poisoning. However, a few months ago, DoD applied for approval for pyridostigmine for that purpose. On May 6, 1994, FDA is scheduled to decide whether DoD has provided enough data for FDA to "file" the NDA and consider Whether or to approve the application. 13

DoD Research Found Problems With Pyridostigmine

We have reviewed all the clinical studies and related research regarding pyridostigmine on healthy individuals which DoD provided to FDA to support their IND and their application for approval. The number of human subjects in most studies was less than 35; several studies included as few as two or four individuals. According to the materials that FDA provided to the Committee, all the studies apparently excluded women. The lack of studies on women is a problem, because dosage should be based on the weight of the person taking the drug, and because some scientists believe that pyridostigmine may affect men and women differently. 14 In addition, a woman on birth control pills may have different levels of AChE than other men or women.

Because of the DoD researchers' concerns about serious adverse reactions, many of the studies screened the men to determine whether they were hypersensitive to pyridostigmine, before allowing their participation in the experiment. In some cases they used test doses; in other cases they asked questions regarding similar medications. In addition, individuals with abnormal blood pressure, asthma, glaucoma, low serum AChE levels, gastrointestinal disorders, urinary or intestinal blockage, hyperthyroidism, and sensitivity to atropine or bromide were excluded from the studies. In many of the studies, patients were excluded if they were taking any medications, since adverse reactions could occur when pyridostigmine as administered with other drugs (ie., propanolol, birth control medications, or anti malarial drugs). In some studies, smokers were excluded; in many studies, participants were told not to drink any alcoholic beverages. Most participants were less than 35 years of age. 15

Despite these precautions, serious adverse reactions were reported for several of the studies. For example, in one study, pyridostigmine was administered to a group of 28 active duty Air Force pilots. One pilot experienced respiratory arrest 91 minutes after swallowing the third in a series of three 30 mg pyridostigmine tablets. This pilot had shown no sensitivity to the test dose of pyridostigmine prior to the study. In another study of 32 male subjects, one subject lost consciousness following visual change and headache. In other studies, abnormal liver tests, unusual electrocardiograms, gastrointestinal disturbances, and anaemia were reported. Results also showed that pyridostigmine impaired performance, including tasks which required short term memory, and prevented a number of test subjects from exercising in hot environments during the second or third day of treatment. A study of the impact of pyridsotigmine on swimming in cold water had to be terminated when it was determined that its use caused severe cramps that could cause drowning.

In August of 1990, DoD scientists requested approval for a study of four men to evaluate the effects of pyridostigmine on vision. This study was deemed urgent because of the situation in Kuwait, and it was approved quickly. It is important to note that this study, to be conducted just prior to the Gulf War, gave medical exams to the men before giving the pyridostigmine. The researchers indicated that pyridostigmine should not be given to individuals who had bronchial asthma, peptic ulcer, liver, kidney, heart disease, or hypersensitivity to pyridostigmine or related drugs. They informed study volunteers that possible adverse side effects include nausea, increased salivation, increased bronchial secretions, and pupil constriction. Other side effects are "weakness, muscle cramps, and muscle twitches...Because of these side effects, all subjects will be admitted to Lyster Army Hospital as in-patients so that they will be medically monitored during evening periods of non testing. A drug will be available at the test site to counteract the possible adverse effects." 16 In addition, the Human Subjects Committee considered whether the possibility of pyridostigmine causing death should be mentioned in the informed consent form; after some discussion, it was decided that such a warning was unnecessary since death was unlikely.

Lack of Safeguards Regarding Pyridostigmine in the Persian Gulf

In contrast to the extensive precautions taken before giving pyridostigmine every 8 hours for 3 days to four volunteers, a few months later the same dosage was given for longer periods of time to approximately 400,000 US soldiers, none of whom had been screened for any of the diseases mentioned in the informed consent form given to the four men, none of whom were warned about the risks associated with the drug, and none of whom were given a choice of whether or not to take it. Additionally, approximately 28,000 of the 400,000 receiving the pyridostigmine were women, who were forced to take an investigational drug that had never been tested on healthy women.

Despite the concern of DoD scientists regarding the potential serious adverse reactions and drug interactions, DoD and FDA have repeatedly claimed and continued to claim that DoD research has proven that pyridostigmine was safe to distribute to hundreds of thousands of US troops, none of which had been tested for sensitivity to pyridostigmine, and most of whom were not screened for medical problems or medication use that could preclude the safe use of pyridostigmine.

Recent Research

The safety of pyridostigmine as also evaluated during and after the Persian Gulf War. In one study, approximately 37% of 213 soldiers reported at least one severe symptom 24 hours after beginning to take 30 mg pyridostigmine tablets. 17 Additionally, the DoD conducted three surveys concerning the use of pyridostigmine in Operation Desert Shield/Storm which were reported in 1992. These surveys indicated that approximately half of the US military personnel experienced side effects from the pyridostigmine. Some medical personnel believed the dose was too high for women. In one study, 16 of 23 medical personnel indicated that no information sheets on the drug were provided to persons who received the pyridostigmine bromide.

Last year, Dr James Moss, a scientist at the US Department of Agriculture, conducted research on cockroaches that could have important implications for Persian Gulf War veterans. He found that when used in combination with pyridostigmine, a common pesticide called DEET became 10 times as toxic as when used alone. DEET and many other pesticides were widely used in the Gulf War, as protection from sand flies, scorpions, and other pests (or vice versa), this could explain the serious neurological symptoms experienced by so many Gulf War veterans.

A relevant issue is that military researchers have stated that carbamates (such as pyridostigmine) must never be used after nerve agent exposure. Because pesticides and nerve agents are both organophosphates, pyridostigmine may have made military personnel more vulnerable to the toxic effects of pesticides. Dr Moss, who works for the Agriculture Research Service, has apparently attempted to notify DoD of his research findings, but nobody at DoD has yet attempted to contact him to learn more about his findings.

References

7. Sidell FR., Clinical considerations in Nerve Agent Intoxication, In: Chemical Warfare Agents, Academic Press, Inc., 1992, pp 155-194.

8. Koplovitz I, Harris LW, Anderson DR, Lennox WJ, Stewart JR, Reduction by pyridostigmine pre treatment of the efficacy of atropine and 2-PAM treatment of sarin and VX poisoning in rodents, Fundamental and Applied Toxicology, 18: 102-106, 1992.

9. Sidell FR, op. cit.

10. Summary of the issues impacting upon the health of the Persian Gulf veterans, Version 1.1: March 3, 1994.

11. The actual data from this study was not provided to our committee, apparently not provided to FDA either.

12. IND Amendment, Reference to IND# 28480, March 28, 1988, Letter from Thomas H Gray, Chef, Operational Training Branch, Department of the Air Force, to Mr David Banks, Consumer Safety Officer, FDA.

13. If FDA does not file the application, they will not even consider approval.

14. Barbarino A, Corsello SM, Tofani A, Sciuto R, Della Casa S, Rota CA, Barini A, Sexual dimorphism of pyridostigmine potentiation of growth hormone (GH) releasing hormone induced GH release in humans, Journal of Clinical Endocrinology Metabolism 73 (1): 75-78, 1991

15. These instructions are consistent over time, and were included in many different studies between 1985-90. Copies are in Committee files.

16. The document describing the study, which includes these quotations, is in Committee files.

17. Israeli Journal of Medical Science, 27: 656-658, 1991.