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pyridostigmine bromide
RE: PYRIDOSTIGMINE BROMIDE - a drug given to protect against the nerve gas soman

PB is a pretreatment drug used to protect against the CW nerve agent soman. By itself PB is not protective against CW nerve agent poisoning. Used as a pretreatment, however, PB might enhance the antidote effects of the standard atropine and 2-PAM treatments used by the U.S. military for nerve agent poisoning.269

Since 1955, FDA has approved PB for use by persons suffering from myasthenia gravis. No long-term health problems thought to be associated with PB have been reported for persons with myasthenia gravis who regularly take PB over many years or decades.196,220 DOD filed a New Drug Application in May 1996, but PB currently has the status of an IND for nerve gas pretreatment use.

According to FDA, its conclusion that PB was safe for use by U.S. service members during the Gulf War was based largely on the extensive cumulative experience with this drug in patients with myasthenia gravis. Typically these patients are treated with PB doses of up to 1,500 mg per day for many years, compared to the prescribed dose of 90 mg per day for a maximum of seven days use during the Gulf War. Reported side effects of PB include increased salivation, increased tearing, urinary urgency and frequency, nausea, vomiting, muscle weakness, abdominal cramps and diarrhea.167 These effects disappear when individuals stop taking PB.

Data from one DOD retrospective study on 30 medical support officers of the 18th Airborne Corps reveal a similar range of short-term health effects from PB. The 18th Airborne Corps instructed 1,650 soldiers (6.5 percent women) to take PB tablets at the onset of Operation Desert Storm in January 1991. Half those surveyed reported gastrointestinal symptoms, 5 to 30 percent reported increased urinary urgency and frequency, and fewer than 5 percent reported headaches and tingling of extremities. The need for a medical visit was reported by less than 1 percent, and the decision to discontinue use based on medical advice was reported by less than 0.1 percent. As with myasthenia patients, DOD reported that side effects ceased when PB use was discontinued.110 Other retrospective studies found similar results.32,270

A survey of 213 Israeli soldiers asked about possible symptoms of PB and their severity. The most frequent health complaints reported were generally mild and nonspecific, including dry mouth, general malaise, fatigue, and weakness, which appeared about 1.6 hours after taking the medication and recurred after each intake. For this group the typical side effects associated with PB, such as nausea, abdominal pain, frequent urination and runny nose, were infrequent.228

DOD recently completed a study begun in November 1994 that looked at differential tolerances to PB between women and men.128,296 Ninety subjects, equally divided by gender and in three weight classes, took 30 mg of PB every 8 hours for 21 days (plus one dose). PB was found to be safe and well-tolerated. All side effects were mild and resolved with no intervention. Headaches, dizziness, nausea, rash, and hair loss were reported in both drug and placebo groups. Diarrhea and abdominal pain were reported in the PB group only (four study participants). Overall, the occurrence of adverse effects did not differ between active and placebo subjects, nor were differences observed among gender or weight groups. Results from a 1-year followup, indicated no long-term effects except possibly a skin rash that resolved with treatment.128

DOD continues to seek FDA approval to use PB for the protection of U.S. troops against CW agents. To support this approval process, DOD has sponsored various research efforts since 1984 to gather information on the effects of PB pretreatment on healthy individuals. To date, DOD reports no serious or long-term reactions from this research.

Genetic predisposition to PB sensitivity. Some scientists suggest that persons who are genetically unable to produce the plasma enzyme butyryl cholinesterase (BuChE) could be more sensitive to PB's known side effects, and at least one apparent case has been reported.139 The estimated frequency in the general population of persons unable to produce BuChE is about 0.03 percent. Exposure to PB (or similar compounds) could cause immediate and marked health effects in these individuals. Based on studies of PB-related compounds in BuChE deficient individuals, however, symptoms vanish when exposure to PB is removed. Limited population genetic data indicate that about four percent of all people have slightly reduced ability to produce functional BuChE. It is unclear whether these individuals could be more susceptible to temporary PB side effects. 1,67,68,71,139,192,193,224,269


Synergistic effects.
Concern has been raised about the possibility of increased health problems from PB when it is combined with other risk factors. Some researchers have hypothesized that PB in combination with stress may create central nervous system effects.59,170,228 The insect repellent DEET and the insecticide permethrin are most often mentioned as cofactors with PB for Gulf War illnesses.

After the Gulf War, one U.S. Department of Agriculture researcher conducted a study on synergistic effects of various chemicals, including DEET and PB, on cockroaches. DEET showed a four-fold increase on the lethality of PB-i.e., it took one fourth as much PB to kill cockroaches in the presence of a sublethal dose of DEET.314 In 1996, another researcher reported that PB given at near lethal levels to chickens could increase the toxicity of DEET and permethrin.1 Under these conditions, nervous system damage to the chickens was reported. A 1995 DOD study with rats reported that PB caused a slight increase in lethality of DEET and permethrin when compared to expected additive values.263

These three studies report enhanced toxic effects from PB, DEET, and permethrin in combination. However, doses used in the laboratory experiments were far greater than exposures U.S. service members could have experienced during the Gulf War. Moreover, for DEET and permethrin, the routes of administration were not comparable to that used by U.S. service members in the Gulf War. For example, in the chicken model, DEET and permethrin were injected underneath the skin and, in the rat study, they were administered orally. During the war, DEET should have been applied to the skin, and permethrin should have been applied to the uniform.

These studies did not address the effect PB, DEET, and permethrin-individually or in combination-would have on morbidity in humans and what illnesses might be induced by such use. Neither did the studies answer whether there would have been detectable harmful effects in humans in-theater under the likely operational use by U.S. troops.

Some researchers suggest the immediate toxicity of the OP pesticides available to Gulf War veterans could have been increased from coexposure to PB,1,150,151 leading to the well-characterized, long-term signs and symptoms of immediate and severe poisoning described earlier in this chapter. As previously mentioned, however, DOD reports that on-site medical personnel did not observe any immediate and severe effects of OP poisoning among U.S. service members, and the current scientific knowledge base indicates that long-term health effects do not occur in the absence of immediate poisoning.

In setting priorities for new research projects on Gulf War veterans' health issues, a subcommittee of the RWG of the Coordinating Board gave priority to toxicology studies on subtoxic exposures to PB and pesticides, either alone or in combination. Several federally funded studies now underway are assessing combined exposure to PB and other chemical risk factors.


What do we conclude about the risks of PB to Gulf War veterans?

Given the extensive cumulative experience with the use of PB in patients with myasthenia gravis and data collected from military personnel, the Committee concludes it is unlikely that health effects reported today by Gulf War veterans are the result of exposure simply to PB. Ongoing federally funded studies should help the scientific community draw conclusions about the synergistic effects of PB and other risk factors.


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