Clarification Re: safety of pyridostigmine, Drug tested in Gulf War

Thu, 27 Feb 2003

Although pyridostigmine bromide (PB) apparently causes only short-term symptoms when used for its two indications (myasthenia gravis and reversal of muscle relaxants post-anesthesia), the issue of whether it was safe when used in the presence of other agents, those that soldiers might use or be exposed to in a chemical warfare setting (eg, sarin) had not been examined until recently.

AHRP was incorrect in saying that PB had not been tested for safety in humans–rather, it had not been tested for safety in humans when given with small doses of other, potentiating substances to which military and service personnel may be exposed to, such as: N.N-diethyl-m-toluamide (DEET) insect repellent, and environmental exposures to jet fuel. This is important, because researchers have shown that tiny doses of these mixtures, when used together, do in fact pierce the blood brain barrier and caused testicular damage and neuronal cell death in animal models.

[See: Duke University studies: Abou-Donia MB, Suliman HB, Khan WA, Abdel-Rahman AA. Testicular germ-cell apoptosis in stressed rats following combined exposure to pyridostigmine bromide, N,N-diethyl m-toluamide (DEET), and permethrin. J Toxicol Environ Health A 2003 Jan 10;66(1):57-73]

[See: Abdel-Rahman A, Shetty AK, Abou-Donia MB. Disruption of the blood-brain barrier and neuronal cell death in cingulate cortex, dentate gyrus, thalamus, and hypothalamus in a rat model of Gulf-War syndrome.Neurobiol Dis 2002 Aug;10(3):306-26]

[See: Univ of South Carolina: Peden-Adam MM, Eudaly J, Eudaly E, Dudley A, Zeigler J, Lee A, Robbs J, Gilkeson G, Keil DE.Evaluation of immunotoxicity induced by single or concurrent exposure to N,N-diethyl-m-toluamide (DEET), pyridostigmine bromide (PYR), and JP-8 jet fuel. Toxicol Ind Health 2001 Jun;17(5-10):192-209

It was therefore important to consider synergistic effects when licensing the drug for this military indication, but there is no evidence FDA has done so.

Meryl Nass, MD Board member Alliance for Human Research Protection