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Pyridostigmine, Diethyltoluamide, Permethrin, and Stress: A Double-Blind, Randomized, Placebo-Controlled Trial to Assess Safety

      OBJECTIVE

      To determine whether short-term human exposure to pyridostigmine bromide, diethyltoluamide, and permethrin, at rest or under stress, adversely affects short-term physical or neurocognitive performance.

      PARTICIPANTS AND METHODS

      A multicenter, prospective, double-blind, placebo-controlled crossover trial exposing 64 volunteers to permethrin-impregnated uniforms, diethyltoluamide-containing skin cream, oral pyridostigmine, and corresponding placebos was performed. Each participant had 4 separate sessions, ensuring exposure to all treatments and placebos under both stress and rest conditions in random order. Outcomes included physical performance (handgrip strength and duration, stair climbing, and pull-ups [males] or push-ups [females]), neurocognitive performance (computerized tests), and self-reported adverse effects.

      RESULTS

      Permethrin was undetectable in the serum of all participants; pyridostigmine levels were higher immediately after stress (41.6 ng/mL; 95% confidence interval, 35.1-48.1 ng/mL) than rest (23.0 ng/mL; 95% confidence interval, 19.2-26.9 ng/mL), whereas diethyltoluamide levels did not significantly differ by stress condition. Heart rate and systolic blood pressure increased significantly with stress compared with rest but did not vary with treatment vs placebo. Physical and neurocognitive outcome measures and self-reported adverse effects did not significantly differ by exposure group.

      CONCLUSION

      Combined, correct use of pyridostigmine, diethyltoluamide, and permethrin is well tolerated and without evidence of short-term physical or neurocognitive impairment.
      AChE (acetylcholinesterase), BMI (body mass index), GWV (Gulf War veteran), WinSCAT (National Aeronautics and Space Administration-1 Spaceflight Cognitive Assessment Tool for Windows)
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      REFERENCES

        • Dunn MA
        • Hackley Jr, BE
        • Sidell FR
        Pretreatment for nerve agent exposure.
        in: Sidell FR Takafuji ET Franz DR Medical Aspects of Chemical and Biological Warfare. Borden Institute, Walter Reed Army Medical Center, Washington, DC1997: 181-196
        • Keeler JR
        • Hurst CG
        • Dunn MA
        Pyridostigmine used as a nerve agent pretreatment under wartime conditions.
        JAMA. 1991; 266: 693-695
        • Cook JE
        • Kolka MA
        • Wenger CB
        Chronic pyridostigmine bromide administration: side effects among soldiers working in a desert environment.
        Mil Med. 1992; 157: 250-254
        • Schiflett SG
        • Stranges SF
        • Slater T
        • Jackson MK
        Interactive effects of pyridostigmine and altitude on performance.
        in: Proceedings of the Sixth Medical Chemical Defense Bioscience Review. US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Md1987: 605-607
        • Schiflett SG
        • Miller JC
        • Gawron VJ
        Pyridostigmine bromide effects of performance of tactical transport aircrews.
        in: Proceedings of the Sixth Medical Chemical Defense Bioscience Review. US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Md1987: 609-611
        • Gall D
        The use of therapeutic mixtures in the treatment of cholinesterase inhibition.
        Fundam Appl Toxicol. 1981; 1: 214-216
        • Glickson M
        • Achiron A
        • Ram Z
        • et al.
        The influence of pyridostigmine administration on human neuromuscular functions—studies in healthy human subjects.
        Fundam Appl Toxicol. 1991; 16: 288-298
        • Roach JM
        • Eliasson AH
        • Phillips YY
        The effect of pyridostigmine on bronchial hyperreactivity.
        Chest. 1993; 103: 1755-1758
        • Golomb BA
        A Review of the Scientific Literature as it Pertains to Gulf War Illnesses. Vol 2. Pyridostigmine Bromide. RAND, Santa Monica, Calif1999
        • Friedman A
        • Kaufer D
        • Shemer J
        • Hendler I
        • Soreq H
        • Tur-Kaspa I
        Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response.
        Nat Med. 1996; 2: 1382-1385
        • Grauer E
        • Alkalai D
        • Kapon J
        • Cohen G
        • Raveh L
        Stress does not enable pyridostigmine to inhibit brain cholinesterase after parenteral administration.
        Toxicol Appl Pharmacol. 2000; 164: 301-304
        • Abou-Donia MB
        • Dechkovskaia AM
        • Goldstein LB
        • Abdel-Rahman A
        • Bullman SL
        • Khan WA
        Co-exposure to pyridostigmine bromide, DEET, and/or permethrin causes sensorimotor deficit and alterations in brain acetylcholinesterase activity.
        Pharmacol Biochem Behav. 2004; 77: 253-262
        • Iowa Persian Gulf Study Group
        Self-reported illness and health status among Gulf War veterans: a population-based study.
        JAMA. 1997; 277: 238-245
        • Centers for Disease Control and Prevention
        Unexplained illness among Persian Gulf War veterans in an Air National Guard unit: preliminary report—August 1990-March 1995.
        MMWR Morb Mortal Wkly Rep. 1995; 44: 443-447
        • Kroenke K
        • Koslowe P
        • Roy M
        Symptoms in 18,495 Persian Gulf War veterans: latency of onset and lack of association with self-reported exposures.
        J Occup Environ Med. 1998; 40: 520-528
        • Hyams KC
        • Wignall FS
        • Roswell R
        War syndromes and their evaluation: from the U.S. Civil War to the Persian Gulf War.
        Ann Intern Med. 1996; 125: 398-405
        • Sartin JS
        Gulf War illnesses: causes and controversies.
        Mayo Clin Proc. 2000; 75: 811-819
        • Riddle JR
        • Hyams KC
        • Murphy FM
        • Mazzuchi JF
        In the borderland between health and disease following the Gulf War.
        Mayo Clin Proc. 2000; 75: 777-779
      1. Bolton HT. Use and safety of pesticides (repellents) in Persian Gulf. Presented at: Department of Veterans Affairs Update on Health Consequences of Persian Gulf Service: Baltimore, Md; July 18, 1995.

        • Robbins PJ
        • Cherniack MG
        Review of the biodistribution and toxicity of the insect repellent N,N-diethyl-m-toluamide (DEET).
        J Toxicol Environ Health. 1986; 18: 503-525
        • Franz TJ
        • Lehman PA
        • Franz SF
        • Guin JD
        Comparative percutaneous absorption of lindane and permethrin.
        Arch Dermatol. 1996; 132: 901-905
        • Haley RW
        • Kurt TL
        Self-reported exposure to neurotoxic chemical combinations in the Gulf War: a cross-sectional epidemiologic study.
        JAMA. 1997; 277: 231-237
        • Abou-Donia MB
        • Wilmarth KR
        • Jensen KF
        • Oehme FW
        • Kurt TL
        Neurotoxicity resulting from coexposure to pyridostigmine bromide, DEET, and permethrin.
        J Toxicol Environ Health. 1996; 48: 35-56
        • McCain WC
        • Lee R
        • Johnson MS
        • et al.
        Acute oral toxicity study of pyridostigmine bromide, permethrin, and DEET in the laboratory rat.
        J Toxicol Environ Health. 1997; 50: 113-124
        • Roy MJ
        • Kraus PL
        • Cooper JA
        • et al.
        Initial evaluation of N,N-diethl-m-toluamide and permethrin absorption in human volunteers under stress conditions.
        Mil Med. 2006; 171: 122-127
        • Armed Forces Pest Management Board Repellents Committee
        Personal Protective Measures Against Insects and Other Arthropods of Military Significance. Defense Pest Management Information Analysis Center, Forest Glen Section, Walter Reed Army Medical Center, Washington, DC1996 (Technical Guide No. 36.)
        • Krantz DS
        • Manuck SB
        Acute psychophysiologic reactivity and risk of cardiovascular disease: a review and methodologic critique.
        Psychol Bull. 1984; 96: 435-464
        • Reeves DL
        • Winter KP
        • LaCour SJ
        • et al.
        Automated Neuropsychological Assessment Metrics Documentation. Vol. 1. Test Administration Guide. Office of Military Performance Assessment Technology, Silver Spring, Md1992
        • Abou-Donia MB
        • Wilmarth KR
        • Abdel-Rahman AA
        • Jensen KF
        • Oehme FW
        • Kurt TL
        Increased neurotoxicity following concurrent exposure to pyridostigmine bromide, DEET, and chlorpyrifos.
        Fundam Appl Toxicol. 1996; 34: 201-222
        • Hong JS
        • Herr DW
        • Hudson PM
        • Tilson HA
        Neurochemical effects of DDT in rat brain in vivo.
        Arch Toxicol Suppl. 1986; 9: 14-26