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Research Topics
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Genetic Studies
Project Summary

Title: Study of Variability In Pyridostigmine Inhibition of Blood Cholinesterases in Healthy Adults and Individuals With Symptoms Following Participation in Operation Desert Storm
Synopsis: A comparative study between Gulf War veterans who took pyridostigmine bromide (PB) and a control group who did not to determine if there is a difference in their blood cholinesterase.
Overall Project Objective: Assess individual differences in blood cholinesterase regulation and response to pyridostigmine.
Status/Results to Date: In the initial study of 40 volunteers 18 of the 20 veterans in the study (90%) presented to the WRAMC Comprehensive Clinical Evaluation Program with post-war symptoms. All Gulf War veterans indicated they had taken pyridostigmine as a pretreatment drug for nerve agent exposure; 15 of 20 recalled having side effects after taking pyridostigmine. Mean red cell lysate acetylcholinesterase for all subjects was 5.7 U/ml +/- 0.7; mean plasma butyrylcholinesterase was 4.9 U/ml +/- 1.1. Mean spontaneous reactivation time (t-1/2 at 2.5 microM pyridostigmine) for all subjects was 42.6 min +/-5.4; mean for veterans was 43.2 +/- 6.2; mean for controls was 42.1 min +/- 4.6. Statistical analysis of reactivation times (repeated measures ANOVA) revealed no statistically significant differences between controls and veterans. However, significant differences in reactivation times (p=0.01) were observed between males and females across both groups. Differences in cholinesterase activities between controls and veterans were not statistically significant, but a differences between sexes was again significantly different. The occurrence of the UU (homozygous, usual, wild type) and UA (heterozygous, usual atypical) phenotypes of butylcholineserase in this study population [95% (38 of 40) and 5% (2 of 40), respectively] is close to the expected frequency, 96% and 4%. All Gulf War veterans in the study had the homozygous usual, wild-type (UU) allele. Symptoms exhibited by these individuals do not appear to be related to either altered ability of red cell acetylcholinesterase to be inhibited by pyridostigmine, to extended spontaneous reactivation time after pyridostigmine, exposure or to a genetic mutation in the butyrylcholinesterase phenotype.
Project:DoD-21
Agency:Department Of Defense
Location:Walter Reed Army Institute of Research
P.I. Name:Bhupendra Doctor, Ph. D.
Research Type:Epidemiology
Research Focus:Pyridostigmine Bromide
Focus Category:Genetic Studies
Status:Complete
Study Start Date:July 11,1995
Estimated Completion Date:June 30,1997
Specific Aims: Determine if individuals have different sensitivities to inhibition of blood cholinesterases by pyridostigmine and/or differences in the rate of spontaneous reactivation of cholinesterases after pyridostigmine exposure. Determine if there is a difference in the cholinesterases of Gulf War veterans who took pyridostigmine and seen at the Gulf War Health Center compared to age and sex matched controls.
Methodology: Blood (in EDTA) is obtained from Gulf War veterans seen at the Gulf War Health Center at Walter Reed Army Medical Center and from age and sex matched controls. Blood samples were assigned code numbers when drawn in the Gulf War Health Center, and the code was broken for the first 40 samples only after results from the data analysis were complete. Estimated spontaneous reactivation times after in vitro pyridostigmine inhibition, red cell acetylcholinesterase activity, and plasma butyrylcholinesterase activity were compared in blood samples from 20 veterans of Operation Desert Storm and 20 control subjects, matched for sex and age. Determination of plasma butyrylcholinesterase phenotypes was done at the Eppley Institute, University of Nebraska, Omaha NE.
Most Recent Publications:

Doctor B. A comparison of blood cholinesterases, in vitro pyridostigmine inhibition, and butyrylcholinesterase phenotypes in Gulf War veterans and controls. The Second Chemical and Biological Medical Treatment Symposium, Spiez, Switzerland, 359-64, Jul 1996. Article

Gordon R, Frazier DS, Herron PC, Saxena A. Effects of DEET, Permethrin and Pyridostigmine Bromide on Cholinergic receptors and cholinesterases. Bioscience Review Proceedings, 1998. Reviews

Doctor B. In vitro pyridostigmine inhibition of red cell acetylcholinesterase: a comparison in Gulf war veterans and normal controls. 1996 Medical Defense Bioscience Review, 1254-61 Baltimore, Maryland, May 1996. Reviews