skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Metabolism of proposed nerve agent pretreatment, pyridostigmine bromide. Final report, December 1995-December 1996

Abstract

A reverse phase High Pressure Liquid Chromatography (HPLC) method was developed to separate pyridostigmine bromide from four potential metabolites. Using male and female microsomes from both rat and human, our data suggest that pyridostigmine bromide is not metabolized by the human live microsomes or DNA expressed human CYP-450s via direct observation of no metabolites being formed for incubations up to 90 minutes. Indirect evidence that pyridostigmine metabolism is not via the major human hepatic CYP-450s involved in drug metabolism, 1A2, 2C9, 2E1, 2D6, and 3A4, was observed by failure to inhibit these isozymes while co-incubated with substrates specific for those isozymes at concentrations of 2-3 times Km. The following CYP-450 substrates were co-incubated with pyridostigmine: phenacetin, tolbutamide, chlorzoxazone, bufuralol, and testosterone. Using unlabelled and 14C-pyridostigmine, metabolite formation was not observed in both male and female rat and human subcellular fractions, specifically cytosol and S9, or under conditions favoring human FMO activity (pH 8.3). These findings indicate the metabolism of pyridostigmine bromide is unlikely to be under any component of sexual dimorphism.

Authors:
Publication Date:
Research Org.:
Walter Reed Army Inst. of Research, Washington, DC (United States)
OSTI Identifier:
502657
Report Number(s):
AD-A-323848/2/XAB
TRN: 71740132
Resource Type:
Technical Report
Resource Relation:
Other Information: PBD: Dec 1996
Country of Publication:
United States
Language:
English
Subject:
45 MILITARY TECHNOLOGY, WEAPONRY, AND NATIONAL DEFENSE; CHEMICAL WARFARE AGENTS; PREVENTIVE MEDICINE; BROMIDES; THERAPEUTIC USES; PROGRESS REPORT

Citation Formats

Leo, K.U. Metabolism of proposed nerve agent pretreatment, pyridostigmine bromide. Final report, December 1995-December 1996. United States: N. p., 1996. Web.
Leo, K.U. Metabolism of proposed nerve agent pretreatment, pyridostigmine bromide. Final report, December 1995-December 1996. United States.
Leo, K.U. Sun . "Metabolism of proposed nerve agent pretreatment, pyridostigmine bromide. Final report, December 1995-December 1996". United States. doi:.
@article{osti_502657,
title = {Metabolism of proposed nerve agent pretreatment, pyridostigmine bromide. Final report, December 1995-December 1996},
author = {Leo, K.U.},
abstractNote = {A reverse phase High Pressure Liquid Chromatography (HPLC) method was developed to separate pyridostigmine bromide from four potential metabolites. Using male and female microsomes from both rat and human, our data suggest that pyridostigmine bromide is not metabolized by the human live microsomes or DNA expressed human CYP-450s via direct observation of no metabolites being formed for incubations up to 90 minutes. Indirect evidence that pyridostigmine metabolism is not via the major human hepatic CYP-450s involved in drug metabolism, 1A2, 2C9, 2E1, 2D6, and 3A4, was observed by failure to inhibit these isozymes while co-incubated with substrates specific for those isozymes at concentrations of 2-3 times Km. The following CYP-450 substrates were co-incubated with pyridostigmine: phenacetin, tolbutamide, chlorzoxazone, bufuralol, and testosterone. Using unlabelled and 14C-pyridostigmine, metabolite formation was not observed in both male and female rat and human subcellular fractions, specifically cytosol and S9, or under conditions favoring human FMO activity (pH 8.3). These findings indicate the metabolism of pyridostigmine bromide is unlikely to be under any component of sexual dimorphism.},
doi = {},
journal = {},
number = ,
volume = ,
place = {United States},
year = {Sun Dec 01 00:00:00 EST 1996},
month = {Sun Dec 01 00:00:00 EST 1996}
}

Technical Report:
Other availability
Please see Document Availability for additional information on obtaining the full-text document. Library patrons may search WorldCat to identify libraries that may hold this item. Keep in mind that many technical reports are not cataloged in WorldCat.

Save / Share:
  • During Operation Desert Storm there was a credible threat of chemical warfare even though there was never actual use of chemical agents. Intelligence reports indicated that the Iraqi chemical arsenal contained nerve, vesicant, and blood agents. Nerve agents are organophosphorus inhibitors of acetylcholinesterase, such as sarin and tabun. The vesicants are skin blistering compounds, such as mustards and arsenicals, while blood agents are the cyanides, inhibitors of cytochrome oxidase. The US Armed Force`s approach to the medical management of actual or anticipated nerve agent injuries employs a regimen that consists of pretreatment with pyridostigmine bromide tablets prior to nerve agentmore » exposure followed by atropine citrate and pralidoxime chloride by autoinjector intramuscularly on actual exposure. Proper administration of this drug combination provides significantly increased survival after lethal exposures to nerve agents above that provided by atropine and pralidoxime therapy alone. The recent addition of pyridostigmine to the US therapeutic regimen for nerve agent poisoning was based on efficacy data in animals and safety studies in humans.« less
  • This study was conducted to evaluate the efficacy of the reversible acetylcholinesterase inhibitor, pyridostigmine bromide, as an addition to standard therapy with atropine pralidoxime bromide, as an addition to standard therapy with atropine and pralidoxime chloride (2-PM), against the acute lethal effects of Soman, GD, using a primate model (male, Rhesus monkey). In addition, the pharmacokinetics of pyridostigmine bromide (intragastric), atropine (intramuscular), and 2-PAM (intramuscular) were individually examined in the primate model using three different dose levels for each compound. In the efficacy study, the combined prophylactic/post/challenge therapy regimen resulted in survival following an intramuscular challenge dose as high asmore » 617 micrograms/kg in contrast to an estimated, unprotected, median lethal GD dose (LD50) of 15.3 micrograms/kg for the same animals.« less
  • In vivo, (2-Puridine Aldoxine Methioidide) reactivates phosphonylated acetylcholinesterase AChE peripherally, but is effective in restoring AChE centrally because the quaternary nitrogen atom of 2-PAM prevents penetration of the brain. The problem was solved by the synthesis of the 1,6-dihyropyridine derivative of 2-PAM, pro-2-PAM (PP). Functional brain AChE is related to return to control performance on an accelerating rotarod (ARR) in animals intoxicated with soman. There should be a difference in the time to recovery of control ARR performance between PP- and 2-PAM-treated, sarin-intoxicated animals. In the present work, an ARR decrement free dosage (DFD) of each of these oximes (30more » mg/kg, im) in combination with DFD of atropine (A) and mecamylamine (M) (0.79 mg/kg each, im) was used as pretreatment against sarin-induced deficit. The same antidotes were given pre-and post- intoxication (as pretreatment and therapy) to anatagonize sarin-induced lethality; the PP containing antidote provided significantly greater protection than that by the 2-PAM antidote which in turn provided significant protection over control. Neither antidote when given as pretreatment and therapy provided protection above control against soman-induced physical incapacitation, but they were equally effective in antagonizing VX-induced physical incapacitation. The reversal of sarin-induced physical debilitation reflects the central actions of PP and supports the notion that functional brain AChE activity is essential for rapid recovery from the debilitating effeclts on nerve agents.« less
  • The report gives results of evaluations of the field performance of 13 EPA-certified woodburning stoves in Crested Butte and Curecanti National Park, CO, during the winter of 1995-96. Measurements included particulate matter (PM), carbon monoxide (CO), and weekly average burn rates. Six non-catalytic Phase II stoves, six catalytic Phase II stoves, and one catalytic Phase I stove were monitored. The study adds to the existing database on the field emissions of newer and older certified stoves. The report compares values with results from previous studies and suggests reasons that field performance is poor relative to what might be expected frommore » certification test results.« less
  • Acute carbamate pretreatment, in conjunction with atropine pretreatment or followed by atropine and oxime therapy has been shown to protect rabbits, rats, guinea pigs and monkeys against multiple lethal doses of soman. In those experiments, pretreated animals were usually challenged with soman at the time of peak whole blood acetylcholinesterase (AChE) inhibition by the carbamate or when the concentration of carbamate in the blood was expected to be rapidly diminishing. However, soldiers in a chemical environment, having taken carbamate orally might well be exposed to nerve agent shortly thereafter. Thus, both active carbamate and nerve agent would be entering themore » blood simultaneously. In a recent study it was reported that subacute administration of physostigmine (Phy), via subcutaneously implanted 28 day osmotic minipump, afforded protection against an iv challenge of soman on the 27th day.« less