| Structural MRI and Cognitive Correlates in Pest-control Personnel from Gulf War I |
Apr-2009 |
35 pages |
| Authors:
Kimberly Sullivan; BOSTON UNIV MA
|
 | Acetylcholinesterase (AChE) inhibitors including organophosphate (OP) pesticides are known to produce chronic neurological symptoms at sufficient exposure levels. Our previous study of cognitive functioning in pest-control personnel from the GWI, found that military pesticide applicators classified as higher pesticide-exposed reported significantly more health symptoms and performed less well on objective cognitive testing than the lower-exposed veterans. It is the goal of this follow-up neuroimaging study to identify the relationships between ... |
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| A Probabilistic Risk Assessment for Deployed Military Personnel After the Implementation of the Leishmaniasis Control Program at Tallil Air Base, Iraq |
Jan-2009 |
11 pages |
| Authors:
Schleier; Jerome J III; Robert K Peterson; Paula A Macedo; Ryan S Davis; Loren M Barber; MONTANA STATE UNIV BOZEMAN DEPT OF LAND RESOURCES AND ENVIRONMENTAL SCIENCES
|
| Leishmaniasis has been of concern to the U.S. military and has re-emerged in importance because of recent deployments to the Middle East. We conducted a retrospective probabilistic risk assessment for military personnel potentially exposed to insecticides during the Leishmaniasis Control Plan (LCP) undertaken in 2003 at Tallil Air Base, Iraq. We estimated acute and subchronic risks from resmethrin, malathion, piperonyl butoxide (PBO), and pyrethrins applied using a truckmounted ultra-low-volume (ULV) ... |
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| PRO-2-PAM: The First Therapeutic Drug for Reactivation of Organo-Phosphate-Inhibited Central (Brain) and Peripheral Cholinesterases |
Dec-2008 |
9 pages |
| Authors:
K; Farhat A Khan; Latoya A Hyson; Angela R Davis; James C DeMar; Ruthie H Ratchiffe; Roberta R Owens; Amy J Campbell; Richard Gordon; Madhusoodana P Nambiar; Elizabeth Marek; WALTER REED ARMY INST OF RESEARCH SILVER SPRING MD
|
| Due to the documented use of organophosphorus (OP) chemical agents in warfare and by terrorists around the globe, Federal, State, and local authorities need novel therapeutics to overcome their deleterious effects. OPs inhibit cholinesterases (ChE), leading to accumulation of the neurotransmitter acetylcholine (ACh). Potentially lethal effects begin with secretion, muscle fasciculation, and paralysis in the peripheral nervous system (PNS). Central nervous system (CNS) perturbations include epileptic seizures leading to neuronal ... |
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| Comparative Kinetics and Distribution to Target Tissues of Organophosphates Using Physiologically - Based Pharmacokinetic Modeling |
01-Mar-2008 |
214 pages |
| Authors:
Rick E Vermillion; AIR FORCE INST OF TECH WRIGHT-PATTERSON AFB OH GRADUATE SCHOOL OF ENGINEERING AND MANAGEMENT
|
| A physiologically-based pharmacokinetic model has been developed to examine the effects of organophosphates on the levels of acetylcholine in different tissues throughout the mammalian body. Many organophosphate-like chemical and kinetic characteristics are tested without reference to a specific chemical. Characteristics include partition coefficients, metabolic constants, the inhibition coefficient, the aging rate, and the regeneration rate. Two separate exposure scenarios are tested and compared against a baseline. The baseline consists of ... |
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| Optimization of Therapeutic Strategies for Organophosphate Poisoning |
MAR 2008 |
88 pages |
| Authors:
Gregory G. Seaman; AIR FORCE INST OF TECH WRIGHT-PATTERSON AFB OH GRADUATE SCHOOL OF ENGINEERING AND MANAGEMENT
|
| The National Preparedness Vision requires the U.S. be prepared to prevent, protect against, respond to, and recover from all hazards associated with a chemical attack. Results of this study demonstrate that we cannot protect service members and first responders as required following a nerve agent attack. The research presented herein aimed to construct a physiologically based pharmacokinetic model to determine optimal therapeutic strategies for organophosphate (nerve agent) poisoning. The constructed ... |
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| Acetylcholinesterase-Based Electrochemical Multiphase Microreactor for Detection of Organophosphorous Compounds (Preprint) |
APR 2007 |
29 pages |
| Authors:
Chelsea N. Monty; IIwhan Oh; Richard I. Masel; ILLINOIS UNIV AT URBANA DEPT OF CHEMISTRY
|
| A dual microchannel device with a gas-liquid interface was developed for use as an amperometric biosensor for the detection of organophosphorus compounds based on acetylcholinesterase inhibition. Electric eel acetylcholinesterase was immobilized on the liquid microchannel by creating a cross-linked gel with glutaraldehyde. The system was tested with malathion, an organophosphorus pesticide. The detection limit of the sensor in the parts-per-trillion range and the detection is rapid, sensitive, and selective to ... |
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| Atropine and Other Anticholinergic Drugs |
2007 |
|
| Authors:
John H. McDonough; Tsung-Ming Shih; ARMY MEDICAL RESEARCH INST OF CHEMICAL DEFENSE ABERDEEN PROVING GROUND MD
|
 | The nerve agents are highly toxic organophosphorous (OP) compounds. The agents of greatest concern, along with their chemical names and two-letter military designations, are tabun (o-ethyl N.N-dimethyl phosphoramidocyanidate; GA), sarin (isopropyl methylphosphonofluoridate; GB), soman (pinacolyl methylphosphonotluoridate; GD), cyclosarin (cyclohexyl methylphosphonofluoridate, GF), VX (o-ethyl S- 2-N,N- diisopropylaminoethyl methyl phosphonofluoridate) and a Russian V-type agent designated VR (0-isobutyl S-(2-diethylamino)ethyl methylphosphonothioate). The nerve agents inhibit the cholinesterase (ChE) family of enzymes that includes ... |
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| Sensitive and Rapid Blood and Tissue HPLC Oxime Assay and Pharmacokinetics of MMB-4 in Guinea Pigs and African Green Monkeys |
NOV 2006 |
8 pages |
| Authors:
Gregory E. Garcia; Harry Singh; Deborah Moorad-Doctor; Ruthie H. Ratcliffe; Katie Wachtel; Andres Castillo; Richard K. Gordon; Todd M. Myers; John H. McDonough; WALTER REED ARMY INST OF RESEARCH SILVER SPRING MD
|
| We developed a rapid and sensitive assay for pyridinium oximes in plasma and tissues. Samples are prepared by acidification and then deproteinized by ultrafiltration. The oximes are measured during sample HPLC fractionation over a cation-exchange column with UV detection. The assay is suitable for analysis of mono- and di-pyridinium oximes, but was originally developed for the measurement of the oxime MMB-4. For both plasma and tissue sources, the LLOD was ... |
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| Neurotoxin Mitigation |
NOV 2006 |
38 pages |
| Authors:
Steven H. Hinrichs; Deborah K. Vetter; NEBRASKA UNIV MEDICAL CENTER OMAHA
|
| Organophosphorus esters (OP) are highly toxic poisons used as chemical nerve agents and as pesticides. It is generally agreed that the toxicity from high dose OP exposure involves inhibition of acetyl cholinesterase. The role of other proteins in the toxicity of OP is unknown. Our hypothesis is that several proteins become modified after exposure to OP and that the biological actions of OP are not explained by inhibition of acetylcholinesterase ... |
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| Hair Follicle Bulb as a Biodosimeter for Low-Level VX Vapor Exposure: Initial Studies Validating the Presence of Potential Protein Biomarkers of Exposure in the Sprague-Dawley Rat Whisker Follicle |
OCT 2006 |
24 pages |
| Authors:
Amanda E. Chambers; Bernard J. Benton; James J. Valdes; Jennifer W. Sekowski; EDGEWOOD CHEMICAL BIOLOGICAL CENTER ABERDEEN PROVING GROUND MD RESEARCH AND TECHNOLOGY DIR
|
| Over the past fifty years, numerous studies have been performed to determine the health effects of exposure to organophosphorus (OP) nerve agents. The traditional approaches to determine OP exposure are invasive (e.g. require blood samples) laboratory-based assays that are not ideal for rapid, reliable testing in the event of a mass exposure scenario. However, advances in biomarker discovery make it possible to develop a less invasive, more expedient assay. The ... |
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| Molecular Targets for Organophosphates in the Central Nervous System |
APR 2006 |
|
| Authors:
Edson X. Albuquerque; MARYLAND UNIV BALTIMORE
|
| This project was a major effort to determine the effects of low-level exposure to the nerve agents sarin, soman, and VX in the mammalian CNS. Actions on synaptic transmission and neuronal cell death were assessed. Studies gave us clues to the mechanism of action of the agents, particularly in regard to cognitive function in humans that could be exposed to nerve agents in a chemical warfare attack. Reversible cholinesterase (ChE) ... |
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| Application of Adenovirus Expression System for the Production of Recombinant Cholinesterases |
01 OCT 2005 |
8 pages |
| Authors:
N. Chilukuri; K. Parikh; R. Naik; C. Chambers; J. M. Watt; P. Tipparaju; B. P. Doctor; A. Saxena; WALTER REED ARMY INST OF RESEARCH SILVER SPRING MD
|
| Previous studies in rodents and nonhuman primates demonstrated that pretreatment of animals with cholinesterases (ChEs) could provide significant protection against behavioral and lethal effects of nerve agent intoxication. Currently, human serum butyrylcholinesterase (BChE) is under development as medical countermeasure against organophosphate chemical warfare agent toxicity. In this study, we report the expression of human BChE and bovine acetylcholinesterase (AChE) using the newly designed adenovirus expression system. The shuttle vector employed ... |
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| Transcriptional Inducers of Acetylcholinesterase Expression as Novel Antidotes for Protection Against Chemical Warfare Agents |
01 OCT 2005 |
19 pages |
| Authors:
Bryan F. Curtin; Lauren M. Tetz; Richard K. Gordon; Bhupendra P. Doctor; Madhusoodana P. Nambiar; WALTER REED ARMY INST OF RESEARCH SILVER SPRING MD
|
| The biological effects of organophosphorous chemical warfare agents (CWAs) are exerted by inhibition of acetylcholinesterase (AChE), which blocks the hydrolysis of acetylcholine leading to hypercholinergy, seizures, status epilepticus, respiratory/ cardiovascular failure and death. Current investigations show that bio-scavenger therapy, using purified fetal bovine AChE and the more recently tested human BChE, is a promising treatment for protection against CWA exposure. Impediments such as the complex structure of AChEs, posttranslational modifications, ... |
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| Real Life Experiences Using the WRAIR Whole Blood and Pyridostigmine Assays |
01 OCT 2005 |
12 pages |
| Authors:
Julian R. Haigh; Gregory E. Garcia; Deborah R. Moorad-Doctor; Marian S. Farah; Bhupendra P. Doctor; Shawn R. Feaster; Richard K. Gordon; David E. Lenz; Connie R. Clark; Michael A. Riel; WALTER REED ARMY INST OF RESEARCH SILVER SPRING MD
|
| Walter Reed Army Institute of Research Whole Blood (WRAIR WB) cholinesterase assay rapidly determines the concentrations of both AChE and BChE in unprocessed whole blood, uses a minimally invasive blood sampling technique (finger prick), and is fully automated (using the Biomek 2000 robotic system). In human blood from volunteers given pyridostigmine bromide (30 mg single dose), RBC-AChE was maximally inhibited by about 30% after 2.5 h, with recovery to 95% ... |
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| Selective Binding of Organophosphate Pesticides Using Molecular Imprinted Polymers |
01 OCT 2005 |
7 pages |
| Authors:
Ali M. Saboori; Richard K. Gordon; WALTER REED ARMY INST OF RESEARCH SILVER SPRING MD
|
| Molecular Imprinted Polymers (MIPs) have been used for recognition and binding of different compounds. We are developing MIPs to selectively bind organophosphate pesticides and toxic chemical warfare nerve agents. MIPs were made to the pesticide Dichlorvos. Control MIPs were made without the template. Dichlorvos-MIPs bound more Dichlorvos in comparison to control-MIPs. The Dichlorvos-MIPs can be regenerated after binding the pesticide and reused at least three times by repeating the washing ... |
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| Organophosphate and Amine Contamination of Cockpit Air in the Hawk, F-111 and C-130 Aircraft |
OCT 2005 |
|
| Authors:
P. J. Hanhela; J. Kibby; G. DeNola; W. Mazurek; DEFENCE SCIENCE AND TECHNOLOGY ORGANISATION VICTORIA (AUSTRALIA) PLATFORM SCIENCES LAB
|
| A survey of cockpit air contamination by organophosphates and amines in the Hawk, F-111 and Hercules C-130 aircraft was undertaken. The air contamination occurred via the engine bleed air supply. The source of tricresyl phosphates, pheny-alpha-naphthylamine and diotyldiphenylamine was jet engine oil while hydraulic fluids are suspected of contributing to the presence of trialkyl phosphates. The concentrations of all contaminants measured were generally very low. Tricresyl phosphate concentrations were below ... |
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| Identification of Stem Cells in a Novel Human Mammary Epithelial Culture (HMEC) System that Reproducibly Demonstrates Ductal Organotypic Architecture in 3 Weeks |
OCT 2005 |
55 pages |
| Authors:
Jean J. Latimer; MAGEE WOMENS HEALTH CORP PITTSBURGH PA
|
| Our laboratory has published a novel culture system for Human Mammary Epithelial Cells (HMEC), both normal and malignant. This system allows for unusually long-term (3 months or longer) establishment of normal primary cultures that begin as three-dimensional "mammospheres," which are structures made up of 40-100 epithelial cells. These mammospheres subsequently differentiate into complex organotypic branching ducts and lobules that demonstrate Epithelial Specific Antibody (ESA) staining, lumen, polarized nuclei, desmosomes along ... |
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| Cytolytic T Lymphocytes in Organotypic Breast Carcinoma Culture |
OCT 2005 |
12 pages |
| Authors:
Dorothee Herlyn; PENNSYLVANIA UNIV PHILADELPHIA WISTAR INST
|
| In the proposed studies, novel T cell immunotherapies against breast cancer will be developed based on studies demonstrating a positive correlation between T lymphocytic infiltration of these tumors and favorable clinical outcome. The major goal of the proposed studies is to isolate and characterize cytolytic T lymphocytes (CTL) with in vivo-like T cell receptors. The CTL provide the basis for adoptive CTL immunotherapy and active immunotherapy with CTtderived peptides/antigens. During ... |
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| Low Level Chemical Toxicity: Relevance to Chemical Agent Defense |
JUL 2005 |
171 pages |
| Authors:
Mariana Morris; Gerald Alter; Steven Berberich; Ina Bicknell; David Cool; Robert Grubbs; James Lucot; James McDougal; Dan Organisciak; John Paietta; Lawrence Prochaska; Nicholas Reo; WRIGHT STATE UNIV DAYTON OH
|
| Wright State University conducted a multidisciplinary project to study the influence of low-level exposure to chemical warfare agents which act via inhibition of acetylcholinesterase (AChE). The problem was covered from the level of the cell to the human subject. Project 1 demonstrated that treatment with AChE inhibitors I (sarin or pyridostigmine, PB) in conjunction with stress produced changes in brain gene and protein expression, autonomic function, muscarinic receptor function and ... |
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| Cholinesterase Structure: Identification of Mechanisms and Residues Involved in Organophosphate Inhibition and Enzyme Reactivation |
MAY 2005 |
166 pages |
| Authors:
Palmer W. Taylor; CALIFORNIA UNIV SAN DIEGO LA JOLLA
|
| Studies on the structural of acetylcholinesterase (AChE) as a target of organophosphate toxicity continue and have yielded several leads of significance and practical outcomes. First, studies on oxime reactivation reveal the importance of achieving a suitable angle of attack for the oxime within the confines of the active center gorge. Through the use of mutant AChE-oxime combinations, oxime-assisted catalytic turnover of organophosphates can be achieved such that mutant AChE can ... |
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| Treatment Strategies fir the NMDA Component of Organophosphorous Convulsions |
APR 2005 |
83 pages |
| Authors:
Steven Peterson; NEW MEXICO UNIV ALBUQUERQUE HEALTH SCIENCES CENTER
|
| The project evaluated anticonvulsant and neuroprotectant properties of novel medical countermeasures to lithium-pilocarpine-induced status epilepticus (SE)used here as a model of organophosphorus nerve agents. Although mefenamate induced modest anticonvulsant effects, survival was reduced and the SE-induced neuropathology was exacerbated. Nicotinamide induced only modest anticonvulsant and neuroprotectant activity at the doses tested. N- acetylcysteine was not anticonvulsant but enhanced both neurological deficit and neuropathology. PBN, but not S-PBN, induced significant neuroprotection. ... |
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| Mechanistic Studies Investigating the Role of Organophosphate Insecticide Exposure in the Development and Exacerbation of Asthma |
APR 2005 |
24 pages |
| Authors:
Ernst W. Spannhake; JOHNS HOPKINS UNIV BALTIMORE MD
|
| This grant proposed to determine whether organophosphate insecticides act upon the cholinergic system in the lungs increasing cholinergic neurotransmission and causing airway hyperresponsiveness, a key characteristic of asthma. Guinea pigs were treated with the organophosphate insecticides, chlorpyrifos, diazinon and parathion. Electrical stimulation of the vagus nerves caused frequency-dependent bronchoconstriction that was used to assess the state of reactivity of the airways. Pharmacologic agents were used to define the roles that ... |
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| A Model for Prediction of Probability of Developing an Adverse Physiological Symptom in Individuals Percutaneously Exposed to VX Nerve Agent |
2005 |
23 pages |
| Authors:
Eva F. Dickson; E. J. Duncan; Paul D. Fedele; Doug Nelson; ROYAL MILITARY COLL OF CANADA KINGSTON (ONTARIO) DEPT OF CHEMISTRY AND CHEMICAL ENGINEERING
|
| A model is developed for the probability of toxic effects resulting from either vapour or liquid acute exposure of the skin to the organophosphonate nerve agent VX (O-ethyl S-2-diisopropylaminoethylmethyl phosphonothiolate), for which considerable relevant human toxicity information is available. This model focuses solely on percutaneous toxicity and incorporates population variability of response and variable permeability of the different regions of the body to the agent. An ECt50 value for nausea ... |
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| Multiplex Immunoassays as an Effective Method to Simultaneously Analyze Inflammatory Mediators in Central Nervous System (CNS) Cells: Human Astrocytes Stimulated With Sarin (GB) |
DEC 2004 |
3 pages |
| Authors:
Carmen M. Arroyo; Elisa D. Purcell; David W. Kahler; Clarence A. Broomfield; Brennie E. Hackley Jr; ARMY MEDICAL RESEARCH INST OF CHEMICAL DEFENSE ABERDEEN PROVING GROUND MD NEUROTOXICOLOGY BRANCH
|
| The central nervous system (CNS) is an immuneprivileged site where the role of immune cells and mediators in brain injury caused by organophosphates (OP) is poorly understood. Many mediators have been identified in nervous system tissue. For instance, interleukin-6 (IL-6), a cytokine that acts on a wide range of tissue influencing cell growth and differentiation, is an agonist for vascular endothelial growth factor (VEGF). CNS cells producing IL-6 include astrocytes, ... |
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| Whole Blood Robotic Cholinesterase Assay for Organophosphate Exposure - Testing Soldiers, First Responders, and Civilians in the Field and Laboratory |
DEC 2004 |
9 pages |
| Authors:
Richard K. Gordon; Julian R. Haigh; Gregory E. Garcia; Shawn R. Feaster; Bhupendra P. Doctor; Michael A. Riel; Lee J. Lefkowitz; David E. Lenz; Paul S. Aisen; Wilson Smart; WALTER REED ARMY INST OF RESEARCH SILVER SPRING MD
|
| Exposure to organophosphate (OP) chemical warfare agents (CWAs), pesticides, anesthetics, drugs such as cocaine, and a variety of therapeutic drugs including donepezil or rivastigmine for Alzheimer's disease reduces red blood cell acetylcholinesterase (RBC-AChE) or serum butyrylcholinesterase (BChE) activity. The activity of RBC-AChE and BChE can be used as potential biomarkers of suppressed and/or heightened function in the central and peripheral nervous systems. For instance, the toxicity of pesticides is well ... |
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| Development of a Rat Diisopropylfluorophosphate-Induced Seizure/Status Epilepticus Model for Screening of Neuroprotectants Following Exposure to Chemical Warfare Agents |
17 NOV 2004 |
17 pages |
| Authors:
Stacy M. Crawford; Jaimee R. Compton; Lauren M. Tetz; Ruthie H. Ratcliffe; Keith H. Steele; Richard K. Gordon; Madhusoodana P. Nambiar; WALTER REED ARMY INST OF RESEARCH SILVER SPRING MD
|
| We have developed a seizure/status epilepticus (SE) rat model using diisopropylfluorophosphate (DEP), an organophosphate (OP) surrogate for chemical warfare nerve agents (CWNA) soman and sarin. Rats were surgically implanted with a radiotelemetry probe that records EEG, ECG, body temperature, and physical activity. After 1 week they were exposed to various concentrations of DFP (1.5-4.0 mg/kg, sc) in the presence of pyridostigmine bromide, 2-PAM and atropine to produce more than 24 ... |
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| Gene and Protein Therapy for Poisoning by Organophosphorus Agents |
SEP 2004 |
88 pages |
| Authors:
Oksana Lockridge; NEBRASKA UNIV MEDICAL CENTER OMAHA
|
| The goal of this work is to protect the soldier from the toxicity of nerve agents. The research plan involves finding new ways to deliver protective cholinesterase enzymes into tissues. Gene therapy and protein therapy protocols are being developed. Test animals are being made to test the idea that an organophosphate hydrolase enzyme in the right location will provide protection against organophosphorus toxins. The G117H knockin mouse and the G117H ... |
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| Biochemical Markers for Exposure to Low Doses of Organophosphorus Insecticides |
AUG 2004 |
50 pages |
| Authors:
Oksana Lockridge; NEBRASKA UNIV MEDICAL CENTER OMAHA
|
| Though acetylcholinesterase is the primary target of organophosphorus toxicants, our finding that acetylcholinesterase knockout mice are supersensitive to the lethal effects of VX, DFP, chlorpyrifos oxon, and iso-OMPA demonstrates that other important targets exist. The goal of this work is to identify non-acetylcholinesterase targets of organophosphorus toxicants. Three living mice were treated with a dose of biotinylated organophosphate that was not toxic to the mice. The biotinylated proteins were extracted ... |
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| EXPRESSION AND Purification of a Potential antidote for Organophosphate Warfare Agents |
AUG 2004 |
38 pages |
| Authors:
Kenneth D. Lanclos; AUGUSTA BIOMEDICAL RESEARCH CORP GA
|
| Serine-dependent carboxylesterases (E.C.3. 1.1.1) are found in a variety of tissues with high activity detected in the human liver. Carboxylesterases (CaE) hydrolyze aliphatic and aromatic esters, and aromatic amides; and play an important role in the detoxification of xenobiotic chemicals that contain organophosphate (OP) compounds. Thus, an injectable form of human hCaE should prove to be a valuable antidote for protecting soldiers from these chemical agents. The goals of this ... |
|
| Molecular Targets for Organophosphates in the Central Nervous System |
JUN 2004 |
23 pages |
| Authors:
Edson X. Albquerque; MARYLAND UNIV BALTIMORE
|
| In a continued effort to determine the actions and effects of low- level exposure to the nerve agents sarin, soman, and VX in the mammalian CNS and to help design countermeasures to treat and/or prevent such effects, we have been worked toward accomplishing the following objectives: 1. Determine whether pyridostigmine and the nicotinic APL galanthamine (also spelled galantamine) can antagonize the effects of VX, soman, and sarin on synaptic transmission ... |
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| Atomic Crystal Structure of an Organophosphorus Acid Anhydrolase |
09 MAY 2004 |
4 pages |
| Authors:
Florante A. Quiocho; Alexei Nickitenko; BAYLOR COLL OF MEDICINE HOUSTON TX
|
| The major aim is to determine the three-dimensional atomic structure of an organophosphorus acid anhydrolase (OPAA) by x ray crystallography. This structure is a prerequisite for remodeling the active site, in collaboration with scientists at ECBC and Geo-Centers, Inc. in order to enhance catalytic activity towards fluorinated U-type and other extremely toxic chemical warfare (CW) nerve agents. A decontamination system based on the remodeled OPAA not only provides rapid removal ... |
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| New Inhibitors of the Peripheral Site in Acetylcholinesterase that Specifically Block Organophosphorylation |
APR 2004 |
23 pages |
| Authors:
Terrone L. Rosenberry; MAYO CLINIC JACKSONVILLE FL
|
| Examination of the enzyme structure for acetylcholinesterase (AChE) reveals two sites of ligand interaction: The peripheral site (P-site) located at the entrance of the gorge, and the acylation site (A-site) at the base of the gorge. Our goal is to develop high affinity cyclic peptide ligands specific for the P-site that would block the access of organophosphate agents while allowing the passage of acetylcholine to the A-site for use by ... |
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| Mechanistic Studies Investigating the Role of Organophosphate Insecticide Exposure in the Development and Exacerbation of Asthma |
APR 2004 |
21 pages |
| Authors:
Ernst W. Spannhake; JOHNS HOPKINS UNIV BALTIMORE MD
|
| This grant proposes to determine whether organophosphate insecticides act upon the cholinergic system in the lungs increasing cholinergic neurotransmission and causing airway hyperresponsiveness, which is characteristic of asthma. Guinea pigs were either treated acutely with a high dose or chronically (7 days) with a low does of the organophosphate chlorpyrifos sc. Electrical stimulation of the vagus nerves caused frequency-dependent bronchoconstriction that was significantly potentiated in animals treated with chlorpyrifos. M2 ... |
|
| Quantitative Method for the Detection of Triethyl Phosphate in Aqueous Solutions |
OCT 2003 |
26 pages |
| Authors:
Rosa L. Bagalawis; Joel Carlson; John Walsh; ARMY SOLDIER AND BIOLOGICAL CHEMICAL COMMAND NATICK MA SOLDIER SYSTEMS CENTER
|
| A gas chromatography (GC) method has been developed to detect and quantify triethyl phosphate (TEP) at the parts per million level in aqueous solution. TEP was used as a chemical agent stimulant to evaluate the penetration characteristics of clothing, gloves, boots and items of personal equipment. The analytical method, initially developed in 1981, combines gas chromatography (OC) , gas chromatography-mass spectrometry (GC-MS) and Fourier-Transform infrared (FTIR) techniques. Quality Assurance and ... |
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| Gene and Protein Therapy for Poisoning by Organophosphorus Agents |
SEP 2003 |
144 pages |
| Authors:
Oksana Lockridge; NEBRASKA UNIV MEDICAL CENTER OMAHA
|
| The goal of this work is to find new protection strategies against the toxicity of nerve agents. A gene therapy protocol capable of delivering human acetylcholinesterase into dividing as well as nondividing cells has been developed, using adeno-associated virus to transfer the gene. Mice treated with this virus expressed human acetylcholinesterase. A transgenic mouse line was established that expresses human Cll7H butyrylcholinesterase in all tissue. The Gll7H butyrylcholinesterase gene was ... |
|
| Surface Chemistry of Enzymes for Detection and Decontamination of Organophosphorus Compounds |
20 AUG 2003 |
27 pages |
| Authors:
Roger M. Leblanc; MIAMI UNIV CORAL GABLES FL DEPT OF CHEMISTRY
|
| The principal objective of this project was to understand the molecular interactions between organophosphorus compounds and the enzymes that catalyze the hydrolysis of these compounds at air water-interface (Langmuir films) and in Langmuir-Blodgett films. The report contains the data on the characterization of the Langmuir films of organophosphorus acid anhydrolase (OPAA), organophosphorus acid hydrolase (OPH), and covalent bonding of the enzyme onto the substrate. Results are encouraging and the studied ... |
|
| WRAIR Protocols for Soldier Status and Readiness to Organophosphate Exposure: Unprocessed Whole Blood Cholinesterase and Pyridostigmine Bromide Quantification |
01 JUL 2003 |
5 pages |
| Authors:
Gregory E. Garcia; Shawn R. Feaster; Deborah R. Moorad; Bhupendra P. Doctor; Richard K. Gordon; Connie R. Clark; J. R. Smith; Brian J. Lukey; Raven E. Reitstetter; WALTER REED ARMY INST OF RESEARCH SILVER SPRING MD
|
| Exposure to nerve agents, OPs, pesticides, anesthetics, terrorists' chemical agents, and drugs of abuse such as cocaine, heroin, and some neuro-degenerative disease states selectively reduces AChE and/or BChE activity. Since urban terrorism is on the rise, Federal, State, and local authorities need a reliable, fast, inexpensive method for confirming such an assault to initiate appropriate containment, decontamination, and treatment measures. Thus, we developed a semi-automated medical diagnostic microplate procedure capable ... |
|
| Expression and Purification of a Potential Antidote for Organophosphate Warfare Agents |
JUL 2003 |
9 pages |
| Authors:
Kenneth D. Lanclos; AUGUSTA BIOMEDICAL RESEARCH CORP GA
|
| Serine-dependent carboxylesterases (E.C.3.1.1.1) are found in a variety of tissues with high activity detected in the human liver. Carboxylesterases (CaE) hydrolyze aliphatic and aromatic esters, and aromatic amides; and play an important role in the detoxification of xenobiotic chemicals that contain organophosphate (OP) compounds. Thus, an injectable form of human hCaE should prove to be a valuable antidote for protecting soldiers from these chemical agents. The goals of this project ... |
|
| Low-Level Sarin Neurotoxicity and its Modulation by Pyridostigmine |
FEB 2003 |
57 pages |
| Authors:
Barry W. Wilson; CALIFORNIA UNIV DAVIS
|
| The possibility that a combination of exposures to organophosphate esters (OPs) and the carbamate pyridostigmine bromide (PB) would lead to nerve damage in Gulf War veterans was studied by treating hens and mice with known neuropathic OPs diisopropyl fluorophosphate (DFP), triorthocresyl phosphate (TOCP), sarin and with PB. Subthreshold and threshold levels inducing nerve damage were established in hens repeatedly treated with TOCP and DFP. Multiple doses of sarin did not ... |
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| Relative Inhibitory Potencies of Chlorpyrifos Oxon, Chlorpyrifos Methyl Oxon, and Mipafox for Acetylcholinesterase Versus Neuropathy Target Esterase |
2003 |
15 pages |
| Authors:
T. J. Kropp; R. J. Richardson; MICHIGAN UNIV ANN ARBOR
|
| The relative inhibitory potency (RIP) of an organophosphorus (OP) inhibitor against acetylcholinesterase(AChE) versus neuropathy target esterase (NTE) is [ki(AChE)/ki(NTE)], where ki is the bimolecular rate constant of inhibition. RIPs>1 correlate with the inability of ageable OP inhibitors or their parent compounds to produce OP induced delayed neurotoxicity (OPIDN) at doses >1 for enzymes from hen brain homogenate, and the parent compound, chlorpyrifos (CPS), cannot produce OPIDN in hens at sublethal ... |
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| Biosensor Detection of Neuropathy Target Esterase in Whole Blood as a Biomarker of Exposure to Neuropathic Organophosphorus Compounds |
15 OCT 2002 |
13 pages |
| Authors:
Galina F. Makhaeva; Larisa V. Sigolaeva; Lyudmila Z. Zhuravleva; Arkady V. Eremenko; Ilya N. Kurochkin; Vladimir V. Malygin; Rudy J. Richardson; RUSSIAN ACADEMY OF SCIENCES MOSCOW INST OF PHYSIOLOGICALLY ACTIVE COMPOUNDS
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| Neuropathy target esterase (NTE) is the target for neuropathic organophosphonts compounds (OPs) that produce delayed neurotoxicity (OPIDN). Inhibition/aging of brain NTE predicts the potential for OPIDN in animal models. Lymphocyte NTE has also found use as a biomarker of human exposure to neuropathic OPs. Recently, a sensitive NTE biosensor was developed using a tyrosinase carbon-paste electrode for amperometric (Amp) detection of phenol produced by hydrolysis of the substrate, phenyl valerate. ... |
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| Design and Production of an Organophosphorus-Bioscavenger via Protein Engineering of the Human Acetylcholinesterase |
SEP 2002 |
194 pages |
| Authors:
Avigdor Shafferman; ISRAEL INST FOR BIOLOGICAL RESEARCH NESS ZIONA
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| The design of novel biocatalysts with potential pharmacological use against organophosphate (OP) poisoning, within the mold of recombinant human acetyicholinesterase (rHuAChE), was carried out by two complementing research approaches: a.) Kinetic studies combined with mass spectrometric analysis of rHuAChE and selected mutants thereof, with a variety of OPs for better understanding of the chemical environment for the OPs in the active center of AChE. Specifically, here we describe the effects ... |
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| Gene and Protein Therapy for Poisoning by Organophosphorus Agents |
SEP 2002 |
66 pages |
| Authors:
Oksana Lockridge; NEBRASKA UNIV MEDICAL CENTER OMAHA
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| The goal of this work is to find new treatment strategies for poisoning by nerve agents. A gene therapy protocol capable of delivering human acetylcholinesterase into dividing as well as nondividing cells is being developed, using adeno-associated virus to transfer the gene. The idea that an organophosphate hydrolase enzyme in the right location will provide protection against organophosphorus agents is being tested in a mouse. A gene targeted mouse that ... |
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| Strategies for Metabolic Engineering of Environmental Microorganisms- Application to Degradation of Organophosphate Contaminants |
30 JUL 2002 |
5 pages |
| Authors:
Jay D. Keasling; CALIFORNIA UNIV BERKELEY DEPT OF CHEMICAL ENGINEERING
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| The goal of this work was to develop the experimental and theoretical methods to introduce multiple, heterologous, biodegradation pathways into a single organism and to optimize the flux through those pathways for the remediation of toxic or recalcitrant organic contaminants. Specifically, we found and cloned a gene that encodes an enzyme capable of degrading diethylphosphate, cloned and expressed a pathway for complete mineralization of p-nitrophenol phosphate, cloned and expressed a ... |
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| Expression and Purification of a Potential Antidote for Organophosphate Warfare Agents |
JUL 2002 |
13 pages |
| Authors:
Kenneth D. Lanclos; AUGUSTA BIOMEDICAL RESEARCH CORP GA
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| Serine-dependent carboxylesterases (E.C.3. 1.1.1) are found in a variety of tissues with high activity detected in the human liver. Carhoxylesterases (hCaE) hydrolyze aliphatic and aromatic esters, and aromatic amides. Carboxylesterase may play an important role in the detoxification of xenobiotic chemicals that contain organophosphate (OP) compounds. Thus, an injectable form of human hCaE should prove to be a valuable antidote for protecting soldiers from these chemical agents. To this end, ... |
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| Chemistry of Destroying of Organophosphorus Compounds in Flame and Mechanism of Their Action as Fire Suppressants |
31 MAR 2002 |
50 pages |
| Authors:
Oleg P. Korobeinichev; Andrey G. Shmakov; Vladimir M. Shvartsberg; Tatyana A. Bolshova; RUSSIAN ACADEMY OF SCIENCES NOVOSIBIRSK INST OF CHEMICAL KINETICS AND COMBUSTION
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| The structure of atmospheric lean (phi=0.8) and rich (phi=1.2) CH4/ O2/Ar and C3H8/O2/Ar flames doped with trimethylphosphate (TMP) was studied by molecular beam mass spectrometry (MBMS) and modeling. Methodic difficulties of MBMS measurement of the structure of atmospheric flames were analyzed and recommendations were elaborated. An influence of TMP additive on the structure of atmospheric flames was demonstrated. A strong influence of equivalence ratio of a flame on the concentration ... |
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| Selective, Specific, and Versatile Personal Biosensors to Organophosphate Chemical Toxins Composed of Polyurethane Immobilized Enzymes |
JAN 2002 |
9 pages |
| Authors:
Richard K. Gordon; Alper T. Gunduz; Shawn R. Feaster; Bhupendra P. Doctor; Tracy Cronin; WALTER REED ARMY INST OF RESEARCH WASHINGTON DC DIV OF BIOCHEMISTRY
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| Organophosphorus (OP) nerve agents are a serious threat to military and civilian personnel, so rapid detection of OP compounds in all of these forms is of paramount importance to prevent casualties. Recently, we combined porous polyurethane foam formed in situ from water-miscible hydrophilic urethane prepolymers and enzymes such as ChEs. One of the advantages of this technique imparted to the immobilized enzymes is resistance to denaturing events. Most important, the ... |
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| New Inhibitors of the Peripheral Site in Acetylcholinesterase That Specifically Block Organophosphorylation |
NOV 2001 |
162 pages |
| Authors:
Terrone Rosenberry; MAYO CLINIC JACKSONVILLE FL
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| Acetyicholinesterase (AChE) is one of the most efficient enzymes known. The AChE active site consists of a narrow gorge with two separate ligand binding sites: an acylation site at the bottom of the gorge where substrate hydrolysis occurs and a peripheral site at the gorge mouth. In recent studies, we showed that ligands which bind specifically to the peripheral site can slow the rates at which other ligands enter and ... |
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| Epidemiological and Clinical Evidence for Residual Organophosphate Neurotoxicity |
OCT 2001 |
76 pages |
| Authors:
Peter S. Spencer; OREGON HEALTH SCIENCES UNIV PORTLAND
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| We sought evidence to support or refute the proposal that Gulf War (GW) veterans who served in the Kuwaiti Theater of Operations (KTO) have nervous-system deficits consistent with prior exposure to organophosphoms chemicals (sarin and insecticides). Focus was placed on Desert Storm veterans present within a 50-km radius of Khamisiyah, Coalition-Occupied Iraq, who may have been exposed to sarin/cyclosarin during the first two weeks of March 1991 (Study Group). Comparison ... |
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| Prevention of Organophosphorous Lethality with OPA Anhydrolase (OPAA-2) Containing Stealth Liposomes |
OCT 2001 |
43 pages |
| Authors:
James Leong-Way; TEXAS A AND M RESEARCH FOUNDATION COLLEGE STATION
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| This research is focused on the use of various liposome-like drug carrier systems containing recombinant organophosphorus (OP) hydrolyzing enzymes (OPH = Organophosphorus Acid Hydrolase; OPAA = Organophosphorus Acid Anhydrolase) to prevent organophosphorus poisoning. The objective is to provide long term protection against OP intoxication by using OP-hydrolyzing enzymes with various liposome-based enzyme carrier Systems such as sterically stabilized liposomes (SL) and modified liposome-like carriers (NT). Present research is focused on: ... |
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*ORGANOPHOSPHATES
