ACTIVITY: Former Insecticide (Organophosphate)

Structure:

DFP is a structural analog of sarin. Ref: Sarin (nerve agent GB)-induced differential expression of mRNA coding for the acetylcholinesterase gene in the rat central nervous system; by Damodaran TV, Jones KH, Patel AG, Abou-Donia MB. Biochemical Pharmacology Volume 65, Issue 12 , 15 June 2003, Pages 2041-2047.

79 Reports available from The National Technical Information Service (NTIS) Order from NTIS by: phone at 1-800-553-NTIS (U.S. customers); (703)605-6000 (other countries); fax at (703)605-6900; and email at orders@ntis.gov. NTIS is located at 5285 Port Royal Road, Springfield, VA, 22161, USA.
Order No.	Title	Abstract or Keywords
NTIS/02210010	2004 - Toward Optically Monitored Cytosensors. Authors: McFadden PN Oregon State Univ., Corvallis.	Final rept. 1 Mar 1996-28 Feb 1999. Fish scales display arrays of thousands of colored living cells known as chromatophores. In this study, the use of color changes in isolated lish scales was evaluated as a rapid warning signal for delayed neurotoxic agents. The focus was on detecting delayed effects of organophosphate nerve agents like sarin, though the less toxic diisopropylfluorophosphate (DFP) was used as a sirnulant. DFP caused rapid and long-lasting scale color changes. These signals were readily visible and quantifiable, especially for the brightly iridescent scale colors. DFP induced color changes in scales at similar dose-sensitivity and about 300 times more rapidly than in standard animal models. Scales thus showed promise as toxicity monitors.
NTIS/00860015 43p	2001 - Prevention of Organophosphorous Lethality with OPA Anhydrolase (OPAA-2) Containing Stealth Liposomes. Authors: Leong-Way J Texas A and M Research Foundation, College Station.	Annual rept. 15 Sep 2000-14 Sep 2001. 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: studying and optimizing of the in vitro efficacy of the OP-comlex- hydrolyzing enzymes; optimizing the carrier systems; studying the in vivo efficacy of the encapsulated enzymes; studying the blood cholinesterase level in the presence of OPs, 2-PAM, and the OP-hydrolyzing enzymes and to monitor and attempt to predict the OP toxicity and antagonism. OPH enzyme has, highly efficient substrate specificity to paraoxon but in general it is less efficient to diisopropylfluorophosphate (DFP), soman and satin. However, OPAA can hydrolyze DFP, soman and satin with a relatively high efficiency. DFP and paraoxon were used as model substrates to study the in vitro OP-hydrolyzing efficiency and the in vivo antidotal efficiency of the encapsulated OPAA and OPH. Hydrolysis of DFP was followed by measuring the amount of the fluoride ions formed by using a fluoride ion selective electrode, Hydrolysis of paraoxon was determined spectrophotometrically by measuring the p-nitrophenol formation. The paraoxon hydrolysis displayed saturation kinetics with increasing substrate concentration both with free OPH and encapsulated OPH. The kinetic parameters suggest that paraoxon can freely enter and exit the enzyme carrier systems. Preliminary toxicology studies indicate that the encapsulated OPH and OPAA, (NT- OPH and NT-OPAA), may strikingly enhance the antidotal effects of the clinically proven OP antidotes, 2-PAM and atropine.
NTIS/03240098 272p	2000 - Neurophysiologic and Neuropathologic Effects in Monkeys of Low Level Exposures to Sarin, Pryidostigmine, Pesticides, and Botulinum Toxoid. Authors: Olson CT, Podell M, Sahenk Z, Lordo R, Kinney P Battelle Memorial Inst., Columbus, OH.	Final rept. 30 Sep 1997-30 Jun 2000. Of approximately 700,000 U.S. military personnel serving in the Persian Gulf region during Operations Desert Storm/Shield, about 30,000 have had a range of unexplained complaints including chronic fatigue, muscle and joint pain, loss of concentration, forgetfulness, headaches, and rashes.%'% In response to concerns about health effects resulting from service in the Persian Gulf area and to investigate the nature of illnesses reported by veterans, the Department of Defense initiated the Comprehensive Clinical Evaluation Program (CCEP) for Persian Gulf War veterans. Clinical examinations have been performed on more than 10,000 individuals. The major categories of primary diagnoses were psychological, musculoskeletal, and nonspecific conditions.%1% The question arises whether these nonspecific symptoms were due to service in the Persian Gulf War or are comparable to the number and type of symptoms expected in a population with similar demographics that did not serve in the Persian Gulf War. Among the keywords: Dip(Diisopropylfluorophosphate)
NTIS/ADA363604	1998 - Chronic Organophosphorus Exposure and Cognition. Authors: Buccafusco JJ Medical Coll. of Georgia, Augusta.	Chronic, low-level exposure to acetylcholinesterase (AChE) inhibitor organophosphorus (OP) insecticides or chemical warfare agents produces abnormalities in the function of brain acetylcholine (ACh) neurons, and in humans they may be associated with impaired cognitive function well after withdrawal from such exposure. The purpose of the present study was to identify the severity of cognitive impairment of rats and monkeys following protracted withdrawal from chronic, Low-level exposure to the OP agent diisopropylfluorophosphate (DFP). Assessment of spatial learning (water maze task) in rats began 1 - 17 days after completion of either a 14 day once daily DFP (50,250, or 500 microngram/kg) or vehicle treatment regimen. During the 14 day regimen, prior to withdrawal, spontaneous activity and olfactory behaviors were initially suppressed during DFP exposure, effects to which the subjects became tolerant after receiving the 'standard' (250 microngram/kg dose) regimen. Performance of the spatial memo [abstract truncated]
NTIS/AD-A332-510/7	1996 - Chronic Organophosphorus Exposure and Cognition. Authors: Buccofusco JJ Medical Coll. of Georgia, Augusta. Research Inst.	Chronic, low-level exposure to acetyleholinesterase (AChE) inhibitor organophosphate (OP) insecticides or chemical warfare agents produces abnormalities in CNS acetyicholine (ACh) function, and in humans, may be associated with impaired cognitive function well after withdrawal from such exposure. The purpose of the present study was to identify the severity of inipairment in spatial learning of rats and monkeys following protracted withdrawal from chronic, low-level exposure to the OP agent diisopropylfluorophosphate (DFP). Annual rept 15 Apr 95-14 Mar 96.
NTIS/PB95-148979 13p	1994 - Repeated Inhibition of Cholinesterase by Chlorpyrifos in Rats: Behavioral, Neurochemical and Pharmacological Indices of Tolerance. Authors: Bushnell PJ, Kelly KL, Ward TR Health Effects Research Lab., Research Triangle Park, NC. Neurotoxicology Div. ManTech Environmental Technology, Inc., Research Triangle Park, NC.	Daily subcutaneous (s.c) injections of the organophosphate diisopropylfluorophosphate caused prolonged inhibition of cholinesterase (ChE) activity in whole blood and brain and downregulation of muscarinic receptors in the central nervous system; these changes were accompanied by progressive, persistent deterioration of working memory and motor function. Further, a single s.c. injection of the organophosphate insecticide chlorpyrifos (O,O',-diethyl O-3,5,6-trichloro-2-pyridyl phosphorothionate, CPF), caused neurochemical changes of the same magnitude and duration, but transient impairment of working memory and motor slowing. In the present study, weekly injections of CPF (0, 15, 30 or 60 mg/kg s.c.) inhibited ChE activity in whole blood of rats by 60% to 90% after 5 weeks; the highest dose also induced tremor, working memory impairment and motor slowing in daily delayed matching-to-position/visual discrimination tests. Reducing the CPF injection frequency to every other week relieved the inhibiti [abstract truncated]
NTIS/AD-A290 426/6 17p	1994 - Genetic and Biochemical Manipulation of a Broad-Spectrum Organophosphate Degrading System. Authors: Wild JR Texas A and M Research Foundation, College Station.	Recent studies on the plasmid-borne organophosphorus-degrading gene of Pseudomonas diminuta and its enzyme have sought to define both the genetic organization and the protein chemistry involved in this system. The bacterial gene encodes a single, unique enzyme, a phosphotriesterase (organophosphorus anhydrase), which is capable of hydrolyzing a wide spectrum of organophosphorus neurotoxins ranging from insecticides such a parathion, orthene, coumaphos and diazinon to mammalian neurotoxins such as diisopropylfluorophosphate (DFP), sarin, soman and mipafox. The organophosphorus degrading genes (opd) from two different plasmids in the soil bacteria P. diminuta and Flavobacterium have been sequenced andtheir structural organizations are being characterized. The cloned geneshave been expressed in a number of biological systems from bacteria to insect tissue culture, and the enzyme has been purified and characterized from several different sources. The catalytic reaction has been determined to involve [abstract truncated]
NTIS/AD-A290 571/9 Pub. in Applied Microbiology and Biotechnology, v41 p352-358, 1994., 8p	1994 - Expression of Organophosphate Hydrolase in the Filamentous Fungus Gilociadium Virens. Authors: Dave KI, Lauriano C, Xu B, Wild JR, Kenerley CM Texas A and M Univ., College Station. Dept. of Biochemistry and Biophysics.	The broad-spectrum organophosphate hydrolase (OPH; EC 3.1.8.1) encoded by the organophosphate-degrading gene (opd) from Pseudomonas diminuta MG and Flavobacterium sp. ATCC 27551 possesses capabilities of both P-O bond hydrolysis (e.g. paraoxon) and P-F bond hydrolysis E.G. SARIN AND DIISOPROPYLFLUOROPHOSPHATE (DFP). In the present study a 9.4-kb plasmid, pCL1, was used to transform the saprophytic fungus Gliocladium virens. pCL1 was derived from pJS294 by placing the fungal promoter (prom1) from Cochliobolus heterostrophus upstream and the trpC terminator from Aspergillus nidulans downstream of the opd gene. Southern analysis of restricted genomic DNA from various transformants indicated that integration occurred non-specifically at multiple sites. Western blot analysis of mycelial extracts from transformants confirmed the production of a processed form of the enzyme in the fungus. Maximal levels of OPH activity (rate of p-nitrophenol production from paraoxon) were observed after 168 h of cultur [abstract truncated]
NTIS/PB95-148045 10p	1994 - 24-Hour Control of Body Temperature in the Rat. 2. Diisopropyl Fluorophosphate-Induced Hypothermia and Hyperthermia. Authors: Gordon CJ Health Effects Research Lab., Research Triangle Park, NC. Neurotoxicology Div.	Diisopropyl fluorophosphate (DFP) and other anticholinesterase (antiChE) agents have been found to induce marked hypothermic responses in laboratory rodents. To characterize the effects of DFP on autonomic and behavioral thermoregulation, rats of the Long-Evans strain were injected with DFP while housed in a temperature gradient. The gradient allowed for the measurement of selected ambient temperature T(sub a) and motor activity (MA) over a 6- to 7-day period. Core temperature T(sub c) and heart rate (HR) were also monitored simultaneously using radiotelemetry. Injection of the peanut oil vehicle led to transient elevations in T(sub c), HR, and MA, but no change in selected T(sub a). The next day animals were injected with 0.25, 1.0, or 1.5 mg/kg DFP. DFP (1.0 and 1.5 mg/kg) led to a marked reduction in T(sub c). The decrease in T(sub c) was accompanied by reductions in HR, MA, and selected T(sub a). During the first night after DFP, selected T(sub a) remained elevated as T(sub c) recovered to i [abstract truncated]
NTIS/PB93-229003 8p	1993 - Effect of Repeated Organophosphate Administration on Carbachol-Stimulated Phosphoinositide Hydrolysis in the Rat Brain. Authors: Mundy WR, Ward TR, Dulchinos VF, Tilson HA Health Effects Research Lab., Research Triangle Park, NC. Neurotoxicology Div.	The effects of repeated exposure to two organophosphates on the turnover of phosphoinositides, the second messenger system coupled to the M1 and M3 subtypes of muscarinic receptors, were examined in the rat hippocampus. Repeated diisopropylfluorophosphate (DFP) exposure (0.2-0.8 mg/kg, SC) decreased brain acetylcholinesterase activity and muscarinic receptor density. The incorporation of (3H)myoinositol into brain slices was also decreased. Phosphoinositide turnover was measured as the accumulation of (3H)inositol phosphates (IP) in the presence of lithium. DFP did not affect basal IP accumulation, but decreased carbachol-stimulated IP accumulation in the hippocampus after 0.4 and 0.8 mg/kg. The effects of repeated disulfoton administration (2.0 mg/kg, IP) were also examined in the hippocampus. Similar to DFP, repeated disulfoton exposure decreased acetylcholinesterase activity, receptor density, and carbachol-stimulated IP accumulation. The incorporation of myoinositol, however, was increased i [abstract truncated]
NTIS/AD-A279-000/4 7p	1993 - Monoclonal Antibody AE-2 Modulates Carbamate and Organophosphate Inhibition of Fetal Bovine Serum Acetylcholinesterase. Authors: Wolfe AD, Chiang PK, Doctor BP, Fryar N, Rhee JP Walter Reed Army Inst. of Research, Washington, DC. Div. of Biochemistry.	The monoclonal antibody AE-2 raised against the human erythrocyte acetylcholinesterase (AChE) dimer (acetylcholine acetylhydrolase, EC 3.1.1.7), binds to other mammalian AChEs, including the tetramer that occurs in fetal bovine serum (FBS). AE2 partially inhibited the rate of hydrolysis of the charged substrate acetylthiocholine by FBS AChE, whereas it increased the rate of hydrolysis of the neutral substrate indophenyl acetate. Present results show that AE-2 decreases the rate of inhibition of FBS AChE by the positively charged organophosphate amition-p-toluene sulfonate and the positively charged carbamates pyridostigmine and neostigmine but accelerate inhibition of FBS AChE by neutral organophosphates paraoxon and diisopropylfluorophosphate. Results suggest that AE-2 may allosterically modulate an anionic site in the catalytic center of FBS AChE.
NTIS/AD-A275 433/1 Pub. in Biochemistry, v32 n49 p13441-13450, 1993., 11p	1993 - Direct Observation and Elucidation of the Structures of Aged and Nonaged Phosphorylated Cholinesterases by 31P NMR Spectroscopy. Authors: Segall Y, Waysbort D, Barak D, Ariel N, Doctor BP Walter Reed Army Inst. of Research, Washington, DC.	31P NMR spectroscopy of butyrylcholinesterase (BChE), acetylcholinesterase (AChE), and chymotrypsin (Cht) inhibited by pinacolyl methylphosphonofluoridate (soman), methylphosphonodifluoridate (MPDF), and diisopropyl phosphorofluoridate (DFP) allowed direct observation of the OP-linked moiety of aged (nonreactivatable)and nonaged organophosphorus(OP)-ChE conjugates. The 31P NMR chemical shifts of OP-ChE conjugates clearly demonstrated insertion of a P-0 bond into the active site of aged OP-ChE adducts. The OP moiety of nonaged OP-ChEs was shown to be uncharged. The OP-bound pinacolyl moiety of soman-inhibited and aged AChE was detached completely, whereas only partial dealkylation of the pinacolyl group was observed for soman-inhibited BChEs. This suggests that the latter enzyme reacted with the less active stereoisomer(s) of soman. In the case of soman-inhibited Cht, no dealkylation could be experimentally detected for any of the four stereoisomers of OP-Cht adducts. Results are consistent with [abstract truncated]
NTIS/AD-P008 828/6 10p	1993 - Effects of Soman on Visual Processing. Authors: Townsend AT, Clarke T, Evans G, Pope C, Tomberlin J Army Aeromedical Research Lab., Fort Rucker, AL.	We have demonstrated previously that diisopropylfluorophosphate (DFP) causes a preferential loss of low spatial frequency information in the visual evoked response (VER) of the adult cat. The effect is dose related, can be reversed with atropine, is closely related to acetylcholinesterase (AChE) activity, and shows spontaneous recovery to baseline conditions over 15-20 hours without recovery of AChE activity. After DFP, dopamine (DA) turnover increases and there are consistent changes in gamma-aminobutyric acid (GABA), and muscarinic, DA, and GABA receptors in visual cortex. The experiments described here were designed to investigate the effect of soman on visual processing in the adult cat. The VER was used as our response measure, and all drugs were given i.v. Following soman (1-5 ug/kg), there is a preferential loss to low spatial frequencies in the VER. The loss is dose related, can be reversed with atropine, seems closely linked to AChE activity, but shows no tendency for spontaneous recove [abstract truncated]
NTIS/AD-P008 811/2 9p	1993 - Modulation of Acetylcholinesterase by Monoclonal Antibody AE-2. Authors: Wolfe AD, Chiang PK, Doctor BP, Rhee JP, Saeed M Walter Reed Army Inst. of Research, Washington, DC.	The monoclonal antibody AE-2 was raised against the human erythrocyte dimer acetylcholinesterase (AChE; acetylcholine acetyl-hydrolase, EC 3.1.1.7), but bound to other mammalian AChEs, including the tetramer which occurs in fetal bovine serum (FBS). AE-2 partially inhibited the rate of hydrolysis of the charged substrate acetylthiocholine (ATC) by FBS AChE, while it increased the rate of hydrolysis of the neutral substrate, indophenyl acetate (IPA). Present results show AE-2 to decrease the rate of inhibition of FBS AChE by the positively charged organophosphate (OP), amiton-p-toluene sulfonate, and the positively charged carbamates (CB) pyridostigmine and neostigmine, but, consistent with its effects upon ATC and IPA, to accelerate inhibition of FBS AChE by the neutral OPs, paraoxon and diisopropylfluorophosphate (DFP). Results suggest that AE-2 may allosterically modulate an anionic site facilitating access to the catalytic center of FBS AChE. This article is from 'Proceedings of the Medical [abstract truncated] Keywords: Acetylcholinesterase Monoclonal antibodies
NTIS/PB94-137130 13p	1993 - Behavioral and Neurochemical Effects of Acute Chlorpyrifos in Rats: Tolerance to Prolonged Inhibition of Cholinesterase. Authors: Bushnell PJ, Pope CN, Padilla S Health Effects Research Lab., Research Triangle Park, NC. Neurotoxicology Div. Northeast Louisiana Univ., Monroe. School of Pharmacy.	To determine whether these functional effects of diisopropylfluorophosphate (DFP) resulted from inhibition of cholinesterase (ChE) and downregulation of muscarinic cholinergic receptors, rats were dosed with chlorpyrifos (CPF), an OP pesticide which inhibits blood and brain ChE of rats for weeks after a single injection. Long-Evans rats were trained to perform an appetitive test of memory and motor function and were then injected s.c. with 0, 60, 125 or 250 mg/kg of CPF in peanut oil and tested 5 days/week for 7 weeks. Unconditioned behavior was also rated for signs of cholinergic toxicity. CPF inhibited ChE activity in whole blood in a dose-related manner for more than 53 days. The degree and time course of ChE inhibition in blood and brain and the downregulation of muscarinic receptors in brain after 125 mg/kg of CPF closely paralleled the previously reported effects of 25 daily injections of 0.2 mg/kg of DFP. In addition, CPF-treated rats were subsensitive to oxotremorine-induced hypothermia [abstract truncated]
NTIS/PB93-228971 14p	1993 - Acute and Delayed Effects of Diisopropyl Fluorophosphate on Body Temperature, Heart Rate and Motor Activity in the Awake, Unrestrained Rat. Authors: Gordon CJ Health Effects Research Lab., Research Triangle Park, NC. Neurotoxicology Div.	Acute exposure to diisopropyl fluorophosphate (DFP) causes irreversible inhibition of acetylcholinesterase activity, leading to various behavioral and autonomic sequelae including hypothermia, reduced motor activity, and other neurological dysfunctions. To characterize the acute response and recovery of autonomic and behavioral processes to DFP exposure, rats of the Long-Evans strain were implanted with radiotransmitters that allowed the monitoring of core temperature, heart rate, and motor activity in unrestrained animals 24 h/d. These parameters were monitored for 96 h following subcutaneous injection of DFP at a dose of 0, 0.1, or 1.0 mg/kg. Rats given 0 and 0.1 mg/kg DFP displayed an increase in core temperature and motor activity during the first 24 h postinjection. Core temperature decreased a maximum of 1.9 C by 5 h after DFP and then started to recover, reaching control levels by 17 h after DFP treatment. Motor activity was also depressed during the first 24-h period in the 1.0 mg/kg gro [absract truncated]
NTIS/PB93-228609 15p	1993 - Strain Comparisons of DFP Neurotoxicity in Rats. Authors: Gordon CJ, MacPhail RC Health Effects Research Lab., Research Triangle Park, NC. Neurotoxicology Div.	The purpose of the study was to assess intraspecies differences in behavioral and autonomic function in three strains of rat following administration of diisopropyl fluorophosphate (DFP), an irreversible inhibitor of acetylcholinesterase activity. Male rats of the Long-Evans (LE), Fischer 344 (F344), and Sprague-Dawley (SD) strains were administered DFP at doses of 0 to 1.5 mg/kg (s.c.). The animals were placed 60 min later into one of two motor activity chambers and tested for 30 min. Motor activity was measured using either a Doppler-based system or a commercial photocell device. Following measurement of motor activity in the Doppler system, body temperature was measured and blood was then withdrawn by cardiac puncture and analyzed for serum cholinesterase activity. The remaining rats were retested 24 hr after DFP administration in the photocell device. The results showed a significant influence of strain on the effects of DFP. Motor activity of LE rats was reduced by DFP at doses of 1.0 and 1 [abstract truncated]
NTIS/AD-A257 540/5 17p	1992 - Cholinesterase Assay for Monitoring the Kinetics of the JD6.5 Organophosphorus Acid Anhydrase in Detoxification of Diisopropylfluorophosphate. Authors: Yeh HR, Cheng TC, DeFrank JJ Chemical Research, Development and Engineering Center, Aberdeen Proving Ground, MD.	In the present studies, cholinesterase was used for monitoring the enzymatic activities of the JD6.5 organophosphorus acid anhydrase. The kinetic data indicated that: (1) the first order of kinetic constants (k) and Vmax values of the enzymatic reactions increased as the concentrations of the enzyme increased; (2) while the half-life (tl/2) of diisopropylfluorophosphate (DFP) hydrolysis decreased as the enzyme concentrations increased; (3) the minimum time required for hydrolysis of 9mM of DFP was 3 min at the concentrations of the enzyme present; Km values of DFP were found to be in range of 5mM; and (4) both MnCl2 and NaCl were found to be required for the optimal activity of the enzyme. Final rept. Jan-Jun 88.
NTIS/AD-A244 435/4 17p	1991 - Effect of Diisopropylfluorophosphate on Muscarinic and Gamma-Aminobutyric Acid Receptors in Visual Cortex of Cats. Authors: Townsend AT, Adams DK, Lopez JB, Kirby AW Army Aeromedical Research Lab., Fort Rucker, AL.	Administration of diisopropylfluorophosphate (DFP), an organophosphorus (OP) compound, irreversibly inhibits acetylcholinesterase (AChE) and results in cholinergic hyperactivity. This study investigated muscarinic and gamma aminobutyric acid (GABA) receptor changes in visual cortex of cats following an acute exposure to DFP. A single acute administration of DFP (4 mg/kg) decreased the number of muscarinic receptors at 2, 10, and 20 hours after treatment. GABA receptors were elevated at 2 and 10 hours but returned to within control levels at 20 hours. No significant alteration in muscarinic or GABA receptor affinity was noted. In all cases cortical AChE activity was inhibited 60-90%. These findings show a down regulation of muscarinic receptors after DFP associated with low AChE activity. GABA receptors also are altered, and may be part of a compensatory mechanism to counteract excess cholinergic stimulation. Final rept. Keywords: Acetylcholinesterase Visual cortex Diisopropylfluorophosphate GABA receptors Muscarinic receptors
NTIS/PB91-200238 11p	1991 - Behavioral and Neurochemical Changes in Rats Dosed Repeatedly with Diisopropylfluorophosphate. Authors: Bushnell PJ, Padilla SS, Ward T, Pope CN, Olszyk VB Health Effects Research Lab., Research Triangle Park, NC. Neurotoxicology Div. Northeast Louisiana Univ., Monroe. School of Pharmacy. Northrop Services, Inc., Research Triangle Park, NC.	Behavioral effects of organophosphates (OPs) typically decrease with repeated exposure, despite persistence of OP-induced inhibition of acetylcholinesterase (AChE) and downregulation of muscarinic acetylcholine (ACh) receptors. To characterize this tolerance phenomenon, rats were trained to perform an appetitive operant task which allowed daily quantification of working memory (delayed matching-to-position), reference memory (visual discrimination) and motor function (choice response latencies and inter-response times (IRTs) during delay). Findings indicate that animals showing a definitive sign of tolerance to OP administration (subsensitivity to a cholinergic agonist) were also functionally impaired on both the motoric and mnemonic demands of a working memory task. The nature of this impairment suggests further that it results from compensatory changes in the CNS, e.g., muscarinic receptor downregulation, considered to produce 'tolerance' to OPs in exposed animals. Journal article. Pub. in J [abstract truncated]
NTIS/PB92-124668 17p	1991 - Acute Effects of Diisopropyl Fluorophosphate (DFP) on Autonomic and Behavioral Thermoregulatory Responses in the Long-Evans Rat. Authors: Gordon CJ, Fogelson L, Lee L, Highfill J Health Effects Research Lab., Research Triangle Park, NC.	Experiments were designed to assess the mechanisms of diisopropyl fluorophosphate (DFP)-induced changes in thermoregulation of the rat. In one study, male rats of the Long-Evans strain were injected with DFP (s.c.) at doses ranging from 0 to 2.0 mg/kg while maintained at an ambient temperature (Ta) of 20-24C. Body (Tb) and tail skin (Tt) temperatures were recorded for 5 h post-injection. DFP doses of > or = 1.0 mg/kg resulted in significant decreases in Tb lasting up to 5 h and increases in Tt lasting up to 1 h post-injection. In a second study, metabolic rate (MR), evaporative water loss (EWL), motor activity (MA), Tb, and Tt, were measured at 2 h post-injection of 0, 0.5, 1.0, and 1.5 mg/kg DFP (s.c.) at Ta values of 10, 20, and 30 C. DFP treatment resulted in hypothermia at all three Ta values, but the effect was attenuated at 30 C. MR was significantly reduced at a Ta of 20 C following 1.5 mg/kg, unaffected by DFP at a Ta of 30 C, and stimulated at 10 C following 0.5 mg/kg DFP. EWL was si [abstract truncated]
NTIS/AD-A239 635/6 56p	1991 - Nicotinic Cholinergic Receptors in Rat Brain. Authors: Kellar KJ Georgetown Univ., Washington, DC. School of Medicine.	Nicotinic cholinergic receptors in rat brain were studied to determine their dependence on intact disulfide bonds, their relationship to catecholamine and serotonin axons, and their regulation by cholinesterase inhibitors and nicotinic agonists. Reduction of disulfide bonds with dithiothreitol decreased the number of nicotinic binding sites labeled by (3H)acetylcholine (3 HAC). This effect was reversed by reoxidation of the reduced sulfhydryl groups to disulfide bonds. Lesioning catecholamine or serotonin axons with specific neurotoxins resulted in a decrease in the number of nicotinic receptor binding sites in the striatum and hypothalamus, indicating that in those brain areas the receptors are located on these axons. The number of nicotinic receptors is decreased by chronic inhibition of cholinesterase enzymes with diisopropylfluorophosphate or soman. In contrast, the receptor number is increased by chronic treatment with nicotine. Final rept. 1 May 83-31 Oct 86.
NTIS/PB92-158658 10p	1991 - Relationship between Cholinesterase Inhibition and Thermoregulation Following Exposure to Diisopropyl Fluorophosphate in the Rat. Authors: Gordon CJ, Fogelson L, Richards J, Highfill J Health Effects Research Lab., Research Triangle Park, NC. NSI Technology Services Corp., Research Triangle Park, NC.	The study examined the relationship between inhibition of cholinesterase activity (CA) and thermoregulatory response in the rat following exposure to the organophosphate (OP), diisopropyl fluorophosphate (DFP). Male Long-Evans rats were injected with DFP dissolved in peanut oil in doses ranging from 0 to 1.5 mg/kg (s.c.). Colonic T(sub col) and tail skin temperature T(sub tail) were recorded at 0, 1, 2, and 3 hr post-injection. At 3 hr post-injection the rat was sacrificed and a blood sample was taken by cardiac puncture and analyzed for CA. There was a biphasic dose effect of DFP on T(sub col) with slight but significant elevation in T(sub col) in the dose range of 0.01 to 0.5 mg/kg and a significant depression in T(sub col) at doses of 1.0 and 1.5 mg/kg. There was a dose-dependent fall in CA with DFP administration in the erythrocyte, plasma, and whole blood fractions. Hypothermia was associated with 80 to 87% inhibition in CA, whereas the elevation in T(sub col) was associated with 20 to 70% [abstract truncated]
NTIS/PB91-217893 24p	1991 - Mechanism of Spontaneous Recovery of Neuromuscular Transmission after Acetylcholinesterase Inhibition in the Rat Neuromuscular Junction (Onderzoek naar het Herstelmechanisme van Neuromusculaire Transmisna Acetylcholinesterase Remming). Authors: Melchers BPC, van der Laaken AL Medical Biological Lab. RVO-TNO, Rijswijk (Netherlands).	Neuromuscular transmission shows a significant degree of spontaneous recovery after being impeded by acetylcholinesterase inhibition. Part of the recovery can be ascribed to de novo synthesis of acetylcholinesterase but another part is independent of enzyme activity. To unravel the mechanism underlying the synaptic adaptation to acetylcholinesterase inhibition a study compared a number of electrophysiological parameters in diaphragms taken from animals that were sacrificed within 15 minutes after a 2xLD50 dose of the acetylcholinesterase inhibitor diisopropylfluorophosphate and from similarly treated animals killed after being kept alive for 3h under artificial respiration. The study found no differences in the quantal content. There was a significantly smaller degree of endplate potential rundown at tetanic stimulation and the mepp amplitude was smaller in the 3h adapted animals. In addition, the desensitization induced by carbachol appeared to be less in the group. It is concluded that postsyn [abstract truncated]
NTIS/DE92004442 8p	1991 - Supercritical fluid extraction and organic solvent microextraction of chemical agent simulants from soil. Authors: Griest WH, Ramsey RS, Ho C, Caldwell WM Oak Ridge National Lab., TN. Sponsored by Department of Energy, Washington, DC.	Experiments with chemical warfare agent simulants suggest that supercritical fluid extraction can achieve good extraction recoveries of agents in soil and produce less laboratory waste than current organic solvent extraction methods. Two-ppm spikes in 1 g of Rocky Mountain Arsenal Standard Soil were extracted using 5% methanol in carbon dioxide at 300 atm for 2 min at 60(degrees)C. Recoveries (n=3) were 79(plus minus)23% for dimethylmethylphosphonate, 93(plus minus)14% for 2-chlorethylethylsulfide, 92(plus minus)13% for diisopropylfluorophosphate, and 95(plus minus)17% for diisopropylmethylphosphonate. A 5 min ultrasonic micro-scale extraction using methanol is more reproducible but less efficient. 1991 U.S. Army chemical research conference on chemical defense, Aberdeen Proving Ground, MD (United States), 19-22 Nov 1991.
NTIS/AD-A236 870/2 43p	1990 - Central Neuronal Mechanisms Involved in the Cardiorespiratory Effects of Organophosphorous Agents. Authors: Gillis R, Dretchen KL Georgetown Univ., Washington, DC.	The organophosphorous anticholinesterase agents diisopropylfluorophosphate (DFP) and soman were applied topically, by way of cotton pledgets placed bilaterally to three different chemosensitive areas of the ventral medulla of the cat, and the effects on cardiorespiratory activity were monitored. The dose range was 6.25-25.0 microgram/side DFP and 0.004-0.5 micrograms/side soman. Comparison of dose-response data upon application to the three areas indicated that both agents exerted their greatest effect at the intermediate area. Oxotremorine, a specific agonist for muscarinic receptors, also had a much greater effect on cardiorespiratory activity when applied to the intermediate area as compared to its effects after application to either the caudal or the rostral areas. Further evidence indicating the role of a muscarinic receptor in mediating the respiratory depressant effects of DFP and soman at the intermediate area was the finding that atropine counteracted the toxic effects of these compound [abstract truncated]
NTIS/AD-A228 521/1 9p Pub. in Chirality and Biological Activity, p169-175 1990.	1990 - Catalytic Properties of Nonstereospecific Diisopropylfluorophosphatases. Authors: Lenz DE, Little JS, Broomfield CA, Ray R Army Medical Research Inst. of Chemical Defense, Aberdeen Proving Ground, MD.	Enzymes that catalyze the hydrolysis of organophosphorus compounds (Mazur, 1946) have been classified as diisopropylfluorophosphatases (DFPase, EC 3.8.2.1). These enzymes often vary in their substrate selectivities depending on their source. Some, isolated from cephalopods, show a preference for diisopropylfluorophosphate (DFP) as the substrate (Hoskin, 1971; Garden et al., 1975), whereas those from mammalian sources tend to hydrolyze other organophosphorus esters such as tabun (GA), soman (GD), or sarin (GB) (Augustinsson and Heimburger, 1954; Mounter, 1963; Hoskin, 1971; Hoskin and Long, 1972; Gay and Hoskin, 1979) in preference to DFP. Tabun, sarin, and soman each has a center of asymmetry at the phosphorus atom giving rise to stereoisomers. (js)
NTIS/AD-A218 409/1 14p	1989 - Actions of Organophosphates on the Mammalian Spinal Cord. Authors: Warnick JE Maryland Univ. at Baltimore. Dept. of Pharmacology and Experimental Therapeutics.	The characteristics of monosynaptic transmission in the isolated spinal cord of the neonatal rat were established to determine optimal temperature and analysis. It was determined that 25 C was suitable and that the area of the reflex was the best measure of motoneuron activity. The action of diisopropylfluorophosphate (DFP) was examined on monosynaptic transmission in the spinal cord of the neonatal rat, in vitro. DFP caused a dose-dependent depression of the monosynaptic reflex which could be prevented or reversed by atropine. Initial experiments suggest that the depression is independent of acetylcholinesterase inhibition. Diazepam was examined in pilot experiments and found to be ineffective in preventing DFP-induced depression. It also appeared that diazepam was only moderately effective in reversing such depression. On the other hand, the tripeptide thyrotropin-releasing hormone effectively and completely reversed the depression caused by DFP. Frequency-dependent depression of the monosynap [abstract truncated]
NTIS/AD-A215 077/9 24p	1989 - Cellular Actions and Interactions of Anticholinesterases and Their Antidotes in Mammalian Autonomic Neurons. Authors: Dun NJ Stritch School of Medicine, Maywood, IL.	The effects of organophosphorus anti-cholinesterase (anti-ChE) agents, soman, tabun, diisopropylfluorophosphate (DFP) and non-organophosphorus anti-ChE agents, eserine and neostigmine on sympathetic neurons and on ganglionic transmission were investigated. Intracellular recordings were obtained from sympathetic neurons of isolated rabbit and guinea pig superior cervical ganglia by means of glass microelectrodes. DFP, soman and eserine increased and blocked nicotinic cholinergic transmission at low and high concentrations, respectively. These agents at lower concentrations, i.e. 1 micro M or lower, facilitated nicotinic transmission by inhibiting ganglionic cholinesterases. Whereas, these agents at higher concentrations, i.e. 1 or 10 micro M appeared to block nicotinic transmission by different mechanisms. The effects of pyridinealdoxine (2-PAM), a cholinesterase reactivator, on sympathetic neurons and on ganglionic transmission were also studied and found to be concentration-dependent as well. T [abstract truncated]
NTIS/AD-A213 677/8 8p	1989 - Biochemical Characterization and Protein Crystallography of OPA Anhydrase. Authors: Ward KB, Deschamps JR, Zuk WM Naval Research Lab., Washington, DC.	Squid, Loligo pealii, hepatopancreas organophosphorous acid anhydrase (OPAase) hydrolyzes and detoxifies nerve agents, such as diisopropylfluorophosphate (DPF) and Soman. Refinements in the purification of OPAase produce an enzyme with a specific activity greater that 300 U/mg, and yield of about 1 mg purified enzyme from a typical purification. Based on results obtained from atomic absorption spectroscopy, only zinc is present in the native active enzyme. Only zinc can completely reactivate the metal free enzyme. The relationship between pH and enzyme activity led to the hypothesis that cysteine may be involved in enzyme activity, however attempts to modify cysteine residues had no effect on enzyme activity. Preliminary results from this study suggest that tyrosine or histidine may be the active site residue. The sequence of the first 15 N-terminal residues has been determined. Experiments to produce polyclonal antibodies against squid OPAase have shown signs of success. The robotics system we [abstract truncated]
NTIS/AD-A212 968/2 50p	1989 - Effect of Organophosphorus Compounds on the Conformation of Acetylcholinesterase and Acetylcholine Receptor: Tacrine Protection of Acetylcholinesterase from Inactivation by Diisopropylfluorophosphate and Interaction of Acetylcholinesterase and Acetylcholine Receptor with Soman and Tabun. Authors: Yang JT, Wu CSC, Sun X California Univ., San Francisco.	Tacrine showed an apparent noncompetitive inhibition of actylcholinesterase (AChE) from Torpedo californica with a dissociation constant, K1, of 8.5 nM. It altered the CD bands of AChE in the near-UV region, which monitor the local conformation of aromatic side groups, but not those in the far-UV region, which measure the secondary structure. With this band as a probe, the bound tacrine could be displaced by edrophonium or decamethonium, both of which are known to bind to the anionic site at the active center of AChE, but not by propidium, which binds to the peripheral site of the enzyme. The inactivation of AChE by potent, irreversible inhibitors such as soman and tabun could be slowed down by adding reversible inhibitors such as tacrine and hexamethonium bromide. Acetylcholine receptor (AChR) seemed to bind soman, which, however, did not alter the conformation of the AChR (based on far- and near-UV CD spectrum). The addition of acetylcholine induced a local conformational change of AChR; this [abstract truncated]
NTIS/AD-A208 405/1 37p	1989 - Effect of Organophosphates on Cholinergic and Other Neurotransmitter Dynamics in Brain. Authors: Dewey WL, Brase DA Medical Coll. of Virginia, Richmond. Dept. of Pharmacology and Toxicology.	The effects of physostigmine, diisopropylfluorophosphate (DFP), sarin, tabun, and soman on a number of neurotransmitter and effector systems in mouse brain after iv administration were studied, in addition to effects on lethality, spontaneous activity, and body temperature in mice. Less extensive studies were also carried out in rats with DFP and soman and in guinea pigs with soman. The order of potency of the irreversible acetylcholinesterase (AChE) inhibitors for both lethality and AChE inhibition was DFP < tabun < sarin < soman. However, there was not a good correlation between the LD50 values and ED50 values of AChE inhibition among these agents. Guinea pigs were much more sensitive to soman-induced lethality than were mice or rats, but none of the six brain areas examined appeared to be uniquely sensitive to soman-induced AChE inhibition. All agents decreased spontaneous activity and body temperature in doses causing inhibition of AChE. Except for physostigmine, the duration of ACh [abstract truncated]
NTIS/AD-A225 636/0 101p	1989 - Tolerance Following Organophosphate Poisoning of Tracheal Muscle. Authors: Farley JM, Dwyer TM Mississippi Univ. Medical Center, Jackson. Dept. of Pharmacology and Toxicology.	The effects of subacute exposure to the organophosphate acetylcholinesterase diisopropylfluorophosphate (DFP) soman, sarin and (VX) were studied on the binding properties of muscarinic receptors of swine tracheal smooth muscle, and on the contractile response and the electrophysiological properties of the muscle. There is no difference between weanling and young adult swine in the density of receptors in tracheal smooth muscle. The nonselective muscarinic antagonists atropine, scopolamine and quinuclidinyl benzilate (3H)QNB competitively inhibited (3H)QNB binding to the homogenate with Hill coefficients of 0.9-1.9 and inhibition constants (Ki) of nanomolar range. Competition with selective antagonists pirenzepine and 3-quinuclicinyl xanthene-9-carboxylate (QNX) gave Ki values of 0.26 Mm and 0.78 nM, respectively, and Hill coefficients of approximately 1. There was a single population of (3H)QNB binding sites of the M3 subtype for all tested muscarinic antagonists. Competition with the selective [abstract truncated]
NTIS/AD-A218 732/6 49p	1989 - Acetylcholinesterase Inhibitors on the Spinal Cord. Authors: Warnick JE Maryland Univ., Baltimore. School of Medicine.	This report concerns ongoing studies on the mechanism and site of action of organophosphate (OP) and carbamate inhibitors of acetylcholinesterase (AChE) in the mammalian spinal cord and the reversal of those effects by known and putative antagonists. Spinal cords isolated from neonatal rats 5- to 9-days old were hemisected and placed in experimental chambers. Recordings were made from ventral roots under varying stimulation and recording paradigms to characterize the actions of these agents. Parallel studies on AChE were performed to determine the role of enzyme inhibition in the observed effects. A full dose-response curve for alteration of synaptic transmission and AChE in the isolated rat spinal cord by diisopropylfluorophosphate (DFP) was completed and studies were expanded to include sarin, other organophosphates and carbamates. The dose-response curve for sarin was extended into the picomolar range, completed and compared with initial results on soman, VX and tabun. In addition, the action [abstract truncated]
NTIS/AD-A208 214/7 9p	1989 - Partial Characterization of an Enzyme That Hydrolyzes Sarin, Soman, Tabun, and Diisopropyl Phosphorofluoridate (DFP), Authors: Little JL, Broomfield CA, Fox-Talbot MK, Boucher LJ, MacIver B Army Medical Research Inst. of Chemical Defense, Aberdeen Proving Ground, MD.	The properties of a rat liver enzyme that hydrolyzes organophosphorus (OP) inhibitors of Cholinesterases were studied. The rates of hydrolysis of OP inhibitors were determined by continuous titration of released hydrogen ions, using a pH stat method. Centrifugation of homogenates at 205,000g for 30 min demonstrated that the activity was in the soluble fraction. Hydrolysis of sarin, soman, and diisopropyl phosphorofluoridate (DFD), but not of tabun, was stimulated by the addition of Mn(2+) and Mg(2+). Unlike other OP hydrolases that preferentially hydrolyze the non-toxic isomers of soman, this enzyme hydrolyzed all four soman isomers at approximately the same rate. This results was obtained in vitro by gas chromatographic analysis of enzyme-catalyzed soman hydrolysis and confirmed in vivo by demonstrating reduced toxicity in mice of soman partially hydrolyzed by this enzyme. Km and Vmax were determined by fitting V vs (S) to a hyperbolic function using regression analysis. Elution profiles from g [abstract truncated]
NTIS/AD-A208 150/3 10p	1988 - Specific Soman-Hydrolyzing Enzyme Activity in a Clonal Neuronal Cell Culture, Authors: Ray R, Boucher LJ, Broomfield CA, Lenz DE Army Medical Research Inst. of Chemical Defense, Aberdeen Proving Ground, MD.	An enzymatic activity that specifically hydrolyzes the highly toxic organophosphorus anticholinesterase compound soman (pinacolyl methylphosphonofluoridate) has been identified and partially characterized in the clonal neuronal neuroblastoma-glioma hybrid NG108-15 cell line. Using the whole cell homogenate as the enzyme source and 1 mM substrate, the relative rate of hydrolysis of two other toxic anticholinesterase compounds sarin (isopropyl methylphosphonofluoridate) and tabun (ethyl-N-dimethyl phosphoramidocyanidate) is approximately one-tenth the rate of hydrolysis of soman, while DFP (diisopropyl phosphorofluoridate), paraoxon (p-nitrophenyl diethylphosphate), and a phosphinate PNMPP (p-nitrophenyl methyl (phenyl)phosphinate) are not hydrolyzed. Analysis of the kinetics of soman hydrolysis reveals two components of the enzyme activity with different affinities and reaction rates. Unlike previously reported enzymes of ths type, this enzyme lacks chiral specificity and thus hydrolyzes both tox [abstract truncated]
NTIS/AD-A188 368/5 10p	1987 - Effects of Chronic Diisopropylfluorophosphate Treatment on Spatial Learning in Mice, Authors: Upchurch M, Wehner JM Colorado Univ. at Boulder. Supporting Agency: Air Force Office of Scientific Research, Bolling AFB, DC.	The Morris water task was used to measure the effects of chronic diisopropylfluorophosphate (DFP) treatment on C57BL/6Ibg mice. Control mice showed good task acquisition and searched accurately for the platform after it was removed from the pool, suggesting that they had formed a spatial map of the platform's location relative to distal cues. In contrast, mice chronically treated with DFP prior to training showed a marked deficit in spatial learning. Chronic DFP treatment did not affect ability to locate a visible platform and did not impair task retention in mice trained to find the hidden platform prior to DFP treatment. The chronic DFP treatment decreased muscarinic binding in cortex, hippocampus, and striatum. These results indicate that C57BL mice are capable of spatial learning in the water task. The ability of chronic DFP treatment to impair place but not cue learning suggests that the cholinergic dysfunction produced by DFP is similar to those produced by lesions of central cholinergic s [abstract truncated]
NTIS/AD-A181 921/8 9p	1987 - Sex Differences in the Recovery of Brain Acetylcholinesterase Activity Following a Single Exposure to DFP (Diisopropylphosphofluoridate), Authors: Smolen A, Smolen TN, Han PC, Collins AC Colorado Univ. at Boulder. Inst. of Behavioral Genetics. Supporting Agency: Air Force Office of Scientific Research, Bolling AFB, DC.	Male and female C57BL, DBA, and C3H mice were injected intraperitioneally with a single 6.33 mg/kg dose of diisopropyl-phosphofluoridate (DFP). The time course of recovery of acetylcholinesterase (AchE) activity as well as effects on choline acetyltransferase (ChAT) activity and brain muscarinic and nicotinic receptors were measured. DFP treatment did not affect ChAT activity or the muscarinic an nicotinic receptors were measured. DFP treatment did not affect ChAT activity or the muscarinic and nicotinic receptors. Near control levels of AChE activity were regained in female mice within the first 20 days. However, levels of whole brain AChE acitivity remained depressed for as long as 40 days following a single dose of DFP in male mice. An analysis of the recovery of AChE acitivity in several brain regions indicated that control activity was regained in striatrum, hindbrain, and hippocampus, but not in cortex, midbrain, and hypothalamus. These data are discussed in terms of potential neurotoxicit [abstract truncated]
NTIS/AD-A221 118/3 12p	1987 - Recovery of the Visual Evoked Response in the Cat Following Administration of Diisopropylfluorophosphate: An Irreversible Cholinesterase Inhibitor. Authors: Kirby AW, Harding TH, Wiley RW Army Aeromedical Research Lab., Fort Rucker, AL.	Visual evoked responses (VER) to counterphased gratings were recorded from area 17 of cat visual cortex prior to and following administration of diisopropylfluorophosphate (DFP). The VER and acetylcholinesterase (AChe) activity of blood, retina, and visual cortex were reduced significantly following DFP administration. Approximately 2 hours after exposure to 4 mg/kg DFP, the VER began to recover and in some cats returned to base line levels. In contrast, blood, retina, and cortex AChe activity showed little, if any, tendency for recovery throughout the experiment. Since atropine sulfate provided at least partial recovery of the VER following DFP without affecting AChE inhibition, an accumulation of acetylcholine (ACh) probably is involved in the initial visual loss. However, recovery of the VER over time while AChE remained severely inhibited implicates mechanisms other than, or in addition to, accumulation of ACh at receptor sites. Keywords: Toxicity. (kt) Final rept. Pub. in Life Sciences, v [abstract truncated]
NTIS/AD-A255 300/6 30p	1987 - Effects of Organophosphate Nerve Agents on Visual Cortical Function. Authors: Bonds AB, DeBruyn EJ Vanderbilt Univ., Nashville, TN.	The effects of intravenous administration of the anticholinesterase agent soman (pinacolyl methylphosphonofluoridate, 5-15 ug/kg) on the visual evoked potential (VEP) were examined in cats using phase-reversed sine wave grating stimuli of different spatial frequencies and contrasts. Soman doses of 5-7 u7/kg caused a depression of the VEP across all spatial frequencies in an abrupt, non-graded fashion. Studies in which contrast was varied showed that VEP depression resulted primarily from a decrease in the response system gain rather than a change in the contrast sensitivity. Administration of a pretreatment regimen of physostigmine (0.25 mg/kg), atropine (0.8 mg/kg) and mecamylamine (0.8 mg/kg) raised the effective soman dose level by a factor of at least 8. The impact of iontophoretically applied physostigmine, pyridostigmine and diisopropylfluorophosphate (DFP) on single neurons in striate cortex was also studied. Of 23 cells in which physostigmine was applied, 2 showed no changes in firing ra [abstract truncated]
NTIS/AD-A224 005/9 38p	1987 - Effects of Organophosphate Nerve Agents on Visual Cortical Function. Authors: Bonds AB, DeBruyn EJ Vanderbilt Univ., Nashville, TN.	The effects of intravenous administration of the anticholinesterase agents physostigmine, pyridostigmine, diisopropylfluorophosphate (DFP), and soman (pinacolyl methylphosphonofluoridate) on the visual evoked potential (VEP) in cats were examined using phase-reversed sine wave grating stimuli of different spatial frequencies and contrasts. All four agents caused a depression of the VEP across all spatial frequencies and at low (1-8 Hz) temporal frequencies. Studies in which contrast was varied showed that VEP depression resulted primarily from a decrease in the response system gain rather than a change in the contrast sensitivity. Physostigmine, pyridostigmine, and DFP yielded response losses that were graded with increasing dosages, while soman acted in an abrupt, nongraded fashion with a threshold dose of 5-7 ug/kg. (jes) Final rept. 15 Jul 83-15 Jan 87.
NTIS/PB89-106819 9p	1987 - Triphenyl Phosphite: In vivo and In vitro Inhibition of Rat Neurotoxic Esterase (Journal Version). Authors: Padilla SS, Grizzle TB, Lyerly D Health Effects Research Lab., Research Triangle Park, NC. Northrop Services, Inc., Research Triangle Park, NC.	Organophosphorus compounds which, after acute administration, inhibit neurotoxic esterase (NTE) by > or = 65% and undergo a subsequent 'aging' reaction, produce a delayed neuropathy characterized by degeneration of large and long nerve fibers. The present studies examine in detail the NTE-inhibiting properties of triphenyl phosphite (TPP), a plasticizer which produces ataxia and degeneration of the spinal cord in animals. A neurotoxic dosing regimen (1184 mg/kg/week, sc, for 2 weeks) inhibited both brain and spinal cord NTE (< or = 40%) only marginally 4 and 48 hr postdosing. By contrast, TPP was shown in vitro to be a potent inhibitor of rat brain NTE relative to Mipafox or diisopropyl phosphorofluoridate. Preincubation of 10 micromolar TPP in buffer (37 deg C) resulted in a time-dependent loss of TPP's ability to inhibit NTE. In summary, TPP is a powerful NTE inhibitor in vitro, but only a marginal NTE inhibitor after in vivo administration. These results raise questions as to the causal [abstract truncated]
NTIS/AD-A211 259/7 32p	1987 - Organophosphate Anticholinesterases: Their Effects on Sleep and Vigilance in a Rodent Model. Authors: Meighen G, Pegram GV, Gnadt J, Atwood C, Crowson J Alabama Univ. in Birmingham.	Cholinergic mechanisms have been implicated in the control of sleep and its various physiological parameters. These systems were manipulated using the organophosphate acetylcholinesterase inhibitors diisopropylfluorophosphate (DEP) and o,1,2,2-trimethyl propyl methylphosphonofluroidate (soman). Results of the DFP studies indicated increased rapid eye movement (REM) sleep in rats administered chronic doses of DFP. In the acute DFP study, the treated rats showed a dose-dependent decrease in all stages of sleep; most likely due to DFP's toxic effects. Results of acute administration of soman included the disturbance of normal sleep patterns and revealed a dose- dependent effect upon the different stages of sleep.Keywords: Cholinesterase inhibitor; Sleep; Toxicity; DFP; Organophosphate; RA 5%. (KT). Final rept. 15 Jan 83-14 Jan 85.
NTIS/AD-A200 182 38p	1987 - Studies on the Effects of Anticholinesterase Compounds on Functions of Neuroglia. Authors: 19HK Albany Medical Coll., NY.	The purpose of this work was to determine whether selected anticholinesterase compounds are likely to have effects on normal astroglial function in the mammalian center nervous system (CNS). To do this, the authors studied the effect of three organophosphates, diisopropyl-fluorophosphonate (DFP), paraoxon, and parathion, and the carbamat physostigmine on the ion transport, volume control, electrophysiological and monoamine transmitter uptake properties of primary astrocyte cultures. Compounds were studied at 1 micrometer -1 mM concentrations and both acute and chronic effects were observed. Physotigmine and parathion inhibited uptake of tritium-labelled serotonin at 10 micrometers, but had no effects at concentrations of 1 micrometer of less. The effects of paration and paraoxon were irreversible within at least 1 hour after removal of the inhibitor. In conclusion, it seems that some acetylcholinesterase (AChE) inhibitors have marked effects on monoamine transmitter uptake, ion transport, and vo [abstract truncated]
NTIS/AD-A199 157/9 38p	1987 - Effect of Organophosphorus Compounds on the Conformation of Acetylcholinesterase and Acetylcholine Receptor. Reconstitution of Globular Dimer of Acetylcholinesterase and Interaction of Acetylcholinesterase and Receptor with Diisopropylfluorophosphate. Authors: Yang JT, Wu CSC, Gan L, Reed WD California Univ., San Francisco.	The detergent-soluble globular dimer of acetylcholinesterase from Torpedo californica was reconstituted through dialysis into egg phosphatidylcholine vesicles. The size of the reconstituted particles depended on the ionic strength of the buffer as well as the molar lipid/protein ration (R). The solution of the protein-lipid complex was turbid at R = 5,000 and I = 0.13, and the particles became heterogeneous at R < 2,000. The enzyme was unstable at R = 1,000 and I = 0.05. Based on circular dichroism studies, the conformation of the enzyme reconstituted at R = 4,000 and I = 0.07 remained unaltered. The enzymatic activity and the Michaelis-Menten constant were also unchanged. The reconstituted enzyme seemed to be more stable against thermal denaturation than in detergent solution. Acetylcholinesterase is irreversibly inhibited by diisopropyl fluorophosphate (DFP). The three isozymes, buffer-soluble globular dimer, asymmetric dodecamer and its derived globular tetramer, had essentially the same b [abstract truncated]
NTIS/AD-A179 677/0 7p	1986 - Strain Comparison of Physiological and Locomotor Responses of Mice to Diisopropylfluorosphosphate, Authors: Smolen A, Smolen TN, Oh EI, Collins AC Colorado Univ. at Boulder. Inst. of Behavioral Genetics. Supporting Agency: Air Force Office of Scientific Research, Bolling AFB, DC.	The effects of acute treatment with the organophosphate, diisopropylfluorophosphate (DFP), were studied in three inbred mouse strains, C57BL, DBA and C3H. A battery of physiological and locomotor tests including respiratory rate, heart rate, body temperature, Y-maze activity and rotarod performance was used. Dose-response and time course studies were carried out. Approximately 15 min after injection the animals were markedly affected by the drug with maximal effects occurring approximately 2 hours after injection. Strain comparisons were made at the 2 hr time point. In all strains, males and females were affected about equally except for respiratory rate and rotarod performance in which females were slightly more effected. Strain comparisons revealed that for most of the test the C57BL mice were most affected by the DFP and the C3H mice were least affected. For the heart rate test the DBA mice were the most sensitive. Previous studies form our laboratory have demonstrated a similar rank ordering [abstract truncated]
NTIS/AD-A182 244/4 10p	1986 - Dissociation of Decreased Numbers of Muscarinic Receptors from Tolerance to DFP (Diisopropylfluorophosphate), Authors: Smolen TN, Smolen A, Collins AC Colorado Univ. at Boulder. Inst. of Behavioral Genetics. Supporting Agency: Air Force Office of Scientific Research, Bolling AFB, DC.	Several studies have demonstrated that chronic treatment with organophosphates, such as DFP, elicits a decreased number of brain muscarinic receptors (measured by the binding of QNB) which has been presented as an explanation for tolerance to the organophosphates. The purpose of the studies presented here was to assess whether graded changed in QNB binding could be atttained following different methods of chronic DFP treatment, and whether tolerance to DFP paralled these changes. Male DBA mice were injected with DFP every 4 days or 2 days for 30 days or daily for 14 days. The animals were subsequently challenged with DFP or the muscarinic agonist, oxotremorine, and respiratory rate, heart rate, body temperature, Y-maze activity and rearing were recorded. Chronic DFP-treated animals were supersensitive to the effects of DFP on respiratory rate, heart rate, and body temperature whereas a modest tolerance to the effects of oxotremorine on respiratory rate, heart rate, and body temperature was seen.
NTIS/AD-A222 361/8 20p	1986 - Central Neuronal Mechanisms Involved in the Cardiorespiratory Effects of Organophosphorus Agents. Authors: Gillis RA, Dretchen KL Georgetown Univ., Washington, DC. Dept. of Pharmacology.	The purpose of our study was to determine where organophosphates act in the brain to cause respiratory depression. Our focus was on the chemosensitive sites on the ventral surface of the medulla of anesthetized cats. For this purpose, drugs were applied bilaterally on the ventral surface of the medulla, specifically at the rostral, intermediate and caudal areas using cottonoid pledgets, while monitoring tidal volume and respiratory rate. Doses of 6.25, 12.5 and 25.0 mu sub g/side of diisopropylfluorophosphate (DFP) applied to the intermediate area produced dose-related increases in tidal volume. In some cases the highest dose tested also resulted in respiratory depression that was characterized by a slowing in respiratory rate. Only minor effects on respiration were observed upon bilateral application of DFP to rostral and caudal areas. Topical application to atropine to the intermediate area counteracted the respiratory effects of both DFP and soman. Furthermore, topical application of oxotremo[abstract truncated]
NTIS/AD-A183 850/7 36p	1986 - Studies on the Biodisposition of Organophosphates in Mice. Authors: Martin BR Medical Coll. of Virginia, Richmond. Dept. of Pharmacology and Toxicology.	The biodisposition of diisopropylfluorophosphate (DFP), soman, and sarin was studied in the major organs of the mouse after i.v. administration of sublethal but pharmacologically active doses. DFP was also administered via inhalation, allowing comparison of disposition data between the two routes of administration. Only trace quantities of parent compounds were found in tissues. The major portion of the radioactivity was determined to be vocalently bound or free metabolites of the parent compounds. All compounds tested induced immediate hypothermia and hypoactivity lasting at least 7 hr. However, substantial quantities of radioactivity remained in the brain following recovery from the pharmacological effects. Cholinesterase inhibition was also not correlated with either free agent or bound or free metabolites, suggesting that non-cholinesterase binding of the parent compounds may play a role in the depression of CNS activity. The pharmacological effects of i.v. administered tabun were also evalu [abstract truncated]
NTIS/AD-A177 917/2 8p	1986 - In Vivo and In Vitro Assays for Organophosphate Poisoning Therapeutic Chemicals Using the House Fly, 'Musca domestica L', Authors: Das YT, Wirtz RA, Andre RG Walter Reed Army Inst. of Research, Washington, DC.	The lethal biochemical lesion of organophosphate (OP) poisoning in animals is the inactivation of acetylcholinesterase (AChE), an enzyme responsible for terminating the action of the neurotransmitter, acetylcholine (ACh), on the acetylcholine receptor (AChE). In mammals, treatment of OP poisoning putatively involves either antagonizing the effect of ACh on AChR or regenerating the inhibited AChE, or both. Historically, this has been done by administering atropine and an oxime such as (2-PAM) although success was limited. For primary testing, insects a cost effective alternative. Thoracic injection of N-methyl pyridinium-2-aldoxime chloride (2-PAM) into house flies one hour before or after diisopropylfluorophosphate (DFP) elevated the baseline LD50 of DEP by 50 and 162 times, respectively. The net increase in the acetylcholinesterase activity by the addition of 2-PAM 3 minutes before or after the addition of DFP to the fly homogenate ranged from 48.5 to 50.5%. Toxogonin was comparable to 2-PAM. H [abstract truncated]
NTIS/AD-A203 991/5 333p	1986 - Effects of Chemical Agents on the Cholinergic Neurotransmitter System. Authors: Jenden DJ, Russell RW California Univ., Los Angeles. Dept. of Pharmacology.	The research investigated behavioral and neurochemical adaptation during acute and chronic exposures to and withdrawal from chemicals affecting the cholinergic neurotransmitter system. Neurochemical assays confirming that the three irreversible anticholinesterases (diisopropylfluorophosphate, DFP; soman; and sarin) initially produced precipitous decreases in normal activity levels of anticholinesterase (AChE), butyrylcholinesterase (BuChE) and aliesterase. During chronic treatment the general trend was for the activity to remain depressed. Accompanying depressed AChE activity was a decrease in the density of muscarinic receptors (mAChR). ACh turnover was depressed and ACh levels increased. Chronic depression was also shown to disinhibit ACh evoked release, results consistent with the role of muscarinic autoreceptors on presynaptic nerve terminals. Two cholinergic agonists, analogs of oxotremorine, were synthesized. They were shown to cause an irreversible reduction in the density of mACHR, e.g. [abstract truncated]
NTIS/AD-A185 158/3 8p	1986 - Organophosphate and Carbamate Compounds have Pre- and Postjunctional Effects at the Insect Glutamatergic Synapse, Authors: Idriss MK, Aguayo LG, Rickett DL, Albuquerque EX Maryland Univ. at Baltimore. Dept. of Pharmacology and Experimental Therapeutics. Supporting Agency: Army Research Office, Research Triangle Park, NC.	The effects of the organophosphate compounds diisopropylfluorophosphate (DFP), dimethylphosphoramidocyanidic acid ethyl ester (tabun), O-ethyl S-2 diisopropylaminoethyl-methyl phosphonothiolate (VX) and the carbamate compound 1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrol (2,3-6Bindol-5-ol methylcarbamate (physostigmine) were studied on the methathoracic flexor and extensor tibialis muscles of Locusta migratoria. These anticholinesterase (anti-ChE) agents interacted with pre- and post-synaptic regions of the glutamatergic neuromuscular synapse. In physiological solution, containing normal calcium concentration (2 mM), these agents initiated spontaneous excitatory post-synaptic potentials (EPSPs) and muscle action potentials (APs) alternating with periods of reduced spontaneous activity in which only miniature excitatory postsynaptic potentials (MEPSPs) could be recorded. This spontaneous EPSP and AP firing was influenced by Ca++0; at low concentrations, the spontaneous APs were abolished but EPS [abstract truncated]
NTIS/AD-A186 594/8 12p	1986 - Effects of Organophosphate Esters on Neuropeptide Systems. Authors: McKelvy JF State Univ. of New York at Albany. Research Foundation.	Organophosphate esters were studied in terms of their ability to affect neuropeptides in the rat central nervous system. The in vivo biosynthesis of enkephalin peptides in the basal ganglia and of vasopressin and oxytocin in the hypothalamus were studied and the effect of subcutaneous administration of diisopropylfluorophosphate (DFP) in the biosynthesis of these neuropeptides was assessed. It was found that DFP inhibited the biosynthesis of vasopressin and oxytocin. These results suggest that organophosphates exert their effects not only on cholinergic systems but also on neuropeptide systems important in endocrine and cardiovascular function. Annual rept. 1983-1984,
NTIS/AD-A181-556/2 6p	1986 - Effects of Diisopropyl Phosphorogluoridate (DFP) of Inter-Response Time and Circadian Patterns of Lever Pressing in Rats, Authors: Raslear TG, Leu JR, Simmons L Walter Reed Army Inst. of Research, Washington, DC. Neuropharmacology Branch.	Rats were injected with saline, 1.0 mg/kg or 2.6 mg/kg of diisopropyl phosphorofluoridate (DFP). Three days later the animals were placed in cages in which they could press a lever to obtain their entire daily ration of food. The time of day at which responses occurred and the time between successive responses were recorded over a six day period to determine the circadian pattern of lever-pressing and the distribution of inter-response times (IRTS). The saline injected rats exhibited a normal nocturnal pattern of feeding, while both DFP treated groups exhibited a significantly greater tendency to eat during the day. Analysis of the IRT distributions of the three groups showed a different pattern of results. The saline and 1.0 mg/kg DFP groups produced nearly identical IRT distributions, while the 2.6 mg/kg group produced an IRT distribution which was marked by significant increases in the interquartile range and median IRT. Keywords: Diisopropy, Phosphorofluoridate, Fluoridates, Phosphorus compounds, Circadian rhythms
NTIS/AD-A180-671/0	1986 - Effects of Diisopropyl Phosphorofluoridate (DFP) on Inter-Response Time and Circadian Patterns of Lever-Pressing in Rats, Authors: Raslear TG, Leu JR, Simmons L Walter Reed Army Inst. of Research, Washington, DC. Pub. Neurobehavioral Toxicology and Teratology, v8 p655-658 1986., 4p	Rats were injected with saline diisopropyl phosphorofluoridate (DFP). Three days later the animals were placed in cages in which they could press a lever to obtain their entire daily ration of food. The time of day at which responses occurred and the time between successive responses were recorded over a six day period to determine the circadian pattern of lever-pressing and the distribution of inter-response times (IRTs). The saline injected rats exhibited a normal nocturnal pattern of feeding, while both DFP treated groups exhibited a significantly greater tendency to eat during the day. Analysis of the IRT distributions of the three groups showed a different pattern of results. The saline and 1.0 mg/kg DFP groups produced identical IRT distributions, while the 2.6 mg/kg groups producted an IRT distribution which was marked by significant increases in the interquartile range and median IRT. Since the 1.0 mg/kg dose of DFP produced a circadian disruption but did not affect the IRT distribution, [abstract truncated]
NTIS/AD-A217 464/7 47p	1986 - Neurochemical Mechanism of Organophosphorus Compounds: Effect on Neuromembrane. Authors: Lee NM California Univ., San Francisco.	The effect of diisopropylfluorophosphate (DFP) and several other organophosphates on brain membranes was studied. DFP bound to a wide range of proteins in synaptic plasma membranes (SPM), but no effect was detected on cross-linking of these proteins by several imidate reagents. DFP, soman, sarin, and tabun administered in vivo significantly altered the levels of endogenous opioids peptides in several brain regions. A search for an endogenous enzyme in brain capable of inactivating DFP was inconclusive, but suggested that one might be present in the soluble fraction. Keywords: RA5, diisopropylfluorophosphate, Synaptic plasma membrane, Cross-linking agents, Endogenous opioids, Nerve gas antidotes, Protein synthesis. Final rept. 1 Jul 82-30 Jun 85.
NTIS/AD-A206 524/1 62p	1985 - New Conceptual Approaches to Prophylaxis and Therapy of Organophosphorus Poisons. Authors: Karczmar A Loyola Univ. Medical Center, Maywood, IL.	Organophosphorus (OP) Anticholinesterases. The compounds that we are discussing are descendants of the earlier agents such as diisopropyl fluorophosphonate (DFP) and tetraethylpyrophosphate (TEPP). The drugs that we are at this time concerned with are principally soman (GD) serine (GB) tabun (GA) and VX. The symptoms of OP toxicity are described, as well as the molecular mechanisms and therapy. Keywords: Antidotes; CNS; Gastric system; Cholinesterase inhibitors; Metabolism; Military medicine. (kt) Final rept. 15 Nov 83-2 Feb 85,[abstract truncated]
NTIS/AD-A202 539/3 22p	1985 - Cardiovascular Effects of Soman. Authors: Brezenhoff HE University of Medicine and Dentistry of New Jersey, Newark.	Soman, sarin, and diisopropylfluorophosphate (DFP) increased blood pressure following injection by various routes in the conscious or anesthetized rat. Sarin and DFP were about 1/2 and 1/20 as potent as soman, but the slopes of the regression lines were similar. There was a close correlation between the magnitude of the pressor response and the degree of acetylcholinesterase (AChE) inhibition in the brainstem, cortex, hippocampus and hypothalamus. Increases in blood pressure became apparent only when brain AChE inhibition was greater than about 70%. The pressor response was blocked by N-(4-diethylamino-2-butynyl) succinimide (DKJ-21), atropine and phenoxybenzamine, but not by methylatropine. Atropine, but not phenoxybenzamine, increased survival. These findings suggest that the pressor response to soman is mediated by central muscarinic receptors acting through increased sympathetic activity. Tolerance developed to the vasoconstrictor effects of norepinephrine during, and for some time following [abstract truncated]
NTIS/AD-A187 186/2 27p	1985 - Cellular Actions and Interactions of Anticholinesterases and Their Antidotes in Mammalian Autonomic Neurons. Authors: Dun NJ Stritch School of Medicine, Maywood, IL.	The major objectives of this study are (1) elucidation of the cellular mechanism of the facilitatory and blocking effects of organophosphorus anti-cholinesterase (anti-ChE) agent, diisopropylfluorophosphate (DFP) on sympathetic neurons and on ganglionic transmission; and (2) clarification of the site and mechanism of action of a cholinesterase (ChE) reactivator, pyridinealdoxime (2-PAM) on cholinergic transmission. Isolated rabbit superior cervical ganglia or guinea pig inferior mesenteric ganglia were used in this study. Intracellular recordings were obtained from neurons of the isolated sympathetic ganglia by means of glass microelectrodes. DFP, 2-PAM and other agents were applied to the ganglia either by superfusion in known concentrations or by pressure ejection from a micropipette containing appropriate agents. DFP exerted a dose-dependent action on nicotinic and muscarinic transmission of the sympathetic neurons. It is concluded that contrary to the long standing concept that DFP and 2-PAM [abstract truncated]
NTIS/AD-A182 614/8 35p	1985 - Effects of Organophosphate Nerve Agents on Visual Cortical Function. Authors: Bonds AB, DeBruyn EJ Vanderbilt Univ., Nashville, TN.	The effects of the anticholinesterase agents pyridostigmine and diisopropylfluorophosphate (DFP) on the visual evoked potential (VEP) were examined using phase-reversed sine wave gratings of varying spatial and temporal frequencies and contrasts. Response amplitudes and noise levels were determined by Fourier transforming the VEP and summing the first 15 even and odd harmonics, respectively. Both agents caused a depression of the VEP in a dose-dependent fashion across all spatial frequencies in 50% of the trials and low frequencies in the remaining trials. Responses to low temporal frequencies were depressed, and high frequencies were enhanced. Studies in which contrast was varied showed that VEP depression resulted from a decrease in the response system gain rather than a change in the contrast sensitivity. Administration of DFP also depressed the VEP equally across all spatial frequencies in the majority of animals and depressed low spatial frequencies in the remaining 25%. The VEP depression [abstract truncated]
NTIS/AD-A171 951/7 7p	1985 - Effects of Soman, in Vivo and in Vitro, on Aldolase Activity, Authors: Lenz DE, Barney BA Army Medical Research Inst. of Chemical Defense, Aberdeen Proving Ground, MD.	We examined the in vivo and in vitro effects of soman on aldolase activity. Male rats were killed at 4, 6, 9 and 12.5 min after subcutaneous (s.c.) administration of 90 micrograms/kg soman. At 4 min after treatment, aldolase activity was inhibited 55-90% compared to control in cerebral cortex, brainstem, mid-brain and cerebellum; and up to 50% of control in diaphragm and muscle. By 12.5 min, aldolase activity in all areas had returned to control levels except in the diaphragm, which still exhibited 36% inhibition. In vitro activity of rabbit muscle aldolase was not inhibited by .001 M soman. In contrast, diisopropyl-fluorophosphonate (DFP, .001 .01 M) acted as a competitive inhibitor of aldolase activity in vitro. The results suggest that in vivo, soman effects on aldolase activity in vitro. The results suggest that in vivo, soman effects on aldolase activity are transitory. Any long-lasting effects of soman on aldolase activity may occur only in the periphery, and not in the central nervous sys [abstract truncated]
NTIS/AD-A161 162/3 9p	1985 - Effects of Diisopropylfluorophosphate on Spatial Frequency Responsivity in the Cat Visual System, Authors: Harding TH, Kirby AW, Wiley RW Army Aeromedical Research Lab., Fort Rucker, AL.	Cholinergic influences have been found at various stages of processing within the primary visual pathway. In the cat, indirect evidence for cholinergic neurons has been found in retina, lateral geniculate nucleus, and visual cortex. Recenty, we have shown that the carbamate physostigmine sulfate preferentially reduces the cortical visual-evoked response (VER) to low spatial frequencies while minimally affecting the response to high spatial frequencies. This non-uniform reduction in VER amplitude was considered cholinergic in nature since it could be reversed by the muscarinic antagonist, atropine sulfate. To further investigate the cholinergic nature of the selective visual loss, we studied the effects of diisopropylfluorophosphate (DFP) on the cortical VER. Visual-evoked responses to counterphased gratings were recorded from area 17 of cat visual cortex before and after diisopropylfluorophosphate (DFP) administration. DFP produced effects similar to those obtained following physostigmine sulfat [abstract truncated]
NTIS/AD-A184 481/0 63p	1985 - Design, Synthesis and Screening of Potential Pyridinium Oxime Prodrugs. Authors: Borchardt RT Kansas Univ., Lawrence. Center for Biomedical Research.	In an attempt to improve the delivery of quaternary pyridinium oxime regenerators of acetylcholinesterase (AChE) to the central nervous system (CNS), structural analogs and prodrugs of N-methylpyridinium 2-carbaldoxime (2-PAM) have been synthesized. The potential prodrugs are dihydropyridinium oximes (pro-2-PAM's) or tetrahydropyridinium oximes, which possess electron-withdrawing substituents in the 3- or 5-position. As precursors to these prodrugs, we have synthesized and characterized a series of 5-substituted-2-PAMs (I, Br, Cl, CH, CN, CONH2-substituted) and a series of 3-substituted PAMs (I, Br, Cl, CH3-substituted). These analogs were tested in vitro for their ability to reactivate diisopropylfluorophosphate (DEP)-inactivated eel AChE. Final rept. 1 Mar 82-31 Jul 85,
NTIS/AD-A184 479/4 54p	1985 - Report March 1, 1984-July 31, 1985, Authors: Borchardt RT Kansas Univ., Lawrence. Center for Biomedical Research.	In an attempt to improve the delivery a quaternary pyridinium oxime regenerators of acetycholinesterase (AChE) to the central nervous system (CNS), structural analogs (I) and potential prodrugs (II) of N-methyl-pyridinium 2-carbaldoxime (2-PAM) have been synthesized. The potential prodrugs are dihydropyridinium oximes (pro-2-PAM's), which posses electron withdrawing substituents in the 3- or 5-position. As precursors to these prodrugs, we have synthesized and characterized this year a series of 5-substituted-2-PAM's (C1, CH3, CN, COHN2 substituted) and a series of 3-substituted-2-PAM's (Br, C1, CH3 substituted). These new analogs and the 5-substituted 2-PAM's (I, Br substituted) and 3-substituted-2-PAM (I substituted) synthesized last year were tested in vitro for their ability to reactivate diisopropylfluorophosphate (DEP)-inactivated AChE, in vivo for their ability to protect mice from a challenge dose (2 X LD50) of DFP and, and in vivo for their ability to protect mice from a challenge dose (abstract truncated]
NTIS/OTS0206895 EPA/OTS; Doc #878216228	1985 - EFFECTS OF ORGANOPHOSPHATES ON MONOCYTE NONSPECIFIC ESTERASE ACTIVITY & PERIPHERAL BLOOD MONOCYTE FUNCTIONS -WITH COVER LETTER DATED 12-0-985 JOHN HOPKINS UNIV	Keywords: GENERAL ELEC CO ARYL PHOSPHATES HEALTH EFFECTS BIOCHEMISTRY MAMMALS HUMANS IN VITRO CAS Registry Numbers: 55-91-4 - DFP [Isoflurophate; C6-H14-F-O3-P] 57-47-6 - Physostigmine [C15-H21-N3-O2] 64-19-7 - Acetic acid [C2-H4-O2] 67-56-1 - Methyl alcohol [C-H4-O] 67-64-1 - Acetone [ C3-H6-O] 75-09-2 - Methylene Chloride [C-H2-Cl2] 78-93-3 - Methylethyl ketone [ C4-H8-O] 80-05-7 - Bisphenol A [ C15-H16-O2] 95-50-1 - 1,2-Dichlorobenzene [ C6-H4-Cl2] 100-41-4 - Ethylbenzene [C8-H10] 108-88-3 - Toluene [C7-H8 ] 111-92-2 - Dibutylamine [C8-H19-N] 115-86-6 - Triphenyl phosphate [C18-H15-O4-P] 121-44-8 - Triethylamine [C6-H15-N] 128-37-0 - Butylated hydroxytoluene [C15-H24-O] 311-45-5 - Paraoxon [C10-H14-N-O6-P] 645-15-8 - Bis(4-nitrophenyl)phosphate [C12-H9-N2-O8-P] 830-81-9 - alpha-Naphthyl acetate [C12-H10-O2] 927-62-8 - 1-Butanamine, N,N-dimethyl- [C6-H15-N] 1300-71-6 - Dimethyl phenol [C8-H10-O] 2929-86-4 - Phosphorous acid, tris(decyl) ester [C30-H63-O3-P] 3121-70-8 - alpha-Naphthyl butyrate [C14-H14-O2] 3121-71-9 - alpha-Naphthyl propionate [C13-H12-O2] 3287-06-7 - Phosphorous acid, decyl diphenyl ester [C22-H31-O3-P] 4013-95-0 - 1,2-Ethanediamine, N,N'-dibutyl- [C10-H24-N2] 4483-62-9 - Octanoic acid, 1-naphthyl ester [C18-H22-O2] 7681-49-4 - Sodium fluoride [Na-F] 25653-16-1 - Tris(3,5-xylenyl)phosphate [C24-H27-O4-P] 28108-99-8 - Isopropylphenyl diphenyl phosphate [C21-H21-O4-P] 28109-00-4 - Bis(isopropylphenyl) phenyl phosphate [C24-H27-O4-P] 56803-37-3 - tert-Butylphenyl diphenyl phosphate [C22-H23-O4-P] 58570-87-9 - no info 63848-94-2 - Reofos 50 [no formula available; a synthetic isopropylated triaryl phosphate ester, which can be used in a wide variety of resins, particularly PVC.- Ref] 66797-44-2 - Kronitex 100 [no formula available; plastic additive] 67426-57-7 - Kronitex 50 [no formula available; flame-retardant hydraulic fluid] 76775-00-3 - Kronitex TXP [no formula available;plasticiser for PVC]
NTIS/OTS0518445 EPA/OTS; Doc #40-8542546	1985 - THE EFFECTS OF ORGANOPHOSPHATES ON MONOCYTE NONSPECIFIC ESTERASE ACTIVITY AND PERIPHERAL BLOOD MONOCYTE FUNCTIONS INCLUDING COVER LETTER DATED 12/09/85 JOHNS HOPKINS U	Keywords: GENERAL ELECTRIC CO ARYL PHOSPHATES HEALTH EFFECTS BIOCHEMISTRY MAMMALS HUMANS IN VITRO CAS Registry Numbers: 1330-78-5 - Imol S-140 [Phosphoric acid, tris(methylphenyl) ester; C21-H21-O4-P] 3437-23-8 - 1,2-Ethanediamine, N-(2-methylpropyl)- [C6-H16-N2] Note: details on the following are in the above citation 55-91-4 - DFP [Isoflurophate; C6-H14-F-O3-P] 57-47-6 64-19-7 67-56-1 67-64-1 75-09-2 78-93-3 80-05-7 95-50-1 830-81-9 100-41-4 108-88-3 111-92-2 115-86-6 121-44-8 128-37-0 311-45-5 645-15-8 927-62-8 1300-71-6 2929-86-4 3121-70-8 3121-71-9 3287-06-7 7681-49-4 25653-16-1 28108-99-8 28109-00-4 56803-37-3 58570-87-9 66797-44-2 67426-57-7 76775-00-3
NTIS/AD-A179 438/7 21p	1984 - Neurochemical Mechanism of Organophosphorus Compounds: Effect on Neuromembrane. Authors: Lee NM California Univ., San Francisco.	Work over the past year has focussed on two major areas: 1) an attempt to identify an endogenous enzyme in brain capable of inactivating diisopropylfluorophosphate (DEP) and other organophosphorus compounds; and 2) effects of DFP on in vivo brain protein synthesis. In addition, we have begun a new project in which the effects of DFP administered in vivo on brain content of several endogenous opioid peptides is to be examined. The possibility of a DFP-inactivating enzyme in brain tissue was examined by incubating mouse brain homogenates and subcellular fractions with DFP under various conditions. DFP hydrolysis was followed indirectly, by testing the effects of supernatants to inhibit acetylcholinesterase (AChE). Our results suggest that the 100,000g supernatant of brain homogenate (S3) may contain a DFP-hydrolyzing enzyme, but further work is needed to establish this conclusion. The results in the brain protein synthesis study, which are still very preliminary, suggest that DFP does alter the sy [abstract truncated]
NTIS/PB85-169167 25p	1984 - Distribution av Diisopropylfluorofosfat (DFP) i Moess: En Autoradiografisk Undersoekning (Distribution of Diisopropylfluorophosphate (DFP) in Mice: An Autoradiographic Study), Authors: Koch B Foersvarets Forskningsanstalt, Umea (Sweden). Text in Swedish.	The distribution of an organophosphorous compound, diisopropylflurorphosphate (DFP), has been studied with whole-body autoradiography to demonstrate the localization, metabolism and excretion of the compound in an intact animal. Considerable accumulation was found in liver, respiratory organs, Harderian glands, urinary tract and in the mucous membrane of intestinal canal. Low content of DFP was seen in salivary glands, bone marrow, brown fat, skin and thyroid gland. 14C-DFP was not detected in brain, spinal marrow and gall-bladder. DFP is probably metabolized through enzymatic hydrolysis by carboxylesterases, primarily in renal cortex and liver. The hydrolyzed product is thereafter excreted with the urine. Furthermore, DFP was not decomposed to any greater extent during its passage through skin.
NTIS/AD-A180 109/1 48p *******	1984 - Characterization of Organophosphate-Induced Epileptiform Activity in the Mammalian Hippocampus. Authors: Lebeda FL, Rutecki PA, Johnston D Baylor Coll. of Medicine, Houston, TX. Dept. of Neurology.	Experiments were performed using the in vitro rat hippocampal slice preparation to investigate the extracellularly recorded epileptogenic effects produced by bath-applied organophosphorus anticholinesterase agents. The frequency of spontaneously occurring interictal-like discharges induced by diisopropyl phosphorofluoridate (DFP) served as a quantitative monitor for epileptiform activity. After relatively long exposures to DFP, washouts with control saline solution could still abolish these discharges. With longer exposures, the washout kinetics became progressively slower and eventually the washouts became ineffective. Investigations with soman also indicated that this agent produced epileptogenic effects with a reversible component. From previous work with DFP and potassium channel blockers, e.g., 4AP, we developed and tested the hypothesis that DFP may be acting in a manner similar to this convulsant. To test further the idea that potassium channels may be involved with DFP's epileptogenic ef [abstract truncated]
NTIS/AD-A142 949/7 5p	1984 - Effects of Diisopropylfluorophosphate (DFP) and Other Cholinergic Agents on Release of Endogenous Dopamine from Rat Brain Striatum In vitro, Authors: Kant GJ, Kenion CC, Meyerhoff JL Walter Reed Army Inst. of Research, Washington, DC.	No abstract available. Pub. in Biochemical Pharmacology, v33 n11 p1823-1925 1984. Keywords: Organophosphates
NTIS/AD-A142 442/3 61p	1984 - Effects of Hyperbaric Pressure on in vitro Neural Receptors. Authors: Taylor RF Little (Arthur D.), Inc., Cambridge, MA.	In vitro preparations of the nicotinic acetylcholine receptor from rat muscle and eel electroplax were chemically and pharmacologically characterized and then subjected to compression/decompression to/from 800 psi. Pressure causes a reversible decrease in cholinergic agent binding to the receptor. This decrease is prevented if agents such as hexamethonium and diisopropylfluorophosphate are present. These studies imply that pressure effects on molecular interactions at neural receptors could account for hyperbaric neurological disorders. In addition, hyperbaric therapy could be successful in cases of toxin and organophosphorus agent intoxication. (Author) Final rept. Aug 80-Sep 83,
NTIS/AD-A182 550/4 62p	1984 - Action of Cholinergic Poisons on the Central Nervous System and Effectiveness of Potential Antidotes. Authors: Samson F, Nelson SR, Pazdernik T Kansas Univ. Medical Center, Kansas City.	The effects of soman and other cholinergic poisons on the structure and function of the brain were studied in rats. Quantitative autoradiography was used to detect changes in local cerebral glucose use (LCGU; 2-deoxyglucose technique) and cholinergic receptors. Major findings reported are: 1) Soman produces continuous, long-lasting seizures, associated with large increases in LCGU in most brain regions. 2) Soman-induced seizures are followed by conspicuous neuropathology (e.g. piriform cortex, amygdala) and a marked reduction in LCGU. 3) Diisopropylfluorophosphate (DFP) has some actions similar to soman but is not an ideal model agent for soman, in particular it fails to induce continuous seizures. 4) Both soman and DFP reduce LCGU in rats pretreated with TAB (trimedoxime, atropine, benactyzine); this reduction is much greater with soman. Thus, soman has both pronounced excitatory and inhibitory effects on brain function. 5) Other convulsants produce characteristic seizure and LCGU patterns, eac [abstract truncated]
NTIS/AD-B120-517/8 38p	1984 - Effect of Intracerebral Injection of Organophosphates on Brain Neurochemistry and Peripheral Physiology. Authors: Robinson SE Virginia Commonwealth Univ., Richmond.	Cholinesterase (ChE) activity in selected brain regions and trunk blood was studied 20 min, 1 hr, and 24 hrs after bilateral injection of various doses of diisopropylfluorophosphonate (DFP), soman and sarin into the corpus striatum of male rats. Locomotor activity was measured after bilateral intrastriatal injection of doses of DFP, soman and sarin that reduced striatal ChE activity to 40% of control or less, with a minimum of inhibition of ChE elsewhere in the brain or blood. DFP appeared to diffuse throughout the brain parenchyma more than soman and sarin, and the latter two compounds appeared also to enter the peripheral circulation. However, no gross signs of toxicity due to peripheral ChE inhibition were observed. Locomotor activity was reduced significantly 20 min after bilateral intrastriatal administration of DFP (81.5 nmol). Keywords: Organophosphates, Striatum, Cholinesterase. Annual rept. 30 Sep 83-29 Sep 84.
NTIS/AD-A135 414/1 6p Pub. in Neurobehavioral Toxicology and Teratology, v5 n4 p407-411 1983.	1983 - Diisopropyl Phosphorofluoridate (DFP) Disrupts Circadian Activity Patterns, Authors: Raslear TG, Kaufman LW Walter Reed Army Inst. of Research, Washington, DC.	No abstract available. Pub. in Neurobehavioral Toxicology and Teratology, v5 n4 p407-411 1983. Keywords: Organophosphates
NTIS/AD-A142 479/5 35p	1983 - Responses of Cholinergic and Noncholinergic Renshaw Cell Receptors After Acute and Chronic Exposure to Anticholinesterases. Authors: Van Meter WG Iowa State Univ., Ames.	Investigation of cat lumbar 7 segment (L-7) ventral horn cells (motoneurones and interneurones-Renshaw cells) in the presence of excess acetylcholine (ACh) are being studied as models of a central cholinergic transmitting synapse. Preliminary studies to investigate effects induced by chronic low dose exposure to diisopropylfluorophosphate (DFP) have begun with a two week exposure to diisopropylfuorophosphate (DFP) have begun with a two week exposure protocol with DFP doses of 0.1, 0.2, 0.5, 0.75, and 1.0 mg/kg/day s.c. Cats tolerate doses of 0.1 to 0.5 mg/kg/day s.c. with symptoms of increased defecation, moderate constriction of pupils slight ataxia and weight loss. The degree of severity increases with dose. Renshaw cell unit potentials (RUP) and their field potentials (RFP) are being studied to determine effects from exposure to DFP in doses according to the protocol above. In control animals, RFP respond similar to RUP during and subsequent to repetitive stimulation. Effects of drug treatmen [abstract truncated]
NTIS/AD-B091-748/4	1983 - Basal Ganglia Dopamine-gamma-Aminobutyric Acid-Acetylcholine Interaction in Organophosphate-Induced Neurotoxicity. Authors: Ho IK, Hoskins B Mississippi Univ. Medical Center, Jackson. Dept. of Pharmacology and Toxicology.	The purpose of the work reported herein has been to study the effects of four organophosphorus cholinesterase inhibitors on central neurotransmitter systems in an effort to gain information on the mechanisms involved in organophosphate-induced neurotoxicity. The compounds used have been diisopropylfluorophosphate (DFP), soman, sarin, tabun. Adult male rats have been used and after a single or subacute s.c. injection of any one of the compounds, we have determined effects on animal behavior and on brain (specifically striatal regions) levels, functions, and metabolism of two inhibitory neurotransmitters, dopamine (DA) and gamma-aminobutyric acid (GABA), and excitatory neurotransmitter, acetylcholine. the studies carried out for the past year include: 1. DFP toxicity and tolerance development; 2. assessment of comparative acute toxicity of DFP, Tabun, Sarin and Soman; 3. studies of behavioral tolerance to the toxicity of soman and sarin; 4. DFP and GABA synaptic function: effect on levels, enzymes [abstract truncated]
NTIS/AD-A148 384/1 52p	1983 - Synaptic Mechanisms of Action of Convulsion-Producing Anticholinesterases. Characterization of Di-Isopropyl Phosphorofluoridate-Induced Epileptiform Activity in the Mammalian Hippocampus. Authors: Lebeda FJ, Rutecki PA, Johnston D Baylor Coll. of Medicine, Houston, TX. Dept. of Neurology.	The purpose of this work was to elucidate the convulsant mechanisms of action of the irreversible organophosphorus anticholinesterase (anti-ChE) di-isopropyl phosphorofluoridate (DFP). In these experiments pyramidal cell responses from rat and guinea-pig hippocampal slices were examined in vitro using standard extra- and intracellular microelectrode recording techniques. When bath-applied at 10-25 micrometers for 30 min, DFP produced spontaneous, rhythmic discharges (50-400 msec in duration at 0.1-0.3 Hz) in the previously quiescent extracellular field recordings. This activity was superficially similar to that produced by other convulsants, e.g., bicuculline and picrotoxin, which interfere with inhibitory synaptic activity that is mediated by gamma-aminobutyric acid. This DFP-induced effect was readily abolished upon washout, even in slices that were exposed for up to 5 hrs. Reintroduction of the DFP solution reinitiated these epileptiform events. The DFP-induced events, however, were not suppr [abstract truncated]
NTIS/AD-B091 643/7 91p	1982 - Basal Ganglia Dopamine-gamma-Aminobutyric Acid-Acetylcholine Interaction in Organophosphate-Induced Neurotoxicity. Appendices. Authors: Ho IK, Hoskins B Mississippi Univ. Medical Center, Jackson. Dept. of Pharmacology and Toxicology.	This report contains the Appendices to the First Annual report on Basal Ganglia Dopamine-Gamma-Aminobutyric Acid-Acetylcholine Interaction in Organophosphate Induced Neurotoxicity. The appendices include information in reference to the following: Variation of Commercial Diisopropyl Fluorophosphate Preparations in Toxicological Studies; Assessment of Diisopropyl-Fluorophosphate (DFP) Toxicity; The Effect of Acute and Chronic Cholinesterase Inhibition with Diisopropylfluorophosphate On Muscarinic, Dopamine and GABA Receptors of the Rat Striatum; Diisopropylfluorophosphate and GABA Synaptic Function: Effect on Levels, Enzymes, Release and Uptake in the Rat Striatum. Annual rept. no. 1, 1 Nov 81-31 Oct 82. See also AD-B091 642.
NTIS/AD-A151 374/6 6p	1982 - Widespread Occurrence of Cholinesterase Activity in Plant Leaves, Authors: Miura GA, Broomfield CA, Lawson MA, Worthley EG Army Medical Research Inst. of Chemical Defense, Aberdeen Proving Ground, MD.	In contrast to previous work, the distribution of cholinesterase was found to be ubiquitious in plant leaves. Cholinesterase activity was detected in 91% of the 70 species surveyed from 50 higher plants and three families of ferns. A radiometric assay was used to determine the hydrolysis of acetylcholine by leaf tissue slices in the presence and absence of 29 micrometer diisopropyl phosphofluoridate. The results obtained using this inhibitor as a creterion for cholinesterase activity were found to be consistent with previous studies using neostigmine as the inhibitor although there were some quantitative differences between the inhibitors. With some of the tested plants acetyl-Beta-methylcholine was also hydrolyzed, indicating that acetylcholinesterase rather than pseudocholinesterase was present at least in these cases. These findings demonstrate that the relative activity of cholinesterase in leaves can serve as an indicator of organophosphorous anticholinesterase contamination of the environm [abstract truncated]

Return DFP Index Page