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
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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] |
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