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PubMed1981

The stability of sarin and soman in dilute aqueous solutions and the catalytic effect of acetate ion.

The hydrolysis of aqueous solutions of organophosphonate compounds such as sarin and soman is a critical factor in biochemical and therapeutic studies. The ability to dilute and transport these compounds with assurance of their purity is imperative to the integrity of such studies. An enzymic method has been used to measure low levels of organophosphonates. Maximum stability data were determined in aqueous and isotonic saline solutions. Acetate ion was found to significantly accelerate hydrolysis.1

Acetates↗
PubMed2004

Inhalation toxicity of Cyclosarin (GF) vapor in rats as a function of exposure concentration and duration: potency comparison to sarin (GB).

The inhalation toxicity of cyclohexyl methylphosphonofluoridate (GF) was examined in male and female Sprague-Dawley rats exposed by whole body in a dynamic 750-L chamber. The objectives of this study were to (1) generate GF vapor in a dynamic inhalation chamber system, starting in the lethal to near-lethal concentration range, (2) examine dose-response effects of inhaled GF vapor and analyze the relationship between concentration (C) and exposure duration (T) in determining probability of lethality, and (3) establish a lethal potency ratio between GF and the more volatile agent Sarin (GB). Using a syringe pump, GF vapor concentrations were generated for exposure times of 10, 60, and 240 min. Dose-response curves with associated slopes were determined for each exposure duration by the Bliss probit method. GF vapor exposures were associated with sublethal clinical signs such as tremors, convulsions, salivation, and miosis. Concentration-exposure time values for lethality in 50% of the exposed population (LCT(50)) were calculated for 24-h and 14-day postexposure periods for 10-, 60-, and 240-min exposures. In general, LCT(50) values were lower in female rats than males and increased with exposure duration; that is, CT was not constant over time. The GF LCT(50) values for female rats were 253 mg min/m(3) at 10 min, 334 mg min/m(3) at 60 min, and 533 mg min/m(3) at 240 min, while the values for males were 371, 396, and 585 mg min/m(3), respectively. The GB LCT(50) values for female rats were 235 mg min/m(3) at 10 min, 355 mg min/m(3) at 60 min, and 840 mg min/m(3) at 240 min, while the values for males were 316, 433, and 1296 mg min/m(3), respectively. At longer exposure durations, the LCT(50) for GF was less than that found for GB but at shorter exposure durations, the LCT(50) for GF was more than that found for GB. Empirical models, consisting of the toxic load model plus higher order terms, were developed and successfully fit to the data.

Administration, Inhalation↗
PubMed2006

Comparison of low-level sarin and cyclosarin vapor exposure on pupil size of the Gottingen minipig: effects of exposure concentration and duration.

The current studies estimated effective (miosis) concentrations of the nerve agents' sarin (GB) and cyclosarin (GF) as a function of exposure duration in the Gottingen minipig and determined dependency of the median effective dosage (ECT50) over time. Male and female Gottingen minipigs were exposed to various concentrations of vapor GB or GF for 10, 60, or 180 min. Infrared images of the pig's pupil before, during, and after nerve agent exposure were captured digitally and pupil area was quantified. An animal was classified "positive" for miosis if there was a 50% reduction in pupil area (as compared to baseline) at any time during or after the GB or GF exposure. Maximum likelihood estimation was used on the resulting quantal data to calculate ECT50 (miosis) values, with approximate 95% confidence intervals, for each of the six gender-exposure duration groups. As a group, male minipigs were significantly more sensitive to the pupil constricting effects of GF than were female minipigs. In male minipigs, GF is approximately equipotent to GB for 60-min exposures and more potent for 10- and 180-min exposures. In the female minipig GF is slightly more potent than GB for 10-min exposures but then progressively becomes less potent over the 60- and 180-min durations of exposure. The values of the toxic load exponents were essentially independent of the model fits used: 1.32 +/- 0.18 for GB exposures and 1.60 +/- 0.22 for GF exposures. Since neither of these intervals overlaps 1, Haber's rule is not an appropriate time-dependence model for these data sets.

Animals↗
PubMed2005

In vitro reactivation of sarin-inhibited brain acetylcholinesterase from different species by various oximes.

In vitro as well as in vivo evaluation of the reactivating efficacy of various oximes against nerve agent-inhibited acetylcholinesterase has been usually done with the help of animal experiments. Nevertheless, previously published data indicate that the reactivation potency of oximes may be different in human and animal species, which may hamper the extrapolation of animal data to human data. Therefore, to better evaluate the efficacy of various oximes (pralidoxime, obidoxime, HI-6, K033) to reactivate brain acetylcholinesterase inhibited by sarin by in vitro methods, human, rat and pig brain acetylcholinesterase were used to calculate kinetic parameters for the reactivation. Our results show differences among the species, depending on the type of oxime, and indicate that data from animal experiments needs to be carefully evaluated before extrapolation to humans.

Acetylcholinesterase↗
PubMed2005

Tolerance to the miotic effect of sarin vapor in rats after multiple low-level exposures.

Inhibition of acetylcholinesterase (AChE) by the organophosphorous compound sarin (GB) results in the accumulation of acetylcholine and excessive cholinergic stimulation. There are few data in the literature regarding the effects of multiple low-level exposures to GB and other organophosphorous compounds via relevant routes of exposure. Therefore, the present study was undertaken, and is the first, to investigate the effect of low-level repeated whole-body inhalation exposures to GB vapor on pupil size and cholinesterase activity in the eyes and blood. Male Sprague-Dawley rats were exposed to 4.0 mg/m3 of GB vapor for 1 h on each of 3 consecutive days. Pupil size and cholinesterase activities were determined at various points throughout the exposure sequence. The results demonstrate that multiple inhalation exposures to GB vapor produce a decrease in the miotic potency of GB in rats. This tolerance developed at a dose of GB that produced no overt signs of intoxication other than miosis. AChE and butyrylcholinesterase activity did not increase throughout the exposure sequence, suggesting that the tolerance cannot be attributed to a reduced inhibitory effect of GB. A decrease in the amount of GB present in the eye occurred after the third exposure. However, this change is insufficient to explain the tolerance, as there was no corresponding increase in AChE activity. Thus, the mechanism mediating the miotic tolerance observed after multiple inhalation exposures to the nerve agent GB remains uncertain, although several possibilities can be excluded based on the results of the present study.

Acetylcholinesterase↗
PubMed2006

Development of miotic cross-tolerance between pyridostigmine and sarin vapor.

The organophosphorous nerve agent sarin (GB) and the carbamate pyridostigmine bromide (PB) both inhibit acetylcholinesterase (AChE), leading to overstimulation of muscarinic receptors. Both GB and PB produce miosis through stimulation of ocular muscarinic receptors. This study investigated 2 hypotheses: (1) that the miotic response to PB would decrease following repeated injections; and (2) that repeated administration of PB would result in tolerance to the miotic effect of GB vapor. Rats were injected intramuscularly with saline, 0.04 mg/kg, 0.5 mg/kg, or 1.4 mg/kg of PB twice daily for 8 consecutive days. After day 3, animals injected with 1.4 mg/kg PB developed miotic tolerance. Twenty-four (24) h following the final PB injection, the rats were exposed to GB vapor (4.0 mg/m(3)). A similar magnitude of miosis was observed in all groups after GB exposure. However, the rate of recovery of pupil size in animals pretreated with 0.5 and 1.4 mg/kg PB was significantly increased. Twenty (20) h following exposure to GB vapor, the pupils of animals pretreated with 1.4 mg/kg PB had recovered to 77% +/- 4% of their pre-exposure baseline, whereas the saline-injected controls had recovered to only 52% +/- 2% of their pre-exposure baseline. The increased rate of recovery does not appear to be a result of protection of pupillary muscarinic receptors by the higher doses of PB, as there was no longer PB present in the animal at the time of GB exposure. These results demonstrate the development of tolerance to the miotic effect of PB following repeated exposures, and also suggest that cross-tolerance between PB and GB occurs. However, because the magnitude of the response was not reduced, the PB pretreatment and its associated miotic cross-tolerance does not appear to diminish the effectiveness of miosis as a biomarker of acute exposure to nerve agent vapor.

Animals↗
PubMed2002

Interaction of exposure concentration and duration in determining acute toxic effects of sarin vapor in rats.

Sarin (GB) vapor exposure is associated with both systemic and local toxic effects occurring primarily via the inhalation and ocular routes. The objective of these studies was to develop models for predicting dose-response effects of GB vapor concentrations as a function of exposure duration. Thus, the probability of GB vapor-induced lethality was estimated in rats exposed to various combinations of exposure concentration and duration. Groups of male and female Sprague-Dawley rats were exposed to one of a series of GB vapor concentrations for a single duration (5-360 min) in a whole-body dynamic chamber. The onset of clinical signs and changes in blood cholinesterase activity were measured with each exposure. Separate effective concentrations for lethality in 50% of the exposed population (LC50) and corresponding dose-response slopes were determined for each exposure duration by the Bliss probit method. Contrary to that predicted by Haber's rule, the interaction of LC50 x time (LCT50) values increased with exposure duration (i.e., the CT for 50% lethality in the exposed population and corresponding dose-response slope was not constant over time). A plot of log (LCT50) versus log (exposure time) showed significant curvature. Predictive models derived from multifactor probit analysis of results describing the relationship between exposure conditions and probability of lethality in the rat are discussed. Overall, female rats were more sensitive to GB vapor toxicity than male rats over the range of exposure concentration and duration studied. Miosis was the initial clinical sign noted after the start of GB vapor exposure. Although blood cholinesterase activity was significantly inhibited by GB vapor exposure, poor correlation between cholinesterase inhibition and exposure conditions or cholinesterase inhibition and severity of clinical signs was noted.

Acetylcholinesterase↗
PubMed2005

Miotic tolerance to sarin vapor exposure: role of the sympathetic and parasympathetic nervous systems.

O-isopropyl methylphosphonofluoridate, also known as sarin or GB, is a highly toxic organophosphorous compound that exerts its effect by inhibiting the enzyme acetylcholinesterase. While the effects of a single exposure to GB vapor are well characterized, the effects of multiple exposures to GB vapor are less clear. Previous studies in the rat and guinea pig have demonstrated that multiple exposures result in tolerance to the miotic effect of nerve agents. The aim of the present study was to examine potential mechanisms responsible for tolerance to the miotic effect of GB vapor that has been observed in the rat after multiple exposures. Multiple whole-body inhalation exposures to GB vapor were conducted in a dynamic airflow chamber. Exposures lasted 60 min and each of the three exposures occurred at 24-h intervals. The results of the present study demonstrate that the alpha-adrenergic antagonist phentolamine and the beta-adrenergic receptor antagonist propranolol did not affect the development of tolerance to the miotic effect of GB vapor, suggesting that enhanced sympathetic tone to the eye is not responsible for the observed tolerance. Administration of atropine before the first exposure prevented the tolerance to the miotic effect of GB vapor after the third exposure, suggesting that the tolerance is the result of muscarinic receptor desensitization secondary to receptor stimulation. The present study extends the findings of previous studies to strengthen the hypothesis that the miotic tolerance observed in the rat upon repeated exposure to nerve agents is due to desensitization of muscarinic acetylcholine receptors located on the pupillary sphincter.

Adrenergic alpha-Antagonists↗
PubMed1981

Effects of selective alkylphosphorylation of propionylcholinesterase on the regeneration of acetylcholinesterase in the aqueous soluble fraction of superior cervical ganglia of the rat following sarin.

The rates of regeneration of acetylcholinesterase (AChE) and propionylcholinesterase (PrChE) in the supernatants of aqueous homogenates of rat superior cervical ganglia, centrifuged at 100,000 g for 90 min, were determined at 1, 3, 6, and 16 h following their inactivation (greater than 90%) by administration of sarin, 2.0 mumol/kg i.v. Values were compared with those in animals in which the PrChE was continually suppressed by the repeated, fractional administration of iso-OMPA, in a total dose of 10 or 20 mumol/kg i.p. These doses of iso-OMPA alone produced 96-99% inactivation of PrChE with no detectable effect on AChE. Significant suppression of AChE regeneration by iso-OMPA administration was noted only at 6 h; in contrast with earlier findings in the cat, administration of iso-OMPA alone caused no significant increase in ganglionic AChE activity.

Acetylcholinesterase↗
PubMed1988

Choline transport and metabolism in soman- or sarin-intoxicated brain.

The metabolism and blood-brain transport of choline (Ch) were investigated in perfused canine brain under control conditions and for 60 min after inhibition of brain cholinesterases by the organophosphorus (OP) compounds soman (pinacolylmethylphosphonofluoridate). Ch and acetylcholine (ACh) in blood and brain samples were analyzed using gas chromatography-mass spectrometry methods. Net transport of Ch was determined by Ch analysis in arterial and venous samples. Unidirectional transport of [3H]Ch was determined using the indicator dilution method. During control perfusion periods of 90 min, net efflux of brain Ch occurred at a rate of 1.6 +/- 0.4 nmol/g/min, and the Ch content of the recirculated perfusate increased 10-fold to approximately 8 microM. Brain Ch content increased in proportion to the increase in perfusate Ch level, but brain ACh was unaltered. Rapid administration of soman (100 micrograms) or sarin (400 micrograms) into the arterial perfusate after a 40-min control period resulted in a greater than 10-fold increase in ACh content in cerebral cortex, brainstem, and hippocampus. The ACh content of cerebellum increased only slightly. The Ch level in all four brain regions studied also increased two- to fourfold above control levels. Ch efflux from brain, however, decreased to 0.2 +/- 0.1 nmol/g/min during the 60 min after OP exposure. Unidirectional influx of [3H]Ch was 0.49 +/- 0.07 nmol/g/min before and did not change significantly 10 or 40 min after OP exposure, thus indicating that the Ch transporter of the brain endothelial cell is not directly inhibited.2+ Based on these results, it is proposed that (a) efflux of brain Ch occurs from the extracellular compartment, which becomes depleted when ACh breakdown is inhibited;(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1996

Sarin: guidelines on the management of victims of a nerve gas attack.

Sarin is now a weapon of the terrorist. Its acute effects are primarily due to unrestricted cholinergic activity at both muscarinic and nicotinic receptors. Treatment is based on the use of large doses of atropine and pralidoxime which may lead to practical problems of sufficient drug supplies for the average hospital. Ventilation may be necessary and present problems. Victim decontamination involves use of bleach, soap and water. Staff handling casualties need protection with respirators and butyl rubber boots and gloves.

Guidelines as Topic↗
PubMed1997

Eighteen cases exposed to sarin in Matsumoto, Japan.

Forty-six patients who were exposed to sarin consulted our hospital because of darkness of vision, and ocular pain, vomiting, dyspnea and headaches on June 27 and 28, 1994. Eighteen patients were admitted and 4 of them were in the critical state. There were 6 features: 1) depression of plasma cholinesterase activity (17 of 18 patients, 94%), 2) hypokalemia (4/18, 22%), 3) depression of triglyceride (12/18, 67%), 4) hypocapnia (5/17, 29%), 5) partial pressure of oxygen (PaO2) <80 mmHg, or requirement of O2 inhalation (15/18, 83%), 6) white blood cells (WBC) >9,000 per mm3 (13/18, 72%). Seventeen patients were discharged from hospital, but one patient is still suffering from akinetic mutism after two years.

Adult↗
PubMed1991

Physostigmine (alone and together with adjunct) pretreatment against soman, sarin, tabun and VX intoxication.

A pretreatment for organophosphorus (OP) anticholinesterase (e.g., soman) intoxication should prevent lethality and convulsions (CNV) at 2 LD50s and be behavioral-decrement-free when given alone. Behavioral-deficit-free pretreatment regimens (PRGs) for guinea pigs consisted of Physostigmine (0.15 mg/kg, im) and adjunct. Adjuncts [mg/kg, im] tested were akineton [0.25], aprophen [8], trihexyphenidyl [2], atropine [16], azaprophen [5], benactyzine [1.25], cogentin [4], dextromethorphan [7.5], ethopropazine [12], kemadrin [1], memantine [5], promethazine [5], scopolamine [0.08] and vontrol [2]. PRGs were given 30 min before soman (60 micrograms/kg, sc; 2 LD50s) or other OP agents. Animals were then observed and graded for signs of intoxication, including CNV at 7 time points and at 24 hr. Physostigmine alone reduced the incidence of CNV and lethality induced by 2 LD50s of soman by 42 and 60%, respectively. All of the PRGs tested abolished lethality and 12 shortened recovery time to 2 hr or less. Also, PRGs including azaprophen or atropine prevented CNV. When selected PRGs were tested against intoxication by sarin, tabun or VX, the efficacy was generally superior to that for soman. The data show that several PRGs are effective against soman intoxication in guinea pigs.

Animals↗
PubMed1998

Neuromuscular effects of low level exposures to Sarin, pyridostigmine, DEET, and chlorpyrifos.

A study is being initiated to investigate subtle neurobehavioral effects and neuropathology in rats due to exposure to combinations of low levels of Sarin (GB), N,N-diethyl-m-toluamide (DEET), chlorpyrifos (CPF), and pyridostigmine bromide (PB). A similar study is being initiated in rhesus monkeys to investigate neurophysiologic effects and neuromuscular pathology due to exposure to a combination of GB, DEET, CPF, and PB, along with vaccination with botulinum toxoid. A description of these studies is presented.

Animals↗
PubMed2001

A comparison of the effects of sarin and succinylcholine on respiratory parameters in anesthetized domestic swine.

Differences in the "respiratory paralysis" caused by sarin (GB) and succinylcholine (SDC) were observed in a domestic swine model using a bedside pulmonary dynamics monitor. GB was administered intravenously (9 micrograms/kg/30 min) and compared with SDC administered intravenously (20 mg/30 min). All animals developed respiratory insufficiency indicated by decreased respiratory frequency. Minute ventilation was relatively maintained in animals that received GB by increasing tidal volume, whereas both of these parameters decreased in animals that received SDC. GB animals showed an increase in airway resistance and work of breathing. The former was unchanged and the latter was decreased in animals that received SDC. Mouth occlusion pressure at 100 milliseconds and tidal volume were relatively maintained in GB animals but decreased in SDC animals, suggesting a central mechanism for respiratory paralysis with GB and a peripheral mechanism for respiratory paralysis with SDC.

Acetylcholinesterase↗
PubMed1992

Potential of memantine, D-tubocurarine, and atropine in preventing acute toxic myopathy induced by organophosphate nerve agents: soman, sarin, tabun and VX.

Male Sprague-Dawley rats when administered sc a sublethal dose of organophosphorus cholinesterase inhibitors such as the nerve agents, soman (100 micrograms/kg, sc), sarin (110 micrograms/kg, sc), tabun (200 micrograms/kg, sc), or VX (12 micrograms/kg, sc), developed seizures and severe muscle fasciculations within 15-20 min, lasting for 4-6 hr. Marked inhibition of acetylcholinesterase (AChE) and necrotic lesions in skeletal muscles such as soleus, extensor digitorum longus, and diaphragm were evident between 1-24 hr following injection. Pretreatment with memantine HCl (MEM, 18 mg/kg, sc) together with atropine sulfate (ATS, 16 mg/kg, sc), 60 min and 15 min, respectively, prior to nerve agents attenuated AChE inhibition, prevented myonecrosis, and muscle fasciculations as well as other signs of cholinergic toxicity. Pretreatment combining d-tubocurarine (d-TC, 0.075 mg/kg, sc) and ATS (16 mg/kg, sc) prevented the myonecrosis and fasciculation without protecting AChE against inhibition by these nerve agents. Neither MEM, d-TC, nor ATS in the concentration given interfered with the normal behavior of the rats. The role of d-TC and ATS interaction with presynaptic receptors regulating ACh release and MEM's role in modulating neural hyperactivity as protective mechanisms are discussed.

Acetylcholinesterase↗
PubMed2005

Physiologic and chemical simulation of cyanide and sarin toxicity and therapy.

The possibility of mass terrorism has become increasingly apparent. Accurate and relevant teaching tools are needed for healthcare givers and emergency personnel of all experience. We describe one of these tools, BODY Simulation, and its use in training caregivers to respond to chemical terrorism. We have implemented two chemical agents--cyanide and sarin, the latter a nerve agent--in a detailed whole-body model and simulation. In the simulation, each agent was administered to a healthy young adult, first without therapy, then with therapy, for a total of four runs. We recorded several variables, each appropriate to the agent used. The recorded variables included physiological variables in addition to the blood and brain concentrations of each agent and its antidotes. In addition, for cyanide, the compounds that resulted as the byproducts of therapy (methemoglobin, for example) were plotted. The results were consistent with those described in the literature, including agent concentrations and pathophysiologic changes.

Computer Simulation↗