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PubMed1985

Analysis of soman and sarin in blood utilizing a sensitive gas chromatography-mass spectrometry method.

Gas chromatography with electron impact mass spectrometry and selected ion monitoring provided a simple and sensitive method for measuring organophosphorus compounds sarin and the two isomers of soman (isomer I and isomer II) in blood. These compounds were extracted from blood or isotonic saline using a modification of the method developed by Sass et al. Blood was deproteinized with perchloric acid before extraction. The acid-induced degradation of the organophosphorus compounds could be minimized by neutralizing the acid immediately after deproteinizing. In saline and blood, 81% of the extractable soman and 74% of the extractable sarin was recovered with a single extraction. The overall recovery of added organophosphorus was less in blood than in saline because of the binding of organophosphorus to blood constituents, probably various enzymes and proteins. A time-dependent decrease in extractable organophosphorus was found in whole blood but not in saline. Although soman isomer II was degraded in blood faster than soman isomer I, no significant difference in the affinities of these two isomers to acetylcholinesterase was observed.

Acetylcholinesterase↗
PubMed1995

Sarin poisoning in Matsumoto, Japan.

A presumed terrorist attack with sarin occurred in a residential area of the city of Matsumoto, Japan, on June 27, 1994. About 600 residents and rescue staff were poisoned; 58 were admitted to hospitals, and 7 died. We examined clinical and laboratory findings of 264 people who sought treatment and the results of health examinations on 155 residents done 3 weeks after the poisoning. Findings for severely poisoned people were decreases in serum cholinesterase, acetylcholinesterase in erythrocytes, serum triglyceride, serum potassium and chloride; and increases in serum creatine kinase, leucocytes, and ketones in urine. Slight fever and epileptiform abnormalities on electroencephalogram were present for up to 30 days. Examination revealed no persisting abnormal physical findings in any individual. Acetylcholinesterase returned to normal within 3 months in all people examined. Although subclinical miosis and neuropathy were present 30 days after exposure, almost all symptoms of sarin exposure disappeared rapidly and left no sequelae in most people.

Acute Disease↗
PubMedDate not supplied

Chronic neurobehavioral and central and autonomic nervous system effects of Tokyo subway sarin poisoning.

To evaluate delayed (prolonged) neurobehavioral and neurophysiological effects of acute sarin poisoning, nine male and nine female patients of the Tokyo subway sarin poisoning in Japan were examined by neurobehavioral tests, posttraumatic stress disorder (PTSD) checklist, brain evoked potentials, computerized static posturography, and electrocardiographic R-R interval variability, 6-8 months after the poisoning. Their serum cholinesterase activities on the day of the poisoning (March 20, 1995) were 13-131 (mean 72.1) IU/L. The results suggested delayed effects on psychomotor performance, the higher and visual nervous system and the vestibulo-cerebellar system with psychiatric symptoms resulting from PTSD.

Autonomic Nervous System Diseases↗
PubMed2005

Ab initio molecular orbital and density functional studies on the solvolysis of sarin and O,S-dimethyl methylphosphonothiolate, a VX-like compound.

[reaction: see text] Potential energy surfaces for the alkaline hydrolysis of sarin and O,S-dimethyl methylphosphonothiolate, a VX model compound, and the perhydrolysis of the latter have been computed at the MP2/6-31+G(d)//mPW1K/MIDI! level of theory. The effect of aqueous solvation was accounted for via the integral equation formalism polarizable continuum model (IEF-PCM) at the HF/6-31+G(d) level. Excellent agreement with the experimental enthalpy of activation for alkaline hydrolysis of sarin was found. For the alkaline hydrolysis of O,S-dimethyl methylphosphonothiolate, it was found that the P-O and P-S bond cleavage processes are kinetically competitive but that the products of P-S bond cleavage are thermodynamically favored. For the perhydrolysis of O,S-dimethyl methylphosphonothiolate, it was found that P-O bond cleavage is not kinetically competitive with P-S bond cleavage. In both cases, the data support initial formation of trigonal bipyramidal intermediates and demonstrate kinetic selectivity for nucleophilic attack on the face opposite the more apicophilic methoxide ligand.

Alkalies↗
PubMed2006

Revisiting the reactivity of oximate alpha-nucleophiles with electrophilic phosphorus centers. Relevance to detoxification of sarin, soman and DFP under mild conditions.

Following a potentiometric determination of the relevant pKa values of the (R1R2)C=NOH functionality, the second order rate constants (k(Ox)) for reaction of a large set of oximate bases with two model organophosphorus esters, i.e. bis-(4-nitrophenyl)phenylphosphonate (BNPPP) and bis-(4-nitrophenyl)methylphosphonate (BNPMP), and three toxic compounds, i.e., sarin (GB), soman (GD) and diisopropylphosphorofluoridate (DFP), in aqueous as well as a 30 : 70 (v/v) H2O-Me2SO mixture have been measured. The corresponding Brønsted-type nucleophilicity plots of log k(Ox)vs. pKa(Ox) reveal a clear tendency of the reactivity of the oximates to suffer a saturation effect with increasing basicity in aqueous solution. In the case of BNPMP and the three toxic esters, this behaviour is reflected in a levelling off at pKa approximately 9 but a more dramatic situation prevails in the BNPPP system where the attainment of maximum reactivity at pKa approximately 9 is followed by a clear decrease in rate at higher pKa's. Interestingly, a number of data reported previously by different authors for the sarin, soman and DFP systems are found to conform rather well to the curvilinear Brønsted correlations built with our data. Based on this and previous results obtained for reactions at carbon centers, it can be concluded that the observed saturation effect is the reflection of an intrinsic property of the oximate functionality. An explanation of this behavior in terms of an especially strong requirement for desolvation of the oximates prior to nucleophilic attack which becomes more and more difficult with increasing basicity is suggested. This proposal is supported by the observed changes in pKa(Ox) and k(Ox) brought about by a transfer from H2O to a 30 : 70 H2O-Me2SO mixture. The implications of the saturation effect on the efficiency of oximates as nucleophilic catalysts for smooth decontamination are emphasized. Also discussed is the effect of basicity on the exalted (alpha-effect) reactivity of these bases.

Hydrogen-Ion Concentration↗
PubMedDate not supplied

Quantitation of fluoride ion released sarin in red blood cell samples by gas chromatography-chemical ionization mass spectrometry using isotope dilution and large-volume injection.

A new method for measuring fluoride ion released isopropyl methylphosphonofluoridate (sarin, GB) in the red blood cell fraction was developed that utilizes an autoinjector, a large-volume injector port (LVI), positive ion ammonia chemical ionization detection in the SIM mode, and a deuterated stable isotope internal standard. This method was applied to red blood cell (RBC) and plasma ethyl acetate extracts from spiked human and animal whole blood samples and from whole blood of minipigs, guinea pigs, and rats exposed by whole-body sarin inhalation. Evidence of nerve agent exposure was detected in plasma and red blood cells at low levels of exposure. The linear method range of quantitation was 10-1000 pg on-column with a detection limit of approximately 2-pg on-column. In the course of method development, several conditions were optimized for the LVI, including type of injector insert, injection volume, initial temperature, pressure, and flow rate. RBC fractions had advantages over the plasma with respect to assessing nerve agent exposure using the fluoride ion method especially in samples with low serum butyrylcholinesterase activity.

Animals↗
PubMed1958

The effect of some oximes in sarin poisoning.

The effects of monoisonitrosoacetone (MINA), diacetylmonoxime (DAM) and pyridine-2-aldoxime methiodide (P2AM) upon the cholinesterase of sarin poisoned rats have been studied. Monoisonitrosoacetone and diacetylmonoxime given before sarin protected blood and brain cholinesterase from inhibition. Monoisonitrosoacetone given after the appearance of signs of poisoning caused a rapid reactivation of brain cholinesterase. Diacetylmonoxime, at an equimolar dose, produced only a slight increase in enzyme activity, and pyridine-2-aldoxime methiodide, the best reactivator in vitro, reactivated blood but not brain cholinesterase. There is a relationship between protection and reactivation of brain cholinesterase and prevention and alleviation of signs of poisoning.

Animals↗
PubMed1998

The Tokyo subway sarin attack: disaster management, Part 1: Community emergency response.

The Tokyo subway sarin attack was the second documented incident of nerve gas poisoning in Japan. Prior to the Tokyo subway sarin attack, there had never been such a large-scale disaster caused by nerve gas in peacetime history. This article provides details related to how the community emergency medical services (EMS) system responded from the viewpoint of disaster management, the problems encountered, and how they were addressed. The authors' assessment was that if EMTs, under Japanese law, had been allowed to maintain an airway with an endotracheal tube or use a laryngeal mask airway without physician oversight, more patients might have been saved during this chemical exposure disaster. Given current legal restrictions, advanced airway control at the scene will require that doctors become more actively involved in out-of-hospital treatment. Other recommendations are: 1) that integration and cooperation of concerned organizations be established through disaster drills; 2) that poison information centers act as regional mediators of all toxicologic information; 3) that a real-time, multidirectional communication system be established; 4) that multiple channels of communication be available for disaster care; 5) that public organizations have access to mobile decontamination facilities; and 6) that respiratory protection and chemical-resistant suits with gloves and boots be available for out-of-hospital providers during chemical disasters.

Disaster Planning↗
PubMed1998

The Tokyo subway sarin attack: disaster management, Part 2: Hospital response.

The Tokyo subway sarin attack was the second documented incident of nerve gas poisoning in Japan. The authors report how St. Luke's Hospital dealt with this disaster from the viewpoint of disaster management. Recommendations derived from the experience include the following: Each hospital in Japan should prepare an emergent decontamination area and have available chemical-resistant suits and masks. Ventilation in the ED and main treatment areas should be well planned at the time a hospital is designed. Hospital disaster planning must include guidance in mass casualties, an emergency staff call-up system, and an efficient emergency medical chart system. Hospitals should establish an information network during routine practice so that it can be called upon at the time of a disaster. The long-term effects of sarin should be monitored, with such investigation ideally organized and integrated by the Japanese government.

Disaster Planning↗
PubMed1984

Sarin poisoning in guinea pigs compared to reactivation of acetylcholinesterase in vitro as a basis for therapy.

Contrary to the large number of publications dealing with treatment of organophosphate poisoning in a variety of animal species, there is no logic reason in the preference of one species, for this purpose. Guinea pigs were reported to respond better to treatment by oximes, than mice and rats. However, in the analysis of data on the effect of obidoxim and atropine or benactyzine on sarin poisoning it is demonstrated, that guinea pigs do not respond differently from mice and rats. Subcutaneous LD50's of sarin in mice ranged from 0.06 to 0.207 mg/kg, and those of guinea pigs from 0.04 to 0.112 mg/kg. The difference in the LD50's may be related to the different susceptibility of various animal species. The importance of "in vivo" dosage, mode of application, kinetics of antagonists, in correlation to the ability to reactivate "in vitro" is discussed.

Acetylcholinesterase↗
PubMed1989

Role of carboxylesterase in soman, sarin and tabun poisoning in rats.

TOCP (triorthocresyl phosphate) inhibits carboxylesterase (CarbE) activity in rat plasma and liver and significantly increases soman, sarin and tabun toxicity. Application of these agents after TOCP caused strong additional inhibition of CarbE and cholinesterases (ChE) in rat red blood cells, plasma, liver, brain, diaphragm and intercostal muscle. After phenobarbital pretreatment, which induced CarbE activity in plasma and liver by 80% and that of plasma ChE by 33%, acute toxicity of soman and tabun was greatly decreased, while that of sarin remained unaffected.

Animals↗
PubMed1998

Distal sensory axonopathy after sarin intoxication.

A 51-year-old man inhaled sarin during a terrorist attack on the Tokyo subway system and died 15 months later. Neuropathologic examination revealed marked nerve fiber decrease in the sural nerve, moderate nerve fiber loss in the sciatic nerve, and unremarkable dorsal root ganglia, dorsal roots, and posterior column of the spinal cord. This pathology is consistent with dying-back degeneration of the peripheral nervous system and could represent a late sequela of sarin intoxication.

Fatal Outcome↗
PubMed1992

Successful pretreatment/therapy of soman, sarin and VX intoxication.

Chemical pretreatment is effective against a 2 LD50 challenge of soman, sarin or VX or a 5 LD50 challenge of tabun. Chemical pretreatment followed by post challenge therapy should be effective against greater levels of agent. Such tests in guinea pigs are reported here; pretreatment regimens (PRGs) consisted of physostigmine (0.15 mg/kg, im) and an adjunct. The adjuncts [mg/kg, im] used were aprophen [8], atropine (AT)[16], azaprophen (AZA)[5], benactyzine [1.25], benztropine (BT) [4], scopolamine [0.08] and trihexyphenidyl [2]. Pretreatment was given 30 min before, and atropine (16 mg/kg, im) and 2-PAM (25 mg/kg, im) therapy (T) at one min after, 5 LD50s of agent. Results indicate that, all of the PRG+T regimens, except BT-not tested with T, prevent lethality by soman; trihexyphenidyl and scopolamine (the only adjuncts used therein) regimens each prevent lethality by sarin and VX. Against soman, all PRG+T regimens (vs PRG only) may shorten the median recovery time to 2 hrs or less. Even without therapy, the PRGs containing AT, AZA or BT prevent lethality by 5 LD50s of soman; however, used alone, only the PRG containing AZA reduces the incidence of convulsions at this level of soman.

Animals↗
PubMedDate not supplied

[The effect of the oxime HI-6 on miosis induced by topical administration of sarin and VX in the rabbit eye].

Effect of oxime HI-6 to rabbit miosis induced by the topical sarin and VX administration is presented. It has been found that effects of both toxins are better antagonized by parenteral than by topical HI-6 administration. The sarin antagonizing effect was found more effective. It has been also confirmed that there was no significant difference concerning the oxime HI-6 effect when topically administered either as 2.5% hypertonic or isotonic solution. Opposite to PAM-2, HI-6 effect was better in parenteral and topical administration of isotonic solutions, and less effective in local administration of hypertonic solutions.

Animals↗
PubMed1997

Differential inhibition of the brain acetylcholinesterase molecular forms following sarin, soman and VX intoxication in laboratory rats.

The female Wistar rats were intoxicated (i.m.) with sarin, soman and VX in doses equal to 1xLD50 and pontomedullar areas of the brain were prepared, homogenized, centrifuged and in these samples, acetylcholinesterase (AChE, EC 3.1.1.7) activities were determined. In the same samples, AChE was separated using polyacrylamide gel electrophoresis and AChE molecular forms were detected and densitometrically evaluated. In control animals, AChE was separated into four forms differing in their electrophoretic mobility and their quantitative content in the sample. The form with lowest electrophoretic mobility represent the main part of AChE activity constituting the whole enzymatic activity. Following intoxication with the nerve agents mentioned, the whole AChE activity in the pontomedullar area of the brain was decreasing in intervals of ten minutes (soman and sarin) or one hour (VX). The AChE activity at the time of death (or terminal stage) was represented 5-30% of controls. Molecular forms of AChE were inhibited in different extent: the form with lowest electrophoretic mobility was diminished to zero level while the form with the highest mobility was practically unaffected, independently on the type of nerve agent. From quantitative expression of percentage content of the forms vs their activity we can imply that value of the total AChE activity represent the "mean" activity of the forms determined.

Acetylcholinesterase↗
PubMedDate not supplied

Inhalation toxicity in mice exposed to sarin (GB) for 20-720 min.

Most of the historical data for the toxicity of sarin (GB) was collected for exposure times of <10 min in attempts to establish the utility of and defence against this agent in offensive military use. However, information concerning the toxicity of GB (and other nerve agents) from longer exposures of 1-12 h is critical for all personnel who must work in or close to low-level concentrations of chemical for extended periods and for all personnel, dressed in Individual Protective Equipment, who need to know when, and if, it is safe to take off these cumbersome garments.The data presented for the toxicity of GB to mice for whole-body exposures of 20 min to 12 h are intended to form part of an ongoing, multi-species effort aimed at establishing toxicity estimates for humans for these longer exposure times: LCT50 values of 430, 540, 900, 1210 and 2210 mg.min m(-3) or LC50 values of 21.5, 9.0, 5.0, 3.4 and 3.1 mg m(-3) were obtained for mice for 20-, 60-, 180-, 360- and 720-min exposures to GB, respectively. The data for longer exposures do not follow Haber's rule (LCT50=CT). The 20- and 60-min data fit the 'toxic load model' involving CnT that was established previously from historical data for 0.17-30 min GB exposures to mice. The LCT(50) and LC50 values for 3, 6 and 12 h are progressively higher (toxicity lower) than predicted by either Haber's rule or the toxic load model.

Animals↗
PubMed1985

Accidental exposure to sarin: vision effects.

Two men were accidentally exposed to vapors of sarin, a cholinesterase inhibitor and extremely toxic nerve gas. Diagnosis was confirmed by depressed cholinesterase activity, and fixed extremely miotic pupils. No other signs or symptoms developed and neither man required treatment. Recovery to normal cholinesterase activity was gradual over a 90-day period. Pupillary reflexes were not detectable until 11 days after exposure; the miotic pupils dilated slowly over a 30-45 day-period. Eye pain and blurred vision did not occur; visual acuity and amplitude of accommodation were improved for several weeks. Other functions not affected significantly were intraocular pressure, visual fields, color vision, heterophorias, and vergences.

Accommodation, Ocular↗
PubMed1998

Quantitative analysis of O-isopropyl methylphosphonic acid in serum samples of Japanese citizens allegedly exposed to sarin: estimation of internal dosage.

A convenient and rapid micro-anion exchange liquid chromatography (LC) tandem electrospray mass spectrometry (MS) procedure was developed for quantitative analysis in serum of O-isopropyl methylphosphonic acid (IMPA), the hydrolysis product of the nerve agent sarin. The mass spectrometric procedure involves negative or positive ion electrospray ionization and multiple reaction monitoring (MRM) detection. The method could be successfully applied to the analysis of serum samples from victims of the Tokyo subway attack and of an earlier incident at Matsumoto, Japan. IMPA levels ranging from 2 to 135 ng/ml were found. High levels of IMPA appear to correlate with low levels of residual butyrylcholinesterase activity in the samples and vice versa. Based on our analyses, the internal and exposure doses of the victims were estimated. In several cases, the doses appeared to be substantially higher than the assumed lethal doses in man.

Butyrylcholinesterase↗