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PubMed1998

[Legionella pneumonia caused by aspiration of hot spring water after sarin exposure].

A 72-year-old man was exposed to the sarin gas attack in a Tokyo subway on March 20 th, 1995. After exposure, he noticed eye discomfort, chest tightness, headache and weakness of the lower limbs and oropharyngeal muscles. Despite these symptoms, he visited a hot spring on the same day with his family. On March 25 th, his muscle weakness progressed, and a low grade fever appeared. His muscle weakness disappeared 8 days after exposure to sarin, but respiratory failure rapidly developed, necessitating artificial ventilation within four day after hospitalization on March 28th. Chemotherapy with erythromycin, imipenem/cilastatin, and steroid pulse therapy was begu. PCR and culture of sputum collected by bronchofiberscopy were positive for Legionella pneumophila, serogroup I. His respiratory state improved, but subsequent infection with Pseudomonous aeruginosa. Enterobacter cloacae, and Candida tropicalis/glabrata caused his death 71 days after admission. Oropharyngeal muscle weakness caused by sarin-mediated cholinesterase inhibition was strongly suspected as the cause of hot spring water aspiration. Transbronchial lung biopsy revealed organizing pneumonia with fibrosis. Bronchoscopic findings included redness, edema and fragility of all visible areas of the airway, which was thought to be due to bronchitis caused by Legionellosis.

Aged↗
PubMed1970

The protective actions of some anticholinergic drugs in sarin poisoning.

1. The central and peripheral anticholinergic activities of a series of drugs comprising atropine, hyoscine, caramiphen and one of its analogues, and three glycollic acid esters, have been measured.2. The ability of the same drugs used alone, and in conjunction with N-methyl pyridinium-2-aldoxime methanesulphonate (P2S), to protect mice, rats and guinea-pigs from the lethal effects of sarin has been assessed.3. No correlation was found to exist between central or peripheral anticholinergic activity and ability to protect from sarin.4. On the indirectly stimulated isolated rat phrenic nerve-diaphragm preparation all drugs with the exception of hyoscine caused potentiation of responses to low frequency stimulation but partial block of responses to high frequency stimulation. The drugs did not reverse the effects of sarin on the phrenic nerve-diaphragm preparation.6. It is concluded that a pharmacological action other than an anticholinergic one is involved, in part, in the protective actions against sarin of some of the drugs studied. Whether their effects on skeletal muscle are of any relevance in this respect is unresolved.

Animals↗
PubMed1970

Actions of sarin on fast-twitch and slow-twitch skeletal muscles of the cat and protective action by anticholinergic drugs.

1. The organophosphate cholinesterase inhibitor sarin has been studied for its effects on the contraction of fast-twitch (flexor hallucis longus, FHL) and slow-twitch (soleus) muscles in the cat.2. In both muscles lower doses (2.5 to 20 mug intra-arterially) potentiated, and higher doses (20 mug and over) depressed, twitches produced by indirect stimulation. Muscle action potentials became repetitive. There was no simple relationship between degree of inhibition of blood cholinesterase and effect on muscle twitch.3. The effects of the drug on repetitively stimulated muscles were dependent on both dose and frequency of stimulation. Doses of 2.5 to 10 mug increased the degree of fusion of low frequency tetani (10 Hz for FHL, 5 Hz for soleus) but depressed and caused non-maintenance of tetani at high frequencies (150 Hz and above for FHL, 60 Hz and above for soleus). Doses of 20 mug and above depressed and caused non-maintenance of tetani at all frequencies.4. The anticholinergic drug N-ethyl-2-pyrrolidylmethylcyclopentylphenyl glycollate (PMCG) injected intra-arterially protected both muscles from the effects of sarin on twitch but less so from effects on tetani. When given after sarin the drug reversed twitch potentiation and repetitive firing. In contrast, atropine had little effect on the responses to sarin.5. The effects of (+)-tubocurarine were compared with those of PMCG.6. The possible mode of action of PMCG is discussed.

Action Potentials↗
PubMed2006

Aminopeptidase p mediated detoxification of organophosphonate analogues of sarin: mechanistic and stereochemical study at the phosphorus atom of the substrate.

The activity of the aminopeptidase P from Escherichia coli in hydrolyzing a series of organophosphonate sarin analogues (1-6) was evaluated. The enzymatic rates of hydrolysis for methylphosphonate 1 with a methoxy group attached to the phosphorus center were 7- to 15-fold higher than those for the corresponding analogues 2-6. Double mutant R153W/R370L was able to hydrolyze the S(p) enantiomer of racemic 1 at a considerable rate. This mutant allowed the preparation of the R(p) isomer of the sarin analogue 1. All the mutants, R370L, R153A, W88L, R153L/R370L, and R153W/R370L, preferred the formation of (S(p))-8 to that of the corresponding (R(p))-8 enantiomer and displayed a better enantiomeric excess of products, by 1.4- to 2-fold as compared to the wild-type enzyme. Enzymatic hydrolysis of O,O-diisopropyl-p-nitrophenyl phosphate (9) in H(2) (18)O led to the formation of the (18)O-labeled O,O-diisopropyl phosphate product and confirmed that the catalytic reaction starts with cleavage of the P--O bond. From chemical and kinetic studies, the utilization of an optically pure S(p) enantiomer of O-methyl-p-nitrophenyl methylphosphonothioate (S(p))-MNMPT, 7) has demonstrated that the enzymatic reaction proceeds through a displacement mechanism and generates a chiral product in situ with an inversion of stereochemical configuration at the phosphorus atom. The results also lead to the conclusion that alteration of the active site through site-directed mutagenesis can result in a preference for (S(p))-MNMPT (7) rather than the R(p) isomer.

Aminopeptidases↗
PubMedDate not supplied

In vitro reactivation potency of some acetylcholinesterase reactivators against sarin- and cyclosarin-induced inhibitions.

In our study, we have tested six acetylcholinesterase (AChE) reactivators (pralidoxime, obidoxime, HI-6, trimedoxime, BI-6 and Hlö-7) for reactivation of sarin- and cyclosarin-inhibited AChE using an in vitro reactivation test. We have used rat brain homogenate as the suitable source of enzyme. All oximes are able to reactivate sarin-inhibited AChE. On the other hand, only HI-6 is able to reactivate satisfactorily cyclosarin-inhibited AChE.

Animals↗
PubMed2004

Dynamic solid phase microextraction for sampling of airborne sarin with gas chromatography-mass spectrometry for rapid field detection and quantification.

A portable dynamic air sampler and solid phase microextraction were used to simultaneously detect, identify, and quantify airborne sarin with immediate analysis of samples using a field portable gas chromatography-mass spectrometry system. A mathematical model was used with knowledge of the mass of sarin trapped, linear air velocity past the exposed sampling fiber, and sample duration allowing calculation of concentration estimates. For organizations with suitable field portable instrumentation, these methods are potentially useful for rapid onsite detection and quantification of high concern analytes, either through direct environmental sampling or through sampling of air collected in bags.

Air↗
PubMed2001

Stereochemical specificity of organophosphorus acid anhydrolase toward p-nitrophenyl analogs of soman and sarin.

Organophosphorus acid anhydrolase (OPAA) catalyzes the hydrolysis of p-nitrophenyl analogs of the organophosphonate nerve agents, sarin and soman. The enzyme is stereoselective toward the chiral phosphorus center by displaying a preference for the R(P)-configuration of these analogs. OPAA also exhibits an additional preference for the stereochemical configuration at the chiral carbon center of the soman analog. The preferred configuration of the chiral carbon center is dependent upon the configuration at the phosphorus center. The enzyme displays a two- to four-fold preference for the R(P)-enantiomer of the sarin analog. The k(cat)/K(m) of the R(P)-enantiomer is 250 M(-1) s(-1), while that of the S(P)-enantiomer is 110 M(-1) s(-1). The order of preference for the stereoisomers of the soman analog is R(P)S(C) > R(P)R(C) > S(P)R(C) > S(P)S(C). The k(cat)/K(m) values are 36,300 M(-1)s(-1), 1250 M(-1) s(-1), 80 M(-1) s(-1) and 5 M(-1) s(-1), respectively. The R(P)S(C)-isomer of the soman analog is therefore preferred by a factor of 7000 over the S(P)S(C)-isomer.

Alteromonas↗
PubMed1997

New method for retrospective detection of exposure to organophosphorus anticholinesterases: application to alleged sarin victims of Japanese terrorists.

With regard to detection of exposure to anticholinesterase, the presently used methods have the disadvantage that they cannot detect either low-level exposures with certainty or the structure of the agent and the extent of poisoning. In principle, organophosphate-inhibited butyrylcholinesterase in human plasma is the most persistent and abundant source for biomonitoring of exposure to organophosphate anticholinesterases. Fluoride ions reactivate the inhibited enzyme readily at pH 4, converting the organophosphate moiety into the corresponding phosphofluoridate. Subsequent quantitation of the latter product provides a reliable, highly sensitive and retrospective method for detection of exposure to, or handling of, organophosphates such as nerve agents and organophosphorus pesticides. We applied the new procedure to serum samples from victims of the Tokyo subway attack by the AUM Shinriyko sect and from an earlier incident at Matsumoto. In serum of 10 of 11 victims from the Tokyo incident and of 2 of the 7 samples from the Matsumoto incident, reactivation with fluoride ions yielded sarin concentrations in the range of 0.2-4.1 ng/ml serum. Evidently, these victims had been exposed to an organophosphate with the structure PriO(CH3)P(O)X, presumably with X = F (sarin). Several applications of the new procedure to establish nerve agent and/or organophosphate (OP) pesticide exposure can be envisaged, e.g., (i) in biomonitoring of exposure for health surveillance of those handling organophosphates, (ii) in cases of alleged exposure to nerve agents and/or OP pesticides in armed conflict situations or terrorist attacks, (iii) in medical treatment of intoxication, and (iv) in forensic cases against suspected terrorists that may have handled anticholinesterases.

Cholinesterase Inhibitors↗
PubMed1998

Pharmacological profile of CEB-1957 and atropine toward brain muscarinic receptors and comparative study of their efficacy against sarin poisoning.

This study consists of two parts, first to compare the pharmacological profile of atropine and CEB-1957 substance toward muscarinic receptor subtypes. In various rat brain structures, binding properties were determined by competition experiments of [3H]pirenzepine, [3H]AF-DX 384, and [3H]4-DAMP in quantitative autoradiography of M1, M2, and M3 muscarinic receptor subtypes, respectively. Competition curves have shown that atropine presents similar nanomolar inhibition constants toward each subtype, while CEB-1957 has distinct affinities (Ki from 0.26 to 73 nM) with the following range order: M3 > or = M2 > M1. The second part is to compare atropine and CEB-1957 (in combination with pralidoxime) for their ability to protect against the lethality induced by 2 x LD50 of the acetylcholinesterase inhibitor sarin. CEB-1957 reduced the mortality at doses 10 times lower than atropine. Finally, from these results, it is proposed that a selective blockade of M2 and M3 receptor subtypes could play a pivotal role in the protective effect against sarin poisoning.

Animals↗
PubMed1999

Sarin-like and soman-like organophosphorous agents activate PLCgamma in rat brains.

We report that there is a time-related change in the phospholipase C (PLC) activities of rat brain cytosol and membrane fractions after iv injection of a soman-like or a sarin-like organophosphorous agent (bis(isopropyl methyl)phosphonate [BIMP] and bis(pinacolyl methyl)phosphonate [BPMP]). PLCgamma was activated in the brain cytosol fraction from BPMP-injected rats. The phosphorylating activity of rat brain membrane fractions were enhanced by BPMP treatment. The brain membrane fractions from BPMP-treated rats phosphorylated several proteins, including supposedly PLCgamma in the brain cytosol fraction from control rats in vitro. These results suggest that soman and sarin may stimulate a membrane tyrosine kinase, including growth factor receptors, directly or indirectly.

Animals↗
PubMed1999

The interaction of sarin and soman with plasma proteins: the identification of a novel phosphonylation site.

Incubation of both sarin and soman with human plasma has shown that binding occurs to a tyrosine residue. Similar binding occurs when sarin and soman are incubated with human serum albumin. This binding may provide an important biological marker, which retains full structural information concerning the identity of the agent, in cases of allegations of chemical warfare use.

Biomarkers↗
PubMed1991

Effects of diisopropyl phosphofluoridate, sarin and soman on the accessibility of proteins, in the electroplax membrane, to lactoperoxidase-catalyzed iodination.

Anticholinesterases (anti-ChE) have some effects on biological properties including behavior, vision, and electroencephalograms, which are often long lasting and which do not appear to be due to cholinesterase (ChE; EC 3.1.1.7) inhibition, but which may be due to alterations in the organization and/or functioning of the cellular membrane. We assessed the effects of anti-ChE agents on the asymmetric organization of proteins in the innervated (excitable) and in the non-innervated (non-excitable) plasma membrane of the electroplax from the electric eel. Lactoperoxidase-catalyzed iodination (LCI) was carried out under impenetrable conditions in intact electroplax (where protein exposure on the external surface is monitored) and in split electroplax (where total protein labeling on both the external and internal monolayers of the plasma membrane bilayer is monitored). Labeling in split electroplax was much greater than in intact electroplax for all molecular weight groupings of proteins (30,000 to greater than 200,000). The anti-ChE agents diisopropyl phosphofluoridate (DFP; 10(-3) M), sarin (10(-4) M) and soman (10(-4) M, 10(-6) M, 2.5 x 10(-9) M) did not alter permeability, protein content or the electrophoretic pattern of the plasma membrane proteins of the electroplax. DFP, sarin and 10(-6) M soman (but not 2.5 x 10(-9) M or 10(-4) M soman) increased labeling of some of the molecular weight fractions in the non-innervated plasma membrane as monitored by LCI in intact electroplax. Under these same conditions, DFP and 10(-4) M soman increased labeling in the innervated plasma membrane while 10(-6) M soman decreased labeling. When LCI was carried out in split electroplax, 10(-4) M soman caused a decrease in labeling in both the innervated and non-innervated plasma membrane indicating a decrease of exposed proteins on the cytoplasmic surface of the plasma membrane. These concentrations of the anti-ChE agents caused almost complete ChE inhibition in the electroplax cells, except for 2.5 x 10(-9) M soman which caused little or no inhibition. These results suggest that alterations in protein asymmetry, as monitored by LCI of accessible proteins, are not directly due to ChE inhibition. These changes in organization of membrane proteins could contribute to a variety of effects of anti-ChE agents which are not due to ChE inhibition.

Animals↗
PubMed1991

Soman and sarin inhibition of molecular forms of acetylcholinesterase in mice. Time course of recovery and reactivation by the oxime HI-6.

The in vivo sensitivity of the molecular forms of the enzyme acetylcholinesterase to inhibition by either soman or sarin, reactivation by HI-6 and the time course of recovery following inhibition by soman were investigated in mice. Administration of HI-6 (50 mg/kg, i.p.) immediately after soman (100 micrograms/kg, s.c.) or sarin (150 micrograms/kg, s.c.) resulted in an apparent selective reactivation of the 10S and 16S molecular forms of acetylcholinesterase and no reactivation of the 4S form of diaphragm acetylcholinesterase. The apparent selectivity of the reactivation of the molecular forms of the acetylcholinesterase was probably due to the fact that the 10S and 16S forms of acetylcholinesterase are located primarily extracellularly and the 4S form intracellularly. The HI-6 was restricted primarily to the extracellular compartment due to its quaternary, hydrophilic nature. If the administration of HI-6 was delayed until 60 min following soman (100 micrograms/kg, s.c.) injection, no reactivation of any of the molecular forms of acetylcholinesterase could be found in the diaphragm. The soman-inhibited acetylcholinesterase had probably aged and, thus, was not susceptible to reactivation by HI-6. The time course of recovery of the molecular forms in the diaphragm occurred rather quickly with the smaller 4S and 10S forms recovering to control levels faster than the larger 16S form. It took between 8 and 16 days for the 16S form to recover to normal. In the brain, hypothalamic acetylcholinesterase molecular forms such as the 4S recovered faster than the 10S form which had not recovered to control 16 days after soman administration; the 16S form of acetylcholinesterase was not detected in the brain.

Acetylcholinesterase↗
PubMed1994

Application of gas chromatography-mass spectrometry and gas chromatography-tandem mass spectrometry to the analysis of chemical warfare samples, found to contain residues of the nerve agent sarin, sulphur mustard and their degradation products.

Samples of clothing, grave debris, soil and munition fragments, collected from the Kurdish village of Birjinni, were analysed by GC-MS with selected ion monitoring (SIM) for traces of chemical warfare agents and their degradation products. Positive analyses were confirmed, where possible, by full scan mass spectra, or at low concentrations by additional GC-MS-SIM analysis using chemical ionisation, by higher resolution GC-MS-SIM, and by GC-tandem mass spectrometry using multiple reaction monitoring. Sulphur mustard and/or thiodiglycol were detected in six soil samples; isopropyl methylphosphonic acid and methylphosphonic acid, the hydrolysis products of the nerve agent sarin, were detected in six different soil samples. Trace amounts of intact sarin were detected on a painted metal fragment associated with one of these soil samples. The results demonstrate the application of different GC-MS and GC-MS-MS techniques to the unequivocal identification of chemical warfare agent residues in the environment at concentrations ranging from low ppb to ppm (w/w). They also provide the first documented unequivocal identification of nerve agent residues in environmental samples collected after a chemical attack.

Chemical Warfare Agents↗
PubMed1985

The protective effect of oxime pretreatment upon the inhalative toxicity of sarin and soman in rats.

The functional set-up of a static inhalation device is described. The closed system consists of a reservoir for the circulating test gas, an inhalator for "nose-only" exposure of 10 rats, and analyzers for the test gas and CO2. It has an overall volume of 200 liters. The following LCt50 values for rats exposed to noxious vapors were determined: DFP 3629, sarin 191, and soman 211 mg X min X m-3. Pretreatment with atropine (10 mg/kg) together with the oximes Toxogonin or HJ6 (each 13 mg/kg) 10 min before the exposure raised the LCt50 of sarin by a factor of 2.5 and 14, respectively. In case of soman poisoning, only HJ6 (50 mg/kg) together with atropine was effective, which increased the LCt50 by a factor of 7.

Aerosols↗
PubMed1989

Tacrine slows the rate of ageing of sarin-inhibited acetylcholinesterase.

Bovine erythrocyte acetylcholinesterase was inhibited by the organophosphate sarin, and the rate of ageing (the time-dependent decrease in the ability of an oxime to reactivate the enzyme) was studied. At pH 7.0 and 37 degrees C, 10(-5) M or 10(-6) M tacrine (tetrahydroaminoacridine) decreased the rate of ageing in low ionic strength buffer. Tacrine at 10(-5) M also significantly decreased the rate of ageing in 150 mM NaCl. The results indirectly demonstrated that the inhibition of substrate hydrolysis by tacrine is reversible, and that tacrine does not prevent reactivation of sarin-inhibited acetylcholinesterase. Both these observations, which were also made for rat brain acetylcholinesterase, are in contrast with reports in the literature.

Acetylcholinesterase↗
PubMed1987

Cardiomyopathy in Soman and Sarin intoxicated rats.

Rats surviving various single dose of the organophosphorus anticholinesterase nerve agents Soman and Sarin were examined by light microscopy at intervals up to 35 days post-exposure. Brain lesions, identical to those that have been reported elsewhere were present, as well as a previously unreported finding associated with Soman or Sarin intoxication: half of all animals that had brain lesions also had areas of myocardial degeneration and necrosis. Depending upon the point in time at which cardiac tissues were examined, findings varied from areas of acute myolysis and necrosis to areas undergoing resolution of damage. The finding of brain lesions in those animals having cardiac lesions suggests a relationship between the convulsion induced neurologic and cardiac lesions. These studies suggest that convulsive doses of chemical warfare agents induce pathological changes in the cardiovascular system of laboratory animals.

Animals↗
PubMed2006

Our recent experiences with sarin poisoning cases in Japan and pesticide users with references to some selected chemicals.

Attention has been paid to neurobehavioral effects of occupational and environmental exposures to chemicals such as pesticides, heavy metals and organic solvents. The area of research that includes neurobehavioral methods and effects in occupational and environmental health has been called "Occupational and Environmental Neurology and Behavioral Medicine." The methods, by which early changes in neurological, cognitive and behavioral function can be assessed, include neurobehavioral test battery, neurophysiological methods, questionnaires and structured interview, biochemical markers and imaging techniques. The author presents his observations of neurobehavioral and neurophysiological effects in Tokyo subway sarin poisoning cases as well as in pesticide users (tobacco farmers) in Malaysia in relation to Green Tobacco Sickness (GTS). In sarin cases, a variety effects were observed 6-8 months after exposure, suggesting delayed neurological effects. Studies on pesticide users revealed that organophosphorus and dithiocarbamate affected peripheral nerve conduction and postural balance; subjective symptoms related to GTS were also observed, indicating the effects of nicotine absorbed from wet tobacco leaves. In addition, non-neurological effects of pesticides and other chemicals are presented, in relation to genetic polymorphism and oxidative stress.

Agricultural Workers' Diseases↗