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International Journal of Molecular... May 2023V-agents are exceedingly toxic organophosphate nerve agents. The most widely known V-agents are the phosphonylated thiocholines VX and VR. Nonetheless, other... (Review)
Review
V-agents are exceedingly toxic organophosphate nerve agents. The most widely known V-agents are the phosphonylated thiocholines VX and VR. Nonetheless, other V-subclasses have been synthesized. Here, a holistic overview of V-agents is provided, where these compounds have been categorized based on their structures to facilitate their study. A total of seven subclasses of V-agents have been identified, including phospho(n/r)ylated selenocholines and non-sulfur-containing agents, such as VP and EA-1576 (EA: Edgewood Arsenal). Certain V-agents have been designed through the conversion of phosphorylated pesticides to their respective phosphonylated analogs, such as EA-1576 derived from mevinphos. Further, this review provides a description of their production, physical properties, toxicity, and stability during storage. Importantly, V-agents constitute a percutaneous hazard, while their high stability ensures the contamination of the exposed area for weeks. The danger of V-agents was highlighted in the 1968 VX accident in Utah. Until now, VX has been used in limited cases of terrorist attacks and assassinations, but there is an increased concern about potential terrorist production and use. For this reason, studying the chemistry of VX and other less-studied V-agents is important to understand their properties and develop potential countermeasures.
Topics: Chemical Warfare Agents; Organothiophosphorus Compounds; Nerve Agents; Pesticides
PubMed: 37239944
DOI: 10.3390/ijms24108600 -
Scientific Reports Jun 2021This study analysed the clinical patterns and outcomes of elderly patients with organophosphate intoxication. A total of 71 elderly patients with organophosphate...
This study analysed the clinical patterns and outcomes of elderly patients with organophosphate intoxication. A total of 71 elderly patients with organophosphate poisoning were seen between 2008 and 2017. Patients were stratified into two subgroups: survivors (n = 57) or nonsurvivors (n = 14). Chlorpyrifos accounted for 33.8% of the cases, followed by methamidophos (12.7%) and mevinphos (11.3%). Mood, adjustment and psychotic disorder were noted in 39.4%, 33.8% and 2.8% of patients, respectively. All patients were treated with atropine and pralidoxime therapies. Acute cholinergic crisis developed in all cases (100.0%). The complications included respiratory failure (52.1%), aspiration pneumonia (50.7%), acute kidney injury (43.7%), severe consciousness disturbance (25.4%), shock (14.1%) and seizures (4.2%). Some patients also developed intermediate syndrome (15.5%) and delayed neuropathy (4.2%). The nonsurvivors suffered higher rates of hypotension (P < 0.001), shock (P < 0.001) and kidney injury (P = 0.001) than survivors did. Kaplan-Meier analysis indicated that patients with shock suffered lower cumulative survival than did patients without shock (log-rank test, P < 0.001). In a multivariate-Cox-regression model, shock was a significant predictor of mortality after intoxication (odds ratio 18.182, 95% confidence interval 2.045-166.667, P = 0.009). The mortality rate was 19.7%. Acute cholinergic crisis, intermediate syndrome, and delayed neuropathy developed in 100.0%, 15.5%, and 4.2% of patients, respectively.
Topics: Acute Kidney Injury; Affect; Aged; Antidotes; Atropine; Chlorpyrifos; Female; Humans; Insecticides; Male; Mevinphos; Middle Aged; Organophosphate Poisoning; Organothiophosphorus Compounds; Pneumonia, Aspiration; Pralidoxime Compounds; Psychotic Disorders; Respiratory Insufficiency; Retrospective Studies; Seizures; Shock; Survival Analysis; Treatment Outcome
PubMed: 34079035
DOI: 10.1038/s41598-021-91230-2 -
The Science of the Total Environment Mar 2022Wild raptors are widely used to assess exposure to different environmental contaminants, including anticoagulant rodenticides (ARs). ARs are used on a global scale for...
Wild raptors are widely used to assess exposure to different environmental contaminants, including anticoagulant rodenticides (ARs). ARs are used on a global scale for rodent control, and act by disruption of the vitamin K cycle that results in haemorrhage usually accompanied by death within days. Some ARs are highly persistent and bioaccumulative, which can cause significant exposure of non-target species. We characterized AR exposure in a heterogeneous sample of dead raptors collected over 12 years (2008-2019) in south-eastern France. Residue analysis of 156 liver samples through LC-MS/MS revealed that 50% (78/156) were positive for ARs, with 13.5% (21/156) having summed second-generation AR (SGAR) concentrations >100 ng/g ww. While SGARs were commonly detected (97.4% of positive samples), first-generation ARs were rarely found (7.7% of positive samples). ARs were more frequently detected and at greater concentration in predators (prevalence: 82.5%) than in scavengers (38.8%). Exposure to multiple ARs was common (64.1% of positive samples). While chlorophacinone exposure decreased over time, an increasing exposure trend was observed for the SGAR brodifacoum, suggesting that public policies may not be efficient at mitigating risk of exposure for non-target species. Haemorrhage was observed in 88 birds, but AR toxicosis was suspected in only 2 of these individuals, and no difference in frequency of haemorrhage was apparent in birds displaying summed SGAR levels above or below 100 ng/g ww. As for other contaminants, 17.2% of liver samples (11/64) exhibited Pb levels compatible with sub-clinical poisoning (>6 μg/g dw), with 6.3% (4/64) above the threshold for severe/lethal poisoning (>30 μg/g dw). Nine individuals with Pb levels >6 μg/g dw also had AR residues, demonstrating exposure to multiple contaminants. Broad toxicological screening for other contaminants was positive for 18 of 126 individuals, with carbofuran and mevinphos exposure being the suspected cause of death of 17 birds. Our findings demonstrate lower but still substantial AR exposure of scavenging birds compared to predatory birds, and also illustrate the complexity of diagnosing AR toxicosis through forensic investigations.
Topics: Animals; Anticoagulants; Birds; Chromatography, Liquid; Environmental Monitoring; Rodenticides; Tandem Mass Spectrometry
PubMed: 34748846
DOI: 10.1016/j.scitotenv.2021.151291 -
Environmental Health and Preventive... Jan 2018Pesticides are an agricultural chemical suspected to be a significant contributor to a global diabetes pandemic. The purpose of this study was to confirm previous...
BACKGROUND
Pesticides are an agricultural chemical suspected to be a significant contributor to a global diabetes pandemic. The purpose of this study was to confirm previous findings of the link between diabetes and some agricultural pesticides and to identify the particular pesticides that are most likely to pose a risk of diabetes in the community.
METHODS
A population-based case-controlled study was conducted among residents in the Bang Rakam district of Phitsanulok Province in Thailand. Lifetime pesticide exposure and other relevant data were collected from 866 participating cases with diabetes mellitus and 1021 healthy controls.
RESULTS
After adjusting for gender, age, BMI, cigarette smoking, alcohol consumption, family history of diabetes, and occupation, it was found that the prevalence of diabetes was positively associated with exposure to all types of pesticides, including insecticides, herbicides, fungicides, rodenticides, and molluscicides, with exposure to rodenticides being statistically significant (OR = 1.35; 95%CI 1.04-1.76). Among 35 individual brand-named pesticides investigated, we found statistically significant ORs with three insecticides, including one organochlorine [endosulfan (OR = 1.40; 95%CI 1.01-1.95)], one organophosphate [mevinphos (OR = 2.22; 95%CI 1.17-4.19)], and one carbamate [carbaryl/Sevin (OR = 1.50; 95%CI 1.02-2.19)]; and one fungicides [benlate (OR = 2.08; 95%CI 1.03-4.20)].
CONCLUSIONS
Our results suggest that the occurrence of diabetes among Thai farmer was associated with pesticide exposure. This finding is in line with previous epidemiological and animal studies. Further study using a larger sample size is needed to confirm the relationship and to identify the more toxic compounds.
Topics: Adult; Aged; Case-Control Studies; Diabetes Mellitus; Farmers; Female; Humans; Male; Middle Aged; Occupational Exposure; Pesticides; Prevalence; Thailand
PubMed: 29374457
DOI: 10.1186/s12199-018-0692-5 -
Journal of Biomedical Science Feb 2012Intoxication from the psychostimulant methamphetamine (METH) because of cardiovascular collapse is a common cause of death within the abuse population. For obvious...
BACKGROUND
Intoxication from the psychostimulant methamphetamine (METH) because of cardiovascular collapse is a common cause of death within the abuse population. For obvious reasons, the heart has been taken as the primary target for this METH-induced toxicity. The demonstration that failure of brain stem cardiovascular regulation, rather than the heart, holds the key to cardiovascular collapse induced by the pesticide mevinphos implicates another potential underlying mechanism. The present study evaluated the hypothesis that METH effects acute cardiovascular depression by dampening the functional integrity of baroreflex via an action on brain stem nuclei that are associated with this homeostatic mechanism.
METHODS
The distribution of METH in brain and heart on intravenous administration in male Sprague-Dawley rats, and the resultant changes in arterial pressure (AP), heart rate (HR) and indices for baroreflex-mediated sympathetic vasomotor tone and cardiac responses were evaluated, alongside survival rate and time.
RESULTS
Intravenous administration of METH (12 or 24 mg/kg) resulted in a time-dependent and dose-dependent distribution of the psychostimulant in brain and heart. The distribution of METH to neural substrates associated with brain stem cardiovascular regulation was significantly larger than brain targets for its neurological and psychological effects; the concentration of METH in cardiac tissues was the lowest among all tissues studied. In animals that succumbed to METH, the baroreflex-mediated sympathetic vasomotor tone and cardiac response were defunct, concomitant with cessation of AP and HR. On the other hand, although depressed, those two indices in animals that survived were maintained, alongside sustainable AP and HR. Linear regression analysis further revealed that the degree of dampening of brain stem cardiovascular regulation was positively and significantly correlated with the concentration of METH in key neural substrate involved in this homeostatic mechanism.
CONCLUSIONS
We conclude that on intravenous administration, METH exhibits a preferential distribution to brain stem nuclei that are associated with cardiovascular regulation. We further found that the concentration of METH in those brain stem sites dictates the extent that baroreflex-mediated sympathetic vasomotor tone and cardiac responses are compromised, which in turn determines survival or fatality because of cardiovascular collapse.
Topics: Animals; Baroreflex; Blood Pressure; Brain Stem; Central Nervous System Stimulants; Dose-Response Relationship, Drug; Heart; Heart Arrest; Heart Rate; Injections, Intravenous; Male; Methamphetamine; Rats; Rats, Sprague-Dawley; Shock
PubMed: 22313577
DOI: 10.1186/1423-0127-19-16 -
Biomedical Journal Dec 2019By measuring the prevalence of neuronal traffic between two brain structures based on the notion that diffusion of water molecules along the axon in parallel bundles...
BACKGROUND
By measuring the prevalence of neuronal traffic between two brain structures based on the notion that diffusion of water molecules along the axon in parallel bundles will create prominent anisotropy in the direction of the passage of action potentials, diffusion tensor imaging (DTI) may be taken as an effective tool for functional investigations. Demonstration of complementary results obtained from synchronized DTI of the baroreflex neural circuit and physiological or pathophysiological evaluation of baroreflex functionality should validate this notion.
METHODS
We implemented concurrent changes in neuronal traffic within the neural circuit of the baroreflex-mediated sympathetic vasomotor tone in the brain stem and alterations of its experimental surrogate under physiological and pathophysiological conditions. We further evaluated the functional and clinical implications of results obtained from this experimental paradigm in conjunction with baroreflex induction and a mevinphos intoxication model of brain stem death.
RESULTS
We found that robust connectivity existed between the nucleus tractus solitarii and rostral ventrolateral medulla, the afferent and efferent nuclei of the baroreflex-mediated sympathetic vasomotor. Intriguingly, this connectivity was either reversibly disrupted or irreversibly severed to reflect alterations in baroreflex responses to physiological or pathophysiological challenges.
CONCLUSIONS
The capability to observe simultaneous and complementary changes in neuronal traffic within the neural circuit of the baroreflex-mediated sympathetic vasomotor tone and alterations of its experimental surrogate that bears technical, scientific and clinical implications sustains the notion that coupled with relevant physiological phenotypes, DTI can be an effective investigative tool for functional evaluations of brain stem activities.
Topics: Animals; Baroreflex; Blood Pressure; Brain Stem; Diffusion Tensor Imaging; Male; Nerve Net; Neurons; Rats, Sprague-Dawley; Solitary Nucleus
PubMed: 31948602
DOI: 10.1016/j.bj.2019.10.006 -
Pharmacognosy Research Jan 2010Methanol extracts from S. jambos leaves were tested for antimicrobial activity and toxicity. S. jambos leaf extract inhibited the growth of 4 of the 14 bacteria tested...
Methanol extracts from S. jambos leaves were tested for antimicrobial activity and toxicity. S. jambos leaf extract inhibited the growth of 4 of the 14 bacteria tested (29%). Both gram-positive and gram-negative bacterial growths were inhibited by S. jambos leaf extract, although gram-positive bacteria appeared more susceptible. Two of the 10 gram-negative bacteria (20%) and 2 of the 4 gram-positive bacteria (50%) tested had their growths inhibited by the extract. The leaf extract also proved to be toxic in the Artemia franciscana bioassay, with a 48-h LC(50) of 387.9 ± 38.8 µg/mL, making it slightly more toxic than Mevinphos (505.3± 37.7 µg/mL) and approximately 5-fold less toxic than potassium dichromate (80.4 ± 4.3 µg/mL). Whilst potassium dichromate's LC(50) remained constant across the 72-hour test period (24-h LC(50), 86.3 ± 5.1; 72-h LC(50), 77.9 ± 4.9), the extract and Mevinphos LC(50) values decreased by 72 hours (87.0 ± 11.3 µg/mL and 103.9 ± 12.8 µg/mL, respectively), indicating their similar levels of toxicity in the assay.
PubMed: 21808530
DOI: 10.4103/0974-8490.60577 -
Journal of Biomedical Science Nov 2012Based on an experimental brain stem death model, we demonstrated previously that activation of the mitogen-activated protein kinase kinase 1/2 (MEK1/2)/extracellular...
BACKGROUND
Based on an experimental brain stem death model, we demonstrated previously that activation of the mitogen-activated protein kinase kinase 1/2 (MEK1/2)/extracellular signal-regulated kinase 1/2 (ERK1/2)/ mitogen-activated protein kinase signal-interacting kinase 1/2 (MNK1/2) cascade plays a pro-life role in the rostral ventrolateral medulla (RVLM), the origin of a life-and-death signal detected from systemic arterial pressure, which sequentially increases (pro-life) and decreases (pro-death) to reflect progressive dysfunction of central cardiovascular regulation during the advancement towards brain stem death in critically ill patients. The present study assessed the hypothesis that, in addition to ERK1/2, c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK), the other two mammalian members of MAPKs that are originally identified as stress-activated protein kinases, are activated specifically by MAPK kinase 4 (MAP2K4) or MAP2K6 and play a pro-life role in RVLM during experimental brain stem death. We further delineated the participation of phosphorylating activating transcriptional factor-2 (ATF-2) and c-Jun, the classical transcription factor activated by JNK or p38MAPK, in this process.
RESULTS
An experimental model of brain stem death that employed microinjection of the organophosphate insecticide mevinphos (Mev; 10 nmol) bilaterally into RVLM of Sprague-Dawley rats was used, alongside cardiovascular, pharmacological and biochemical evaluations. Results from ELISA showed that whereas the total JNK, p38MAPK, MAP2K4 and MAP2K6 were not affected, augmented phosphorylation of JNK at Thr183 and Tyr185 and p38MAPK at Thr180 and Tyr182, accompanied by phosphorylation of their upstream activators MAP2K4 at Ser257 and Thr261 and MAP2K6 at Ser207 and Thr211 in RVLM occurred preferentially during the pro-life phase of experimental brain stem death. Moreover, the activity of transcription factors ATF-2 at Thr71 and c-Jun at Ser73, rather than Elk-1 at Ser383 in RVLM were also augmented during the pro-life phase. Furthermore, pretreatment by microinjection into the bilateral RVLM of specific JNK inhibitors, JNK inhibitor I (100 pmol) or SP600125 (5 pmol), or specific p38MAPK inhibitors, p38MAPK inhibitor III (500 pmol) or SB203580 (2 nmol), exacerbated the depressor effect and blunted the augmented life-and-death signal exhibited during the pro-life phase. On the other hand, pretreatment with the negative control for JNK or p38MAPK inhibitor, JNK inhibitor I negative control (100 pmol) or SB202474 (2 nmol), was ineffective in the vehicle-controls and Mev-treatment groups.
CONCLUSIONS
Our results demonstrated that activation of JNK or p38MAPK in RVLM by their upstream activators MAP2K4 or MAP2K6 plays a preferential pro-life role by sustaining the central cardiovascular regulatory machinery during experimental brain stem death via phosphorylation and activation of nuclear transcription factor ATF-2 or c-Jun.
Topics: Activating Transcription Factors; Animals; Brain Death; Brain Stem; Genes, jun; Humans; Imidazoles; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 4; MAP Kinase Kinase 6; Male; Mevinphos; Phosphorylation; Rats; Rats, Sprague-Dawley; Signal Transduction; p38 Mitogen-Activated Protein Kinases
PubMed: 23157661
DOI: 10.1186/1423-0127-19-96 -
Chemosphere Jul 2016Bee products, such as honey, are widely consumed as food and consumer interest is currently oriented towards organic foods. Regarding this, the European Commission...
Bee products, such as honey, are widely consumed as food and consumer interest is currently oriented towards organic foods. Regarding this, the European Commission establishes that the qualification of organic honey and other beekeeping products as being from organic production is closely bound with the characteristics of hive treatments as well as the quality of the environment. Agricultural contamination with pesticides is a challenging problem that needs to be fully addressed, in particular in the field of organic production systems. In this study, the occurrence of different classes of contaminants selected as representative of potential contamination sources were investigated in 59 organic honeys: organochlorines, OCs; organophosphates, OPs; polychlorobiphenyls, PCBs and polybromodiphenylethers, PBDEs. A method based on Accelerated Solvent Extraction with "in line" clean-up and GC-MS/MS detection was developed to detect contaminants. Residues of many pesticides were found in most of the samples investigated. The majority of honey samples contained at least one of the pesticides, even if their concentrations were found to be lower than its MRL. Diazinon, Mevinphos, Coumaphos, Chlorpyrifos and Quinoxyfen were the residues frequently detected in samples coming from the apple and citrus orchard areas. Furthermore, the results of the present study show that the presence of the residue in organic honey may also be affected by the geographical area (e.g. the presence of an agricultural system) confirming honey bee and beehive matrices as appropriate sentinels for monitoring contamination in the environment. The optimised method proved to be simple and rapid, requiring small sample sizes and minimising solvent consumption, due to the ASE having an "in line" clean-up step.
Topics: Agriculture; Animals; Bees; Environmental Monitoring; Environmental Pollutants; Food Contamination; Honey; Italy; Pesticides; Tandem Mass Spectrometry; Volatile Organic Compounds
PubMed: 27085062
DOI: 10.1016/j.chemosphere.2016.04.004 -
The Journal of Physiology Jun 2007As the origin of a 'life-and-death' signal that reflects central cardiovascular regulatory failure during brain stem death, the rostral ventrolateral medulla (RVLM) is a...
Transcriptional up-regulation of nitric oxide synthase II by nuclear factor-kappaB at rostral ventrolateral medulla in a rat mevinphos intoxication model of brain stem death.
As the origin of a 'life-and-death' signal that reflects central cardiovascular regulatory failure during brain stem death, the rostral ventrolateral medulla (RVLM) is a suitable neural substrate for mechanistic delineation of this vital phenomenon. Using a clinically relevant animal model that employed the organophosphate pesticide mevinphos (Mev) as the experimental insult, we evaluated the hypothesis that transcriptional up-regulation of nitric oxide synthase I or II (NOS I or II) gene expression by nuclear factor-kappaB (NF-kappaB) on activation of muscarinic receptors in the RVLM underlies brain stem death. In Sprague-Dawley rats maintained under propofol anaesthesia, co-microinjection of muscarinic M2R (methoctramine) or M4R (tropicamide), but not M1R (pirenzepine) or M3R (4-diphenylacetoxy-N-dimethylpiperidinium) antagonist significantly reduced the enhanced NOS I-protein kinase G signalling ('pro-life' phase) or augmented NOS II-peroxynitrite cascade ('pro-death' phase) in ventrolateral medulla, blunted the biphasic increase and decrease in baroreceptor reflex-mediated sympathetic vasomotor tone that reflect the transition from life to death, and diminished the elevated DNA binding activity or nucleus-bound translocation of NF-kappaB in RVLM neurons induced by microinjection of Mev into the bilateral RVLM. However, NF-kappaB inhibitors (diethyldithiocarbamate or pyrrolidine dithiocarbamate) or double-stranded kappaB decoy DNA preferentially antagonized the augmented NOS II-peroxynitrite cascade and the associated cardiovascular depression exhibited during the 'pro-death' phase. We conclude that transcriptional up-regulation of NOS II gene expression by activation of NF-kappaB on selective stimulation of muscarinic M2 or M4 subtype receptors in the RVLM underlies the elicited cardiovascular depression during the 'pro-death' phase in our Mev intoxication model of brain stem death.
Topics: Animals; Blood Pressure; Brain Death; Cyclic GMP-Dependent Protein Kinases; Diamines; Disease Models, Animal; Ditiocarb; Enzyme Induction; Heart Rate; Male; Medulla Oblongata; Mevinphos; Muscarinic Antagonists; NF-kappa B; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M2; Receptor, Muscarinic M4; Reproducibility of Results; Thiocarbamates; Time Factors; Transcription, Genetic; Tropicamide; Tyrosine
PubMed: 17395621
DOI: 10.1113/jphysiol.2007.130872