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Extracorporeal removal of organophosphate from blood has been proposed, but the efficacy of hemodialysis and hemoperfusion has not been established. We report a case of organophosphate poisoning in which continuous renal replacement therapy (CRRT) was applied with conventional indications and was found to increase plasma cholinesterase levels by hemodiafiltration. A 73-year-old male was found unconscious at home and was brought to the emergency department by ambulance. An empty bottle of Supracide insecticide, of which the active ingredient is methidathion, was found beside him. CRRT was initiated because he showed signs of oliguria and acidosis with an unstable hemodynamic condition. Although his condition improved temporarily after CRRT initiation, it subsequently deteriorated, and he died despite maximal supportive effort. His prefilter plasma cholinesterase levels remained at

Background Paraquat is an inexpensive herbicide used in agriculture because it is easily available and the cost of labour for manual clearance of weeds is prohibitive. Paraquat is toxic to human beings and is also used for committing suicide. We studied the reasons for under-reporting of paraquat poisoning including those related to the training of doctors. Methods In this mixed-methods study, we describe a series of patients with paraquat poisoning. We recorded their demographic data, clinical features, treatment and outcome with an intention to explore the reason for an initial misdiagnosis. We also explored whether deficiencies in curricula contributed to the misdiagnosis. Results The patients of paraquat poisoning (n=28) were mostly young illiterate men driven by impulsive behaviour rather than chronic depression. Paraquat was consumed by patients from non-agricultural background as well, implying easy access to the poison. Many patients could not name the agent and so initial treatment was directed at organophosphorus poisoning. The diagnostic signs included paraquat tongue, renal failure and jaundice. Most of the casualty medical officers and residents were unfamiliar with the symptoms and signs of paraquat poisoning as was evident by their answers to the questionnaire. Knowledge of medical students about paraquat poisoning was not assessed in the theory examinations and viva. Conclusion Factors contributing to the limitation in establishing the diagnosis are illiteracy and ignorance of the patients, lack of specific signs and lack of training of medical officers in treating patients with paraquat poisoning.

Organophosphorus (OP) cholinesterase inhibitors, which include insecticides and chemical warfare nerve agents, are very potent neurotoxicants. Given that the actual treatment has several limitations, the present study provides a general method, called the zebrafish-OP-antidote test (ZOAT), and basic scientific data, to identify new antidotes that are more effective than the reference pyridinium oximes after acute OP poisoning. The reactivation capacity of a chemical compound can be measured using in vivo and ex vivo acetylcholinesterase (AChE) assays. We demonstrated that it is possible to differentiate between chemical compound protective efficacies in the central and peripheral nervous system via the visual motor response and electric field pulse motor response tests, respectively. Moreover, the ability to cross the brain-blood barrier can be estimated in a physiological context by combining an AChE assay on the head and trunk-tail fractions and the cellular and tissue localization of AChE activity in the whole-mount animal. ZOAT is an innovative method suitable for the screening and rapid identification of chemicals and mixtures used as antidote for OP poisoning. The method will make it easier to identify more effective medical countermeasures for chemical threat agents, including combinatorial therapies.

Oxime reactivators of acetylcholinesterase (AChE) represent an integral part of standard antidote treatment of organophosphate poisoning. Oxime K869 is a novel bisquaternary non-symmetric pyridinium aldoxime with two pyridinium rings connected by a tetramethylene bridge where two chlorines modify the pyridinium ring bearing the oxime moiety. Based on in vitro assays, K869 is a potent AChE and butyrylcholinesterase (BChE) reactivator. For the investigation of the basic pharmacokinetic properties of K869 after its intramuscular application, new HPLC-UV and LC-MS/MS methods were developed and validated for its determination in rat body fluids and tissues. In this study, the SPE procedure for sample pretreatment was optimized as an alternative to routine protein precipitation widely used in oxime pharmacokinetics studies. K869 oxime is quickly absorbed into the central compartment reaching its maximum in plasma (39 ± 4 μg/mL) between 15 and 20 min. The majority of K869 was eliminated by kidneys via urine when compared with biliary excretion. However, only a limited amount of K869 (65 ± 4 ng/g of brain tissue) was found in the brain 30 min after oxime administration. Regarding the brain/plasma ratio calculated (less than 1%), the penetration of K869 into the brain did not exceed conventionally used oximes.

Acute organophosphate (OP) toxicity is a major health problem in different populations. Nearly three million cases are affected annually all over the world. The most common clinical presentations include muscarinic, nicotinic and central nervous system manifestations resulting from cholinergic overload. Nevertheless, endocrine toxicity and affection of glucose homeostasis are reported. The current study aimed to study random blood sugar (RBS) as a simple, inexpensive tool to predict mortality and major outcome events in acute organophosphate poisonings. Ninety adult patients with acute organophosphate poisoning were included in the study. Patients already known to be diabetic before exposure and those with mixed intoxication were excluded. RBS was done to all included patients on admission before receiving any medications. Patients were categorized into euglycemics (62.2%), hyperglycemic (28.9%) and hypoglycemics (8.9%). The severity of organophosphorus poisoning symptoms and signs was graded into; Mild (32.2%), Moderate (38.9%) and Severe (28.9%) grades with a statistically significant association between RBS and poisoning severity at the time of admission. In addition, RBS showed a statistically significant association with each of serum cholinesterase levels, the delay time before hospital admission, the need for intubation, mechanical ventilation and death. Meanwhile, RBS had no statistically significant association with either doses of atropine & toxogonine nor the duration of hospital stay.

Organophosphates are highly toxic compounds as they are involved in irreversible inhibition of acetylcholinesterase, causing various neurotoxic effects via acetylcholine accumulation throughout the nervous system. Traditional treatments for organophosphate poisoning are not effective enough to overcome all the toxic effects. There is a need for alternate treatment of life threatening poisoning of organophosphates. For this purpose a biomimetic nanosponge of poly (lactic- co-glycolic acid) is prepared, characterized and analysed as an antidote for organophosphate poisoning. In this nanosponge red blood cell membranes are used for coating poly lactic co-glycolic acid nanoparticles. In vitro studies are conducted to investigate the retention of acetylcholinesterase activity on the prepared nanosponge as well as to assess the scavenging ability of prepared nanosponge for model organophosphate, chlorpyrifos. In vivo studies are conducted to evaluate the detoxification potential of nanosponge in rabbit model, poisoned with chlorpyrifos. Hepatotoxicity and renal toxicity of nanosponge/chlorpyrifos complex is also studied in survived rabbits and the data is analysed statistically.

This study evaluated the most common toxic agents affecting domestic cats, the clinical signs of toxicity, and the therapeutic approaches for recovery. A survey on poisoning in cats was conducted among small animal veterinary practitioners from 2017 to 2018. Of the 748 completed questionnaires, 543 (72.6%) were evaluated. Pesticides and household cleaning supplies were the most common causes of poisoning in cats. The toxicant groups included pesticides and household cleaning supplies (organophosphates), human drugs (acetaminophen), plants/plant derivatives (lily), and veterinary drugs (tramadol). The major clinical signs for these four groups of toxicants were (1) acetaminophen poisoning, which caused oxidative erythrocyte damage; (2) muscarinic and nicotinic cholinergic syndrome, which resulted from organophosphate poisoning; (3) acute kidney injury, which resulted from intoxication of lily; and (4) serotonin syndrome, which resulted from tramadol toxicosis. Interventions for treating poisoning in cats were based on the clinical presentation of animals. In the present study, the significant toxins identified to be dangerous for cats were characterized using the obtained data in Brazil as well as the main associated clinical signs and therapy recommended by veterinarians.

We designed this study to identify the factors associated with time to successful weaning in mechanically ventilated organophosphate (OP)-poisoned patients as the primary outcomes while duration of mechanical ventilation (MV) support, intensive care unit (ICU), and hospital length of stay (LOS) and in-hospital mortality as the secondary outcomes. We conducted a retrospective study of mechanically ventilated OP-poisoned patients admitted to the ICU of Poison Control Center of Ain Shams, Cairo, Egypt, starting from January 2019 to December 2019. Weaning was considered successful if the patient succeeded in the first spontaneous breathing trial of weaning and did not need reinstitution of MV. We used Cox proportional hazards regression models to identify factors associated with time to successful weaning in the studied patients. A total of 55 patients were enrolled in the study. Thirty-eight patients were weaned successfully. Lower initial red cell distribution width (RDW) levels [adjusted hazard ratio (HR), 0.299, 95% confidence interval (CI) (0.184-0.486)] and lower initial doses of atropine [adjusted HR, 0.97, 95% CI (0.935-0.999)] were independently associated with shorter time to achieve successful weaning. Successfully weaned patients had significantly longer hospital LOS (

Accidental poisoning in children, though underreported in our environment, is common and could prove fatal. It is important to identify the primary chemical agent that is responsible for the poisoning. We present a case of accidental ingestion of fish poisoned with aluminum phosphide (AlP) used as rat poisoning by a 14-month-old girl. At presentation, the actual chemical content of the poison was not available and clinical features were suggestive of organophosphate poisoning. She was commenced on atropine together with other treatment, on which she made remarkable improvement. The atropine was continued with complete resolution of symptoms on the third day of admission. We, therefore, report a serendipitous use of atropine in the management of AlP poisoning with successful outcome.

Inhibition of acetylcholinesterase by either organophosphates or carbamates causes anti-cholinesterase poisoning. This arises through a wide range of neurotoxic effects triggered by the overstimulation of the cholinergic receptors at synapses and neuromuscular junctions. Without intervention, this poisoning can lead to profound toxic effects, including death, and the incomplete efficacy of the current treatments, particularly for oxime-insensitive agents, provokes the need to find better antidotes. Here we show how the non-parasitic nematode Caenorhabditis elegans offers an excellent tool for investigating the acetylcholinesterase intoxication. The C. elegans neuromuscular junctions show a high degree of molecular and functional conservation with the cholinergic transmission that operates in the autonomic, central and neuromuscular synapses in mammals. In fact, the anti-cholinesterase intoxication of the worm’s body wall neuromuscular junction has been unprecedented in understanding molecular determinants of cholinergic function in nematodes and other organisms. We extend the use of the model organism’s feeding behaviour as a tool to investigate carbamate and organophosphate mode of action. We show that inhibition of the cholinergic-dependent rhythmic pumping of the pharyngeal muscle correlates with the inhibition of the acetylcholinesterase activity caused by aldicarb, paraoxons and DFP exposure. Further, this bio-assay allows one to address oxime dependent reversal of cholinesterase inhibition in the context of whole organism recovery. Interestingly, the recovery of the pharyngeal function after such anti-cholinesterase poisoning represents a sensitive and easily quantifiable phenotype that is indicative of the spontaneous recovery or irreversible modification of the worm acetylcholinesterase after inhibition. These observations highlight the pharynx of C. elegans as a new tractable approach to explore anti-cholinesterase intoxication and recovery with the potential to resolve critical genetic determinants of these neurotoxins’ mode of action.

Poisoning by organophosphorus agents (OPs) is a serious public health issue across the world. These compounds irreversibly inhibit acetylcholinesterase (AChE), resulting in the accumulation of acetylcholine (ACh) and overstimulation of ACh receptors. A supramolecular detoxification system (SDS) has been designed with a view to deliver pyridine-2-aldoxime methochloride (PAM) with a synergistic inhibition effect on the ACh-induced hyperstimulation through host–guest encapsulation. NMR and fluorescence titration served to confirm the complexation between carboxylatopillar[6]arene (CP6A) and PAM as well as ACh with robust affinities. Patch-clamp studies proved that CP6A could exert an inhibition effect on the ACh-induced hyperstimulation of ACh receptors. Support for the feasibility of this strategy came from fluorescence imaging results. In vivo studies revealed that complexation by CP6A serves to increase the AChE reactivation efficiency of PAM. The formation of the PAM/CP6A complex contributed to enhance in a statistically significant way the ability of PAM not only to relieve symptoms of seizures but also to improve the survival ratio in paraoxon-poisoned model rats. These favorable findings are attributed to synergistic effects that PAM reactivates AChE to hydrolyze ACh and excess ACh is encapsulated in the cavity of CP6A to relieve cholinergic crisis symptoms., This work provides a feasible supramolecular strategy for improving the emergency treatment effect of OPs poisoning through synergistic effect.

Acute organophosphorus pesticide poisoning (AOPP) is a worldwide health concern that has threatened human lives for decades, which attacks acetylcholinesterase (AChE) and causes nervous system disorders. Classical treatment options are associated with short in vivo half-life and side effects. As a potential alternative, delivery of mammalian-derived butyrylcholinesterase (BChE) offers a cost-effective way to block organophosphorus attack on acetylcholinesterase, a key enzyme in the neurotransmitter cycle. Yet the use of exotic BChE as a prophylactic or therapeutic agent is compromised by short plasma residence, immune response and unfavorable biodistribution. To overcome these obstacles, BChE nanodepots (nBChE) composed of a BChE core/polymorpholine shell structure were prepared via in situ polymerization, which showed enhanced stability, prolonged plasma circulation, attenuated antigenicity and reduced accumulation in non-targeted tissues. In vivo administration of nBChE pre- or post-organophosphorus exposure in a BALB/C mouse model resulted in potent prophylactic and therapeutic efficiency. To our knowledge, this is the first systematic delivery of non-human BChE to tackle AOPP. In addition, this work also opens up a new avenue for real applications in both research and clinical settings to cope with acute intoxication-related diseases.

Introduction: Organophosphorus poisoning (OPP) is one of the common medical emergencies among rural population in India due to suicide attempts. The purpose of this study was to investigate the relationship between the initial emergency laboratory parameters (electrolytes, liver function test, random blood glucose (RBS), renal function test, Hb, RBC and WBC) and severity of organophosphate poisoning based on Bardin’s Classification and type of OP compound consumed in patients admitted to emergency department with OPP. Materials and Methods: A retrospective observational study was done in OPP patients admitted to emergency medicine department. Based on Bardin’s classification all OPP cases were classified into 3 Grades of severity of poisoning.1-3 Hematological and biochemical parameters were compared based on this severity of poisoning. Results: With random sampling of 45 patients, 19 male and 26 female patients aged between 25-35 years, admitted with OPP were included in the study. The severity of poisoning was worst in females. The pseudocholinesterase, potassium and creatinine levels were significantly low in patients of grade 3 than grade 1 and grade 2 (p Conclusion: Emergency laboratory parameters in acute oraganophosphorus poisoning reflect the need for basic diagnostic facility in rural area. Laboratory parameters can also serve as possible predictive markers for severe outcomes and prognosis in OP poisoning. The knowledge of type of OP compound consumed can predict the severity of OP intoxication and need for emergency intervention. Keywords: Oragano phosphorous poisoning, Biochemical parameters.

Background: Our recent work has been treating the pharmacokinetics of pyridinium aldoximes of various structures including their time-dependent distribution in the body of male rats and also the extent of blood-brain-barrier penetration. Objective: Our overall aim was to find a proper antidote in organophosphate poisoning with fast elimination. Methods: White male Wistar rats were intramuscularly injected with the aqueous solution of 3 µmol of K-347. The animals were sacrificed at different time periods following treatment; various tissues and body fluids were taken and homogenised. The level of K-347 was determined using reversed-phase HPLC. Dose-dependence of tissue level was also determined by using various doses, 3 µmol through 100 µmol of K-347. Results: The serum level of K-347 showed a definitely fast decline. K347 did not have any effect on Gram-positive and Gram-negative bacteria that we tested. Conclusion: The kinetics of K-347 showed an extremely fast offset, even in comparison with several other pyridinium aldoximes in clinical practice and in developmental stages.

Organophosphorus agents (OP) are widely used as pesticides due to their cost effectiveness, yet they present a significant public health risk owing to their high toxicity, especially in cases of occupational exposure in agriculture, during suicide attempts using pesticides, and as nerve agents in warfare. Their vigorous permeability through inhalation, ingestion, and dermal exposure results in a high number of reported OP poisoning cases and alarming mortality rates. Initial first-aid management involves decontamination, ventilation, and hemodialysis. Additionally, current treatment guidelines recommend prompt administration of atropine as a first-line antidote, oximes as a follow-up, benzodiazepines for seizure control, and pyridostigmine for prophylaxis. Nevertheless, current treatment options are associated with several challenges. Thus, recent research has focused on investigating novel approaches for their potential in improving current management strategies. This article intends to review recent advances in OP poisoning treatment, including agents investigated for their use as an alternative or adjunctive therapy, novel formulations such as nasal drops or sublingual tablets for emergency administration of atropine, as well as innovative strategies for enhanced oximes delivery and overall efficacy. However, two major barriers may limit these innovations, ethical issues associated with their clinical assessment in emergencies, and limited profitability in countries where most cases occur.

Despite organophosphate pesticide is the most prevalent cause of acute poisoning in low- and middle-income countries, data on organophosphate induced delayed neuropathy (OPIDN) are limited. We aimed to characterize organophosphates' long-term effects on the peripheral nervous system after an acute cholinergic crisis in adults.We performed a prospective observational study in an academic hospital of north India in patients aged 13-40 years with acute organophosphate ingestion. After resolving the cholinergic crisis, the patients were followed for six months with neurologic assessments, including history, neurologic examination, and nerve conduction study (NCS).Twenty-three patients were recruited to the study. All but one had normal neurological examination and NCS at discharge from hospital a median duration of six days (interquartile range, 3-10) after self-poisoning. Eight (34.8%) developed OPIDN during the six-month follow-up. Three patients had symptomatic neuropathy, and NCS detected subclinical peripheral nerve involvement in five. All cases were associated with chlorpyrifos ingestion (8/17 total chlorpyrifos cases). Two OPIDN cases had foot drop and gait ataxia at three-month which persist at six-month. One patient had distal paresthesia at three months, which improved at a six-month follow-up. NCS in OPIDN cases invariably revealed axonal degeneration, injury to motor fibers more than sensory fibers, and frequent peroneal nerve involvement. None of the baseline characteristics, including the ingested amount, predicted clinical or subclinical OPIDN in chlorpyrifos self-poisoned patients on a univariant analysis.Peripheral nerve involvement is not uncommon after recovery from a cholinergic crisis in chlorpyrifos self-poisoning and debilitating in some patients. Detection of subclinical injury on NCS may provide an early window to prevent severe symptomatic neuropathy.

International audience; Novel 6-alkyl- and 6-alkenyl-3-fluoro-2-pyridinaldoximes have been synthesised by using a mild and efficient chemoselective hydrogenation of 6-alkynyl-3-fluoro-2-pyridinaldoxime scaffolds, without altering the reducible, unprotected, sensitive oxime functionality and the C-F bond. These novel 6-alkyl-3-fluoro-2-pyridinaldoximes may find medicinal application as antidotes to organophosphate poisoning. Indeed, one low-molecular-weight compound exhibited increased affinity for sarin-inhibited acetylcholinesterase (hAChE) and greater reactivation efficiency or resurrection for sarin-inhibited hAChE, compared with those of 2-pyridinaldoxime (2-PAM) and 1-({[4-(aminocarbonyl)pyridinio]methoxy}methyl)-2-[(hydroxyimino)methyl]pyridinium chloride (HI-6), two pyridinium salts currently used as antidote by several countries. In addition, the uncharged 3-fluorinated bifunctional hybrid showed increased in vitro blood-brain barrier permeability compared with those of 2-PAM, HI-6 and obidoxime. These promising features of novel low-molecular-weight alkylfluoropyridinaldoxime open up a new era for the design, synthesis and discovery of central non-quaternary broad spectrum reactivators for organophosphate-inhibited cholinesterases.

Therapeutic efficacy of antidotal treatment of acute poisoning by nerve agents is generally assessed by the evaluation of LD50 values of nerve agents over 24 h following poisoning without or with a...

To evaluating the efficacy of fresh frozen plasma (FFP) in comparison with conventional regimen in the treatment of organophosphate (OP) poisoning.PubMed, ScopeMed, Cochrane, Scopus, and Google Scholar databases were searched. The search strategy used the following key words "organophosphate" and "poisoning or toxicity", "(atropine and oxime)", "fresh frozen plasma", "clinical trial", "outcome". The treatment with atropine or/and oxime was considered conventional therapy. The length of hospitalization, the length of ICU admission, need for mechanical ventilation and its duration, clinical recovery point, choline esterase level, mortality rate, and intermediate syndrome (IMS) occurrence were the key outcomes of interest. Databases were searched during the period of 2003-2019. Five studies were included in the analysis.Pooling of data showed that the relative risk (RR) of mortality in OP poisoning for five included trials comparing FFP-treated group with conventional regimen therapy was [0.563 (95% CI (0.252, 1.255)]. The summary of RR for IMS in two studies was [RR: 1.34, 95% CI (0.655, 2.742)]. In addition, there was a non-significant mean difference (MD) in hospital stay [MD: -0.106, 95% CI (-0.434, 0.223)] in three included trials. A significant MD was observed in the length of ICU admission in two trials between FFP-treated group compared to the conventional treatment group [MD: -2.672, 95% CI (-4.189, -1.154)], but after random effects meta-analysis, the changes were not significant [MD: -2.015, 95% CI (-6.308, 2.277)]. The summary of fixed-effect meta-analysis for choline esterase level in three trails was [MD: -0.117, 95% CI (-0.468, 0.234)]. The RR of ventilation requirement for two included trials in the FFP-treated group comparing to the conventional regimen therapy was [0.84, 95% CI (0.691, 1.022)] while for ventilation duration in two studies was [MD: -0.183, 95% CI (-0.567, 0.201)].The addition of FFP to conventional therapy did not improve the outcomes of mortality, IMS, hospital length of stay, cholinesterase levels, need or duration of mechanical ventilation, and only the length of ICU stay could affect in the treated group.

Some epidemiological evidence implicates acute organophosphate (OP) pesticide poisoning in long-term neurocognitive deficits. However, no study has prospectively followed up poisoned patients long-term from the time of intoxication. We aimed to determine whether clinically significant acute OP self-poisoning leads to subacute and chronic neurocognitive deficits, in a prospective follow up study.Employing Mini Mental State Examination, Digit Span and Cambridge Neuropsychological Test Automated Battery (CANTAB), we compared multiple cognitive functions in 222 patients hospitalized with acute OP pesticide self-poisoning with a control group of 52 patients hospitalized with paracetamol overdose, at three time points: on discharge following clinical recovery, 6 weeks and 6 months post-ingestion. Intergroup comparisons at each time point were done in multiple regression models, adjusting for sex, age, education and psychiatric comorbidities. OP within-group analysis was done to determine a dose-response relationship.After adjusting for covariates, the OP poisoned group had significantly poorer working memory (Digit Span) and episodic memory (CANTAB Paired Associates Learning); impaired spatial planning (CANTAB Stocking of Cambridge); and slower response speed in the sustained attention task (CANTAB Rapid Visual Information Processing), in the post-discharge assessment. Only working memory and episodic memory measures were impaired in the OP group at 6 weeks, whereas no significant intergroup differences were observed at 6 months. The OP subgroup who had complete red cell acetylcholinesterase inhibition on admission had poorer episodic memory when tested post-discharge than those who had partial inhibition, but no significant subgroup differences were observed at 6 weeks or 6 months.Acute OP pesticide poisoning may cause neuropsychological impairment that outlasts the cholinergic phase on a subacute time scale; but does not cause measurable chronic neuropsychological deficits.

Background: Individuals have the chance to get exposed to organophosphates either at domestic, or industrial spheres. Organophosphate poisoning is a worldwide problem. Organophosphate insecticides inhibit Cholinesterase enzymatic activity. Chlorpyrifos, Phorate 10% granules and Monocrotophos are insecticides and pesticides commonly used in India by farmers. Aim: The present study aims at determining the effect oforganophosphate compounds on thyroid profile in individuals exposed to acute poisoning. Materials and Methods: In this study, those individuals who were acutely presented at the emergency department, SVS Medical College, Mahabubnagar, with a history of intentional or accidental intake of either chlorpyrifos or Phorate 10% granules or Monocrotophos (Organophosphorus compounds) were taken as cases. Intake of these compounds was confirmed by analyzing serum cholinesterase levels. Those patients having a serum cholinesterase levels value below 4000 U/L were included in this study. Simultaneously, the sample was analyzed for thyroid profile that includes Total triiodothyronine (TT3), Total tetraiodothyronine (TT4) and Thyroid stimulating hormone (TSH). Reanalyzing of thyroid profile was done after a time gap of one month from the day of discharge from hospital after recovery. Results: Total T3, Total T4 and TSH values showed statistically significant change (p-value between the acute poisoning phase and one month follow up phase of after recovery. Conclusion: Total T4 values are significantly higher in acute organophosphorus poisoned phase mimicking thyrotoxicosis, and return to normal biological reference range after recovery, whereas TSH values in acute opiates poisoned phase were significant lower than that of recovery phase. Keywords: Organophosphorus compounds (OPC), Total triiodothyronine(TT3), Total tetraiodothyronine(TT4), Thyroid stimulating hormone (TSH), Cholinesterase enzyme.

Organophosphorus (OP) insecticide poisoning is a significant health problem in South Asian countries. Although cholinergic receptors are present at the junction between photoreceptors and the retinal pigment epithelium (RPE), human studies of the effects of OP poisoning on the visual pathways are very few. This study aims to demonstrate the pattern of changes in retina and post retinal pathways in patients with acute OP poisoning using visual electrophysiological tests.This is an observational, cross-sectional study conducted at the Neurophysiology Unit, Teaching Hospital, Peradeniya, Sri Lanka. We tested 16 patients recovered from cholinergic phase, at least 24 h after deatropinization and within 8 weeks of OP ingestion. We assessed the functional integrity of the photoreceptors and ganglion cells of the macula by pattern electroretinography (PERG); RPE by electro-oculography (EOG); and post retinal pathways by pattern reversal visual evoked potentials (PR-VEP). Latencies and amplitudes of PR-VEP and PERG, light peak (LP), dark trough (DT) and Arden ratio of EOG were determined in patients and compared with 16 controls using the Mann-Whitney U test.Of the 16 OP-poisoned patients (median age of 37 ± IQR 20 years), six (37.5%) had reduced Arden ratio with reference to the International Society of Clinical Electrophysiology of Vision cut-off value of 1.7. The median Arden ratio in patients (1.69 ± IQR 0.36) was significantly lower compared to controls (1.90 ± IQR 0.4). The median latencies and amplitudes of PR-VEP or PERG were not significantly different between patients and controls. However, three patients had prolonged P100 latencies in PR-VEP and one had prolonged P50 latency in PERG.Acute OP poisoning seems to affect the functions of the RPE and the visual electrophysiological changes outlast the cholinergic phase. Limited evidence suggests that photoreceptors of the macula region and post retinal pathway might be affected in some patients.

Aims: The present study aims to determine the phototoxic and haemolytic activity of organophosphorus. The use of alternative in vitro assays with human erythrocytes is suggested to predict the polluting effect of these products on health. Methodology: Human erythrocytes from Toluca Blood Bank were used. Sodium dodecyl sulfate was employed as a positive control. Additionally, the haemolysis percentage of three organophosphate (Acetate, Chlorpyrifos, Malathion, Methamidophos, Methyl Parathion) induced photo haemolysis formulated with surfactants on a concentration of 2 x 109 erythrocytes were evaluated. Finally, the products were classified as irritant or phototoxic. Results: Results showed that the HC50 red blood cells were similar for each organophosphate (Malathion and Methamidophos) indicating very irritant action with ratio classification (L/D) of 0.041 and 0.053, respectively. On the other hand, Chlorpyrifos was classified as an irritant with L/D= 0.14. On the other hand, the HC50 obtained photo hemolysis assays irradiated red blood cells was similar for each organophosphate (Acetate, Chlorpyrifos, Malathion, Methamidophos, Methyl Parathion) indicating no phototoxic action. Conclusion: As a conclusion, it can be said that the parameters of haemolysis and denaturation of proteins are good indicators to classify organophosphorus formulated with surfactants as irritating or phototoxic.

Patients intoxicated with organophosphorous compounds may need general anaesthesia to enable mechanical ventilation or for control of epileptiform seizures. It is well known that cholinergic overstimulation attenuates the efficacy of general anaesthetics to reduce spontaneous network activity in the cortex. However, it is not clear how propofol, the most frequently used intravenous anaesthetic today, is affected. Here, we investigated the effects of cholinergic overstimulation induced by soman and acetylcholine on the ability of propofol to depress spontaneous action potential activity in organotypic cortical slices measured by extracellular voltage recordings. Cholinergic overstimulation by co-application of soman and acetylcholine (10 μM each) did not reduce the relative inhibition of propofol (1.0 μM; mean normalized action potential firing rate 0.49 ± 0.06 of control condition, p < 0.001, Wilcoxon signed rank test) but clearly reduced its efficacy. Co-application of atropine (10 nM) did not improve the efficacy. Propofol preserved its relative inhibitory potential but did not produce a degree of neuronal depression which can be expected to assure hypnosis in humans. Since a combination with atropine did not improve its efficacy, an increase in dosage will probably be necessary when propofol is used in victims suffering from organophosphorous intoxication.

Nerve agents inhibit acetylcholinesterase (AChE), leading to a build-up of acetylcholine (ACh) and overstimulation at cholinergic synapses. Current post-exposure nerve agent treatment includes atropine to treat overstimulation at muscarinic synapses, a benzodiazepine anti-convulsant, and an oxime to restore the function of AChE. Aside from the oxime, the components do not act directly to reduce the overstimulation at nicotinic synapses. The false transmitters acetylmonoethylcholine (AMECh) and acetyldiethylcholine (ADECh) are analogs of ACh, synthesised similarly at synapses. AMECh and ADECh are partial agonists, with reduced activity compared to ACh, so it was hypothesised the false transmitters could reduce overstimulation. Synthetic routes to AMECh and ADECh, and their precursors, monoethylcholine (MECh) and diethylcholine (DECh), were devised, allowing them to be produced easily on a laboratory-scale. The mechanism of action of the false transmitters was investigated in vitro. AMECh acted as a partial agonist at human muscarinic (M1 and M3) and muscle-type nicotinic receptors, and ADECh was a partial agonist only at certain muscarinic subtypes. Their precursors acted as antagonists at muscle-type nicotinic, but not muscarinic receptors. Administration of MECh and DECh improved neuromuscular function in the soman-exposed guinea-pig hemi-diaphragm preparation. False transmitters may therefore help reduce nerve agent induced overstimulation at cholinergic synapses.

Organophosphate pesticide poisoning is a common clinical problem in developing countries, bringing with it significant morbidity and mortality. There is limited evidence on the mobility status in patients who survive acute intoxication by organophosphates. The purpose of this study is to assess the mobility patterns and barriers to mobilization in organophosphate poisoning survivors in the intensive care unit. This cross-sectional study looked at 37 patients with acute intoxication from organophosphate compounds. Patients with Acute Physiology and Chronic Health Evaluation scores of less than 93 and Richmond Agitation and Sedation scores between −2 and +2 were included. Potential mobility barriers, bed mobility, functional strength, transfers, and endurance were assessed using the Perme Intensive Care Unit Mobility score on alternative days for the first ten days of intensive care unit admission. Perme scores (2.50–6.0, p ≤ 0.01) improved significantly with improvement in the subcomponents of bed mobility score (1.83 ± 0.35 to 7.23 ± 3.84), transfers (0.37 ± 0.02 to 4.78 ± 3.84), and gait (1.83 ± 0.35 to 5.23 ± 1.27) from day 2 through day 10 of hospital admission. The endotracheal tube and continuous infusion were identified as major barriers to mobilization (66.6%) using Perme scores. Perme scores improved gradually in organophosphate poisoning patients in the intensive care unit. Identification of mobility barriers may help in the modification of rehabilitation goals.

Introduction: Acute organophosphate (OP) poisoning is a global health problem and responsible for many deaths worldwide every year. It acts by inhibition of acetylcholinesterase causing cholinergic crises that lead to muscarinic, nicotinic and central manifestations. One of the most serious complications of organophosphate exposure is cardiac toxicity including electrocardiogram changes.This study aimed to evaluate corrected QT interval as predictor of major outcome events which included mortality, need for mechanical ventilation, number of atropine and toxogonine ampoules and duration of hospital stay in acute organophosphate toxicity. Methods: The study recruited 98 patients suffering from acute OP poisoning, who were admitted to Tanta University Poison Control Unit. QTc interval length and the different outcomes of the patients were recorded. Results: Fifty five patients (56.1 %) showed a prolonged QTc interval. Significant statistical association was recorded between QTc interval and delay time, manner & route of poisoning, severity of oranophosphrous toxicity and pseudocholinesterase level. Also, significant statistical association was recorded between QTc interval and need for mechanical ventilation, mortality, number of atropine & toxogonine ampoules and duration of hospital stay. Conclusion: Finally, it was concluded that QTc interval could be a good predictor for outcomes of acute organophosphrous poisoning.

Background: Monitoring a patient's serum acetylcholinesterase (AChE) status after clinical score of organophosphate poisoning enables the verification of exposure to anticholinesterase agents. Methods: A cross-sectional study was conducted among the patients fulfilling the inclusion criteria and was categorized according to POP (Peradeniya Organophosphorus Poisoning) score. The study was conducted at a tertiary hospital for one year in the period of Jan 2016 to Dec 2016. POP score was applied and serum acetylcholinesterase level was determined in the lab. Spearman’s rho coefficient method was applied for correlation. Results: Seventy four patients survived in emergency ward who presented within (4.1 ± 2.9; 95% confidence interval [CI], 3.43- 4.80; P= 0.021) hours of ingestion of OP compounds, POP score 3 (Q1, Q3, 2, 4), serum AChE 2221 (Q1, Q3, 768.5, 4703.5) IU/L with 9 ( Q1,Q3, 8.75, 34.75) mg of atropine used, 94% received PAM for 5 (Q1, Q3, 3, 7) days of hospital stay. Four patients died within (7.5 ± 5.4; 95% CI, -1.16- 16.16; P= 0.021) hours of presentation, POP score of 4 (Q1, Q3, 4, 7.75), serum AChE 588 (Q1, Q3, 173, 1912) IU/L, atropine used 170 (Q1, Q3, 152.5, 297) mg, 5.1% received PAM for 3.5 (Q1, Q3, 1, 11.25) days of hospital stay. Spearman’s rho coefficient showed well correlation between POP score and serum AChE level (coefficient -0.356; P= 0.001), POP score for the need of atropine (coefficient= 0.536; P= 0.001). Serum AChE also correlated with the length of hospital stay (coefficient= 0.414; P= 0.001) compared to POP score (coefficient= 0.420; P= 0.001). Conclusions: The higher degree of POP score correlated to higher degree of serum acetylcholinesterase derangement, need for atropine, PAM and length of hospital stay. Thus, it enhances in the prediction of outcome among patients with acute organophosphate poisoning at index visit.

Self-poisoning with organophosphorus (OP) insecticides is an important means of global self-harm. The insecticides are formulated with solvents that may also contribute to toxicity. We set up a study to detect changes in osmolal and anion gaps following ingestion of OP insecticides. We recruited consecutive patients admitted to a Teaching Hospital, Sri Lanka, with a history of OP self-poisoning. The osmolal and anion gaps were calculated on admission and at 4, 24 and 72 h post-ingestion together with ethanol concentration. Forty-nine patients were recruited (28 profenofos, 10 diazinon, one coumaphos, one chlorpyrifos, one phenthoate and eight unknown OP). Only modest increases in osmolal and anion gaps were noted. Small rises in osmolal gap above the upper limit of normal were noted in 16/49 (32.7%) of all cases, 9/28 (32.1%) profenofos cases and 4/10 (40.0%) diazinon cases. The anion gap was raised in 24/49 (49.0%) of all cases, 15/28 (53.6%) profenofos cases and 5/10 (50.0%) diazinon cases. We observed a trend for a fall in osmolal gap during the first 24 h, followed by an increase up to 72 h. There was no correlation between the anion gap and serum lactate concentration, indicating that a lactic acidosis was not responsible for the anion gap. Formate, which could have explained the increased gap, was not detected in any of the samples; ketoacids (beta-hydroxybutyrate and acetoacetate) were not measured. This pilot study found that profenofos and diazinon poisoning caused only modest increases in the osmolal and anion gaps in a minority of cases.

Objective - to identify the morphological equivalents of the cardiotoxic action of organophosphate poisoning. It was studied 110 fatal organophosphate poisonings in toxicogenic and somatogenic stages. The study of the heart was a comprehensive in term of clinical, biochemical, histological, micromorphometric, histochemical and histoenzymological approaches. We have identified a complex of deep metabolic disorders and necrobiotic changes in the heart muscle and the level of cholinesterase activity inhibition in the cholinergic structures of the heart in the toxicogenic and somatogenic stages of fatal organophosphate poisoning.Работы — выявление морфологических эквивалентов кардиотоксического действия фосфорорганических соединений (ФОС). Изучены 110 случаев смертельных отравлений ФОС в токсикогенной и соматогенной стадиях. Провели комплексное клиническое, биохимическое, гистологическое, микроморфометрическое, гистохимическое и гистоэнзимологическое исследования сердца. Выявили комплекс глубоких обменных нарушений и некробиотических изменений в сердечной мышце и степень угнетения активности холинэстеразы в холинергических структурах сердца, характерных для токсикогенной и соматогенной стадий смертельных отравлений ФОС.

Organophosphate (OP) poisoning is one of the serious occupational hazards worldwide and easily accessible pesticides for suicidal poisoning. It is associated with high mortality and morbidity. OP poisoning is characterized by three main syndromes – cholinergic syndrome, intermediate syndrome and syndrome of delayed polyneuropathy. Other rare complications of OP poisoning are arrhythmias, pancreatitis and hepatic dysfunction. We present 46-year-old male patient with history of OP poisoning, who developed features of intermediate syndrome and pancreatitis. The patient was immediately intubated and managed on mechanical ventilation. Patient was given symptomatic treatment and recovered completely on day 14 of illness.

Accidental poisoning in children is a common pediatric emergency. Here, we report the case of a 7-year-old girl with Amitraz poisoning. Ingestion and dermal contact with a dissolved solution of Amitraz lead to acute toxicity, which mimicked organophosphate poisoning. The patient lost consciousness which prompted their presentation to the pediatric emergency department. Limited literature is available regarding Amitraz poisoning. This case report attempts to document the findings and raise awareness to hasten identification and treatment of a rare and newer poison, Amitraz.

Summary Organophosphorus (OP) nerve agent poisoning made the headlines in 2018 with the nerve agent ‘Novichok' poisonings in Salisbury, England. This event highlighted a gap in the knowledge of most clinicians in the UK. In response, this special article aims to enlighten and signpost anaesthetists and intensivists towards the general management of OP nerve agent poisoned patients. Drawing on a broad range of sources, we will discuss what OP nerve agents are, how they work, and how to recognise and treat OP nerve agent poisoning. OP nerve agents primarily act by inhibiting the enzyme acetylcholinesterase, causing an acute cholinergic crisis; death usually occurs through respiratory failure. The antimuscarinic agent atropine, oximes (to reactivate acetylcholinesterase), neuroprotective drugs, and critical care remain the mainstays of treatment. The risk to medical staff from OP poisoned patients appears low, especially if there is a thorough decontamination of the poisoned patient and staff wear appropriate personal protective equipment. The events in Salisbury in the past year were shocking, and the staff at Salisbury District General Hospital performed admirably in treating those affected by Novichok nerve agent poisoning. We eagerly anticipate their future clinical publications so that the medical community might learn from their valuable experiences.

Organophosphorus insecticides, such as parathion-ethyl, quinalphos, chlorpyrifos, chlorfenvinphos or diazinon, are still widely used for pest control on crops. These compounds are extremely toxic to humans, and, even though specific legislation exists that controls the use of these substances, the frequency of toxic and/or fatal events and the existing data suggest that they are still easily accessed and the knowledge associated to the risks is not well-recognized. For these reasons, the determination of the exposure to these compounds, their detection (and of their metabolites as well) in biological samples, is of great importance in clinical and forensic toxicology, and, therefore, the development of techniques for this evaluation is an important task for laboratories. Most confirmatory analyses use blood, serum, plasma and urine as biological samples and are performed by either gas chromatographic-mass spectrometric or liquid chromatographic-mass spectrometric instrumentation, which represents the gold standard in what concerns high sensitivity. This paper will not only address the physical-chemical and toxicological aspects of this class of compounds but also perform a comprehensive and critical review on the analytical methods available for their determination in biological specimens, with special focus on the latest instrumental developments and sample preparation approaches.

Background Few cases of organophosphate poisoning in developing countries have been investigated using clinical and epidemiological methods. On 30 October 2015, 3 students at Mukuju School, Tororo District, Uganda, died soon after eating chapatti (locally-made flat bread) from the same food stand. Ministry of Health investigated to identify the cause and recommend prevention measures. Methods We defined a case as onset during 30–31 October 2015 in a resident of Mukuju Town of ≥1 of the following symptoms: excessive saliva, profuse sweating, dizziness, low blood pressure, constricted pupils or loss of consciousness. We reviewed medical/police records and interviewed survivors, healthcare workers, and police officers. We collected samples of implicated food for toxicological analysis. Autopsies were performed on decedents to identify the cause of death. Results We identified 7 cases with 3 deaths (case-fatality ratio = 43%). Clinical manifestations included acute onset of confusion (100%), constricted pupils (43%), excessive saliva (43%), and low blood pressure (43%). All 7 cases had onset from 16:00–18:00 h on 30 October, with a point-source exposure pattern. Of the 7 cases, 86% (6/7) were men; the mean age was 24 (range: 20–32) years. The 3 decedents each ate a whole chapatti while the other 4 cases ate half or less. Autopsy findings of the 3 decedents indicated organophosphate poisoning. Toxicological analysis found high levels of malathion in leftover foods (266 mg/L in dough and 258 mg/L in chapatti) and malaoxon (a highly toxic malathion derivative) in decedents’ postmortem specimens (mean levels of 19 mg/L in the blood and 22 mg/L in the gastric contents). There was a delay of 4 h before the patients received appropriate treatment. Police investigations revealed that flour used to make the chapatti was intentionally contaminated with an organophosphate pesticide. Conclusion This fatal outbreak of organophosphate poisoning was associated with consumption of roadside-vended chapatti made of flour contaminated with pesticide. Clinicians should be aware of symptoms of organophosphate poisoning and prepared to treat it quickly. Street vendors should carefully consider the source of their ingredients. An in-depth surveillance review of such poisonings in Uganda would guide policymakers in reducing access by criminals and accidental exposures for the public. Electronic supplementary material The online version of this article (10.1186/s12889-019-7143-0) contains supplementary material, which is available to authorized users.

The global use of organophosphorus compounds (OP) for pest control and nerve agents being used in military conflicts and for assassinations renders intoxications by these agents a public health concern. OP-poisoned patients often suffer from dysrhythmias which may ultimately result in death. In this study, human-induced pluripotent stem cells derived cardiomyocytes were exposed to OP compounds in a microelectrode array system (MEA). The MEA system is widely accepted to assess the proarrhythmic properties of (candidate) drugs. The directly acting cholinergic compounds acetylcholine and carbachol and the irreversible acetylcholinesterase inhibitor cyclosarin - a highly toxic nerve agent - were assessed. All three compounds induced a dose-dependent (up to 600 nmol/L) corrected field potential duration (FPDc) prolongation of 9.7 ± 0.6% for carbachol, for 9.7 ± 1.2% acetylcholine and 9.4 ± 0.5% for cyclosarin. Additionally, the electrophysiological alterations of the clinically approved oxime reactivators obidoxime, pralidoxime and the oximes in development HI-6 and MMB-4 were investigated in the absence of OP. Neither of these oximes (up to a concentration of 300 μmol/L) caused dysrhythmia nor beat arrest. The competitive muscarinic receptor antagonist atropine as a cornerstone in the treatment of OP poisoning was also analyzed. Interestingly, atropine caused a drop in the beat rate which might result from a non-receptor action of this substance in the absence of OP. Atropine in combination with the OP nerve agent cyclosarin and the direct cholinergics acetylcholine or carabachol completely reversed the induced FPDc prolongation. However, the oxime HI-6 as potent reactivator of cyclosarin-inhibited AChE was not able to prevent the FPDc prolongation in this model. In conclusion, the current model allows the assessment of FPDc prolongation by the nerve agent cyclosarin, the cholinergic compounds carbachol, acetylcholine and the block of this effect by atropine.

In previous experiments, human and rat small bowel samples have been successfully used to study the spasmolytic effect of (potential) therapeutics in carbamate-constricted bowel specimens. Additionally, transferability from rat to human data was shown in the previous study. In the present study, the effects of atropine, scopolamine, MB327, HI-6 as well as obidoxime were examined in organophosphorus-poisoned human small bowel specimens. All substances were tested with at least seven concentrations in samples previously exposed to the nerve agent sarin. Furthermore, the cholinesterase reactivation potential of all substances was investigated. The test substances displayed a spasmolytic effect allowing the calculation of dose-response curves and EC50s. The parasympatholytic compound scopolamine had the strongest relaxing effect (EC50 = 0.05 μM) followed by atropine (EC50 = 0.07 μM). HI-6 and obidoxime were capable to reactivate the sarin-inhibited cholinesterase activity in small bowel samples. Both substances restored AChE activity in a dose-dependent way, with HI-6 being more potent (HI-6 EC50 = 3.8 μM vs obidoxime EC50 = 197.8 μM). Summarizing, our isolated human small bowel setup is a suitable tool to investigate the smooth muscle relaxing effect of (candidate) therapeutics for organophosphorus compound poisoning i.e. sarin exposure in a complex 3D tissue model.

Introduction: Irreversible inhibition of the acetylcholinesterase upon intoxication with organophosphorus compounds leads to an accumulation of acetylcholine in the synaptic cleft and a subsequent desensitization of nicotinic acetylcholine receptors which may ultimately result in respiratory failure. A direct intervention at the nicotinic acetylcholine receptor (nAChR) was proposed as an alternative therapeutic approach to the treatment with atropine and oximes. Methods: The bispyridinium compound MB327 has been found to recover functional activity of nAChR thus representing a promising starting point for the development of new drugs for the treatment of organophosphate poisoning. Recent solid-supported membrane-based electrophysiological experiments have identified symmetrically substituted bispyridinium compounds e.g. MB327, MB583, and PTM0001 that are able to resensitize nAChR of Torpedo californica. In addition, six compounds have been found not to show any resensitizing potential and were thus classified as inactive. This set of active and inactive bispyridinium compounds was taken to develop a pharmacophore model and in silico screening of a virtual database of bispyridinium compounds to identify new compounds that are able to restore the functional activity of desensitized nAChR. Results: Screening of a virtual compound database of symmetrically substituted bispyridinium compounds with the derived pharmacophore yielded several promising compounds which satisfy the pharmacophore and ought to have the same or even better resensitizing effect on nAChR as the parent compound MB327.

Rats poisoned with sarin enter into ahyper-cholinergic crisis characterized by excessive salivation, respiratory distress, tremors, seizures, and death. Through the use of rescue medications and an anticonvulsant, death can be avoided in many animals, with the long-term consequences of poisoning partly ameliorated, especially when countermeasures are made available immediately after exposure. However, when anticonvulsant measures are delayed by as little as 30 min, clinical, neurological, cognitive, and psychiatric abnormalities may persist long after the initial exposure. This study sought to determine if the addition of the NMDA receptor antagonist Ketamine to human standard-of-care countermeasures consisting of two rescue medications (2-PAM and atropine) and an anti-convulsant (Midazolam), would afford protection against persistent neurobiological compromise. Rats were exposed to sarin (105 μg/kg via subcutaneous injection), and treated 1 min later with 2-PAM and Atropine Methyl Nitrate (IM) to minimize mortality. One of four anti-convulsant protocols was then initiated at 50 min postsarin:Midazolam alone (MDZ, a single injection (IM) at 0.66 mg/kg); Ketamine alone (KET, a series of five injections (IM) of Ketamine at 7.5 mg/kg, 90 min apart); Midazolam + low dose Ketamine (MDZ + lowKET, a single injection of Midazolam (IM) at 0.66 mg/kg, plus five sequential doses of ketamine (IM) at 2.5 mg/kg, starting at the time of Midazolam dosing and then 90 min apart); Midazolam + high dose Ketamine (MDZ + highKET, a single injection of Midazolam (IM) at 0.66 mg/kg, plus five sequential injections of 7.5 mg/kg Ketamine (IM), starting at the time of Midazolam dosing and then 90 min apart). Animals were preassigned to groups culled at post-exposure Days 1, 7 or 30, for histopathology. For all surviving animals, EEG activity was monitored through skull electrodes for 24-h beginning immediately after sarin exposure. Surviving animals also underwent 24-h EEG monitoring on Days 6, 13, and/or 29, post-sarin. Memory assessment using the Morris Water Maze was performed on Days 1, 4, 7, 14 and 30. Following sarin exposure, 85% of surviving animals demonstrated status epilepticus within 20 min. Each of the anti-convulsant protocols was sufficient to stop convulsions within 1 h of anti-convulsant administration, but all of the animals still showed signs of electrographic status for an additional 2-12 h, without substantial differentiation between treatment groups. However, for post-sarin hours 13-24, the MDZ + highKET group showed significantly less severe EEG abnormalities than the MDZ and KET groups (Mood's Median Test, p 0.005). At one month post-exposure, 90% of animals that had received Midazolam alone still showed evidence of some epileptiform activity. In contrast, 90% of animals that had received Midazolam + high dose Ketamine combination therapy had EEG profiles that were within normal limits. This difference in EEG outcomes was highly significant (Mood's Median Test, p 0.001). Likewise, on the water maze, the majority of animals that had received Midazolam combined with either high or low dose Ketamine therapy returned to near baseline levels of mnemonic performance within 2 weeks, whereas the majority of the animals that had received midazolam alone or ketamine alone demonstrated persistent and significant memory impairments even at one month postexposure (Mood's Median Test, p 0.005). With respect to neuronal necrosis, animals in the MDZ + highKET group showed significantly less overall damage than animals in other treatment groups (Mood's Median Test, p 0.001). Of special note were findings in the hippocampus, where only 12% of animals in the MDZ + highKET group showed evidence of necrosis on HE staining, whereas 100% of animals in the KET group, 70% of animals in the MDZ group, and 40% of animals in the MDZ + lowKET group showed evidence of hippocampal necrosis. Overall, the data demonstrate that Ketamine augmentation of an atropine, 2PAM, and Midazolam standard-ofcare for sarin exposure provides clinically-relevant additional protection against the negative neurobiological consequences of sarin, even when initiation of the anti-convulsant countermeasures is delayed by 50 min.

In this article the neurotoxic disorders appearing in patients exposed to organophosphorus pesticides and known mechanisms involved are reviewed. Organophosphorus compounds cause four main neurotoxic effects in humans: the cholinergic syndrome, the intermediate syndrome, organophosphate-induced delayed polyneuropathy and chronic organophosphate-induced neuropsychiatric disorder. Compared to the cholinergic syndrome, that causes millions of cases of poisoning with fatality of more than 15% each year, other disorders involve much smaller number of patients. Possible link of exposure to organophosphorus pesticides with neurodegenerative diseases, dementia, attention deficit hyperactivity disorder and Parkinson's disease in man is also approached. This article is focused on neurotoxic disorders appearing after acute and chronic exposure to organophosphates with emphasis on molecular mechanisms, clinical presentation, pathogenesis, and possibilities for prevention/medical treatment.

Oxime-based molecules are used for the treatment of patients to reactivate acetylcholinesterase (AChE) function after organophosphate intoxication. However, their efficacy is limited by low penetration through the blood-brain barrier and fast elimination. In this work, the cucurbit[7]uril (CB[7]) carrier was used for the encapsulation of the clinical agent asoxime to enhance brain bioavailability and the treatment window. We present a pharmacokinetic study of asoxime and the asoxime-CB[7] complex in an in vivo mouse model. Ultrahigh-performance liquid chromatography with electrospray ionization-mass spectrometry detection was developed to determine asoxime and CB[7] in biological fluids and tissues after thorough optimization of chromatographic conditions. The dihydroxypropane-silica stationary phase using hydrophilic interaction liquid chromatography conditions provided the best chromatographic performance. The final method was validated and applied for the pharmacokinetic study of mouse plasma, urine, bile, liver, kidney, and brain samples at different times after administration of asoxime and the asoxime-CB[7] complex. The results showed a greater than 3-fold increase in the area under the curve (AUC) in the brain for asoxime administered as a complex with CB[7] relative to that for the administration of asoxime alone. The effectiveness of the treatment strategy was evaluated using a reactivation study and a functional observatory battery. Protection of brain AChE activity is crucial for saving human lives or reducing the consequences of poisoning. The asoxime administered as a complex increased the brain activity by approximately 30% compared to that with atropine alone. CB[7] coadministration improved the AChE activity by 11%, which agrees with the higher asoxime AUC assessed in the pharmacokinetic study.

Organophosphorus compounds (OPs) are neurotoxic molecules developed as pesticides and chemical warfare nerve agents (CWNAs). Most of them are covalent inhibitors of acetylcholinesterase (AChE), a key enzyme in nervous systems, and are therefore responsible for numerous poisonings around the world. Many animal models have been studied over the years in order to decipher the toxicity of OPs and to provide insights for therapeutic and decontamination purposes. Environmental impact on wild animal species has been analyzed to understand the consequences of OP uses in agriculture. In complement, various laboratory models, from invertebrates to aquatic organisms, rodents and primates, have been chosen to study chronic and acute toxicity as well as neurobehavioral impact, immune response, developmental disruption, and other pathological signs. Several decontamination approaches were developed to counteract the poisoning effects of OPs. Among these, enzyme-based strategies are particularly attractive as they allow efficient external decontamination without toxicity or environmental impact and may be of interest for treatment. Approaches using bioscavengers for prophylaxis, treatment, and external decontamination are emphasized and their potential is discussed in the light of toxicological observations from various animal models. The relevance of animal models, regarding their cholinergic system and the abundance of naturally protecting enzymes, is also discussed for better extrapolation of results to human.

The phosphotriesterase of the bacterium Brevundimonas diminuta (BdPTE) is a naturally occurring enzyme that catalyzes the hydrolysis of organophosphate (OP) nerve agents as well as pesticides and offers a potential treatment of corresponding intoxications. While BdPTE mutants with improved catalytic efficiencies against several OPs have been described, unexpectedly, less efficient breakdown of an OP was observed upon application in an animal model compared with in vitro measurements. Here, we describe detailed inhibition studies with the high-activity BdPTE mutant 10-2C3(C59M/C227A) by human plasma components, indicating that this enzyme is inhibited by serum albumin. The inhibitory activity is mediated by depletion of crucial zinc ions from the BdPTE active site, either via the known high-affinity zinc binding site of albumin or via chemical complex formation with its free thiol side chain at position Cys34. Albumin pre-charged with zinc ions or carrying a chemically blocked Cys34 side chain showed significantly reduced inhibitory activity; in fact, the combination of both measures completely abolished BdPTE inhibition. Consequently, the available zinc ion concentration in blood plays an important role for BdPTE activity in vivo and should be taken into account for therapeutic development and application of a catalytic OP scavenger.

Organophosphate poisoning by self-injection is rare. Current case report describes a man with subcutaneous self-injected OP. poisoning presenting with delayed. He was treated with pralidoxime. Through the observation, dose and the time between poisoning until time to start treatment we can conclude different presentations and outcomes of OP poisoning.

Background: Organophosphate (OP) insecticides are important compounds as the most probable common cause of acute poisonings in developing countries. OP intoxication often presents as medical emergencies, and its related morbidity and mortality have not decreased despite major advances in critical care. This study aims to determine the impact of serum amylase level for estimation of prognosis in patients with acute OP poisoning. Methods: This observational case-control study was done during two years on 332 consecutive patients with acute OP poisoning. Clinical and demographic data, serum amylase level on early admission time, morbidity, and outcome were determined. Data were analyzed in the form of a frequency distribution table by using SPSS 11.0 version software. Results: The mean age of patients with acute OP poisoning was 28.9 ± 23.95 with slightly female dominance. All patients were intoxicated via the gastrointestinal route. The mean amylase level of patients with deterioration of mental status, tachycardia, ICU admission, and death was significantly higher. Conclusion: Among patients with OP poisoning, higher serum amylase than normal was associated with severe clinical course and increased risk for mortality. Determination of serum amylase can be effective in the quick prediction of the outcome.

The efficacy of albumin and fresh frozen plasma (FFP) and their effects on biomarkers of oxidative stress has been evaluated. In a randomized clinical control trial, 33 poisoned patients by Organophosphate (OP) were enrolled in the research and divided into three groups. The first group underwent conventional treatments by atropine and pralidoxime (control group); the second and third groups, in addition to traditional treatments, received albumin and FFP. Cholinesterase (ChE) enzyme activity, total antioxidant capacity (TAC), serum thiol groups (TTG), malonyl aldehyde (MDA) and DNA damage were measured in all treatment and control groups. Patients were matched in terms of demographic characteristics at the beginning of the study. ChE activity was increased in all three groups during treatment, which was more noticeable in the FFP group and was statistically significant in both albumin and FFP group compared to the control group (p

In this study, by rationally designing the stimulus response of graphene quantum dot (GQD)-sensitized terbium/guanine monophosphate (Tb/GMP) infinite coordination polymer (ICP) nanoparticles, we have constructed a smartphone-based colorimetric assay with ratiometric fluorescence, which could be applied for the detection of acetylcholinesterase (AChE) and organophosphorus pesticides (OPs) directly. First, GQDs with abundant functional groups were chosen as the guest, which not only could be used as one of the signal readouts but also served as the antenna ligand to further sensitize the fluorescence of the host Tb/GMP. Upon being excited at 330 nm, the green fluorescence of the Tb/GMP host is highly enhanced, while the blue fluorescence of GQDs is suppressed due to the confinement of the ICP host. With the presence of thiocholine (TCh), an enzymatic product hydrolyzed from acetylthiocholine (ATCh) by AChE, the competitive coordination of Tb3+ between GMP and TCh results in the collapse of the ICP network and thereby the release of GQDs into the solution; thus, the fluorescence of Tb/GMP turns off and the fluorescence of GQDs turns on. The dual-responsive ratiometric fluorescent intensity change leads to the corresponding green-to-blue fluorescent color change obviously, which constitutes a novel mechanism for the colorimetric analysis of AChE. Moreover, when OPs are subsequently introduced, the activity of AChE is blocked, thus preventing the stimulus response of GQD@Tb/GMP ICP nanoparticles, leading to the fluorescent color change from greenish-blue to green, which could also be employed for OP detection. Benefitting from the high sensitivity, good reliability, and the obvious color changes, the method demonstrated here is a promising candidate to realize smartphone-based point-of-use applications, which is of great importance for timely clinical diagnosis and treatment of OPs related to health issues with AChE as an exposure biomarker in less industrialized countries, in remote settings, or even in home care services.

Amitraz is a formamidine group of compounds used in many parts of the world as an agriculturalpesticide and an ectoparasiticide. Amitraz intoxication secondary to the oral, dermal or inhalationalroutes, both accidental and suicidal, has been encountered in humans leading to severe life-threateningside effects. Only very few cases of amitraz toxicity have been reported to date. This emphasizesthe importance to ascertain amitraz intoxication from more commonly encountered pesticides likeorganophosphorus poisoning to avoid erroneous management of the patient. We report a case of atwenty-seven-year-old man who presented to the emergency room following suicidal ingestion ofamitraz with the clinical manifestations of vomiting, altered sensorium, bradycardia and hypotensionand complete recovery following supportive management.

Background Sri Lanka has reduced its overall suicide rate by 70% over the last two decades through means restriction, through a series of government regulations and bans removing highly hazardous pesticides from agriculture. We aimed to identify the key pesticide(s) now responsible for suicides in rural Sri Lanka to provide data for further pesticide regulation. Methods We performed a secondary analysis of data collected prospectively during a cluster randomized controlled trial in the Anuradhapura district of Sri Lanka from 2011 to 16. The identity of pesticides responsible for suicides were sought from medical or judicial medical notes, coroners’ records, and the person’s family. Trend analysis was done using a regression analysis with curve estimation to identify relative importance of key pesticides. Results We identified 337 suicidal deaths. Among them, the majority 193 (57.3%) were due to ingestion of pesticides while 82 (24.3%) were due to hanging. A specific pesticide was identified in 105 (54.4%) of the pesticide suicides. Ingestion of carbosulfan or profenofos was responsible for 59 (56.2%) of the suicides with a known pesticide and 17.5% of all suicides. The increasing trend of suicides due to carbosulfan and profenofos over time was statistically significant (R square 0.846, F 16.541, p 0.027). Conclusion Ingestion of pesticides remains the most important means of suicides in rural Sri Lanka. The pesticides that were once responsible for most pesticide suicides have now been replaced by carbosulfan and profenofos. Their regulation and replacement in agriculture with less hazardous pesticides will further reduce the incidence of both pesticide and overall suicides in rural Sri Lanka.

Organophosphate use represents one of the main causes of intentional and accidental poisoning in Brazil. Because they induce alteration in carcass decomposition and succession of necrophagous Diptera, they are important investigative tool in forensic entomology for determining the postmortem interval (PMI) and cause of death. Thus, this work aimed to evaluate the influence of Terbufos, the most commonly used organophosphate for suicides in Rio Grande do Norte, Brazil, in the decomposition process and necrophagous fly assemblies in intoxicated rat carcasses. For this, 150g female Wistar rats received, by gavage, 200µL of Terbufos (5mg/kg or 10mg/kg) or distilled water (control). Approximately 30 minutes after administration, animals were euthanized and distributed in suspended traps to decompose under environmental conditions. Decomposition was monitored daily, with photographic record and collection of the visiting dipterofauna until the dry phase. Data show that the higher dose of Terbufos i) accelerates carcass decomposition in 24h; ii) decreases the species richness and abundance of scavengers flies when compared to the control; iii) changes the succession pattern, delaying the arrival of important species for the PMI estimate and iv) causes 8% mortality of the visiting dipterofauna. This work provides relevant information about dipteran assemblages and changes in the cadaver decomposition process associated with Terbufos intoxication, which may assist in future investigative processes with suspected organophosphate poisoning.