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Acute intoxication with organophosphate (OP) cholinesterase inhibitors poses a significant public health risk. While currently approved medical countermeasures can improve survival rates, they often fail to prevent chronic neurological damage. Therefore, there is need to develop effective therapies and quantitative metrics for assessing OP-induced brain injury and its rescue by these therapies. In this study we used a rat model of acute intoxication with the OP, diisopropylfluorophosphate (DFP), to test the hypothesis that T2 measures obtained from brain magnetic resonance imaging (MRI) scans provide quantitative metrics of brain injury and therapeutic efficacy. Adult male Sprague Dawley rats were imaged on a 7T MRI scanner at 3, 7 and 28 days post-exposure to DFP or vehicle (VEH) with or without treatment with the standard of care antiseizure drug, midazolam (MDZ); a novel antiseizure medication, allopregnanolone (ALLO); or combination therapy with MDZ and ALLO (DUO). Our results show that mean T2 values in DFP-exposed animals were: (1) higher than VEH in all volumes of interest (VOIs) at day 3; (2) decreased with time; and (3) decreased in the thalamus at day 28. Treatment with ALLO or DUO, but not MDZ alone, significantly decreased mean T2 values relative to untreated DFP animals in the piriform cortex at day 3. On day 28, the DUO group showed the most favorable T2 characteristics. This study supports the utility of T2 mapping for longitudinally monitoring brain injury and highlights the therapeutic potential of ALLO as an adjunct therapy to mitigate chronic morbidity associated with acute OP intoxication.

Recent experimental evidence suggests combined treatment with midazolam and allopregnanolone is more effective than midazolam alone in terminating seizures triggered by acute organophosphate (OP) intoxication. However, there are concerns that combined midazolam and allopregnanolone increases risk of adverse cardiovascular events. To address this, we used telemetry devices to record cardiovascular responses in adult male Sprague-Dawley rats acutely intoxicated with diisopropylfluorophosphate (DFP). Animals were administered DFP (4 mg/kg, sc), followed immediately by atropine (2 mg/kg, i.m.) and 2-PAM (25 mg/kg, i.m.). At 40 min post-exposure, a subset of animals received midazolam (0.65 mg/kg, im); at 50 min, these rats received a second dose of midazolam or allopregnanolone (12 mg/kg, im). DFP significantly increased blood pressure by ~ 80 mmHg and pulse pressure by ~ 34 mmHg that peaked within 12 min. DFP also increased core temperature by ~ 3.5 °C and heart rate by ~ 250 bpm that peaked at ~ 2 h. Heart rate variability (HRV), an index of autonomic function, was reduced by ~ 80%. All acute (within 15 min of exposure) and two-thirds of delayed (hours after exposure) mortalities were associated with non-ventricular cardiac events within 10 min of cardiovascular collapse, suggesting that non-ventricular events should be closely monitored in OP-poisoned patients. Compared to rats that survived DFP intoxication without treatment, midazolam significantly improved recovery of cardiovascular parameters and HRV, an effect enhanced by allopregnanolone. These data demonstrate that midazolam improved recovery of cardiovascular and autonomic function and that the combination of midazolam and allopregnanolone may be a better therapeutic strategy than midazolam alone.

Organophosphate (OP) poisoning can trigger cholinergic crisis, a life-threatening toxidrome that includes seizures and status epilepticus. These acute toxic responses are associated with persistent neuroinflammation and spontaneous recurrent seizures (SRS), also known as acquired epilepsy. Blood-brain barrier (BBB) impairment has recently been proposed as a pathogenic mechanism linking acute OP intoxication to chronic adverse neurologic outcomes. In this review, we briefly describe the cellular and molecular components of the BBB, review evidence of altered BBB integrity following acute OP intoxication, and discuss potential mechanisms by which acute OP intoxication may promote BBB dysfunction. We highlight the complex interplay between neuroinflammation and BBB dysfunction that suggests a positive feedforward interaction. Lastly, we examine research from diverse models and disease states that suggest mechanisms by which loss of BBB integrity may contribute to epileptogenic processes. Collectively, the literature identifies BBB impairment as a convergent mechanism of neurologic disease and justifies further mechanistic research into how acute OP intoxication causes BBB impairment and its role in the pathogenesis of SRS and potentially other long-term neurologic sequelae. Such research is critical for evaluating BBB stabilization as a neuroprotective strategy for mitigating OP-induced epilepsy and possibly seizure disorders of other etiologies. SIGNIFICANCE STATEMENT: Clinical and preclinical studies support a link between blood-brain barrier (BBB) dysfunction and epileptogenesis; however, a causal relationship has been difficult to prove. Mechanistic studies to delineate relationships between BBB dysfunction and epilepsy may provide novel insights into BBB stabilization as a neuroprotective strategy for mitigating epilepsy resulting from acute organophosphate (OP) intoxication and non-OP causes and potentially other adverse neurological conditions associated with acute OP intoxication, such as cognitive impairment.

We have shown that briefly inhaled isoflurane rapidly halts convulsions and protects the central nervous system (CNS) from organophosphate-induced neuronal loss when administered at 5% for 5 min, even as late as 1 h after organophosphate exposure. In the current study we investigated if an injectable form of isoflurane was as effective as inhaled isoflurane. We used a mixture of 10% isoflurane dissolved in an IV-compatible lipid-water emulsion for intravenous administration. Rats with an implanted jugular vein cannula were infused with 1,000 µL of the 10% isoflurane-lipid emulsion (ILE) mixture at a rate of 200 µL per minute, which achieved full anesthesia lasting approximately 10 min. When administered 30 min after a highly lethal dose of the organophosphate insecticide paraoxon (POX), the short-duration administration halted convulsions over the course of the study and prevented the great majority of neuronal loss as shown by Fluoro-Jade B staining (FJB). Our results indicate that injectable isoflurane is very effective for treating organophosphate poisoning, negating the need for vaporizer equipment and enabling intravenous therapy. [ABSTRACT FROM AUTHOR]

Paraquat is a widely used non-selective herbicide in Indian agriculture. It has gained popularity for its misuse in suicidal poisoning, primarily because it lacks an antidote, and ingestion often leads to death. When examining the historical trends of pesticide-related suicidal poisonings in India, there is a noticeable transition from endrin, organophosphates and rodenticides to the current prevalent use of paraquat. This review delves into globally reported cases of homicidal paraquat poisonings, which are sporadically reported in India as well, although not published in mainstream academia. Clinicians must remain vigilant in homicidal paraquat poisoning situations as there is often improper history at the time of presentation. Such cases typically present with some non-specific symptoms such as oral and pharyngeal burns and appear like any other typical acute gastroenteritis or a flu-like illness which ultimately leads to death as a result of pulmonary complications. At the same time, forensic pathologists need to be well versed in the characteristic autopsy findings and analytical toxicology considerations of paraquat-induced criminal poisoning, given the occasional incidents in India. The use of paraquat as a weapon in poisoning cases is a significant public health concern that underscores the need for a ban on paraquat in India.

Organophosphate poisoning remains a global health crisis without efficacious treatments to prevent neurotoxicity. We examined whether antidotal tiger nut and coconut dietary intervention could ameliorate neurobehavioral deficits from organophosphate dichlorvos-induced gut-brain axis dysregulation in a mouse model. Mice were divided into groups given control diet, dichlorvos-contaminated diets, or dichlorvos plus nut-enriched diets. They were exposed to a DDVP-contaminated diet for 4 weeks before exposure to the treatment diets for another 8 weeks. This was followed by behavioural assessments for cognitive, motor, anxiety-, and depressive-like behaviours. Faecal samples (pre- and post-treatment), as well as blood, brain, and gut tissues, were collected for biochemical assessments following euthanasia. Dichlorvos-exposed mice displayed impairments in cognition, motor function, and mood along with disrupted inflammatory and antioxidant responses, neurotrophic factor levels, and acetylcholinesterase activity in brain and intestinal tissues. Weight loss and altered short-chain fatty acid levels additionally indicated gut dysfunction. However, intervention with tiger nut and/or coconut- enriched diet after dichlorvos exposure attenuated these neurobehavioral, and biochemical alterations. Our findings demonstrate organophosphate-induced communication disruptions between the gut and brain pathways that manifest in neuropsychiatric disturbances. Overall, incorporating fibre-rich nuts may represent an antidotal dietary strategy to reduce neurotoxicity and prevent brain disorders associated with organophosphate poisoning.

We have shown that briefly inhaled isoflurane rapidly halts convulsions and protects the central nervous system (CNS) from organophosphate-induced neuronal loss when administered at 5% for 5 min, even as late as 1 h after organophosphate exposure. In the current study we investigated if an injectable form of isoflurane was as effective as inhaled isoflurane. We used a mixture of 10% isoflurane dissolved in an IV-compatible lipid-water emulsion for intravenous administration. Rats with an implanted jugular vein cannula were infused with 1,000 μL of the 10% isoflurane-lipid emulsion (ILE) mixture at a rate of 200 μL per minute, which achieved full anesthesia lasting approximately 10 min. When administered 30 min after a highly lethal dose of the organophosphate insecticide paraoxon (POX), the short-duration administration halted convulsions over the course of the study and prevented the great majority of neuronal loss as shown by Fluoro-Jade B staining (FJB). Our results indicate that injectable isoflurane is very effective for treating organophosphate poisoning, negating the need for vaporizer equipment and enabling intravenous therapy.

Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood–brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 10–30% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes. [ABSTRACT FROM AUTHOR]

Background and Aim: 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. The present study was conducted to find the incidence of increased levels of serum amylase and serum lipase in OPC poisoning and to identify the relation with prognosis and clinical outcome, out of which one outcome was acute pancreatitis. Material and Methods: The study was conducted at department of General Medicine, Tertiary care institute of Gujarat among the patients suffering from acute Organophosphate poisoning and admitted in emergency/ICU/medicine ward within 24 hours of intoxication event. This was an observational study conducted for the duration of 2 year with sample size of 85 patients out of which only 60 patients fulfill the inclusion and exclusion criteria. Patients were divided in 3 groups as mild, moderate and severe using q SOFA score at the time of admission. Results: Mean serum amylase level values in various q SOFA categories (0, 1, 2 and 3) were 65.03, 81.95, 118.8 and 330.78 IU/l respectively with p value < 0.001 and that of mean serum lipase level values were 41.45, 44.2, 38.9 and 115.69 IU/l respectively with p value 0.05. Serum amylase levels were positively correlated with duration of ICU stay and were better predictor for acute pancreatitis. Conclusion: Organophosphate poisoning is associated with multiple complications, including acute pancreatitis. The study found that levels of serum amylase & lipase were increased in statistically significant number of cases of acute organophosphate poisoning. [ABSTRACT FROM AUTHOR]

Objective: Organophosphates are the insecticides commonly used worldwide. Inadequate treatment in organophosphates poisoning increases morbidity, and mortality. Purpose of the work was to determine the effect of standard treatment alone versus standard treatment plus plasmapheresis on the levels of serum pseudo-cholinesterase, and erythrocyte acetyl cholinesterase in severe patients with organophosphates poisoning. Material and Method: This research is a prospective study. Patients diagnosed with organophosphates poisoning were included in the work. The patients were divided into two groups as the intervention group, and the standard group. The intervention group, plasmapheresis was performed in addition to the standard treatment. Results: The research was conducted with forty cases. (Intervention group n:21, standard group n:19). Serum pseudo-cholinesterase values were 482.5 u/L at baseline, 3723 u/L after plasmapheresis. Erythrocyte acetyl cholinesterase values were 1.91 u/mL on admission, 2.53 u/mL after plasmapheresis. Erythrocyte acetyl cholinesterase and serum pseudo-cholinesterase values were compared between the two groups daily from the admission of patients to intensive care units during the first 5 days, and on the last day in the intensive care units. There was no statistical difference between two groups (p gt; 0.05), except for the second day. It was observed that there was a statistically significant difference between the pseudo-cholinesterase values in the second day comparison of both groups (p=0.028). Conclusion: In conclusion, plasmapheresis treatment may contribute positively to pseudo-cholinesterase level. This treatment may have provided additional time for the organophosphates to be eliminated from the body. Although acetyl cholinesterase reactivation is achieved with oxime treatment, the clinical effect of this treatment is not clear.

Dichlorvos, an organophosphate compound, has the potential to cause acute kidney injury (AKI) besides its well-known neuromuscular complications. We report a case of severe-recurrent AKI that progressed to end-stage-renal-disease (ESRD) following accidental exposure to Dichlorvos. A 52-year-old male farmer presented with breathlessness after accidental exposure while spraying in the field. He required mechanical ventilation due to allergic pneumonitis and developed anuric AKI, requiring renal replacement therapy (RRT). Biopsy revealed severe acute tubulointerstitial nephritis (ATIN), which responded to steroids, and the patient became dialysis-independent by 4 weeks. Two weeks later, the patient had recurrent AKI requiring RRT. A repeat biopsy revealed severe ATIN. However, despite steroid treatment, he progressed to ESRD. Organophosphate compounds can cause renal injury with a wide spectrum of presentations, ranging from subclinical AKI to severe dialysis-dependent renal failure, which may eventually progress to end-stage renal disease. [ABSTRACT FROM AUTHOR]

Encapsulated phosphotriesterase nanoreactors show their efficacy in the prophylaxis and post-exposure treatment of poisoning by paraoxon. A new enzyme nanoreactor (E-nRs) containing an evolved multiple mutant (L72C/Y97F/Y99F/W263V/I280T) of Saccharolobus solfataricus phosphotriesterase (PTE) for in vivo detoxification of organophosphorous compounds (OP) was made. A comparison of nanoreactors made of three- and di-block copolymers was carried out. Two types of morphology nanoreactors made of di-block copolymers were prepared and characterized as spherical micelles and polymersomes with sizes of 40 nm and 100 nm, respectively. The polymer concentrations were varied from 0.1 to 0.5% (w/w) and enzyme concentrations were varied from 2.5 to 12.5 μM. In vivo experiments using E-nRs of diameter 106 nm, polydispersity 0.17, zeta-potential −8.3 mV, and loading capacity 15% showed that the detoxification efficacy against paraoxon was improved: the LD50 shift was 23.7xLD50 for prophylaxis and 8xLD50 for post-exposure treatment without behavioral alteration or functional physiological changes up to one month after injection. The pharmacokinetic profiles of i.v.-injected E-nRs made of three- and di-block copolymers were similar to the profiles of the injected free enzyme, suggesting partial enzyme encapsulation. Indeed, ELISA and Western blot analyses showed that animals developed an immune response against the enzyme. However, animals that received several injections did not develop iatrogenic symptoms. [ABSTRACT FROM AUTHOR]

Objective: Organophosphates are the insecticides commonly used worldwide. Inadequate treatment for organophosphates poisoning increases morbidity, and mortality. Purpose of the work was to determine the effect of standard treatment alone versus standard treatment plus plasmapheresis on the levels of serum pseudo-cholinesterase, and erythrocyte acetyl cholinesterase in severe patients with organophosphates poisoning. Material and Method: This research is a prospective study. Patients diagnosed with organophosphates poisoning were included in the work. The patients were divided into two groups as the intervention group, and the standard group. The intervention group, plasmapheresis was performed in addition to the standard treatment. Results: The research was conducted with forty cases. (Intervention group n=21, standard group n=19). Serum pseudo-cholinesterase values were 482.5 u/L at baseline, 3723 u/L after plasmapheresis. Erythrocyte acetyl cholinesterase values were 1.91 u/mL on admission, 2.53 u/mL after plasmapheresis. Erythrocyte acetyl cholinesterase and serum pseudo-cholinesterase values were compared between the two groups daily from the admission of patients to intensive care units during the first 5 days, and on the last day in the intensive care units. There was no statistical difference between two groups (p> 0.05), except for the second day. It was observed that there was a statistically significant difference between the pseudo-cholinesterase values in the second day comparison of both groups (p=0.028). Conclusion: In conclusion, plasmapheresis treatment may contribute positively to pseudo-cholinesterase level. This treatment may have provided additional time for the organophosphates to be eliminated from the body. Although acetyl cholinesterase reactivation is achieved with oxime treatment, the clinical effect of this treatment is not clear. [ABSTRACT FROM AUTHOR]

Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood–brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 10–30% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes.

Acetylcholinesterase (AChE) is a pivotal enzyme in neurotransmission. Its inhibition leads to cholinergic crises and could ultimately result in death. A related enzyme, butyrylcholinesterase (BChE), may act in the CNS as a co-regulator in terminating nerve impulses and is a natural plasma scavenger upon exposure to organophosphate (OP) nerve agents that irreversibly inhibit both enzymes. With the aim of improving reactivation of cholinesterases phosphylated by nerve agents sarin, VX, cyclosarin, and tabun, ten phenyltetrahydroisoquinoline (PIQ) aldoximes were synthesized by Huisgen 1,3 dipolar cycloaddition between alkyne- and azide-building blocks. The PIQ moiety may serve as a peripheral site anchor positioning the aldoxime moiety at the AChE active site. In terms of evaluated dissociation inhibition constants, the aldoximes could be characterized as high-affinity ligands. Nevertheless, high binding affinity of these oximes to AChE or its phosphylated conjugates did not assure rapid and selective AChE reactivation. Rather, potential reactivators of phosphylated BChE, with its enlarged acyl pocket, were identified, especially in case of cyclosarin, where the reactivation rates of the lead reactivator was 100- and 6-times that of 2-PAM and HI-6, respectively. Nevertheless, the return of the enzyme activity was affected by the nerve agent conjugated to catalytic serine, which highlights the lack of the universality of reactivators with respect to both the target enzyme and OP structure.

Current medical countermeasures for organophosphate (OP)-induced status epilepticus (SE) are not effective in preventing long-term morbidity and there is an urgent need for improved therapies. Rat models of acute intoxication with the OP, diisopropylfluorophosphate (DFP), are increasingly being used to evaluate therapeutic candidates for efficacy in mitigating the long-term neurologic effects associated with OP-induced SE. Many of these therapeutic candidates target neuroinflammation and oxidative stress because of their implication in the pathogenesis of persistent neurologic deficits associated with OP-induced SE. Critical to these efforts is the rigorous characterization of the rat DFP model with respect to outcomes associated with acute OP intoxication in humans, which include long-term electroencephalographic, neurobehavioral, and neuropathologic effects, and their temporal relationship to neuroinflammation and oxidative stress. To address these needs, we examined a range of outcomes at later times post-exposure than have previously been reported for this model. Adult male Sprague-Dawley rats were given pyridostigmine bromide (0.1 mg/kg, im) 30 min prior to administration of DFP (4 mg/kg, sc), which was immediately followed by atropine sulfate (2 mg/kg, im) and pralidoxime (25 mg/kg, im). This exposure paradigm triggered robust electroencephalographic and behavioral seizures that rapidly progressed to SE lasting several hours in 90% of exposed animals. Animals that survived DFP-induced SE (~70%) exhibited spontaneous recurrent seizures and hyperreactive responses to tactile stimuli over the first 2 months post-exposure. Performance in the elevated plus maze, open field, and Pavlovian fear conditioning tests indicated that acute DFP intoxication reduced anxiety-like behavior and impaired learning and memory at 1 and 2 months post-exposure in the absence of effects on general locomotor behavior. Immunohistochemical analyses revealed significantly increased expression of biomarkers of reactive astrogliosis, microglial activation and oxidative stress in multiple brain regions at 1 and 2 months post-DFP, although there was significant spatiotemporal heterogeneity across these endpoints. Collectively, these data largely support the relevance of the rat model of acute DFP intoxication as a model for acute OP intoxication in the human, and support the hypothesis that neuroinflammation and/or oxidative stress represent potential therapeutic targets for mitigating the long-term neurologic sequelae of acute OP intoxication.

Background: Organophosphorus compounds are widely used as pesticides in agriculture practicing countries like India. Since it is readily available and accessible, it is one of the most commonly used agents for suicidal poisoning. The current study was undertaken to evaluate the performance of the SOFA score (scoring system) and the serum lactate level (laboratory parameter) as a mortality predictor in organophosphorus poisoning. Material and Methods: This prospective observational study was conducted at AIIMS, Bhubaneswar, for 17 months. The study population included all patients with an alleged history of ingestion of organophosphorus (OP) compounds reporting to the casualty. The receiver operating characteristic (ROC) curve and the logistic regression analysis were used for the analysis. Results: In our study, 75 patients with OP poisoning were studied after satisfying the inclusion criteria. OP poisoning was commonly seen in married males aged 21–40 years. Twelve (16%) patients died during the process of treatment. There was a statistically significant difference in the mean SOFA score, serum lactate level, pH value, and mean duration of hospital stay between the discharged and the deceased patients. In the current study, the ROC curve analysis used to assess the predictor of the outcome of OP poisoning showed that the area under the curve for SOFA score and serum lactate level were 0.794 (95% CI 0.641–0.948) and 0.659 (95% CI 0.472–0.847), respectively. Conclusion: Sequential Organ Failure Assessment (SOFA) score is significantly associated with the outcome of organophosphate poisoning and can be utilized to predict mortality.

Industrial production of food for animals and humans needs increasing amounts of pesticides, especially of organophosphates, which are now easily available worldwide. More than 3 million cases of acute severe poisoning are estimated to occur worldwide every year, and even more cases remain unreported, while 200,000–350,000 incidentally or intentionally poisoned people die every year. Diagnostic and therapeutic procedures in organophosphate poisoning have, however, remained unchanged. In addition to several neurologic symptoms (miosis, fasciculations), hypersecretion of salivary, bronchial, and sweat glands, vomiting, diarrhea, and loss of urine rapidly induce dehydration, hypovolemia, loss of conscience and respiratory distress. Within hours, signs of acidosis due to systemic hypoxia can be observed at first laboratory investigation after hospitalization. While determination of serum-cholinesterase does not have any diagnostic value, it has been established that hypoalbuminemia alone or accompanied by an increase in creatinine, lactate, or C-reactive protein serum levels has negative prognostic value. Increased serum levels of C-reactive protein are a sign of systemic ischemia. Protective mechanical ventilation should be avoided, if possible. In fact, acute respiratory distress syndrome characterized by congestion and increased weight of the lung, accompanied by heart failure, may become the cause of death. As the excess of acetylcholine at the neuronal level can persist for weeks until enough newly, locally synthesized acetylcholinesterase becomes available (the value of oximes in reducing this time is still under debate), after atropine administration, intravenous albumin and fluid infusion should be the first therapeutic interventions to reestablish normal blood volume and normal tissue oxygenation, avoiding death by cardiac arrest. [ABSTRACT FROM AUTHOR]

Background: Organophosphorus compounds are widely used as pesticides in agriculture practicing countries like India. Since it is readily available and accessible, it is one of the most commonly used agents for suicidal poisoning. The current study was undertaken to evaluate the performance of the SOFA score (scoring system) and the serum lactate level (laboratory parameter) as a mortality predictor in organophosphorus poisoning. Material and Methods: This prospective observational study was conducted at AIIMS, Bhubaneswar, for 17 months. The study population included all patients with an alleged history of ingestion of organophosphorus (OP) compounds reporting to the casualty. The receiver operating characteristic (ROC) curve and the logistic regression analysis were used for the analysis. Results: In our study, 75 patients with OP poisoning were studied after satisfying the inclusion criteria. OP poisoning was commonly seen in married males aged 21–40 years. Twelve (16%) patients died during the process of treatment. There was a statistically significant difference in the mean SOFA score, serum lactate level, pH value, and mean duration of hospital stay between the discharged and the deceased patients. In the current study, the ROC curve analysis used to assess the predictor of the outcome of OP poisoning showed that the area under the curve for SOFA score and serum lactate level were 0.794 (95% CI 0.641–0.948) and 0.659 (95% CI 0.472–0.847), respectively. Conclusion: Sequential Organ Failure Assessment (SOFA) score is significantly associated with the outcome of organophosphate poisoning and can be utilized to predict mortality. [ABSTRACT FROM AUTHOR]

Introduction: Poisoning is a serious public health issue in developing countries like Nepal. Information about poisoning may be helpful for poisoning prevention and hospital treatment, aiding in the development of measures that lower the morbidity and mortality associated with poisoning. This study aimed to find out the prevalence of poisoning among autopsies conducted in the Department of Forensic Medicine and Toxicology in a tertiary care centre. Methods: A descriptive cross-sectional study was conducted among autopsied cases in the Department of Forensic Medicine and Toxicology in a tertiary care centre. Data from 1 October 2020 to 1 April 2022 was collected between 22 December 2022 to 30 December 2022 from records after receiving ethical approval from the Institutional Review Committee. All autopsied cases during the study period were included with the exclusion of decomposed bodies. Convenience sampling method was used. The point estimate was calculated at a 95% Confidence Interval. Results: Among 399 autopsies, 63 (15.79%) (12.21-19.37, 95% Confidence Interval) were found to be cases of poisoning. Among 63 cases, 35 (55.56%) were male and 28 (44.44%) were female. The most common substance causing poisoning was unknown with 31 (49.21%) cases, followed by organophosphates with 24 (38.10%) cases and rodenticide with 8 (12.70%) cases. Conclusions: The prevalence of poisoning among autopsies was found to be higher than similar studies conducted in similar settings.

Acute intoxication with organophosphate cholinesterase inhibitors (OPs) is a significant human health threat, and current medical countermeasures for OP poisoning are of limited therapeutic efficacy. The rat model of acute intoxication with diisopropylfluorophosphate (DFP) is increasingly being used to test candidate compounds for efficacy in protecting against the immediate and long-term consequences of acute OP toxicity. In this model, rats are typically pretreated with pyridostigmine bromide (PB), a reversible cholinesterase inhibitor, to enhance survival. However, PB pretreatment is not likely in most scenarios of civilian exposure to acutely neurotoxic levels of OPs. Therefore, the goal of this study was to determine whether PB pretreatment significantly increases survival in DFP-intoxicated rats. Adult male Sprague Dawley rats were injected with DFP (4 mg/kg, s.c.) or vehicle (VEH) followed 1 min later by combined i.m. injection of atropine sulfate (2 mg/kg) and 2-pralidoxime (25 mg/kg). Animals were pretreated 30 min prior to these injections with PB (0.1 mg/kg, i.m.) or an equal volume of saline. DFP triggered rapid and sustained seizure behavior irrespective of PB pretreatment, and there was no significant difference in average seizure behavior score during the first 4 h following injection between DFP animals pretreated with PB or not. PB pretreatment also had no significant effect on survival or brain AChE activity at 24 h post-DFP exposure. In summary, PB pretreatment is not necessary to ensure survival of rats acutely intoxicated with DFP, and eliminating PB pretreatment in the rat model of acute DFP intoxication would increase its relevance to acute OP intoxication in civilians.

2-Pyridinealdoxime methiodide (2-PAM) is a widely used antidote for the treatment of organophosphorus (OP) exposure that reactivates the target protein acetylcholinesterase. Carbon-11 2-PAM was prepared to more fully understand the in vivo mode of action, distribution, and dynamic qualities of this important countermeasure. Alkylation of 2-pyridinealdoxime with [11C]CH3I provided the first-in-class [11C]2-PAM tracer in 3.5% decay corrected radiochemical yield from [11C]CH3I, >99% radiochemical purity, and 4831 Ci/mmol molar activity. [11C]2-PAM tracer distribution was evaluated by ex vivo biodistribution and in vivo dynamic positron emission tomography (PET) imaging in naïve (OP exposure deficient) rats. Tracer alone and tracer coinjected with a body mass-scaled human therapeutic dose of 30 mg/kg nonradioactive 2-PAM demonstrated statistically similar tissue and blood distribution profiles with the greatest uptake in kidney and significantly lower levels in liver, heart, and lung with lesser amounts in blood and brain. The imaging and biodistribution data show that radioactivity uptake in brain and peripheral organs is rapid and characterized by differential tissue radioactivity washout profiles. Analysis of arterial blood samples taken 5 min after injection showed ∼82% parent [11C]2-PAM tracer. The imaging and biodistribution data are now established, enabling future comparisons to outcomes acquired in OP intoxicated rodent models.

In poisoning with organophosphorus compounds (OP), patients can only profit from the regeneration of acetylcholinesterase, when the poison load has dropped below a toxic level. Every measure that allows an increase of synaptic acetylcholinesterase (AChE) activity at the earliest is essential for timely termination of the cholinergic crisis. Only drug‐induced reactivation allows fast restoration of the inhibited AChE. Obidoxime and pralidoxime have proved to be able to reactivate inhibited cholinesterase thereby saving life of poisoned animals. A plasma level of obidoxime or pralidoxime allowing reactivation in humans poisoned by OP can be adjusted. There is no doubt that obidoxime and pralidoxime are able to reactivate OP‐inhibited AChE activity in poisoned patients, thereby increasing AChE activity and contributing substantially to terminate cholinergic crisis. Hence, a benefit may be expected when substantial reactivation is achieved. A test system allowing determination of red blood cell AChE activity, reactivatability, inhibitory equivalents and butyrylcholinesterase activity is available for relatively low cost. If any reactivation is possible while inhibiting equivalents are present, oxime therapy should be maintained. In particular, when balancing the benefit risk assessment, obidoxime or palidoxime should be given as soon as possible and as long as a substantial reactivation may be expected. [ABSTRACT FROM AUTHOR]

For the first time, the efficacy of post-exposure treatment of organophosphate (OP) poisoning was increased by transdermal delivery of acetylcholinesterase (AChE) reactivator pyridine-2-aldoxime methochloride (2-PAM) as a preventive countermeasure. By selecting the optimal ratio of components, classical transfersomes (based on soybean phosphatidylcholine and Tween 20) and modified transfersomes (based on soybean phosphatidylcholine, Tween 20 and pyrrolidinium cationic surfactants with different hydrocarbon tail lengths) were obtained for 2-PAM encapsulation. Transfersomes modified with tetradecylpyrrolidinium bromide showed the best results in encapsulation efficiency and sustained release of 2-PAM from vesicles. Using Franz cells, it was found that the incorporation of surfactants into PC liposomes results in a more prolonged release of 2-PAM through the rat skin. Transfersomes containing 2-PAM, after exhaustive physical and chemical characterization, were embedded in a gel based on Carbopol® 940. A significantly high degree of erythrocyte AChE reactivation (23 ± 7%) was shown for 2-PAM in unmodified transfersomes in vivo. Preliminary transdermal administration of 2-PAM 24 h before emergency post-exposure treatment of OP poisoning leads to an increase in the survival rate of rats from 55% to 90%. [ABSTRACT FROM AUTHOR]

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

Objective: There is insufficient evidence on the effectiveness of gastric lavage in organophosphorus poisoning. This study was done to quantitate the level of chlorpyrifos and quinalphos retrieved in gastric lavage fluid.Methods: Patients presenting within six hours of ingesting quinalphos or chlorpyrifos with International Program on Chemical Safety Poison Severity Score (IPCS PSS) grade 2 or more were included in the study. After the stabilisation of patients, gastric lavage was performed with alliquotes of 200 ml of normal saline till aspirate became clear. Quantification of the pesticide was done in the first 10 ml of lavage fluid aspirated out and in blood with gas chromatography with triple quadruple mass spectrometer (GC-MSMS).Results: There were six patients in each pesticide group. Mean time for reaching hospital after the ingestion of pesticide was 2.8 ± 1.1(range 1.25-6) hours. Median quantity of chlorpyrifos in the lavage fluid was 10.24 (IQR 14.36) µg/L and in quinalphos, it was 1360.62 (IQR 1691.2) µg/L. Other compounds detected in lavage fluid and confirmed in blood were endosulfan, diazinon, pirimiphos, pyridafenthion, pyrazophos, pirimiphos ethyl, and azinphos.Conclusion: Chlorpyrifos and quinalphos are detected in lavage fluid after one hour of ingestion and few milligrams are retrieved by gastric lavage. The presence of other pesticides including endosulfan were confirmed in lavage fluid.

Encapsulated phosphotriesterase nanoreactors show their efficacy in the prophylaxis and post-exposure treatment of poisoning by paraoxon. A new enzyme nanoreactor (E-nRs) containing an evolved multiple mutant (L72C/Y97F/Y99F/W263V/I280T) of Saccharolobus solfataricus phosphotriesterase (PTE) for in vivo detoxification of organophosphorous compounds (OP) was made. A comparison of nanoreactors made of three- and di-block copolymers was carried out. Two types of morphology nanoreactors made of di-block copolymers were prepared and characterized as spherical micelles and polymersomes with sizes of 40 nm and 100 nm, respectively. The polymer concentrations were varied from 0.1 to 0.5% (w/w) and enzyme concentrations were varied from 2.5 to 12.5 μM. In vivo experiments using E-nRs of diameter 106 nm, polydispersity 0.17, zeta-potential −8.3 mV, and loading capacity 15% showed that the detoxification efficacy against paraoxon was improved: the LD50 shift was 23.7xLD50 for prophylaxis and 8xLD50 for post-exposure treatment without behavioral alteration or functional physiological changes up to one month after injection. The pharmacokinetic profiles of i.v.-injected E-nRs made of three- and di-block copolymers were similar to the profiles of the injected free enzyme, suggesting partial enzyme encapsulation. Indeed, ELISA and Western blot analyses showed that animals developed an immune response against the enzyme. However, animals that received several injections did not develop iatrogenic symptoms.

In the development of antidotal therapy for treatment of organophosphate exposure from pesticides used in agriculture and nerve agents insidiously employed in terrorism, the alkylpyridinium aldoximes have received primary attention since their early development by I. B. Wilson in the 1950s. Yet these agents, by virtue of their quaternary structure, are limited in rates of crossing the blood-brain barrier, and they require administration parenterally to achieve full distribution in the body. Oximes lacking cationic charges or presenting a tertiary amine have been considered as alternatives. Herein, we examine the pharmacokinetic properties of a lead ionizable, zwitterionic hydroxyiminoacetamido alkylamine in mice to develop a framework for studying these agents in vivo and generate sufficient data for their consideration as appropriate antidotes for humans. Consequently, in vitro and in vivo efficacies of immediate structural congeners were explored as leads or backups for animal studies. We compared oral and parenteral dosing, and we developed an intramuscular loading and oral maintenance dosing scheme in mice. Steady-state plasma and brain levels of the antidote were achieved with sequential administrations out to 10 hours, with brain levels exceeding plasma levels shortly after administration. Moreover, the zwitterionic oxime showed substantial protection after gavage, whereas the classic methylpyridinium aldoxime (2-pyridinealdoxime methiodide) was without evident protection. Although further studies in other animal species are necessary, ionizing zwitterionic aldoximes present viable alternatives to existing antidotes for prophylaxis and treatment of large numbers of individuals in terrorist-led events with nerve agent organophosphates, such as sarin, and in organophosphate pesticide exposure.

Fatalities from organophosphate (OP) insecticide result from both occupational and deliberate exposure; significantly impacting human health. Like nerve agents, insecticides are neurotoxins which target and inhibit acetylcholinesterases (AChE) in central and peripheral synapses in the cholinergic nervous system. Post-exposure therapeutic countermeasures generally include administration of atropine with a pyridinium aldoxime e.g. pralidoxime, to reactivate the OP-inhibited AChE. However, commonly used oximes inefficiently cross the bloodbrain barrier and are rapidly cleared and their benefit is debated. Recent findings have demonstrated the ability of a novel zwitterionic, centrally acting, brain penetrating oxime (RS194B) to reverse severe symptoms and rapidly reactivate sarin-inhibited AChE in macaques, but it has not been tested following OP pesticide poisoning. In the present study, the symptoms following a lethal dose of inhaled paraoxon (100ug/kg), were shown to mimic those in insecticide poisoned individuals and were also rapidly reversed in macaques by post-exposure IM administration of 80mg/kg of RS194B. This occurred with a concomitant reactivation of AChE to 40-100% in

BackgroundCognitive impairment is a major health concern among older Mexican Americans, associated with significant morbidity and mortality, and may be influenced by environmental exposures.ObjectivesTo investigate whether agricultural based ambient organophosphorus (OP) exposure influences 1) the rate of cognitive decline and mortality and 2) whether these associations are mediated through metabolic or inflammatory biomarkers.MethodsIn a subset of older Mexican Americans from the Sacramento Area Latino Study on Aging (n = 430), who completed modified mini-mental state exams (3MSE) up to 7 times (1998-2007), we examined the relationship between estimated ambient OP exposures and cognitive decline (linear repeated measures model) and time to dementia or being cognitively impaired but not demented (CIND) and time to mortality (cox proportional hazards model). We then explored metabolic and inflammatory biomarkers as potential mediators of these relationships (additive hazards mediation). OP exposures at residential addresses were estimated with a geographic information system (GIS) based exposure assessment tool.ResultsParticipants with high OP exposure in the five years prior to baseline experienced faster cognitive decline (β = 0.038, p = 0.02) and higher mortality over follow-up (HR = 1.91, 95% CI = 1.12, 3.26). The direct effect of OP exposure was estimated at 241 (95% CI = 27-455) additional deaths per 100,000 person-years, and the proportion mediated through the metabolic hormone adiponectin was estimated to be 4% 1.5-19.2). No other biomarkers were associated with OP exposure.ConclusionsOur study provides support for the involvement of OP pesticides in cognitive decline and mortality among older Mexican Americans, possibly through biologic pathways involving adiponectin.

Abstract Background Organophosphate poisoning is a serious issue and it results in significant casualties in developing countries. Since agriculture remains an important and necessary sector of human society and organophosphate are commonly used in agriculture, it is difficult to prevent organophosphate poisoning. Gastrointestinal bleeding is not a common but life threatening symptom of organophosphate poisoning. We report a rare case of gastrointestine bleeding due to organophosphate poisoning. Case presentation A 78-year-old woman presented to our hospital approximately 12 h after ingesting a mouthful of organophosphate and benzodiazepines in a suicide attempt. Six weeks after successful medical treatment for respiratory failure, she developed recurring melena. Colonoscopy and esophagogastroduodenoscopy findings were negative for ulcers or bleeding. Enteroscopy revealed severe circumferential ulcers with luminal narrowing 10 cm proximal to the ileocecal valve. The patient underwent a 100-cm ileum resection after failed medical treatment and recovered uneventfully. The resected terminal ileum demonstrated severe inflammation and a sharp transitional zone between the healthy and injured mucosa approximately 50 cm proximal to the ileocecal valve. Pathological examination revealed an injured mucosa with inflammatory cell infiltration and structural damage. This case highlights a rare event of OP poisoning with late-onset lower gastrointestinal bleeding, which prolonged the patient’s recovery course and parenteral alimentation period. Conclusion We report a rare case of a patient with organophosphate poisoning, with late-onset lower GI tract bleeding, which raised clinical awareness regarding the organophosphate poisoning that induce intestinal symptoms.

Introduction: Major cases of poisoning are associated with organophosphates. Cholinergic effects and an intermediate phase seen with organophosphate poisoning may implicate myopathy. Creatine kinase is a marker of muscle tissue damage. This study aimed to find out the mean serum creatine kinase among organophosphate poisoning cases in a tertiary care centre. Methods: A descriptive cross-sectional study was carried out among organophosphate poisoning cases in a tertiary care hospital from 13 October 2017 to 30 March 2018. Ethical approval was taken from the Institutional Review Committee [Reference number: 117(6-11-E) 2/074/075]. Blood samples were assayed for serum acetylcholinesterase in the pharmacology laboratory and for serum creatine kinase and lactate dehydrogenase in the biochemistry laboratory. Low serum acetylcholinesterase was taken as the basis for the establishment of organophosphate poisoning. A convenience sampling technique was used. Point estimate and 95% Confidence Interval were calculated. Results: Among 103 organophosphate poisoning cases, the mean serum creatine kinase was 931.35±446.60 IU/l (845.10-1017.60, 95% Confidence Interval). Conclusions: The mean serum creatine kinase level among organophosphate poisoning cases was higher than in other studies done in similar settings.

Organophosphate (OP) compounds include highly toxic chemicals widely used both as pesticides and as warfare nerve agents. Existing countermeasures are lifesaving, but do not alleviate all long-term neurological sequelae, making OP poisoning a public health concern worldwide and the search for fully efficient antidotes an urgent need. OPs cause irreversible acetylcholinesterase (AChE) inhibition, inducing the so-called cholinergic syndrome characterized by peripheral manifestations and seizures associated with permanent psychomotor deficits. Besides immediate neurotoxicity, recent data have also identified neuroinflammation and microglia activation as two processes that likely play an important, albeit poorly understood, role in the physiopathology of OP intoxication and its long-term consequences. To gain insight into the response of microglia to OP poisoning, we used a previously described model of diisopropylfluorophosphate (DFP) intoxication of zebrafish larvae. This model reproduces almost all the defects seen in poisoned humans and preclinical models, including AChE inhibition, neuronal epileptiform hyperexcitation, and increased neuronal death. Here, we investigated in vivo the consequences of acute DFP exposure on microglia morphology and behaviour, and on the expression of a set of pro- and anti-inflammatory cytokines. We also used a genetic method of microglial ablation to evaluate the role in the OP-induced neuropathology. We first showed that DFP intoxication rapidly induced deep microglial phenotypic remodelling resembling that seen in M1-type activated macrophages and characterized by an amoeboid morphology, reduced branching, and increased mobility. DFP intoxication also caused massive expression of genes encoding pro-inflammatory cytokines Il1β, Tnfα, Il8, and to a lesser extent, immuno-modulatory cytokine Il4, suggesting complex microglial reprogramming that included neuroinflammatory activities. Finally, microglia-depleted larvae were instrumental in showing that microglia were major actors in DFP-induced neuroinflammation and, more importantly, that OP-induced neuronal hyperactivation was markedly reduced in larvae fully devoid of microglia. DFP poisoning rapidly triggered massive microglia-mediated neuroinflammation, probably as a result of DFP-induced neuronal hyperexcitation, which in turn further exacerbated neuronal activation. Microglia are thus a relevant therapeutic target, and identifying substances reducing microglial activation could add efficacy to existing OP antidote cocktails. [ABSTRACT FROM AUTHOR]

Introduction: Organophosphorus compounds are pesticides commonly used for agricultural purposes. However, by nature they are poisonous, and administration either accidental or intentional is a medical emergency requiring prompt evaluation and treatment, and can even lead to death. In addition due to the ease of their availability, they are commonly used for self-harm/suicidal purposes. Many of the patients are initially managed at primary or secondary healthcare setups before being referred to tertiary care hospitals. The purpose of our study is to find a prognostic marker in the initial blood work of these patients. Materials and Methods: A total of 46 patients were included in this retrospective cross-sectional survey conducted at the Department of Emergency Medicine, Holy Family Hospital, Rawalpindi. Data were collected from patient files using specific questionnaires. Outcomes were defined in terms of Emergency Department disposition. Data were analysed using SPSS v25. A univariate analysis, followed by Spearman's Correlation was used. Results: Patients with a higher WBC to Platelet ratio had worse outcomes. The Spearman's rho correlation coefficient was calculated and a moderately strong correlation (rho = .458, p < .001) was found. Conclusion: WBC to Platelet ratio is a hematological parameter determined to be most strongly correlated with adverse outcomes in Organophosphate Poisoning. It has a statistically significant stronger correlation than the WBC count alone. However, further extensive and focused studies are needed to corroborate these findings and substantiate them as a definite marker of prognostic significance. [ABSTRACT FROM AUTHOR]

BackgroundExposures to cholinesterase inhibitor pesticides (e.g. organophosphates) have been associated with children's neurobehavioral alterations, including attention deficit and impulsivity. Animal studies have observed transient alterations in neurobehavioral performance in relation to cholinesterase inhibitor pesticide exposures; however, limited evidence exists regarding transient effects in humans.MethodsWe estimated the associations between neurobehavioral performance and time after Mother's Day flower harvest (the end of a heightened pesticide usage period) among 308 4-to 9-year-old children living in floricultural communities in Ecuador in 2008 who participated in the ESPINA study. Children's neurobehavior was examined once (NEPSY-II: 11 subtests covering 5 domains), between 63 and 100days (SD: 10.8days) after Mother's Day harvest (blood acetylcholinesterase activity levels can take 82days to normalize after irreversible inhibition with organophosphates).ResultsThe mean (SD) neurobehavioral scaled scores across domains ranged from 6.6 (2.4) to 9.9 (3.3); higher values reflect greater performance. Children examined sooner after Mother's Day had lower neurobehavioral scores than children examined later, in the domains of (score difference per 10.8days, 95%CI): Attention/Inhibitory Control (0.38, 0.10-0.65), Visuospatial Processing (0.60, 0.25-0.95) and Sensorimotor (0.43, 0.10-0.77). Scores were higher with longer time post-harvest among girls (vs. boys) in Attention/Inhibitory Control.ConclusionsOur findings, although cross-sectional, are among the first in non-worker children to suggest that a peak pesticide use period may transiently affect neurobehavioral performance, as children examined sooner after the flower harvest had lower neurobehavioral performance than children examined later. Studies assessing pre- and post-exposure measures are needed.

Organophosphate pesticide (OP) poisoning is quite common and can cause cardiovascular complications and even direct myocardial injury. However, no guideline has included an acute poisoning as a potential cause for a type 2 myocardial infarction (MI) so far. Here we present a case of a 61-year-old woman brought by ambulance to emergency department one hour after accidental ingestion of an unknown quantity of a solution she used against flea infestation. The patient presented with dizziness, myosis, excessive sweating, hypersalivation, sphincteric incontinence, muscle fasciculation, tremor of the extremities, pale skin, alcoholic and pesticide breath odour. Even though we had no guidelines to fall back on, we successfully treated the patient with low-molecular-weight heparin, antiplatelets, statin, diltiazem, antidote therapy, and supportive care. Physicians should be aware that OP poisoning can induce type 2 MI as a complication within a few hours since exposure, and emergency management should always include close cardiac monitoring.

Industrial production of food for animals and humans needs increasing amounts of pesticides, especially of organophosphates, which are now easily available worldwide. More than 3 million cases of acute severe poisoning are estimated to occur worldwide every year, and even more cases remain unreported, while 200,000–350,000 incidentally or intentionally poisoned people die every year. Diagnostic and therapeutic procedures in organophosphate poisoning have, however, remained unchanged. In addition to several neurologic symptoms (miosis, fasciculations), hypersecretion of salivary, bronchial, and sweat glands, vomiting, diarrhea, and loss of urine rapidly induce dehydration, hypovolemia, loss of conscience and respiratory distress. Within hours, signs of acidosis due to systemic hypoxia can be observed at first laboratory investigation after hospitalization. While determination of serum-cholinesterase does not have any diagnostic value, it has been established that hypoalbuminemia alone or accompanied by an increase in creatinine, lactate, or C-reactive protein serum levels has negative prognostic value. Increased serum levels of C-reactive protein are a sign of systemic ischemia. Protective mechanical ventilation should be avoided, if possible. In fact, acute respiratory distress syndrome characterized by congestion and increased weight of the lung, accompanied by heart failure, may become the cause of death. As the excess of acetylcholine at the neuronal level can persist for weeks until enough newly, locally synthesized acetylcholinesterase becomes available (the value of oximes in reducing this time is still under debate), after atropine administration, intravenous albumin and fluid infusion should be the first therapeutic interventions to reestablish normal blood volume and normal tissue oxygenation, avoiding death by cardiac arrest.

Background and Objective: Organophosphates poisoning is among the most prevalent forms of intentional and unintentional poisoning in Pakistan. However, the actual burden of AKI secondary to organophosphate poisoning in Pakistani population is still not known. This study aimed to determine the actual burden of AKI among patients admitted at National Poison Control Centre, Karachi. Methods: A cross-sectional survey was conducted at National Poison Control Centre, Karachi November, 2013 to April, 2014. A sample of 300 patients of age 18 years and above, presenting with organophosphate poisoning within 24 of exposure or ingestion were included in the study. Frequency of acute kidney injury was calculated using the diagnostic criteria of serum creatinine level of >1.4 mg/dL. Data was analyzed using SPSS version 19. Results: The frequency of AKI which was defined as creatinine level >1.4 mg/dL was 22.3% (n=67). However, there was no statistically significant difference was found in frequency of AKI on the basis of age, sex, amount of organophosphates ingested and BMI. This study found statistically significant differences in the AKI frequency on the basis of lag time. Those who presented earlier after poisoning had relatively low frequency of AKI. Conclusion: This study concludes that AKI is a common complication among patients presenting with organophosphate poisoning at National Poison Control Center, Karachi. Lag time is a key determinant of AKI among patients with organophosphate poisoning. Timely treatment can prevent this critical complication among patients with organophosphate poisoning. [ABSTRACT FROM AUTHOR]

Objective: There is insufficient evidence on the effectiveness of gastric lavage in organophosphorus poisoning. This study was done to quantitate the level of chlorpyrifos and quinalphos retrieved in gastric lavage fluid. Methods: Patients presenting within six hours of ingesting quinalphos or chlorpyrifos with International Program on Chemical Safety Poison Severity Score (IPCS PSS) grade 2 or more were included in the study. After the stabilisation of patients, gastric lavage was performed with alliquotes of 200 ml of normal saline till aspirate became clear. Quantification of the pesticide was done in the first 10 ml of lavage fluid aspirated out and in blood with gas chromatography with triple quadruple mass spectrometer (GC-MSMS). Results: There were six patients in each pesticide group. Mean time for reaching hospital after the ingestion of pesticide was 2.8 ± 1.1(range 1.25-6) hours. Median quantity of chlorpyrifos in the lavage fluid was 10.24 (IQR 14.36) µg/L and in quinalphos, it was 1360.62 (IQR 1691.2) µg/L. Other compounds detected in lavage fluid and confirmed in blood were endosulfan, diazinon, pirimiphos, pyridafenthion, pyrazophos, pirimiphos ethyl, and azinphos. Conclusion: Chlorpyrifos and quinalphos are detected in lavage fluid after one hour of ingestion and few milligrams are retrieved by gastric lavage. The presence of other pesticides including endosulfan were confirmed in lavage fluid. [ABSTRACT FROM AUTHOR]

The high toxicity of organophosphorus compounds originates from covalent inhibition of acetylcholinesterase (AChE), an essential enzyme in cholinergic neurotransmission. Poisonings that lead to life-threatening toxic manifestations require immediate treatment that combines administration of anticholinergic drugs and an aldoxime as a reactivator of AChE. An alternative approach to reduce the in vivo toxicity of OPs focuses on the use of bioscavengers against the parent organophosphate. Our previous research showed that AChE mutagenesis can enable aldoximes to substantially accelerate the reactivation of OP-enzyme conjugates, while dramatically slowing down rates of OP-conjugate dealkylation (aging). Herein, we demonstrate an efficient HI-6-assisted VX detoxification, both ex vivo in human blood and in vivo in mice by hAChE mutants modified at the choline binding site (Y337A and Y337A/F338A). The catalytic scavenging of VX in mice improved therapeutic outcomes preventing lethality and resulted in a delayed onset of toxicity symptoms.

Acetylcholinesterase (AChE; EC 3.1.1.7), an essential enzyme of cholinergic neurotransmission in vertebrates, is a primary target in acute nerve agent and organophosphate (OP) pesticide intoxication. Catalytically inactive OP-AChE conjugates formed between the active-center serine and phosphorus of OPs can, in principle, be reactivated by nucleophilic oxime antidotes. Antidote efficacy is limited by the structural diversity of OP-AChE conjugates resulting from differences in the structure of the conjugated OP, the different active-center volumes they occupy when conjugated to the active-center serine of AChE, and the distinct chemical characteristics of both OPs and oximes documented in numerous X-ray structures of OP-conjugated AChEs. Efforts to improve oxime reactivation efficacy by AChE structure-based enhancement of oxime structure have yielded only limited success. We outline here the potential limitations of available AChE X-ray structures that preclude an accurate prediction of oxime structures, which are necessary for association in the OP-AChE gorge and nucleophilic attack of the OP-conjugated phosphorus.