Zebrafish Models for Human Acute Organophosphorus Poisoning.
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ABSTRACT:
SUBMITTER: Faria M
PROVIDER: S-EPMC4614985 | biostudies-literature | 2015 Oct
REPOSITORIES: biostudies-literature
Publications
Zebrafish Models for Human Acute Organophosphorus Poisoning.
Faria Melissa M Garcia-Reyero Natàlia N Padrós Francesc F Babin Patrick J PJ Sebastián David D Cachot Jérôme J Prats Eva E Arick Ii Mark M Rial Eduardo E Knoll-Gellida Anja A Mathieu Guilaine G Le Bihanic Florane F Escalon B Lynn BL Zorzano Antonio A Soares Amadeu M V M AM Raldúa Demetrio D
Scientific reports 20151022
Terrorist use of organophosphorus-based nerve agents and toxic industrial chemicals against civilian populations constitutes a real threat, as demonstrated by the terrorist attacks in Japan in the 1990 s or, even more recently, in the Syrian civil war. Thus, development of more effective countermeasures against acute organophosphorus poisoning is urgently needed. Here, we have generated and validated zebrafish models for mild, moderate and severe acute organophosphorus poisoning by exposing zebr ...[more]
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Project description:BackgroundPoisoning with organophosphorus (OP) insecticides is a major global public health problem, causing an estimated 200,000 deaths each year. Although the World Health Organization recommends use of pralidoxime, this antidote's effectiveness remains unclear. We aimed to determine whether the addition of pralidoxime chloride to atropine and supportive care offers benefit.Methods and findingsWe performed a double-blind randomised placebo-controlled trial of pralidoxime chloride (2 g loading dose over 20 min, followed by a constant infusion of 0.5 g/h for up to 7 d) versus saline in patients with organophosphorus insecticide self-poisoning. Mortality was the primary outcome; secondary outcomes included intubation, duration of intubation, and time to death. We measured baseline markers of exposure and pharmacodynamic markers of response to aid interpretation of clinical outcomes. Two hundred thirty-five patients were randomised to receive pralidoxime (121) or saline placebo (114). Pralidoxime produced substantial and moderate red cell acetylcholinesterase reactivation in patients poisoned by diethyl and dimethyl compounds, respectively. Mortality was nonsignificantly higher in patients receiving pralidoxime: 30/121 (24.8%) receiving pralidoxime died, compared with 18/114 (15.8%) receiving placebo (adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 0.88-3.26, p = 0.12). Incorporating the baseline amount of acetylcholinesterase already aged and plasma OP concentration into the analysis increased the HR for patients receiving pralidoxime compared to placebo, further decreasing the likelihood that pralidoxime is beneficial. The need for intubation was similar in both groups (pralidoxime 26/121 [21.5%], placebo 24/114 [21.1%], adjusted HR 1.27 [95% CI 0.71-2.29]). To reduce confounding due to ingestion of different insecticides, we further analysed patients with confirmed chlorpyrifos or dimethoate poisoning alone, finding no evidence of benefit.ConclusionsDespite clear reactivation of red cell acetylcholinesterase in diethyl organophosphorus pesticide poisoned patients, we found no evidence that this regimen improves survival or reduces need for intubation in patients with organophosphorus insecticide poisoning. The reason for this failure to benefit patients was not apparent. Further studies of different dose regimens or different oximes are required.
| S-EPMC2696321 | biostudies-literature
Project description:BACKGROUND:Organophosphorus (OP) compounds have been widely available for decades in agriculture for crop protection and as cheap pest controllers, which increases the rate of exposure and poisoning cases. Using serum cholinesterase as prognostic markers for the acute OP toxicity is controversial; therefore, we aim to find out prognostic biomarkers that best correlate with mortality and outcomes of patients with acute OP toxicity. Levels of serum oxidative stress biomarkers (malondialdehyde (MDA) and total antioxidant capacity (TAC)) and activity of the apoptotic biomarkers (caspase 3 and caspase 9) and pseudo-cholinesterase (p.ChE) were performed. Also, we evaluated the apoptotic capacity through determining the genotoxic effects and chromosomal abnormalities among OP intoxicated patients. RESULTS:We found the activity of caspases and serum MDA and TAC were significantly increased after OP poisoning and decreased after the appropriate atropine and oxime treatment course. The ROC curve suggested caspases as mortality and outcome predictive markers for acute OP poisoning patients. However, OP poisoning cases before treatment showed significant DNA damage, and they did not show any chromosomal aberration. CONCLUSION:The mentioned results strongly suggest apoptotic-related markers (caspase 3, caspase 9) as prognostic markers for evaluation of the treatment, outcomes, and mortality rate in the acute OP toxicity patients.
| S-EPMC7152583 | biostudies-literature
Project description:BackgroundDespite the apparent benefits of organophosphate compounds (OPCs) acute organophosphate (OP) pesticide poison is an increasing problem worldwide. In a country like Ethiopia, where agriculture is a major component of the economy, these compounds are readily available to the general public. There is paucity of evidence from Ethiopia showing the pattern of organophosphate poisoning (OPP) in healthcare facilities. The objective of this study was to evaluate retrospectively the pattern of acute OPP at the University of Gondar Teaching Hospital in northwest Ethiopia, during September 2010 through December 2014 was conducted. Data was collected through chart review of patients who were admitted due to poisoning. Data was analysed using SPSS 20.ResultsOrganophosphate poisoning in University of Gondar teaching hospital accounts for about 38.46% of all emergency room admissions for poisoning. Out of the 90 cases studied 60% (54) were women, with male to female ratio of 1:1.5. The mean age of the patients was 25.5 with a standard deviation of 9.45. 56.7% of the cases studies lived in an urban environment compared to 43.3% who lived rurally. In the vast majority of patients, 90% (81) patients had ingested OP as an act of suicide. Regarding the route of exposure, oral ingestion was most common in suicidal cases (88.9%). The elapsed time between the time of poison ingestion and the start of the treatment, ranged from 13 min to 1 day. Health care professionals' useds decontamination methods such as gastric lavage and activated charcoal (45.6%) and 36.7% use atropine for OPP treatment. The mean hospital stay was 0.74 days. In the present study family problems were a leading cause of suicides and accounted for 45.8% of all cases.ConclusionAs a developing nation who economy relies heavily on agriculture, Ethiopia continues to have OP compounds remain a common cause of acute poisonings. This is particularly concerning for younger generation who have high rates of OPP and whose numbers continue to raise. This data suggests that it is essential to strengthen Ethiopians regulatory policy concerning the availability of OPCs. Additionally, it will be important to design an appropriate health education program for the prevention of both suicidal and accidental OPPs for the benefit of the public at large.
| S-EPMC5381028 | biostudies-literature
Project description:Pesticide poisoning in pediatric patients is still an important reason for presenting to the emergency department in Romania. In this context, the present study aims to raise awareness of the toxicological impact of pesticides on human health in pediatrics. For this purpose, the demographic characteristics, clinical assessment, and outcome of pediatric patients with acute pesticide poisoning admitted to the toxicology department of "Saint Mary" Emergency Children's Hospital from Iasi, were analyzed. This retrospective study focused on the clinical and laboratory data of patients aged under 18 years diagnosed with acute pesticide poisoning between 2010-2020. The statistical analysis was performed using the Statistica 10 package. A total of 49 patients presented with manifestations of acute pesticide poisoning, and the most common pesticide involved was diazinon. The most frequent exposure route was accidentally ingesting pesticide products (95%). The primary clinical manifestations were toxic encephalopathy, coma, depressive disorder, gastric disorders, and respiratory failure. Changes in the glycemic status, liver, and kidney damage were also present. Treatment included decontamination, administration of antidote, supportive care, and recommendations to be closely monitored to avoid a new incident. These results highlight the toxic potential of pesticides on human health and their biological consequences, which require an increase in consciousness of the precautions imposed on their use, especially when children are nearby.
| S-EPMC9609388 | biostudies-literature
Project description:BACKGROUND:Acute organophosphorus (OP) poisoning is one of the major causes of mortality among patients presenting to emergency departments in developing countries. Although various predictors of mortality among OP poisoning patients have been identified, the role of repeated measurements of vital signs in determining the risk of mortality is not yet clear. Therefore, the present study examined the relationship between trajectories of vital signs and mortality among OP poisoning patients using latent class growth analysis (LCGA). METHODS:This was a retrospective cohort study using data for 449 OP poisoning patients admitted to Civil-Hospital Karachi from Aug'10 to Sep'16. Demographic data and vital signs, including body temperature, blood pressure, heart rate, respiratory rate, and partial-oxygen pressure, were retrieved from medical records. The trajectories of vital signs were formed using LCGA, and these trajectories were applied as independent variables to determine the risk of mortality using Cox-proportional hazards models. P-values of <?0.05 were considered statistically significant. RESULTS:Data for 449 patients, with a mean age of 25.4?years (range 13-85?years), were included. Overall mortality was 13.4%(n?=?60). In trajectory analysis, a low-declining systolic blood pressure, high-declining heart rate trajectory, high-remitting respiratory rate trajectory and normal-remitting partial-oxygen pressure trajectory resulted in the greatest mortality, i.e. 38.9,40.0,50.0, and 60.0%, respectively, compared with other trajectories of the same parameters. Based on multivariable analysis, patients with low-declining systolic blood pressure were three times [HR:3.0,95%CI:1.2-7.1] more likely to die compared with those who had a normal-stable systolic blood pressure. Moreover, patients with a high-declining heart rate were three times [HR:3.0,95%CI:1.5-6.2] more likely to die compared with those who had a high-stable heart rate. Patients with a high-remitting respiratory rate were six times [HR:5.7,95%CI:1.3-23.8] more likely to die than those with a high-stable respiratory rate. Patients with normal-remitting partial oxygen pressure were five times [HR:4.7,95%CI:1.4-15.1] more likely to die compared with those who had a normal-stable partial-oxygen pressure. CONCLUSION:The trajectories of systolic blood pressure, heart rate, respiratory rate and partial-oxygen pressure were significantly associated with an increased risk of mortality among OP poisoning patients.
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Project description:Organophosphorus (OP) pesticides are a diverse class of acetylcholinesterase (AChE) inhibitors that are responsible for tremendous morbidity and mortality worldwide, killing approximately 300,000 people annually. Enzymatic hydrolysis of OPs is a potential therapy for acute poisoning. OpdA, an OP hydrolase isolated from Agrobacterium radiobacter, has been shown to decrease lethality in rodent models of OP poisoning. This study investigated the effects of OpdA on AChE activity, plasma concentrations of OP, and signs of toxicity after administration of dichlorvos to nonhuman primates. A dose of 75 mg/kg dichlorvos given orally caused apnea within 10 min with a progressive decrease in heart rate. Blood AChE activity decreased to zero within 10 min. Respirations and AChE activity did not recover. The mean dichlorvos concentration rose to a peak of 0.66 μg/ml. Treated monkeys received 1.2mg/kg OpdA iv immediately after poisoning with dichlorvos. In Opda-treated animals, heart and respiratory rates were unchanged from baseline over a 240-minute observation period. AChE activity slowly declined, but remained above 25% of baseline for the entire duration. Dichlorvos concentrations reached a mean peak of 0.19 μg/ml at 40 min after poisoning and decreased to a mean of 0.05 μg/ml at 240 min. These results show that OpdA hydrolyzes dichlorvos in an African green monkey model of lethal poisoning, delays AChE inhibition, and prevents lethality.
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Project description:Organophosphorus compound exposure remains a present threat through agricultural accidents, warfare, or terrorist activity. The primary mechanism of organophosphorus toxicity is through inhibition of the enzyme acetylcholinesterase, with current emergency treatment including anticholinergics, benzodiazepines, and oxime reactivators. However, a need for more effective and broadly acting countermeasures remains. This study aimed to develop larval zebrafish as a high-throughput model for evaluating novel therapeutics against acute organophosphorus exposure. Larval zebrafish at six days post-fertilization were exposed to acute concentrations of seven organophosphorus compounds and treated with one of three oximes. Lethality studies indicated similar relative toxicity to that seen in the established rodent model, with chemical warfare agents proving more lethal than organophosphorus pesticides. Additionally, the organophosphorus-specific response for oxime reactivation of acetylcholinesterase was comparable to what has been previously reported. Behavioral studies measuring the visual motor response demonstrated greater efficacy for centrally acting oxime compounds than for those that are contained to the peripheral tissue. Overall, these results support the use of this larval zebrafish model as a high-throughput screening platform for evaluating novel treatments following acute organophosphorus exposure.
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Project description:Acute organophosphorus (OP) intoxication is a worldwide clinical and public health problem. In addition to cholinergic crisis, neurodegeneration and brain damage are hallmarks of the severe form of this toxidrome. Recently, we generated a chemical model of severe acute OP intoxication in zebrafish that is characterized by altered head morphology and brain degeneration. The pathophysiological pathways resulting in brain toxicity in this model are similar to those described in humans. The aim of this study was to assess the predictive power of this zebrafish model by testing the effect of a panel of drugs that provide protection in mammalian models. The selected drugs included "standard therapy" drugs (atropine and pralidoxime), reversible acetylcholinesterase inhibitors (huperzine A, galantamine, physostigmine and pyridostigmine), N-methyl-D-aspartate (NMDA) receptor antagonists (MK-801 and memantine), dual-function NMDA receptor and acetylcholine receptor antagonists (caramiphen and benactyzine) and anti-inflammatory drugs (dexamethasone and ibuprofen). The effects of these drugs on zebrafish survival and the prevalence of abnormal head morphology in the larvae exposed to 4 µM chlorpyrifos oxon [1 × median lethal concentration (LC50)] were determined. Moreover, the neuroprotective effects of pralidoxime, memantine, caramiphen and dexamethasone at the gross morphological level were confirmed by histopathological and transcriptional analyses. Our results demonstrated that the zebrafish model for severe acute OP intoxication has a high predictive value and can be used to identify new compounds that provide neuroprotection against severe acute OP intoxication.
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Project description:Various muscular dystrophies are associated with the defective glycosylation of alpha-dystroglycan and are known to result from mutations in genes encoding glycosyltransferases. Fukutin-related protein (FKRP) was identified as a homolog of fukutin, the defective protein in Fukuyama-type congenital muscular dystrophy (FCMD), that is thought to function as a glycosyltransferase. Mutations in FKRP have been linked to a variety of phenotypes including Walker-Warburg syndrome (WWS), limb girdle muscular dystrophy (LGMD) 2I and congenital muscular dystrophy 1C (MDC1C). Zebrafish are a useful animal model to reveal the mechanism of these diseases caused by mutations in FKRP gene. Downregulating FKRP expression in zebrafish by two different morpholinos resulted in embryos which had developmental defects similar to those observed in human muscular dystrophies associated with mutations in FKRP. The FKRP morphants showed phenotypes involving alterations in somitic structure and muscle fiber organization, as well as defects in developing eye morphology. Additionally, they were found to have a reduction in alpha-dystroglycan glycosylation and a shortened myofiber length. Moreover, co-injection of fish or human FKRP mRNA along with the morpholino restored normal development, alpha-dystroglycan glycosylation and laminin binding activity of alpha-dystroglycan in the morphants. Co-injection of the human FKRP mRNA containing causative mutations found in human patients of WWS, MDC1C and LGMD2I could not restore their phenotypes significantly. Interestingly, these morphant fish having human FKRP mutations showed a wide phenotypic range similar to that seen in humans.
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