Organophosphate Pesticide Poisoning Research Articles

Prevalence and management outcomes of organophosphorus poisoning in emergency departments: systematic review

Organophosphorus poisoning (OPP) is a significant public health concern in various regions, with its prevalence and outcomes influenced by diverse sociodemographic factors. This systematic review aimed to collate and analyze data from multiple studies to provide a comprehensive understanding of the prevalence, risk factors, and management outcomes of OPP in emergency departments. A systematic search was conducted in October 2023, adhering to the PRISMA guidelines, primarily using PubMed. Studies were selected based on specific inclusion and exclusion criteria, with a focus on those that investigated OPP prevalence and management outcomes in emergency departments. Out of 87 initial studies, 9 met the inclusion criteria, encompassing a total of 1,469 participants from countries like Nepal, India, Korea, China, and Turkey. The studies predominantly included the younger to middle-aged demographic, with a significant male representation indicating that young males. Key findings highlighted the role of pesticides, especially organophosphorus compounds, in intentional poisonings, which can be seen more in young and unmarried females. Additionally, the therapeutic efficacy of treatments like plasma exchange has proven to be another promising tool for management. Finally, the importance of specific prognostic indicators such as D-CRP and the sequential organ failure assessment (SOFA) score, when combined with lactate levels (SOFA-Lac), are superior predictors of mortality in patients with acute organophosphate pesticide poisoning. The insights from this review emphasize the need for targeted interventions, both therapeutic and preventive, to address the challenges posed by OPP, especially in high-risk populations.

A study of white blood cell counts as a prognostic marker among patients sustaining organophosphate poisoning presenting to the Emergency Department of a Tertiary Care Hospital

Abstract Background: Organophosphate (OP) pesticide poisoning is a primary concern in rural regions of developing nations, posing a significant clinical challenge. The mortality rate from acute OP compound poisoning surpasses any other harmful substance. In the case of stressful events like injuries and poisoning, the observed leucocytosis and neutrophilia can be attributed to neutrophil margination rather than an increase in bone marrow production. Materials and Methods: Between June 2020 and September 2021, a prospective observational study was conducted at a tertiary care institute in Tamil Nadu. The study included 50 patients admitted to the Institute’s Medical Emergency Ward with suspected Organophosphorus poisoning. These patients were categorized into three grades, mild, moderate, and severe, using Dresbach’s classification based on the severity of their manifestations. Results: Among the 50 cases studied, 29 were females, and 21 were males. The predominant agent is responsible for organophosphate (OP) poisoning was chlorpyrifos, affecting 37 patients. Most cases (78%) presented with mild manifestations, 12% presented with moderate presentations, and 10% had severe manifestations. Most (72%) of patients sought medical attention within 4 h of consumption (n = 36). Conclusion: While insufficient to confirm or rule out severe poisoning, leukocyte counts hold some moderate capacity to differentiate between patients with and without significant poisoning. As a result, these counts could have a meaningful impact on decisions regarding patient disposition.

Investigation of acute organophosphate poisoning in humans based on sociodemographic and role of neurotransmitters with survival study in South India

The aim of this study was to investigate the sociodemographic characteristics of patients based on the poison chosen and different types of organophosphorus compounds. The data were collected to explore the sociodemographic characteristics of organophosphate (OP)-poisoned patients based on the source, site, and route of poisoning, education level, occupational status, and the purpose of poisoning. Furthermore, we estimated the serotonin and dopamine levels in the plasma samples of patients, and survival plots were also described. During the study of OP pesticide poisoning in 116 human subjects and 5 healthy volunteers, we observed, based on the survival plot, that75.9% of the patients were discharged, and the remaining patients died (24.1% of the patients) due to respiratory failure followed by cardiac arrest. Our findings suggest that the serotonin levels significantly (p < 0.01 and p < 0.001) decreased from 12 to 36 h, whereas the dopamine levels slightly increased from 12 to 36 h in the group with OP poisoning compared to the control group. Based on these findings, this study may aid in deciphering the precise mechanism by which pesticides cause behavioural changes that influence serotonin and dopamine levels in OP-poisoned patients. The purpose of this work was to serve as a small reminder of the risk to public health associated with organophosphate pesticides.

Clinical Profile of Adult Organophosphorus Compound Poisoning in a Tertiary Care Hospital

Despite the apparent benefits of organophosphate compounds (OPCs) acute organophosphate (OP) pesticide poisoning is an increasing problem worldwide. In a country like Bangladesh, where agriculture is a major component of the economy, these compounds are readily available to the general public. There is paucity of evidence from Bangladesh showing the pattern of organophosphate poisoning (OPP) in healthcare facilities. The aim of this study is to see the clinical profile of organophosphorus compound poisoning in admitted patients of tertiary care hospital.&#x0D; Methods: This observational cross-sectional study was carried out over all admitted patient with OPC poisoning in the department of Medicine, Cumilla Medical college, Cumilla from July 2019 to January 2020. A total of 100 cases were enrolled in the study. Patients having history of poisoning with OPC compound were stabilized by ABC care system and then assessed according to detailed history, physical examination and paradeniya organophosphorus poisoning (POP) scale.&#x0D; Results: The mean age was found 25.0±8.0 years and male to female ratio was 1:1.2, were mostly married (78.0%) and most of them from poor family (86%). The commonest manner of poisoning was suicidal (90.0%) with oral ingestion. More than eighty (84.0%) percent patients came from rural area. Commonest symptoms were abdominal pain (88.0%), vomiting (63.0%), excessive sweating (58.0%), salivation (35.0%), breathlessness (34.0%) and lacrimation (27.0%). Total hospitalization period was more than one week and less than two weeks in majority of cases (73%) and mortality rate was 2.0%.&#x0D; Conclusion: Due to increasing numbers of organophosphorus poisoning cases in younger age groups strict legislature on the availability of organophosphate compounds, preventive measures and appropriate health education should be introduced to decrease the incidence.&#x0D; Central Medical College Journal Vol 5 No 2 Jul 2021 PP 76-83

A case of severe organophosphate poisoning used a high-dose atropine

In this study, we report the case of a 59-year-old male patient with organophosphate pesticide poisoning. He visited the local emergency medical center after ingesting 250 ml of organophosphate pesticide. The patient's symptoms improved after the initial intravenous infusion of pralidoxime 5 g and atropine 0.5 mg. However, 18 hours after admission, there was a worsening of the symptoms. A high dose of atropine was administered to improve muscarinic symptoms. A total dose of 5091.4 mg of atropine was used for 30 days, and fever and paralytic ileus appeared as side effects of atropine. Anticholinergic symptoms disappeared only after reducing the atropine dose, and the patient was discharged on the 35th day without any neurologic complications.

The relationship of hs-CRP, vitronectin and NT-proBNP serum levels with the extent and severity of cardiac complications in patients with organophosphate pesticide poisoning.

Acute organophosphate poisoning kills tens of thousands of people annually around the world. These substances are widely used as insecticides in homes, industry, and agricultural environments. Due to the ease of access, they can cause accidental or intentional risks of exposure through the skin or respiratory contact. This study aimed to evaluate the serum levels of hs-CRP, Vitronectin, and NT-proBNP and their relationship with the extent and severity of cardiac complications in patients with organophosphate pesticide poisoning. In this descriptive-comparative study, 160 patients were studied with acute organophosphate poisoning. Also, for better comparison, 40 healthy individuals participated in this study. Diagnosis of organophosphate poisoning was based on clinical findings of serum butyrylcholinesterase levels. The hs-CRP measurement was performed by an autoanalyzer (Abbott, model Alcyon 300, USA) with the ELISA hs-CRP kit (The apDia Company, Belgium). Vitronectin (VN) measurements were performed by ELISA method and Glory science human VN kit with Catalog No: 11668. NT-ProBNP serum levels were analyzed by ProBNP assay kit (Roche, Germany) by ECLIA method using Elecsys 2010 Analyzer. The most important variables studied in this study were the electrical activity and conduction system of the heart, PR distance, QTC interval, and T-wave changes. In this study, most of the patients were women and girls (60.78%). The highest percentage of organophosphate poisoning was in the age group of 15-24 years (37.25%). In most cases (78.43%), poisoning was intentional or suicidal. Evaluation of electrophysiological abnormalities of the heart showed that 89 patients (55.62%) had long QTC interval (>450 msec), 43 cases (26.87%) had possible long QTC (431-450 msec), and 28 cases (17.5%) had normal QTC (<430 msec). Only 9.37% of cases (n = 15) showed an increase in P-R distance, which is characteristic of the first-degree ventricular atrial block. Sinus bradycardia occurred in 57 cases (35.62%) and sinus tachycardia in 43 cases (26.87%); in 60 cases (37.5%), the pulse rate was normal. Smooth T-wave changes were observed in 9.8% of patients and reverse T-wave was observed in 17.6%. A long T-wave was not reported in any case. In only two cases (1.25%) was grade 1 ventricular atrial block and grade 2 and 3 blocks were not observed. In general, there was a significant difference in the hs-CRP, vitronectin, and NT-proBNP serum levels between the patient and control groups in all studied variables. These parameters were also related to the extent and severity of the disease.

Changes of attention-related brain activity over 6 months after acute organophosphate pesticide poisoning: a prospective follow-up study

Context Ingestion of organophosphate (OP) pesticides is a common method of self-harm in developing countries. Apart from acute cholinergic effects, limited evidence implicates OP poisoning in long-term neurocognitive deficits. However, prospective neurophysiological evidence of long-term deficits is scarce in humans. We aimed to determine long-term cognitive changes of acute OP pesticide self-poisoning in a prospective follow-up study, using event-related potentials (ERPs), an electroencephalographic index of cognitive functioning. Methods We recruited 203 patients (147 men) hospitalised with OP pesticide ingestion (OP group; all had significant erythrocyte cholinesterase inhibition) and 50 patients (23 men) with paracetamol overdose (control group) as a means of self-harm. We recorded their ERPs and behavioural performance in a selective attention task at three post-exposure time points: on discharge from hospital (around 14 days post-ingestion), 6 weeks and 6 months post-ingestion. We compared the reaction time and ERP components of the two groups at each time point, adjusting for sex, age, education and comorbid depression in multiple regression models. Results OP group had significantly slower reaction times than the control group on discharge and at 6 weeks, but not at 6 months. On discharge, the OP group also showed significantly prolonged latency of the parietal P3b component, signifying delayed attentional processing. P3b amplitudes were also significantly smaller in the OP group on discharge and at 6 months. Within the OP group, greater clinical severity of poisoning was associated with smaller P3b amplitudes. Early pre-attentive cortical processing (as indexed by N1 ERP component) showed no significant intergroup differences. Conclusions Acute OP pesticide poisoning was associated with impaired behavioural and neurophysiological indices of selective attention. These deficits outlast the cholinergic phase of intoxication. The neurobehavioral impairment disappears over months, but neurophysiological deficits seem to last even after 6 months. This impairment could potentially compromise the performance and safety of patients for months following clinical recovery.

Serum High-sensitivity C-reactive Protein Level and Corrected QT Interval in Agricultural Workers in Myanmar Exposed to Chronic Occupational Organophosphate Pesticides.

Although acute organophosphate (OP) pesticide poisoning is associated with the risk cardiovascular diseases (CVD), the association between chronic occupational OP pesticide exposure and CVD risk is limited. We investigated serum high-sensitivity C-reactive protein (hs-CRP) levels and QTc intervals in 45 agricultural workers who were chronically exposed to OP pesticides and 45 non-exposed subjects. Serum hs-CRP level was determined by enzyme-linked immunosorbent assay (ELISA) and a level >1.0 mg/l was regarded as CVD risk. The QT interval was measured by routine 12-lead Electrocardiogram (ECG) with Lead II rhythm, and QTc was calculated. The median value of the serum hs-CRP level [1.20 (0.67-2.38) vs 0.74 (0.41-1.17) mg/l, P <0.05] and the mean QTc interval (422.71 ± 23.73 vs 396.27 ± 18.48 ms, P <0.0001) was significantly higher in the OP pesticide exposed subjects. Pesticide exposure was significantly associated with CVD risk (Chi-Square χ2 = 6.480, P = 0.011) and QTc interval prolongation (χ2 = 13.846, P <0.001). A higher risk of CVD (odds ratio = 3.030; 95% confidence interval = 1.276 - 7.197) was observed in the OP pesticide exposed subjects. This study suggested that OP pesticide exposure should be considered as one of the significant risk factors for CVDs.

Organophosphate poisoning\xa0of Hyacinth Macaws in\xa0the Southern Pantanal, Brazil

The populations of hyacinth macaws (Anodorhynchus hyacinthinus), an emblematic species, have suffered declines due to many environmental factors. The Hyacinth Macaw Institute’s actions are showing positive outcomes for the conservation of A. hyacinthinus. However, environmental issues, such as fires and deforestation due to inefficient and unsustainable cattle ranching practices, are a threat to the biodiversity. Another major threat is the reckless use of pesticides. The objective of this manuscript is to describe the findings, in the Pantanal, of three dead hyacinth macaws and to investigate their cause of death and conservation implications. A necropsy was conducted on two individuals and biological samples were collected and sent to conduct toxicological exams to test for organophosphates, organochlorines, and carbomates. Compatible with other findings, results showed a highly dangerous level of organophosphate, 158.44 ppb. We describe for the first time, a rare, isolated but unusual mortality event associated with organophosphate pesticide poisoning of hyacinth macaws. Mortality reports for bees and other bird species on how the improper use of pesticides can potentially cause the contamination of food and water resources are discussed. These factors are antagonistic to long-term efforts to preserve wildlife and carry out other conservation efforts in Brazil’s southern Pantanal.

Subacute and chronic neuropsychological sequalae of acute organophosphate pesticide self-poisoning: a prospective cohort study from Sri Lanka

Context 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. Methods 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. Results 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. Discussion 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.

The antidotes atropine and pralidoxime distinctively recover cardiorespiratory components impaired by acute poisoning with chlorpyrifos in rats

In a previous work we showed that the organophosphate pesticide (OP) chlorpyrifos (CPF) reduces the protective chemoreflex and baroreflex responses in rats. However, whether the antidotes atropine (ATR) and pralidoxime (2-PAM) are capable of restoring these reflex functions remains unexplored. Rats were poisoned with CPF (30 mg.kg−1, i.p.) and one hour after the intoxication, ATR (10 mg.kg−1, i.p.) and 2-PAM (40 mg.kg−1, i.p.) were administrated separately or in combination. Cardiorespiratory parameters were recorded in awake rats 24 h after CPF. Systolic blood pressure (SBP) and heart rate (HR) variability and spontaneous baroreflex sensitivity (sBRS) were derived from undisturbed recordings (30 min), while chemoreflex was assessed through potassium cyanide (KCN) i.v. injections (10, 20, 40, 80 μg/rat). CPF poisoning increased SBP variability and low frequency/high frequency (LF/HF) ratio of the HR variability spectrum, indicating autonomic imbalance with increased cardiac sympathetic tone. sBRS was not changed. Treatment with 2-PAM restored SBP variability, whilst both antidotes increased LF/HF ratio. CPF poisoning reduced the hypertensive, bradycardic and tachypneic chemoreflex responses. Chemoreflex-induced hypertensive response was restored by 2-PAM treatment, while ATR recovered the bradycardic response. Both antidotes restored the chemoreflex tachypneic response. Our data show distinct effects of ATR and 2-PAM on cardiorespiratory parameters affected by OP poisoning. While 2-PAM rescued the chemoreflex hypertensive response, ATR reversed chemoreflex bradycardic dysfunction. Although 2-PAM clinical use is questioned in some countries, our data indicate that summation of effects of both antidotes appears beneficial on the cardiorespiratory system and peripheral chemoreflex function.

Recovery Pattern and Barriers to Mobilization during Acute Rehabilitation Phase in Organophosphate Poisoning Patients

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.

Effect of structure and function of paraoxonase-1 (PON-1) on organophosphate pesticides metabolism

Paraoxonase-1 (PON1) is an important enzyme in various pathologies such as pesticide poisoning, diabetes, atherosclerosis, neuronal disorders, and cancer, due to its multifunctional activity since it acts on different metabolites. However, one of its main functions is the hydrolysis of organophosphate (OP) compounds from pesticides that cause fatal poisoning at the level of the central nervous system (CNS). The objective of this review was to investigate whether the structure, genetics, and function of PON1 affect the metabolism of organophosphate pesticides or other abnormalities. Information was selected from articles in the database PubMed–NCBI (https://www.ncbi.nlm.nih.gov/ pubmed/) with a publication date between 2011 and 2019. The enzymatic activity of PON1 can be modified depending on its chemical structure since there are different genetic polymorphisms that change PONI morphologies or the levels of expression in the bloodstream. This leads to differences in susceptibilities to organophosphate pesticide poisoning. The results of this review reveal that phenotypic variants of PON1 have differences in affinities for OP substrates.

Epidemiology, Clinical Profile and Outcome of Organophosphorous Poisoning in North-Western Rajasthan

Introduction: Organophosphate pesticide poisoning (OPP) is continued to be a major global health problem especially in developing countries. This study was planned to evaluate epidemiological, clinical profile and outcome of OPP admitted in tertiary care hospital North West zone of Rajasthan, India. Materials and Methods: A total of 96 patients suffering from OP poisoning were evaluated for epidemiology, clinical profile and outcome. Diagnosis of OP poisoning was done by history, clinical examination and serum butyrylcholinesterase level assay. All patients were evaluated as per Performa and follow up till discharge. Severity of OPP was assessed by POP score and GCS score. Results: Out of 96 cases 76 were males 20 females, age ranging 14-55 years, mean age 26 ± 8, 85.4% were below age 30 years. Most of the patients were farmer, illiterate and belonging to rural area. Most common cause of poisoning was suicidal intention and most common route of poisoning was ingestion. Chlorpyrifos was the most common salt used followed by Monocrotophos, Phorate 10%, Dimethoate 30% and Quinalphos 25%. 8.3% had mild poisoning, 65.6% had moderately severe while 26% had severe OPP as evaluated by POP score. 19 patients required ventilator support, 10 cases developed ARDS and 6 had IMS. Mortality rate was 9.4%. Monocrotophos poison, amount of poison, long duration of poisoning, Hypokalemia, high bicarbonate level, high POP score and low GCS score were associated with poor outcome Conclusions: Thorough clinical evaluation is important for diagnosis and assessment of severity of OPP. POP score and GCS score help in assessing severity of OPP and its outcome. OPP is associated with life-threatening complications. Early detection and immediate treatment in intensive care units can increase the chances of survival rate in such cases. Banning of the most toxic pesticides may reduce the number of significant unintentional and intentional poisoning episodes.

The Experimental Oxime K027-A Promising Protector From Organophosphate Pesticide Poisoning. A Review Comparing K027, K048, Pralidoxime, and Obidoxime.

Poisoning with organophosphorus compounds (OPCs) is a major problem worldwide. Standard therapy with atropine and established oxime-type enzyme reactivators (pralidoxime, obidoxime) is unsatisfactory. In search of more efficacious broad-spectrum oximes, new bispyridinium (K-) oximes have been synthesized, with K027 being among the most promising. This review summarizes pharmacokinetic characteristics of K027, its toxicity and in vivo efficacy to protect from OPC toxicity and compares this oxime with another experimental bisquaternary asymmetric pyridinium aldoxime (K048) and two established oximes (pralidoxime, obidoxime). After intramuscular (i.m.) injection, K027 reaches maximum plasma concentration within ∼30 min; only ∼2% enter the brain. Its intrinsic cholinesterase inhibitory activity is low, making it relatively non-toxic. In vitro reactivation potency is high for ethyl-paraoxon-, methyl-paraoxon-, dichlorvos-, diisopropylfluorophosphate (DFP)- and tabun-inhibited cholinesterase. When administered in vivo after exposure to the same OPCs, K027 is comparable or more efficacious than pralidoxime and obidoxime. When given as a pretreatment before exposure to ethyl-paraoxon, methyl-paraoxon, DFP, or azinphos-methyl, it is superior to the Food and Drug Administration-approved compound pyridostigmine and comparable to physostigmine, which because of its entry into the brain may cause unwanted behavioral effects. Because of its low toxicity, K027 can be given in high dosages, making it a very efficacious oxime not only for postexposure treatment but also for prophylactic administration, especially when brain penetration is undesirable.

Clinical Evaluation of Significance of 25(Oh)D Levels in Patients with Organophosphorus Poisoning

Introduction: Organophosphate (OP) pesticide poisoning is a major challenging public-health problem in developing countries. Vitamin D deficiency is pandemic, yet it is the most under-diagnosed and under-treated nutritional deficiency in the world and it has been reported to be clinically correlated with psychiatric illness and manifestation of severe systemic inflammatory response syndrome like ARDS. Thus vitamin D deficiency may affect clinical course and outcome in cases of OPP. Aim: To evaluate status of 25 hydroxyvitamin D (25(OH)D) level in OP poisoning and its correlation with outcome of such patients. Materials and Methods: Serum 25(OH)D levels were measured at the time of hospitalization by electro-chemiluminescent Assay in 96 patients (76 male and 20 female) suffering from OP poisoning. Diagnosis of OP poisoning was made by history of poisoning including container of the poison brought by patient’s relative, clinical examination and measurement of serum butyrylcholinesterase activity. All patients were evaluated as per Performa and follow up till discharge. Results: Mean level of 25(OH)D in our cases was 24.57±9.91ng/ml and 66.7% had low levels of 25(OH)D. Our study shows linear relationship between 25(OH)D level and duration of hospital stay. All cases of OP poisoning who developed severe manifestations like ARDS, Intermediate syndrome (IMS) were having significant 25(OH)D deficiency. Our study also shows lower levels of 25(OH)D were associated with poor outcome (11.27±3.21vs 27.02±8.54, p&lt;0.001). Conclusion: Vitamin D deficiency in OP poisoning is associated with longer hospital stay, more requirement of ventilator support and high prevalence of complication (ARDS and IMS) and poor outcome. Awareness of 25(OH)D level in patients with OP poisoning may be important to improve outcome.

Xuebijing injection induces anti-inflammatory-like effects and downregulates the expression of TLR4 and NF-κB in lung injury caused by dichlorvos poisoning

BackgroundThe mechanism in lung injury caused by acute organophosphate pesticide poisoning (AOPP) and an effective treatment remains unclear. We aim to clarify how the inflammatory lung injury caused by AOPP might be modulated by Xuebijing (XBJ) injection. MethodsAOPP-induced lung injury model was induced by dichlorvos (DDVP) subcutaneous administration in rats and XBJ injection was administered by intraperitoneal injection after DDVP challenge. The effects of XBJ injection were assessed by lung histopathological analysis and lung injury scores, lung wet-to-dry weight ratios (WDR) and oxygenation, differential immune cell count in bronchoalveolar lavage fluid (BALF), IL-6 and TNF-α levels in blood, the levels of TLR4 and NF-κB proteins in lung tissue and blood acetylcholinesterase (AChE) activity. ResultsDDVP administration resulted in damage of lung histopathology and lower PaO2/FiO2 ratios (P < 0.05), which were notably attenuated by XBJ injection (P < 0.05). Total cell, macrophage, and neutrophils count in BALF and TNF-α and IL-6 levels in blood were significantly increased after DDVP exposure (P < 0.05), which were notably ameliorated by XBJ injection (P < 0.05). TLR4 and NF-κB protein in lung tissue expression after DDVP challenge were markedly increased (P < 0.05), and they were substantially downregulated by XBJ injection (P < 0.05). In addition, blood AChE activity was significantly decreased by DDVP administration (P < 0.05), however, there was no significant improvement after XBJ injection. ConclusionXBJ injection prevents DDVP poisoning induced lung injury by attenuating the inflammatory response. The protective effect appears to be mediated through downregulation of the TLR4 and NF-κB expression.

Behavioral, Pharmacokinetic, and Cardiovascular Evaluation of Candidate Oximes in African Green Monkeys.

Oxime reactivators are critical antidotes after organophosphate pesticide or nerve agent poisoning, directly restoring the function of inhibited acetylcholinesterase. In the continuing search for more broad-spectrum acetylcholinesterase reactivators, this study evaluated one of the leading next-generation oxime reactivators: methoxime, (1,1'-trimethylene bis[4-(hydroxyimino)methyl]pyridinium dichloride (MMB-4). The pharmacokinetics of both salts of MMB-4 (dichloride [2Cl] and dimethanesulphonate [DMS]) were characterized across a range of relevant doses (19, 58, and 116 µmol/kg, intramuscular) in a nonhuman primate model (male African green monkeys), and only subtle differences were observed between the salts. Additionally, the behavioral and cardiovascular safety of these MMB-4 salts was compared directly to other available oximes (HI-6 2Cl, HI-6 DMS, and pyridine-2-aldoxime chloride (2-PAM Cl)) at comparable projected doses. Automated operant behavioral tests were used to examine attention, motivation, visual discrimination, concept execution, and fine motor coordination after high doses of all oxime salts, and of all oximes studied, only the highest dose of 2-PAM Cl (447 µmol/kg) disrupted behavioral performance. Likewise, the effects of a range of doses of MMB-4 2Cl or DMS, HI-6 2Cl or DMS, or 2-PAM Cl on cardiovascular parameters were measured in African green monkeys implanted with telemetry devices. Only a small transient decrease in pulse pressure was observed following administration of the highest dose of MMB-4 DMS (116 µmol/kg). Thus, MMB-4 salts, up to the 9× equivalent of a projected autoinjector dose in humans, did not produce behavioral or cardiovascular toxicity in African green monkeys in the current study, and the pharmacokinetic parameters were orderly and predictable.

Post-exposure treatment with the oxime RS194B rapidly reactivates and reverses advanced symptoms of lethal inhaled paraoxon in macaques

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<1hr and BChE (40% in 8h). These findings will be used to develop a macaque model with RS194B as a post-exposure treatment for insecticide poisoning and generate efficacy data for approval under the FDA Animal rule.

Cognitive toxicity: from pesticides to pharmaceuticals

Impairment of cognitive functions following neurotoxic exposure is collectively termed cognitive toxicity. This oration is based on a series of studies carried out over last 12 years on cognitive toxicity of two groups of substances, viz. organophosphate (OP) pesticides and sedative psychotropic drugs. OP pesticide poisoning is a major clinical and public health problem in South Asia. OPs act as cholinesterase inhibitors, and bring about acute neurological deficits following exposure. Using neurophysiological and neuropsychological techniques, we assess long-term neurocognitive deficits of OPs, a less known yet important adverse effect of OP exposure. The findings hitherto indicate both acute large-dose poisoning and subclinical occupational exposure are associated with long-term cognitive impairment. In the same way the pesticide use and misuse are common in agricultural communities, use and misuse of sedative psychotropic medications are common in urbanised societies. Sedative drugs, even in therapeutic doses impair driving and underlying cognitive functions, and increase the risk of traffic accidents. When taken in overdose, these drugs have cognitively impairing effects that last beyond clinical recovery from acute poisoning. These patients are more prone to traffic crashes at least up to 4 weeks following exposure, and the cognitive recovery over this period mirrors the crash risk at different post-overdose time points. The above findings raise a number of clinical and medico legal implications in post-discharge management of patients with sedative drug overdose. As the agricultural communities transform into urban industrialised societies in Sri Lanka, the pattern of poisoning changes from agrochemicals into pharmaceuticals, particularly psychotropic dugs. The two lines of research discussed above highlight how this changing social fabric poses new challenges for the neurophysiologists, neurologists and psychiatrists who study cognition and apply their findings in clinical settings. Our latest work in generating age-, sex- and education-adjusted norms for cognitive tests for Sri Lankans, would set the foundation in interpreting the cognitive test results of clinical populations.