Treatment Of Organophosphorus Poisoning Research Articles

Oxime Derivatives: A Valid Pharmacophore in Medicinal Chemistry

AbstractOximes, belonging to imines with the general formula of RR'C=NOH, are produced by the nucleophilic addition reaction between hydroxylamine with ketones or aldehydes, yielding corresponding aldoxime and ketoxime. The presence of hydrogen bond acceptor and donor is the classical feature of oxime‐containing structural framework. This review presents a summary of the role of oximes and its structure activity relationships including antimicrobial, anticancer, anti‐inflammatory, antihyperglycemic, insecticidal agents, along with their involvement in the treatment of organophosphorus poisoning. The review also focused on the pharmacological profile of lead molecules of several classes of oxime‐containing compounds.

Efficacy and Safety of Plasma Exchange Combined with Hemoperfusion in the Treatment of Organophosphorus Poisoning: A Meta-Analysis

Introduction: The aim of the study was to systematically evaluate the efficacy and safety of plasma exchange combined with hemoperfusion in the treatment of organophosphorus poisoning. Methods: PubMed, Embase, the Cochrane Library, China National Knowledge Internet, Wanfang database, and Weipu database were searched for articles about this subject. Literature screening and selection were conducted in strict accordance with the inclusion and exclusion criteria. Results: 14 randomized controlled trials with 1,034 participants were included in this meta-analysis study, including 518 cases in plasma exchange combined with hemoperfusion group (the combination treatment group) and 516 cases in hemoperfusion group (the control group). Compared with the control group, the combination treatment group was associated with a higher effective rate (relative risk [RR] = 1.20, 95% confidence interval [CI] [1.11, 1.30], p < 0.00001) and lower fatality rate (RR = 0.28, 95% CI [0.15, 0.52], p< 0.0001); reduced TNF-α (standardized mean difference [SMD] = −1.95, 95% CI [−2.42, −1.48], p < 0.00001), IL-6 (SMD = −1.94, 95% CI [−3.08, −0.80], p = 0.0009), and C-reactive protein (CRP) (SMD = −1.94, 95% CI [−2.86, −1.03], p < 0.0001); shorten coma time (SMD = −1.99, 95% CI [−2.75, −1.24], p < 0.00001), recovery time of cholinesterase activity (SMD = −1.71, 95% CI [−1.90, −1.53], p < 0.00001), and hospital stay (SMD = −1.29, 95% CI [−1.59, −0.98], p < 0.00001). The incidence of complications in the combination treatment group such as liver and kidney damage (RR = 0.30, 95% CI [0.18, 0.50], p < 0.00001), pulmonary infection (RR = 0.29, 95% CI [0.18, 0.47], p < 0.00001), and intermediate syndrome (RR = 0.32, 95% CI [0.21, 0.49], p < 0.00001) was lower than that in the control group. Conclusions: The current evidence suggests that the combination of plasma exchange with hemoperfusion therapy can reduce the mortality of patients with organophosphorus poisoning, shorten the recovery time of cholinesterase activity and the time of coma, reduce the average length of hospital stay, and reduce the levels of IL-6, TNF-α, and CRP, but high-quality randomized double-blind controlled trials are still required to confirm the current findings in the future.

Severe Accidental Organophosphorus Poisoning in Two Children

Background: Organophosphorus (OP) compounds have intense anticholinesterase activity and are commonly used as insecticides and pesticides. OP poisoning is a global health problem and poses a threat to human health. Case Report: Here we report two sisters, aged 3 and 4 years, who had inadvertently eaten agricultural pesticides. These patients had a decreased level of consciousness, nausea, and vomiting. We do not have pralidoxime in this center and the adjacent center, so we used atropine as the primary drug in treating these patients. However, after 4 days, the 3-year-old patient felt a weakness in upper and lower limb movements. Conclusion: In the treatment of OP poisoning, it is necessary to pay special attention to delayed complications such as intermediate syndrome.

Investigation of the effects of dichlorvos poisoning on AMPK signaling pathway in chicken brain tissues

Dichlorvos is a common crop insecticide widely used by people which causes extensive and serious environmental pollution. However, it has been shown that organophosphorus poisoning causes energy metabolism and neural disorders. The overall purpose of this study was to investigate the damage to brain tissue and the changes in AMPK signaling pathway-related gene expression after dichlorvos poisoning in chickens. White-feathered broiler chickens, as the research subjects of this experiment, were divided into three groups: control group, low-dose group (77.5% dichlorvos at 1.13 mg/kg dose) and high-dose group (77.5% dichlorvos at 10.2 mg/kg dose). Clinical symptoms were observed after modeling, and an integrative analysis was conducted using HE staining microscopy, immune-histochemical microscopy, electron microscopy and PCR arrays. The results showed that the high-dose group had more obvious dyspnea, salivation, convulsion and other neurological phenomena. Pathological sections showed that nuclear disintegration of neurons was most obvious in the low-dose group, and apoptosis of brain cells was most obvious in the high-dose group, and the mitochondrial structure was destroyed in the two poisoned group, i.e. low-dose group and high-dose group. PCR arrays showed that AMPK signaling pathway was inhibited and the expressions of genes involved in energy metabolism (ACACA and PRKAA1) were significantly changed. Furthermore, genes associated with protein synthesis (EIF4EBP1) were significantly upregulated. FASN and HMGCR expressions were significantly increased. There were significant changes in the expressions of cell cycle-related genes (STK11, TP53 and FOXO3). Organophosphate poisoning can cause a lot of nuclear disintegration of brain neurons, increases cell apoptosis, disrupts the energy metabolism of mitochondrial structure, and inhibits the AMPK signaling pathway. These results provide a certain idea and basis for studying the mechanism of AMPK signaling after organophosphorus poisoning and provide a research basis for the prevention and treatment of organophosphorus poisoning.

Therapeutic Effect of Adding Magnesium Sulfate in Treatment of Organophosphorus Poisoning.

BACKGROUND:In recent years, the prevalence of poisoning has increased dramatically due to population growth and access to drugs and toxins. Today poisoning is one of the important reasons for visiting hospitals.AIM:The present study aimed to investigate the effect of magnesium sulfate on organophosphorous toxicity.METHODS:Patients who had inclusion criteria in the study were randomly assigned to one of two groups (control group or case group) by an emergency medicine specialist. Patients’ data including age, sex, ECG, vital signs, arterial oxygen saturation were recorded for patients. Patients in the case group (40 subjects) received 2 mg magnesium sulfate 50%, while the control group (40 subjects) received 100 cc normal saline (as placebo) as an intravenous infusionRESULTS:The distribution of gender in the two groups of patients was the same. Also, the mean age, Stature and weight of patients were similar in both groups. In the group receiving magnesium sulfate, diastolic blood pressure was lower when compared with another group, at 0 and 2 hours after intervention. Moreover, the mean of systolic blood pressure in both groups was determined to be the same at all hours. Furthermore, the heart rate in the group receiving sulfate was lower as compared to the control group for 8 hours, 16 and 24 hours after intervention.CONCLUSION:The use of magnesium sulfate in organophosphate poisoning reduces therapeutic costs an average hospital length of stay and mortality compared to those who did not receive magnesium sulfate.

Pleiotropic effects and pharmacological properties of penehyclidine hydrochloride.

BackgroundPenehyclidine hydrochloride (PHC) is an anticholinergic drug manufactured in China. It is used widely in clinics as a reversal agent in cases of organic phosphorus poisoning and as a preanesthetic medication. Compared with other anticholinergic agents, PHC confers substantial advantages. Here, in this review, we focus on its important clinical effects for organic phosphorus poisoning, preanesthetic medication, and the protective effects on certain visceral organs.Materials and methodsOur bibliographic sources include the PubMed and China National Knowledge Infrastructure (CNKI) databases, updated in March 2018. To assess the data in detail, we used the search terms “penehyclidine hydrochloride,” “preanesthetic medication,” and “organic phosphorus.” Papers were restricted to those published in the English and Chinese languages, and to “paper” and “review” as the document type.ResultsPHC can effectively antagonize the symptoms of central and peripheral poisoning caused by organophosphorus poisoning. As a preanesthetic medication, it can not only effectively reduce mucus secretion and vascular infiltration but can also relax airway smooth muscles, dilate bronchioles in pulmonary conditions such as bronchiectasis, and increase pulmonary dynamic compliance. It can also prevent reflexive actions of the vagus nerve caused by excessive acetylcholine release such as abnormal airway contraction. Furthermore, it can strengthen sedation, bidirectionally regulate heart rate, and effectively inhibit respiratory secretions. In recent studies, PHC was shown to also have protective effects on various organs, such as the heart, lungs, brain, kidneys, intestines, and liver.ConclusionPHC has beneficial pharmacological properties used in the treatment of organophosphorus poisoning and as a preanesthetic medication for its few side effects. It also has protective effects on multiple organs, suggesting that PHC has extensive clinical application value which is worth further research. This review should be of help to those intending to research these topics further.

Sodium Bicarbonate and N-Acetyl Cysteine in Treatment of Organophosphorus Poisoning Cases: A Randomized Controlled Clinical Trial

Introduction: Organophosphorus poisoning (OPP) is an important health problem in many parts of the world particularly in developing countries. However, the treatment did not change since many years, despite the increasing complications and case fatalities of the exposure. From the clinical experience, some pharmacologic agents had proved useful in improving the outcome and decreasing the complications of this exposure. Aim: This study was conducted to test the efficacy of N-acetyl cysteine; the famous antioxidant, and of blood alkalization by sodium bicarbonate in improving the outcome of OPP cases. Methods: Seventy patients of OPP were given N-acetylcysteine (NAC) and NaHCO3 together with classic treatment of OPP. Serum Malondialdehyde (MDA), Glutathione peroxidase (GPx), pH, plasma butyrylcholinesterase were measured and compared of a matched group of patients, who received classic treatment only, on presentation and after 24 hours of classic treatment only. Results: There were no significant differences between the two groups of study in initial levels of MDA, GPx, pH, plasma butyrylcholinesterase that turned highly significant after 24 h of treatment and observation. There was a highly significant difference (P=0.001) in length of hospital stay (LOS) between the two groups. No adverse effects for the supplements were observed. Conclusion: NAC and sodium bicarbonate are affordable agents and are very helpful in improving the outcome in OPP and decreasing LOS.

Novel approaches in prophylaxis/pretreatment and treatment of organophosphorus poisoning

GRAPHICAL ABSTRACT

Respiratory complications of organophosphorus nerve agent and insecticide poisoning. Implications for respiratory and critical care.

Organophosphorus (OP) compound poisoning is a major global public health problem. Acute OP insecticide self-poisoning kills over 200,000 people every year, the majority from self-harm in rural Asia. Highly toxic OP nerve agents (e.g., sarin) are a significant current terrorist threat, as shown by attacks in Damascus during 2013. These anticholinesterase compounds are classically considered to cause an acute cholinergic syndrome with decreased consciousness, respiratory failure, and, in the case of insecticides, a delayed intermediate syndrome that requires prolonged ventilation. Acute respiratory failure, by central and peripheral mechanisms, is the primary cause of death in most cases. However, preclinical and clinical research over the last two decades has indicated a more complex picture of respiratory complications after OP insecticide poisoning, including onset of delayed neuromuscular junction dysfunction during the cholinergic syndrome, aspiration causing pneumonia and acute respiratory distress syndrome, and the involvement of solvents in OP toxicity. The treatment of OP poisoning has not changed over the last 50 years. However, a better understanding of the multiple respiratory complications of OP poisoning offers additional therapeutic opportunities.

Open-label randomized controlled study comparing continuous infusion versus intermittent bolus dose of atropine with or without pralidoxime in the treatment of organophosphorus poisoning in a teaching hospital

Background: Severe organophosphorus (OPC) poisoning is one of the serious problems in developing world, taking great toll on life. Though Atropine is used as an antidote, there are no clear guidelines. We conducted an open label randomized controlled clinical study to compare the efficacy of continuous infusion of atropine to that of intermittent bolus dose in the treatment of OPC poisoning. Methods and Material: Patients aged above 12 years with clinical evidence of OPC poisoning were studied. Both the groups received initial bolus of 1to3 mg of atropine. Then, Group-A received intermittent bolus and group-B, continuous infusion, until adequately atropinized. Results: Out of 743 patients (group-A: 356 and group-B: 387), females were 54%. 83% had suicidal intent. Mean atropine dose was 126.6mg in group-A and 78mg in group-B (P < 0.0001) . 21.07% (group-A) and 12.92% (group-B) developed intermediate syndrome (P = 0.003) , mortality was 27.25%(97) in group-A v/s 13%(50) in group-B (P < 0.0001) . Ventilator support needed in 36%(group-A) against 17% in group-B (P < 0.0001) and duration of ventilation was 1.5 days lesser in group B (P < 0.0001) . 23.03% had atropine toxicity in group-A as compared to 8% in group-B (P < 0.0001) . Hospital stay was 1.67 (P < 0.0001) days shorter for group-B. Conclusion: Continuous atropine infusion should be standard of care in treating OPC poisoning.

Qualitative GC-MS Assessment of TCP and Tamorf Elimination in Rats

Nerve agents are highly toxic organophosphorus (OP) compounds. They inhibit acetylcholinesterase (AChE), an enzyme that hydrolyses acetycholine (ACh) in the nervous system. Pathophysiological changes caused by OP poisonings are primarily the consequence of surplus ACh on cholinergic receptors and in the central nervous system. Standard treatment of OP poisoning includes combined administration of carbamates, atropine, oximes and anticonvulsants. In order to improve therapy, new compounds have been synthesised and tested. Tenocyclidine (TCP) and its adamantane derivative 1-[2-(2-thienyl)-2-adamantyl] morpholine (TAMORF) have shown interesting properties against soman poisoning. In this study, we developed a qualitative GC-MS method to measure elimination of TCP and TAMORF through rat urine in order to learn more about the mechanisms through which TCP protects an organism from OP poisoning and to determine the duration of this protective effect. GC-MS showed that six hours after treatment with TCP, rat urine contained only its metabolite 1-thienylcyclohexene, while urine of rats treated with TAMORF contained both TAMORF and its metabolites.

Intravenous lipid emulsions combine extracorporeal blood purification: A novel therapeutic strategy for severe organophosphate poisoning

Organophosphorus (OP) pesticide self-poisoning is a major clinical problem in rural Asia and it results in the death of 200,000 people every year. At present, it is lack of effective methods to treat severe organophosphate poisoning. The high mortality rate lies on the amount of toxic absorption. Intravenous lipid emulsions can be used as an antidote in fat-soluble drug poisoning. The detoxification mechanism of intravenous lipid emulsions is “lipid sink”, which lipid emulsions can dissolve the fat-soluble drugs and separate poison away from the sites of toxicity. Most of organophosphorus pesticides are highly fat-soluble. So, intravenous lipid emulsions have the potentially clinical applications in treatment of OP poisoning. Extracorporeal blood purification especially charcoal hemoperfusion is an efficient way to eliminate the poison contents from the blood. We hypothesize that the combination of intravenous lipid emulsions and charcoal hemoperfusion can be used to cure severe organophosphate poisoning. This novel protocol of therapy comprises two steps: one is obtained intravenous access to infuse lipid emulsions as soon as possible; another is that charcoal hemoperfusion will be used to clear the OP substances before the distribution of OP compounds in tissue is not complete. The advantages of this strategy lie in three points. Firstly, it will alleviate the toxic effect of OP pesticide in the patients by isolation and removal the toxic contents. Secondly, the dosage of antidotes can be reduced and its side-effects will be eased. Thirdly, a large bolus of fatty acids provide energy substrate for the patients who are nil by mouth. We consider that it would become a feasible, safe and efficient detoxification intervention in the alleviation of severe organophosphate poisoning, which would also improve the outcome of the patients.

Dose-response effects of atropine and HI-6 treatment of organophosphorus poisoning in guinea pigs.

HI-6 (1-2-hydroxyiminomethyl-1-pyridino-3-(4-carbamoyl-1-pyridino -2- oxapropane dichloride) has been evaluated as an oxime alternative to pralidoxime, and toxogonin in the treatment of organophosphorus (OP) poisoning. The dose response effects of atropine (ATR) and HI-6 were investigated to more fully explore the interaction of these compounds in the treatment of OP poisoning. ATR, HI-6 and various combinations of the two drugs were evaluated against lethal poisoning by soman (GD) and tabun (GA) in guinea pigs. The effect of adjunctive diazepam treatment on the efficacy of atropine and HI-6 against soman was also investigated. Animals of either sex were challenged s.c. with OP and treated i.m. 1 min later with ATR and/or HI-6. When used, diazepam was injected immediately after ATR+HI6. LD50s of each treatment were calculated from probit models based on 24-hour survival against 5 levels of nerve agent and 6 animals per challenge level. A protective index (PI) was calculated by dividing the nerve agent LD50 in the presence of treatment by the LD50 in the absence of treatment. Treatment with HI6 alone had little effect on the toxicity of either OP. Treatment with ATR alone was more effective than HI-6 alone and was significantly more effective against soman than against tabun. When used in combination atropine and HI-6 had a strong synergistic effect against both agents. The dose of atropine used with HI-6 was critical in determining the efficacy of HI-6 against either agent. The slopes of the dose-lethality curves were minimally affected by the dose of ATR or HI-6. Adjunctive treatment with diazepam enhanced the efficacy of HI-6 and atropine against soman. It is concluded that 1) ATR has a large effect on the efficacy of HI-6 against OP poisoning, 2) the dose of ATR must be carefully selected in studies investigating the efficacy of HI-6 against OP poisoning, 3) the effective dose of ATR in the guinea pig is approximately 16 mg/kg, and 4) diazepam is a useful adjunct to atropine and HI-6.

Cholinolytics in the treatment of anticholinesterase poisoning. V. The effectiveness of Parpanit with oximes in the treatment of organophosphorus poisoning

The effectiveness of Parpanit in the treatment of organophosphorus poisoning was examined and compared with that of atropine sulfate. The potency of Parpanit was assessed in the mouse, rat, hamster, guinea pig, and rabbit against sarin, tabun, soman, CMPF, and DSDP in treatments in which the oximes P2S and TMB4 were used both singly and together. The effectiveness of the treatments utilizing both cholinolytics varied with the species used for assay, with the oxime used in combination, and with the nature and level of challenge of the organophosphorus inhibitors. The mean activity of Parpanit relative to atropine taken from a total of 102 trials indicated it to be 4.2 times as effective, with the potency ratio varying from 0.17 to 100 depending on the specific test. The acute oral toxicity of Parpanit in weanling rats was 2.9 g/kg (2.4–3.4). In a chronic toxicity study where daily oral doses as high as 1/5 LD50 were applied for 30 days, no evidence of accumulative effects could be found nor was there any evidence that the protective capacity of Parpanit against sarin was affected by the extended application of the drug.

A New Synthesis of 2-Pyridine Aldoximes

Abstract : The use of 2-pyridine aldoxime methochloride (2-PAM) in the treatment of organophosphorus poisoning has stimulated interest in finding new convenient routes for the synthesis of the precursor 2-pyridine aldoximes. We have found that the reaction of 2-chloromethyl pyridines with buffered solutions of aqueous hydroxylamine gives good yields of the corresponding 2-pyridine aldoximes.

Treatment of Organophosphorus Poisoning

Treatment of Organophosphorus Poisoning