pralidoxime and Organophosphate-Poisoning

Organophosphates (OP) account for the majority of pesticide-related unintentional or intentional poisonings in lower- and middle-income countries. The therapeutic role of atropine is well-established for patients with acute OP poisoning. The benefit of adding 2-pyridine aldoxime methyl chloride (2-PAM), however, is controversial. We performed a systematic review and meta-analysis of available randomized controlled trials (RCT) to compare 2-PAM plus atropine in comparison to atropine alone for acute OP poisoning. We searched PubMed, EMBASE, and SCOPUS up to March 2017. The Cochrane review handbook was used to assess the risk of bias. Data were abstracted and risk ratios (RR) were calculated for mortality, rate of intubation, duration of intubation, intermediate syndrome, and complications such as hospital-acquired infections, dysrhythmias, and pulmonary edema. We found five studies comprising 586 patients with varying risks of bias. The risk of death (RR = 1.5, 95% CI 0.9-2.5); intubation (RR = 1.3, 95% CI 1.0-1.6); intermediate syndrome (RR = 1.6, 95% CI 1.0-2.6); complications (RR = 1.2, 95% CI 0.8-1.8); and the duration of intubation (mean difference 0.0, 95% CI - 1.6-1.6) were not significantly different between the atropine plus 2-PAM and atropine alone. Based on our meta-analysis of the available RCTs, 2-PAM was not shown to improve outcomes in patients with acute OP poisoning.

Topics: Animals; Antidotes; Cholinesterase Reactivators; Humans; Organophosphate Poisoning; Pralidoxime Compounds

Oxime-type acetylcholinesterase reactivators (oxime-AChER) are used as an adjunct in the treatment for organophosphorus anticholinesterase poisoning. Because of the widespread usage and exposure of organophosphorus compounds (OPCs), its poisoning and fatalities is obvious in pregnant women, embryos and fetuses. OPCs irreversibly inhibit acetylcholinesterase (AChE) at nerve synapses. Furthermore, the role of AChE other than neurotransmission termination has been defined in the literature. The growing evidences show that cholinergic mechanisms are involved during growth and development of other organ systems. In contrary to the fact, the data on the use of oxime-AChER in OPC poisoning in pregnancy are scanty. The present review aimed to comprehend the status of oximes in pregnancy in lieu of the published literature. A thorough literature search was performed in January 2013, using ten popular search engines including Medline/PubMed, Google scholar, etc., using nine standard keywords. The search period was set from 1966 to present. The search did not reveal substantial data. No considerable studies were retrieved which could really demonstrate either the beneficial, harmful or even null effect of oxime-AChER usage in pregnancy. Only eighteen relevant articles were obtained for a period of about 47 years. In the literature, there is no report available to demonstrate the risk of using oxime-AChER in pregnancy for the treatment of OPC poisoning. The study reveals that the use of oxime-AChER in pregnancy is largely un-addressed, inconclusive and based on speculation albeit the incidences of OPC poisoning are quite prevalent. Well-designed studies are warranted for a tangible conclusion.

Topics: Antidotes; Cholinesterase Reactivators; Female; Humans; Organophosphate Poisoning; Oximes; Pralidoxime Compounds; Pregnancy

Self-poisoning with pesticides or plants is a major clinical problem in rural Asia, killing several hundred thousand people every year. Over the last 17 years, our clinical toxicology and pharmacology group has carried out clinical studies in the North Central Province of Sri Lanka to improve treatment and reduce deaths. Studies have looked at the effectiveness of anti-digoxin Fab in cardiac glycoside plant poisoning, multiple dose activated charcoal in all poisoning, and pralidoxime in moderate toxicity organophosphorus insecticide poisoning. More recently, using a Haddon matrix as a guide, we have started conducting public health and animal studies to find strategies that may work outside of the hospital. Based on the 2009 GSK Research in Clinical Pharmacology prize lecture, this review shows the evolution of the group's research from a clinical pharmacology approach to one that studies possible interventions at multiple levels, including the patient, the community and government legislation.

Topics: Acetylcholine; Antidotes; Asia; Biomedical Research; Charcoal; Cholinergic Agonists; Humans; Nerium; Organophosphate Poisoning; Pesticides; Pharmacology, Clinical; Pralidoxime Compounds; Randomized Controlled Trials as Topic; Rural Health; Sri Lanka

Topics: Acute Disease; Cholinesterase Inhibitors; Cholinesterase Reactivators; Humans; Insecticides; Organophosphate Poisoning; Pralidoxime Compounds; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Antidotes; Atropine; Cholinesterase Inhibitors; Cholinesterase Reactivators; Humans; Organophosphate Poisoning; Pesticides; Pralidoxime Compounds

The use of organophosphorus pesticides results in toxicity risk to non-target organisms. Organophosphorus compounds share a common mode of action, exerting their toxic effects primarily via acetylcholinesterase (AChE) inhibition. Consequently, acetylcholine accumulates in the synaptic clefts of muscles and nerves, leading to overstimulation of cholinergic receptors. Acute cholinergic crisis immediately follows exposure to organophosphate and includes signs and symptoms resulting from hyperstimulation of central and peripheral muscarinic and nicotinic receptors. The current view of the treatment of organophosphate poisoning includes three strategies, i.e. the use of an anticholinergic drug (e.g., atropine), cholinesterase-reactivating agents (e.g., oximes) and anticonvulsant drugs (e.g., benzodiazepines). Oximes, as a part of antidotal therapy, ensure the recovery of phosphylated enzymes via a process denoted as reactivation of inhibited AChE. However, both experimental results and clinical findings have demonstrated that different oximes are not equally effective against poisonings caused by structurally different organophosphorus compounds. Therefore, antidotal characteristics of conventionally used oximes can be evaluated regarding how close the certain substance is to the theoretical concept of the universal oxime. Pralidoxime (PAM-2), trimedoxime (TMB-4), obidoxime (LüH-6), HI-6 and HLö-7 have all been demonstrated to be very effective in experimental poisonings with sarin and VX. TMB-4 and LüH-6 may reactivate tabun-inhibited AChE, whereas HI-6 possesses the ability to reactivate the soman-inhibited enzyme. An oxime HLö-7 seems to be an efficient reactivator of AChE inhibited by any of the four organophosphorus warfare agents. According to the available literature, the oximes LüH-6 and TMB-4, although relatively toxic, are the most potent to induce reactivation of AChE inhibited by the majority of organophosphorus pesticides. Since there are no reports of controlled clinical trials on the use of TMB-4 in human organophosphate pesticide poisoning, LüH-6 may be a better option.

Topics: Acetylcholinesterase; Antidotes; Chemical Warfare Agents; Cholinesterase Reactivators; Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Humans; Insecticides; Obidoxime Chloride; Organophosphate Poisoning; Organothiophosphorus Compounds; Oximes; Pralidoxime Compounds; Sarin; Trimedoxime

Chemical terrorism presents a threat to the civilian population, including children. Nerve agent antidotes are available in prepackaged autoinjectors that can be delivered rapidly following an exposure. The published evidence on the use of nerve agent antidotes consists of case reports, extrapolation from pediatric organophosphate poisonings, and expert opinion. This review examines the evidence supporting the use of nerve agent antidotes in children.. The use of adult formulated atropine and pralidoxime autoinjectors will deliver doses above current recommendations for infants and children. Data demonstrate, however, that atropine overdose is generally well tolerated in young children. Children symptomatic of nerve agent poisoning will likely need both supraphysiologic doses and frequent re-dosing of atropine.. Based on limited data, the Mark 1 autoinjector kit (Meridian Medical Technologies, Columbia, Maryland, USA) appears to be the most efficacious antidote delivery system following a nerve agent attack. Symptomatic children under 1 year of age should be given a full atropine dose from the Atropen (Meridian Medical Technologies) (0.5 mg) or Mark 1 kits (2 mg), while children over 1 year of age should be given a full dose of both atropine and pralidoxime from the Mark 1 kit when more accurate weight-based dosing of antidotes is impossible.

Topics: Adult; Antidotes; Atropine; Chemical Warfare Agents; Child; Humans; Organophosphate Poisoning; Pralidoxime Compounds

The status of oximes in human organophosphate poisoning is controversial. This analysis compares the outcomes of therapy with or without oximes.. Quantitative analysis using meta-analytic techniques.. Controlled trials of oximes in human organophosphate poisoning were identified by search of MEDLINE and TOXLINE (1966 to May 2005) and review of published articles.. Of the 3,122 articles on organophosphate poisoning identified by electronic search, 116 related to oxime use in human organophosphate poisoning. Seven trials, including two randomized controlled trials, compared oximes with standard medical care. Varying dosage schedules of pralidoxime or obidoxime were used. The effects of oxime therapy on mortality rate, mechanical ventilation, incidence of intermediate syndrome, and need for intensive care therapy were analyzed and expressed as risk difference (positive values indicating oxime harm). The random effects estimator was reported because of underlying heterogeneity of treatment effects between study types. No statistically significant association of oxime therapy was demonstrated for either mortality (risk difference 0.09, 95% confidence interval -0.08 to 0.27), ventilatory requirements (risk difference 0.16, 95% confidence interval -0.07 to 0.38), or the incidence of intermediate syndrome (risk difference 0.16, 95% confidence interval -0.12 to 0.45), although point estimates of effect suggested harm. An increased need for intensive care therapy (risk difference 0.19, 95% confidence interval 0.01 to 0.36) was apparent with oxime therapy.. Based on the current available data on human organophosphate poisoning, oxime was associated with either a null effect or possible harm. The lack of current prospective randomized controlled trials, with appropriate patient stratification, mandates ongoing assessment of the role of oximes in organophosphate poisoning.

Topics: Adult; Cholinesterase Reactivators; Clinical Trials as Topic; Female; Humans; Insecticides; Male; Mortality; Obidoxime Chloride; Organophosphate Poisoning; Pralidoxime Compounds; Respiration, Artificial; Treatment Outcome

Acute organophosphorus pesticide poisoning causes tens of thousands of deaths each year across the developing world. Standard treatment involves administration of intravenous atropine and oxime to counter acetylcholinesterase inhibition at the synapse. The usefulness of oximes, such as pralidoxime and obidoxime, has been challenged over the past 20 years by physicians in many parts of the world, who have failed to see benefit in their clinical practice.. To find the clinical trial evidence for oximes producing clinical benefit in acute organophosphorus pesticide-poisoned patients.. We carried out a systematic search to find randomised clinical trials (RCTs) of oximes in acute organophosphorus pesticide poisoning, using MEDLINE, EMBASE and Cochrane databases. All articles with the text words 'organophosphate' or 'oxime' together with 'poisoning' or 'overdose' were examined. (Search last updated November 2003.). Articles that could possibly be randomised clinical trials were retrieved to determine if this was the case.. The published methodology of the possible RCTs located is not clear. One was found in abstract form only and two other published trials also had many gaps in the published methodology. We have attempted to contact the principal authors of all three trials but have been unable to obtain further information.. Two RCTs have been published, involving 182 patients treated with pralidoxime. These trials did not find benefit. However, the studies did not take into account a number of issues important for outcome and the methodology is unclear. Therefore, a generalised statement on effectiveness cannot be supported by the published results. In particular, characteristics at baseline were not evenly balanced, the dose of oxime was much lower than recommended in guidelines, there were substantial delays to treatment, and the type of organophosphate was not taken into account. The abstract of the third trial, a small possible RCT, is uninterpretable without further data.. Current evidence is insufficient to indicate whether oximes are harmful or beneficial in the management of acute organophosphorus pesticide poisoning. A much larger RCT is required to compare the World Health Organization recommended pralidoxime regimen (>30 mg/kg bolus followed by >8 mg/kg/hr infusion) with placebo. There are many theoretical and practical reasons why oximes may not be useful to patients with overwhelming self-poisoning. Such a study will need to be designed with pre-defined sub-group analysis to allow identification of patient sub-groups that may benefit from oximes.

Topics: Antidotes; Cholinesterase Reactivators; Humans; Organophosphate Poisoning; Oximes; Pesticides; Poisoning; Pralidoxime Compounds; Randomized Controlled Trials as Topic

The organic phosphorous compounds (OPC) include both the military grade nerve agents and the organic phosphorous pesticides. The major mechanism of OPC toxicity is through inhibition of acetylcholinesterase in neuronal synapses leading to excess acetylcholine and overstimulation of target organs. Signs and symptoms depend on the affinity of the OPC for muscarinic versus nicotinic receptors, and are likely to include both. Muscarinic symptoms may include diarrhea, urination, bronchospasm, bronchorrhea, emesis, and salivation. Nicotinic symptoms such as paralysis and fasciculations may also occur. Central nervous system toxicity may include seizures, altered mental status, and apnea, and require prompt intervention. Treatment includes early airway and ventilatory support as well as antidotal therapy with atropine, pralidoxime, and diazepam. Goals of therapy include prevention and rapid treatment of hypoxia and seizures, as these are linked to patient outcome.

Topics: Antidotes; Chemical Warfare; Cholinesterase Inhibitors; Humans; Organophosphate Poisoning; Organophosphorus Compounds; Pralidoxime Compounds; Prognosis; Terrorism

Neurologists need to familiarize themselves with nerve agents, the most toxic of the chemical warfare agents. Their mode of action lies within the nervous system, and nonneurologists will look to neurologists for expert advice on therapy. These agents cause rapid-onset cholinergic crisis amenable to prompt treatment with specific antidotes. Experience on the battlefield and in terrorist attacks demonstrates that therapy saves lives.

Topics: Antidotes; Atropine; Chemical Warfare Agents; Humans; Neurotoxicity Syndromes; Neurotoxins; Organophosphate Poisoning; Organophosphates; Organothiophosphorus Compounds; Pralidoxime Compounds; Pyridostigmine Bromide; Sarin; Soman

Topics: Acetylcholinesterase; Adult; Cholinesterase Reactivators; Humans; Male; Nervous System; Organophosphate Poisoning; Organophosphorus Compounds; Peripheral Nervous System; Poisoning; Pralidoxime Compounds; Sarin

The mortality rate caused by organophosphate (OP) poisoning is still high, even the standard treatment such as atropine and oxime improves a lot. To search for alternative therapies, this study was aimed to investigate the effects of packed red blood cell (RBC) transfusion in acute OP poisoning, and compare the therapeutic effects of RBCs at different storage times.Patients diagnosed with OP poisoning were included in this prospective study. Fresh RBCs (packed RBCs stored less than 10 days) and longer-storage RBCs (stored more than 10 days but less than 35 days) were randomly transfused or not into OP poisoning patients. Cholinesterase (ChE) levels in blood, atropine usage and durations, pralidoxime durations were measured.We found that both fresh and longer-storage RBCs (200-400 mL) significantly increased blood ChE levels 6 hours after transfusion, shortened the duration for ChE recovery and length of hospital stay, and reduced the usage of atropine and pralidoxime. In addition, fresh RBCs demonstrated stronger therapeutic effects than longer-storage RBCs.Packed RBCs might be an alternative approach in patients with OP poisoning, especially during early stages.

Topics: Acute Disease; Atropine; Cholinesterase Reactivators; Cholinesterases; Erythrocyte Transfusion; Female; Gastric Lavage; Humans; Male; Organophosphate Poisoning; Pralidoxime Compounds; Prospective Studies; Time Factors

To observe the effect of sodium bicarbonate combined with ulinastatin on cholinesterase activity for patients with acute phoxim pesticide poisoning.. A total of 67 eligible patients with acute phoxim pesticide poisoning, Who were admitted to the emeryency department of hospital from March 2011 to February 2014, Acording to different treatments au patients were randomly divided into the conventional treatment group (n=34) and the sodium bicarbonate+ulinastatin group (n=35) . The conventional treatment group were given thorough gastric lavage with water, the sodium bicarbonate + ulinastatin group were given gastric lavage with 2% sodium bicarbonate solution. Both groups were given such treatments as catharsis, administration of oxygen, fluid infusion, diuresis, and antidotes such as atropine and pralidoxime methylchloride. On the basis of comprehensive treatment, people in the sodium bicarbonate+ulinastatin group were given 5% sodium bicarbonate injection and ulinastatin. The clinical effect of the two groups were compared.. The serum cholinesterase activity of the sodium bicarbonate+ulinastatin group was significantly higher than the conventional treatment group from the 5th day, and the difference was statistically significant (P<0.05) . The total atropine dosage, total pralidoxime methylchloride dosage and hospitalization days were better than the conventional treatment group, and the differences were statistically significant (P<0.05) . The difference in the time of atropinization between the two groups was not statistically significant (P>0.05) . The results of arterial blood pH, HCO3- of the sodium bicarbonate + ulinastatin group were higher than the conventional treatment group, and the difference of HCO3- at the 10th day was statistically significant (P<0.05) .. Sodium bicarbonate combined with ulinastatin can improve the therapeutic effect and reduce complications in the treatment of acute phoxim pesticide poisoning, and have beneficial effects on the recovery of cholinesterase activity.

Topics: Atropine; Cholinesterases; Glycoproteins; Humans; Organophosphate Poisoning; Organothiophosphorus Compounds; Pesticides; Pralidoxime Compounds; Sodium Bicarbonate

To determine a new pralidoxime (PAM) treatment guideline based on the severity of acute organophosphate intoxication patients, APACHE II score, and dynamic changes in serum butyrylcholinesterase (BuChE) activity.. This is a randomization trial. All patients received supportive care measurements and atropinization. Each enrolled patient was treated with 2 gm PAM intravenously as the loading dose. The control group was treated according to the WHO's recommended PAM regimen, and the experimental group was treated according to their APACHE II scores and dynamic changes in BuChE activity. If a patient's APACHE II score was ≧26 or there was no elevation in BuChE activity at the 12th hour when compared to the 6th, doses of 1 g/h PAM (i.e., doubled WHO's recommended PAM regimen) were given. The levels of the serum BuChE and red blood cells acetylcholinesterase and the serum PAM levels were also measured.. Forty-six organophosphate poisoning patients were enrolled in this study. There were 24 patients in the control group and 22 patients in the experimental group. The hazard ratio of death in the control group to that of the experimental group was 111.51 (95% CI: 1.17-1.613.45; p = 0.04). The RBC acetylcholinesterase level was elevated in the experimental group but was not in the control group. The experimental group did not exhibit a higher PAM blood level than did the control group.. The use of PAM can be guided by patient severity. Thus, may help to improve the outcomes of organophosphate poisoning patients.

Topics: Acetylcholinesterase; Acute Disease; Adult; Aged; Erythrocytes; Female; Humans; Male; Middle Aged; Organophosphate Poisoning; Pralidoxime Compounds; Treatment Outcome

Our study sought to assess the effectiveness of a constant micropump infusion of atropine and pralidoxime chloride compared with repeated-bolus doses in patients with severe acute organophosphorus insecticide poisoning (AOPP).. A total of 60 patients with severe AOPP, defined as cholinergic crisis with respiratory failure or cerebral edema, were randomly divided into two groups of 30 patients each. In the experimental group, patients received a continuous micropump of atropine and pralidoxime chloride; in the control group, patients were given intermittent injections of atropine and pralidoxime chloride. Primary outcome measures were the dose of atropine required for atropinization, Acute Physiology and Chronic Health Evaluation II (APACHE II) score at atropinization, time to atropinization and acetylcholinesterase (AchE) recovery time. Additionally, the case fatality rate was measured as a secondary outcome.. Compared to patients in the control group, the time to atropinization, AchE recovery time, dose of atropine when atropinization occurred, and APACHE II score in the experimental group showed a statistically significant therapeutic effect (p < 0.05), and the case fatality rate of the experimental group was lower than that of the control group (p < 0.05).. Continuous micropump of atropine and pralidoxime chloride combined is more effective than the use of repeated-bolus injection in the treatment of severe acute organophosphorus insecticide poisoning.

Topics: Adult; Atropine; Drug Therapy, Combination; Female; Humans; Infusions, Intravenous; Insecticides; Male; Organophosphate Poisoning; Pralidoxime Compounds

Some clinicians assess the efficacy of pralidoxime in organophosphorus (OP) poisoned patients by measuring reactivation of butyrylcholinesterase (BuChE). However, the degree of BuChE inhibition varies by OP insecticide, and it is unclear how well oximes reactivate BuChE in vivo. We aimed to assess the usefulness of BuChE activity to monitor pralidoxime treatment by studying its reactivation after pralidoxime administration to patients with laboratory-proven World Health Organization (WHO) class II OP insecticide poisoning. Patient data were derived from 2 studies, a cohort study (using a bolus treatment of 1g pralidoxime chloride) and a randomized controlled trial (RCT) (comparing 2g pralidoxime over 20 min, followed by an infusion of 0.5 g/h, with placebo). Two grams of pralidoxime variably reactivated BuChE in patients poisoned by 2 diethyl OP insecticides, chlorpyrifos and quinalphos; however, unlike acetylcholinesterase reactivation, this reactivation was not sustained. It did not reactivate BuChE inhibited by the dimethyl OPs dimethoate or fenthion. The 1-g dose produced no reactivation. Pralidoxime produced variable reactivation of BuChE in WHO class II OP-poisoned patients according to the pralidoxime dose administered, OP ingested, and individual patient. The use of BuChE assays for monitoring the effect of pralidoxime treatment is unlikely to be clinically useful.

Topics: Antidotes; Butyrylcholinesterase; Cohort Studies; Enzyme Reactivators; Humans; Insecticides; Organophosphate Poisoning; Pralidoxime Compounds

Acute organophosphorus (OP) poisoning is relatively common and a major cause of death from poisoning in developing countries. Magnesium has been shown to be of benefit in animal models.. We conducted a phase II study of bolus doses of (MgSO4) in 50 patients with acute organophosphate poisoning. Patients eligible for inclusion had ingested OP and had cholinergic symptoms consistent with moderate or severe poisoning. All patients received standard care of atropinization titrated to control muscarinic symptoms and pralidoxime. The trial was run in 4 sequential groups of patients. Participants in each group received a different total dose of MgSO4 (20%) administered as intermittent bolus doses infused over 10-15 min or placebo. There was one control patient for every 4 patients who received MgSO4. Group A (16 patients) received a total of 4 gm MgSO4 as a single bolus, group B (8 patients) received 8 gm (in two 4 gm doses q4H), group C (8 patients) received 12 gm (in three 4 gm doses q4H) group D (8 patients) received 16 gm (in four 4 gm doses q4H) and control (10 patients) received placebo). Patients were closely monitored for any adverse reaction like significant clinical neuromuscular disturbance and respiratory depression.. No adverse reactions to magnesium were observed. The 24 hour urinary magnesium concentration were statistically different between 16 gm (234.74 ± 74.18 mg/dl) and control (118.06 ± 30.76 mg/dl) (p = 0.019), while it was much lower than the 80% of the intravenous magnesium load. Six patients died in control group compared to 3 in 4 gm, 2 in 8 gm and 1 in 12 gm group. There was no mortality in 16 gm group.. Magnesium was well tolerated in this study. Larger studies are required to examine for efficacy.

Topics: Acute Disease; Adolescent; Adult; Atropine; Bangladesh; Cholinesterase Reactivators; Dose-Response Relationship, Drug; Female; Hospitals, University; Humans; Infusions, Intravenous; Magnesium; Magnesium Sulfate; Male; Middle Aged; Muscarinic Antagonists; Organophosphate Poisoning; Pralidoxime Compounds; Severity of Illness Index; Young Adult

With the establishment of the inadequate efficiency of atropines and oximes in reducing morbidity and mortality of patients poisoned by organophosphates, more attention is given to using other methods such as Fresh Frozen Plasma (FFP) as a bioscavenger to mop up organophosphate toxins. This randomized clinical trial was conducted on 56 organophosphate poisoned patients who were randomly assigned to the FFP and control groups in order of admission. The routine treatment in both groups included atropine and, in moderate to severe cases of poisoning, pralidoxime. The FFP group received four packs of FFP as stat dose at the beginning of treatment. No significant difference was seen between the two groups on the atropine and pralidoxime dosage, hospitalization length and mortality. The present study showed that using four packs of FFP as stat dose at the onset of treatment had no significant effect on the clinical course of organophosphate poisoned patients.

Topics: Adult; Atropine; Female; Humans; Male; Middle Aged; Organophosphate Poisoning; Plasma; Pralidoxime Compounds

The role of oximes for the treatment of organophosphorus pesticide poisoning has not been conclusively established. We aimed to assess the effectiveness of a constant pralidoxime infusion compared with repeated bolus doses to treat patients with moderately severe poisoning from organophosphorus pesticides.. 200 patients were recruited to our single-centre, open randomised controlled trial after moderately severe poisoning by anticholinesterase pesticide. All were given a 2 g loading dose of pralidoxime over 30 min. Patients were then randomly assigned to control and study groups. Controls were given a bolus dose of 1 g pralidoxime over 1 h every 4 h for 48 h. The study group had a constant infusion of 1 g over an hour every hour for 48 h. Thereafter, all patients were given 1 g every 4 h until they could be weaned from ventilators. Analysis was by intention to treat. Primary outcome measures were median atropine dose needed within 24 h, proportion of patients who needed intubation, and number of days on ventilation. The study is registered at http://www.clinicaltrials.gov with the identifier NCT00333944.. 100 patients were assigned the high-dose regimen, and 100 the control regimen. There were no drop-outs. Patients receiving the high-dose pralidoxime regimen required less atropine during the first 24 h than controls (median 6 mg vs 30 mg; difference 24 mg [95% CI 24-26, p<0.0001]). 88 (88%) and 64 (64%) of controls and high-dose patients, respectively, needed intubation during admission to hospital (relative risk=0.72, 0.62-0.86, p=0.0001). Control patients required ventilatory support for longer (median 10 days vs 5 days; difference 5 days [5-6, p<0.0001]).. A high-dose regimen of pralidoxime, consisting of a constant infusion of 1 g/h for 48 h after a 2 g loading dose, reduces morbidity and mortality in moderately severe cases of acute organophosphorus-pesticide poisoning.

Topics: Adult; Blood Pressure; Cholinesterase Reactivators; Female; Humans; India; Infusions, Intravenous; Injections, Intravenous; Logistic Models; Male; Organophosphate Poisoning; Pesticides; Pralidoxime Compounds

Organophosphorus (OP) compounds are the most common suicidal poison in developing countries and mortality continues to be high.. A study was done to see butyryl cholinesterase (BuChE) profile after OP poisoning in pralidoxime (P2AM) and placebo treated cases. Highest recommended dose of P2AM was used to study the reactivation of cholinesterase. Clinical outcomes like, correlation of BuChE and severity of poisoning, mortality and complications like Type I and II paralysis, need for ventilation and ICU stay were also studied.. Twenty one cases of moderate and severe poisoning with OP compounds were included in the study. Mean BuChE levels came up gradually over 6-7 days, some taking up to two weeks. There was no. difference between the treatment and placebo groups. BuChE levels did not correlate with severity of poisoning nor did it correlate with Type I or II paralysis, need for ventilation, ICU stay or mortality.. Treatment with P2AM does not make any difference in BuChE reactivation or complications of moderate and severe OP poisoning. We have not been using P2AM for OP poisoning in our medical ICU with good patient outcomes.

Topics: Antidotes; Butyrylcholinesterase; Chemical Warfare Agents; Cholinesterase Reactivators; Developing Countries; Humans; Occupational Exposure; Organophosphate Poisoning; Pesticides; Poisoning; Pralidoxime Compounds; Suicide, Attempted; Treatment Outcome

The aim of this study is to determine the effects of fresh frozen plasma, as a source of cholinesterase, on butyrylcholinesterase (BuChE; plasma or pseudo cholinesterase) levels and outcomes in patients with organophosphate poisoning.. This prospective study was performed at the Department of Intensive Care of Erciyes University Medical School. Over 2 yrs, patients admitted to the ICU for OP poisoning were entered into the study. OP poisoning was diagnosed on the basis of history and BuChE levels. All patients received atropine. Fresh frozen plasma was given to 12 patients. The study was approved by the Ethical Committee, and verbal informed consent was obtained.. Thirty-three patients were included in the study. BuChE levels measured at admission and the pralidoxime and atropine doses administered were not different between groups (p>0.05). Although intermediate syndrome developed in 28.6% of patients receiving pralidoxime, there were no intermediate syndrome cases in patients receiving plasma prior to developing intermediate syndrome. The mortality rates were 14.3% in the pralidoxime group and 0% in the plasma+atropine+pralidoxime group. Two patients received plasma after developing the intermediate syndrome, and one patient who received only atropine died. BuChE levels of fresh frozen plasma were 4069.5 +/- 565.1 IU/L. Every two bags of plasma provided an increase in BuChE levels of approximately 461.7 +/- 142.1 IU/L.. Fresh frozen plasma therapy increases BuChE levels in patients with organophosphate poisonings. The administration of plasma may also prevent the development of intermediate syndrome and related mortality. Plasma (fresh frozen or freshly prepared) therapy may be used as an alternative or adjunctive treatment method in patients with organophosphate pesticide poisoning, especially in cases not given pralidoxime. Further randomized controlled and animal studies are required to infer a definitive result.

Topics: Atropine; Butyrylcholinesterase; Cholinesterase Reactivators; Humans; Length of Stay; Muscarinic Antagonists; Organophosphate Poisoning; Plasma; Pralidoxime Compounds; Prospective Studies; Treatment Outcome

Organophosphorus chemicals (OPs) are the pesticides most often involved in serious human poisoning. Treatment of intoxication with OPs conventionally involves atropine for reduction of muscarinic signs and oximes that increase the rate of hydrolysis of the phosphorylated enzyme acetylcholinesterase (AChE). Although atropine and oximes (pralidoxime or obidoxime) are traditionally used in the management of such poisoning, their efficacy remains a major issue of debate; thus, the goal of this prospective clinical trial was to elaborate the value of magnesium sulfate (MgSO4) in the management and outcome of OP insecticide poisoning. This unicenter, randomized, single-blind trial study was conducted on patients who were acutely poisoned with OPs and admitted to the Poisoning Center of Loghman-Hakim Hospital in Tehran, Iran. In a systematic sampling, every fourth eligible patient was chosen to undergo MgSO4 treatment. Magnesium sulfate was administered at dose of 4 g/day i.v. continued for only the first 24 hours after admission. The mean daily oxime requirement and the mean daily atropine requirement were not statistically significant between two treated groups. The mortality rate and hospitalization days of patients who received MgSO4 treatment were significantly lower than those who had not received MgSO4 (P < 0.01). It is concluded that administration of MgSO4, in a dose of 4 g/day concurrent to conventional therapy, in OP acute human poisoning is beneficial by reducing the hospitalization days and rate of mortality.

Topics: Adolescent; Adult; Aged; Atropine; Cholinesterase Reactivators; Drug Therapy, Combination; Female; Humans; Insecticides; Magnesium Sulfate; Male; Middle Aged; Muscarinic Antagonists; Obidoxime Chloride; Organophosphate Poisoning; Organophosphates; Pralidoxime Compounds; Single-Blind Method

Organophosphorus (OP) poisoning is most frequently encountered among our community. Treatment of poisoning is primarily aimed at reversing the effects of the compound by administration of atropine. Oximes have been shown to be efficacious in case reports. The dose of this drug in these reports varies from 1 gm which is a very low dose and physiologically no dose, to doses upto 16 gm. This is also a very expensive imported drug which causes the nation considerable loss of foreign exchange. We report our experience with the use of two treatment regimens of Pralidoxime (P2AM) in the management of patients with OP poisoning in a prospective trial. Seventy-two adult patients presenting to a large university affiliated teaching institution with a history of consumption of OP compounds and requiring intensive care were entered into the trial. Patients were randomized using a block randomisation to receive either a single bolus dose of 1 gm P2AM at admission (Low dose group) followed by placebo infusion over the next 4 days or a single placebo bolus at admission followed by P2AM 12 gm as a continuous infusion over the next 4 days. Outcome measures analyzed were mortality, duration of ICU stay, need for ventilation and duration of ventilation, time to recovery of consciousness, development of intermediate syndrome and infections. A higher prevalence of intermediate syndrome (p = 0.08) was observed in the high dose group. Ventilatory requirement was also more in the high dose group (p = 0.09). Since this was an equivalence study designed to show that the low dose was as effective as the high dose, these results attain greater significance as the low dose group fared better than the high dose group, even though the pre-test hypothesis was in the reverse direction. Subgroup analysis of patients who received at least 1 gm of P2AM within 12 hours of ingestion of the OP poison with those who received P2AM after 12 hours, showed that there was a significant reduction of intermediate syndrome (p = 0.05) but no significant difference was noted in number ventilated. High dose P2AM infusion has no role in the routine management of patients with OP poisoning. These results also suggest that the time of administration of P2AM after the ingestion of the poison mabe a crucial factor which determines response to therapy. A prospective double blind placebo controlled trial is now justified in the light of the above findings.

Topics: Adult; Antidotes; Cholinesterase Reactivators; Female; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Organophosphate Poisoning; Poisoning; Pralidoxime Compounds

Seventy two patients admitted to the Intensive Care Unit following ingestion of organophosphorus compounds were studied prospectively with two different doses of pralidoxime (PAM). One group received 1 gm immediately after admission and no further PAM and the other group received infusion of PAM, 1 gm 8 hourly for four days (total 12 gms). The incidence of type II paralysis or intermediate syndrome was 47%. We observed a higher incidence in the 4 days of infusion of PAM group (61%) (20 patients) as compared to the single Bolus dose group (39%) (13 patients). Relative risk 1.48 (confidence interval = 0.9-2.4).

Topics: Adult; Cholinesterase Reactivators; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Overdose; Female; Humans; Infusions, Intravenous; Male; Organophosphate Poisoning; Paralysis; Pralidoxime Compounds; Prospective Studies; Respiratory Paralysis; Syndrome

Acute organophosphorus (OP) poisoning is usually treated with atropine plus cholinesterase reactivators such as oximes, but controlled trials to assess the efficacy of oximes in OP poisoning have not been done. A period when the acetyl cholinesterase reactivator pralidoxime chloride was not available in Sri Lanka gave us the opportunity to compare atropine alone for treatment of moderate to severe OP poisoning (21 patients) with atropine plus pralixodime (24 patients). Outcome, as assessed clinically, was similar in the two groups. These results cast doubt on the necessity of cholinesterase reactivators for treatment of acute OP poisoning.

Topics: Adolescent; Adult; Aged; Atropine; Cholinesterase Reactivators; Critical Care; Drug Therapy, Combination; Female; Humans; Length of Stay; Male; Middle Aged; Organophosphate Poisoning; Poisoning; Pralidoxime Compounds; Sri Lanka; Treatment Outcome; Ventilators, Mechanical

A series of new uncharged conjugates of adenine, 3,6-dimetyl-, 1,6-dimethyl- and 6-methyluracil with 1,2,4-triazole-3-hydroxamic and 1,2,3-triazole-4-hydroxamic acid moieties were synthesized and studied as reactivators of organophosphate-inhibited cholinesterase. It is shown that triazole-hydroxamic acids can reactivate acetylcholinesterase (AChE) inhibited by paraoxon (POX) in vitro, offering reactivation constants comparable to those of pralidoxime (2-PAM). However, in contrast to 2-PAM, triazole-hydroxamic acids demonstrated the ability to reactivate AChE in the brain of rats poisoned with POX. At a dose of 200 mg/kg (i.v.), the lead compound 3e reactivated 22.6 ± 7.3% of brain AChE in rats poisoned with POX. In a rat model of POX-induced delayed neurodegeneration, compound 3e reduced the neuronal injury labeled with FJB upon double administration 1 and 3 h after poisoning. Compound 3e was also shown to prevent memory impairment of POX-poisoned rats as tested in a Morris water maze.

Topics: Acetylcholinesterase; Animals; Cholinesterase Inhibitors; Cholinesterase Reactivators; Hydroxamic Acids; Organophosphate Poisoning; Oximes; Paraoxon; Rats

Acetylcholinesterase (AChE, EC 3.1.1.7) reactivators (2-PAM, trimedoxime, obidoxime, asoxime) have become an integral part of antidotal treatment in cases of nerve agent and organophosphorus (OP) pesticide poisonings. They are often referred to as specific antidotes due to their ability to restore AChE function when it has been covalently inhibited by an OP compound. Currently available commercial reactivators exhibit limited ability to penetrate the blood-brain barrier, where reactivation of inhibited AChE is crucial. Consequently, there have been numerous efforts to discover more brain-penetrating AChE reactivators. In this study, we examined a derivative of 2-PAM designed to possess increased lipophilicity. This enhanced lipophilicity was achieved through the incorporation of a benzyl group into its molecular structure. Initially, a molecular modeling study was conducted, followed by a comparison of its reactivation efficacy with that of 2-PAM against 10 different AChE inhibitors in vitro. Unfortunately, this relatively significant structural modification of 2-PAM resulted in a decrease in its reactivation potency. Consequently, this derivative cannot be considered as a broad-spectrum AChE reactivator.

Topics: Acetylcholinesterase; Antidotes; Cholinesterase Inhibitors; Cholinesterase Reactivators; Humans; Organophosphate Poisoning; Oximes; Pralidoxime Compounds

Organophosphorus (OP) insecticide poisoning causes respiratory failure due to acetylcholinesterase (AChE) inhibition. The AChE reactivating antidote pralidoxime was developed in the 1950s and was soon noted to benefit patients occupationally poisoned with the highly potent OP insecticide parathion. Routine use of pralidoxime and other oximes such as obidoxime then became widely recommended. However, nearly all severe cases of OP poisoning now result from self-poisoning with large volumes of less potent (WHO hazard class Ib and II) insecticides and co-formulated solvents. Unfortunately, oxime clinical trials have never shown benefit from their use for these patients, and some have shown that pralidoxime may be associated with harm, including increased mortality. Oximes should not be used routinely for the care of OP insecticide-poisoned patients until translational and clinical studies have identified a safe and effective oxime regimen and identified the patients who benefit.

Topics: Acetylcholinesterase; Cholinesterase Inhibitors; Humans; Insecticides; Organophosphate Poisoning; Organophosphorus Compounds; Oximes; Poisoning

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.

Topics: Acetylcholinesterase; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Cholinesterase Reactivators; Humans; Obidoxime Chloride; Organophosphate Poisoning; Oximes

A platform of novel lipophilic substituted phenoxyalkyl pyridinium oximes was invented to reactivate organophosphate-inhibited acetylcholinesterase. This platform has provided superior efficacy in rats to the current standard of care, 2-PAM, for survival of lethal doses of nerve agent surrogates as well as evidence of brain penetration and neuroprotection. The pharmacokinetics of three of these novel oximes in female rats was studied for comparison to previous data in male rats. Compared to the published half-life of 2-PAM (less than 2 h), the lead novel oxime, Oxime 20, displayed a plasma half-life of about 5 h in both sexes of rats following intramuscular administration. Very few sex differences in pharmacokinetic parameters were apparent. Oxime 20 displayed an increase in brain concentration to plasma concentration over the initial 2 h following intramuscular administration in male rats, with a plateau at 1 h; there were no differences in brain concentrations between the sexes at 2 h. Hepatic metabolism of Oxime 20 was higher in rat microsomes than in human microsomes. The relatively long plasma half-life is likely an important factor in both the enhanced survival and the neuroprotection previously observed for Oxime 20. The metabolism data suggest that the clearance of Oxime 20 could be slower in humans than was observed in rats, which might allow less frequent administration than 2-PAM for therapy of organophosphate acute toxicity. Therefore, the pharmacokinetic data combined with our earlier efficacy data suggest that Oxime 20 has potential as a superior therapeutic for nerve agent poisoning.

Topics: Acetylcholinesterase; Animals; Antidotes; Cholinesterase Inhibitors; Cholinesterase Reactivators; Female; Male; Nerve Agents; Organophosphate Poisoning; Organophosphates; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rats

Pesticides account for hundreds of millions of cases of acute poisoning worldwide each year, with organophosphates (OPs) being responsible for the majority of all pesticide-related deaths. OPs inhibit the enzyme acetylcholinesterase (AChE), which leads to impairment of the central- and peripheral nervous system. Current standard of care (SOC) alleviates acute neurologic-, cardiovascular- and respiratory symptoms and reduces short term mortality. However, survivors often demonstrate significant neurologic sequelae. This highlights the critical need for further development of adjunctive therapies with novel targets. While the inhibition of AChE is thought to be the main mechanism of injury, mitochondrial dysfunction and resulting metabolic crisis may contribute to the overall toxicity of these agents. We hypothesized that the mitochondrially targeted succinate prodrug NV354 would support mitochondrial function and reduce brain injury during acute intoxication with the OP diisopropylfluorophosphate (DFP). To this end, we developed a rat model of acute DFP intoxication and evaluated the efficacy of NV354 as adjunctive therapy to SOC treatment with atropine and pralidoxime. We demonstrate that NV354, in combination with atropine and pralidoxime therapy, significantly improved cerebral mitochondrial complex IV-linked respiration and reduced signs of brain injury in a rodent model of acute DFP exposure.

Topics: Acetylcholinesterase; Animals; Atropine; Brain Injuries; Isoflurophate; Mitochondria; Organophosphate Poisoning; Prodrugs; Rats; Rodentia; Succinates; Succinic Acid

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

Topics: Acetylcholinesterase; Administration, Cutaneous; Animals; Antidotes; Organophosphate Poisoning; Phosphatidylcholines; Rats; Surface-Active Agents

The brain is a critical target for the toxic action of organophosphorus (OP) inhibitors of acetylcholinesterase (AChE) such as the nerve agent sarin. However, the available oxime antidote 2-PAM only reactivates OP-inhibited AChE in peripheral tissues. Monoisonitrosoacetone (MINA), a tertiary oxime, reportedly reactivates AChE in the central nervous system (CNS). The current study investigated whether MINA would be beneficial as a supplemental oxime treatment in preventing lethality and reducing morbidity following lethal sarin exposure, MINA supplement would improve AChE recovery in the body, and MINA would be detectable in the CNS. Guinea pigs were exposed to sarin and treated with atropine sulfate and 2-PAM at one minute. Additional 2-PAM or MINA was administered at 3, 5, 15, or 30 min after sarin exposure. Survival and morbidity were assessed at 2 and 24 h. AChE activity in brain and peripheral tissues was evaluated one hour after MINA and 2-PAM treatment. An in vivo microdialysis technique was used to determine partitioning of MINA into the brain. A liquid chromatography-tandem mass spectrometry method was developed for the analysis of MINA in microdialysates. MINA-treated animals exhibited significantly higher survival and lower morbidity compared to 2-PAM-treated animals. 2-PAM was significantly more effective in reactivating AChE in peripheral tissues, but only MINA reactivated AChE in the CNS. MINA was found in guinea pig brain microdialysate samples beginning at ~10 min after administration in a dose-related manner. The data strongly suggest that a centrally penetrating oxime could provide significant benefit as an adjunct to atropine and 2-PAM therapy for OP intoxication.

Topics: Acetylcholinesterase; Animals; Antidotes; Brain; Cholinesterase Reactivators; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Guinea Pigs; Male; Microdialysis; Organophosphate Poisoning; Oximes; Permeability; Pralidoxime Compounds; Sarin; Tissue Distribution

This study analysed the clinical patterns and outcomes of elderly patients with organophosphate intoxication. A total of 71 elderly patients with organophosphate poisoning were seen between 2008 and 2017. Patients were stratified into two subgroups: survivors (n = 57) or nonsurvivors (n = 14). Chlorpyrifos accounted for 33.8% of the cases, followed by methamidophos (12.7%) and mevinphos (11.3%). Mood, adjustment and psychotic disorder were noted in 39.4%, 33.8% and 2.8% of patients, respectively. All patients were treated with atropine and pralidoxime therapies. Acute cholinergic crisis developed in all cases (100.0%). The complications included respiratory failure (52.1%), aspiration pneumonia (50.7%), acute kidney injury (43.7%), severe consciousness disturbance (25.4%), shock (14.1%) and seizures (4.2%). Some patients also developed intermediate syndrome (15.5%) and delayed neuropathy (4.2%). The nonsurvivors suffered higher rates of hypotension (P < 0.001), shock (P < 0.001) and kidney injury (P = 0.001) than survivors did. Kaplan-Meier analysis indicated that patients with shock suffered lower cumulative survival than did patients without shock (log-rank test, P < 0.001). In a multivariate-Cox-regression model, shock was a significant predictor of mortality after intoxication (odds ratio 18.182, 95% confidence interval 2.045-166.667, P = 0.009). The mortality rate was 19.7%. Acute cholinergic crisis, intermediate syndrome, and delayed neuropathy developed in 100.0%, 15.5%, and 4.2% of patients, respectively.

Topics: Acute Kidney Injury; Affect; Aged; Antidotes; Atropine; Chlorpyrifos; Female; Humans; Insecticides; Male; Mevinphos; Middle Aged; Organophosphate Poisoning; Organothiophosphorus Compounds; Pneumonia, Aspiration; Pralidoxime Compounds; Psychotic Disorders; Respiratory Insufficiency; Retrospective Studies; Seizures; Shock; Survival Analysis; Treatment Outcome

Topics: Animals; Antidotes; Atropine; Baroreflex; Blood Pressure; Bradycardia; Cardiovascular System; Chlorpyrifos; Cholinesterase Inhibitors; Heart Rate; Insecticides; Male; Organophosphate Poisoning; Pralidoxime Compounds; Rats; Rats, Wistar; Respiratory System

Organophosphorus (OP) compounds inhibit central and peripheral acetylcholinesterase (AChE) activity, overstimulating cholinergic receptors and causing autonomic dysfunction (e.g., bronchoconstriction, excess secretions), respiratory impairment, seizure and death at high doses. Current treatment for OP poisoning in the United States includes reactivation of OP-inhibited AChE by the pyridinium oxime 2-pyridine aldoxime (2-PAM). However, 2-PAM has a narrow therapeutic index and its efficacy is confined to a limited number of OP agents. The bis-pyridinium oxime MMB4, which is a more potent reactivator than 2-PAM with improved pharmaceutical properties and therapeutic range, is under consideration as a potential replacement for 2-PAM. Similar to other pyridinium oximes, high doses of MMB4 lead to off-target effects culminating in respiratory depression and death. To understand the toxic mechanisms contributing to respiratory depression, we evaluated the effects of MMB4 (0.25-16 mM) on functional and neurophysiological parameters of diaphragm and limb muscle function in rabbits and rats. In both species, MMB4 depressed nerve-elicited muscle contraction by blocking muscle endplate nicotinic receptor currents while simultaneously prolonging endplate potentials by inhibiting AChE. MMB4 increased quantal content, endplate potential rundown and tetanic fade during high frequency stimulation in rat but not rabbit muscles, suggesting species-specific effects on feedback mechanisms involved in sustaining neurotransmission. These data reveal multifactorial effects of MMB4 on cholinergic neurotransmission, with the primary toxic modality being reduced muscle nicotinic endplate currents. Evidence of species-specific effects on neuromuscular function illustrates the importance of comparative toxicology when studying pyridinium oximes and, by inference, other quaternary ammonium compounds.

Topics: Acetylcholinesterase; Animals; Cholinesterase Reactivators; Dose-Response Relationship, Drug; Female; Male; Muscles; Organophosphate Poisoning; Oximes; Pralidoxime Compounds; Rabbits; Rats; Rats, Sprague-Dawley; Respiratory Insufficiency; Species Specificity; Synaptic Transmission

Whether central apnoea or hypopnoea can be induced by organophosphorus poisoning remains unknown to date. By using the acute brainstem slice method and multi-electrode array system, we established a paraoxon (a typical acetylcholinesterase inhibitor) poisoning model to investigate the time-dependent changes in respiratory burst amplitudes of the pre-Bötzinger complex (respiratory rhythm generator). We then determined whether pralidoxime or atropine, which are antidotes of paraoxon, could counteract the effects of paraoxon. Herein, we showed that paraoxon significantly decreased the respiratory burst amplitude of the pre-Bötzinger complex (p < 0.05). Moreover, pralidoxime and atropine could suppress the decrease in amplitude by paraoxon (p < 0.05). Paraoxon directly impaired the pre-Bötzinger complex, and the findings implied that this impairment caused central apnoea or hypopnoea. Pralidoxime and atropine could therapeutically attenuate the impairment. This study is the first to prove the usefulness of the multi-electrode array method for electrophysiological and toxicological studies in the mammalian brainstem.

Topics: Animals; Atropine; Brain; Organophosphate Poisoning; Paraoxon; Pralidoxime Compounds; Rats; Respiratory Burst; Sleep Apnea, Central

A 54-year-old man with a history of schizophrenia presented to the emergency room for weakness with associated lacrimosis, drooling, nausea, emesis, diarrhoea, diplopia and burning sensation on his skin that began 6 hours after spraying five cans of Raid on his carpet. He was noted to have miotic pupils and hyperactive bowel sounds. Given the clinical presentation, the patient was diagnosed with organophosphate (OP) toxicity. After being admitted, he developed symptoms associated with his OP toxicity and was successfully treated with atropine and pralidoxime. Most Raid products contain pyrethroids; however, both OPs and pyrethroids are available in commercial pesticides and patients may misidentify ingestions. There are limited data reporting the toxicity of pyrethroid overdose in humans and to guide its subsequent treatment. It is crucial to keep a low threshold for diagnosing and treating patients with acute onset of symptoms suspicious for an OP or pyrethroid toxidrome.

Topics: Antidotes; Atropine; Diagnosis, Differential; Household Products; Humans; Insecticides; Male; Middle Aged; Organophosphate Poisoning; Pralidoxime Compounds; Pyrethrins

Organophosphorus compounds (OPC) are widely used insecticides. Such poisoning is very rare in neonate. A 23 days old infant was admitted with severe respiratory distress, excessive secretion from nose and mouth, bluish discoloration of extremities and poor feeding for 4 hours. He was pale, cyanosed and lethargic with gasping respiration. Frothing was coming through mouth and nose. There was watering of eyes, pupils were pin pointed and light reflex was sluggish. The baby was hypothermic, hypotonic with altered sensorium. Capillary refill time was <3 sec. The neonate was gasping; there was crepitation over lung fields. Precordium and abdomen was normal. An odor of OPC was smelt on clothing and secretions of the infant. The baby was wrapped with a cloth that was ware during pesticide spraying in the field. In addition to general measures, decontamination of skin and clothing and gastric lavage was done. Empirical antibiotic, injection atropine and pralidoxime were given. Patient showed clinical improvement with disappearance of cholinergic signs. The baby was discharged on 7th day of admission after full recovery.

Topics: Antidotes; Atropine; Humans; Infant, Newborn; Insecticides; Male; Organophosphate Poisoning; Organophosphorus Compounds; Pralidoxime Compounds; Treatment Outcome

Organophosphate (OP) poisoning is a major global health issue; while compounds from this group have been used intensively over the last century, an effective antidote is still lacking. Oxime-type acetylcholinesterase (AChE) reactivators are used to reactivate the OP inhibited AChE. Pralidoxime is the only US Food and Drug Administration approved oxime for therapeutic use but its efficacy has been disappointing. Two novel oximes (K378 and K727) were investigated in silico and in vitro and compared with an experimental oxime (kamiloxime; K-27) and pralidoxime. In silico the molecular interactions between AChE and oximes were examined and binding energies were assessed. LogP (predicted log of the octanol/water partition coefficient) was estimated. In vitro the intrinsic ability of the oximes to inhibit AChE (IC

Topics: Acetylcholinesterase; Antidotes; Binding Sites; Cholinesterase Inhibitors; Cholinesterase Reactivators; Dose-Response Relationship, Drug; GPI-Linked Proteins; Humans; Male; Molecular Docking Simulation; Organophosphate Poisoning; Oximes; Paraoxon; Pralidoxime Compounds; Protein Binding; Protein Conformation; Pyridinium Compounds; Structure-Activity Relationship

Beside the key inhibition of acetylcholinesterase (AChE), involvement of oxidative stress in organophosphate (OP)-induced toxicity has been supported by experimental and human studies. On the other hand, according to our best knowledge, possible antioxidant properties of oximes, the only causal antidotes to OP-inhibited AChE, have been examined only by a few studies. Thus, we have determined the effect of four conventional (obidoxime, trimedoxime, pralidoxime, asoxime) and two promising experimental oximes (K027, K203) on dichlorvos (DDVP)-induced oxidative changes in vivo. Wistar rats (5/group) were treated with oxime (5% LD

Topics: Animals; Aryldialkylphosphatase; Biomarkers; Brain; Cholinesterase Inhibitors; Dichlorvos; Male; Malondialdehyde; Obidoxime Chloride; Organophosphate Poisoning; Oxidative Stress; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rats; Superoxide Dismutase; Trimedoxime

Topics: Antidotes; Cholinesterase Reactivators; Humans; Insecticides; Organophosphate Poisoning; Oximes; Pralidoxime Compounds; Suicide, Attempted

The main therapeutic basis for a case of organophosphate poisoning is a combination therapy which includes atropine as an anticholinergic drug and pralidoxime. If the poisoning is severe, a high dose of this combination of medicines may be needed, but this may cause serious side effects: paralytic ileus or even megacolon; however, these gastrointestinal events are very rare. Here, we report a case of organophosphate poisoning where atropine therapy was given and led to drug-associated toxic megacolon.

Topics: Antidotes; Atropine; Drug Therapy, Combination; Humans; Male; Megacolon, Toxic; Middle Aged; Organophosphate Poisoning; Pralidoxime Compounds

Yükselmiş U, Özçetin M, Çağ Y, Yıldızdaş D, Yılmaz HL. The role of plasmapheresis in organophosphate poisoning: Case reports of three pediatric patients. Turk J Pediatr 2017; 59: 491-496. The aim of the study was to assess the impact of plasmapheresis treatment in the management of three pediatric patients with organophosphate poisoning who did not respond to standard treatment. The treatment of signs and symptoms, and supportive treatment has been evaluated in this paper. Patients were initially given atropine infusion and 0.05 mg/kg atropine with five-minute intervals. Despite pralidoxime loading and three consecutively infusions clinical symptoms did not respond to the treatment and plasma pseudocholinesterase levels did not decrease. At this point, plasmapheresis was used on three consecutive days. Accordingly, the clinical signs improved and mechanical ventilation was no longer necessary. Patients were discharged on the sixteenth day after their admission to the hospital. Plasmapheresis may be an option for the patients who do not respond to atropine and pralidoxime treatment in organophosphate poisoning.

Topics: Adolescent; Atropine; Child; Child, Preschool; Cholinesterase Reactivators; Female; Humans; Male; Organophosphate Poisoning; Plasmapheresis; Pralidoxime Compounds

Acute severe organophosphate poisoning is a serious complication seen in developing and agricultural countries. Pralidoxime and high dose atropine are the standard treatments. There is no consensus about acute severe organophosphate poisonings that are unresponsive to pralidoxime, atropine, and supportive therapies. We report a case of acute severe organophosphate poisoning that was unresponsive to standard treatments and successfully treated with high-volume continuous venovenous hemodiafiltration and therapeutic plasma exchange combined with lipid infusion. J. Clin. Apheresis 31:467-469, 2016. © 2015 Wiley Periodicals, Inc.

Topics: Atropine; Child; Hemodiafiltration; Humans; Infusions, Intravenous; Lipids; Organophosphate Poisoning; Plasma Exchange; Pralidoxime Compounds; Salvage Therapy

Intranasal delivery is an emerging method for bypassing the blood brain barrier (BBB) and targeting therapeutics to the CNS. Oximes are used to counteract the effects of organophosphate poisoning, but they do not readily cross the BBB. Therefore, they cannot effectively counteract the central neuropathologies caused by cholinergic over-activation when administered peripherally. For these reasons we examined intranasal administration of oximes in an animal model of severe organophosphate poisoning to determine their effectiveness in reducing mortality and seizure-induced neuronal degeneration. Using the paraoxon model of organophosphate poisoning, we administered the standard treatment (intramuscular pralidoxime plus atropine sulphate) to all animals and then compared the effectiveness of intranasal application of obidoxime (OBD) to saline in the control groups. Intranasally administered OBD was effective in partially reducing paraoxon-induced acetylcholinesterase inhibition in the brain and substantially reduced seizure severity and duration. Further, intranasal OBD completely prevented mortality, which was 41% in the animals given standard treatment plus intranasal saline. Fluoro-Jade-B staining revealed extensive neuronal degeneration in the surviving saline-treated animals 24h after paraoxon administration, whereas no detectable degenerating neurons were observed in any of the animals given intranasal OBD 30min before or 5min after paraoxon administration. These findings demonstrate that intranasally administered oximes bypass the BBB more effectively than those administered peripherally and provide an effective method for protecting the brain from organophosphates. The addition of intranasally administered oximes to the current treatment regimen for organophosphate poisoning would improve efficacy, reducing both brain damage and mortality.

Topics: Acetylcholinesterase; Administration, Intranasal; Animals; Biological Availability; Brain; Central Nervous System Diseases; Cholinesterase Reactivators; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Male; Obidoxime Chloride; Organophosphate Poisoning; Pralidoxime Compounds; Rats; Rats, Sprague-Dawley; Statistics, Nonparametric; Tritium

Currently fielded treatments for nerve agent intoxication include atropine, an acetylcholine receptor antagonist, and pralidoxime (2PAM), a small molecule reactivator of acetylcholinesterase (AChE). 2PAM reactivates nerve agent-inhibited AChE via direct nucleophilic attack by the oxime moiety on the phosphorus center of the bound nerve agent. Due to a permanently charged pyridinium motif, 2PAM is not thought to cross the blood brain barrier and therefore cannot act directly in the neuronal junctions of the brain. In this study, ADOC, a non-permanently charged, non-oxime molecule initially identified using pesticide-inhibited AChE, was characterized in vitro against nerve agent-inhibited recombinant human AChE. The inhibitory and reactivation potentials of ADOC were determined with native AChE and AChE inhibited with tabun, sarin, soman, cyclosarin, VX, or VR and then compared to those of 2PAM. Several structural analogs of ADOC were used to probe the reactivation mechanism of the molecule. Finally, guinea pigs were used to examine the protective efficacy of the compound after exposure to sarin. The results of both in vitro and in vivo testing will be useful in the design of future small molecule reactivators.

Topics: Acetylcholinesterase; Animals; Cholinesterase Reactivators; Erythrocytes; Guinea Pigs; Half-Life; Humans; Kinetics; Male; Nerve Agents; Organophosphate Poisoning; Organophosphates; Oximes; Phenols; Pralidoxime Compounds; Recombinant Proteins; Sarin; Soman; Structure-Activity Relationship

Aldicarb and methomyl are carbamate pesticides commonly implicated in human poisonings. The primary toxic mechanism of action for carbamate poisoning is cholinesterase (ChE) inhibition. As such, it is logical to assume that the currently accepted therapies for organophosphate poisoning (muscarinic antagonist atropine and the oxime acetylcholinesterase reactivator pralidoxime chloride [2-PAM Cl]) could afford therapeutic protection. However, oximes have been shown to be contraindicated for poisoning by some carbamates.. A protective ratio study was conducted in guinea pigs to evaluate the efficacy of atropine and 2-PAM Cl. The ChE activity was determined in both the blood and the cerebral cortex.. Coadministration of atropine free base (0.4 mg/kg) and 2-PAM Cl (25.7 mg/kg) demonstrated protective ratios of 2 and 3 against aldicarb and methomyl, respectively, relative to saline. The data reported here show that this protection was primarily mediated by the action of atropine. The reactivator 2-PAM Cl had neither positive nor negative effects on survival. Both blood acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities were significantly reduced at 15 minutes postchallenge but gradually returned to normal within 24 hours. Analysis of cerebral cortex showed that BChE, but not AChE, activity was reduced in animals that succumbed prior to 24 hours after challenge.. The results suggest that coadministration of atropine and 2-PAM Cl at the currently recommended human equivalent doses for use in the prehospital setting to treat organophosphorus nerve agent and pesticide poisoning would likely also be effective against aldicarb or methomyl poisoning.

Topics: Acetylcholinesterase; Aldicarb; Animals; Antidotes; Atropine; Blood-Brain Barrier; Butyrylcholinesterase; Cholinesterase Inhibitors; Cholinesterase Reactivators; Emergency Medical Services; Guinea Pigs; Humans; Insecticides; Male; Methomyl; Muscarinic Antagonists; Organophosphate Poisoning; Pralidoxime Compounds

Anticholinesterases, such as organophosphorus pesticides and warfare nerve agents, present a significant health threat. Onset of symptoms after exposure can be rapid, requiring quick-acting, efficacious therapy to mitigate the effects. The goal of the current study was to identify the safest antidote with the highest therapeutic index (TI = oxime 24-hr LD50/oxime ED50) from a panel of four oximes deemed most efficacious in a previous study. The oximes tested were pralidoxime chloride (2-PAM Cl), MMB4 DMS, HLö-7 DMS, and obidoxime Cl2. The 24-hr median lethal dose (LD50) for the four by intramuscular (IM) injection and the median effective dose (ED50) were determined. In the ED50 study, male guinea pigs clipped of hair received 2x LD50 topical challenges of undiluted Russian VX (VR), VX, or phorate oxon (PHO) and, at the onset of cholinergic signs, IM therapy of atropine (0.4 mg/kg) and varying levels of oxime. Survival was assessed at 3 hr after onset clinical signs. The 3-hr 90th percentile dose (ED90) for each oxime was compared to the guinea pig pre-hospital human-equivalent dose of 2-PAM Cl, 149 µmol/kg. The TI was calculated for each OP/oxime combination. Against VR, MMB4 DMS had a higher TI than HLö-7 DMS, whereas 2-PAM Cl and obidoxime Cl2 were ineffective. Against VX, MMB4 DMS > HLö-7 DMS > 2-PAM Cl > obidoxime Cl2. Against PHO, all performed better than 2-PAM Cl. MMB4 DMS was the most effective oxime as it was the only oxime with ED90 < 149 µmol/kg against all three topical OPs tested.

Topics: Animals; Antidotes; Atropine; Chemical Warfare Agents; Cholinesterase Inhibitors; Cholinesterase Reactivators; Dose-Response Relationship, Drug; Guinea Pigs; Lethal Dose 50; Male; Muscarinic Antagonists; Obidoxime Chloride; Organophosphate Poisoning; Organothiophosphorus Compounds; Oximes; Pesticides; Pralidoxime Compounds; Pyridinium Compounds; Time Factors

In this issue of the Biomedical Journal, we highlight new data supporting the use of pralidoxime in the treatment of cases of organophosphate poisoning, which also suggest that WHO treatment guidelines should be updated. We also learn about a modified surgical technique to repair severe spinal injuries, as well as new insight into the structure of human adenovirus that could inform vaccine development.

Topics: Humans; Organophosphate Poisoning; Pesticides; Pralidoxime Compounds

The use of nerve agents such as sarin is as much a threat today as any other time in our history. The events in Syria in 2013 are proof of this. "The Obama administration asserted Sunday for the first time that the Syrian government used the nerve gas sarin to kill more than 1,400 people (August 21, 2013) in the world's gravest chemical weapons attack in 25 years." With these recent events clear in our mind, we must focus on the horrific nature of these chemical agents to devise a strategy that will enable first responders to counteract these insidious chemicals. This paper presents research on a physiologically based pharmacokinetic model to determine whether the current treatment protocol prescribed by the Center for Disease Control (CDC) and the US Army is effective in treating victims suffering from acute exposure symptoms. The model was used to determine what treatment should be used for victims suffering from mild exposure symptoms. The results indicate that the current CDC and US Army treatment is effective, but treatment with oxime therapy was not effective in alleviating symptoms of mild exposure. By applying these results, an effective treatment protocol was developed.

Topics: Antidotes; Centers for Disease Control and Prevention, U.S.; Chemical Warfare Agents; Humans; Models, Theoretical; Organophosphate Poisoning; Oximes; Practice Guidelines as Topic; Pralidoxime Compounds; Sarin; Systems Analysis; United States

The effects of activated charcoal (AC) mixed with cathartics for gastric decontamination in the management of organophosphate (OP) poisoning remain unknown due to limited clinical evidence. This exploratory study assessed the effectiveness of premixed AC-sorbitol as a treatment for OP poisoning.. This retrospective observational case study included patients who either did not receive AC-sorbitol or received a single dose of AC-sorbitol within 24 h after OP ingestion. The patients were divided into three groups: no AC-sorbitol treatment, patients who received AC-sorbitol within 1 h of OP ingestion, and patients who received AC-sorbitol more than 1 h after OP ingestion. Mortality, the development of respiratory failure, and the duration of mechanical ventilation were used as outcome measurements for effectiveness, whereas aspiration pneumonia and electrolyte imbalance were employed as safety measurements.. Among 262 patients with OP poisoning, 198 were included. Of these, 133 patients did not receive AC-sorbitol, whereas 14 and 51 patients received AC-sorbitol within 1 h or more than 1 h after ingestion, respectively. The time from ingestion to hospital arrival and time from ingestion to administration of atropine and pralidoxime differed among the groups, whereas other characteristics, including age, amount ingested, and type of ingested OP, were similar among the groups. Univariate and multivariate analysis demonstrated that the administration of AC-sorbitol was not associated with outcome measures for effectiveness and did not significantly increase either aspiration pneumonia or electrolyte imbalances during hospitalization.. The administration of AC-sorbitol exerted neither beneficial nor harmful effects on the outcomes of OP-poisoned patients regardless of the time from OP ingestion to administration, compared with those of patients who did not receive AC-sorbitol. However, this study enrolled a small number of patients who received AC-sorbitol; further qualified trials with a sufficient number of patients are therefore needed.

Topics: Adult; Aged; Antidotes; Atropine; Cathartics; Charcoal; Cholinesterase Reactivators; Drug Combinations; Female; Glasgow Coma Scale; Humans; Male; Middle Aged; Muscarinic Antagonists; Organophosphate Poisoning; Pesticides; Pralidoxime Compounds; Retrospective Studies; Sorbitol

Topics: Adult; Cholinesterase Reactivators; Diazinon; Heart Arrest; Humans; Infusions, Intravenous; Insecticides; Male; Medical Errors; Organophosphate Poisoning; Pralidoxime Compounds; Respiration, Artificial

Amitraz is used as an ectoparasiticide for dogs and cattle. Human poisoning due to amitraz may be misdiagnosed as organophosphate/carbamate (OPC) toxicity, since amitraz poisoning shares several clinical features (miosis, bradycardia and hypotension) encountered with OPC poisoning. A 19-year-old man with an alleged history of suicidal ingestion of a pesticide presented with drowsiness and was found to have constricted pupils, hypotension and bradycardia. He was diagnosed as a case of OPC poisoning and was treated with atropine and pralidoxime prior to presentation to our centre. Absence of a hypersecretory state, and the presence of hyperglycaemia and hypothermia along with a normal serum cholinesterase level suggested an alternate possibility. Retrieval of the poison container confirmed the diagnosis of amitraz poisoning. The patient made a rapid recovery with supportive management. Clinician awareness is key to successful management of this poisoning, which carries a good prognosis.

Topics: Atropine; Bradycardia; Cholinesterase Reactivators; Diagnosis, Differential; Diagnostic Errors; Follow-Up Studies; Humans; Hyperglycemia; Hypotension; Male; Miosis; Organophosphate Poisoning; Parasympatholytics; Pralidoxime Compounds; Suicide, Attempted; Toluidines; Treatment Outcome; Young Adult

A case of organophosphate (OP) poisoning was admitted to the emergency room. The patient accepted treatment with pralidoxime (PAM), atropine, and supporting therapy. It was observed that even after 22 h after treatment, 960 mg of atropine was not enough for the patient to be atropinized. However, a 160-mg follow-up treatment of anisodamine was quite enough for atropinization after 4 h. As a case report, more studies are required before any definite conclusion can be reached regarding the use of anisodamine as a potential substitute for high-dose atropine in cases of OP poisoning.

Topics: Antidotes; Atropine; Cholinesterase Reactivators; Female; Humans; Insecticides; Middle Aged; Muscarinic Antagonists; Organophosphate Poisoning; Pralidoxime Compounds; Solanaceous Alkaloids

Paraoxon (POX) is an active metabolite of organophosphate (OP) pesticide parathion that has been weaponized and used against civilian populations. Exposure to POX produces high mortality. OP poisoning is often associated with chronic neurological disorders. In this study, we optimize a rat survival model of lethal POX exposures in order to mimic both acute and long-term effects of POX intoxication. Male Sprague-Dawley rats injected with POX (4mg/kg, ice-cold PBS, s.c.) produced a rapid cholinergic crisis that evolved into status epilepticus (SE) and death within 6-8min. The EEG profile for POX induced SE was characterized and showed clinical and electrographic seizures with 7-10Hz spike activity. Treatment of 100% lethal POX intoxication with an optimized three drug regimen (atropine, 2mg/kg, i.p., 2-PAM, 25mg/kg, i.m. and diazepam, 5mg/kg, i.p.) promptly stopped SE and reduced acute mortality to 12% and chronic mortality to 18%. This model is ideally suited to test effective countermeasures against lethal POX exposure. Animals that survived the POX SE manifested prolonged elevations in hippocampal [Ca(2+)]i (Ca(2+) plateau) and significant multifocal neuronal injury. POX SE induced Ca(2+) plateau had its origin in Ca(2+) release from intracellular Ca(2+) stores since inhibition of ryanodine/IP3 receptor lowered elevated Ca(2+) levels post SE. POX SE induced neuronal injury and alterations in Ca(2+) dynamics may underlie some of the long term morbidity associated with OP toxicity.

Topics: Animals; Anticonvulsants; Atropine; Brain; Calcium; Diazepam; Disease Models, Animal; Electroencephalography; Hippocampus; Male; Neurons; Organophosphate Poisoning; Paraoxon; Pralidoxime Compounds; Rats; Rats, Sprague-Dawley; Status Epilepticus

Organophosphate poisoning is a serious clinical entity and considerable morbidity and mortality. Several factors have been identified to predict outcomes of organophosphate poisoning. Organophosphates are lipophilic and therefore predicted to have a large volume of distribution and to rapidly distribute into tissue and fat. Thus, toxic effects of organophosphate would be expected to last longer in obese patients. We investigated the relationship between obesity and clinical course in 112 acute organophosphate-poisoned patients from an initial medical record review of 234 patients. One hundred twenty-two patients were excluded: 6 were children, 14 had an uncertain history of exposure and of uncertain agent, 10 were transferred to another hospital, 67 were discharged from the emergency department because their toxicity was mild, 21 had carbamate poisoning, and 4 did not have height or weight checked. Clinical features, body mass index, Glasgow Coma Scale, laboratory findings, serum cholinesterase activity, electrocardiogram finding, management, and outcomes were examined. The lipid solubility of the implicated organophosphate was characterized by its octanol/water coefficient. Forty of 112 patients were obese. Obese patients who were poisoned by high lipophilicity organophosphate compounds had a need for longer use of mechanical ventilation, intensive care unit care, and total length of admission. Body mass index can provide a guide to physicians in predicting clinical course and management in organophosphate-poisoned patients.

Topics: Adult; Aged; Atropine; Body Mass Index; Cholinesterase Reactivators; Cohort Studies; Female; Glasgow Coma Scale; Humans; Intensive Care Units; Length of Stay; Male; Middle Aged; Muscarinic Antagonists; Obesity; Organophosphate Poisoning; Organophosphates; Pralidoxime Compounds; Prognosis; Respiration, Artificial; Retrospective Studies; Severity of Illness Index; Solubility

Organophosphate (OP) compounds, including paraoxon (POX), are similar to nerve agents such as sarin. There is a growing concern that OP agents could be weaponized to cause mass civilian causalities. We have developed a rodent survival model of POX toxicity that is being used to evaluate chronic morbidity and to screen for medical countermeasures against severe OP exposure. It is well known that the survivors of nerve gas and chronic OP exposure exhibit neurobehavioral deficits such as mood changes, depression, and memory impairments. In this study we investigated whether animals surviving severe POX exposure exhibited long-term neurological impairments. POX exposure produced overt signs of cholinergic toxicity. Rats were rescued using an optimized atropine, 2-PAM and diazepam therapy. Surviving rats were studied using established behavioral assays for identifying symptoms of depression and memory impairment 3-months after POX exposure. In the forced swim test, POX rats exhibited increased immobility time indicative of a despair-like state. In the sucrose preference test, POX rats consumed significantly less sucrose water indicating anhedonia-like condition. POX rats also displayed increased anxiety as characterized by significantly lower performance in the open arm of the elevated plus maze. Further, when tested with a novel object recognition paradigm, POX rats exhibited a negative discrimination ratio indicative of impaired recognition memory. The results indicate that this model of survival from severe POX exposure can be employed to study some of the molecular bases for OP-induced chronic behavioral and cognitive comorbidities and develop therapies for their treatment.

Topics: Anhedonia; Animals; Anxiety; Atropine; Behavior, Animal; Cognition Disorders; Depression; Diazepam; Male; Memory Disorders; Organophosphate Poisoning; Paraoxon; Pralidoxime Compounds; Rats; Rats, Sprague-Dawley; Recognition, Psychology

Topics: Administration, Intravenous; Antidotes; Atropine; Child; Cholinesterases; Diabetic Ketoacidosis; Diagnosis, Differential; Humans; Male; Organophosphate Poisoning; Pesticides; Pralidoxime Compounds; Treatment Outcome

Organophosphate poisoning (OPP) accounts for 200,000 deaths annually in developing countries. Serum cholinesterase (SChE) is of diagnostic value in patients with OPP and is checked repeatedly during the course of treatment. This study aimed to investigate the recovery pattern in patients with OPP using linear mixed models.. Using a retrospective cohort study design, we included 212 adult OPP patients who had visited the emergency department (ED) in a tertiary medical center between 2000 and 2010. One hundred and thirty-one patients were available for analysis, as 81 patients did not meet the criteria and were excluded. Information regarding basic personal characteristics, initial vital signs and severity scores, laboratory data, type and amount of organophosphate ingested, treatment, and serial SChE values was collected. A random coefficient model with a random intercept and a random slope of time were added to address the dynamic relationships of SChE with time and other associated factors.. The initial SChE activity and recovery rates varied among patients with OPP. The type of organophosphate, the first SChE activity, and the initial APACHE II score were significantly related to the SChE recovery trend. Chlorpyrifos and methamidophos had significantly slower and faster SChE recovery rates, respectively, than other organophosphates. Sex, dose of Pralidoxim (2-PAM), and delay in obtaining medical assistance did not significantly affect SChE recovery.. This study demonstrated the pattern and associated correlates of SChE activity recovery in patients with acute OPP. Chlorpyrifos appeared to have a slower SChE activity recovery rate than other organophosphates.

Topics: Acute Disease; Antidotes; Chlorpyrifos; Cholinesterases; Critical Illness; Female; Humans; Insecticides; Male; Middle Aged; Organophosphate Poisoning; Organothiophosphorus Compounds; Pralidoxime Compounds; Retrospective Studies; Severity of Illness Index; Suicide, Attempted; Tertiary Care Centers; Time Factors

This study aimed to clarify the efficacy of 2 therapies for patients with severe acute organophosphorus pesticide poisoning, including atropine adverse effects, the length of intensive care unit (ICU) stay, complications, and mortality.. A retrospective cohort study of 152 cases collected from May 2008 to November 2012 at 2 urban university hospitals was conducted. Patients admitted to the hospital for organophosphate poisoning were divided into 2 groups with different therapeutic regimens: group A was administered a repeated pulse intramuscular injection of pralidoxime chloride, and group B received the same initial dosage of atropine and pralidoxime chloride, but pralidoxime chloride intravenous therapy was administered for only 3 days, regardless of the length of atropine therapy. Subsequently, atropine adverse effects, length of ICU stay, complications, and mortality were statistically analyzed and compared between the 2 groups.. The total dose of atropine was 57.40 ± 15.14 mg in group A and 308.26 ± 139.16 mg in group B; group A received less atropine than did group B (P = .001). The length of ICU stay in group A was reduced (P = .025), and group A had fewer atropine adverse effects (P = .002). However, there was no significant difference in the mortality or complication rate between the 2 groups (P > .05).. In patients with severe poisoning, group A used less atropine, had fewer atropine adverse effects, and had a shorter ICU stay. We suggest that therapy should be started as early as possible using a sufficient amount of pralidoxime chloride started intramuscularly in combination with atropine and that the drugs should not be prematurely discontinued.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antidotes; Atropine; Drug Therapy, Combination; Female; Humans; Injections, Intramuscular; Intensive Care Units; Length of Stay; Male; Middle Aged; Organophosphate Poisoning; Pralidoxime Compounds; Retrospective Studies; Young Adult

Despite improvements to intensive care management and specific pharmacological treatments (atropine, oxime, diazepam), the mortality associated with organophosphate (OP) poisoning has not substantially decreased. The objective of this examination was to describe the role of fresh frozen plasma (FFP) in acute OP poisoning. After a deliberate ingestion of malathion, a 55-year-old male suffering from miosis, somnolence, bradycardia, muscular fasciculations, rales on auscultation, respiratory insufficiency, as well as from an inhibition of red blood cell acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BuChE), was admitted to hospital. Malathion was confirmed in a concentration of 18.01 mg L(-1). Apart from supportive measures (including mechanical ventilation for four days), antidotal treatment with atropine, oxime-pralidoxime methylsulphate (Contrathion(R)), and diazepam was administered, along with FFP. The potentially beneficial effects of FFP therapy included a prompt increase of BuChE activity (from 926 IU L(-1) to 3277 IU L(-1); reference range from 7000 IU L(-1) to 19000 IU L(-1)) and a reduction in the malathion concentration, followed by clinical recovery. Due to BuChE replacement, albumin content, and volume restitution, FFP treatment may be used as an alternative approach in patients with acute OP poisoning, especially when oximes are not available.

Topics: Acetylcholinesterase; Antidotes; Atropine; Blood Transfusion; Butyrylcholinesterase; Erythrocytes; Gastric Lavage; Humans; Insecticides; Malathion; Male; Middle Aged; Organophosphate Poisoning; Plasma; Pralidoxime Compounds; Serum Albumin; Serum Albumin, Human

The aim of this study was to examine the effects of ubiquinone (CoQ10) on heart tissue and erythrocytes in acute organophosphate poisoning (AOP). A total of 20 rabbits were divided into three groups: sham (n = 8), pralidoxime (PAM) + atropine (n = 6), and CoQ10 + PAM + atropine (n = 6). Blood samples were taken from each test subject to measure the values of acetylcholinesterase (AChE), nitric oxide (NO), and malondialdehyde (MDA) in the plasma and erythrocyte before administration of 50 mg/kg dichlorvos by orogastric tube. Blood samples were then taken at 1, 12, and 24 h post-dichlorvos to determine plasma and erythrocyte levels of AChE, NO, and MDA. Sham group received no treatment. PAM + atropine group received 0.05 mg/kg atropine with repeated doses and PAM: first a 30-mg/kg intravenous (IV) bolus, then a 15-mg/kg IV bolus every 4 h. CoQ10 + PAM + atropine group received same dose PAM and atropine and a 50-mg bolus of IV CoQ10. Thoracotomy was performed in all the animals 24 h after poisoning and then heart tissue samples were obtained. At 12 and 24 h, erythrocyte AChE levels in the CoQ10 animals were considerably higher than those in PAM + atropine animals (p = 0.023 and 0.017, respectively). At 12 and 24 h, erythrocyte MDA and NO levels in CoQ10 animals were significantly lower than those in PAM + atropine animals (p < 0.05). Heart tissue AChE levels in CoQ10 animals were considerably higher than those of the sham and PAM + atropine animals (p = 0.001). Heart tissue MDA and NO levels of CoQ10 animals were significantly lower than those of the sham and PAM + atropine animals (p < 0.01). Treatment of AOP with CoQ10 + PAM + atropine in this animal model had a beneficial effect on both erythrocyte and heart tissue lipid peroxidation and AChE activity.

Topics: Acetylcholinesterase; Animals; Antioxidants; Atropine; Cholinesterase Reactivators; Drug Therapy, Combination; Erythrocytes; Female; Heart Diseases; Lipid Peroxidation; Male; Malondialdehyde; Myocardium; Nitric Oxide; Organophosphate Poisoning; Pralidoxime Compounds; Rabbits; Ubiquinone

Organophosphate pesticides have emerged as a common cause of poisoning, particularly in developing countries. The most common electrocardiographic abnormalities observed in organophosphate poisoning are sinus tachycardia, QT interval prolongation, and, very rarely, ventricular arrhythmias. We report a case of organophosphate poisoning associated with atrial fibrillation, right bundle branch block, QT interval prolongation, and intermittent narrow QRS complexes that were most likely due to automaticity from the region of the left posterior fascicle.

Topics: Anti-Arrhythmia Agents; Antidotes; Atrial Fibrillation; Atropine; Bundle-Branch Block; Drug Therapy, Combination; Electrocardiography; Heart; Humans; Long QT Syndrome; Male; Middle Aged; Organophosphate Poisoning; Pralidoxime Compounds; Suicide, Attempted; Tachycardia, Paroxysmal; Treatment Outcome

Management of chemical weapon casualties includes the timely administration of antidotes without contamination of rescuers. Personal protective equipment makes intravenous access difficult but does not prevent intraosseous drug administration. We therefore measured the systemic bioavailability of antidotes for organophosphorus nerve agent and cyanide poisoning when administered by the intraosseous, intravenous, and intramuscular routes in a small study of Göttingen minipigs.. Animals were randomly allocated to sequentially receive atropine (0.12 mg/kg by rapid injection), pralidoxime (25 mg/kg by injection during 2 minutes), and hydroxocobalamin (75 mg/kg during 10 minutes) by the intravenous or intraosseous route, or atropine and pralidoxime by the intramuscular route. Plasma concentrations were measured for 6 hours to characterize the antidote concentration-time profiles for each route.. Maximum plasma concentrations of atropine and pralidoxime occurred within 2 minutes when administered by the intraosseous route compared with 8 minutes by the intramuscular route. Maximum plasma hydroxocobalamin concentration occurred at the end of the infusion when administered by the intraosseous route. The mean area under the concentration-time curve by the intraosseous route was similar to the intravenous route for all 3 drugs and similar to the intramuscular route for atropine and pralidoxime.. This study showed rapid and substantial antidote bioavailability after intraosseous administration that appeared similar to that of the intravenous route. The intraosseous route of antidote administration should be considered when intravenous access is difficult.

Topics: Animals; Antidotes; Atropine; Biological Availability; Chemical Warfare Agents; Cyanides; Hydroxocobalamin; Infusions, Intraosseous; Infusions, Intravenous; Injections, Intramuscular; Male; Organophosphate Poisoning; Pralidoxime Compounds; Swine; Swine, Miniature; Time Factors

Organophosphorus poisoning in neonates is extremely rare and needs high index of suspicion to diagnose it. The clinical presentation is often confused with the features of sepsis like apnea, copious oral secretions, diarrhea, letharginess, seizures. There may be recurrence of manifestations due to chronic exposure. We report a classic case admitted in the intensive care unit of our hospital.

Topics: Atropine; Diazinon; Female; Humans; Infant, Newborn; Insecticides; Organophosphate Poisoning; Pralidoxime Compounds; Recurrence

Topics: Antidotes; Dichlorvos; Emergency Service, Hospital; Follow-Up Studies; Glasgow Coma Scale; Humans; Infusions, Intravenous; Male; Organophosphate Poisoning; Organophosphorus Compounds; Poisoning; Pralidoxime Compounds; Risk Assessment; Severity of Illness Index; Time Factors; Treatment Outcome; Young Adult

Topics: Acute Disease; Adult; Antidotes; Antiparkinson Agents; Benserazide; Cholinesterase Inhibitors; Humans; Insecticides; Levodopa; Male; Organophosphate Poisoning; Parkinson Disease; Pralidoxime Compounds; Trihexyphenidyl

Extrapyramidal syndrome is an uncommon sequelae of acute organophosphorous (OP) poisoning. It is a manifestation of the intermediate syndrome described in OP poisoning. It may or may not be associated with neuroimaging changes in the striatum. We present a case of acute OP poisoning with interesting positive CT scan findings.

Topics: Adult; Antidotes; Atropine; Basal Ganglia Diseases; Brain; Dimethoate; Female; Humans; Insecticides; Muscarinic Antagonists; Organophosphate Poisoning; Pralidoxime Compounds; Tomography, X-Ray Computed

Despite extensive research for more than six decades on medical countermeasures against poisoning by organophosphorus compounds (OP) the treatment options are meagre. The presently established acetylcholinesterase (AChE) reactivators (oximes), e.g. obidoxime and pralidoxime, are insufficient against a number of nerve agents and there is ongoing debate on the benefit of oxime treatment in human OP pesticide poisoning. Up to now, the therapeutic efficacy of oximes was mostly evaluated in animal models but substantial species differences prevent direct extrapolation of animal data to humans. Hence, it was considered essential to establish relevant experimental in vitro models for the investigation of oximes as antidotes and to develop computer models for the simulation of oxime efficacy in different scenarios of OP poisoning. Kinetic studies on the various interactions between erythrocyte AChE from various species, structurally different OP and different oximes provided a basis for the initial assessment of the ability of oximes to reactivate inhibited AChE. In the present study, in vitro enzyme-kinetic and pharmacokinetic data from a minipig model of dimethoate poisoning and oxime treatment were used to calculate dynamic changes of AChE activities. It could be shown that there is a close agreement between calculated and in vivo AChE activities. Moreover, computer simulations provided insight into the potential and limitations of oxime treatment. In the end, such data may be a versatile tool for the ongoing discussion of the pros and cons of oxime treatment in human OP pesticide poisoning.

Topics: Acetylcholinesterase; Animal Experimentation; Animals; Antidotes; Cholinesterase Inhibitors; Cholinesterase Reactivators; Computer Simulation; Dimethoate; Enzyme Activation; Humans; Kinetics; Male; Models, Biological; Organophosphate Poisoning; Organophosphorus Compounds; Pesticides; Pralidoxime Compounds

Topics: Aged; Bradycardia; Cholinesterase Inhibitors; Cholinesterase Reactivators; Cholinesterases; Combined Modality Therapy; Diagnosis, Differential; Diagnostic Errors; Fatal Outcome; Humans; Hypertension; Male; Organophosphate Poisoning; Poisoning; Pralidoxime Compounds; Pulmonary Edema; Respiration, Artificial; Respiratory Paralysis; Syndrome

There have been many animal studies on the effects of organophosphorus pesticide (OP) poisoning on thermoregulation with inconsistent results. There have been no prospective human studies. Our aim was to document the changes in body temperature with OP poisoning. A prospective study was conducted in a rural hospital in Polonnaruwa, Sri Lanka. We collected data on sequential patients with OP poisoning and analyzed 12 patients selected from 53 presentations who had overt signs and symptoms of OP poisoning and who had not received atropine prior to arrival. All patients subsequently received specific management with atropine and/or pralidoxime and general supportive care. Tympanic temperature, ambient temperature, heart rate, and clinical examination and interventions were recorded prospectively throughout their hospitalization. Initial hypothermia as low as 32°C was observed in untreated patients. Tympanic temperature increased over time from an early hypothermia (<35°C in 6/12 patients) to later fever (7/12 patients >38°C at some later point). While some of the late high temperatures occurred in the setting of marked tachycardia, it was also apparent that in some cases fever was not accompanied by tachycardia, making excessive atropine or severe infection an unlikely explanation for all the fevers. In humans, OP poisoning causes an initial hypothermia, and this is followed by a period of normal to high body temperature. Atropine and respiratory complications may contribute to fever but do not account for all cases.

Topics: Adolescent; Adult; Aged; Antidotes; Atropine; Body Temperature Regulation; Female; Fever; Humans; Hypothermia; Insecticides; Male; Middle Aged; Organophosphate Poisoning; Palliative Care; Pralidoxime Compounds; Prospective Studies; Suicide, Attempted; Young Adult

Topics: Animals; Aryldialkylphosphatase; Atropine; Bacterial Proteins; Cholinesterase Reactivators; Drug Synergism; Organophosphate Poisoning; Parasympathetic Nervous System; Pralidoxime Compounds; Rats; Synapses

Organophosphate compounds are possibly the most widely-used insecticides worldwide. Organophosphate compounds cause poisoning, inhibiting acetylcholinesterase at the cholinergic synapses. Civilian casualties resulted from a terrorist attack with sarin in a Tokyo subway. Recent terrorist activities have also raised concerns that organophosphate or nerve agents may be used as a weapon of terror or mass destruction.. In this study, an extraordinary type of mass poisoning was evaluated. Especially by focusing on the way of poisoning, the demographic features and clinical findings of patients were analyzed.. After eating a wheat bagel, 13 patients with organophosphate poisoning were admitted to our emergency department. Seven were males and 6 were females. The mean age of the patients was 26 +/- 13.9. The mean serum acetylcholinesterase level was 2945.1+/-2648.9 U/L. Nine patients who had supportive treatment and who were given atropine and pralidoxime were hospitalized approximately 6.8+/-6.5 days. All of the patients recovered after the treatment and no deaths occurred.. If organophosphate poisoning is not diagnosed and treated in time, it may be fatal. When cases of food poisoning are admitted to the hospital, attention must be taken especially if it is a mass poisoning.

Topics: Acetylcholinesterase; Adolescent; Adult; Antidotes; Atropine; Cholinesterase Inhibitors; Cholinesterase Reactivators; Dichlorvos; Female; Food Contamination; Foodborne Diseases; Humans; Insecticides; Male; Organophosphate Poisoning; Pralidoxime Compounds; Retrospective Studies; Triticum; Turkey; Young Adult

Potentially lethal cardiac complications can occur in patients with acute organophosphate poisoning (OPP) and may be overlooked.. Thirty-six patients with acute OPP were studied. Clinical features and the nature of compound involved were recorded. The QT interval was plotted against heart rate to determine the risk for Torsades de Pointes using the Fossa nomogram. Echocardiography was undertaken in 29 patients. Twenty-four-hour Holter monitoring was performed on day 1 in five patients. Thirteen died. Necropsy was performed and hearts were studied both grossly and microscopically.. Gross examination of the heart in 13 cases revealed cardiac discoloration or blotchiness in 12, patchy pericarditis in six, auricular thrombus in six, right ventricular hypertrophy in four, and dilatation in three. On histopathology, all 13 cases had myocardial interstitial edema and vascular congestion, eight had patchy interstitial inflammation, two had patchy myocarditis, and six had a mural thrombus. Sinus tachycardia was the most common electrocardiographic abnormality. The others were corrected QT interval prolongation, ST-T changes, U waves, and ventricular premature contractions. Echocardiography in 29 patients showed minor abnormalities in 10. On Holter monitoring, episodic tachycardia and ST-T changes were observed in four, QT prolongation in three, and episodic bradycardia in two.. Patchy myocardial involvement as a result of direct cardiac toxicity could be one of the factors responsible for serious cardiac complications. As myocardial involvement is patchy, it may not be manifest clinically or on echocardiography. Continuous cardiac monitoring should be undertaken to detect dynamic cardiac changes.

Topics: Adolescent; Adult; Arrhythmias, Cardiac; Blood Pressure Monitoring, Ambulatory; Body Temperature; Cholinesterase Reactivators; Electrocardiography; Female; Heart Diseases; Hemodynamics; Humans; Insecticides; Male; Middle Aged; Organophosphate Poisoning; Pralidoxime Compounds; Prospective Studies; Radiography; Respiratory Mechanics; Survivors; Young Adult

Anticholinesterase poisoning is an important health problem in our country, and a complete understanding of its underlying mechanisms is essential for the emergency physician. Thus, we aimed to investigate the cardiac biochemical parameters and mortality in dichlorvos-induced poisoning in rats. Rats were randomly divided into 5 groups as control (corn oil), dichlorvos, atropine, pralidoxime, and atropine+pralidoxime groups. Immunohistochemical analyses of apoptosis and inducible nitric oxide synthase showed no change in cardiac tissue for all of the groups. Serum cholinesterase levels were suppressed with dichlorvos, and these reductions were inhibited with atropine and/or pralidoxime pretreatment. Serum levels of creatine kinase, creatine kinase-MB, cardiac troponin I, myoglobin, and N-terminal probrain natriuretic peptide were not affected with poisoning. Malondialdehyde and glutathione levels were not statistically significant between the groups. Although serum nitric oxide levels in the dichlorvos group were lower than those in the control group, cardiac nitric oxide levels in the atropine+pralidoxime group were markedly higher than those in the dichlorvos group. Atropine, pralidoxime, and atropine+pralidoxime pretreatments markedly reduced the mortality. In conclusion, our results implied that measured cardiac markers especially N-terminal probrain natriuretic peptide may not contribute to the early (first 6 hours) diagnosis of cardiotoxicity in dichlorvos-induced poisoning in rats. These results also showed that acute dichlorvos administration did not cause significant cardiac damage, and oxidative stress does not play a marked role in dichlorvos-induced poisoning. Besides, cardiac nitric oxide may produce protective effect on myocardium with atropine+pralidoxime therapy in rats.

Topics: Acute Disease; Analysis of Variance; Animals; Antidotes; Atropine; Biomarkers; Cholinesterase Inhibitors; Dichlorvos; Heart; Immunohistochemistry; In Situ Nick-End Labeling; Male; Nitric Oxide; Organophosphate Poisoning; Pralidoxime Compounds; Random Allocation; Rats; Rats, Wistar; Survival Rate

The widespread use of organophosphorus compounds (OPs) as pesticides and the frequent misuse of OP nerve agents in military conflicts or terrorist attacks emphasize the high clinical relevance of OP poisoning. The toxic symptomatology is caused by inhibition of acetylcholinesterase (AChE). A mainstay of standard antidotal treatment is atropine for antagonizing effects mediated by over stimulation of muscarinic ACh-receptors and oxime to reactivate OP-inhibited AChE. For therapeutic monitoring of oxime treatment in OP poisoning, measurement of erythrocyte AChE is suitable because erythrocyte AChE is an easily accessible surrogate for synaptic AChE. However, measurement of erythrocyte AChE is not standard practice. In contrast, determination of plasma butyrylcholinesterase (BChE) activity is in routine use for monitoring the benefit of oxime therapy. As oxime efficacy is limited with certain OPs (e.g. dimethoate, tabun, soman) alternative therapeutic approaches, e.g. the application of scavengers (BChE) which may sequester OPs before they reach their physiological target, are under investigation. To assess the eligibility of BChE as laboratory parameter and (pseudo catalytic or stoichiometric) scavenger in OP poisoning we initiated an in vitro study under standardized experimental conditions with the objective of determination of kinetic constants for inhibition, reactivation and aging of plasma BChE. It could be shown that, due to limited efficacy of obidoxime, pralidoxime, HI 6 and MMB4 with OP-inhibited BChE, plasma BChE activity is an inappropriate parameter for therapeutic monitoring of oxime treatment in OP poisoning. Furthermore, oxime-induced reactivation is too slow to accomplish a pseudo catalytic function, so that administered BChE may be merely effective as a stoichiometric scavenger.

Topics: Acetylcholinesterase; Biomarkers; Butyrylcholinesterase; Chemical Warfare Agents; Cholinesterase Inhibitors; Cholinesterase Reactivators; Erythrocyte Membrane; Humans; Kinetics; Obidoxime Chloride; Organophosphate Poisoning; Organophosphorus Compounds; Oximes; Pesticides; Pralidoxime Compounds; Pyridinium Compounds

Organophosphate (OP) poisoning is a worldwide concern. Several factors have been identified to predict outcomes of OP poisoned patients. This study focuses on the relationship between the trend in Serum cholinesterase (SChE) activity and its clinical outcome in acute OP poisoned patients.. We retrospectively reviewed the medical records of all adult acute OP poisoned patients that visited the Emergency Department from 2000 to 2006. These patients were divided into two groups: the deceased patients as the sample group and all others as the control group. We collected data on the following: demographical factors, poisoning history, clinical manifestation, Glasgow Coma Scale (GCS), APACHE II score, all SChE data within 48 hours, hourly 2-PAM dosage, intubation, and mortality. Chi-Square test then examined the relationship between the trend of SChE activity and mortality.. 86 patients were enrolled. Follow-up measurements of SChE activity within 48 hours of poisoning were available in 50 cases. Among these, eight patients died. We found no significant difference between the sample and control groups on initial SChE activity, time interval to initial SChE data, and hourly 2-PAM dosage. The sampled group possessed a worse GCS score, lower systolic blood pressure, and a higher APACH II score. Increase patient mortality rates associated with the absence of elevating SChE activity within 48 hours of poisoning. (P = .006, odds ratio:11).. We propose that the absence of elevating SChE activity level within 48 hours of poisoning appears to associate with higher mortality in acute OP poisoned patients.

Topics: Adult; Aged; Antidotes; Cholinesterases; Cohort Studies; Emergency Service, Hospital; Female; Humans; Male; Middle Aged; Organophosphate Poisoning; Pesticides; Poisoning; Pralidoxime Compounds; Predictive Value of Tests; Retrospective Studies; Survival Rate; Treatment Outcome

Topics: Antidotes; Clinical Trials as Topic; Humans; Organophosphate Poisoning; Pesticides; Pralidoxime Compounds

The nationwide epidemiology of organophosphate pesticide (OP) poisoning has never been reported in detail for Taiwan.. This study retrospectively reviewed all human OP exposures reported to Taiwan's Poison Control Centers (PCCs) from July 1985 through December 2006.. There were 4799 OP exposures. Most OP exposures were acute (98.37%) ingestions (74.50%) of a single OP (80.37%) to attempt suicide (64.72%) in adults (93.25%). Males were the most common gender (64.95%). Most patients (61.97%) received atropine and/or pralidoxime. The mortality rate for all 4799 OP exposures was 12.71%. Exposures to single OPs without co-intoxicants caused 524 deaths; of these, 63.36% were due to dimethyl OPs.. Dimethyl OPs cause the majority of deaths in Taiwan.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antidotes; Atropine; Child; Child, Preschool; Female; Humans; Infant; Male; Middle Aged; Organophosphate Poisoning; Pesticides; Poison Control Centers; Poisoning; Pralidoxime Compounds; Retrospective Studies; Suicide, Attempted; Taiwan

Organophosphorus (OP) pesticides poison more than 3,000,000 people every year in the developing world, mostly through intentional self-poisoning. Advances in medical therapy for OP poisoning have lagged, and current treatment is not highly effective with mortality of up to 40% in even the most advanced Western medical facilities. Administration of a broadly active bacterial OP hydrolase to patients in order to hydrolyze OPs in circulation might allow current therapies to be more effective. The objective of this work was to evaluate the efficacy of a new recombinant bacterial OP hydrolase (OpdA), cloned from Agrobacterium radiobacter, in rat models of two chemically distinct but highly toxic and rapidly acting OP pesticides: dichlorvos and parathion. Without OpdA treatment, median time to death in rats poisoned with 3x LD(50) of dichlorvos or parathion was 6 min and 25.5 min, respectively. Administration of a single dose of OpdA immediately after dichlorvos resulted in 100% survival at 24h, with no additional antidotal therapy. After parathion poisoning, OpdA alone caused only a delay to death. However, an additional two doses of OpdA resulted in 62.5% survival at 24 h after parathion poisoning. In combination with pralidoxime therapy, a single dose of OpdA increased survival to 75% after parathion poisoning. Our results demonstrate that OpdA is able to improve survival after poisoning by two chemically distinct and highly toxic OP pesticides.

Topics: Animals; Aryldialkylphosphatase; Bacterial Proteins; Dichlorvos; Insecticides; Male; Organophosphate Poisoning; Parathion; Pralidoxime Compounds; Rats; Rats, Wistar

Anesthesia providers may be called to treat injuries from chemical weapons or spills, for which prompt treatment is vital. It is therefore important to understand the mechanism of action of nerve agents and the resultant pathophysiology and to be able to quickly recognize the signs and symptoms of nerve agent exposure. This review article addresses the different types of nerve agents that are currently being manufactured as well as the symptomatic and definitive treatment of the patient who presents with acute nerve agent toxicity. This article also reviews the physiology of the neuromuscular junction and the autonomic nervous system receptors that nerve agent toxicity affects.

Topics: Antidotes; Atropine; Chemical Terrorism; Chemical Warfare Agents; Cholinesterase Inhibitors; Cholinesterase Reactivators; Decontamination; Humans; Muscarinic Antagonists; Nurse Anesthetists; Nurse's Role; Organophosphate Poisoning; Organophosphates; Organothiophosphorus Compounds; Pralidoxime Compounds; Sarin; Soman; Time Factors

Organophosphate compounds (OP) are usual insecticides and may poison human beings in a suicide attempt or accidental exposure. They inhibit activity of cholinesterase. Poisoning may be enough sever for intensive care support. In this paper, we study the prevalence and management of sever cases as well.. We studied patients with OP poisoning, from November 2002 to November 2005 in Sina Hospital, Tabriz, Iran, retrospectively and found patients who needed intensive care. During 4 years study, we documented 80 patients who were hospitalized due to OP poisoning and used drugs. Treatment with intravenous atropine and pralidoxime was started as soon as possible. We did not administer pralidoxim for 20 patients due to late admission (5 patients) and unavailability of the medicine (15 patients).. Forty-five male and 35 female patients were enrolled in our study. The majority of the patients used OP for suicide attempt and 4 patients had accidental exposure. The mortality rate was 18% in patients who were treated with pralidoxim and patients without pralidoxim had a mortality rate of 21%. Ten patients were mechanically ventilated and the mortality rate was 50%. In patients without MV the mortality rate was 11.7%. The duration of intensive care stay was 7.1 +/- 2 days.. Organophosphate compounds poisoning is a serious and lethal condition and needs early diagnosis and appropriate treatment. In patients with respiratory failure the mortality is very high; therefore we recommended early diagnosis, careful monitoring and appropriate management of complications in reducing the mortality rate.

Topics: Adolescent; Adult; Age Distribution; Antidotes; Atropine; Chi-Square Distribution; Cohort Studies; Emergency Service, Hospital; Female; Humans; Incidence; Infusions, Intravenous; Insecticides; Iran; Male; Middle Aged; Organophosphate Poisoning; Pralidoxime Compounds; Prognosis; Respiratory Insufficiency; Retrospective Studies; Risk Assessment; Severity of Illness Index; Sex Distribution; Suicide, Attempted; Survival Analysis; Treatment Outcome

In this prospective case series study, we consider the different factors between death and survival groups of organophosphate poisoning. Patients in tertiary-care medical center who had been exposed to organophosphate were included in the study. Pralidoxime (PAM) was discontinued after atropine had controlled the clinical situation. We recorded the demographic data, amount of organophosphate consumption, duration of coma, duration of ventilator use, duration of hospitalization, findings of chest X-ray, white blood cell count, acetylcholinesterase concentration, plasma cholinesterase concentration, total atropine amount, duration of atropine use, total PAM amount, duration of PAM use, urine organophosphate peak concentration, duration of urine organophosphate and mortality rate. Urine was collected every 8 hours and was analyzed by gas chromatography equipped with a flame photometric detector and gas chromatography with mass spectrometer detector for organophosphate determination. The urine organophosphate peak concentration was recorded. Wilcoxon rank sum test was used to compare the factors between death and survival groups. Fisher's exact test was used to compare the different findings of chest X-ray between the death and survival groups. Evidently, the death group had a higher amount of organophosphate consumption, duration of coma, and higher white blood cell count than those in the survival group. Also, the death group had lower duration of hospitalization, and decreased concentrations of acetylcholinesterase and plasma cholinesterase. Total PAM amount use and duration of PAM use were lower. However, the duration of ventilator use, findings of chest X-ray, total atropine amount, duration of atropine, urine organophosphate peak concentration and duration of urine organophosphate were similar in both groups. The mortality rate of our 50 cases was 20%. As stated earlier, the cases of the death group had insufficient PAM therapy. The maximum duration of PAM use was shorter than the maximum duration of urine organophosphate, although the medians of duration of PAM use were more than the medians of duration of urine organophosphate in both the survival and death groups. Prolonged coma duration, lower level of acetylcholinesterase and lower level of plasma cholinesterase were related to the poor prognosis of the patients.

Topics: Acetylcholinesterase; Adolescent; Adult; Aged; Female; Humans; Male; Middle Aged; Organophosphate Poisoning; Poisoning; Pralidoxime Compounds; Prognosis; Prospective Studies

Topics: Cholinesterase Reactivators; Humans; India; Organophosphate Poisoning; Pesticides; Poverty; Pralidoxime Compounds; Rural Population; Suicide, Attempted

Topics: Atropine; Cholinesterase Reactivators; Dose-Response Relationship, Drug; Humans; Organophosphate Poisoning; Parasympatholytics; Pralidoxime Compounds; Randomized Controlled Trials as Topic

Topics: Atropine; Cholinesterase Reactivators; Clinical Trials as Topic; Ethics, Research; Humans; Mortality; Muscarinic Antagonists; Organophosphate Poisoning; Pralidoxime Compounds

Topics: Atropine; Cholinesterase Reactivators; Humans; Intubation, Intratracheal; Muscarinic Antagonists; Organophosphate Poisoning; Pralidoxime Compounds; Respiration, Artificial; Time Factors

Acute organophosphate poisoning leads to a cholinergic crisis secondary to an acetylcholine rise, developed by an acetylcholinesterase inhibition. In some cases, after the resolution of the initial cholinergic signs and symptoms, an intermediate syndrome occurs, characterized by a delayed development of proximal and diaphragmatic muscle paralysis. We describe a case of a 67-year-old man who developed an intermediate syndrome after oxydemeton-metryl ingestion in a suicide attempt, despite a continuous pralidoxime infusion. Several hypotheses have been developed to explain the aetiology of this intermediate syndrome (neuromuscular junction dysfunction, inadequate poisoning treatment, late beginning of the oxime administration, etc). Intermediate syndrome manifestation will depend on the organophosphate's organism persistence and its chemical structure, and also on the time elapsed between the poisoning and the antidote administration.

Topics: Aged; Antidotes; Humans; Insecticides; Male; Organophosphate Poisoning; Organothiophosphorus Compounds; Pralidoxime Compounds; Respiratory Paralysis; Suicide, Attempted; Treatment Failure

A prospective study was undertaken to find the incidence of hyperamylasemia and acute pancreatitis in patients with anticholinesterase poisoning. This was done by serial estimation of total serum amylase and pancreatic imaging by ultrasonography and confirmed, if necessary, by computerized tomography. Anticholinesterase poisoning was caused by either ingestion or accidental exposure to organophosphates or carbamates; it was diagnosed when patients presented with features of cholinergic crisis, depressed serum butyrylcholinesterase activity of >50% and showed improvement following administration of atropine alone or atropine and 2-PAM. All the patients admitted with anticholinesterase poisoning between July 2001 and June 2005 were prospectively studied for elevated serum amylase. The serum amylase levels were estimated daily up to 10 days in survivors and in nonsurvivors till they survived. Ultrasonography of the abdomen was carried out in all to find swelling of the pancreas. Computerized tomography was undertaken in those who had a swollen pancreas or whose serum amylase levels were elevated significantly (> or =800 S.U). Of the 86 patients enrolled, 79 were taken up for analysis as data were incomplete in 7. Of the 79 patients, serum amylase was found to be elevated that is, >200 S.U. in 37 patients (46.95%). In three patients it was 800 S.U. One of them showed swollen pancreas on ultrasonography, which was confirmed by computerized tomography. This patient had ingested propoxyfur. In the other two patients, evidence of acute pancreatitis was not observed (on autopsy in one who died and on imaging in the other who survived). They had ingested chlorpyrifos. There was no significant correlation between the nature of the compounds (organophosphate or carbamates), inhibition of serum BUChE at admission, duration and severity of cholinergic syndrome and increase and time course of increase in serum amylase. Except for fenthion, significant persistent increase in serum amylase was not observed with individual compounds. The other associated abnormalities were polymorphonuclear leukocytosis (TLC >11,000/cumm) in all 37 patients who had elevated amylase, hyperglycemia (6/37) and, elevated transaminases (6/37). Mild elevation of serum amylase is common in patients with anticholinesterase poisoning. However, acute pancreatitis is rare.

Topics: Acute Disease; Adolescent; Adult; Amylases; Atropine; Butyrylcholinesterase; Carbamates; Cholinesterase Inhibitors; Cholinesterase Reactivators; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Hyperamylasemia; Male; Middle Aged; Occupational Exposure; Organophosphate Poisoning; Organophosphates; Pancreatitis; Pralidoxime Compounds; Prospective Studies; Radiography; Respiration, Artificial; Suicide, Attempted; Transaminases; Ultrasonography

To observe the treatments on the patients with acute methamidophos dichlorvos (DDV) and omethoate poisoning and provide the reliable basis for the rational treatments on these three organophosphorus pesticides poisoning.. 101 patients with AOPP in 7 hospitals were divided into three groups: Group A, 59 patients with acute methamidophos poisoning, Group B, 32 patients with acute DDV/dipterex (DEP) poisoning, Group C, 10 patients with acute omethoate/dimethoate poisoning. The levels of erythrocyte AChE and the therapeutic efficacies of pralidoxime chloride (PAM-Cl) were compared among the three groups.. The AChE activities of all the three groups were inhibited on level of (9.12 +/- 7.99) U/g Hb (group A), 7.32 +/- 4.62 U/g Hb (group B) and (12.01 +/- 9.53) U/g Hb (group C), among which no significant difference was found (P > 0.05). All the patients recovered from acute cholinergic excitation or crisis after the treatment of PAM-Cl. The erythrocyte AChE activities were obviously reactivated in group A three hours later after admission to hospital, each on level of (11.37 +/- 8.67) U/g Hb, (12.51 +/- 6.98) U/g Hb, (15.90 +/- 7.31) U/g Hb, (18.33 +/- 4.78) U/g Hb and (18.91 +/- 7.00) U/g Hb at the 12th, 24th, 48th, 72nd hour and discharge (P < 0.05), and the upgrade tendency was continuous. AChE activities in group B were also reactivated after treatment, each on level of (8.91 +/- 5.89) U/g Hb, (1.31 +/- 6.61) U/g Hb, (13.00 +/- 7.55) U/g Hb, (14.22 +/- 7.80) U/g Hb, (12.78 +/- 7.07) U/g Hb and (16.87 +/- 7.06) U/g Hb at the 3rd, 12th, 24th, 48th, 72nd hour and discharge, but the upgrade tendency turned slowly after 12 hours, the inhibited AChE activities were not reactivated in group C from the beginning to the end.. After the treatment of PAM-Cl, the AChE activities of the patients with acute methamidophos poisoning could be continuously reactivated, the AChE activities of the patients with acute DDV/DEP poisoning could also be reactivated in 12 hours, and then keep stable, but the AChE activities of the patients with acute omethoate/dimethoate poisoning could not be reactivated. However, PAM-Cl has therapeutic efficacy against acute toxicity of all the three organophosphorus pesticides. Oximes should be vigorously used in the treatment of AOPP, including acute omethoate/dimethoate poisoning.

Topics: Acetylcholinesterase; Acute Disease; Adult; Cholinesterase Reactivators; Dichlorvos; Dimethoate; Female; Humans; Male; Middle Aged; Organophosphate Poisoning; Organothiophosphorus Compounds; Pralidoxime Compounds; Retrospective Studies

Topics: Acetylcholine; Acetylcholinesterase; Animals; Atropine; Benzodiazepines; Blood-Brain Barrier; Brain; Chemical Warfare Agents; Cholinesterase Inhibitors; Drug Therapy, Combination; Galantamine; Guinea Pigs; Insecticides; Neurons; Neurotransmitter Agents; Organophosphate Poisoning; Organophosphates; Organophosphorus Compounds; Paraoxon; Pralidoxime Compounds; Pyridostigmine Bromide; Receptors, Cholinergic; Receptors, Muscarinic; Sarin; Seizures; Soman; Time Factors

Topics: Cholinesterase Reactivators; Drug Administration Schedule; Humans; Infusions, Intravenous; Insecticides; Organophosphate Poisoning; Pralidoxime Compounds; Randomized Controlled Trials as Topic

Early diagnoses of poisoning by organothiophosphate insecticide enables us to offer the appropriate treatment, which is in most cases crucial for the outcome of the poisoning. Our case was the serious accidental poisoning of a five year-old child, at home with organothiophosphate insecticide, which was packed in an attractively wrapped juice bottle, and within reach of the child. The history, general condition of the patient and the level of pseudoholinesterasis of 0.62 U/ml (reference limits are 7-10 U/nml) showed the severe nature of the poisoning. After emergency measures and several administrations of atropine with a total dosage of 1mg, we attained hyperatropinisation (or full atropinisation), and after two doses of the specific antagonist pralidoxim (whose "use by" date had expired three years earlier) every four hours, there was an increase in the level of pseudoholinesterasis to 1.66 Ulml. On the eighth day of hospitalization our patient was discharged in good health and his level of pseudoholinesterasis was 6.60 U/ml. Examination of the antidote pralidoxim (Neopam), was performed later and showed that its activityin relation to the standard substance was 90 9, which is good for safe treatment and adequate treatment efficacy. In conclusion, it should be emphasized that through measures of prevention, poisoning of children can be stopped, and in the case of poisoning, what is most important is prompt diagnosis and the appropriate administration of two extremely effective antidotes: atropine sulfates and pralidoxim. There should be no legal barriers to purchasing these antidotes, because the possibility of poisoning with very toxic substances such as organothiophosphate insecticides cannot be excluded.

Topics: Antidotes; Child, Preschool; Cholinesterase Reactivators; Humans; Insecticides; Male; Organophosphate Poisoning; Pralidoxime Compounds

Topics: Agriculture; Antidotes; Cholinesterase Reactivators; Humans; India; Occupational Exposure; Organophosphate Poisoning; Organophosphates; Pesticides; Poisoning; Pralidoxime Compounds; Suicide, Attempted

The purpose of this study was to evaluate the impact of the Glasgow Coma Scale (GCS), Acute Physiology and Chronic Health Evaluation (APACHE) II and Simplified Acute Physiology Score (SAPS) II scoring systems for organophosphate poisoning (OPP) in an intensive care unit (ICU). The following data were collected on all consecutive patients who were admitted to the ICU between June 1999 and December 2004. Demographic data, GCS, APACHE II and SAPS II scoring systems were recorded. Predicted mortality was calculated using original regression formulas. Standardized mortality ratio (SMR) was computed with 95% confidence intervals (CI). The sensitivity and specificity for each scoring system were evaluated by calculating the Area Under the Receiver Operating Characteristic Curves. The actual mortality in OPP was 21.9%. Predicted mortality by all systems was not significantly different from actual mortality [SMR and 95% CI for GCS: 1.00 (0.65 1.35), APACHE II: 0.87 (0.54-1.03), SAPS II: 1.40 (0.98-1.82)]. The area under the ROC curve for APACHE II is largest, but there is no statistically significant difference when compared with SAPS II and GCS (GCS 0.900 +/- 0.059, APACHE II 0.929 +/- 0.045 and SAPS II 0.891 +/- 0.057). In our ICU group of patients, in predicting the mortality rates in OPP, the three scoring systems, which are GCS, APACHE II and SAPS II, had similar impacts; however, GCS system has superiority over the other systems in being easy to perform, and not requiring complex physiologic parameters and laboratory methods.

Topics: Adolescent; Adult; Aged; Antidotes; APACHE; Female; Glasgow Coma Scale; Humans; Intensive Care Units; Male; Middle Aged; Mortality; Organophosphate Poisoning; Pralidoxime Compounds; Predictive Value of Tests; ROC Curve; Severity of Illness Index

Pralidoxime methylsulfate (Contrathion) is widely used to treat organophosphate poisoning. For the first time, we developed a specific assay for urinary pralidoxime using capillary zone electrophoresis (CZE) in the following conditions: fused-silica capillary (length: 47 cm, internal diameter: 75 microm), electrolyte solution: 25 mM sodium borate (pH 9.1), voltage: 15 kV, temperature: 25 degrees C, injection time: 1 or 2s, on-line UV detection: 280 nm. Sample preparation did not require a deproteinization step (1:5 dilution in water). The method was linear between 0.125 and 2 mg mL-1 of pralidoxime (quantification limit: 0.10 mg mL-1). Coefficients of variation for intra- and inter-assay precision were below 10% for all three control levels (0.15-1.15 mg mL-1). This assay was successfully applied to urine specimens from organophosphate poisoned patients treated by Contrathion (n=10). This CZE method allows the measure of pralidoxime in urine within 15 min with excellent precision, selectivity, and sensitivity. It is simple (no pretreatment) and convenient, thus suitable for the monitoring of Contrathion therapy in organophosphate poisoned patients.

Topics: Antidotes; Electrophoresis, Capillary; Humans; Organophosphate Poisoning; Poisoning; Pralidoxime Compounds; Reproducibility of Results; Sensitivity and Specificity

The authors report 2 cases of organophosphate poisoning which developed intermediate syndrome. The first case was a man who took an organophosphate insecticide, monocrotophos, and developed severe organophosphate poisoning. Respiratory support was needed. He was treated with atropine and 2-PAM. Weakness of neck muscles, proximal limb and respiratory muscle developed in the 3rd day after ingestion. By supportive treatment and careful monitoring, however, he recovered after 11 days of the poisoning. The second case was a lady who took dicrotophos. She developed severe organophosphate poisoning for which respiratory support was also needed High dose of atropine, but without 2-PAM, was administered. She developed bulbar palsy, proximal muscle and respiratory weakness 3 day after the ingestion. Ventilation support was needed for 13 days before weaning was successful. This report did not support an efficacy of pralidoxime (2-PAM) in alleviation of the intermediate syndrome, but aims to alert physicians to recognize the intermediate syndrome for which adequate respiratory care is the crucial key for its management.

Topics: Adult; Atropine; Female; Humans; Insecticides; Male; Muscle Weakness; Organophosphate Poisoning; Paralysis; Pralidoxime Compounds; Respiratory Insufficiency; Syndrome; Thailand; Time Factors

We encountered three cases of organophosphate poisoning treated with pralidoxime iodide (PAM) and whole-bowel irrigation without atropine sulfate. All patients recovered without persistence or recurrence of toxic symptoms and without any somatic after effects. In case 1, a 48-year-old woman ingested approximately 5 g of ethylthiometon in a suicide attempt. She was transferred to the hospital because of cardiopulmonary arrest. After resuscitation, she was transferred to our center. She was placed on a ventilator and received i.v. PAM and polyethylene glycol-electrolyte through a nasojejunal tube for whole-bowel irrigation. Six days later, serum ChE was improved. In case 2, a 51-year-old man ingested approximately 30 g of malathion in a suicide attempt and was transferred to our center because of dyspnea. He was treated with PAM and whole-bowel irrigation, but did not require a respirator. Serum ChE already showed improvement the following day. In case 3, a 31-year-old man ingested approximately 50 g of DEP in a suicide attempt and was transferred to our center because of unconsciousness. He was treated with a respirator, PAM and whole-bowel irrigation. Serum ChE improved within two days. These cases suggest the possibility that preferential whole-bowel irrigation without atropine sulfate prevents the persistence or recurrence of the toxic effects of organophosphate.

Topics: Adult; Antidotes; Cholinesterase Reactivators; Female; Humans; Insecticides; Intestines; Malathion; Male; Middle Aged; Organophosphate Poisoning; Organophosphorus Compounds; Pralidoxime Compounds; Pyrrolidines; Suicide, Attempted; Therapeutic Irrigation; Treatment Outcome

Topics: Adult; Atropine; Cholinesterase Inhibitors; Cholinesterase Reactivators; Dichlorvos; Female; Humans; Insecticides; Male; Monocrotophos; Muscarinic Antagonists; Neurotoxicity Syndromes; Organophosphate Poisoning; Pralidoxime Compounds; Suicide, Attempted

The neuroprotective effects of antidotes (atropine, pralidoxime/atropine, obidoxime/atropine and HI-6/atropine mixtures) on rats poisoned with tabun at a lethal dose (220 microg/kg intramuscularly; 100% of LD50 value) were studied. The tabun-induced neurotoxicity was monitored using a functional observational battery and an automatic measurement of motor activity. The neurotoxicity of tabun was monitored at 24 hr and 7 days after tabun challenge. The results indicate that atropine alone is not able to protect the rats from the lethal effects of tabun. Three non-treated tabun-poisoned rats and one tabun-poisoned rat treated with atropine alone died within 24 hr. On the other hand, atropine combined with all tested oximes allows all tabun-poisoned rats to survive at least 7 days following tabun challenge. Obidoxime combined with atropine seems to be the most effective antidotal treatment for the elimination of tabun-induced neurotoxicity in the case of lethal poisoning among tested antidotal mixtures. The antidotal mixture consisting of atropine and HI-6 is significantly less effective than the combination of atropine with obidoxime in the elimination of tabun-induced neurotoxicity in rats at 24 hr following tabun challenge. Pralidoxime in combination with atropine appears to be practically ineffective to decrease tabun-induced neurotoxicity at 24 hours as well as 7 days following tabun poisoning. Due to its neuroprotective effects, obidoxime seems to be the most effective and most suitable oxime for the antidotal treatment of acute tabun exposure among currently used oximes. Thus, the replacement of obidoxime by a more effective acetylcholinesterase reactivator for soman poisoning, the oxime HI-6, can to a small extent diminish the neuroprotective efficacy of antidotal treatment in the case of acute tabun poisonings.

Topics: Animals; Antidotes; Atropine; Chemical Warfare Agents; Cholinesterase Reactivators; Drug Therapy, Combination; Male; Motor Activity; Obidoxime Chloride; Organophosphate Poisoning; Organophosphates; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rats; Rats, Wistar

Topics: Antidotes; Atropine; Child, Preschool; Drug Therapy, Combination; Humans; Insecticides; Male; Muscarinic Antagonists; Organophosphate Poisoning; Positive-Pressure Respiration; Pralidoxime Compounds

Topics: Antidotes; Clinical Trials as Topic; Dose-Response Relationship, Drug; Follow-Up Studies; Guidelines as Topic; Humans; Organophosphate Poisoning; Patient Care; Poisoning; Pralidoxime Compounds; Severity of Illness Index; Treatment Outcome

Topics: Adolescent; Adult; Antidotes; Biomarkers; Butyrylcholinesterase; Controlled Clinical Trials as Topic; Female; Humans; India; Logistic Models; Male; Middle Aged; Organophosphate Poisoning; Poisoning; Pralidoxime Compounds; Risk Assessment; Severity of Illness Index; Treatment Outcome

Topics: Antidotes; Humans; Organophosphate Poisoning; Poisoning; Pralidoxime Compounds

1 In vitro studies with human erythrocyte acetylcholinesterase (AChE) and the mouse diaphragm model were performed to unravel the various microscopic reaction parameters that contribute to the dynamic equilibrium of AChE inhibition, ageing and reactivation. These data may help to define more precisely the indications and limitations of oxime therapy in organophosphate (OP) poisoning. 2 Diethylphosphoryl-AChE resulting from intoxications with parathion, chlorpyrifos, chlorfenvinphos, diazinon and other OPs is characterized by slow spontaneous reactivation and low propensity for ageing. This kind of phosphorylated enzyme is particularly susceptible to reactivation by oximes. 3 None of the oximes tested (pralidoxime, obidoxime, HI 6 and HLö 7) can be regarded as a universally suitable reactivator. Obidoxime turned out to be the most potent and most efficacious oxime in reactivating AChE inhibited by various classes of OP insecticides and tabun. Obidoxime, however, was inferior to HI 6 against soman, sarin, cyclosarin and VX. Pralidoxime was generally less potent. 4 The kinetic data of reactivation established for diethylphosphoryl-AChE of human red cells indicate that the usually recommended dosage to attain a plasma concentration of 4 micrograms/ml does not permit exploitation of the full therapeutic potential of the oximes, in particular of pralidoxime. However, in suicidal mega-dose poisoning, oximes, even at optimal plasma concentrations, may be unable to cope with the fast re-inhibition of reactivated AChE in the first days following intoxication. 5 It is suggested that oximes be administered by continuous infusion following an initial bolus dose as long as reactivation can be expected and until permanent clinical improvement is achieved.

Topics: Acetylcholinesterase; Animals; Antidotes; Cholinesterase Reactivators; Erythrocyte Membrane; Humans; Mice; Obidoxime Chloride; Organophosphate Poisoning; Organophosphorus Compounds; Poisoning; Pralidoxime Compounds

Topics: Anticonvulsants; Antidotes; Atropine; Chemical Warfare Agents; Cholinesterase Inhibitors; Gases; Humans; Organophosphate Poisoning; Organophosphates; Organothiophosphorus Compounds; Pralidoxime Compounds; Pyridostigmine Bromide; Respiratory Protective Devices; Sarin; Soman

We report a 60-yr-old woman with schizophrenia, who manifested a neuroleptic malignant (NM)-like syndrome after acute organophosphate poisoning (OPP). She attempted suicide by ingesting 40% emulsions of DMTP (S-2,3-dihydro-5-methoxy-2-oxo-1,3,4-thiadizol-3-yl-methyl O,O-dimethyl phosphorodithioate) 100 ml. On admission, she was unconscious and demonstrated convulsions, depressed respiratory movements, miosis and profuse salivation. Plasma cholinesterase concentration (842 IU.L-1) was very low and OPP was diagnosed. She was treated with gastric lavage, atropine and pralidoxime (PAM). By the seventh day after admission, symptoms of OPP disappeared and serum ChE had recovered to a sub-normal level. On the 13th day, she demonstrated coma, high fever (41.0 degrees C) and lead-pipe rigidity. Serum CPK was increased (1631 IU.L-1). Dantrolene sodium iv was administered for three days. Body temperature began to decrease in 24 hr, and her consciousness, muscle rigidity and other neurological symptoms returned to normal by the 16th day after admission. She was discharged from the hospital without sequelae 55 days after admission. We conclude that OPP can predispose to an NM-like syndrome and that dantrolene may be effective in the management.

Topics: Atropine; Cholinesterase Reactivators; Cholinesterases; Dantrolene; Female; Humans; Middle Aged; Miosis; Muscarinic Antagonists; Muscle Relaxants, Central; Neuroleptic Malignant Syndrome; Organophosphate Poisoning; Organothiophosphorus Compounds; Poisoning; Pralidoxime Compounds; Respiration; Salivation; Schizophrenia; Seizures; Suicide, Attempted; Therapeutic Irrigation

This study compared the efficacy of HI6 and 2-PAM against nerve agent (soman, tabun, sarin, and VX)-induced lethality in the atropinesterase-free rabbits pretreated with vehicle (controls) or pyridostigmine. Treatment was administered at signs or 2 min after agent challenge and consisted of oxime (100 mumol/kg) + atropine (13 mg/kg) (alone or together with diazepam). Twenty-four-h LD50 values were calculated for soman- and tabun-intoxicated animals, whereas 24-h survival was noted in animals given 10 LD50s of sarin or VX. In pyridostigmine and control rabbits intoxicated with soman and treated with oxime + atropine (alone or together with diazepam), HI6 was 3-5 times more effective than 2-PAM. In contrast, HI6 was less effective than 2-PAM against tabun poisoning. In pyridostigmine-pretreated animals exposed to tabun, efficacy was increased more than 3-fold when compare to tabun-challenged animals treated with atropine + HI6 alone. Both oximes were highly effective against sarin and VX. These findings suggest that HI6 could replace 2-PAM as therapy for nerve agent poisoning, because it is superior to 2-PAM against soman, and when used in pyridostigmine-pretreated animals, it affords excellent protection against all four nerve agents when used in combination with atropine (alone or together with diazepam) therapy.

Topics: Animals; Antidotes; Atropine; Chemical Warfare Agents; Cholinesterase Inhibitors; Cholinesterase Reactivators; Diazepam; Lethal Dose 50; Male; Organophosphate Poisoning; Organophosphates; Organophosphorus Compounds; Organothiophosphorus Compounds; Oximes; Poisoning; Pralidoxime Compounds; Pyridinium Compounds; Pyridostigmine Bromide; Rabbits; Sarin; Soman; Specific Pathogen-Free Organisms

Various organophosphorus compounds with low acute toxicity levels are widely used as insecticides. Human acute poisoning by organophosphates has often occurred accidentally. We determined the activity and isoenzyme patterns of serum cholinesterase (ChE) obtained from 13 human patients who attempted suicide with various organophosphates, i.e. Fenitrothion, Malathion, Isoxathion, Pyridaphenthion and Trichlorfon, and studied on the changes in the activity and isoenzyme patterns of serum ChE after ingestion. The following results were obtained. 1) Twenty ChE isoenzyme bands from normal human serum were detected by electrophoretic separation on polyacrylamide gradient gel. The main bands in the ChE isoenzyme pattern in normal serum were bands 4 and 5 which had the highest activity of acetylcholinesterase (AChE) with a molecular weight of 600,000-800,000, and bands 7, 12, 14, 17 and 18. 2) Inhibition of serum ChE activity was more severe as the amount ingested increased in patients who took Fenitrothion and Malathion. Reactivation of serum ChE activity was very slow in patients treated with PAM (2-pyridine aldoxime methiodide) in the late stage of ingestion or whose symptoms reappeared. 3) There were no differences in the patterns of serum ChE isoenzyme by organophosphorus compound. Band 7 disappeared in the serum ChE isoenzyme of almost every patient, and bands 12, 18, 14 and 17 of the serum ChE isoenzyme disappeared successively with the decline of serum ChE activity. Only band 5 of the isoenzyme remained in cases who had serum ChE activity lower than 5% of normal. 4) All 13 patients were treated with PAM and atropine immediately after being admitted to hospitals. We could not clearly determine the efficacy of PAM on reactivation of serum ChE activity and isoenzyme, because it was impossible in human poisoning to compare PAM efficacy with no treatment and with pre- and post-PAM treatment. 5) The activity and isoenzyme patterns of serum ChE recovered rapidly after combined hemoperfusion and hemodialysis treatment (HP-HD treatment) of the patients poisoned with Malathion. But HP-HD treatment had no effect on poisoning by Fenitrothion and Isoxathion. These findings demonstrated the changes in the activity and isoenzyme pattern of serum ChE in patients poisoned with several organophosphates after PAM and HP-HD treatment.

Topics: Acute Disease; Adult; Aged; Animals; Cholinesterases; Female; Hemoperfusion; Humans; Isoenzymes; Male; Middle Aged; Organophosphate Poisoning; Poisoning; Pralidoxime Compounds; Rats; Renal Dialysis

We studied the ability of 2-PAM to reactivate cholinesterase (ChE) inhibited by organophosphorus compounds (OPs) and aging. We estimated the reactivation rate with 2-PAM following inhibition of ChE by fenitrothion, methylparathion or ethylparathion using erythrocytes of rat and rabbit and rat brain. The period of time during which inhibited ChE could be reactivated was shorter in the case of inhibition by fenitrothion or methylparathion than in the case of inhibition by ethylparathion. This results suggest that aging is related to the presence of the alkyl group in OPs, and occurs faster in the case of inhibition by OPs with an O,O-dimethyl moiety than in the case of inhibition by OPs with an O,O-diethyl moiety.

Topics: Animals; Antidotes; Cholinesterase Reactivators; Cholinesterases; Male; Organophosphate Poisoning; Pralidoxime Compounds; Rabbits; Rats; Rats, Sprague-Dawley; Time Factors

The metabolic fate of 2-PAM and its antidotal effect on organophosphorus compound poisoning in rats were studied. When 14C-2-PAM was administered intravenously, the amount of 14C reaching the brain was small. Following administration by intramedullary injection, 14C was present in high concentrations in the brain, and 72-90% of the 14C present in the brain corresponded to the unchanged form of 2-PAM. 2-PAM was rapidly excreted into the urine and feces following either intramedullary or intravenous administration. The half-life of 2-PAM in the brain following intramedullary administration was 1.52 hr. Intramedullary administration of 2-PAM to rats poisoned with fenitrothion or malathion enabled their survival and induced reactivation of brain cholinesterase.

Topics: Animals; Antidotes; Brain; Cholinesterase Reactivators; Cholinesterases; Enzyme Activation; Fenitrothion; Half-Life; Injections; Injections, Intravenous; Malathion; Male; Organophosphate Poisoning; Poisoning; Pralidoxime Compounds; Rats; Rats, Sprague-Dawley; Subarachnoid Space; Tissue Distribution

We measured in nine patients, poisoned by organophosphorus agents (ethyl parathion, ethyl and methyl parathion, dimethoate, or bromophos), erythrocyte and serum cholinesterase activities, and plasma concentrations of the organophosphorus agent. These patients were treated with pralidoxime methylsulphate (Contrathion), administered as a bolus injection of 4.42 mg.kg-1 followed by a continuous infusion of 2.14 mg.kg-1/h, a dose regimen calculated to obtain the presumed "therapeutic" plasma level of 4 mg.l-1, or by a multiple of this infusion rate. Oxime plasma concentrations were also measured. The organophosphorus agent was still detectable in some patients after several days or weeks. In the patients with ethyl and methyl several days or weeks. In the patients with ethyl and methyl parathion poisoning, enzyme reactivation could be obtained in some at oxime concentrations as low as 2.88 mg.l-1; in others, however, oxime concentrations as high as 14.6 mg.l-1 remained without effect. The therapeutic effect of the oxime seemed to depend on the plasma concentrations of ethyl and methyl parathion, enzyme reactivation being absent as long as these concentrations remained above 30 micrograms.l-1. The bromophos poisoning was rather mild, cholinesterases were moderately inhibited and increased under oxime therapy. The omethoate inhibited enzyme could not be reactivated.

Topics: Adult; Aged; Cholinesterase Inhibitors; Cholinesterase Reactivators; Cholinesterases; Dimethoate; Erythrocytes; Female; Humans; Insecticides; Male; Methyl Parathion; Middle Aged; Organophosphate Poisoning; Organophosphorus Compounds; Organothiophosphates; Parathion; Pralidoxime Compounds

Topics: Antidotes; Humans; Infusions, Intravenous; Organophosphate Poisoning; Poisoning; Pralidoxime Compounds

Cyclohexylmethylphosphonofluoridate (CMPF) is an organophosphate cholinesterase inhibitor with military significance. The purpose of these studies was 1) to determine the acute toxicity of CMPF in the male rhesus monkey, 2) to evaluate the efficacy of pyridostigmine (PYR) pretreatment plus atropine and oxime (2-PAM or H16) treatment, and 3) to evaluate the pathological consequences of acute poisoning. An i.m. LD50 of CMPF was estimated using an up-and-down dose selection procedure and 12 animals. The 48-h and 7-day LD50 was 46.6 micrograms/kg, i.m. In the protection experiments, pyridostigmine (0.3-0.7 mg/kg/24 h) was administered by surgically implanted osmotic minipumps for 3-12 days resulting in 21-65% inhibition of erythrocyte acetylcholinesterase activity. Animals were challenged with 5 x L50 CMPF (233 micrograms/kg) and treated with atropine (0.4 mg/kg) and either 2-PAM (25.7 mg/kg) or HI6 (37.8 mg/kg) at the onset of signs or 1 min after challenge. Osmotic pumps were removed within 30 min after agent challenge. Pyridostigmine, atropine, and either 2-PAM or H16 were completely effective against CMPF, saving ten of ten animals in each group. In comparison, three of five animals challenged with 5 x LD50 of soman and treated with atropine and 2-PAM survived 7 days. The primary histologic lesions in the acute toxicity group were neuronal degeneration/necrosis and spinal cord hemorrhage. The CMPF treated groups (total of 20 animals) had minimal nervous system changes with no significant lesion difference resulting from the different oxime therapies. The primary non-neural lesions were degenerative cardiomyopathy and skeletal muscle degeneration which occasionally progressed to necrosis and mineralization.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetylcholinesterase; Animals; Antidotes; Atropine; Chemical Warfare Agents; Cholinesterase Inhibitors; Cholinesterase Reactivators; Lethal Dose 50; Macaca mulatta; Male; Organophosphate Poisoning; Organophosphorus Compounds; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Pyridostigmine Bromide

The efficacy of oxime (HI-6, toxogonin or PAM Cl) therapy against GF (cyclohexyl methylphosphonofluoridate) poisoning was assessed in mice. It was found that the combinations of atropine and either toxogonin or HI-6 were effective therapies against GF poisoning. PAM therapy was ineffective. HI-6 was the only oxime which reactivated GF inhibited acetylcholinesterase. This might explain the reason why the HI-6 treated mice appeared to recover more quickly from the incapacitating effects following GF poisoning.

Topics: Animals; Antidotes; Atropine; Chemical Warfare Agents; Cholinesterase Reactivators; In Vitro Techniques; Lethal Dose 50; Male; Mice; Mice, Inbred Strains; Nervous System Diseases; Obidoxime Chloride; Organophosphate Poisoning; Organophosphorus Compounds; Oximes; Pralidoxime Compounds; Pyridinium Compounds

Isolated rat diaphragm preparations treated with soman or with the irreversible and oxime resistant cholinesterase (ChE) inhibitor S27 showed a considerable recovery of neuromuscular transmission (NMT) during incubation with the (bis)pyridinium oximes HI-6, HGG-12, P2S and obidoxime. In the soman-treated preparations this NMT recovery was predominantly caused by reactivation of acetylcholinesterase (AChE) but in the S27-treated preparations it was caused by a direct (pharmacological) effect unrelated to enzyme reactivation. Atropinized rats were artificially ventilated after injection with 3 x LD50 soman for 3 h and then treated with HI-6, i.e. at a time when oxime reactivation of soman inhibited ChE is no longer possible. Nevertheless, these rats started to breathe spontaneously and 50-60% survived more than 24 h, whereas all control animals (saline instead of HI-6) died within 10 min after artificial ventilation was terminated. In such animals no significant reactivation of ChE activity at various time intervals following HI-6 treatment was found, either in the diaphragms or in the brains. There was a significant amount of NMT (50%) in vitro in diaphragms obtained from these animals. This NMT did not improve in vitro in the presence of HI-6 and was not inhibited by soman administered to the medium. It is concluded that in this case the NMT found was based on synaptic adaptation to the continued inhibition of ChE and that the survival of the animals might be due to a combination of this synaptic adaptation and central direct effects of HI-6.

Topics: Animals; Antidotes; Blood-Brain Barrier; Cholinesterase Reactivators; Diaphragm; In Vitro Techniques; Male; Neuromuscular Junction; Obidoxime Chloride; Organophosphate Poisoning; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rats; Respiratory Insufficiency; Synaptic Transmission

1. The dispositions of the acetylcholinesterase reactivators: 2PAM-I, TMB4 and R665, labelled with 14C on the oxime group, have been studied in normal rats and rats poisoned by the organophosphates Soman and A4. 2. For all three compounds, radioactivity was eliminated mostly in the urine (60-90% dose in 24 h). Faecal elimination was low (5.8-17.2% in 72 h). 3. All three compounds concentrated in kidney, but only 2PAM-I and R665 concentrated in liver. TMB4 and R665 concentrated in mucopolysaccharide-containing tissues such as cartilage and intervertebral disc. Other tissues were weakly and uniformly labelled. Soman poisoning does not modify the kinetic parameters of both compounds, but A4 poisoning increases 2PAM-I tissue concentration. 4. Chromatography of urine and plasma showed only unchanged 2PAM-I, TMB4 and R665 in both healthy and poisoned animals. Despite the high concentration of 2PAM-I and R665 in liver, these oximes are not metabolized.

Topics: Acetylcholinesterase; Animals; Carbon Radioisotopes; Cholinesterase Reactivators; Male; Organophosphate Poisoning; Oximes; Poisoning; Pralidoxime Compounds; Rats; Rats, Inbred Strains; Tissue Distribution; Trimedoxime

1. The effect of cold environment on the acute toxicity of organophosphates (OP), without and with atropine-oxime treatment, was studied in rats and mice by exposing them to +5 and -5 degrees C temperature. The tested OPs and oximes (given intraperitoneally) were diisopropylfluorophosphate (DFP), isopropyl methylphosphonofluoridate (sarin) and dichlorovinyl phosphate (DDVP), pralidoxime (PAM) and obidoxime. 2. An exposure to low environmental temperature decreased the effectiveness of atropine-oxime therapy in OP poisoned rats and mice, evaluated by means of acute LD50 values. 3. The lowering of environmental temperature did not influence the ability of PAM to reactivate tissue cholinesterase in rats intoxicated by 0.5 x LD50 doses of DFP. 4. The acute toxicity of atropine and oximes was not affected by cold environment in rats, but in mice it was increased by 1.1-2.1 times. 5. The decrease in the effectiveness of atropine-oxime therapy at cold environment may be explained by the observation that the cold temperature sensitizes the animals to the inhibition of brain acetylcholinesterase by OP.

Topics: Animals; Antidotes; Atropine; Carboxylic Ester Hydrolases; Cholinesterase Reactivators; Cold Temperature; Enzyme Reactivators; Isoflurophate; Lethal Dose 50; Mice; Obidoxime Chloride; Organophosphate Poisoning; Oximes; Pralidoxime Compounds; Rats; Rats, Inbred F344

Topics: Accidents; Atropine; Child, Preschool; Drug Therapy, Combination; Fenthion; Humans; Male; Muscle Tonus; Organophosphate Poisoning; Pesticides; Pralidoxime Compounds; Respiration; Respiration, Artificial

A comparison of serum concentrations of the oximes HI-6 [1-(((4-aminocarbonyl)-pyridino)methoxy)methyl)-2(hydroxy imino)methyl- pyridinium dichloride], PAM [2-[hydroxyimino)methyl-1-methylpyridinium chloride], and obidoxime [1,1'-(oxybis(methylene]bis(4-((hydroxyimino) methyl)-pyridinium dichloride] to the efficacy against sarin (350 micrograms/kg; sc) lethality was evaluated in rats. The oximes were administered prophylactically by means of Alzet osmotic minipumps. Atropine (17.4 mg/kg; im) was administered immediately following sarin (350 micrograms/kg; sc) administration. At serum concentrations of 3.6, 3.6, and 3.3 micrograms/ml for HI-6, obidoxime, and PAM, respectively, the 24-hr mortality following sarin poisoning was 0, 90, and 20%. The serum oxime concentrations (ED50 values) for HI-6, obidoxime, and PAM against a 3 LD50 dose of sarin were 0.72, 9.05, and 2.56 micrograms/ml, respectively. HI-6 was determined to be the most efficacious oxime when combined with atropine against sarin poisoning followed in order by PAM and obidoxime.

Topics: Acetylcholinesterase; Animals; Male; Obidoxime Chloride; Organophosphate Poisoning; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rats; Rats, Inbred Strains; Sarin

Topics: Adolescent; Adult; Aged; Antidotes; Butyrylcholinesterase; Cholinesterase Reactivators; Cholinesterases; Female; Humans; Male; Middle Aged; Organophosphate Poisoning; Pralidoxime Compounds

Organophosphate insecticides are widely used agents which are quickly absorbed through the skin and mucous membranes. The effects of acute exposure to these agents can be severe and intensive therapy may be required. Specific drugs are available to reverse the muscarinic, nicotinic and central effects of these poisons. When given early they are very effective and early diagnosis and treatment may therefore be life-saving. A case of acute poisoning with an organophosphate anticholinesterase insecticide is reported. The signs and symptoms of acute poisoning are described and a rational approach to specific treatment is discussed.

Topics: Acute Disease; Adult; Atropine; Cholinesterase Reactivators; Critical Care; Humans; Insecticides; Male; Organophosphate Poisoning; Organothiophosphates; Organothiophosphorus Compounds; Pralidoxime Compounds

Groups of guinea pigs were injected with a range of dosages for sarin (0, 140, 279, 557 micrograms/kg) followed by pralidoxime (2-PAM) and atropine sulfate (16 mg/kg). Poisoning by sarin in these animals elevated plasma pralidoxime content in a dose-dependent manner within 10 min of intoxication. Plasma levels after administration of 3.12 mg/kg of 2-PAM were elevated from a control mean of 6.18 micrograms/ml to a maximum of 13.78 micrograms/ml in animals given 557 micrograms/kg of sarin at 2 min after the injection of the therapeutic compounds. This suggests that pathophysiological changes following intoxication by potent inhibitors of cholinesterase result in a decrease in the rate and extent of distribution of therapeutic compounds. This effect is most likely a consequence of changes in cardiovascular functions influencing blood flow to various organs.

Topics: Animals; Guinea Pigs; Organophosphate Poisoning; Pralidoxime Compounds; Regional Blood Flow; Sarin

It has been shown that HI-6 was the most potent oxime so far known in poisoning by sarin, VX , and soman, but its protective effect in tabun poisoning, allegedly due to poor reactivation of inhibited ChE, was much less pronounced. We have found that the thiocholine-like analog of tabun , O-ethyl, N-N- dimethyamino -S-(2-diethylaminoethyl)- thiophosphatemethylsul fomethylate (Ta-S-N+), was very useful in resolving this problem and established the relationship between reactivating and protective effects of PAM-2 Cl, HI-6, and HGG-12 in rats. PAM-2 Cl (protective ratio (PR) = 22.1) and HI-6 (PR = 24.8), combined with atropine, were very effective against Ta-S-N+ poisoning and reactivating inhibited RBC AChE in vitro and rat blood ChE in vivo. The inefficiency of PAM-2 Cl (PR = 1.6) and HI-6 (PR = 2) in tabun poisoning was due to their inadequacy to reactive tabun -inhibited ChEs . The protective effects of HGG-12 in tabun (PR = 2.8) and Ta-S-N+ poisoning (PR = 2.6) were low, and in the absence of any reactivation of inhibited ChEs , have been attributed to its direct pharmacological effects, which were much more potent in the comparison with PAM-2 Cl or HI-6. It is concluded that the reactivation of inhibited ChE is of decisive importance in the efficient protection in poisoning by tabun and other known chemical warfare nerve agents, whereas their direct pharmacological effects are of limited value, allowing survival of animals only against a few LD50s .

Topics: Animals; Atropine; Choline; Cholinesterase Reactivators; Cholinesterases; Female; Guinea Pigs; Heart; Humans; Lethal Dose 50; Male; Muscle Contraction; Muscle, Smooth; Organophosphate Poisoning; Organophosphates; Oximes; Phrenic Nerve; Pralidoxime Compounds; Pyridinium Compounds; Rats; Thiocholine

Acute sc toxicity of soman increased in the order, mice----rats----guinea pigs----dogs, being 12.6 times more toxic to dogs (LD50 = 0.05 mumol/kg) than to mice. It was 2.8 times more toxic than tabun to mice and 35 times more toxic to dogs. HI-6 was the least toxic and had similar toxicity values to the four animal species studied and HGG-12 the most toxic of the three oximes used. HGG-12 has shown the greatest interspecies variation (rats:dogs = 1:19.5). HI-6, HGG-12, and PAM-2 Cl (in conjunction with atropine and diazepam) revealed the best protective effect in soman-poisoned dogs, with the respective protective indices of 9, 6.3, and 3.5, followed by guinea pigs. In tabun poisoning the best, but relatively low, protective effect was found only in guinea pigs. The introduction of diazepam increased the protective effects of atropine-oxime combination in soman and tabun poisoning by 10 to 80%. We suggest that the high toxicity of soman and low toxicity of HI-6 may be anticipated in man. The inefficiency of HI-6, HGG-12, and PAM-2 Cl in tabun poisoning points either to the search of new compounds or to the use of the mixture of the oximes found to be effective against the known chemical warfare nerve agents.

Topics: Acetylcholinesterase; Animals; Antidotes; Atropine; Cholinesterase Inhibitors; Cholinesterase Reactivators; Diazepam; Dogs; Guinea Pigs; Lethal Dose 50; Male; Mice; Organophosphate Poisoning; Organophosphates; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rats; Soman; Species Specificity

Topics: Aged; Atropine; Cholinesterase Reactivators; Cholinesterases; Erythrocytes; Humans; Male; Middle Aged; Organophosphate Poisoning; Pralidoxime Compounds

Topics: Atropine; Child; Diphosphates; Drug-Related Side Effects and Adverse Reactions; Organophosphate Poisoning; Oximes; Parathion; Phosphorus; Poisons; Pralidoxime Compounds; Pyridines; Toxicology

Topics: Drug-Related Side Effects and Adverse Reactions; Methane; Organophosphate Poisoning; Phosphorus; Poisons; Pralidoxime Compounds

Topics: Blood Chemical Analysis; Chemistry, Pharmaceutical; Gas Poisoning; Injections, Intramuscular; Organophosphate Poisoning; Oximes; Phosphorus; Poisons; Pralidoxime Compounds; Pyridines; Toxicology

Topics: Atropine; Drug-Related Side Effects and Adverse Reactions; Iodides; Organophosphate Poisoning; Oximes; Phosphorus; Poisons; Pralidoxime Compounds; Pyridines

Topics: Biomedical Research; Hydroxylamines; Organophosphate Poisoning; Parathion; Pralidoxime Compounds; Pyridines

Topics: Hydroxylamines; Organophosphate Poisoning; Parathion; Pralidoxime Compounds; Pyridines

The soluble methanesulphonate of the oxime 2-hydroxyiminomethyl-N-methylpyridinium (P2S) has been used to treat animals poisoned with sarin or ethyl pyrophosphate. The effect of the size of the dose, and its time of administration in relation to poisoning, have been examined. This oxime is very efficient in conjunction with atropine when given either before or after poisoning. About 30 mg./kg. seems to be the optimum therapeutic dose of the methanesulphonate. The significance of this optimum is discussed in relation to the treatment of accidental poisoning by organophosphate insecticides in man.

Topics: Animals; Atropine; Diphosphates; Humans; Insecticides; Male; Mesylates; Organophosphate Poisoning; Oximes; Phosphates; Pralidoxime Compounds; Pyrans; Pyridinium Compounds; Sarin

The effect of 18 pyridinium aldoximes on diethylphosphoryl-acetocholinesterase in vitro and the protection against lethal poisoning by ethyl pyrophosphate (TEPP) in mice pretreated with 0.095 m.mole/kg. of these oximes was investigated. Monoximes and dioximes of polymethylenebispyridinium compounds were studied in greater detail since they were up to 22 times more potent than pyridine-2-aldoxime methiodide (2-hydroxyiminomethyl-N-methylpyridinium iodide) in reactivating diethylphosphoryl-acetocholinesterase in vitro and protected mice against lethal poisoning by up to 15 LD100 of ethyl pyrophosphate. These oximes were also up to 52 times more potent than pyridine-2-aldoxime methiodide in reactivating di-isopropylphosphoryl-acetocholinesterase in vitro and were effective in preventing lethal poisoning by dyflos (di-isopropyl phosphorofluoridate). The antidotal action against diethyl phosphostigmine (Ro 3-0340) was even greater than that against ethyl pyrophosphate. Some of the most effective oximes had antidotal actions in poisoning by ethyl pyrophosphate, diethyl phosphostigmine and dyflos when given in 0.0095 m.mole/kg. and this effect was enhanced by 1 mg./kg. atropine sulphate. In vivo reactivation of diethylphosphoryl-acetocholinesterases by 0.0095 or 0.095 m.mole/kg. of oximes of polymethylenebispyridinium compounds was demonstrated in blood but not in brain. Atropine-like and neuromuscular blocking activities were studied on isolated organs and protection against lethal doses of neostigmine and related anticholinesterases were also investigated. Some of the oximes of polymethylenebispyridinium compounds have, relative to pyridine-2-aldoxime methiodide, a higher therapeutic ratio in mice and considerably greater water-solubility. The possible advantages to be gained from their use in preference to pyridine-2-aldoxime methiodide are discussed.

Topics: Animals; Antidotes; Atropine; Cholinesterase Inhibitors; Hydroxylamines; Isoflurophate; Mice; Neostigmine; Organophosphate Poisoning; Oximes; Phosphates; Pralidoxime Compounds; Pyrans; Pyridines; Pyridinium Compounds

Topics: Antidotes; Mesylates; Organophosphate Poisoning; Pralidoxime Compounds; Pyridines; Pyridinium Compounds

Topics: Drug-Related Side Effects and Adverse Reactions; Organophosphate Poisoning; Phosphates; Picolines; Pralidoxime Compounds

Topics: Organophosphate Poisoning; Parathion; Pralidoxime Compounds; Pyridines

Topics: Diacetyl; Drug-Related Side Effects and Adverse Reactions; Hydroxylamines; Organophosphate Poisoning; Phosphates; Pralidoxime Compounds; Pyridines

Three oximes, monoisonitrosoacetone (MINA), pyridine-2-aldoxime methiodide (PAM) and diacetylmonoxime (DAM), have been examined in combination with atropine as antidotes in sarin poisoning. When treatment was administered 15 min. before sarin, atropine enhanced the protective effect of MINA and DAM 2 to 3 times and of PAM 9 to 10 times in mice and rats. In mice, rats, and guinea-pigs, atropine increased by no more than 2 times the protective effect of all three oximes when given 30 sec. after sarin. Atropine given to monkeys 1 min. after sarin raised the LD50 approximately 3 times. When given in conjunction with MINA or DAM, the LD50 of sarin was raised 7 to 14 times.

Topics: Animals; Antidotes; Atropine; Cholinesterase Inhibitors; Diacetyl; Drug-Related Side Effects and Adverse Reactions; Guinea Pigs; Hydroxylamines; Mice; Organophosphate Poisoning; Oximes; Phosphates; Pralidoxime Compounds; Rats; Sarin

Topics: Cholinesterase Inhibitors; Organophosphate Poisoning; Organophosphates; Phosphates; Picolines; Pralidoxime Compounds; Sarin