Michael Eddleston

Publications of Michael Eddleston

• Effects of a provincial ban of two toxic organophosphorus insecticides on pesticide poisoning hospital admissions.

  Authors: Michael Eddleston, Sriyantha Adhikari, Samitha Egodage, Hasantha Ranganath, Fahim Mohamed, Gamini Manuweera, Shifa Azher, Shaluka Jayamanne, Edmund Juzczak, Mh Rezvi Sheriff, Andrew H Dawson, Nick A Buckley

  Clinical toxicology (Philadelphia, Pa.). 03/2012; 50(3):202-9.

  Pesticide self-poisoning causes one third of global suicides. Sri Lanka halved its suicide rate by banning WHO Class I organophosphorus (OP) insecticides and then endosulfan. However, poisoning withPesticide self-poisoning causes one third of global suicides. Sri Lanka halved its suicide rate by banning WHO Class I organophosphorus (OP) insecticides and then endosulfan. However, poisoning with Class II toxicity OPs, particularly dimethoate and fenthion, remains a problem. We aimed to determine the effect and feasibility of a ban of the two insecticides in one Sri Lankan district. Sale was banned in June 2003 in most of Polonnaruwa District, but not Anuradhapura District. Admissions with pesticide poisoning to the district general hospitals was prospectively recorded from 2002. Hospital admissions for dimethoate and fenthion poisoning fell by 43% after the ban in Polonnaruwa, while increasing by 23% in Anuradhapura. The pesticide case fatality fell from 14.4% to 9.0% in Polonnaruwa (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.41-0.84) and 11.3% to 10.6% in Anuradhapura (OR 0.93, 95%CI 0.70-1.25; p = 0.051). This reduction was not sustained, with case fatality in Polonnaruwa rising to 12.1% in 2006-2007. Further data analysis indicated that the fall in case fatality had actually been due to a coincidental reduction in case fatality for pesticide poisoning overall, in particular for paraquat poisoning. We found that the insecticides could be effectively banned from agricultural practice, as shown by the fall in hospital admissions, with few negative consequences. However, the ban had only a minor effect on pesticide poisoning deaths because it was too narrow. A study assessing the agricultural and health effects of a more comprehensive ban of highly toxic pesticides is necessary to determine the balance between increased costs of agriculture and reduced health care costs and fewer deaths.

• A role for solvents in the toxicity of agricultural organophosphorus pesticides.

  Authors: Michael Eddleston, Jonathan M Street, Ian Self, Adrian Thompson, Tim King, Nicola Williams, Gregorio Naredo, Kosala Dissanayake, Ly-Mee Yu, Franz Worek, Harald John, Sionagh Smith, Horst Thiermann, John B Harris, R Eddie Clutton

  Toxicology. 02/2012; 294(2-3):94-103.

  Organophosphorus (OP) insecticide self-poisoning is responsible for about one-quarter of global suicides. Treatment focuses on the fact that OP compounds inhibit acetylcholinesterase (AChE); however,Organophosphorus (OP) insecticide self-poisoning is responsible for about one-quarter of global suicides. Treatment focuses on the fact that OP compounds inhibit acetylcholinesterase (AChE); however, AChE-reactivating drugs do not benefit poisoned humans. We therefore studied the role of solvent coformulants in OP toxicity in a novel minipig model of agricultural OP poisoning. Gottingen minipigs were orally poisoned with clinically relevant doses of agricultural emulsifiable concentrate (EC) dimethoate, dimethoate active ingredient (AI) alone, or solvents. Cardiorespiratory physiology and neuromuscular (NMJ) function, blood AChE activity, and arterial lactate concentration were monitored for 12h to assess poisoning severity. Poisoning with agricultural dimethoate EC40, but not saline, caused respiratory arrest within 30min, severe distributive shock and NMJ dysfunction, that was similar to human poisoning. Mean arterial lactate rose to 15.6 [SD 2.8] mM in poisoned pigs compared to 1.4 [0.4] in controls. Moderate toxicity resulted from poisoning with dimethoate AI alone, or the major solvent cyclohexanone. Combining dimethoate with cyclohexanone reproduced severe poisoning characteristic of agricultural dimethoate EC poisoning. A formulation without cyclohexanone showed less mammalian toxicity. These results indicate that solvents play a crucial role in dimethoate toxicity. Regulatory assessment of pesticide toxicity should include solvents as well as the AIs which currently dominate the assessment. Reformulation of OP insecticides to ensure that the agricultural product has lower mammalian toxicity could result in fewer deaths after suicidal ingestion and rapidly reduce global suicide rates.

• Mechanisms for an effect of acetylcysteine on renal function after exposure to radio-graphic contrast material: study protocol.

  Authors: Euan A Sandilands, Sharon Cameron, Frances Paterson, Sam Donaldson, Lesley Briody, Jane Crowe, Julie Donnelly, Adrian Thompson, Neil R Johnston, Ivor Mackenzie, Neal Uren, Jane Goddard, David J Webb, Ian L Megson, Nicholas Bateman, Michael Eddleston

  BMC clinical pharmacology. 01/2012; 12:3.

  ABSTRACT: Contrast-induced nephropathy is a common complication of contrast administration in patients with chronic kidney disease and diabetes. Its pathophysiology is not well understood; similarlyABSTRACT: Contrast-induced nephropathy is a common complication of contrast administration in patients with chronic kidney disease and diabetes. Its pathophysiology is not well understood; similarly the role of intravenous or oral acetylcysteine is unclear. Randomized controlled trials to date have been conducted without detailed knowledge of the effect of acetylcysteine on renal function. We are conducting a detailed mechanistic study of acetylcysteine on normal and impaired kidneys, both with and without contrast. This information would guide the choice of dose, route, and appropriate outcome measure for future clinical trials in patients with chronic kidney disease. We designed a 4-part study. We have set up randomised controlled cross-over studies to assess the effect of intravenous (50 mg/kg/hr for 2 hrs before contrast exposure, then 20 mg/kg/hr for 5 hrs) or oral acetylcysteine (1200 mg twice daily for 2 days, starting the day before contrast exposure) on renal function in normal and diseased kidneys, and normal kidneys exposed to contrast. We have also set up a parallel-group randomized controlled trial to assess the effect of intravenous or oral acetylcysteine on patients with chronic kidney disease stage III undergoing elective coronary angiography. The primary outcome is change in renal blood flow; secondary outcomes include change in glomerular filtration rate, tubular function, urinary proteins, and oxidative balance. Contrast-induced nephropathy represents a significant source of hospital morbidity and mortality. Over the last ten years, acetylcysteine has been administered prior to contrast to reduce the risk of contrast-induced nephropathy. Randomized controlled trials, however, have not reliably demonstrated renoprotection; a recent large randomized controlled trial assessing a dose of oral acetylcysteine selected without mechanistic insight did not reduce the incidence of contrast-induced nephropathy. Our study should reveal the mechanism of effect of acetylcysteine on renal function and identify an appropriate route for future dose response studies and in time randomized controlled trials. Clinical Trials.gov: NCT00558142; EudraCT: 2006-003509-18.

• A community-based cluster randomised trial of safe storage to reduce pesticide self-poisoning in rural Sri Lanka: study protocol.

  Authors: Melissa Pearson, Flemming Konradsen, David Gunnell, Andrew H Dawson, Ravi Pieris, Manjula Weerasinghe, Duleeka W Knipe, Shaluka Jayamanne, Chris Metcalfe, Keith Hawton, A Rajitha Wickramasinghe, W Atapattu, Palitha Bandara, Dhammika de Silva, Asanga Ranasinghe, Fahim Mohamed, Nicholas A Buckley, Indika Gawarammana, Michael Eddleston

  BMC public health. 11/2011; 11:879.

  The WHO recognises pesticide poisoning to be the single most important means of suicide globally. Pesticide self-poisoning is a major public health and clinical problem in rural Asia, where it hasThe WHO recognises pesticide poisoning to be the single most important means of suicide globally. Pesticide self-poisoning is a major public health and clinical problem in rural Asia, where it has led to case fatality ratios 20-30 times higher than self-poisoning in the developed world. One approach to reducing access to pesticides is for households to store pesticides in lockable "safe-storage" containers. However, before this approach can be promoted, evidence is required on its effectiveness and safety. A community-based cluster randomised controlled trial has been set up in 44,000 households in the North Central Province, Sri Lanka. A census is being performed, collecting baseline demographic data, socio-economic status, pesticide usage, self-harm and alcohol. Participating villages are then randomised and eligible households in the intervention arm given a lockable safe storage container for agrochemicals. The primary outcome will be incidence of pesticide self-poisoning over three years amongst individuals aged 14 years and over. 217,944 person years of follow-up are required in each arm to detect a 33% reduction in pesticide self-poisoning with 80% power at the 5% significance level. Secondary outcomes will include the incidence of all pesticide poisoning and total self-harm. This paper describes a large effectiveness study of a community intervention to reduce the burden of intentional poisoning in rural Sri Lanka. The study builds on a strong partnership between provincial health services, local and international researchers, and local communities. We discuss issues in relation to randomisation and contamination, engaging control villages, the intervention, and strategies to improve adherence.

• Quantification of pralidoxime (2-PAM) in urine by ion pair chromatography-diode array detection: application to in vivo samples from minipig.

  Authors: Harald John, Michael Eddleston, R Eddie Clutton, Franz Worek, Horst Thiermann

  Drug testing and analysis. 11/2011;

  Pralidoxime (2-PAM) is a monopyridinium oxime used as an antidote for the treatment of poisoning with organophosphorus (OP) compounds, for example, pesticides and nerve agents, reactivatingPralidoxime (2-PAM) is a monopyridinium oxime used as an antidote for the treatment of poisoning with organophosphorus (OP) compounds, for example, pesticides and nerve agents, reactivating OP-inhibited acetylcholinesterase. However, appropriate dosing and efficacy remains a matter of discussion requiring experimental data. Therefore, we developed and validated an ion pair chromatography-diode array detection (IPC-DAD) method suitable for quantitative analysis of 2-PAM in human and porcine urine. Before injection of 20 µl, urine was acidified with trichloroacetic acid, mixed with internal standard (pyridine-4-aldoxime, 4-PAO), and diluted with IPC solvent yielding a total dilution of 1:49.5 and a 100% recovery. Isocratic separation was carried out at 25 °C on a LiChrospher 60 RP-select B column (125 x 4.0 mm I.D.) using phosphate buffer (7.5 mM Na(2) HPO(4) , 7.5 mM KH(2) PO(4) , pH 2.6) mixed with octanesulfonate (2.5 mM) as ion pair reagent and acetonitrile (6% v/v) as organic modifier (1 ml/min). 2-PAM was detected at 293 nm and 4-PAO at 275 nm. The method is rugged, selective, and characterized by good intra-day and inter-day precision (RSD, 1.3-6.0%) and accuracy (88-100%) with a limit of detection at 4.9 µg/ml, a limit of quantification at 9.8 µg/ml, and a broad calibration range from 4.9-2500 µg/ml. The procedure was applied to urine samples obtained from dimethoate poisoned minipigs receiving 2-PAM therapy (intravenous bolus injection and infusion). Results indicate that 60-80% of infused 2-PAM is rapidly (within 1-2 h) excreted in the urine. Copyright © 2011 John Wiley & Sons, Ltd.

• A strategy for changing plasma pralidoxime kinetics and, perhaps, effect in organophosphorus insecticide poisoning.

  Authors: Michael Eddleston, Nicholas A Buckley

  Critical care medicine. 04/2011; 39(4):908-9.

• Oximes for acute organophosphate pesticide poisoning.

  Authors: Nick A Buckley, Michael Eddleston, Yi Li, Marc Bevan, Jane Robertson

  Cochrane database of systematic reviews (Online). 01/2011;

  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 toAcute 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 reactivate inhibited acetylcholinesterase. The clinical usefulness of oximes, such as pralidoxime and obidoxime, has been challenged over the past 20 years by physicians in many parts of the world. To quantify the effectiveness and safety of the administration of oximes in acute organophosphorus pesticide-poisoned patients. We searched both English and Chinese databases: Cochrane Injuries Group Specialised Register, Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE (Ovid SP), EMBASE (Ovid SP), ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED), ISI Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) and the Chinese language databases CNKI and WANGFANG. All searches were run in September 2009. Articles that could possibly be RCTs were retrieved to determine if they were randomised. The published methodology of three RCTs was not clear. We contacted the principal authors of these, but did not obtain further information. Seven pralidoxime RCTs were found. Three RCTs including 366 patients studied pralidoxime vs placebo and four RCTs including 479 patients compared two or more different doses. These trials found quite disparate results with treatment effects ranging from benefit to harm. However, many studies did not take into account several issues important for outcomes. In particular, baseline characteristics were not balanced, oxime doses varied widely, there were substantial delays to treatment, and the type of organophosphate was not taken into account. Only one RCT compared the World Health Organization (WHO) recommended doses with placebo. This trial showed no clinical benefits and a trend towards harm in all sub-groups, despite clear evidence that these doses reactivated acetylcholinesterase in the blood. Current evidence is insufficient to indicate whether oximes are harmful or beneficial. The WHO recommended regimen (30 mg/kg pralidoxime chloride bolus followed by 8 mg/kg/hr infusion) is not supported. Further RCTs are required to examine other strategies and regimens. There are many theoretical and practical reasons why oximes may not be useful, particularly for late presentations of dimethyl OP and those with a large excess of OP that simply re-inhibits reactivated enzymes. Future studies should screen for patient sub-groups that may benefit and may need flexible dosing strategies as clinical effectiveness and doses may depend on the type of OP.

• The use of mid-trial reviews for design modifications in small scale clinical studies.

  Authors: M R Sooriyarachchi, R V Jayatillake, H Ranganath, Michael Eddleston

  Contemporary clinical trials. 11/2010; 31(6):579-86.

  Many clinical studies such as those in the areas of toxicology, early phase clinical trials and bioequivalence studies use small samples due to the high cost of experimentation. These studies testMany clinical studies such as those in the areas of toxicology, early phase clinical trials and bioequivalence studies use small samples due to the high cost of experimentation. These studies test hypotheses based on small samples. These small samples result in low power and therefore even if the alternative hypotheses may be true the chance of it being rejected is low. The sample size is determined in an ad-hoc way and no proper scientific approach is used. Sample size calculations for clinical studies are usually conducted to determine the total number of patients needed to satisfy a specified power requirement, and their validity is dependent on pre-trial knowledge of nuisance parameters and distributional and modelling assumptions. Another short coming is that often hypotheses are tested without checking the assumptions required by the test. This paper looks at design reviews in the context of small samples. It examines several design modifications done with a small internal pilot study. In the past similar techniques have been applied to large scale studies but its performance is yet to be established in small scale clinical studies thus the contribution of this paper is in justifying the validity of these techniques for small samples too. The methodology is illustrated on an uncontrolled observational toxicology study. In this paper simulations will be presented showing that the design modifications would not influence the type-I error rate and that these would be successful in preserving the power, and the implementation of the design review procedure will be described.

• Simultaneous quantification of the organophosphorus pesticides dimethoate and omethoate in porcine plasma and urine by LC-ESI-MS/MS and flow-injection-ESI-MS/MS.

  Authors: Harald John, Michael Eddleston, R Eddie Clutton, Franz Worek, Horst Thiermann

  Journal of chromatography. B, Analytical technologies in the biomedical and life sciences. 05/2010; 878(17-18):1234-45.

  Dimethoate is an organophosphorus toxicant used in agri- and horticulture as a systemic broad-spectrum insecticide. It also exhibits toxic activity towards mammalian organism provoked by catalyticDimethoate is an organophosphorus toxicant used in agri- and horticulture as a systemic broad-spectrum insecticide. It also exhibits toxic activity towards mammalian organism provoked by catalytic desulfuration in the liver producing its oxon-derivative omethoate thus inhibiting acetylcholinesterase, initiating cholinergic crisis and ultimately leading to death by respiratory paralysis and cardiovascular collapse. Pharmaco- and toxicokinetic studies in animal models help to broaden basic understanding of medical intervention by antidotes and supportive care. Therefore, we developed and validated a LC-ESI-MS/MS method suitable for the simultaneous, selective, precise (RSD(intra-day) 1-8%; RSD(inter-day) 5-14%), accurate (intra-day: 95-107%; inter-day: 90-115%), and robust quantification of both pesticides from porcine urine and plasma after deproteinization by precipitation and extensive dilution (1:11,250 for plasma and 1:40,000 for urine). Accordingly, lower limits of quantification (0.24-0.49 microg/ml plasma and 0.78-1.56 microg/ml urine) and lower limits of detection (0.12-0.24 microg/ml plasma and 0.39-0.78 microg/ml urine) were equivalent to quite low absolute on-column amounts (1.1-2.1 pg for plasma and 2.0-3.9 pg for urine). The calibration range (0.24-250 microg/ml plasma and 0.78-200 microg/ml urine) was subdivided into two linear ranges (r(2)>or=0.998) each covering nearly two orders of magnitude. The lack of any interfering peak in 6 individual blank specimens from plasma and urine demonstrated the high selectivity of the method. Furthermore, extensive sample dilution causing lowest concentration of potentially interfering matrix ingredients prompted us to develop and validate an additional flow-injection method (FI-ESI-MS/MS). Validation characteristics were as good as for the chromatographic method but sample throughput was enhanced by a factor of 6. Effects on ionization provoked by plasma and urine matrix from 6 individuals as well as in the presence of therapeutics (antidotes) administered in an animal study were investigated systematically underlying in the reliability of the presented methods. Both methods were applied to porcine samples derived from an in vivo animal study.

• IV versus oral acetylcysteine.

  Authors: Nick A Buckley, Michael Eddleston, Yi Li

  Annals of emergency medicine. 04/2010; 55(4):393-4; author reply 394-5.

• The prevalence of previous self-harm amongst self-poisoning patients in Sri Lanka.

  Authors: Fahim Mohamed, Aravinda Perera, Kusal Wijayaweera, Keerthi Kularatne, Shaluka Jayamanne, Michael Eddleston, Andrew Dawson, Flemming Konradsen, David Gunnell

  Social psychiatry and psychiatric epidemiology. 04/2010; 46(6):517-20.

  One of the most important components of suicide prevention strategies is to target people who repeat self-harm as they are a high risk group. However, there is some evidence that the incidence ofOne of the most important components of suicide prevention strategies is to target people who repeat self-harm as they are a high risk group. However, there is some evidence that the incidence of repeat self-harm is lower in Asia than in the West. The objective of this study was to investigate the prevalence of previous self-harm among a consecutive series of self-harm patients presenting to hospitals in rural Sri Lanka. Six hundred and ninety-eight self-poisoning patients presenting to medical wards at two hospitals in Sri Lanka were interviewed about their previous episodes of self-harm. Sixty-one (8.7%, 95% CI 6.7-11%) patients reported at least one previous episode of self-harm [37 (10.7%) male, 24 (6.8%) female]; only 19 (2.7%, 95% CI 1.6-4.2%) patients had made more than one previous attempt. The low prevalence of previous self-harm is consistent with previous Asian research and is considerably lower than that seen in the West. Explanations for these low levels of repeat self-harm require investigation. Our data indicate that a focus on the aftercare of those who attempt suicide in Sri Lanka may have a smaller impact on suicide incidence than may be possible in the West.

• Hypothermia and Fever after organophosphorus poisoning in humans--a prospective case series.

  Authors: Alison Moffatt, Fahim Mohammed, Michael Eddleston, Shifa Azher, Peter Eyer, Nick A Buckley

  Journal of medical toxicology : official journal of the American College of Medical Toxicology. 03/2010; 6(4):379-85.

  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 aimThere 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.

• A prospective observational study of the clinical toxicology of glyphosate-containing herbicides in adults with acute self-poisoning.

  Authors: Darren M Roberts, Nick A Buckley, Fahim Mohamed, Michael Eddleston, Daniel A Goldstein, Akbar Mehrsheikh, Marian S Bleeke, Andrew H Dawson

  Clinical toxicology (Philadelphia, Pa.). 02/2010; 48(2):129-36.

  The case fatality from acute poisoning with glyphosate-containing herbicides is approximately 7.7% from the available studies but these have major limitations. Large prospective studies of patientsThe case fatality from acute poisoning with glyphosate-containing herbicides is approximately 7.7% from the available studies but these have major limitations. Large prospective studies of patients with self-poisoning from known formulations who present to primary or secondary hospitals are needed to better describe the outcome from acute poisoning with glyphosate-containing herbicides. Furthermore, the clinical utility of the glyphosate plasma concentration for predicting clinical outcomes and guiding treatment has not been determined. To describe the clinical outcomes, dose-response, and glyphosate kinetics following self-poisoning with glyphosate-containing herbicides. This prospective observational case series was conducted in two hospitals in Sri Lanka between 2002 and 2007. We included patients with a history of acute poisoning. Clinical observations were recorded until discharge or death. During a specified time period, we collected admission (n = 216, including five deaths) and serial (n = 26) blood samples in patients. Severity of poisoning was graded using simple clinical criteria. Six hundred one patients were identified; the majority ingested a concentrated formulation (36%, w/v glyphosate). Twenty-seven percent were asymptomatic, 63.7% had minor poisoning, and 5.5% of patients had moderate to severe poisoning. There were 19 deaths (case fatality 3.2%) with a median time to death of 20 h. Gastrointestinal symptoms, respiratory distress, hypotension, altered level of consciousness, and oliguria were observed in fatal cases. Death was strongly associated with greater age, larger ingestions, and high plasma glyphosate concentrations on admission (>734 microg/mL). The apparent elimination half-life of glyphosate was 3.1 h (95% CI = 2.7-3.6 h). Despite treatment in rural hospitals with limited resources, the mortality was 3.2%, which is lower than that reported in previous case series. More research is required to define the mechanism of toxicity, better predict the small group at risk of death, and find effective treatments.

• Acute human lethal toxicity of agricultural pesticides: a prospective cohort study.

  Authors: Andrew H Dawson, Michael Eddleston, Lalith Senarathna, Fahim Mohamed, Indika Gawarammana, Steven J Bowe, Gamini Manuweera, Nicholas A Buckley

  PLoS medicine. 01/2010; 7(10):e1000357.

  agricultural pesticide poisoning is a major public health problem in the developing world, killing at least 250,000-370,000 people each year. Targeted pesticide restrictions in Sri Lanka over theagricultural pesticide poisoning is a major public health problem in the developing world, killing at least 250,000-370,000 people each year. Targeted pesticide restrictions in Sri Lanka over the last 20 years have reduced pesticide deaths by 50% without decreasing agricultural output. However, regulatory decisions have thus far not been based on the human toxicity of formulated agricultural pesticides but on the surrogate of rat toxicity using pure unformulated pesticides. We aimed to determine the relative human toxicity of formulated agricultural pesticides to improve the effectiveness of regulatory policy. we examined the case fatality of different agricultural pesticides in a prospective cohort of patients presenting with pesticide self-poisoning to two clinical trial centers from April 2002 to November 2008. Identification of the pesticide ingested was based on history or positive identification of the container. A single pesticide was ingested by 9,302 patients. A specific pesticide was identified in 7,461 patients; 1,841 ingested an unknown pesticide. In a subset of 808 patients, the history of ingestion was confirmed by laboratory analysis in 95% of patients. There was a large variation in case fatality between pesticides-from 0% to 42%. This marked variation in lethality was observed for compounds within the same chemical and/or WHO toxicity classification of pesticides and for those used for similar agricultural indications. the human data provided toxicity rankings for some pesticides that contrasted strongly with the WHO toxicity classification based on rat toxicity. Basing regulation on human toxicity will make pesticide poisoning less hazardous, preventing hundreds of thousands of deaths globally without compromising agricultural needs. Ongoing monitoring of patterns of use and clinical toxicity for new pesticides is needed to identify highly toxic pesticides in a timely manner.

• Relationship between blood alcohol concentration on admission and outcome in dimethoate organophosphorus self-poisoning.

  Authors: Michael Eddleston, David Gunnell, Ludwig von Meyer, Peter Eyer

  British journal of clinical pharmacology. 12/2009; 68(6):916-9.

  WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Acute alcohol intoxication often complicates acute organophosphorus pesticide poisoning. * No data are available on how alcohol intoxication affectsWHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Acute alcohol intoxication often complicates acute organophosphorus pesticide poisoning. * No data are available on how alcohol intoxication affects outcome in acute organophosphorus pesticide poisoning. * In particular, the relationships between plasma alcohol concentration and plasma organophosphorus concentration or outcome are unclear. WHAT THIS STUDY ADDS: * Alcohol co-ingestion is associated with higher concentrations of the organophosphorus insecticide dimethoate, probably due to larger ingestions. * The higher concentrations of dimethoate found with alcohol co-ingestion increase the risk of death in dimethoate poisoning. There was no detectable effect of the alcohol itself on outcome. * Efforts to reduce deaths from insecticide self-poisoning may benefit from concurrent efforts to reduce alcohol consumption. AIMS: Many patients acutely poisoned with organophosphorus insecticides have co-ingested alcohol. Although clinical experience suggests that this makes management more difficult, the relationship between plasma concentration of alcohol and insecticide is unknown. We aimed to determine whether acute intoxication results in ingestion of larger quantities of insecticide in dimethoate self-poisoning and a worse clinical outcome. METHODS: We set up a prospective study of acute dimethoate self-poisoning in Sri Lankan district hospitals. An admission plasma sample was analysed to identify the ingested insecticide; in patients with detectable dimethoate, plasma alcohol was measured. RESULTS: Plasma from 37 of 72 (51.4%) dimethoate-poisoned patients had detectable alcohol [median concentration 1.10 g l(-1)[110 mg dl(-1)][interquartile range (IQR) 0.78-1.65]] a median of 3 h post ingestion. The median plasma dimethoate concentration was higher in patients who had ingested alcohol [479 micromol l(-1) (IQR 268-701) vs. 145 micromol l(-1) (IQR 25-337); P < 0.001]. Plasma dimethoate concentration was positively correlated with plasma alcohol (Spearman's rho= 0.34; P= 0.0032). The median alcohol concentration was higher in the 21 patients who died compared with survivors (0.94 vs. 0.0 g l(-1), P= 0.018). Risk of death was greater amongst individuals who consumed alcohol [odds ratio (OR) 4.3, 95% confidence interval (CI) 1.2, 16.4]; this risk was abolished by controlling for dimethoate concentration (OR 0.3, 95% CI 0.0, 8.8), indicating that deaths were not due to the direct toxic effects of alcohol. CONCLUSIONS: Alcohol co-ingestion is associated with higher plasma concentrations of dimethoate and increased risk of death. Larger studies are required to assess this finding's generalizability, since efforts to reduce deaths from self-poisoning may benefit from concurrent efforts to reduce alcohol consumption.

• Evaluation of medical countermeasures against organophosphorus compounds: The value of experimental data and computer simulations.

  Authors: Franz Worek, Nadine Aurbek, Nadja M Herkert, Harald John, Michael Eddleston, Peter Eyer, Horst Thiermann

  Chemico-biological interactions. 11/2009;

  Despite extensive research for more than six decades on medical countermeasures against poisoning by organophosphorus compounds (OP) the treatment options are meagre. The presently establishedDespite 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.

• Pattern of pesticide storage before pesticide self-poisoning in rural Sri Lanka.

  Authors: Fahim Mohamed, Gamini Manuweera, David Gunnell, Shifa Azher, Michael Eddleston, Andrew Dawson, Flemming Konradsen

  BMC public health. 11/2009; 9(1):405.

  ABSTRACT: BACKGROUND: Deliberate self-poisoning with agricultural pesticides is the commonest means of suicide in rural Asia. It is mostly impulsive and facilitated by easy access to pesticides. TheABSTRACT: BACKGROUND: Deliberate self-poisoning with agricultural pesticides is the commonest means of suicide in rural Asia. It is mostly impulsive and facilitated by easy access to pesticides. The aim of this large observational study was to investigate the immediate source of pesticides used for self-harm to help inform suicide prevention strategies such as reducing domestic access to pesticides. METHODS: The study was conducted in a district hospital serving an agricultural region of Sri Lanka. Patients who had self-poisoned with pesticides and were admitted to the adult medical wards were interviewed by study doctors following initial resuscitation to identify the source of pesticides they have ingested. RESULTS: Of the 669 patients included in the analysis, 425 (63.5%) were male; the median age was 26 (IQR 20-36). In 511 (76%) cases, the pesticides had been stored either inside or immediately outside the house; among this group only eight patients obtained pesticides that were kept in a locked container. Ten percent (n = 67) of the patients used pesticides stored in the field while 14% (n=91) purchased pesticides from shops within a few hours of the episode. The most common reasons for choosing the particular pesticide for self-harm were its easy accessibility (n=311, 46%) or its popularity as a suicide agent in their village (n= 290, 43%). CONCLUSIONS: Three quarters of people who ingested pesticides in acts of self-harm used products that were available within the home or in close proximity; relatively few patients purchased the pesticide for the act. The study highlights the importance of reducing the accessibility of toxic pesticides in the domestic environment.

• Paradox findings may challenge orthodox reasoning in acute organophosphate poisoning.

  Authors: Peter Eyer, Franz Worek, Horst Thiermann, Michael Eddleston

  Chemico-biological interactions. 10/2009;

  It is generally accepted that inhibition of acetylcholinesterase (AChE) is the most important acute toxic action of organophosphorus compounds, leading to accumulation of acetylcholine followed by aIt is generally accepted that inhibition of acetylcholinesterase (AChE) is the most important acute toxic action of organophosphorus compounds, leading to accumulation of acetylcholine followed by a dysfunction of cholinergic signaling. However, the degree of AChE inhibition is not uniformly correlated with cholinergic dysfunction, probably because the excess of essential AChE varies among tissues. Moreover, the cholinergic system shows remarkable plasticity, allowing modulations to compensate for dysfunctions of the canonical pathway. A prominent example is the living (-/-) AChE knockout mouse. Clinical experience indicates that precipitous inhibition of AChE leads to more severe poisoning than more protracted yet finally complete inhibition. The former situation is seen in parathion, the latter in oxydemeton methyl poisoning. At first glance, this dichotomy is surprising since parathion is a pro-poison and has to be activated to the oxon, while the latter is still the ultimate inhibitor. Also oxime therapy in organophosphorus poisoning apparently gives perplexing results: Oximes are usually able to reactivate diethylphosphorylated AChE, but the efficiency may be occasionally markedly smaller than expected from kinetic data. Dimethylphosphorylated AChE is in general less amenable to oxime therapy, which largely fails in some cases of dimethoate poisoning where aging was much faster than expected from a dimethylphosphorylated enzyme. Similarly, poisoning by profenofos, an O,S-dialkyl phosphate, leads to a rapidly aged enzyme. Most surprisingly, these patients were usually well on admission, yet their erythrocyte AChE was completely inhibited. Analysis of the kinetic constants of the most important reaction pathways, determination of the reactant concentrations in vivo and comparison with computer simulations may reveal unexpected toxic reactions. Pertinent examples will be presented and the potentially underlying phenomena discussed.

• Acute intentional self-poisoning with a herbicide product containing fenoxaprop-P-ethyl, ethoxysulfuron, and isoxadifen ethyl: a prospective observational study.

  Authors: Shukry Zawahir, Darren M Roberts, Chathura Palangasinghe, Fahim Mohamed, Michael Eddleston, Andrew H Dawson, Nick A Buckley, Lingling Ren, Gregory A Medley, Indika Gawarammana

  Clinical toxicology (Philadelphia, Pa.). 08/2009;

  Background. Herbicides are commonly ingested for self-harm, but relatively little has been published on poisoning with herbicides other than paraquat and glyphosate. We report here a case series ofBackground. Herbicides are commonly ingested for self-harm, but relatively little has been published on poisoning with herbicides other than paraquat and glyphosate. We report here a case series of patients with acute exposure to a product containing the selective phenoxy herbicide compounds fenoxaprop-P-ethyl and ethoxysulfuron and a safener isoxadifen ethyl. Method. Clinical data on all patients presenting with Tiller Gold or Whip Super poisoning to two General Hospitals in Sri Lanka from 2002-2008 were collected prospectively until discharge. Results. Eighty-six patients with a history of Tiller Gold or Whip Super ingestion were included. The main clinical features were an epigastric burning sensation and vomiting; however, most of those who vomited had received gastric lavage or forced emesis. Eight patients had a reduced level of consciousness on admission (Glasgow coma scale 9-14) that resolved without intervention over several hours. Only symptomatic and supportive care was required. The median hospital stay was 1 day (IQR: 1-2) and the case fatality was zero (95% confidence interval: 0-4.2%). This low case fatality compared favorably with the case fatality of other common herbicides in our cohort: paraquat >40%, propanil >10%, 4-chloro-2-methylphenoxyacetic acid > 5%, and glyphosate >2%. Conclusion. This combination herbicide product appears to be safe in patients with acute self-poisoning, particularly in comparison with other herbicides, and causing few clinical features.

• Pralidoxime in acute organophosphorus insecticide poisoning--a randomised controlled trial.

  Authors: Michael Eddleston, Peter Eyer, Franz Worek, Edmund Juszczak, Nicola Alder, Fahim Mohamed, Lalith Senarathna, Ariyasena Hittarage, Shifa Azher, K Jeganathan, Shaluka Jayamanne, Ludwig von Meyer, Andrew H Dawson, Mohamed Hussain Rezvi Sheriff, Nick A Buckley

  PLoS medicine. 07/2009; 6(6):e1000104.

  BACKGROUND: Poisoning with organophosphorus (OP) insecticides is a major global public health problem, causing an estimated 200,000 deaths each year. Although the World Health Organization recommendsBACKGROUND: Poisoning with organophosphorus (OP) insecticides is a major global public health problem, causing an estimated 200,000 deaths each year. Although the World Health Organization recommends use of pralidoxime, this antidote's effectiveness remains unclear. We aimed to determine whether the addition of pralidoxime chloride to atropine and supportive care offers benefit. METHODS AND FINDINGS: We performed a double-blind randomised placebo-controlled trial of pralidoxime chloride (2 g loading dose over 20 min, followed by a constant infusion of 0.5 g/h for up to 7 d) versus saline in patients with organophosphorus insecticide self-poisoning. Mortality was the primary outcome; secondary outcomes included intubation, duration of intubation, and time to death. We measured baseline markers of exposure and pharmacodynamic markers of response to aid interpretation of clinical outcomes. Two hundred thirty-five patients were randomised to receive pralidoxime (121) or saline placebo (114). Pralidoxime produced substantial and moderate red cell acetylcholinesterase reactivation in patients poisoned by diethyl and dimethyl compounds, respectively. Mortality was nonsignificantly higher in patients receiving pralidoxime: 30/121 (24.8%) receiving pralidoxime died, compared with 18/114 (15.8%) receiving placebo (adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 0.88-3.26, p = 0.12). Incorporating the baseline amount of acetylcholinesterase already aged and plasma OP concentration into the analysis increased the HR for patients receiving pralidoxime compared to placebo, further decreasing the likelihood that pralidoxime is beneficial. The need for intubation was similar in both groups (pralidoxime 26/121 [21.5%], placebo 24/114 [21.1%], adjusted HR 1.27 [95% CI 0.71-2.29]). To reduce confounding due to ingestion of different insecticides, we further analysed patients with confirmed chlorpyrifos or dimethoate poisoning alone, finding no evidence of benefit. CONCLUSIONS: Despite clear reactivation of red cell acetylcholinesterase in diethyl organophosphorus pesticide poisoned patients, we found no evidence that this regimen improves survival or reduces need for intubation in patients with organophosphorus insecticide poisoning. The reason for this failure to benefit patients was not apparent. Further studies of different dose regimens or different oximes are required. TRIAL REGISTRATION: Controlled-trials.com ISRCTN55264358 Please see later in the article for Editors' Summary.