Publications by authors named "Michael Eddleston"

228 Publications

Trends in hospital presentations following analytically confirmed synthetic cannabinoid receptor agonist exposure before and after implementation of the 2016 UK Psychoactive Substances Act.

Addiction 2022 Jun 6. Epub 2022 Jun 6.

Translational and Clinical Research Institute, Newcastle University, Newcastle, UK.

Background And Aims: The United Kingdom (UK) Psychoactive Substances Act (PSA), implemented on the 26  May 2016, made the production, supply and sale of all non-exempted psychoactive substances illegal. The aim of this study was to measure trends in hospital presentations for severe toxicity following analytically confirmed synthetic cannabinoid receptor agonist (SCRA) exposure before and after implementation of the PSA.

Design: Observational study.

Setting: Thirty-four hospitals across the UK participating in the Identification of Novel Psychoactive Substances (IONA) study.

Participants: A total of 627 (79.9% male) consenting individuals who presented to participating hospitals between July 2015 and December 2019 with severe acute toxicity and suspected novel psychoactive substances exposure.

Measurements: Toxicological analyses of patient samples were conducted using liquid-chromatography tandem mass-spectrometry. Time-series analysis was conducted on the monthly number of patients with and without analytically confirmed SCRA exposure using Poisson segmented regression.

Findings: SCRAs were detected in 35.7% (n = 224) of patients. After adjusting for seasonality and the number of active sites, models showed no clear evidence of an upward or downward trend in the number of SCRA exposure cases in the period before (incidence rate ratio [IRR], 1.12; 95% CI, 0.99-1.26; P = 0.068) or after (IRR, 0.97; 95% CI, 0.94-1.01; P = 0.202) the implementation of the PSA. There was also no clear evidence of an upward or downward trend in non-SCRA exposure cases before (IRR, 1.12; 95% CI, 0.98-1.27; P = 0.105) or after (IRR, 1.01; 95% CI, 0.98-1.04; P = 0.478) implementation of the PSA.

Conclusions: There is no clear evidence of an upward or downward trend in the number of patients presenting to UK hospitals with severe acute toxicity following analytically confirmed synthetic cannabinoid receptor agonist exposure since the implementation of the Psychoactive Substances Act.
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http://dx.doi.org/10.1111/add.15967DOI Listing
June 2022

Trends in hospital presentations following analytically confirmed synthetic cannabinoid receptor agonist exposure before and after implementation of the 2016 UK Psychoactive Substances Act.

Addiction 2022 Jun 6. Epub 2022 Jun 6.

Translational and Clinical Research Institute, Newcastle University, Newcastle, UK.

Background And Aims: The United Kingdom (UK) Psychoactive Substances Act (PSA), implemented on the 26  May 2016, made the production, supply and sale of all non-exempted psychoactive substances illegal. The aim of this study was to measure trends in hospital presentations for severe toxicity following analytically confirmed synthetic cannabinoid receptor agonist (SCRA) exposure before and after implementation of the PSA.

Design: Observational study.

Setting: Thirty-four hospitals across the UK participating in the Identification of Novel Psychoactive Substances (IONA) study.

Participants: A total of 627 (79.9% male) consenting individuals who presented to participating hospitals between July 2015 and December 2019 with severe acute toxicity and suspected novel psychoactive substances exposure.

Measurements: Toxicological analyses of patient samples were conducted using liquid-chromatography tandem mass-spectrometry. Time-series analysis was conducted on the monthly number of patients with and without analytically confirmed SCRA exposure using Poisson segmented regression.

Findings: SCRAs were detected in 35.7% (n = 224) of patients. After adjusting for seasonality and the number of active sites, models showed no clear evidence of an upward or downward trend in the number of SCRA exposure cases in the period before (incidence rate ratio [IRR], 1.12; 95% CI, 0.99-1.26; P = 0.068) or after (IRR, 0.97; 95% CI, 0.94-1.01; P = 0.202) the implementation of the PSA. There was also no clear evidence of an upward or downward trend in non-SCRA exposure cases before (IRR, 1.12; 95% CI, 0.98-1.27; P = 0.105) or after (IRR, 1.01; 95% CI, 0.98-1.04; P = 0.478) implementation of the PSA.

Conclusions: There is no clear evidence of an upward or downward trend in the number of patients presenting to UK hospitals with severe acute toxicity following analytically confirmed synthetic cannabinoid receptor agonist exposure since the implementation of the Psychoactive Substances Act.
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http://dx.doi.org/10.1111/add.15967DOI Listing
June 2022

Toxicity of phosphate enemas - an updated review.

Clin Toxicol (Phila) 2022 06 5;60(6):672-680. Epub 2022 May 5.

Pharmacology, Toxicology & Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.

Introduction: Enemas containing phosphate are widely prescribed and may cause important adverse effects. A systemic review published in 2007 reported the literature on the adverse effects of phosphate enemas from January 1957 to March 2007 and identified 12 deaths. These were thought due to electrolyte disturbances, heart failure and kidney injury. These data raised concerns about the use of phosphate enemas in routine practice. Newer osmotic-based enema alternatives are now available that do not contain absorbable ions. We sought to review the literature since this review and evaluate the latest data on the toxicity of phosphate-containing enemas. To gain a fuller picture we included case series and larger studies as well as case reports.

Objectives: To review the toxicity of phosphate enemas, particularly with respect to acute metabolic consequences and their associated clinical features. To identify risk factors for metabolic toxicity and consider whether phosphate enemas should be relatively contra-indicated in specific patient groups.

Methods: A systematic literature review was conducted in PubMed, Google Scholar, and Cochrane Reviews (2005-2021) using the search terms 'phosphate enema or sodium phosphate enema' or 'phosphate-based enema' or (phosphate AND enema) or (Fleet AND enema) or 'sodium phosphate laxatives' or 'sodium phosphate catharsis' or 'sodium phosphate cathartic'. Relevant papers were read, and data were extracted.

Results: The searches identified 489 papers of which 25 were relevant: seven papers were case reports or small case series of metabolic abnormalities from the use of phosphate enemas in nine children, six were case reports on 16 adults. Nine papers were large case series or clinical studies that included data on systemic metabolic effects, of varying size from 24 healthy volunteers to a cohort of 70,499 patients. Case reports identified seven adult deaths but none in children. Children most often presented with decreased consciousness (6/9), and tetany (4/9). In adults overall only five cases had clinical features reported, hypotension was seen in four and QT prolongation in two. Treatment was generally symptomatic, with intravenous fluid and calcium salts for electrolyte changes and hypocalcaemia, and vasopressors for severe hypotension. Haemodialysis was used in three children and peritoneal dialysis in one, all of whom survived. In adults, haemodialysis did not prevent death in two of four cases in whom it was used. Common factors underlying toxicity were inappropriately high phosphate dose, or enema retention, both resulting in greater absorption of phosphate. Associated pre-disposing conditions included Hirschsprung disease in children and co-morbidity and renal impairment (2/5) in older adults. Absolute reported changes in serum phosphate or calcium were not accurate indicators of outcome. Larger case series and clinical trials confirm an acute effect of phosphate enemas on serum phosphate, which was related to both dose and retention time. These effects were not seen with non-phosphate preparations. In these cases series, adverse events were rarely reported.

Conclusion: Phosphate enemas are potentially toxic, particularly in young children with Hirschsprung disease and in the elderly with co-morbidity. Raised awareness of the risk of phosphate enemas is still required. Other less toxic enema preparations are available and should be considered in patients at extremes of age. If phosphate enemas are the only clinical option careful monitoring of biochemical sequelae should be undertaken.
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http://dx.doi.org/10.1080/15563650.2022.2054424DOI Listing
June 2022

Peppermint protocol: first results for gas chromatography-ion mobility spectrometry.

J Breath Res 2022 May 26;16(3). Epub 2022 May 26.

Centre for Analytical Science, Department of Chemistry, Loughborough University, Loughborough, United Kingdom.

Theseeks to inform the standardisation of breath analysis methods. Fivewith gas chromatography-ion mobility spectrometry (GC-IMS), operating in the positive mode with a tritiumH 5.68 keV, 370 MBq ionisation source, were undertaken to provide benchmarkdata for this technique, to support its use in breath-testing, analysis, and research. Headspace analysis of a peppermint-oil capsule by GC-IMS with on-column injection (0.5 cm) identified 12 IMS responsive compounds, of which the four most abundant were: eucalyptol;-pinene;-pinene; and limonene. Elevated concentrations of these four compounds were identified in exhaled-breath following ingestion of a peppermint-oil capsule. An unidentified compound attributed as a volatile catabolite of peppermint-oil was also observed. The most intense exhaled peppermint-oil component was eucalyptol, which was selected as a peppermint marker for benchmarking GC-IMS. Twenty-five washout experiments monitored levels of exhaled eucalyptol, by GC-IMS with on-column injection (0.5 cm), at= 0 min, and then at+ 60,+ 90,+ 165,+ 285 and+ 360 min from ingestion of a peppermint capsule resulting in 148 peppermint breath analyses. Additionally, thedata was used to evaluate clinical deployments with a further five washout tests run in clinical settings generating an additional 35 breath samples. Regression analysis yielded an average extrapolated time taken for exhaled eucalyptol levels to return to baseline values to be 429 ± 62 min (±95% confidence-interval). The benchmark value was assigned to the lower 95% confidence-interval, 367 min. Further evaluation of the data indicated that the maximum number of volatile organic compounds discernible from a 0.5 cmbreath sample was 69, while the use of an in-line biofilter appeared to reduce this to 34.
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http://dx.doi.org/10.1088/1752-7163/ac6ca0DOI Listing
May 2022

Peppermint protocol: first results for gas chromatography-ion mobility spectrometry.

J Breath Res 2022 May 26;16(3). Epub 2022 May 26.

Centre for Analytical Science, Department of Chemistry, Loughborough University, Loughborough, United Kingdom.

Theseeks to inform the standardisation of breath analysis methods. Fivewith gas chromatography-ion mobility spectrometry (GC-IMS), operating in the positive mode with a tritiumH 5.68 keV, 370 MBq ionisation source, were undertaken to provide benchmarkdata for this technique, to support its use in breath-testing, analysis, and research. Headspace analysis of a peppermint-oil capsule by GC-IMS with on-column injection (0.5 cm) identified 12 IMS responsive compounds, of which the four most abundant were: eucalyptol;-pinene;-pinene; and limonene. Elevated concentrations of these four compounds were identified in exhaled-breath following ingestion of a peppermint-oil capsule. An unidentified compound attributed as a volatile catabolite of peppermint-oil was also observed. The most intense exhaled peppermint-oil component was eucalyptol, which was selected as a peppermint marker for benchmarking GC-IMS. Twenty-five washout experiments monitored levels of exhaled eucalyptol, by GC-IMS with on-column injection (0.5 cm), at= 0 min, and then at+ 60,+ 90,+ 165,+ 285 and+ 360 min from ingestion of a peppermint capsule resulting in 148 peppermint breath analyses. Additionally, thedata was used to evaluate clinical deployments with a further five washout tests run in clinical settings generating an additional 35 breath samples. Regression analysis yielded an average extrapolated time taken for exhaled eucalyptol levels to return to baseline values to be 429 ± 62 min (±95% confidence-interval). The benchmark value was assigned to the lower 95% confidence-interval, 367 min. Further evaluation of the data indicated that the maximum number of volatile organic compounds discernible from a 0.5 cmbreath sample was 69, while the use of an in-line biofilter appeared to reduce this to 34.
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http://dx.doi.org/10.1088/1752-7163/ac6ca0DOI Listing
May 2022

Fast and automated biomarker detection in breath samples with machine learning.

PLoS One 2022 12;17(4):e0265399. Epub 2022 Apr 12.

Computer Science Department, School of Science, Loughborough University, Loughborough, United Kingdom.

Volatile organic compounds (VOCs) in human breath can reveal a large spectrum of health conditions and can be used for fast, accurate and non-invasive diagnostics. Gas chromatography-mass spectrometry (GC-MS) is used to measure VOCs, but its application is limited by expert-driven data analysis that is time-consuming, subjective and may introduce errors. We propose a machine learning-based system to perform GC-MS data analysis that exploits deep learning pattern recognition ability to learn and automatically detect VOCs directly from raw data, thus bypassing expert-led processing. We evaluate this new approach on clinical samples and with four types of convolutional neural networks (CNNs): VGG16, VGG-like, densely connected and residual CNNs. The proposed machine learning methods showed to outperform the expert-led analysis by detecting a significantly higher number of VOCs in just a fraction of time while maintaining high specificity. These results suggest that the proposed novel approach can help the large-scale deployment of breath-based diagnosis by reducing time and cost, and increasing accuracy and consistency.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0265399PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9004778PMC
April 2022

Impact of large-scale, government legislated and funded organic farming training on pesticide use in Andhra Pradesh, India: a cross-sectional study.

Lancet Planet Health 2022 04;6(4):e310-e319

Centre for Pesticide Suicide Prevention, University of Edinburgh, Edinburgh, UK.

Background: The use of pesticides in agriculture has been associated with the destruction of biodiversity and damage to human health. A marked reduction in pesticide use is urgently required globally, but whether this can be achieved rapidly and at scale is unclear. We aimed to assess whether government-legislated and funded organic farming training in Andhra Pradesh, India, reduced pesticide use by farmers and sales of pesticides by pesticide retailers.

Methods: We did a cross-sectional survey between Aug 11 and Nov 26, 2020, among farmers and pesticide retailers in Kurnool District of Andhra Pradesh (India). We assessed the impact of the Andhra Pradesh Community Managed Natural Farming (APCNF) programme, which aims to transition 100% of the agricultural land of Andhra Pradesh (population approximately 49 million, 6 million of whom are farmers) to organic farming practices by 2030. We did cross-sectional phone interview surveys of farmers and face-to-face surveys of pesticide retailers. We used multivariable Poisson regression models to estimate relative risks (RRs) and logistic regression models to estimate odds ratios (ORs).

Findings: 962 farmers were invited to participate, of whom 894 (93%) consented (709 conventional farmers and 149 APCNF farmers). 47 pesticide retailers were invited to participate, of whom 38 (81%) consented. APCNF farmers had practised APCNF for a median of 2 years (IQR 1-3). APCNF farmers were less likely to use pesticides than conventional farmers (adjusted RR 0·65 [95% CI 0·57-0·75]), although pesticide use remained high among both APCNF and conventional farmers (73 [49%] of 148 APCNF farmers vs 695 [99%] of 700 conventional farmers; p<0·0001). APCNF farmers had lower pesticide expenditures than conventional farmers (median US$0 [IQR 0-170] for APCNF farmers vs $175 [91-281] for conventional farmers; p=0·0001). Increased frequency of meeting with agricultural extension workers was associated with reduced pesticide use among ACPNF farmers. Seven (18%) of 38 retailers reported a decrease in sales of pesticides in the past 4 years; no difference in the odds of reporting a decrease in pesticide sales in the past 4 years was identified between APCNF retailers and conventional retailers (OR 0·95 [95% CI 0·58-1·57]).

Interpretation: Despite a major government drive for organic agriculture, about half of APCNF farmers continued to use pesticides and no impact on pesticide sales at local retailers was observed. A combination of policy instruments (eg, bans on highly hazardous pesticides), not solely training for farmers, might be needed to eliminate pesticide use in agriculture.

Funding: Scottish Funding Council and UK Research and Innovation.
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http://dx.doi.org/10.1016/S2542-5196(22)00062-6DOI Listing
April 2022

Impact of large-scale, government legislated and funded organic farming training on pesticide use in Andhra Pradesh, India: a cross-sectional study.

Lancet Planet Health 2022 04;6(4):e310-e319

Centre for Pesticide Suicide Prevention, University of Edinburgh, Edinburgh, UK.

Background: The use of pesticides in agriculture has been associated with the destruction of biodiversity and damage to human health. A marked reduction in pesticide use is urgently required globally, but whether this can be achieved rapidly and at scale is unclear. We aimed to assess whether government-legislated and funded organic farming training in Andhra Pradesh, India, reduced pesticide use by farmers and sales of pesticides by pesticide retailers.

Methods: We did a cross-sectional survey between Aug 11 and Nov 26, 2020, among farmers and pesticide retailers in Kurnool District of Andhra Pradesh (India). We assessed the impact of the Andhra Pradesh Community Managed Natural Farming (APCNF) programme, which aims to transition 100% of the agricultural land of Andhra Pradesh (population approximately 49 million, 6 million of whom are farmers) to organic farming practices by 2030. We did cross-sectional phone interview surveys of farmers and face-to-face surveys of pesticide retailers. We used multivariable Poisson regression models to estimate relative risks (RRs) and logistic regression models to estimate odds ratios (ORs).

Findings: 962 farmers were invited to participate, of whom 894 (93%) consented (709 conventional farmers and 149 APCNF farmers). 47 pesticide retailers were invited to participate, of whom 38 (81%) consented. APCNF farmers had practised APCNF for a median of 2 years (IQR 1-3). APCNF farmers were less likely to use pesticides than conventional farmers (adjusted RR 0·65 [95% CI 0·57-0·75]), although pesticide use remained high among both APCNF and conventional farmers (73 [49%] of 148 APCNF farmers vs 695 [99%] of 700 conventional farmers; p<0·0001). APCNF farmers had lower pesticide expenditures than conventional farmers (median US$0 [IQR 0-170] for APCNF farmers vs $175 [91-281] for conventional farmers; p=0·0001). Increased frequency of meeting with agricultural extension workers was associated with reduced pesticide use among ACPNF farmers. Seven (18%) of 38 retailers reported a decrease in sales of pesticides in the past 4 years; no difference in the odds of reporting a decrease in pesticide sales in the past 4 years was identified between APCNF retailers and conventional retailers (OR 0·95 [95% CI 0·58-1·57]).

Interpretation: Despite a major government drive for organic agriculture, about half of APCNF farmers continued to use pesticides and no impact on pesticide sales at local retailers was observed. A combination of policy instruments (eg, bans on highly hazardous pesticides), not solely training for farmers, might be needed to eliminate pesticide use in agriculture.

Funding: Scottish Funding Council and UK Research and Innovation.
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http://dx.doi.org/10.1016/S2542-5196(22)00062-6DOI Listing
April 2022

Lung injury caused by aspiration of organophosphorus insecticide and gastric contents in pigs.

Clin Toxicol (Phila) 2022 06 11;60(6):725-736. Epub 2022 Feb 11.

Pharmacology, Toxicology, and Therapeutics Department, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.

Introduction: Patients who require mechanical ventilation after self-poisoning with ingested organophosphorus (OP) insecticides often die. Aspiration of stomach contents may contribute to lung injury and lethality. This study was designed to assess the severity of direct and indirect pulmonary injury created by pulmonary instillation of mixtures of OP insecticide, solvent (Solv) and porcine gastric juice (GJ) compared to controls.

Methods: Terminally anaesthetised minipigs (groups  = 5) were exposed to sham bronchoscopy or given mixtures (0.5 mL/kg) of: saline, GJ, OP insecticide and GJ (OP + GJ), or Solv and GJ (Solv + GJ), placed into the right lung, and monitored for 48 h. Lung injury was assessed through analysis of bronchoalveolar lavage fluid (BALF), computed tomography and histopathology.

Results: OP + GJ created a direct lung injury consisting of neutrophil infiltration, oedema and haemorrhage, as well as indirect injury to the other lung. OP + GJ directly-injured lung parenchyma had increased concentrations of BALF protein, albumin, IL-6, IL-8 and C-reactive protein (CRP) at 24 h ( < 0.05), and BALF protein, albumin and CRP at 48 h ( < 0.05), when compared with controls. Aspiration of GJ produced similar direct effects to OP + GJ but less indirect lung injury. Lung injury was less severe after Solv + GJ, for combined lung histopathology scores (vs. OP + GJ,  < 0.05) and for the proportion of directly-injured lung that was poorly/non-aerated at 48 h.

Conclusion: Pulmonary instillation of OP + GJ created more lung damage than controls or Solv + GJ. In patients with severe OP insecticide poisoning and reduced consciousness, early airway protection is likely to reduce pulmonary damage.
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http://dx.doi.org/10.1080/15563650.2022.2028803DOI Listing
June 2022

Acetylcysteine has No Mechanistic Effect in Patients at Risk of Contrast-Induced Nephropathy: A Failure of Academic Clinical Science.

Clin Pharmacol Ther 2022 Jun 23;111(6):1222-1238. Epub 2022 Feb 23.

Pharmacology, Toxicology, and Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.

Contrast-induced nephropathy (CIN) is a major complication of imaging in patients with chronic kidney disease (CKD). The publication of an academic randomized controlled trial (RCT; n = 83) reporting oral (N)-acetylcysteine (NAC) to reduce CIN led to > 70 clinical trials, 23 systematic reviews, and 2 large RCTs showing no benefit. However, no mechanistic studies were conducted to determine how NAC might work; proposed mechanisms included renal artery vasodilatation and antioxidant boosting. We evaluated the proposed mechanisms of NAC action in participants with healthy and diseased kidneys. Four substudies were performed. Two randomized, double-blind, placebo-controlled, three-period crossover studies (n = 8) assessed the effect of oral and intravenous (i.v.) NAC in healthy kidneys in the presence/absence of iso-osmolar contrast (iodixanol). A third crossover study in patients with CKD stage III (CKD3) (n = 8) assessed the effect of oral and i.v. NAC without contrast. A three-arm randomized, double-blind, placebo-controlled parallel-group study, recruiting patients with CKD3 (n = 66) undergoing coronary angiography, assessed the effect of oral and i.v. NAC in the presence of contrast. We recorded systemic (blood pressure and heart rate) and renal (renal blood flow (RBF) and glomerular filtration rate (GFR)) hemodynamics, and antioxidant status, plus biomarkers of renal injury in patients with CKD3 undergoing angiography. Primary outcome for all studies was RBF over 8 hours after the start of i.v. NAC/placebo. NAC at doses used in previous trials of renal prophylaxis was essentially undetectable in plasma after oral administration. In healthy volunteers, i.v. NAC, but not oral NAC, increased blood pressure (mean area under the curve (AUC) mean arterial pressure (MAP): mean difference 29 h⋅mmHg, P = 0.019 vs. placebo), heart rate (28 h⋅bpm, P < 0.001), and RBF (714 h⋅mL/min, 8.0% increase, P = 0.006). Renal vasodilatation also occurred in the presence of contrast (RBF 917 h⋅mL/min, 12% increase, P = 0.005). In patients with CKD3 without contrast, only a rise in heart rate (34 h⋅bpm, P = 0.010) and RBF (288 h⋅mL/min, 6.0% increase, P = 0.001) occurred with i.v. NAC, with no significant effect on blood pressure (MAP rise 26 h⋅mmHg, P = 0.156). Oral NAC showed no effect. In patients with CKD3 receiving contrast, i.v. NAC increased blood pressure (MAP rise 52 h⋅mmHg, P = 0.008) but had no effect on RBF (151 h⋅mL/min, 3.0% increase, P = 0.470), GFR (29 h⋅mL/min/1.73m², P = 0.122), or markers of renal injury. Neither i.v. nor oral NAC affected plasma antioxidant status. We found oral NAC to be poorly absorbed and have no reno-protective effects. Intravenous, not oral, NAC caused renal artery vasodilatation in healthy volunteers but offered no protection to patients with CKD3 at risk of CIN. These findings emphasize the importance of mechanistic clinical studies before progressing to RCTs for novel interventions. Thousands were recruited to academic clinical trials without the necessary mechanistic studies being performed to confirm the approach had any chance of working.
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http://dx.doi.org/10.1002/cpt.2541DOI Listing
June 2022

CON: Oximes should not be used routinely in organophosphorus insecticide poisoning.

Br J Clin Pharmacol 2022 Jan 5. Epub 2022 Jan 5.

Pharmacology, Therapeutics & Toxicology, Centre for Cardiovascular Science, and Centre for Pesticide Suicide Prevention, University of Edinburgh, Edinburgh, UK.

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.
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http://dx.doi.org/10.1111/bcp.15217DOI Listing
January 2022

Characteristics and psychopathology of 1,086 patients who self-poisoned using pesticides in Taiwan (2012-2019): A comparison across pesticide groups.

J Affect Disord 2022 03 21;300:17-26. Epub 2021 Dec 21.

South Asian Clinical Toxicology Research Collaboration, University of Peradeniya, Peradeniya, Sri Lanka; Institute of Health Behaviors and Community Sciences and Global Health Program, and College of Public Health, National Taiwan University, Taipei, Taiwan; Psychiatric Research Center, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan. Electronic address:

Background Previous studies, mainly from low- and middle-income settings, showed that pesticide self-poisonings were mostly impulsive with low levels of psychopathology. We aimed to investigate whether pesticide self-poisoning in a high-income country showed similar profiles, and whether those with certain characteristics and psychopathology were more likely to use specific pesticides. Methods Data were extracted from hospital records of pesticide self-poisoning patients treated at eight major hospitals in Taiwan between 2012 and 2019. Multinomial logistic regression was used to investigate the association of interpersonal conflicts, triggers of self-poisoning, and psychopathology with the groups of pesticides ingested. Results A total of 1,086 patients who self-poisoned using pesticides were identified; 67.0% were male and 39.8% aged 65+ years. Approximately three quarters (75.7%) of patients who received psychiatric assessment had at least one psychiatric diagnosis, and the prevalence was 48.3% in all patients. No association was found between the pesticide groups ingested and interpersonal conflicts, most of the triggers, past psychiatric service use, or having psychiatric diagnoses. Limitations Data were collected from hospital records retrospectively. Only 60.3% of the patients received a psychiatric assessment. Conclusions The majority of patients who self-poisoned using pesticides and received psychiatric assessment in Taiwan had psychiatric illness. Patients who ingested different groups of pesticides were similar in their characteristics. The choice of pesticides used in self-poisoning more likely relates to availability rather than intentional selection. Psychiatric assessment and treatment are important in patients who self-poisoned using pesticides, while restricting access to highly hazardous pesticides is likely to prevent many deaths from pesticide self-poisoning.
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http://dx.doi.org/10.1016/j.jad.2021.12.058DOI Listing
March 2022

Comment on Fomepizole as an adjunct in acetylcysteine treated acetaminophen overdose patients: a case series.

Clin Toxicol (Phila) 2022 05 23;60(5):666-667. Epub 2021 Dec 23.

City Hospital, Birmingham and University of Birmingham, Birmingham, UK.

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http://dx.doi.org/10.1080/15563650.2021.2009849DOI Listing
May 2022

Comment on Fomepizole as an adjunct in acetylcysteine treated acetaminophen overdose patients: a case series.

Clin Toxicol (Phila) 2022 05 23;60(5):666-667. Epub 2021 Dec 23.

City Hospital, Birmingham and University of Birmingham, Birmingham, UK.

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http://dx.doi.org/10.1080/15563650.2021.2009849DOI Listing
May 2022

Osmolal and anion gaps after acute self-poisoning with agricultural formulations of the organophosphorus insecticides profenofos and diazinon: A pilot study.

Basic Clin Pharmacol Toxicol 2022 Feb 3;130(2):320-327. Epub 2021 Dec 3.

South Asian Clinical Toxicology Research Collaboration, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka.

Self-poisoning with organophosphorus (OP) insecticides is an important means of global self-harm. The insecticides are formulated with solvents that may also contribute to toxicity. We set up a study to detect changes in osmolal and anion gaps following ingestion of OP insecticides. We recruited consecutive patients admitted to a Teaching Hospital, Sri Lanka, with a history of OP self-poisoning. The osmolal and anion gaps were calculated on admission and at 4, 24 and 72 h post-ingestion together with ethanol concentration. Forty-nine patients were recruited (28 profenofos, 10 diazinon, one coumaphos, one chlorpyrifos, one phenthoate and eight unknown OP). Only modest increases in osmolal and anion gaps were noted. Small rises in osmolal gap above the upper limit of normal were noted in 16/49 (32.7%) of all cases, 9/28 (32.1%) profenofos cases and 4/10 (40.0%) diazinon cases. The anion gap was raised in 24/49 (49.0%) of all cases, 15/28 (53.6%) profenofos cases and 5/10 (50.0%) diazinon cases. We observed a trend for a fall in osmolal gap during the first 24 h, followed by an increase up to 72 h. There was no correlation between the anion gap and serum lactate concentration, indicating that a lactic acidosis was not responsible for the anion gap. Formate, which could have explained the increased gap, was not detected in any of the samples; ketoacids (beta-hydroxybutyrate and acetoacetate) were not measured. This pilot study found that profenofos and diazinon poisoning caused only modest increases in the osmolal and anion gaps in a minority of cases.
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http://dx.doi.org/10.1111/bcpt.13686DOI Listing
February 2022

Comment on Glatstein's case series of envenoming in children.

Clin Toxicol (Phila) 2022 05 15;60(5):661-662. Epub 2021 Nov 15.

Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science University of Edinburgh, Edinburgh, UK.

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May 2022

Antagonistic postsynaptic and presynaptic actions of cyclohexanol on neuromuscular synaptic transmission and function.

J Physiol 2021 12 26;599(24):5417-5449. Epub 2021 Nov 26.

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.

Intentional ingestion of agricultural organophosphorus insecticides is a significant public health issue in rural Asia, causing thousands of deaths annually. Some survivors develop a severe, acute or delayed myasthenic syndrome. In animal models, similar myasthenia has been associated with increasing plasma concentration of one insecticide solvent metabolite, cyclohexanol. We investigated possible mechanisms using voltage and current recordings from mouse neuromuscular junctions (NMJs) and transfected human cell lines. Cyclohexanol (10-25 mM) reduced endplate potential (EPP) amplitudes by 10-40% and enhanced depression during repetitive (2-20 Hz) stimulation by up to 60%. EPP decay was prolonged more than twofold. Miniature EPPs were attenuated by more than 50%. Cyclohexanol inhibited whole-cell currents recorded from CN21 cells expressing human postjunctional acetylcholine receptors (hnAChR) with an IC of 3.74 mM. Cyclohexanol (10-20 mM) also caused prolonged episodes of reduced-current, multi-channel bursting in outside-out patch recordings from hnAChRs expressed in transfected HEK293T cells, reducing charge transfer by more than 50%. Molecular modelling indicated cyclohexanol binding (-6 kcal/mol) to a previously identified alcohol binding site on nicotinic AChR α-subunits. Cyclohexanol also increased quantal content of evoked transmitter release by ∼50%. In perineurial recordings, cyclohexanol selectively inhibited presynaptic K currents. Modelling indicated cyclohexanol binding (-3.8 kcal/mol) to voltage-sensitive K channels at the same site as tetraethylammonium (TEA). TEA (10 mM) blocked K channels more effectively than cyclohexanol but EPPs were more prolonged in 20 mM cyclohexanol. The results explain the pattern of neuromuscular dysfunction following ingestion of organophosphorus insecticides containing cyclohexanol precursors and suggest that cyclohexanol may facilitate investigation of mechanisms regulating synaptic strength at NMJs. KEY POINTS: Intentional ingestion of agricultural organophosphorus insecticides is a significant public health issue in rural Asia, causing thousands of deaths annually. Survivors may develop a severe myasthenic syndrome or paralysis, associated with increased plasma levels of cyclohexanol, an insecticide solvent metabolite. Analysis of synaptic transmission at neuromuscular junctions in isolated mouse skeletal muscle, using isometric tension recording and microelectrode recording of endplate voltages and currents, showed that cyclohexanol reduced postsynaptic sensitivity to acetylcholine neurotransmitter (reduced quantal size) while simultaneously enhancing evoked transmitter release (increased quantal content). Patch recording from transfected cell lines, together with molecular modelling, indicated that cyclohexanol causes selective, allosteric antagonism of postsynaptic nicotinic acetylcholine receptors and block of presynaptic K -channel function. The data provide insight into the cellular and molecular mechanisms of neuromuscular weakness following intentional ingestion of agricultural organophosphorus insecticides. Our findings also extend understanding of the effects of alcohols on synaptic transmission and homeostatic synaptic function.
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December 2021

The 20-minute whole blood clotting test (20WBCT) for snakebite coagulopathy-A systematic review and meta-analysis of diagnostic test accuracy.

PLoS Negl Trop Dis 2021 08 10;15(8):e0009657. Epub 2021 Aug 10.

Pharmacology, Toxicology & Therapeutics, University/BHF Centre for Cardiovascular Science University of Edinburgh, Edinburgh, United Kingdom.

Background: The 20-minute whole blood clotting test (20WBCT) has been used to detect coagulopathy following snakebite for almost 50 years. A systematic review and meta-analysis of the 20WBCT was conducted to evaluate the accuracy of the 20WBCT to detect coagulopathy, indicative of systemic envenoming.

Methods And Findings: Databases were searched from inception up to 09/12/2020 to identify studies that compared the 20WBCT and INR/fibrinogen on five or more subjects. Data was extracted from full-text articles by two reviewers using a predetermined form. Authors of 29 studies that lacked sufficient details in the manuscript were contacted and included if data meeting the inclusion criteria were provided. Included studies were evaluated for bias using a tailored QUADAS-2 checklist. The study protocol was prospectively registered on PROSPERO database (CRD42020168953). The searches identified 3,599 studies, 15 met the inclusion criteria and 12 were included in the meta-analysis. Data was reported from 6 countries and included a total of 2,270 patients. The aggregate weighted sensitivity of the 20WBCT at detecting INR >1.4 was 0.84 (CI 0.61 to 0.94), the specificity was 0.91 (0.76 to 0.97) and the SROC AUC was 0.94 (CI 0.91 to 0.96). The aggregate weighted sensitivity of the 20WBCT at detecting fibrinogen <100 mg/dL was 0.72 (CI 0.58 to 0.83), the specificity was 0.94 (CI 0.88 to 0.98) and the SROC AUC was 0.93 (0.91 to 0.95). Both analyses that used INR and fibrinogen as the reference test displayed considerable heterogeneity.

Conclusions: In the absence of laboratory clotting assays, the 20WBCT remains a highly specific and fairly sensitive bedside test at detecting coagulopathy following snakebite. However, clinicians should be aware of the importance of operator training, standardized equipment and the lower sensitivity of the 20WBCT at detecting mild coagulopathy and resolution of coagulopathy following antivenom.
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http://dx.doi.org/10.1371/journal.pntd.0009657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405032PMC
August 2021

Importance of pesticides for lethal poisoning in India during 1999 to 2018: a systematic review.

BMC Public Health 2021 07 22;21(1):1441. Epub 2021 Jul 22.

Centre for Pesticide Suicide Prevention, and Pharmacology, Toxicology & Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.

Background: Poisoning is a major problem in India. However, there is little systematic information on the key poisons responsible for most deaths by geographical area and over time. We aimed to review the literature to identify the poison classes causing the greatest number of deaths in India over the last 20 years.

Methods: We performed a systematic literature review in Medline, Embase and Google Scholar (1999-2018), and Indian online medical journals, to find papers that reported deaths from all forms of poisoning in India, with last search 20 April 2020. We included epidemiological studies, observational studies, randomised trials, interventional studies, and case series published from 1999 to 2018 that showed the number of deaths and autopsy studies indicating the specific poisons or poison classes. Studies providing the case fatality for specific poisons or classes, which enabled calculation of the number of deaths, were also included. We excluded deaths due to animal bites and stings, ethanol or methanol poisoning, and gas inhalation as well as papers reporting a single death (case study of single patient). We grouped the papers into 5-year intervals and identified the two most common poison classes in each paper. We used descriptive statistics to summarise the findings over time based on the causative poison and the location of the study.

Results: We identified 186 papers reporting 16,659 poisoning deaths between 1999 and 2018. The number of publications per 5-year interval showed no clear trend over the period (48, 38, 67, and 36 for consecutive periods). Half of the deaths (n = 8338, 50.0%) were reported during the first 5 years of the study (1999-2003), the number of deaths declining thereafter (to n = 1714 in 2014-2018). Deaths due to pesticide poisoning (94.5%) were dominant across the study period compared to other classes of poison [hair dye paraphenylenediamine poisoning (2.6%), medicine overdose (1.4%) or plant poisoning (1.0%)]. Among the pesticides, aluminium phosphide was the most important lethal poison during the first 10 years before declining markedly; organophosphorus insecticides were important throughout the period, becoming dominant in the last decade as aluminium phosphide cases declined. Unfortunately, few papers identified the specific organophosphorus insecticide responsible for deaths.

Conclusion: Use of the published literature to better understand the epidemiology of lethal poisoning in India has clear limitations, including secular variation in publishing practices and interest in poisoning. Unfortunately, there are no long-term detailed, combination hospital and community studies from India to provide this information. In their absence, our review indicates that pesticides are the most important poison in India, with organophosphorus insecticides replacing aluminium phosphide as the key lethal poison after government regulatory changes in 2001 reduced the latter's lethality. Plant and hair dye poisoning and medicines overdose caused few deaths. Aluminium phosphide deaths mostly occurred in northern Indian states, whereas deaths from organophosphorus insecticide poisoning occurred throughout India. Paraquat poisoning has become a clinical problem in the last 10 years. Lethal pesticide poisoning remains alarmingly common, emphasising the need for additional regulatory interventions to curtail the burden of pesticide poisoning deaths in India. More detailed reporting about the specific pesticide involved in lethal poisoning will be helpful to guide regulatory decisions.
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http://dx.doi.org/10.1186/s12889-021-11156-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296580PMC
July 2021

Importance of pesticides for lethal poisoning in India during 1999 to 2018: a systematic review.

BMC Public Health 2021 07 22;21(1):1441. Epub 2021 Jul 22.

Centre for Pesticide Suicide Prevention, and Pharmacology, Toxicology & Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.

Background: Poisoning is a major problem in India. However, there is little systematic information on the key poisons responsible for most deaths by geographical area and over time. We aimed to review the literature to identify the poison classes causing the greatest number of deaths in India over the last 20 years.

Methods: We performed a systematic literature review in Medline, Embase and Google Scholar (1999-2018), and Indian online medical journals, to find papers that reported deaths from all forms of poisoning in India, with last search 20 April 2020. We included epidemiological studies, observational studies, randomised trials, interventional studies, and case series published from 1999 to 2018 that showed the number of deaths and autopsy studies indicating the specific poisons or poison classes. Studies providing the case fatality for specific poisons or classes, which enabled calculation of the number of deaths, were also included. We excluded deaths due to animal bites and stings, ethanol or methanol poisoning, and gas inhalation as well as papers reporting a single death (case study of single patient). We grouped the papers into 5-year intervals and identified the two most common poison classes in each paper. We used descriptive statistics to summarise the findings over time based on the causative poison and the location of the study.

Results: We identified 186 papers reporting 16,659 poisoning deaths between 1999 and 2018. The number of publications per 5-year interval showed no clear trend over the period (48, 38, 67, and 36 for consecutive periods). Half of the deaths (n = 8338, 50.0%) were reported during the first 5 years of the study (1999-2003), the number of deaths declining thereafter (to n = 1714 in 2014-2018). Deaths due to pesticide poisoning (94.5%) were dominant across the study period compared to other classes of poison [hair dye paraphenylenediamine poisoning (2.6%), medicine overdose (1.4%) or plant poisoning (1.0%)]. Among the pesticides, aluminium phosphide was the most important lethal poison during the first 10 years before declining markedly; organophosphorus insecticides were important throughout the period, becoming dominant in the last decade as aluminium phosphide cases declined. Unfortunately, few papers identified the specific organophosphorus insecticide responsible for deaths.

Conclusion: Use of the published literature to better understand the epidemiology of lethal poisoning in India has clear limitations, including secular variation in publishing practices and interest in poisoning. Unfortunately, there are no long-term detailed, combination hospital and community studies from India to provide this information. In their absence, our review indicates that pesticides are the most important poison in India, with organophosphorus insecticides replacing aluminium phosphide as the key lethal poison after government regulatory changes in 2001 reduced the latter's lethality. Plant and hair dye poisoning and medicines overdose caused few deaths. Aluminium phosphide deaths mostly occurred in northern Indian states, whereas deaths from organophosphorus insecticide poisoning occurred throughout India. Paraquat poisoning has become a clinical problem in the last 10 years. Lethal pesticide poisoning remains alarmingly common, emphasising the need for additional regulatory interventions to curtail the burden of pesticide poisoning deaths in India. More detailed reporting about the specific pesticide involved in lethal poisoning will be helpful to guide regulatory decisions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296580PMC
July 2021

Importance of pesticides for lethal poisoning in India during 1999 to 2018: a systematic review.

BMC Public Health 2021 07 22;21(1):1441. Epub 2021 Jul 22.

Centre for Pesticide Suicide Prevention, and Pharmacology, Toxicology & Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.

Background: Poisoning is a major problem in India. However, there is little systematic information on the key poisons responsible for most deaths by geographical area and over time. We aimed to review the literature to identify the poison classes causing the greatest number of deaths in India over the last 20 years.

Methods: We performed a systematic literature review in Medline, Embase and Google Scholar (1999-2018), and Indian online medical journals, to find papers that reported deaths from all forms of poisoning in India, with last search 20 April 2020. We included epidemiological studies, observational studies, randomised trials, interventional studies, and case series published from 1999 to 2018 that showed the number of deaths and autopsy studies indicating the specific poisons or poison classes. Studies providing the case fatality for specific poisons or classes, which enabled calculation of the number of deaths, were also included. We excluded deaths due to animal bites and stings, ethanol or methanol poisoning, and gas inhalation as well as papers reporting a single death (case study of single patient). We grouped the papers into 5-year intervals and identified the two most common poison classes in each paper. We used descriptive statistics to summarise the findings over time based on the causative poison and the location of the study.

Results: We identified 186 papers reporting 16,659 poisoning deaths between 1999 and 2018. The number of publications per 5-year interval showed no clear trend over the period (48, 38, 67, and 36 for consecutive periods). Half of the deaths (n = 8338, 50.0%) were reported during the first 5 years of the study (1999-2003), the number of deaths declining thereafter (to n = 1714 in 2014-2018). Deaths due to pesticide poisoning (94.5%) were dominant across the study period compared to other classes of poison [hair dye paraphenylenediamine poisoning (2.6%), medicine overdose (1.4%) or plant poisoning (1.0%)]. Among the pesticides, aluminium phosphide was the most important lethal poison during the first 10 years before declining markedly; organophosphorus insecticides were important throughout the period, becoming dominant in the last decade as aluminium phosphide cases declined. Unfortunately, few papers identified the specific organophosphorus insecticide responsible for deaths.

Conclusion: Use of the published literature to better understand the epidemiology of lethal poisoning in India has clear limitations, including secular variation in publishing practices and interest in poisoning. Unfortunately, there are no long-term detailed, combination hospital and community studies from India to provide this information. In their absence, our review indicates that pesticides are the most important poison in India, with organophosphorus insecticides replacing aluminium phosphide as the key lethal poison after government regulatory changes in 2001 reduced the latter's lethality. Plant and hair dye poisoning and medicines overdose caused few deaths. Aluminium phosphide deaths mostly occurred in northern Indian states, whereas deaths from organophosphorus insecticide poisoning occurred throughout India. Paraquat poisoning has become a clinical problem in the last 10 years. Lethal pesticide poisoning remains alarmingly common, emphasising the need for additional regulatory interventions to curtail the burden of pesticide poisoning deaths in India. More detailed reporting about the specific pesticide involved in lethal poisoning will be helpful to guide regulatory decisions.
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http://dx.doi.org/10.1186/s12889-021-11156-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296580PMC
July 2021

Importance of pesticides for lethal poisoning in India during 1999 to 2018: a systematic review.

BMC Public Health 2021 07 22;21(1):1441. Epub 2021 Jul 22.

Centre for Pesticide Suicide Prevention, and Pharmacology, Toxicology & Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.

Background: Poisoning is a major problem in India. However, there is little systematic information on the key poisons responsible for most deaths by geographical area and over time. We aimed to review the literature to identify the poison classes causing the greatest number of deaths in India over the last 20 years.

Methods: We performed a systematic literature review in Medline, Embase and Google Scholar (1999-2018), and Indian online medical journals, to find papers that reported deaths from all forms of poisoning in India, with last search 20 April 2020. We included epidemiological studies, observational studies, randomised trials, interventional studies, and case series published from 1999 to 2018 that showed the number of deaths and autopsy studies indicating the specific poisons or poison classes. Studies providing the case fatality for specific poisons or classes, which enabled calculation of the number of deaths, were also included. We excluded deaths due to animal bites and stings, ethanol or methanol poisoning, and gas inhalation as well as papers reporting a single death (case study of single patient). We grouped the papers into 5-year intervals and identified the two most common poison classes in each paper. We used descriptive statistics to summarise the findings over time based on the causative poison and the location of the study.

Results: We identified 186 papers reporting 16,659 poisoning deaths between 1999 and 2018. The number of publications per 5-year interval showed no clear trend over the period (48, 38, 67, and 36 for consecutive periods). Half of the deaths (n = 8338, 50.0%) were reported during the first 5 years of the study (1999-2003), the number of deaths declining thereafter (to n = 1714 in 2014-2018). Deaths due to pesticide poisoning (94.5%) were dominant across the study period compared to other classes of poison [hair dye paraphenylenediamine poisoning (2.6%), medicine overdose (1.4%) or plant poisoning (1.0%)]. Among the pesticides, aluminium phosphide was the most important lethal poison during the first 10 years before declining markedly; organophosphorus insecticides were important throughout the period, becoming dominant in the last decade as aluminium phosphide cases declined. Unfortunately, few papers identified the specific organophosphorus insecticide responsible for deaths.

Conclusion: Use of the published literature to better understand the epidemiology of lethal poisoning in India has clear limitations, including secular variation in publishing practices and interest in poisoning. Unfortunately, there are no long-term detailed, combination hospital and community studies from India to provide this information. In their absence, our review indicates that pesticides are the most important poison in India, with organophosphorus insecticides replacing aluminium phosphide as the key lethal poison after government regulatory changes in 2001 reduced the latter's lethality. Plant and hair dye poisoning and medicines overdose caused few deaths. Aluminium phosphide deaths mostly occurred in northern Indian states, whereas deaths from organophosphorus insecticide poisoning occurred throughout India. Paraquat poisoning has become a clinical problem in the last 10 years. Lethal pesticide poisoning remains alarmingly common, emphasising the need for additional regulatory interventions to curtail the burden of pesticide poisoning deaths in India. More detailed reporting about the specific pesticide involved in lethal poisoning will be helpful to guide regulatory decisions.
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http://dx.doi.org/10.1186/s12889-021-11156-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296580PMC
July 2021

Detection of flubromazolam in patients with suspected non-medical drug use attending emergency departments in the United Kingdom.

Clin Toxicol (Phila) 2022 Jan 3;60(1):33-37. Epub 2021 Jun 3.

Clinical Toxicology, Newcastle Hospitals NHS Foundation Trust, Newcastle, UK.

Introduction: Non-medical use of novel benzodiazepines has recently become common. Here, we describe the recent frequent detection of flubromazolam in patients attending United Kingdom emergency departments.

Methods: Adults presenting to participating hospitals with toxicity after suspected drug misuse were studied between March 2015 and January 2021. Clinical features were recorded using consistent methodology and biological samples analysed using liquid chromatography-tandem mass-spectrometry.

Results: Flubromazolam and/or its mono-hydroxylated metabolite were detected in samples from 14 of 957 patients, all presenting since July 2020. Reported clinical features included reduced level of consciousness (10), confusion/agitation (6) and acidosis (5) but multiple other substances were detected in all patients. All patients survived to discharge (length of hospital stay 3.0 to 213 h, median 24.1 h). There was no correlation between admission blood/serum flubromazolam concentrations (range 1.7-480.5 ng/ml, median 7.4 ng/ml) and Glasgow Coma Scale or length of hospital stay. In one patient who needed intubation and ventilation for five days, there was an exponential decline in flubromazolam concentrations with time (calculated half-life 39.8 h). Hydroxyl-flubromazolam was also identified at all time points.

Conclusions: Flubromazolam has been detected frequently in drug users presenting to UK emergency departments since July 2020. Prolonged toxicity may occur as a result of the long half-life of flubromazolam and the production of metabolites likely to be active.
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January 2022

Impaired neuromuscular function by conjoint actions of organophosphorus insecticide metabolites omethoate and cyclohexanol with implications for treatment of respiratory failure.

Clin Toxicol (Phila) 2021 Dec 14;59(12):1239-1258. Epub 2021 May 14.

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.

Background: Ingestion of agricultural organophosphorus insecticides is a significant cause of death in rural Asia. Patients often show acute respiratory failure and/or delayed, unexplained signs of neuromuscular paralysis, sometimes diagnosed as "Intermediate Syndrome". We tested the hypothesis that omethoate and cyclohexanol, circulating metabolites of one agricultural formulation, cause muscle weakness and paralysis.

Methods: Acetylcholinesterase activity of insecticide components and metabolites was measured using purified enzyme from eel electroplaque or muscle homogenates. Mechanomyographic recording of pelvic limb responses to nerve stimulation was made in anaesthetized pigs and isometric force was recorded from isolated nerve-muscle preparations from mice. Omethoate and cyclohexanol were administered intravenously or added to physiological saline bathing isolated muscle. We also assessed the effect of MgSO and cooling on neuromuscular function.

Results: Omethoate caused tetanic fade in pig muscles and long-lasting contractions of the motor innervation zone in mouse muscle. Both effects were mitigated, either by i.v. administration of MgSO or by adding 5 mM Mg to the medium bathing isolated preparations. Combination of omethoate and cyclohexanol initially potentiated muscle contractions but then rapidly blocked them. Cyclohexanol alone caused fade and block of muscle contractions in pigs and in isolated preparations. Similar effects were observed with cyclohexanone and xylene. Cyclohexanol-induced neuromuscular block was temperature-sensitive and rapidly reversible.

Conclusions: The data indicate a crucial role for organophosphorus and solvent metabolites in muscle weakness following ingestion of agricultural OP insecticide formulations. The metabolites omethoate and cyclohexanol acted conjointly to impair neuromuscular function but their effects were mitigated by elevating extracellular Mg and decreasing core temperature, respectively. Clinical studies of MgSO therapy and targeted temperature management in insecticide-poisoned patients are required to determine whether they may be effective adjuncts to treatment.
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December 2021

Acute phenthoate self-poisoning: a prospective case series.

Clin Toxicol (Phila) 2022 Feb 7;60(2):214-220. Epub 2021 May 7.

Pharmacology, Toxicology, & Therapeutics, University/BHF Centre for Cardiovascular Science, Edinburgh, UK.

Background: The clinical characteristics following self-poisoning with organophosphorus (OP) insecticides differs according to the insecticide ingested. Phenthoate is a dimethoxy WHO Hazard Class II OP pesticide with limited literature on its clinical characteristics and outcome. We aimed to better understand its clinical characteristics by studying patients with phenthoate self-poisoning in Sri Lanka.

Methods: We conducted a prospective cohort study of patients presenting with phenthoate self-poisoning to eight hospitals in Sri Lanka between 2002 and 2018. Clinical outcomes were recorded for each patient. Blood samples for measuring plasma phenthoate concentration, cholinesterase activity, and response to oximes were available for a very small number of patients recruited to a clinical trial.

Results: Two hundred and ninety-two patients who ingested agricultural phenthoate formulations were included in the study. Median time to admission was 3.9 (IQR 2.4 - 6.8) h. Forty-two (14.4%) patients were intubated, mostly (30/37, 81%) within 24 h of ingestion (median time to intubation 7.2 [IQR 2.6-20.9] h). Median duration of intubation was 74.8 (IQR 26.8-232.5) h; the longest duration in a survivor was 592 h. Nineteen died (case fatality 6.5%, 95% CI 4.0-10.0); median time to death was 37 (IQR 16 - 101.7) h. Median plasma phenthoate concentration in patients with samples ( = 81) was 135 (IQR 62.7-356.5) ng/mL (0.42 µmol/mL [0.2 to 1.1 µmol/mL]). Five of six patients receiving pralidoxime chloride 2 g showed an initial increase in AChE and BuChE activity that was not sustained despite an infusion of pralidoxime.

Conclusion: Phenthoate self-poisoning has a 6.5% case fatality rate. Most patients who experience respiratory failure undergo early intubation; most deaths occurred among those patients who were intubated less than 24 h after ingestion. There was a non-sustained increase in cholinesterase activity with pralidoxime, but further studies are required to analyse the extent to which oximes are clinically effective in phenthoate self-poisoning.
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February 2022

Acute phenthoate self-poisoning: a prospective case series.

Clin Toxicol (Phila) 2022 Feb 7;60(2):214-220. Epub 2021 May 7.

Pharmacology, Toxicology, & Therapeutics, University/BHF Centre for Cardiovascular Science, Edinburgh, UK.

Background: The clinical characteristics following self-poisoning with organophosphorus (OP) insecticides differs according to the insecticide ingested. Phenthoate is a dimethoxy WHO Hazard Class II OP pesticide with limited literature on its clinical characteristics and outcome. We aimed to better understand its clinical characteristics by studying patients with phenthoate self-poisoning in Sri Lanka.

Methods: We conducted a prospective cohort study of patients presenting with phenthoate self-poisoning to eight hospitals in Sri Lanka between 2002 and 2018. Clinical outcomes were recorded for each patient. Blood samples for measuring plasma phenthoate concentration, cholinesterase activity, and response to oximes were available for a very small number of patients recruited to a clinical trial.

Results: Two hundred and ninety-two patients who ingested agricultural phenthoate formulations were included in the study. Median time to admission was 3.9 (IQR 2.4 - 6.8) h. Forty-two (14.4%) patients were intubated, mostly (30/37, 81%) within 24 h of ingestion (median time to intubation 7.2 [IQR 2.6-20.9] h). Median duration of intubation was 74.8 (IQR 26.8-232.5) h; the longest duration in a survivor was 592 h. Nineteen died (case fatality 6.5%, 95% CI 4.0-10.0); median time to death was 37 (IQR 16 - 101.7) h. Median plasma phenthoate concentration in patients with samples ( = 81) was 135 (IQR 62.7-356.5) ng/mL (0.42 µmol/mL [0.2 to 1.1 µmol/mL]). Five of six patients receiving pralidoxime chloride 2 g showed an initial increase in AChE and BuChE activity that was not sustained despite an infusion of pralidoxime.

Conclusion: Phenthoate self-poisoning has a 6.5% case fatality rate. Most patients who experience respiratory failure undergo early intubation; most deaths occurred among those patients who were intubated less than 24 h after ingestion. There was a non-sustained increase in cholinesterase activity with pralidoxime, but further studies are required to analyse the extent to which oximes are clinically effective in phenthoate self-poisoning.
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February 2022

Acute toxicity from the synthetic cathinone -ethylpentylone (ephylone) in the United Kingdom.

Clin Toxicol (Phila) 2021 Dec 15;59(12):1270-1273. Epub 2021 Apr 15.

NIHR Health Protection Research Unit for Chemical Threats and Hazards, Newcastle University, Newcastle, UK.

Introduction: Acute toxicity caused by New Psychoactive Substances (NPS) has created a significant burden for Emergency Departments (EDs). Here we report characteristics of people presenting with toxicity after exposure to the synthetic cathinone -ethylpentylone (NEP).

Methods: Adults presenting to hospital with severe acute toxicity after suspected NPS use were recruited between March 2015 and October 2020. Clinical features were recorded using consistent methodology and biological samples analysed using liquid chromatography-tandem mass-spectrometry.

Results: NEP was detected in at least one sample from 9 of 893 patients recruited during the period of study, all presenting between 2016 and 2019 and 8 presenting in southern England. Commonly reported clinical features included tachycardia (6), agitation (6), confusion (6), mydriasis (5), hallucinations (4), acidosis (3) and elevated creatine kinase (3). Co-used drugs, detected in 6 patients, may have contributed to these features, but agitation and hallucinations were also reported in all 3 patients without analytical evidence of co-use.

Conclusions: NEP was detected infrequently in episodes of drug toxicity in the UK between 2016 and 2019, especially in southern England. Clinical characteristics of toxicity are similar to those of other cathinones, although co-use of other drugs is common and may contribute to the features observed.
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December 2021

Moderate-to-severe envenoming requiring ViperaTAb antivenom therapy in the UK.

Clin Toxicol (Phila) 2021 Nov 15;59(11):992-1001. Epub 2021 Mar 15.

National Poisons Information Service - Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK.

Background: Bites by the European adder () in the UK are uncommon but potentially life threatening, and can be associated with marked limb swelling and disability. Following an interruption in Zagreb Imunološki zavod antivenom supply around 2012, the UK changed its national choice of antivenom for to ViperaTAb, an ovine Fab monospecific antivenom. In the absence of randomised controlled trials, we established an audit to review its use in clinical practice.

Methods: A prospective audit of ViperaTAb use was conducted from March 2016 until November 2020 by the UK National Poison Information Service (NPIS). Users of the NPIS online toxicology database, TOXBASE, considering the use of antivenom for envenoming were invited to discuss the case with the on-call clinical toxicology consultant. Information was collected prospectively on indications, administration, adverse reactions and outcome of patients administered ViperaTAb antivenom.

Results: One hundred and seventy patients were administered ViperaTAb antivenom over five years. One hundred and thirty-two were adults and 38 children (median age and range: 38, 2-87 years). Bites occurred across the UK, but most commonly in coastal regions of Wales and of South-West and East England. Median time to presentation was 2.1 (IQR 1.5-4.0) h and to antivenom administration from presentation was 2.0 (IQR 0.9-3.6) h. A minority of patients presented to hospital more than 12 h after being bitten ( = 19, 11.2%) or received antivenom more than 12 h after presenting to hospital ( = 17, 10.0%). Features of systemic envenoming were present in 64/170 (37.6%) patients, including 23 (13.5%) with anaphylaxis and 26 (15.3%) with hypotension (nine with both). Clinician assessment considered the initial antivenom to have been effective in 122/169 (72.2%) patients. Repeated dosing was common, occurring in 55/169 (32.5%), predominantly due to persisting or worsening local effects (46/51, 90.2%). There were three cases of probable early adverse reaction. No deaths occurred during the study. Complications of envenoming were rare but included four patients that underwent surgery, three patients each with acute kidney injury, mild coagulopathy, or thrombocytopenia (one severe). The median duration of hospital stay was 43.7 (IQR 22.5-66.5) h, longer for children than adults (52.5 vs 41.3 h).

Conclusion: ViperaTAb antivenom appears to be effective and safe and should be administered as soon as possible for patients meeting clinical criteria. Patients require close observation following antivenom to detect adverse reactions and progression or recurrence of envenoming. Close collaboration with expert NPIS consultant advice can help optimise antivenom timing, ensure repeated dosing is given appropriately, and avoid unnecessary surgical intervention. All hospitals, particularly those located in areas of relatively high incidence, should stock sufficient antivenom available at short notice, 24 h a day.
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November 2021

Moderate-to-severe envenoming requiring ViperaTAb antivenom therapy in the UK.

Clin Toxicol (Phila) 2021 Nov 15;59(11):992-1001. Epub 2021 Mar 15.

National Poisons Information Service - Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK.

Background: Bites by the European adder () in the UK are uncommon but potentially life threatening, and can be associated with marked limb swelling and disability. Following an interruption in Zagreb Imunološki zavod antivenom supply around 2012, the UK changed its national choice of antivenom for to ViperaTAb, an ovine Fab monospecific antivenom. In the absence of randomised controlled trials, we established an audit to review its use in clinical practice.

Methods: A prospective audit of ViperaTAb use was conducted from March 2016 until November 2020 by the UK National Poison Information Service (NPIS). Users of the NPIS online toxicology database, TOXBASE, considering the use of antivenom for envenoming were invited to discuss the case with the on-call clinical toxicology consultant. Information was collected prospectively on indications, administration, adverse reactions and outcome of patients administered ViperaTAb antivenom.

Results: One hundred and seventy patients were administered ViperaTAb antivenom over five years. One hundred and thirty-two were adults and 38 children (median age and range: 38, 2-87 years). Bites occurred across the UK, but most commonly in coastal regions of Wales and of South-West and East England. Median time to presentation was 2.1 (IQR 1.5-4.0) h and to antivenom administration from presentation was 2.0 (IQR 0.9-3.6) h. A minority of patients presented to hospital more than 12 h after being bitten ( = 19, 11.2%) or received antivenom more than 12 h after presenting to hospital ( = 17, 10.0%). Features of systemic envenoming were present in 64/170 (37.6%) patients, including 23 (13.5%) with anaphylaxis and 26 (15.3%) with hypotension (nine with both). Clinician assessment considered the initial antivenom to have been effective in 122/169 (72.2%) patients. Repeated dosing was common, occurring in 55/169 (32.5%), predominantly due to persisting or worsening local effects (46/51, 90.2%). There were three cases of probable early adverse reaction. No deaths occurred during the study. Complications of envenoming were rare but included four patients that underwent surgery, three patients each with acute kidney injury, mild coagulopathy, or thrombocytopenia (one severe). The median duration of hospital stay was 43.7 (IQR 22.5-66.5) h, longer for children than adults (52.5 vs 41.3 h).

Conclusion: ViperaTAb antivenom appears to be effective and safe and should be administered as soon as possible for patients meeting clinical criteria. Patients require close observation following antivenom to detect adverse reactions and progression or recurrence of envenoming. Close collaboration with expert NPIS consultant advice can help optimise antivenom timing, ensure repeated dosing is given appropriately, and avoid unnecessary surgical intervention. All hospitals, particularly those located in areas of relatively high incidence, should stock sufficient antivenom available at short notice, 24 h a day.
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November 2021

Factors associated with purchasing pesticide from shops for intentional self-poisoning in Sri Lanka.

Trop Med Int Health 2020 10 5;25(10):1198-1204. Epub 2020 Aug 5.

Department of Community Medicine, Faculty of Medicine and Allied Sciences, Rajarata University of Sri Lanka, Anuradhapura, Sri Lanka.

Objective: In South Asia, up to one in five individuals who ingest pesticides for self-poisoning and survive purchased them from a shop immediately prior to the event. Thus far, no research has taken place to determine whether interventions implemented through the pesticide sellers might be acceptable or effective, despite the hundreds of thousands of such risk purchases each year. We aimed to investigate factors associated with purchasing pesticides for self-poisoning in Sri Lanka.

Methods: We used a case-control study. Cases (n = 50) were individuals who ingested pesticides after purchasing them for the act, and controls (n = 200) were customers who bought pesticides but did not use them for self-harm. Logistic regression analysis was used to assess socio-demographic and purchase-specific risk factors.

Results: Alcohol intoxication (adjusted odds ratios [AOR] 36.5, 95% confidence intervals [CI] 1.7-783.4) and being a non-farmer AOR 13.3, 95% CI 1.8-99.6 were the main distinguishing factors when purchasing pesticides for self-poisoning. The positive predictive values were 93.3% (95% CI 68.0-99.8%) and 88.2% (95% CI 72.5-96.7%), respectively. One and/or other of these factors characterised 72.0% of cases but only 2.5% controls.

Conclusion: While results need to be interpreted cautiously, sales restrictions to prevent alcohol-intoxicated persons and non-farmers purchasing pesticides for self-poisoning may be effective.
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http://dx.doi.org/10.1111/tmi.13469DOI Listing
October 2020
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