Restrictions on Pesticides and Deliberate Self-Poisoning in Sri Lanka.

Importance: Deliberate self-poisoning using pesticides as a means of suicide is an important public health problem in low- and middle-income countries. Three highly toxic pesticides-dimethoate, fenthion, and paraquat-were removed from the market in Sri Lanka between 2008 and 2011. In 2015, less toxic pesticides (chlorpyrifos, glyphosate, carbofuran, and carbaryl) were restricted. Subsequent outcomes have not been well described. Objective: To explore the association of pesticide bans with pesticide self-poisonings and in-hospital deaths. Design, Setting, and Participants: In this cross-sectional study with an interrupted time series design, data were prospectively collected on all patients with deliberate self-poisonings presenting to 10 Sri Lankan hospitals between March 31, 2002, and December 31, 2019, and analyzed by aggregated types of poisoning. The correlates of pesticide bans were estimated within the pesticide group and on self-poisonings within other substance groups. The data analysis was performed between April 1, 2002, and December 31, 2019. Exposures: Implementation of 2 sets of pesticide bans. Main Outcomes and Measures: The main outcomes were changes in hospital presentations and in-hospital deaths related to pesticide self-poisoning as measured using segmented Poisson regression. Results: A total of 79 780 patients (median [IQR] age, 24 [18-34] years; 50.1% male) with self-poisoning from all causes were admitted to the study hospitals, with 29 389 poisonings (36.8%) due to pesticides. A total of 2859 patients died, 2084 (72.9%) of whom had ingested a pesticide. The first restrictions that targeted acutely toxic, highly hazardous pesticides were associated with an abrupt and sustained decline of the proportion of poisonings with pesticides (rate ratio [RR], 0.85; 95% CI, 0.78-0.92) over the study period and increases in poisonings with medications (RR, 1.11; 95% CI, 1.02-1.21) and household and industrial chemicals (RR, 1.20; 95% CI, 1.05-1.36). The overall case fatality of pesticides significantly decreased (RR, 0.33; 95% CI, 0.26-0.42) following the implementation of the 2008 to 2011 restrictions of highly hazardous pesticides. Following the 2015 restrictions of low-toxicity pesticides, hospitalizations were unchanged, and the number of deaths increased (RR, 1.98; 95% CI, 1.39-2.83). Conclusions and Relevance: These findings support the restriction of acutely toxic pesticides in resource-poor countries to help reduce hospitalization for and deaths from deliberate self-poisonings and caution against arbitrary bans of less toxic pesticides while more toxic pesticides remain available.

Clinical toxicology of acute glyphosate self-poisoning: impact of plasma concentrations of glyphosate, its metabolite and polyethoxylated tallow amine surfactants on the toxicity.

INTRODUCTION: Common major co-formulants in glyphosate-based herbicides, polyethoxylated tallow amine surfactants, are suspected of being more toxic than glyphosate, contributing to the toxicity in humans. However, limited information exists on using polyethoxylated tallow amine concentrations to predict clinical outcomes. We investigated if plasma concentrations of glyphosate, its metabolite and polyethoxylated tallow amines can predict acute kidney injury and case fatality in glyphosate poisoning. METHODS: We enrolled 151 patients with acute glyphosate poisoning between 2010 and 2013. Plasma concentrations of glyphosate, its metabolite, aminomethylphosphonic acid, and polyethoxylated tallow amines were determined in 2020 using liquid chromatography-tandem mass spectrometry. Associations between exposure and poisoning severity were assessed. RESULTS: Plasma concentrations of glyphosate and aminomethylphosphonic acid demonstrated good and moderate performances in predicting acute kidney injury (≥2), with an area under the receiver operating characteristic curve of 0.83 (95% CI 0.69-0.97) and 0.76 (95% CI 0.59-0.94), respectively. Polyethoxylated tallow amines were detected in one-fifth of symptomatic patients, including one of four fatalities and those with unsaturated tallow moieties being good indicators of acute kidney injury (area under the receiver operating characteristic curve ≥0.7). As the number of repeating ethoxylate units in tallow moieties decreased, the odds of acute kidney injury increased. Glyphosate and aminomethylphosphonic acid concentrations were excellent predictors of case fatality (area under the receiver operating characteristic curve >0.9). DISCUSSION: The 2.7% case fatality rate with 49% acute, albeit mild, acute kidney injury following glyphosate poisoning is consistent with previously published data. A population approach using model-based metrics might better explore the relationship of exposure to severity of poisoning. CONCLUSIONS: Plasma concentrations of glyphosate and its metabolite predicted the severity of clinical toxicity in glyphosate poisoning. The co-formulated polyethoxylated tallow amine surfactants were even more strongly predictive of acute kidney injury but were only detected in a minority of patients.

Navigating methotrexate toxicity: Examining the therapeutic roles of folinic acid and glucarpidase.

Methotrexate (MTX) toxicity varies depending on factors such as dosing frequency (acute or repeated), dosage (low or high) and the administration route (oral, parenteral or intrathecal). Renal impairment can trigger or exacerbate MTX toxicity. Acute oral low-dose MTX (LDMTX) overdoses seldom lead to toxicity due to the saturable maximal bioavailable dose, but toxicity risks increase with repeated low doses (>3 days), high-dose MTX (HDMTX) or intrathecal poisoning. Folinic acid shares MTX transporters in the gut and cells and bypasses the MTX-induced dihydrofolate reductase inhibition. The required folinic acid dosage differs for low-dose and high-dose MTX toxicities. Acute LDMTX poisoning rarely requires folinic acid, while chronic LDMTX poisoning needs low-dose folinic acid until cellular function is restored. In HDMTX toxicities, early intravenous folinic acid administration is recommended, with dose and duration being guided by MTX concentrations and clinical improvement. In intrathecal MTX poisoning, folinic acid should be administered intravenously. Glucarpidase, a recombinant bacterial enzyme, has a high affinity for MTX and folate analogues in the intravascular or intrathecal systems. It decreases serum MTX concentrations by 90%-95% within 15 min. Its primary indication is for intrathecal MTX poisoning. It is rarely indicated in HDMTX toxicity unless patients have renal injury. However, there is no literature evidence supporting its use in HDMTX poisoning. Its use is limited by its significant cost and lack of availability. Haemodialysis can be potentially useful for MTX removal in cases where glucarpidase is not available. Additionally, fluid hydration, renal support and urine alkalinization are important adjunctive therapies for managing MTX toxicities.

A randomized controlled trial and prospective cohort investigating antivenom for red-bellied black snake envenomation.

INTRODUCTION: Antivenom is first line treatment for snake envenomation worldwide, despite few placebo controlled clinical trials demonstrating effectiveness. We aimed to investigate whether early antivenom in red-bellied black snake (Pseudechis porphyriacus) bites would prevent systemic myotoxicity. METHODS: We undertook a multicentre randomized placebo-controlled trial of antivenom for red-bellied black snake bites with patients recruited from the Australian Snakebite Project (July 2014 to June 2020). In addition, we report all patients with red-bellied black snake bites during the same period, comparing the same outcomes. Patients over 2 years of age with definite red-bellied black snake bites and early systemic effects were randomized to receive 50 per cent glucose (placebo) or tiger snake antivenom within 6 hours post-bite, or in the cohort group received antivenom determined by the treating clinician. The primary outcome was the proportion of patients with myotoxicity (peak creatine kinase activity >1,000 U/L). Secondary outcomes were: area under the curve of total creatine kinase elevation over 48 hours, presence of venom post-antivenom, and adverse reactions. We analyzed both the randomized control trial patients and the combination of randomized control trial and cohort patients. RESULTS: Fifteen patients were recruited to the randomized controlled trial, and a cohort of 68 patients who were not randomized were included in the analysis. After treatment, two of seven patients given placebo had a peak creatine kinase activity >1,000 U/L versus none of the eight given antivenom (difference in favour of antivenom; 29 per cent; 95 per cent confidence interval:-18 per cent to +70 per cent; P = 0.2). The median area under the curve of total creatine kinase elevation over 48 hours in patients given placebo was 0 U/L*h (interquartile range: 0-124 U/L*h), which was not significantly different to those given antivenom: 197 U/L*h (interquartile range: 0-66,353 U/L*h; P = 0.26). Venom was not detected post-antivenom in six patients with measured venom concentrations given antivenom. Two patients given antivenom had immediate hypersensitivity reactions, one severe anaphylaxis, and another had serum sickness. Combining randomized and not randomized patients, three of 36 (8 per cent) administered antivenom less than 6 hours post-bite had a peak creatine kinase activity >1,000 U/L versus 17/47 (36 per cent) patients not receiving antivenom less than 6 hours post-bite (difference in favour of antivenom 29 per cent; 95 per cent confidence interval: 8 per cent to 44 per cent; P < 0.004). Overall, 13/36 (36 per cent) patients administered antivenom within 6 hours had hypersensitivity reactions, six severe anaphylaxis (17 per cent). DISCUSSION: We found that early antivenom was effective in red-bellied black snake bites, and only three patients need to be given antivenom within 6 hours to prevent myotoxicity in one (number needed to treat = 3). However, one in three patients administered antivenom developed a hypersensitivity reaction, and one in six had severe anaphylaxis. The major limitation of this study was the small number of patients recruited to the randomized controlled trial. CONCLUSION: Administration of antivenom in red-bellied black snake envenomation within 6 hours post-bite appeared to decrease the proportion of patients with myotoxicity, but a third of patients had adverse reactions.

Serial repetitive nerve stimulation studies in organophosphorus poisoning indicate two distinct pathophysiological processes occur at the neuromuscular junction in the intermediate syndrome.

INTRODUCTION: Intermediate syndrome is an important cause of respiratory failure following acute organophosphorus pesticide poisoning. The objective of this study was to examine the pathophysiology of this syndrome by analysis of sequential repetitive nerve stimulation studies in patients with acute organophosphorus pesticide poisoning. METHODS: Thirty-four consenting symptomatic patients with acute organophosphorus pesticide poisoning with intermediate syndrome (n = 10) or a milder forme fruste intermediate syndrome (n = 24) were assessed prospectively with daily physical examination and repetitive nerve stimulation done on the right and left median and ulnar nerves. The compound muscle action potential at 1, 3, 10, 15, 20 and 30 Hertz was measured with a train of ten stimuli. The amplitudes of the resulting stimuli were normalized to the first stimulus (100 per cent) and plotted against time. The decrease in the area under the curve of all the second stimulus compound muscle action potentials in the first 0.3 seconds was measured as a means of quantifying the refractory block. The decrease in the area under the curve under the 10, 15, 20 and 30 Hertz compound muscle action potentials relative to this pooled second stimulus compound muscle action potentials-area under the curve indicated the extent of additional rate-dependent block (decreasing compound muscle action potential-area under the curve over the first 0.3 seconds after the first stimulus with increasing Hertz). RESULTS: These new measurements strongly correlated with the severity of weakness. Refractory block was seen in most patients but was more severe in those with intermediate syndrome than those with forme fruste (partial) intermediate syndrome (median 55 per cent versus 16 per cent, P = 0.0001). Similar large differences were found for rate-dependent block (30 per cent versus 7 per cent, P = 0.001), which was uncommon in forme fruste intermediate syndrome but found in nine out of 10 patients with intermediate syndrome. Rate dependent block was generally only observed after 24 hours. The simplest strong predictor was total block at 30 Hertz repetitive nerve stimulation (89 per cent [interquartile range 73 to 94 per cent] versus 21 per cent [4 to 55 per cent]; P < 0.0001), which was very similar to total block calculated by summing other calculations. DISCUSSION: These findings likely represent depolarization and desensitization block from prolonged excessive cholinergic stimulation but it is not clear if these are from pre- or post-synaptic pathology. An animal model of intermediate syndrome with repetitive nerve stimulation studies might enable a better pathophysiological understanding of the two types of block. LIMITATIONS: The limited number of repetitive nerve stimulation studies performed were sufficient to demonstrate proof-of-concept, but further studies with more patients are needed to better define the correlates, clinical relevance and possible diagnostic/prognostic roles for the use of this technique. CONCLUSION: There are two easily distinguishable pathophysiological abnormalities in the neuromuscular block in intermediate syndrome. While they often coincide, both may be observed in isolation. The total and rate-dependent block at 30 Hertz are strongly associated with more severe weakness.

Impact of coordinated care on adherence to antihypertensive medicines among adults experiencing polypharmacy in Australia.

BACKGROUND: Adherence to antihypertensives is key for blood pressure control. Most people with hypertension have several comorbidities and require multiple medicines, leading to complex care pathways. Strategies for coordinating medicine use can improve adherence, but cumulative benefits of multiple strategies are unknown. METHODS: Using dispensing claims for a 10% sample of eligible Australians, we identified adult users of antihypertensives during July 2018-June 2019 who experienced polypharmacy (≥5 unique medicines). We measured medicine use reflecting coordinated medicine management in 3 months before and including first observed dispensing, including: use of simple regimens for each cardiovascular medicine; prescriber continuity; and coordination of dispensings at the pharmacy. We measured adherence (proportion of days covered) to antihypertensive medicines in the following 12 months, and used logistic regression to assess independent associations and interactions of adherence with these measures of care. RESULTS: We identified 202 708 people, of which two-thirds (66.6%) had simple cardiovascular medicine regimens (one tablet per day for each medicine), two-thirds (63.3%) were prescribed >75% of medicines from the same prescriber, and two-thirds (65.5%) filled >50% of their medicine on the same day. One-third (28.4%) of people experienced all three measures of coordinated care. Although all measures were significantly associated with higher adherence, adherence was greatest among people experiencing all three measures (odds ratio = 1.63; 95% confidence interval: 1.55-1.72). This interaction was driven primarily by effects of prescriber continuity and dispensing coordination. CONCLUSIONS: Coordinating both prescribing and dispensing of medicines can improve adherence to antihypertensives, which supports strategies consolidating both prescribing and supply of patients' medicines.

Common pitfalls in the use of hypertonic sodium bicarbonate for cardiac toxic drug poisonings.

BACKGROUND: Hypertonic sodium bicarbonate is advocated for the treatment of sodium channel blocker poisoning, but its efficacy varies amongst different sodium channel blockers. This Commentary addresses common pitfalls and appropriate usage of hypertonic sodium bicarbonate therapy in cardiotoxic drug poisonings. SODIUM BICARBONATE WORKS SYNERGISTICALLY WITH HYPERVENTILATION: Serum alkalinization is best achieved by the synergistic effect of hypertonic sodium bicarbonate and hyperventilation (PCO2 ∼ 30-35 mmHg [0.47-0.6 kPa]). This reduces the dose of sodium bicarbonate required to achieve serum alkalinization (pH ∼ 7.45-7.55) and avoids adverse effects from excessive doses of hypertonic sodium bicarbonate. VARIABILITY IN RESPONSE TO SODIUM BICARBONATE TREATMENT: Tricyclic antidepressant poisoning responds well to sodium bicarbonate therapy, but many other sodium channel blockers may not. For instance, drugs that block the intercellular gap junctions, such as bupropion, do not respond well to alkalinization. For sodium channel blocker poisonings in which the expected response is unknown, a bolus of 1-2 mmol/kg sodium bicarbonate can be used to assess the response to alkalinization. SODIUM BICARBONATE CAN EXACERBATE TOXICITY FROM DRUGS ACTING ON MULTIPLE CARDIAC CHANNELS: Hypertonic sodium bicarbonate can cause electrolyte abnormalities such as hypokalaemia and hypocalcaemia, leading to QT interval prolongation and torsade de pointes in poisonings with drugs that have mixed sodium and potassium cardiac channel properties, such as hydroxychloroquine and flecainide. THE GOAL FOR HYPERTONIC SODIUM BICARBONATE IS TO ACHIEVE THE ALKALINIZATION TARGET (∼PH 7.5), NOT COMPLETE CORRECTION OF QRS COMPLEX PROLONGATION: Excessive doses of hypertonic sodium bicarbonate commonly occur if it is administered until the QRS complex duration is < 100 ms. A prolonged QRS complex duration is not specific for sodium channel blocker toxicity. Some sodium channel blockers do not respond, and even when there is a response, it takes a few hours for the QRS complex duration to return completely to normal. In addition, QRS complex prolongation can be due to a rate-dependent bundle branch block. So, no further doses should be given after achieving serum alkalinization (pH ∼ 7.45-7.55). MAXIMAL DOSING FOR HYPERTONIC SODIUM BICARBONATE: A further strategy to avoid overdosing patients with hypertonic sodium bicarbonate is to set maximum doses. Exceeding 6 mmol/kg is likely to cause hypernatremia, fluid overload, metabolic alkalosis, and cerebral oedema in many patients and potentially be lethal. RECOMMENDATION FOR THE USE OF HYPERTONIC SODIUM BICARBONATE IN SODIUM CHANNEL BLOCKER POISONING: We propose that hypertonic sodium bicarbonate therapy be used in patients with sodium channel blocker poisoning who have clinically significant toxicities such as seizures, shock (systolic blood pressure < 90 mmHg, mean arterial pressure <65 mmHg) or ventricular dysrhythmia. We recommend initial bolus dosing of hypertonic sodium bicarbonate of 1-2 mmol/kg, which can be repeated if the patient remains unstable, up to a maximum dose of 6 mmol/kg. This is recommended to be administered in conjunction with mechanical ventilation and hyperventilation to achieve serum alkalinization (PCO2∼30-35 mmHg [4-4.7 kPa]) and a pH of ∼7.45-7.55. With repeated bolus doses of hypertonic sodium bicarbonate, it is imperative to monitor and correct potassium and sodium abnormalities and observe changes in serum pH and on the electrocardiogram. CONCLUSIONS: Hypertonic sodium bicarbonate is an effective antidote for certain sodium channel blocker poisonings, such as tricyclic antidepressants, and when used in appropriate dosing, it works synergistically with hyperventilation to achieve serum alkalinization and to reduce sodium channel blockade. However, there are many pitfalls that can lead to excessive sodium bicarbonate therapy and severe adverse effects.

The impact of tightened prescribing restrictions for PBS-subsidised opioid medicines and the introduction of half-pack sizes, Australia, 2020-21: an interrupted time series analysis.

OBJECTIVES: To evaluate the impact of the tightened Pharmaceutical Benefits Scheme (PBS) prescribing rules for immediate release (IR) and controlled release (CR) opioid medicines (1 June 2020), which also eliminated repeat dispensing without authorisation for codeine/paracetamol and tramadol IR and introduced half-pack size item codes for IR formulations. DESIGN, SETTING: Population-based interrupted time series analysis of PBS dispensing data claims for a 10% sample of PBS-eligible residents and IQVIA national opioid medicine sales data (PBS-subsidised and private prescriptions), 28 May 2018 - 6 June 2021. MAIN OUTCOME MEASURES: Mean amount of PBS-subsidised opioid medicines dispensed per day and mean overall amount sold per day - each expressed as oral morphine equivalent milligrams (OME) - overall, by formulation type (IR, CR), and by specific formulation. RESULTS: During the twelve months following the PBS changes, daily PBS-subsidised opioid medicine dispensing was 81 565 OME lower (95% CI, -106 146 to -56 984 OME) than the mean daily level for 2018-20, a decline of 3.8% after adjusting for the pre-intervention trend; the relative reduction was greater for IR (8.4%) than CR formulations (2.6%). Total daily sales of all, IR formulation, and CR formulation opioid medicines did not change significantly after the PBS changes. Repeat dispensing of prescriptions comprised 7.4% of PBS-subsidised opioid dispensing before 1 June 2020, and 1.3% after the changes. Half-pack sizes comprised 8.4% of PBS-subsidised IR opioid medicine dispensing and 2.8% of all opioid medicines sold in the twelve months after the PBS changes. CONCLUSIONS: The introduction of new PBS rules for subsidised opioid medicines was followed by a decline in PBS-subsidised dispensing. Some people may have bypassed the new restrictions by switching to private prescriptions, but our findings suggest that opioid medicine use in Australia declined as a result of the new restrictions.

Quality use of publicly subsidised tapentadol in Australia: a population-based analysis.

BACKGROUND: Sustained-release (SR) tapentadol was listed on Australia's Pharmaceutical Benefits Scheme (PBS) in 2014 for chronic severe pain requiring long-term opioid treatment. Dispensings have increased since listing despite declining trends in other PBS-listed opioids. Preferential prescribing of SR opioids may increase the risk of dependence and accidental overdose, particularly when used to treat acute pain. AIMS: To explore the quality use of publicly subsidised tapentadol in Australia. METHODS: We examined annual initiation rates and patterns of use of tapentadol (SR) in the dispensing records of a 10% random sample of PBS-eligible Australians (2014-2021). We used national tapentadol sales data to assess the proportion of sales attributable to the PBS. RESULTS: Tapentadol initiation increased from 2014, peaking at 7.5/1000 adult population in 2019 before declining to 5.3/1000 in 2021. We identified 63 766 new users between 2014 and 2020, of whom 92.8% discontinued in the first year following initiation, 58.0% had only a single dispensing and 34.3% had no other opioids dispensed in the 3 months before or after initiation. 27.8% of new users were dispensed tapentadol on the same day as potentially interacting medicines. There was a sustained drop in the proportion of sales attributable to the PBS from June 2020 onwards, from an average of 69.1%, to 63.9% of pack sales. CONCLUSIONS: Patterns of use suggest tapentadol (SR) is generally used for short duration. Although most tapentadol sold in Australia is subsidised, there is evidence of a shift towards private sales.

Correction: Neonatal blood lead concentration predicts medium term lead-related outcomes in children ≤5 years old with congenital lead poisoning: A retrospective cohort study in Northern Nigeria.

[This corrects the article DOI: 10.1371/journal.pgph.0001644.].

On- and off-label utilisation of antipsychotics in Australia (2000-2021): Retrospective analysis of two medication datasets.

OBJECTIVE: To determine antipsychotic utilisation patterns in Australian adults from 2005 to 2021, with a focus on on-label and off-label prescriptions. METHODS: We examined antipsychotic dispensing trends in adults from 2005 to 2021 using a 10% sample of the Pharmaceutical Benefits Scheme (PBS) dataset, which contains patient-level information on medicines dispensed throughout Australia. The lack of diagnostic information in PBS was substituted by analysing BEACH (Bettering the Evaluation And Care of Health) dataset, a cross-sectional national survey from 2000 to 2016, consisting of data from general practitioner-patient encounters. RESULTS: There were 5.6 million dispensings for 164,993 patients in PBS throughout this period; 69% patients had >1 dispensing, with a median of 6 per patient. Calculating the estimated period of exposure gave a total of 693,562 treatment episodes, with a median duration of 80 days. There were steady increases in both the incidence and prevalence of antipsychotic dispensings, mainly due to oral second-generation antipsychotics. The most commonly prescribed antipsychotics were quetiapine, olanzapine and risperidone, with a significant portion of patients receiving low-dose quetiapine without dose titration. Analysis of diagnostic indications from BEACH indicated that 27% of antipsychotic prescriptions were off-label for indications such as depression, dementia, anxiety and insomnia, at much lower prescribed daily dosages. CONCLUSION: The increasing prescribing and off-label use highlights concerns about chronic adverse effects caused by antipsychotics. The combined analysis of medication dispensings and the diagnostic indications for which they are prescribed is a novel approach and throws a spotlight on the need for additional monitoring of antipsychotics.

Intestinal injury in paracetamol overdose (ATOM-8).

BACKGROUND AND AIM: Paracetamol, a widely used medication, is known for its delayed hepatotoxicity in cases of overdose. However, the potential for intestinal toxicity resulting from very high paracetamol concentrations during absorption is not well explored. This study aims to investigate the presence of intestinal toxicity and its correlation with observations in early and late paracetamol toxicity. METHODS: Serial samples of 30 patients with acute paracetamol overdose (> 10 g or 200 mg/kg) were prospectively tested. Markers of enterocyte damage, including plasma intestinal fatty acid binding protein (IFABP) and selected gut-related microRNAs (miR-21, miR-122, miR-194, and miR-215), were analyzed. Sub-analysis was performed on patients presenting with hyperlactatemia defined as a lactate greater than 2 mmol/L within 12 h post ingestion. RESULTS: In paracetamol overdose patients, median plasma IFABP was significantly elevated compared with healthy controls (720 µg/L [interquartile range, IQR, 533-1644] vs 270 µg/L [IQR 153-558], P < 0.001). Four patients had early hyperlactatemia and had significantly higher median plasma IFABP compared with those without early hyperlactatemia (3028 µg/L [IQR 1399-3556] vs 574 µg/L [IQR 526-943], P = 0.007). Furthermore, two microRNAs (miR-122 and miR-215) were downregulated in early hyperlactatemia (P = 0.019 and P = 0.006, respectively). Plasma IFABP concentrations correlated with paracetamol concentration (Spearman's r = 0.55) and lactate (r = 0.60). CONCLUSIONS: Paracetamol overdose causes concentration-related intestinal toxicity, and this is a possible explanation for the early hyperlactatemia syndrome. Intestinal toxicity has potential impacts on pharmacokinetics of other agents ingested and on the evolution of hepatotoxicity. Further studies are required to explore the mechanisms and prognostic implications of intestinal toxicity.

Measurement of an intestinal biomarker during poisonings from select toxicants and toxins.

INTRODUCTION: Intestinal toxicity can occur following ingestion of various drugs, chemicals, and toxins. Intestinal fatty acid binding protein is a cytosolic protein specific to intestinal epithelial cells released into the systemic circulation following intestinal injury. Understanding intestinal toxicity in poisoning has the potential to explain mechanisms of toxicity and gastrointestinal symptoms. METHODS: Plasma samples were retrospectively analysed for intestinal fatty acid binding protein in 25 healthy controls and in those poisoned with Gloriosa superba (n = 18), Thevetia peruviana (n = 26), organophosphates (in various solvents) (n = 17), paracetamol (n = 14), glyphosate (n = 20), 2-methyl-4-chlorophenoxyacetic acid (n = 18) and propanil (n = 19). RESULTS: Median peak plasma intestinal fatty acid binding protein concentrations were significantly higher in patients poisoned with Gloriosa superba (2,994.1 µg/L; interquartile range 600.0-5,158.2, P < 0.001), Thevetia peruviana (1,292.5 µg/L; interquartile range 760.3 - 2,076.2; P < 0.001), glyphosate (1,803.6 µg/L; interquartile range 225.7-8,927.7; P < 0.001), 2-methyl-4-chlorophenoxyacetic acid (1,236.2 µg/L; interquartile range 192.6 - 1,709.7; P = 0.010), paracetamol (1,066.5 µg/L; interquartile range 512.9 - 1,336.9; P = 0.035), and organophosphate poisoning (729.8 µg/L; interquartile range 431.5 - 1,588.2; P = 0.046) than in healthy controls (221.6 µg/L; interquartile range 134.8 - 460.1). Median intestinal fatty acid binding protein was not statistically significantly increased compared to controls after propanil poisoning (630.0 µg/L; interquartile range 23.5 - 1,390.3; P = 0.423). CONCLUSIONS: Our pilot study describes intestinal injury assessed by elevated plasma intestinal fatty acid binding protein concentrations following the ingestion of several poisons. This serves as a foundation for further exploration into enterocyte damage in toxicology.

Five healthcare trajectories in the year before suicide and what they tell us about opportunities for prevention: a population-level case series study.

Background: Suicide prevention requires a shift from relying on an at-risk individual to engage with the healthcare system. Understanding patterns of healthcare engagement by people who have died by suicide may provide alternative directions for suicide prevention. Methods: This is a population-based case-series study of all suicide decedents (n = 3895) in New South Wales (NSW), Australia (2013-2019), with linked coronial, health services and medicine dispensing data. Healthcare trajectories were identified using a k-means longitudinal 3d analysis, based on the number and type of healthcare contacts in the year before death. Characteristics of each trajectory were described. Findings: Five trajectories of healthcare utilisation were identified: (A) none or low (n = 2598, 66.7%), (B) moderate, predominantly for physical health (n = 601, 15.4%), (C) moderate, with high mental health medicine use (n = 397, 10.2%), (D) high, predominantly for physical health (n = 206, 5.3%) and E) high, predominantly for mental health (n = 93, 2.4%). Given that most decedents belonged to Trajectory A this suggests a great need for suicide preventive interventions delivered in the community, workplace, schools or online. Trajectories B and D might benefit from opioid dispensing limits and access to psychological pain management. Trajectory C had high mental health medicine use, indicating that the time that medicines are prescribed or dispensed are important touchpoints. Trajectory E had high mental health service predominantly delivered by psychiatrists and community mental health, but limited psychologist use. Interpretation: Although most suicide decedents made at least one healthcare contact in the year before death, contact frequency was overall very low. Given the characteristics of this group, useful access points for such intervention could be delivered through schools and workplaces, with a focus on alcohol and drug intervention alongide suicide awareness. Funding: Australia's National Health and Medical Research Council.

Substances Detected During Coroner Postmortem Toxicology Analyses in Poisoning- and Nonpoisoning-Related Suicides.

Importance: Determining the association between drug use and suicide is complicated but can help to inform targeted suicide prevention strategies. Objective: To examine the substances prevalent in poisoning- and nonpoisoning-related suicides in Australia. Design, Setting, and Participants: This was a multiple-year, cross-sectional study of suicides from July 2013 to October 2019 in Australia with toxicology data available in a national coronial database. The cause of death was classified as poisoning related if any type of poisoning was determined by the coroner to contribute to the cause of death. Prevalence ratios (PRs) were calculated to compare substance detection in poisoning- vs nonpoisoning-related suicides. Data were analyzed from October 2021 to April 2023. Exposures: All substances detected in decedents at the time of death according to toxicology reports were recorded. Main Outcome(s) and Measure(s): The most common individual substances and substance classes were identified. From these, blood concentrations of substances of interest were analyzed, and the most commonly occurring combinations of substance classes were listed. Results: Toxicology was performed on 13 664 suicide decedents (median [IQR] age, 44 [31-57] years; 10 350 male [76%]). From these, 3397 (25%) were poisoning-related suicides (median [IQR] age, 50 [38-63] years; 2124 male [63%]). The remainder were classified as nonpoisoning-related suicides (median [IQR] age, 42 [29-55] years; 8226 male [80%]). PRs for common medicine classes being detected in poisoning-related suicides compared with nonpoisoning-related suicides were as follows: antidepressants (PR, 1.63; 95% CI, 1.54-1.73), benzodiazepines (PR, 2.01; 95% CI, 1.90-2.13), nonopioid analgesics/anti-inflammatory drugs (PR, 1.88; 95% CI, 1.78-2.00), and opioids (PR, 2.72; 95% CI, 2.58-2.87). Alcohol (as ethanol ≥0.03 g/100 mL) was almost equally prevalent in poisoning- and nonpoisoning-related deaths (PR, 1.07; 95% CI, 1.01-1.14), whereas amphetamines (PR, 0.68; 95% CI, 0.61-0.77) and cannabinoids (PR, 0.67; 95% CI, 0.60-0.74) were detected more often in nonpoisoning-related suicides. Combinations of multiple sedative agents in poisoning-related suicides were common. Conclusions and Relevance: Both poisoning- and nonpoisoning-related suicide deaths featured a high prevalence of psychotropic medicines or potential intoxication, which suggests the association of suicide with poor mental health and substance misuse. Findings suggest that substances with a high involvement in poisoning-related suicides should be prescribed cautiously, including antidepressants that are toxic in overdose, sedatives, opioids, and potentially lethal combinations.

Paracetamol (acetaminophen) overdose and hepatotoxicity: mechanism, treatment, prevention measures, and estimates of burden of disease.

INTRODUCTION: Paracetamol is one of the most used medicines worldwide and is the most common important poisoning in high-income countries. In overdose, paracetamol causes dose-dependent hepatotoxicity. Acetylcysteine is an effective antidote, however despite its use hepatotoxicity and many deaths still occur. AREAS COVERED: This review summarizes paracetamol overdose and toxicity (including mechanisms, risk factors, risk assessment, and treatment). In addition, we summarize the epidemiology of paracetamol overdose worldwide. A literature search on PubMed for poisoning epidemiology and mortality from 1 January 2017 to 26 October 2022 was performed to estimate rates of paracetamol overdose, liver injury, and deaths worldwide. EXPERT OPINION: Paracetamol is widely available and yet is substantially more toxic than other analgesics available without prescription. Where data were available, we estimate that paracetamol is involved in 6% of poisonings, 56% of severe acute liver injury and acute liver failure, and 7% of drug-induced liver injury. These estimates are limited by lack of available data from many countries, particularly in Asia, South America, and Africa. Harm reduction from paracetamol is possible through better identification of high-risk overdoses, and better treatment regimens. Large overdoses and those involving modified-release paracetamol are high-risk and can be targeted through legislative change.

The impact of cannabis legalization and decriminalization on acute poisoning: A systematic review.

BACKGROUND AND AIMS: Many countries have recently legalized medicinal and recreational cannabis. With increasing use and access come the potential for harms. We aimed to examine the effect of cannabis legalization/decriminalization on acute poisoning. METHODS: A systematic review and meta-analysis registered with PROSPERO (CRD42022323437). We searched Embase, Medline, Scopus and Cochrane Central Register of Controlled Trials from inception to March 2022. No restrictions on language, age or geography were applied. Abstracts from three main clinical toxicology conferences were hand-searched. Included studies had to report on poisonings before and after changes in cannabis legislation, including legalization and decriminalization of medicinal and recreational cannabis. Where possible, relative risk (RR) of poisoning after legalization (versus before) was calculated and pooled. Risk of bias was assessed with ROBINS-I. RESULTS: Of the 1065 articles retrieved, 30 met inclusion criteria (including 10 conference abstracts). Studies used data from the United States, Canada and Thailand. Studies examined legalization of medicinal cannabis (n = 14) and decriminalization or legalization of recreational cannabis (n = 21). Common data sources included poisons centre records (n = 18) and hospital presentations/admissions (n = 15, individual studies could report multiple intervention types and multiple data sources). Most studies (n = 19) investigated paediatric poisoning. Most (n = 24) reported an increase in poisonings; however, the magnitude varied greatly. Twenty studies were included in quantitative analysis, with RRs ranging from 0.81 to 29.00. Our pooled estimate indicated an increase in poisoning after legalization [RR = 3.56, 95% confidence interval (CI) = 2.43-5.20], which was greater in studies that focused on paediatric patients (RR = 4.31, 95% CI = 2.30-8.07). CONCLUSIONS: Most studies on the effect of medicinal or recreational cannabis legalization/decriminalization on acute poisoning reported a rise in cannabis poisoning after legalization/decriminalization. Most evidence is from US legalization, despite legalization and decriminalization in many countries.

Patterns of suboptimal antipsychotic use and misuse in Australia: What can routinely collected data tell us?

AIMS: There are increasing concerns about harms related to suboptimal antipsychotic use. Here we describe recent population-based trends in antipsychotic use and harms in Australia and identify population groups exhibiting patterns of use likely to contribute to these harms. METHODS: Using population-based data from the Australian Pharmaceutical Benefits Scheme (2015-2020), poisoning calls to the New South Wales (NSW) Poisons Information Centre (2015-2020) and poisoning deaths in all coronial records (2005-2018) in Australia, we measured trends in the prevalence of antipsychotic use and related deaths and poisonings. We applied latent class analyses to identify patterns of antipsychotic use that may contribute to harms. RESULTS: Quetiapine and olanzapine had the highest prevalence of use between 2015 and 2020. Noteworthy trends included increases of 9.1% and 30.8% in quetiapine use and poisonings, while olanzapine use decreased by 4.5% but poisonings increased by 32.7%. Quetiapine and olanzapine poisonings and related deaths had the highest rates of co-ingestion of opioids, benzodiazepines and pregabalin compared to other antipsychotics. We identified six distinct population groups using antipsychotics: (i) ongoing high-dose use with sedatives (8%), (ii) ongoing use (42%), (iii) ongoing use with analgesics and sedatives (11%), (iv) long-term low-dose use (9%), (v) sporadic use (20%) and (vi) sporadic use with analgesics (10%). CONCLUSION: Ongoing potentially suboptimal antipsychotic use and associated harms highlight the need to monitor such patterns of use, for example through prescription monitoring systems.

Persistence and Adherence to Cardiovascular Medicines in Australia.

Background The burden of cardiovascular disease is increasing, with many people treated for multiple cardiovascular conditions. We examined persistence and adherence to medicines for cardiovascular disease treatment or prevention in Australia. Methods and Results Using national dispensing claims for a 10% random sample of people, we identified adults (≥18 years) initiating antihypertensives, statins, oral anticoagulants, or antiplatelets in 2018. We measured persistence to therapy using a 60-day permissible gap, and adherence using the proportion of days covered up to 3 years from initiation, and from first to last dispensing. We reported outcomes by age, sex, and cardiovascular multimedicine use. We identified 83 687 people initiating antihypertensives (n=37 941), statins (n=34 582), oral anticoagulants (n=15 435), or antiplatelets (n=7726). Around one-fifth of people discontinued therapy within 90 days, with 50% discontinuing within the first year. Although many people achieved high adherence (proportion of days covered ≥80%) within the first year, these rates were higher when measured from first to last dispensing (40.5% and 53.2% for statins; 55.6% and 80.5% for antiplatelets, respectively). Persistence was low at 3 years (17.5% antiplatelets to 37.3% anticoagulants). Persistence and adherence increased with age, with minor differences by sex. Over one-third of people had cardiovascular multimedicine use (reaching 92% among antiplatelet users): they had higher persistence and adherence than people using medicines from only 1 cardiovascular group. Conclusions Persistence to cardiovascular medicines decreases substantially following initiation, but adherence remains high while people are using therapy. Cardiovascular multimedicine use is common, and people using multiple cardiovascular medicines have higher rates of persistence and adherence.

Community-based alcohol education intervention (THEATRE) study to reduce harmful effects of alcohol in rural Sri Lanka: design and adaptation of a mixed-methods stepped wedge cluster randomised control trial.

INTRODUCTION: Alcohol consumption is a leading cause of mortality, morbidity and adverse social sequelae in Sri Lanka. Effective community-based, culturally adapted or context-specific interventions are required to minimise these harms. We designed a mixed-methods stepped wedge cluster randomised control trial of a complex alcohol intervention. This paper describes the initial trial protocol and subsequent modifications following COVID-19. METHODS AND ANALYSIS: We aimed to recruit 20 villages (approximately n=4000) in rural Sri Lanka. The proposed intervention consisted of health screening clinics, alcohol brief intervention, participatory drama, film, and public health promotion materials to be delivered over 12 weeks.Following disruptions to the trial resulting from the Easter bombings in 2019, COVID-19 and a national financial crisis, we adapted the study in two main ways. First, the interventions were reconfigured for hybrid delivery. Second, a rolling pre-post study evaluating changes in alcohol use, mental health, social capital and financial stress as the primary outcome and implementation and ex-ante economic analysis as secondary outcomes. ETHICS AND DISSEMINATION: The original study and amendments have been reviewed and granted ethical approval by Rajarata University of Sri Lanka (ERC/2018/21-July 2018 and February 2022) and the University of Sydney (2019/006). Findings will be disseminated locally in collaboration with the community and stakeholders.The new hybrid approach may be more adaptable, scalable and generalisable than the planned intervention. The changes will allow a closer assessment of individual interventions while enabling the evaluation of this discontinuous event through a naturalistic trial design. This may assist other researchers facing similar disruptions to community-based studies. TRIAL REGISTRATION: The trial is registered with the Sri Lanka Clinical Trials Registry; https://slctr.lk/trials/slctr-2018-037.