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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. [ABSTRACT FROM AUTHOR]

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. 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. 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). 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. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]