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Sarbjeet S Kalsi1,2, Paul I Dargan2–4, W Stephen Waring5, David M Wood2–41Emergency Department, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 2Clinical Toxicology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 3King’s Health Partners, London, UK; 4King’s College London, London, UK; 5York Teaching Hospital NHS Foundation Trust, York, UKAbstract: Paracetamol (acetaminophen) poisoning is common throughout the world. The management of nonstaggered (acute) paracetamol overdose is based on the plasma paracetamol concentration plotted on a treatment nomogram. In the UK there are two treatment lines on this nomogram, with the lower treatment line used for individuals felt to be at ‘high risk’ of paracetamol-related hepatotoxicity either as a result of induction of cytochrome P450 isoenzymes or reduction of intrahepatic glutathione. In this article we review the risk factors that, in current guidelines, are felt to increase risk due to a reduction in intrahepatic glutathione concentrations. Based on our review of the published literature, we feel that cystic fibrosis, acute viral illness, malnutrition, and eating disorders such as anorexia nervosa are likely to be associated with reduction in intrahepatic glutathione concentrations, and that this risk is likely to be related to malnutrition secondary to the disease. Chronic hepatitis C infection is also associated with reduced glutathione concentrations, although this appears to be independent of any associated malnutrition. Ageing and acute fasting are not associated with an increased risk of paracetamol-related hepatotoxicity due to reductions in glutathione concentrations. Finally, the evidence for HIV infection is inconclusive, particularly as the majority of studies were conducted in the pre-anti-viral treatment (HAART) era; however it is likely that patients with symptomatic HIV/AIDS have reduced glutathione concentrations due to associated malnutrition. Although there have been few studies which have specifically investigated whether there is an association between reduced intrahepatic glutathione concentrations and increased risk of paracetamol-related hepatotoxicity, in our opinion, it is likely that the above conditions that are associated with reduced glutathione concentrations, will be associated with an increased risk of paracetamol-related hepatotoxicity.Keywords: glutathione, GSH, paracetamol, acetaminophen, hepatotoxicity, NAPQI

Sarbjeet S Kalsi1,2, David M Wood2–4, W Stephen Waring5, Paul I Dargan2–4 1Emergency Department, 2Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust, London; 3King's Health Partners, 4King's College London, London; 5York Teaching Hospital NHS Foundation Trust, York, UK Abstract: Paracetamol (acetaminophen, N-acetyl-p-aminophenol, 4-hydroxyacetanilide) is the most common cause of acute liver failure in developed countries. There are a number of factors which potentially impact on the risk of an individual developing hepatotoxicity following an acute paracetamol overdose. These include the dose of paracetamol ingested, time to presentation, decreased liver glutathione, and induction of cytochrome P450 (CYP) isoenzymes responsible for the metabolism of paracetamol to its toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI). In this paper, we review the currently published literature to determine whether induction of relevant CYP isoenzymes is a risk factor for hepatotoxicity in patients with acute paracetamol overdose. Animal and human in vitro studies have shown that the CYP isoenzyme responsible for the majority of human biotransformation of paracetamol to NAPQI is CYP2E1 at both therapeutic and toxic doses of paracetamol. Current UK treatment guidelines suggest that patients who use a number of drugs therapeutically should be treated as “high-risk” after paracetamol overdose. However, based on our review of the available literature, it appears that the only drugs for which there is evidence of the potential for an increased risk of hepatotoxicity associated with paracetamol overdose are phenobarbital, primidone, isoniazid, and perhaps St John's wort. There is no evidence that other drugs often quoted as increasing risk, such as carbamazepine, phenytoin, primidone, rifampicin, rifabutin, efavirenz, or nevirapine, should be considered risk factors for hepatotoxicity in patients presenting with acute paracetamol overdose. Keywords: paracetamol, overdose, hepatotoxicity, isoenzymes

This article reports the time course and clinical features of acute ethanol poisoning in an elderly man who had previously abstained from alcohol. Several hours after ingestion, severe hypotension and hypothermia developed, and the consciousness level was reduced. Supportive measures were sufficient to allow the patient's blood pressure and temperature to recover by 24 h post ingestion. The clinical manifestations of ethanol toxicity are often confounded by coexistent drug ingestion and variable periods of unconsciousness before arrival at hospital. This case highlights that hypotension and hypothermia may be explained on the basis of severe ethanol poisoning alone, in the absence of any other contributing factors. Clinical features of poisoning may be delayed by several hours and, therefore, patients presenting at the hospital should be considered for observation for at least 4 h after consumption of potentially toxic quantities. More severe toxicity should be anticipated in patients who normally abstain from alcohol. [ABSTRACT FROM AUTHOR]

Introduction: Cannabis is the most common recreational drug worldwide and synthetic cannabinoid receptor agonists are currently the largest group of new psychoactive substances. The aim of this study was to compare the clinical features and outcomes of lone acute cannabis toxicity with lone acute synthetic cannabinoid receptor agonist toxicity in a large series of presentations to European emergency departments between 2013-2020., Methods: Self-reported drug exposure, clinical, and outcome data were extracted from the European Drug Emergencies Network Plus which is a surveillance network that records data on drug-related emergency department presentations to 36 centres in 24 European countries. Cannabis exposure was considered the control in all analyses. To compare the lone cannabis and lone synthetic cannabinoid receptor agonist groups, univariate analysis using chi squared testing was used for categorical variables and non-parametric Mann-Whitney U- testing for continuous variables. Statistical significance was defined as a P value of <0.05., Results: Between 2013-2020 there were 54,314 drug related presentations of which 2,657 were lone cannabis exposures and 503 lone synthetic cannabinoid receptor agonist exposures. Synthetic cannabinoid receptor agonist presentations had statistically significantly higher rates of drowsiness, coma, agitation, seizures and bradycardia at the time of presentation. Cannabis presentations were significantly more likely to have palpitations, chest pain, hypertension, tachycardia, anxiety, vomiting and headache., Discussion: Emergency department presentations involving lone synthetic cannabinoid receptor agonist exposures were more likely to have neuropsychiatric features and be admitted to a psychiatric ward, and lone cannabis exposures were more likely to have cardiovascular features. Previous studies have shown variability in the acute toxicity of synthetic cannabinoid receptor agonists compared with cannabis but there is little comparative data available on lone exposures. There is limited direct comparison in the current literature between lone synthetic cannabinoid receptor agonist and lone cannabis exposure, with only two previous poison centre series and two clinical series. Whilst this study is limited by self-report being used to identify the drug(s) involved in the presentations, previous studies have demonstrated that self-report is reliable in emergency department presentations with acute drug toxicity., Conclusion: This study directly compares presentations with acute drug toxicity related to the lone use of cannabis or synthetic cannabinoid receptor agonists. It supports previous findings of increased neuropsychiatric toxicity from synthetic cannabinoid receptor agonists compared to cannabis and provides further data on cardiovascular toxicity in lone cannabis use.

Objective: To analyse the relative percentage of acute recreational drug toxicity emergency department (ED) presentations involving the main drug groups according to age and sex and investigate different patterns based on sex and age strata., Methods: We analysed all patients with acute recreational drug toxicity included by the Euro-DEN Plus dataset (22 EDs in 14 European countries) between October 2013 and December 2016 (39 months). Drugs were grouped as: opioids, cocaine, cannabis, amphetamines, gamma-hydroxybutyrate (GHB), hallucinogens, new psychoactive substances (NPS), benzodiazepines and ketamine. Descriptive data by age and sex are presented and compared among age/sex categories and among drug families., Results: Of 17,371 patients were included during the 39-month period, 17,198 (99.0%) had taken at least one of the investigated drugs (median age: 31 years; 23.9% female; ethanol co-ingestion recorded in 41.5%, unknown in 31.2%; multiple drug use in 37.9%). Opioids (in 31.4% of patients) and amphetamines (23.3%) were the most frequently involved and hallucinogens (1.9%) and ketamine (1.7%) the least. Overall, female patients were younger than males, both in the whole cohort (median age 29 vs. 32 years; p  < 0.001) and in all drug groups except benzodiazepines (median age 36 vs. 36 years; p  = 0.83). The relative proportion of each drug group was different at every age strata and some patterns could be clearly described: cannabis, NPS and hallucinogens were the most common in patients <20 years; amphetamines, ketamine and cocaine in the 20- to 39-year group; GHB/GBL in the 30- to 39-year group; and opioids and benzodiazepines in patients ≥40 years. Ethanol and other drug co-ingestion was more frequent at middle-ages, and multidrug co-ingestion was more common in females than males., Conclusion: Differences in the drugs involved in acute drug toxicity presentations according to age and sex may be relevant for developing drug-prevention and education programs for some particular subgroups of the population based on the increased risk of adverse events in specific sex and/or age strata.

Background: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder. Dysregulation of the gut-brain axis plays a central role in the pathophysiology of IBS. It is increasingly clear that the microbiome plays a key role in the development and normal functioning of the gut-brain axis., Aim: To facilitate the identification of specific areas of focus that may be of relevance to future research. This study represents a bibliometric analysis of the literature pertaining to the microbiome in IBS to understand the development of this field., Methods: The data used in our bibliometric analysis were retrieved from the Scopus database. The terms related to IBS and microbiome were searched in titles or abstracts within the period of 2000-2019. VOSviewer software was used for data visualization., Results: A total of 13055 documents related to IBS were retrieved at the global level. There were 1872 scientific publications focused on the microbiome in IBS. There was a strong positive correlation between publication productivity related to IBS in all fields and productivity related to the microbiome in IBS ( r = 0.951, P < 0.001). The United States was the most prolific country with 449 (24%) publications, followed by the United Kingdom ( n = 176, 9.4%), China ( n = 154, 8.2%), and Italy ( n = 151, 8.1%). The h-index for all retrieved publications related to the microbiome in IBS was 138. The hot topics were stratified into four clusters: (1) The gut-brain axis related to IBS; (2) Clinical trials related to IBS and the microbiome; (3) Drug-mediated manipulation of the gut microbiome; and (4) The role of the altered composition of intestinal microbiota in IBS prevention., Conclusion: This is the first study to evaluate and quantify global research productivity pertaining to the microbiome in IBS. The number of publications regarding the gut microbiota in IBS has continuously grown since 2013. This finding suggests that the future outlook for interventions targeting the gut microbiota in IBS remains promising., Competing Interests: Conflict-of-interest statement: The authors have no financial disclosures or conflicts of interest to declare., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Digoxin is a cardiac glycoside derived from the common foxglove digitalis purpurea and has been available for several centuries as a medicinal agent. Despite extensive patient experience over many years, there remains some controversy regarding the possibility that digoxin might have a deleterious effect on survival. This study was constructed to assess trends in digoxin toxicity research using well-established qualitative and quantitative bibliometric indicators. The current study is based on publications that have been indexed in Scopus. Articles referring to the subject of digoxin toxicity between 1849 and 2015 were assessed according to the document type, publication language, countries/territories, institutions, journal, impact factors, total number of citations, h -index, average number of citations per publication, and international collaborations. There were 2900 publications that included 2542 (87.7%) original research articles, while 5.3% were reviews and 4.6% letters. The country of origin was the USA in 849 publications, Germany in 241, the UK in 150, and France in 143. The USA and the UK had the highest number of international collaborations. The average number of citations per publications related to digoxin toxicity was 8.1, and the h -index was 59. The USA and Canada had the highest h -indices by country at 46 and 22, respectively. This study presents the first bibliometric analysis on digoxin toxicity publications. The USA was the most important contributors to digoxin toxicity literature with the greatest international collaboration, largest number of articles and highest h -index, followed by Germany and the UK. There has been a trend towards reduced publication numbers related to digoxin toxicity at global level, although it is still an important issue and we present the current research themes related to digoxin toxicity that were identified.

Background: The pathways and mechanism by which associations between the gut microbiome and the brain, termed the microbiome-gut-brain axis (MGBA), are manifest but remain to be fully elucidated. This study aims to use bibliometric analysis to estimate the global activity within this rapidly developing field and to identify particular areas of focus that are of current relevance to the MGBA during the last decade (2009-2018)., Methods: The current study uses the Scopus for data collection. We used the key terms "microbiome-gut-brain axis" and its synonyms because we are concerned with MGBA per se as a new concept in research rather than related topics. A VOSviewer version 1.6.11 was used to visualize collaboration pattern between countries and authors, and evolving research topics by analysis of the term co-occurrence in the title and abstract of publications., Results: Between 2009 and 2018, there were 51,504 published documents related to the microbiome, including 1713 articles related to the MGBA: 829 (48.4%) original articles, 658(38.4%) reviews, and 226 (13.2%) other articles such as notes, editorials or letters. The USA took the first place with 385 appearances, followed by Ireland (n = 161), China (n = 155), and Canada (n = 144).The overall citation h-index was 106, and the countries with the highest h-index values were the USA (69), Ireland (58), and Canada (43). The cluster analysis demonstrated that the dominant fields of the MGBA include four clusters with four research directions: "modeling MGBA in animal systems", "interplay between the gut microbiota and the immune system", "irritable bowel syndrome related to gut microbiota", and "neurodegenerative diseases related to gut microbiota"., Conclusions: This study demonstrates that the research on the MGBA has been becoming progressively more extensive at global level over the past 10 years. Overall, our study found that a large amount of work on MGBA focused on immunomodulation, irritable bowel syndrome, and neurodevelopmental disorders. Despite considerable progress illustrating the communication between the gut microbiome and the brain over the past 10 years, many issues remain about their relevance for therapeutic intervention of many diseases.

Introduction : Intravenous lipid emulsion (ILE) administration is capable of reversing the acute cardiac and neurological toxicity caused by local anesthetic agents. In recent years, ILE has also been explored as a potential antidote for cardiotoxicity caused by non-anesthetic agents too. Areas covered : The potential mechanisms, safety, and efficacy of this approach are considered. Data were sought from published reports listed in PubMed and EMBASE, and abstracts of meetings of the North American Congress of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists. There were reports involving 298 patients where ILE has been administered for severe drug toxicity. Clinical improvement was observed in 57 of 59 patients with local anesthetic toxicity (96.6%); there were 239 patients where toxicity was due to non-anesthetic agents, and ILE apparently improved clinical outcome in 215 (72.1%). Expert opinion : Response rates were similar between ILE treated toxicity caused by lipid soluble and non-lipid soluble drugs. Potential adverse effects of ILE include interference with laboratory assays, acute pancreatitis, and adult respiratory distress syndrome, although the rate of occurrence is difficult to ascertain.

Background: Androgenic anabolic steroids (AASs) have a number of licensed clinical indications but are also subject to abuse within the body building community. They have a number of potentially important adverse pharmacological effects, and users require health monitoring, including selected laboratory investigations. The extent to which AAS users are able to seek medical supervision and the ability of healthcare providers to respond to the needs of users is uncertain. The present study sought to ascertain how AAS abusers interact with healthcare providers, and self-reported knowledge among doctors regarding the healthcare effects and need for monitoring of AAS users., Methods: Questionnaires were administered, and there were 216 respondents among AAS users and 134 doctors., Results: A high proportion of AAS users cited various barriers to accessing healthcare, including 136 of 189 (72%) that reported a fear of reproach, and 107 of 194 (55%) that had avoided seeking medical advice; 137 of 193 respondents (71%) did not disclose AAS use to healthcare professionals. Doctors across a broad range of seniority stated a lack of knowledge of AASs; 130 (97%) had received no formal training, and 109 (82%) did not know which blood tests could be used for safety monitoring., Conclusions: The present study has highlighted some perceptions among the body-building community that create obstacles to them accessing appropriate safety monitoring while using AASs. Doctors may not have adequate knowledge of AASs, which may prevent them giving accurate and complete information. Further work is needed to address the barriers of communication between users and health professionals in order to facilitate better healthcare monitoring and drug safety., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Chloroform is a recognised cause of acute liver injury, although now rarely encountered in clinical practice. We present a case of inhalational chloroform self-poisoning in a 47-year-old man that presented to hospital initially with reduced conscious level and later developed acute liver injury that was treated with intravenous acetylcysteine. This paper reviews the existing literature and presents a summary of the mechanisms of chloroform hepatotoxicity. Published cases show that there is a characteristic delay of 24 to 48 hours between chloroform exposure and elevation of liver transaminase activity. Therefore, clinicians need to provide an appropriate duration of monitoring in order to detect the occurrence of this important toxic effect.

Objectives: To analyze epidemiologic, clinical, and care characteristics in cases in which patients came to 2 Spanish emergency departments (EDs) with symptoms caused by recreational drug abuse. To compare the characteristics with those reported for other areas of Europe., Material and Methods: Secondary analysis of the registry of the European Drug Emergencies Network (Euro-DEN Plus), which collects cases in 14 European countries and 20 EDs. The registry included all patients attending EDs with symptoms of recreational drug abuse (excepting cases involving alcohol alone) over a period of 39 consecutive months (October 2013 to December 2016). We compared the cases from the 2 Spanish EDs (in Barcelona and Palma de Mallorca) to those from the 5 EDs in Ireland and the UK, 6 in northern Europe, and 7 in central Europe., Results: A total of 17 104 patients' cases were included: Spain, 1186; UK and Ireland, 6653; northern Europe, 6097; and central Europe, 3168. Spain saw more emergencies related to cocaine (48.4%) and fewer related to opioids (12.4%) than the other areas. The Spanish patients were younger (32.2 years) on average than those in northern Europe and older than those in the UK and Ireland and central Europe. Fewer patients were women in Spain (21.9%) than in northern or central Europe. Fewer arrived in ambulances in Spain (70.0%) than in the UK and Ireland or northern Europe. The Spanish EDs recorded the temperature and respiratory frequency of fewer patients (29.8% and 30.3%, respectively). Clinical signs differed between geographical areas attributable to differences in drug-use patterns. In Spain, naloxone was used by fewer patients (9.6%) than in the UK and Ireland and northern Europe, and flumazenil was used by more patients (5.6%) than in other areas. Spain saw lower percentages of admissions (4.6%) and patients who left without an ED discharge (6.2%) in comparison with other areas. Mortality rates in the Spanish EDs (0.4%) and after discharge from them (0.7%) were higher than in northern Europe., Conclusion: The characteristics of emergencies related to recreational drug abuse registered by the Spanish EDs were differed from those registered in other parts of Europe due to different patterns of drug use. We also detected differences between the Spanish and other European EDs with respect to examinations or tests performed, treatment given, and discharge disposition.

Objective: To study the profile of European gamma-hydroxybutyrate (GHB) and gammabutyrolactone (GBL) intoxication and analyse the differences in the clinical manifestations produced by intoxication by GHB/GBL alone and in combination with other substances of abuse., Method: We prospectively collected data on all the patients attended in the Emergency Departments (ED) of the centres participating in the Euro-DEN network over 12 months (October 2013 to September 2014) with a primary presenting complaint of drug intoxication (excluding ethanol alone) and registered the epidemiological and clinical data and outcomes., Results: We included 710 cases (83% males, mean age 31 years), representing 12.6% of the total cases attended for drug intoxication. Of these, 73.5% arrived at the ED by ambulance, predominantly during weekend, and 71.7% consumed GHB/GBL in combination with other substances of abuse, the most frequent additional agents being ethanol (50%), amphetamine derivatives (36%), cocaine (12%) and cannabis (8%). Among 15 clinical features pre-defined in the project database, the 3 most frequently identified were altered behaviour (39%), reduced consciousness (34%) and anxiety (14%). The severity ranged from mild cases requiring no treatment (308 cases, 43.4%) to severe cases requiring admission to intensive care (103 cases, 14.6%) and mechanical ventilation (49 cases, 6.9%). No deaths were reported. In comparison with only GHB/GBL consumption, patients consuming GHB/GBL with co-intoxicants presented more vomiting (15% vs. 3%, p<0.001) and cardiovascular symptoms (5.3% vs. 1.5%, p<0.05), a greater need for treatment (59.8% vs. 48.3%, p<0.01) and a longer ED stay (11.3% vs. 3.6% patients with ED stay >12h, p<0.01)., Conclusions: The profile of the typical GHB/GBL-intoxicated European is a young male, requiring care for altered behaviour and reduced level of consciousness, mainly during the weekend. The clinical features are more severe when GHB is consumed in combination with other substances of abuse., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Lithium salts have been used to treat psychiatric disorders since the 1940s and are currently used in prophylaxis and treatment of depression and bipolar disorder. Therefore, we conducted this study to assess lithium toxicity-related publications using bibliometric approaches from a health point of view to assess global research trends in the lithium toxicity field to offer guidance to future research in this field. The data were retrieved from the online version of Scopus database on 6 August 2016. All records with the term 'lithium' in the title were retrieved, and those related to lithium toxicity were evaluated. There were a total of 1241 publications related to lithium toxicity published from 1913 to 2016. Articles (971 or 78.2%) were the most common type, followed by letters (179 or 14.4%) and reviews (61 or 4.9%). The annual publication of articles increased slightly after 1950 and the total number of publications related to lithium toxicity fluctuated with three peaks occurred in 1978, 1985 and 2014. The USA was the predominant country (25.38%), followed by the UK (7.82%), France (6.85%) and Canada (3.55%). Denmark had the highest productivity of publication after standardization by gross domestic product and population size. The average number of citations per article was 9.24, and the h-index for all publications in the field of lithium toxicity was 46. The highest h-index value was achieved by the USA (31) followed by the UK (21) and Canada (13). The Lancet was the highest ranked journal with 27 articles, followed by American Journal of Psychiatry with 23 articles. This study provides a bibliometric analysis on the global research trends in lithium toxicity studies during 1913-2015. There has been a progressive increase in the number of publications related to lithium toxicity published in the last decade, and most of the studies related to lithium toxicity arose from the USA and the UK., (© 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background: Cocaine is subject to recreational abuse as a stimulant and psychoactive agent, which poses a major worldwide health problem. The aim of the present study was to perform a bibliometric analysis of publication related to cocaine intoxication an insight of the research trends at a global level to enable recommendations for future research strategies in this field., Methods: Publications about cocaine intoxication were retrieved from the Web of Science (WoS) Core Collection database on December 28, 2016, and analysed regarding the following bibliometric indicators: research trends, document types, languages, countries/territories with their h-index, collaboration patterns, journals with their impact factors (IF), and institutions., Results: In total, 2,902 scientific publications from 1975 to 2015 were retrieved from the WoS database. The annual number of publications related to cocaine toxicity increased slightly after 1990 and reached a peak of 148 in 1992, with an average of 103 publications per year. The USA outranked other countries/territories with 2,089 publications, of which 1,927 arose exclusively from the USA and 162 involved international collaborations. The h-index for all publications related to cocaine was 212, and the h-index for all publications related to cocaine intoxication was 99. Moreover, the USA had the highest h-index of 95, followed by Spain with h-index of 24, and Canada with h-index of 24. The main research topics were consistently reproductive toxicity, clinical management of acute cocaine exposure, laboratory methods for detection of exposure to cocaine, cocaine metabolism, and cocaine toxicity in animals., Conclusions: This is the first bibliometric approach to examining research related to cocaine toxicity and shows that research activity has become more global and extensive since 1990. The USA remains the leading country regarding published literature, the highest h-index, and greatest role in international collaborations.

Background: The licensed intravenous acetylcysteine regimen for treating paracetamol overdose in most countries uses three separate infusions over 21 h. This complex regimen, requiring different infusion concentrations and rates, has been associated with administration errors. The aim of the present study was to assess the extent of administration delays occurring during this acetylcysteine regimen., Method: A 6-month retrospective observational study was conducted at three English teaching hospitals with clinical toxicology services from October 2014. Patients aged 16 years and over, treated with intravenous acetylcysteine for paracetamol overdose, were included. The start times for infusions were recorded and the delays compared with the prescribed infusion times were calculated. Anaphylactoid reactions, intravenous cannula problems, overdose intent and smoking status were recorded to assess their contribution to delays., Results: From 263 cases identified, 198 met the study inclusion criteria. The median time between the start of infusions 1 and 3 was delayed from the intended 5 h by a median (interquartile range) of 90 (50-163) min, with 135 (68%) cases delayed by more than 1 h. Significantly longer delays were observed in patients with anaphylactoid reactions [median delay 267 (217-413) min, n = 8] and accidental/supratherapeutic overdose [median delay 170 (95-260) min, n = 29]. There were no significant differences between smokers and nonsmokers, or for patients with intravenous cannula problems., Conclusion: Long delays were identified during the three-infusion acetylcysteine regimen for the treatment of paracetamol overdose. These were of clinical significance and could lead to periods of subtherapeutic plasma acetylcysteine concentrations and potentially avoidable hepatotoxicity, as well as delaying hospital discharge., (© 2016 The British Pharmacological Society.)

In recent years, there has been increasing interest in the role of intravenous lipid formulations as potential antidotes in patients with severe cardiotoxicity caused by drug toxicity. The aim of this study was to conduct a comprehensive bibliometric analysis of all human and animal studies featuring lipid emulsion as an antidote for the treatment of acute poisoning. The Scopus database search was performed on 5 February 2016 to analyse the research output related to intravenous lipid emulsion as an antidote for the treatment of acute poisoning. Research indicators used for analysis included total number of articles, date (year) of publication, total citations, value of the h-index, document types, countries of publication, journal names, collaboration patterns and institutions. A total of 594 articles were retrieved from Scopus database for the period of 1955-2015. The percentage share of global intravenous lipid emulsion research output showed that research output was 85.86% in 2006-2015 with yearly average growth in this field of 51 articles per year. The USA, United Kingdom (UK), France, Canada, New Zealand, Germany, Australia, China, Turkey and Japan accounted for 449 (75.6%) of all the publications. The total number of citations for all documents was 9,333, with an average of 15.7 citations per document. The h-index of the retrieved documents for lipid emulsion research as antidote for the treatment of acute poisoning was 49. The USA and the UK achieved the highest h-indices, 34 and 14, respectively. New Zealand produced the greatest number of documents with international collaboration (51.9%) followed by Australia (50%) and Canada (41.4%) out of the total number of publications for each country. In summary, we found an increase in the number of publications in the field of lipid emulsion after 2006. The results of this study demonstrate that the majority of publications in the field of lipid emulsion were published by high-income countries. Researchers from institutions in the USA led scientific production on lipid emulsion research. There is an obvious need to promote a deeper engagement through international collaborative research projects and funding mechanisms., (© 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background: Analysis of the most influential publications within paracetamol poisoning treatment can be helpful in recognizing main and novel treatment issues within the field of toxicology. The current study was performed to recognize and describe the most highly cited articles related to paracetamol poisoning treatment., Methods: The 100 most highly cited articles in paracetamol poisoning treatment were identified from the Scopus database in November 2015. All eligible articles were read for basic information, including total number of citations, average citations per year, authors' names, journal name, impact factors, document types and countries of authors of publications., Results: The median number of citations was 75 (interquartile range 56-137). These publications were published between 1974 and 2013. The average number of years since publication was 17.6 years, and 45 of the publications were from the 2000s. A significant, modest positive correlation was found between years since publication and the number of citations among the top 100 cited articles (r = 0.316; p = 0.001). A total of 55 journals published these 100 most cited articles. Nine documents were published in Clinical Toxicology, whereas eight documents were published in Annals of Emergency Medicine. Citations per year since publication for the top 100 most-cited articles ranged from 1.5 to 42.6 and had a mean of 8.5 citations per year and a median of 5.9 with an interquartile range of 3.75-10.35. In relation to the origin of the research publications, they were from 8 countries. The USA had the largest number of articles, 47, followed by the UK and Australia with 38 and nine articles respectively., Conclusions: This study is the first bibliometric assessment of the top 100 cited articles in toxicology literature. Interest in paracetamol poisoning as a serious clinical problem continues to grow. Research published in high-impact journals and from high income countries is most likely to be cited in published paracetamol research.

MDMA (3,4-methylenedioxymethamfetamine, Ecstasy) is a widely used recreational drug. We present a case of pneumomediastinum as a complication of MDMA use in a 21-year-old man with no previous history of lung or gastrointestinal pathology. We have performed a literature review, and summarised the symptoms, signs, and prognosis for this under-recognised complication of a commonly used recreational drug. We recommend enquiring about illicit drug use in any patient presenting with spontaneous pneumomediastinum.

Background: Methanol poisoning is on the rise and has been associated with high morbidity and mortality; it has resulted in growing research in the field of toxicology. The aim of this study was to reveal underlying patterns in scientific outputs related to methanol poisoning at the global level by evaluating different bibliometric indices., Methods: We searched for publications that contained specific words regarding methanol poisoning in Scopus database., Results: A total of 912 articles, with 8,317 citations and with an average of 9.1 citations per document, were retrieved on methanol poisoning, and the bulk of the articles were published from the USA (20.9%), followed by Spain (4.4%), Canada (4.3%), India (3.1%), and France (3.0%). The articles were published belonging to 57 countries. No data related to methanol poisoning were published from 155 (73.1%) out of 212 countries. Twenty-one documents (2.3%) were published in Clinical Toxicology, whereas 18 (2.0%) were published in The Lancet., Conclusions: Scientific production related to methanol poisoning is increasing. articles have been published in a wide range of journals with a variety of subject areas, most notably clinical toxicology; and the country with the greatest production was the USA.

Immediate management of drug overdose relies upon the patient account of what was ingested and how much. Paracetamol (acetaminophen) is involved in around 40% of intentional overdose episodes, and remains the leading cause of acute liver failure in many countries including the United Kingdom. In recent years, consumers have had increasing access to medications supplied by international retailers via the internet, which may have different proprietary or generic names than in the country of purchase. We describe a patient that presented to hospital after intentional overdose involving 'acetaminophen' purchased via the internet. The patient had difficulty recalling the drug name, which was inadvertently attributed to 'Advil', a proprietary non-steroidal anti-inflammatory drug. The error was later recognised when the drug packaging became available, but the diagnosis of paracetamol overdose and initiation of acetylcysteine antidote were delayed. This case illustrates the benefit of routinely measuring paracetamol concentrations in all patients with suspected poisoning, although this is not universally accepted in practice. Moreover, it highlights the importance of the internet as a source of medications for intentional overdose, and emphasises the need for harmonisation of international drug names to improve patient safety.

In September 2012, the Medicines and Healthcare products Regulatory Agency (MHRA) substantially amended the Marketing Authorisation for acetylcysteine following an extensive review. The present study examined the impact of this license change on patterns of acetylcysteine use in patients presenting to hospital after paracetamol (acetaminophen) overdose. Between September 2011 and April 2013, 785 consecutive patients presented to York Hospital due to paracetamol overdose, and a before-after analysis was used to compare outcomes. There were 483 patients before and 302 patients after the license amendment, and age, gender, acute or staggered overdose pattern, and dose were similar in both groups. In the patients with paracetamol concentrations between the "100-line" and "200-line," a significantly higher proportion received acetylcysteine treatment (51% before versus 98% after, P = 0.0029), as expected. A modest increase was also observed in relation to late or staggered overdose or cases where the time of ingestion was uncertain (53% versus 74%, P = 0.0430). The median duration of hospital stay increased across the entire study population, from 15 to 24 hours (P = 0.0159) due to the increased proportion of patients requiring acetylcysteine treatment. The findings indicate that the MHRA amendment is a financially costly intervention, and further studies are needed to examine clinical outcomes so that its cost effectiveness might be addressed.

The decision to administer antidote after paracetamol overdose is based on the extent of drug exposure, and this often relies on the reported dose. Few data exist concerning the validity of this approach in children. The present observational study sought to examine the relationship between the reported dose and paracetamol concentrations in patients aged ≤18 years admitted to York Hospital between October 2008 and November 2010 inclusive. There were 77 cases and casenotes were evaluable in 61, with median age 14 years (IQR 3-15 years), and weight 54.0 kg (18.2-63.5 kg), including 47 females (71%). Paracetamol dose was 83 mg/kg (57-148 mg/kg), and interval between ingestion and serum concentration was 4.5 hours (4.0-5.4 hours). There was a positive correlation between dose and equivalent 4-hour paracetamol concentration: Spearman's rho=0.57, 95% CI 0.36-0.73, P< 0.0001. These findings support the importance of reported dose as part of initial risk assessment, especially in situations where laboratory determination is unhelpful, such as after a staggered ingestion.

Purpose: Citalopram is a selective serotonin reuptake inhibitor (SSRI) antidepressant that is widely used in clinical practice. Recent data have indicated that high therapeutic citalopram doses may cause electrocardiographic abnormalities, and the regulatory authorities have amended its licenced dosage. The present manuscript reviews the available data concerning citalopram and cardiac toxicity., Methods: Published data concerning the cardiac effects of citalopram were ascertained, and clinical data were considered separately between adverse effects arising from therapeutic use versus toxicity in the setting of intentional overdose., Results: The occurrence of electrocardiographic abnormalities has long been recognised as a complication of acute citalopram overdose; a dose-effect relationship for QT prolongation has been described in a number of large case series, including several cases of torsades de pointes. In contrast, few data indicate the occurrence of QT prolongation and arrhythmia after therapeutic doses, and a dose-effect relationship within the therapeutic range has only recently been established. Citalopram is more likely to cause QT prolongation in patients with metabolic disturbance or pre-existing cardiac disease., Conclusions: A dose-effect relationship for QT prolongation exists across a broad range of citalopram doses, such that caution must be exercised when prescribing high doses or if there are co-existent risk factors for QT effects. The available data illustrate how clinical toxicity data may offer an earlier signal of cardiac effects than ascertained from conventional pharmacovigilance methods.

Background: Alcohol-related presentations to hospital have been increasing in the UK in recent years, including the occurrence of acute withdrawal. This study sought to better characterize the clinical features, patterns of treatment and outcomes in this patient group., Methods: Patients admitted to the Acute Medical Unit of York Hospital due to acute alcohol withdrawal are normally treated according to a protocol that involves both fixed-dose and symptom-triggered drug administration. Admissions between 2010 and 2011 inclusive were studied., Results: There were 211 admission episodes solely due to acute alcohol withdrawal, involving 127 patients (97 men, 76.4%) with median age of 45 years (interquartile range: 39-52 years). There was a high prevalence of depression (34%), alcoholic liver disease (22%) and drug misuse (12%). Total dose of chlordiazepoxide varied between 0 and 610 mg and tapered rapidly after the first day of admission. Vitamin supplements were administered to >90% of patients, including parenteral and oral in 74%, parenteral alone in 9% and oral alone in 9%. A specialist alcohol nurse reviewed patients while in hospital in 40% of cases. Approximately one-third of patients had multiple admissions for alcohol withdrawal during the study period., Conclusion: A high prevalence of physical and mental health disorders was observed. The local policy permitted high initial chlordiazepoxide doses and prompt downward titration, with a broad range of doses between individuals. Approximately 10% required no specific therapy, and there may be opportunities for developing alternative pathways for delivery of care in an ambulatory setting for these patients.

Paracetamol (acetaminophen) overdose remains the leading cause of death or transplantation due to acute liver failure in many parts of the world. Acetylcysteine has long been recognized as an effective antidote, via oral or intravenous administration, minimizing the risk and severity of acute liver injury if administered sufficiently early after a paracetamol overdose. Despite this, its mechanisms of action remain obscure, and there is uncertainty regarding the optimal dose and duration of treatment. The intravenous infusion protocol was originally developed as a three-step loading regimen; it causes very high early peak plasma concentrations of acetylcysteine whereas the later maintenance infusion is associated with much lower concentrations. This pharmacokinetic profile is associated with two particular concerns: a high rate of occurrence of adverse effects that occur after the initial loading infusion, and the possibility that the maintenance phase of treatment might deliver too low a dose of acetylcysteine for optimum protection against liver injury. Recently described novel administration regimens offer different rates of intravenous acetylcysteine administration in both the loading and maintenance phases. These alternative regimens appear to be well tolerated in small patient groups, but too few clinical data are available to evaluate their comparative efficacy in preventing paracetamol-induced liver injury.

Self-poisoning is a common reason for acute presentation to hospital. Commonly involved drugs have been reported, but few data exist concerning the different combinations of agents or comparative doses ingested. The present study sought to better characterise the typical patterns of drug overdose that may present via the emergency department. Consecutive adults ≥16 years of age that presented to York Hospital owing to self-poisoning were studied for 2010-2011 inclusive. The primary outcome measure was reported dose, expressed as a multiple of the defined daily dose (DDD) to allow comparison between different agents. There were 1024 patients, including 622 women (60.7%), and median age was 32 years (range, 16 to 92 years). Overdose in men was associated with a higher overall quantity of drugs: arithmetic mean of 20 DDD multiples (95% CI, 15-26) versus 13 (11-15), p = 0.001. Overdose involved a single agent only in 538 patients (52.5%). The mean paracetamol dose was 4.0 (95% CI, 3.7-4.3) DDD multiples; the doses of antidepressants (19.4, 17.0-21.7, p < 0.0001) and benzodiazepines (18.0, 12.8-23.2, p < 0.0001) were comparatively higher. The types of agents involved in self-poisoning and common combinations of agents are characterised. Psychotropic medications were ingested in comparatively larger quantities than analgesic agents and had worse clinical outcome. Further work is required to understand the factors that determine the quantity of drug ingested in patients at risk of drug overdose so as to minimise the risk of significant toxicity., (© 2012 The Authors Basic & Clinical Pharmacology & Toxicology © 2012 Nordic Pharmacological Society.)

Purpose: Clinical guidelines concerning treatment of infection are incorporated into prescribing formularies and antimicrobial stewardship policies. The extent to which these influence prescribing is uncertain. In this study, we sought to examine antimicrobial prescribing patterns in patients with cellulitis., Methods: Consecutive adults admitted to hospital due to acute cellulitis between 2008 and 2010 were studied. Data collected were clinical and laboratory markers of sepsis, antimicrobial agent, route of administration, number of i.v. dosages, duration of antimicrobial treatment, and hospital length of stay. Three groups were defined by prescribing that was (i) identical to formulary, (ii) modified appropriately due to microbiological data or prior drug allergy, and (iii) nonformulary prescribing. Comparisons were made between groups using Mann-Whitney tests., Results: There were 306 patients: 167 men (54.6%), median age 66 (range 18-100) years. Prescribing was consistent with formulary recommendations in 253 (82.7%), modified appropriately in 24 (7.8%), and nonformulary in 29 (9.5%). Median [interquartile range (IQR)] duration of hospital stay was 5 (3-8), 7 (5-9, P = 0.026), and 7 (5-14, P = 0.0006) days, and overall duration of antimicrobial therapy was 12 (9-16), 13 (8-15), and 15 (12-19, P = 0.0479) days, respectively. No differences were observed in clinical or laboratory markers of sepsis., Conclusions: Prescribing patterns accorded with prevailing guidelines in the majority of patients. Nonetheless, there was nonformulary prescribing in 10% of patients, and this could not be explained by clinical or laboratory measures of disease severity. Further work is needed to explore the factors that contribute to nonformulary prescribing in this group of patients.

Following the discovery that administration of intravenous lipid emulsion (ILE) may reverse the cardiac and neurological toxicity of certain local anesthetic agents, ILE's potential role has recently been explored in the setting of toxicity attributed to a variety of different drugs. The potential mechanisms, safety and efficacy of this approach are considered in this review. Data are reviewed from 76 published reports involving ILE administration for severe drug toxicity, including 55 where toxicity was due to nonanesthetic agents. ILE was reported to exert a positive therapeutic effect in only a proportion of the reported cases, with greatest evidence of efficacy concerning local anesthetic agents. Administration has typically involved bolus administration followed by continuous maintenance infusion, and a number of different mechanisms are proposed, from preferential partitioning of the drug from cardiac tissue to the circulating lipid fraction and direct inotropic effects related to carnitine pathways and fatty acid oxidative metabolism. No major adverse effects have been encountered, but too few data exist to adequately address the safety profile of ILE.

Context: There have been recent concerns about increasing use and accessibility of methoxetamine, a ketamine derivative. Few data are available to describe the clinical features associated with methoxetamine exposure. We report three cases that presented to hospital with acute neurological toxicity associated with analytically confirmed methoxetamine exposure., Case Details: A 19-year-old male presented with severe truncal ataxia, nystagmus, incoordination and reduced conscious level several hours after nasal insufflation of what was initially thought to be ketamine. Features of cerebellar toxicity persisted for 3-4 days before gradual recovery. Two more patients aged 17 and 18 years presented with severe cerebellar ataxia, imbalance and reduced conscious level 40 minutes after nasal insufflation of methoxetamine (MXE). Both had slurred speech, incoordination and cerebellar ataxia that resolved within 24 hours. Serum methoxetamine concentrations were 0.24 mg/L, 0.45 mg/L and 0.16 mg/L, respectively, and no other drugs were identified on an extended toxicological screen., Discussion: Methoxetamine may cause rapid onset of neurological impairment, characterised by acute cerebellar toxicity. Spontaneous recovery was observed, but the duration of recovery may extend to several days. Presentation with an acute cerebellar toxidrome should alert clinicians to the possibility of methoxetamine exposure.

Acetylcysteine is an effective antidote for paracetamol (acetaminophen) poisoning, but different treatment criteria exist internationally. In the UK, acetylcysteine is indicated by paracetamol concentrations higher than the Prescott nomogram or higher than 50% of the nomogram in patients with increased susceptibility to liver toxicity. In the USA, a single '150-line' nomogram has been used that removes the need for additional clinical risk assessment. The latter approach has recently been adopted in Australia, New Zealand and elsewhere. Few data exist to allow direct comparison of these different international approaches. An existing database of 1191 patients admitted to hospital after paracetamol overdose identified that the 4-h equivalent paracetamol concentration was: ≥200 mg/l in 163 patients (15.6%; 95% CI: 13.3-18.2%), ≥150 mg/l in 264 (24.3%; 95% CI: 21.5-27.5%) and ≥100 mg/l in 426 patients (39.3%; 95% CI: 35.6-43.2%), and acute liver injury occurred in 3.7% (95% CI: 1.4-8.0%), 2.3% (95% CI: 0.8-5.0%) and 1.9% (95% CI: 0.8-3.7%), respectively. The different indications for acetylcysteine used by the UK and USA would result in similar numbers of patients treated, although the criteria would define patients with different characteristics and patterns of overdose. The relative merit of these different international approaches to acetylcysteine administration is considered in this article.

The United Kingdom National Health Service has recently prioritised the need for ambulatory care pathways for acute headache. The present study sought to better characterise patients referred to an Acute Medical Unit so as to inform pathway development. In 2011, York Hospital received 306 referrals due to acute headache, representing 3% of acute medical admissions. Investigations included CT scan (38%), lumbar puncture (38%), and MRI (18%); there were no specialised investigations in 26%, and 18% of patients were discharged on the day of presentation. Subarachnoid haemorrhage occurred in only 4 patients (1%), meningitis in 10 (3%), and intracranial tumour in 5 (2%). The findings indicate that a significant proportion of patients with acute headache could be managed by ambulatory care.

A number of different psychotropic agents have been associated with an increased risk of cardiovascular disease, and these relationships have been difficult to interpret due to the presence of confounding factors. Recently, there has been renewed interest in the potential for certain antidepressants to cause QT prolongation, which is a predisposing factor for arrhythmia. However, the optimum means of determining QT remains contentious due to discrepancies between methods that may be readily applied in a clinical setting versus more detailed techniques during regulatory assessment. A number of different pharmacological mechanisms might explain the occurrence of adverse cardiac effects, and these differ according to the type of antidepressant agent. Emerging data indicate that citalopram exhibits a dose-effect relationship for QT prolongation. Whereas cardiotoxicity is readily apparent in the context of intentional antidepressant overdose, the occurrence of cardiac effects as a result of therapeutic administration is less certain. Pre-existing cardiac disease and other factors that independently predispose to arrhythmia are important considerations. Therefore, clinical judgment is needed to evaluate the overall risk or benefit of a particular antidepressant in any patient. Close monitoring should be considered for those at greatest risk of QT prolongation and arrhythmia.

An Acute Medical Unit has recently been established at York Hospital. The present study sought to characterise the case mix of acutely unwell medical patients to allow identification of priorities for ongoing service development and to assess educational opportunities for trainees in the region. Data were collected for 16001 admission episodes between January 2010 and April 2011 inclusive. These allowed characterisation of the case mix, and identified key priorities where clinical pathway do not yet exist, namely heart failure, urinary tract infection, and acute diarrhoea. Good educational opportunities exist for most aspects of the Acute Medicine curriculum; several weaknesses were identified, and trainees might address these by undertaking a specific period of specialty training in endocrinology and neurology.

Context: A broad range of drugs and chemicals are capable of evoking acute kidney injury, which is conventionally determined by rising serum creatinine concentrations. However there are important limitations to this approach, and there has been interest in alternative biomarkers that might provide a more sensitive and rapid means of detecting acute kidney injury. Most of the available clinical data have thus far been ascertained in patients requiring critical care or with acute sepsis. However, if a sensitive indicator of acute kidney injury were developed, then this could provide a significantly improved means of detecting the effects of acute drug or toxin exposure., Objective: To review the available data concerning potential biomarkers of acute kidney injury and to assess their relative strengths and weaknesses in comparison to existing methods based on serum creatinine concentrations. A large number of possible biomarkers have been proposed. Evidence for individual biomarkers is reviewed with a particular emphasis on those with potential application in clinical toxicology. Where available, comparative data are presented., Methods: There were 236 papers identified using Medline, Embase, and Google Scholar databases, of which 52 were considered directly relevant. CREATININE: Creatinine is subject to glomerular filtration and, to a lesser extent tubular secretion. Serum concentrations are an insensitive marker of acute kidney injury, and the speed of an increase from baseline depends on the magnitude of the acute injury and pre-existing kidney functional reserve. A wide range of inter-individual concentrations means that single time-point determinations are difficult to interpret, and acute kidney injury may not manifest as a detectable increase in serum creatinine concentrations until at least 24-48 h after the primary insult. KIDNEY ENZYMES: Enzymes are often localised to specific anatomical locations, and acute injury may cause a detectable increase in urinary activity due to up-regulated activity or leakage due to cell membrane disruption. Key examples include gamma-glutamyl transpeptidase (GGT), glutathione-S-transferase (GST), and N-acetyl-glucosaminidase (NAG), which are found predominantly in the proximal tubule and urinary enzyme activity increases after acute exposure to heavy metals and other nephrotoxins. NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN: Neutrophil gelatinase-associated lipocalin (NGAL) is expressed by renal tubular epithelium, and a rise in urinary concentrations may provide an indicator of acute renal injury caused by any one of a broad range of provoking factors that is detectable before a rise in serum creatinine concentrations. CYSTATIN C: Serum and urinary cystatin C concentrations are closely related to kidney function and, for example, in acute tubular necrosis allow better prediction of the need for renal replacement therapy than serum creatinine concentrations. KIDNEY INJURY MOLECULE 1: Kidney injury molecule 1 (KIM-1) is expressed in the proximal tubule in the setting of acute ischaemia. For example, urinary KIM-1 concentrations becomes detectable within 24 h of acute tubular necrosis. Urinary KIM-1 expression may be detected after exposure to a variety of nephrotoxic agents, even when serum creatinine concentrations do not increase, and this has been accepted by regulatory authorities as a sensitive biomarker of acute kidney injury during early drug development., Conclusions: Novel biomarkers appear capable of offering a more sensitive means of detecting acute kidney injury than existing approaches. Certain of these allow discrimination between the various mechanisms and anatomical site of acute injury. Ultimately, clinical assessment might incorporate a panel of different biomarkers, each informing on the integrated aspects of glomerular, tubular and interstitial function. Presence of biomarkers may in some cases detect mild or transient renal dysfunction that is presently undetected, and the clinical relevance needs further exploration. Whilst many potentially useful biomarkers have been proposed, comparatively few clinical data exist to support their validity in routine practice. Further prospective clinical studies are required to examine the validity of biomarkers after acute drug or toxin exposure, and to establish whether they might offer improved clinical outcomes in the setting of clinical toxicology.

The Medicines and Healthcare products Regulatory Authority (MHRA) is the government body with responsibility for regulating new and existing medicines and medical devices in the United Kingdom. The Yellow Card scheme is a well-established pharmacovigilance system that collects voluntary reports of adverse effects associated with therapeutic drug use. In contrast, data concerning clinical toxicological effects are more poorly characterised. No comparable surveillance processes exist in the United Kingdom or elsewhere in Europe that might allow systematic collection of clinical data and outcomes after drug overdose. Toxicological effects are normally ascertained from individual patient reports or small case series from a few specialised poisons units, so that these data are generally under-represented in post-marketing consideration of risks and benefits. Safety concerns may lead to withdrawal of the Marketing Authorisation or restricted prescribing conditions, which are conveyed to health care professionals by means of safety warnings. These may have a variable impact, and three selected examples are presented to illustrate the complex interaction between drug regulation and clinical toxicology. First, the effects of the withdrawal of rofecoxib in 2004 shows that regulatory responses may reduce the prescribing of drugs across a particular class, and this has resulted in fewer enquiries to Poisons Control Centres regarding all cyclooxygenase-2 selective inhibitors. Secondly, data concerning the impact of safety warnings about antipsychotic medications illustrate that regulatory decisions may have a variable impact due to other factors that influence prescribing, including clinical guidelines, marketing pressures, and lack of alternative safe medications. Finally, the recent withdrawal of co-proxamol serves as an example of how clinical toxicology data can inform the drug regulation process and improve safety by minimising the risk of death associated with overdose. Greater reliance on clinical toxicology data could better inform the drug regulation process, perhaps through coordinated data collection systems that already exist in certain national poisons centres. Routine collection of high quality data concerning the effects of drug overdose could allow a more comprehensive review of risk and benefit by the regulatory authorities.