Review of the fluoropyrimidine antidote uridine triacetate.

In 2015, the United States Food and Drug Administration (FDA) approved uridine triacetate to treat overdose and severe toxicity of the fluoropyrimidine chemotherapy agents 5-fluorouracil (5-FU) and its oral prodrug capecitabine. Uridine triacetate is as an oral prodrug of uridine that competes with cytotoxic fluoropyrimidine metabolites for incorporation into nucleotides. Two million people worldwide start fluoropyrimidine chemotherapy each year, with 20-30% developing severe or life-threatening adverse effects, often attributable to a genetic predisposition such as dihydropyrimidine dehydrogenase deficiency. Whilst genetic prescreening is recommended prior to starting fluoropyrimidine agents, this only prevents 20-30% of early-onset life-threatening toxicity and so does not obviate the need for an antidote. Initial in-human studies established that uridine triacetate more than doubles the maximum tolerated weekly 5-FU bolus dose. A lack of clinical equipoise meant a placebo-controlled phase III trial was not ethical and so the phase III trials used historical controls. These found that uridine triacetate improved survival in those with fluoropyrimidine overdose and severe toxicity from 16% to 94%, with 34% able to resume chemotherapy within 30 days. Five case reports of delayed fluoropyrimidine toxicity demonstrate improvement following uridine triacetate treatment 120-504 h after last fluoropyrimidine administration, suggesting efficacy beyond the FDA licencing indications. Mechanistically uridine triacetate would be expected to be effective for overdose and severe toxicity of tegafur (a 5-FU prodrug), but there are no published case reports describing this. Uridine triacetate is available internationally through an expanded access scheme and has been available in the UK since 2019 on a named patient basis.

Artificial intelligence in clinical pharmacology: A case study and scoping review of large language models and bioweapon potential.

This paper aims to explore the possibility of employing large language models (LLMs) - a type of artificial intelligence (AI) - in clinical pharmacology, with a focus on its possible misuse in bioweapon development. Additionally, ethical considerations, legislation and potential risk reduction measures are analysed. The existing literature is reviewed to investigate the potential misuse of AI and LLMs in bioweapon creation. The search includes articles from PubMed, Scopus and Web of Science Core Collection that were identified using a specific protocol. To explore the regulatory landscape, the OECD.ai platform was used. The review highlights the dual-use vulnerability of AI and LLMs, with a focus on bioweapon development. Subsequently, a case study is used to illustrate the potential of AI manipulation resulting in harmful substance synthesis. Existing regulations inadequately address the ethical concerns tied to AI and LLMs. Mitigation measures are proposed, including technical solutions (explainable AI), establishing ethical guidelines through collaborative efforts, and implementing policy changes to create a comprehensive regulatory framework. The integration of AI and LLMs into clinical pharmacology presents invaluable opportunities, while also introducing significant ethical and safety considerations. Addressing the dual-use nature of AI requires robust regulations, as well as adopting a strategic approach grounded in technical solutions and ethical values following the principles of transparency, accountability and safety. Additionally, AI's potential role in developing countermeasures against novel hazardous substances is underscored. By adopting a proactive approach, the potential benefits of AI and LLMs can be fully harnessed while minimizing the associated risks.

The INTOXICATE study: methodology and preliminary results of a prospective observational study.

BACKGROUND: There is currently no practice-based, multicenter database of poisoned patients admitted to intensive care units (ICUs). The INTOXICATE study, endorsed by the ESICM and EAPCCT, aimed to determine the rate of eventful admissions among acutely intoxicated adult ICU patients. METHODS: Ethical approval was obtained for this multicenter, prospective observational study, and data-sharing agreements were signed with each participating center. An electronic case report form was used to collect data on patient demographics, exposure, clinical characteristics, investigations, treatment, and in-hospital mortality data. The primary outcome, 'eventful admission', was a composite outcome defined as the rate of patients who received any of the following treatments in the first 24 h after the ICU admission: oxygen supplementation with a FiO2 > 40%, mechanical ventilation, vasopressors, renal replacement therapy (RRT), cardiopulmonary resuscitation, antidotes, active cooling, fluid resuscitation (> 1.5 L of intravenous fluid of any kind), sedation, or who died in the hospital. RESULTS: Seventy-eight ICUs, mainly from Europe, but also from Australia and the Eastern Mediterranean, participated. A total of 2,273 patients were enrolled between November 2020 and June 2023. The median age of the patients was 41 years, 72% were exposed to intoxicating drugs. The observed rate of patients with an eventful ICU admission was 68% (n = 1546/2273 patients). The hospital mortality was 4.5% (n = 103/2273). CONCLUSIONS: The vast majority of patients survive, and approximately one third of patients do not receive any ICU-specific interventions after admission in an intensive care unit for acute intoxication. High-quality detailed clinical data have been collected from a large cohort of acutely intoxicated ICU patients, providing information on the pattern of severe acute poisoning requiring intensive care admission and the outcomes of these patients. TRIAL REGISTRATION: OSF registration ID: osf.io/7e5uy.

Joint RCEM and NPIS best practice guideline: assessment and management of acute opioid toxicity in adults in the emergency department.

The Royal College of Emergency Medicine Toxicology Special Interest Group in collaboration with the UK National Poisons Information Service and the Clinical Toxicology Department at Guy's and St Thomas' NHS Foundation Trust has produced guidance to support clinicians working in the ED with the assessment and management of adults with acute opioid toxicity.Considerations regarding identification of acute opioid toxicity are discussed and recommendations regarding treatment options and secondary prevention are made. There is a focus on making recommendations on the best available evidence.

Extracorporeal treatment for ethylene glycol poisoning: systematic review and recommendations from the EXTRIP workgroup.

Ethylene glycol (EG) is metabolized into glycolate and oxalate and may cause metabolic acidemia, neurotoxicity, acute kidney injury (AKI), and death. Historically, treatment of EG toxicity included supportive care, correction of acid-base disturbances and antidotes (ethanol or fomepizole), and extracorporeal treatments (ECTRs), such as hemodialysis. With the wider availability of fomepizole, the indications for ECTRs in EG poisoning are debated. We conducted systematic reviews of the literature following published EXTRIP methods to determine the utility of ECTRs in the management of EG toxicity. The quality of the evidence and the strength of recommendations, either strong ("we recommend") or weak/conditional ("we suggest"), were graded according to the GRADE approach. A total of 226 articles met inclusion criteria. EG was assessed as dialyzable by intermittent hemodialysis (level of evidence = B) as was glycolate (Level of evidence = C). Clinical data were available for analysis on 446 patients, in whom overall mortality was 18.7%. In the subgroup of patients with a glycolate concentration ≤ 12 mmol/L (or anion gap ≤ 28 mmol/L), mortality was 3.6%; in this subgroup, outcomes in patients receiving ECTR were not better than in those who did not receive ECTR. The EXTRIP workgroup made the following recommendations for the use of ECTR in addition to supportive care over supportive care alone in the management of EG poisoning (very low quality of evidence for all recommendations): i) Suggest ECTR if fomepizole is used and EG concentration > 50 mmol/L OR osmol gap > 50; or ii) Recommend ECTR if ethanol is used and EG concentration > 50 mmol/L OR osmol gap > 50; or iii) Recommend ECTR if glycolate concentration is > 12 mmol/L or anion gap > 27 mmol/L; or iv) Suggest ECTR if glycolate concentration 8-12 mmol/L or anion gap 23-27 mmol/L; or v) Recommend ECTR if there are severe clinical features (coma, seizures, or AKI). In most settings, the workgroup recommends using intermittent hemodialysis over other ECTRs. If intermittent hemodialysis is not available, CKRT is recommended over other types of ECTR. Cessation of ECTR is recommended once the anion gap is < 18 mmol/L or suggested if EG concentration is < 4 mmol/L. The dosage of antidotes (fomepizole or ethanol) needs to be adjusted during ECTR.

Machine Learning to Assist in Large-Scale, Activity-Based Synthetic Cannabinoid Receptor Agonist Screening of Serum Samples.

BACKGROUND: Synthetic cannabinoid receptor agonists (SCRAs) are amongst the largest groups of new psychoactive substances (NPS). Their often high activity at the CB1 cannabinoid receptor frequently results in intoxication, imposing serious health risks. Hence, continuous monitoring of these compounds is important, but challenged by the rapid emergence of novel analogues that are missed by traditional targeted detection strategies. We addressed this need by performing an activity-based, universal screening on a large set (n = 968) of serum samples from patients presenting to the emergency department with acute recreational drug or NPS toxicity. METHODS: We assessed the performance of an activity-based method in detecting newly circulating SCRAs compared with liquid chromatography coupled to high-resolution mass spectrometry. Additionally, we developed and evaluated machine learning models to reduce the screening workload by automating interpretation of the activity-based screening output. RESULTS: Activity-based screening delivered outstanding performance, with a sensitivity of 94.6% and a specificity of 98.5%. Furthermore, the developed machine learning models allowed accurate distinction between positive and negative patient samples in an automatic manner, closely matching the manual scoring of samples. The performance of the model depended on the predefined threshold, e.g., at a threshold of 0.055, sensitivity and specificity were both 94.0%. CONCLUSION: The activity-based bioassay is an ideal candidate for untargeted screening of novel SCRAs. The combination of this universal screening assay and a machine learning approach for automated sample scoring is a promising complement to conventional analytical methods in clinical practice.

Paracetamol toxicity in mild overdose in combination with opioids: A retrospective observational study.

AIMS: Toxicity in paracetamol overdose with opioid co-ingestion is poorly understood. We compared outcomes in both paracetamol-only and paracetamol-opioid overdoses to determine whether toxicity differed significantly between the groups, and to assess the utility of the ratio of measured plasma paracetamol concentration relative to the 4-hour nomogram-adjusted level (APAPpl /APAPt ). METHODS: We conducted a retrospective observational study of all patients (n = 1159) presenting to 2 large UK hospitals between 2005 and 2013 with acute single-dose ingestion paracetamol overdose, with (n = 221) or without (n = 938) opioid co-ingestion. Adverse outcomes included biomarkers of hepatotoxicity and the need for extended treatment. Several outcomes were assessed in relation to the APAPpl /APAPt ratio. RESULTS: Median ingested dose of paracetamol was low in both groups (10 g). Statistical comparison of the median APAPpl /APAPt ratios showed a significant difference (0.65 vs. 0.56 for the paracetamol-only and paracetamol-opioid groups respectively, P = .0329). Although there was a trend towards a lower risk of predefined toxic outcomes with opioid co-ingestion, statistical analysis did not show a significant difference, with outcomes for the paracetamol-only and paracetamol-opioid groups including the following: alanine transaminase >2× upper limit of normal, 7.7 vs. 5.7% (P = .6480); alanine transaminase >1000 IU/L, 2.4 vs. 0% (P = .2145); international normalised ratio > 1.3, 8.6 vs. 4.4% (P = .2774); and transfer to tertiary liver unit, 0.2 vs. 0% (P nonsignificant). CONCLUSION: Our study does not support a change in current clinical practise beyond standard testing at 4 hours or longer post ingestion for mixed low dose paracetamol-opioid overdose.

The association between the availability of over the counter codeine and the prevalence of non-medical use.

PURPOSE: To investigate the prevalence of non-medical use (NMU) of codeine in Germany, Italy, Spain and the UK and whether availability of OTC codeine has any association with NMU of the drug. METHODS: Data collected in the online Survey of Non-Medical Use of Prescription Drugs, in surveys launched in the second half of 2018 from (Germany (n = 14,969), Italy, (n = 9974), Spain (n = 9912) and the UK (n = 9819) were analysed. For each survey, the estimated prevalence and 95% confidence interval (CI) of respondents reporting NMU of prescription and/or OTC codeine within the last 12 months were calculated and compared. RESULTS: The prevalence of last 12-month NMU in Spain was 12.6% (95% CI 11.7-13.6) for prescription codeine, 6.3% (5.6-7.0) for OTC codeine and 16.1% (15.1-17.3) for any codeine (prescription and/or OTC). The prevalence of last 12-month NMU in the UK was 5.4% (4.9-5.8) for prescription codeine, 4.5% (4.1-5.0) for OTC codeine and 8.3% (7.8-8.9) for any codeine (prescription and/or OTC). The prevalence of last 12-month NMU for prescription codeine was 2.1% (1.9-2.4) in Germany and 1.9% (1.7-2.2) in Italy. CONCLUSION: The prevalence of last 12-month NMU of any codeine product is approximately eight times greater in Spain and four times greater in the UK compared to Germany and Italy where the drug is only available by prescription. While other factors may contribute, these findings suggest that availability of codeine OTC is associated with greater NMU.

Linking in vitro and ex vivo CB1 activity with serum concentrations and clinical features in 5F-MDMB-PICA users to better understand SCRAs and their metabolites.

Synthetic cannabinoid receptor agonists (SCRAs) pose a danger to public health. This study focused on individuals experiencing recreational drug toxicity who had used 5F-MDMB-PICA.Patient records were evaluated regarding vital signs, Glasgow Coma Scale (GCS) and clinical features. Liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) confirmed and quantified the presence of 5F-MDMB-PICA (and/or metabolites) as the only SCRA present in the serum of 71 patients. Cannabinoid activity was evaluated by a cannabinoid receptor (CB1) bioassay, to assess the relationship between serum concentrations and ex vivo human CB1 activation potential. Furthermore, a link with the clinical presentation was appraised.5F-MDMB-PICA and five metabolites were pharmacologically profiled in vitro, revealing theoretically possible contributions of two active in vivo metabolites to overall cannabinoid activity. Serum concentrations of 5F-MDMB-PICA were correlated to the ex vivo cannabinoid activity, revealing a sigmoidal relationship. The latter could also be predicted based on pharmacological characterization of 5F-MDMB-PICA and its metabolites and an in-depth investigation of the bioassay outcome. Clinically, the GCS showed a significant trend (decrease) with increasing ex vivo cannabinoid activity.This is the first study to evaluate possible toxic effects of 5F-MDMB-PICA in a unique large patient cohort. It allows a better understanding of 5F-MDMB-PICA and metabolites in humans, suggesting a negligible contribution by 5F-MDMB-PICA metabolites to the overall cannabinoid activity in serum. Additionally, this work shows that in vitro pharmacological characterization allows close prediction of an individual's ex vivo CB1 activity, the latter showing a relationship with the level of consciousness.

Increasing emergency department attendances in central London with methamphetamine toxicity and associated harms.

BACKGROUND: Methamphetamine is a stimulant drug of abuse with increasing prevalence of use worldwide leading to public health concern. While previous research by our group a decade ago found no evidence of increasing harms associated with methamphetamine use in the UK, there are conflicting data on whether or not this is still the case. This paper aims to identify trends in methamphetamine-related harms and characterise the clinical features of ED presentations involving methamphetamine with gamma-hydroxybutyrate/gamma-butyrolactone (GHB/GBL). METHODS: We retrospectively interrogated a database of all toxicology-related presentations to two central London EDs, extracting data on drugs involved for presentations relating to methamphetamine between 2005 and 2018 to enable analysis of trends. Further clinical data were extracted for presentations between 2014 and 2018 to give a 4-year case series. RESULTS: A total of 1244 presentations involving the use of methamphetamine were identified. The number of presentations rose from 4 in 2005 (1.9% of all recreational drug presentations) to 294 (16.2%) in 2018. A total of 850 cases were identified for the 2014-2018 case series, 94.9% were male with a median (range) age of 35.1 (16-67) years. The most common clinical features in the methamphetamine presentations were neuropsychiatric: agitation (41.5%), anxiety (35.2%), hallucinations (16.5%) and psychosis (14.8%). GHB/GBL was co-used in 54.2% of presentations and appeared to attenuate the neuropsychiatric features seen. Use of GHB/GBL was associated with a higher Poisoning Severity Score and requirement for level 2/3 (high dependency unit/intensive care unit (ICU)) care. CONCLUSION: ED attendances in central London relating to methamphetamine use have risen over the last decade. Combining methamphetamine with GHB/GBL is common and is associated with a higher Poisoning Severity Score and need for ICU level care. Further work is required to establish whether further resources need to be directed at this clinical and public health problem.

Using cryo-EM to uncover mechanisms of bacterial transcriptional regulation.

Transcription is the principal control point for bacterial gene expression, and it enables a global cellular response to an intracellular or environmental trigger. Transcriptional regulation is orchestrated by transcription factors, which activate or repress transcription of target genes by modulating the activity of RNA polymerase. Dissecting the nature and precise choreography of these interactions is essential for developing a molecular understanding of transcriptional regulation. While the contribution of X-ray crystallography has been invaluable, the 'resolution revolution' of cryo-electron microscopy has transformed our structural investigations, enabling large, dynamic and often transient transcription complexes to be resolved that in many cases had resisted crystallisation. In this review, we highlight the impact cryo-electron microscopy has had in gaining a deeper understanding of transcriptional regulation in bacteria. We also provide readers working within the field with an overview of the recent innovations available for cryo-electron microscopy sample preparation and image reconstruction of transcription complexes.

Regional, national and international datasets: How they improve our understanding of the acute harms associated with prescription medicine misuse.

Prescription medicine misuse is a significant problem in many areas of the world. Understanding the acute and chronic harms related to misuse of prescription medicines allows healthcare professionals, drug addiction treatment services and legislative authorities to determine what interventions may be beneficial to reduce these harms and protect individuals and society. However, it is difficult to obtain systematic data on the harms associated with prescription medicine misuse because of how patient visits to clinics and hospitals are recorded and coded in regional or national databases. In this review, we discuss how regional, national and international sources of information can help develop a greater understanding of the prevalence and pattern of acute harms related to prescription medicine misuse using data from ambulance attendances, emergency department presentations and poisons information services.

Prescription medicine misuse in the Asia-Pacific region: An evolving issue?

Prescription medicine misuse, especially misuse of opioids has become a major public healthcare issue in many developed countries such as the USA and Australia where this is associated with significant morbidity (Emergency Department visits due to acute toxicity) and mortality. In this review, we looked at the available data obtained from peer-reviewed articles and population surveys to gain an insight into the current situation in the Asia-Pacific region. There is currently limited information available, but data from subpopulation surveys in a number of countries suggests that prescription medicine misuse is likely to be an issue of concern from a public health perspective in the Asia-Pacific region. The available data suggest that misuse prevalence rates and the medicines that are commonly misused are similar to countries such as the USA and UK. Further studies are required to determine the overall prevalence of misuse, the harms associated with this and the sources of drugs being misused so that appropriate interventions can be implemented to tackle issues related to prescription medicine misuse in this region.

An evaluation of online discussion relating to nonmedical use of prescription opioids within the UK.

AIM: To identify and describe the nature of online discussion relating to prescription opioids within the UK. METHODS: We performed analysis of posts originating in the UK related to buprenorphine, hydrocodone, oxycodone and tramadol using Social Studio, a web-monitoring platform. The study included posts published between January 2014 and December 2016. The data were cleaned to produce a final dataset consisting only of substantive mentions, which were then categorised by defined themes. RESULTS: The final dataset included a total of 17 361 substantive mentions (2936 buprenorphine, 2894 hydrocodone, 3826 oxycodone and 7705 tramadol). The most common theme for all 4 drugs was sharing experience or opinion comprising over 90% of mentions for each drug, while discussion related to polysubstance use was present in >1/4 of mentions across drug substances. Mentions related to diversion were more common for hydrocodone and oxycodone (8.1% [6.3-10.1 95% confidence interval] and 7.8% [6.5-9.2], respectively) than buprenorphine or tramadol (4.1 and 3.9% [3.5-4.3], respectively). CONCLUSION: This investigation shows that there is substantial online discussion relating to a variety of nonmedical use (NMU) behaviours of prescription opioids within the UK, including for hydrocodone, which is not medically available. Web monitoring provides useful data and merits future investigation; this could include expansion to other categories of drugs and a more in-depth analysis of motivations behind NMU, both of which could add timely evidence regarding the current situation in the UK and help inform public health interventions for NMU of prescription drugs.

Non-medical use of benzodiazepines and GABA analogues in Europe.

AIMS: We investigated the prevalence of non-medical use (NMU) of benzodiazepines and GABA analogues in Europe. METHODS: Data were collected using the online Non-Medical Use of Prescription Drugs (NMURx) survey from France, Germany, Italy, Spain and the UK. RESULTS: The study included 55 223 eligible surveys which, after post-stratification weights were applied, represented approximately 260 million European adults. Lifetime NMU of benzodiazepines was highest in Spain (6.5%, 95% CI: 6.0-7.0) and lowest in Germany (1.7%, 1.5-2.0). Lifetime NMU of GABA analogues was highest in Germany (5.4%, 5.0-5.7) and lowest in France (2.2%, 1.9-2.5) and the UK (2.2%, 1.9-2.6) While no notable difference was observed for France or the UK, there was a higher prevalence of last 12-month NMU of benzodiazepines compared to GABA analogues in Italy (2.4 times higher) and Spain (3.0 times higher) and a higher prevalence of NMU of GABA analogues compared to benzodiazepines in Germany (2.6 times higher). CONCLUSION: This study shows that there is variation in NMU of benzodiazepines and GABA analogues among countries. Of particular interest is the high incidence of GABA analogue NMU in Germany and benzodiazepine NMU in Spain. Further research to identify factors and motivations responsible for the higher prevalence observed are essential to inform public health policies in those countries.

Nonmedical use of benzodiazepines and Z-drugs in the UK.

AIMS: To estimate prevalence of last 12-month nonmedical use (NMU) of benzodiazepines and Z-drugs (the nonbenzodiazepine hypnotics zaleplon, zolpidem and zopiclone) in the UK. METHODS: Data were collected using the Non-Medical Use of Prescription Drugs survey with poststratification weighting applied to be representative of the UK population (≥16 years). Participants were questioned about whether they had nonmedically used benzodiazepines and/or Z-drugs in the last 12-months and from where they had obtained the drug (including via a prescription, or illicitly from a friend/family member, a dealer or via the internet). Additional questions were asked about last 12-month use of illicit drugs (cannabis, cocaine, 3,4-methylenedioxymethylamphetamine [MDMA], non-pharmaceutical amphetamine, crack cocaine and/or heroin). RESULTS: The study included 10 006 eligible participants representing approximately 52 927 000 UK adults. The estimated prevalence of past 12-month NMU of any benzodiazepine and/or Z-drug was 1.2% (95% confidence interval: 1.0-1.5) corresponding to approximately 635 000 adults; amongst this group only an estimated 4.6% (1.2-8.0) had NMU of both a benzodiazepine and a Z-drug. The highest prevalence of NMU for only Z-drugs was among those who had used heroin in the last 12-months (5.4%, 2.7-10.5), whilst the highest prevalence of NMU for only benzodiazepines was among those who had used illicit stimulants in the last 12-months: cocaine (5.9%, 3.8-8.9), amphetamine (5.6%, 3.1-10.0) and MDMA (5.2%, 3.1-8.8). The drug non-medically used was more commonly acquired without than with a prescription for both only benzodiazepines (70.2%, 59.4-81.1 compared to 51.3%, 41.5-64.6) and only Z-drugs (75.6%, 61.6-89.7 compared to 33.9%, 16.9-51.0). CONCLUSION: There is little overlap between benzodiazepine and Z-drug NMU suggesting distinct nonmedical use of the drugs; future studies need to explore whether this relates to personal preference, drug availability or other factors. A significant proportion are acquiring these drugs for NMU without a prescription, so without guidance and monitoring from a medical practitioner. While the dangers of mixing benzodiazepines and heroin/other opioids are well documented, there is a paucity of data regarding concomitant NMU of benzodiazepines and stimulant drugs, or NMU of Z-drugs and opioids, and, given the prevalence of these combinations, this requires further investigation.

Acute toxicity related to misuse (nonmedical use) of tramadol: Experience of the European Drug Emergencies Network Plus.

Following the development of the tramadol crisis currently affecting countries in the Middle East, and Africa, there has been increasing international interest in the regulation of tramadol. This study investigates the misuse of tramadol in patients presenting to emergency departments across Europe. Data from 32 emergency departments in 21 countries were extracted from the Euro-DEN Plus database for the 4-year period from 1 January 2014 to 31 December 2017. Of the reported 24,957 emergency department presentations, tramadol misuse was reported in 105 (0.4% presentations). Tramadol misuse was most common in Bratislava (Slovakia; n = 11, 7.5% of all presentations to this centre), Riga (Latvia; n = 4, 4.9%) and Munich (Germany; n = 17, 2.9%). On arrival, 14 (13.3%) of presentations were in coma/Glasgow coma score ≤ 8 and 9 of these had a respiratory rate <12 breaths/min. These presentations potentially pose a significant burden on emergency departments with a large proportion requiring admission to hospital for ongoing care.

Evaluation of long-term detection trends of new psychoactive substances in pooled urine from city street portable urinals (London, UK).

AIMS: To evaluate the long-term trends of new psychoactive substance (NPS) detection in pooled urine samples collected across a city centre. METHODS: Pooled urine samples from portable stand-alone urinals were collected on a monthly basis over 5.5 years (July 2013-December 2018) across a city centre. These were analysed using a high-performance liquid chromatography system, interfaced to a high-resolution accurate mass spectrometer. Data were processed against a database containing over 2000 drugs/metabolites including over 800 NPS. RESULTS: In total, 44 NPS were detected with variation over time including cathinones (15, 34.1%), synthetic cannabinoids (8, 18.2%) and 21 (47.7%) other NPS. Since the introduction of the UK Psychoactive Substances Act (May 2016) cathinone detection has decreased with minimal detection over the last 4 months of the study. Synthetic cannabinoids were not detected on a regular basis until July 2016 with a subsequent variable detection frequency. There was a consistent, low level detection frequency of all other NPS throughout the study, but which appears to have increased alongside the decrease in cathinone detection. CONCLUSION: Pooled urine analysis of samples taken from portable urinals in a city centre can be used as an effective monitoring tool to determine long-term trends in the use of NPS. The results of this study demonstrate the impact of the Psychoactive Substances Act and reflect the findings of population surveys and clinical studies. Triangulation of these data with other data sources will enable greater insight into the NPS phenomenon.

The Availability of Modafinil and Methylphenidate Purchased from the Internet in the United Kingdom Without a Prescription.

Background: There are reports of prescription stimulants being purchased online for use as cognitive enhancers or "smart drugs." Objectives: The aim of this study was to investigate availability of modafinil and methylphenidate from internet suppliers from the perspective of a typical United Kingdom (UK) based customer. Methods: Using European Monitoring Center for Drugs and Drug Addiction (EMCDDA) internet snapshot methodology, we undertook an English language internet snapshot survey in July-August 2018 to gather information on the availability and price of modafinil and methylphenidate from online retailers. Results: A total of 55 modafinil and 14 methylphenidate websites were identified from which the drug could be purchased without a prescription. Minimum purchase quantities ranged from 10 to 90 tablets for modafinil and 1-1,005 tablets for methylphenidate with no apparent upper limit to the number that could be purchased. The price per tablet varied from £0.38-5.31 for modafinil and £0.16-5.70 for methylphenidate. Free shipping was offered if more than a certain amount was spent on 46 (83.6%) modafinil and 7 (50.0%) methylphenidate websites and discounts were offered on 43 (78.2%) modafinil and 4 (28.6%) methylphenidate websites. Conclusions: Modafinil and methylphenidate are widely available to purchase via internet from the UK without a prescription. The pricing on websites encourages users to buy greater quantities to qualify for discounts and free shipping. The quantities available suggest these purchases may be used in greater amounts than would be legitimately prescribed, increasing the risk of misuse or diversion to other individuals.

An evaluation of the role of mixing techniques in the observed variation in acetylcysteine infusion concentrations.

Intravenous acetylcysteine is commonly prescribed as a course of three infusions for the management of paracetamol poisoning. Previous studies have demonstrated large variation in administered doses of intravenous acetylcysteine, which has been attributed to numerous factors, including inadequate mixing of infusion bags. The aim of this study was to determine whether the amount of mixing of infusion bags contributes significantly to this variation. Using acetylcysteine doses for a 60-69 kg patient, we added the appropriate volume of acetylcysteine to 5% glucose and subsequently inverted the infusion bags 0-5 times to mix the solutions. Infusion bags were then run through using an infusion pump and acetylcysteine concentrations measured at the beginning and end of the infusions. We found no significant difference between the beginning and end concentrations of acetylcysteine regardless of whether bags were mixed or not; infusion 1 (150 mg kg-1 ) showed beginning and end concentrations of 44.61 and 42.48 mg ml-1 respectively after 0 mixes, whilst beginning and end concentrations were 44.45 and 44.58 mg ml-1 respectively after five mixes. The same trend was observed for infusions 2 and 3. This confirmed that mixing does not play a substantial role in variation of drug concentrations; these are likely to be caused by an accumulation of small errors in infusion preparation.